Clinical Significance of Albumin-Bilirubin Grade in Thoracic Esophageal Squamous Cell Carcinoma.

INTRODUCTION: The albumin-bilirubin (ALBI) score evaluates liver dysfunction severity. However, this score had prognostic effects in patients with hepatocellular, pancreatic, and gastric carcinomas. We aimed to assess the predictive value of the ALBI score in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Data from 154 patients with ESCC who consecutively underwent neoadjuvant chemotherapy (NAC) and subtotal esophagectomy were retrospectively investigated. The ALBI score was calculated as pre-NAC ALBI and categorized into grades 1, 2a, 2b, and 3; low-ALBI group (n = 134) was assigned with ALBI grade 1 and the other grades were assigned to the high-ALBI group (n = 20). RESULTS: The pre-NAC ALBI was significantly associated with relapse-free survival (RFS) and overall survival (P = 0.003 and P = 0.014, respectively). Based on multivariate analysis, pre-NAC ALBI, pathological T factor, and N factor were identified as independent prognostic factors for poor RFS. Multivariate and univariate analyses limited to factors were obtained before treatment, indicating high pre-NAC ALBI as an independent prognostic factor of poor overall survival (P = 0.039) and RFS (P = 0.008). With respect to pathological response to NAC, patients in the high pre-NAC ALBI group had a significantly lower response than patients in the low pre-NAC ALBI group (P = 0.010). CONCLUSIONS: Our results suggested that the pre-NAC ALBI marker predicts the long-term outcome and pathological response to NAC in patients with ESCC consecutively undergoing NAC and a subtotal esophagectomy.

Risk evaluation of ampicillin/sulbactam-induced liver injury based on albumin-bilirubin score.

BACKGROUND: Drug-induced liver injury (DILI) is an adverse reaction caused by ampicillin/sulbactam (ABPC/SBT). The albumin-bilirubin (ALBI) score is an index of hepatic functional reserve. However, the relationship between ABPC/SBT-induced DILI and ALBI score remains unknown; therefore, we aimed to elucidate the risk of ABPC/SBT-induced DILI based on the ALBI score. METHODS: This was a single-center, retrospective, case-control study using electronic medical records. A total of 380 patients were enrolled in the present study, and the primary outcome was ABPC/SBT-induced DILI. The ALBI score was calculated using serum albumin and total bilirubin levels. In addition, we performed COX regression analysis using age ≥75 years, dose ≥9 g/day, alanine aminotransferase (ALT) ≥21 IU/L, and ALBI score ≥-2.00 as covariates. We also performed 1:1 propensity score matching between non-DILI and DILI groups. RESULTS: The incidence of DILI was 9.5% (36/380). According to COX regression analysis, the adjusted hazard ratio for ABPC/SBT-induced DILI with an ALBI score ≥-2.00 was 2.55 (95% confidence interval: 1.256-5.191, P = 0.010), suggesting that patients with baseline ALBI score ≥-2.00 may be at high risk for ABPC/SBT-induced DILI. However, significant differences were not observed in cumulative risk for DILI between non-DILI and DILI patients regarding an ALBI score ≥-2.00 after propensity score matching (P = 0.146). CONCLUSION: These findings suggest that ALBI score may be a simple and potentially useful index for predicting ABPC/SBT-induced DILI. In patients with an ALBI score ≥-2.00, frequent liver function monitoring should be considered to prevent ABPC/SBT-induced DILI.

Association of Different Total Bilirubin Levels with Prognosis of Peritoneal Dialysis-Associated Peritonitis.

Background and Objectives: Peritoneal dialysis-associated peritonitis (PDAP) poses significant challenges in peritoneal dialysis (PD) patient management and outcomes. Total bilirubin has gained attention due to its antioxidant and immunomodulatory properties. However, its relationship with PDAP prognosis remains underexplored. Materials and Methods: We conducted a retrospective single-center study involving 243 PDAP patients stratified into tertile-based groups according to total bilirubin levels. The association between total bilirubin levels and treatment failure risk was investigated through statistical analyses and restricted cubic spline curve analysis. Results: Our analysis revealed a non-linear correlation between total bilirubin levels and PDAP treatment failure risk. At total bilirubin levels below 8.24 µmol/L, a protective effect was observed, while levels exceeding this threshold heightened the risk of treatment failure. Conclusions: This study unveils a dual role of total bilirubin in PDAP prognosis. Below a certain threshold, it confers protection, while higher levels exacerbate the risk of treatment failure. These findings emphasize the need for further investigation in larger, multicenter prospective studies to validate and elucidate the mechanisms behind bilirubin's impact on PDAP, potentially guiding the development of targeted therapeutic strategies.

FUNCTIONAL STATE OF THE LIVER IN PULMONARY TUBERCULOSIS IN THE DYNAMICS OF PATHOGENETIC TREATMENT WITH A COMPLEX OF AMINO ACIDS.

OBJECTIVE: The aim: To investigate the in!uence of prescribing a complex of amino acids in pathogenetic therapy in patients with pulmonary tuberculosis on liver function. PATIENTS AND METHODS: Materials and methods: The study included 50 patients with drug susceptible TB and 50 patients with drug-resistant TB (multidrug-resistant and extensively drug-resistant). RESULTS: Results: The study included 50 patients with drug susceptible tuberculosis (TB) and 50 patients with drug-resistant TB. When comparing biochemical pa-rameters characterizing liver function in patients with drug-susceptible TB after 1 month of anti-tuberculosis therapy, it was found that patients receiving additional therapy with a complex of amino acids had a lower level of bilirubin, p <0.05. After 60 doses, patients receiving additional therapy with amino acids had significantly lower bilirubin levels alanine aminotransferase (ALT) and aspartate aminotransferase (AST), p <0.05. When comparing the biochemical parameters characterizing liver function in patients with drug-resistant tuberculosis after a month of anti-tuberculosis therapy, significantly higher protein level was found in the groups of patients receiving additional therapy with amino acids, as well as significantly lower ALT level, AST and creatinine p <0.05. CONCLUSION: Conclusions: The additional appointment of the complex of amino acids in the pathogenetic therapy of patients with pulmonary tuberculosis makes it possible to reduce the severity of hepatotoxic reactions manifested by the main parameters (AST, ALT, total bilirubin) and to increase the protein-synthetic function of the liver, which allows us to recommend their appointment to improve the tolerance of anti-tuberculosis therapy.

UGT1A1 genetic variants are associated with increases in bilirubin levels in rheumatoid arthritis patients treated with sarilumab.

Sarilumab is a human monoclonal antibody against interleukin (IL)-6Rα that has been approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Mild liver function test abnormalities have been observed in patients treated with sarilumab. We describe a genome-wide association study of bilirubin elevations in RA patients treated with sarilumab. Array genotyping and exome sequencing were performed on DNA samples from 1075 patients. Variants in the UGT1A1 gene were strongly associated with maximum bilirubin elevations in sarilumab-treated patients (rs4148325; p = 2.88 × 10-41) but were not associated with aminotransferase elevations. No other independent loci showed evidence of association with bilirubin elevations after sarilumab treatment. These findings suggest that most bilirubin increases during sarilumab treatment are related to genetic variation in UGT1A1 rather than underlying liver injury.

Drug repurposing strategy: An emerging approach to identify potential therapeutics for treatment of bovine mastitis.

The current study was designed to characterize methicillin-resistant Staphylococcus aureus (MRSA) isolated from bovine milk, along with its response to antibiotics, and ultimately reverse its mechanism of resistance by modulation with non-antibiotics. The synergistic combination of antibiotics with NSAIDs were tested in-vivo by giving MRSA challenge to rabbits. The current study reported an overall 23.79% prevalence of MRSA. The BLAST alignment of current study sequences revealed 99% similarity with mecA gene of MRSA from NCBI database. The current study isolates were more similar to each other and also with reference sequences as compared to other mecA gene sequences from Turkey, India, and Russia. Antibiogram of MRSA isolates showed a highly resistant response to cefoxitin, amoxicillin, and gentamicin. Amoxicillin, gentamicin, tylosin, vancomycin, and ciprofloxacin elicited a significant response (p < 0.05) in combination with non-antibiotics against tested MRSA isolates. The highest zone of inhibition (ZOI) increase was noted for vancomycin in combination with flunixin meglumine (145.45%) and meloxicam (139.36%); gentamicin with flunixin meglumine (85.71%) and ciprofloxacin with ivermectin (71.13%). Synergistic behavior was observed in the combination of gentamicin with ketoprofen; sulfamethoxazole and oxytetracycline with meloxicam. Hematological analysis showed significant differences (p < 0.05) among lymphocyte count and bilirubin. On histopathological examination of skin tissue, hyperplasia of epithelium, sloughed off epidermis, hyperkeratosis, infiltration of inflammatory cells, and hemorrhages were observed. The highest cure rate was observed in case of gentamicin in combination with ketoprofen as compared to other treatment groups. The current study concluded antibiotics in combination with non-antibiotics as potential therapeutic agents for resistance modulation against MRSA. This study will help to devise treatment and control strategies against bovine mastitis. Although the prospect of using NSAIDs to manage infections caused by MRSA appears to be a promising direction, further studies should be conducted to test these medications using suitable in-vivo models in controlled clinical trials to justify their repurposing as a treatment for MRSA infections.

The liver-gut-axis: initiator and responder to sepsis.

PURPOSE OF REVIEW: The 'gut-liver axis' is thought to play an important role in pathogenesis of sepsis. Despite a wealth of experimental data to support the concept of reciprocal crosstalk between gut and liver through bacterial translocation and shaping of the microbiome by liver-derived molecules, for example bile acids, clinical data, and in particular diagnostic and therapeutic options, are limited. RECENT FINDINGS: Assessment of organ failure in the current definition of sepsis is operationalized by means of the Sequential Organ Failure Assessment (SOFA) score, including exclusively bilirubin to reflect the complex functions of the liver but ignoring the gut. However, our understanding of the intestinal microbiome and how it is affected by critical illness has clearly improved. Microbiota maintain gut-barrier function and modulate the innate and adaptive immune system. The best-defined intervention affecting the gut microbiome, that is selective decontamination of the digestive tract (SDD) is clinically studied regarding prevention of nosocomial lung infection and antibiotic resistance patterns, although its impact on liver function has not been systematically evaluated in critical illness. SUMMARY: Characterization of liver function beyond bilirubin and the microbiome can be achieved with contemporary sequencing and metabolomic techniques. Such studies are essential to understand how gut-liver crosstalk and 'dysbiosis' affect susceptibility to and outcome of sepsis.

The Inhibitory Effect of Phycocyanin Peptide on Pulmonary Fibrosis In Vitro.

Phycocyanin is an excellent antioxidant with anti-inflammatory effects on which recent studies are growing; however, its specific target remains unclear. Linear tetrapyrrole compounds such as bilirubin have been shown to lead to the induction of heme oxygenase 1 expression in vivo, thus achieving antioxidant and anti-inflammatory effects. Phycocyanin is bound internally with linear tetrapyrrole phycocyanobilin in a similar structure to bilirubin. We speculate that there is probably a way of inducing the expression of heme oxygenase 1, with which tissue oxidative stress and inflammation can be inhibited, thus inhibiting pulmonary fibrosis caused by oxidative damage and inflammation of lung. By optimizing the enzymatic hydrolysis process, phycocyanobilin-bound phycocyanin peptide were obtained, and its in vitro antioxidant, anti-inflammatory, and anti-pulmonary fibrosis activities were investigated. The results show that the phycocyanobilin peptide was able to alleviate oxidative and inflammatory damage in cells through the Keap1-Nrf2-HO-1 pathway, which in turn relieved pulmonary fibrosis symptoms.

Bilirubin Prevents the TH+ Dopaminergic Neuron Loss in a Parkinson's Disease Model by Acting on TNF-α.

Parkinson's disease (PD), the fastest-growing movement disorder, is still challenged by the unavailability of disease-modifying therapy. Mildly elevated levels of unconjugated bilirubin (UCB, PubChem CID 5280352) have been shown to be protective against several extra-CNS diseases, and the effect is attributed to its well-known anti-oxidant and anti-inflammatory capability. We explored the neuroprotective effect of low concentrations of UCB (from 0.5 to 4 µM) in our PD model based on organotypic brain cultures of substantia nigra (OBCs-SN) challenged with a low dose of rotenone (Rot). UCB at 0.5 and 1 µM fully protects against the loss of TH+ (dopaminergic) neurons (DOPAn). The alteration in oxidative stress is involved in TH+ positive neuron demise induced by Rot, but is not the key player in UCB-conferred protection. On the contrary, inflammation, specifically tumor necrosis factor alpha (TNF-α), was found to be the key to UCB protection against DOPAn sufferance. Further work will be needed to introduce the use of UCB into clinical settings, but determining that TNF-α plays a key role in PD may be crucial in designing therapeutic options.

[The results of phase III multicenter open randomized controlled study REM-Chol-III-16 in patients with intrahepatic cholestasis syndrome caused by chronic diffuse liver diseases].

AIM: To assess the safety and efficacy of Remaxol, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology. MATERIALS AND METHODS: In a multicenter open-label comparative study of the safety and efficacy of Remaxol (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol, solution for infusion, 400 ml, and patients of the control group (n=149) Heptral (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by 40%, and/or alkaline phosphatase level by 30%, and/or decrease total bilirubin level by 30% from baseline by the end of the treatment course. RESULTS: The proportion of responders was 51% in the Remaxol group vs. 44.9% in the Heptral group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment. CONCLUSION: Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified.

Bilirubin Nanomedicines for the Treatment of Reactive Oxygen Species (ROS)-Mediated Diseases.

Reactive oxygen species (ROS) are chemically reactive species that are produced in cellular aerobic metabolism. They mainly include superoxide anion, hydrogen peroxide, hydroxyl radicals, singlet oxygen, ozone, and nitric oxide and are implicated in many physiological and pathological processes. Bilirubin, a cardinal pigment in the bile, has been increasingly investigated to treat cancer, diabetes, ischemia-reperfusion injury, asthma, and inflammatory bowel diseases (IBD). Indeed, bilirubin has been shown to eliminate ROS production, so it is now considered as a promising therapeutic agent for ROS-mediated diseases and can be used for the development of antioxidative nanomedicines. This review summarizes the current knowledge of the physiological mechanisms of ROS production and its role in pathological changes and focuses on discussing the antioxidative effects of bilirubin and its application in the experimental studies of nanomedicines. Previous studies have shown that bilirubin was mainly used as a responsive molecule in the microenvironment of ROS overproduction in neoplastic tissues for the development of anticancer nanodrugs; however, it could also exert powerful ROS scavenging activity in chronic inflammation and ischemia-reperfusion injury. Therefore, bilirubin, as an inartificial ROS scavenger, is expected to be used for the development of nanomedicines against more diseases due to the universality of ROS involvement in human pathological conditions.

The impact of bilirubin ditaurate on platelet quality during storage.

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.

Pharmacological actions and therapeutic potentials of bilirubin in islet transplantation for the treatment of diabetes.

Islet transplantation is the experimental strategy to treat type 1 diabetes by transplanting isolated islets from a donor pancreas into the recipient. While significant progress has been made in the islet transplantation field, islet loss before and after transplantation is still the major obstacle that currently precludes its widespread application. Islet must survive from possible cellular damages during the isolation procedure, storage time, islet injection process and post-transplantation immune rejection, only then the survived islets could produce insulin, actively regulating the blood glucose level. Therefore, islet protection needs to be addressed, especially regarding oxidative stress and immune response induced islet cell damages in diabetic patients. Many clinical data have shown that mildly elevated bilirubin levels in the body negatively correlate to the occurrence of an array of diseases that are related to increased oxidative stress, especially diabetes, and its complications. Recent studies confirmed that bilirubin helps receivers to suppress immune reaction and enable prolonged tolerance to islet transplantation. In this paper, we will review the pharmacological mechanism of bilirubin to modulate oxidative cellular damage and chronic inflammatory reaction in both diabetes and islet transplantation process. Also, we will present the clinical evidence of a strong correlation in bilirubin and diabetes. More importantly, we will summarize undergoing therapeutic applications of bilirubin in islet transplantation and discuss formulation approaches designed to overcome bilirubin delivery issues for future use.

Bilirubin Attenuates ER Stress-Mediated Inflammation, Escalates Apoptosis and Reduces Proliferation in the LS174T Colonic Epithelial Cell Line.

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.

Black Pigment Gallstone Inspired Platinum-Chelated Bilirubin Nanoparticles for Combined Photoacoustic Imaging and Photothermal Therapy of Cancers.

Bilirubin (BR), a bile pigment that exerts potent antioxidant and anti-inflammatory effects, is also a major constituent of black pigment gallstones found in bile ducts under certain pathological conditions. Inspired by the intrinsic metal-chelating power of BR found in gallstones, herein we report a cisplatin-chelated BR-based nanoparticle (cisPt@BRNP) for use as a new photonic nanomedicine for combined photoacoustic imaging and photothermal therapy of cancers. The cisPt@BRNPs were prepared by simply mixing cisplatin with BRNPs, yielding ca. 150-nm-size NPs. Upon near-IR laser irradiation at 808 nm, cisPt@BRNPs generated considerable heat and induced clear death of cancer cells in vitro. Following intravenous injection into human colon cancer-bearing mice, cisPt@BRNPs allowed effective tumor visualization by photoacoustic imaging and remarkable antitumor efficacy by photothermal therapy, suggesting their potential for use as a new photonic nanomedicine for cancer therapy.

Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich's Ataxia Transgenic Mice.

Friedreich's ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 µg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA.

Bilirubin provides perforator flap protection from ischaemia-reperfusion injury in a rat model: a preliminary result.

The use of bilirubin, a well-known and powerful antioxidant, has gained popularity in recent years because of its role in the prevention of ischaemic heart disease in patients with Gilbert's syndrome. We investigate the effects of bilirubin on ischaemia-reperfusion (I/R) injury using a rat perforator flap model. Forty-eight rats were randomly divided into two groups: experimental (bilirubin) group (n = 24) and control group (n = 24). In each group, elevated bilateral deep inferior epigastric perforator (DIEP) flaps were created. The right (no ischaemia side) and left (ischaemia side) DIEP flaps were separated according to the presence of ischaemia induction. Ischaemia was induced in anaesthetised rats by perforator clamping for 15 or 30 minutes. After surgery, the flap survival was assessed daily on postoperative days 0 to 5, and overall histological changes of DIEP flaps above the perforator were analysed at postoperative day 5. The flap survival rate in the bilirubin group was significantly higher than that in the control group at the ischaemia side following perforator clamping for 15 or 30 minutes (93·42 ± 4·48% versus 89·63 ± 3·98%, P = 0·002; and 83·96 ± 4·23% versus 36·46 ± 6·38%, P < 0·001, respectively). The difference in flap survival between the two groups was the most prominent on the ischaemic side following 30 minutes of perforator clamping. From a morphologic perspective, pre-treatment with bilirubin was found to alleviate perforator flap necrosis caused by I/R injury in this experimental rat model.

Bilirubin Nanoparticles as a Nanomedicine for Anti-inflammation Therapy.

Despite the high potency of bilirubin as an endogenous anti-inflammatory compound, its clinical translation has been hampered because of its insolubility in water. Bilirubin-based nanoparticles that may overcome this critical issue are presented. A polyethylene glycol compound (PEG) was covalently attached to bilirubin, yielding PEGylated bilirubin (PEG-BR). The PEG-BR self-assembled into nanoscale particles with a size of approximately 110 nm, termed bilirubin nanoparticles (BRNPs). BRNPs are highly efficient hydrogen peroxide scavengers, thereby protecting cells from H2 O2 -induced cytotoxicity. In a murine model of ulcerative colitis, intravenous injection of BRNPs showed preferential accumulation of nanoparticles at the sites of inflammation and significantly inhibited the progression of acute inflammation in the colon. Taken together, BRNPs show potential for use as a therapeutic nanomedicine in various inflammatory diseases.

Bilirubin rinse of the graft ameliorates ischemia reperfusion injury in heart transplantation.

Ischemia and reperfusion contribute to substantial organ damage in transplantation. Clinically feasible measures for the prevention thereof are scarce. We tested whether rinsing rodent hearts with the antioxidant bilirubin ameliorates ischemia reperfusion injury (IRI). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDevP), rate per pressure product (RPP), coronary flow, maximum (+dP/dt) and minimum (-dP/dt) rate of contraction were analyzed in Lewis rat hearts rinsed with bilirubin prior to reperfusion on a Langendorff apparatus after 12 h of cold ischemia. In vivo, isogenic C57Bl/6 mouse hearts rinsed with bilirubin were transplanted after 12 h of cold ischemia. Cardiac function and apoptosis were assessed 24 h after reperfusion. Heart lysates recovered 15 min after reperfusion were probed for the total and the phosphorylated forms of extracellular signal-related protein kinases (ERK), JNK, p38-MAPK, and Akt. In isolated perfused hearts, bilirubin rinse resulted in significantly lower LVEDP and improved LVDevP, RPP, coronary flow, +dP/dt and -dP/dt. In vivo, after reperfusion, all mitogen-activated protein kinases (MAPKs) were suppressed significantly by bilirubin pretreatment. Bilirubin rinse improved cardiac scores (3.4 ± 0.5 vs. 2.0 ± 1.0 in controls, P < 0.05) and significantly suppressed apoptosis. Ex vivo administration of bilirubin to heart grafts prior reperfusion ameliorates IRI and provides a simple and effective tool to ameliorate outcome in heart transplantation.

Effect of bilirubin on triglyceride synthesis in streptozotocin-induced diabetic nephropathy.

We aimed to elucidate the effect of bilirubin on dyslipidemia and nephropathy in a diabetes mellitus (DM) type I animal model. Sprague-Dawley rats were separated into control, DM, and bilirubin-treated DM (Bil) groups. The Bil group was injected intraperitoneally with 60 mg/kg bilirubin 3 times per week and hepatoma cells were cultured with bilirubin at a concentration of 0.3 mg/dL. The Bil group showed lower serum creatinine levels 5 weeks after diabetes onset. Bilirubin treatment also decreased the amount of mesangial matrix, lowered the expression of renal collagen IV and transforming growth factor (TGF)-ß1, and reduced the level of apoptosis in the kidney, compared to the DM group. These changes were accompanied by decreased tissue levels of hydrogen superoxide and NADPH oxidase subunit proteins. Bilirubin decreased serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), free fatty acids, and triglycerides (TGs), as well as the TG content in the liver tissues. Bilirubin suppressed protein expression of LXRα, SREBP-1, SCD-1, and FAS, factors involved in TG synthesis that were elevated in the livers of DM rats and hepatoma cells under high-glucose conditions. In conclusion, bilirubin attenuates renal dysfunction and dyslipidemia in diabetes by suppressing LXRα and SREBP-1 expression and oxidative stress.