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Crystal structure of the S187F variant of human liver alanine: aminotransferase associated with primary hyperoxaluria type I and its functional implications.  


The substitution of Ser187, a residue located far from the active site of human liver peroxisomal alanine:glyoxylate aminotransferase (AGT), by Phe gives rise to a variant associated with primary hyperoxaluria type I. Unexpectedly, previous studies revealed that the recombinant form of S187F exhibits a remarkable loss of catalytic activity, an increased pyridoxal 5'-phosphate (PLP) binding affinity and a different coenzyme binding mode compared with normal AGT. To shed light on the structural elements responsible for these defects, we solved the crystal structure of the variant to a resolution of 2.9 Å. Although the overall conformation of the variant is similar to that of normal AGT, we noticed: (i) a displacement of the PLP-binding Lys209 and Val185, located on the re and si side of PLP, respectively, and (ii) slight conformational changes of other active site residues, in particular Trp108, the base stacking residue with the pyridine cofactor moiety. This active site perturbation results in a mispositioning of the AGT-pyridoxamine 5'-phosphate (PMP) complex and of the external aldimine, as predicted by molecular modeling studies. Taken together, both predicted and observed movements caused by the S187F mutation are consistent with the following functional properties of the variant: (i) a 300- to 500-fold decrease in both the rate constant of L-alanine half-transamination and the kcat of the overall transamination, (ii) a different PMP binding mode and affinity, and (iii) a different microenvironment of the external aldimine. Proposals for the treatment of patients bearing S187F mutation are discussed on the basis of these results. PMID:23589421

Oppici, Elisa; Fodor, Krisztian; Paiardini, Alessandro; Williams, Chris; Voltattorni, Carla Borri; Wilmanns, Matthias; Cellini, Barbara



Alanine uptake by liver of mid-lactating rats.  


L-Alanine transport in liver plasma membrane vesicle preparations from fed virgin and 15-day-lactating rats was studied. Lactation was found to induce a decrease of the maximal rate (Vmax) of a high-capacity-low-affinity component of the Na(+)-dependent L-alanine uptake. However, a high-affinity-low-capacity agency was significantly induced in lactating-rat livers. L-Alanine uptake was differentially inhibited by other amino acids in those preparations from lactating rats, and showed different sensitivity to Li+ as a cosubstrate instead of Na+ and to inhibition by sulfhydryl modifying reagents (N-ethylmaleimide [NEM] and p-chloromercuribenzosulfonate [PCMBS]). All of these observations taken together suggest that system A is upregulated in lactating-rat livers, thus resulting in a different contribution of both agencies A and ASC to the total Na(+)-dependent alanine transport into liver plasma membrane vesicles. This was demonstrated using the analogue alpha-methyl-aminoisobutyric acid (MeAIB), a specific system A substrate. L-Alanine uptake rates, as calculated from plasma membrane enzyme marker recoveries, were also enhanced in the physiologic range of alanine concentrations in blood. Our results prove that the physiologic adaptation to lactation involves modulation of system A activity in the liver. PMID:8412762

Felipe, A; Remesar, X; Pastor-Anglada, M



Functional Characterization of Alanine Racemase from Schizosaccharomyces pombe: a Eucaryotic Counterpart to Bacterial Alanine Racemase  

PubMed Central

Schizosaccharomyces pombe has an open reading frame, which we named alr1+, encoding a putative protein similar to bacterial alanine racemase. We cloned the alr1+ gene in Escherichia coli and purified the gene product (Alr1p), with an Mr of 41,590, to homogeneity. Alr1p contains pyridoxal 5?-phosphate as a coenzyme and catalyzes the racemization of alanine with apparent Km and Vmax values as follows: for l-alanine, 5.0 mM and 670 ?mol/min/mg, respectively, and for d-alanine, 2.4 mM and 350 ?mol/min/mg, respectively. The enzyme is almost specific to alanine, but l-serine and l-2-aminobutyrate are racemized slowly at rates 3.7 and 0.37% of that of l-alanine, respectively. S. pombe uses d-alanine as a sole nitrogen source, but deletion of the alr1+ gene resulted in retarded growth on the same medium. This indicates that S. pombe has catabolic pathways for both enantiomers of alanine and that the pathway for l-alanine coupled with racemization plays a major role in the catabolism of d-alanine. Saccharomyces cerevisiae differs markedly from S. pombe: S. cerevisiae uses l-alanine but not d-alanine as a sole nitrogen source. Moreover, d-alanine is toxic to S. cerevisiae. However, heterologous expression of the alr1+ gene enabled S. cerevisiae to grow efficiently on d-alanine as a sole nitrogen source. The recombinant yeast was relieved from the toxicity of d-alanine.

Uo, Takuma; Yoshimura, Tohru; Tanaka, Naotaka; Takegawa, Kaoru; Esaki, Nobuyoshi



Higher Concentrations of Alanine Aminotransferase within the Reference Interval Predict Nonalcoholic Fatty Liver Disease  

Microsoft Academic Search

Background: In nonalcoholic fatty liver disease (NAFLD), increased alanine aminotransferase (ALT) concentrations are considered to be a consequence of hepatocyte damage. We performed a prospective study to examine the association between ALT within its reference interval and risk for subsequent development of NAFLD. Methods: The study cohort comprised 5237 healthy men without diagnosed NAFLD and without increases of either ALT

Yoosoo Chang; Seungho Ryu; Eunju Sung; Yumi Jang



Requirement for alanine in the amino acid control of deprivation-induced protein degradation in liver.  

PubMed Central

Protein degradation in liver is actively controlled by a small group of inhibitory amino acids--leucine, tyrosine (or phenylalanine), glutamine, proline, histidine, tryptophan, and methionine. Other evidence, however, suggests that one or more of the remaining 12 noninhibitory amino acids is also required for suppression of proteolysis at normal concentrations. This question was investigated in livers of fed rats perfused in the single-pass mode. The deletion of alanine at normal (1x), but not at 4x or 10x normal, plasma amino acid concentrations evoked a near-maximal acceleration of protein degradation. No other noninhibitory amino acid was effective. Because alanine alone was not directly inhibitory and its omission was not associated with a decrease in inhibitory amino acid pools, alanine was presumed to act as a coregulator in the expression of inhibitory activity. When tested alone, the inhibitory group was as effective as the complete mixture at 0.5x and 4x levels, but it lost its suppressive ability within a narrow zone of concentration centered slightly above 1x. The addition of 1x (0.48 mM) alanine completely restored the inhibition. Pyruvate and lactate could be effectively substituted, but only at concentrations 10-20 times greater than that of alanine. These, together with earlier findings, indicate the existence of a regulatory complex that recognizes specific amino acids and transmits positive and negative signals to proteolytic sites. The results also suggest that alanine can provide an important regulatory link between energy demands and protein degradation.

Poso, A R; Mortimore, G E



Effect of ?-N-methylamino-L-alanine on oxidative stress of liver and kidney in rat.  


?-N-methylamino-(L)-alanine (L)-BMAA) is a neurotoxic amino acid, found in the majority of cyanbacterial genera tested. Evidence for implication of (L)-BMAA in neurodegenerative disorders, like amyotrophic lateral sclerosis (ALS), relies on bioaccumulation and biomagnification from symbiotic cyanobacteria. The involvement of (L)-BMAA in oxidative stress was demonstrated in several studies in the central nervous system. In the present study, we investigated the effect of (L)-BMAA on the oxidative stress responses of liver and kidney in rats treated by intraperitoneal administration with this amino acid. Oxidative stress was demonstrated by the quantification of lipid peroxidation, the measurement of both catalase and glutathione peroxidase activities, as well as the quantification of glutathione (GSH) levels and the total antioxidant capacity. It was observed that (L)-BMAA caused a significant increase in the degree of lipid peroxidation and catalase activity in both organs. A significant increase in glutathione peroxidase activity was obtained only in liver, whereas glutathione levels were also increased in both organs. The total antioxidant capacity decreased in liver and increased in kidney. These results suggest that the oxidative stress was higher in liver than in kidney, and might be crucial for (L)-BMAA toxicological action. PMID:23328118

de Munck, Estefanía; Muñoz-Sáez, Emma; Antonio, María Teresa; Pineda, Javier; Herrera, Amparo; Miguel, Begoña G; Arahuetes, Rosa María



Purification and properties of cytosolic alanine aminotransferase from the liver of two freshwater fish, Clarias batrachus and Labeo rohita  

Microsoft Academic Search

Cytosolic alanine aminotransferase (c-AAT) was purified up to 203- and 120-fold, from the liver of two freshwater teleosts Clarias batrachus (air-breathing, carnivorous) and Labeo rohita (water-breathing, herbivorous), respectively. The enzyme from both fish showed similar elution profiles on a DEAE-Sephacel ion exchange column. SDS-PAGE of purified enzymes revealed two subunits of 54 and 56 kDa, in both fish. The apparent

Anand S. Srivastava; Ichiro Oohara; Tohru Suzuki; Steve Shenouda; Surender N. Singh; Dharam P. Chauhan; Ewa Carrier



Contribution of liver and skeletal muscle to alanine and lactate metabolism in humans  

SciTech Connect

To quantitate alanine and lactate gluconeogenesis in postabsorptive humans and to test the hypothesis that muscle is the principal source of these precursors, we infused normal volunteers with (3-14C)lactate, (3-13C)alanine, and (6-3H)glucose and calculated alanine and lactate incorporation into plasma glucose corrected for tricarboxylic acid cycle carbon exchange, the systemic appearance of these substrates, and their forearm fractional extraction, uptake, and release. Forearm alanine and lactate fractional extraction averaged 37 +/- 3 and 27 +/- 2%, respectively; muscle alanine release (2.94 +/- 0.27 body wt-1.min-1) accounted for approximately 70% of its systemic appearance (4.18 +/- 0.31 body wt-1.min-1); muscle lactate release (5.51 +/- 0.42 body wt-1.min-1) accounted for approximately 40% of its systemic appearance (12.66 +/- 0.77 body wt-1.min-1); muscle alanine and lactate uptake (1.60 +/- 0.7 and 3.29 +/- 0.36 body wt-1.min-1, respectively) accounted for approximately 30% of their overall disappearance from plasma, whereas alanine and lactate incorporation into plasma glucose (1.83 +/- 0.20 and 4.24 +/- 0.44 body wt-1.min-1, respectively) accounted for approximately 50% of their disappearance from plasma. We therefore conclude that muscle is the major source of plasma alanine and lactate in postabsorptive humans and that factors regulating their release from muscle may thus exert an important influence on hepatic gluconeogenesis.

Consoli, A.; Nurjhan, N.; Reilly, J.J. Jr.; Bier, D.M.; Gerich, J.E. (Univ. of Pittsburgh School of Medicine, PA (USA))



Drug-induced liver injury in hospitalized patients with notably elevated alanine aminotransferase  

PubMed Central

AIM: To identify the proportion, causes and the nature of drug-induced liver injury (DILI) in patients with notably elevated alanine aminotransferase (ALT). METHODS: All the inpatients with ALT levels above 10 times upper limit of normal range (ULN) were retrospectively identified from a computerized clinical laboratory database at our hospital covering a 12-mo period. Relevant clinical information was obtained from medical records. Alternative causes of ALT elevations were examined for each patient, including biliary abnormality, viral hepatitis, hemodynamic injury, malignancy, DILI or undetermined and other causes. All suspected DILI cases were causality assessed using the Council for International Organizations of Medical Sciences scale, and only the cases classified as highly probable, probable, or possible were diagnosed as DILI. Comments related to the diagnosis of DILI in the medical record and in the discharge letter for each case were also examined to evaluate DILI detection by the treating doctors. RESULTS: A total of 129 cases with ALT > 10 ULN were identified. Hemodynamic injury (n = 46, 35.7%), DILI (n = 25, 19.4%) and malignancy (n = 21, 16.3%) were the top three causes of liver injury. Peak ALT values were lower in DILI patients than in patients with hemodynamic injury (14.5 ± 5.6 ULN vs 32.5 ± 30.7 ULN, P = 0.001). Among DILI patients, one (4%) case was classified as definite, 19 (76%) cases were classified as probable and 5 (20%) as possible according to the CIOMS scale. A hepatocellular pattern was observed in 23 (92%) cases and mixed in 2 (8%). The extent of severity of liver injury was mild in 21 (84%) patients and moderate in 4 (16%). Before discharge, 10 (40%) patients were recovered and the other 15 (60%) were improved. The improved patients tended to have a higher peak ALT (808 ± 348 U/L vs 623 ± 118 U/L, P = 0.016) and shorter treatment duration before discharge (8 ± 6 d vs 28 ± 12 d, P = 0.008) compared with the recovered patients. Twenty-two drugs and 6 herbs were found associated with DILI. Antibacterials were the most common agents causing DILI in 8 (32%) cases, followed by glucocorticoids in 6 (24%) cases. Twenty-four (96%) cases received treatment of DILI with at least one adjunctive drug. Agents for treatment of DILI included anti-inflammatory drugs (e.g., glycyrrhizinate), antioxidants (e.g., glutathione, ademetionine 1,4-butanedisulfonate and tiopronin), polyene phosphatidyl choline and herbal extracts (e.g., protoporphyrin disodium and silymarin). Diagnosis of DILI was not mentioned in the discharge letter in 60% of the cases. Relative to prevalent cases and cases from wards of internal medicine, incident cases and cases from surgical wards had a higher risk of missed diagnosis in discharge letter [odds ratio (OR) 32.7, 95%CI (2.8-374.1), and OR 58.5, 95%CI (4.6-746.6), respectively]. CONCLUSION: DILI is mostly caused by use of antibacterials and glucocorticoids, and constitutes about one fifth of hospitalized patients with ALT > 10 ULN. DILI is underdiagnosed frequently.

Xu, Hui-Min; Chen, Yan; Xu, Jie; Zhou, Quan



Pregnancy and Liver Function  


... affect of alcohol on a pregnant woman's liver? Moderate alcohol consumption (one or two drinks daily) probably does not affect the liver of an otherwise normal pregnant woman, but even moderate doses may cause damage to the fetus. (updated ...


Segmental liver hyperintensity in malignant biliary obstruction on diffusion weighted MRI: associated MRI findings and relationship with serum alanine aminotransferase levels  

PubMed Central

Objectives Segmental liver hyperintensity can be observed in malignant biliary obstruction on diffusion weighted MRI (DW-MRI). We describe MRI findings associated with this sign and evaluate whether DW-MRI segmental hyperintensity has any relationship with serum alanine aminotransferase (ALT) levels. Methods The DW-MRI T1 weighted, T2 weighted and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced T1 weighted images obtained in 21 patients with hepatic malignancy, who demonstrated biliary obstruction and segmental hyperintensity on DW-MRI (b=0–750 s mm–2), were retrospectively reviewed by 2 readers blinded to clinical results. DW-MRI hyperintense liver segments were recorded as hypointense, isointense or hyperintense relative to normal liver on T1/T2 weighted imaging. It was also noted whether contrast enhancement was similar to that observed in normal liver or diminished in the hepatocellular phase. The mean apparent diffusion coefficient (ADC) value (×10?3 s mm–2) of DW-MRI hyperintense segments, normal liver and tumour were compared using Student’s t-test. The frequency of MRI findings was corroborated with serum ALT levels, which reflect hepatocyte injury. Results DW-MRI hyperintense segments frequently showed T1 hyperintensity (10/21), T2 hyperintensity (19/21) and/or diminished contrast enhancement (15/21). Tumours showed significantly lower mean ADC values than liver (1.23±0.08 vs 1.43±0.05; p=0.013). Segments showing concomitant T1 hyperintensity had lower mean ADC values than liver (1.30±0.05 vs 1.43±0.05; p=0.023). The patients (8/10) with concomitant T1 and DW-MRI segmental hyperintensity showed elevated ALT levels (p=0.030, Fisher’s exact test). Conclusion Concomitantly high T1 weighted and DW-MRI signal in liver segments was associated with lower ADC values and abnormal liver function tests, which could reflect underlying cellular swelling and damage.

Tam, H H; Collins, D J; Wallace, T; Brown, G; Riddell, A; Koh, D-M



Oral contraceptives and liver function  

PubMed Central

Oral contraceptives can cause liver damage and jaundice but this is very rare in women in the United Kingdom. The drugs are contraindicated where there is a history of recurrent intrahepatic cholestasis of pregnancy and acute or chronic disturbance of liver function which can be congenital or acquired. It is not yet known whether the oestrogenic or progestogenic components of oral contraceptives cause the hepatic abnormalities. The available data suggest that neither oestrogens nor progestogens in low doses impair hepatic excretory processes. The full implications of the continued administration of oestrogens and progestogens for many years on liver proteins are not yet known.

Hargreaves, Tom



Oxygen radical-mediated oxidation reactions of an alanine peptide motif - density functional theory and transition state theory study  

PubMed Central

Background Oxygen-base (O-base) oxidation in protein backbone is important in the protein backbone fragmentation due to the attack from reactive oxygen species (ROS). In this study, an alanine peptide was used model system to investigate this O-base oxidation by employing density functional theory (DFT) calculations combining with continuum solvent model. Detailed reaction steps were analyzed along with their reaction rate constants. Results Most of the O-base oxidation reactions for this alanine peptide are exothermic except for the bond-breakage of the C?-N bond to form hydroperoxy alanine radical. Among the reactions investigated in this study, the activated energy of OH ?-H abstraction is the lowest one, while the generation of alkylperoxy peptide radical must overcome the highest energy barrier. The aqueous situation facilitates the oxidation reactions to generate hydroxyl alanine peptide derivatives except for the fragmentations of alkoxyl alanine peptide radical. The C?-C? bond of the alkoxyl alanine peptide radical is more labile than the peptide bond. Conclusion the rate-determining step of oxidation in protein backbone is the generation of hydroperoxy peptide radical via the reaction of alkylperoxy peptide radical with HO2. The stabilities of alkylperoxy peptide radical and complex of alkylperoxy peptide radical with HO2 are crucial in this O-base oxidation reaction.



?-Alanine supplementation.  


?-Alanine is rapidly developing as one of the most popular sport supplements used by strength/power athletes worldwide. The popularity of ?-alanine stems from its unique ability to enhance intramuscular buffering capacity and thereby attenuating fatigue. This review will provide an overview of the physiology that underlies the mechanisms of action behind ?-alanine, examine dosing schemes, and examine the studies that have been conducted on the efficacy of this supplement. In addition, the effect that ?-alanine has on body mass changes or whether it can stimulate changes in aerobic capacity also will be discussed. The review also will begin to explore the potential health benefits that ?-alanine may have on older adult populations. Discussion will examine the potential adverse effects associated with this supplement as well as the added benefits of combining ?-alanine with creatine. PMID:22777329

Hoffman, Jay R; Emerson, Nadia S; Stout, Jeffrey R


Alanine scan of an immunosuppressive peptide (CP): analysis of structure-function relationships.  


Core peptide is a hydrophobic peptide, the sequence of which is derived from the T-cell antigen receptor alpha-chain transmembrane region. Previous studies have shown that core peptide can inhibit T-cell-mediated immune responses both in vitro and in vivo. Here, we report the role each constituent amino acid plays within core peptide using an alanine scan and the amino acid effect on function using a biological antigen presentation assay. The biophysical behaviour of these analogues in model membranes was analysed using surface plasmon resonance studies and then binding correlated with T-cell function. Removal of any single hydrophobic amino acid between the two charged amino acids in core peptide (R, K) resulted in lower binding. Changing the overall net charge of core peptide, by removing either of the positively charged residues (R or K), had varying effects on peptide binding and IL-2 production. There was a direct correlation (? = 0.718) between peptide binding to model membranes and peptide ability to inhibit IL-2. Except for IL-2 inhibition, production of other T-cell cytokines such as GM-CSF, IFN-?, IL-1?, IL-4, IL-5, IL-6, IL-10, IL-17 and T-cell antigen receptor alpha-chain was not detected using a fluorescent bead immunoassay. This study provides important structure-function relationships essential for further drug design. PMID:23066996

Raguine, Laura; Ali, Marina; Bender, Veronika; Diefenbach, Eve; Doddareddy, Munikumar Reddy; Hibbs, David; Manolios, Nicholas



Evaluation of abnormal liver function tests  

PubMed Central

Interpretation of abnormalities in liver function tests is a common problem faced by clinicians. This has become more common with the introduction of automated routine laboratory testing. Not all persons with one or more abnormalities in these tests actually have liver disease. The various biochemical tests, their pathophysiology, and an approach to the interpretation of abnormal liver function tests are discussed in this review.

Limdi, J; Hyde, G



Ir-192 HDR transit dose and radial dose function determination using alanine/EPR dosimetry  

NASA Astrophysics Data System (ADS)

Source positioning close to the tumour in high dose rate (HDR) brachytherapy is not instantaneous. An increment of dose will be delivered during the movement of the source in the trajectory to its static position. This increment is the transit dose, often not taken into account in brachytherapeutic treatment planning. The transit dose depends on the prescribed dose, number of treatment fractions, velocity and activity of the source. Combining all these factors, the transit dose can be 5% higher than the prescribed absorbed dose value (Sang-Hyun and Muller-Runkel, 1994 Phys. Med. Biol. 39 1181 8, Nath et al 1995 Med. Phys. 22 209 34). However, it cannot exceed this percentage (Nath et al 1995). In this work, we use the alanine-EPR (electron paramagnetic resonance) dosimetric system using analysis of the first derivative of the signal. The transit dose was evaluated for an HDR system and is consistent with that already presented for TLD dosimeters (Bastin et al 1993 Int. J. Radiat. Oncol. Biol. Phys. 26 695 702). Also using the same dosimetric system, the radial dose function, used to evaluate the geometric dose degradation around the source, was determined and its behaviour agrees better with those obtained by Monte Carlo simulations (Nath et al 1995, Williamson and Nath 1991 Med. Phys. 18 434 48, Ballester et al 1997 Med. Phys. 24 1221 8, Ballester et al 2001 Phys. Med. Biol. 46 N79 90) than with TLD measurements (Nath et al 1990 Med. Phys. 17 1032 40).

Guzmán Calcina, Carmen S.; de Almeida, Adelaide; Oliveira Rocha, José R.; Abrego, Felipe Chen; Baffa, Oswaldo



Grape Seed Extract to Improve Liver Function in Patients with Nonalcoholic Fatty Liver Change  

PubMed Central

Background/Aim: Therapeutic interventions in nonalcoholic fatty liver disease are limited, while antioxidative materials have shown benefi ts in animal models. This study aimed to evaluate grape seed extract as an anti-oxidative material in this process. Therapeutic effects of grape seed extract were evaluated in comparison to vitamin C in a double-blind setting. Materials and Methods: Fifteen patients were enrolled in each group. Liver function tests were done; also, grade of steatosis and pattern of echogenicity of the liver were determined. Patients were followed up by the same evaluation repeated in first, second and third months. Results: Mean age ± standard deviation was 43.2 ± 10.3 years. Grape seed extract (GSE) significantly improved the grade of fatty liver change; and resulted in significant decrease in alanine aminotransferase in patients receiving the concentrate compared to those receiving vitamin C independently, from the initial grade of steatosis. Conclusions: This study describes the beneficial effect of using grape seed extract for three months in patients with nonalcoholic fatty liver disease. These results may improve with a longer period of follow-up.

Khoshbaten, Manouchehr; Aliasgarzadeh, Akbar; Masnadi, Koorosh; Farhang, Sara; Tarzamani, Mohammad K.; Babaei, Hosain; Kiani, Javad; Zaare, Maryam; Najafipoor, Farzad



Assessment of Liver Function in Clinical Practice  

Microsoft Academic Search

\\u000a A broad array of biochemical tests are used to assess the various functions of the liver and evaluate patients with suspected\\u000a or established liver disease. These tests are collectively referred to as “liver function tests,” a term that is often criticized\\u000a because the most commonly used tests—the aminotransferases and alkaline phosphatase—are not true measures of liver synthetic,\\u000a excretory, or metabolic

Hamed Khalili; Barham Abu Dayyeh; Lawrence S. Friedman


Association of Reduced Renal Function with Hepatitis B Virus Infection and Elevated Alanine Aminotransferase  

PubMed Central

Summary Background and objectives Clinically, hepatitis B virus (HBV) infection is observed to be associated with nephropathy. However, previous population-based studies failed to show an association between HBV infection and CKD. Therefore, this cross-sectional study was designed to further explore this association. Design, setting, participants, & measurements A representative sample of 6854 Chinese adults aged 30–75 years was tested for levels of serum hepatitis B surface antigen, alanine aminotransferase (ALT), creatinine, urinary albumin/creatinine ratio, and potential CKD risk factors. Results Neither HBV infection nor elevated ALT (ALT+; ? sex-specific 90th percentile of ALT levels of noninfected persons) was significantly associated with reduced estimated GFR (eGFR < 60 ml/min per 1.73 m2). Compared with noninfected persons, HBV-infected persons with ALT+, but not those with ALT? (P=0.26), were more likely to have reduced eGFR (odds ratio, 4.07; 95% confidence interval, 1.18–14.0; P=0.03). Further analysis with a general linear model revealed a significant difference in eGFR (mean ± SEM) between HBV-infected and noninfected persons (87.8±0.8 versus 90.2±0.4 ml/min per 1.73 m2; P=0.002). This difference was mainly derived from that between HBV-infected persons with ALT+ and noninfected persons, with an average difference in eGFR of ?4.5 (95% confidence interval, ?0.9 to ?8.1; P=0.01). HBV infection and ALT+, alone or in combination, were not significantly associated with albuminuria or CKD. Conclusions HBV infection with elevated ALT, rather than HBV infection alone, was associated with reduced renal function.

Cai, Jianfang; Fan, Xiaohong; Mou, Lijun; Gao, Bixia; Liu, Xuejiao; Li, Jinhong; Liu, Lili; Wang, Haiyun; Guo, Zengyu; Liu, Xiaoqing; Li, Hang; Li, Xuemei



Functional Classification of Amino Acid Decarboxylases from the Alanine Racemase Structural Family by Phylogenetic Studies  

Microsoft Academic Search

Arginine decarboxylase (ADC) and ornithine decarboxylase (ODC) are involved in the biosynthesis of putrescine, which is the precursor of other polyamines in animals, plants, and bacteria. These pyridoxal-5#-phosphate-dependent decarbox- ylases belong to the alanine racemase (AR) structural family together with diaminopimelate decarboxylase (DapDC), which catalyzes the final step of lysine biosynthesis in bacteria. We have constructed a multiple-sequence alignment of

Heidi Kidron; Susanna Repo; Mark S. Johnson; Tiina A. Salminen



Impact of distal aortic and visceral perfusion on liver function during thoracoabdominal and descending thoracic aortic repair  

Microsoft Academic Search

Purpose: We examined the impact of distal aortic and visceral perfusion on liver function during thoracoabdominal and descending thoracic aortic repair. Methods: Between January 1991 and July 1996, 367 patients underwent thoracoabdominal and descending thoracic aortic repair. Baseline and postoperative total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, fibrinogen, prothrombin time (PT), and partial thromboplastin time (PTT) were

Hazim J. Safi; Charles C. Miller III; David H. Yawn; Dimitrious C. Iliopoulos; Mahesh Subramaniam; Stuart Harlin; George V. Letsou



Serum Phenylalanine Concentration as a Marker of Liver Function in Obese Patients Before and After Bariatric Surgery  

Microsoft Academic Search

Background  Human obesity is associated with increased serum phenylalanine concentration, which is probably caused by liver dysfunction\\u000a related to liver steatosis. This study examines whether improvements of liver function after bariatric surgery is associated\\u000a with a decrease of serum phenylalanine concentration caused by an increase of phenylalanine metabolism.\\u000a \\u000a \\u000a \\u000a Method  Serum phenylalanine and alanine aminotransferase (an independent predictor of liver steatosis) concentrations as

Julian Swierczynski; Tomasz Sledzinski; Ewa Slominska; Ryszard Smolenski; Zbigniew Sledzinski



Effect of 6-Month Calorie Restriction and Exercise on Serum and Liver Lipids and Markers of Liver Function  

PubMed Central

objective Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures. Methods and Procedures Forty-six white and black overweight men and women (BMI = 24.7-31.3 kg/m2) were randomized to “control (CO)” = 100% energy requirements; “CR” = 25%; “caloric restriction and increased structured exercise (CR+EX)”= 12.5% CR + 12.5% increase in energy expenditure through exercise; or “low-calorie diet (LCD)” = 15% weight loss by liquid diet followed by weight-maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole-body inflammation (tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)) were measured in fasting blood. Results At baseline, increased liver lipid content (by MRS) correlated (P < 0.05) with elevated fasting triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high-density lipoprotein (HDL)-cholesterol, or markers of whole-body inflammation. Discussion CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD.

Larson-Meyer, D. Enette; Newcomer, Bradley R.; Heilbronn, Leonie K.; Volaufova, Julia; Smith, Steven R.; Alfonso, Anthony J.; Lefevre, Michael; Rood, Jennifer C.; Williamson, Donald A.; Ravussin, Eric



Attenuation of liver normothermic ischemia-reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative 1 1 Abbreviations: ASAT, aspartate aminotransferase; ALAT, alanine aminotransferase; PTP, permeability transition pore; RCR, respiratory control ratio; ROS, reactive oxygen species; and ??, mitochondrial membrane potential  

Microsoft Academic Search

We investigated the antiischemic properties of a new compound, S-15176, in an experimental model of rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of S-15176 (1.25, 2.5, 5 and 10 mg\\/kg\\/day by intramuscular injection) or solvent alone, and subjected to the ischemia-reperfusion process. Another group served as the

Aziz Elimadi; Rosa Sapena; Abdellatif Settaf; Herve Le Louet; Jean-Paul Tillement; Didier Morin



Construction and functional analyses of a comprehensive ?54 site-directed mutant library using alanine-cysteine mutagenesis  

PubMed Central

The ?54 factor associates with core RNA polymerase (RNAP) to form a holoenzyme that is unable to initiate transcription unless acted on by an activator protein. ?54 is closely involved in many steps of activator-dependent transcription, such as core RNAP binding, promoter recognition, activator interaction and open complex formation. To systematically define ?54 residues that contribute to each of these functions and to generate a resource for site specific protein labeling, a complete mutant library of ?54 was constructed by alanine–cysteine scanning mutagenesis. Amino acid residues from 3 to 476 of Cys(-)?54 were systematically mutated to alanine and cysteine in groups of two adjacent residues at a time. The influences of each substitution pair upon the functions of ?54 were analyzed in vivo and in vitro and the functions of many residues were revealed for the first time. Increased ?54 isomerization activity seldom corresponded with an increased transcription activity of the holoenzyme, suggesting the steps after ?54 isomerization, likely to be changes in core RNAP structure, are also strictly regulated or rate limiting to open complex formation. A linkage between core RNAP-binding activity and activator responsiveness indicates that the ?54-core RNAP interface changes upon activation.

Xiao, Yan; Wigneshweraraj, Siva R.; Weinzierl, Robert; Wang, Yi-Ping; Buck, Martin



Impact of mild to moderate elevations of alanine aminotransferase on liver stiffness measurement in chronic hepatitis B patients during antiviral therapy.  


Aim:? The accuracy of liver stiffness measurement (LSM) in the diagnosis of liver fibrosis is affected by elevated serum alanine aminotransferase (ALT) levels. The aim of this study was to assess the impact of mild to moderate elevations of ALT on LSM in patients with chronic hepatitis B (CHB) during antiviral therapy. Methods:? A total of 58 CHB patients with their ALT levels falling into the range of ×2 to ×10 the upper limit of normal (ULN) were recruited. ALT and LSM values were periodically assessed at baseline and 12, 24 and 48?weeks. Results:? The median ALT levels were 153.5 (76-544), 50.5 (11-475), 36.5 (9-265) and 30 (12-239) IU/L at baseline and 12, 24 and 48?weeks, respectively. The corresponding median value of LSM was 8.8 (3.2-47.3), 6.15 (3.2-31.2), 5.9 (3.1-29.1) and 5.5 (2.8-21.5) kpa. However, after the ALT levels were normalized by the treatment, the values of LSM did not vary significantly (6.1 [3.0-17.7] vs 5.25 [2.8-21.5] kpa, P?=?0.381). Pretreatment fibrosis stages of liver biopsies corresponded with LSM after ALT normalization rather than baseline LSM (F0-1, 12/27 vs 23/25, P?liver fibrosis or cirrhosis in CHB patients after the elevated ALT level has been treated to normal level. PMID:22978384

Yan, Li-Bo; Zhu, Xia; Bai, Lang; Liang, Ling-Bo; Chen, En-Qiang; Du, Ling-Yao; Wang, Li-Chun; Chen, Li-Yu; Tang, Hong



Detoxification Functions of the Liver  

Microsoft Academic Search

\\u000a The body is exposed to a variety of chemicals everyday in the form of pharmaceutical agents, household chemicals, dietary\\u000a supplements, and environmental contaminants, many of which are extremely toxic. The primary defense mechanisms against xenobiotics\\u000a in the body are the drug metabolizing enzymes (DMEs) involved in metabolism and excretion of xenobiotics [1]. Liver is the\\u000a primary organ involved in the

Udayan Apte; Partha Krishnamurthy


MicroRNAs and liver function.  


MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate gene expression post-transcriptionally through complementary base pairing with thousands of messenger RNAs. Although the target genes and precise biological functions of individual miRNAs remain largely unknown, miRNAs are speculated to play important roles in diverse biological processes in both normal and pathological states. The liver is a vital organ that plays major roles in a number of physiological functions. Recent advances in the study of liver miRNAs using gene-modified mice or in vivo nucleic acid delivery to overexpress specific miRNAs or inhibit miRNA functions have revealed the crucial biological roles of individual miRNAs in physiologically essential liver functions in vivo. Because miRNA-based strategies are being applied to clinical therapeutics, the importance of precise knowledge of miRNA functions cannot be underestimated, not only from a scientific point of view, but also from a clinical perspective to make the most of such drugs and avoid unexpected harmful effects. The aims of this review are to describe current knowledge regarding both known and as-yet-undiscovered molecular aspects of the biological roles of miRNAs in the liver, with a special emphasis on lipid, glucose, drug, and iron metabolism as vital functions of the liver as well as important therapeutic targets. PMID:23831909

Takata, A; Otsuka, M; Yoshikawa, T; Kishikawa, T; Ohno, M; Koike, K



Liver-Spleen Scintigrams, Epigastric Sonograms and Liver Function Scintigram for Comparative Studies of Various Cases of Liver Cirrhosis.  

National Technical Information Service (NTIS)

23 patients where liver cirrhosis was established were subjected to an epigastric sonogram, a liver-spleen scintigram, a liver-function scintigram, and to various relevant laboratory tests. The liver-spleen scintigram was evaluated for size of the liver, ...

R. Geiger



Splenic function in alcoholic liver disease  

Microsoft Academic Search

Splenic function was assessed in 42 patients with alcoholic liver disease by counting the percentage of erythrocytes with indentations or pits, seen by differential interference contrast microscopy. These pits represent cellular debris normally removed by the spleen. The findings were compared with 42 age and sex matched controls. Mean (SEM) pitted red cell counts in the patients was 2.7 (0.4)%

A F Muller; P J Toghill



Catabolic Function of Compartmentalized Alanine Dehydrogenase in the Heterocyst-Forming Cyanobacterium Anabaena sp. Strain PCC 7120?  

PubMed Central

In the diazotrophic filaments of heterocyst-forming cyanobacteria, an exchange of metabolites takes place between vegetative cells and heterocysts that results in a net transfer of reduced carbon to the heterocysts and of fixed nitrogen to the vegetative cells. Open reading frame alr2355 of the genome of Anabaena sp. strain PCC 7120 is the ald gene encoding alanine dehydrogenase. A strain carrying a green fluorescent protein (GFP) fusion to the N terminus of Ald (Ald-N-GFP) showed that the ald gene is expressed in differentiating and mature heterocysts. Inactivation of ald resulted in a lack of alanine dehydrogenase activity, a substantially decreased nitrogenase activity, and a 50% reduction in the rate of diazotrophic growth. Whereas production of alanine was not affected in the ald mutant, in vivo labeling with [14C]alanine (in whole filaments and isolated heterocysts) or [14C]pyruvate (in whole filaments) showed that alanine catabolism was hampered. Thus, alanine catabolism in the heterocysts is needed for normal diazotrophic growth. Our results extend the significance of a previous work that suggested that alanine is transported from vegetative cells into heterocysts in the diazotrophic Anabaena filament.

Pernil, Rafael; Herrero, Antonia; Flores, Enrique



Functional validation of GWAS gene candidates for abnormal liver function during zebrafish liver development  

PubMed Central

SUMMARY Genome-wide association studies (GWAS) have revealed numerous associations between many phenotypes and gene candidates. Frequently, however, further elucidation of gene function has not been achieved. A recent GWAS identified 69 candidate genes associated with elevated liver enzyme concentrations, which are clinical markers of liver disease. To investigate the role of these genes in liver homeostasis, we narrowed down this list to 12 genes based on zebrafish orthology, zebrafish liver expression and disease correlation. To assess the function of gene candidates during liver development, we assayed hepatic progenitors at 48 hours post fertilization (hpf) and hepatocytes at 72 hpf using in situ hybridization following morpholino knockdown in zebrafish embryos. Knockdown of three genes (pnpla3, pklr and mapk10) decreased expression of hepatic progenitor cells, whereas knockdown of eight genes (pnpla3, cpn1, trib1, fads2, slc2a2, pklr, mapk10 and samm50) decreased cell-specific hepatocyte expression. We then induced liver injury in zebrafish embryos using acetaminophen exposure and observed changes in liver toxicity incidence in morphants. Prioritization of GWAS candidates and morpholino knockdown expedites the study of newly identified genes impacting liver development and represents a feasible method for initial assessment of candidate genes to instruct further mechanistic analyses. Our analysis can be extended to GWAS for additional disease-associated phenotypes.

Liu, Leah Y.; Fox, Caroline S.; North, Trista E.; Goessling, Wolfram



Liver function tests’ on the intensive care unit: a prospective, observational study  

Microsoft Academic Search

Aims  To evaluate the prevalence, patterns and significance of deranged liver function tests (LFT) in critically ill patients.\\u000a \\u000a \\u000a \\u000a Methods  A prospective, observational data collection of the LFT [bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (AKP),\\u000a gamma glutaryl transferase (?GT)] and critical care parameters in all admissions to the general intensive care unit (ICU)\\u000a of our institution. Prevalence of abnormal LFT on the day

S. J. Thomson; M. L. Cowan; I. Johnston; S. Musa; M. Grounds; T. M. Rahman



The Effect of Pioglitazone and Metformin on Liver Function Tests, Insulin Resistance, and Liver Fat Content in Nonalcoholic Fatty Liver Disease: A Randomized Double Blinded Clinical Trial  

PubMed Central

Background Non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of insulin resistance (IR) syndrome. The effect of insulin sensitizers on liver function tests and metabolic indices in NAFLD patients is a matter of debate. Objectives The aim of study was to compare the effects of two different insulin sensitizers, pioglitazone, and metformin, on liver function tests (LFT), lipid profile, homeostasis model assessment-IR (HOMA-IR) index, and liver fat content (LFC) in NAFLD patients. Materials and Methods This double blind clinical trial was performed on patients who were referred to a gastroenterology clinic with evidence of fatty liver in ultrasonography. After excluding other causes, participants with persistent elevated alanine aminotransferase (ALT) levels and “NAFLD liver fat score” greater than -0.64 were presumed to have NAFLD and were enrolled. They were randomly assigned to take metformin (1 g/day) or pioglitazone (30 mg/day) for four months. Fasting serum glucose (FSG), ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride, cholesterol (CHOL), high and low density lipoprotein (HDL, LDL), HOMA-IR, and LFC were checked at the baseline, two and four months post-treatment. LFC was measured by a validated formula. Results Eighty patients (68 males) with mean age of 35.27 (± 7.98) were included. After 2 months, LFT was improved significantly in the pioglitazone group and did not change in the metformin group. After four months, both medications significantly decreased serum levels of LFT, FSG, CHOL, LDL, HOMA-IR, and LFC, and increased serum level of HDL. No statistically significant differences were seen between the two treatment groups with regard to the changes of laboratory parameters and LFC from baseline to four months post-treatment. Conclusions During the four months, the use of metformin (1 g/day) and pioglitazone (30 mg/day) were safe and might have equally affected LFT, HOMA-IR, lipid profile, and LFC in NAFLD patients.

Razavizade, Mohsen; Jamali, Raika; Arj, Abbas; Matini, Seyyed Mohammad; Moraveji, Alireza; Taherkhani, Effat



Molecular Insight into the Synergism between the Minor Allele of Human Liver Peroxisomal Alanine:Glyoxylate Aminotransferase and the F152I Mutation*  

PubMed Central

Human liver peroxisomal alanine:glyoxylate aminotransferase (AGT) is a pyridoxal 5?-phosphate (PLP)-dependent enzyme that converts glyoxylate into glycine. AGT deficiency causes primary hyperoxaluria type 1 (PH1), a rare autosomal recessive disorder, due to a marked increase in hepatic oxalate production. Normal human AGT exists as two polymorphic variants: the major (AGT-Ma) and the minor (AGT-Mi) allele. AGT-Mi causes the PH1 disease only when combined with some mutations. In this study, the molecular basis of the synergism between AGT-Mi and F152I mutation has been investigated through a detailed biochemical characterization of AGT-Mi and the Phe152 variants combined either with the major (F152I-Ma, F152A-Ma) or the minor allele (F152I-Mi). Although these species show spectral features, kinetic parameters, and PLP binding affinity similar to those of AGT-Ma, the Phe152 variants exhibit the following differences with respect to AGT-Ma and AGT-Mi: (i) pyridoxamine 5?-phosphate (PMP) is released during the overall transamination leading to the conversion into apoenzymes, and (ii) the PMP binding affinity is at least 200–1400-fold lower. Thus, Phe152 is not an essential residue for transaminase activity, but plays a role in selectively stabilizing the AGT-PMP complex, by a proper orientation of Trp108, as suggested by bioinformatic analysis. These data, together with the finding that apoF152I-Mi is the only species that at physiological temperature undergoes a time-dependent inactivation and concomitant aggregation, shed light on the molecular defects resulting from the association of the F152I mutation with AGT-Mi, and allow to speculate on the responsiveness to pyridoxine therapy of PH1 patients carrying this mutation.

Cellini, Barbara; Montioli, Riccardo; Paiardini, Alessandro; Lorenzetto, Antonio; Voltattorni, Carla Borri



The N-terminal extension is essential for the formation of the active dimeric structure of liver peroxisomal alanine:glyoxylate aminotransferase.  


Alanine:glyoxylate aminotransferase (AGT) is a pyridoxal-phosphate (PLP)-dependent enzyme. Its deficiency causes the hereditary kidney stone disease primary hyperoxaluria type 1. AGT is a highly stable compact dimer and the first 21 residues of each subunit form an extension which wraps over the surface of the neighboring subunit. Naturally occurring and artificial amino acid replacements in this extension create changes in the functional properties of AGT in mammalian cells, including relocation of the enzyme from peroxisomes to mitochondria. In order to elucidate the structural and functional role of this N-terminal extension, we have analyzed the consequences of its removal using a variety of biochemical and cell biological methods. When expressed in Escherichia coli, the N-terminal deleted form of AGT showed the presence of the protein but in an insoluble form resulting in only a 10% soluble yield as compared to the full-length version. The purified soluble fraction showed reduced affinity for PLP and greatly reduced catalytic activity. Although maintaining a dimer form, it was highly prone to self-aggregation. When expressed in a mammalian cell line, the truncated construct was normally targeted to peroxisomes, where it formed large stable but catalytically inactive aggregates. These results suggest that the N-terminal extension plays an essential role in allowing AGT to attain its correct conformation and functional activity. The precise mechanism of this effect is still under investigation. PMID:22198249

Montioli, Riccardo; Fargue, Sonia; Lewin, Jackie; Zamparelli, Carlotta; Danpure, Christopher J; Borri Voltattorni, Carla; Cellini, Barbara



Optimization of an Isolated Perfused Rainbow Trout Liver Model: Clearance Studies with 7-Ethoxycoumarin  

EPA Science Inventory

Isolated trout livers were perfused using methods designed to preserve tissue viability and function. Liver performance was evaluated by measuring O2 consumption (VO2), vascular resistance, K+ leakage, glucose flux, lactate flux, alanine aminotransferase (ALT) leakage, and meta...


Proposal of Noninvasive Liver Function Measurement Method via Saliva  

NASA Astrophysics Data System (ADS)

The authors studied the correlation between serum alanine aminotransferase (ALT) activity and salivary ALT activity using ten healthy young adults and ten liver disease patients. Firstly, in order to establish the experimental conditions, we investigated the influence of occult blood and salivary secretion rate on the salivary ALT activity using healthy subjects. Then, simultaneous analysis of the serum and salivary ALT activities were conducted to investigate the correlation using the twenty subjects. As the results, although salivary ALT activity was as low as one third of serum ALT activity, the presence of salivary ALT activity was confirmed in healthy young adults whose saliva was not contaminated with serum. The salivary ALT activity of liver disease patients showed higher values than that of healthy young adults. In other word, if a threshold of salivary ALT activity was established, healthy young adults could be distinguished from liver disease patients.

Yamaguchi, Masaki; Kawabata, Yuji; Hatakeyama, Toyomasa; Kashii, Yoshiro


Experimental and computational thermochemical study of ?-alanine (DL) and ?-alanine.  


This paper reports an experimental and theoretical study of the gas phase standard (p° = 0.1 MPa) molar enthalpies of formation, at T = 298.15 K, of ?-alanine (DL) and ?-alanine. The standard (p° = 0.1 MPa) molar enthalpies of formation of crystalline ?-alanine (DL) and ?-alanine were calculated from the standard molar energies of combustion, in oxygen, to yield CO2(g), N2(g), and H2O(l), measured by static-bomb combustion calorimetry at T = 298.15 K. The vapor pressures of both amino acids were measured as function of temperature by the Knudsen effusion mass-loss technique. The standard molar enthalpies of sublimation at T = 298.15 K was derived from the Clausius?Clapeyron equation. The experimental values were used to calculate the standard (p° = 0.1 MPa) enthalpy of formation of ?-alanine (DL) and ?-alanine in the gaseous phase, ?(f)H(m)°(g), as ?426.3 ± 2.9 and ?421.2 ± 1.9 kJ·mol(?1), respectively. Standard ab initio molecular orbital calculations at the G3 level were performed. Enthalpies of formation, using atomization reactions, were calculated and compared with experimental data. Detailed inspections of the molecular and electronic structures of the compounds studied were carried out. PMID:21087063

da Silva, Manuel A V Ribeiro; da Silva, Maria das Dores M C Ribeiro; Santos, Ana Filipa L O M; Roux, Maria Victoria; Foces-Foces, Concepción; Notario, Rafael; Guzmán-Mejía, Ramón; Juaristi, Eusebio



Functional role of the interaction between polysialic acid and myristoylated alanine-rich C kinase substrate at the plasma membrane.  


Polysialic acid (PSA) is a homopolymeric glycan that plays crucial roles in the developing and adult nervous system. So far only a few PSA-binding proteins have been identified. Here, we identify myristoylated alanine-rich C kinase substrate (MARCKS) as novel PSA binding partner. Binding assays showed a direct interaction between PSA and a peptide comprising the effector domain of MARCKS (MARCKS-ED). Co-immunoprecipitation of PSA-carrying neural cell adhesion molecule (PSA-NCAM) with MARCKS and co-immunostaining of MARCKS and PSA at the cell membrane of hippocampal neurons confirm the interaction between PSA and MARCKS. Co-localization and an intimate interaction of PSA and MARCKS at the cell surface was seen by confocal microscopy and fluorescence resonance energy transfer (FRET) analysis after the addition of fluorescently labeled PSA or PSA-NCAM to live CHO cells or hippocampal neurons expressing MARCKS as a fusion protein with green fluorescent protein (GFP). Cross-linking experiments showed that extracellularly applied PSA or PSA-NCAM and intracellularly expressed MARCKS-GFP are in close contact, suggesting that PSA and MARCKS interact with each other at the plasma membrane from opposite sides. Insertion of PSA and MARCKS-ED peptide into lipid bilayers from opposite sides alters the electric properties of the bilayer confirming the notion that PSA and the effector domain of MARCKS interact at and/or within the plane of the membrane. The MARCKS-ED peptide abolished PSA-induced enhancement of neurite outgrowth from cultured hippocampal neurons indicating an important functional role for the interaction between MARCKS and PSA in the developing and adult nervous system. PMID:23329829

Theis, Thomas; Mishra, Bibhudatta; von der Ohe, Maren; Loers, Gabriele; Prondzynski, Maksymilian; Pless, Ole; Blackshear, Perry J; Schachner, Melitta; Kleene, Ralf



The orphan transporter Rxt1/NTT4 (SLC6A17) functions as a synaptic vesicle amino acid transporter selective for proline, glycine, leucine, and alanine.  


Rxt1/NTT4 (SLC6A17) belongs to a gene family of "orphan transporters" whose substrates and consequently functions remain unidentified. Although Rxt1/NTT4 was previously thought to function as a sodium-dependent plasma membrane transporter, recent studies localized the protein to synaptic vesicles of glutamatergic and GABAergic neurons. Here, we provide evidence indicating that Rxt1/NTT4 functions as a vesicular transporter selective for proline, glycine, leucine, and alanine. Using Western blot, immunoprecipitation, immunocytochemistry, and polymerase chain reaction approaches, we demonstrate that PC12 cells express the Rxt1/NTT4 gene and protein. Small interfering RNA (siRNA)-mediated knockdown of Rxt1/NTT4 in PC12 cells resulted in selective reductions in uptake levels for proline, glycine, leucine, and alanine. Likewise, gas chromatography analysis of amino acid content in an enriched synaptic vesicle fraction from wild-type and siRNA-Rxt1/NTT4 PC12 cells revealed that proline, glycine, leucine, and alanine levels were decreased in siRNA-treated cells compared with wild-type cells. Furthermore, Rxt1/NTT4-transfected Chinese hamster ovary (CHO) cells exhibited significant uptake increases of these amino acids compared with mock-transfected CHO cells. Finally, proline uptake in both PC12 cells and Rxt1/NTT4-transfected CHO cells was dependent on the electrochemical gradient maintained by the vacuolar-type H(+)-ATPase. These data indicate that the orphan Rxt1/NTT4 protein functions as a vesicular transporter for proline, glycine, leucine, and alanine, further suggesting its important role in synaptic transmission. PMID:18768736

Parra, Leonardo A; Baust, Tracy; El Mestikawy, Salah; Quiroz, Marisol; Hoffman, Beth; Haflett, Jack M; Yao, Jeffrey K; Torres, Gonzalo E



Effect of rosiglitazone on liver structure and function in genetically diabetic akita mice.  


Genetically diabetic Akita mice, kept on a high-fat and high-cholesterol diet, and treated with the peroxisome proliferator-activated receptor-? agonist rosiglitazone (10 mg/kg per day during 4 months), displayed rosiglitazone-induced side effects, similar to those observed in patients, including weight and fat gain and early signs of hypertrophic cardiomyopathy. As several cases of hepatotoxicity were reported in patients receiving rosiglitazone treatment, this study evaluated whether rosiglitazone also induced hepatotoxicity in these diabetic animals. Liver structure and function was analysed in wild-type and rosiglitazone-treated and untreated Akita mice, kept for 4 months on the high-fat and high-cholesterol diet. Decreased circulating levels of the liver enzymes aspartate and alanine aminotransferase and increased levels of alkaline phosphatases were observed upon rosiglitazone treatment, whereas liver weight was markedly increased. Rosiglitazone administration was associated with liver steatosis, as demonstrated by triglyceride accumulation. However, gene expression of steatosis markers in liver tissue was not markedly affected by rosiglitazone treatment, while expression of fatty acid transport protein was reduced by rosiglitazone treatment, suggesting an impairment of the fatty acid ?-oxidation pathway. mRNA expression of pro- and anti-oxidant enzymes and liver 3-nitrotyrosine content was not affected. Furthermore, gene and protein expression of macrophage markers and of cell adhesion molecules did not indicate progression to steatohepatitis, whereas an unaltered collagen deposition did not suggest steatofibrosis. In conclusion, rosiglitazone treatment of diabetic Akita mice induced liver steatosis without, however, progression to more advanced stages of liver disease. PMID:23789962

Hemmeryckx, Bianca; Gaekens, Marijke; Gallacher, David J; Lu, Hua Rong; Lijnen, Henri Roger



Combined effects of fluoride and cadmium on liver and kidney function in male rats.  


It has been shown that cadmium and fluoride may both have adverse effects on liver and kidney functions, but most studies focus on a single agent. In this study, we observed the effects of cadmium and fluoride on liver and kidney functions using a rat model. Total of 24 Sprague-Dawley male rats were divided into four groups, one control group and three exposure groups that were given cadmium (50 mg/L) and fluoride (100 mg/L) alone or in combination via drinking water. At the 12th week, urine, blood, and kidney tissues were collected. Aspartate transaminase, alanine transaminase (ALT), urinary ?2-microglobulin, and albumin were determined. Contents of malondialdehyde (MDA) and superoxide dismutase (SOD) in liver and kidney homogenates were measured to evaluate oxidative stress. There was a significant increase in serum ALT and urinary ?2-microglobulin of rats in exposure groups compared with control. Serum ALT and urinary ?2-microglobulin of rats exposed to cadmium and fluoride in combination was significantly higher than those treated with cadmium alone and fluoride alone. SOD declined significantly and MDA increased in combination group compared with control and those treated with cadmium and fluoride alone. Cadmium and fluoride co-exposure increase the liver and kidney damage compared with that exposed to cadmium or fluoride alone. PMID:24006106

Zhang, Junmin; Song, Jingjuan; Zhang, Jun; Chen, Xiao; Zhou, Meixia; Cheng, Guang; Xie, Xinyou



Role of liver function enzymes in diagnosis of choledocholithiasis in biliary colic patients.  


Liver functional tests due to inflammatory process which induced by cholecystitis might changed and some clinicians suggested that these changes might help us to stone prediction in common bile ducts and decrease hazards of performing ERCP and other invasive procedures. Present study was performed for assessment of role of liver functional test in diagnosis of common bile duct stone in patients with cholecystitis and help in their management. Present prospective study was performed between April 2010 and March 2011 on 350 patients who come to our hospital with cholecystitis or biliary colic diagnosis. Patients with cholesistitis diagnosis were underwent operation for removing gall bladder stone and retrograde cholangiopancreatography (ERCP) was performed for patients with suspicious to biliary colic and common bile duct (CBD) stones. Ultrasonography, aspartate aminotransferases (AST), alanine aminotransferases (ALT), alkaline phosphatase (ALP) and direct and total serum bilirubin were measured for all of participated patients. Mean of AST. ALT, ALP and total and direct bilirubin were had no significant differences between two study groups. In logistic regression analysis, after entering into the model only CBD diameter (OR: 20; P=0.00) and elevated serum level of ALT (OR: 2; P=0.04) were remained into the model and were known as independent predictor of cholelithiasis. Elevated level of liver enzymes had not main role in CBD diagnosis and ERCP had no to perform for suspicious CBD stone only with elevated liver enzyme and even with normal ultrasonography findings. Endosonography as non invasive procedure recommend for patients before ERCP. PMID:22071641

Zare, Mohammad; Kargar, Saeed; Akhondi, Mohsen; Mirshamsi, Mohammad Hussein



Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis  

PubMed Central

Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl4)–induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl4 treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl4 injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injury-driven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth.

Wang, Hua; Lafdil, Fouad; Wang, Lei; Park, Ogyi; Yin, Shi; Niu, Junyang; Miller, Andrew M.; Sun, Zhaoli; Gao, Bin



Preoperative assessment of postoperative remnant liver function using hepatobiliary scintigraphy  

Microsoft Academic Search

Hepatic resection is the therapy of choice for malignant and symp- tomatic benign hepatobiliary tumors. The concept of remnant liver volume (RLV) has been introduced and can be assessed with CT. However, inhomogeneous liver function distribution and a lack of correlation between morphologic hypertrophy and functional re- covery fuelled the enthusiasm for functional imaging. The aim of the present study

Roelof J. Bennink; Sander Dinant; Deha Erdogan; Bob H. Heijnen; Irene H. Straatsburg; Vliet van A. K; Gulik van T. M



Influence of black cohosh (Cimicifuga racemosa) use by postmenopausal women on total hepatic perfusion and liver functions.  


In this prospective longitudinal clinical trial, 87 postmenopausal women receiving for 12 consecutive months a daily dose of 40 mg of a dry extract preparation of Cimicifuga racemosa (Klimadynon) for relief of vasomotor symptoms were followed up by evaluation of total hepatic blood flow, assessed by color Doppler ultrasound, as well as prothrombin time and concentration, serum albumin, bilirubin, gamma-glutamyltransferase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase. Because no significant changes in total hepatic blood flow or any of the liver functions tested were reported, we concluded that use of C. racemosa for 1 year by healthy postmenopausal women without evidence of liver disease does not seem to influence the liver. PMID:19539907

Nasr, Ahmed; Nafeh, Hanan



Yellow Fever Virus NS2B–NS3 Protease: Charged-to-Alanine Mutagenesis and Deletion Analysis Define Regions Important for Protease Complex Formation and Function  

Microsoft Academic Search

Charged-to-alanine substitutions and deletions within the yellow fever virus NS2B–NS3181 protease were analyzed for effects on protease function. During cell-free translation of NS2B–3181 polyproteins, mutations at three charge clusters markedly impaired cis cleavage activity: a single N-terminal cluster in the conserved domain of NS2B (residues ELKK52–55) and two in NS3 (ED21–22, and residue H47). These mutations inhibited other protease-dependent cleavages

Deborah A. Droll; H. M. Krishna Murthy; Thomas J. Chambers



Mechanisms of Aging and Liver Functions  

Microsoft Academic Search

Background\\/Aims: Morphofunctional studies suggest that the liver, compared with other organs, ages fairly well. Its success is ascribable to its lasting ability to regenerate, even if the potential of the cells to replicate progressively declines with age. The aim of this study was to analyze some aspects of the early phases of liver regeneration, its capacity to mount a stress

Nicoletta Gagliano; Fabio Grizzi; Giorgio Annoni



Healthy centenarian subjects: the effect of red wine consumption on liver function tests.  


Liver function is well maintained with increasing age. The aim of our study was to investigate if long-term moderate (liver function in healthy centenarians. Wine consumption habits were classified as moderate red wine drinkers (D) (alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AST was higher in A (Mean+/-SE=8.40+/-0.32 U/l) in comparison to D (Mean+/-SE=6.25+/-0.72 U/l), but this difference was not statistically significant. Total-bilirubin (Tbil), alkaline phosphatase (AlkP), gamma- glutamyltransferase (GGT) and pseudocholinesterase (CHE) were in the normal range, and there was no difference between D and A. We conclude that red wine consumption in centenarians had no negative effect on circulating liver enzyme activities. PMID:16760640

Pinzani, P; Petruzzi, E; Orlando, C; Malentacchi, F; Petruzzi, I; Pazzagli, M; Masotti, G



Abnormal liver function test results are related to metabolic syndrome and BMI in Taiwanese adults without chronic hepatitis B or C  

Microsoft Academic Search

Background:Metabolic syndrome (MS) is considered a cause of abnormal deposition of fat into hepatocytes, which might be associated with hepatic steatosis or abnormal liver function.Objective:The aim of this study was to explore the factors associated with MS and the relationship between MS and abnormal aspartate aminotransferase (AST), alanine aminotransferase (ALT) and ?-glutamyl transferase (GGT) levels in Taiwanese subjects without chronic

M-H Hsieh; C-K Ho; N-J Hou; M-Y Hsieh; W-Y Lin; J-F Yang; C-C Chiu; J-F Huang; N-C Chang; C-L Wang; C-Y Dai; W-L Chuang; M-L Yu



Dosimetric applications of ?-alanine  

Microsoft Academic Search

Irradiation of solid polycrystalline alanine creates a free radical, whose concentration can be measured from its ESR signal. The radical CH3HCOO– of practically unlimited stability at room temperature shows an electronic absorption spectrum in the UV. Modern methods of diffuse reflectance spectrophotometry allow to measure the radical concentration which is proportional to the absorbed dose of radiation. The alanine dosimeter

Z. P. Zagórski



Peroxisomal Alanine: Glyoxylate Aminotransferase AGT1 Is Indispensable for Appressorium Function of the Rice Blast Pathogen, Magnaporthe oryzae  

PubMed Central

The role of ?-oxidation and the glyoxylate cycle in fungal pathogenesis is well documented. However, an ambiguity still remains over their interaction in peroxisomes to facilitate fungal pathogenicity and virulence. In this report, we characterize a gene encoding an alanine, glyoxylate aminotransferase 1 (AGT1) in Magnaporthe oryzae, the causative agent of rice blast disease, and demonstrate that AGT1 is required for pathogenicity of M. oryzae. Targeted deletion of AGT1 resulted in the failure of penetration via appressoria; therefore, mutants lacking the gene were unable to induce blast symptoms on the hosts rice and barley. This penetration failure may be associated with a disruption in lipid mobilization during conidial germination as turgor generation in the appressorium requires mobilization of lipid reserves from the conidium. Analysis of enhanced green fluorescent protein expression using the transcriptional and translational fusion with the AGT1 promoter and open reading frame, respectively, revealed that AGT1 expressed constitutively in all in vitro grown cell types and during in planta colonization, and localized in peroxisomes. Peroxisomal localization was further confirmed by colocalization with red fluorescent protein fused with the peroxisomal targeting signal 1. Surprisingly, conidia produced by the ?agt1 mutant were unable to form appressoria on artificial inductive surfaces, even after prolonged incubation. When supplemented with nicotinamide adenine dinucleotide (NAD+)+pyruvate, appressorium formation was restored on an artificial inductive surface. Taken together, our data indicate that AGT1-dependent pyruvate formation by transferring an amino group of alanine to glyoxylate, an intermediate of the glyoxylate cycle is required for lipid mobilization and utilization. This pyruvate can be converted to non-fermentable carbon sources, which may require reoxidation of NADH generated by the ?-oxidation of fatty acids to NAD+ in peroxisomes. Therefore, it may provide a means to maintain redox homeostasis in appressoria.

Bhadauria, Vijai; Banniza, Sabine; Vandenberg, Albert; Selvaraj, Gopalan; Wei, Yangdou



Alanine 32 in PilA is important for PilA stability and type IV pili function in Myxococcus xanthus  

PubMed Central

Type IV pili (TFP) are membrane-anchored filaments with a number of important biological functions. In the model organism Myxococcus xanthus, TFP act as molecular engines that power social (S) motility through cycles of extension and retraction. TFP filaments consist of several thousand copies of a protein called PilA or pilin. PilA contains an N-terminal ?-helix essential for TFP assembly and a C-terminal globular domain important for its activity. The role of the PilA sequence and its structure–function relationship in TFP-dependent S motility remain active areas of research. In this study, we identified an M. xanthus PilA mutant carrying an alanine to valine substitution at position 32 in the ?-helix, which produced structurally intact but retraction-defective TFP. Characterization of this mutant and additional single-residue variants at this position in PilA demonstrated the critical role of alanine 32 in PilA stability, TFP assembly and retraction.

Yang, Zhe; Hu, Wei; Chen, Kevin; Wang, Jing; Lux, Renate; Zhou, Z. Hong



In Vitro studies of non poly alanine PHOX2B mutations argue against a loss-of-function mechanism for congenital central hypoventilation.  


A wide range of autonomic dysfunctions, i.e. Central Hypoventilation Syndromes, Hirschsprung disease and Tumours of the Sympathetic Nervous System have been ascribed to heterozygous PHOX2B mutations in man. The PHOX2B mutations reported include polyalanine expansions in a 20 alanines tract, missense, frameshift mutations and nonsense mutation. Some genotype/phenotype correlations have been drawn, but the molecular mechanism(s) underlying them remain(s) unclear. So far, loss-of-function, gain-of-function and dominant negative effects have been proposed as disease-causing mechanisms for polyalanine expansions. Indeed, mutant with an expanded polyalanine tract result in decreased transactivation of known target genes and protein misfolding leading to oligomerisation in vitro for all expansions and to cytoplasmic protein aggregation for longer expansions. We extended the molecular studies to other non-polyalanine expansion mutations and show that most PHOX2B protein mutants oligomerize even in the absence of the normal 20 alanines tract. Conversely, a premature stop codon mutation in a CHS patient leads to the production of an N-terminally truncated protein by re-initiation of translation that does not form oligomers. Therefore, PHOX2B misfolding is not the only mechanism leading to dysfunction of the ventilatory autonomic system. PMID:19058226

Trochet, Delphine; Mathieu, Yves; Pontual, Loïc de; Savarirayan, Ravi; Munnich, Arnold; Brunet, Jean-François; Lyonnet, Stanislas; Goridis, Christo; Amiel, Jeanne



Liver structure and function in print workers exposed to toluene.  


An unresolved controversy is whether exposure to organic solvents in the workplace causes hepatotoxicity. From a medical surveillance study of 289 printing factory employees who were exposed primarily to toluene, we identified eight workers who had persistently abnormal serum transaminase and/or alkaline phosphatase values. The eight men were generally healthy and gave no history of taking medications or of drinking ethanol to excess. None was obese or diabetic. Six patients had hepatomegaly based on physical examination. All eight had mild elevations (less than 2 to 3 times the upper value of normal) of serum transaminases [alanine (ALT) and aspartate aminotransferase (AST)]. However, there was a marked increase in the ratio of ALT/AST (mean = 1.61). In each case, liver biopsy revealed mild, pericentral fatty change. Our results, consistent with those previously published by some others, suggest that pericentral fatty liver with mild "reactive hepatitis" is the most likely diagnosis in workers exposed to solvents for whom common causes of mild liver test abnormalities have been excluded. An increased ALT/AST ratio may represent a convenient, previously unrecognized indicator of this condition. PMID:3230426

Guzelian, P; Mills, S; Fallon, H J



Antigen-presenting cell function in the tolerogenic liver environment  

Microsoft Academic Search

The demands that are imposed on the liver as a result of its function as a metabolic organ that extracts nutrients and clears gut-derived microbial products from the blood are met by a unique microanatomical and immunological environment. The inherent tolerogenicity of the liver and its role in the regulation of innate and adaptive immunity are mediated by parenchymal and

Angus W. Thomson; Percy A. Knolle



Liver Function Test Abnormalities in Users of Aqueous Kava Extracts  

Microsoft Academic Search

Introduction. Hepatic toxicity from manufactured herbal remedies that contain kava lactones has been reported in Europe, North America, and Australia. There is no evidence for serious liver damage in kava-using populations in Pacific Island societies or in Indigenous Australians who have used aqueous kava extracts. This article presents evidence that liver function changes in users of aqueous kava extracts appear

Alan R. Clough; Ross S. Bailie; Bart Currie




Microsoft Academic Search

Scrub typhus is one kind of rickettsial disease and may cause fever, cough, and skin rashes in infected humans. Regarding liver involvement, it was uncommon to be reported in previous medical literature from Western countries. This study observes the relationship between scrub typhus and liver function. From January 1998 to August 2003 in Kaohsiung Chang Gung Memorial Hospital in Taiwan,



Serum leptin levels in alcoholic liver cirrhosis: relationship with gender, nutritional status, liver function and energy metabolism  

Microsoft Academic Search

Objective: To determine serum leptin levels in alcoholic liver cirrhosis and the relationship with gender, nutritional status, liver function, energy metabolism, inflammatory state and refeeding.Subjects: Thirty-seven hospitalized alcoholic cirrhotic patients (M\\/F: 24\\/13), 27 hospitalized patients at risk of malnutrition but with normal liver function (M\\/F: 15\\/12) as control patients, and 31 healthy control subjects (M\\/F: 17\\/14) participated.Design: Liver function was

B Campillo; E Sherman; JP Richardet; PN Bories



Erosive esophagitis associated with metabolic syndrome, impaired liver function, and dyslipidemia  

PubMed Central

AIM: To investigate whether erosive esophagitis is correlated with metabolic syndrome and its components, abnormal liver function, and lipoprotein profiles. METHODS: We conducted a cross-sectional, case control study of subjects who underwent upper endoscopy during a health examination at the Health Management and Evaluation Center of a tertiary medical care facility located in Southern Taiwan. Metabolic syndrome components, body mass index (BMI), liver function, dyslipidemia, and cardiovascular risk factors, as defined by the ratio of total cholesterol to high-density lipoprotein cholesterol (HDL-C), and the ratio of low-density lipoprotein cholesterol to HDL-C were compared between individuals with and without erosive esophagitis. Risk factors for erosive esophagitis were evaluated by multivariate logistic regression. RESULTS: Erosive esophagitis was diagnosed in 507 of 5015 subjects who were individually age and sex matched to 507 esophagitis-free control subjects. In patients with erosive esophagitis, BMI, waist circumference, blood pressure, fasting plasma glucose, triglyceride levels, aspartate aminotransferase, alanine aminotransferase, the ratio of total cholesterol to HDL-C, and the ratio of low-density lipoprotein cholesterol to HDL-C were significantly higher and HDL-C was significantly lower compared to patients without erosive esophagitis (all P < 0.05). In a multivariate analysis, central obesity (OR = 1.38; 95%CI: 1.0-1.86), hypertension (OR = 1.35; 95%CI: 1.04-1.76), hypertriglyceridemia (OR = 1.34; 95%CI: 1.02-1.76), cardiovascular risk factors as defined by a ratio of total cholesterol to HDL-C > 5 (OR = 1.45; 95%CI: 1.06-1.97), and aspartate aminotransferase (OR = 1.59; 95%CI: 1.08-2.34) were significantly associated with erosive esophagitis. CONCLUSION: Metabolic syndrome, impaired liver function, and a higher ratio of total cholesterol to HDL-C were associated with erosive esophagitis.

Loke, Song-Seng; Yang, Kuender D; Chen, Kuang-Den; Chen, Jung-Fu



Functional role of chemokines in liver disease models.  


Chemokines are a class of small cytokine-like molecules that orchestrate immune cell infiltration into the liver in response to acute and chronic injuries. Apart from their chemotactic effect, however, chemokines seem to mediate many other aspects of liver diseases, including a direct activation of stellate cells, the modulation of hepatocyte proliferation and angiogenesis. The identification of specific biological functions for chemokines in liver diseases has been hampered by the finding that resident and infiltrating cells in the liver are often a source, as well as a target, of chemokines. Furthermore, chemokines might cause differing effects depending on the etiology of liver damage, their local concentrations and their ability to form multimers and heterodimers. Nevertheless, the functions of a number of important chemokines and their associated receptors have been identified in both in vivo and in vitro studies. Indeed, harmful (proinflammatory, profibrogenic) and beneficial (antifibrogenic, antiangiogenic) effects of chemokines have been discovered in experimental liver disease models. In this Review, the current knowledge of chemokines in experimental liver disease models is summarized. Advances that might lead to preclinical applications are discussed, as are the roles of chemokine receptors as promising pharmacologically targetable molecules. PMID:20975742

Sahin, Hacer; Trautwein, Christian; Wasmuth, Hermann E



Evaluation of liver function tests in scleroderma patients.  


Systemic sclerosis is a clinically heterogeneous, systemic disorder which affects the connective tissue of the skin, internal organs, and the walls of blood vessels. It is characterized by alterations of the microvasculature, disturbances of the immune system and by massive deposition of collagen and other matrix substances in the connective tissue. This study was done to evaluate the frequency of liver disease in patients with scleroderma and, secondarily, to study the frequency of infection of hepatitis B and C virus in these patients and determine frequency of serum auto-antibodies in this disease. We studied patients with scleroderma, localized or systemic, in the outpatient clinic of rheumatology and dermatology departments, at King Khalid University Hospital. As for a comparison, healthy persons coming to the clinic with the same mean age were considered as control group. Forty patients with the diagnosis of scleroderma included in this work, 35% had elevated gamma-glutamyl-transferase (?-GT), 30% had elevated alkaline phosphatase (AP) and in 17.5%, the alanine-amino-transferase (ALT) was above the reference values. The ALT had changed to be more in scleroderma patients than in controls. Twenty percent (20%) of the patients tested positive for anti-smooth muscle antibodies (anti-SMA) and only one patient had anti-mitochondrial antibodies (AMA). There was no statistical difference between the two groups regarding antibody testing. Anti-HCV antibodies were observed in one patient, and HBsAg was detected in another scleroderma patient. There was no patient with clinically significant hepatic disease. In this study, although changes in liver enzymes in patients with scleroderma were not uncommon, there was no scleroderma patient with clinical manifestations of liver disease. PMID:21644046

Salem, Gehan Ibrahim Abdelrazek; Abdulrahman, Awni Ali



Expression and Function of TRP Channels in Liver Cells  

Microsoft Academic Search

\\u000a The liver plays a central role in whole body homeostasis by mediating the metabolism of carbohydrates, fats, proteins, drugs\\u000a and xenobiotic compounds, and bile acid and protein secretion. Hepatocytes together with endothelial cells, Kupffer cells,\\u000a smooth muscle cells, stellate and oval cells comprise the functioning liver. Many members of the TRP family of proteins are\\u000a expressed in hepatocytes. However, knowledge

Grigori Y. Rychkov; Gregory J. Barritt


Liver and gastrointestinal function in pregnancy.  

PubMed Central

Difficulties arise in the interpretation of liver tests in the pregnant subject, since some values increase (alkaline phosphatase) whilst others remain unchanged (transaminases) or fall during pregnancy. The diagnosis and management of some causes of jaundice in pregnancy, such as viral hepatitis, gall stones, benign intrahepatic cholestasis and acute fatty liver of pregnancy are discussed. Little is known about the commonest symptoms of pregnancy (nausea, vomiting and constipation) other than that they might be due to hormonally induced alteration of sphincter tone. However, pre-existing bowel disease has a greater effect on pregnancy. Fertility is reduced in poor nutritional states (e.g. coeliac and Crohn's diseases) and an increased occurrence of spontaneous abortion has been noted. For inflammatory bowel diseases, the time of onset is important in determining the outcome of pregnancy. Relapse in the disease is commonest in the first trimester and in the puerperium. Treatment of these conditions is essentially as in the non-pregnant subject. The controversial subject of sulphasalazine and steroid usage in pregnancy is discussed.

Seymour, C. A.; Chadwick, V. S.



Alanine Scan of Endothelin.  

National Technical Information Service (NTIS)

In Order to get an insight into the endothelin's (ET) structural requirements for vasoconstrictor activity, a series of analogs was synthesized by SPPS, using the Boc-benzyl protecting group strategy. The paper describes the L-alanine scan, in which each ...

R. de Castiglione J. P. Tam W. Liu J. W. Zhang M. Galantino



Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain.  


1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic PLZ administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GABA transaminase (GABA-T). 2. Previous preliminary reports have indicated that acute PLZ treatment also elevates brain alanine levels. As with GABA, the metabolism of alanine involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute PLZ treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only GABA and alanine levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain alanine levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of PLZ on alanine transaminase (ALA-T), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in alanine levels and the inhibition of alanine transaminase in the brain are retained after 14 days of PLZ treatment, and that PLZ produces a marked increase in extracellular levels of alanine. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of PLZ. PMID:11775064

Tanay, V A; Parent, M B; Wong, J T; Paslawski, T; Martin, I L; Baker, G B



Normalization of the altered liver function tests after islet transplantation in diabetic rats.  


The purpose of our study was to determine if streptozotocin induced diabetes (SID) in rats produces alterations in hepatic function, as described in poorly controlled diabetic patients, and if islet transplantation (islet-Tx) would subsequently ameliorate this status. Hepatocellular dysfunction was evaluated by the aspartate aminotransferase (SGOT) and the alanine aminotransferase (SGPT) activities in plasma. For the evaluation of cholestasis the plasma alkaline phosphatase (APase) activity was used. These determinations were performed in normal, SID, SID with Islet-Tx, and SID Wistar rats with sham-Tx. Also, glucose was measured in plasma samples, as well as histological studies of the liver were performed. More than 1,000 isogeneic islets (islet-Tx group) or non viable insular tissue (sham-Tx group) were transplanted via mesenteric ileal vein three weeks after SID. The results showed that SID in rats produces alterations in the hepatic function as well as in the structure of the hepatocytes, and the normalization of carbohydrate metabolism by islet transplantation restores normal hepatic function and morphology. PMID:2265734

Barneo, L; Esteban, M M; Garcia-Pravia, C; Diaz, F; Marin, B


Assessment of hepatic function, operative candidacy, and medical management after liver resection in the patient with underlying liver disease.  


Liver resection in patients with underlying liver disease remains a formidable challenge. It requires adequate patient selection, a precise surgical plan, and avoidance of additional ischemic insults during surgery. Precise estimation of the residual liver volume using computed tomography or magnetic resonance imaging and computer-assisted volumetry allows the calculation of residual to total liver volume (RLV/TLV) ratios. Although RLV/TLV ratios over 20 to 25% are considered sufficient in healthy livers, patients with cirrhosis may only tolerate resections that result in RLV/TLV ratios over 40% and higher. Conventional laboratory tests may not be able to sufficiently predict liver reserve after resection. Dynamic tests such as indocyanine green clearance have been used to assess residual liver function and assist in deciding about operability of patients with underlying liver disease undergoing extensive resections. Intraoperative management should focus on avoiding blood loss and ischemic injury to the liver. Low central venous pressure may reduce blood loss and is recommended if tolerated without impeding renal perfusion. Portal vein and hepatic artery occlusion during resection can reduce blood loss, but will cause ischemic insult to the liver that may jeopardize residual liver function and induce postoperative hepatic failure. When feasible, vascular occlusion should be avoided in patients with underlying liver disease. The postoperative recovery is usually fast if sufficient liver remains. However, vigilance is required to detect liver dysfunction and treat its complications. PMID:23943101

Wagener, Gebhard



Assembly of collagen fibril meshes using gold nanoparticles functionalized with tris(hydroxymethyl)phosphine-alanine as multivalent cross-linking agents.  


We report on the use of tris(hydroxymethyl)phosphine-alanine (THPAL) functionalized gold nanoparticles as a multivalent cross-linking agent to assemble collagen fibrils into a mesh-like structure. Atomic force microscopy (AFM) was used for characterization of the structure after adsorption onto an atomically flat mica substrate, revealing a mesh-like construct in which the collagen fibrils and the gold nanoparticles interact to form interconnected nodes measuring from 100 to 500 nm. As expected, the density of the collagen mesh can be increased with a higher initial concentration of gold nanoparticles. The maximum thickness of the meshes (? 20 nm) obtained through cross-sectional height measurements confirms that the adsorbed structure consists of a single layer of collagen fibrils/gold nanoparticles assembled in two-dimensions. We propose that the capability of gold nanoparticles functionalized with the THPAL to bind to several collagen fibrils combined with the large persistence length of the fibrils, which was reported to be in the hundreds of nanometer range, are determinant factors for the preferential 2D growth of the mesh in solution. PMID:21504026

Graham, John S; Miron, Yannick; Grandbois, Michel


Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver  

Microsoft Academic Search

Background & Aims: Based on a recently cloned rat liver organic anion transporter, we attempted to clone the corresponding human liver organic anion transporting polypeptide. Methods: A human liver complementary DNA library was screened with a specific rat liver complementary DNA probe. The human liver transporter was cloned by homology with the rat protein and functionally characterized in Xenopus laevis

Gerd A. Kullak-Ublick; Bruno Hagenbuch; Bruno Stieger; Claudio D. Schteingart; Alan F. Hofmann; Allan W. Wolkoff; Peter J. Meier



Functional Significance of an Evolutionarily Conserved Alanine (GCA) Resume Codon in tmRNA in Escherichia coli?  

PubMed Central

Occasionally, ribosomes stall on mRNAs prior to the completion of the polypeptide chain. In Escherichia coli and other eubacteria, tmRNA-mediated trans-translation is a major mechanism that recycles the stalled ribosomes. The tmRNA possesses a tRNA-like domain and a short mRNA region encoding a short peptide (ANDENYALAA in E. coli) followed by a termination codon. The first amino acid (Ala) of this peptide encoded by the resume codon (GCN) is highly conserved in tmRNAs in different species. However, reasons for the high evolutionary conservation of the resume codon identity have remained unclear. In this study, we show that changing the E. coli tmRNA resume codon to other efficiently translatable codons retains efficient functioning of the tmRNA. However, when the resume codon was replaced with the low-usage codons, its function was adversely affected. Interestingly, expression of tRNAs decoding the low-usage codon from plasmid-borne gene copies restored efficient utilization of tmRNA. We discuss why in E. coli, the GCA (Ala) is one of the best codons and why all codons in the short mRNA of the tmRNA are decoded by the abundant tRNAs.

Kapoor, Suman; Samhita, Laasya; Varshney, Umesh



[Cellular composition and regulatory function of fetal liver stroma].  


Hematopoietic differentiation and formation of hepatic tissue both take place in mammalian liver during its prenatal development. Hematopoietic and hepatic stem cells self-renew, proliferate and differentiate within specific microenvironment that is organized by stromal elements. Stroma of developing liver consists of different cell populations such as mesenchymal stromal cells, Ito cells, portal fibroblasts and myofibroblasts, vascular endothelial and smooth muscle cells, cells undergoing epithelial-to-mesenchymal transition. In this review, their phenotypical and functional properties, possible derivation and role in the regulation of hematopoiesis and hepatogenesis are discussed. PMID:22827034

Paiushina, O V; Domaratskaia, E I; Starostin, V I



Evaluation of mitochondrial respiratory function in small biopsies of liver.  


Mitochondrial respiratory function was studied in permeabilized pig liver biopsies. The cell membrane was permeabilized mechanically in tissue samples of 2-7 mg, for application of a standardized substrate/inhibitor titration protocol in high-resolution respirometry. Specific respirometric tests demonstrated complete plasma membrane permeabilization and accessibility of substrates to intact mitochondria. High respiratory adenylate control ratios and cytochrome c conservation in the tissue preparation were comparable or even better than in isolated mitochondria. Citrate synthase and cytochrome c oxidase activities remained at 85% of controls after up to 98 h storage of liver tissue at 0 degrees C in histidine-tryptophan-ketoglutarate solution. Multiple mitochondrial defects, however, were indicated after 48 h cold storage by the decline in respiratory capacity, which was lowered to a larger extent with complex I substrates compared to respiration with substrates for complex II or IV, measured in the absence of cytochrome c. After prolonged ischemia, the adenylate control ratio was significantly reduced, and cytochrome c depletion was detected by the stimulatory effect of cytochrome c. High-resolution respirometry allows the assessment of mitochondrial function in a few milligrams of permeabilized liver tissue, without isolation of mitochondria. This provides a basis for the analysis of mitochondrial function in human liver biopsies. PMID:12054447

Kuznetsov, Andrey V; Strobl, Daniela; Ruttmann, Elfriede; Königsrainer, Alfred; Margreiter, Raimund; Gnaiger, Erich



Relationship between liver function and brain shrinkage in patients with alcohol dependence  

PubMed Central

Background Oxidative stress has been proposed as one of the mechanisms of alcohol-induced brain shrinkage and alcohol-induced hepatotoxicity. The study aim was to assess the correlations between liver function and brain volume measurements in patients with alcohol dependence. Methods We recruited 124 patients with alcohol dependence and 111 healthy control subjects from National Institute of Health, National Institute on Alcohol Abuse and Alcoholism inpatient alcohol treatment program. Gamma glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) as well as hematocrit (Hct) and albumin were assayed shortly after admission. MRI examination was conducted in both groups (after 3-week abstinence in the patient group). We used stepwise linear regression analyses to determine the variables most strongly correlated with brain shrinkage. Results Patients with alcohol dependence had lower brain volume (BV), and greater brain shrinkage as measured by gray matter ratio (GMR), white matter ratio (WMR), and brain ratio (BR) and higher CSF ratio (CSFR) compared to their healthy counterparts. Age and sex were significantly correlated with some brain volume measurements in both patient and control groups. Body mass index (BMI) was significantly correlated with CSFR, BR, GMR, and WMR; Hct with CSFR and BR; serum GGT level with BV, CSFR, BR, GMR, and WMF in the patient group. No biological variables were correlated with brain volume indices in the control group. In gender-stratified analysis, age was significantly correlated with brain shrinkage in male patients, but not in female patients. Serum GGT level in male and female patients, Hct in male patients, and AST levels in female patients were significantly correlated with brain shrinkage. Conclusions Our results showed that the higher levels of liver function indices, especially GGT, correlated with brain volume shrinkage as measured using CSFR, BR, GMR, and WMR in patients with alcohol dependence, but not in controls. Serum GGT level outweighed aging effect on brain shrinkage in female patients.

Chen, Chun-Hsin; Walker, Jonathan; Momenan, Reza; Rawlings, Robert; Heilig, Markus; Hommer, Daniel W.



Extinction of liver-specific functions in hybrids between differentiated and dedifferentiated rat hepatoma cells  

Microsoft Academic Search

A cross has been performed between dedifferentiated rat hepatoma cells and the differentiated cells from which they were derived. 10 hybrid clones, containing the complete chromosome sets of both parents, show extinction of 4 liver-specific enzymes: tyrosine aminotransferase (E.C., alanine aminotransferase (E.C., and the liver-specific isozymes of alcohol dehydrogenase (E.C. and aldolase (E.C. Moreover, the 4

Jean Deschatrette; Mary C. Weiss



Penicillamine as an adjuvant to antimonial therapy of schistosomiasis: effect on liver function tests in rabbits and on antischistosomal activity*  

PubMed Central

Earlier work has shown that penicillamine reduces the acute toxicity of antimonyl potassium tartrate (APT) as well as the abnormal ECG changes it induces. In the present study, the possible protective effect of penicillamine on the hepatic toxicity of APT was investigated. Tests of liver function showed changes in the level of serum aspartate and alanine aminotransferase and of alkaline phosphatase, and in the beta-/alpha-lipoprotein ratio, in response to antimony treatment. The changes were significantly reduced by penicillamine, though the effect depended on the dose. Penicillamine was found to give the best overall protection without affecting the antischistosomal efficacy of the antimonial when a 1:2 APT/penicillamine ratio was used. The findings provide further evidence of the potential usefulness of penicillamine in the antimonial treatment of schistosomiasis.

Khayyal, M. T.; Saleh, S.; El Masri, A. M.



The impact of ions on allosteric functions in human liver pyruvate kinase  

PubMed Central

Experimental designs used to monitor the magnitude of an allosteric response can greatly influence observed values. We report here the impact of buffer, monovalent cation, divalent cation and anion on the magnitude of the allosteric regulation of the affinity of human liver pyruvate kinase (hL-PYK) for substrate, phosphoenolpyruvate (PEP). The magnitudes of the allosteric activation by fructose-1,6-bisphosphate (Fru-1,6-BP) and the allosteric inhibition by alanine are independent of most, but not all buffers tested. However, these magnitudes are dependent on whether Mg2+ or Mn2+ is included as the divalent cation. In the presence of Mn2+, any change in Kapp-PEP caused by Fru-1,6-BP is minimal. hL-PYK activity does not appear to require monovalent cation. Monovalent cation binding in the active site impacts PEP affinity with minimum influence on the magnitude of allosteric coupling. However, Na+ and Li+ reduce the magnitude of the allosteric response to Fru-1,6-BP, likely due to mechanisms outside of the active site. Which anion is used to maintain a constant monovalent cation concentration also influences the magnitude of the allosteric response. The value of determining the impact of ions on allosteric function can be appreciated by considering that representative structures used in comparative studies have often been determined using protein crystals grown in diverse buffer and salt conditions.

Alontaga, Aileen Y.



beta-alanine N-methyltransferase of Limonium latifolium. cDNA cloning and functional expression of a novel N-methyltransferase implicated in the synthesis of the osmoprotectant beta-alanine betaine.  


Beta-alanine (Ala) betaine, an osmoprotectant suitable under saline and hypoxic environments, is found in most members of the halophytic plant family Plumbaginaceae. In Limonium latifolium (Plumbaginaceae), it is synthesized via methylation of beta-Ala by the action of a trifunctional S-adenosyl L-methionine (Ado-Met): beta-Ala N-methyltransferase (NMTase). Peptide sequences from purified beta-Ala NMTase were used to design primers for reverse transcriptase-PCR, and several cDNA clones were isolated. The 5' end of the cDNA was cloned using a 5'-rapid amplification of cDNA ends protocol. A 500-bp cDNA was used as a probe to screen a lambda-gt10 L. latifolium leaf cDNA library. Partial cDNA clones represented two groups, NMTase A and NMTase B, differing only in their 3'-untranslated regions. The full-length NMTase A cDNA was 1,414 bp and included a 1128-bp open reading frame and a 119-bp 5'-untranslated region. The deduced amino acid sequence of 375 residues had motifs known to be involved in the binding of Ado-Met. The NMTase mRNA was expressed in L. latifolium leaves but was absent in Limonium sinuatum, a member of the genus that lacks the synthetic pathway for beta-Ala betaine. NMTase mRNA expression was high in young and mature leaves and was enhanced by light. NMTase cDNA was expressed in yeast (Saccharomyces cerevisiae) under the control of a galactose-inducible promoter. Protein extracts of galactose-induced recombinant yeast had Ado-Met-specific NMTase activities that were highly specific to beta-Ala, N-methyl beta-Ala, and N,N-dimethyl beta-Ala as methyl acceptors. NMTase activities were not detectable in comparable protein extracts of yeast, transformed with vector control. The NMTase protein sequence shared homology with plant caffeic acid O-methyltransferases and related enzymes. Phylogenetic analyses suggested that beta-Ala NMTase represents a novel family of N-methyltransferases that are evolutionarily related to O-methyltransferases. PMID:12857843

Raman, Suresh Babu; Rathinasabapathi, Bala



Antifibrotic activity of galangin, a novel function evaluated in animal liver fibrosis model.  


This study aimed to investigate the effects of galangin on liver fibrosis in rats induced by subcutaneous injection of carbon tetrachloride (CCl4). The administration of CCl4 to rats for 12 weeks caused significant increase of hyaluronic acid, laminin, alanine transaminase, aspartate transaminase and decrease of total protein, albumin in serum, while the influences could be reversed by galangin. Galangin markedly reduced hepatic malondialdehyde, hydroxyproline concentration, increased activities of liver superoxide dismutase, glutathione peroxidase compared with CCl4-treated rats. Histological results indicated that galangin alleviated liver damage. In addition, treatment with galangin significantly down-regulated expressions of ?-smooth muscle actin and transforming growth factor ?1. These results suggest galangin can inhibit liver fibrosis induced by CCl4 in rats, which was probably associated with its effect on removing oxygen free radicals, decreasing lipid peroxidation, as well as inhibiting hepatic stellate cells activation and proliferation. PMID:23686009

Wang, Xinhui; Gong, Guoqing; Yang, Wenhui; Li, Yunzhan; Jiang, Meiling; Li, Linlin



Markerless Mutagenesis in Methanococcus maripaludis Demonstrates Roles for Alanine Dehydrogenase, Alanine Racemase, and Alanine Permease  

PubMed Central

Among the archaea, Methanococcus maripaludis has the unusual ability to use l- or d-alanine as a nitrogen source. To understand how this occurs, we tested the roles of three adjacent genes encoding homologs of alanine dehydrogenase, alanine racemase, and alanine permease. To produce mutations in these genes, we devised a method for markerless mutagenesis that builds on previously established genetic tools for M. maripaludis. The technique uses a negative selection strategy that takes advantage of the ability of the M. maripaludis hpt gene encoding hypoxanthine phosphoribosyltransferase to confer sensitivity to the base analog 8-azahypoxanthine. In addition, we developed a negative selection method to stably incorporate constructs into the genome at the site of the upt gene encoding uracil phosphoribosyltransferase. Mutants with in-frame deletion mutations in the genes for alanine dehydrogenase and alanine permease lost the ability to grow on either isomer of alanine, while a mutant with an in-frame deletion mutation in the gene for alanine racemase lost only the ability to grow on d-alanine. The wild-type gene for alanine dehydrogenase, incorporated into the upt site, complemented the alanine dehydrogenase mutation. Hence, the permease is required for the transport of either isomer, the dehydrogenase is specific for the l isomer, and the racemase converts the d isomer to the l isomer. Phylogenetic analysis indicated that all three genes had been acquired by lateral gene transfer from the low-moles-percent G+C gram-positive bacteria.

Moore, Brian C.; Leigh, John A.



STE20/SPS1-Related Proline/Alanine-Rich Kinase Is Involved in Plasticity of GABA Signaling Function in a Mouse Model of Acquired Epilepsy.  


The intracellular concentration of chloride ([Cl(-)]i) determines the strength and polarity of GABA neurotransmission. STE20/SPS1-related proline/alanine-rich kinase (SPAK) is known as an indirect regulator of [Cl(-)]i for its activation of Na-K-2 Cl(-)co-transporters (NKCC) and inhibition of K-Cl(-)co-transporters (KCC) in many organs. NKCC1 or KCC2 expression changes have been demonstrated previously in the hippocampal neurons of mice with pilocarpine-induced status epilepticus (PISE). However, it remains unclear whether SPAK modulates [Cl(-)]i via NKCC1 or KCC2 in the brain. Also, there are no data clearly characterizing SPAK expression in cortical or hippocampal neurons or confirming an association between SPAK and epilepsy. In the present study, we examined SPAK expression and co-expression with NKCC1 and KCC2 in the hippocampal neurons of mice with PISE, and we investigated alterations in SPAK expression in the hippocampus of such mice. Significant increases in SPAK mRNA and protein levels were detected during various stages of PISE in the PISE mice in comparison to levels in age-matched sham (control) and blank treatment (control) mice. SPAK and NKCC1 expression increased in vitro, while KCC2 was down-regulated in hippocampal neurons following hypoxic conditioning. However, SPAK overexpression did not influence the expression levels of NKCC1 or KCC2. Using co-immunoprecipitation, we determined that the intensity of interaction between SPAK and NKCC1 and between SPAK and KCC2 increased markedly after oxygen-deprivation, whereas SPAK overexpression strengthened the relationships. The [Cl(-)]i of hippocampal neurons changed in a corresponding manner under the different conditions. Our data suggests that SPAK is involved in the plasticity of GABA signaling function in acquired epilepsy via adjustment of [Cl(-)]i in hippocampal neurons. PMID:24058604

Yang, Libai; Cai, Xiaodong; Zhou, Jueqian; Chen, Shuda; Chen, Yishu; Chen, Ziyi; Wang, Qian; Fang, Ziyan; Zhou, Liemin



Evaluation of Mitochondrial Respiratory Function in Small Biopsies of Liver  

Microsoft Academic Search

Mitochondrial respiratory function was studied in permeabilized pig liver biopsies. The cell membrane was permeabilized mechanically in tissue samples of 2–7 mg, for application of a standardized substrate\\/inhibitor titration protocol in high-resolution respirometry. Specific respirometric tests demonstrated complete plasma membrane permeabilization and accessibility of substrates to intact mitochondria. High respiratory adenylate control ratios and cytochrome c conservation in the tissue

Andrey V. Kuznetsov; Daniela Strobl; Elfriede Ruttmann; Alfred Königsrainer; Raimund Margreiter; Erich Gnaiger



Liver structure and function following small bowel resection  

PubMed Central

The observation that patients with extensive small bowel resection have impaired hepatocellular function with reduced BSP clearance and fatty change in biopsies from the liver led to a systematic study of liver structure and function following proximal and distal small bowel resection in the rat. While anaesthesia and surgery impaired BSP clearance per se, small bowel resection further reduced BSP clearance with impairment of both uptake and excretion phases of BSP excretion. The increased BSP retention was more marked after distal than after proximal small bowel resection, but in both experimental groups the abnormalities of BSP excretion spontaneously returned to normal three to four weeks after surgery. Circulating liver enzymes were normal but serum alkaline phosphatase was significantly depressed, particularly after distal resection. Isoenzyme studies showed that the depression of serum AP was due to a reduced intestinal isoenzyme. While serum levels remained consistently depressed up to eight weeks after proximal resection, in parallel with mucosal regeneration, serum AP returned to normal two to four weeks after ileectomy. While these minor changes in hepatic structure and function would normally be of little clinical importance, the additional insult of hepatic dysfunction may well be important in malnourished patients after extensive small bowel resection.

Gupta, M. C.; Neale, Graham; Dowling, R. Hermon



Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones  

Microsoft Academic Search

To increase our understanding of the effect of thiazolidinediones, a new class of antidiabetic drugs, on liver function as well as glycemic control, we investigated liver function before, during, and after treatment with troglitazone and pioglitazone.A total of 32 patients with type 2 diabetes were studied. Glycemic control and liver function were measured before, during, and after 4 to 12

Masaya Ono; Hiroshi Ikegami; Tomomi Fujisawa; Koji Nojima; Yumiko Kawabata; Masanori Nishino; Hidenori Taniguchi; Michiko Itoi-Babaya; Naru Babaya; Kaori Inoue; Toshio Ogihara



ALT (Alanine Aminotransferase) Test  


... as blood clotting factors, and breaks down potentially toxic substances into harmless ones that the body can ... due to hepatitis and drugs or other substances toxic to the liver. ALT, however, is not entirely ...


Cellular Transfection to Deliver Alanine-Glyoxylate Aminotransferase to Hepatocytes: A Rational Gene Therapy for Primary Hyperoxaluria1 (PH1)  

Microsoft Academic Search

Background: Primary hyperoxaluria-type 1 (PH-1) is a rare autosomal recessive disorder of glyoxalate metabolism caused by deficiency in the liver-specific peroxisomal enzyme alanine-glyoxalate transaminase 1 (AGT) resulting in the increased oxidation of glyoxalate to oxalate. Accumulation of oxalate in the kidney and other soft tissues results in loss of renal function and significant morbidity. The present treatment options offer some

Sweaty Koul; Thomas Johnson; Saroj Pramanik; Hari Koul



[Liver function in cattle in experimental rumen acidosis].  


The investigations were performed on 6 Friesian-Holstein heifers, weighing 410-504 kg, in which acid indigestion was induced by intraruminal administration of saccharose in a dose of 12 g/kg body weight. The animals were observed for 9 days after the treatment. Functional state of the liver was evaluated on the basis of bromosulphthalein clearance, total bilirubin level and aspartate amino-transferase (AspAT) activity in serum, concentration of blood glucose, total serum protein and protein fractions. Within the first 24 hours, all heifers developed acute symptoms of rumen acidosis which persisted for 3 days after saccharose administration. Afterwards, a phase of gradual spontaneous recovery was observed. In the course of rumen acidosis a reduction in bromosulphthalein clearance, an increase in bilirubin level and AspAT activity, a decrease and then an increase in glucose concentration and a reduction in albumin content and, as a consequence, in albumin/globulin ratio were found. The results indicate that experimental rumen acidosis produced disturbances in excretory and metabolic functions of the liver in the examined heifers. Changes in biochemical parameters were preceded by an increase in AspAT activity and were most remarkable between 48 and 144 hours after saccharose administration. Liver dysfunction was of a various degree in individual animals and recovered within a relatively short period following the disappearance of rumen acidosis symptoms. PMID:7301626

Bieniek, K



Biochemical Parameters for Longitudinal Monitoring of Liver Function in Rat Models of Partial Hepatectomy Following Liver Injury  

PubMed Central

Background While evaluation of liver function in preclinical animal studies is commonly performed at selected time-points by invasive determination of the liver/body weight ratio and histological analyses, the validation of longitudinal measurement tools for monitoring liver function are of major interest. Aims To longitudinally evaluate serum cholinesterase (CHE) and total serum bilirubin (TSB) levels as non-invasive markers to determine injury- and partial hepatectomy (PHx)-induced alterations of liver function in rats. Methods Male and female Lewis rats were subjected to either methionine/choline deficient (MCD) diet or treatment with FOLFOX chemotherapy prior to PHx. Body weight and CHE/TSB levels are determined weekly. Following PHx and at the study end, histological analyses of liver tissue are performed. Results Following MCD diet, but not after FOLFOX chemotherapy treatment, results indicate gender-specific alterations in serum CHE levels and gender-independent alterations in TSB levels. Likewise, histological analyses of resected liver parts indicate significant liver injury following MCD-diet, but not following FOLFOX treatment. While TSB levels rapidly recover following MCD diet/FOLFOX treatment combined with a PHx, serum CHE levels are subject to significant model- and gender-specific differences, despite full histopathological recovery of liver tissue. Conclusions Longitudinal measurements of serum CHE levels and TSB levels in rats are highly complementary as non-invasive parameters for evaluation of liver injury and/or recovery.

Boeykens, Nele; Ponsaerts, Peter; Ysebaert, Dirk; De Greef, Kathleen



Functional hyposplenism in alcoholic liver disease: a toxic effect of alcohol?  

Microsoft Academic Search

Functional hyposplenism, seen in some patients with alcoholic liver disease, may contribute to the increased susceptibility to infections. As hyposplenism does not complicate non-alcohol related chronic liver disease, it is probably secondary to a toxic effect of alcohol. Over a two year period the case notes of 82 patients with alcoholic liver disease, whose splenic function had been assessed by

A F Muller; P J Toghill



Factors influencing the caffeine test for cytochrome P 448-dependent liver function  

Microsoft Academic Search

Liver function in patients with liver disease can be estimated by caffeine clearance. Our data, however, demonstrate the additional influence of factors other than liver disease on the caffeine test. Smoking enhances caffeine clearance in both healthy volunteers and patients with severe hepatic disorders, whereas co-medication with mexiletine strongly inhibits caffeine elimination.

R. Joeres; H. Klinker; H. Heusler; J. Epping; G. Hofstetter; D. Drost; H. Reuss; W. Zilly; E. Richter



Persistent elevation of liver function enzymes within the reference range is associated with increased cardiovascular risk in young adults: the Bogalusa Heart Study  

Microsoft Academic Search

Elevations in alanine aminotransferase (ALT) and ?-glutamyl transferase (GGT), markers of liver dysfunction and nonalcoholic fatty liver, are considered as part of the metabolic syndrome and related diseases. However, information is limited regarding the persistence (tracking) in levels of these enzymes over time and their influence on cardiovascular (CV) risk in young adults. The study sample consisted of white and

Dharmendrakumar A. Patel; Sathanur R. Srinivasan; Ji-Hua Xu; Wei Chen; Gerald S. Berenson



FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration.  


The liver is a unique organ with a remarkably high potential to regenerate upon injuries. In severely damaged livers where hepatocyte proliferation is impaired, facultative liver progenitor cells (LPCs) proliferate and are assumed to contribute to regeneration. An expansion of LPCs is often observed in patients with various types of liver diseases. However, the underlying mechanism of LPC activation still remains largely unknown. Here we show that a member of the fibroblast growth factor (FGF) family, FGF7, is a critical regulator of LPCs. Its expression was induced concomitantly with LPC response in the liver of mouse models as well as in the serum of patients with acute liver failure. Fgf7-deficient mice exhibited markedly depressed LPC expansion and higher mortality upon toxin-induced hepatic injury. Transgenic expression of FGF7 in vivo led to the induction of cells with characteristics of LPCs and ameliorated hepatic dysfunction. We revealed that Thy1(+) mesenchymal cells produced FGF7 and appeared in close proximity to LPCs, implicating a role for those cells as the functional LPC niche in the regenerating liver. These findings provide new insights into the cellular and molecular basis for LPC regulation and identify FGF7 as a potential therapeutic target for liver diseases. PMID:23322300

Takase, Hinako M; Itoh, Tohru; Ino, Seitaro; Wang, Ting; Koji, Takehiko; Akira, Shizuo; Takikawa, Yasuhiro; Miyajima, Atsushi



Clinical research on liver reserve function by 13C-phenylalanine breath test in aged patients with chronic liver diseases  

Microsoft Academic Search

BACKGROUND: The objective of this study was to investigate whether the 13C-phenylalanine breath test could be useful for the evaluation of hepatic function in elderly volunteers and patients with chronic hepatitis B and liver cirrhosis. METHODS: L-[1-13C] phenylalanine was administered orally at a dose of 100 mg to 55 elderly patients with liver cirrhosis, 30 patients with chronic hepatitis B

Gan-sheng Zhang; Zhi-jun Bao; Jian Zou; Shu-ming Yin; Yi-qin Huang; Hai Huang; De-kai Qiu



Liver function tests in women using oral contraceptive.  


58 women who had taken the oral contraceptive Ovulen (1 mg ethynodiol diacetate plus .1 mg mestranol) for between 1 and 3 years and 29 controls were studied for the effects of the contraceptive on liver function tests. Values were significantly higher for both thymol turbidity (p less than .01) and cholesterol (p less than .001) in patients who had used Ovulen. Total protein levels were significantly greater (p less than .05) in women who had used the pill for 1 to 2 years, but not in women who had taken the contraceptive for 3 years. No significant differences in A.G. Ratio, bilirubin, or icteric index were found between the contraceptive users and the controls. PMID:12332882

Gupta, P; Sharma, P A



Structural and functional importance of transmembrane domain 3 (TM3) in the aspartate:alanine antiporter AspT: topology and function of the residues of TM3 and oligomerization of AspT.  


AspT, the aspartate:alanine antiporter of Tetragenococcus halophilus, a membrane protein of 543 amino acids with 10 putative transmembrane (TM) helices, is the prototype of the aspartate:alanine exchanger (AAE) family of transporters. Because TM3 (isoleucine 64 to methionine 85) has many amino acid residues that are conserved among members of the AAE family and because TM3 contains two charged residues and four polar residues, it is thought to be located near (or to form part of) the substrate translocation pathway that includes the binding site for the substrates. To elucidate the role of TM3 in the transport process, we carried out cysteine-scanning mutagenesis. The substitutions of tyrosine 75 and serine 84 had the strongest inhibitory effects on transport (initial rates of l-aspartate transport were below 15% of the rate for cysteine-less AspT). Considerable but less-marked effects were observed upon the replacement of methionine 70, phenylalanine 71, glycine 74, arginine 76, serine 83, and methionine 85 (initial rates between 15% and 30% of the rate for cysteine-less AspT). Introduced cysteine residues at the cytoplasmic half of TM3 could be labeled with Oregon green maleimide (OGM), whereas cysteines close to the periplasmic half (residues 64 to 75) were not labeled. These results suggest that TM3 has a hydrophobic core on the periplasmic half and that hydrophilic residues on the cytoplasmic half of TM3 participate in the formation of an aqueous cavity in membranes. Furthermore, the presence of l-aspartate protected the cysteine introduced at glycine 62 against a reaction with OGM. In contrast, l-aspartate stimulated the reactivity of the cysteine introduced at proline 79 with OGM. These results demonstrate that TM3 undergoes l-aspartate-induced conformational alterations. In addition, nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses and a glutaraldehyde cross-linking assay suggest that functional AspT forms homo-oligomers as a functional unit. PMID:19181816

Nanatani, Kei; Maloney, Peter C; Abe, Keietsu



A rapid and accurate new bedside test to assess maximal liver function: a case report.  


BACKGROUND: In liver surgery, appropriate preoperative evaluation and preparation of the patient is of cardinal importance. The up-to-date, preoperative prediction of residual liver function has thus far been limited. As post-hepatectomy liver failure is a major cause of mortality, a new and simple bedside test (LiMAx) has been developed to predict postoperative liver function in conjunction with preoperative volumetric analysis of the liver. CASE PRESENTATION: A 45-year-old patient presented with a cecal carcinoma and a large synchronous liver metastasis for major liver surgery. Liver function was determined by the LiMAx-test for the enzymatic capacity of cytochrome P450 1A2, which is ubiquitously and solely active in the liver. A solution of 2 mg/kg body weight 13C-labeled methacetin was injected as a bolus into an intravenous catheter and, thereafter, was metabolized into acetaminophen and 13CO2 and pulmonarily exhaled. The analysis of the 13CO2/12CO2 ratio was performed using online breath sampling over a period of maximally 60 minutes. Based on this test, a value of more than 315 mug/kg/h represents normal liver function. A laparoscopic right hemihepatectomy was planned during virtual resection with a residual liver volume of 48% and a preoperative anticipated residual LiMAx of 301 mug/kg/h. After successful resection, the initial postoperative LiMAx value was 316 mug/kg/h, indicating good liver function and a correct prediction of the outcome. CONCLUSION: In the presented patient, residual liver function could be accurately predicted preoperatively using a combination of the new LiMax test with CT-volumetry. This test might significantly improve preoperative evaluation and postoperative outcomes in liver surgery. PMID:23618221

Müller, Sascha A; Tarantino, Ignazio; Corazza, Marcello; Pianka, Frank; Fornaro, Jürgen; Beutner, Ulrich; Lüthi, Cornelia; Schmied, Bruno M



Structural and functional changes in acute liver injury.  

PubMed Central

Carbon tetrachloride produces liver cell injury in a variety of animal species. The first structurally recognizable changes occur in the endoplasmic reticulum, with alteration in ribosome-membrane interactions. Later there is an increase in intracellular fat, and the formation of tangled nets of the ergastoplasm. At no time are there changes in mitochondria or single membrane limited bodies in cells with intact plasmalemma, although a relative increase in cell sap may appear. In dead cells (those with plasmalemma discontinuties) crystalline deposits of calcium phosphatase may be noted. Functional changes are related to the endoplasmic reticulum and the plasma membrane. An early decrease in protein synthesis takes place; an accumulation of neutral lipid is related to this change. Later alterations in the ergastoplasmic functions (e.g., mixed function oxidation) occurs. Carbon tetrachloride is not the active agent; rather, a product of its metabolism, probably the CC1, free radical, is. The mechanisms of injury include macromolecular adduction and peroxide propagation. A third possibility includes a cascade effect with the production of secondary and tertiary products, also toxic in nature, with the ability to produce more widespread damage to intracellular structures. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 11.

Smuckler, E A



DifferentiationBetweenL-Alanine-Glutamateand L-Alanine-Glycine Transaminasesin Trichoderma viride  

Microsoft Academic Search

Cellfree extracts of Trichoderma viridewere found to contain two L-alanine transaminase activities namely L-alanine-glycine and L-alanine-glutamate transaminase. The reaction catalyzed by L...-alanine-glutamate transaminase was found to be reversibile. However, the transamination reaction catalyzed by L-alanine _glycine transaminase was found to be irreversible. The optimum activity of L-alanine-glycine transaminase obtained at pH 9, while that of L-alanine-glutamate transaminase obtained at pH

Kingdomof Saudia Arabia


The Functional Interrelationship between Gap Junctions and Fenestrae in Endothelial Cells of the Liver Organoid  

Microsoft Academic Search

Functional intact liver organoid can be reconstructed in a radial-flow bioreactor when human hepatocellular carcinoma (FLC-5),\\u000a mouse immortalized sinusoidal endothelial M1 (SEC) and A7 (HSC) hepatic stellate cell lines are cocultured. The structural\\u000a and functional characteristics of the reconstructed organoid closely resemble the in vivo liver situation. Previous liver organoid studies indicated that cell-to-cell communications might be an important factor

Masaya Saito; Tomokazu Matsuura; Keisuke Nagatsuma; Ken Tanaka; Haruka Maehashi; Keiko Shimizu; Yoshiaki Hataba; Fumitaka Kato; Isao Kashimori; Hisao Tajiri; Filip Braet



Pharmacokinetics and safety of Marqibo (vincristine sulfate liposomes injection) in cancer patients with impaired liver function.  


Marqibo (vincristine sulfate liposome injection, VSLI) is a novel liposomal formulation of vincristine sulfate (VCR) being developed for the systemic treatment of cancer. This study evaluated the pharmacokinetics (PK) of Marqibo in subjects with melanoma and impaired hepatic function. Calculated PK parameters were similar in subjects with impaired liver function compared with those in subjects with adequate liver function. Subjects with impaired liver function universally had a monoexponential total plasma VCR concentration versus time decline, whereas two thirds of subjects with adequate liver function had a biexponential decline profile. Because one third of subjects with normal hepatic function demonstrated monoexponential disposition, lack of biexponential disposition in the hepatically impaired subjects cannot be clearly attributed to liver impairment. VSLI was generally well tolerated in all subjects. PMID:20978276

Bedikian, Agop Y; Silverman, Jeffrey A; Papadopoulos, Nicholas E; Kim, Kevin B; Hagey, Anne E; Vardeleon, Anna; Hwu, Wen-Jen; Homsi, Jade; Davies, Michael; Hwu, Patrick



Effect of liver glycogen concentration on mitochondrial function after different times of hypothermic liver preservation  

Microsoft Academic Search

The aim of the present study was to determine whether glycogen confers protection on hepatocytes during hypothermic ischemic liver preservation. Sixteen male Wistar rats (250–300 g) were divided into two groups. FAST animals (n = 8) were fasted (low hepatic glycogen levels) and FEED animals (n = 8) were fed (high hepatic glycogen levels). The livers were removed and preserved

Cláudia Carvalho Rizzo-Oliveira; Orlando De Castro E. Silva; Sérgio Zucoloto; João Kazuyuki Kajiwara



The role of CUGBP1 in age-dependent changes of liver functions.  


Aging liver is characterized by alterations of liver biology and by a reduction of many functions which are important for the maintenance of body homeostasis. The main dysfunctions include appearance of enlarged hepatocytes, impaired liver regeneration after partial hepatectomy (PH), development of hepatic steatosis, reduction of secretion of proteins and alterations in the hepatic sinusoid. RNA binding proteins are involved in the regulation of gene expression in all tissues including regulation of biological processes in the liver. This review is focused on the role of a conserved, multi-functional RNA-binding protein, CUGBP1, in the development of aging phenotype in the liver. CUGBP1 has been identified as a protein which binds to RNA CUG repeats expanded in Myotonic Dystrophy type 1 (DM1). CUGBP1 is highly expressed in the liver and regulates translation of proteins which are critical for maintenance of liver functions. In livers of young mice, CUGBP1 forms complexes with eukaryotic translation initiation factor eIF2 and supports translation of C/EBP? and HDAC1 proteins, which are involved in liver growth, differentiation and liver cancer. Aging changes several signaling pathways which lead to the elevation of the CUGBP1-eIF2? complex and to an increase of translation of C/EBP? and HDAC1. These proteins form multi-protein complexes with additional transcription factors and with chromatin remodeling proteins causing epigenetic alterations of gene expression in livers of old mice. It appears that CUGBP1-mediated translational elevation of HDAC1 is one of the key events in the epigenetic changes in livers of old mice, leading to the development of age-associated dysfunctions of the liver. This review will also discuss a possible role of CUGBP1 in liver dysfunction in patients affected with DM1. PMID:22446383

Jones, Karlie; Timchenko, Lubov; Timchenko, Nikolai A



Effects of simulated heliox diving at high altitudes on blood cells, liver functions and renal functions.  


The aim of the present study was to examine the effects of simulated heliox diving at high altitudes on divers' blood cells, liver functions and renal functions. In this experiment, four divers lived for nine consecutive days in a dual-function high-low pressure chamber, which simulated air pressure at an altitude of 3,000 meters and at a 30-meter depth; an altitude of 4,000 meters and 30-meter depth; and at an altitude of 5,200 meters and 30 meters and 50 meters in depth. Total time underwater was 60 minutes. The subjects breathed heliox (with oxygen at 40% and helium at 60%) during the simulated 30-meter dive from zero altitude to 30 meters and while remaining underwater; they breathed air while ascending from 30 meters to 18. They breathed heliox (with oxygen at 26.7% and helium at 73.3%) in the simulated dive from zero altitude to 50 meters underwater, in remaining underwater and in ascending from 50 meters to 29; air while ascending from 29 meters to 18. Pure oxygen was breathed while ascending from 18 meters to the surface; then air. Results indicated: (1) the correlating indices of routine blood, liver and renal functions, and urine routine were all within normal reference ranges; and (2) the indices tested at other periods of time were not significantly different (p > 0.05) from the results at zero-meter level and 3,000-meter level. The study suggests that the heliox diving processes at different high altitudes simulated in this experiment have no significant impact upon divers' blood routine, liver functions and renal functions. PMID:23957203

Hu, Hui-Jun; Fan, Dan-Feng; Lv, Yan; Zhang, Yu; Yang, Chen; Zhao, Ling; Zhao, Ru-Gang; Pan, Xiao-Wen


L-alanine-glyoxylate aminotransferase II of rat kidney and liver mitochondria possesses cysteine S-conjugate beta-lyase activity: a contributing factor to the nephrotoxicity/hepatotoxicity of halogenated alkenes?  

PubMed Central

Several halogenated alkenes are metabolized in part to cysteine S-conjugates, which are mitochondrial toxicants of kidney and, to a lesser extent, other organs. Toxicity is due to cysteine S-conjugate beta-lyases, which convert the cysteine S-conjugate into pyruvate, ammonia and a reactive sulphur-containing fragment. A section of the human population is exposed to halogenated alkenes. To understand the health effects of such exposure, it is important to identify cysteine S-conjugate beta-lyases that contribute to mitochondrial damage. Mitochondrial aspartate aminotransferase [Cooper, Bruschi, Iriarte and Martinez-Carrion (2002) Biochem. J. 368, 253-261] and mitochondrial branched-chain aminotransferase [Cooper, Bruschi, Conway and Hutson (2003) Biochem. Pharmacol. 65, 181-192] exhibit beta-lyase activity toward S -(1,2-dichlorovinyl)-L-cysteine (the cysteine S-conjugate of trichloroethylene) and S -(1,1,2,2-tetrafluoroethyl)-L-cysteine (the cysteine S-conjugate of tetrafluoroethylene). Turnover leads to eventual inactivation of these enzymes. Here we report that mitochondrial L-alanine-glyoxylate aminotransferase II, which, in the rat, is most active in kidney, catalyses cysteine S-conjugate beta-lyase reactions with S -(1,1,2,2-tetrafluoroethyl)-L-cysteine, S -(1,2-dichlorovinyl)-L-cysteine and S -(benzothiazolyl-L-cysteine); turnover leads to inactivation. Previous workers showed that the reactive-sulphur-containing fragment released from S -(1,1,2,2-tetrafluoroethyl)-L-cysteine and S -(1,2-dichlorovinyl)-L-cysteine is toxic by acting as a thioacylating agent - particularly of lysine residues in nearby proteins. Toxicity, however, may also involve 'self-inactivation' of key enzymes. The present findings suggest that alanine-glyoxylate aminotransferase II may be an important factor in the well-established targeting of rat kidney mitochondria by toxic halogenated cysteine S-conjugates. Previous reports suggest that alanine-glyoxylate aminotransferase II is absent in some humans, but present in others. Alanine-glyoxylate aminotransferase II may contribute to the bioactivation (toxification) of halogenated cysteine S-conjugates in a subset of individuals exposed to halogenated alkenes.

Cooper, Arthur J L; Krasnikov, Boris F; Okuno, Etsuo; Jeitner, Thomas M



Dynamic Liver Scintigraphy: A New Way of Measuring the Function of the Reticuloendothelial System of the Liver  

Microsoft Academic Search

The phagocytic function and biokinetics of the hepatic reticuloendothelial system (RES) were evaluated using a 25-nm diameter colloid (NanocollTM) and a scintillation camera technique in opossums with obstruction of the pancreatic duct (group I) and additional obstruction of the common bile duct (group II). The liver net uptake curve was analysed using natural log regression. The regression curves proved to

J. Baas; N. Senninger; H. Elser; Ch. Herfarth



Liver mitochondrial function and redox status in an experimental model of non-alcoholic fatty liver disease induced by monosodium l-glutamate in rats  

Microsoft Academic Search

The purpose of this work was to determine if mitochondrial dysfunction is involved in the development of non-alcoholic fatty liver disease (NAFLD). Using a model of obesity induced by the neonatal treatment of rats with monosodium l-glutamate (MSG), several parameters of liver mitochondrial function and their impact on liver redox status were evaluated. Specifically, fatty acid ?-oxidation, oxidative phosphorylation and

Murilo de Oliveira Lazarin; Emy Luiza Ishii-Iwamoto; Nair Seiko Yamamoto; Rodrigo Polimeni Constantin; Rosângela Fernandes Garcia; Cecília E. Mareze da Costa; Adriana de Souza Vitoriano; Monique Cristine de Oliveira; Clairce L. Salgueiro-Pagadigorria



Peptide-functionalized gold nanorods increase liver injury in hepatitis.  


Targeted nanomedicine holds enormous potential for advanced diagnostics and therapy. Although it is known that nanoparticles accumulate in liver in vivo, the impact of cell-targeting particles on the liver, especially in disease conditions, is largely obscure. We had previously demonstrated that peptide-conjugated nanoparticles differentially impact macrophage activation in vitro. We thus comprehensively studied the distribution of gold nanorods (AuNR) in mice in vivo and assessed their hepatotoxicity and impact on systemic and hepatic immune cells in healthy animals and experimental liver disease models. Gold nanorods were stabilized with either cetyltrimethylammonium bromide or poly(ethylene glycol) and additional bioactive tripeptides RGD or GLF. Gold nanorods mostly accumulated in liver upon systemic injection in mice, as evidenced by inductively coupled plasma mass spectrometry from different organs and by non-invasive microcomputerized tomography whole-body imaging. In liver, AuNR were only found in macrophages by seedless deposition and electron microscopy. In healthy animals, AuNR did not cause significant hepatotoxicity as evidenced by biochemical and histological analyses, even at high AuNR doses. However, flow cytometry and gene expression studies revealed that AuNR polarized hepatic macrophages, even at low doses, dependent on the respective peptide sequence, toward M1 or M2 activation. While peptide-modified AuNR did not influence liver scarring, termed fibrosis, in chronic hepatic injury models, AuNR-induced preactivation of hepatic macrophages significantly exacerbated liver damage and disease activity in experimental immune-mediated hepatitis in mice. Bioactively targeted gold nanoparticles are thus potentially harmful in clinically relevant settings of liver injury, as they can aggravate hepatitis severity. PMID:22994679

Bartneck, Matthias; Ritz, Thomas; Keul, Heidrun A; Wambach, Mona; Bornemann, Jörg; Gbureck, Uwe; Ehling, Josef; Lammers, Twan; Heymann, Felix; Gassler, Nikolaus; Lüdde, Tom; Trautwein, Christian; Groll, Jürgen; Tacke, Frank



Pivotal role of ADAMTS13 function in liver diseases  

Microsoft Academic Search

The liver is a major source of clotting and fibrinolytic proteins, and plays a central role in thrombo-regulation. Patients\\u000a with advanced liver diseases tend to bleed because of reduced plasma levels of several clotting factors and thrombocytopenia,\\u000a but they do also exhibit thrombotic complications. ADAMTS13 is a metalloproteinase, produced exclusively in hepatic stellate\\u000a cells, and specifically cleaves highly multimeric von

Masahito Uemura; Yoshihiro Fujimura; Saiho Ko; Masanori Matsumoto; Yoshiyuki Nakajima; Hiroshi Fukui



Liver Panel  


... Hepatitis , Hemochromatosis , Wilson Disease , Cirrhosis Elsewhere On The Web American Liver Foundation Liver function tests KidsHealth from Nemours: Hepatic [Liver] Function Panel National ...


Alanine Aminotransferase Decreases with Age: The Rancho Bernardo Study  

Microsoft Academic Search

BackgroundSerum alanine aminotransferase (ALT) is a marker of liver injury. The 2005 American Gastroenterology Association Future Trends Committee report states that serum ALT levels remain constant with age. This study examines the association between serum ALT and age in a community-dwelling cohort in the United States.MethodsA cross-sectional study of 2,364 (54% female) participants aged 30–93 years from the Rancho Bernardo

Mamie H. Dong; Ricki Bettencourt; Elizabeth Barrett-Connor; Rohit Loomba; Man-Fung Yuen



In vitro photothermal study of gold nanoshells functionalized with small targeting peptides to liver cancer cells.  


Gold nanoshells functionalized with a small peptide as a targeting agent were designed and synthesized for photothermal therapy of hepatocarcinoma. The nanoshells exhibited high absorption in the near-infrared (NIR) range, 800-1,100 nm, and were functionalized with 12-amino acid sequence peptides for targeting liver cancer cells. The nanoshells were characterized by Dynamic Light Scattering (DLS), Transmission Electron Microscope (TEM) and IR spectra. The functionalized gold nanoshells showed good targeting ability to liver cancer cells BEL-7404 and BEL-7402 while not to the normal healthy liver cell HL-7702, and also had a low cytotoxic activity. The fluorescence images showed that the gold nanoshells caused death to the liver cancer cells efficiently after being treated with a NIR light in vitro. These simple, stable, low cytotoxic, cancer-cell targeting gold nanoshells present a great promise as delivery agents for the selective photothermal treatment of liver cancer cells. PMID:19834788

Liu, Shun-Ying; Liang, Zhong-Shi; Gao, Feng; Luo, Shu-Fang; Lu, Guo-Quan



Architectural and Functional Aspects of the Liver with Implications for Cancer Metastasis  

Microsoft Academic Search

\\u000a The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on its specialized\\u000a microcirculation and parenchymal\\/non-parenchymal cell heterogeneity. The same architectural and functional aspects of the\\u000a liver that guarantee hepatic homeostasis are also determinants of the malignant behavior of cancer cells through the various\\u000a stages of the metastatic process. First, the functional heterogeneity of

Fernando Vidal-Vanaclocha



Technology Transfer Automated Retrieval System (TEKTRAN)

Extracorporeal artificial liver device (ALD) support systems may offer a feasible approach for patients suffering from liver disease. The overall objective of this work is to develop an ALD using the pig epiblast-derived PICM-19H cell line. PICM-19H cells exhibit hepatocyte functions including ammon...


Renal function in tyrosinaemia type I after liver transplantation: a long-term follow-up.  


Hereditary tyrosinaemia type I is an autosomal recessive inborn error of tyrosine catabolism caused by a deficiency of the enzyme fumarylacetoacetase that results in liver failure, hepatocellular carcinoma, renal tubular dysfunction and acute intermittent porphyria. When treated with liver transplantation, tyrosinaemia type I was considered to be cured. Some years after the first liver transplantations in these patients, some reports focused on the renal function after transplantation. These reports showed that urinary succinylacetone excretion remained but that tubular function normalized. In this report we discuss the long-term renal follow-up (mean follow-up time 11 years, range 7-14 years) after liver transplantation in 9 patients with tyrosinaemia type I treated by liver transplantation in our centre. An evaluation was made of renal function and succinylacetone excretion in urine. In all patients we found a persistent excretion of succinylacetone in the urine. With respect to the glomerular function, we can conclude that there is no clear change in GFR. At the same time, tubulopathy persisted in some patients. We consider that excretion of metabolites such as succinylacetone will be an important contributing factor to tubular dysfunction after liver transplantation in patients with tyrosinaemia type I. Therefore, notwithstanding the major effect of liver transplantation on tyrosine metabolism, renal tubular dysfunction remains at risk and needs careful monitoring. Progressive tubular dysfunction can cause glomerular damage. The use of low-dose NTBC might be considered after liver transplantation in case of tubulopathy to prevent progression of tubular and glomerular dysfunction. PMID:16435179

Pierik, L J W M; van Spronsen, F J; Bijleveld, C M A; van Dael, C M L



Alteration of liver function due to H1N1 infection: a case report  

PubMed Central

H1N1 virus is known to affect the respiratory tract. The majority of healthcare providers focus on the respiratory complications attributed to H1N1 infection, overlooking possible multi-organ involvement. We present a rare case of abnormal liver function in a child who was admitted for respiratory illness due to the H1N1 virus. There was a marked elevation in liver function tests concurrent with the respiratory disease. Our patient was treated with oseltamavir for the H1N1 infection, and the liver function levels decreased dramatically in 72 hours.

Alhammadi, Ahmed H; Hendaus, Mohamed A; Kayoum, Anas A



Evaluation of liver function using gadoxetate disodium (Gd-EOB-DTPA) enhanced MR imaging  

NASA Astrophysics Data System (ADS)

Indocyanine green (ICG) is widely used for its clearance test in the evaluation of liver function. Gadoxetate disodium (Gd-EOB-DTPA) is a targeted MR contrast agent partially taken up by hepatocytes. The objective of this study was to evaluate the feasibility of an estimation of the liver function corresponding to plasma disappearance rate of indocyanine green (ICG-PDR) by use of the signal intensity of the liver alone in Gd-EOB-DTPA enhanced MR imaging (EOB-MRI). We evaluated fourteen patients who had EOB-MRI and ICG clearance test within 1 month. 2D-GRE T1 weighted images were obtained at pre contrast, 3 min (equilibrium phase) and 20 min (hepatobiliary phase) after the intravenous administration of Gd-EOB-DTPA, and the mean signal intensity of the liver was measured. The correlation between ICG-PDR and many parameters derived from the signal intensity of the liver in EOB-MRI was evaluated. The correlation coefficient between ICG-PDR and many parameters derived from the signal intensity of the liver in EOBMRI was low and not significant. The estimation of the liver function corresponding to ICG-PDR by use of the signal intensity of the liver alone in EOB-MRI would not be reliable.

Yamada, Akira; Hara, Takeshi; Li, Feng; Doi, Kunio



Functional Relationships between Lipid Metabolism and Liver Regeneration  

PubMed Central

The regenerative capacity of the liver is well known, and the mechanisms that regulate this process have been extensively studied using experimental model systems including surgical resection and hepatotoxin exposure. The response to primary mitogens has also been used to investigate the regulation of hepatocellular proliferation. Such analyses have identified many specific cytokines and growth factors, intracellular signaling events, and transcription factors that are regulated during and necessary for normal liver regeneration. Nevertheless, the nature and identities of the most proximal events that initiate hepatic regeneration as well as those distal signals that terminate this process remain unknown. Here, we review the data implicating acute alterations in lipid metabolism as important determinants of experimental liver regeneration and propose a novel metabolic model of regeneration based on these data. We also discuss the association between chronic hepatic steatosis and impaired regeneration in animal models and humans and consider important areas for future research.

Rudnick, David A.; Davidson, Nicholas O.



Baseline Blood Levels of the Chimpanzee (Pan Troglodytes): Liver Function Tests.  

National Technical Information Service (NTIS)

The biological variation within chimpanzees, the effect of sequential sampling, and the effects of age and sex on selected liver function tests in colony-stabilized chimpanzees were determined. The biological variation within chimpanzees (sample time X an...

W. G. Wisecup H. H. Hodson W. C. Hanly P. E. Felts



[The correction of the liver detoxifying function with phenobarbital and ziksorin before and after ischemia].  


Rat experiments have shown preliminary administration of phenobarbital and zixoryn (before ischemia) fails to prevent the hepatic monoxygenase system from ischemic lesion, followed by profound destructive changes in the liver, though the functional activity of the microsomal system remained high. Phenobarbital and zixoryn induction of monooxygenases in the postischemic period contributed to the complete restoration of the levels of microsomal cytochromes and the metabolic activity of xenobiotics in the liver just in its early periods. It is concluded that it is advisable to use the inductors in the postischemic restorative period to correct the detoxifying function of the liver. PMID:8312805

Grek, O R; Rybakova, T A; Sharapov, V I; Zakharova, M V; Shkurupi?, V A


Expression of differentiated functions in hepatoma cell hybrids: IX extinction and reexpression of liver-specific enzymes in rat hepatoma-Chinese hamster fibroblast hybrids  

Microsoft Academic Search

Most of the hybrid clones derived from a cross of Chinese hamster fibroblasts (DON) with rat hepatoma cells (Faza 967) showed preferential loss of rat chromosomes. Two of the hybrid clones retained the rat chromosomes, and both showed extinction of 4 liverspecific enzymes: aldolase B, liver alcohol dehydrogenase, and the inducible enzymes tyrosine aminotransferase and alanine aminotransferase. Subcloning of 1

Mary C. Weiss; Robert S. Sparkes; Roger Bertolotti



Alanine Aminotransferase, ?-Glutamyltransferase, and Incident Diabetes  

PubMed Central

OBJECTIVE To estimate and compare associations of alanine aminotransferase (ALT) and ?-glutamyltransferase (GGT) with incident diabetes. RESEARCH DESIGN AND METHODS ALT and GGT were studied as determinants of diabetes in the British Women's Heart and Health Study, a cohort of 4,286 women 60–79 years old (median follow-up 7.3 years). A systematic review and a meta-analysis of 21 prospective, population-based studies of ultrasonography, which diagnosed nonalcoholic fatty liver disease (NAFLD), ALT, and GGT as determinants of diabetes, were conducted, and associations of ALT and GGT with diabetes were compared. RESULTS Ultrasonography-diagnosed NAFLD was associated with more than a doubling in the risk of incident diabetes (three studies). ALT and GGT both predicted diabetes. The fully adjusted hazard ratio (HR) for diabetes per increase in one unit of logged ALT was 1.83 (95% CI 1.57–2.14, I2 = 8%) and for GGT was 1.92 (1.66–2.21, I2 = 55%). To directly compare ALT and GGT as determinants of diabetes, the fully adjusted risk of diabetes in the top versus bottom fourth of the ALT and GGT distributions was estimated using data from studies that included results for both markers. For ALT, the HR was 2.02 (1.59–2.58, I2 = 27%), and for GGT the HR was 2.94 (1.98–3.88, I2 = 20%), suggesting that GGT may be a better predictor (P = 0.05). CONCLUSIONS Findings are consistent with the role of liver fat in diabetes pathogenesis. GGT may be a better diabetes predictor than ALT, but additional studies with directly determined liver fat content, ALT, and GGT are needed to confirm this finding.

Fraser, Abigail; Harris, Ross; Sattar, Naveed; Ebrahim, Shah; Davey Smith, George; Lawlor, Debbie A.



[An evaluation of predicting postoperative residual liver function using 99mTc tin colloid].  


The rate of clearance (K value) of 99mTc tin colloid in the liver differentiates normal subjects from liver cirrhosis patients; so 99mTc tin colloid is as useful as 198Au colloid as a marker of liver function. There are several reports concerning volume estimation using liver scintigraphy. Our original method was devised to measure the effective liver volume by scintigraphy. By combining the K value with effective liver volume, a predictive index was obtained in order to predict the residual liver function before hepatic resection. The index in 24 patients with liver diseases was investigated before hepatic resection. Three of them died due to hepatic failure after hepatic resection. The indices were between 0.40 and 0.45 in two of these three patients and 0.338 in one. Among the patients without hepatic failure, the indices showed more than 0.45 in 19 patients and between 0.40 and 0.45 in two. These results indicate that the limitation of hepatic resection is between 0.40 and 0.45 of the predictive index. PMID:3201005

Tamai, T; Hino, I; Tanabe, M; Seo, H; Kawase, Y; Kawasaki, Y; Mizukawa, K; Maeba, T; Tanaka, S




PubMed Central

Background If ‘bridging’ to allotransplantation is to be achieved by a pig liver xenograft, adequate hepatic function needs to be assured. Methods We have studied hepatic function in baboons after transplantation of livers from ?1,3-galactosyltransferase gene-knockout (GTKO,n=1) or GTKO pigs transgenic for CD46 (GTKO/CD46,n=5). Monitoring was by liver function tests and coagulation parameters. Pig-specific proteins in the baboon serum/plasma were identified by Western blot. In 4 baboons, coagulation factors were measured. The results were compared with values from healthy humans, baboons, and pigs. Results Recipient baboons died or were euthanized after 4-7 days following internal bleeding associated with profound thrombocytopenia. However, parameters of liver function, including coagulation, remained in the near-normal range, except for some cholestasis. Western blot demonstrated that pig proteins (albumin, fibrinogen, haptoglobin, plasminogen) were produced by the liver from day 1. Production of several pig coagulation factors was confirmed. Conclusions After the transplantation of genetically-engineered pig livers into baboons (1) many parameters of hepatic function, including coagulation, were normal or near-normal; (2) there was evidence for production of pig proteins, including coagulation factors, and (3) these appeared to function adequately in baboons, though inter-species compatibility of such proteins remains to be confirmed.

Ekser, Burcin; Echeverri, Gabriel J.; Hassett, Andrea Cortese; Yazer, Mark H.; Long, Cassandra; Meyer, Michael; Ezzelarab, Mohamed; Lin, Chih Che; Hara, Hidetaka; van der Windt, Dirk J.; Dons, Eefje M.; Phelps, Carol; Ayares, David; Cooper, David K.C.; Gridelli, Bruno



S-Adenosylmethionine: a control switch that regulates liver function  

Microsoft Academic Search

Genome sequence analysis reveals that all organisms synthesize S-adenosylmethionine (AdoMet) and that a large fraction of all genes is AdoMet- dependent methyltransferases. AdoMet-dependent methylation has been shown to be central to many biological processes. Up to 85% of all methylation reactions and as much as 48% of methionine metabo- lism occur in the liver, which indicates the crucial importance of




Structural and functional analyses of chicken liver ferritin.  


Characterization of ferritins from different species has provided insight into iron regulation mechanisms and evolutionary relationships. Here, we examined chicken liver ferritin, which comprises only H subunit and has 14.8 µg of Fe/100 µg of protein. The chicken H subunit apo homopolymer showed the same iron uptake rate as bovine H subunit homopolymer expressed with a baculovirus expression system (0.31 and 0.28 mmol of Fe/min per micromole of protein for chicken and bovine H subunit, respectively). Chicken H subunit apo homopolymer showed a significantly higher biotinylated hemin-binding activity than liver holoferritin. Although bovine spleen apoferritin, which has an L (liver or light):H (heart or heavy) subunit ratio of 1:1, also shows a significantly higher biotinylated hemin-binding activity than its holoferritin, these biotinylated hemin-binding activities were markedly lower than those of both chicken holo- and apoferritins. Binding of chicken holo- and apoferritin with biotinylated hemin was strongly inhibited by hemin but not iron-free hemin, protoporphyrin IX, or Zn-protoporphyrin. These findings demonstrate that chicken ferritin comprises only an H subunit, possesses ferroxidase activity as in mammalian ferritin H subunits, and binds heme more strongly than mammalian ferritins. PMID:21673164

Watanabe, M; Yuge, M; Uda, A; Yoshikawa, Y; Watanabe, K; Orino, K



Making sense of liver enzymes, liver function tests, and hepatobiliary disorders at the reference desk.  


This paper discusses concepts and terminology of some aspects of the laboratory diagnosis of liver (hepatic) disease and biliary tract disease (hepatobiliary disease) as it relates to medical reference work. Details of anatomic, biochemical, and pathologic processes are not discussed. Knowledge of the specific terminology involved in this area may help to ensure a good approach to developing prudent strategies for database searching of the medical literature and therefore is reviewed. MeSH and EMBASE thesauri terms are discussed and textword synonyms are presented that provide tools for thorough searching techniques. Commonly used medical jargon for this area is also explained. Examples of specific search strategies are illustrated. PMID:14527136

Fikar, Charles R



Liver Facts  


... Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Liver Facts How the Liver Works The liver is one of the largest and most complex ... a spongy mass of wedge-shaped lobes. The liver has numerous functions that are necessary for life. ...


The functional interrelationship between gap junctions and fenestrae in endothelial cells of the liver organoid.  


Functional intact liver organoid can be reconstructed in a radial-flow bioreactor when human hepatocellular carcinoma (FLC-5), mouse immortalized sinusoidal endothelial M1 (SEC) and A7 (HSC) hepatic stellate cell lines are cocultured. The structural and functional characteristics of the reconstructed organoid closely resemble the in vivo liver situation. Previous liver organoid studies indicated that cell-to-cell communications might be an important factor for the functional and structural integrity of the reconstructed organoid, including the expression of fenestrae. Therefore, we examined the possible relationship between functional intact gap junctional intercellular communication (GJIC) and fenestrae dynamics in M1-SEC cells. The fine morphology of liver organoid was studied in the presence of (1) irsogladine maleate (IM), (2) oleamide and (3) oleamide followed by IM treatment. Fine ultrastructural changes were studied by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and compared with control liver organoid data. TEM revealed that oleamide affected the integrity of cell-to-cell contacts predominantly in FLC-5 hepatocytes. SEM observation showed the presence of fenestrae on M1-SEC cells; however, oleamide inhibited fenestrae expression on the surface of endothelial cells. Interestingly, fenestrae reappeared when IM was added after initial oleamide exposure. GJIC mediates the number of fenestrae in endothelial cells of the liver organoid. PMID:17568973

Saito, Masaya; Matsuura, Tomokazu; Nagatsuma, Keisuke; Tanaka, Ken; Maehashi, Haruka; Shimizu, Keiko; Hataba, Yoshiaki; Kato, Fumitaka; Kashimori, Isao; Tajiri, Hisao; Braet, Filip



Altered functional and immunophenotypical properties of neutrophilic granulocytes in postpartum cows associated with fatty liver.  


The intention of the study was to analyze the relationship between liver triacyl glycerol content (liver TAG content) and immunophenotypical and functional properties of polymorphonuclear neutrophilic granulocytes (PMN) of dairy cows in the peripartum period. We investigated characteristics of bovine PMN from the blood and uterus of clinically healthy cows in the periparturient period. The numbers of circulating leukocytes and segmented granulocytes continuously increased until parturition and declined afterwards to starting values. This was independent of the liver TAG content and mainly affected neutrophils. The liver TAG content exceeded 40 mg/g liver, the reference value, in 12 of 19 cows in the first two weeks postpartum. Increased liver TAG content, > 40 mg/g, went in parallel with a reduced expression of function-associated surface molecules on blood neutrophils (e.g. CD11b/CD18 = CR3 and CD11c/CD18 = CR4). Moreover, in cows with high liver TAG levels the antibody-independent and -dependent cellular cytotoxicity (AICC, ADCC) of blood PMN was markedly reduced. PMN also were less capable of ROS generation after stimulation with Phorbol Myristate Acetate (PMA). In comparison with contemporarily harvested blood PMN, neutrophils recovered from the uterine lumen showed a decreased expression of 4/6 examined surface structures. Only the expression densities of CR3 molecules and those detected by mAb IL-A110 were enhanced on uterine PMN. The cytotoxic capacity and the ROS generation were significantly lower for uterine PMN than for blood PMN. The results suggest that increased liver TAG content in the first and second week after calving is associated with decreased functional capacities of PMN derived from blood and uterus. This may help to explain why cows who are too fat at calving (who therefore have an increased liver TAG content) have a higher incidence of infectious diseases such as endometritis PMID:11101037

Zerbe, H; Schneider, N; Leibold, W; Wensing, T; Kruip, T A; Schuberth, H J



Molecular regulation of hepatic dendritic cell function and its relation to liver transplant outcome  

PubMed Central

Studies on liver interstitial dendritic cells (DC) indicate that the maturation and function of these important antigen-presenting cells may be downregulated by continual exposure to microbial products from the gut, in particular, bacterial lipopolysaccharide. New evidence is emerging for a role of specific intracellular regulators of signal transduction, and of cytokines in the hepatic microenvironment, that may contribute to a hyporesponsive state in liver DC. Analysis of signaling molecule expression within DC in liver transplant tissue is likely to uncover its relation to allograft outcome.

Sumpter, Tina L.; Lunz, John G.; Demetris, A. Jake; Thomson, Angus W.



Influence of Visceral Obesity and Liver Fat on Vascular Structure and Function in Obese Subjects  

Microsoft Academic Search

Endothelial dysfunction and increased intima–media thickness (IMT) have been found in obese patients. Both regional fat distribution and liver steatosis may influence these markers of subclinical atherosclerosis. We sought to determine the interrelationships of endothelial function, carotid IMT, visceral and subcutaneous adipose tissue accumulation, and liver steatosis in severely obese subjects. In 64 severely obese patients (BMI 42.3 ± 4.3

Wolfgang Sturm; Anton Sandhofer; Julia Engl; Markus Laimer; Clemens Molnar; Susanne Kaser; Helmut Weiss; Herbert Tilg; Christoph F. Ebenbichler; Josef R. Patsch



Glycine conjugation of para-aminobenzoic acid (PABA): A quantitative test of liver function  

Microsoft Academic Search

To evaluate glycine conjugation of para-aminobenzoic acid (PABA) to the hippurated metabolites, para-aminohippuric acid (PAHA), and para-acetamidohippuric acid (PAAHA) as a quantitative liver function test in patients with liver disease.Serum concentrations of PABA and metabolites were measured by high pressure liquid chromatography in 24 controls and 50 patients with hepatobiliary disease.Hippurate formation was significantly decreased in all patient groups with

Katryn N. Furuya; Peter R. Durie; Eve A. Roberts; Steven J. Soldin; Zul Verjee; Linda Yung-Jato; Esther Giesbrecht; Lynda Ellis



Glycyrrhetinic acid-functionalized degradable micelles as liver-targeted drug carrier  

Microsoft Academic Search

Recently, many efforts have been devoted to investigating the application of functionalized micelles as targeted drug delivery\\u000a carriers. In this study, glycyrrhetinic acid (GA, a liver targeting ligand) modified poly(ethylene glycol)-b-poly(?-benzyl l-glutamate) micelles were prepared and evaluated as a potential liver-targeted drug carrier. The aggregation behavior, stability,\\u000a size and morphology of the micelles were investigated. Anticancer drug doxorubicin (DOX) was

Wei Huang; Wei Wang; Ping Wang; Chuang-Nian Zhang; Qin Tian; Yue Zhang; Xiu-Hua Wang; Rui-Tao Cha; Chun-Hong Wang; Zhi Yuan



Self-assembling functionalized nanopeptides for immediate hemostasis and accelerative liver tissue regeneration  

NASA Astrophysics Data System (ADS)

Traumatic injury or surgery may trigger extensive bleeding. However, conventional hemostatic methods have limited efficacy and may cause surrounding tissue damage. In this study, we use self-assembling peptides (SAPs) and specifically extend fragments of functional motifs derived from fibronectin and laminin to evaluate the capability of these functionalized SAPs in the effect of hemostasis and liver tissue regeneration. From the results, these peptides can self-assemble into nanofibrous network structure and gelate into hydrogel with pH adjustment. In animal studies, the efficacy of hemostasis is achieved immediately within seconds in a rat liver model. The histological analyses by hematoxylin-eosin stain and immunohistochemistry reveal that SAPs with these functionalized motifs significantly enhance liver tissue regeneration. In brief, these SAPs may have potential as pharmacological tools to extensively advance clinical therapeutic applications in hemostasis and tissue regeneration in the field of regenerative medicine.Traumatic injury or surgery may trigger extensive bleeding. However, conventional hemostatic methods have limited efficacy and may cause surrounding tissue damage. In this study, we use self-assembling peptides (SAPs) and specifically extend fragments of functional motifs derived from fibronectin and laminin to evaluate the capability of these functionalized SAPs in the effect of hemostasis and liver tissue regeneration. From the results, these peptides can self-assemble into nanofibrous network structure and gelate into hydrogel with pH adjustment. In animal studies, the efficacy of hemostasis is achieved immediately within seconds in a rat liver model. The histological analyses by hematoxylin-eosin stain and immunohistochemistry reveal that SAPs with these functionalized motifs significantly enhance liver tissue regeneration. In brief, these SAPs may have potential as pharmacological tools to extensively advance clinical therapeutic applications in hemostasis and tissue regeneration in the field of regenerative medicine. Electronic supplementary information (ESI) available: Fig. S1. Experimental models of rat liver injury. See DOI: 10.1039/c3nr33710c

Cheng, Tzu-Yun; Wu, Hsi-Chin; Huang, Ming-Yuan; Chang, Wen-Han; Lee, Chao-Hsiung; Wang, Tzu-Wei



Genistein Modifies Liver Fibrosis and Improves Liver Function by Inducing uPA Expression and Proteolytic Activity in CCl4Treated Rats  

Microsoft Academic Search

Aim: To evaluate the effect of genistein on the fibrosis and matrix degradation caused by experimentally induced fibrosis in rats. Methods: Hepatic fibrosis was brought about by chronic administration of carbon tetrachloride to rats. To evaluate the effect of genistein on liver fibrosis and function, total collagen content and proteolytic activity in the liver were quantified. Urokinase-type plasminogen activator (uPA)

Alfonso Leija Salas; Tania Díaz Montezuma; German Garrido Fariña; Jorge Reyes-Esparza; Lourdes Rodríguez-Fragoso



Health-related quality of life and family function following pediatric liver transplantation  

Microsoft Academic Search

This multicenter study compared health-related quality of life (HRQOL) and family function of pediatric liver transplant recipients to those of healthy children to determine if this population differed from a healthy population and to distinguish which pretransplant and posttransplant factors impact HRQOL and family function. HRQOL data from 102 patients achieving 2-year survival were collected with the Infant Toddler Quality

Estella M. Alonso; Katie Neighbors; Franca B. Barton; Sue V. McDiarmid; Stephen P. Dunn; George V. Mazariegos; Jeanne M. Landgraf; John C. Bucuvalas



Influence of Mycophenolate Mofetil on Preservation of Kidney Function in Liver Transplant Patients  

Microsoft Academic Search

BackgroundThere are numerous studies on the effect of immunosuppressive therapy with mycophenolate mofetil (MMF) on preservation of kidney function in liver transplant (OLT) patients with chronic kidney damage. However, we have noted few studies that evaluate the role of this drug prescribed from induction on kidney function.

L. Barrera-Pulido; M. D. Espinosa-Aguilar; D. Marín; F. Nuñez-Garcia; M. Jiménez-Pérez; M. de la Mata-Garcia; M. A. Gómez-Bravo



Clinical evaluation of liver structure and function in humans exposed to halogenated hydrocarbons.  

PubMed Central

An unresolved question is whether humans exposed to comparatively low doses of persistent environmental chemicals such as polyhalogenated biphenyls or organochlorine pesticides are at risk for injury to the liver. Cross-sectional epidemiologic studies suggest that these chemicals may produce statistically significant but clinically mild abnormalities in the commonly employed chemical tests of liver function. The few reports of human liver morphology reveal nonspecific changes reflecting effects of lipophilic chemicals. There is evidence that chemicals of this category in at least some doses cause induction of liver microsomal enzymes involved in biotransformation of foreign substances. This finding has been documented by measurements of the clearance of model drugs or the appearance in the urine of steroid metabolites or glucaric acid. Although a positive statistical correlation between the concentrations of these chemicals in serum and the serum gamma-glutamyltranspeptidase activity has been reported, the non-specificity of the latter enzyme precludes conclusion that this change is indicative of induction of liver microsomal enzymes. Although the effects of this type of environmental chemical are not indicative of progressive liver disease, only prospective clinical trials can resolve the issue of the risk for future development of liver malignancy.

Guzelian, P S



Decomposition study of the electron paramagnetic resonance spectrum of irradiated alanine  

Microsoft Academic Search

Recent Electron Paramagnetic Resonance (EPR) studies on alanine powders as a function of irradiation dose and temperature on the one hand and single crystal Electron Nuclear DOuble Resonance (ENDOR) studies on the other hand, showed the presence of at least three radicals contributing to the total alanine EPR spectrum. The latter spectrum obtained after irradiation at room temperature (RT), is

Gauthier C. A. M Vanhaelewyn; Sami A Amira; Wim K. P. G Mondelaers; Freddy J Callens



Mutations affecting liver development and function in Medaka, Oryzias latipes, screened by multiple criteria.  


We report here mutations affecting various aspects of liver development and function identified by multiple assays in a systematic mutagenesis screen in Medaka. The 22 identified recessive mutations assigned to 19 complementation groups fell into five phenotypic groups. Group 1, showing defective liver morphogenesis, comprises mutations in four genes, which may be involved in the regulation of growth or patterning of the gut endoderm. Group 2 comprises mutations in three genes that affect the laterality of the liver; in kendama mutants of this group, the laterality of the heart and liver is uncoupled and randomized. Group 3 includes mutations in three genes altering bile color, indicative of defects in hemoglobin-bilirubin metabolism and globin synthesis. Group 4 consists of mutations in three genes, characterized by a decrease in the accumulation of fluorescent metabolite of a phospholipase A(2) substrate, PED6, in the gall bladder. Lipid metabolism or the transport of lipid metabolites may be affected by these mutations. Mutations in Groups 3 and 4 may provide animal models for relevant human diseases. Group 5 mutations in six genes affect the formation of endoderm, endodermal rods and hepatic bud from which the liver develops. These Medaka mutations, identified by morphological and metabolite marker screens, should provide clues to understanding molecular mechanisms underlying formation of a functional liver. PMID:15210186

Watanabe, Tomomi; Asaka, Satoshi; Kitagawa, Daiju; Saito, Kota; Kurashige, Ryumei; Sasado, Takao; Morinaga, Chikako; Suwa, Hiroshi; Niwa, Katsutoshi; Henrich, Thorsten; Hirose, Yukihiro; Yasuoka, Akihito; Yoda, Hiroki; Deguchi, Tomonori; Iwanami, Norimasa; Kunimatsu, Sanae; Osakada, Masakazu; Loosli, Felix; Quiring, Rebecca; Carl, Matthias; Grabher, Clemens; Winkler, Sylke; Del Bene, Filippo; Wittbrodt, Joachim; Abe, Keiko; Takahama, Yousuke; Takahashi, Katsuhito; Katada, Toshiaki; Nishina, Hiroshi; Kondoh, Hisato; Furutani-Seiki, Makoto



N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver.  


Due to its efficient and specific gene silencing ability, RNA interference has shown great potential in the treatment of liver diseases. However, achieving in vivo delivery of siRNA to critical liver cells remains the biggest obstacle for this technique to be a real clinic therapeutic modality. Here, we describe a promising liver targeting siRNA delivery system based on N-acetylgalactosamine functionalized mixed micellar nanoparticles (Gal-MNP), which can efficiently deliver siRNA to hepatocytes and silence the target gene expression after systemic administration. The Gal-MNP were assembled in aqueous solution from mixed N-acetylgalactosamine functionalized poly(ethylene glycol)-b-poly(?-caprolactone) and cationic poly(?-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) (PCL-b-PPEEA); the properties of nanoparticles, including particle size, zeta potential and the density of poly(ethylene glycol) could be easily regulated. The hepatocyte-targeting effect of Gal-MNP was demonstrated by significant enriching of fluorescent siRNA in primary hepatocytes in vitro and in vivo. Successful down-regulation of liver-specific apolipoprotein B (apoB) expression was achieved in mouse liver, at both the transcriptional and protein level, following intravenous injection of Gal-MNP/siapoB to BALB/c mice. Systemic delivery of Gal-MNP/siRNA did not induce the innate immune response or positive hepatotoxicity. The results of this study suggested therapeutic potential for the Gal-MNP/siRNA system in liver disease. PMID:23266452

Wang, Hong-Xia; Xiong, Meng-Hua; Wang, Yu-Cai; Zhu, Jing; Wang, Jun



[Radionuclide study of liver function in polycythemia vera and other types of polycythemia].  


Clinico-laboratory and radionuclide (radio-hepatography with 131I-rose bengal and liver scanning with 198Au colloid solution) investigation of liver function was performed in 110 patients with polycythemia vera during exacerbation, in 16 patients with symptomatic erythrocytosis (10--chronic pulmonary disease, 3--polycystic kidney, 2--obesity, 1--peptic ulcer), and in 11 patients with a polycythemic form of myelofibrosis. The results of the radionuclide method showed disturbed liver function in 51 (46.3%) patients with polycythemia, in 4 patients with myelofibrosis and in 3 with erythrocytosis which were characterized by a decrease in hepatocytic absorptive-excretory function and a decrease in the activity of the reticulo-histiocytic stroma. Liver changes depended on a stage of disease and were detected earlier than with the use of biochemical methods. As distinct from erythrocytes, one-type disorders were noted in the patients with myelofibrosis. Correlation in the lever of RP accumulation in the spleen, its sizes and stage of disease was established. Liver function returned to normal after cytostatic therapy in the patients with stage IIA polycythemia, partially IIB stage, during remission. PMID:2828815

Kotsiubinski?, N N; Dudarev, A L; Dygin, V P; Filev, L V



Protein-synthesizing function of the liver in rabbits with experimental myocardial infarction  

SciTech Connect

This paper studies the function of the cell-free protein-synthesizing system obtained from the liver of intact rabbits (control) and 6, 12, and 24 h after production of experimental myocardial infarction (EMI). The incorporation of C 14-leucine into the TCA-insoluble translation product of the endogenous mRNA of cell-free protein-synthesizing systems is shown. Analysis of the results shows that, despite the high level of total protein biosynthesis in a cell-free system containing purified S-30 fraction of the liver from rabbits with EMI, the fraction of albumin synthesized in it decreased. Activity of the protein-synthesizing apparatus of the liver does not decline in EMI, but there is a redistribution of the levels of synthesis of individual proteins. In EMI, however, the protein-synthesizing capacity of the liver is evidently not fully realized because of a reduction in the energy resources of the cell.

Liekis, A.V.; Bul'dakova, O.V.; El'skaya, A.V.; Kovalenko, M.I.; Lukosevicius, I.J.



Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease [HTA03/38/02]. Abnormal Liver Function Investigations Evaluation (ALFIE)  

PubMed Central

Background Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs. Methods/Design A population-based retrospective cohort study will follow up all those who have had an incident liver function test (LFT) in primary care to subsequent liver disease or mortality over a period of 15 years (approx. 2.3 million tests in 99,000 people). The study is set in Primary Care in the region of Tayside, Scotland (pop approx. 429,000) between 1989 and 2003. The target population consists of patients with no recorded clinical signs or symptoms of liver disease and registered with a GP. The health technologies being assessed are LFTs, viral and auto-antibody tests, ultrasound, CT, MRI and liver biopsy. The study will utilise the Epidemiology of Liver Disease In Tayside (ELDIT) database to determine the outcomes of liver disease. These are based on hospital admission data (Scottish Morbidity Record 1), dispensed medication records, death certificates, and examination of medical records from Tayside hospitals. A sample of patients (n = 150) with recent initial ALF tests or invitation to biopsy will complete questionnaires to obtain quality of life data and anxiety measures. Cost-effectiveness and cost utility Markov model analyses will be performed from health service and patient perspectives using standard NHS costs. The findings will also be used to develop a computerised clinical decision support tool. Discussion The results of this study will be widely disseminated to primary care, as well as G.I. hospital specialists through publications and presentations at local and national meetings and the project website. This will facilitate optimal decision-making both for the benefit of the patient and the National Health Service.

Donnan, Peter T; McLernon, David; Steinke, Douglas; Ryder, Stephen; Roderick, Paul; Sullivan, Frank M; Rosenberg, William; Dillon, John F



Inhibition of kupffer cell activity improves transplantation of human adipose-derived stem cells and liver functions.  


Numerous approaches to cell transplantation of the hepatic or the extrahepatic origin into liver tissue have been developed; however, the efficiency of cell transplantation remains low and liver functions are not well corrected. The liver is a highly immunoreactive organ that contains many resident macrophages known as Kupffer cells. Here, we show that the inhibition of Kupffer cell activity improves stem cell transplantation into liver tissue and corrects some of the liver functions under conditions of liver injury. We found that, when Kupffer cells were inhibited by glycine, numerous adipose-derived stem cells (ASCs) were successfully transplanted into livers, and these transplanted cells showed hepatoprotective effects, including decrease of liver injury factors, increase of liver regeneration, and albumin production. On the contrary, injected ASCs without glycine recruited numerous Kupffer cells, not lymphocytes, and showed low transplantation efficiency. Intriguingly, successfully transplanted ASCs in liver tissue modulated Kupffer cell activity to inhibit tumor necrosis factor-? secretion. Thus, our data show that Kupffer cell inactivation is an important step in order to improve ASC transplantation efficiency and therapeutic potential in liver injuries. In addition, the hepatoprotective function of glycine has synergic effects on liver protection and the engraftment of ASCs. PMID:22546493

Hong, Il-Hwa; Han, Seon-Young; Ki, Mi-Ran; Moon, Young-Mi; Park, Jin-Kyu; You, Sang-Young; Lee, Eun-Mi; Kim, Ah-Young; Lee, Eun-Joo; Jeong, Jae-Ho; Kang, Kyung-Sun; Jeong, Kyu-Shik



[Liver detoxifying function disorders in children with chronic hepatic disease and their correction].  


In the present study liver detoxifying function state in children with chronic hepatitis and pigmentary hepatosis was examined. An endogenous intoxication level increase, peroxide processes and biotransformation system activation were established against the background of endotoxicosis substrate accumulation in blood. The dynamics of clinical symptoms and liver detoxifying function indicators was estimated against the background of the complex treatment with Reamberin. In our study we have noticed detoxication mechanisms improvement, and that fact has been confirmed by a decrease of endogenous intoxication level and significant middle-mass molecules decreasing in blood plasma as well as intoxication index and glutathione enzymes activity in blood. PMID:22573753

Romanova, S V; Vidmanova, T A; Zhukova, E A; Korkotashvili, L V; Iazykova, A B



Maintenance of Human Hepatocyte Function In Vitro by Liver-Derived Extracellular Matrix Gels  

PubMed Central

Tissue engineering and regenerative medicine (TE&RM) approaches to treating liver disease have the potential to provide temporary support with biohybrid-liver-assist devices or long-term therapy by replacing the diseased liver with functional constructs. A rate-limiting step for TE&RM strategies has been the loss of hepatocyte-specific functions after hepatocytes are isolated from their highly specialized in vivo microenvironment and placed in in vitro culture systems. The identification of a biologic substrate that can maintain a functional hepatocyte differentiation profile during in vitro culture would advance potential TE&RM therapeutic strategies. The present study compared two different biologic substrates for their ability to support human hepatocyte function in vitro: porcine-liver-derived extracellular matrix (PLECM) or MatrigelTM. Because Matrigel has been shown to be the most useful matrix for static, traditional hepatocyte culture, we directly compared PLECM with Matrigel in each experiment. Albumin secretion, hepatic transport activity, and ammonia metabolism were used to determine hepatocyte function. Hepatocytes cultured between two layers of PLECM or Matrigel showed equally high levels of albumin expression and secretion, ammonia metabolism, and hepatic transporter expression and function. We conclude that like Matrigel, PLECM represents a favorable substrate for in vitro culture of human hepatocytes.

Sellaro, Tiffany L.; Ranade, Aarati; Faulk, Denver M.; McCabe, George P.; Dorko, Kenneth; Strom, Stephen C.



Effects of gomisin A on liver functions in hepatotoxic chemicals-treated rats.  


The effects of gomisin A, which is a lignan component of schizandra fruits, on liver functions in various experimental liver injuries and on bile secretion in CCl4-induced liver injury were studied. Gomisin A weakly accelerated the disappearance of plasma ICG by itself at a high dose (100 mg/kg, i.p.). All of the hepatotoxic chemicals used in this study inhibited the excretion of ICG from plasma. Gomisin A showed a tendency to prevent the delays of the disappearance of plasma ICG induced by CCl4, d-galactosamine and orotic acid, but not that by ANIT. Bile flow and biliary outputs of total bile acids and electrolytes (Na+, K+, Cl- and HCO3-) were decreased in CCl4-treated rats. Gomisin A maintained bile flow and biliary output of each electrolyte nearly to the level of the vehicle-treated group, but did not affect biliary output of total bile acids. These findings suggest that gomisin A possesses a liver function-facilitating property in normal and liver injured rats and that its preventive action on CCl4-induced cholestasis is due to maintaining the function of the bile acids-independent fraction. PMID:4068375

Maeda, S; Takeda, S; Miyamoto, Y; Aburada, M; Harada, M



Alanine Racemase Mutants of Burkholderia pseudomallei and Burkholderia mallei and Use of Alanine Racemase as a Non-Antibiotic-Based Selectable Marker  

PubMed Central

Burkholderia pseudomallei and Burkholderia mallei are category B select agents and must be studied under BSL3 containment in the United States. They are typically resistant to multiple antibiotics, and the antibiotics used to treat B. pseudomallei or B. mallei infections may not be used as selective agents with the corresponding Burkholderia species. Here, we investigated alanine racemase deficient mutants of B. pseudomallei and B. mallei for development of non-antibiotic-based genetic selection methods and for attenuation of virulence. The genome of B. pseudomallei K96243 has two annotated alanine racemase genes (bpsl2179 and bpss0711), and B. mallei ATCC 23344 has one (bma1575). Each of these genes encodes a functional enzyme that can complement the alanine racemase deficiency of Escherichia coli strain ALA1. Herein, we show that B. pseudomallei with in-frame deletions in both bpsl2179 and bpss0711, or B. mallei with an in-frame deletion in bma1575, requires exogenous d-alanine for growth. Introduction of bpsl2179 on a multicopy plasmid into alanine racemase deficient variants of either Burkholderia species eliminated the requirement for d-alanine. During log phase growth without d-alanine, the viable counts of alanine racemase deficient mutants of B. pseudomallei and B. mallei decreased within 2 hours by about 1000-fold and 10-fold, respectively, and no viable bacteria were present at 24 hours. We constructed several genetic tools with bpsl2179 as a selectable genetic marker, and we used them without any antibiotic selection to construct an in-frame ?flgK mutant in the alanine racemase deficient variant of B. pseudomallei K96243. In murine peritoneal macrophages, wild type B. mallei ATCC 23344 was killed much more rapidly than wild type B. pseudomallei K96243. In addition, the alanine racemase deficient mutant of B. pseudomallei K96243 exhibited attenuation versus its isogenic parental strain with respect to growth and survival in murine peritoneal macrophages.

Zajdowicz, Sheryl L. W.; Jones-Carson, Jessica; Vazquez-Torres, Andres; Jobling, Michael G.; Gill, Ronald E.; Holmes, Randall K.



Liver mitochondrial function and redox status in an experimental model of non-alcoholic fatty liver disease induced by monosodium L-glutamate in rats.  


The purpose of this work was to determine if mitochondrial dysfunction is involved in the development of non-alcoholic fatty liver disease (NAFLD). Using a model of obesity induced by the neonatal treatment of rats with monosodium L-glutamate (MSG), several parameters of liver mitochondrial function and their impact on liver redox status were evaluated. Specifically, fatty acid ?-oxidation, oxidative phosphorylation and Ca(2+)-induced mitochondrial permeability transition were assessed in isolated liver mitochondria, and reduced glutathione (GSH), linked thiol contents and the activities of several enzymes involved in the control of redox status were measured in the liver homogenate. Our results demonstrate that liver mitochondria from MSG-obese rats exhibit a higher ?-oxidation capacity and an increased capacity for oxidising succinate, without loss in the efficiency of oxidative phosphorylation. Also, liver mitochondria from obese rats were less susceptible to the permeability transition pore (PTP) opening induced by 1.0 ?M CaCl(2). Cellular levels of GSH were unaffected in the livers from the MSG-obese rats, whereas reduced linked thiol contents were increased. The activities of glucose-6-phosphate dehydrogenase, glutathione reductase and glutathione peroxidase were increased, while catalase activity was unaffected and superoxide dismutase activity was reduced in the livers from the MSG-obese rats. In this model of obesity, liver fat accumulation is not a consequence of mitochondrial dysfunction. The enhanced glucose-6-phosphate dehydrogenase activity observed in the livers of MSG-obese rats could be associated with liver fat accumulation and likely plays a central role in the mitochondrial defence against oxidative stress. PMID:21821020

Lazarin, Murilo de Oliveira; Ishii-Iwamoto, Emy Luiza; Yamamoto, Nair Seiko; Constantin, Rodrigo Polimeni; Garcia, Rosângela Fernandes; da Costa, Cecília E Mareze; Vitoriano, Adriana de Souza; de Oliveira, Monique Cristine; Salgueiro-Pagadigorria, Clairce L



Probing alanine transaminase catalysis with hyperpolarized 13CD3-pyruvate  

NASA Astrophysics Data System (ADS)

Hyperpolarized metabolites offer a tremendous sensitivity advantage (>104 fold) when measuring flux and enzyme activity in living tissues by magnetic resonance methods. These sensitivity gains can also be applied to mechanistic studies that impose time and metabolite concentration limitations. Here we explore the use of hyperpolarization by dissolution dynamic nuclear polarization (DNP) in mechanistic studies of alanine transaminase (ALT), a well-established biomarker of liver disease and cancer that converts pyruvate to alanine using glutamate as a nitrogen donor. A specific deuterated, 13C-enriched analog of pyruvic acid, 13C3D3-pyruvic acid, is demonstrated to have advantages in terms of detection by both direct 13C observation and indirect observation through methyl protons introduced by ALT-catalyzed H-D exchange. Exchange on injecting hyperpolarized 13C3D3-pyruvate into ALT dissolved in buffered 1H2O, combined with an experimental approach to measure proton incorporation, provided information on mechanistic details of transaminase action on a 1.5 s timescale. ALT introduced, on average, 0.8 new protons into the methyl group of the alanine produced, indicating the presence of an off-pathway enamine intermediate. The opportunities for exploiting mechanism-dependent molecular signatures as well as indirect detection of hyperpolarized 13C3-pyruvate and products in imaging applications are discussed.

Barb, A. W.; Hekmatyar, S. K.; Glushka, J. N.; Prestegard, J. H.



Probing alanine transaminase catalysis with hyperpolarized 13CD3-pyruvate.  


Hyperpolarized metabolites offer a tremendous sensitivity advantage (>10(4) fold) when measuring flux and enzyme activity in living tissues by magnetic resonance methods. These sensitivity gains can also be applied to mechanistic studies that impose time and metabolite concentration limitations. Here we explore the use of hyperpolarization by dissolution dynamic nuclear polarization (DNP) in mechanistic studies of alanine transaminase (ALT), a well-established biomarker of liver disease and cancer that converts pyruvate to alanine using glutamate as a nitrogen donor. A specific deuterated, (13)C-enriched analog of pyruvic acid, (13)C3D(3)-pyruvic acid, is demonstrated to have advantages in terms of detection by both direct (13)C observation and indirect observation through methyl protons introduced by ALT-catalyzed H-D exchange. Exchange on injecting hyperpolarized (13)C3D(3)-pyruvate into ALT dissolved in buffered (1)H(2)O, combined with an experimental approach to measure proton incorporation, provided information on mechanistic details of transaminase action on a 1.5s timescale. ALT introduced, on average, 0.8 new protons into the methyl group of the alanine produced, indicating the presence of an off-pathway enamine intermediate. The opportunities for exploiting mechanism-dependent molecular signatures as well as indirect detection of hyperpolarized (13)C3-pyruvate and products in imaging applications are discussed. PMID:23357427

Barb, A W; Hekmatyar, S K; Glushka, J N; Prestegard, J H



Mechanisms of itch evoked by ?-alanine  

PubMed Central

?-alanine, a popular supplement for muscle building, induces itch and tingling after consumption, but the underlying molecular and neural mechanisms are obscure. Here we show that, in mice, ?-alanine elicited itch-associated behavior that requires MrgprD, a G protein-coupled receptor expressed by a subpopulation of primary sensory neurons. These neurons exclusively innervate the skin, respond to ?-alanine, heat and mechanical noxious stimuli but do not respond to histamine. In humans, intradermally injected ?-alanine induced itch but neither wheal nor flare suggesting that the itch was not mediated by histamine. Thus, the primary sensory neurons responsive to ?-alanine are likely part of a histamine-independent itch neural circuit and a target for treating clinical itch that is unrelieved by anti-histamines.

Liu, Qin; Sikand, Parul; Ma, Chao; Tang, Zongxiang; Han, Liang; Li, Zhe; Sun, Shuohao; LaMotte, Robert H.; Dong, Xinzhong



Use of ?-alanine as an ergogenic aid.  


Despite the large variety of so-called ergogenic supplements used by the sporting community, only few of them are effectively supported by scientific proof. One of the recent evidence-based supplements that entered the market is ?-alanine. ?-Alanine is the rate-limiting precursor for the synthesis of the dipeptide carnosine (?-alanyl-L-histidine) in human muscle. The chronic daily ingestion of ?-alanine can markedly elevate muscle carnosine content, which results in improved exercise capacity, especially in sports that include high-intensity exercise episodes. The use of ?-alanine is exponentially growing in recent years. This chapter aims to (1) discuss the scientific basis and physiological background of ?-alanine and its synthesis product carnosine, and (2) translate these scientific findings to practical applications in sports. PMID:23765354

Derave, Wim



Characterization of liver-specific structure and function during hepatocyte spheroid self-assembly: Implications for a bioartificial liver device  

NASA Astrophysics Data System (ADS)

A hollow fiber bioreactor containing collagen-entrapped hepatocytes has been developed as a bioartificial liver device. For clinical application, further scale-up of the device is desirable. This may be achieved through the use of hepatocyte spheroids, which are compacted aggregates that exhibit prolonged viability, higher liver-specific function and a more tissue-like ultrastructure compared to hepatocytes cultured as monolayers. In order to gain a better understanding of structural changes in spheroids over the course of their self-assembly, confocal microscopy was used to optically section spheroids and monitor changes in situ. Channels within spheroids hypothesized to be bile canaliculi were first evaluated by monitoring the diffusion of a fluorescent tracer, FITC-dextran, into spheroids. Three-dimensional reconstruction of spheroids showed that a continuous network of channels was forming within spheroids. Functionality of these channels as bile canaliculi was demonstrated by monitoring secretion of a fluorescently tagged bile acid, FITC-glycocholate, by hepatocytes in spheroids. Secretion of FITC-glycocholate could be seen in both rat and porcine hepatocyte spheroids. To elucidate changes in metabolism occurring during spheroid self-assembly, metabolic flux analysis was applied to hepatocyte spinner cultures. Glucose, lactate, amino acid, albumin and urea concentration in culture medium were measured and used to estimate intracellular fluxes within hepatocytes. Metabolism before and after spheroid formation was compared. Overall, little difference was seen in metabolism before and after spheroid self-assembly. As the BAL approaches clinical trials, methods of bioreactor storage for shipping and inventory purposed need to be developed. Storage conditions were tested in various hepatocyte culture systems. A protocol for storing reactors for 24 hours without significant loss in function was developed. Further optimization will be necessary for storage for longer times.

Friend, Julie Renee


The differentiation of MSCs into functional hepatocyte-like cells in a liver biomatrix scaffold and their transplantation into liver-fibrotic mice.  


Hepatocytes derived from mesenchymal stem cells (MSCs) hold great potential for cell-based therapies for liver diseases. The cell-based therapies are critically dependent on the hepatic differentiation of the MSCs with a high efficiency and on a considerable scale. Recent results have shown that decellularized organs provide a three-dimensional extracellular matrix for the lineage restriction of stem cell maturation. In this study, we compared the cell proliferation and hepatic differentiation of murine MSCs in a biomatrix scaffold from rat liver and in the presence and absence growth factors (GF) with a two-dimensional substrate. In the absence or presence of GF, the dynamic cultured scaffold (DCS) stimulated the MSCs to express endodermal and hepatocyte-specific genes and proteins associated with improved functions, and the cells exhibited the ultrastructural characteristics of mature hepatocytes. When transplanted into CCl(4)-injured mice, the cells pretreated with a combination of the DCS and GF exhibited increased survival, liver function, engraftment into the host liver and further hepatic differentiation. The paracrine effect of the transplanted cells on hepatic stellate cells and native hepatocytes played a key role in the treatment of the liver pathology. These studies define an effective method that facilitates the hepatic differentiation of MSCs exhibiting extensive functions and support further research into the use of a decellularized liver matrix as a bioscaffold for liver tissue engineering. PMID:22985996

Ji, Ru; Zhang, Ning; You, Nan; Li, Qiang; Liu, Weihui; Jiang, Nan; Liu, Jie; Zhang, Hongtao; Wang, Desheng; Tao, Kaishan; Dou, Kefeng



Alanine: then there was water.  


An ab initio study of the addition of successive water molecules to the amino acid l-alanine in both the nonionized (N) and zwitterionic (Z) forms are presented. The main focus is the number of waters needed to stabilize the Z form and how the solvent affects conformational preference. The solvent is modeled by ab initio electronic structure theory, the EFP (effective fragment potential) model, and the isotropic dielectric PCM (polarizable continuum method) bulk solvation techniques. The EFP discrete solvation model is used with a Monte Carlo algorithm to sample the configuration space to find the global minimum. Bridging structures are predicted to be the lowest energy Z minima after 3-5 discrete waters are included in the calculations, depending on the level of theory. Second-order perturbation theory and PCM stabilize the Z structures by approximately 3-6 and 7 kcal/mol, respectively, relative to the N global minimum through the addition of up to 8 waters. Subsequently, the contributions of each are approximately 1 kcal/mol relative to the N global minimum. The presence of 32 waters appears to be close to converging the N-Z enthalpy difference, DeltaH(N-Z). PMID:19485320

Mullin, Jonathan M; Gordon, Mark S



Enhanced external counterpulsation: a new technique to augment renal function in liver cirrhosis  

Microsoft Academic Search

Background. Advanced liver cirrhosis is characterized by cardiovascular changes, such as low arterial blood pressure, peripheral vasodilation and renal vasocon- striction. As a consequence, renal hypoperfusion, impaired diuresis and natriuresis and eventual hepato- renal syndrome may ensue. Previous studies using head-out water immersion to increase central blood volume have demonstrated the functional nature of the renal abnormalities. Enhanced external counter-

Dierk Werner; Peter Tragner; Andrea Wawer; Heiner Porst; Werner G. Daniel; Peter Gross



Effects of Occupational and Nonoccupational Factors on Liver Function Tests in Workers Exposed to Solvent Mixtures  

Microsoft Academic Search

A total of 368 workers from six paint-manufacturing factories participated in this study. The workers were classified according to type of exposure: direct, intermittent, and no exposure. The workers' liver-function tests were influenced greatly by gender, hepatitis B, alcohol consumption, and body mass index. Both the serum concentration and the odds of abnormality of total serum bile acids were elevated

Jong-Dar Chen; Jung-Der Wang; Song-Yen Tsai; Wen-Ing Chao



Infammation and Altered Liver Function is Present in 13 Year Olds with Features of Metabolic Syndrome  

Microsoft Academic Search

Aims: Investigation of inflammation in Australian adolescents with features similar to the metabolic syndrome. Study design, Subjects and Outcome measures: A prospective longitudinal pregnancy cohort was followed up at 13 years. 1377 children underwent anthropometric, fasting lipid, insulin, inflammatory markers, liver function tests and blood pressure measurements. Cluster analysis defined a group at risk withfeatures akin to adult metabolic syndrome.

Rae-Chi Huang; Trevor Mori; Fiona Stanley; Garth Kendall; Lyle Palmer; Wendy Oddy; Nick Sloan; Beth Hands; Lawrence Beilin



Comparison of five incubation systems for rat liver slices using functional and viability parameters.  


Precision-cut liver slices are presently used for various research objects, e.g. to study metabolism, transport, and toxicity of xenobiotics. Various incubation systems are presently employed, but a systematic comparison between these incubation systems with respect to preservation of slice function has not been performed yet. Therefore, we started a comparative study to evaluate five of these systems: the shaken flask (an Erlenmeyer in a shaking water bath), the stirred-well (24-well culture plate equipped with grids and magnetic stirrers), rocker platform (6-well culture plate with Netwell insert rocked on a platform), the roller system (dynamic organ culture rolled on an insert in a glass vial), and the 6-well shaker (6-well culture plate in a shaking water bath). The liver slices were incubated in these incubation systems for 0.5, 1.5, and 24.5 h and subsequently subjected to viability and metabolic function tests. The viability of the incubated liver slices was evaluated by: potassium content, MTT assay, energy charge, histomorphology, and LDH leakage. Their metabolic functions were studied by determination of the metabolism of lidocaine, testosterone, and antipyrine. Up to 1.5 h of incubation all five incubation systems gave similar results with respect to viability and metabolic function of the liver slices. However, after 24 h, the shaken flask, the rocker platform, and the 6-well shaker incubation systems appeared to be superior to the stirred well and the roller incubation systems. PMID:9403776

Olinga, P; Groen, K; Hof, I H; De Kanter, R; Koster, H J; Leeman, W R; Rutten, A A; Van Twillert, K; Groothuis, G M



Non-invasive assessment of choledocholithiasis in patients with gallstones and abnormal liver function  

PubMed Central

AIM: To find a non-invasive strategy for detecting choledocholithiasis before cholecystectomy, with an acceptable negative rate of endoscopic retrograde cholangiopancreatography. METHODS: All patients with symptomatic gallstones were included in the study. Patients with abnormal liver functions and common bile duct abnormalities on ultrasound were referred for endoscopic retrograde cholangiopancreatography. Patients with normal ultrasound were referred to magnetic resonance cholangiopancreatography. All those who had a negative magnetic resonance or endoscopic retrograde cholangiopancreatography underwent laparoscopic cholecystectomy with intraoperative cholangiography. RESULTS: Seventy-eight point five percent of patients had laparoscopic cholecystectomy directly with no further investigations. Twenty-one point five percent had abnormal liver function tests, of which 52.8% had normal ultrasound results. This strategy avoided unnecessary magnetic resonance cholangiopancreatography in 47.2% of patients with abnormal liver function tests with a negative endoscopic retrograde cholangiopancreatography rate of 10%. It also avoided un-necessary endoscopic retrograde cholangiopancreatography in 35.2% of patients with abnormal liver function. CONCLUSION: This strategy reduces the cost of the routine use of magnetic resonance cholangiopancreatography, in the diagnosis and treatment of common bile duct stones before laparoscopic cholecystectomy.

Al-Jiffry, Bilal O; Elfateh, Abdeen; Chundrigar, Tariq; Othman, Bassem; AlMalki, Owaid; Rayza, Fares; Niyaz, Hashem; Elmakhzangy, Hesham; Hatem, Mohammed



The Mushroom Agaricus blazei Murill Extract Normalizes Liver Function in Patients with Chronic Hepatitis B  

Microsoft Academic Search

Background: Hepatitis B is a global health problem. Use of complementary and alternative medicine has been popular among patients with hepatitis B. This 1-year open-label pilot study aims to observe whether Agar- icus blazei Murill extract improves liver function in patients with hepatitis B. Methods: This study involved 12 months of clinical observation. Four (4) patients with hepatitis B who

Chung-Hua Hsu; Kung-Chang Hwang; Yi-Hsiung Chiang; Pesus Chou



Prep1 Controls Insulin Glucoregulatory Function in Liver by Transcriptional Targeting of SHP1 Tyrosine Phosphatase  

PubMed Central

OBJECTIVE We investigated the function of the Prep1 gene in insulin-dependent glucose homeostasis in liver. RESEARCH DESIGN AND METHODS Prep1 action on insulin glucoregulatory function has been analyzed in liver of Prep1-hypomorphic mice (Prep1i/i), which express 2–3% of Prep1 mRNA. RESULTS Based on euglycemic hyperinsulinemic clamp studies and measurement of glycogen content, livers from Prep1i/i mice feature increased sensitivity to insulin. Tyrosine phosphorylation of both insulin receptor (IR) and insulin receptor substrate (IRS)1/2 was significantly enhanced in Prep1i/i livers accompanied by a specific downregulation of the SYP and SHP1 tyrosine phosphatases. Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content. Consistently, overexpression of the Prep1 partner Pbx1, but not of p160MBP, mimicked Prep1 effects on tyrosine phosphorylations, glycogen content, and on SYP and SHP1 expression. In Prep1 overexpressing cells, antisense silencing of SHP1, but not that of SYP, rescued insulin-dependent IR phosphorylation and glycogen accumulation. Both Prep1 and Pbx1 bind SHP1 promoter at a site located between nucleotides ?2,113 and ?1,778. This fragment features enhancer activity and induces luciferase function by 7-, 6-, and 30-fold, respectively, in response to Prep1, Pbx1, or both. CONCLUSIONS SHP1, a known silencer of insulin signal, is a transcriptional target of Prep1. In liver, transcriptional activation of SHP1 gene by Prep1 attenuates insulin signal transduction and reduces glucose storage.

Oriente, Francesco; Iovino, Salvatore; Cabaro, Serena; Cassese, Angela; Longobardi, Elena; Miele, Claudia; Ungaro, Paola; Formisano, Pietro; Blasi, Francesco; Beguinot, Francesco



Effects of polysaccharide ginsan from Panax ginseng on liver function  

Microsoft Academic Search

Ginsan, a polysaccharide isolated fromPanax ginseng, has been shown to be a potent immunomodulator, producing a variety of cytokines such as TNF-?, IL-1? IL-2, IL-6, IL-12,\\u000a IFN-? and GM-CSF, and stimulating lymphoid cells to proliferate. In the present study, we analyzed some immune functions 1st-5th days after ginsan i.p. injection, including the level of non-protein thiols (NPSH) as antioxidants, heme

Jie-Young Song; Medea Akhalaia; Alexander Platonov; Hyung-Doo Kim; In-Sung Jung; Young-Soo Han; Yeon-Sook Yun



Dose–effect relationship between drinking water fluoride levels and damage to liver and kidney functions in children  

Microsoft Academic Search

Although a dose–effect relationship between water fluoride levels and damage to liver and kidney functions in animals has been reported, it was not demonstrated in humans. To evaluate the effects of drinking water fluoride levels on the liver and kidney functions in children with and without dental fluorosis, we identified 210 children who were divided into seven groups with 30

XianZhi Xiong; JunLing Liu; WeiHong He; Tao Xia; Ping He; XueMin Chen; KeDi Yang; AiGuo Wang



[Disturbance of liver functions and dysbiosis in patients with lipid distress syndrome and its treatment with lactulose preparation "Duphalac" (lactulose)].  


Disturbances of liver's functions and its connection with microflora pathology of large intestine were examined in the patients with lipid dysstress-syndrome. Severe dysbiosis (reduce of light fatty acids level and increase of anaerobe index) was revealed. Efficiency of "Dufalak" (lactulose disaccharide) on liver's functions was estimated. PMID:11681193

Petukhov, V A; Karalkin, A V; Ibragimov, T I; Petukhova, N A; Briushkov, A Iu; Vashchenko, N E



Effects of degree of cell-cell contact on liver specific functions of rat primary hepatocytes  

Microsoft Academic Search

Cell-cell interaction and the extracellular matrix (ECM) are believed to play essential roles duringin vitro culturing of primary hepatocytes in the control of differentiation and in the maintenance of tissue specific functions. The\\u000a objective of this study was to examine the effects of degree of cell-cell contact (DCC) on liver specific function of rat\\u000a primary hepatocytes. Hepatocyte aggregates with various

Sung Mun Yang; Doo Hoon Lee; Jung Keug Park



New insights into family functioning and quality of life after pediatric liver transplantation.  


Thorough research of the medical aspects of pediatric liver transplantation has given way to recent interest in the impact of the transplantation process on the QOL of recipients and their families. In this cross-sectional study, we compared the family functioning and QOL of children (n = 30) aged between three and 16 yr (M = 10.10, s.d. = 3.62) who had received a liver transplant in the previous 1-12 yr (M = 5.31, s.d. = 3.44) with non-transplant children (n = 33), as reported via parent proxy. Results showed that parents of pediatric liver transplant recipients made significantly more adjustments to family routines to accommodate their children, particularly in relation to childcare. Impaired family functioning was also found to be associated with decreased QOL. These preliminary findings of relative deficits in family functioning may inform psychosocial interventions to assist pediatric liver transplant patients and their families. Further investigation beyond a single-center study incorporating subjective information from pediatric patients and their parents is recommended. PMID:22775776

Denny, Bianca; Beyerle, Kathe; Kienhuis, Mandy; Cora, Ancuta; Gavidia-Payne, Susana; Hardikar, Winita



[Effects of dehydrocholic acid (Biliton) on metabolism and liver function in cows].  


Dehydrocholic acid (Biliton) was given to 9 cows with a predisposition for the fat mobilization syndrome in daily doses of 5.5 g each. This was done two weeks after parturition and the results were compared with those from 9 untreated cows. Five other cows suffering from ketosis or indigestion symptoms were treated too. Decreased concentrations of liver lipids, free fatty acids (FFA), bilirubin, beta-OH-butyrate and urea as well as increased glucose in blood plasma indicated a favourable action of Dehydrocholic acid on metabolism and liver function. We did not observe a significant influence on milk and reproduction parameters. The use of Dehydrocholic acid is recommended for use in liver disturbances. PMID:8223242

Fürll, M



Intestinal epithelial barrier function in liver cirrhosis: an extensive review of the literature.  


Recent evidence suggests that translocation of bacteria and bacterial products, such as endotoxin from the intestinal lumen into the systemic circulation is a contributing factor in the pathogenesis of chronic liver diseases and the development of complications in cirrhosis. In addition to alterations in the intestinal microbiota and immune system, dysfunction of the intestinal epithelial barrier may be an important factor facilitating bacterial translocation. This review aims to provide an overview of the current evidence of intestinal epithelial barrier dysfunction in human chronic liver diseases and cirrhosis, and to discuss possible contributing factors and mechanisms. Data suggest the presence of intestinal epithelial barrier dysfunction in patients with chronic liver diseases, but are more convincing in patients with cirrhosis, especially in those with complications. The barrier dysfunction can result from both direct and indirect effects of aetiological factors, such as alcohol and obesity, which can cause chronic liver diseases and ultimately cirrhosis. On the other hand characteristics of cirrhosis itself, including portal hypertension, alterations in the intestinal microbiota, inflammation and oxidative stress can affect barrier function of both small and large intestine and may contribute to the development of complications. In conclusion, there are indications for intestinal epithelial barrier dysfunction in patients with chronic liver diseases and especially in patients with cirrhosis, which can be caused by various factors affecting both the small and large intestine. PMID:23879434

Pijls, Kirsten E; Jonkers, Daisy M A E; Elamin, Elhaseen E; Masclee, Ad A M; Koek, Ger H



Production of Alanine by Fusarium moniliforme  

PubMed Central

Fusarium moniliforme grown in a chemically defined medium in submerged culture accumulated amino acids extracellularly. Alanine and glutamic acid were present in greatest amounts, with traces of glycine, lysine, threonine, and valine detectable. Increasing the glucose and urea concentrations of the medium increased yields of alanine. Further increases in alanine production occurred with elevated levels of mineral salts in the medium, whereas the addition of a vitamin mixture proved to be inhibitory. Chemical changes resulting from the growth of F. moniliforme in the final fermentation medium disclosed maximal alanine production, mycelial weight, and glucose consumption after 72 hr of incubation at 28.5 C. Total soluble nitrogen, by contrast, was minimal at the same time period. The pH remained in the alkaline range throughout the fermentation.

Carito, Sebastian L.; Pisano, Michael A.



Forkhead box class O transcription factors in liver function and disease.  


The forkhead box transcription factor class O (FOXO) family represents a group of transcription factors that is required for a number of stress-related transcriptional programs including antioxidant response, gluconeogenesis, cell cycle control, apoptosis, and autophagy. The liver utilizes several FOXO-dependent pathways to adapt to its routine cycles of feeding and fasting and to respond to the stresses induced by disease. FOXO1 is a direct transcriptional regulator of gluconeogenesis, reciprocally regulated by insulin, and has profound effects on hepatic lipid metabolism. FOXO3 is required for antioxidant responses and autophagy and is altered in hepatitis C infection and fatty liver. Emerging evidence suggests dysregulation of FOXO3 in some hepatocellular carcinomas. FOXOs are notable for the extensive number of functionally significant posttranslational modifications that they undergo. Recent advances in our understanding how FOXOs are regulated are providing a more detailed picture of how specific combinations of posttranslational modifications alter both nuclear translocation as well as transcriptional specificity under different conditions. This review summarizes emerging knowledge of FOXO function in the liver, FOXO changes in liver disease, and the posttranslational modifications responsible for these effects. PMID:23855308

Tikhanovich, Irina; Cox, Josiah; Weinman, Steven A



Oat prevents obesity and abdominal fat distribution, and improves liver function in humans.  


Obesity is associated with a great diversity of diseases including non-alcoholic fatty liver disease. Our recent report suggested that oat, rich in beta-glucan, had a metabolic-regulating and liver-protecting effect in an animal model. In this study, we performed a clinical trial to further confirm the effect of oat. Subjects with BMI ?27 and aged 18-65, were randomly divided into a control (n=18) and an oat-treated (n=16) group, taking a placebo or beta glucan-containing oat cereal, respectively, for 12 weeks. Our data showed that consumption of oat reduced body weight, BMI, body fat and the waist-to-hip ratio. Profiles of hepatic function, including AST, but especially ALT, were useful resources to help in the evaluation of the liver, since both showed decrements in patients with oat consumption. Nevertheless, anatomic changes were still not observed by ultrasonic image analysis. Ingestion of oat was well tolerated and there was no adverse effect during the trial. In conclusion, consumption of oat reduced obesity, abdominal fat, and improved lipid profiles and liver functions. Taken as a daily supplement, oat could act as an adjuvant therapy for metabolic disorders. PMID:23371785

Chang, Hong-Chou; Huang, Chien-Ning; Yeh, Da-Ming; Wang, Shing-Jung; Peng, Chiung-Huei; Wang, Chau-Jong



Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma  

SciTech Connect

Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials: The subjects were 259 patients treated with PBT at University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of {>=}2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

Mizumoto, Masashi; Okumura, Toshiyuki; Hashimoto, Takayuki [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Fukuda, Kuniaki [Department of Gastroenterology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Oshiro, Yoshiko; Fukumitsu, Nobuyoshi [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Abei, Masato [Department of Gastroenterology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Kawaguchi, Atsushi [Biostatistics Center, Kurume University, Kurume-shi, Fukuoka (Japan); Hayashi, Yasutaka; Ohkawa, Ayako; Hashii, Haruko; Kanemoto, Ayae [Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Moritake, Takashi [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Tohno, Eriko [Department of Diagnostic Radiology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Tsuboi, Koji [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Sakae, Takeji [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Sakurai, Hideyuki, E-mail: [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan)



Enhanced liver functions of hepatocytes cocultured with NIH 3T3 in the alginate\\/galactosylated chitosan scaffold  

Microsoft Academic Search

Formation of primary hepatocyte spheroids in the hydrogel scaffold is a promising approach for enhancing liver-specific functions in liver tissue engineering as well as for developing bioartificial liver (BAL) devices. In the present study, a highly porous hydrogel scaffold composed of alginate (AL) and galactosylated chitosan (GC) as a synthetic extracellular matrix (ECM) for hepatocytes was fabricated with 150–200?m pore

Seog-Jin Seo; In-Yong Kim; Yun-Jaie Choi; Toshihiro Akaike; Chong-Su Cho



Liver injury in hypervitaminosis A: Evidence for activation of Kupffer cell function  

SciTech Connect

The most important and novel finding of this work was enhanced liver Kupffer cell phagocytic and metabolic function by hypervitaminosis A. An animal model of hypervitaminosis A was developed in male Sprague-Dawley rats gavaged with 250,000 I.U. retinol/kg body weight/day for 3 weeks. Presence of hypervitaminosis A was indicated by characteristic changes in the fur coat, presence of brittle bones and spontaneous fractures and a significant increase in plasma and liver concentrations of retinyl palmitate while retinol levels remained the same as in controls. Hypervitaminosis A did not cause severe liver abnormalities as reflected by normal plasma glutamate pyruvate transaminase activity and bilirubin. The main change was a marked increase in size of the fat or Vitamin A storing cells. Measurement of clearance from blood of indocyanine green and {sup 99m}Tc-disofenin indicated this hepatocyte function was normal. Kupffer cell phagocytic function was enhanced in hypervitaminosis A as determined by clearance from blood of {sup 99m}Tc-sulfur colloid. In vitro, there was also evidence that treatment with high doses of Vitamin A activated or enhanced Kupffer cell function. Kupffer cells from control and Vitamin A treated rats were isolated by enzymatic dispersion, purified by centrifugal elutriation, and placed in culture. Activation was indicated by (1) increased phagocytosis of {sup 51}Cr-labeled opsonized sheep red blood cells (2) enhanced release of superoxide anion and (3) enhanced production of tumor cytolytic factor by Kupffer cells from Vitamin A treated rats.

Sim, W.L.W.



13C-breath tests in the study of microsomal liver function.  


Conventional liver tests can be used to estimate a mixture of injury and function but none of these may be regarded as a reliable marker either to quantify functional hepatic reserve or to reflect life-threatening complications of acute and chronic liver diseases. To overcome this limit, many dynamic tests have been developed in order to evaluate the "hepatic functional mass". Among these tests we can include breath tests with 13C-labeled substrates undergoing different metabolic pathways. As concerning the evaluation of microsomal function, two main categories of breath tests have been developed based on the limiting step in the different substrates metabolism. The first group include aminopyrine, caffeine and diazepam, all substrates with a metabolism independent from hepatic blood flow and dependent almost exclusively from the enzymatic activity of different cytochromes P450. The other group is composed of substrates with flow dependent metabolism like methacetin, phenacetin, erythromycin. The aim of this review is to describe the clinical applications of microsomal liver breath tests in different hepatic diseases. PMID:15209153

Nista, E C; Fini, L; Armuzzi, A; Candelli, M; Zocco, M A; Cazzato, I A; Merra, G; Finizio, R; Miele, L; Grieco, A; Gasbarrini, G; Gasbarrini, A


A useful ELISA system for human liver-type arginase, and its utility in diagnosis of liver diseases 1 1 Abbreviations used: ELISA, enzyme-linked immunosorbent assay; HRP, horseradish peroxidase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; SDS, sodium dodecyl sulfate; SDS-PAGE, polyacrylamide gel electrophoresis in the presence of SDS  

Microsoft Academic Search

Objectives: To develop a new ELISA system for liver-type arginase using monoclonal antibodies against the enzyme, and to verify the utility of the arginase in diagnosis of hepatic disorders.Design and Methods: We have developed an enzyme-linked immunosorbent assay (ELISA), using two kinds of monoclonal antibodies (Mo6G3 and Mo9C5) for human liver-type arginase as the first and second antibodies respectively. We

Masaki Ikemoto; Shoji Tsunekawa; Masaaki Awane; Yoshihiro Fukuda; Hiroshi Murayama; Makoto Igarashi; Atsuo Nagata; Yasunari Kasai; Masayuki Totani



The metabolism of histamine in the Drosophila optic lobe involves an ommatidial pathway: ?-alanine recycles through the retina.  


Flies recycle the photoreceptor neurotransmitter histamine by conjugating it to ?-alanine to form ?-alanyl-histamine (carcinine). The conjugation is regulated by Ebony, while Tan hydrolyses carcinine, releasing histamine and ?-alanine. In Drosophila, ?-alanine synthesis occurs either from uracil or from the decarboxylation of aspartate but detailed roles for the enzymes responsible remain unclear. Immunohistochemically detected ?-alanine is present throughout the fly's entire brain, and is enhanced in the retina especially in the pseudocone, pigment and photoreceptor cells of the ommatidia. HPLC determinations reveal 10.7 ng of ?-alanine in the wild-type head, roughly five times more than histamine. When wild-type flies drink uracil their head ?-alanine increases more than after drinking l-aspartic acid, indicating the effectiveness of the uracil pathway. Mutants of black, which lack aspartate decarboxylase, cannot synthesize ?-alanine from l-aspartate but can still synthesize it efficiently from uracil. Our findings demonstrate a novel function for pigment cells, which not only screen ommatidia from stray light but also store and transport ?-alanine and carcinine. This role is consistent with a ?-alanine-dependent histamine recycling pathway occurring not only in the photoreceptor terminals in the lamina neuropile, where carcinine occurs in marginal glia, but vertically via a long pathway that involves the retina. The lamina's marginal glia are also a hub involved in the storage and/or disposal of carcinine and ?-alanine. PMID:22442379

Borycz, Janusz; Borycz, Jolanta A; Edwards, Tara N; Boulianne, Gabrielle L; Meinertzhagen, Ian A



Valproate-induced hyperammonemic encephalopathy and normal liver functions: possible synergism with topiramate.  


A patient with valproate-induced hyperammonemic encephalopathy presented with altered mental status and hyperammonemia in the context of normal liver functions. Fortunately, altered mental status and elevated plasma ammonia level normalized 1 day after discontinuation of divalproex sodium (Depakote). The case analysis suggests a possible synergistic interaction of valproic acid and topiramate with respect to the emergence of hyperammonemic encephalopathy in the context of normal liver functions. Possible mechanisms of the encephalopathy and hyperammonemia are discussed. For example, valproate has diverse metabolic effects that include regulating levels of ammonia by altering activity of the urea cycle, whose first step uses HCO3 in the synthesis of carbamoylphosphate. Topiramate's inhibition of carbonic anhydrase activity may be the basis of its possible synergy with valproate by affecting levels of HCO3. PMID:19952878

Deutsch, Stephen I; Burket, Jessica A; Rosse, Richard B


Restoration of Liver Function and Portosystemic Pressure Gradient after TIPSS and Late TIPSS Occlusion  

SciTech Connect

TIPSS (transjugular intrahepatic portosystemic shunt) may be indicated to control bleeding from esophageal and gastric varicose veins, to reduce ascites, and to treat patients with Budd-Chiari syndrome and veno-occlusive disease. Numerous measures to improve the safety and methodology of the procedure have helped to increase the technical and clinical success. Follow-up of TIPSS patients has revealed shunt stenosis to occur more often in patients with preserved liver function (Child A, Child B). In addition, the extent of liver cirrhosis is the main factor that determines prognosis in the long term. Little is known about the effects of TIPSS with respect to portosystemic hemodynamics. This report deals with a cirrhotic patient who stopped drinking 7 months prior to admission. He received TIPSS to control ascites and recurrent esophageal bleeding. Two years later remarkable hypertrophy of the left liver lobe and shunt occlusion was observed. The portosystemic pressure gradient dropped from 24 mmHg before TIPSS to 11 mmHg and remained stable after shunt occlusion. The Child's B cirrhosis prior to TIPSS turned into Child's A cirrhosis and remained stable during the follow-up period of 32 months. This indicates that liver function of TIPSS patients may recover due to hypertrophy of the remaining non-cirrhotic liver tissue. In addition the hepatic hemodynamics may return to normal. In conclusion, TIPSS cannot cure cirrhosis but its progress may be halted if the cause can be removed. This may result in a normal portosystemic gradient, leading consequently to shunt occlusion.

Maedler, U.; Hansmann, J.; Duex, M.; Noeldge, G. [Department of Diagnostic Radiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120Heidelberg (Germany); Sauer, P. [Department of Gastroenterology, University of Heidelberg, Heidelberg (Germany); Richter, G.M. [Department of Diagnostic Radiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120Heidelberg (Germany)



Functional and Structural Alterations of Liver Ergastoplasmic Membranes during DL-Ethionine Hepatocarcinogenesis  

Microsoft Academic Search

SUMMARY Different functional and structural properties of rat liver microsomes were studied during hepatocarcinogenesis in- duced by 0.25% m-ethionine. During the first to fourth months of ethionine feeding, great decreases of cytochrome P-450 content, reduced nicotinamide adenine dinucleotide phosphate-dependent lipid peroxidation, and aminopyrine demethylase activity occurred. No changes in the reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase activity were observed.

E. Gravela; F. Feo; R. A. Canuto; R. Garcea; L. Gabriel


Osteopontin as a Mediator of NKT Cell Function in T Cell-Mediated Liver Diseases  

Microsoft Academic Search

Both osteopontin (OPN) and natural killer T (NKT) cells play a role in the development of immunological disorders. We examined a functional link between OPN and NKT cells. Concanavalin A (Con A)-induced hepatitis is a well-characterized murine model of T cell-mediated liver diseases. Here, we show that NKT cells secrete OPN, which augments NKT cell activation and triggers neutrophil infiltration

Hongyan Diao; Shigeyuki Kon; Kazuya Iwabuchi; Chiemi Kimura; Junko Morimoto; Daisuke Ito; Tatsuya Segawa; Masahiro Maeda; Junji Hamuro; Toshinori Nakayama; Masaru Taniguchi; Hideo Yagita; Luc Van Kaer; Kazunori Onóe; David Denhardt; Susan Rittling; Toshimitsu Uede



Investigation on liver function among population in high background of rare earth area in South China  

Microsoft Academic Search

The health effects of long-term ingestion of rare earth elements (REEs) on the villagers living in high-REE-background areas\\u000a in South Jangxi Province, China were studied. Major health complaints from the REE area population included indigestion, diarrhea,\\u000a abdominal distension, anorexia, weakness, and fatigue, especially after high-fat or high-protein intake. Liver function tests\\u000a were conducted for adult villagers. Among them, 45 live

Weifang Zhu; Suqin Xu; Pinpin Shao; Hui Zhang; Donseng Wu; Wenjia Yang; Jia Feng; Lei Feng



Extrahepatic biliary atresia: Correlation of histopathology and liver function tests with surgical outcomes  

PubMed Central

Aims: To correlate the age at surgery, liver function tests, and hepatic and portal tract histo-pathological changes with surgical outcome in the form of disappearance of jaundice in extrahepatic biliary atresia (EHBA). Materials and Methods: This is a retrospective study of 39 cases of EHBA. There were 19 males and 10 females. Kasai's portoenterostomy (KPE) along with liver biopsy was performed in these patients; for purpose of correlation this biopsy was considered to be the preoperative biopsy. These patients were divided into three groups based upon surgical outcome: (A) disappearance of jaundice; (B) initial disappearance of jaundice with recurrence after 3 months; and (C) persistence of jaundice. Postoperatively, liver function tests and liver biopsies were repeated at 3 months after the KPE. Results: There were 11 patients in group A (28%), 21 patients in group B (54%), and seven patients in group C (18%). The age at surgery was comparable in all the three groups. The postoperative levels of serum bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGTP) showed statistically significant improvement as compared with the preoperative levels in group A and B patients. Patients belonging to group C showed no improvement in the liver functions following surgery. The preoperative hepatic histopathological changes (hepatocellular alteration, cholestasis, bile ductular proliferation, and bile duct inflammation) showed a significant difference among the three groups; patients with lesser degrees of pre-existing histopathological changes had better outcome following surgery. Fibrosis was seen in all the three groups preoperatively but the difference was not statistically significant. Group C had significant fibrosis in more than 50% patients. Additional findings, viz. ductal plate malformation (9 patients, 23%) and giant cell transformation (19 patients, 49%) did not show any correlation with surgical outcomes. Conclusions: The liver function tests and the histopathological features appeared to affect the final surgical outcome of these patients. Higher degree of cholestasis, hepatocellular alteration, bile ductule proliferation, bile duct inflammation showed definite correlation with poor surgical outcome. High grade hepatic fibrosis and portal edema showed a trend towards poor outcome but did not achieve statistical significance.

Gupta, Lucky; Gupta, Siddhartha D.; Bhatnagar, Veereshwar



Dose-response relationship between arsenic exposure and the serum enzymes for liver function tests in the individuals exposed to arsenic: a cross sectional study in Bangladesh  

PubMed Central

Background Chronic arsenic exposure has been shown to cause liver damage. However, serum hepatic enzyme activity as recognized on liver function tests (LFTs) showing a dose-response relationship with arsenic exposure has not yet been clearly documented. The aim of our study was to investigate the dose-response relationship between arsenic exposure and major serum enzyme marker activity associated with LFTs in the population living in arsenic-endemic areas in Bangladesh. Methods A total of 200 residents living in arsenic-endemic areas in Bangladesh were selected as study subjects. Arsenic concentrations in the drinking water, hair and nails were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The study subjects were stratified into quartile groups as follows, based on concentrations of arsenic in the drinking water, as well as in subjects' hair and nails: lowest, low, medium and high. The serum hepatic enzyme activities of alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) were then assayed. Results Arsenic concentrations in the subjects' hair and nails were positively correlated with arsenic levels in the drinking water. As regards the exposure-response relationship with arsenic in the drinking water, the respective activities of ALP, AST and ALT were found to be significantly increased in the high-exposure groups compared to the lowest-exposure groups before and after adjustments were made for different covariates. With internal exposure markers (arsenic in hair and nails), the ALP, AST and ALT activity profiles assumed a similar shape of dose-response relationship, with very few differences seen in the higher groups compared to the lowest group, most likely due to the temporalities of exposure metrics. Conclusions The present study demonstrated that arsenic concentrations in the drinking water were strongly correlated with arsenic concentrations in the subjects' hair and nails. Further, this study revealed a novel exposure- and dose- response relationship between arsenic exposure metrics and serum hepatic enzyme activity. Elevated serum hepatic enzyme activities in the higher exposure gradients provided new insights into arsenic-induced liver toxicity that might be helpful for the early prognosis of arsenic-induced liver diseases.



Genome-Wide Association Study of Liver Enzymes in Korean Children  

PubMed Central

Liver enzyme elevations, as an indicator of liver function, are widely associated with metabolic diseases. Genome-wide population-based association studies have identified a genetic susceptibility to liver enzyme elevations and their related traits; however, the genetic architecture in childhood remains largely unknown. We performed a genome-wide association study to identify new genetic loci for liver enzyme levels in a Korean childhood cohort (n = 484). We observed three novel loci (rs4949718, rs80311637, and rs596406) that were multiply associated with elevated levels of alanine transaminase and aspartate transaminase. Although there are some limitations, including genetic power, additional replication and functional characterization will support the clarity on the genetic contribution that the ST6GALNAC3, ADAMTS9, and CELF2 genes have in childhood liver function.

Park, Tae-Joon; Hwang, Joo-Yeon; Go, Min Jin; Lee, Hye-Ja; Jang, Han Byul; Choi, Youngshim; Kang, Jae Heon; Park, Kyung Hee; Choi, Min-Gyu; Song, Jihyun; Kim, Bong-Jo; Lee, Jong-Young



Resistive training and chromium picolinate: effects on inositols and liver and kidney functions in older adults.  


This study assessed the effects of resistive training (RT) with or without chromium picolinate (Cr-pic) supplementation on the 24-h urinary excretions of myo-inositol, D-chiro-inositol, and pinitol, as well as clinical indices of kidney and liver functions. Thirty-two nondiabetic subjects, age 62 +/- 4 y, performed RT twice weekly for 12 wk and consumed either 924 ug Cr/d as Cr-pic (n = 17) or a placebo (n = 15). Whole-body strength increased in all subjects by 20 % and urinary chromium excretion increased 47-fold in the Cr-pic group. Urinary myo-inositol, D-chiro-inositol, and pinitol were not changed with RT or influenced by Cr-pic. Serum indices of kidney and liver functions were within clinically normal ranges at baseline and the end of the study. These results suggest that RT did not influence the urinary excretions of inositols. High dose Cr-pic did not influence the urinary excretion of inositols and the selected indices of kidney and liver functions in conjunction with RT. PMID:15467101

Campbell, Wayne W; Joseph, Lyndon J O; Ostlund, Richard E; Anderson, Richard A; Farrell, Peter A; Evans, William J



Acetyl-l-carnitine and lipoic acid improve mitochondrial abnormalities and serum levels of liver enzymes in a mouse model of nonalcoholic fatty liver disease.  


Mitochondrial abnormalities are suggested to be associated with the development of nonalcoholic fatty liver. Liver mitochondrial content and function have been shown to improve in oral feeding of acetyl-l-carnitine (ALC) to rodents. Carnitine is involved in the transport of acyl-coenzyme A across the mitochondrial membrane to be used in mitochondrial ?-oxidation. We hypothesized that oral administration ALC with the antioxidant lipoic acid (ALC + LA) would benefit nonalcoholic fatty liver. To test our hypothesis, we fed Balb/C mice a standard diet (SF) or SF with ALC + LA or high-fat diet (HF) or HF with ALC + LA for 6 months. Acetyl-l-carnitine and LA were dissolved at 0.2:0.1% (wt/vol) in drinking water, and mice were allowed free access to food and water. Along with physical parameters, insulin resistance (blood glucose, insulin, glucose tolerance), liver function (alanine transaminase [ALT], aspartate transaminase [AST]), liver histology (hematoxylin and eosin), oxidative stress (malondialdehyde), and mitochondrial abnormalities (carbamoyl phosphate synthase 1 and electron microscopy) were done. Compared with SF, HF had higher body, liver, liver-to-body weight ratio, white adipose tissue, ALT, AST, liver fat, oxidative stress, and insulin resistance. Coadministration of ALC + LA to HF animals significantly improved the mitochondrial marker carbamoyl phosphate synthase 1 and the size of the mitochondria in liver. Alanine transaminase and AST levels were decreased. In a nonalcoholic fatty liver mice model, ALC + LA combination improved liver mitochondrial content, size, serum ALT, and AST without significant changes in oxidative stress, insulin resistance, and liver fat accumulation. PMID:24176233

Kathirvel, Elango; Morgan, Kengathevy; French, Samuel W; Morgan, Timothy R



Effect of glucose, independent of changes in insulin and glucagon secretion, on alanine metabolism in the conscious dog.  

PubMed Central

To study the effects of hyperglycemia on the metabolism of alanine and lactate independent of changes in plasma insulin and glucagon, glucose was infused into five 36-h-fasted dogs along with somatostatin and constant replacement amounts of both insulin and glucagon. Hepatic uptakes of alanine and lactate were calculated using the arteriovenous difference technique. [14C]Alanine was infused to measure the conversion of alanine and lactate into glucose. Hyperglycemia (delta 115 mg/dl) of 2 h duration caused the plasma alanine level to increase by over 50%. This change was caused by an increase in the inflow of alanine into plasma since the net hepatic uptake of the amino acid did not change. Taken together, the above findings indicate that glucose per se can significantly impair the fractional extraction of alanine by the liver. Hepatic extraction of lactate was also affected by hyperglycemia and had fallen to zero within 90 min of starting the glucose infusion. This fall was associated with a doubling of arterial lactate level. Conversion of [14C]-alanine and [14C]lactate into [14C]glucose was suppressed by 60 +/- 11% after 2 h of hyperglycemia, and because this fall could not be entirely accounted for by decreased lactate extraction an inhibitory effect of glucose on gluconeogenesis within the liver is suggested. These studies indicate that the plasma glucose level per se can be an important determinant of the level of alanine and lactate in plasma as well as the rate at which they are converted to glucose.

Shulman, G I; Lacy, W W; Liljenquist, J E; Keller, U; Williams, P E; Cherrington, A D



Cardiac Structural and Functional Alterations in Infants and Children with Biliary Atresia, Listed for Liver Transplantation  

PubMed Central

Background & Aims Cirrhotic liver diseases are associated with abnormalities in cardiac geometry and function in adults (cirrhotic cardiomyopathy), but rarely explored in cirrhotic infants or children. We proposed that features of cirrhotic cardiomyopathy are present in infants with cirrhosis due to biliary atresia (BA) as early as the time of evaluation for liver transplantation and will correlate with mortality and post-operative morbidity. Methods Two-dimensional echocardiography (2DE) of infants with BA (n=40, median age 8 months), listed for transplantation at the Texas Children’s Hospital from 2004 to 2010, were reviewed and compared to age- and sex-matched infants without cardiac or liver disease (controls). Length of stay and correlation with 2DE results were assessed. Results Compared to controls, children with BA had significant increases in multiple 2DE parameters, notably left ventricle (LV) wall thickness (23% increase), LV mass indexed to body surface area (51% increase) and LV shortening fraction (8% increase). Overall, features of cirrhotic cardiomyopathy were observed in most infants (29/40; 72%); 17 had hyperdynamic contractility and 24 had altered LV geometry. After liver transplantation (33), infants with abnormal 2DE results had longer stays in the intensive care unit (median 6 vs 4 days) and the hospital (21 vs 11 days), compared with infants who had normal 2DE reports. On univariate analysis, the length of hospital stay correlated with LV mass index. Conclusions Cardiomyopathy is a prevalent condition in infants with end-stage cirrhotic liver disease due to BA (>70%). This under-recognized condition likely contributes to the prolongation of post-transplant hospitalization.

Desai, Moreshwar S.; Zainuer, Shabier; Kennedy, Curtis; Kearney, Debra; Goss, John; Karpen, Saul J.



Effect of scheduled monitoring of liver function during anti-Tuberculosis treatment in a retrospective cohort in China  

PubMed Central

Background Data on effect of regular liver function monitoring during anti-TB treatment is limited in China. This study aimed to evaluate the effects of scheduled liver function monitoring on identification of asymptomatic liver damage and anti-TB treatment outcomes during anti-TB treatment. Methods A retrospective analysis was performed based on a national-level cohort study. A total of 273 patients developing liver dysfunction were divided into two groups, 111 patients who were diagnosed through scheduled liver function test within two months after initiation of anti-TB treatment formed scheduled monitoring group, others who were diagnosed due to developing symptoms formed passive detection group (n?=?162). The two groups were compared through clinical features, prognosis of liver dysfunction and impact on anti-TB treatment using propensity score weighting analysis. Results 33.3% of 273 patients did not have any clinical symptoms, including 8 with severe hepatotoxicity. 1.8% in scheduled monitoring group and 11.1% in passive detection group required hospitalization (P?=?0.004). Regarding the prognosis of liver dysfunction, most patients recovered, no death happened in scheduled monitoring group while 3 died in passive detection group. In terms of impact on anti-TB treatment, 35.1% in scheduled monitoring group and 56.8% in passive detection group changed their anti-TB treatment (P?=?0.001). Conclusions Scheduled monitoring is effective in identifying asymptomatic liver damage, reducing hospitalization rate and improving compliance of anti-TB treatment.



Examination of the liver in personnel working with liquid rocket propellant  

PubMed Central

Petersen, P., Bredahl, E., Lauritsen, O., and Laursen, T. (1970).Brit. J. industr. Med.,27, 141-146. Examination of the liver in personnel working with liquid rocket propellants. Personnel working with liquid rocket propellants were subjected to routine health examinations, including liver function tests, as the propellant, unsymmetrical dimethylhydrazine (UDMH) is potentially toxic to the liver. In 46 persons the concentrations of serum alanine aminotransferase (SGPT) were raised. Liver biopsy was performed in 26 of these men; 6 specimens were pathological (fatty degeneration), 5 were uncertain, and 15 were normal. All 6 pathological biopsies were from patients with a raised SGPT at the time of biopsy. Of the 15 persons with a normal liver biopsy, 14 had a normal SGPT, while one (who was an alcoholic) had a raised SGPT. The connection between SGPT and histology of the liver, as well as the possible causal relation between the pathological findings and exposure to UDMH, is discussed. Images

Petersen, Palle; Bredahl, Erik; Lauritsen, Ove; Laursen, Thomas



In vitro gene regulatory networks predict in vivo function of liver  

PubMed Central

Background Evolution of toxicity testing is predicated upon using in vitro cell based systems to rapidly screen and predict how a chemical might cause toxicity to an organ in vivo. However, the degree to which we can extend in vitro results to in vivo activity and possible mechanisms of action remains to be fully addressed. Results Here we use the nitroaromatic 2,4,6-trinitrotoluene (TNT) as a model chemical to compare and determine how we might extrapolate from in vitro data to in vivo effects. We found 341 transcripts differentially expressed in common among in vitro and in vivo assays in response to TNT. The major functional term corresponding to these transcripts was cell cycle. Similarly modulated common pathways were identified between in vitro and in vivo. Furthermore, we uncovered the conserved common transcriptional gene regulatory networks between in vitro and in vivo cellular liver systems that responded to TNT exposure, which mainly contain 2 subnetwork modules: PTTG1 and PIR centered networks. Interestingly, all 7 genes in the PTTG1 module were involved in cell cycle and downregulated by TNT both in vitro and in vivo. Conclusions The results of our investigation of TNT effects on gene expression in liver suggest that gene regulatory networks obtained from an in vitro system can predict in vivo function and mechanisms. Inhibiting PTTG1 and its targeted cell cyle related genes could be key machanism for TNT induced liver toxicity.



Functional hyposplenism in alcoholic liver disease: a toxic effect of alcohol?  

PubMed Central

Functional hyposplenism, seen in some patients with alcoholic liver disease, may contribute to the increased susceptibility to infections. As hyposplenism does not complicate non-alcohol related chronic liver disease, it is probably secondary to a toxic effect of alcohol. Over a two year period the case notes of 82 patients with alcoholic liver disease, whose splenic function had been assessed by the counting of pitted erythrocytes using differential interference microscopy, were reviewed to monitor mortality and the effects of hyposplenism. Thirteen patients (seven with hyposplenism) had serial measurements of pitted erythrocyte count made to assess the effect of abstinence from alcohol on splenic function. Thirty one of the 82 alcoholic patients had pitted erythrocyte counts greater than 2%. Eighteen of 82 (16%) patients died over the two years and 11 of these had been unable to stop drinking. Only one patient died of sepsis. Five patients (6%) had pitted erythrocyte counts comparable with those in splenectomised patients. In 12 of 13 patients who had abstained from alcohol for two months, the pitted erythrocyte count fell from a median of 3 to 1.3% (mean: 8.1 to 2.6%. p = 0.01). The pitted red cell count in two patients increased. One had abstained, the other had continued to drink heavily. Short term mortality in alcoholics is high, particularly if they continue to drink heavily. Only a few of these deaths are secondary to infection. Splenic function, as assessed by these methods, improves in most patients with abstinence, suggesting that the functional hyposplenism may be a result of a direct toxic effect of alcohol on the spleen.

Muller, A F; Toghill, P J



Comparison of liver function tests after hepatic lobectomy and hepatic wedge resection.  


Prior studies have suggested that changes in liver function tests may vary with the postoperative time interval and may be related to the extent of hepatic resection. This study describes characteristic profiles in parenchymal liver enzymes and other serum liver function tests over a 4-week course comparing anatomic to nonanatomic hepatic resections. The records of 48 patients undergoing successful major hepatic resection during a 3-year period were retrospectively reviewed. Of these 48 patients, 28 underwent formal anatomic resection (hepatic lobectomy), and 20 underwent nonanatomic resections (wedge resection). Routine postoperative management in lobectomy patients included drawing liver function tests and enzymes daily for the first week, then at approximately 2 and 4 weeks postoperatively. These tests included: prothrombin time (PT), partial thromboplastin time, total serum bilirubin, total protein (TP), aspartate transaminase, lactate dehydrogenase (LDH), alkaline phosphatase, albumin (A), and glucose. Patients undergoing wedge resections had these values checked less frequently, approximately 3 to 5 days, 2 weeks, and 4 weeks postoperatively. Profiles of these values were plotted over the 4-week postoperative time course for each group of patients. Patients undergoing hepatic lobectomy showed a characteristic laboratory value profile. PT elevated within 48 hours to a mean high of 16.0 seconds, then returned to normal by postoperative day 4. Partial thromboplastin time levels remained normal throughout the entire perioperative course. Total bilirubin rose slightly, to a mean high of 2.6 mg/100 cc, then returned to normal by postoperative day (POD) 14. Parenchymal liver enzymes aspartate transaminase and LDH rose abruptly to very high levels, then returned abruptly to normal (by POD 5). TP and A both fell to approximately 50 per cent of normal, gradually rising to normal by POD 14. Glucose rose to a mean high of 199 mg/100 cc within the first 5 days, then returned to normal by POD 7. Alkaline phosphatase remained normal initially, then showed a progressive rise to a high of 288 mg/100 cc on POD 14. Patients undergoing wedge resections did not show the same changes in total serum bilirubin, but showed similar trends in all other tests, although the magnitude of these changes was smaller. TP and A levels fell acutely after resection, then began a slow rise toward normal by POD 21. TP and A profiles were similar for both lobectomy patients and those undergoing wedge resection. The only tests that may have altered clinical management were the PT and total bilirubin. Patients undergoing major hepatic resection have characteristic postoperative profiles of liver enzymes and liver function tests. These laboratory profiles differ with the extent of hepatic resection. The profiles reflect changes in volume status, parenchymal liver destruction, transient hepatic insufficiency, and postoperative hepatic regeneration. However, except possibly for PT and bilirubin, the routine use of these tests is not recommended, given that the results do not alter clinical management. PMID:9585773

Pelton, J J; Hoffman, J P; Eisenberg, B L



Coffee and liver diseases  

Microsoft Academic Search

Coffee consumption is worldwide spread with few side effects. Interestingly, coffee intake has been inversely related to the serum enzyme activities gamma-glutamyltransferase, and alanine aminotransferase in studies performed in various countries. In addition, epidemiological results, taken together, indicate that coffee consumption is inversely related with hepatic cirrhosis; however, they cannot demonstrate a causative role of coffee with prevention of liver

Pablo Muriel; Jonathan Arauz



l-Alanine fermentation by an alanine racemase-deficient mutant of the dl-alanine hyperproducing bacterium Arthrobacter oxydans HAP1  

Microsoft Academic Search

Arthrobacter oxydans HAP-1 produces a large amount of dl-alanine from glucose via the reductive amination of pyruvate catalyzed by l-alanine dehydrogenase (ALD). This bacterium was found to be capable of growing on either d- or l-alanine as a sole carbon source with lower growth rates than on glucose. The effects of an alanine racemase (AR) inhibitor on the accumulation and\\/or

Shin-Ichi Hashimoto; Ryoichi Katsumata



Acute stress show great influences on liver function and the expression of hepatic genes associated with lipid metabolism in rats  

PubMed Central

Background The theory of Chinese medicine believes rage harms normal liver function, namely ’raged impairing liver' in short. The purpose of this study is to investigate the impact of acute stress on liver lipid metabolism in rats. Methods and results Comparison of liver function indicators, serum lipid level of rats under acute stress and normal rats, as well as detection of liver tissue in the SR - BI, ABCG5 and ABCG8 protein and gene expression changes. Acute stressed rats had shown a lower serum levels of albumin (P<0.01), HDL- cholesterol (P<0.01) than normal rats, with higher serum levels of globulin (P<0.01) and LDL-cholesterol (P<0.05). Acute stressed rat’s liver tissue exhibited a lower protein expression of ABCG5 (P<0.05), ABCG8 (P<0.01) and a higher level of SR-BI (P<0.05), compared with to normal rats. Furthermore, liver gene expression of ABCG5 (P<0.01) and ABCG8 (P<0.05) were lower in acute stressed rats than in normal rats, while SR-BI was higher in acute stressed rats than in normal rats (P<0.01). Conclusions Acute stress had a direct influence on rat’s liver lipid metabolism.



Effect of L-arginine supplement on liver regeneration after partial hepatectomy in rats  

PubMed Central

Background Nitric oxide (NO) has been reported to be a key mediator in hepatocyte proliferation during liver regeneration. NO is the oxidative metabolite of L-arginine, and is produced by a family of enzymes, collective termed nitric oxide synthase (NOS). Thus, administration of L-arginine might enhance liver regeneration after a hepatectomy. Another amino acid, L-glutamine, which plays an important role in catabolic states and is a crucial factor in various cellular and organ functions, is widely known to enhance liver regeneration experimentally. Thus, the present study was undertaken to evaluate the effects of an L-arginine supplement on liver regeneration, and to compared this with supplementation with L-glutamine and L-alanine (the latter as a negative control), using a rat partial hepatectomy model. Methods Before and after a 70% hepatectomy, rats received one of three amino acid solutions (L-arginine, L-glutamine, or L-alanine). The effects on liver regeneration of the administered solutions were examined by assessment of restituted liver mass, staining for proliferating cell nuclear antigen (PCNA), and total RNA and DNA content 24 and 72 hours after the operation. Results At 72 hours after the hepatectomy, the restituted liver mass, the PCNA labeling index and the DNA quantity were all significantly higher in the L-arginine and L-glutamine groups than in the control. There were no significant differences in those parameters between the L-arginine and L-glutamine groups, nor were any significant differences found between the L-alanine group and the control. Conclusion Oral supplements of L-arginine and L-glutamine enhanced liver regeneration after hepatectomy in rats, suggesting that an oral arginine supplement can clinically improve recovery after a major liver resection.



Alterations in immune function are associated with liver enzyme elevation in HIV and HCV co-infection after commencement of combination antiretroviral therapy.  


The cause of liver enzyme elevation during combination antiretroviral therapy in people with human immunodeficiency virus and hepatitis C virus co-infection is unclear. We followed 12 subjects (five with alanine transaminase elevation) for 24 weeks after combination antiretroviral therapy commencement. Immune responses against hepatitis C virus, human immunodeficiency virus and other viruses were assessed by interferon-? ELISpot. Plasma cytokines, chemokines and anti-hepatitis C virus antibody levels were measured. Those with liver enzyme elevation had higher ELISpot responses both against hepatitis C virus non-structural regions and other viral antigens, and their anti-hepatitis C virus antibody levels were consistently higher, suggesting that reconstitution of both hepatitis C virus-specific and non-hepatitis C virus-specific immune responses may be associated with liver transaminase elevation during combination antiretroviral therapy. PMID:21932111

Cameron, Barbara Anne; Emerson, Carol R; Workman, Cassy; Kelly, Mark D; Lloyd, Andrew R; Post, Jeffrey J



Effect of combination of aripiprazole with carbamazepine and fluvoxamine on liver functions in experimental animals  

PubMed Central

Objectives: Aripiprazole, a new atypical antipsychotic drug extensively metabolized by enzyme CYP3A4, is found to produce asymptomatic elevation of serum transaminase levels on long-term treatment. The present study aims to evaluate the hepatotoxic effect of aripiprazole when coprescribed with carbamazepine and fluvoxamine. Materials and Methods: The rats were subjected to chronic treatment with two different doses, therapeutic dose (TD) and maximum therapeutic dose (MTD), of aripiprazole in combination with carbamazepine and fluvoxamine. The changes in hepatic function was assessed by various biochemical liver enzyme markers like serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, histological studies, and physical parameters (liver weight, liver volume, and body weight). Results: The combination of aripiprazole with fluvoxamine at both TD and MTD showed the hepatic damage and significant elevation in serum transaminase level which is supported by histological reports. The coadministration of aripiprazole with carbamazepine leads to significant decrease in blood concentration of aripiprazole possibly due to induction of enzyme CYP3A4 resulting in loss or reduction of clinical efficacy. Conclusions: There would be an accumulation of aripiprazole when coadministered with fluvoxamine, a known inhibitor of CYP3A4, leading to hepatic damage and reduction in aripiprazole when administered along with carbamazepine. Therefore, aripiprazole with fluvoxamine and carbamazepine should be coprescribed with caution. The patients should be monitored for signs of adverse effects like hepatic damage or decreased efficacy of these drugs.

Shastry, Chakrakodi S.; Shafeeque, Aboobakar A.; Ashwathnarayana, Badavanahalli J.



Spontaneous origin from human embryonic stem cells of liver cells displaying conjoint meso-endodermal phenotype with hepatic functions  

PubMed Central

Understanding the identity of lineage-specific cells arising during manipulations of stem cells is necessary for developing their potential applications. For instance, replacement of crucial functions in organ failure by transplantation of suitable stem-cell-derived cells will be applicable to numerous disorders, but requires insights into the origin, function and fate of specific cell populations. We studied mechanisms by which the identity of differentiated cells arising from stem cells could be verified in the context of natural liver-specific stem cells and whether such differentiated cells could be effective for supporting the liver following cell therapy in a mouse model of drug-induced acute liver failure. By comparing the identity of naturally occurring fetal human liver stem cells, we found that cells arising in cultures of human embryonic stem cells (hESCs) recapitulated an early fetal stage of liver cells, which was characterized by conjoint meso-endoderm properties. Despite this fetal stage, hESC-derived cells could provide liver support with appropriate metabolic and ammonia-fixation functions, as well as cytoprotection, such that mice were rescued from acute liver failure. Therefore, spontaneous or induced differentiation of human embryonic stem cells along the hepatic endoderm will require transition through fetal-like stages. This offers opportunities to prospectively identify whether suitable cells have been generated through manipulation of stem cells for cell therapy and other applications.

Bandi, Sriram; Cheng, Kang; Joseph, Brigid; Gupta, Sanjeev



Lanthanum associated abnormal liver function tests in two patients on dialysis: a case report  

PubMed Central

Lanthanum (La) is a phosphate binder used in patients on dialysis in the UK. As it has only recently been in use, there are no long-term data about safety of this rare metal in human subjects with renal failure on renal replacement therapy. La has not been previously reported to cause any adverse reactions apart from nausea, sickness, dialysis graft occlusion and abdominal pain. We report here La induced abnormal liver function tests in a male and a female patient of 70 and 44 years old each, on peritoneal dialysis (PD) and haemodialysis (HD) respectively, the first report of such an adverse reaction to this agent.



Structural and functional aspects of the liver and liver sinusoidal cells in relation to colon carcinoma metastasis  

Microsoft Academic Search

The liver is surrounded by connective tissue, designated as Glisson's capsule. It is composed of polygonal lobules separated by connective tissue. At the periphery of the lobule, are regions that consist of bile ducts, lymphatics, nerves and branches of the hepatic artery and the portal vein. At the center of the lobule is the central vein. Hepatocytes (parenchymal cells) are

Katrien Vekemans; Filip Braet


Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.  


In the current Model for End-Stage Liver Disease allocation system, patients are at risk of suffering repeated episodes of hepatic encephalopathy (HE) while waiting for an orthotopic liver transplantation (OLT); the posttransplantation impact of these episodes has not been well explored. We evaluated the cognitive function and quality of life in a group of OLT recipients (n = 25) who had suffered from overt HE prior to their procedure (HE-PreLT group) and compared their performance to that of a similar group of patients (n = 14) without overt HE (No HE-PreLT group) as well as to controls. Patients were selected from a cohort of 280 patients who underwent OLT during this period; the presence of clinical confounders excluded many of the remaining subjects. Demographic and clinical characteristics were balanced among groups. At an average of 18 months after OLT, we administered 2 neuropsychological batteries [Psychometric Hepatic Encephalopathy Score (PHES) test battery and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]; a pyschophysiological test (critical flicker frequency); and the SF-36 quality of life score. The HE-PreLT group scored below controls in 5 of 6 cognitive domains tested by RBANS, 3 of 6 PHES subtests, as well as the critical flicker frequency test. The No HE-PreLT group scored below the controls in 1 of the 6 cognitive domains tested by RBANS. The more severe neurocognitive abnormalities seen in the HE-PreLT group did not appear to affect quality of life, as lower values than normative data were only found in 1 of the 8 SF-36 scales. In conclusion, neurocognitive abnormalities were more severe in liver transplant recipients that had suffered from overt HE prior to OLT. Prospective studies of neurocognitive function pre-OLT and post-OLT are needed to fully determine the impact of such abnormalities. PMID:19177446

Sotil, Eva U; Gottstein, Jeanne; Ayala, Edgar; Randolph, Christopher; Blei, Andres T



Failure of oxygen-free radical scavengers to improve postischemic liver function.  


Previous investigations have demonstrated reduction of postischemic organ injury with improved flow rates following administration of superoxide dismutase (SOD) and catalase (CAT) just before reperfusion. Presumably these oxygen-free radical scavengers provide protection against oxygen-free radicals produced during reoxygenation, but the site of action remains unclear. The present study was designed to determine the effect of SOD/CAT on hepatic function following global ischemia independent of flow. Livers obtained from Sprague-Dawley rats fasted 24 hours were perfused with Krebs-Henseleit buffer containing 5 mM lactate for 130 minutes. Following a 30-minute control period, livers were subjected to 55 minutes of warm, global ischemia. The control group (N = 12) was reperfused under oxygenated conditions for an additional 45 minutes. Two other groups (N = 9; N = 4) were reperfused under identical conditions with administration of 150,000 U/L or 450,000 U/L of SOD/CAT 3 minutes before reperfusion. Hepatic flow returned to normal levels following ischemia, but gluconeogenic activity and bile production remained significantly depressed. No significant recovery of gluconeogenic activity or bile production was noted when SOD/CAT was administered before reperfusion. These results demonstrate that in the absence of flow augmentation SOD/CAT do not provide protection from oxygen-free radicals following global ischemia in the isolated rat liver. This implies that previously reported reductions of postischemic reperfusion injury, where blood flow improved as well, may be due to oxygen-free radical scavenging within the vascular network resulting in enhanced organ perfusion and, therefore, improved organ function. PMID:3772996

McEnroe, C S; Pearce, F J; Ricotta, J J; Drucker, W R



Suppression of intralysosomal proteolysis aggravates structural damage and functional impairment of liver lysosomes in rats with toxic hepatitis  

SciTech Connect

This paper estimates the effect of lowering protein catabolism in the lysosomes on structural and functional properties of the latter during liver damage. For comparison, polyvinylpyrrolidone (PVP), which is inert relative to intralysosomal proteolysis, and which also accumulates largely in lysosomes of the kupffer cells of the liver, was used. The uptake of labeled bovine serum albuman (C 14-BSA) by the liver is shown and the rate of intralysosomal proteolysis is given 24 hours after administration of suramin an CCl/sub 4/ to rats. It is suggested that it is risky to use drugs which inhibit intralysosomal proteolysis in the treatment of patients with acute hepatitis.

Korolenko, T.A.; Gavrilova, N.I.; Kurysheva, N.G.; Malygin, A.E.; Pupyshev, A.B.



Health-related quality of life and family function following pediatric liver transplantation.  


This multicenter study compared health-related quality of life (HRQOL) and family function of pediatric liver transplant recipients to those of healthy children to determine if this population differed from a healthy population and to distinguish which pretransplant and posttransplant factors impact HRQOL and family function. HRQOL data from 102 patients achieving 2-year survival were collected with the Infant Toddler Quality of Life Instrument or the Child Health Questionnaire Parent Form 50 parent surveys. Family functioning was assessed with the Family Assessment Device (FAD) completed by each participant's family members. Demographic and clinical information were retrieved from the Studies of Pediatric Liver Transplant database. Recipients 5 years of age and older scored lower than a normative sample in physical health (P < 0.001), general health (P < 0.001), parental emotional impact (P < 0.001), and disruption of family activities (P < 0.001). Younger children, 2 to 5 years of age, scored lower than controls in global health (P = 0.004) and general health perceptions (P < 0.001) but did not differ in subscales measuring physical and psychosocial outcomes. Univariate analysis among the subscales identified demographic but not clinical variables as significant predictors of HRQOL. Mean scores of FAD scales were below published thresholds indicating healthy family functioning. As reported in previous studies, parents of older recipients reported higher levels of stress, although their level of family function appears normal. Significant associations were also observed between FAD scores and demographic variables, suggesting that further investigation of the impact of race, parental marital status, and socio-economic status on the patient rehabilitation process is needed. PMID:18383090

Alonso, Estella M; Neighbors, Katie; Barton, Franca B; McDiarmid, Sue V; Dunn, Stephen P; Mazariegos, George V; Landgraf, Jeanne M; Bucuvalas, John C



Exercise training improves cutaneous microvascular function in nonalcoholic fatty liver disease.  


The leading causes of mortality in nonalcoholic fatty liver disease (NAFLD) relate to cardiovascular disease (CVD). The contribution of nitric oxide (NO) to endothelial function, a surrogate of CVD risk, is currently unknown in NAFLD. We hypothesize that NO-mediated cutaneous microvessel function would be impaired in NAFLD compared with controls and that exercise would enhance microvessel function compared with conventional care. Thirteen NAFLD patients (aged 50 ± 3 yr, BMI 31 ± 1 kg/m²) and seven controls (48 ± 4 yr, 30 ± 2 kg/m²) were studied. NAFLD patients were randomized to either 16 wk of exercise or conventional care. Cutaneous microvessel function was examined using laser Doppler flowmetry combined with intradermal microdialysis of N(G)-monomethyl-l-arginine to assay the NO dilator response to local forearm heating. Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively, and cardiorespiratory fitness was assessed. Differences in NO contribution to cutaneous blood flow between NAFLD and control individuals and between interventions were analyzed using general linear modeling. NO contribution to cutaneous blood flow was similar between NAFLD and controls (P = 0.47). Cardiorespiratory fitness was greater following exercise training compared with conventional care. NO contribution to cutaneous blood flow in response to heating at 42°C was 20.4% CVCmax (95% CI = 4.4, 36.4) greater following exercise training compared with conventional care (P = 0.02). Exercise training improves cutaneous microvascular NO function in NAFLD patients. The benefit of exercise training compared with conventional care strongly supports a role for exercise in the prevention of CVD in NAFLD. PMID:23651847

Pugh, Christopher J A; Cuthbertson, Daniel J; Sprung, Victoria S; Kemp, Graham J; Richardson, Paul; Umpleby, A Margot; Green, Daniel J; Cable, N Timothy; Jones, Helen



Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver.  


Kupffer cells and liver sinusoidal endothelial cells (LSEC) clear portal venous blood from gut-derived bacterial degradation products such as lipopolysaccharide (LPS) without inducing a local inflammatory reaction. LPS tolerance was reported for Kupffer cells, but little is known whether sensitivity of LSEC toward LPS is dynamically regulated. Here, we demonstrate that LSEC react to LPS directly as a function of constitutive Toll-like receptor 4 (TLR4)/CD14 expression but gain a LPS-refractory state upon repetitive stimulation without loss of scavenger activity. LPS tolerance in LSEC is characterized by reduced nuclear localization of nuclear factor-kappaB upon LPS rechallenge. In contrast to monocytes, however, TLR4 surface expression of LSEC is not altered by LPS stimulation and thus does not account for LPS tolerance. Mechanistically, LPS tolerance in LSEC is linked to prostanoid production and may account for cross-tolerance of LPS-treated LSEC to interferon-gamma stimulation. Functionally, LPS tolerance in LSEC results in reduced leukocyte adhesion following LPS rechallenge as a consequence of decreased CD54 surface expression. Furthermore, LPS tolerance is operative in vivo, as we observed by intravital microscopy-reduced leukocyte adhesion to LSEC and improved sinusoidal microcirculation in the liver after repetitive LPS challenges. Our results support the notion that LPS tolerance in organ-resident scavenger LSEC contributes to local hepatic control of inflammation. PMID:15860798

Uhrig, Anja; Banafsche, Ramin; Kremer, Michael; Hegenbarth, Silke; Hamann, Alf; Neurath, Markus; Gerken, Guido; Limmer, Andreas; Knolle, Percy A



Mechanochemical manipulation of hepatocyte aggregation can selectively induce or repress liver-specific function.  


Controlled activation of hepatocyte aggregation is critical to three-dimensional (3D) multicellular morphogenesis during native regeneration of liver as well as tissue reconstruction therapies. In this work, we quantify the stimulatory effects of two model hepatotrophic activators, epidermal growth factor (EGF) and hepatocyte growth factor (HGF), on the aggregation kinetics and liver-specific function of hepatocytes cultured on organotypic substrates with differing mechanical resistivity. Substrate-specific morphogenesis of cultured hepatocytes is induced on a tissue basement membrane extract, Matrigel, formulated at two distinct levels of mechanical compliance (storage modulus G', at oscillatory shear rate 1 rad/s, was 34 Pa for basal Matrigel and 118 Pa for crosslinked Matrigel). Overall, we report that growth factor stimulation selectively promotes the kinetics of aggregation in the form of two-dimensional corded aggregates on basal Matrigel and three-dimensional spheroidal aggregates on crosslinked Matrigel. Our analysis also indicates that costimulation with EGF and HGF (20 ng/mL each) cooperatively maximizes the kinetics of aggregation in a substrate-specific manner. In addition, we show that the role of growth factor stimulation on hepatocyte function is sensitively governed by the mechanical compliance of the substrate. In particular, on matrices with high compliance, costimulatory aggregation is shown to elicit a marked increase in albumin secretion rate, whereas on matrices with low compliance aggregation results in effective functional repression to basal, unstimulated levels. Thus, our studies highlight a novel interplay of physicochemical parameters of the culture microenvironment, leading to selective enhancement or repression of differentiated functions of hepatocytes, in concert with the activation of cellular morphogenesis. PMID:10862674

Semler, E J; Ranucci, C S; Moghe, P V



The Influence of histamine H1-receptor on liver functions in immunized rabbits  

PubMed Central

This study was designed to investigate the functional roles of histamine and histamine H1-receptor agonist and antagonist in the development of liver function impairment in immunized rabbits. The study comprised of six groups containing 18 rabbits each. Group III–VI received histamine (100 ?g/kg, s.c.), H1R-agonist (HTMT, 10 ?g/kg, s.c.), H1R-antagonist (pheniramine, 10 mg/kg, i.m.), and H1R-antagonist (pheniramine, 10 mg/kg, i.m.) plus histamine (100 ?g/kg, s.c.), respectively, b.i.d. for 10 days. Group I (negative control) and group II (positive control) received sterile distilled water intramuscularly b.i.d. for 10 days. Groups II–VI were immunized on day 3 with intravenous injection of SRBC (1 × 109 cells/ml). Blood samples were collected on pre-immunization day 0, as well as on days 7-, 14-, 21-, 28-, and 58-post-immunization. Biochemical parameters AST, ALT, alkaline phosphatase and bilirubin [total bilirubin (TB), direct bilirubin (DB), and indirect bilirubin (IB)] were determined. On each experimental day, the mean values of serum enzymes and bilirubin in group I and group II showed no significant changes while in group III, IV, V, and VI, these enzymes and bilirubin levels showed significant changes (p < 0.05), when compared with their experimental values within the group. The levels of serum enzymes and bilirubin showed significant difference (p < 0.05) in group III, IV, V, and VI on each experimental day, when compared with the corresponding values of each other, and also compared with the corresponding values of group I and II. Histamine, HTMT, pheniramine, and combination of histamine + pheniramine cause hepatic function impairment in terms of altered serum enzymes and bilirubin levels. The present findings suggest that HTMT causes moderate liver function impairment while others show mild impairment.

Tripathi, Trivendra; Shahid, Mohammad; Khan, Haris M.; Khan, Rahat Ali; Siddiqui, Mashiatullah; Mahdi, Abbas Ali



Beneficial effects of ventromedial hypothalamus (VMH) lesioning on function and morphology of the liver after hepatectomy in rats.  


Liver has a high regenerative capacity and restores its mass and function shortly after partial hepatectomy through increased proliferation and metabolic modification of hepatocytes. The proliferation of hepatocytes can be triggered by its mass reduction after hepatectomy or by the neural factors including lesioning of the ventromedial hypothalamus (VMH). In the present study, we examined the effect of VMH lesioning on liver regeneration in hepatectomized rats by evaluating liver function and morphology. We found that functional deficits caused by partial hepatectomy [prolonged prothrombin time (PT), increased indocyanine green (ICG) retention, and decrease in PAS (periodic Acid-Schiff staining)-positive hepatocytes] were restored by VMH lesioning at 1 week after the surgery, whereas these alterations disappeared at 4 weeks. Morphologically, lipid microdroplets, which are considered to be important for maintaining contiguous liver function via supplying fuel for cell proliferation, were found to accumulate in hepatocytes of the hepatectomized rats at early period (1 day) after partial hepatectomy. Interestingly, such lipid microdroplets were also detected in the VMH lesioned rats and the more abundantly in the VMH lesioned, hepatectomized rats up to 1 week after the surgery. In conclusion, our results suggest that VMH lesioning in rats promotes recovery of liver anatomically and functionally after partial hepatectomy by promoting cell proliferation process. PMID:21962532

Lee, Eun Young; Inoue, Shuji; Senoo, Akira; Shimizu, Hiroyuki; Suzuki, Yoko; Ishizuka, Noriko; Imazeki, Nobuo; Sasaki, Kahoru; Kako, Masako; Osaka, Toshimasa; Miki, Takashi



Novel immortalized human fetal liver cell line, cBAL111, has the potential to differentiate into functional hepatocytes  

Microsoft Academic Search

BACKGROUND: A clonal cell line that combines both stable hepatic function and proliferation capacity is desirable for in vitro applications that depend on hepatic function, such as pharmacological or toxicological assays and bioartificial liver systems. Here we describe the generation and characterization of a clonal human cell line for in vitro hepatocyte applications. RESULTS: Cell clones derived from human fetal

Tanja Deurholt; Niek P van Til; Aniska A Chhatta; Lysbeth ten Bloemendaal; Ruth Schwartlander; Catherine Payne; John N Plevris; Igor M Sauer; Robert AFM Chamuleau; R. P. J. Oude Elferink; Jurgen Seppen; Ruurdtje Hoekstra



Engineering nitrogen use efficiency with alanine aminotransferase  

Microsoft Academic Search

Nitrogen (N) is the most important factor limiting crop productivity worldwide. The ability of plants to acquire N from applied fertilizers is one of the critical steps limiting the efficient use of nitrogen. To improve N use efficiency, genetically modified plants that overexpress alanine aminotransferase (AlaAT) were engineered by introducing a barley AlaAT cDNA driven by a canola root specific

Allen G. Good; Susan J. Johnson; Mary De Pauw; Rebecka T. Carroll; Nic Savidov; John Vidmar; Zhongjin Lu; Gregory Taylor; Virginia Stroeher



TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBP? function.  


Dysregulation of Wnt signaling is closely associated with human liver tumorigenesis. However, liver cancer-specific Wnt transcriptional programs and downstream effectors remain poorly understood. Here, we identify tribbles homolog 2 (TRIB2) as a direct target of Wnt/TCF in liver cancer and demonstrate that transcription of Wnt target genes, including TRIB2, is coordinated by the TCF and FoxA transcription factors in liver cancer cells. We show that Wnt-TRIB2 activation is critical for cancer cell survival and transformation. Mechanistically, TRIB2 promotes protein stabilization of the YAP transcription coactivator through interaction with the ?TrCP ubiquitin ligase. Furthermore, we find that TRIB2 relieves the liver tumor suppressor protein C/EBP?-mediated inhibition of YAP/TEAD transcriptional activation in liver cancer cells. Altogether, our study uncovers a regulatory mechanism underlying liver cancer-specific Wnt transcriptional output, and suggests that TRIB2 functions as a signaling nexus to integrate the Wnt/?-catenin, Hippo/YAP, and C/EBP? pathways in cancer cells. PMID:23769673

Wang, Jiayi; Park, Joo-Seop; Wei, Yingying; Rajurkar, Mihir; Cotton, Jennifer L; Fan, Qishi; Lewis, Brian C; Ji, Hongkai; Mao, Junhao



Imaging of normal lung, liver and parotid gland function for radiotherapy.  


There is growing clinical evidence that functional imaging is useful for target volume definition and early assessment of tumour response to external beam radiotherapy. A subject that has perhaps received less attention, but is no less promising, is the application of functional imaging to the prediction or measurement of radiation adverse effects in normal tissues. In this manuscript, we review the current published literature describing the use of positron emission tomography (PET), four-dimensional computed tomography (4D-CT), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) to study normal tissue function in the context of radiotherapy to the lung, liver and head & neck. Published results to date demonstrate that functional imaging can be used to preferentially avoid normal tissues not easily identifiable on solely anatomical images. It is also a potentially very powerful tool for the early detection of radiotherapy-induced normal tissue adverse effects and could provide valuable data for building predictive models of outcome. However, one of the major challenges to building useful predictive models is that, to date, there are very little data available with combined images of normal function, 3D delivered radiation dose and clinical outcomes. Prospective data collection through well-constructed studies which use established morbidity scores is clearly a priority if significant progress is to be made in this area. PMID:20831488

Partridge, Mike; Yamamoto, Tokihiro; Grau, Cai; Høyer, Morten; Muren, Ludvig Paul



Association between the catechol-O-methyltransferase (rs4680: Val158Met) polymorphism and serum alanine aminotransferase activity.  


In our previous proteomic study in rat liver damaged by carbon tetrachloride, soluble catechol-O-methyltransferase (COMT) increased as a phosphorylated form and decreased as a dephosphorylated form. This finding raised the possibility that the COMT protein is associated with liver function. Thus, we hypothesized that (1) the COMT gene contributes to liver homeostasis and (2) a COMT polymorphism (rs4680: Val158Met) causing thermolability of enzymatic activity affects liver enzymes (e.g., aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (?-GT)) in serum. To investigate (2), we statistically analyzed the association between COMT genotypes and serum ALT activity in a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We conducted a multiple logistic regression analysis for males (n=838) and females (n=970). Those participants having missing values or a past history of liver cirrhosis or liver cancer were excluded. ALT values were divided into two; elevated (30IU/L ?; males n=239, females n=90) and normal (<30IU/L; males n=599, females n=880). In females, non-adjusted and adjusted odds ratios for ALT values in the rs4680 A/A homozygote (n=126) compared with the wild-type G/G homozygote (n=397) were 0.37 (95% CI 0.14-0.96) and 0.34 (95% CI 0.13-0.93), respectively. In males, an analysis of the population aged 35-69 did not reveal any significant difference, but the population aged 45-54 had a significant difference in the non-adjusted and adjusted odds ratio in the G/A heterozygote (n=89) (0.50 (95% CI 0.27-0.92) and 0.35 (95% CI 0.18-0.71)) and in the A/A homozygote (n=22) (0.34 (95% CI 0.11-0.99) and 0.22 (95% CI 0.07-0.72)), compared with the G/G homozygote (n=88). These data suggest that the COMT polymorphism affects serum ALT activity to maintain liver function. PMID:22293393

Hiyoshi, Mineyoshi; Uemura, Hirokazu; Arisawa, Kokichi; Nakamoto, Mariko; Hishida, Asahi; Okada, Rieko; Matsuo, Keitaro; Kita, Yoshikuni; Niimura, Hideshi; Kuriyama, Nagato; Nanri, Hinako; Ohnaka, Keizo; Suzuki, Sadao; Mikami, Haruo; Kubo, Michiaki; Tanaka, Hideo; Hamajima, Nobuyuki



Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds  

PubMed Central

Background Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals. Methodology/Principal Findings Sprague-Dawley female rats were exposed via gavage to one of five concentrations of one of five nitrotoluenes [2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2ADNT) 4-amino-2,6-dinitrotoulene (4ADNT), 2,4-dinitrotoluene (2,4DNT) and 2,6-dinitrotoluene (2,6DNT)] with necropsy and tissue collection at 24 or 48 h. Gene expression profile results correlated well with clinical data and liver histopathology that lead to the concept that hematotoxicity was followed by hepatotoxicity. Overall, 2,4DNT, 2,6DNT and TNT had stronger effects than 2ADNT and 4ADNT. Common functional terms, gene expression patterns, pathways and networks were regulated across all nitrotoluenes. These pathways included NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signaling, LPS/IL-1 mediated inhibition of RXR function, xenobiotic metabolism signaling and metabolism of xenobiotics by cytochrome P450. One biological process common to all compounds, lipid metabolism, was found to be impacted both at the transcriptional and lipid production level. Conclusions/Significance A systems biology strategy was used to identify biochemical pathways affected by five nitroaromatic compounds and to integrate data that tie biochemical alterations to pathological changes. An integrative graphical network model was constructed by combining genomic, gene pathway, lipidomic, and physiological endpoint results to better understand mechanisms of liver toxicity and physiological endpoints affected by these compounds.

Deng, Youping; Meyer, Sharon A.; Guan, Xin; Escalon, Barbara Lynn; Ai, Junmei; Wilbanks, Mitchell S.; Welti, Ruth; Garcia-Reyero, Natalia; Perkins, Edward J.



Comparative effects of oyster mushrooms on lipid profile, liver and kidney function in hypercholesterolemic rats.  


Comparative effects of oyster mushrooms on plasma and fecal lipid profiles and on liver and kidney function were evaluated in hyper and normocholesterolemic rats. Feeding of hypercholesterolemic rats a 5% powder of oyster mushrooms (Pleurotus ostreatus, P. sajor-caju and P. florida) reduced the plasma total cholesterol level by 37%, 21% and 16%, respectively and reduced the triglyceride level by 45%, 24% and 14%, respectively. LDL/HDL ratio decreased by 64%, 45% and 41% for P. sajor-caju, P. ostreatus and P. florida fed rats, respectively. Mushroom feeding also reduced body weight in hypercholesterolemic rats. However, it had no adverse effect on plasma bilirubin, creatinin and urea nitrogen level. Mushroom feeding also increased the total lipid and cholesterol excretion in the feces. The present study reveals that feeding of 5% oyster mushroom powder does not have detrimental effects on the liver and kidneys rather may provide health benefits for the cardiovascular-related complication by decreasing the atherogenic lipid profiles. PMID:23983505

Alam, Nuhu; Amin, Ruhul; Khan, Asaduzzaman; Ara, Ismot; Shim, Mi Ja; Lee, Min Woong; Lee, U Youn; Lee, Tae Soo



Liver in systemic disease  

PubMed Central

Potential causes of abnormal liver function tests include viral hepatitis, alcohol intake, nonalcoholic fatty liver disease, autoimmune liver diseases, hereditary diseases, hepatobiliary malignancies or infection, gallstones and drug-induced liver injury. Moreover, the liver may be involved in systemic diseases that mainly affect other organs. Therefore, in patients without etiology of liver injury by screening serology and diagnostic imaging, but who have systemic diseases, the abnormal liver function test results might be caused by the systemic disease. In most of these patients, the systemic disease should be treated primarily. However, some patients with systemic disease and severe liver injury or fulminant hepatic failure require intensive treatments of the liver.

Shimizu, Yukihiro



Keratinocyte serum-free medium maintains long-term liver gene expression and function in cultured rat hepatocytes by preventing the loss of liver-enriched transcription factors  

PubMed Central

Freshly isolated hepatocytes rapidly lose their differentiated properties when placed in culture. Therefore, production of a simple culture system for maintaining the phenotype of hepatocytes in culture would greatly facilitate their study. Our aim was to identify conditions that could maintain the differentiated properties of hepatocytes for up to 28 days of culture. Adult rat hepatocytes were isolated and attached in Williams’ medium E containing 10% serum. The medium was changed to either fresh Williams’ medium E or keratinocyte serum-free medium supplemented with dexamethasone, epidermal growth factor and pituitary gland extract. The hepatic phenotype was then analysed using RT-PCR, immunohistochemistry, Western blotting and assays of liver function. Cells cultured in keratinocyte serum-free medium supplemented with dexamethasone, epidermal growth factor and pituitary gland extract maintained their phenotype for 3–4 weeks, based on expression of liver proteins, ureagensis and response to xenobiotics. In contrast, hepatocytes cultured in Williams’ medium E rapidly lost the expression of liver proteins after 3 days. Cells cultured in keratinocyte serum-free medium supplemented with dexamethasone, epidermal growth factor and pituitary gland extract maintained their expression of liver-enriched transcription factors (C/EBP? and ?, HNF4? and RXR?) while expression was either lost or reduced in cells cultured in Williams’ medium E. These results suggest that keratinocyte serum-free medium supplemented with dexamethasone, epidermal growth factor and pituitary gland extract can maintain the hepatic phenotype for a prolonged period and that this is probably related to the continued expression of the liver-enriched transcription factors.

Li, Wan-Chun; Ralphs, Kate L.; Slack, Jonathan M.W.; Tosh, David



Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review  

PubMed Central

This review provides a detailed overview of the current state of knowledge about the ultrastructure and dynamics of liver sinusoidal endothelial fenestrae. Various aspects of liver sinusoidal endothelial fenestrae regarding their structure, origin, species specificity, dynamics and formation will be explored. In addition, the role of liver sinusoidal endothelial fenestrae in relation to lipoprotein metabolism, fibrosis and cancer will be approached.

Braet, Filip; Wisse, Eddie



Effect of flow on the detoxification function of rat hepatocytes in a bioartificial liver reactor.  


Ethoxyresorufin-o-deethylation (EROD) can be used as a sensitive measure of hepatic detoxification function. In this study, we employed a fluorescence assay based on EROD to study the effect of varying Peclet number (or flow) on hepatic function in a microchannel flat-plate bioartificial liver (BAL) reactor containing a coculture of hepatocytes and fibroblasts. Static culture and reactor flow experiments established that: 1) a pseudo-steady-state detoxification rate could be attained at each Peclet number, 2) the steady-state detoxification rate increased nonlinearly with Peclet number (ranging from 167 to 2500), 3) the uptake rate of substrate was a linear function of cell surface substrate concentration (<1 microM), and 4) a shear stress of 10 dyne/cm2 did not adversely affect hepatic function for at least 12 h. A convection-diffusion-reaction model supports the conclusion that increased convective mass transfer of substrate to the cell surface is the primary cause of the observed increase in EROD rate with Peclet number. Our results suggest that detoxification rates can be enhanced by an order of magnitude by choosing an appropriate Peclet number. For our bioreactor configuration, this optimum corresponds to a Peclet number range of 1000-2000 at a Damkohler number of 0.55. The usefulness of the mathematical model is discussed in the context of scale-up to a clinical BAL reactor for human application. PMID:11714195

Roy, P; Washizu, J; Tilles, A W; Yarmush, M L; Toner, M



The major allele of the alanine:glyoxylate aminotransferase gene: Nine novel mutations and polymorphisms associated with primary hyperoxaluria type 1  

Microsoft Academic Search

We describe nine novel mutations and polymorphisms occurring on the major allele of the human alanine:glyoxylate aminotransferase gene in patients with primary hyperoxaluria type 1, an autosomal recessive disease resulting from a deficiency of the liver peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT; EC The PH1 mutations include two small frameshift mutations, 327delG and 117_118insCA, a large deletion spanning exon 9

Marion B. Coulter-Mackie; Qun Lian; Derek Applegarth; Jennifer Toone



A paper-based multiplexed transaminase test for low-cost, point-of-care liver function testing  

PubMed Central

In developed nations, monitoring for drug-induced liver injury via serial measurements of serum transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) in at-risk individuals is the standard of care. Despite the need, monitoring for drug-related hepatotoxicity in resource-limited settings is often limited by expense and logistics, even for patients at highest risk. This manuscript describes the development and clinical testing of a paper-based, multiplexed microfluidic assay designed for rapid, semi-quantitative measurement of AST and ALT in a fingerstick specimen. Using 223 clinical specimens obtained by venipuncture and 10 fingerstick specimens from healthy volunteers, we have shown that our assay can, in 15 minutes, provide visual measurements of AST and ALT in whole blood or serum which allow the user to place those values into one of three readout “bins” (<3x upper limit of normal (ULN), 3-5x ULN, and >5x ULN, corresponding to tuberculosis/HIV treatment guidelines) with >90% accuracy. These data suggest that the ultimate point-of-care fingerstick device will have high impact on patient care in low-resource settings.

Pollock, Nira R.; Rolland, Jason P.; Kumar, Shailendra; Beattie, Patrick D.; Jain, Sidhartha; Noubary, Farzad; Wong, Vicki L.; Pohlmann, Rebecca A.; Ryan, Una S.; Whitesides, George M.



A molecular dynamics study of the dielectric properties of aqueous solutions of alanine and alanine dipeptide  

NASA Astrophysics Data System (ADS)

Molecular dynamics simulations were used to compute the frequency-dependent dielectric susceptibility of aqueous solutions of alanine and alanine dipeptide. We studied four alanine solutions, ranging in concentration from 0.13-0.55 mol/liter, and two solutions of alanine dipeptide (0.13 and 0.27 mol/liter). In accord with experiment we find a strong dielectric increment for both solutes, whose molecular origin is shown to be the zwitterionic nature of the solutes. The dynamic properties were analyzed based on a dielectric component analysis into solute, a first hydration shell, and all remaining (bulk) waters. The results of this three component decomposition were interpreted directly, as well as by uniting the solute and hydration shell component to a ``suprasolute'' component. In both approaches three contributions to the frequency-dependent dielectric properties can be discerned. The quantitatively largest and fastest component arises from bulk water [i.e., water not influenced by the solute(s)]. The interaction between waters surrounding the solute(s) (the hydration shell) and bulk water molecules leads to a relaxation process occurring on an intermediate time scale. The slowest relaxation process originates from the solute(s) and the interaction of the solute(s) with the first hydration shell and bulk water. The primary importance of the hydration shell is the exchange of shell and bulk waters; the self-contribution from bound water molecules is comparatively small. While in the alanine solutions the solute-water cross-terms are more important than the solute self-term, the solute contribution is larger in the dipeptide solutions. In the latter systems a much clearer separation of time scales between water and alanine dipeptide related properties is observed. The similarities and differences of the dielectric properties of the amino acid/peptide solutions studied in this work and of solutions of mono- and disaccharides and of the protein ubiquitin are discussed.

Boresch, Stefan; Willensdorfer, Martin; Steinhauser, Othmar



Functional ultrasound imaging for assessment of extracellular matrix scaffolds used for liver organoid formation.  


A method of 3D functional ultrasound imaging has been developed to enable non-destructive assessment of extracellular matrix scaffolds that have been prepared by decellularization protocols and are intended for recellularization to create organoids. A major challenge in organ decellularization is retaining patent micro-vascular structures crucial for nutrient access and functionality of organoids. The imaging method described here provides statistical distributions of flow rates throughout the tissue volumes, 3D vessel network architecture visualization, characterization of microvessel volumes and sizes, and delineation of matrix from vascular circuits. The imaging protocol was tested on matrix scaffolds that are tissue-specific, but not species-specific, matrix extracts, prepared by a process that preserved >98% of the collagens, collagen-associated matrix components, and matrix-bound growth factors and cytokines. Image-derived data are discussed with respect to assessment of scaffolds followed by proof-of-concept studies in organoid establishment using Hep3B, a human hepatoblast-like cell line. Histology showed that the cells attached to scaffolds with patent vasculature within minutes, achieved engraftment at near 100%, expressed liver-specific functions within 24 h, and yielded evidence of proliferation and increasing differentiation of cells throughout the two weeks of culture studies. This imaging method should prove valuable in analyses of such matrix scaffolds. PMID:24011714

Gessner, Ryan C; Hanson, Ariel D; Feingold, Steven; Cashion, Avery T; Corcimaru, Ana; Wu, Bryant T; Mullins, Christopher R; Aylward, Stephen R; Reid, Lola M; Dayton, Paul A



Abundant stage-dependent Ly49E expression by liver NK cells is not essential for their differentiation and function.  


The NKR Ly49E has several unique characteristics. Unlike most NKRs, Ly49E is highly expressed on fetal NK cells, whereas expression is decreased on bone marrow-derived NK cells in adult mice. To investigate a possible role for Ly49E in NK cell differentiation and function, we have generated an Ly49E KO mouse. Our results show that bone marrow and splenic NK cells are present in normal numbers in Ly49E KO mice, expressing an unaltered panel of NKRs and differentiation markers. Furthermore, cytokine production and cytotoxicity by these cells are unaffected. Surprisingly, WT DX5(-) liver NK cells express high Ly49E levels in fetal and adult mice. Ly49E(+)DX5(-) liver NK cells transferred into Rag-2(-/-)/gc(-/-) mice maintain high Ly49E expression in the liver and differentiate into DX5(+) NK cells in spleen and bone marrow. Ly49E expression is not crucial for liver NK cell differentiation during ontogeny, as the DX5(-)/DX5(+) ratio, the NKR repertoire, and the granzyme B and TRAIL levels are comparable in Ly49E KO versus WT mice, except for lower TRAIL expression on DX5(-) liver NK cells in 20-day-old mice. The TRAIL-, perforin-, and FasL-mediated cytolysis by liver NK cells is unaffected in Ly49E KO mice. Collectively, we show that in addition to high Ly49E expression on fetal NK cells versus low Ly49E expression on conventional NK cells in adult life, Ly49E remains highly expressed on DX5(-) liver NK cells. However, Ly49E expression does not have a crucial role in differentiation and/or function of these NK cells. PMID:23475576

Filtjens, Jessica; Taveirne, Sylvie; Van Acker, Aline; Van Ammel, Els; Vanhees, Mandy; Kerre, Tessa; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; Leclercq, Georges



Should We Look for Celiac Disease among all Patients with Liver Function Test Abnormalities?  

PubMed Central

Background: Celiac disease (CD) has been found in up to 10% of the patients presenting with unexplained abnormal liver function tests (LFT). As there is no precise data from our country in this regard, we investigated the prevalence of CD in patients presenting with abnormal LFT. Methods: From 2003 to 2008, we measured IgA anti-tissue transglutaminase (t-TG) antibody (with ELISA technique) within the first-level screening steps for all patients presenting with abnormal LFT to three outpatient gastroenterology clinics in Isfahan, IRAN. All subjects with an IgA anti-tTG antibody value of >10 ?/ml (seropositive) were undergone upper gastrointestinal endoscopy and duodenal biopsy. Histopathological changes were assessed according to the Marsh classification. CD was defined as being seropositive with Marsh I or above in histopathology and having a good response to gluten free diet (GFD). Results: During the study, 224 patients were evaluated, out of which, 10 patients (4.4%) were seropositive for CD. Duodenal biopsies were performed in eight patients and revealed six (2.7%) cases of Marsh I or above (four Marsh IIIA, two Marsh I), all of them had good response to GFD. The overall prevalence of CD among patients with hypertransaminasemia, autoimmune hepatitis, and cryptogenic cirrhosis was determined as 10.7% (3/28), 3.4% (2/59), and 5.3% (1/19), respectively. Conclusion: Serological screening with IgA anti-tTG antibody test should be routinely performed in patients presenting with abnormal LFT and especially those with chronic liver diseases including hypertransaminasemia, autoimmune hepatitis, and cryptogenic cirrhosis.

Emami, Mohammad Hassan; Hashemi, Marzieh; Kouhestani, Soheila; Taheri, Hajar; Karimi, Somayeh



13C-Phenylalanine and 13C-Methacetin breath test to evaluate functional capacity of hepatocyte in chronic liver disease  

Microsoft Academic Search

Background. To grade liver damage, Child-Pugh classification is used but these tests do not reflect the quantitative functional hepatic reserve.Aims.13C-Phenylalanine Breath Test and 13C-Methacetin Breath Test are evaluated as possible tools, being both safe and easy to perform, to quantify functional hepatic reserve in chronic liver disease patients.Patients. Both tests were performed in 48 healthy volunteers and 48 chronic liver

S. Lara Baruque; M. Razquin; I. Jimenez; A. Vazquez; J. P. Gisbert; J. M. Pajares




EPA Science Inventory

Specimens of mullet (Mugil cephalus), a marine fish, were given single doses of 3-methylcholanthrene intraperitoneally and the activity of the microsomal mixed-function oxygenase system in the liver was measured by the metabolism of benzo(a)-pyrene. The enzyme system was found to...


Novel immortalized human fetal liver cell line, cBAL111, has the potential to differentiate into functional hepatocytes  

PubMed Central

Background A clonal cell line that combines both stable hepatic function and proliferation capacity is desirable for in vitro applications that depend on hepatic function, such as pharmacological or toxicological assays and bioartificial liver systems. Here we describe the generation and characterization of a clonal human cell line for in vitro hepatocyte applications. Results Cell clones derived from human fetal liver cells were immortalized by over-expression of telomerase reverse transcriptase. The resulting cell line, cBAL111, displayed hepatic functionality similar to the parental cells prior to immortalization, and did not grow in soft agar. Cell line cBAL111 expressed markers of immature hepatocytes, like glutathione S transferase and cytokeratin 19, as well as progenitor cell marker CD146 and was negative for lidocaine elimination. On the other hand, the cBAL111 cells produced urea, albumin and cytokeratin 18 and eliminated galactose. In contrast to hepatic cell lines NKNT-3 and HepG2, all hepatic functions were expressed in cBAL111, although there was considerable variation in their levels compared with primary mature hepatocytes. When transplanted in the spleen of immunodeficient mice, cBAL111 engrafted into the liver and partly differentiated into hepatocytes showing expression of human albumin and carbamoylphosphate synthetase without signs of cell fusion. Conclusion This novel liver cell line has the potential to differentiate into mature hepatocytes to be used for in vitro hepatocyte applications.

Deurholt, Tanja; van Til, Niek P; Chhatta, Aniska A; ten Bloemendaal, Lysbeth; Schwartlander, Ruth; Payne, Catherine; Plevris, John N; Sauer, Igor M; Chamuleau, Robert AFM; Elferink, Ronald PJ Oude; Seppen, Jurgen; Hoekstra, Ruurdtje



Liver function assessment with three C breath tests by two-point measurements  

Microsoft Academic Search

In this study, we performed three breath tests – l-[1-C ]phenylalanine breath test (PBT), l-[1-C ] methionine breath test, and [C]methacetin breath test (MethaBT) – in patients with chronic liver disease to determine the optimal timing of expired air collection for diagnosing chronic liver disease and evaluating the grade of fibrosis. The subjects were 61 adults with normal livers, 98

Yukimoto Ishii; Shigeru Suzuki; Satoshi Asai; Ichirou Murai



Effect of different liver resection methods on liver damage and regeneration factors VEGF and FGF-2 in mice  

PubMed Central

Background Different approaches to study liver regeneration in murine models have been proposed. We investigated the effect of different liver resection models on liver damage and regeneration parameters in mice. Methods We compared the technical aspect of the 2 most commonly used techniques of 50% and 70% liver resection. Liver damage, as determined by the change in serum alanine aminotransferase and aspartate aminotransferase, as well as the regeneration parameters VEGF and FGF-2 were analyzed at 6 time points. A postoperative vitality score was introduced. Results Cholestasis was not observed for either technique. Both resection techniques resulted in full weight recovery of the liver after 240 hours, with no significant difference between sham and resection groups. Postoperative animal morbidity and total protein levels did not differ significantly for either method, indicating early and full functional recovery. However, comparing the mitogenic growth factors FGF-2 and VEGF, a significant increase in serum levels and, therefore, increased growth stimulus, was shown in the extended resection group. Conclusion Extended resection led to a greater response in growth factor expression. This finding is important since it shows that growth factor response differs acdording to the extent of resection. We have demonstrated the need to standardize murine hepatic resection models to adequately compare the resulting liver damage.

Bonninghoff, Roderich; Schwenke, Kay; Keese, Michael; Magdeburg, Richard; Bitter-Suermann, Hinrich; Otto, Mirko; Hasenberg, Till; Post, Stefan; Sturm, Jorg



Racemization of alanine by the alanine racemases from Salmonella typhimurium and Bacillus stearothermophilus: energetic reaction profiles  

SciTech Connect

Alanine racemases are bacterial pyridoxal 5'-phosphate (PLP) dependent enzymes providing D-alanine as an essential building block for biosynthesis of the peptidoglycan layer of the cell wall. Two isozymic alanine racemases, encoded by the dadB gene and the alr gene, from the Gram-negative mesophilic Salmonella typhimurium and one from the Gram-positive thermophilic Bacillus stearothermophilus have been examined for the racemization mechanism. Substrate deuterium isotope effects and solvent deuterium isotope effects have been measured in both L ..-->.. D and D..-->.. L directions for all three enzymes to assess the degree to which abstraction of the ..cap alpha..-proton or protonation of substrate PLP carbanion is limiting in catalysis. Additionally, experiments measuring internal return of ..cap alpha..-/sup 3/H from substrate to product and solvent exchange/substrate conversion experiments in /sup 3/H/sub 2/O have been used with each enzyme to examine the partitioning of substrate PLP carbanion intermediates and to obtain the relative heights of kinetically significant energy barriers in alanine racemase catalysis.

Faraci, W.S.; Walsh, C.T.



A Role for Serotonin (5-HT) in Hepatic Stellate Cell Function and Liver Fibrosis  

PubMed Central

Hepatic stellate cells (HSCs) are key cellular components of hepatic wound healing and fibrosis. There is emerging evidence that the fibrogenic function of HSCs may be influenced by neurochemical and neurotrophic factors. This study addresses the potential for the serotonin (5-HT) system to influence HSC biology. Rat and human HSCs express the 5-HT1B, 5-HT1F 5-HT2A 5-HT2B, and 5-HT7 receptors, with expression of 5-HT1B 5-HT2A and 5-HT2B being induced on HSC activation. Induction of 5-HT2A and 5-HT2B was 106 ± 39- and 52 ± 8.5-fold that of quiescent cells, respectively. 5-HT2B was strongly associated with fibrotic tissue in diseased rat liver. Treatment of HSCs with 5-HT2 antagonists suppressed proliferation and elevated their rate of apoptosis; by contrast 5-HT was protective against nerve growth factor-induced apoptosis. 5-HT synergized with platelet-derived growth factor to stimulate increased HSC proliferation. HSCs were shown to express a functional serotonin transporter and to participate in both active uptake and release of 5-HT. We conclude that HSCs express key regulatory components of the 5-HT system enabling them to store and release 5-HT and to respond to the neurotransmitter in a profibrogenic manner. Antagonists that selectively target the 5-HT class of receptors may be exploited as antifibrotic drugs.

Ruddell, Richard G.; Oakley, Fiona; Hussain, Ziafat; Yeung, Irene; Bryan-Lluka, Lesley J.; Ramm, Grant A.; Mann, Derek A.



Functional involvement of protein kinase C-?II and its substrate, myristoylated alanine-rich C-kinase substrate (MARCKS), in insulin-stimulated glucose transport in L6 rat skeletal muscle cells  

PubMed Central

Aims/hypothesis Insulin stimulates phosphorylation cascades, including phosphatidylinositol-3-kinase (PI3K), phosphatidylinositol-dependent kinase (PDK1), Akt, and protein kinase C (PKC). Myristoylated alanine-rich C-kinase substrate (MARCKS), a PKC?II substrate, could link the effects of insulin to insulin-stimulated glucose transport (ISGT) via phosphorylation of its effector domain since MARCKS has a role in cytoskeletal rearrangements. Methods We examined phosphoPKC?II after insulin treatment of L6 myocytes, and cytosolic and membrane phosphoMARCKS, MARCKS and phospholipase D1 in cells pretreated with LY294002 (PI3K inhibitor), CG53353 (PKC?II inhibitor) or W13 (calmodulin inhibitor), PI3K, PKC?II and calmodulin inhibitors, respectively, before insulin treatment, using western blots. ISGT was examined after cells had been treated with inhibitors, small inhibitory RNA (siRNA) for MARCKS, or transfection with MARCKS mutated at a PKC site. MARCKS, PKC?II, GLUT4 and insulin receptor were immunoblotted in subcellular fractions with F-actin antibody immunoprecipitates to demonstrate changes following insulin treatment. GLUT4 membrane insertion was followed after insulin with or without CG53353. Results Insulin increased phosphoPKC?II(Ser660 and Thr641); LY294002 blocked this, indicating its activation by PI3K. Insulin treatment increased cytosolic phosphoMARCKS, decreased membrane MARCKS and increased membrane phospholipase D1 (PLD1), a protein regulating glucose transporter vesicle fusion resulted. PhosphoMARCKS was attenuated by CG53353 or MARCKS siRNA. MARCKS siRNA blocked ISGT. Association of PKC?II and GLUT4 with membrane F-actin was enhanced by insulin, as was that of cytosolic and membrane MARCKS. ISGT was attenuated in myocytes transfected with mutated MARCKS (Ser152Ala), whereas overproduction of wild-type MARCKS enhanced ISGT. CG53353 blocked insertion of GLUT4 into membranes of insulin treated cells. Conclusions/interpretation The results suggest that PKC?II is involved in mediating downstream steps of ISGT through MARCKS phosphorylation and cytoskeletal remodelling.

Chappell, D. S.; Patel, N. A.; Jiang, K.; Li, P.; Watson, J. E.; Byers, D. M.



Serum bile acid in the evaluation of colchicine treatment of carbon tetrachloride-induced liver injury.  


