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Frontiers in Endocrinology 2024This current study represents a novel endeavor to scrutinize the correlation between the temporal alteration in serum total bilirubin (TBIL) concentrations and the rate...
OBJECTIVE
This current study represents a novel endeavor to scrutinize the correlation between the temporal alteration in serum total bilirubin (TBIL) concentrations and the rate of estimated glomerular filtration rate (eGFR). Additionally, this study aims to probe the plausible molecular mechanism underpinning the renoprotective effects of bilirubin concerning its hormonal characteristics.
MATERIALS AND METHODS
In this study, a cohort of 103 patients diagnosed with DKD and receiving medical care at Dongzhimen Hospital were recruited and monitored over a period of 2-7 years. The progression of DKD was ascertained using a threshold of eGFR decline > -5.48%/year. To assess the relationship between the annual change in serum TBIL levels (%/year) and the slope of eGFR, multivariate binary logistic regression analysis was employed. Furthermore, the ROC curve analysis was employed to determine the cut-off value for TBIL levels (%/year).
RESULTS
The use of multivariate binary logistic regression models revealed that serum TBIL levels (%/year) exhibited a significant correlation with the slope of eGFR. Moreover, the ROC curve analysis indicated a cut-off value of -6.729%/year for TBIL levels (%/year) with a sensitivity of 0.75 and specificity of 0.603, in diagnosing eGFR decline >-5.48%/year.
CONCLUSIONS
The findings of this study suggest that the sustained elevation of serum bilirubin concentration within the physiological range can effectively retard the progression of Diabetic Kidney Disease (DKD). Furthermore, the hormonal attributes of bilirubin may underlie its renoprotective effects.
Topics: Humans; Bilirubin; Male; Female; Diabetic Nephropathies; Glomerular Filtration Rate; Middle Aged; Aged; Adult; Disease Progression; Cohort Studies
PubMed: 38756998
DOI: 10.3389/fendo.2024.1361840 -
Lipids in Health and Disease May 2024Sickle cell disease (SCD) is a lifelong blood disorder affecting approximately 100,000 people in the United States and is one of the most common monogenic diseases. A...
Sickle cell disease (SCD) is a lifelong blood disorder affecting approximately 100,000 people in the United States and is one of the most common monogenic diseases. A serious complication of SCD is acute chest syndrome (ACS). ACS is a condition with a high rate of morbidity and mortality. The aim of the study was to assess hemolysis and lipid parameters in a cohort of confirmed SCD patients to predict ACS development in the following year.Standard lipid were performed (triglycerides, total cholesterol, high-density cholesterol, low-density cholesterol) panel to calculate of non-HDL-C, large buoyant LDL cholesterol (lbLDL-C) and small dense LDL cholesterol (sdLDL-C) with Sampson equation. Hemolysis and hematologic parameters were also evaluated.Among 91 patients included between September 2018 and June 2021, thirty-seven patients had history of ACS and 6 patients developed ACS during following year. In unadjusted logistic regression, total bilirubin was associated with ACS occurrence (RR: 1.2 [1.05-1.51] p = 0.013). Concerning lipid profile, non-HDL-C (RR: 0.87 [0.0.67-0.99] p = 0.04) and sdLDL-C (RR: 0.78 [0.49-0.96] p = 0.03) were associated with ACS occurrence decrease. C-reactive protein was associated with ACS occurrence (RR: 1.27 [1.065-1.85] p = 0.011).Based on these findings, this study demonstrated that several biomarker easily available can be used at steady state to predict ACS in the following year. The validation of these results are required to ensure the reproducibility of the findings.
Topics: Humans; Anemia, Sickle Cell; Male; Female; Acute Chest Syndrome; Adult; Hemolysis; Cholesterol, LDL; Middle Aged; Triglycerides; Cholesterol, HDL; Bilirubin; Lipids
PubMed: 38755670
DOI: 10.1186/s12944-024-02135-8 -
Scientific Reports May 2024Although patients with alpha-fetoprotein-negative hepatocellular carcinoma (AFPNHCC) have a favorable prognosis, a high risk of postoperative recurrence remains. We...
Although patients with alpha-fetoprotein-negative hepatocellular carcinoma (AFPNHCC) have a favorable prognosis, a high risk of postoperative recurrence remains. We developed and validated a novel liver fibrosis assessment index, the direct bilirubin-gamma-glutamyl transpeptidase-to-platelet ratio (DGPRI). DGPRI was calculated for each of the 378 patients with AFPNHCC who underwent hepatic resection. The patients were divided into high- and low-score groups using the optimal cutoff value. The Lasso-Cox method was used to identify the characteristics of postoperative recurrence, followed by multivariate Cox regression analysis to determine the independent risk factors associated with recurrence. A nomogram model incorporating the DGPRI was developed and validated. High DGPRI was identified as an independent risk factor (hazard ratio = 2.086) for postoperative recurrence in patients with AFPNHCC. DGPRI exhibited better predictive ability for recurrence 1-5 years after surgery than direct bilirubin and the gamma-glutamyl transpeptidase-to-platelet ratio. The DGPRI-nomogram model demonstrated good predictive ability, with a C-index of 0.674 (95% CI 0.621-0.727). The calibration curves and clinical decision analysis demonstrated its clinical utility. The DGPRI nomogram model performed better than the TNM and BCLC staging systems for predicting recurrence-free survival. DGPRI is a novel and effective predictor of postoperative recurrence in patients with AFPNHCC and provides a superior assessment of preoperative liver fibrosis.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Male; Female; Liver Cirrhosis; Middle Aged; Retrospective Studies; Neoplasm Recurrence, Local; gamma-Glutamyltransferase; Hepatectomy; alpha-Fetoproteins; Nomograms; Aged; Prognosis; Bilirubin; Risk Factors; Platelet Count; Adult
PubMed: 38730095
DOI: 10.1038/s41598-024-61615-0 -
JNCI Cancer Spectrum Apr 2024Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose...
BACKGROUND
Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer.
METHODS
Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25.
RESULTS
Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks.
CONCLUSIONS
The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted.
CLINICALTRIALS.GOV IDENTIFIER
NCT02393755.
Topics: Humans; Capecitabine; Male; Female; Middle Aged; Indoles; Aged; Progression-Free Survival; Colorectal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Adult; Fatigue; Hand-Foot Syndrome; Aged, 80 and over; Drug Resistance, Neoplasm; Bilirubin
PubMed: 38697618
DOI: 10.1093/jncics/pkae017 -
Journal of Cellular and Molecular... May 2024Lung adenocarcinoma (LUAD) is a major subtype of non-small-cell lung cancer and accompanies high mortality rates. While the role of bilirubin metabolism in cancer is...
Lung adenocarcinoma (LUAD) is a major subtype of non-small-cell lung cancer and accompanies high mortality rates. While the role of bilirubin metabolism in cancer is recognized, its specific impact on LUAD and patient response to immunotherapy needs to be elucidated. This study aimed to develop a prognostic signature of bilirubin metabolism-associated genes (BMAGs) to predict outcomes and efficacy of immunotherapy in LUAD. We analysed gene expression data from The Cancer Genome Atlas (TCGA) to identify survival-related BMAGs and construct a prognostic model in LUAD. The prognostic efficacy of our model was corroborated by employing TCGA-LUAD and five Gene Expression Omnibus datasets, effectively stratifying patients into risk-defined cohorts with marked disparities in survival. The BMAG signature was indeed an independent prognostic determinant, outperforming established clinical parameters. The low-risk group exhibited a more favourable response to immunotherapy, highlighted by increased immune checkpoint expression and immune cell infiltration. Further, somatic mutation profiling differentiated the molecular landscapes of the risk categories. Our screening further identified potential drug candidates preferentially targeting the high-risk group. Our analysis of critical BMAGs showed the tumour-suppressive role of FBP1, highlighting its suppression in LUAD and its inhibitory effects on tumour proliferation, migration and invasion, in addition to its involvement in cell cycle and apoptosis regulation. These findings introduce a potent BMAG-based prognostic indicator and offer valuable insights for prognostication and tailored immunotherapy in LUAD.
Topics: Humans; Bilirubin; Prognosis; Adenocarcinoma of Lung; Immunotherapy; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Biomarkers, Tumor; Male; Female; Gene Expression Profiling
PubMed: 38693853
DOI: 10.1111/jcmm.18346 -
World Journal of Gastroenterology Apr 2024The success of liver resection relies on the ability of the remnant liver to regenerate. Most of the knowledge regarding the pathophysiological basis of liver...
BACKGROUND
The success of liver resection relies on the ability of the remnant liver to regenerate. Most of the knowledge regarding the pathophysiological basis of liver regeneration comes from rodent studies, and data on humans are scarce. Additionally, there is limited knowledge about the preoperative factors that influence postoperative regeneration.
AIM
To quantify postoperative remnant liver volume by the latest volumetric software and investigate perioperative factors that affect posthepatectomy liver regeneration.
METHODS
A total of 268 patients who received partial hepatectomy were enrolled. Patients were grouped into right hepatectomy/trisegmentectomy (RH/Tri), left hepatectomy (LH), segmentectomy (Seg), and subsegmentectomy/nonanatomical hepatectomy (Sub/Non) groups. The regeneration index (RI) and late regeneration rate were defined as (postoperative liver volume)/[total functional liver volume (TFLV)] × 100 and (RI at 6-months - RI at 3-months)/RI at 6-months, respectively. The lower 25 percentile of RI and the higher 25 percentile of late regeneration rate in each group were defined as "low regeneration" and "delayed regeneration". "Restoration to the original size" was defined as regeneration of the liver volume by more than 90% of the TFLV at 12 months postsurgery.
RESULTS
The numbers of patients in the RH/Tri, LH, Seg, and Sub/Non groups were 41, 53, 99 and 75, respectively. The RI plateaued at 3 months in the LH, Seg, and Sub/Non groups, whereas the RI increased until 12 months in the RH/Tri group. According to our multivariate analysis, the preoperative albumin-bilirubin (ALBI) score was an independent factor for low regeneration at 3 months [odds ratio (OR) 95%CI = 2.80 (1.17-6.69), = 0.02; per 1.0 up] and 12 months [OR = 2.27 (1.01-5.09), = 0.04; per 1.0 up]. Multivariate analysis revealed that only liver resection percentage [OR = 1.03 (1.00-1.05), = 0.04] was associated with delayed regeneration. Furthermore, multivariate analysis demonstrated that the preoperative ALBI score [OR = 2.63 (1.00-1.05), = 0.02; per 1.0 up] and liver resection percentage [OR = 1.02 (1.00-1.05), = 0.04; per 1.0 up] were found to be independent risk factors associated with volume restoration failure.
CONCLUSION
Liver regeneration posthepatectomy was determined by the resection percentage and preoperative ALBI score. This knowledge helps surgeons decide the timing and type of rehepatectomy for recurrent cases.
Topics: Liver Regeneration; Hepatectomy; Humans; Male; Female; Middle Aged; Bilirubin; Liver; Aged; Liver Neoplasms; Organ Size; Retrospective Studies; Treatment Outcome; Postoperative Period; Preoperative Period; Serum Albumin; Adult; Time Factors
PubMed: 38681122
DOI: 10.3748/wjg.v30.i14.2006 -
Biochemia Medica Jun 2024This study aimed to examine whether the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) reference intervals for 19 commonly used biochemical...
INTRODUCTION
This study aimed to examine whether the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) reference intervals for 19 commonly used biochemical assays (potassium, sodium, chloride, calcium, magnesium, inorganic phosphorous, glucose, urea, creatinine, direct and total bilirubin, C-reactive protein (CRP), total protein, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and lactate dehydrogenase (LD)) could be applied to the newborn population of one Croatian clinical hospital.
MATERIALS AND METHODS
Reference interval verification was performed according to the CLSI EP28-A3c guidelines. Samples of healthy newborns were selected using the direct sampling method and analyzed on the Beckman Coulter AU680 biochemical analyzer. If verification wasn't satisfactory, further procedure included determination of own reference intervals by analyzing 120 samples of healthy newborns.
RESULTS
After the first set of measurements, 14/19 tested reference intervals were adopted for use: calcium, inorganic phosphorous, glucose, urea, creatinine, total bilirubin, CRP, total protein, albumin, AST, ALT, GGT, ALP and LD. A second set of samples was tested for 5 analytes: potassium, sodium, chloride, magnesium and direct bilirubin. The verification results of the additional samples for sodium and chloride were satisfactory, while the results for potassium, magnesium and direct bilirubin remained unsatisfactory and new reference intervals were determined.
CONCLUSIONS
The CALIPER reference intervals can be implemented into routine laboratory and clinical practice for the tested newborn population for most of the analyzed assays, while own reference intervals for potassium, magnesium and direct bilirubin have been determined.
Topics: Humans; Infant, Newborn; Reference Values; Croatia; Bilirubin; Male; Female; C-Reactive Protein; Creatinine; Aspartate Aminotransferases; Alanine Transaminase; Blood Chemical Analysis; gamma-Glutamyltransferase; Alkaline Phosphatase; Potassium; Magnesium; L-Lactate Dehydrogenase; Chlorides; Calcium; Blood Glucose; Sodium
PubMed: 38665867
DOI: 10.11613/BM.2024.020705 -
Frontiers in Pediatrics 2024Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often...
INTRODUCTION
Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often fail, requiring surgical intervention. MI typically occurs in newborns with pancreatic insufficiency from CF. Meconium contains mucin glycoprotein, a potential substrate for pancreatic enzymes or mucolytics. Our study aim was to determine whether pancreatic enzymes in combination with mucolytic treatments dissolve obstructive meconium using the CF pig model.
METHODS
We collected meconium from CF pigs at birth and submerged it in solutions with and without pancreatic enzymes, including normal saline, 7% hypertonic saline, and the reducing agents N-acetylcysteine (NAC) and dithiothreitol (DTT). We digested meconium at 37 °C with agitation, and measured meconium pigment release by spectrophotometry and residual meconium solids by filtration.
RESULTS AND DISCUSSION
In CF pigs, meconium appeared as a solid pigmented mass obstructing the ileum. