Mildly elevated serum bilirubin and its correlations with lipid levels among male patients undergoing health checkups.

BACKGROUND: Bilirubin's ability to lower lipid levels was confirmed by several studies, but those studies mainly focused on total bilirubin (TBil). The present study aimed to elucidate the correlations of the two subtypes of bilirubin with lipid levels. METHODS: A total of 1732 male patients undergoing health checkups were categorized into three groups according to the levels of direct bilirubin (DBil) and indirect bilirubin (IBil). The differences in medical characteristics among the three groups were analysed. RESULTS: Subjects in the elevated DBil group had the lowest serum alanine aminotransferase (ALT), total cholesterol (TC), blood urea nitrogen (BUN), γ-glutamyl transpeptidase (γ-GT), fasting blood glucose (FBG), haemoglobin (HGB), and triglyceride (TG) levels in contrast to the other groups (P < 0.01), while subjects in the elevated IBil group had the highest ALT, γ-GT, BUN, serum creatinine (SCR), HGB, TC, and TG levels among the three groups (P < 0.01). DBil levels exhibited a significant negative correlation with TC (r = -0.777, P < 0.01) and TG (r = -0.397, P < 0.01) levels, while IBil levels exhibited a significant positive correlation with TC (r = 0.790, P < 0.01) and TG (r = 0.302, P < 0.01) levels. The frequencies of abnormal TC, TG, HGB and BUN levels were the lowest in the elevated DBil group, while the levels of these four variables were the highest in the elevated IBil group. Mildly elevated DBil levels were related to lower TG (OR = 0.112, 95% CI = 0.027-0.458) and TC (OR = 0.097, 95% CI = 0.013-0.700), and mildly elevated IBil levels were connected with increased TC (OR = 3.436, 95% CI = 2.398-4.924) and TG (OR = 1.636, 95% CI = 1.163-2.303). DBil was an independent protective factor against increased TC (OR = 0.702, 95% CI = 0.602-0.817, P < 0.01) and TG (OR = 0.632, 95% CI = 0.541-0.739, P < 0.01) levels, and IBil was an independent risk factors for increased TC (OR = 1.251, 95% CI = 1.176-1.331, P < 0.01). CONCLUSIONS: DBil was an independent protective factor against high TC and TG levels. IBil was an independent risk factors for elevated TC levels. The prognostic value of IBil levels warrants further attention.

Causal relationships of neonatal jaundice, direct bilirubin and indirect bilirubin with autism spectrum disorder: A two-sample Mendelian randomization analysis.

Background: Multiple systematic reviews and meta-analyses have examined the association between neonatal jaundice and autism spectrum disorder (ASD) risk, but their results have been inconsistent. This may be because the included observational studies could not adjust for all potential confounders. Mendelian randomization study can overcome this drawback and explore the causal relationship between the both. Methods: We used the data of neonatal jaundice, direct bilirubin (DBIL), indirect bilirubin (IBIL), and ASD collected by genome-wide association study (GWAS) to evaluate the effects of neonatal jaundice, DBIL and IBIL on ASD by using a two-sample Mendelian randomized (MR). The inverse variance-weighted method (IVW) was the main method of MR analysis in this study. Weighted median method, MR-Egger regression and mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analysis. Results: There was no evidence of an effect of neonatal jaundice (OR, 1.002, 95% CI, 0.977-1.027), DBIL (OR, 0.970, 95% CI, 0.884-1.064) and IBIL (OR, 1.074, 95% CI, 0.882-1.308) on ASD risk by IVW test. In the weighted median method, MR-Egger regression and leave-one-out analysis, the results were robust and no heterogeneity or pleiotropy was observed. Conclusions: We found that neonatal jaundice, DBIL and IBIL were not associated with ASD in this study. However, this paper did not explore the effect of severity and duration of jaundice on ASD in different ethnic populations, which may require further research.

IBIL Measurement and Optical Simulation of the DI Center in 4H-SiC.

In this paper, DI defects are studied via experiments and calculations. The 2 MeV H+ is used to carry on an ion-beam-induced luminescence (IBIL) experiment to measure the in-situ luminescence of untreated and annealed 4H-SiC at 100 K. The results show that the luminescence intensity decreases rapidly with increasing H+ fluence, which means the losses of optical defect centers. In addition, the evident peak at 597 nm (2.07 eV) is the characteristic peak of 4H-SiC, and the weak peak between 400 nm and 450 nm is attributed to the DI optical center. Moreover, the first-principles calculation of 4H-SiC is adopted to discuss the origin of DI defects. The optical transition of the defect SiC(CSi)2 from q = 0 to q = 1 is considered the experimental value of the DI defect center.

Indirect bilirubin impairs invasion of osteosarcoma cells via inhibiting the PI3K/AKT/MMP-2 signaling pathway by suppressing intracellular ROS.

Background: Osteosarcoma is most prevalently found primary malignant bone tumors, with primary metastatic patients accounting for approximately 25% of all osteosarcoma patients, yet their 5-year OS remains below 30%. Bilirubin plays a key role in oxidative stress-associated events, including malignancies, making the regulation of its serum levels a potential anti-tumor strategy. Herein, we investigated the association of osteosarcoma prognosis with serum levels of TBIL, IBIL and DBIL, and further explored the mechanisms by which bilirubin affects tumor invasion and migration. Methods: ROC curve was plotted to assess survival conditions based on the determined optimal cut-off values and the AUC. Then, Kaplan-Meier curves, along with Cox proportional hazards model, was applied for survival analysis. Inhibitory function of IBIL on the malignant properties of osteosarcoma cells was examined using the qRT-PCR, transwell assays, western blotting, and flow cytometry. Results: We found that, versus osteosarcoma patients with pre-operative higher IBIL (>8.9 µmol/L), those with low IBIL (≤8.9 µmol/L) had shorter OS and PFS. As indicated by the Cox proportional hazards model, pre-operative IBIL functioned as an independent prognostic factor for OS and PFS in total and gender-stratified osteosarcoma patients (P < 0.05 for all). In vitro experiments further confirmed that IBIL inhibits PI3K/AKT phosphorylation and downregulates MMP-2 expression via reducing intracellular ROS, thereby decreasing the invasion of osteosarcoma cells. Conclusions: IBIL may serve as an independent prognostic predictor for osteosarcoma patients. IBIL impairs invasion of osteosarcoma cells through repressing the PI3K/AKT/MMP-2 pathway by suppressing intracellular ROS, thus inhibiting its metastatic potential.

Relationship between serum indirect bilirubin and prostate volume in patients with benign prostatic hyperplasia: a cross-sectional study.

Background: Due to its anti-oxidative effects, bilirubin may protect against a spectrum of diseases. However, the role of bilirubin in patients with benign prostatic hyperplasia (BPH) is poorly explored. This study aimed to investigate the cross-sectional associations between serum indirect bilirubin (IBIL) and prostate volume (PV) in patients with BPH. Methods: The medical records of 722 BPH patients were retrospectively analyzed. Body mass index (BMI) was calculated as body weight (kg)/height (m)2. PV was obtained as height (cm) × width (cm) × length (cm) × π/6. Other biochemical indexes were measured by the automatic biochemical analyzer. A univariable linear regression analysis was performed to detect confounders. The IBIL-PV relationship was examined using unadjusted and covariate-adjusted regression models. Furthermore, a segmented linear regression was conducted to analyze the linear trend of IBIL levels and PV. Finally, the sensitivity analysis was stratified by BMI and low-density lipoprotein cholesterol (LDL-C) cutoffs. Results: In this study, the mean age of the patients was 68 (range, 43-93) years. By univariable line regression test, we observed that PV was positively correlated with age, BMI, and LDL-C (ß=0.113, 0.096, and 0.135, respectively). IBIL was negatively associated with PV in full adjusted model in men age ≤75 years (ß=-1.01; 95% CI: -1.81, -0.22; P=0.01). A statistically significant inverse trend was observed between serum IBIL intervals and PV in patients aged ≤75 years (adjusted for age, BMI, and LDL-C, P for trend =0.015). In sensitivity analysis, significantly negative IBIL-PV relationship only existed in men with normal BMI (adjusted ß=-1.328; 95% CI: -2.467, -0.190; P=0.022), overweight men (adjusted ß=-1.296; 95% CI: -2.519, -0.074; P=0.038), and men with normal LDL-C level (adjusted ß=-1.017; 95% CI: -1.869, -0.164; P=0.019). Conclusions: IBIL is negatively associated with PV in the non-obese population ≤75 years with normal LDL-C. These results suggest that higher serum IBIL possibly provides a degree of protection to BPH by mitigating oxidative stress (OS) related to aging and lipid peroxidation. Nevertheless, these preliminary findings from a single-center, retrospective study have limitations and need to be confirmed by future studies.

Characterization of organic anion transporting polypeptide 1b2 knockout rats generated by CRISPR/Cas9: a novel model for drug transport and hyperbilirubinemia disease.

Organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/3) as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells. Rat OATP1B2, encoded by the Slco1b2 gene, is homologous to human OATP1B1/3. Although OATP1B1/3 is very important, few animal models can be used to study its properties. In this report, we successfully constructed the Slco1b2 knockout (KO) rat model via using the CRISPR/Cas9 technology for the first time. The novel rat model showed the absence of OATP1B2 protein expression, with no off-target effects as well as compensatory regulation of other transporters. Further pharmacokinetic study of pitavastatin, a typical substrate of OATP1B2, confirmed the OATP1B2 function was absent. Since bilirubin and bile acids are the substrates of OATP1B2, the contents of total bilirubin, direct bilirubin, indirect bilirubin, and total bile acids in serum are significantly higher in Slco1b2 KO rats than the data of wild-type rats. These results are consistent with the symptoms caused by the absence of OATP1B1/3 in Rotor syndrome. Therefore, this rat model is not only a powerful tool for the study of OATP1B2-mediated drug transportation, but also a good disease model to study hyperbilirubinemia-related diseases.

Relationship between serum bilirubin levels and mortality in patients on peritoneal dialysis.

Background: Studies have shown that the serum total bilirubin (TBil) is associated with the mortality of the general population and of hemodialysis patients. However, few studies have examined the associations of the direct bilirubin (DBil) and indirect bilirubin (IBil) with the mortality of peritoneal dialysis (PD) patients. Methods: This was a retrospective cohort study. Clinical and laboratory data were collected from 740 PD patients. The primary endpoint was 5-year all-cause mortality. Survival analysis was performed using the Kaplan-Meier method with the log-rank test. The mortality hazard ratio was evaluated using Cox regression models. Results: Among the 740 PD patients, the mean age was 49.9 ± 15.0 years, 54.9% were men, and 20.3% had diabetes. During the median follow-up period of 28 months (interquartile range, 14-41 months), 178 patients died. Kaplan-Meier analysis revealed that all-cause mortality was higher in the patients in the higher TBil group than in the lower TBil group (25.6% vs. 18.3%, p = .017) and in patients in the higher IBil group than in the lower IBil group (24.3% vs. 19%, p = .026). Multivariate analysis showed that compared with the lower TBil group, the 5-year mortality risk was higher in the higher TBil group (HR = 1.69, 95% CI: 1.11-2.56, p = .014). Similarly, there was a 56% higher risk of 5-year mortality in the higher IBil group than in the lower IBil group (HR = 1.56, 95% CI: 1.04-2.34, p = .032). However, no such associations were observed between the DBil and the mortality risk. Conclusions: The baseline serum TBil and IBil levels were significantly associated with 5-year all-cause mortality among PD patients.

Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan.

Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by Irinotecan (CPT-11), and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually, two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine.

PARAFAC analysis of IBIL spectra from silver ion exchanged glasses.

In this work we present for the first time an application of PARAllel FACtor (PARAFAC) analysis to the investigation of Ion Beam Induced Luminescence (IBIL) spectra of Ag+↔Na+ ion exchanged silicate glasses, in order to check the possibility to obtain additional information on the formation of silver aggregates under ion irradiation by a proper statistical rearrangement of experimental spectra. We decomposed the data by PARAFAC taking into account both IBIL emission features and their evolution as a function of the time. Shape and trend under irradiation of the extracted components were correlated to silver concentration and aggregates in the investigated systems. Strength and weakness of this statistical approach applied to IBIL spectra recorded as a function of time were evidenced and discussed.

Carbonate and Silicate Abundance Indexing in Coarse-Grained River Sediments Using Diffuse Reflection Infrared Spectroscopy (DRIFTS) and Ion-Beam-Induced Luminescence (IBIL) Spectroscopies.

Two different types of spectroscopic methods, namely diffuse reflection infrared spectroscopy (DRIFTS) as a vibrational spectroscopy and ion-beam-induced luminescence (IBIL) as an optical spectroscopy, have been exploited for the analysis of three sand samples collected from the Adige, Bacchiglione, and Brenta rivers (Veneto, Northern Italy) with the aim to set up a procedure for the comparison of the relative abundance of silicates, carbonates, and feldspars. By fitting the spectra, the features corresponding to different geological compounds have been identified and descriptive indexes of their relative amount have been obtained by comparing the peak area ratios.

Kallistatin, a new and reliable biomarker for the diagnosis of liver cirrhosis.

Kallistatin, which protects organs and cells against inflammation, fibrosis and oxidative stress, is mainly synthesized and secreted in liver. However, its relationship to human liver disease remains unclear. The purpose of this study was to explore the relationship between serum kallistatin and clinical evidence of both cirrhosis and hepatocellular carcinoma (HCC), and to determine if serum kallistatin levels could be used as a diagnostic indicator of hepatic health status, especially human liver cirrhosis (LC). Our cohort consisted of 115 patients with clinically proven liver fibrosis (LF), LC, or HCC by liver biopsies, and 31 healthy controls (CON). Serum kallistatin levels were quantified by ELISA. Results of the present study demonstrated that irrespective of the underlying etiology, serum kallistatin levels were significantly lower in the LF/LC group when compared with the CON group. A decrease in serum kallistatin levels appeared to reflect the extent of cirrhosis, with the lowest levels associated with higher grades of cirrhosis. Patients with LC had a noticeable correlation between serum kallistatin levels and other serum biochemical indicators. The area under the curve (AUC) for LC, viral liver cirrhosis (VLC) and alcoholic liver cirrhosis (ALC) was 0.845, 0.757 and 0.931, respectively. In conclusion, our findings demonstrated that kallistatin, a plasma protein produced by the liver, can be a useful and reliable diagnostic indicator of hepatic health status, especially for LC.

Ion Beam Induced Luminescence capabilities for the analysis of coarse-grained river sediments.

In this work the Ion Beam Induced Luminescence (IBIL) capabilities for the analysis of geological mobile sediment samples from the beds of three major rivers flowing in the Veneto Region (North-Eastern Italy) is presented in the first application of this technique to characterize such samples. Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS) spectra were also measured and discussed to give indications for the identification of the main luminescence features. The evolution of the different IBIL components with the irradiation dose was studied and their correlation to matrix defects outlined. Finally, a Principal Component Analysis (PCA) of the IBIL evolving spectra was performed to verify the capability of this approach to discriminate among the different samples.

Ultra-Violet Light Emission from HPV-G Cells Irradiated with Low Let Radiation From (90)Y; Consequences for Radiation Induced Bystander Effects.

In this study, we aimed to establish the emission of UV photons when HPV-G cells and associated materials (such as the cell substrate and cell growth media) are exposed to low LET radiation. The potential role of UV photons in the secondary triggering of biological processes led us to hypothesize that the emission and absorption of photons at this wavelength explain some radiation induced "bystander effects" that have previously been thought to be chemically mediated. Cells were plated in Petri-dishes of two different sizes, having different thicknesses of polystyrene (PS) substrate, and were exposed to ß-radiation from (90)Y produced by the McMaster Nuclear Reactor. UV measurements were performed using a single photon counting system employing an interference-type filter for selection of a narrow wavelength range, 340±5 nm, of photons. Exposure of the cell substrates (which were made of polystyrene) determined that UV photons were being emitted as a consequence of ß particle irradiation of the Petri-dishes. For a tightly collimated ß-particle beam exposure, we observed 167 photons in the detector per unit µCi in the shielded source for a 1.76 mm thick substrate and 158 photons/µCi for a 0.878 mm thick substrate. A unit µCi source activity was equivalent to an exposure to the substrate of 18 ß-particles/cm(2) in this case. The presence of cells and medium in a Petri-dish was found to significantly increase (up to a maximum of 250%) the measured number of photons in a narrow band of wavelengths of 340±5 nm (i.e. UVA) as compared to the signal from an empty control Petri-dish. When coloured growth medium was added to the cells, it reduced the measured count rate, while the addition of transparent medium in equal volume increased the count rate, compared to cells alone. We attribute this to the fact that emission, scattering and absorption of light by cells and media are all variables in the experiment. Under collimated irradiation conditions, it was observed that increasing cell density in medium of fixed volume resulted in a decrease in the observed light output. This followed a roughly exponential decline. We suggest that this may be due to increased scattering at the cell boundary and absorption of the UV in the cells. We conclude that we have measured UVA emitted by cells, cell medium and cell substrates as a consequence of their irradiation by low LET ß-particle radiation. We suggest that these secondary UV photons could lead to effects in non-targetted cells. Some effects that had previously been attributed to a chemically mediated "bystander effect" may in fact be due to secondary UV emission. Some radiation bystander effect studies may require re-interpretation as this phenomenon of UV emission is further investigated.