End Product Of Catabolism Research Articles

Influence of muscle mass on the serum uric acid levels in children and adolescents

Background and aimUric acid (UA) is an end-product of purine catabolism and its increase in blood is a risk factor for several diseases. UA levels in men are usually higher than in women. This difference is partially due to sex hormones. We sought to investigate the onset of sexual difference in UA levels during pubertal development and the determinants of UA levels in children and adolescents. Methods and resultsThe muscle mass and fat mass were measured by multi-frequency bioelectrical impedance in a cross-sectional study involving 823 children and adolescents (both sexes; 6–18 years). Serum UA was determined using a commercially available kit. UA levels started to become higher in boys (5.0 ± 1.0 mg/dL) than in girls (4.1 ± 0.9 mg/dL) around 13 years. Boys in the highest quartile of muscle mass presented higher UA levels (5.2 ± 0.7 mg/dL) when compared with the third (4.2 ± 0.7 mg/dL), second (3.7 ± 0.9 mg/dL) and first (3.4 ± 0.9 mg/dL). Similarly, girls in the highest quartile of muscle mass presented higher UA levels (4.2 ± 0.7 mg/dL) when compared with the second (3.8 ± 0.9 mg/dL) and first (3.3 ± 0.9 mg/dL). Muscle mass explained 43.0% and 7.7% of the variability of UA in boys and girls, respectively. ConclusionSexual differences in serum UA levels begin at puberty and partially result from a direct influence of muscle mass.

Abstract 133: The Role of Xanthine Dehydrogenase ( XDH ) and Uric Acid in Renal Damage

Uric acid is the end product of purine catabolism in humans and is capable of acting as both an antioxidant scavenging reactive oxygen species and conditionally a pro-oxidant. Increased or decreased serum uric acid level (hyperuricemia or hypouricemia, respectively) are associated with a number of prevalent diseases including hypertension and chronic kidney disease as well as with rare disorders, such as primarily hereditary xanthinuria. Despite the clear association of uric acid dysregulation with pathophysiology, the mechanisms involved remain unclear. Xanthine oxidoreductase (XOR), XDH or xanthine oxidase (XO) is a complex metalloflavoenzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. To assess the physiological and pathophysiological role of this pathway, we created a genetic ablation of Xdh gene in the Dahl salt-sensitive rat background (SS Xdh-/- ). Genomic DNA sequencing of the SS Xdh-/- rat model confirmed a 7-base-pair-deletion in exon 4 of the Xdh gene located on chromosome 6. SS Xdh-/- rats exhibited early mortality with 75% (21/28 rats) survival probability up to 45 days of age compared to SS Xdh+/- and SS Xdh+/+ littermates, all of whom survived. Plasma uric acid of 6 weeks old male rats was 0.27±0.03 mg/dl (N=3) and in SS Xdh+/+ rats decreased to a level out of the detectable range by the test in the SS Xdh-/- group. The uric acid/creatinine ratio in urine for SS Xdh+/+ rats was 0.27±0.01 (N=3) and extremely decreased for SS Xdh-/- rats (out of the range). In addition, the SS Xdh-/- rats showed severe renal damage with interstitial fibrosis and dilated tubules by Masson’s Trichrome staining. Kidney damage was further evident by the increased levels of albumin excretion in the SS Xdh-/- rats (1.21±0.28 (N=3) and 2.86±0.91 (N=6) for SS Xdh+/+ and SS Xdh-/- , respectively). The kidney weight / total body weight ratio was increased in SS Xdh-/- rats, indicating renal hypertrophy compared to control (10.97±0.2 (N=3) and 15.92±0.81 (N=5) for SS Xdh+/+ vs SS Xdh-/- rats). These results suggest that genetic ablation of Xdh caused uric acid depletion and severe renal damage. Xdh may be essential for the development of the kidney and survival of the rats by regulating purine catabolism.

