Publications by authors named "Josif Vidimce"

6 Publications

  • Page 1 of 1

Maternal and Postnatal High Linoleic Acid Diet Impacts Lipid Metabolism in Adult Rat Offspring in a Sex-Specific Manner.

Int J Mol Sci 2021 Mar 14;22(6). Epub 2021 Mar 14.

Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. We aimed to investigate the effect of maternal and postnatal high LA (HLA) diet on plasma FA composition, plasma and hepatic lipids and genes involved in lipid metabolism in the liver of adult offspring. Female rats were fed with low LA (LLA; 1.44% LA) or HLA (6.21% LA) diets for 10 weeks before pregnancy, and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), fed either LLA or HLA diets and sacrificed at PN180. Postnatal HLA diet decreased circulating total n-3 PUFA and alpha-linolenic acid (ALA), while increased total n-6 PUFA, LA and arachidonic acid (AA) in both male and female offspring. Maternal HLA diet increased circulating leptin in female offspring, but not in males. Maternal HLA diet decreased circulating adiponectin in males. Postnatal HLA diet significantly decreased aspartate transaminase (AST) in females and downregulated total cholesterol, HDL-cholesterol and triglycerides in the plasma of males. Maternal HLA diet downregulated the hepatic mRNA expression of in both male and female offspring and decreased the hepatic mRNA expression of and in females. Both maternal and postnatal HLA diet decreased hepatic mRNA expression of in females. Postnatal diet significantly altered circulating fatty acid concentrations, with sex-specific differences in genes that control lipid metabolism in the adult offspring following exposure to high LA diet in utero.
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http://dx.doi.org/10.3390/ijms22062946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999727PMC
March 2021

Mitochondrial Function, Fatty Acid Metabolism, and Body Composition in the Hyperbilirubinemic Gunn Rat.

Front Pharmacol 2021 8;12:586715. Epub 2021 Mar 8.

School of Medical Science, Griffith University, Gold Coast, QLD, Australia.

Circulating bilirubin is associated with reduced adiposity in human and animal studies. A possible explanation is provided by 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. To investigate the impact of unconjugated hyperbilirubinemia on body composition, and mitochondrial function in hepatic tissue and skeletal muscle. 1) Food intake and bodyweight gain of 14-week old hyperbilirubinemic Gunn ( = 19) and normobilirubinemic littermate (control; = 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. Female hyperbilirubinemic rats had significantly reduced fat mass (Gunn: 9.94 ± 5.35 vs. Control: 16.6 ± 6.90 g, < 0.05) and hepatic triglyceride concentration (Gunn: 2.39 ± 0.92 vs. Control: 4.65 ± 1.67 mg g, < 0.01) compared to normobilirubinemic controls. Furthermore, hyperbilirubinemic rats consumed fewer calories daily ( < 0.01) and were less energetically efficient (Gunn: 8.09 ± 5.75 vs. Control: 14.9 ± 5.10 g bodyweight kcal, < 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, < 0.05). Similarly, exogenous addition of 31.3 or 62.5 μM unconjugated bilirubin to control liver homogenates significantly increased CI+II FCR ( < 0.05). Hepatic gene expression was significantly increased in hyperbilirubinemic females while and was significantly greater in male hyperbilirubinemic rats ( < 0.05). Finally, hepatic mitochondrial complex IV subunit 1 protein expression was significantly increased in female hyperbilirubinemic rats ( < 0.01). 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.
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http://dx.doi.org/10.3389/fphar.2021.586715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982585PMC
March 2021

Pharmacokinetics of bilirubin-10-sulfonate and biliverdin in the rat.

Eur J Pharm Sci 2021 Apr 24;159:105684. Epub 2020 Dec 24.

School of Medical Science, Australia. Electronic address:

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 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). 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.
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http://dx.doi.org/10.1016/j.ejps.2020.105684DOI Listing
April 2021

Biliverdin and bilirubin sulfonate inhibit monosodium urate induced sterile inflammation in the rat.

Eur J Pharm Sci 2020 Dec 12;155:105546. Epub 2020 Sep 12.

School of Medical Science, Griffith University, Gold Coast, Queensland, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia. Electronic address:

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 cells mL) and BV (0.17 ± 0.03 × 10 cells mL) compared to MSU only (3.51 ± 1.07 × 10 cells mL). Both BV and BRS significantly (p < 0.05) reduced pouch GM-CSF (BV: 5.8 ± 1.2 pg mL, BRS: 6.9 ± 1.5 pg mL vs MSU only: 13.0 ± 1.9 pg mL) and MCP-1 concentrations at 6 h (BV: 1804 ± 269 pg mL, BRS: 7927 ± 2668 pg mL vs MSU only: 17,290 ± 4503 pg ml), whilst BV additionally inhibited IL-6 (4354 ± 977 pg mL vs MSU only: 25,070 ± 5178 pg mL) and IL-18 (17.6 ± 2.0 pg mL vs MSU only: 81.5 ± 19.9 pg mL) 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.
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http://dx.doi.org/10.1016/j.ejps.2020.105546DOI Listing
December 2020

The impact of bilirubin ditaurate on platelet quality during storage.

Platelets 2020 Oct 20;31(7):884-896. Epub 2019 Nov 20.

School of Medical Science, Griffith University , Gold Coast, Australia.

Bilirubin ditaurate (BRT), a conjugated bilirubin analogue, has demonstrated anti-platelet characteristics following acute 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 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.
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http://dx.doi.org/10.1080/09537104.2019.1693038DOI Listing
October 2020

Unprecedented Microbial Conversion of Biliverdin into Bilirubin-10-sulfonate.

Sci Rep 2019 02 27;9(1):2988. Epub 2019 Feb 27.

School of Medical Science, Griffith University, Gold Coast, Queensland, Australia.

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 CNOHS, which conformed to the predicted structure of bilirubin-10-sulfonate (BRS) and possessed a λ 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.
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http://dx.doi.org/10.1038/s41598-019-39548-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393463PMC
February 2019