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PURPOSE: To investigate the effects of maximal static apnea on plasma antioxidant status, oxidative stress, and antioxidant enzyme activities in trained free divers. METHODS: Blood was taken from apnea-trained (Tr) and control (Con) subjects at baseline (B) and after one (A1), three (A3), and five (A5) apneas. Trolox equivalent antioxidant capacity (TEAC), ferric reducing ability of plasma (FRAP), uric acid, and bilirubin assays assessed plasma antioxidant status and malondialdehyde (MDA) quantified the oxidative stress response. The activities of erythrocyte antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were determined at baseline and after the fifth apnea. RESULTS: TEAC was significantly higher in divers versus controls after A1 (P < 0.05). A group effect of SOD activity indicated higher activity throughout the protocol in Tr (mean +/- SD; Con, 43.2 +/- 10.1 U.g Hb; Tr, 50.1 +/- 7.3 U.g Hb; P = 0.04). With no other group differences, the groups' data were combined. Apnea significantly increased SOD (B, 44.1 +/- 11.1 U.g Hb; A5, 48.1 +/- 7.5 U.g Hb; P < 0.05) and GPx activity (B, 60.5 +/- 14.9 U.g Hb; A5, 70.1 +/- 16.0 U.g Hb; P = 0.02); however, CAT activity decreased (B, 5.25 +/- 0.59 U.mg Hb; A5, 5.00 +/- 0.53 U.mg Hb; P = 0.03). MDA was unaffected by apnea (P = 0.32). CONCLUSIONS: Trained free divers have increased SOD activity during apnea; however, there is little difference in their antioxidant and oxidative stress responses compared with controls. In both groups, acute changes in antioxidant enzyme activities suggest that they may protect from excessive antioxidant depletion and oxidative stress during apnea. [ABSTRACT FROM AUTHOR]

Recent studies have shown that elevated concentrations of unconjugated bilirubin (UCB) may be a protective host factor against the development of noncommunicable diseases (NCDs), whereas low levels of UCB are associated with the opposite effect. The results of this European study, in which 2,489 samples were tested for their UCB concentration using high-performance liquid chromatography (HPLC) and additional data from the MARK-AGE database were used for analysis, provide further evidence that elevated UCB concentrations are linked to a lower risk of developing NCDs and may act as a predictive marker of biological aging as individuals with elevated UCB concentrations showed favorable outcomes in metabolic health and oxidative-stress-related biomarkers. These findings underline the significance of studying individuals with moderate hyperbilirubinemia and investigate UCB routinely, also in the setting of aging, since this condition affects millions of people worldwide but has been underrepresented in clinical research and practice until now., Competing Interests: The authors declare no competing interests., (© 2024 The Authors. Published by Elsevier Inc.)

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. A maternal high LA (HLA) diet alters cardiovascular development in adolescent rats and hepatic function in adult rats in a sex-specific manner. We investigated the effects of an HLA diet on adolescent offspring hepatic lipids and hepatic lipid metabolism gene expression, and the ability of the postnatal diet to alter these effects. Female Wistar Kyoto rats were fed low LA (LLA; 1.44% energy from LA) or high LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring, weaned at postnatal day (PN) 25, were fed LLA or HLA and euthanised at PN40 ( n = 6-8). Maternal HLA increased circulating uric acid, decreased hepatic cholesterol and increased hepatic Pparg in males, whereas only hepatic Srebf1 and Hmgcr increased in females. Postnatal (post-weaning) HLA decreased liver weight (% body weight) and increased hepatic Hmgcr in males, and decreased hepatic triglycerides in females. Maternal and postnatal HLA had an interaction effect on Lpl , Cpt1a and Pparg in females. These findings suggest that an HLA diet both during and after pregnancy should be avoided to improve offspring disease risk.

Although poly(aspartic acid) (PASP), a strong calcium chelating agent, may be potentially effective in inhibition of vascular calcification, its direct administration may lead to side effects. In this study, we employed polysuccinimide, a precursor of PASP, to prepare targeted polysuccinimide-based nanoparticles (PSI NPs) that not only acted as a prodrug but also functioned as a carrier of additional therapeutics to provide powerful synergistic vascular anticalcification effect. This paper shows that chemically modified PSI-NPs can serve as effective nanocarriers for loading of hydrophobic drugs, in addition to anticalcification and antireactive oxygen species (anti-ROS) activities. Curcumin (Cur), with high loading efficiency, was encapsulated into the NPs. The NPs were stable for 16 h in physiological conditions and then slowly dissolved/hydrolyzed to release the therapeutic PASP and the encapsulated drug. The drug release profile was found to be in good agreement with the NP dissolution profile such that complete release occurred after 48 h at physiological conditions. However, under acidic conditions, the NPs were stable, and Cur cumulative release reached only 30% after 1 week. Though highly effective in the prevention of calcium deposition, PSI NPs could not prevent the osteogenic trans-differentiation of vascular smooth muscle cells (VSMCs). The presence of Cur addressed this problem. It not only further reduced ROS level in macrophages but also prevented osteogenic differentiation of VSMCs in vitro . The NPs were examined in vivo in a rat model of vascular calcification induced by kidney failure through an adenine diet. The inclusion of Cur and PSI NPs combined the therapeutic effects of both. Cur-loaded NPs significantly reduced calcium deposition in the aorta without adversely affecting bone integrity or noticeable side effects/toxicity as examined by organ histological and serum biochemistry analyses.

Nanophotothermal therapy based on nanoparticles (NPs) that convert near-infrared (NIR) light to generate heat to selectively kill cancer cells has attracted immense interest due to its high efficacy and being free of ionizing radiation damage. Here, for the first time, we have designed a novel nanohybrid, silver-iron oxide NP (AgIONP), which was successfully tuned for strong absorbance at NIR wavelengths to be effective in photothermal treatment and dual-imaging strategy using MRI and photoacoustic imaging (PAI) in a cancer model in vivo and in vitro, respectively. We strategically combine the inherent anticancer activity of silver and photothermal therapy to render excellent therapeutic capability of AgIONPs. In vitro phantoms and in vivo imaging studies displayed preferential uptake of folate-targeted NPs in a cancer mice model, indicating the selective targeting efficiency of NPs. Importantly, a single intravenous injection of NPs in a cancer mice model resulted in significant tumor reduction, and photothermal laser resulted in a further substantial synergistic decrease in tumor size. Additionally, biosafety and biochemical assessment performed in mice displayed no significant difference between NP treatment and control groups. Overall, our folic acid AgIONPs displayed excellent potential in the simultaneous application for safe and successful targeted synergistic photothermal treatment and imaging of a cancer model.

Cystic fibrosis (CF), the result of mutations in the CF transmembrane conductance regulator (CFTR), causes essential fatty acid deficiency. The aim of this study was to characterize fatty acid handling in two rodent models of CF; one strain which harbors the loss of phenylalanine at position 508 (Phe508del) in CFTR and the other lacks functional CFTR (510X). Fatty acid concentrations were determined using gas chromatography in serum from Phe508del and 510X rats. The relative expression of genes responsible for fatty acid transport and metabolism were quantified using real-time PCR. Ileal tissue morphology was assessed histologically. There was an age-dependent decrease in eicosapentaenoic acid and the linoleic acid:α-linolenic acid ratio, a genotype-dependent decrease in docosapentaenoic acid (n-3) and an increase in the arachidonic acid:docosahexaenoic acid ratio in Phe508del rat serum, which was not observed in 510X rats. In the ileum, Cftr mRNA was increased in Phe508del rats but decreased in 510X rats. Further, Elvol2 , Slc27a1 , Slc27a2 and Got2 mRNA were increased in Phe508del rats only. As assessed by Sirius Red staining, collagen was increased in Phe508del and 510X ileum. Thus, CF rat models exhibit alterations in the concentration of circulating fatty acids, which may be due to altered transport and metabolism, in addition to fibrosis and microscopic structural changes in the ileum.

Abstract: Zadow, EK, Edwards, KH, Kitic, CM, Fell, JW, Adams, MJ, Singh, I, Kundur, A, Johnstone, ANB, Crilly, J, Bulmer, AC, Halson, SL, and, and Wu, SSX. Compression socks reduce running-induced intestinal damage. J Strength Cond Res 36(9): 2461-2464, 2022-Exercise is associated with a reduction in splanchnic blood flow that leads to the disruption of intestinal epithelium integrity, contributing to exercise-induced gastrointestinal syndrome. Strategies that promote intestinal blood flow during exercise may reduce intestinal damage, which may be advantageous for subsequent recovery and performance. This study aimed to explore if exercise-associated intestinal damage was influenced by wearing compression garments, which may improve central blood flow. Subjects were randomly allocated to wear compression socks ( n = 23) or no compression socks (control, n = 23) during a marathon race. Blood samples were collected 24 hours before and immediately after marathon and analyzed for intestinal fatty acid-binding protein (I-FABP) concentration as a marker of intestinal damage. The magnitude of increase in postmarathon plasma I-FABP concentration was significantly greater in control group (107%; 95% confidence interval [CI], 72-428%) when compared with runners wearing compression socks (38%; 95% CI, 20-120%; p = 0.046; d = 0.59). Wearing compression socks during a marathon run reduced exercise-associated intestinal damage. Compression socks may prove an effective strategy to minimize the intestinal damage component of exercise-induced gastrointestinal syndrome., (Copyright © 2020 National Strength and Conditioning Association.)

Circulating bilirubin is associated with reduced serum cholesterol concentrations in humans and in hyperbilirubinaemic Gunn rats. However, mechanisms contributing to hypocholesterolaemia remain unknown. Therefore, this study aimed to investigate cholesterol synthesis, transport and excretion in mutant Gunn rats. Adult Gunn and control rats were assessed for daily faecal sterol excretion using metabolic cages, and water was supplemented with [1- 13 C]-acetate to determine cholesterol synthesis. Bile was collected to measure biliary lipid secretion. Serum and liver were collected for biochemical analysis and for gene/protein expression using RT-qPCR and western blot, respectively. Additionally, serum was collected and analysed from juvenile rats. A significant interaction of sex, age and phenotype on circulating lipids was found with adult female Gunn rats reporting significantly lower cholesterol and phospholipids. Female Gunn rats also demonstrated elevated cholesterol synthesis, greater biliary lipid secretion and increased total faecal cholesterol and bile acid excretion. Furthermore, they possessed increased hepatic low-density lipoprotein (LDL) receptor and SREBP2 expression. In contrast, there were no changes to sterol metabolism in adult male Gunn rats. This is the first study to demonstrate elevated faecal sterol excretion in female hyperbilirubinaemic Gunn rats. Increased sterol excretion creates a negative intestinal sterol balance that is compensated for by increased cholesterol synthesis and LDL receptor expression. Therefore, reduced circulating cholesterol is potentially caused by increased hepatic uptake via the LDL receptor. Future studies are required to further evaluate the sexual dimorphism of this response and whether similar findings occur in females with benign unconjugated hyperbilirubinaemia (Gilbert's syndrome). KEY POINTS: Female adult hyperbilirubinaemic (Gunn) rats demonstrated lower circulating cholesterol, corroborating human studies that report a negative association between bilirubin and cholesterol concentrations. Furthermore, female Gunn rats had elevated sterol excretion creating a negative intestinal sterol balance that was compensated for by elevated cholesterol synthesis and increased hepatic low-density lipoprotein (LDL) receptor expression. Therefore, elevated LDL receptor expression potentially leads to reduced circulating cholesterol levels in female Gunn rats providing an explanation for the hypocholesterolaemia observed in humans with elevated bilirubin levels. This study also reports a novel interaction of sex with the hyperbilirubinaemic phenotype on sterol metabolism because changes were only reported in females and not in male Gunn rats. Future studies are required to further evaluate the sexual dimorphism of this response and whether similar findings occur in females with benign unconjugated hyperbilirubinaemia (Gilbert's syndrome)., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: The protective role of mildly elevated bilirubin against CVD and diabetes mellitus type 2 (DMT2) is associated with a favorable lipid phenotype. As the mechanistic understanding of this protection in humans remains elusive, we aimed to assess the metabolomics profile of mildly hyperbilirubinemic (Gilbert's syndrome; GS) individuals especially targeting lipid catabolism., Methods and Results: Using NMR serum metabolomics of 56 GS individuals and 56 age and gender-matched healthy controls, GS individuals demonstrated significantly greater concentrations of acetylcarnitine (+20%, p < 0.001) and the ketone bodies, 3-hydroxybutyric acid (+132%, p < 0.001), acetoacetic acid (+95%, p < 0.001) and acetone (+46%, p < 0.001). Metabolites associated with an increased mitochondrial lipid metabolism such as citrate (+15%, p < 0.001), anaplerotic amino acid intermediates and creatinine were significantly greater and creatine significantly reduced in GS individuals. Stimulators of lipid catabolism including AMPK (+59%, p < 0.001), pPPARα (+24%, p < 0.001) and T3 (+9%, p = 0.009) supported the metabolomics data while concomitantly blood glucose and insulin (-33%, p = 0.002) levels were significantly reduced. We further showed that the increased lipid catabolism partially mediates the favorable lipid phenotype (lower triglycerides) of GS individuals. Increased trimethylamine (+35%, p < 0.001) indicated changes in trimethylamine metabolism, an emerging predictor of metabolic health., Conclusion: We showed an enhanced lipid catabolism in mildly hyperbilirubinemic individuals, novel evidence as to why these individuals are leaner and protected against chronic metabolic diseases emphasizing bilirubin to be a promising future target in obese and dyslipidemia patients., Competing Interests: Declaration of competing interest None, the authors have declared that no conflict of interest exists., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

This clinical trial (ACTRN12619001296123) investigated the impact of silymarin (Legalon®) on circulating bilirubin concentration, lipid status, systemic inflammation, and antioxidant status. The study design was a randomized, placebo-controlled, single-blind crossover trial of healthy men (18-65 years), conducted at Griffith University, Gold Coast, Australia. Participants were recruited from Griffith University and were randomized to silymarin (140 mg silymarin capsules thrice daily) or placebo (3 capsules containing mannitol taken daily) for 14 days followed by a ≥4-week washout and crossover to the other arm. The main outcomes were whether silymarin treatment would increase serum bilirubin concentration by >0.29 mg/dL, change serum lipid status (cholesterol and triglycerides), inflammation (c-reactive protein), and antioxidant capacity (ferric reducing ability of plasma) compared with baseline. Silymarin consumption (n = 17) did not affect serum concentrations of unconjugated bilirubin (0.73 versus 0.67 mg/dL, P = .79), cholesterol (185 versus 189 mg/dL, P = .19), triglycerides (94.2 versus 92.3 mg/dL, P = .79), c-reactive protein (0.17 versus 0.09 mg/dL, P = .23), or antioxidant status (6.61 versus 6.67 mg Fe 2+ /dL, P = .40). These findings challenge previous reports and manufacturer claims of hyperbilirubinemia following silymarin treatment and are critical to guiding researchers toward an effective means to mildly elevate bilirubin, which evidence suggests could protect from cardiovascular disease., (© 2021, The American College of Clinical Pharmacology.)

The heme catabolite bilirubin has anti-inflammatory, anti-oxidative and anti-mutagenic effects and its relation to colorectal cancer (CRC) risk is currently under evaluation. Although the main metabolic steps of bilirubin metabolism, including the formation of stercobilin and urobilin, take place in the human gastrointestinal tract, potential interactions with the human gut microbiota are unexplored. This study investigated, whether gut microbiota composition is altered in Gilbert's Syndrome (GS), a mild form of chronically elevated serum unconjugated bilirubin (UCB) compared to matched controls. Potential differences in the incidence of CRC-associated bacterial species in GS were also assessed. To this end, a secondary investigation of the BILIHEALTH study was performed, assessing 45 adults with elevated UCB levels (GS) against 45 age- and sex-matched controls (C). Fecal microbiota analysis was performed using 16S rRNA gene sequencing. No association between mildly increased UCB and the composition of the gut microbiota in this healthy cohort was found. The alpha and beta diversity did not differ between C and GS and both groups showed a typical representation of the known dominant phyla. Furthermore, no difference in abundance of Firmicutes and Proteobacteria , which have been associated with the mucosa of CRC patients were observed between the groups. A sequence related to the Christensenella minuta strain YIT 12065 was identified with a weak association value of 0.521 as an indicator species in the GS group. This strain has been previously associated with a lower body mass index, which is typical for the GS phenotype. Overall, sex was the only driver for an identifiable difference in the study groups, as demonstrated by a greater bacterial diversity in women. After adjusting for confounding factors and multiple testing, we can conclude that the GS phenotype does not affect the composition of the human gut microbiota in this generally healthy study group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zöhrer, Hana, Seyed Khoei, Mölzer, Hörmann-Wallner, Tosevska, Doberer, Marculescu, Bulmer, Herbold, Berry and Wagner.)

Bilirubin is an important antioxidant and a modulator of biological functions. However, most of the protection against oxidative stress was shown in vitro or ex vivo. The aim of this case-control study was to investigate whether subjects with Gilbert's syndrome (GS) experience different levels of lipid and protein oxidation (as well as differences in oxidative stress related markers) compared to healthy controls. GS subjects ( n =119) demonstrated higher serum levels of unconjugated bilirubin ( p < 0.001), a lower BMI ( p < 0.001), 37% higher antioxidant potential assessed as ferric reducing ability potential ( p < 0.001), higher advanced oxidation protein products ( p < 0.01) andlower apolipoprotein B ( p < 0.05), hs-C-reactive protein ( p < 0.05), interleukin 6 ( p < 0.001) and interleukin 1 beta ( p < 0.05) values compared to healthy controls ( n =119). Furthermore, the resting heart rate was significantly lower in the GS group ( p < 0.05). Stronger protective effects for GS subjects were demonstrated in the older subgroup ( n =104, average age 50 years) compared to those of the younger group ( n =134, average age 27 years). Although not all markers related to oxidative stress were different between the groups (e.g., malondialdehyde, homocysteine, oxLDL, and myeloperoxidase; p >0.05), the observed differences contribute to the explanation of why GS serves as an important protector in the pathogenesis of metabolic, oxidative stress related diseases.

Background: Transfusion of red blood cell (RBC) concentrates is a common procedure to restore blood volume and tissue oxygen delivery in patients with trauma. Although RBC warmers may prevent hypothermia, some warming or infusion equipment may lead to haemolysis and patient injury., Objectives: The aim of this study was to test the effect of (i) RBC warming and (ii) administration via manual vs. pump infusion on haemolysis., Methods: This experimental ex vivo study studied haemolysis markers of RBC injury. The sample consisted of 90 RBC infusions in two simulations, randomly, 45 warmed RBC infusions and 45 nonwarmed RBC infusions, in two or three stages: before the intervention (baseline-warming, N= 45; nonwarming, N= 45), after water bath warming at 42 °C (warmed, N= 45), and then after the warmed or nonwarmed RBCs were infused by manual or pump infusion at a rate of 100 mL/h (infusion-warming, N= 45; nonwarming, N= 45)., Results: Warmed RBCs showed significantly lower total haemoglobin (Hb) and haematocrit levels and increase in free Hb levels, haemolysis levels, and lactate dehydrogenase (LDH) activity (all p<0.05) than baseline RBCs. Pump infusion RBCs were associated with reduced total Hb and increased free Hb, haemolysis, and potassium (K) levels (all p<0.05) compared with warmed RBCs. In contrast, manual infusion of warmed RBCs resulted in significantly reduced total Hb levels and increased LDH activity (both <0.05). After infusion, total Hb, free Hb, haematocrit, haemolysis, and LDH values were significantly different for warmed vs. nonwarmed RBCs (p<0.05)., Conclusions: Haemolysis biomarkers increase with RBC warming and infusion, especially when using infusion pumps. Critically ill patients should be carefully monitored for possible complications during and after RBC infusion., (Copyright © 2020 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Biliverdin (BV) administration induces antioxidant and anti-inflammatory effects, with previous reports also identifying anti-anaphylactic potential. Interestingly however, intra-duodenal administration of BV in rats leads to the formation of bilirubin-10-sulfonate (BRS), which might be responsible for BV's purported effects., Experimental Approach: This study aimed to assess the intravenous, intraperitoneal and intraduodenal pharmacokinetics of BRS and BV in order to assess their therapeutic potential in future studies. Bile and venous blood were intermittently collected before and after administration, which was subsequently analysed using liquid chromatography-mass spectrometry for quantification of bile pigment concentrations., Key Results: Interestingly, i.p. BRS administration led to a greater circulating concentration and had a reduced excretion rate, which resulted in a substantially elevated AUC 180 when compared to BV administration. Furthermore, BRS was excreted intact in the bile, in contrast to BV which was excreted after chemical reduction and conjugation. Intraperitoneal and intraduodenal administration substantially increased blood BRS concentrations (p<0.05), however, the bioavailability of BV was higher than BRS following i.p. administration (i.p. BV 28.4%, BRS 15.5%) but lower following i.d. administration (i.d. BV 0.04%, BRS 0.07%), over 180 minutes. When BRS was administered i.v., BRS had a significantly (p<0.05) longer distribution (191.9 vs 54.1 minutes) half-life compared to BV, and significantly reduced (p<0.05) volume of distribution (0.026 vs 0.145 L kg -1 ). As a consequence, intraperitoneal and intraduodenal administration resulted in significantly greater blood concentrations of BRS (p<0.05) over 180 minutes. Therefore, BRS may be more likely to induce antioxidant or molecular effects, when compared to BV, due to greater concentrations and a longer half-life., Conclusions and Implications: Cumulatively, these data demonstrate that BRS has a superior pharmacokinetic profile when compared to BV, which is a result of its resistance to hepatic metabolism and excretion. These data therefore provide a basis to explore the capacity of BRS to protect from inflammatory pathology., (Copyright © 2020. Published by Elsevier B.V.)

Background: Circulating bilirubin is associated with reduced adiposity in human and animal studies. A possible explanation is provided by in vitro data that demonstrates that bilirubin inhibits mitochondrial function and decreases efficient energy production. However, it remains unclear whether hyperbilirubinemic animals have similar perturbed mitochondrial function and whether this is important for regulation of energy homeostasis. Aim: To investigate the impact of unconjugated hyperbilirubinemia on body composition, and mitochondrial function in hepatic tissue and skeletal muscle. Materials and Methods: 1) Food intake and bodyweight gain of 14-week old hyperbilirubinemic Gunn ( n = 19) and normobilirubinemic littermate (control; n = 19) rats were measured over a 17-day period. 2) Body composition was determined using dual-energy X-ray absorptiometry and by measuring organ and skeletal muscle masses. 3) Mitochondrial function was assessed using high-resolution respirometry of homogenized liver and intact permeabilized extensor digitorum longus and soleus fibers. 4) Liver tissue was flash frozen for later gene (qPCR), protein (Western Blot and citrate synthase activity) and lipid analysis. Results: Female hyperbilirubinemic rats had significantly reduced fat mass (Gunn: 9.94 ± 5.35 vs. Control: 16.6 ± 6.90 g, p < 0.05) and hepatic triglyceride concentration (Gunn: 2.39 ± 0.92 vs. Control: 4.65 ± 1.67 mg g -1 , p < 0.01) compared to normobilirubinemic controls. Furthermore, hyperbilirubinemic rats consumed fewer calories daily ( p < 0.01) and were less energetically efficient (Gunn: 8.09 ± 5.75 vs. Control: 14.9 ± 5.10 g bodyweight kcal -1 , p < 0.05). Hepatic mitochondria of hyperbilirubinemic rats demonstrated increased flux control ratio (FCR) via complex I and II (CI+II) (Gunn: 0.78 ± 0.16 vs. Control: 0.62 ± 0.09, p < 0.05). Similarly, exogenous addition of 31.3 or 62.5 μM unconjugated bilirubin to control liver homogenates significantly increased CI+II FCR ( p < 0.05). Hepatic PGC-1α gene expression was significantly increased in hyperbilirubinemic females while FGF21 and ACOX1 was significantly greater in male hyperbilirubinemic rats ( p < 0.05). Finally, hepatic mitochondrial complex IV subunit 1 protein expression was significantly increased in female hyperbilirubinemic rats ( p < 0.01). Conclusions: This is the first study to comprehensively assess body composition, fat metabolism, and mitochondrial function in hyperbilirubinemic rats. Our findings show that hyperbilirubinemia is associated with reduced fat mass, and increased hepatic mitochondrial biogenesis, specifically in female animals, suggesting a dual role of elevated bilirubin and reduced UGT1A1 function on adiposity and body composition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors AB., (Copyright © 2021 Vidimce, Pillay, Shrestha, Dong, Neuzil, Wagner, Holland and Bulmer.)

Background: Biliverdin, a by-product of haem catabolism, possesses potent endogenous antioxidant and anti-inflammatory properties. Bilirubin-C10-sulfonate (BRS), an active metabolite formed after enteral administration of BV in the rat, also possess antioxidant properties. Therefore, we investigated the anti-inflammatory and antioxidant activity of BV and BRS in an in vivo model of monosodium urate induced sterile inflammation., Methods: Subcutaneous air pouches were created on the dorsal flanks of Wistar rats (10-12 weeks of age). Prior to stimulation of the 6-day old pouch with monosodium urate (25 mg), groups were pre-treated with intraperitoneal BRS (27 mg/kg) and BV (27 mg/kg). Total and differential leukocyte counts were determined in pouch fluid aspirate at 1, 6, 12, 24 and 48 h after monosodium urate stimulation. Biliverdin (BV), BRS and unconjugated bilirubin (UCB) concentrations in the serum and pouch fluid were quantified using liquid chromatography-mass spectrometry. Pouch fluid cytokine concentrations (IL-1β, IL-1α, TNF-α, IL-17A, IL-12, GM-CSF, IL-33, IFN-γ, IL-18, IL-10, MCP-1, CXCL-1 and IL-6) were assessed after 6 h. In addition, 24 h protein carbonyl and chloramine concentrations were assessed in pouch fluid using ELISA and spectrophotometry, respectively., Results: BRS and BV significantly (p < 0.05) inhibited leukocyte (total, neutrophil and macrophage) infiltration into the pouch fluid from 6 to 48 h. For example, after 6 h neutrophil counts decreased following BRS (0.32 ± 0.11 × 10 6 cells mL -1 ) and BV (0.17 ± 0.03 × 10 6 cells mL -1 ) compared to MSU only (3.51 ± 1.07 × 10 6 cells mL -1 ). Both BV and BRS significantly (p < 0.05) reduced pouch GM-CSF (BV: 5.8 ± 1.2 pg mL -1 , BRS: 6.9 ± 1.5 pg mL -1  vs MSU only: 13.0 ± 1.9 pg mL -1 ) and MCP-1 concentrations at 6 h (BV: 1804 ± 269 pg mL -1 , BRS: 7927 ± 2668 pg mL -1  vs MSU only: 17,290 ± 4503 pg ml -1 ), whilst BV additionally inhibited IL-6 (4354 ± 977 pg mL -1  vs MSU only: 25,070 ± 5178 pg mL -1 ) and IL-18 (17.6 ± 2.0 pg mL -1  vs MSU only: 81.5 ± 19.9 pg mL -1 ) concentrations at 6 h (p < 0.05). Despite these differences, no change in pouch chloramine or protein carbonyl concentrations occurred at 24 h (p > 0.05). Serum BV concentrations rapidly diminished over 6 h, however, BRS was readily detected in the serum over 48 h, and in pouch fluid over 12 h., Conclusions: This study is the first to elucidate anti-inflammatory activity of BRS and the efficacy of BV administration in a model of gouty inflammation. Reduced leukocyte infiltration and cytokine production in response to sterile inflammation further support the importance of these molecules in physiology and their therapeutic potential in sterile inflammation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Bilirubin ditaurate (BRT), a conjugated bilirubin analogue, has demonstrated anti-platelet characteristics following acute ex vivo exposure. Scavenging of mitochondrial superoxide and attenuation of granule exocytosis suggested a potential benefit for including BRT for storage. With no reports of cytotoxicity following acute exposure, the impact of 35µM BRT on platelet function was investigated, in clinically suppled units, for up to seven days. Exposure to 35µM BRT significantly reduced mitochondrial membrane potential and increased glucose consumption until exhaustion after 72 hours. Platelet aggregation and activation was significantly impaired by BRT. Mitochondrial superoxide production and phosphatidylserine expression were significantly elevated following glucose exhaustion, with decreased viability observed from day five onwards. Lactate accumulation and loss of bicarbonate, support a metabolic disturbance, leading to a decline of quality following BRT inclusion. Although acute ex vivo BRT exposure reported potentially beneficial effects, translation from acute to chronic exposure failed to combat declining platelet function during storage. BRT exposure resulted in perturbations of platelet quality, with the utility of BRT during storage therefore limited. However, these are the first data of prolonged platelet exposure to analogues of conjugated bilirubin and may improve our understanding of platelet function in the context of conjugated hyperbilirubinemia.