The usefulness of measuring serum-conjugated bile acid concentrations by radioimmunoassay in colchicine-modified carbon tetrachloride-induced liver lesions in rats was assessed by comparing the concentrations with the results of some routinely employed liver function tests such as serum aspartate transaminase, alanine transaminase, alkaline phosphatase, and serum total protein. The serum cholylglycine levels were significantly (P less than 0.003) raised along with the serum aspartate transaminase (P less than 0.01) and alanine transaminase (P less than 0.01) activity levels in the carbon tetrachloride-treated group of rats when compared with the group treated with carbon tetrachloride plus colchicine. Colchicine prevented the increase in serum cholylglycine, aspartate transaminase, alanine transaminase, and alkaline phosphatase induced by carbon tetrachloride but had no effect on serum total protein levels. This study suggests that radioimmunoassay of serum cholyglycine is a sensitive and specific indicator of liver injury and it is a useful tool in monitoring the treatment provided. PMID:6510512

Bolarin, D M



Antimicrobial activity of antihypertensive food-derived peptides and selected alanine analogues.  


This study evaluated four food-derived peptides with known antihypertensive activities for antimicrobial activity against pathogenic microorganisms, and assessed structure-function relationships using alanine analogues. The peptides (EVSLNSGYY, barley; PGTAVFK, soybean; TTMPLW, ?-casein; VHLPP, ?-zein) and the six alanine substitution peptides of PGTAVFK were synthesised, characterised and evaluated for antimicrobial activity using the bacteria, Escherichia coli, Staphylococcus aureus, and Micrococcus luteus and the yeast, Candida albicans. The peptides TTMPLW and PGTAVFK inhibited growth of all four microorganisms tested, with activities of a similar order of magnitude to ampicillin and ethanol controls. EVSLNSGYY inhibited the growth of the bacteria, but VHLPP showed no antimicrobial activity. The alanine analogue, PGAAVFK showed the highest overall antimicrobial activity and PGTAVFA showed no activity; overall, the activities of the analogues were consistent with their structures. Some peptides with antihypertensive activity also show antimicrobial activity, suggesting that food-derived peptides may exert beneficial effects via a number of mechanisms. PMID:24176365

McClean, Stephen; Beggs, Louise B; Welch, Robert W



Robust reference intervals for Liver function test (LFT) analytes in newborns and infants  

PubMed Central

Background Reference intervals (RIs) are ranges of upper and lower limits of a given analyte which are used for a laboratory test to determine whether a disease is present or absent or to know if the patient is at risk for future disease states. In Ethiopia, a country with highly diversified population groups and geographical sites, there are no established RIs to metabolic analytes including the liver function test (LFT) analytes for the pediatric population though it has been known that liver function assessment in this population is vital as a result of varied vulnerability to both endogenous and xenobiotic substances. Methods A cross sectional study was conducted in Tikur Anbessa Specialized Hospital (TASH) and Teklehaymanot Health Center (THC) from November 2010 to April 2011. 117 cord blood (from newborns) and venous blood samples (from infants) were collected and analyzed using HumaStar 300. All pre-analytical, analytical and post-analytical aspects were thoroughly controlled. A robust, CLSI/ IFCC recommended, method was used for the determination of upper and lower end points covering 95% of the reference values of each analyte with respective 90% CIs using MedCalc® software. Results Combined RIs for newborns and infants were established for albumin, AST, ALP, direct bilirubin and total bilirubin to be 3.88-5.82 g/dl, 16.1-55.4U/l, 130-831U/l, <0.41 mg/dl and <1.37 mg/dl respectively. But, separated RIs were indicated for ALT and GGT as 1.2-23.1U/l and 6.94-24.8U/l ALT; and 30.6-160.7U/L and 10–28.2U/l GGT for newborns and infants respectively. Some maternal and infantile factors were identified to affect the values of analytes. Conclusion Almost all analytes were different from previously reported values for other target population of similar age group, kit insert values and adult values. So, interpretation of values of these analytes in newborns and infants of Ethiopian population sounds better to be performed by using such RIs taking the effect of some maternal and infantile factors in to account.



Differential alterations in mitochondrial function induced by a choline-deficient diet: understanding fatty liver disease progression.  


Non-alcoholic fatty liver disease (NAFLD) is an increasingly reported pathology, characterized by fat accumulation within the hepatocyte. Growing evidences suggest specific effects on mitochondrial metabolism, but it is still unclear the relationship between fatty liver progression and mitochondrial function. In the present work we have investigated the impact of fatty liver on mitochondrial bioenergetic functions and susceptibility to mitochondrial permeability transition (MPT) induction in animals fed a choline-deficient diet (CDD) for 4, 8, 12 or 16 weeks. Mitochondria isolated from CDD animals always exhibited higher state 4 respiration. Mitochondrial membrane potential was decreased in CDD animals at 4 and 16 weeks. At 12 weeks, oxidative phosphorylation was more efficient in CDD animals, suggesting a possible early response trying to revert the deleterious effect of increased triglyceride storage in the liver. However, mitochondrial dysfunction was evident in CDD animals at 16 weeks as indicated by decreased RCR and ADP/O, with a corresponding decrease in respiratory chain enzymes activities. Such loss of respiratory efficiency was associated with accumulation of protein oxidation products, in tissue and mitochondrial fraction. Additionally, although no differences in ATPase activity, the lag phase was increased in mitochondria from CDD animals at 16 weeks, associated with decreased content of the adenine nucleotide translocator. Increased susceptibility to calcium-induced MPT was evident in CDD animals at all time points. These results suggest a dynamic mechanism for the development of NALFD associated with altered mitochondrial function. PMID:18765303

Teodoro, João S; Rolo, Anabela P; Duarte, Filipe V; Simões, Anabela M; Palmeira, Carlos M



Failure of fibrotic liver regeneration in mice is linked to a severe fibrogenic response driven by hepatic progenitor cell activation.  


Failure of fibrotic liver to regenerate after resection limits therapeutic options and increases demand for liver transplantation, representing a significant clinical problem. The mechanism underlying regenerative failure in fibrosis is poorly understood. Seventy percent partial hepatectomy (PHx) was performed in C57Bl/6 mice with or without carbon tetrachloride (CCl4)-induced liver fibrosis. Liver function and regeneration was monitored at 1 to 14 days thereafter by assessing liver mass, alanine aminotransferase (ALT), mRNA expression, and histology. Progenitor (oval) cell mitogen tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and TWEAK-neutralizing antibody were used to manipulate progenitor cell proliferation in vivo. In fibrotic liver, hepatocytes failed to replicate efficiently after PHx. Fibrotic livers showed late (day 5) peak of serum ALT (3542 ± 355 IU/L compared to 93 ± 65 IU/L in nonfibrotic livers), which coincided with progenitor cell expansion, increase in profibrogenic gene expression and de novo collagen deposition. In fibrotic mice, inhibition of progenitor activation using TWEAK-neutralizing antibody after PHx resulted in strongly down-regulated profibrogenic mRNA, reduced serum ALT levels and improved regeneration. Failure of hepatocyte-mediated regeneration in fibrotic liver triggers activation of the progenitor (oval) cell compartment and a severe fibrogenic response. Inhibition of progenitor cell proliferation using anti-TWEAK antibody prevents fibrogenic response and augments fibrotic liver regeneration. Targeting the fibrogenic progenitor response represents a promising strategy to improve hepatectomy outcomes in patients with liver fibrosis. PMID:23680654

Kuramitsu, Kaori; Sverdlov, Deanna Y; Liu, Susan B; Csizmadia, Eva; Burkly, Linda; Schuppan, Detlef; Hanto, Douglas W; Otterbein, Leo E; Popov, Yury



Puerarin improves metabolic function leading to hepatoprotective effects in chronic alcohol-induced liver injury in rats.  


Puerarin (PR), an active component extracted from the kudzu root, has been widely used as an ethno-medicine to treat hepatopathy in China. Therefore, the aim of the present study was to investigate the hepatoprotective action of PR in chronic alcohol-induced liver injury in rats. Data showed that the serum levels of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) were elevated following PR administration. In addition, the levels of endogenous CYP2E1, CYP1A2, and CYP3A proteins in liver tissue were also gradually decreased following PR treatment. Histopathological examinations suggested that alcohol-induced hepatocellular lesions were mitigated by PR treatment. Collectively, these data indicate that PR contributes to cytoprotection against alcohol-induced liver lesions through improving metabolic function. PMID:23669266

Chen, Xu; Li, Rong; Liang, Tao; Zhang, Kefeng; Gao, Ya; Xu, Lingyuan



Amino acid-dependent activation of liver estrogen receptor alpha integrates metabolic and reproductive functions via IGF-1.  


Throughout evolution, organisms have devised strategies to limit fertility in case of prolonged starvation. In mammals, the liver plays a central role in the orchestration of mechanisms allowing for the maintenance of energy homeostasis. We here demonstrate that dietary amino acids regulate the transcriptional activity of hepatic estrogen receptor alpha (ER?) through an mTOR-dependent mechanism. As a result of ER? activation, hepatic IGF-1 mRNA and blood IGF-1 are increased. Conversely, calorie restriction or selective ablation of ER? in the liver decrease blood IGF-1 to levels inadequate for the correct proliferation of the lumen epithelium in the uterus and the progression of the estrous cycle. We propose that the liver acts as critical mediator of energetic and reproductive functions responsible for the blockade of the estrous cycle in case of protein scarcity. Our findings may provide novel insights to understand the cause of selected forms of infertility and metabolic alterations in women after menopause. PMID:21284987

Della Torre, Sara; Rando, Gianpaolo; Meda, Clara; Stell, Alessia; Chambon, Pierre; Krust, Andrée; Ibarra, Cristian; Magni, Paolo; Ciana, Paolo; Maggi, Adriana



A novel human hepatoma cell line, FLC-4, exhibits highly enhanced liver differentiation functions through the three-dimensional cell shape.  


We characterized three-dimensional human hepatoma cell lines, functional liver cell (FLC) cell lines, to establish a highly differentiated hepatoma cell line. We investigated the effect of extracellular matrix and cell morphology on liver-specific gene expression in FLC cells. The hepatocyte nuclear factor-4? (HNF-4?) and other liver-specific gene expressions were enhanced in spherical FLC-4 cells on EHS-gel, but other human hepatoma cells such as HepG2 did not show the enhancement. Importantly, the liver-specific gene expression levels in spherical FLC-4 cells cultured on EHS-gel were comparable to those of human liver and were much higher than those of other human hepatoma cell lines. The major matrix components and growth factors in EHS-gel did not affect cell shape and liver functions. To exclude any effect of the extracellular matrix, we made spherical FLC-4 cells by actin filament disruption. The actin-disrupted spherical cells also showed an enhanced liver-specific gene expression. We concluded that three-dimensional cell shape per se is one of the most important determinants of liver differentiation functions in FLC-4 cells. Cell morphology-dependent induction of liver-specific gene expression was mediated through microtubule organization. In conclusion, differentiation of FLC-4 human hepatoma cell line can be enhanced to a human liver-like level through the three-dimensional cell shape in a microtubule-dependent manner. PMID:21960466

Laurent, Thomas; Murase, Daiki; Tsukioka, Sayaka; Matsuura, Tomokazu; Nagamori, Seishi; Oda, Hiroaki



Effects of hyperbaric oxygen treatment on liver functions, oxidative status and histology in septic rats  

Microsoft Academic Search

Objective: The liver is thought to be responsible for multiple organ failure during sepsis. Increase in tissue oxygen consumption is a major component of the septic re- sponse. Hyperbaric oxygen (HBO) therapy provides more oxygenation in the whole body. This study exam- ined the effect of HBO alone or in combination with cefepime (CEF) on the liver in septic rats.

Sukru Oter; Mustafa Edremitlioglu; Ahmet Korkmaz; Omer Coskun; Dilek Kilic; Ucler Kisa; Hakan Yaren; Hayati Bilgic



Functional Characterization of Liver Enhancers That Regulate Drug-Associated Transporters  

Microsoft Academic Search

Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The

M J Kim; P Skewes-Cox; H Fukushima; S Hesselson; S W Yee; L B Ramsey; L Nguyen; J L Eshragh; R A Castro; C C Wen; D Stryke; S J Johns; T E Ferrin; P-Y Kwok; M V Relling; K M Giacomini; D L Kroetz; N Ahituv



Functional changes in rat liver mitochondria on administration of 2-methyl-4-dimethylaminoazobenzene.  

PubMed Central

Administration of 2-methyl-4-dimethylaminobenzene in the diet (0.1%, w/w) for 85-90 days doubled the content of mitochondria in the livers of rats. The azodye was covalently bound to liver proteins, and about 15% of the amount found in liver was associated with the mitochondrial fraction. Mitochondria isolated from the livers of azodye-fed animals showed drastically lowered ability to oxidize NAD+-linked substrates. The inhibited electron-transfer step was the reduction of ubiquinone. The organelles showed a large increase in succinate oxidase activity. The activity of cytochrome oxidase and the content of cytochrome aa3 were substantially higher in these organelles. Azodye-fed animals showed depressed serum cholesterol concentrations. The content of ubiquinone in liver also registered a small increase.

Saikumar, P; Kurup, C K



Green tea with high-density catechins improves liver function and fat infiltration in non-alcoholic fatty liver disease (NAFLD) patients: A double-blind placebo-controlled study.  


Catechins, a major component of green tea extract, have anti-hyperlipidemic effects. The present study investigated the effects of consumption of green tea with high-density catechins in non-alcoholic fatty liver disease (NAFLD) patients. Seventeen patients with NAFLD consumed green tea with high-density catechins, low-density catechins or a placebo for 12 weeks in a randomized double-blind study. Ultrasonography and computed tomography (CT) were performed at baseline and after 12 weeks. Serum alanine aminotransferase (ALT) levels and urine 8-isoprostane were monitored and compared to baseline at 4, 8 and 12 weeks. Body fat was significantly decreased in the high-density catechin group compared with the placebo and low-density catechin groups after 12 weeks of consumption. All the patients in the high-density catechin group showed a significantly improved liver-to-spleen CT attenuation ratio compared with the placebo and low-density catechin groups after 12 weeks of consumption. The high-density catechin group significantly decreased serum ALT levels and reduced urinary 8-isoprostane excretion compared with the placebo and low-density catechin group after 12 weeks of consumption. Based on a reduced proportion of body fat as estimated by bioimpedance measurement, increased liver-to-spleen CT attenuation ratio, decreased serum ALT levels and reduced urinary 8-isoprostane excretion, we concluded that 12 weeks of 700 ml per day of green tea containing >1 g catechin improved liver fat content and inflammation by reducing oxidative stress in patients with NAFLD. PMID:24065295

Sakata, Ryuichiro; Nakamura, Toru; Torimura, Takuji; Ueno, Takato; Sata, Michio



Effects of coffee, smoking, and alcohol on liver function tests: a comprehensive cross-sectional study  

PubMed Central

Background Liver function tests (LFTs) can be affected by many factors and the proposed effects of coffee on LFT require a comprehensive evaluation. The aim of this study was to elucidate whether drinking coffee, smoking, or drinking alcohol have independent effects on LFTs in Korean health-check examinees. Methods We used the responses of 500 health-check examinees, who had participated in a self-administered questionnaire survey about coffee, alcohol drinking, and smoking habits. Results Coffee consumption was closely related to male gender, high body mass index (BMI), alcohol drinking, and smoking. On univariable and multivariable analyses, drinking coffee lowered serum levels of total protein, albumin, and aspartate aminotransferases (AST). On multivariable analyses, smoking raised serum ?-glutamyl transferase (GGT) level and decreased serum protein and albumin levels, while alcohol drinking raised GGT level after adjustment for age, gender, regular medication, BMI, coffee and alcohol drinking amounts, and smoking. Conclusions Coffee consumption, smoking, and alcohol drinking affect the individual components of LFT in different ways, and the above 3 habits each have an impact on LFTs. Therefore, their effects on LFTs should be carefully interpreted, and further study on the mechanism of the effects is warranted.



Primary graft dysfunction after living donor liver transplantation is characterized by delayed functional hyperbilirubinemia.  


The purpose of this study is to propose a new concept of primary graft dysfunction (PGD) after living donor liver transplantation (LDLT), characterized by delayed functional hyperbilirubinemia (DFH) and a high early graft mortality rate. A total of 210 adult-to-adult LDLT grafts without anatomical, immunological or hepatitis-related issues were included. All of the grafts with early mortality (n = 13) caused by PGD in LDLT had maximum total bilirubin levels >20 mg/dL after postoperative day 7 (p < 0.001). No other factors, including prothrombin time, ammonia level or ascites output after surgery were associated with early mortality. Thus, DFH of >20 mg/dL for >seven consecutive days occurring after postoperative day 7 (DFH-20) was used to characterize PGD. DFH-20 showed high sensitivity (100%) and specificity (95.4%) for PGD with early mortality. Among the grafts with DFH-20 (n = 22), those with early mortality (n = 13) showed coagulopathy (PT-INR > 2), compared with those without mortality (p = 0.002). Pathological findings in the grafts with DFH-20 included hepatocyte ballooning and cholestasis, which were particularly prominent in the centrilobular zone. PGD after LDLT is associated with DFH-20 caused by graft, recipient and surgical factors, and increases the risk of early graft mortality. PMID:22494784

Ikegami, T; Shirabe, K; Yoshizumi, T; Aishima, S; Taketomi, Y A; Soejima, Y; Uchiyama, H; Kayashima, H; Toshima, T; Maehara, Y



A dual-functionally modified chitosan derivative for efficient liver-targeted gene delivery.  


Galactosylated chitosan-hydroxypropyltrimethylammonium (gal-HTCC) was synthesized by galactosylating and quaternizing chitosan to endue chitosan with targeting specificity for potential applications as gene vectors. The composition and physicochemical properties of gal-HTCC were characterized by FT-IR, (1) H NMR, elemental analysis, X-ray diffraction, and turbidity measurement. It was found that water-soluble gal-HTCC showed a more amorphous structure than chitosan, and it also had a much better plasmid condensation capability than galactosylated chitosan. Cytotoxicity measurements revealed that gal-HTCC showed significantly lower cytotoxicity in HepG2 and HeLa cell lines compared to branched polyethylenimine (bPEI, 25 kDa) which was used as a positive control. The nanoparticles (NPs) consisted of gal-HTCC and plasmid DNA had desirable particle size (around 250 nm) with a narrow size distribution. Confocal laser scanning microscopy confirmed that NPs could be internalized and transported to the nucleus efficiently within 6 h. In vitro gene transfection results indicated that gal-HTCC had significantly higher transfection efficiency (7- to 32-fold) compared to chitosan and gal-chitosan for targetable delivery of pGL3 luciferase plasmid to HepG2, and its transfection efficiency was highly inhibited in the presence of galactose (20 mM). All these results suggest that gal-HTCC can function as a promising nonviral gene vector for efficient liver-targeted gene delivery. PMID:23203540

Xiao, Bo; Wang, Xiaoyu; Qiu, Zhiye; Ma, Jun; Zhou, Lei; Wan, Ying; Zhang, Shengmin



The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis  

PubMed Central

Summary Liver fibrosis is an outcome of chronic liver injury of any etiology. It is manifested by extensive deposition of extracellular matrix (ECM) proteins that produce a fibrous scar in the injured liver. Bone marrow (BM) cells may play an important role in pathogenesis and resolution of liver fibrosis. BM cells contribute to the inflammatory response by TGF-?1 secretion and activation of liver resident myofibroblasts. Moreover, BM itself can serve as a source of collagen expressing cells, e.g. BM-derived fibrocytes and mesenchymal progenitors, which in turn, have a potential to in situ differentiate into fibrogenic myofibroblasts and facilitate fibrosis. Finally, BM cells play an active part in resolution of liver fibrosis after cessation of fibrogenic stimuli. While natural killer (NK) cells are implicated in apoptosis of activated hepatic stellate cells/myofibroblasts, cells of myelo-monocitic lineage secrete matrix metalloproteinases to actively degrade the fibrous scar. The focus of this review is on the current understanding of the role of different subsets of BM cells in the onset, development and resolution of liver fibrosis.

Kisseleva, Tatiana; Brenner, David A.



ATP competitive inhibitors of D-alanine-D-alanine ligase based on protein kinase inhibitor scaffolds.  


D-Alanine-D-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. Here, we describe a new approach to identify new inhibitor scaffolds for DDl based on similarity in the ATP binding region of different kinases and DDl. After an initial screening of several protein kinase inhibitors, we found that the Brutons's tyrosine kinase inhibitor LFM-A13, an analog of the Leflunomide metabolite A771726, inhibits DDl with a K(i) of 185 microM. A series of malononitrilamide and salicylamide derivatives of LFM-A13 has been synthesized to confirm the validity of this scaffold as an inhibitor of DDl. PMID:18321716

Triola, Gemma; Wetzel, Stefan; Ellinger, Bernhard; Koch, Marcus A; Hübel, Katja; Rauh, Daniel; Waldmann, Herbert



Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort  

Microsoft Academic Search

Background  Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation\\u000a Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident\\u000a liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies\\u000a for detection of this serious

David T Arnold; Louise M Bentham; Ruth P Jacob; Richard J Lilford; Alan J Girling



Sodium-coupled neutral amino acid transporter 4 functions as a regulator of protein synthesis during liver development.  


AIM: The molecular mechanisms by which hepatocyte nuclear factor (HNF)4? regulates fetal liver development have not been fully elucidated. We screened the downstream molecules of HNF4? during liver development and identified sodium-coupled neutral amino acid transporter (SNAT)4. The aim of this study is to investigate the regulation of SNAT4 by HNF4? and to clarify its roles in differentiating hepatocytes. METHODS: HNF4? was overexpressed in cultured liver buds using adenovirus, and suppression subtractive hybridization screening was performed. Temporal and spatial expression of SNAT4 during liver development was investigated. Regulation of SNAT4 by HNF4? was examined by promoter analyses and electrophoretic mobility shift assays (EMSA). Metabolic labeling and western blotting were carried out using primary hepatoblasts with SNAT4 overexpression. RESULTS: The expression of Slc38a4 encoding SNAT4 showed a marked perinatal increase, and was predominant among system A amino acid transporters. It was first detected in embryonic day 18.5 liver, and found in most hepatocytes after birth. Three alternative first exons were found in the SNAT4 gene. Promoter analyses using approximately 3-kb fragments corresponding to each first exon (AP1, AP2, AP3) revealed that AP1 and AP2 exhibited strong promoter activity in mouse hepatoblasts with endogenous HNF4?. Transactivation of AP2 was upregulated by HNF4? in HeLa cells without endogenous HNF4?. EMSA has demonstrated that HNF4? directly binds to cis-elements in AP2. Overexpression of SNAT4 facilitated amino acid uptake and de novo protein synthesis in primary hepatoblasts. CONCLUSION: SNAT4 functions downstream of HNF4? and plays significant roles in liver development through mechanisms of amino acid uptake and protein synthesis. PMID:23607685

Kondou, Hiroki; Kawai, Masanobu; Tachikawa, Kanako; Kimoto, Akihito; Yamagata, Masayo; Koinuma, Tomoko; Yamazaki, Miwa; Nakayama, Masahiro; Mushiake, Sotaro; Ozono, Keiichi; Michigami, Toshimi



A prospective experimental study of liver fibrosis with ultrasound and its correlation with hepatic reserve function and hemodynamics  

PubMed Central

Background Progressive hepatic fibrosis is the eventual cause of liver cirrhosis. Doppler ultrasound has been used to detect hemodynamic changes that are known to be present during the pre-cirrhotic stages of hepatic fibrogenesis. However, the relationship between the Doppler ultrasound parameters and the impairment of the liver function has not been fully investigated. The purpose of this study was to explore the hepatic function reserve and its relationship with the hepatic hemodynamics in a rabbit model of liver fibrosis using Doppler ultrasound. Methods A prospective study was performed. Sixty healthy New Zealand rabbits were included in this study. Eleven of them served as controls and were normally fed and provided with water drink; the rest of 49 rabbits that served as fibrosis group were normally fed but provided with 1.2 g/L of thioacetamide to create liver fibrosis model. Doppler measurements were performed in the portal trunk, proper hepatic artery and proper splenic artery. The hepatic circulation index (HCI) was calculated. Hepatic function reverse was evaluated by measuring the indocyanine green clearance and retention rate at 15 min (ICG R15) test. Portal venous pressure (PVP) was measured using the portal vein punctuation equipment. Results HCI was significantly decreased and PVP increased in the advanced fibrotic stage (F4) compared to mild and moderate fibrotic stage (F1-3), respectively (p<0.05). PVP and ICG R15 in the fibrotic group were significantly higher than that in the control group (ICG: 0.209±0.086 vs. 0.093±0.023, p<0.01). Within the fibrotic groups, PVP was higher in advanced fibrotic stage (F4) than those in mild (F1-2) or moderate (F3) fibrotic stages (p<0.05). Both HCI and PVP correlated well with ICG R15 (r = ?0.890, and r = 0.780, p <0.01). Conclusions Hepatic function reserve closely relates to the hepatic hemodynamics in the rabbit model of liver fibrosis. Doppler Ultrasound could be reliably used to assess the hepatic function reserve and hemodynamic changes in different stages of liver fibrosis.



Liver fibrosis in overweight patients  

Microsoft Academic Search

Background & Aims: A common clinical issue is whether overweight patients with abnormal liver function test results should undergo liver biopsy. Although serious liver injury can occur, its prevalence and risk factors are not well known. Methods: Ninety-three consecutive patients with abnormal liver function tests (but without overt liver disease), body mass index (BMI) > 25 kg\\/m2, and no alcoholic,

Vlad Ratziu; Philippe Giral; Frederic Charlotte; Eric Bruckert; Vincent Thibault; Ioannis Theodorou; Lina Khalil; Gérard Turpin; Pierre Opolon; Thierry Poynard



Expression of Functional Cell-Cell Channels from Cloned Rat Liver Gap Junction Complementary DNA  

Microsoft Academic Search

An oocyte expression system was used to test the relation between a complementary DNA (cDNA) clone encoding the liver gap junction protein and cell-cell channels. Total liver polyadenylated messenger RNA injected into oocytes induced cell-cell channels between paired oocytes. This induction was blocked by simultaneous injection of antisense RNA transcribed from the gap junction cDNA. Messenger RNA selected by hybridization

G. Dahl; T. Miller; D. Paul; R. Voellmy; R. Werner



Comparison of pathways of copper metabolism in aorta and liver. A functional test of metallothionein.  

PubMed Central

Soluble fractions from chick liver and aorta were examined for copper-binding proteins. In liver a zinc-binding thionein appeared to be the major binding protein for copper. Aortic tissue contained only traces of this thionein protein. Unlike liver, moderate amounts of soluble copper in aorta showed no association with macromolecules. Chicks fed on copper-deficient diets for 8 days had one-third the liver copper concentrations of controls. Aortic copper concentration was decreased only slightly, but the activity of lysyl oxidase, a copper-dependent enzyme in aorta, was decreased significantly. Treating the deficient chicks with CuSO4 (1 mg/kg) restored liver copper rapidly. The increase correlated with the binding of copper to a 10 000-mol.wt. component in the soluble fraction. Aortic copper concentrations responded much less to the CuSO4 treatment, but lysyl oxidase activity was again measurable in the tissue. Radioactive isotopes of copper bound almost exclusively to the 10 000-mol.wt. component in liver and to components of mol.wt. 30 000 or above in aorta. Hardly any of the administered radioactivity appeared with the 10 000-mol.wt. components in aorta, and none was found with unbound copper. The 30 000-mol.wt. components in aorta showed superoxide dismutase activity that was sensitive to NaCN. They also showed the highest specific activity of copper of any other aorta component. A clear distinction was seen between the metabolism of copper in liver and aortic tissues. Whereas a copper thionein, metallothionein, was a major component in the liver pathway, it is doubtful that this protein plays a major role in the intracellular metabolism of copper in aortic tissue.

Balthrop, J E; Dameron, C T; Harris, E D



In situ demonstration of improvement of liver mitochondria function by melatonin after cold ischemia.  


In a previous investigation, reperfusion with a melatonin-containing medium was demonstrated to enhance bile production and tissue ATP levels in rat livers, cold-preserved with University of Wisconsin (UW) or Celsior solutions, with respect to melatonin-free reperfusion; lipid peroxidation products in the perfusate were not influenced by the indole. This was ascribed to an increased efficiency of the hepatocyte mitochondria induced by melatonin. Reactive oxygen species (ROS) normally leak from the electron transfer chain in mitochondria and excessive ROS production is presumed to mediate ischemia-reperfusion (I/R) damage. A histochemical reaction was used to demonstrate ROS on the same model. Compared to the lobular zonation of ROS in control livers, the stained area of cold-preserved livers reperfused without melatonin was restricted to a narrow portal region, in keeping with the much lower ATP content. When reperfusion was performed with melatonin, the liver morphology was improved and the ROS reaction in hepatocytes more intense, though not reaching the control liver pattern. Sinusoidal cells were poorly-stained in both cases. In conclusion, with this different approach, melatonin was confirmed to improve mitochondrial performance and to discriminate parenchymal from sinusoidal cell behavior. Our observations confirm that melatonin mitigates I/R injury and support its potential in liver transplantation. PMID:16634523

Freitas, Isabel; Bertone, Vittorio; Guarnaschelli, Catia; Ferrigno, Andrea; Boncompagni, Eleonora; Rizzo, Vittoria; Reiter, Russel J; Barni, Sergio; Vairetti, Mariapia


Functional units in rainbow trout (Salmo gairdneri) liver: I. Arrangement and histochemical properties of hepatocytes.  


The architectural arrangement and selected histochemical properties of hepatocytes in the rainbow trout (Salmo gairdneri Richardson) were examined. Light and transmission electron microscopic (TEM) examination following fixation by portal venous perfusion revealed a tubular arrangement of hepatocytes. Lobules, as defined in the adult mammal, were absent. Biliary epithelial cells associated with bile preductules and ductules were a prominent feature of trout liver. Patterns and location of reaction products for glucose-6-phosphatase (G-6-Pase), glucose-6-phosphate dehydrogenase (G-6-PDH), and magnesium-dependent adenosine triphosphatase (ATPase), enzymes preferentially distributed in mammalian liver, were demonstrated in trout liver. A slightly heavier staining pattern for G-6-Pase was seen around presumptive portal venules but all other enzyme reaction patterns were uniform throughout the liver parenchyma. Following ATPase localization, four sizes of biliary passageways (canaliculi, bile preductules, ductules, and ducts) were visualized. Maximum glycogen retention was achieved with freeze-drying and glycolmethacrylate embedding and with this method intense, uniform glycogen staining was observed in all areas of the liver. Companion TEM examinations revealed large depots of glycogen within hepatocytes. The results are important for interpretation and description of the effects of toxic/carcinogenic alteration on trout liver. PMID:3000224

Hampton, J A; McCuskey, P A; McCuskey, R S; Hinton, D E



Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO  

PubMed Central

Hepatic stellate cells (HSCs) are critical for hepatic wound repair and tissue remodeling. They also produce cytokines and chemokines that may contribute to the maintenance of hepatic immune homeostasis and the inherent tolerogenicity of the liver. The functional relationship between HSCs and the professional migratory APCs in the liver, i.e. dendritic cells (DCs), has not been evaluated. Here, we report that murine liver DCs co-localize with HSCs in vivo under normal, steady-state conditions, and cluster with HSCs in vitro. In vitro, HSCs secrete high levels of DC chemoattractants, such as MIP1? and MCP-1, as well as cytokines that modulate DC activation, including TNF?, IL-6 and IL-1?. Culture of HSCs with conventional liver myeloid (m) DCs resulted in increased IL-6 and IL-10 secretion compared to that of either cell population alone. Co-culture also resulted in enhanced expression of co-stimulatory (CD80, CD86) and co-inhibitory (B7-H1) molecules on mDCs. HSC-induced mDC maturation required cell-cell contact and could be blocked, in part, by neutralizing MIP1? or MCP-1. HSC-induced mDC maturation was dependent on activation of STAT3 in mDCs and in part on HSC-secreted IL-6. Despite up-regulation of co-stimulatory molecules, mDCs conditioned by HSCs demonstrated impaired ability to induce allogeneic T cell proliferation, which was independent of B7-H1, but dependent upon HSC-induced STAT3 activation and subsequent up-regulation of IDO. In conclusion, by promoting IDO expression, HSCs may act as potent regulators of liver mDCs and function to maintain hepatic homeostasis and tolerogenicity.

Sumpter, Tina L.; Dangi, Anil; Matta, Benjamin M.; Huang, Chao; Stolz, Donna B.; Vodovotz, Yoram; Thomson, Angus W.; Gandhi, Chandrashekhar R.



Living with Your Liver  

NSDL National Science Digital Library

Students learn the function of the liver and how biomedical engineers can use liver regeneration to help people. Students test the effects of toxic chemicals on a beef liver by adding hydrogen peroxide to various liver and salt solutions. They observe, record and graph their results.

Integrated Teaching And Learning Program


Growth and characterization of pure and semiorganic nonlinear optical Lithium Sulphate admixtured l-alanine crystal  

NASA Astrophysics Data System (ADS)

Lithium sulphate admixtured l-alanine (LSLA) salt was synthesized and the solubility of the commercially available l-alanine and the synthesized LSLA sample was determined in de-ionized water at various temperatures. In accordance with the solubility data, the saturated aqueous solutions of l-alanine and lithium admixtured l-alanine were prepared separately and the single crystals of the samples were grown by the solution method with a slow evaporation technique. Studying single x-ray diffraction shows that pure and LSLA crystal belong to the orthorhombic system with a non-centrosymmetric space group P212121. Using the powder x-ray diffraction study, the crystallinity of the grown crystals is confirmed and the diffraction peaks are indexed. The various functional groups present in the pure and LSLA crystal are elucidated from Fourier transform infrared spectroscopy study. UV-visible transmittance is recorded to study the optical transmittance range for the grown crystals. The powder second harmonic generation test confirms the nonlinear optical property of the grown crystals. From the microhardness test, the hardness of the grown crystals is estimated. The dielectric behaviour, such as the dielectric constant and the loss of the sample, are measured as a function of temperature and frequency. The ac conductivity of the grown crystals is also studied and the activation energy is calculated.

Vela, T.; Selvarajan, P.; Freeda, T. H.; Balasubramanian, K.



Modulating influence of cytochrome P-450 MspI polymorphism on serum liver function profiles in coke oven workers  

Microsoft Academic Search

OBJECTIVES: It was reported previously that topside oven workers with heavy exposure to coke oven emissions had increased serum activities of hepatic aminotransferase in one coke oven plant. This study was conducted to investigate the modifying effect of CYP1A1 MspI polymorphism on liver function profiles in coke oven workers. METHODS: 88 coke oven workers from a large steel company in

M. T. Wu; C. K. Ho; S. L. Huang; Y. F. Yeh; C. L. Liu; I. F. Mao; D. C. Christiani



Effect of in utero exposure of Toddy (coconut palm wine) on liver function and lipid metabolism in rat fetuses  

Microsoft Academic Search

The objective of this study was to determine the effects of a country liquor Toddy (Coconut palm wine) and an equivalent quantity of ethanol on liver function and lipid metabolism in utero. Female albino rats with an average weight of 125± 5 g were exposed to Toddy from coconut palm (24.5 ml\\/kg-1 body weight\\/day) and ethanol (0.52 ml\\/kg body weight\\/day)

John. J. Lal; C. V. Sreeranjit Kumar; M. V. Suresh; M. Indira; P. L. Vijayammal



Investigation of the Potential Relationships Between Plasma Voriconazole Concentrations and Visual Adverse Events or Liver Function Test Abnormalities  

Microsoft Academic Search

This study investigated the relationship between plasma voriconazole concentrations (pVC) and risk of visual adverse events (VAEs) or liver function test (LFT) abnormalities using longitudinal logistic regression. Seven-day mean pVC were calculated from 2925 plasma samples (1053 patients); in each 7-day period, the presence or absence of VAEs\\/abnormal LFTs was analyzed as a binary outcome variable. There was a relationship

Keith Tan; Nigel Brayshaw; Konrad Tomaszewski; Peter Troke; Nolan Wood



The effect of nanofibrous galactosylated chitosan scaffolds on the formation of rat primary hepatocyte aggregates and the maintenance of liver function  

Microsoft Academic Search

Liver tissue engineering requires a perfect extracellular matrix (ECM) for primary hepatocytes culture to maintain high level of liver-specific functions and desirable mechanical stability. The aim of this study was to develop a novel natural nanofibrous scaffold with surface-galactose ligands to enhance the bioactivity and mechanical stability of primary hepatocytes in culture. The nanofibrous scaffold was fabricated by electrospinning a

Zhang-Qi Feng; Xuehui Chu; Ning-Ping Huang; Tao Wang; Yichun Wang; Xiaolei Shi; Yitao Ding; Zhong-Ze Gu



Functional and morphological characterization of cultures of Kupffer cells and liver endothelial cells prepared by means of density separation in Percoll, and selective substrate adherence  

Microsoft Academic Search

This paper presents a study on the structure and function of Kupffer cells (KC) and liver endothelial cells (LEC) isolated by a simple and rapid technique involving 1) perfusion of the liver with collagenase; 2) cell separation by means of density centrifugation in Percoll; and 3) cell culture, taking advantage of the fact that KC and LEC differ in their

Bård Smedsrød; Håkan Pertoft; Gösta Eggertsen; Christer Sundström



Characterization of the effects of erythromycin estolate and erythromycin base on the excretory function of the isolated rat liver  

SciTech Connect

To investigate the mechanisms of erythromycin cholestasis, the effects of erythromycin estolate (EE) on the excretory function of the isolated perfused rat liver and on liver plasma membrane (LM) preparations were studied and compared to those of erythromycin base (EB) and lauryl sulfate (LS), added alone or in combination. EE (at 125 to 200 microM) caused dose-dependent reductions of bile and perfusate flows, bile acid (BA) excretion, and biliary BA concentration. The alterations of the excretory function were only in part due to the decreased perfusate flow. In contrast, both 200 and 300 microM concentrations of EB elicited similar choleretic responses, which were presumably related to the osmotic activity of the drug excreted in the bile. LS did not affect hepatic excretory functions. However, the simultaneous addition of EB and LS resulted in a rate of bile flow lower than that observed with EB alone. EE, but not EB, increased canalicular permeability to (/sup 14/C)sucrose as measured by bile to plasma (B:P) ratio. Neither drugs altered (/sup 14/C)erythritol B:P ratio. In LM preparations both Na+,K+- and Mg2+-ATPase activities were inhibited in a dose-dependent manner by EE, but not by EB. The data suggest that EE could affect bile flow by inhibiting cotransport of Na+ and BA and by altering LM permeability and support the view that the effect of erythromycins on the liver may be related to their surface activity.

Gaeta, G.B.; Utili, R.; Adinolfi, L.E.; Abernathy, C.O.; Giusti, G.



ATP-dependent degradation of a mutant serine: pyruvate\\/alanine:glyoxylate aminotransferase in a primary hyperoxaluria type 1 case  

Microsoft Academic Search

Primary hyperoxaluria type 1 (PH 1), an in- born error of glyoxylate metabolism characterized by excessive synthesis of oxalate and glycolate, is caused by a defect in serine:pyruvate\\/alanine:glyoxylate aminotransferase (SPT\\/AGT). This enzyme is per- oxisomal in human liver. Recently, we cloned SPT\\/ AGT-cDNA from a PH 1 case, and demonstrated a point mutation of T to C in the coding

Kozo Nishiyama; Tsuneyoshi Funai; Sadaki Yokota; Arata Ichiyama



Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: The tumor selectivity of the treatment as a function of tumor to liver flow ratio  

PubMed Central

Background Treatment records and follow-up data on 40 patients with primary and metastatic liver malignancies who underwent a single whole-liver treatment with Y-90 resin microspheres (SIR-Spheres® Sirtex Medical, Lake Forest, IL) were retrospectively reviewed. The objective of the study was to evaluate the anatomic and physiologic determinants of radiation dose distribution, and the dose response of tumor and liver toxicity in patients with liver malignancies who underwent hepatic arterial Y-90 resin microsphere treatment. Methods Liver and tumor volume calculations were performed on pre-treatment CT scans. Fractional tumor and liver flow characteristics and lung shunt fractions were determined using hepatic arterial Tc-99m MAA imaging. Absorbed dose calculations were performed using the MIRD equations. Liver toxicity was assessed clinically and by liver function tests. Tumor response to therapy was assessed by CT and/or tumor markers. Results Of the 40 patients, 5 had hepatocellular cancer (HCC), and 35 had metastatic liver tumors (15 colorectal cancer, 10 neuroendocrine tumors, 4 breast cancer, 2 lung cancer, 1 ovarian cancer, 1 endometrial cancer, and 2 unknown primary adenocarcinoma). All patients were treated in a salvage setting with a 3 to 80 week follow-up (mean: 19 weeks). Tumor volumes ranged from 15.0 to 984.2 cc (mean: 294.9 cc) and tumor to normal liver uptake ratios ranged from 2.8 to 15.4 (mean: 5.4). Average administered activity was 1.2 GBq (0.4 to 2.4 GBq). Liver absorbed doses ranged from 0.7 to 99.5 Gy (mean: 17.2 Gy). Tumor absorbed doses ranged from 40.1 to 494.8 Gy (mean: 121.5 Gy). None of the patients had clinical venoocclusive disease or therapy-induced liver failure. Seven patients (17.5 %) had transient and 7 patients (17.5 %) had persistent LFT abnormalities. There were 27 (67.5%) responders (complete response, partial response, and stable disease). Tumor response correlated with higher tumor flow ratio as measured by Tc-99m MAA imaging. Conclusion Doses up to 99.5 Gy to uninvolved liver are tolerated with no clinical venoocclusive disease or liver failure. The lowest tumor dose producing a detectable response is 40.1 Gy. The utilization of MAA-based imaging techniques to determine tumor and liver blood flow for clinical treatment planning and the calculation of administered activity may improve clinical outcomes.

Gulec, Seza A; Mesoloras, Geraldine; Dezarn, William A; McNeillie, Patrick; Kennedy, Andrew S



Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function.  


The chromosomal passenger complex (CPC) acts as a key regulator of mitosis, preventing asymmetric segregation of chromosomal material into daughter cells. The CPC is composed of three non-enzymatic components termed Survivin, the inner centromere protein (INCENP) and Borealin, and an enzymatic component, Aurora B kinase. Survivin is necessary for the appropriate separation of sister chromatids during mitosis and is involved in liver regeneration, but its role in regenerative processes is incompletely elucidated. Whether Survivin, which is classified as an inhibitor of apoptosis protein (IAP) based on domain composition, also has a role in apoptosis is controversial. The present study examined the in vivo effects of Survivin ablation in the liver and during liver regeneration after 70% hepatectomy in a hepatocyte-specific knockout mouse model. The absence of Survivin caused a reduction in the number of hepatocytes in the liver, together with an increase in cell volume, macronucleation and polyploidy, but no changes in apoptosis. During liver regeneration, mitosis of hepatocytes was associated with mislocalization of the members of the CPC, which were no longer detectable at the centromere despite an unchanged protein amount. Furthermore, the loss of survivin in regenerating hepatocytes was associated with reduced levels of phosphorylated Histone H3 at serine 28 and abolished phosphorylation of CENP-A and Hec1 at serine 55, which is a consequence of decreased Aurora B kinase activity. These data indicate that Survivin expression determines hepatocyte number during liver development and liver regeneration. Lack of Survivin causes mislocalization of the CPC members in combination with reduced Aurora B activity, leading to impaired phosphorylation of its centromeric target proteins and inappropriate cytokinesis. PMID:23519077

Hagemann, S; Wohlschlaeger, J; Bertram, S; Levkau, B; Musacchio, A; Conway, E M; Moellmann, D; Kneiseler, G; Pless-Petig, G; Lorenz, K; Sitek, B; Baba, H A



Synthesis and evaluation of 18F labeled alanine derivatives as potential tumor imaging agents  

PubMed Central

Introduction This paper reports the synthesis and labeling of 18F alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents mediated by alanine-serine-cysteine preferring (ASC) transporter system. Methods Three new 18F alanine derivatives were prepared from corresponding tosylate-precursors through a two-step labelling reaction. In vitro uptake studies to evaluate and to compare these three analogs were carried out in 9L glioma and PC-3 prostate cancer cell lines. Potential transport mechanisms, protein incorporation and stability of 3-(1-[18F]fluoromethyl)-L-alanine (L[18F]FMA) were investigated in 9L glioma cells. Its biodistribution was determined in a rat-bearing 9L tumor model. PET imaging studies were performed on rat bearing 9L glioma tumors and transgenic mouse carrying spontaneous generated M/tomND tumor (mammary gland adenocarcinoma). Results New 18F alanine derivatives were prepared with 7–34% uncorrected radiochemical yields, excellent enantiomeric purity (>99%) and good radiochemical purity (>99%). In vitro uptake of the L-[18F]FMA in 9L glioma and PC-3 prostate cancer cells was higher than those observed for other two alanine derivatives and [18F]FDG in first 1 h. Inhibition of cell uptake studies suggested that L-[18F]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L-[18F]FMA remained stable and was not incorporated into protein within 2 h. In vivo biodistribution studies demonstrated that L-[18F]FMA had relatively high uptake in liver and kidney. Tumor uptake was fast, reaching a maximum within 30 min. The tumor-to-muscle, tumor-to-blood and tumor-to-brain ratios at 60 min post injection were 2.2, 1.9 and 3.0, respectively. In PET imaging studies, tumors were visualized with L-[18F]FMA in both 9L rat and transgenic mouse. Conclusion L-[18F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor proliferation.

Wang, Limin; Zha, Zhihao; Qu, Wenchao; Qiao, Hongwen; Lieberman, Brian P.; Plossl, Karl; Kung, Hank F.



Liver Regeneration  

PubMed Central

Liver regeneration after partial hepatectomy is a very complex and well-orchestrated phenomenon. It is carried out by the participation of all mature liver cell types. The process is associated with signaling cascades involving growth factors, cytokines, matrix remodeling, and several feedbacks of stimulation and inhibition of growth related signals. Liver manages to restore any lost mass and adjust its size to that of the organism, while at the same time providing full support for body homeostasis during the entire regenerative process. In situations when hepatocytes or biliary cells are blocked from regeneration, these cell types can function as facultative stem cells for each other.

Michalopoulos, George K.



Effect of protein and fat content in feed on plasma alanine-aminotransferase and hepatic fatty infiltration in mink.  


The effect of the content of protein and fat in the feed on the development of fatty infiltration of the liver in the period from weaning until pelting was measured in two groups of male scanblack mink (Mustela vision) fed 20% and 45%, respectively, of metabolizable energy (ME) from protein. Furthermore, plasma activity of alanine-aminotransferase and the content of specifically chosen clinical-chemical variables in the blood were measured. At pelting time in December, the liver weights were absolutely and relatively heavier to body weight and had a considerably higher fat content at 20% of ME from protein than at 45% of ME from protein. From August to pelting time, the activity of alanine-aminotransferase in plasma was higher at a low protein level than at a higher protein level in the feed. It is concluded that the content of protein and fat in the feed affects the incidence of hepatic fatty infiltration in mink. In the growth period, it is possible, based on plasma activity of alanine-aminotransferase, to select animals with histological fatty infiltration of the liver. PMID:7732739

Damgaard, B M; Clausen, T N; Henriksen, P



Risperidone rechallenge for marked liver function test abnormalities in an autistic child.  


Risperidone have been reported to commonly lead to asymptomatic elevation of liver enzymes in adult population, and recently in children and adolescents. Results from controlled clinical trials, reports of spontaneous adverse events, and published studies/ case reports suggest that severe hepatotoxicity may be rare but can occur in the pediatric population. In the following case report, we describe a 5-year-old male patient diagnosed as autism with severe distruptive behavior. Substantial improvement was achieved with risperidone therapy. Increase in liver enzymes at the beginning of the risperidone treatment was successfully managed with multidisciplinary approach as the treatment was initially withdrawn, afterwards restarted and carefully continued. We demonstrated that risperidone may be cautiously rechallenged in selected pediatric patients who showed marked psychiatric improvement with risperidone on the face of liver enzymes elevation. Some important patents on risperidone delivery and their use for the treatment of autism are also outlined. PMID:21913889

Copur, Mazlum; Erdogan, Ayten



Ketamine-Xylazine-Acepromazine Compared with Isoflurane for Anesthesia during Liver Transplantation in Rodents  

PubMed Central

Orthotopic liver transplantation in mice and rats is used to study a wide range of scientific questions. Inhalant anesthesia is widely used in liver transplantation models in rodents, but drawbacks of inhalant anesthetics include issues of cost, safety, and ease of use. The goal here was to find an effective injection anesthesia protocol that would not directly influence metabolic or functional parameters after liver transplantation. We compared intraperitoneal injection of a ketamine–xylazine–acepromazine cocktail (KXA) with isoflurane during 50% liver transplantation in mice and rats. Anesthesia with KXA had rapid induction (5 ± 3 min) and a long duration of surgical anesthesia (70 ± 10 min). The 2 methods of anesthesia produced no significant differences in liver injury (histology, serum alanine aminotransferase and total bilirubin concentrations), inflammation (IL6, TNF?, myeloperoxidase activity), regeneration (incorporation of 5-bromo-2?-deoxyuridine, mitotic index, restitution of liver weight), or 7-d survival. In conclusion, a KXA regimen is a safe and effective injectable anesthetic for rodent liver transplantation and is a suitable substitute for currently used inhalant anesthesia. Injectable anesthetics offer advantages in terms of cost, personal safety, and ease of use and will be particularly beneficial to microsurgeons during their training period in liver transplantation.

He, Songqing; Atkinson, Carl; Qiao, Fei; Chen, Xiaoping; Tomlinson, Stephen



The heat transfer analysis of nanoparticle heat source in alanine tissue by molecular dynamics.  


The purpose of this study is to simulate the heat transfer problem when the 3-D Alanine tissue is heated by the gold nanoparticle in the field of molecular dynamics. In this paper, the Alanine molecule is adopted and its parameters are available in the GROMACS protein data bank. A computing algorithm is developed to evaluate the heat transfer phenomena in the nano-scale biological system based on the molecular dynamics and the protein data bank. The value of the thermal conductivity of Alanine is calculated from the autocorrelation function of the Green-Kubo formalism and this result has a roughly approximation with the bulk thermal conductivity reported by experimental data . Two kinds of problems are investigated in the paper. One is the Alanine tissue heated by the constant heat source and the other is by the time-varying heat source. The numerical results show that a temperature jump exists around the source and the temperature profiles drop to the environmental temperature within a very short distance. It concludes that only a small region around the nano-scale heat source is affected by the heated process. Therefore, the results of the nanoparticle-heated method could be applied to the clinical therapy of tumor, and the normal cells are destroyed only within a smaller region than those of chemotherapy or surgery. PMID:16076483

Lin, David T W; Yang, Ching-yu



Development of tyrosine aminotransferase in perinatal rat liver: changes in function messenger RNA and the role of inducing hormones  

SciTech Connect

Expression of the hepatic enzyme tyrosine aminotranferase was analyzed in the perinatal period of development in the rat, when this expression undergoes significant changes associated with hepatocyte differentiation. In late prenatal liver both enzyme and functional mRNA gene products are present at levels 10- to 15-fold below those in the fully differentiated adult liver. This low level of expression in fetal liver is refractory to induction by glucocorticoids, but both gene products are increased to a limited extent by cyclic AMP. This induction by cyclic AMP (cAMP) does not confer glucocorticoid-responsiveness on expression. By 3 hr after birth both functional mRNA and enzyme levels are significantly increased, an increase which continues until a peak is reached at 12 hr that is appreciably above the adult levels. Both gene products then decline until adult levels are reached by 24 hr. The postnatal shift in aminotransferase expression is accompanied by acquisition of the capacity to respond to glucocorticoids. Treatment of newborns with an antiglucocorticoid steroid or with glucose suppresses the postnatal overshoot of expression, but neither treatment affects the increase from fetal to adult levels of expression. The results indicate that prior to birth, expression of the aminotransferase gene is partially repressed, a repression that is lifted essentially immediately upon birth. The hormones capable of inducing aminotranferase synthesis have no apparent necessary role in this process.

Perry, S.T.; Rothrock, R.; Isham, K.R.; Lee, K.L.; Kenney, F.T.



Alternative pig liver esterase (APLE) - cloning, identification and functional expression in Pichia pastoris of a versatile new biocatalyst.  


Isolated from pig liver as a crude, inhomogeneous enzyme fraction, pig liver esterase (PLE) was found to metabolize a wide range of substrates; often in a highly stereoselective manner. This crude esterase preparation, however, contains several iso-enzymes at proportions varying from batch to batch. Racemic methyl-(4E)-5-chloro-2-isopropyl-4-pentenoate is cleaved enantioselectively by crude PLE, but not by recombinantly expressed gamma-isoform of PLE. Concluding that another PLE iso-enzyme must carry the relevant activity, we cloned and sequenced cDNAs of several PLE isoforms and functionally expressed them in Pichia pastoris. One novel isoform termed alternative pig liver esterase (APLE) was found to hydrolyze methyl-(2R,4E)-5-chloro-2-isopropyl-4-pentenoate in a highly stereoselective manner (E>200). When heterologously expressed and directed for secretion in P. pastoris, APLE was found to be localized in the periplasm. The presence or absence of a putative C-terminal ER retention signal did neither influence functional expression nor cellular localization. The recombinant enzyme, purified by ion exchange chromatography, had a specific activity of 36U (mg protein)(-1) towards racemic methyl-(4E)-5-chloro-2-isopropyl-4-pentenoate. PMID:18078679

Hermann, Manuela; Kietzmann, Martin U; Ivanci?, Mirela; Zenzmaier, Christoph; Luiten, Ruud G M; Skranc, Wolfgang; Wubbolts, Marcel; Winkler, Margit; Birner-Gruenberger, Ruth; Pichler, Harald; Schwab, Helmut



Alanine Synthesis by Bundle Sheath Cells of Maize 1  

PubMed Central

Because in the phloem sap of maize (Zea mays L.) leaves a quarter of the total amino nitrogen can be found as alanine, the capacity of a de novo synthesis of alanine from 3-phosphoglycerate (3-PGA) was studied with isolated bundle sheath (BS) strands of maize. Inasmuch as these cells have retained their plasmodesmatic openings, it was possible to study the formation of alanine from 3-PGA when glutamate and ADP were being added. Alanine synthesis required the existence of the intact cell structure. From the formation of the intermediates, partially released to the medium, the activities of the enzymes of the reaction chain from 3-PGA to alanine could be measured in the intact cells. The results show that in the BS cells the rate of alanine production from pyruvate (0.5 micromole/minute per milligram BS chlorophyll) is more than sufficient to produce one-fourth of the assimilated nitrogen as alanine. As the activity of pyruvate kinase in intact bundle sheath cells in the light was found to be only 0.2 micromole/minute per milligram BS chlorophyll, it is concluded that in the light part of the conversion of 3-PGA to pyruvate may not occur via pyruvate kinase reaction, but via phosphoeno/pyruvate carboxylase, NADP-malate dehydrogenase, and NADP-malic enzyme in the mesophyll and BS cells.

Valle, Estela M.; Heldt, Hans W.



Liver Wellness  


... Liver Foundation 1-800-GO-LIVER © 2009 American Liver Foundation. All rights reserved. Increasing Public Awareness of Liver Health Liver Wellness • The liver is the second ...


Liver Transplant  


... Handouts Education Resources Support Services Helpful Links For Liver Health Information Call 1-800-GO-LIVER Email ... Home > Your Liver > Liver Disease Information > Liver Transplant Liver Transplant Explore this section to learn more about ...


Liver Cancer  


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[Changes in the functional state of rat liver and kidney mitochondria under the effect of electromagnetic fields].  


Oxidative phosphorylation and optical density of the rat liver and kidney mitochondria were studied under the effect of UHF and SHF electromagnetic fields of different power and duration of the action. It is established that a single action of these fields induces changes in the functional state of the mitochondria. The action by the UHF and SHF fields of 30W for 10 min increases the activity of respiration and phosphorylation in the liver and kidney mitochondria. The actions of the SHF electric field of 50 and 50W and UHF fields of 80W induce the splitting of oxidation phosphoryation, in the mitochondria. In this case there arise a considerable swelling of the mitochondria, which is evidenced by a decrease in their optic density. PMID:1209775

Faitel'berg, V R; Shapovalova, L A


Nucleation kinetics, growth and studies of ?-alanine single crystals  

NASA Astrophysics Data System (ADS)

Solubility and metastable zone width for the re-crystallized salt of ?-alanine was determined. Induction period measurement for the selected supersaturation ratios at room temperature (31 °C) was carried out for supersaturated aqueous solutions of ?-alanine and it is noticed that induction period decreases with increase of supersaturation ratio. The nucleation parameters such as Gibbs free energy change, radius and number of molecules of the critical nucleus, interfacial tension and the nucleation rate have been evaluated by classical nucleation theory. Single crystals of ?-alanine were grown using the optimized nucleation parameters by solution method and grown crystals have been subjected to various studies like XRD studies, FTIR, optical, thermal and SHG studies.

Shanthi, D.; Selvarajan, P.; HemaDurga, K. K.; Lincy Mary Ponmani, S.




EPA Science Inventory

Sixteen adult male squirrel monkeys (Saimiri sciureus) were randomly divided into three treatment groups and one control group. Each treatment group received 10 mg/kg oral doses of diphenylhydantoin and/or chloroquine. Following sacrifice, in vitro assays for activity of liver mi...


Functional Characterization of Liver Enhancers That Regulate Drug-Associated Transporters  

PubMed Central

Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five—located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1—exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response.

Kim, MJ; Skewes-Cox, P; Fukushima, H; Hesselson, S; Yee, SW; Ramsey, LB; Nguyen, L; Eshragh, JL; Castro, RA; Wen, CC; Stryke, D; Johns, SJ; Ferrin, TE; Kwok, P-Y; Relling, MV; Giacomini, KM; Kroetz, DL; Ahituv, N



Effect of Lactobacillus fermentum MG590 on Alcohol Metabolism and Liver Function in Rats  

Microsoft Academic Search

Alcohol consumption has numerous health consequences for the human body. For example, heavy drinking on a daily basis causes liver diseases, and certain products such as acetaldehyde produced from alcohol metabolism are more toxic than alcohol itself. Accordingly, the current study evaluated the role of Lactobacillus fermentum MG590 to enhance the removal of the toxic effect of alcohol in alcohol




Massive culture of human liver cancer cells in a newly developed radial flow bioreactor system: Ultrafine structure of functionally enhanced hepatocarcinoma cell lines  

Microsoft Academic Search

Summary  With a view to initiating clinical trials, cell morphology and function for a newly developed artificial liver support system\\u000a employing highly functional human liver cell line, FLC-7, cultured in a radial flow bioreactor were compared to cells grown\\u000a in a conventional monolayer culture.\\u000a \\u000a The radial flow bioreactor consists of a vertically extended cylindrical matrix comprised of porous glass bead microcarriers

Masaaki Kawada; Seishi Nagamori; Hideki Aizaki; Kenichi Fukaya; Minoru Niiya; Tomokazu Matsuura; Hajime Sujino; Satoshi Hasumura; Hitoshi Yashida; Satoru Mizutani; Hiroshi Ikenaga



Conditional knockout of heparin-binding epidermal growth factor-like growth factor in the liver accelerates carbon tetrachloride-induced liver injury in mice.  


Aim:? We previously demonstrated that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is induced in response to several liver injuries. Because the HB-EGF knockout (KO) mice die in utero or immediately after birth due to cardiac defects, the loss of function study in vivo is limited. Here, we generated liver-specific HB-EGF conditional knockout mice using the interferon-inducible Mx-1 promoter driven cre recombinase transgene and investigated its role during acute liver injury. Methods:? We induced acute liver injury by a single i.p. injection of carbon tetrachloride (CCl4 ) in HB-EGF KO mice and wild-type mice and liver damage was assessed by biochemical and immunohistochemical analysis. We also used AML12 mouse hepatocyte cell lines to examine the molecular mechanism of HB-EGF-dependent anti-apoptosis and wound-healing process of the liver in vitro. Results:? HB-EGF KO mice exhibited a significant increase of alanine aminotransferase level and also showed a significant increase in the number of apoptotic hepatocytes assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining at 24?h after CCl4 injection. We also demonstrated that HB-EGF treatment inhibited tumor necrosis factor-?-induced apoptosis of AML12 mouse hepatocytes and promoted the wound-healing response of these cells. Conclusion:? This study showed that HB-EGF plays a protective role during acute liver injury. PMID:22882498

Takemura, Takayo; Yoshida, Yuichi; Kiso, Shinichi; Saji, Yukiko; Ezaki, Hisao; Hamano, Mina; Kizu, Takashi; Egawa, Mayumi; Chatani, Norihiro; Furuta, Kunimaro; Kamada, Yoshihiro; Iwamoto, Ryo; Mekada, Eisuke; Higashiyama, Shigeki; Hayashi, Norio; Takehara, Tetsuo



Enhanced liver functions of hepatocytes cocultured with NIH 3T3 in the alginate/galactosylated chitosan scaffold.  


Formation of primary hepatocyte spheroids in the hydrogel scaffold is a promising approach for enhancing liver-specific functions in liver tissue engineering as well as for developing bioartificial liver (BAL) devices. In the present study, a highly porous hydrogel scaffold composed of alginate (AL) and galactosylated chitosan (GC) as a synthetic extracellular matrix (ECM) for hepatocytes was fabricated with 150-200 microm pore size in diameter. Cell adhesion onto AL/GC and AL/chitosan film was 72.7 and 45% at 1 wt% of GC (or chitosan) to AL content whereas cell adhesion onto AL film was 28.5%. The optimal concentration of GC in AL/GC sponge was 1 wt% to AL content by the measurement of albumin secretion. Cell viabilities performed on AL and AL/GC sponges were 72.2+/-3.6 and 81.3+/-3.5% of control, respectively, after 10 days incubation. Hepatocytes were aggregated to form multicellular spheroids in AL/GC sponge with diameter enlarged up to about 100 microm, 36 h postseeding, whereas most of them in the AL sponge remained as single cells and only a few cells began to form aggregates. Intercellular molecules such as connexin32 and E-cadherin genes related with cell-cell contact were expressed in hepatocytes within AL/GC sponge at 36 h after incubation, but not in AL sponge. Treatment with a gap junctional intercellular communication (GJIC) inhibitor, 18beta-glycyrrhetinic acid, resulted in a 1.5-fold marked decrease in albumin secretion levels in AL/GC sponge. Specially, coculture of hepatocytes in AL and AL/GC sponges with NIH3T3 in a transwell insert resulted in enhanced increase of liver-specific functions, such as albumin secretion rates, ammonia elimination rates, and ethoxyresorufin-O-deethylase activity by cytochrome P4501A1, compared to those in hepatocyte monoculture. The results suggest that formation of hepatocyte spheroids in coculture system enhances liver-specific functions for the AL/GC sponge as a new synthetic ECM to design developed BAL devices. PMID:16188312

Seo, Seog-Jin; Kim, In-Yong; Choi, Yun-Jaie; Akaike, Toshihiro; Cho, Chong-Su



Alcoholic liver disease.  


In the United States, approximately 100,000 deaths are attributed to alcohol abuse each year. In 2009, the World Health Organization listed alcohol use as one of the leading causes of the global burden of disease and injury. Alcoholic liver disease, a direct result of chronic alcohol abuse, insidiously destroys the normal functions of the liver. The end result of the disease, cirrhosis, culminates in a dysfunctional and diffusely scarred liver. This article discusses the clinical manifestations, imaging considerations, and treatment of alcoholic liver disease and cirrhosis. Normal liver function, liver hemodynamics, the disease of alcoholism, and the deleterious effects of alcohol also are reviewed. PMID:23861518

Penny, Steven M


Screening and simple purification of alanine dehydrogenase in Bacillus strains.  


Alanine dehydrogenase (EC, in the presence of NAD+, catalyzes the reversible deamination of L-alanine. Screening of alanine dehydrogenase in bacillus strains was carried out to develop its utilization as an industrial and analytical catalyst. Eight bacillus strains were used, including Bacillus megaterium LA 199 which abundantly produces enzymes. Alanine dehydrogenase was purified simply from Bacillus megaterium LA 199 by heat treatment at pH 5.4, followed by DEAE-Sepharose CL-6B and Sepharose CL-2B chromotography. The enzyme consisted of six subunits with an identical molecular mass of 42.5 kDa. The Km were 1.17 x 10(-2) mM for NADH and 5.12 x 10(-2) mM for pyruvate. PMID:12375815

Baysal, Senay Hamarat; Yasa, Ihsan; Uslan, Arif H



Alanine and Sodium Fluxes Across Mucosal Border of Rabbit Ileum  

Microsoft Academic Search

A B S T R A C T Unidirectional influxes of L-alanine and Na from the mucosal solution into the epithelium of in vitro rabbit ileum have been determined. In the presence of 140 mM Na, alanine influx is approximately 2.2 izmoles\\/hr cm ~, but is inhibited if the NaC1 in the mucosal solution is replaced by choline C1, Tris-Cl,




A case of elevated liver function tests after crown-of-thorns (Acanthaster planci) envenomation.  


The crown-of-thorns starfish (Acanthaster planci) inhabits coral reefs, largely throughout the Indo-Pacific region. Its dorsal surface is covered with stout thorn-like spines. When handled or stepped on by humans, the spines can puncture the skin, causing an immediate painful reaction, followed by inflammation and possible infection. Initial pain and swelling may last for days. Effects of envenomation on the liver have been demonstrated previously in animal models, but hepatic toxicity has not previously been described in humans. We describe elevated liver enzymes in a 19-year-old female associated with A planci spine puncture wounds. To our knowledge, this is the first documented report of transaminitis in a human after A planci envenomation. PMID:19099322

Lin, Brian; Norris, Robert L; Auerbach, Paul S



Unexpected discovery of massive liver echinococcosis. A clinical, morphological, and functional diagnosis.  


We report a case of symptomatic massive liver echinococcosis due to Echinococcus granulosus, unexpectedly found in a 34 year old woman living in Apulia, Italy. Based on size (max diameter 18 cm), clinical presentation, geographical area, and natural history of echinococcosis, we estimate that the initial infection should have occurred 9-20 yrs before. Presenting symptoms were those of typical mass effect with RUQ pain, pruritus, malaise, and recent weight loss. Abdominal ultrasound diagnosis of probable echinococcal cyst was subsequentely confirmed by positive serology and further detailed by radiological imaging. The cyst was massively occupying subdiaphragmatic liver segments and extending to the omentum and the stomach. The characteristics of the lesion were compatible with the WHO 2003 classification type CE2l, indicating a large active fertile cyst with daughter cysts. The cyst was successfully treated with medical therapy followed by surgery. The prevalence, diagnostic workup, management, and costs of echinococcosis are discussed in this case presentation. PMID:23813143

Bonfrate, L; Giuliante, F; Palasciano, G; Lamont, J T; Portincasa, P


Metabolic Functions of Liver-Derived (Endocrine) Insulin-Like Growth Factor I  

Microsoft Academic Search

Until now it has been difficult to determine the relative importance of locally produced (autocrine\\/paracrine) versus systemically derived (endocrine) insulin-like growth factor I (IGF-I) in the intact organism. We recently eliminated IGF-I production in the livers of mice using the Cre\\/loxP recombination system. These mice displayed a reduction in serum IGF-I levels of more than 80%, but demonstrated normal body

Olle G. P. Isaksson; John-Olov Jansson; Klara Sjögren; Claes Ohlsson



Transcriptional Networks in the Liver: Hepatocyte Nuclear Factor 6 Function Is Largely Independent of Foxa2  

PubMed Central

A complex network of hepatocyte nuclear transcription factors, including HNF6 and Foxa2, regulates the expression of liver-specific genes. The current model, based on in vitro studies, suggests that HNF6 and Foxa2 interact physically. This interaction is thought to synergistically stimulate Foxa2-dependent transcription through the recruitment of p300/CBP by HNF6 and to inhibit HNF6-mediated transcription due to the interference of Foxa2 with DNA binding by HNF6. To test this model in vivo, we utilized hepatocyte-specific gene ablation to study the binding of HNF6 to its targets in the absence of Foxa2. Chromatin immunoprecipitation using anti-HNF6 antibodies was performed on chromatin isolated from Foxa2loxP/loxP Alfp.Cre and control mouse livers, and HNF6 binding to its target, Glut2, was determined by quantitative PCR. In contrast to the current model, we found no significant difference in HNF6 occupancy at the Glut2 promoter between Foxa2-deficient and control livers. In order to evaluate the Foxa2/HNF6 interaction model on a global scale, we performed a location analysis using a microarray with 7,000 mouse promoter fragments. Again, we found no evidence that HNF6 binding to its targets in chromatin is reduced in the presence of Foxa2. We also examined the mRNA levels of HNF6 targets in the liver using a cDNA array and found that their expression was similar in Foxa2-deficient and control mice. Overall, our studies demonstrate that HNF6 binds to and regulates its target promoters in vivo in the presence and absence of Foxa2.

Rubins, Nir E.; Friedman, Joshua R.; Le, Phillip P.; Zhang, Liping; Brestelli, John; Kaestner, Klaus H.



Dose response of alanine detectors irradiated with carbon ion beams  

SciTech Connect

Purpose: The dose response of the alanine detector shows a dependence on particle energy and type when irradiated with ion beams. The purpose of this study is to investigate the response behavior of the alanine detector in clinical carbon ion beams and compare the results to model predictions. Methods: Alanine detectors have been irradiated with carbon ions with an energy range of 89-400 MeV/u. The relative effectiveness of alanine has been measured in this regime. Pristine and spread out Bragg peak depth-dose curves have been measured with alanine dosimeters. The track structure based alanine response model developed by Hansen and Olsen has been implemented in the Monte Carlo code FLUKA and calculations were compared to experimental results. Results: Calculations of the relative effectiveness deviate less than 5% from the measured values for monoenergetic beams. Measured depth-dose curves deviate from predictions in the peak region, most pronounced at the distal edge of the peak. Conclusions: The used model and its implementation show a good overall agreement for quasimonoenergetic measurements. Deviations in depth-dose measurements are mainly attributed to uncertainties of the detector geometry implemented in the Monte Carlo simulations.

Herrmann, Rochus; Jaekel, Oliver; Palmans, Hugo; Sharpe, Peter; Bassler, Niels [Department of Physics and Astronomy, Aarhus University, 8000 Aarhus (Denmark); Division of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg (Germany) and Department of Experimental Clinical Oncology, Aarhus University Hospital, 8000 Aarhus (Denmark); Division of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg (Germany) and Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg University Hospital, 69120 Heidelberg (Germany); National Physical Laboratory, Teddington, Middlesex, TW 11 OLW (United Kingdom); Department of Physics and Astronomy, Aarhus University, 8000 Aarhus (Denmark); Division of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg (Germany) and Department of Experimental Clinical Oncology, Aarhus University Hospital, 8000 Aarhus (Denmark)





Oral ?-alanine doses larger than 800 mg commonly result in side effects known as paraesthesia. However, the side effects experienced when consuming an absolute or a dose relative to body weight of ?-alanine have not been examined. The aim of this study was to report all of the side effects experienced and to determine if the symptoms of paraesthesia differed between the two doses and to determine if body mass and composition were related to these side effects. 25 healthy male subjects completed three supplementation treatments: a placebo; a relative dose of 0.02 g·kg(-1) body weight and an absolute dose of 1.6 g ?-alanine. For 90 min following supplementation in each condition, participants completed a questionnaire relating to various sensations. Symptoms peaked after 20 min and the combined incidence rate for both ?-alanine conditions was 29% ("pins and needles"), 19% ("tickling, itching"), 16% (''flush and/or shiver''), 8% (''tactile hypersensitivity and/or irritation''), and 6% (''numbness and/or insensitivity''). No significant relationships were found between body fat, lean mass or body mass and symptoms of paraesthesia. The present investigation found subjects weighing less than 75 kg experienced a higher incidence of side effects when taking an absolute dose of ?-alanine, whereas for participants over 85 kg the dose relative to body weight resulted in a greater incidence of side effects. The results of the current investigation may be useful in providing guidelines to reduce side effects for specific individuals following ?-alanine supplementation. PMID:24159145

Kelly, Vg; Jenkins, Dg; Leveritt, Md; Slater, Gj



Directed evolution of bacterial alanine racemases with higher expression level.  


Bacterial alanine racemase (EC is a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the interconversion of L-alanine and D-alanine. It can be classified into two groups: biosynthetic enzymes with low catalytic activity and catabolic enzymes with high catalytic activity. It can react with serine to a limited extent. Two biosynthetic alanine racemase genes in Escherichia coli and Salmonella typhimurium were DNA shuffled, and a very diverse chimeric gene library was constructed. An E. coli serine auxotroph was transformed with the shuffled genes, and the recombinant clones were screened on selective media supplemented with 0.5-5 mM D-serine as an L-serine supplier. Selected clones were expected to contain racemases exhibiting higher catalytic activities toward alanine as well as serine. Three independent clones that grew on selective media were isolated. The specific activities of crude extracts prepared from cells expressing the chimeric racemases were increased up to approximately three times more than those expressing the parental enzymes. The best chimera Ser15 racemase was expressed at a level approximately twofold higher than the parental alanine racemases. This high protein expression was demonstrated to be posttranscriptionally achieved. PMID:16243272

Ju, Jiansong; Misono, Haruo; Ohnishi, Kouhei



A Pediatric Amino Acid Solution for Total Parenteral Nutrition Does Not Affect Liver Function Test Results in Neonates  

Microsoft Academic Search

.\\u000a Purpose:   We studied the effects of an amino acid mixture used for total parenteral nutrition (TPN) in pediatrics, on the liver function\\u000a test results (LFTs) of neonates.\\u000a \\u000a \\u000a \\u000a Methods:   Thirty neonatal surgical patients were randomly divided into three groups according to the dose of amino acids given: group\\u000a H (n= 12, 3.45 ± 0.07?g\\/kg per day), group M (n= 8,

Shinsuke Hata; Akio Kubota; Akira Okada



Kava for the Treatment of Generalized Anxiety Disorder RCT: Analysis of Adverse Reactions, Liver Function, Addiction, and Sexual Effects.  


Presently, little is known about a number issues concerning kava (Piper methysticum), including (i) whether kava has any withdrawal or addictive effects; (ii) if genetic polymorphisms of the cytochrome (CYP) P450 2D6 liver enzyme moderates any potential adverse effects; and (iii) if medicinal application of kava has any negative or beneficial effect on sexual function and experience. The study design was a 6-week, double-blind, randomized controlled trial (n?=?75) involving chronic administration of kava (one tablet of kava twice per day; 120?mg of kavalactones per day, titrated in non-response to two tablets of kava twice per day; 240?mg of kavalactones) or placebo for participants with generalized anxiety disorder. Results showed no significant differences across groups for liver function tests, nor were there any significant adverse reactions that could be attributed to kava. No differences in withdrawal or addiction were found between groups. Interesting, kava significantly increased female's sexual drive compared to placebo (p?=?0.040) on a sub-domain of the Arizona Sexual Experience Scale (ASEX), with no negative effects seen in males. Further, it was found that there was a highly significant correlation between ASEX reduction (improved sexual function and performance) and anxiety reduction in the whole sample. Copyright © 2013 John Wiley & Sons, Ltd. PMID:23348842

Sarris, J; Stough, C; Teschke, R; Wahid, Z T; Bousman, C A; Murray, G; Savage, K M; Mouatt, P; Ng, C; Schweitzer, I



How van der Waals interactions affect alanine-based polypeptides  

NASA Astrophysics Data System (ADS)

van der Waals interactions play a critical role among the intramolecular interactions that stabilize secondary structure folding motifs in polypeptides. In this work, we quantify its influence ab initio for the series of helix-forming alanine based polypeptides Ac-Alan-LysH^+ (n= 4-15). We show that: (i) applying a van der Waals (vdW) correction based on the self-consistent electron density [2] to the PBE functional, a clear ?-helical conformational preference emerges at n=8, in agreement with experiment [1], while a mostly 310 helical structure is preferred at plain PBE; (ii) a numeric atom-centered orbital basis enhanced specifically to converge conformational energy differences from explicitly correlated methods (MP2, EX+cRPA and beyond [3]) gives us benchmark capabilities for treatments that include long-range correlations outrightly; (iii) exploring the free energy surface through ab initio dynamics for longer helices (n=15) we see a dramatic influence of vdW interactions for high temperature stability and surface explored by these molecules. Our results demonstrate that we are now in a position to quantify vdW contributions accurately, and thus unravel their critical qualitative role in comparison to other contributions (strain, H-bonds) in medium-sized biomolecules. [1] Kohtani and Jarrold, JACS 108, 8454 (2004); [2] Tkatchenko and Scheffler, PRL 102, 073055 (2009); [3]

Rossi, M.; Blum, V.; Ren, X.; Tkatchenko, A.; Scheffler, M.



Energy landscapes and global thermodynamics for alanine peptides  

NASA Astrophysics Data System (ADS)

We compare different approaches for computing the thermodynamics of biomolecular systems. Techniques based on parallel replicas evolving via molecular dynamics or Monte Carlo simulations produce overlapping histograms for the densities of states. In contrast, energy landscape methods employ a superposition partition function constructed from local minima of the potential energy surface. The latter approach is particularly powerful for systems exhibiting broken ergodicity, and it is usually implemented using a harmonic normal mode approximation, which has not been extensively tested for biomolecules. The present contribution compares these alternative approaches for small alanine peptides modelled using the CHARMM and AMBER force fields. Densities of states produced from canonical sampling using multiple temperature replicas provide accurate reference data to evaluate the effect of the harmonic normal mode approximation in the superposition calculations. This benchmarking lays foundations for the application of energy landscape methods to larger biomolecules. It will also provide well characterised model systems for developing enhanced sampling methods, and for the treatment of anharmonicity corresponding to individual local minima.

Somani, Sandeep; Wales, David J.



Energy landscapes and global thermodynamics for alanine peptides.  


We compare different approaches for computing the thermodynamics of biomolecular systems. Techniques based on parallel replicas evolving via molecular dynamics or Monte Carlo simulations produce overlapping histograms for the densities of states. In contrast, energy landscape methods employ a superposition partition function constructed from local minima of the potential energy surface. The latter approach is particularly powerful for systems exhibiting broken ergodicity, and it is usually implemented using a harmonic normal mode approximation, which has not been extensively tested for biomolecules. The present contribution compares these alternative approaches for small alanine peptides modelled using the CHARMM and AMBER force fields. Densities of states produced from canonical sampling using multiple temperature replicas provide accurate reference data to evaluate the effect of the harmonic normal mode approximation in the superposition calculations. This benchmarking lays foundations for the application of energy landscape methods to larger biomolecules. It will also provide well characterised model systems for developing enhanced sampling methods, and for the treatment of anharmonicity corresponding to individual local minima. PMID:24089721

Somani, Sandeep; Wales, David J



Oxidative Modifications of Rat Liver Cell Components During Fasciola hepatica Infection  

PubMed Central

The aim of this paper was to assess the influence of Fasciola hepatica infection on oxidative modifications of rat liver cell components such as proteins and lipids. Wistar rats were infected per os with 30 metacercariae of F. hepatica. Activities and concentrations of liver damage markers were determined in the 4th, 7th, and 10th week postinfection (wpi). A decrease in antioxidant capacity of the host liver, manifested by a decrease in total antioxidant status (TAS), was observed. Diminution of antioxidant abilities resulted in enhanced oxidative modifications of lipids and proteins. F. hepatica infection enhanced lipid peroxidation, which was visible in the statistically significant increase in the level of different lipid peroxidation products such as conjugated dienes (CDs), lipid hydroperoxides (LOOHs), malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). The level of protein modification markers in the rat liver was also significantly changed and the most intensified changes were observed at seventh week postinfection. Concentration of carbonyl groups and dityrosine was significantly increased, whereas the level of tryptophan and sulfhydryl and amino groups was decreased. Changes in the antioxidant abilities of the liver and in the lipid and protein structure of the cell components resulted in destruction of the function of the liver. F. hepatica infection was accompanied by raising serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers of liver damage. A significant decrease in lysosomal as well as in the total activity of cathepsin B during fasciolosis was also observed.

Siemieniuk, Ewa; Kolodziejczyk, Lidia; Skrzydlewska, Elzbieta



Human liver methionine cycle: MAT1A and GNMT gene resequencing, functional genomics, and hepatic genotype-phenotype correlation.  


The "methionine cycle" plays a critical role in the regulation of concentrations of (S)-adenosylmethionine (AdoMet), the major biological methyl donor. We set out to study sequence variation in genes encoding the enzyme that synthesizes AdoMet in liver, methionine adenosyltransferase 1A (MAT1A) and the major hepatic AdoMet using enzyme, glycine N-methyltransferase (GNMT), as well as functional implications of that variation. We resequenced MAT1A and GNMT using DNA from 288 subjects of three ethnicities, followed by functional genomic and genotype-phenotype correlation studies performed with 268 hepatic biopsy samples. We identified 44 and 42 polymorphisms in MAT1A and GNMT, respectively. Quantitative Western blot analyses for the human liver samples showed large individual variation in MAT1A and GNMT protein expression. Genotype-phenotype correlation identified two genotyped single-nucleotide polymorphisms (SNPs), reference SNP (rs) 9471976 (corrected p = 3.9 × 10(-10)) and rs11752813 (corrected p = 1.8 × 10(-5)), and 42 imputed SNPs surrounding GNMT that were significantly associated with hepatic GNMT protein levels (corrected p values < 0.01). Reporter gene studies showed that variant alleles for both genotyped SNPs resulted in decreased transcriptional activity. Correlation analyses among hepatic protein levels for methionine cycle enzymes showed significant correlations between GNMT and MAT1A (p = 1.5 × 10(-3)) and between GNMT and betaine homocysteine methyltransferase (p = 1.6 × 10(-7)). Our discovery of SNPs that are highly associated with hepatic GNMT protein expression as well as the "coordinate regulation" of methionine cycle enzyme protein levels provide novel insight into the regulation of this important human liver biochemical pathway. PMID:22807109

Ji, Yuan; Nordgren, Kendra K S; Chai, Yubo; Hebbring, Scott J; Jenkins, Gregory D; Abo, Ryan P; Peng, Yi; Pelleymounter, Linda L; Moon, Irene; Eckloff, Bruce W; Chai, Xiaoshan; Zhang, Jianping; Fridley, Brooke L; Yee, Vivien C; Wieben, Eric D; Weinshilboum, Richard M



Human Liver Methionine Cycle: MAT1A and GNMT Gene Resequencing, Functional Genomics, and Hepatic Genotype-Phenotype Correlation  

PubMed Central

The “methionine cycle” plays a critical role in the regulation of concentrations of (S)-adenosylmethionine (AdoMet), the major biological methyl donor. We set out to study sequence variation in genes encoding the enzyme that synthesizes AdoMet in liver, methionine adenosyltransferase 1A (MAT1A) and the major hepatic AdoMet using enzyme, glycine N-methyltransferase (GNMT), as well as functional implications of that variation. We resequenced MAT1A and GNMT using DNA from 288 subjects of three ethnicities, followed by functional genomic and genotype-phenotype correlation studies performed with 268 hepatic biopsy samples. We identified 44 and 42 polymorphisms in MAT1A and GNMT, respectively. Quantitative Western blot analyses for the human liver samples showed large individual variation in MAT1A and GNMT protein expression. Genotype-phenotype correlation identified two genotyped single-nucleotide polymorphisms (SNPs), reference SNP (rs) 9471976 (corrected p = 3.9 × 10?10) and rs11752813 (corrected p = 1.8 × 10?5), and 42 imputed SNPs surrounding GNMT that were significantly associated with hepatic GNMT protein levels (corrected p values < 0.01). Reporter gene studies showed that variant alleles for both genotyped SNPs resulted in decreased transcriptional activity. Correlation analyses among hepatic protein levels for methionine cycle enzymes showed significant correlations between GNMT and MAT1A (p = 1.5 × 10?3) and between GNMT and betaine homocysteine methyltransferase (p = 1.6 × 10?7). Our discovery of SNPs that are highly associated with hepatic GNMT protein expression as well as the “coordinate regulation” of methionine cycle enzyme protein levels provide novel insight into the regulation of this important human liver biochemical pathway.

Ji, Yuan; Nordgren, Kendra K. S.; Chai, Yubo; Hebbring, Scott J.; Jenkins, Gregory D.; Abo, Ryan P.; Peng, Yi; Pelleymounter, Linda L.; Moon, Irene; Eckloff, Bruce W.; Chai, Xiaoshan; Zhang, Jianping; Fridley, Brooke L.; Yee, Vivien C.; Wieben, Eric D.



Cloning and functional characterization of the bile acid-sensitive methotrexate carrier from rat liver cells.  


We have cloned two complementary DNAs (cDNAs), RL-Mtx-1 and RL-Mtx-2, corresponding to the bile acid- sensitive methotrexate carrier from rat liver by direct full-length rapid amplification of cDNA ends polymerase chain reaction (RACE-PCR) using degenerated primers that were deduced from published sequences of tumor cell methotrexate transporters. When expressed in Xenopus laevis oocytes and cosM6 cells, both clones mediate methotrexate and bumetanide transport. RL-Mtx-1 consists of 2,445 bp with an open reading frame of 1,536 bp. The corresponding protein with 512 amino acids has a molecular weight of 58 kd. RL-Mtx-2 (2,654 bp) differs by an additional insert of 203 bp. This insert is located in frame at position 1,196 of the RL-Mtx-1 and contains the typical splice junction sites at the 5' and 3' end, indicating that the RL-Mtx-2 messenger RNA (mRNA) is generated by alternative splicing. The insert contains a stop codon that shortens the RL-Mtx-2 protein to 330 amino acids (38 kd). Both cDNAs contain the binding site sequence for the dioxin/nuclear translocator responsive element (Ah/Arnt-receptor) in conjunction with a barbiturate recognition sequence (Barbie box). Preliminary results show that the Barbie box acts as a negative regulatory element. The two liver cDNA clones show homologies to the published sequences of folate and the reduced folate carriers, but no homology is found to the transport systems for organic anions like the Ntcp1, oatp1, OAT-K1, and OAT1. Expression of the mRNA for the methotrexate carrier is found in liver, kidney, heart, brain, spleen, lung, and skeletal muscle, but not in the testis as revealed by Northern blot analysis. The highest abundance of the mRNA is found in the kidney. PMID:10827155

Honscha, W; Dötsch, K U; Thomsen, N; Petzinger, E



CYP2E1: biochemistry, toxicology, regulation and function in ethanol-induced liver injury.  


Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by ethanol. CYP2E1 is of interest because of its ability to metabolize and activate many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of HepG2 cell lines developed to constitutively express the human CYP2E1 in assessing the actions of CYP2E1. Regulation of CYP2E1 is quite complex and will be briefly reviewed. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury. PMID:14527082

Kessova, Irina; Cederbaum, Arthur I



Liver abnormalities in Turner syndrome  

Microsoft Academic Search

We evaluated whether hepatic abnormalities represent a specific feature in girls with Turner syndrome (TS) or whether they\\u000a are related to an increased susceptibility to hormonal therapies and\\/or other factors. Alanine aminotransferase, aspartate\\u000a aminotransferase and ?-glutamyl transferase were monitored in 70 patients with TS for a mean period of 7.6?±?4.2 years. An\\u000a increase in serum liver enzymes was observed in

M. Salerno; S. Di Maio; N. Gasparini; M. Rizzo; P. Ferri; P. Vajro



Heap of stones: an unusual cause for biliary colic and elevated liver function tests.  


A 40-year old woman presented with symptomatic intrahepatic gallstones in one liver segment only four years after cholecystectomy for cholelithiasis. Multiple small, yellow and round calculi were completely removed from the intrahepatic bile ducts via ERCP. The young age of the patient, recurrence of gallstones after cholecystectomy and intrahepatic gallstones suggested a subtype of the low-phospholipid associated cholelithiasis syndrome, a monogenic form of cholesterol cholelithiasis due to variations of the ABCB4 gene that encodes the canalicular phospholipid transporter MDR3. PMID:23619268

Wittenburg, Henning; Keim, Volker; Hoffmeister, Albrecht


Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis  

PubMed Central

SUMMARY Background Non-alcoholic steatohepatitis (NASH) is a common cause of serum alanine aminotransferase (ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations reflect the liver injury. Aim To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy. Methods The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non-alcoholic Steatohepatitis (PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to ?40 U/L and by ?30% of baseline. Liver biopsies taken before and after treatment were scored for non-alcoholic fatty liver disease activity (NAS) and fibrosis. Results ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients (P < 0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS (P < 0.001), but not fibrosis scores (P = 0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both (P < 0.05). Weight loss (?2 kg) was also associated with ALT response (P < 0.001), improvements in NAS (P < 0.001) and fibrosis (P < 0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (?2 kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E. Conclusions Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. Clinical Trial Number: NCT00063622.

Hoofnagle, J. H.; Van Natta, M. L.; Kleiner, D. E.; Clark, J. M.; Kowdley, K. V.; Loomba, R.; Neuschwander-Tetri, B. A.; Sanyal, A. J.; Tonascia, J.



Safety of oligonol, a highly bioavailable lychee-derived polyphenolic antioxidant, on liver, kidney and heart function in rats.  


Oligonol (OLG), derived from lychee fruit, is a novel compound produced from the oligomerization of polyphenols. In this study, the acute effect of OLG treatment was investigated on heart, liver and kidney in rats. OLG treatment at two different doses (15 or 30?mg/kg body weight) and two different time points (1 day or 7 days of treatment) demonstrated that no toxic effects were observed on heart, liver and renal functions. Moreover, OLG did not induce any DNA damage or oxidative stress as measured by 8-hydroxy-2'-deoxyguanosine levels in plasma. OLG supplementation increased the phosphorylation of myocardial endothelial nitric oxide (NO) level (p-eNOS) in both the treatment groups. Even the low dose OLG treatment (15mg/kg b.w) demonstrated an increase in p-eNOS/eNOS ratio after normalization of p-eNOS values with eNOS on day 1 (1.5-fold) and day 7 (2.2-fold) groups as compared to control. The above results suggest that OLG treatment increases endothelial NO levels and may play a role in NO-mediated vasodilatory effects without adverse side effects on cardiovascular function. This endothelial NO production may underlie the beneficial effect of OLG in cardiovascular health. PMID:22694591

Thirunavukkarasu, Mahesh; Zhan, Lijun; Wakame, Koji; Fujii, Hajime; Moriyama, Hiroyoshi; Bagchi, Manashi



[Isoflavone genistein-8-c-glycoside prevents the oxidative damages in structure and function of rat liver microsomal membranes].  


Bioflavonoids (polyhydroxyphenols) are ubiquitous components of plants, fruits and vegetables; these compounds are efficient scavengers of free oxygen radicals and peroxides. The aim of this study was to investigate the antioxidant and radioprotective effects of genistein-8-C-glicoside (G8CG), an isoflavone, isolated from the flowers of Lipinus luteusl L. G8CG prevents dose-dependently the destruction of the cytochrome P-450 and its conversion to an inactive form cytochrome P-420, inhibits membrane lipid peroxidation and membrane SH-group oxidation in isolated rat liver microsomal membranes under tert-butylhydroperoxide-induced oxidative stress. Single whole-body gamma-irradiation (1 Gy) of rats results in blood plasma and liver microsomal membrane lipid peroxidation, impairments of microsomal membrane structure and function. Rat treatment with G8CG (75 mg/kg) developed the clear protective effect, stabilized membrane structure and improved the parameters of the monooxygenase function. We can conclude that G8CG can be used as antioxidant and radioprotective agent. PMID:14608676

Zavodnik, L B


Effect of heme oxygenase-1 on renal function in rats with liver cirrhosis  

PubMed Central

AIM: To investigate the role of heme oxygenase-1 (HO-1) in pathogenesis of experimental hepatorenal syndrome (HRS). METHODS: Rats were divided into liver cirrhotic group, zinc protoporphyrin IX (ZnPP) treatment group, cobalt protoporphyrin (CoPP) treatment group and sham group. Biliary cirrhosis was established by bile duct ligation in the first three groups. Rats in the ZnPP and CoPP treatment groups received intraperitoneal injection of ZnPP and CoPP, respectively, 24 h before sample collection. Expression of HO-1 mRNA in kidney was detected by reverse-transcription polymerase chain reaction, while protein expression was determined by immunohistochemical analysis. Hematoxylin and eosin staining was performed to observe liver cirrhosis and renal structure. Renal artery blood flow, mean arterial pressure and portal vein pressure, 24 h total urinary volume, serum and urine sodium concentrations, and creatinine clearance rate (Ccr) were also measured. RESULTS: The HO-1 mRNA and protein expression levels in kidney, 24 h total urinary volume, renal artery blood flow, serum and urine sodium concentration and Ccr were lower in cirrhotic group than in sham group (P < 0.05). However, they were significantly lower in ZnPP treatment group than in cirrhotic group and significantly higher in CoPP treatment group than in cirrhotic group (P < 0.05). CONCLUSION: Low HO-1 expression level in kidney is an important factor for experimental HRS.

Guo, Shi-Bin; Duan, Zhi-Jun; Li, Qing; Sun, Xiao-Yu



Effects of acute ethanol administration of female rat liver as a function of aging  

SciTech Connect

Female Fischer 344 rats, aged 4, 14, and 25 months, received 4.0 g/kg of ethanol by intraperitoneal (i.p.) injection. Blood alcohol concentrations 2.5, 6 and 16 hr after ethanol injection were similar in the three age groups. Hepatic glutathione (GSH) levels were diminished 6 hr after ethanol injection, and there were no age-dependent differences in the depleted levels (3.2 {plus minus} 0.1, 3.5 {plus minus} 0.2, and 3.0 {plus minus} 0.5 {mu}g GSH/g liver). However, GSH contents in livers of young-adult rats approached control levels after 16 hr, whereas they remained depressed in older rats. Serum levels of hepatic enzymes were significantly elevated 6 hr after ethanol administration. The increases were greater in middle-aged and old rats than in young-adult rats. The results suggest that middle-aged and old rats are more susceptible than young rats to the acute toxicity of ethanol.

Rikans, L.E.; Snowden, C.D. (Univ. of Oklahoma College of Medicine, Oklahoma City (USA))



Spatial imaging of cooperative systems in capillaries (Hb, HbO2) and cells (Redox states and changes of subcellular functional structures) in perfused liver  

NASA Astrophysics Data System (ADS)

Light scattering in living tissues is mainly caused by subcellular particles like mitochondria. The size of mitochondria changes according to differences in the functional status. Therefore light scattering should be a useful technique for monitoring the functional state in tissues. We investigated functional parameters in our model of the isolated perfused rat liver. For the measurements of light scattering we used the EMPHO SSK Oxyscan. Backscattered light from tissue is shown in 3D images. We found an interesting relation between structures of the liver and the patterns of the relating 3D images. In addition, our underlying spectra show the redox state of cytochromes. This new method of tissue imaging should give the opportunity of new insights into liver function.

Boehnert, Markus; Rauh, Robert; Kessler, Manfred D.



A versatile proline/alanine transporter in the unicellular pathogen Leishmania donovani regulates amino acid homoeostasis and osmotic stress responses.  


Unlike all other organisms, parasitic protozoa of the family Trypanosomatidae maintain a large cellular pool of proline that, together with the alanine pool, serve as alternative carbon sources as well as reservoirs of organic osmolytes. These reflect adaptation to their insect vectors whose haemolymphs are exceptionally rich in the two amino acids. In the present study we identify and characterize a new neutral amino acid transporter, LdAAP24, that translocates proline and alanine across the Leishmania donovani plasma membrane. This transporter fulfils multiple functions: it is the sole supplier for the intracellular pool of proline and contributes to the alanine pool; it is essential for cell volume regulation after osmotic stress; and it regulates the transport and homoeostasis of glutamate and arginine, none of which are its substrates. Notably, we provide evidence that proline and alanine exhibit different roles in the parasitic response to hypotonic shock; alanine affects swelling, whereas proline influences the rate of volume recovery. On the basis of our data we suggest that LdAAP24 plays a key role in parasite adaptation to its varying environments in host and vector, a phenomenon essential for successful parasitism. PMID:22994895

Inbar, Ehud; Schlisselberg, Doreen; Suter Grotemeyer, Marianne; Rentsch, Doris; Zilberstein, Dan



Kinetics of l-Alanine Escape from Xylem Vessels  

PubMed Central

Labeled (3H or 14C) l-alanine was perfused through the xylem vessels of isolated tomato internodes (Lycopersicon esculentum cv. Moneymaker) at various concentrations (10?6 molar to 10?2 molar). At each concentration the escape of l-alanine from the xylem vessels was apparently a first order process, which is in agreement with Horwitz' (1958, Plant Physiology 33:81-93) model for irreversible escape from the xylem vessels. The escape constant (K) decreased at higher concentrations of l-alanine, which implies that Horwitz' model is inappropriate to describe the kinetics of l-alanine escape, and that the escape at least partly is a saturable process. To obtain data that relate the concentration of l-alanine in the xylem vessels and the escape rate of the amino acid, average escape rates per internode were measured and the corresponding concentrations were calculated from the integrated form of the Michaelis-Menten equation. As the concentration dependence of the escape rate was biphasic, three possible mechanisms were considered, escape being caused by: (a) saturable amino acid uptake of cells around the xylem vessels and diffusion into the free space; (b) saturable uptake of the cells around the xylem vessels, but at higher amino acid concentrations in the xylem vessels the number of cells, that participate in the uptake, increases; (c) two, simultaneously operating, saturable uptake systems in the cells around the xylem vessels.

van Bel, Aart J. E.; Mostert, Elias; Borstlap, Adrianus C.



Inhibition of mycobacterial alanine racemase activity and growth by thiadiazolidinones.  


The genus Mycobacterium includes non-pathogenic species such as M. smegmatis, and pathogenic species such as M. tuberculosis, the causative agent of tuberculosis (TB). Treatment of TB requires a lengthy regimen of several antibiotics, whose effectiveness has been compromised by the emergence of resistant strains. New antibiotics that can shorten the treatment course and those that have not been compromised by bacterial resistance are needed. In this study, we report that thiadiazolidinones, a relatively little-studied heterocyclic class, inhibit the activity of mycobacterial alanine racemase, an essential enzyme that converts l-alanine to d-alanine for peptidoglycan synthesis. Twelve members of the thiadiazolidinone family were evaluated for inhibition of M. tuberculosis and M. smegmatis alanine racemase activity and bacterial growth. Thiadiazolidinones inhibited M. tuberculosis and M. smegmatis alanine racemases to different extents with 50% inhibitory concentrations (IC50) ranging from <0.03 to 28?M and 23 to >150?M, respectively. The compounds also inhibited the growth of these bacteria, including multidrug resistant strains of M. tuberculosis. The minimal inhibitory concentrations (MIC) for drug-susceptible M. tuberculosis and M. smegmatis ranged from 6.25?g/ml to 100?g/ml, and from 1.56 to 6.25?g/ml for drug-resistant M. tuberculosis. The in vitro activities of thiadiazolidinones suggest that this family of compounds might represent starting points for medicinal chemistry efforts aimed at developing novel antimycobacterial agents. PMID:23680030

Lee, Yashang; Mootien, Sara; Shoen, Carolyn; Destefano, Michelle; Cirillo, Pier; Asojo, Oluwatoyin A; Yeung, Kacheong R; Ledizet, Michel; Cynamon, Michael H; Aristoff, Paul A; Koski, Raymond A; Kaplan, Paul A; Anthony, Karen G



Comparative study of glycine, alanine or casein as inert nitrogen sources in endotoxemic rats.  


Pharmacological effects of dietary amino acids (AA) and peptides must be compared to an isonitrogenous control that is as inert as possible. To establish a rationale for the choice of such a control, potential metabolic and nutritional effects of three currently used nitrogenous controls (glycine, alanine, and casein) were evaluated in an endotoxemic rat model that has well-defined alterations in AA and protein metabolism. Five-week-old male Sprague-Dawley rats (113 +/- 1 g) were randomly assigned to four groups and received at d 0 an intraperitoneal injection of endotoxin (3 mg/kg). After withdrawal of food for 24 h, the rats were enterally refed for 48 h with a liquid diet (Osmolite((R))) supplemented with 0.19 g N. kg(-1). d(-1) in the form of glycine [lipopolysaccharide (LPS)-GLY group], alanine (LPS-ALA group) or casein (LPS-CAS group). One group (LPS group) received only Osmolite((R)). Plasma, two skeletal muscles, the liver and the intestine were then removed. Body and tissue weights and tissue protein contents did not differ among the four groups. Intestine histomorphometry showed no significant difference among groups. Jejunal hydrolase activities were significantly affected by the nitrogenous supplementations, but no effect was observed in the ileum. Only limited significant effects were observed on plasma and tissue-free AA concentrations, except for an accumulation of glycine in the plasma and tissues from the LPS-GLY group, compared to other groups. Overall, whereas glycine as a nitrogenous control should be used with care, either alanine or casein may be used as the "placebo," with the choice depending on the study to be performed. PMID:10498760

Chambon-Savanovitch, C; Felgines, C; Farges, M C; Raul, F; Cézard, J P; Davot, P; Vasson, M P; Cynober, L A



Clinical, biochemical, and histological studies of osteomalacia, osteoporosis, and parathyroid function in chronic liver disease.  

PubMed Central

Twenty of 32 patients with either chronic cholestatic or hepatocellular liver disease had bone pain or recent fractures. On bone biopsy five patients had normal bone, 15 had osteomalacia, five had osteoporosis, and seven had a combination of osteomalacia and osteoporosis. In the presence of osteoporosis, osteomalacia was minimal or absent. There was no biochemical, radiological, or histological evidence of excess parathyroid activity. No significant correlations were demonstrated between the plasma and urinary biochemical findings and the presence of either osteoporosis or osteomalacia and bone biopsy was essential for correct diagnosis. There was no statistical relationship between low serum 25-hydroxy vitamin D values and the presence of osteomalacia. Bone disease was not prevented by regular intramuscular vitamin D2, although biochemical changes were improved. Drugs such as corticosteroids and cholestyramine may be important aetiological factors in hepatic osteodystrophy.

Long, R G; Meinhard, E; Skinner, R K; Varghese, Z; Wills, M R; Sherlock, S



Structural and function changes in organelles of liver cells in rats exposed to magnetic fields  

SciTech Connect

Exposure of rats to magnetic fields of 10{sup {minus}3} and 10{sup {minus}2} T for 1 hr daily generated structural changes in hepatocytes mitochondria, endoplasmic reticulum, and ribosomes. Simultaneously there was an increase in the activities of the mitochondrial respiratory enzymes: NADH dehydrogenase, succinic dehydrogenase, and cytochrome oxidase. The extent of the changes in liver cell properties following exposure depend on the duration of exposure to and the strength of the applied magnetic fields. Ultrastructural studies did not reveal any changes in external membranes of hepatocytes or in the membranes of cell nuclei. An increase in the amount of glycogen in hepatocytes of rats exposed to both 10{sup {minus}3} and 10{sup {minus}2} T was noted. The high level of cortisol in serum of exposed rats suggests that magnetic field may be a stress generating factor.

Gorczynska, E. (Pomeranian Medical Academy, Szczecin (Poland)); Wegrzynowicz, R. (Academy of Agriculture, Szczecin (Poland))



Hypophysectomy does not alter the acinar zonation of gluconeogenesis or the mitochondrial redox state in rat liver.  

PubMed Central

The biochemical and functional heterogeneity of hepatocytes in different zones of the liver acinus may be related to the concentrations of hormones within the liver acinus. We examined the effects of hypophysectomy, which causes marked changes in plasma hormone levels and in activities of hepatic enzymes that are normally heterogeneously distributed, on the degree of metabolic zonation within the liver acinus. In hypophysectomized rats the activity of alanine aminotransferase was increased, but its normal zonation (predominance in the periportal zone) was preserved. The activity in cultured periportal and perivenous hepatocytes was increased by dexamethasone, but not by glucagon. Periportal hepatocytes from hypophysectomized rats expressed higher rates of gluconeogenesis in culture than did perivenous hepatocytes, irrespective of the absence or presence of dexamethasone, glucagon or insulin. Similar differences in rates of ketogenesis and in the mitochondrial redox state in response to glucagon were observed between periportal and perivenous hepatocytes from hypophysectomized rats as between cell populations from normal rats. Although hypophysectomy causes marked changes in hepatic enzyme activities, it does not alter the degree of zonation of alanine aminotransferase, gluconeogenesis or the mitochondrial redox state within the liver acinus.

Tosh, D; Alberti, K G; Agius, L



Nucleation kinetics, growth and studies of ?-alanine single crystals.  


Solubility and metastable zone width for the re-crystallized salt of ?-alanine was determined. Induction period measurement for the selected supersaturation ratios at room temperature (31 °C) was carried out for supersaturated aqueous solutions of ?-alanine and it is noticed that induction period decreases with increase of supersaturation ratio. The nucleation parameters such as Gibbs free energy change, radius and number of molecules of the critical nucleus, interfacial tension and the nucleation rate have been evaluated by classical nucleation theory. Single crystals of ?-alanine were grown using the optimized nucleation parameters by solution method and grown crystals have been subjected to various studies like XRD studies, FTIR, optical, thermal and SHG studies. PMID:23548638

Shanthi, D; Selvarajan, P; HemaDurga, K K; Lincy Mary Ponmani, S



Uncertainties in alanine dosimetry in the therapeutic dose range.  


A method for evaluating the overall uncertainty of alanine EPR transfer dosimetry in the therapeutic dose range is described. The method uses experimental data on EPR signal reproducibility from replicate dosimeters irradiated to low doses (1-5 Gy), estimates of Type B uncertainties, and Monte Carlo simulations of heteroscedastic orthogonal linear regression. A Bruker ECS106 spectrometer and Bruker alanine dosimeters have been used for this evaluation. The results demonstrate that alanine dosimetry can be used for transfer dosimetry in that range with the overall uncertainty 1.5-4% (1sigma) depending on the dose, the number of replicate dosimeters. and the duration of the calibration session (the session should not exceed one working day). PMID:12102352

Nag, Vitaly; Sholom, Sergey V; Chumak, Vadim V; Desrosiers, Marc F



Living donor liver transplantation for acute liver failure in pediatric patients caused by the ingestion of fireworks containing yellow phosphorus.  


Yellow phosphorus is a protoplasmic toxicant that targets the liver. The ingestion of fireworks containing yellow phosphorus, either by children who accidentally consume them or by adults who are attempting suicide, often results in death due to acute liver failure (ALF). We present the outcomes of 10 children who ingested fireworks containing yellow phosphorus. There were 6 boys and 4 girls, and their ages ranged from 21 to 60 months. One patient remained stable without liver complications and was discharged. Three patients died of hepatorenal failure and cardiovascular collapse, and living donor liver transplantation (LDLT) was performed for 6 patients. The patients had grade II or III encephalopathy, a mean alanine aminotransferase level of 1148.2 IU/L, a mean aspartate aminotransferase level of 1437.5 IU/L, a mean total bilirubin level of 6.9 mg/dL, a mean international normalized ratio of 6.6, a mean Pediatric End-Stage Liver Disease score of 33.7, and a mean Child-Pugh score of 11.3. Postoperatively, 2 patients had persistent encephalopathy and died on the second or third postoperative day, and 1 patient died of cardiac arrest on the first postoperative day despite a well-functioning graft. The other 3 patients were still alive at a mean of 204 days. In conclusion, the ingestion of fireworks containing yellow phosphorus causes ALF with a high mortality rate. When signs of irreversible ALF are detected, emergency LDLT should be considered as a lifesaving procedure; however, if yellow phosphorus toxicity affects both the brain and the heart in addition to the liver, the mortality rate remains very high despite liver transplantation. PMID:21761550

Ates, Mustafa; Dirican, Abuzer; Ozgor, Dincer; Aydin, Cemalettin; Isik, Burak; Ara, Cengiz; Yilmaz, Mehmet; Ayse Selimoglu, M; Kayaalp, Cuneyt; Yilmaz, Sezai



On the existence of ``l-threonine formate'', ``l-alanine lithium chloride'' and ``bis l-alanine lithium chloride'' crystals  

NASA Astrophysics Data System (ADS)

We argue that the recently reported crystals "L-threonine formate" as well as "L-alanine lithium chloride" and "bis L-alanine lithium chloride" actually are the well-known crystals L-threonine and L-alanine, respectively.

Petrosyan, A. M.; Ghazaryan, V. V.; Fleck, M.



A comparison of tacrolimus and cyclosporine in liver transplantation: effects on renal function and cardiovascular risk status.  


A retrospective chart review of 1065 consecutive liver allograft recipients in 11 centers from January 1997 to September 1998 was performed. Patients were followed for 3 years or until graft loss. Patients received either tacrolimus (n = 594), cyclosporine (n = 450) or no calcineurin inhibitor (n = 21). Model for end-stage liver disease (MELD) scores at time of transplant were similar between the two groups. During follow-up, more patients switched from cyclosporine to tacrolimus (26.7%) than from tacrolimus to cyclosporine (12.8%; p < 0.0001). Patient and graft survival were equivalent. Corticosteroid use was more common in cyclosporine-treated patients (p < 0.00001). Patients receiving tacrolimus experienced lower serum creatinine levels at months 3 through 36 (p < 0.0001). Systolic blood pressure was lower in patients receiving tacrolimus (p < 0.001) despite a reduced requirement for anti-hypertensive agents (p < 0.0001). In addition, tacrolimus was associated with lower total cholesterol and triglyceride levels for months 3 through 24 and 3 through 12, respectively (p < 0.01), despite a reduced requirement for anti-hyperlipidemic agents. The incidence of new-onset diabetes mellitus was similar in both groups. While both calcineurin inhibitors were associated with excellent patient and graft survival, renal function, blood pressure and serum lipid levels were significantly better with tacrolimus treatment. PMID:15816894

Lucey, Michael R; Abdelmalek, Manal F; Gagliardi, Rosemarie; Granger, Darla; Holt, Curtis; Kam, Igal; Klintmalm, Goran; Langnas, Alan; Shetty, Kirti; Tzakis, Andreas; Woodle, E Steve



Metabolism of benzene and phenol by a reconstituted purified phenobarbital induced rat liver mixed function oxidase system  

SciTech Connect

Cytochrome P-450 and the electron-donor, NADPH-cytochrome c reductase were isolated from phenobarbital induced rat liver microsomes. Both benzene and its primary metabolite phenol, were substrates for the reconstituted purified phenobarbital induced rat liver mixed function oxidase system. Benzene was metabolized to phenol and the polyhydroxylated metabolites; catechol, hydroquinone and 1,2,4 benzenetriol. Benzene elicited a Type I spectral change upon its interaction with the cytochrome P-450 while phenol's interaction with the cytochrome P-450 produced a reverse Type I spectra. The formation of phenol showed a pH optimum of 7.0 compared with 6.6-6.8 for the production of the polyhyrdoxylated metabolites. Cytochrome P-450 inhibitors, such as metyrapone and SKF 525A, diminished the production of phenol from benzene but not the production of the polyhydroxylated metabolites from phenol. The radical trapping agents, DMSO, KTBA and mannitol, decreased the recovery of polyhydroxylated metabolites, from /sup 14/C-labeled benzene and/or phenol. As KTBA and DMSO interacted with OH. There was a concomitant release of ethylene and methane, which was measured. Desferrioxamine, an iron-chelator and catalase also depressed the recovery of polyhydroxylated metabolites. In summary, benzene and phenol were both substrates for this reconstituted purified enzyme system, but they differed in binding to cytochrome P-450, pH optima and mode of hydroxylation.

Griffiths, J.C.



Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver  

PubMed Central

Background Natural high-density lipoproteins (HDL) possess important physiological functions to the transport of cholesterol from the peripheral tissues to the liver for metabolic degradation and excretion in the bile. Methods and results In this work, we took advantage of this pathway and prepared two different gadolinium (Gd)-DTPA-labeled cholesterol-containing recombinant HDL nanoparticles (Gd-chol-HDL) and Gd-(chol)2-HDL as liver-specific magnetic resonance imaging (MRI) contrast agents. The reconstituted HDL nanoparticles had structural similarity to native HDL, and could be taken up by HepG2 cells via interaction with HDL receptors in vitro. In vivo MRI studies in rats after intravenous injections of 10 ?mol gadolinium per kg of recombinant HDL nanoparticles indicated that both nanoparticles could provide signal enhancement in the liver and related organs. However, different T1-weighted image details suggested that they participated in different cholesterol metabolism and excretion pathways in the liver. Conclusion Such information could be highly useful to differentiate functional changes as well as anatomic differences in the liver. These cholesterol-derived contrast agents and their recombinant HDL preparations may warrant further development as a new class of contrast agents for MRI of the liver and related organs.

Rui, Mengjie; Guo, Wei; Ding, Qian; Wei, Xiaohui; Xu, Jianrong; Xu, Yuhong



Biochemical and functional characterization of the rat liver glucose-transport system. Comparisons with the adipocyte glucose-transport system.  

PubMed Central

The properties of the glucose-transport systems in rat adipocytes and hepatocytes were compared in cells prepared from the same animals. Hormones and other agents which cause a large stimulation of 3-O-methylglucose transport in adipocytes were without acute effect in hepatocytes. Hepatocytes displayed a lower affinity for 3-O-methylglucose (20 mM) and alternative substrates than adipocytes (6 mM), whereas inhibitor affinities were similar in both cell types. The concentration and distribution of glucose transporters were determined by Scatchard analysis of D-glucose-inhibitable [3H]cytochalasin B binding to subcellular fractions. In liver, most of the transporters were located in the plasma membrane (42 +/- 5 pmol/mg of protein) with a small amount (4 +/- 3 pmol/mg) in the low-density microsomal fraction ('microsomes'), the reverse of the situation in adipocytes. Glucose transporters were covalently labelled with [3H]cytochalasin B by using the photochemical cross-linking agent hydroxysuccinimidyl-4-azidobenzoate and analysed by SDS/polyacrylamide-gel electrophoresis. A single D-glucose-inhibitable peak with a molecular mass of 40-50 kDa was seen in both plasma membrane and low-density microsomes. This peak was further characterized by isoelectric focusing and revealed a single peak of specific [3H]cytochalasin B binding at pI 6.05 in both low-density microsomes and plasma membrane, compared with peaks at pI 6.4 and 5.6 in adipocyte membranes. In summary: the glucose-transport system in hepatocytes has a lower affinity and higher capacity than that in adipocytes, and is also not accurately modulated by insulin; the subcellular distribution of glucose transporters in the liver suggests that few intracellular transporters would be available for translocation; the liver transporter has a molecular mass similar to that of the adipocyte transporter; the liver glucose transporter exists as a single charged form (pI 6.05), compared with the multiple forms in adipocytes. This difference in charge could reflect a functionally important difference in molecular structure between the two cell types.

Ciaraldi, T P; Horuk, R; Matthaei, S



Engineered liver for transplantation.  


Orthotopic liver transplantation is the only definitive treatment for end stage liver failure and the shortage of donor organs severely limits the number of patients receiving transplants. Liver tissue engineering aims to address the donor liver shortage by creating functional tissue constructs to replace a damaged or failing liver. Despite decades of work, various bottoms-up, synthetic biomaterials approaches have failed to produce a functional construct suitable for transplantation. Recently, a new strategy has emerged using whole organ scaffolds as a vehicle for tissue engineering. This technique involves preparation of these organ scaffolds via perfusion decellularization with the resulting scaffold retaining the circulatory network of the native organ. This important phenomenon allows for the construct to be repopulated with cells and to be connected to the blood torrent upon transplantation. This opinion paper presents the current advances and discusses the challenges of creating fully functional transplantable liver grafts with this whole liver engineering approach. PMID:23791465

Uygun, Basak E; Yarmush, Martin L



Transients and stable radical from the deamination of ?-alanine  

Microsoft Academic Search

The objects of investigation were single crystals of L-?-alanine, in which radical anion CH3 C?H CO\\u000a 2\\u000a ?\\u000a has been formed by radiation induced deamination of alanine. Previously, this stable radical has been spectrally identified\\u000a (?max, ?=1100 M?1·cm?1), and its characteristics have found to be identical with characteristics of the same radical obtained by pulse radiolysis\\u000a in aqueous solution. The

Z. P. Zagórski; K. Sehested




PubMed Central

The title compound, [Li2(SO4)(C3H7NO2)(H2O)]n, is a coordination polymer in which the ?-alanine residues remain in the zwitterionic form. The crystal structure consists of corrugated sheets of [LiO4] and [SO4] tetra­hedra parallel to (010) with the ?-alanine mol­ecules located between the sheets. The two independent Li+ cations are four-coordinated by O atoms in a distorted tetra­hedral geometry. The crystal structure is formed by stacking of alternate organic and inorganic layers along the a axis. The crystal structure is further stabilized by N—H?O hydrogen bonds.

Sweetlin, M. Daniel; Eapen, Shibu M.; Perumal, S.; Ramalingom, S.



Paradox of mistranslation of serine for alanine caused by AlaRS recognition dilemma.  


Mistranslation arising from confusion of serine for alanine by alanyl-tRNA synthetases (AlaRSs) has profound functional consequences. Throughout evolution, two editing checkpoints prevent disease-causing mistranslation from confusing glycine or serine for alanine at the active site of AlaRS. In both bacteria and mice, Ser poses a bigger challenge than Gly. One checkpoint is the AlaRS editing centre, and the other is from widely distributed AlaXps-free-standing, genome-encoded editing proteins that clear Ser-tRNA(Ala). The paradox of misincorporating both a smaller (glycine) and a larger (serine) amino acid suggests a deep conflict for nature-designed AlaRS. Here we show the chemical basis for this conflict. Nine crystal structures, together with kinetic and mutational analysis, provided snapshots of adenylate formation for each amino acid. An inherent dilemma is posed by constraints of a structural design that pins down the alpha-amino group of the bound amino acid by using an acidic residue. This design, dating back more than 3 billion years, creates a serendipitous interaction with the serine OH that is difficult to avoid. Apparently because no better architecture for the recognition of alanine could be found, the serine misactivation problem was solved through free-standing AlaXps, which appeared contemporaneously with early AlaRSs. The results reveal unconventional problems and solutions arising from the historical design of the protein synthesis machinery. PMID:20010690

Guo, Min; Chong, Yeeting E; Shapiro, Ryan; Beebe, Kirk; Yang, Xiang-Lei; Schimmel, Paul



Paradox of mistranslation of serine for alanine caused by AlaRS recognition dilemma  

PubMed Central

Mistranslation from confusion of serine for alanine by alanyl-tRNA synthetases (AlaRSs) has profound functional consequences1-3. Throughout evolution, two editing-checkpoints prevent disease-causing mistranslation from confusing glycine or serine for alanine at the active site of AlaRS. In both bacteria and mice, Ser poses a bigger challenge than Gly1,2. One checkpoint is the AlaRS editing center, while the other is from widely distributed AlaXps—free-standing, genome-encoded editing proteins that clear Ser-tRNAAla. The paradox of misincorporating both a smaller (glycine) and a larger amino acid (serine) suggests a deep conflict for nature-designed AlaRS. To understand the chemical basis for this conflict, kinetic and mutational analysis, together with nine crystal structures, provided snapshots of adenylate formation for each amino acid. An inherent dilemma is posed by constraints of a structural design that pins down the ?–amino group of the bound amino acid using an acidic residue. This design, of more than 3 billion years, creates a serendipitous interaction with the serine OH that is difficult to avoid. Apparently not able to find better architecture for recognition of alanine, the serine misactivation problem was solved through free-standing AlaXps, which appeared contemporaneously with early AlaRSs. The results reveal unconventional problems and solutions arising from the historical design of the protein synthesis machinery.

Guo, Min; Chong, Yeeting E.; Shapiro, Ryan; Beebe, Kirk; Yang, Xiang-Lei; Schimmel, Paul



Upper Limits of Normal for Serum Alanine Aminotransferase Levels in Chinese Han Population  

PubMed Central

Background and Objectives Serum alanine aminotransferase (ALT) activity is the most common tool for the assessment of liver diseases. However, it is not clear whether the current normal ALT range really discriminate patients with or without liver diseases. The present study was to establish a new normal range of ALT and examine its ability to identify patients with hepatitis B or nonalcoholic fatty liver disease (NAFLD) in Chinese Han population. Methods 53037 adults were included in this study from January 1st 2008 to August 31st 2010. The 95th percentile of ALT in population with relative low risk factors for liver diseases was set as the new upper limits of normal ALT in gender-specific manner. Results The 95th percentile levels at low risk factors for liver diseases were achieved at 35 U/L for men and 23 U/L for women. The concordance statistics for detection were 0.873 (95%CI: 0.865–0.881) for HBV and 0.932 (95%CI: 0.927–0.937) for NAFLD in men while 0.857 (95%CI: 0.850–0.864) for HBV and 0.909 (95%CI: 0.903–0.915) for NAFLD in women. The median sensitivity of the current used ALT upper limit (40 U/L) was 6.6% for HBV and 29.7% for NAFLD and median specificity was 98.7% for men and 99.4% for women. Using our new-derived thresholds, the sensitivities ranged from 35.3% to 61.1% and the specificities were 94.8% for men and 94.6% for women. Conclusions Our results suggest that upper limits of ALT 35 U/L for men and 23 U/L for women in Chinese Han population. Re-consideration of normal limits of ALT should be recommended. Trial Registration ChiCTR-OCS-11001173

Zheng, Ming-Hua; Shi, Ke-Qing; Fan, Yu-Chen; Liu, Wen-Yue; Lin, Xian-Feng; Li, Ling-Fei; Chen, Yong-Ping



Dissociation of reticuloendothelial cell and hepatocyte functions in alcoholic liver disease: a clinical study with a new Tc-99m-labeled hepatobiliary agent  

SciTech Connect

Tc-99m-sulfur colloid scintigrams were abnormal in four patients with hepatic dysfunction due to chronic alcohol abuse. Minimal uptake of radiocolloid in the liver suggested local reticuloendothelial (RE) cell failure. Imaging with a new hepatobiliary agent, Tc-99m-PIPIDA, revealed rapid hepatic accumulation and excretion of radiotracer with adequate visualization of the organ. Scintigraphic findings in these patients indicated a dissociation of hepatocyte and RE cell functions. Demonstration of adequate hepatocyte function with severe RE failure in alcoholic liver disease using a Tc-99m-labeled hepatobiliary agent has not been previously reported.

Rao, B.K.; Weir, G.J. Jr.; Lieberman, L.M.



Some liver functions in the Oriental hornet (Vespa orientalis) are performed in its cuticle: exposure to UV light influences these activities.  


The Oriental hornet Vespa orientalis (Hymenoptera, Vespinae) coordinates its daily activities (e.g. flights out of the nest associated with digging activities and removal of the dug soil from the nest) with the amount of insolation. Thus, the stronger the insolation, the more intense the flight activity and vise versa. The hornet's cuticle bears a few yellow stripes interposed among brown parts of the gastral cuticle. These yellow stripes are composed of two elements, namely, a transparent cuticle and underneath it a layer of yellow granules. When the hornets are exposed to UV light, the layer containing the yellow granules is less active than in hornets kept in the dark. This diminished activity entails a lower production of glucose as well as of several enzymes prevalent also in the liver of mammals, like creatine kinase, alanine aminotransferase, aspartate transaminase. Thus solar irradiation stimulates and produces a change in the metabolic activities of the hornet. The fact that hornets link their flight activity with the insolation leads us to speculate that the sun contributes energetically to the hornet's activity. PMID:19535034

Plotkin, Marian; Volynchik, Stanislav; Itzhaky, Dganit; Lis, Monica; Bergman, David J; Ishay, Jacob S



Liver Transplantation  


... you on a waiting list for a liver transplant. Doctors do liver transplants when other treatment cannot keep a damaged liver ... and replaces it with a healthy one. Most transplant livers come from a donor who has died. ...


Evaluation of liver function impairment and lipid peroxidation induced by lantana camara leaf powder administration in adult rat serum and liver.  


Lantana camara is a common weed and certain medicinal properties have been attributed to this plant, but most varieties of this plant are reported to be highly toxic to animals. The plant is a native of America but a few varieties are indigenous to tropical Asia and Africa. The present investigation was done to study the hepatotoxic and lipid peroxidative effects of this noxious weed on female Wistar rats. Eighty four percent (84%) increase was observed in the activity of AST in group B and 120% increase was noted in group C in serum. In, liver tissue this increase was 66% and 258%. In the case of ALT, 165% increase was observed in group B and 219% increase was observed in group C in serum. In, liver there was 46% increase in group B and 216% increase in group C in the ALT activity. Similarly, 30% and 50% increase in group B and 120% and 300% increase in group C in the activity of ALP was observed with respect to control group. The overall protein concentration was increased in serum and decreased in liver tissue. Lipid peroxidation in liver tissue was inhibited by 22% in group B and 55% in group C. Thus Lantana camara is a toxic plant which produces severe hepatotoxicity in rats, but it also prevented lipid peroxidation that may suggest that Lantana camara may be acting as antioxidant but, exactly which of its component is responsible for this activity is not known and needs future investigations. PMID:17543236

Saini, N; Singh, J; Sehgal, R; Ojha, S



Emerging Therapies for Liver Fibrosis  

Microsoft Academic Search

Liver fibrosis occurs as a result of a wide range of injurious processes and in its end-stage results in cirrhosis. This gross disruption of liver architecture is associated with impaired hepatic function, portal hypertension and significant resultant morbidity and mortality. Indeed, liver fibrosis and cirrhosis represent a major worldwide healthcare burden. Recent progress in liver transplantation, the management of portal

Andrew J. Fowell; John P. Iredale



The major allele of the alanine:glyoxylate aminotransferase gene: seven novel mutations causing primary hyperoxaluria type 1  

Microsoft Academic Search

We describe 7 novel mutations occurring on the major allele of the human AGT gene in patients with primary hyperoxaluria type 1, an autosomal recessive disease resulting from a deficiency of the liver peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT; EC These mutations include 3 small deletions, 570delG, 744delC, and 983_988del, two splice junction mutations, IVS7?1G?C and IVS8+1G?T, and two nonsense

Marion B Coulter-Mackie; Derek Applegarth; Jennifer R Toone; Howard Henderson



Deletion of Smad2 in Mouse Liver Reveals Novel Functions in Hepatocyte Growth and Differentiation  

Microsoft Academic Search

Smad family proteins Smad2 and Smad3 are activated by transforming growth factor (TGF-)\\/activin\\/ nodal receptors and mediate transcriptional regulation. Although differential functional roles of Smad2 and Smad3 are apparent in mammalian development, the relative functional roles of Smad2 and Smad3 in postnatal systems remain unclear. We used Cre\\/loxP-mediated gene targeting for hepatocyte-specific deletion of Smad2 (S2HeKO) in adult mice and

Wenjun Ju; Atsushi Ogawa; Joerg Heyer; Dirk Nierhof; Liping Yu; Raju Kucherlapati; David A. Shafritz; Erwin P. Bottinger



Alanine flux in obese and healthy humans as evaluated by /sup 15/N- and /sup 2/H/sub 3/-labeled alanines  

SciTech Connect

Estimates of plasma alanine flux as measured in humans using L-(/sup 15/N)-alanine or L-(3,3,3-/sup 2/H/sub 3/)alanine were compared by simultaneous intravenous infusion of both tracers. Plasma isotope enrichments were measured by chemical ionization gas chromatography-mass spectrometry. In 16 obese women before and during a hypocaloric diet and in 4 normal men in the postabsorptive and fed states, the fluxes were highly correlated (r2 = 0.93) although plasma alanine flux with the /sup 2/H tracer was two to three times greater than that obtained with (/sup 15/N)alanine. The fluxes decreased with the hypocaloric diet in obese subjects and increased during the fed state in healthy adults. Thus, although the estimates of alanine flux differed according to the tracer used, both appear to give equivalent information about changes in alanine kinetics induced by the nutritional conditions examined.

Hoffer, L.J.; Yang, R.D.; Matthews, D.E.; Bistrian, B.R.; Bier, D.M.; Young, V.R.



Levels of Alanine Aminotransferase Confound Use of Transient Elastography to Diagnose Fibrosis in Patients with Chronic HCV Infection  

PubMed Central

Background & Aims Hepatic elastography (HE) is a non-invasive technique that measures liver stiffness and is used to diagnose hepatic fibrosis. It can help patients thought to have early-stage disease avoid a staging liver biopsy, but only when confounding variables that increase liver stiffness are excluded. Chronic inflammation from hepatitis C virus (HCV) infection is not considered to be one of these variables. Methods We identified 684 patients with HCV and METAVIR fibrosis scores of 0–2 from a prospective, multi-institutional study of liver stiffness in 2880 patients with chronic liver disease. Patients were 49.6±9.0 years old, 64.3% male, and had an average body mass index of 26.7±4.1. Results In a multivariate analysis, inflammation (based on histologic analysis) and level of alanine aminotransferase (ALT) were associated with liver stiffness. The chances of a patient having a level of stiffness that indicates cirrhosis increased with grade of inflammation and level of ALT. Using a conservative, 14.5 kPa cutoff for the diagnosis of cirrhosis, grade 3 inflammation had an odds ratio (OR) of 9.10 (95% confidence interval [CI], 2.49–33.4). Likewise, levels of ALT greater than 80 IU/L and 120 IU/L had ORs of 3.84 (95% CI, 2.10–7.00) and 4.10% (95% CI, 2.18– 7.69), respectively. The effect of the level of ALT persisted when analysis was restricted to patients with fibrosis scores of F0 to F1. Conclusion In patients with HCV infection and early-stage fibrosis, increased levels of ALT correlate with liver stiffness among patients in the lowest strata of fibrosis (METAVIR scores 0–2). Patients without fibrosis but high levels of ALT could have liver stiffness within the range for cirrhosis. Inflammation should be considered a confounding variable in analysis of liver stiffness.

Tapper, Elliot B.; Cohen, Eric B.; Patel, Keyur; Bacon, Bruce; Gordon, Stuart; Lawitz, Eric; Nelson, David; Nasser, Imad A.; Challies, Tracy; Afdhal, Nezam



The unresolved puzzle why alanine extensions cause disease.  


The prospective increase in life expectancy will be accompanied by a rise in the number of elderly people who suffer from ill health caused by old age. Many diseases caused by aging are protein misfolding diseases. The molecular mechanisms underlying these disorders receive constant scientific interest. In addition to old age, mutations also cause congenital protein misfolding disorders. Chorea Huntington, one of the most well-known examples, is caused by triplet extensions that can lead to more than 100 glutamines in the N-terminal region of huntingtin, accompanied by huntingtin aggregation. So far, nine disease-associated triplet extensions have also been described for alanine codons. The extensions lead primarily to skeletal malformations. Eight of these proteins represent transcription factors, while the nuclear poly-adenylate binding protein 1, PABPN1, is an RNA binding protein. Additional alanines in PABPN1 lead to the disease oculopharyngeal muscular dystrophy (OPMD). The alanine extension affects the N-terminal domain of the protein, which has been shown to lack tertiary contacts. Biochemical analyses of the N-terminal domain revealed an alanine-dependent fibril formation. However, fibril formation of full-length protein did not recapitulate the findings of the N-terminal domain. Fibril formation of intact PABPN1 was independent of the alanine segment, and the fibrils displayed biochemical properties that were completely different from those of the N-terminal domain. Although intranuclear inclusions have been shown to represent the histochemical hallmark of OPMD, their role in pathogenesis is currently unclear. Several cell culture and animal models have been generated to study the molecular processes involved in OPMD. These studies revealed a number of promising future therapeutic strategies that could one day improve the quality of life for the patients. PMID:23612654

Winter, Reno; Liebold, Jens; Schwarz, Elisabeth



Therapeutic effect of transplanting magnetically labeled bone marrow stromal stem cells in a liver injury rat model with 70%-hepatectomy  

PubMed Central

Summary Background There are only few reports about the use of bone marrow stromal stem cells (BMSCs) for the treatment of traumatic liver injury. This study aimed to study the therapeutic effect of fluorescence-labeled BMSCs administered to rats subject to traumatic liver injury. Material/Methods Male SD rats with a 70% resection of the liver were injected with feridex-labeled BMSCs which could be induced to functional hepatocytes in vitro. Liver function was assayed and the liver scanned by 1.5-T MRI at 12 hrs and on days 1, 3, 5, 7, and 14 post-operation. The pathological changes of liver sections were monitored. Results The serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, direct bilirubin, and total bilirubin in the transplantation group were significantly lower than the control group. The MRI showed rats of the transplantation group had an oval low signal area at 12 hr after operation; the low signal range gradually expanded and the signal intensity gradually decreased over 14 days after operation. The low signal range in the control group disappeared 12 hr after the operation. After Prussian blue staining, rats of the transplantation group contained blue granules with no significant hypertrophy or edema in hepatocytes, while the control group showed no blue granules with significant hypertrophy and edema. Conclusions The BMSCs transplanted into the injured rat liver gradually migrate to the surrounding liver tissue and partially repair the liver surgical injury in rats. BMSCs may represent an effective therapeutic approach for acute liver injury.

Chen, Xiao-Wu; Zhu, Da-Jian; Ju, Yong-Le; Zhou, Shu-Feng



Prevalence and risk factors for liver involvement in individuals with PiZZ-related lung disease.  


Rationale: ?1-Antitrypsin deficiency is one of the most common heritable human diseases, predisposing to liver and lung injury. Significant heterogeneity in phenotypic expression is well documented, but less is known of the prevalence, severity, and correlates of chronic liver disease among individuals presenting with lung disease. Objectives: To determine the frequency of and risk factors for severe liver fibrosis and cirrhosis among individuals with PiZZ-related lung disease. Methods: A well-characterized cohort of 57 PiZZ adults attending a tertiary referral respiratory clinic was screened prospectively for clinical, laboratory, radiologic, and (when appropriate) histologic evidence of chronic liver disease. Measurements and Main Results: Thirty-six (63.2%) of 57 had a history or clinical findings suggestive of liver disease; or had one or more abnormalities of liver function, or liver ultrasound, and 24 of these underwent liver biopsy. Ten (17.5%) had evidence of severe fibrosis or cirrhosis and were more likely to have higher body mass index (P = 0.04), alanine transaminase (P = 0.0001), alkaline phosphatase (P = 0.0009), prothrombin time (P = 0.0005), and maximal vital capacity (VCmax) (P = 0.04); lower platelet count (P = 0.007); abnormal liver echogenicity (P < 0.001); and splenomegaly (P = 0.001) at ultrasound. Screening with liver ultrasound provided a sensitivity and negative predictive value for severe fibrosis or cirrhosis of 100%, as were the specificity and positive predictive value for platelet count less than or equal to 174,000 per mm(3) and splenomegaly. Among individuals undergoing liver biopsy, fibrosis stage correlated with increasing VCmax (P = 0.02) and % predicted VCmax (P = 0.05), and decreasing residual volume/total lung capacity (TLC) (P = 0.02) and % predicted residual volume/TLC (P = 0.05). Conclusions: Significant chronic liver disease is common in PiZZ individuals with lung disease and can be screened effectively by a combination of conventional tests of liver function, platelet count, and liver ultrasound. PMID:23262512

Dawwas, Muhammad F; Davies, Susan E; Griffiths, William J H; Lomas, David A; Alexander, Graeme J



Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.  


In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant. PMID:23714399

Saliba, F; De Simone, P; Nevens, F; De Carlis, L; Metselaar, H J; Beckebaum, S; Jonas, S; Sudan, D; Fischer, L; Duvoux, C; Chavin, K D; Koneru, B; Huang, M A; Chapman, W C; Foltys, D; Dong, G; Lopez, P M; Fung, J; Junge, G



Enzymological and mutational analysis of a complex primary hyperoxaluria type I phenotype involving alanine: Glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation  

Microsoft Academic Search

Primary hyperoxaluri type 1 (PH1) is a rare autosomal recessive disease caused by a deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). Three unrelated PH1 patients, who possess a novel complex phenotype, are described. At the enzymological level, this phenotype is characterized by a complete, or nearly complete, absence of AGT catalytic activity and reduced AGT immunoreactivity. Unlike normal

C. J. Danpure; P. E. Purdue; J. Allsop; M. J. Lumb; P. R. Jennings; J. I. Scheinman; S. M. Mauer; N. O. Davidson



Quantitative analysis of liver function in percutaneous transhepatic biliary drainage patients  

SciTech Connect

The diagnostic usefulness of Tc-99m DISIDA cholescintigraphy as a predictor of eventual catheter and hepatic function in patients who have undergone percutaneous transhepatic biliary drainage (PTBD) for extrahepatic biliary obstruction was evaluated. Twenty-nine cholescintigrams were performed in 14 patients. The examinations were divided into two groups: Group A (N = 17), in which the patient's clinical status deteriorated within two to three days post-PTBD, and Group B (N = 12), in which the patients did well clinically post-PTBD. No significant difference between the two groups was demonstrated by visual analysis of the analog images or by analysis of serum bilirubin levels. A computer program, developed by the authors, quantitates several parameters of DISIDA kinetics, reflecting hepatic function based upon compartmental analysis. A significant difference (P less than .001) was demonstrated between the mean transport constants (blood clearance constant = k1; hepatic clearance constant = k2) for the two groups. It is concluded that serum bilirubin levels and visual inspection of analog images are inadequate independent predictors of hepatic function in patients post PTBD. The transport constants k1 and k2 are quantitative parameters of hepatic function that may be of prognostic value in patients post PTBD.

Velchik, M.G.; Schwartz, W.; London, J.W.; Makler, P.T. Jr.; Alavi, A.



Ageing-related changes in the in vivo function of rat liver macroautophagy and proteolysis  

Microsoft Academic Search

Autophagy is a universal, highly regulated mechanism responsible for the degradation of long-lived proteins, cytomembranes and organelles during fasting and may be the cell repair mechanism that mediates the anti-ageing effects of calorie restriction (Bergamini and Gori, 1995). The function of autophagy was studied in vivo on male Sprague Dawley rats fed ad libitum or 40% food restricted. Autophagy was

Alessandra Del Roso; Simona Vittorini; Gabriella Cavallini; Alessio Donati; Zina Gori; Matilde Masini; Maria Pollera; Ettore Bergamini



The effects of high-dose qinggan huoxue recipe on acute liver failure induced by d-galactosamine in rats.  


Qinggan Huoxue Recipe is a traditional Chinese medicine, which has been usually used to improve liver function in hepatitis. In order to investigate the effects of high-dose Qinggan Huoxue Recipe on acute liver failure and explore the potential mechanism, we had built acute liver failure models in rats by intraperitoneal injection of D-galactosamine (D-GalN). High-dose Qinggan Huoxue Recipe was delivered by gavage. After treatment, the blood alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumin (ALB), cholinesterase (CHE), and prothrombin time (PT) were determined. The pathological score of liver tissue was recorded. Proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and fluorescence quantitative reverse transcription polymerase chain reaction (qRT-PCR) of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF- ? B), and Caspase-3 were performed. The survival curve was also depicted. Our results demonstrated that high-dose Qinggan Huoxue Recipe could significantly improve liver function and increase survival rates in rats with acute liver failure. These effects were supposed to be mediated by suppressing inflammatory reaction and apoptosis. PMID:23554835

Zhu, Hong; Zhang, Yang; Hu, Xiaoyu; Yi, Cheng; Zhong, Sen; Wang, Yanyan; Yang, Fang



Change in Growth Performance and Liver Function Enzymes of Broiler Chickens Challenged with Infectious Bursal Disease Virus to Dietary Supplementation of Methionine and Threonine  

Microsoft Academic Search

Problem statement: The aim of this study was to verify the effects of methionine and threonine supplementations higher than the NRC recommendation on growth performance, liver function enzymes, blood parameters and immune tissues of broiler chickens challenged with infectious bursal disease. Approach: A total of 450 day-old male broiler chicks were as signed to nine groups. Chickens were fed by

Elham Maroufyan; Azhar Kasim; Seyed Reza Hashemi



Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus\\/liver and CD34 cell transplantation  

Microsoft Academic Search

Studies of the human immune system have been limited by the lack of an appro- priate in vivo model. For this reason, efforts have been made to develop mu- rine models with a functional human im- mune system. We report here that cotrans- plantation of human fetal thymus\\/liver tissues and CD34 hematopoietic stem\\/ progenitor cells led to the development of

Ping Lan; Noriko Tonomura; Akira Shimizu; Shumei Wang; Yong-Guang Yang



Killed Escherichia coli stimulates macrophage-mediated alterations in hepatocellular function during in vitro coculture: a mechanism of altered liver function in sepsis.  

PubMed Central

Hepatic dysfunction is a poorly understood and highly lethal component of multiple-system organ failure. Both in vivo and in vitro studies of "liver" function have generally neglected hepatocyte-Kupffer cell interactions. In the following experiments, isolated hepatocytes were cocultivated with unstimulated peritoneal cells, predominately macrophages, which served as a readily available Kupffer cell analog. Coculture of hepatocytes with peritoneal cells resulted in little or no change in [3H]leucine incorporation into hepatocyte protein. When gentamicin-killed Escherichia coli cells (GKEC) were added to coculture, there was a marked decrease in hepatocyte [3H]leucine incorporation. In contrast, GKEC added to hepatocytes alone had no effect. Kinetic data revealed an 8-h delay before any significant decrease in leucine incorporation into hepatocyte protein after the addition of GKEC to the coculture. The maximal decrease in hepatocyte [3H]leucine incorporation occurred 24 h after GKEC were added. The decrease observed 24 h after GKEC were added disappeared almost completely after 48 h of coculture. Similar alterations in cocultured hepatocyte protein synthesis were observed after the addition of phorbol myristate acetate, lipopolysaccharide, or muramyl dipeptide, a component of bacterial peptidoglycan. Hepatocyte viability by trypan blue exclusion was unchanged, and gross morphology by light or electron microscopy was unaffected. We propose that during sepsis, macrophages (Kupffer cells) respond to circulating microbial products and mediate alterations in hepatocyte function. These experiments underscore the important role of Kupffer cell function in attempts to understand hepatic malfunction in multiple-system organ failure.

West, M A; Keller, G A; Cerra, F B; Simmons, R L



Testing the validity of a receptor kinetic model via TcNGA functional imaging of liver transplant recipients. Final report  

SciTech Connect

The author had accomplished the expertise for I-125-HSA plasma volume, galactose clearance for determination of hepatic plasma flow as well as finalizing the kinetic model. They have just completed modifying the microscale Scatchard assay for greater precision of receptor measurement using only 5--10 mg of liver tissue. In addition, he determined during the past year that the most practical method and clinically reasonable measurement of liver volume was to measure the transplanted liver in vivo using Tc-NGA images in the anterior, posterior, and right lateral projections, using the method of Rollo and DeLand. Direct measurement of liver weight obtained during transplant operation was not reliable due to variability of fluid retention in the donor liver secondary to ischemia, preservation fluid, etc., which thereby did not reflect an accurate liver weight which is needed in the kinetic analysis comparison, i.e., V{sub h} (hepatic plasma volume).

Stadalnik, R.C.



Structure of the Mycobacterium tuberculosis D-Alanine:D-Alanine Ligase, a Target of the Antituberculosis Drug D-Cycloserine  

SciTech Connect

D-Alanine:D-alanine ligase (EC; Ddl) catalyzes the ATP-driven ligation of two D-alanine (D-Ala) molecules to form the D-alanyl:D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development. D-Cycloserine (DCS), an analog of D-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure of Mycobacterium tuberculosis Ddl at a resolution of 2.1 {angstrom}. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoined by several loop regions. The M. tuberculosis apo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide and D-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP and D-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed for D-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC{sub 50}) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors.

Bruning, John B.; Murillo, Ana C.; Chacon, Ofelia; Barletta, Raúl G.; Sacchettini, James C. (TAM); (UNL)



Molecular characterization and functional regulation of a novel rat liver-specific organic anion transporter rlst-1  

Microsoft Academic Search

Background & Aims: Recently, we isolated a new complementary DNA (cDNA) encoding human liver-specific organic anion transporter (LST-1), representing the multispecificity of human liver. The aim of this study was to isolate a rat counterpart of human LST-1 and examine the expression regulation of its messenger RNA (mRNA) to clarify the molecular basis of cholestasis. Methods: A rat liver cDNA

Masayuki Kakyo; Michiaki Unno; Taro Tokui; Rie Nakagomi; Toshiyuki Nishio; Hajime Iwasashi; Daisuke Nakai; Makoto Seki; Masanori Suzuki; Takeshi Naitoh; Seiki Matsuno; Hiromu Yawo; Takaaki Abe



Effect of garlic-derived organosulfur compounds on mitochondrial function and integrity in isolated mouse liver mitochondria.  


The objectives of this work were to evaluate the direct effects of diallysulfide (DAS) and diallyldisulfide (DADS), two major organosulfur compounds of garlic oil, on mitochondrial function and integrity, by using isolated mouse liver mitochondria in a cell-free system. DADS produced concentration-dependent mitochondrial swelling over the range 125-1000?M, while DAS was ineffective. Swelling experiments performed with de-energized or energized mitochondria showed similar maximal swelling amplitudes. Cyclosporin A (1?M), or ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA, 1mM) were ineffective in inhibiting DADS-induced mitochondrial swelling. DADS produced a minor (12%) decrease in mitochondrial membrane protein thiols, but did not induce clustering of mitochondrial membrane proteins. Incubation of mitochondria with DADS (but not DAS) produced an increase in the oxidation rate of 2',7' dichlorofluorescein diacetate (DCFH-DA), together with depletion of reduced glutathione (GSH) and increased lipid peroxidation. DADS (but not DAS) produced a concentration-dependent dissipation of the mitochondrial membrane potential, but did not induce cytochrome c release. DADS-dependent effects, including mitochondrial swelling, DCFH-DA oxidation, lipid peroxidation and loss of mitochondrial membrane potential, were inhibited by antioxidants and iron chelators. These results suggest that DADS causes direct impairment of mitochondrial function as the result of oxidation of the membrane lipid phase initiated by the GSH- and iron-dependent generation of oxidants. PMID:22960305

Caro, Andres A; Adlong, Luke W; Crocker, Samuel J; Gardner, Michael W; Luikart, Emily F; Gron, Liz U



Effect of garlic-derived organosulfur compounds on mitochondrial function and integrity in isolated mouse liver mitochondria  

PubMed Central

The objectives of this work were to evaluate the direct effects of diallysulfide (DAS) and diallyldisulfide (DADS), two major organosulfur compounds of garlic oil, on mitochondrial function and integrity, by using isolated mouse liver mitochondria in a cell-free system. DADS produced concentration-dependent mitochondrial swelling over the range 125–1000 ?M, while DAS was ineffective. Swelling experiments performed with de-energized or energized mitochondria showed similar maximal swelling amplitudes. Cyclosporin A (1 ?M), or ethylene glycol-bis(2-aminoethylether)-N,N,N?,N?-tetraacetic acid (EGTA, 1 mM) were ineffective in inhibiting DADS-induced mitochondrial swelling. DADS produced a minor (12%) decrease in mitochondrial membrane protein thiols, but did not induce clustering of mitochondrial membrane proteins. Incubation of mitochondria with DADS (but not DAS) produced an increase in the oxidation rate of 2?,7? dichlorofluorescein diacetate (DCFH-DA), together with depletion of reduced glutathione (GSH) and increased lipid peroxidation. DADS (but not DAS) produced a concentration-dependent dissipation of the mitochondrial membrane potential, but did not induce cytochrome c release. DADS-dependent effects, including mitochondrial swelling, DCFH-DA oxidation, lipid peroxidation and loss of mitochondrial membrane potential, were inhibited by antioxidants and iron chelators. These results suggest that DADS causes direct impairment of mitochondrial function as the result of oxidation of the membrane lipid phase initiated by the GSH- and iron-dependent generation of oxidants.

Caro, Andres A.; Adlong, Luke W.; Crocker, Samuel J.; Gardner, Michael W.; Luikart, Emily F.; Gron, Liz U.



Structural and functional analyses of liver cysts from the BALB/c-cpk mouse model of polycystic kidney disease.  


Liver cysts arising from hepatic bile ducts are a common extra-renal pathology associated with both autosomal dominant and recessive polycystic kidney disease in humans. To elucidate the functional and structural changes inherent in cyst formation and growth, hepatic bile duct epithelia were isolated from the BALB/ c-cpk mouse model of polycystic kidney disease. Light and transmission electron microscopy revealed substantial fibrosis in the basal lamina surrounding hepatic bile duct cysts isolated from heterozygous (BALB/c-cpk/+) and homozygous (BALB/c-cpk/cpk) animals. Scanning electron microscopy and length analysis of normal, precystic and cystic bile ducts provided the unique observation that primary cilia in cholangiocytes isolated from bile ducts and cysts of animals expressing the mutated cpk gene had lengths outside the minimal and maximal ranges of those in cells lining bile ducts of wild-type animals. Based on the hypothesis that PKD is one of several diseases characterized as ciliopathies, this abnormal variability in the length of the primary cilia may have functional implications. Electrophysiological analyses of freshly isolated cysts indicate that the amiloride-sensitive epithelial Na(+) channel (ENaC) is inactive/absent and cAMP-mediated anion secretion is the electrogenic transport process contributing to cyst fluid accumulation. Anion secretion can be stimulated by the luminal stimulation of adenylyl cyclase. PMID:18997107

Muchatuta, Monalisa N; Gattone, Vincent H; Witzmann, Frank A; Blazer-Yost, Bonnie L



Liver biochemical and histopathological findings in dogs with experimentally induced exocrine pancreatic insufficiency  

PubMed Central

Abstract Routine liver biochemical parameters were evaluated in 8 dogs with exocrine pancreatic insufficiency (EPI) induced by surgical ligation of the pancreatic duct and the pancreatic branch of the pancreaticoduodenal artery and confirmed with the trypsin-like immunoreactivity test. Eight additional dogs were used as healthy controls. Data collection began at the 4th week postoperatively and continued weekly to the 21st week. In the dogs with EPI, the serum activity of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were consistently elevated. The serum total and conjugated bilirubin concentrations remained within normal limits throughout the experimental period. Histopathological study revealed hepatic lipidosis in the dogs with EPI. Therefore, since this condition seems to be an additional consequence of EPI in dogs, laboratory evaluation of dogs with EPI must include assessment of liver function, to determine if additional or different therapeutic measures are indicated.



Liver abnormalities in pregnancy.  


Abnormalities of liver function (notably rise in alkaline phosphatase and fall in serum albumin) are common in normal pregnancy, whereas rise in serum bilirubin and aminotransferase suggest either exacerbation of underlying pre-existing liver disease, liver disease related to pregnancy or liver disease unrelated to pregnancy. Pregnant women appear to have a worse outcome when infected with Hepatitis E virus. Liver diseases associated with pregnancy include abnormalities associated hyperemesis gravidarum, acute fatty liver disease, pre-eclampsia, cholestasis of pregnancy and HELLP syndrome. Prompt investigation and diagnosis is important in ensuring a successful maternal and foetal outcome. In general, prompt delivery is the treatment of choice for acute fatty liver, pre-eclampsia and HELLP syndrome and ursodeoxycholic acid is used for cholestasis of pregnancy although it is not licenced for this indication. PMID:24090943

Than, Nwe Ni; Neuberger, James



An ex vivo perfusion system emulating in vivo conditions in noncirrhotic and cirrhotic human liver.  


Various models are used for investigating human liver diseases and testing new drugs. However, data generated in such models have only limited relevance for in vivo conditions in humans. We present here an ex vivo perfusion system using human liver samples that enables the characterization of parameters in a functionally intact tissue context. Resected samples of noncirrhotic liver (NC; n = 10) and cirrhotic liver (CL; n = 12) were perfused for 6-h periods. General and liver-specific parameters (glucose, lactate, oxygen, albumin, urea, and bile acids), liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glutamate dehydrogenase, and ?-glutamyl transferase), overall (M65) and apoptotic (M30) cell-death markers, and indicators of phase-I/phase-II biotransformations were analyzed. The measurement readings closely resembled (patho)physiological characteristics in patients with NC and CL. Mean courses of glucose levels reflected the CLs' reduced glycogen storage capability. Furthermore, CL samples exhibited significantly stronger increases in lactate, bile acids, and the M30/M65 ratio than NC specimens. Likewise, NC samples exhibited more rapid phase-I transformations of phenacetin, midazolam, and diclofenac and phase-I to phase-II turnover rates of the respective intermediates than CL tissue. Collectively, these findings reveal the better hepatic functionality in NC. Perfusion of human liver tissue with this system emulates in vivo conditions and clearly discriminates between noncirrhotic and cirrhotic tissue. This highly reliable device for investigating basic hepatic functionality and testing safety/toxicity, pharmacokinetics/pharmacodynamics and efficacies of novel therapeutic modalities promises to generate superior data compared with those obtained via existing economic perfusion systems. PMID:22674469

Schreiter, Thomas; Marquitan, Guido; Darnell, Malin; Sowa, Jan-Peter; Bröcker-Preuss, Martina; Andersson, Tommy B; Baba, Hideo A; Furch, Marcus; Arteel, Gavin E; Mathé, Zoltan; Treckmann, Jürgen; Gerken, Guido; Gieseler, Robert K; Canbay, Ali



Acrolein is a mitochondrial toxin: Effects on respiratory function and enzyme activities in isolated rat liver mitochondria  

Microsoft Academic Search

Acrolein is an air pollutant from cigarette smoking and other pollutions and also a by-product of lipid peroxidation. Studies have demonstrated that acrolein causes cytotoxicity and genotoxicity, including liver damage and death of hepatocytes. However, the toxic effects and the underlying mechanisms of acrolein on mitochondria, especially, on liver mitochondria, have not been well studied. In the present study, we

Lijuan Sun; Cheng Luo; Jiangang Long; Dongzhi Wei; Jiankang Liu



Mechanism of alterations in isolated rat liver mitochondrial function induced by gold complexes of bidentate phosphines.  


Au(DPPE)+2 (bis[1,2-bis(diphenylphosphino)ethane] gold(I] is an organo-gold antineoplastic agent that has anti-tumor activity in a variety of in vitro cell lines and in vivo rodent tumor models. Preliminary studies suggested that this compound represented a novel class of inhibitors of mitochondrial function. The purpose of this study was, therefore, to determine the mechanism of mitochondrial dysfunction induced by Au(DPPE)+2. Au(DPPE)+2 induced a rapid, dose-related collapse of the inner mitochondrial membrane potential (EC50 = 28.0 microM) that was not potentiated by Ca2+ preloading. Au(DPPE)+2-induced dissipation of mitochondrial membrane potential was accompanied by an efflux of Ca2+ from mitochondria upon exposure to Au(DPPE)+2. Ca2+ efflux in these experiments was via a reversal of the Ca2+ uniporter as efflux could be inhibited with ruthenium red. Au(DPPE)+2 did not increase the permeability of mitochondria to oxalacetate, indicating that the collapse of membrane potential may not be a result of gross increased inner membrane permeability. However, Au(DPPE)+2 may mediate an increased permeability of the inner membrane to cations and protons. Au(DPPE)+2 caused passive swelling in potassium acetate buffer in the absence of valinomycin, suggesting Au(DPPE)+2 facilitated the exchange of H+ and K+. Ca2+ cycling was not extensive and did not contribute to the decrease in membrane potential. These data suggest that one possible mechanism of Au(DPPE+2-induced uncoupling of mitochondrial oxidative phosphorylation is via increased permeability of the inner mitochondrial membrane to cations. The disruption of mitochondrial function may be a key process leading to hepatocyte cell injury by this drug. PMID:2457018

Hoke, G D; Rush, G F; Bossard, G F; McArdle, J V; Jensen, B D; Mirabelli, C K



Liver Facts  


Liver Facts | LIVER FACTS The liver is critical to a person's well-being. The liver: Processes all food and (most) drugs we eat Stores iron reserves, as ... breathe Top Ten Facts You Should Know About Liver Disease In The United States! 1. 4 - 5 ...


?-alanine supplementation improves isometric endurance of the knee extensor muscles  

PubMed Central

Background We examined the effect of four weeks of ?-alanine supplementation on isometric endurance of the knee extensors at 45% maximal voluntary isometric contraction (MVIC). Methods Thirteen males (age 23?±?6 y; height 1.80?±?0.05?m; body mass 81.0?±?10.5?kg), matched for pre-supplementation isometric endurance, were allocated to either a placebo (n?=?6) or ?-alanine (n?=?7; 6.4?g·d-1 over 4?weeks) supplementation group. Participants completed an isometric knee extension test (IKET) to fatigue, at an intensity of 45% MVIC, before and after supplementation. In addition, two habituation tests were completed in the week prior to the pre-supplementation test and a further practice test was completed in the week prior to the post-supplementation test. MVIC force, IKET hold-time, and impulse generated were recorded. Results IKET hold-time increased by 9.7?±?9.4?s (13.2%) and impulse by 3.7?±?1.3 kN·s-1 (13.9%) following ?-alanine supplementation. These changes were significantly greater than those in the placebo group (IKET: t(11)?=?2.9, p ?0.05; impulse: t(11)?=?3.1, p???0.05). There were no significant changes in MVIC force in either group. Conclusion Four weeks of ?-alanine supplementation at 6.4?g·d-1 improved endurance capacity of the knee extensors at 45% MVIC, which most likely results from improved pH regulation within the muscle cell as a result of elevated muscle carnosine levels.



Crystal Structures of Aedes Aegypt Alanine Glyoxylate Aminotransferase  

SciTech Connect

Mosquitoes are unique in having evolved two alanine glyoxylate aminotransferases (AGTs). One is 3-hydroxykynurenine transaminase (HKT), which is primarily responsible for catalyzing the transamination of 3-hydroxykynurenine (3-HK) to xanthurenic acid (XA). Interestingly, XA is used by malaria parasites as a chemical trigger for their development within the mosquito. This 3-HK to XA conversion is considered the major mechanism mosquitoes use to detoxify the chemically reactive and potentially toxic 3-HK. The other AGT is a typical dipteran insect AGT and is specific for converting glyoxylic acid to glycine. Here we report the 1.75{angstrom} high-resolution three-dimensional crystal structure of AGT from the mosquito Aedes aegypti (AeAGT) and structures of its complexes with reactants glyoxylic acid and alanine at 1.75 and 2.1{angstrom} resolution, respectively. This is the first time that the three-dimensional crystal structures of an AGT with its amino acceptor, glyoxylic acid, and amino donor, alanine, have been determined. The protein is dimeric and adopts the type I-fold of pyridoxal 5-phosphate (PLP)-dependent aminotransferases. The PLP co-factor is covalently bound to the active site in the crystal structure, and its binding site is similar to those of other AGTs. The comparison of the AeAGT-glyoxylic acid structure with other AGT structures revealed that these glyoxylic acid binding residues are conserved in most AGTs. Comparison of the AeAGT-alanine structure with that of the Anopheles HKT-inhibitor complex suggests that a Ser-Asn-Phe motif in the latter may be responsible for the substrate specificity of HKT enzymes for 3-HK.

Han,Q.; Robinson, H.; Gao, Y.; Vogelaar, N.; Wilson, S.; Rizzi, M.; Li, J.



?-alanine supplementation improves YoYo intermittent recovery test performance  

PubMed Central

Background ?-alanine supplementation has been shown to improve high-intensity exercise performance and capacity. However, the effects on intermittent exercise are less clear, with no effect shown on repeated sprint activity. The aim of this study was to investigate the effects of ?-alanine supplementation on YoYo Intermittent Recovery Test Level 2 (YoYo IR2) performance. Methods Seventeen amateur footballers were allocated to either a placebo (PLA; N = 8) or ?-alanine (BA; N = 9) supplementation group, and performed the YoYo IR2 on two separate occasions, pre and post 12 weeks of supplementation during a competitive season. Specifically, players were supplemented from early to mid-season (PLA: N = 5; BA: N = 6) or mid- to the end of the season (PLA: N = 3; BA: N = 3). Data were analysed using a two factor ANOVA with Tukey post-hoc analyses. Results Pre supplementation scores were 1185 ± 216 and 1093 ± 148 m for PLA and BA, with no differences between groups (P = 0.41). YoYo performance was significantly improved for BA (+34.3%, P ? 0.001) but not PLA (?7.3%, P = 0.24) following supplementation. 2 of 8 (Early – Mid: 2 of 5; Mid – End: 0 of 3) players improved their YoYo scores in PLA (Range: -37.5 to + 14.7%) and 8 of 9 (Early – Mid: 6 of 6; Mid – End: 2 of 3) improved for BA (Range: +0.0 to +72.7%). Conclusions 12 weeks of ?-alanine supplementation improved YoYo IR2 performance, likely due to an increased muscle buffering capacity resulting in an attenuation of the reduction in intracellular pH during high-intensity intermittent exercise.



Transferability of ASTM\\/NIST alanine–polyethylene recipe at ISS  

Microsoft Academic Search

Alanine–polyethylene solid state dosimeters were prepared at Istituto Superiore di Sanità (ISS) following the recipe proposed by National Institute of Standards and Technology (NIST) with the goal of testing its transferability. Dosimeters were prepared using 95% alanine and 5% polyethylene, by weight. They are rugged and of increased sensitivity, repeatability and reproducibility as respect to the ISS alanine-paraffin pellets. Reproducibility

C. De Angelis; P. Fattibene; S. Onori; E. Petetti; A. Bartolotta; A. Sansone Santamaria



Dimethylformamide-induced liver damage among synthetic leather workers  

SciTech Connect

Prevalence of liver injury associated with dimethylformamide (DMF) exposure was determined. Medical examinations, liver function tests, and creatine phosphokinase (CPK) determinations were performed on 183 of 204 (76%) employees of a synthetic leather factory. Air concentrations of solvents were measured with personal samplers and gas chromatography. The concentration of DMF in air to which each worker was exposed was categorized. High exposure concentrations of DMF (i.e., 25-60 ppm) were significantly associated with elevated alanine aminotransferase (ALT) levels (ALT greater than or equal to 35 IU/l), a result that did not change even after stratification by hepatitis B carrier status. Modeling by logistic regression demonstrated that exposure to high concentrations of DMF was associated with an elevated ALT (p = .01), whereas hepatitis B surface antigen (HBsAg) was slightly but independently associated with an elevated ALT (p = .07). In those workers who had normal ALT values, there occurred still significantly higher mean ALT and aspartate aminotransferase (AST) activities, especially among those who were not HBsAg carriers. A significant association existed between elevated CPK levels and exposure to DMF. However, an analysis of the CPK isoenzyme among 143 workers did not reveal any specific damage to muscles. This outbreak of liver injury among synthetic leather workers is ascribed to DMF. It is recommended that the occupational standard for DMF and its toxicity among HBsAg carriers be evaluated further.

Wang, J.D.; Lai, M.Y.; Chen, J.S.; Lin, J.M.; Chiang, J.R.; Shiau, S.J.; Chang, W.S. (Center for the Research of Environmental and Occupational Disease, Graduate Institute of Public Health and Department of Internal Medicine, National Taiwan University, College of Medicine (China))



Polarized endocytosis by Madin-Darby canine kidney cells transfected with functional chicken liver glycoprotein receptor  

PubMed Central

We have studied the expression of the chicken hepatic glycoprotein receptor (chicken hepatic lectin [CHL]) in Madin-Darby canine kidney (MDCK) cells, by transfection of its cDNA under the control of a retroviral promotor. Transfected cell lines stably express 87,000 surface receptors/cell with a kd = 13 nM. In confluent monolayers, approximately 40% of CHL is localized at the plasma membrane. 98% of the surface CHL is expressed at the basolateral surface where it performs polarized endocytosis and degradation of glycoproteins carrying terminal N-acetylglucosamine at a rate of 50,000 ligand molecules/h. Studies of the half-life of metabolically labeled receptor and of the stability of biotinylated cell surface receptor after internalization indicate that transfected CHL performs several rounds of uptake and recycling before it gets degraded. The successful expression of a functional basolateral receptor in MDCK cells opens the way for the characterization of the mechanisms that control targeting and recycling of proteins to the basolateral membrane of epithelial cells.



Relationship between renal resistance index and renal function in liver transplant recipients after cessation of calcineurin inhibitor.  


End stage renal disease is a major complication after orthotopic liver transplantation (OLT). Vasoconstriction of renal arterial vessels because of calcineurin inhibitor (CNI) treatment plays a pivotal role in the development of renal insufficiency following OLT. Renal resistance can be measured non-invasively by determining the resistance index (RI) of segmental arteries by color-coded duplex ultrasonography, a measure with predictive value for future renal failure. Sixteen OLT patients on long-term CNI therapy were recruited prospectively and randomly assigned either to receive the m-TOR inhibitor sirolimus (SRL) or to continue on CNI treatment, and were followed for one yr. Serum creatinine (crea) declined after conversion to SRL, whereas it tended to increase in patients remaining on CNI (meanDelta crea SRL: -27, -18, -18, -15 micromol/L; meanDelta crea CNI: 4, 5, 8, 11 micromol/L at 1, 3, 6, 12 months, p = 0.02). RI improved after switching to SRL and was lower on SRL than on CNI (meanDeltaRI SRL: -0.04, -0.04, -0.03, -0.03; meanDeltaRI CNI: -0.006, 0.004, -0.007, -0.01 after 1, 3, 6, 12 months, p = 0.016). Individual changes of RI correlated significantly with individual changes of crea (r = 0.54, p < 0.001). Conversion from CNI to SRL can ameliorate renal function accompanied by a reduction of intrarenal RI after OLT. PMID:19486346

Eisenberger, Ute; Sollinger, Daniel; Stickel, Felix; Burckhardt, Beat; Frey, Felix J



Liver biopsy  


Biopsy - liver; Percutaneous biopsy ... the biopsy needle to be inserted into the liver. The skin will be cleansed, and a small ... chance of puncturing the lung or tearing the liver. The needle is removed quickly. Pressure will be ...


Hepatocyte nuclear factor 4? transactivates the mitochondrial alanine aminotransferase gene in the kidney of Sparus aurata.  


Alanine aminotransferase (ALT) plays an important role in amino acid metabolism and gluconeogenesis. The preference of carnivorous fish for protein amino acids instead of carbohydrates as a source of energy lead us to study the transcriptional regulation of the mitochondrial ALT (mALT) gene and to characterize the enzyme kinetics and modulation of mALT expression in the kidney of gilthead sea bream (Sparus aurata) under different nutritional and hormonal conditions. 5'-Deletion analysis of mALT promoter in transiently transfected HEK293 cells, site-directed mutagenesis and electrophoretic mobility shift assays allowed us to identify HNF4? as a new factor involved in the transcriptional regulation of mALT expression. Quantitative RT-PCR assays showed that starvation and the administration of streptozotocin (STZ) decreased HNF4? levels in the kidney of S. aurata, leading to the downregulation of mALT transcription. Analysis of the tissue distribution showed that kidney, liver, and intestine were the tissues with higher mALT and HNF4? expression. Kinetic analysis indicates that mALT enzyme is more efficient in catalyzing the conversion of L: -alanine to pyruvate than the reverse reaction. From these results, we conclude that HNF4? transactivates the mALT promoter and that the low levels of mALT expression found in the kidney of starved and STZ-treated fish result from a decreased expression of HNF4?. Our findings suggest that the mALT isoenzyme plays a major role in oxidazing dietary amino acids, and points to ALT as a target for a biotechnological action to spare protein and optimize the use of dietary nutrients for fish culture. PMID:21607544

Salgado, María C; Metón, Isidoro; Anemaet, Ida G; González, J Diego; Fernández, Felipe; Baanante, Isabel V