Antioxidant Bilirubin Research Articles

Association of per- and polyfluoroalkyl substances with the antioxidant bilirubin across pregnancy

BackgroundIn mechanistic and preliminary human studies, prenatal exposure to per- and polyfluoroalkyl substances (PFAS) is associated with oxidative stress, a potential contributor to maternal liver disease. Bilirubin is an endogenous antioxidant abundant in the liver that may serve as a physiological modulator of oxidative stress in pregnant people. Hence, our objective was to estimate the association between repeated measures of PFAS and bilirubin during pregnancy. MethodsThe study population included 332 participants in the Atlanta African American Maternal-Child Cohort between 2014 and 2020. Serum samples were collected up to two times (early pregnancy: 6–18 gestational weeks; late pregnancy: 21–36 gestational weeks) for the measurement of perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and total bilirubin. We analyzed single PFAS with linear mixed effect regression and a mixture of the four PFAS with quantile g-computation. Models were repeated with a multiplicative interaction term to explore effect modification by study visit. ResultsOverall, PFHxS was positively associated with bilirubin (β = 0.08, 95 % CI = 0.01, 0.15). We also found during late pregnancy, there was a positive association of PFHxS and the PFAS mixture with bilirubin (β = 0.12, 95 % CI = 0.02, 0.22; ψ = 0.19, 95 % CI = 0.03, 0.34, respectively). Finally, study visit modified the PFOA-bilirubin association (interaction p-value = 0.09), which was greater during early pregnancy (β = 0.08, 95 % CI = 0.01, 0.15). ConclusionIn a prospective cohort of pregnant African Americans, an increase in PFOA, PFHxS, and the PFAS mixture was associated with an increase in bilirubin. Our results suggest that, depending on pregnancy stage, prenatal PFAS exposure disrupts the maternal liver antioxidant capacity.

Dissecting clinical and biological heterogeneity in clinical states of bipolar disorder: a 10-year retrospective study from China.

To dissect clinical and biological heterogeneity in clinical states of bipolar disorder (BD), and investigate if neuropsychological symptomatology, comorbidity, vital signs, and blood laboratory indicators are predictors of distinct BD states. A retrospective BD cohort was established with data extracted from a Chinese hospital's electronic medical records (EMR) between 2009 and 2018. Subjects were inpatients with a main discharge diagnosis of BD and were assessed for clinical state at hospitalization. We categorized all subjects into manic state, depressive state, and mixed state. Four machine learning classifiers were utilized to classify the subjects. A Shapley additive explanations (SHAP) algorithm was applied to the classifiers to aid in quantifying and visualizing the contributions of each feature that drive patient-specific classifications. A sample of 3,085 records was included (38.54% as manic, 56.69% as depressive, and 4.77% as mixed state). Mixed state showed more severe suicidal ideation and psychomotor abnormalities, while depressive state showed more common anxiety, sleep, and somatic-related symptoms and more comorbid conditions. Higher levels of body temperature, pulse, and systolic and diastolic blood pressures were present during manic episodes. Xgboost achieved the best AUC of 88.54% in manic/depressive states classification; Logistic regression and Random forest achieved the best AUCs of 75.5 and 75% in manic/mixed states and depressive/mixed states classifications, respectively. Myocardial enzymes and the non-enzymatic antioxidant uric acid and bilirubin contributed significantly to distinguish BD clinical states. The observed novel biological associations with BD clinical states confirm that biological heterogeneity contributes to clinical heterogeneity of BD.

Heme Attenuates T Cell Exhaustion and Drives Effector Function: Implications for Immune and Adoptive T Cell Therapy

Introduction: Though frontline agents have been effective in multiple myeloma (MM) therapy, a significant proportion of MM patients relapse and succumb to refractory disease. B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T therapy represents an exciting novel therapeutic strategy for MM but still suffers from limited in vivo T cell expansion and CAR T cytotoxicity. Altering the CAR T manufacturing process to produce CAR T cells with less exhausted phenotypes and robust killing is an active area of research. Mitochondrial function and energetics play a central role in regulating T cell fate and function, and heme (iron-protoporphyrin IX) is critical for maintaining electron transport chain activity and oxidative phosphorylation. Heme can be sourced from the extracellular milieu, diet, or intrinsic heme biosynthesis and has a multitude of cellular functions throughserving as a cofactor for enzymatic and metabolic reactions. Additionally, heme is catabolized by heme oxygenase 1, producing the antioxidants biliverdin and bilirubin critical to preserving cellular redox homeostasis. In the present study, we investigate the effects of heme on CAR T cell efficacy. Our results suggest that heme supplementation during ex vivo CAR T manufacturing or supplementation during CAR T-tumor cell engagement can lead to decreased T cell exhaustion and increased tumor killing. Methods: Human healthy donor and MM patient T cells were activated and expanded with α-CD3/CD28 and IL-2 for 7 days +/- hemin, after which immunostaining and metabolic assays were conducted. For CAR T manufacture, T cells were transduced with CAR construct starting on day 3 and were co-cultured with antigen-expressing tumor cells in vitro on day 7-8. Cytotoxicity and cytokine production were assayed after 24 hours of co-culture. Results: In a dose-dependent manner, heme supplementation significantly decreases proportions of LAG3 + and TIM3 + and decreases proportions of CD62L + and TCF1 + cells in both CD4 + and CD8 + subsets isolated from healthy donor and MM patient peripheral blood. Supportive of these observations, inhibition of de novo heme biosynthesis leads to the opposite effect with an increase in proportions of PD1 +, LAG3 +, TIM3 +, and CD62-L + cells. CAR T cells manufactured with heme (heme-CAR T cells) have significantly reduced terminally exhausted phenotypes (PD1 +/LAG3 +/TIM3 +) and increased enrichment of effector memory cells (CD62L -CD45RA -) in both CD4 + and CD8 + subsets. Inquiry of cellular energetics of heme supplemented CAR T cells reveals reduced reactive oxygen species (ROS) and increased mitochondrial membrane potential, consistent with previous reports showing increased membrane potential in effector T cells for greater production of cytokines such as IL-17A, IL-17F, and IFNγ. In co-culture with tumor cells in vitro, heme-CAR T cells have higher tumor-specific lysis and production of TNFα and IL-2. CAR T-tumor cell engagement in the presence of heme resulted in significantly decreased proportions of exhausted CAR T cells and increased production of TNFα. Heme also increases BCMA surface expression in several MM cell lines, highlighting a viable strategy for enhancing BCMA CAR T engagement with MM. Lastly, MM patient bone marrow-localized T cells demonstrate significantly decreased terminally exhausted phenotypes and increased differentiation into effector subsets when expanded with heme. Conclusion: We show that heme increases effector T and CAR T cell function and decreases T cell exhaustion. Increased cytotoxicity of heme-supplemented CAR T cells was associated with reduced ROS and increased membrane potential. Ongoing in vivo studies aim to characterize the efficacy of heme-supplemented CAR T cells in MM xenograft models. Our studies have broader implications for investigating heme supplementation in ex vivo CAR T manufacturing for a wide range of hematological cancers and underscore the need for further investigation of heme uptake and metabolism for strategic enhancement of T-cell based immunotherapies.

Metabolic Functions of Biliverdin IXβ Reductase in Redox-Regulated Hematopoietic Cell Fate.

Cytoprotective heme oxygenases derivatize heme to generate carbon monoxide, ferrous iron, and isomeric biliverdins, followed by rapid NAD(P)H-dependent biliverdin reduction to the antioxidant bilirubin. Recent studies have implicated biliverdin IXβ reductase (BLVRB) in a redox-regulated mechanism of hematopoietic lineage fate restricted to megakaryocyte and erythroid development, a function distinct and non-overlapping from the BLVRA (biliverdin IXα reductase) homologue. In this review, we focus on recent progress in BLVRB biochemistry and genetics, highlighting human, murine, and cell-based studies that position BLVRB-regulated redox function (or ROS accumulation) as a developmentally tuned trigger that governs megakaryocyte/erythroid lineage fate arising from hematopoietic stem cells. BLVRB crystallographic and thermodynamic studies have elucidated critical determinants of substrate utilization, redox coupling and cytoprotection, and have established that inhibitors and substrates bind within the single-Rossmann fold. These advances provide unique opportunities for the development of BLVRB-selective redox inhibitors as novel cellular targets that retain potential for therapeutic applicability in hematopoietic (and other) disorders.

The variable associations between PFASs and biological aging by sex and reproductive stage in NHANES 1999–2018

BackgroundPer- and polyfluoroalkyl substances (PFASs) are endocrine disrupting chemicals that have myriad effects on human physiology. Estrogenic PFASs may influence biological aging by mimicking the activity of endogenous estrogens, which can decrease inflammation and oxidative stress and enhance telomerase activity. We hypothesized that PFAS exposure would be differentially associated with measures of biological aging based on biological sex and reproductive stage. MethodsWe analyzed associations between serum PFAS levels and measures of biological aging for pre- and postmenopausal women and men (n = 3193) using data from the 2003 to 2018 waves of the National Health and Nutrition Examination Survey. Examining PFASs both individually and in mixture models, we investigated four measures of clinical aging (Homeostatic Dysregulation, the Klemera-Doubal Method, Phenotypic Age Acceleration, and Allostatic Load), oxidative stress, and telomere length. ResultsPFOA and PFOS were negatively associated with Phenotypic Age Acceleration (e.g. decelerated aging) for men B = −0.22, 95% CI: −0.32, −0.12; B = −0.04, 95% CI: −0.06, −0.03) , premenopausal women (B = −0.58, 95% CI: −0.83, −0.32; B = −0.15, 95% CI: −0.20, −0.09), and postmenopausal women (B= −0.22, 95% CI: −0.43, −0.01; B = −0.05, 95% CI: −0.08, −0.02). In mixture models, we found net negative effects for Phenotypic Age Acceleration and Allostatic Load for men, premenopausal women, and postmenopausal women. We also found significant mixture effects for the antioxidants bilirubin and albumin among the three sample groups. We found no evidence to support effects on telomere length. DiscussionOur findings suggest that PFAS exposure may be inversely associated with some measures of biological aging at the relatively low levels of exposure in this sample, regardless of reproductive stage and sex, which does not support our hypothesis. This research provides insights into how PFAS exposure may variably influence aging measures depending on the physiological process investigated.

Cutting edge concepts: Does bilirubin enhance exercise performance?

Exercise performance is dependent on many factors, such as muscular strength and endurance, cardiovascular capacity, liver health, and metabolic flexibility. Recent studies show that plasma levels of bilirubin, which has classically been viewed as a liver dysfunction biomarker, are elevated by exercise training and that elite athletes may have significantly higher levels. Other studies have shown higher plasma bilirubin levels in athletes and active individuals compared to general, sedentary populations. The reason for these adaptions is unclear, but it could be related to bilirubin's antioxidant properties in response to a large number of reactive oxygen species (ROS) that originates from mitochondria during exercise. However, the mechanisms of these are unknown. Current research has re-defined bilirubin as a metabolic hormone that interacts with nuclear receptors to drive gene transcription, which reduces body weight. Bilirubin has been shown to reduce adiposity and improve the cardiovascular system, which might be related to the adaption of bilirubin increasing during exercise. No studies have directly tested if elevating bilirubin levels can influence athletic performance. However, based on the mechanisms proposed in the present review, this seems plausible and an area to consider for future studies. Here, we discuss the importance of bilirubin and exercise and how the combination might improve metabolic health outcomes and possibly athletic performance.

Oxidative stress parameters and their relation to motor subtype of Parkinson's disease and levodopa treatment status.

Parkinson's disease (PD) is an oxidative stress-linked neurodegenerative disorder, with the highest prevalence among seniors. The objective of this study were: (1) to analyse levels of following oxidative stress parameters: total antioxidant capacity (TAC), uric acid (UA), total glutathione (tGSH), bilirubin (Bil) and albumin (Alb), in blood of PD patients and healthy controls; (2) to find possible associations of examined oxidative stress parameters with PD subtypes and levodopa treatment status; and (3) to evaluate power and relevance of the aforementioned oxidative stress parameter for the prediction of onset and progression of PD by utilizing Random Forest machine learning (RFML). Oxidative stress parameters were determined in 125 PD patients and 55 healthy controls. Evaluated with frequentist statistics, our data revealed that UA is the only oxidative stress parameter associated with PD. However, when the PD cohort was divided in gender-dependent manner, tGSH and Bil were also significantly associated with PD in subgroup of female patients. RFML rendered no predictive power of any of the tested oxidative stress parameters in respect to PD, its subtypes, and/or status of levodopa treatment. In conclusion, despite the positive association of UA with PD (in complete cohort of PD patients) and of tGSH and Bil with PD but only in female patients, these oxidative stress parameters are of no use in clinical practice due to the lack of the predictive/diagnostic power.

Effects of Midazolam on Antioxidant Levels, Biochemical and Metabolic Parameters in Eurygaster integriceps Puton (Hemiptera: Scutelleridae) Eggs Parasitized by Trissolcus semistriatus Nees (Hymenoptera: Scelionidae)

Eurygaster integriceps Puton (Hemiptera: Scutelleridae) is among the most important insect pests of wheat (Triticum sativum L.) and barley (Hordeum vulgare L.) grown in the Middle East. Biological and chemical methods are insufficient to control E. integriceps populations below economic thresholds. In this study, we investigated the effects of midazolam, a clinical drug, on selected metabolic enzyme activity, antioxidant levels, and biochemical parameters in E. integriceps eggs parasitized by Trissolcus semistriatus Nees (Hymenoptera: Scelionidae). Increasing concentrations of midazolam caused cell damage in the parasitized eggs due to its oxidative effects. Transferase enzymes, such as, aspartate transferase, alanine transferase, and gamma glutamyl transferase activities were altered following exposure. Metabolic enzymes, such as, creatine kinase, alkaline phosphatase, amylase, and lactate dehydrogenase also were adversely affected. Levels of the non-enzymatic antioxidants uric acid, bilirubin, and albumin also were altered.

The Effect of Renal Hemodialysis on Serum Endogenous Antioxidants Defense of Patient with Chronic Renal Failure

Hemodialysis means removes waste and excess fluid from the blood when thekidneyscannot do so sufficiently usually performed three or more times a week for 4 hours or more.The present work was aimed to investigate the effect of renal hemodialysis on serum anenzymatic and non-enzymatic endogenousantioxidantsdefenses. Forty five patientswere taken for this study, 25males (55.54%) with age range (11-70) years and 20 females (44.46%) with age range (6-65)years, while the subjects of control group was thirty five individuals non-undergoing hemodialysis treatment, 23 males (65.71%) with age range (15-65) years and 12 females (34.29%) with age range (18-62) years. The present results showed highly significantly decrease (p<0.05) in serum enzymatic endogenous antioxidant (catalase) andnon-enzymatic antioxidants (transferrin and bilirubin), while serum non enzymatic antioxidant uric acid showed highly increase (p<0.05) in patient with chronic renal failure.In conclusion, the present data showed that patients with chronic renal failure (CRF) undergoing hemodialysis treatmenthave physiological disturbances in both serum enzymatic and non-enzymaticendogenous antioxidants levels in all age ranges may be related to oxidative stress by renal failure disease.

Self-assembled nanoparticles with bilirubin/JPH203 alleviate imiquimod-induced psoriasis by reducing oxidative stress and suppressing Th17 expansion

Psoriasis is a chronic inflammatory skin disease with dysregulation of the immune system, which usually manifests as erythematous scleroma with hyperplasia of the epidermis. Although the pathogenesis remains unclear, oxidative stress and inflammation are inextricably linked during the development of psoriasis. Therefore, scavenging of ROS and suppression of inflammation may be a rational and effective strategy to ameliorate psoriasis and delay its further development. Here, a “Tanghulu”-like nanoplatform (BJN) is developed using the endogenous antioxidant bilirubin and a specific inhibitor (JPH203) of LAT1, an amino acid transporter involved in the activation of mTOR, for treatment of psoriasis by scavenging ROS and interfering with mTOR signaling, consequently blocking Th17 and IL-17 release. The nanoparticles show increased uptake in inflamed keratinocytes and display an efficient ROS scavenging capability. In an in vivo psoriasis model, BJN effectively permeate into the inflamed skin and be retained there, thereby reversing the psoriasis-specific changes in the imiquimod-induced mice as evident from suppression of keratinocyte hyperplasia and decrease in immune cell infiltration. This study shows that BJN can exert a superior anti-psoriasis effect by scavenging ROS, blocking the LAT1-mTOR pathway, inactivating immune reaction, restricting Th17 differentiation, and decreasing IL-17A secretion, offering a promising strategy for psoriasis treatment.

Ecotoxicological effects of dietary titanium dioxide nanoparticles on metabolic and biochemical parameters of model organism Galleria mellonella (Lepidoptera: Pyralidae)

Nanoparticles (NPs) are now being used in many industrial activities, such as mining, paint and glass industries. The frequent industrial use of NPs contributes to environmental pollution and may cause cellular and oxidative damage in native organisms. In this study, the toxic effects of titanium dioxide nanoparticles (TiO2 NPs) were investigated using Galleria mellonella larvae as a model insect species. Alterations in cell damage indicators, such as alanine transferase, aspartate transferase, lactate dehydrogenase, non-enzymatic antioxidants and biochemical parameters, were determined in the hemolymph of G. mellonella larvae exposed to TiO2 NPs at different concentrations (5, 50, 250 and 1250 μg/mL) in their diets. TiO2 NPs caused concentration-dependent cellular damage in the hemolymph of G. mellonella larvae and increased the levels of the non-enzymatic antioxidants uric acid and bilirubin. In addition, total protein in hemolymph significantly decreased at the highest concentration (1250 μg/mL) of TiO2 NPs. Level of the urea increased at the highest concentration (1250 μg/mL) of TiO2 NPs, whereas the amount of glucose was not affected. These findings demonstrated that TiO2 NPs caused concentration-dependent toxic effects on G. mellonella larvae.

PERIPHERAL NON_ ENZYMATIC ANTIOXIDANTS LEVELS IN SCHIZOPHRENIA AND BIPOLAR ILLNESS A COMPARATIVE CROSS-SECTIONAL STUDY

Background: Nervous tissue is extremely sensitive to oxidative damage Recent studies show an elevated level of oxidative stress indicators in Schizophrenia. Current studies on oxidative stress in Schizophrenia mainly focus on enzymatic antioxidants, while limited studies have been carried out on non-enzymatic antioxidants Some studies discovered that plasma non-enzymatic antioxidants (uric acid, bilirubin, and albumin) in Schizophrenia are lower than those of healthy controls.
 Aim: To compare levels of nonenzymatic antioxidants in Schizophrenia and bipolar illness.
 Material and Methods: The present study is a hospital_ based cross-sectional study conducted among 100 patients with Schizophrenia and Bipolar Affective disorder included as per inclusion and exclusion criteria and undergone psychiatric assessment as per diagnostic criteria.
 Results: S. albumin, S.bilirubin, S.uric acid were found to be low in Schizophrenia but statistically, the significant difference was evaluated for S.uric acid.
 Conclusion: S. uric acid lower significant levels in Schizophrenia as compared to bipolar affective disorder shows the more impaired peripheral antioxidant scavenging system in Schizophrenia. However, pure peripheral antioxidant system dysfunction could not be ascertained in Schizophrenia through this study.
 Keywords: nonenzymatic antioxidants, Schizophrenia, bipolar illness.

Biochemical and immune responses of model organism Galleria mellonella after infection with Escherichia coli

AbstractGalleria mellonella L. (Lepidoptera: Pyralidae) is used as an invertebrate model organism to study the virulence of bacteria pathogenic to humans. In this study, the oxidative effects of uropathogenic Escherichia coli (Migula) (Enterobacteriaceae) on the model organism were investigated. The levels of metabolic enzymes, non‐enzymatic antioxidants, and biochemical parameters were measured in the hemolymph of G. mellonella larvae 2, 4, 6, and 8 h after E. coli inoculation. The results show that the levels of cell damage indicators – such as aspartate transferase, alanine transferase, and lactate dehydrogenase – increased 8 h after E. coli infection. The levels of creatine kinase, alkaline phosphatase, and amylase increased in order to regulate the energy metabolism (negatively affected by the E. coli infection) and to reduce the biochemical effects of oxidative damage. Amounts of the non‐enzymatic antioxidants uric acid, bilirubin, and albumin also increased after E. coli infection, whereas the amount of total protein was not affected. Altogether, E. coli infection caused oxidative stress and damage to the hemolymph of G. mellonella.

Electronic and Tobacco Cigarettes Alter Polyunsaturated Fatty Acids and Oxidative Biomarkers.

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Plasma bilirubin levels are reduced in first-episode psychosis patients and associates to working memory and duration of untreated psychosis

Schizophrenia is a severe mental disorder and one of its characteristics is cognitive impairments. Findings regarding levels of the heme metabolite and plasma antioxidant bilirubin in schizophrenia are inconclusive. However, a recently published study indicate that low levels of bilirubin may be implicated in the memory impairments seen in the disorder. The aim of this cross-sectional study was to investigate the levels of bilirubin in individuals with a first-episode psychosis (FEP) and to examine if bilirubin levels were associated to cognitive impairments, symptoms and duration of untreated psychosis (DUP). Bilirubin levels were reduced in 39 individuals with FEP compared with 20 HC (median [IQR]: 11.0 [9.0–13.0] µM vs. 15.0 [11.5–18.5] µM). In individuals with FEP, bilirubin levels were also positively correlated to two working memory tests (r = 0.40 and r = 0.32) and inversely correlated to DUP (r = − 0.36). Findings were not influenced by confounding factors. The results confirm the antioxidant deficit previously seen in schizophrenia, but also indicate that these changes may be related to DUP. The study also confirms that bilirubin may be implicated in the cognitive deficits that accompanies the disorder, here for the first time presented in individuals with FEP.

Intra-Individual Variation and Reliability of Biomarkers of the Antioxidant Defense System by Considering Dietary and Lifestyle Factors in Premenopausal Women.

Epidemiological studies frequently rely on a single biomarker measurement to assess the relationship between antioxidant status and diseases. This bears an inherent risk for misclassification, if the respective biomarker has a high intra-individual variability. The present study investigates the intra-individual variation and reliability of enzymatic and non-enzymatic biomarkers of the antioxidant system in premenopausal women. Forty-four apparently healthy females provided three consecutive fasting blood samples in a four-week rhythm. Analyzed blood biomarkers included Trolox equivalent antioxidant capacity (TEAC), catalase, glutathione peroxidase, glutathione, vitamin C, bilirubin, uric acid, coenzyme Q10, tocopherols, carotenoids and retinol. Intra- and inter-individual variances for each biomarker were estimated before and after adjusting for relevant influencing factors, such as diet, lifestyle and use of contraceptives. Intraclass correlation coefficient (ICC), index of individuality, reference change value and number of measurements needed to confine attenuation in regression coefficients were calculated. Except for glutathione and TEAC, all biomarkers showed a crude ICC ≥ 0.50 and a high degree of individuality indicating that the reference change value is more appropriate than population-based reference values to scrutinize and classify intra-individual changes. Apart from glutathione and TEAC, between 1 and 9 measurements were necessary to reduce attenuation in regression coefficients to 10%. The results indicate that the majority of the assessed biomarkers have a fair to very good reliability in healthy premenopausal women, except for glutathione and TEAC. To assess the status of the antioxidant system, the use of multiple measurements and biomarkers is recommended.

Serum bilirubin and chronic obstructive pulmonary disease (COPD): a systematic review

BackgroundBilirubin is a potent antioxidant and higher serum bilirubin levels have been associated with improved COPD outcomes. We performed a systematic review to evaluate the association between serum bilirubin levels and lung function (FEV1), prevalence/incidence of COPD, acute exacerbations of COPD, respiratory health status, and mortality.MethodsMEDLINE® and Embase were searched using Ovid® (search updated October 1st, 2019). We included studies that measured serum bilirubin levels and outcomes of interest in adults with or without underlying lung disease. We excluded studies of those with liver disease or drug-induced elevations in bilirubin. We used the Newcastle–Ottawa scale to assess individual study risk of bias (ROB) and the US Agency for Healthcare Research and Quality—Evidence Based Practice tool to assess overall strength of evidence (SOE). Two authors independently determined eligibility, performed data abstraction, assessed ROB, and determined SOE.ResultsThirteen studies (5 low risk of bias, 3 moderate and 5 high risk) were included. We found low strength of evidence for the association between higher bilirubin levels and lower risk of acute exacerbations of COPD (2 studies), mortality (3 studies), COPD diagnosis (4 studies), and lung function (FEV1) (8 studies). We found insufficient evidence on the relationship between serum bilirubin and respiratory health status/exercise capacity (1 study) and airflow obstruction (FEV1/FVC ratio) (4 studies).ConclusionHigher bilirubin levels may be associated with lower mortality and improved COPD outcomes. Randomized trials are needed to evaluate the effect of medications that raise serum bilirubin on COPD outcomes.PROSPERO registration: CRD42019145747.

Divergent erythroid megakaryocyte fates in Blvrb-deficient mice establish non-overlapping cytoprotective functions during stress hematopoiesis

Cytoprotective mechanisms of heme oxygenases function by derivatizing heme to generate carbon monoxide, ferrous iron, and isomeric biliverdins, followed by rapid NAD(P)H-dependent biliverdin reduction to the antioxidant bilirubin using two non-overlapping biliverdin reductases that display biliverdin isomer-restricted redox activity. Although cytoprotective functions of heme oxygenases are widely recognized, concomitant effects of downstream biliverdin reductases remain incomplete. A computational model predicated on murine hematopoietic single-cell transcriptomic data identified Blvrb as a biological driver linked to the tumor necrosis factor stress pathway as a predominant source of variation defining hematopoietic cell heterogeneity. In vivo studies using Blvrb-deficient mice established the dispensable role of Blvrb in steady-state hematopoiesis, although model validation using aged Blvrb-deficient mice established an important cytoprotective function in stress hematopoiesis with dichotomous megakaryocyte-biased hematopoietic recovery. Defective stress erythropoiesis was evident in Blvrb−/− spleens and in bone marrow erythroid development, occurring in conjunction with defective lipid peroxidation as a marker of oxidant mishandling. Cell autonomous effects on megakaryocyte lineage bias were documented using multipotential progenitor assays. These data provide the first physiological function of murine Blvrb in a non-redundant pathway of stress cytoprotection. Divergent effects on erythroid/megakaryocyte lineage speciation impute a novel redox-regulated mechanism for lineage partitioning.

THE TOTAL ANTIOXIDANT CAPACITY MAY NOT BE RELATED TO BILIRUBIN AND URIC ACID LEVEL IN PATIENTS WITH BETA THALASSEMIA

Objective: Iron burden resulting from ineffective erythropoiesis and multiple transfusions can cause oxidative stress in patients with ß-thalassemia. Here we aimed to examine the total antioxidant and oxidant capacity (TAC and TOC) along with its relation to endogenous antioxidants (bilirubin and uric acid) in patients with ß-thalassemia. Material and Method: Forty-five patients with transfusion-dependent (TDT) (n=30) and non-transfusion-dependent (NTDT) (n=15) ß-thalassemia and 20 healthy subjects were enrolled in the study. Analyses were done using Total Antioxidant Status (TAS) and Total Oxidant Status (TOS) kits. Results: The TAC level of the patients was significantly increased compared to healthy subjects (2.75 vs. 2.10 mmol/L; p=0.01). The total bilirubin level was significantly elevated in NTDT patients compared to TDT patients (5.7±3.3 vs.1.9±1.4; p<0.001). No significant relationship between endogenous antioxidants and total antioxidant capacity of patients was detected (p=0.20) Conclusion: The total antioxidant capacity of patients with ß-thalassemia might not be directly related to endogenous anti-oxidative status. 

Bilirubin nanomedicine alleviates psoriatic skin inflammation by reducing oxidative stress and suppressing pathogenic signaling

Psoriasis is a prevalent chronic inflammatory skin disease characterized by thickening of the epidermis accompanied by lesional erythema, scaling, and induration as a result of abnormal proliferation of keratinocytes. During the development of psoriasis, levels of intracellular reactive oxygen species (ROS) within psoriatic lesions are elevated, activating a pro-inflammatory signaling cascade. Here, we evaluated the therapeutic efficacy and mode of action of bilirubin nanoparticles (BRNPs), based on the potent, endogenous antioxidant bilirubin, in a preclinical psoriasis model. We found that topical treatment of psoriatic lesions with BRNPs effectively attenuated upregulation of intracellular ROS levels within keratinocytes and ameliorated the symptoms of psoriasis. A subsequent mechanistic study showed that preventing oxidative stress in activated keratinocytes suppressed the secretion of inflammatory mediators and recruitment of immune cells. Subsequent expression of the antigen-presenting cell (APC) maturation markers, class II major histocompatibility complex (MHC class II), cluster of differentiation (CD) 80 and CD86, was significantly decreased, resulting in a reduction in the differentiation of naïve CD4+ T cells into interleukin (IL)-17–producing T-helper (Th) 17 cells. Unlike the commercial corticosteroid drug, clobetasol propionate (CLQ), BRNPs, composed of the endogenous antioxidant bilirubin and the approved polymer polyethylene glycol (PEG), did not exert systemic cytotoxicity. Collectively, these findings highlight the potential of BRNPs as a novel nanomedicine for ameliorating psoriasis-like skin inflammation through topical treatment and suggest that their use could be further expanded to treat other chronic skin inflammation diseases, including atopic dermatitis.