Background: Severe traumatic haemorrhage is the leading cause of death in young adults. Trauma Induced Coagulopathy is a complex and multifactorial phenomenon associated with severe traumatic haemorrhage. Fibrinogen is one of the first coagulation factors to become depleted in TIC and evidence suggests that severely injured trauma patients with hypofibrinogenaemia have poor outcomes. It is postulated that early fibrinogen replacement can improve clinical outcomes. This study investigated cryoprecipitate transfusion in hyopfibrinogeneamic trauma patients., Methods: This retrospective, single center, observational study investigated the use of cryoprecipitate in severely injured trauma patients admitted to an Australian Level I Trauma Centre. The primary outcome was time to administration of cryoprecipitate after identification of hypofibrinogenaemia using ROTEM (FIBTEM A5). Data collected included demographics, ISS, laboratory values of coagulation and blood product usage., Results: 71 patients received cryoprecipitate with a median time of 61 minutes [IQR 37-93] from FIBTEM A5 result to initial cryoprecipitate administration. At 24 hours following admission to ED, Clauss Fibrinogen levels increased by 1.30g/L [IQR 0.45-1.85] and FIBTEM A5 assay increased by 8mm [IQR 3.0-11.3]. Changes in both variables were highly significant (p<0.001) and Clauss Fibrinogen versus FIBTEM A5 values showed moderate to strong correlation (R=0.75-0.80)., Conclusion: This study demonstrated that early administration of cryoprecipitate was both feasible and efficacious in fibrinogen replacement in severe traumatic haemorrhage. High-level evidence supporting cryoprecipitate or fibrinogen concentrate replacement with regards to efficacy and feasibility is required to guide future clinical practice. This study provided baseline data to inform the design of further clinical trials investigating fibrinogen replacement in traumatic haemorrhage., Competing Interests: Declaration of Competing Interest JW has received educational and research support from CSL Behring and Haemoview Diagnostics. The other authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Human papilloma virus (HPV) is the main culprit in cervical cancers. Although the HPV vaccine is now available, the slow and gradual process for HPV cancers to form means little will change, even for vaccinated individuals. This warrants the development of new therapeutic strategies in both the newly diagnosed and recurrent patients. We have previously shown that Alisertib (MLN8237), an Aurora A kinase inhibitor, potently and selectively kills HPV-positive cervical cancer cells. However, Alisertib is known for its unfavorable side effects when administered systemically. A targeted delivery approach is therefore warranted. The topical delivery of drugs to the cervix for the treatment of cervical cancer is an underexplored area of research that has the potential to significantly improve therapeutic outcome. Here, we design a novel topical drug delivery system for localized delivery in the vaginal tract using intravaginal silicone rings loaded with Alisertib. We assessed the suitability of the drug for the application and delivery method and develop a high-performance liquid chromatography method, then show that the vaginal rings were effective at releasing Alisertib over an extended period of time. Furthermore, we showed that Alisertib-loaded vaginal rings did not induce overt inflammation in the mouse vaginal tract. Our work has major translational implications for the future development of vaginal ring devices for the topical treatment of cervical cancer., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Vascular access devices are commonly inserted devices that facilitate the administration of fluids and drugs, as well as blood sampling. Despite their common use in clinical settings, these devices are prone to occlusion and failure, requiring replacement and exposing the patient to ongoing discomfort/pain, local vessel inflammation and risk of infection. A range of insertion and maintenance strategies are employed to optimize device performance; however, the evidence base for many of these mechanisms is limited and the mechanisms contributing to the failure of these devices are largely unknown., Aims/objectives: (1) To revisit existing understanding of blood, vessel physiology and biological fluid dynamics; (2) develop an understanding of the implications that different clinical practices have on vessel health, and (3) apply these understandings to vascular access device research and practice., Method: Narrative review of biomedical and bioengineering studies related to vascular access practice., Results/outcomes: Current vascular access device insertion and maintenance practice and policy are variable with limited clinical evidence to support the theoretical assumptions underpinning these regimens. This review demonstrates the physiological response to vascular access device insertion, flushing and infusion on the vein, blood components and blood flow. These appear to be associated with changes in intravascular fluid dynamics. Variable forces are at play that impact blood componentry and the endothelium. These may explain the mechanisms contributing to vascular access failure., Conclusion: This review provides an update to our current knowledge and understanding of vascular physiology and the hemodynamic response, challenging some previously held assumptions regarding vascular access device maintenance, which require further investigation.

Objective: Fibrinogen is one of the first coagulation factors to be depleted during traumatic haemorrhage, and evidence suggests hypofibrinogenaemia leads to poor outcomes. A number of fibrinogen replacement products are currently available, with no clear consensus on the ideal product to use in severe traumatic haemorrhage. We hypothesised that it will be possible to rapidly administer fibrinogen concentrate (FC) guided by rotational thromboelastometry (ROTEM) FIBTEM A5 in patients presenting with trauma haemorrhage., Methods: We examined 36 consecutive patients with trauma admitted to a level 1 trauma centre in Australia who received FC as part of their initial resuscitation. ROTEM analysis was conducted at various time points from emergency department (ED) admission to 48 hours after admission. The primary outcome was time to administration of FC after identification of hypofibrinogenaemia using ROTEM FIBTEM A5. Data were collected on quantity and timing of product transfusion, demographics, Injury Severity Score and laboratory values of coagulation. Spearman rank order correlation was used to determine the correlation between FIBTEM A5 and Clauss fibrinogen (FibC)., Results: Thirty-six patients received FC as their initial form of fibrinogen replacement during the study. Patients were hypofibrinogenaemic by both FIBTEM A5 (6 mm) and FibC (1.7 g/L) on presentation to the ED. It took a median of 22 minutes (IQR, 17-30 minutes) from time of a FIBTEM A5 analysis to FC administration. Both parameters increased significantly ( P < 0.05) by 24 hours after admission., Conclusion: This study suggests that administration of FC represents a rapid and feasible method to replace fibrinogen in severe traumatic haemorrhage. However, the optimal method for replacing fibrinogen in traumatic haemorrhage is controversial and large multicentre randomised controlled trials are needed to provide further evidence. This study provided baseline data to inform the design of further clinical trials investigating fibrinogen replacement in traumatic haemorrhage.

Background: Bilirubin, a by-product of haem catabolism, possesses potent endogenous antioxidant and platelet inhibitory properties. These properties may be useful in inhibiting inappropriate platelet activation and ROS production; for example, during storage for transfusion. Given the hydrophobicity of unconjugated bilirubin (UCB), we investigated the acute platelet inhibitory and ROS scavenging ability of a water-soluble bilirubin analogue, bilirubin ditaurate (BRT) on ex vivo platelet function to ascertain its potential suitability for inclusion during platelet storage., Methods: The inhibitory potential of BRT (10-100 μM) was assessed using agonist induced platelet aggregation, dense granule exocytosis and flow cytometric analysis of P-selectin and GPIIb/IIIa expression. ROS production was investigated by analysis of H 2 DCFDA fluorescence following agonist simulation while mitochondrial ROS production investigated using MitoSOX™ Red. Platelet mitochondrial membrane potential and viability was assessed using TMRE and Zombie Green™ respectively., Results: Our data shows ≤35 μM BRT significantly inhibits both dense and alpha granule exocytosis as measured by ATP release and P-selectin surface expression, respectively. Significant inhibition of GPIIb/IIIa expression was also reported upon ≤35 μM BRT exposure. Furthermore, platelet exposure to ≤10 μM BRT significantly reduces platelet mitochondrial ROS production. Despite the inhibitory effect of BRT, platelet viability, mitochondrial membrane potential and agonist induced aggregation were not perturbed., Conclusions: These data indicate, for the first time, that BRT, a water-soluble bilirubin analogue, inhibits platelet activation and reduces platelet ROS production ex vivo and may, therefore, may be of use in preserving platelet function during storage., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Key Points: Linoleic acid consumption is increasing in Western populations. We investigated whether elevated linoleic acid in pregnancy was deleterious to mothers or offspring. Maternal and fetal body and organ weights were not affected by elevated linoleic acid consumption. Maternal lipids and leptin were altered following elevated linoleic acid consumption. Male offspring numbers were reduced following elevated linoleic acid consumption., Abstract: Dietary intakes of linoleic acid (LA) have increased dramatically in Western populations, including in women of reproductive age. Pro-inflammatory effects of LA may have detrimental effects on maternal and offspring outcomes. We aimed to investigate whether consumption of a maternal diet with elevated LA altered maternal inflammatory or metabolic markers during pregnancy, fetal growth and/or the sex ratio of the offspring. Female Wistar Kyoto rats consumed a diet high in LA (HLA) (6.21% of energy) or a diet low in LA (LLA) (1.44% of energy) for 10 weeks prior to mating and during pregnancy. Pregnant rats were killed at embryonic day 20 (E20). There were no differences in maternal or fetal body weights or organ weights in the HLA group compared to the LLA group. There was no difference in maternal circulating cytokine concentrations between dietary groups. In the maternal liver, IL-1α concentrations were significantly lower, and TNF-α and IL-7 significantly higher in the HLA group. Total plasma cholesterol, LDL-cholesterol, HDL cholesterol and the total:HDL cholesterol ratio were lower in dams fed the HLA diet. mRNA expression of sterol regulatory element binding transcription factor 1 (SREBF-1) and leptin in maternal adipose tissue was lower in the HLA group, as were circulating leptin concentrations. The proportion of male fetuses was lower and circulating prostaglandin E metabolite concentrations were increased in the HLA group. In conclusion, consumption of a maternal diet high in linoleic acid alters cholesterol metabolism and prostaglandin E metabolite concentrations, which may contribute to the reduced proportion of male offspring., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Biliverdin reductase (BVR)-A is a pleotropic enzyme converting biliverdin to bilirubin and a signaling molecule that has cytoprotective and immunomodulatory effects. We recently showed that biliverdin inhibits the expression of complement activation fragment 5a receptor one (C5aR1) in RAW 264.7 macrophages. In this study, we investigated the role of BVR-A in determining macrophage inflammatory phenotype and function via regulation of C5aR1. We assessed expression of C5aR1, M1-like macrophage markers, including chemokines (RANTES, IP-10), as well as chemotaxis in response to LPS and C5a in bone marrow-derived macrophages from BVR fl/fl and LysM-Cre:BVR fl / fl mice (conditional deletion of BVR-A in myeloid cells). In response to LPS, macrophages isolated from LysM-Cre:BVR fl/fl showed significantly elevated levels of C5aR1 as well as chemokines (RANTES, IP10) but not proinflammatory markers, such as iNOS and TNF. An increase in C5aR1 expression was also observed in peritoneal macrophages and several tissues from LysM-Cre:BVR fl/fl mice in a model of endotoxemia. In addition, knockdown of BVR-A resulted in enhanced macrophage chemotaxis toward C5a. Part of the effects of BVR-A deletion on chemotaxis and RANTES expression were blocked in the presence of a C5aR1 neutralizing Ab, confirming the role of C5a-C5aR1 signaling in mediating the effects of BVR. In summary, BVR-A plays an important role in regulating macrophage chemotaxis in response to C5a via modulation of C5aR1 expression. In addition, macrophages lacking BVR-A are characterized by the expression of M1 polarization-associated chemokines, the levels of which depend in part on C5aR1 signaling., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Biliverdin (BV) possesses antioxidant and anti-inflammatory properties, with previous reports identifying protection against oxidant and inflammatory injury in animal models. Recent reports indicate that intra-duodenal administration of BV results in the formation of an uncharacterised metabolite, which is potently absorbed into the blood and excreted into the bile. This compound may be responsible for protection against inflammatory responses. This study aimed to identify novel, enterally-derived BV metabolites and determine the source of their metabolic transformation. Rat duodena and bacterial cultures of Citrobacter youngae were treated with BV and subsequently analysed via high performance liquid chromatography/high resolution tandem mass spectrometry to identify and characterise metabolites of BV. A highly abundant metabolite was detected in duodenal wash and bacterial culture supernatants with a 663.215 m/z (3 ppm mass accuracy) and a composition of C 33 N 4 O 9 H 36 S, which conformed to the predicted structure of bilirubin-10-sulfonate (BRS) and possessed a λ max of 440 nm. Bilirubin-10-sulfonate was then synthesized for comparative LCMS/MS analysis and matched with that of the biologically formed BV metabolite. This report confirms the formation of a previously undocumented metabolite of BV in mammals, indicating that a new metabolic pathway likely exists for BV metabolism requiring enteric bacteria, Citrobacter youngae. These data may have important implications with regard to understanding and harnessing the therapeutic efficacy of oral BV administration.

Mildly elevated serum unconjugated bilirubin (UCB) concentrations are associated with protection against disease conditions underpinned by cellular and metabolic stress. To determine the potential therapeutic efficacy of UCB we tested it in an in vitro model of gut inflammation. Tunicamycin TUN (10 µg/mL) was used to induce endoplasmic reticular stress (ERS) affecting N-glycosylation in LS174T cells. Cultured cells were investigated with addition of UCB at doses 0.1, 1 and 10µM (resulting in bilirubin:albumin ratios of 0.325-0.003)against ER stress-mediated effects including inflammation, cell survival (determined by apoptosis) and proliferation. Gene expression of ER stress markers (Grp78, Perk, XBP1 and ATF6) were evaluated in addition to cytokine concentrations in media after six hours of treatment. We then verified the potential role of UCB in executing programmed cell death via PARP, Caspase3 and Annexin V assays and further explored cell proliferation using the Click-iT EdU assay. A dose of 10µM UCB most potently reduced tunicamycin-mediated effects on enhanced UPR markers, inflammatory cytokines and proliferation; however all the doses (i.e.0.1-10µM) reduced the expression of ER stress and inflammatory markers Grp78, NLRP3, IL1-b, XBP1, PERK and ATF6. Furthermore, media concentrations of pro-inflammatory cytokines IL-8, IL-4 and TNFα decreased and the anti-inflammatory cytokine IL-10 increased (P<0.05). A dose of 10µM UCB initiated intrinsic apoptosis via Caspase 3 and in addition reduced cellular proliferation. Collectively, these data indicate that co treatment with UCB resulted in reducing ER stress response to TUN in gastrointestinal epithelial cells, reduced the subsequent inflammatory response, induced cancer cell death and decreased cellular proliferation. These data suggest that mildly elevated circulating or enteric UCB might protect against gastrointestinal inflammatory disorders., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Introduction: Thrombotic complications associated with peripherally inserted central catheters (PICCs) are common, as most synthetic materials when placed in the presence of serum often result in platelet activation, fibrin deposition, thrombotic occlusion, and potentially embolization. A current innovation focus has been the development of antithrombogenic catheter materials, including hydrophilic and hydrophobic surfaces. These are being incorporated into PICCs in an attempt to prevent the normal thrombotic cascade leading to patient harm., Areas Covered: This review focuses on the laboratory efficacy and clinical effectiveness of antithrombogenic PICCs to prevent PICC-associated thrombosis, as well as their efficiency and safety. This synthesis was informed by a systematic identification of published and unpublished laboratory and clinical studies evaluating these technologies., Expert Commentary: A range of PICCs have been developed with antithrombogenic claims, using varying technologies. However, to date, there is no peer-reviewed laboratory research describing the individual PICCs' effectiveness. Despite promising early clinical trials, adequately powered trials to establish efficacy, effectiveness, efficiency, and safety of all of the individual products have not yet been undertaken.

Purpose: To compare prefrontal cortex oxygenation in recreationally-active women using oral contraceptives (WomenOC; n = 8) to women with a natural menstrual cycle (WomenNC; n = 8) during incremental exercise to exhaustion., Methods: Participants performed incremental cycling to exhaustion to determine lactate threshold 1 (LT1) and 2 (LT2) and peak oxygen uptake (VO 2 peak). Prefrontal cortex oxygenation was monitored via near-infrared spectroscopy through concentration changes in oxy-haemoglobin (Δ[HbO 2 ]), deoxy-haemoglobin (Δ[HHb]), total-haemoglobin (Δ[tHb]) and tissue saturation index (TSI)., Results: 17β-oestradiol and progesterone were lower in WomenOC (35 ± 26; 318 ± 127 pmol·L -1 , respectively) than WomenNC (261 ± 156; 858 ± 541 pmol·L -1 , respectively). There were no differences in full blood examination results or serum nitric oxide (p > 0.05). However, WomenOC presented lower concentrations in ferric-reducing ability of plasma (- 8%; effect size; ES - 0.52 ± 0.61), bilirubin (- 32%; ES - 0.56 ± 0.62) and uric acid (- 17%; ES - 0.53 ± 0.61). Cardiopulmonary parameters were similar between groups during cycling, including VO 2 peak (p = 0.99). While there was a significant effect of time on all parameters measured by near-infrared spectroscopy during incremental cycling, there was no effect of OC at LT1, LT2 or exhaustion calculated as a change from baseline (TSI; p = 0.096, Δ[HbO 2 ]; p = 0.143, Δ[HHb]; p = 0.085 and Δ[tHb]; p = 0.226). The change in TSI from LT1 to LT2 was significantly different between groups (WomenNC; mean difference + 2.06%, WomenOC; mean difference - 1.73%; p = 0.003)., Conclusion: Prefrontal tissue oxygenation declined at a lower relative exercise intensity in WomenOC as compared to WomenNC, however, this did not influence VO 2 peak. The results provide the first evidence for variance in the cerebral oxygenation response to exercise, which may be associated with female sex hormones.

Purpose: Compression socks are frequently used in the treatment and prevention of lower-limb pathologies; however, when combined with endurance-based exercise, the impact of compression socks on haemostatic activation remains unclear., Objectives: To investigate the effect of wearing compression socks on coagulation and fibrinolysis following a marathon., Methods: Sixty-seven participants [43 males (mean ± SD: age: 46.7 ± 10.3 year) and 24 females (age: 40.0 ± 11.0 year)] were allocated into a compression (SOCK, n = 34) or control (CONTROL, n = 33) group. Venous blood samples were obtained 24 h prior to and immediately POST-marathon, and were analyzed for thrombin-anti-thrombin complex (TAT), tissue factor (TF), tissue factor pathway inhibitor (TFPI), and D-Dimer., Results: Compression significantly attenuated the post-exercise increase in D-Dimer compared to the control group [median (range) SOCK: + 9.02 (- 0.34 to 60.7) ng/mL, CONTROL: + 25.48 (0.95-73.24) ng/mL]. TF increased following the marathon run [median (range), SOCK: + 1.19 (- 7.47 to 9.11) pg/mL, CONTROL: + 3.47 (- 5.01 to 38.56) pg/mL] in all runners. No significant post-exercise changes were observed for TAT and TFPI., Conclusions: While activation of coagulation and fibrinolysis was apparent in all runners POST-marathon, wearing compression socks was shown to reduce fibrinolytic activity, as demonstrated by lower D-Dimer concentrations. Compression may reduce exercise-associated haemostatic activation when completing prolonged exercise.

Bilirubin, a potentially toxic catabolite of heme and indicator of hepatobiliary insufficiency, exhibits potent cardiac and vascular protective properties. Individuals with Gilbert's syndrome (GS) may experience hyperbilirubinemia in response to stressors including reduced hepatic bilirubin excretion/increased red blood cell breakdown, with individuals usually informed by their clinician that their condition is of little consequence. However, GS appears to protect from all-cause mortality, with progressively elevated total bilirubin associated with protection from ischemic heart and chronic obstructive pulmonary diseases. Bilirubin may protect against these diseases and associated mortality by reducing circulating cholesterol, oxidative lipid/protein modifications, and blood pressure. In addition, bilirubin inhibits platelet activation and protects the heart from ischemia-reperfusion injury. These effects attenuate multiple stages of the atherosclerotic process in addition to protecting the heart during resultant ischemic stress, likely underpinning the profound reduction in cardiovascular mortality in hyperbilirubinemic GS. This review outlines our current knowledge of and uses for bilirubin in clinical medicine and summarizes recent progress in revealing the physiological importance of this poorly understood molecule. We believe that this review will be of significant interest to clinicians, medical researchers, and individuals who have GS.

Background: Accessing the peripheral veins for blood sampling and short-term peripheral intravenous catheter insertion is common in contemporary healthcare. Clinicians may apply heat or promote oral hydration to increase vein diameter and reveal veins to improve success rates. However, there is limited research that has examined the effect of these interventions on vein diameter and depth., Objectives: To determine the effect of localised heat and oral hydration on vein diameter and depth., Design: A three arm parallel randomised controlled trial was undertaken with 39 healthy participants from a University. All participants fasted from food and fluid from midnight. At 10 am the next day, a mark was made at the cephalic (120 mm proximal from the radial styloid) and median cubital veins (at cubital fossa) with non-permanent ink and participants underwent baseline vein diameter and depth measurement using ultrasound. Participants were randomised to either a control, heat or hydration group. Participants in the hydration arm consumed 1 L of room temperature tap water, those in the heat group had a wheat bag applied to the area for 10 min and those in the control group had no intervention and were asked to sit quietly. A second measurement was undertaken immediately after the heat intervention and 1 h after the baseline measurement for those in the hydration and control groups., Results: The application of localised heat and oral hydration did not affect the depth of the cephalic vein. Whilst hydration had no effect on median cubital vein depth, the application of heat did make this vein more superficial compared to the control group (p = 0.033). The application of heat resulted in a statistically significant (p = 0.006) increase in cephalic vein diameter compared to the control group, this effect did not occur with the median cubital vein (p = 0.087). Oral hydration resulted in a reduction in the mean diameter of both veins. Compared to the control group, the average median cubital vein diameter decreased by 0.57 mm (p = 0.003; 95% CI -0.940 to -0.193) and the cephalic vein reduced by 0.33 mm (p = 0.015; 95% CI -0.593 to -0.064) after oral hydration., Conclusion: The use of localised heat was inconsistent in its effect on vein diameter and depth. Oral hydration caused a reduction in vascular calibre in both the cephalic and median cubital veins. The promotion of water consumption to improve venepuncture success is not supported., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Purpose: Modulating gut bacteria via regular prebiotics/probiotics consumption may improve the metabolism of acute alcohol ingestion. This study investigated the impact of 8-weeks prebiotics/probiotics supplementation on microbiome changes and responses to acute alcohol consumption., Methods: 38 participants (21 females, 23.6 ± 3.4 kg m -2 , mean ± SD) attended the laboratory on two occasions separated by an 8-week intervention period. On each of these visits, a dose of alcohol (0.40 ± 0.04 g kg -1 , Vodka + Soda-Water) was consumed over 10 min. Breath alcohol concentration was sampled over 5 h and alcohol pharmacokinetics was analysed using WinNonlin non-compartmental modelling (C max , t max , AUC last ). For the intervention, participants were randomised to receive Placebo + Placebo (PLA), Placebo + Prebiotics (PRE), Probiotics + Placebo (PRO), or Probiotics + Prebiotics (SYN) in a double-blinded manner. Probiotics were a commercially available source of Lactobacillus acidophilus (NCFM ® ) and Bifidobacterium lactis (Bi-07). Prebiotics were a commercially available source of Larch Gum (from Larix occidentalis). Placebo was microcrystalline cellulose. Each visit, participants provided a stool sample, which was analysed to determine the presence of L. acidophilus and B. lactis. Differences between trials were analysed using paired samples t tests., Results: Increased counts for at least one bacterial strain (L. acidophilus or B. lactis) were observed for all participants on SYN (n = 10) and PRO (n = 10) trials. No difference in C max or t max was observed between trials when analysed by treatment condition or microbiome outcome. A significant decrease in AUC last was observed between trials for PLA (p = 0.039) and PRE (p = 0.030) treatments, and when increases in at least one bacterial strain (p = 0.003) and no microbiome changes (p = 0.016) were observed., Conclusion: Consumption of probiotics appears to alter faecal counts of supplemental bacterial strains in otherwise healthy individuals. However, translation to any possible beneficial impact on alcohol metabolism remains to be elucidated.

Hyperbilirubinemia is a well-known condition in the clinical setting; however, the causes of elevated serum bilirubin are diverse, as are the clinical ramifications of this condition. For example, diagnoses of individuals vary depending on whether they exhibit an unconjugated or conjugated hyperbilirubinemia. Diagnoses can include conditions of disordered bilirubin metabolism (Gilbert's, Crigler-Najjar, Rotor, or Dubin-Johnson syndromes) or an acquired disease, including alcoholic/non-alcoholic fatty liver disease, hepatotropic hepatitis, cirrhosis, or hepato-biliary malignancy. Assessment of bilirubin concentrations is typically conducted as part of routine liver function testing. Mildly elevated total bilirubin with normal serum activities of liver transaminases, biliary damage markers, and red blood cell counts, however, may indicate the presence of Gilbert's syndrome (GS), a benign condition that is present in ∼5-10% of the population. In this case, mildly elevated unconjugated bilirubin in GS is strongly associated with "reduced" prevalence of chronic diseases, particularly cardiovascular diseases (CVD) and type 2 diabetes mellitus (and associated risk factors), as well as CVD-related and all-cause mortality. These reports challenge the dogma that bilirubin is simply a potentially neurotoxic by-product of heme catabolism and emphasize the importance of understanding its potential beneficial physiologic and detrimental pathophysiologic effects, in order to appropriately consider bilirubin test results within the clinical laboratory setting. With this information, we hope to improve the understanding of disorders of bilirubin metabolism, emphasize the diagnostic importance of these conditions, and outline the potential impact GS may have on resistance to disease.

Peripheral intravenous catheters (PIVCs) are the most commonly used invasive medical device, yet up to 50% fail. Many pathways to failure are mechanistic and related to fluid mechanics, thus can be investigated using computational fluid dynamics (CFD). Here we used CFD to investigate typical PIVC parameters (infusion rate, catheter size, insertion angle and tip position) and report the hemodynamic environment (wall shear stress (WSS), blood damage, particle residence time and venous stasis volumes) within the vein and catheter, and show the effect of each PIVC parameter on each hemodynamic measure. Catheter infusion rate has the greatest impact on our measures, with catheter orientation also playing a significant role. In some PIVC configurations WSS was 3254 times higher than the patent vein, and blood damage was 512 times greater, when compared to control conditions. Residence time is geometry-dependent and decreases exponentially with increasing insertion angle. Stasis volume decreased with increasing infusion rate and, to a lesser degree, insertion angle. Even without infusion, the presence of the catheter changes the flow field, causing low velocity recirculation at the catheter tip. This research demonstrates how several controllable factors impact important mechanisms of PIVC failure. These data, the first of their kind, suggest limiting excessive infusion rates in PIVC.

Danshensu (DSS) is an active ingredient extracted from the root of the Danshen that could ameliorate oxidative stress via upregulation of heme oxygenase- (HO-) 1. Little is known about the treatment effects of DSS on kidney function in diabetic mice. Therefore, the primary aim of the present study was to characterize the renal clearance kinetics of IRdye800CW in db/db mice after DSS treatment. The secondary aim was to measure several biomarkers of renal function and oxidative stress (urinary F2-isoprostane, HO-1 in kidney and serum bilirubin). Fourteen db/db diabetic mice were randomly assigned into two groups and received either DSS treatment (DM + DSS) or vehicle treatment (DM). A third group that comprised of db/+ nondiabetic mice (non-DM control) received no DSS treatment and served as the nondiabetic control. At the end of a 3-week intervention period, serum and urinary biomarkers of renal function and oxidative stress were assessed and the renal clearance of IRdye800CW dye in all mice was determined noninvasively using Multispectral Optoacoustic Tomography. The major finding from this study suggested that DSS treatment in db/db mice improved renal clearance. Increased expression of HO-1 after DSS treatment also suggested that DSS might represent a potential therapeutic avenue for clinical intervention in diabetic nephropathy.

Gilbert's syndrome (GS) is associated with a mild unconjugated hyperbilirubinemia, increased circulating antioxidant capacity, and reduced cardiovascular disease (CVD) risk. The current study investigated whether mildly elevated circulating unconjugated bilirubin (UCB) is negatively associated with multiple thrombotic risk factors including platelet activity, hemostatic function, and inflammation in individuals with GS. Blood samples were collected from matched GS and control subjects (14 per group). Activation-dependent platelet surface marker expression of PAC-1 (binds to GPIIb/IIIa surface receptors on activated platelets) and CD62P (marker for P-selectin released from activated degranulated platelets) was assessed in adenosine diphosphate (ADP)-stimulated platelets using flow cytometry. Exogenous agonists, ADP, collagen, and arachidonic acid (AA), were used to stimulate platelet aggregation. A statistically significant decrease in the expression of P-selectin (P = 0.030) on activated platelets was observed in GS subjects. Collagen and AA-induced platelet aggregation were significantly (P = 0.018; P = 0.032 for respective agonists) reduced in GS versus control group. Elevated UCB (P = 0.001) and high density lipoprotein (P = 0.033) in addition to reduced low density lipoprotein (P = 0.024) and high sensitive C-reactive protein (P = 0.043) were also observed in GS when compared to the control group. Reduced P-selectin expression suggests decreased platelet activation-dependent degranulation, while reduced platelet aggregation by AA and collagen indicates a quantitative decrease in platelet aggregation consequently targeting the cyclooxygenase-1 and GP VI pathways, respectively. These findings are the first to demonstrate that the activation of platelets is mildly inhibited in individuals with GS, an effect that might contribute to protection from platelet hyperactivation-induced thrombosis and thus cardiovascular mortality in individuals with benign hyperbilirubinemia.

Aims: Bilirubin is associated with reduced risk of cardiovascular disease, as evidenced in conditions of mild hyperbilirubinaemia (Gilbert's Syndrome). Little is known regarding myocardial stress resistance in hyperbilirubinaemic conditions or whether life-long exposure modifies cardiac function, which might contribute to protection from cardiovascular disease., Methods: Hyperbilirubinaemic rats and littermate controls underwent echocardiography at 3, 6 and 12 months of age, with hearts subsequently assessed for resistance to 30 min of ischaemia. Heart tissue was then collected for assessment of bilirubin content., Results: No difference in baseline cardiac function was evident until 6 months onwards, where Gunn rats demonstrated aortic dilatation and reduced peak ejection velocities. Additionally, duration of ventricular ejection increased progressively, indicating a negative inotropic effect of bilirubin in vivo. Ex vivo analysis of baseline function revealed reduced left ventricular pressure development (LVDP) and contractility in hyperbilirubinaemic rats. Furthermore, stress resistance was improved in Gunn hearts: post-ischaemic recoveries of LVDP (76 ± 22% vs. 29 ± 17% Control, P < 0.01) and coronary flow (96 ± 9% vs. 86 ± 16% Control, P < 0.01) were improved in Gunn hearts, accompanied by reduced infarct area (21 ± 5% vs. 47 ± 15% Control, P < 0.01), and ventricular malondialdehyde and protein carbonyl content. Expression of myocardial nitric oxide-regulating genes including Nos1 and Noa1 were not significantly different., Conclusions: These data reveal life-long hyperbilirubinaemia induces age-dependent hypocontractility in male Gunn rats, and improved stress resistance. In addition, bilirubin exerts sex-independent effects on vascular structure, myocardial function and ischaemic tolerance, the latter likely mediated via bilirubin's antioxidant properties., (© 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

It remains incompletely understood whether there is an association between the transcriptome profiles of skeletal muscle and blood leukocytes in response to exercise or other physiological stressors. We have previously analyzed the changes in the muscle and blood neutrophil transcriptome in eight trained men before and 3, 48, and 96 h after 2 h cycling and running. Because we collected muscle and blood in the same individuals and under the same conditions, we were able to directly compare gene expression between the muscle and blood neutrophils. Applying weighted gene coexpression network analysis (WGCNA) as an advanced network-driven method to these original data sets enabled us to compare the muscle and neutrophil transcriptomes in a rigorous and systematic manner. Two gene networks were identified that were preserved between skeletal muscle and blood neutrophils, functionally related to mitochondria and posttranslational processes. Strong preservation measures ( Z summary > 10) for both muscle-neutrophil gene networks were evident within the postexercise recovery period. Muscle and neutrophil gene coexpression was strongly correlated in the mitochondria-related network ( r = 0.97; P = 3.17E-2). We also identified multiple correlations between muscular gene subnetworks and exercise-induced changes in blood leukocyte counts, inflammation, and muscle damage markers. These data reveal previously unidentified gene coexpression between skeletal muscle and blood neutrophils following exercise, showing the value of WGCNA to understand exercise physiology. Furthermore, these findings provide preliminary evidence in support of the notion that blood neutrophil gene networks may potentially help us to track physiological and pathophysiological changes in the muscle. NEW & NOTEWORTHY By using weighted gene coexpression network analysis, an advanced bioinformatics method, we have identified previously unknown, functional gene networks that are preserved between skeletal muscle and blood neutrophils during recovery from exercise. These novel preliminary data suggest that muscular gene networks are coexpressed in blood leukocytes following physiological stress. This is a step forward toward the development of blood neutrophil gene subnetworks as part of blood biomarker panels to assess muscle health and disease., (Copyright © 2017 the American Physiological Society.)

Augmented renal clearance (ARC) is being increasingly described in neurocritical care practice. The mechanisms driving this phenomenon are largely unknown. The aim of this project was therefore to explore changes in renal function, cardiac output (CO), and atrial natriuretic peptide (ANP) concentrations in patients with isolated traumatic brain injury (TBI). This prospective observational cohort study was conducted in a tertiary-level, university-affiliated intensive care unit (ICU). Patients with normal plasma creatinine concentrations (<120 μmol/L) at admission and no history of chronic kidney disease, admitted with isolated TBI, were eligible for enrollment. Continuous CO measures were obtained using arterial pulse waveform analysis. Eight-hour urinary creatinine clearances (CL CR ) were used to quantify renal function. ANP concentrations in plasma were measured on alternate days. Data were collected from study enrollment until ICU discharge, death, or day 15, which ever came first. Eleven patients, contributing 100 ICU days of physiological data, were enrolled into the study. Most participants were young men, requiring mechanical ventilation. Median ICU length of stay was 9.6 [7.8-13.0] days. Elevated CL CR measures (>150 mL/min) were frequent and appeared to parallel changes in CO. Plasma ANP concentrations were also significantly elevated over the study period (minimum value = 243 pg/mL). These data suggest that ARC is likely to complicate the care of TBI patients with normal plasma creatinine concentrations, and may be driven by associated cardiovascular changes and/or elevated plasma ANP concentrations. However, significant additional research is required to further understand these findings.

Background: Unconjugated bilirubin (UCB), an endogenous antioxidant, may protect the heart against ischemia-reperfusion (I-R) injury. However, the 'cardioprotective' potential of bilirubin therapy remains unclear. We tested whether pre- or post-ischemic treatment of ex vivo perfused hearts with bilirubin ditaurate (BRT) improves post-ischemic functional outcomes and myocardial oxidative damage., Methods: Isolated Langendorff perfused hearts (male, Wistar rats) were treated with 50 μM BRT for 30 min before (Pre) or after (Post) 30 min of zero-flow ischemia. Functional outcomes were monitored, with myocardial damage estimated from creatine kinase efflux, infarct size, and left ventricular lipid/protein oxidation assessed by measuring malondialdehyde and protein carbonyls. Ischemia induced contractile dysfunction and cellular injury, with both BRT treatments improving I-R outcomes., Results: Final post-ischemic recoveries for left ventricular diastolic/developed pressures were significantly enhanced in treated groups: end-diastolic pressure (Control, 78±14, Pre, 51±15*, Post, 51±13 mm Hg*); left ventricular developed pressure, (LVDP; Control 44±15, Pre, 71±19*, Post, 84±13 mm Hg*). Myocardial injury/infarction (MI) was also significantly reduced with BRT treatment: post-ischemic creatine kinase efflux (Control, 1.24±0.41, Pre, 0.86±0.31*, Post, 0.51±0.29 U/g/mL*; infarct size, Control, 67±17, Pre, 39±15*, Post, 22±11%*). These changes were accompanied by significantly reduced malondialdehyde and protein carbonyl content in Pre and Post treated hearts (*P<0.05 vs. Control)., Conclusions: These data collectively reveal significant cardioprotection upon BRT treatment, with post-treatment being particularly effective. Significant reductions in infarct size and lipid and protein oxidation indicate a mechanism related to protection from oxidative damage and indicate the potential utility of this molecule as a post-MI treatment., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The increasing prevalence of obesity adds another dimension to the pathophysiology of testosterone (TEST) deficiency (TD) and potentially impairs the therapeutic efficacy of classical TEST replacement therapy. We investigated the therapeutic effects of selective androgen receptor modulation with trenbolone (TREN) in a model of TD with the metabolic syndrome (MetS). Male Wistar rats (n=50) were fed either a control standard rat chow (CTRL) or a high-fat/high-sucrose (HF/HS) diet. After 8 weeks of feeding, rats underwent sham surgery or an orchiectomy (ORX). Alzet miniosmotic pumps containing either vehicle, 2-mg/kg·d TEST or 2-mg/kg·d TREN were implanted in HF/HS+ORX rats. Body composition, fat distribution, lipid profile, and insulin sensitivity were assessed. Infarct size was quantified to assess myocardial damage after in vivo ischaemia reperfusion, before cardiac and prostate histology was performed. The HF/HS+ORX animals had increased sc and visceral adiposity; circulating triglycerides, cholesterol, and insulin; and myocardial damage, with low circulating TEST compared with CTRLs. Both TEST and TREN protected HF/HS+ORX animals against sc fat accumulation, hypercholesterolaemia, and myocardial damage. However, only TREN protected against visceral fat accumulation, hypertriglyceridaemia, and hyperinsulinaemia and reduced myocardial damage relative to CTRLs. TEST caused widespread cardiac fibrosis and prostate hyperplasia, which were less pronounced with TREN. We propose that TEST replacement therapy may have contraindications for males with TD and obesity-related MetS. TREN treatment may be more effective in restoring androgen status and reducing cardiovascular risk in males with TD and MetS.

Background: Upregulation of the endothelin axis has been observed in pulmonary tissue after brain death, contributing to primary graft dysfunction and ischaemia reperfusion injury. The current study aimed to develop a novel, 24-h, clinically relevant, ovine model of brain death to investigate the profile of the endothelin axis during brain death-associated cardiopulmonary injury. We hypothesised that brain death in sheep would also result in demonstrable injury to other transplantable organs., Methods: Twelve merino cross ewes were randomised into two groups. Following induction of general anaesthesia and placement of invasive monitoring, brain death was induced in six animals by inflation of an extradural catheter. All animals were supported in an intensive care unit environment for 24 h. Animal management reflected current human donor management, including administration of vasopressors, inotropes and hormone resuscitation therapy. Activation of the endothelin axis and transplantable organ injury were assessed using ELISA, immunohistochemistry and standard biochemical markers., Results: All animals were successfully supported for 24 h. ELISA suggested early endothelin-1 and big endothelin-1 release, peaking 1 and 6 h after BD, respectively, but there was no difference at 24 h. Immunohistochemistry confirmed the presence of the endothelin axis in pulmonary tissue. Brain dead animals demonstrated tachycardia and hypertension, followed by haemodynamic collapse, typified by a reduction in systemic vascular resistance to 46 ± 1 % of baseline. Mean pulmonary artery pressure rose to 186 ± 20 % of baseline at induction and remained elevated throughout the protocol, reaching 25 ± 2.2 mmHg at 24 h. Right ventricular stroke work increased 25.9 % above baseline by 24 h. Systemic markers of cardiac and hepatocellular injury were significantly elevated, with no evidence of renal dysfunction., Conclusions: This novel, clinically relevant, ovine model of brain death demonstrated that increased pulmonary artery pressures are observed after brain death. This may contribute to right ventricular dysfunction and pulmonary injury. The development of this model will allow for further investigation of therapeutic strategies to minimise the deleterious effects of brain death on potentially transplantable organs.

Mildly elevated bilirubin is associated with a reduction in the presence and progression of chronic kidney disease and related mortality, which may be attributed to bilirubin's antioxidant properties. This study investigated whether endogenously elevated bilirubin would protect against adenine-induced kidney damage in male hyperbilirubinaemic Gunn rats and littermate controls. Animals were orally administered adenine or methylcellulose solvent (vehicle) daily for 10 days and were then monitored for 28 days. Serum and urine were assessed throughout the protocol for parameters of kidney function and antioxidant/oxidative stress status and kidneys were harvested for histological examination upon completion of the study. Adenine-treated animals experienced weight-loss, polyuria and polydipsia; however, these effects were significantly attenuated in adenine-treated Gunn rats. No difference in the presence of dihydroadenine crystals, lymphocytic infiltration and fibrosis were noted in Gunn rat kidneys versus controls. However, plasma protein carbonyl and F2-isoprostane concentrations were significantly decreased in Gunn rats versus controls, with no change in urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine or kidney tissue F2-isoprostane concentrations. These data indicated that endogenously elevated bilirubin specifically protects from systemic oxidative stress in the vascular compartment. These data may help to clarify the protective relationship between bilirubin, kidney function and cardiovascular mortality in clinical investigations.

Introduction: Current models of obesity utilise normogonadic animals and neglect the strong relationships between obesity-associated metabolic syndrome (MetS) and male testosterone deficiency (TD). The joint presentation of these conditions has complex implications for the cardiovascular system that are not well understood. We have characterised and investigated three models in male rats: one of diet-induced obesity with the MetS; a second using orchiectomised rats mimicking TD; and a third combining MetS with TD which we propose is representative of males with testosterone deficiency and the metabolic syndrome (TDMetS)., Methods: Male Wistar rats (n = 24) were randomly assigned to two groups and provided ad libitum access to normal rat chow (CTRL) or a high fat/high sugar/low protein "obesogenic" diet (OGD) for 28 weeks (n = 12/group). These groups were further sub-divided into sham-operated or orchiectomised (ORX) animals to mimic hypogonadism, with and without diet-induced obesity (n = 6/group). Serum lipids, glucose, insulin and sex hormone concentrations were determined. Body composition, cardiovascular structure and function; and myocardial tolerance to ischemia-reperfusion were assessed., Results: OGD-fed animals had 72% greater fat mass; 2.4-fold greater serum cholesterol; 2.3-fold greater serum triglycerides and 3-fold greater fasting glucose (indicative of diabetes mellitus) compared to CTRLs (all p<0.05). The ORX animals had reduced serum testosterone and left ventricle mass (p<0.05). In addition to the combined differences observed in each of the isolated models, the OGD, ORX and OGD+ORX models each had greater CK-MB levels following in vivo cardiac ischemia-reperfusion insult compared to CTRLs (p<0.05)., Conclusion: Our findings provide evidence to support that the MetS and TD independently impair myocardial tolerance to ischemia-reperfusion. The combined OGD+ORX phenotype described in this study is a novel animal model with associated cardiovascular risk factors and complex myocardial pathology which may be representative of male patients presenting with TDMetS.

Hypochlorous acid (HOCl), an oxidant produced by myeloperoxidase (MPO), induces protein and lipid oxidation, which is implicated in the pathogenesis of atherosclerosis. Individuals with mildly elevated bilirubin concentrations (i.e., Gilbert syndrome; GS) are protected from atherosclerosis, cardiovascular disease, and related mortality. We aimed to investigate whether exogenous/endogenous unconjugated bilirubin (UCB), at physiological concentrations, can protect proteins/lipids from oxidation induced by reagent and enzymatically generated HOCl. Serum/plasma samples supplemented with exogenous UCB (≤250µM) were assessed for their susceptibility to HOCl and MPO/H2O2/Cl(-) oxidation, by measuring chloramine, protein carbonyl, and malondialdehyde (MDA) formation. Serum/plasma samples from hyperbilirubinemic Gunn rats and humans with GS were also exposed to MPO/H2O2/Cl(-) to: (1) validate in vitro data and (2) determine the relevance of endogenously elevated UCB in preventing protein and lipid oxidation. Exogenous UCB dose-dependently (P<0.05) inhibited HOCl and MPO/H2O2/Cl(-)-induced chloramine formation. Albumin-bound UCB efficiently and specifically (3.9-125µM; P<0.05) scavenged taurine, glycine, and N-α-acetyllysine chloramines. These results were translated into Gunn rat and GS serum/plasma, which showed significantly (P<0.01) reduced chloramine formation after MPO-induced oxidation. Protein carbonyl and MDA formation was also reduced after MPO oxidation in plasma supplemented with UCB (P<0.05; 25 and 50µM, respectively). Significant inhibition of protein and lipid oxidation was demonstrated within the physiological range of UCB, providing a hypothetical link to protection from atherosclerosis in hyperbilirubinemic individuals. These data demonstrate a novel and physiologically relevant mechanism whereby UCB could inhibit protein and lipid modification by quenching chloramines induced by MPO-induced HOCl., (Copyright © 2015 Elsevier Inc. All rights reserved.)