Serum Bilirubin Levels Can be Used as a Potential Biomarker in the Progression of Diabetic Nephropathy in Rats

AbstractBackground: Diabetes mellitus is a widespread syndrome and a major cause of morbidity and mortality all over the world. Diabetic nephropathy is a progressive and irreversible renal affection that may end by renal failure in sever conditions. Bilirubin is the end product of heme catabolism. It has been recognized as a strong antioxidant. Many studies relate bilirubin to diabetes.Aim of Study: The present investigation aimed to study the changes in serum billirubin level in diabetic nephropathy and to know whether there is a correlation between its level and the stages of nephropathy in diabetic rats.Material and Methods: Sixty male albino rats were used and divided into the following groups; non-diabetic control group, diabetic nephropathy group and insulin-treated diabetic nephropathy group. By the end of the experimental period, 24 hours urine samples were collected to measure urine volume & urinary creatinine concentration and calculation of creatinine clearance. Then systolic blood pressure (SBP) was measured using rat tail sphygmomanometer technique. Fasting blood samples were collected for estimation of glycemic state, liver function tests and renal function tests. Finally both kidneys were fixed in 10% formalin solution for histopathology by using H&E & periodic acid schiffe (PAS).Results: Our data showed that streptozotocin injection significantly elevated glycemic state, aspartate transaminase (AST), alanine transaminase (ALT), serum urea, serum creat-inin, SBP and significantly decreased seum albumin, creatinin clearance, total and direct bilirubin. Alkaline phosphatase (ALP) and serum albumin showed insignificant change. Histopathological examination of the same group showed slight thickening of the basement membrane, arterioles, few inflammatory cells and hydropic changes in renal tubules. Insulin treatment significantly decreased glycemic state, AST, ALT, serum urea, serum creatinin, SBP and significantly elevated seum albumin, creatinin clearance, total and direct bilirubin. Histopathological examination of the same group showed some healthy glomeruli but still hydropic changes in renal tubules.Conclusion: Regular monitoring of bilirubin in diabetic patients is essential marker for progression and prognosis of diabetic nephropathy and effect of treatment.

Signaling from Intestine to the Host: How Bile Acids Regulate Intestinal and Liver Immunity.

Primary bile acids (BAs) are generated in the liver as the end products of cholesterol catabolism; they are then conjugated and accumulated in the gallbladder. After a meal ingestion, BAs are reversed into the duodenum to facilitate the lipid absorption. At the intestinal level, the 95% of BAs are reabsorbed and redirected into enterohepatic circulation; indeed only a small amount of them are then subjected to chemical modifications by the intestinal microbiota, which plays a very important role in the generation of secondary bile acids and in regulating host's metabolism and activity of the immune system. Behind their role in nutrients absorption, bile acids act as signaling molecules, activating several receptors, known as bile acid-activated receptors (BARs), including the farnesoid-X-receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1 or Takeda G-protein receptor 5). Both receptors appear to contribute to maintain the tolerogenic state of the liver and intestine immunity. In particular, FXR and GPBAR1 are highly expressed in cells of innate immunity including intestinal and liver macrophages, dendritic cells, and natural killer T cells. In this chapter, we provide an overview on mechanisms through which FXR and GPBAR1 modulate the signaling between microbiota and intestinal and liver innate immune system. This overview could help to explain beneficial effects exerted by GPBAR1 and FXR agonists in the treatment of metabolic and immuno-mediated diseases.

Effect of Ammonia Exposure on the Non-Specific Immunity of Fresh Water Pearl Mussel Hyriopsis cumingii

Ammonia-N, the principal end-product of protein catabolism, is an important environmental toxic factor in ponds. Elevated environmental ammonia-N is very toxic to aquatic animals and has a deleterious effect on their immune system. However, its effect on their immune system remains unclear. In this study, the effects of ammonia-N (0, 5, 10 and 30 mg/L) on immune responses of Fresh Water Pearl Mussel Hyriopsis cumingii were determined. When exposed to 5 mg/L ammonia-N lysozyme activity increased significantly. Superoxide dismutase activity was highest in the 5 mg/L group followed by the 10 mg/L group. The marked decrease of Lysozyme activity of Fresh Water Pearl Mussel Hyriopsis cumingii in 10 mg/L and 30 mg/L ammonia-N groups suggests that the higher concentrations of ammonia-N reduces or inhibits their non-specific immunity. Compared to the control group, superoxide dismutase activity in 30 mg/L ammonia also decreased significantly. When exposed to 5mg/L ammonia-N, catalase, acid phosphatase and alkaline phosphatase activity enhanced. In the 10 mg/L and 30 mg/L group, ammonia-N decreased significantly The lysozyme, catalase, acid phosphatase and alkaline phosphatase activity showed a similar tendency. This suggests that in H. cumingii immunostimulatory response is enhanced at low ammoniaN concentrations. The results of this study provide a theoretical basis for disease prevention in the freshwater pearl mussel.

Photoluminescence sensing of bilirubin in human serum using l-cysteine tailored manganese doped zinc sulphide quantum dots

Bilirubin (BR) is a protective antioxidant generated as end-product of heme catabolism in human. However, BR accumulation in biological tissues in connection with neonatal and hereditary jaundice causes severe hyperbilirubinemia and neurotoxicity. Herein, a fluorescence turn-off sensor for the detection of BR, a major biomarker for jaundice, is designed based on l-cysteine capped manganese doped zinc sulphide quantum dots (Mn:ZnS QDs). The QDs were synthesized by a microwave assisted chemical co-precipitation method. Under optimum conditions, the luminescence quenching response of Mn:ZnS QDs can be effectively used for detection of BR in the linear range of 10.99 μM - 63.84 μM BR. The limit of detection (LOD) is as low as 1.8 μM and limit of quantification (LOQ) is 6 μM. The plausible mechanism behind BR induced luminescence quenching is reductive photo-induced electron transfer (PET) in which Mn:ZnS QDs act as electron acceptor and BR act as electron donor. The developed sensor show good selectivity for BR over other co-existing biomolecules such as creatine, cholesterol, bisphenol, glutathione, uric acid, urea, hemoglobin, fructose, galactose and glucose. The developed sensor was validated by the detection of BR in spiked human serum and urine samples. For practical applications, a paper strip based sensor was also developed.

Hubungan Obesitas dengan Kadar Asam Urat Darah pada Mahasiswa Program Studi Pendidikan Dokter Fakultas Kedokteran Universitas Sriwijaya

Uric acid is the end product of purine catabolism which is sinthesized especially by the liver and excreted through urinary tract. Increased blood uric acid levels can cause many disease such as gout arthritis, hipertension, and renal disease. Individual with obesity often have lower renal excretion rate and may have increased production of uric acid. This study is conducted to determine the relationship of obesity and blood uric acid levels.This Study with cross-sectional design took a sample of 119 students of Medical Education Program Study at Medical Faculty of the Sriwijaya University by consecutive sampling. Body weight, body height, and uric acid levels then are taken using measurement tools appropriate, categorized, and processed according to research objectivesThe study found that 27,5% female and 10,3% male have hyperuricemia. A total of 39,3% obese students and 16,5% non-obese students have high level of uric acid. The result of bivariate analysis showed that there is a significant relationship between obesity and gender with blood uric acid levels (p=0,022 and 0,035 respectively). After multivariate analysis, factor that has relationship with uric acid level is obesity.Obesity have a significant relationship with uric acid levels.

Role of Uric Acid in Semen.

Since 1963, various research studies and reports have demonstrated the role of uric acid (2,6,8-trihydroxypurine), an end product of adenosine and guanosine catabolism, on semen quality and sperm function. However, this effect has not yet been collectively discussed, even though uric acid has been a well-recognized constituent in semen. Here, we systematically and comprehensively discuss and summarize the role/effect of uric acid in semen quality by searching the main databases for English language articles considering this topic. Additionally, certain significant and relevant papers were considered to support discussions and perceptions. In conclusion, uric acid contributes to maintaining and enhancing sperm motility, viability, and morphology; therefore, protecting sperm function and fertilizing ability. This contribution is performed mainly by neutralizing the damaging effect of oxidizing (e.g., endogenous free radicals and exogenous toxins) and nitrating agents and enhancing certain bioactive enzymes in spermatozoa. In contrast, high levels of uric acid may induce adverse effects to sperm function, at least in part, by reducing the activity of vital enzymes in spermatozoa. However, further research, mainly clinical, is still required to fully explore the role/effect of uric acid in semen.

Uptake of l-Alanine and Its Distinct Roles in the Bioenergetics of Trypanosoma cruzi.

Amino acids participate in several critical processes in the biology of trypanosomatids, such as osmoregulation, cell differentiation, and host cell invasion. Some of them provide reducing power for mitochondrial ATP synthesis. It was previously shown that alanine, which is formed mainly by the amination of pyruvate, is a metabolic end product formed when parasites are replicating in a medium rich in glucose and amino acids. It was shown as well that this amino acid can also be used for the regulation of cell volume and resistance to osmotic stress. In this work, we demonstrate that, despite it being an end product of its metabolism, Trypanosoma cruzi can take up and metabolize l-Ala through a low-specificity nonstereoselective active transport system. The uptake was dependent on the temperature in the range between 10 and 40°C, which allowed us to calculate an activation energy of 66.4kJ/mol and estimate the number of transporters per cell at ~436,000. We show as well that, once taken up by the cells, l-Ala can be completely oxidized to CO2, supplying electrons to the electron transport chain, maintaining the electrochemical proton gradient across the mitochondrial inner membrane, and supporting ATP synthesis in T.cruzi epimastigotes. Our data demonstrate a dual role for Ala in the parasite's bioenergetics, by being a secreted end product of glucose catabolism and taken up as nutrient for oxidative mitochondrial metabolism.IMPORTANCE It is well known that trypanosomatids such as the etiological agent of Chagas' disease, Trypanosoma cruzi, produce alanine as a main end product of their energy metabolism when they grow in a medium containing glucose and amino acids. In this work, we investigated if under starvation conditions (which happen during the parasite life cycle) the secreted alanine could be recovered from the extracellular medium and used as an energy source. Herein we show that indeed, in parasites submitted to metabolic stress, this metabolite can be taken up and used as an energy source for ATP synthesis, allowing the parasite to extend its survival under starvation conditions. The obtained results point to a dual role for Ala in the parasite's bioenergetics, by being a secreted end product of glucose catabolism and taken up as nutrient for oxidative mitochondrial metabolism.

PO-063 Pre-diagnostic unconjugated bilirubin levels and colorectal cancer risk in the european prospective investigation into cancer and nutrition (EPIC)

IntroductionUnconjugated Bilirubin (UCB), the end product of heme catabolism, is a powerful antioxidant. A mild chronic elevation of circulating UCB, known as Gilbert’s Syndrome (GS), is a relatively common condition affecting 5%–10% (depending on ethnicity and gender) of the adult population. Individuals with endogenously elevated UCB appear to be at lower risk of developing certain diseases where oxidative stress has been implicated in the disease process, such as cancer.Material and methodsWe investigated the association between pre-diagnostic plasma UCB concentrations and risk of colorectal cancer (CRC) development in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, a multicenter prospective study carried out in 23 centres from 10 European countries including 5 19 978 participants.Plasma UCB was measured by High Performance Liquid Chromatography (HPLC) in 1387 cases and 1387 controls matched on age, centre, follow-up time, time of blood collection, fasting status and menopausal status in women.Odds ratios (OR) and 95% confidence intervals (CI) for CRC risk were estimated using multivariable conditional logistic regression models stratified by sex, which were adjusted for potential confounders. UCB was Log2- transformed when used as a continuous variable to improve linearity.Results and discussionsIn a multivariable model that included potential confounding factors, higher Log2- transformed UCB, corresponding to a doubling of UCB concentration, was associated with increased CRC risk in men (OR=1.27; 95% CI: 1.05,1.52; p=0.01) whereas an inverse association with CRC risk was observed in women (OR=0.83; 95% CI: 0.70,0.99; p=0.04).ConclusionThese results suggest that higher levels of circulating UCB may confer protection against CRC in women but may elevate risk in men. Additional studies are necessary to confirm these findings and to further investigate potential underlying mechanisms for the role of circulating UCB in CRC development.

Nuclear Receptor Regulation of Aquaglyceroporins in Metabolic Organs.

Nuclear receptors, such as the farnesoid X receptor (FXR) and the peroxisome proliferator-activated receptors gamma and alpha (PPAR-γ, -α), are major metabolic regulators in adipose tissue and the liver, where they govern lipid, glucose, and bile acid homeostasis, as well as inflammatory cascades. Glycerol and free fatty acids are the end products of lipid droplet catabolism driven by PPARs. Aquaporins (AQPs), a family of 13 small transmembrane proteins, facilitate the shuttling of water, urea, and/or glycerol. The peculiar role of AQPs in glycerol transport makes them pivotal targets in lipid metabolism, especially considering their tissue-specific regulation by the nuclear receptors PPARγ and PPARα. Here, we review the role of nuclear receptors in the regulation of glycerol shuttling in liver and adipose tissue through the function and expression of AQPs.

Systemic regulation of bilirubin homeostasis: Potential benefits of hyperbilirubinemia.

Neurotoxic bilirubin is the end product of heme catabolism in mammals. Bilirubin is solely conjugated by uridine diphospho-glucuronosyltransferase 1A1, which is a membrane-bound enzyme that catalyzes the transfer of glucuronic acid. Due to low function of hepatic and intestinal uridine diphospho-glucuronosyltransferase 1A1 during the neonatal period, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage, termed kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does this most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk-induced hyperbilirubinemia might bring certain benefits that outweigh those risks. While bilirubin is neurotoxic and cytotoxic, this compound is also a potent antioxidant. There are studies showing improved clinical conditions in patients with hyperbilirubinemia. Accumulating evidence also shows that genetic polymorphisms linked to hyperbilirubinemia are beneficial against various diseases. In this review article, we first introduce the production, metabolism, and transport of bilirubin. We then discuss the potential benefits of neonatal and adult hyperbilirubinemia. Finally, epigenetic factors as well as metabolomic information associated with hyperbilirubinemia are described. This review article advances the understanding of the physiological importance of the paradoxical compound bilirubin. (Hepatology 2018;67:1609-1619).

Higher D-lactate levels are associated with higher prevalence of small dense low-density lipoprotein in obese adolescents.

Childhood obesity is associated with insulin resistance (IR), increased levels of small dense low-density lipoprotein (sd-LDL) as well as with augmented hepatic de novo lipogenesis, which implies increased triose phosphate fluxes that may lead to increased methylglyoxal (MG) and its catabolic end product D-lactate. We hypothesized that obese adolescents have increased D-lactate serum levels associated with high incidence of sd-LDL. This is a cross-sectional study where the anthropometric characteristics, atherogenic dyslipidemia complex, sd-LDL (Lipoprint, Quantimetrix) and D-lactate (kinetic enzymatic analysis) were explored in 30 lean vs. 30 obese adolescents (16 females and 14 males per group) without metabolic syndrome (MetS). Endothelial function by flow-mediated dilation (FMD, by ultrasound) and arterial lesion by carotid intima media thickness (CIMT, by ultrasound) were also measured. The mean age of participants was 16.8 ± 1.4 years. Obese adolescents had a body mass index of 32.7 ± 3.8 vs. 21.8 ± 2.1 in lean participants. The obesity group showed higher D-lactate levels: 6.2 ± 3.0 vs. 4.5 ± 2.5 μmol/L, higher levels of insulin: 15 (9.6-23.5) vs. 7.9 (6.5-10.5) μIU/mL; triglyceride (TG): 1.46 (1.1-1.8) vs. 0.84 (0.6-1.2) mmol/L; non-high-density lipoprotein-cholesterol (NON-HDL-C): 2.8 ± 0.9 vs. 2.3 ± 0.7 mmol/L; total cholesterol (TC)/HDL-C) index: 2.9 ± 0.7 vs. 2.4 ± 0.5; TG/HDL-C index: 2.2 (1.5-2.8) vs. 1.1 (0.8-1.8); %LDL-3: 4.2 ± 4.07 vs. 1.9 ± 2.7; smaller LDL size: 270.6 ± 3 vs. 272.2 ± 1.1 Å. D-lactate correlated positively with LDL-2: r = 0.44 and LDL-3 (sd-LDL): r = 0.49 and negatively with large LDL-1: r = -0.48 and LDL size: r = -0.46; (p<0.05, p<0.01, p<0.001 and p<0.0001, respectively). Obese adolescents showed higher CIMT: 0.51 ± 0.08 vs. 0.46 ± 0.08 mm and lower FMD: 20.3% ± 6.7% vs. 26.0% ± 9.3%. Obese adolescents display subclinical signs of IR and endothelial dysfunction. Higher serum sd-LDL levels correlated positively with D-lactate levels. These findings suggest an association between atherogenic dyslipoproteinemia and whole body MG fluxes already detectable in apparently healthy obese adolescents.

Role of bile acids in inflammatory bowel disease.

Bile acids (BAs) are the end product of cholesterol catabolism. Their synthesis is regulated by the nuclear receptor farnesoid X receptor, also involved in the control of their enterohepatic circulation. Inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), are multifactorial diseases characterized by diarrhea. The pathogenesis of diarrhea in IBD is still debated. The most important factor is the inflammatory process of the intestinal wall, causing alterations of solute and water absorption/secretion, deterioration of epithelial cell integrity, disruption of the intestinal microflora homeostasis, and impairment of specific transport mechanisms within the gut (including that of BAs). In this review, we summarize the current state of the art in this area and we critically evaluate the alterations of BA metabolism in patients with CD and UC.

Effect of urate, an end product of purine nucleosides catabolism, on sperm function

Effect of urate, an end product of purine nucleosides catabolism, on sperm function

The Role of Bile Acids in Glucose Metabolism and Their Relation with Diabetes

Bile acids (BAs), the end products of cholesterol catabolism, are essential for the absorption of lipids and fat-soluble vitamins; but they have also emerged as novel signaling molecules that act as metabolic regulators. It has been well described that the enterohe-patic circulation, a nuclear (FXR) and a cytoplasmic (TGR5/M-BAR) receptor aid in controlling hepatic bile acid synthesis. Modulating bile acid synthesis greatly impacts in metabolism, because these receptors also are implicated in glucose, lipid, and energy expenditure. Recent studies had revealed the way these receptors participate in regulating gluconeogenesis, peripheral insulin sensitivity, glycogen synthesis, glucagon like peptide 1 (GLP-1) and insulin secretion. Nowadays, it is demonstrated that enhancing bile acid signaling in the intestine contributes to the metabolic benefits of bile acid sequestrants and bariatric surgery on glucose homeos-tasis. This paper discusses the role of bile acid as regulators of glucose metabolism and their potential as therapeutic targets for diabetes.

Interactions between bile salts, gut microbiota, and hepatic innate immunity.

Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed.

Severe Neonatal Hyperbilirubinemia in Crigler-Najjar Syndrome Model Mice Can Be Reversed With Zinc Protoporphyrin.

Neurotoxic bilirubin is solely conjugated by UDP‐glucuronosyltransferase (UGT) 1A1. Due to an inadequate function of UGT1A1, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage called kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does the most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk‐induced neonatal hyperbilirubinemia might bring certain benefits to the body. One of the barriers to answering the above question is the lack of animal models that display mild to severe neonatal hyperbilirubinemia. A mouse model that develops neonatal hyperbilirubinemia was previously developed by a knockout of the Ugt1 locus. Deletion of Ugt1a1 results in neonatal lethality from bilirubin neurotoxicity. Bilirubin is the end product of heme catabolism in which heme oxygenase‐I is largely involved. When zinc protoporphyrin, an inhibitor of heme oxygenase I, was administered to newborn Ugt1 −/− mice, serum bilirubin levels dropped dramatically, rescuing the mice from bilirubin‐induced neonatal lethality. Zinc protoporphyrin‐treated Ugt1 −/− mice developed normally as adults capable of reproducing, but their newborns showed even more severe hyperbilirubinemia. Microarray analysis of the hyperbilirubinemic livers indicated that a number of genes associated with nucleotide, transport, and immune response were significantly down‐regulated in a serum bilirubin level‐dependent manner. Conclusion: Our study provides an opportunity to advance the development of effective therapeutics to effectively and rapidly prevent bilirubin‐induced toxicity. Neonatal hyperbilirubinemia has various impacts on the body that could be driven by the antioxidant property of bilirubin. (Hepatology Communications 2017;1:792–802)

Lactobacillus caviae sp. nov., an obligately heterofermentative bacterium isolated from the oral cavity of a guinea pig (Cavia aperea f. porcellus).

A Gram-stain-positive, facultatively anaerobic, and catalase- and oxidase-negative bacterial strain designated MOZM2T, having 98.4 % 16S rRNA gene sequence identity with Lactobacillus reuteri DSM 20016T, was isolated from a swab of the oral cavity of a home-bred guinea pig. Comparative analyses based on the hsp60, pheS and tuf genes confirmed L. reuteri as its closest relative species, with calculated sequence similarities of 92.8, 88.8 and 96.9 %, respectively. DNA-DNA hybridisation revealed a 42 % degree of genetic similarity between the novel strain and L. reuteri DSM 20016T. Strain MOZM2T degrades carbohydrates via the 6-phosphogluconate/phosphoketolase pathway, evidenced by its production of gas from glucose and the end products of hexose catabolism. Comparative analysis of the cellular fatty acid profiles determined significant differences between MOZM2T and L. reuteri DSM 20016T in their proportions of C8 : 0, C14 : 1, C17 : 0, C18 : 2ω6t and C20 : 0 fatty acids. Results of genotypic analyses also demonstrated differences between these two strains. They also differed in DNA G+C content, and some biochemical and physiological characteristics. We therefore believe that the examined bacterial isolate should be considered as a new taxon within the group of obligately heterofermentative lactobacilli. The species name Lactobacillus caviae sp. nov. is proposed, of which the type strain is MOZM2T (=CCM 8609T=DSM 100239T=LMG 28780T).

Impact of higher-order heme degradation products on hepatic function and hemodynamics

Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions. Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia. Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton. Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia. Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats.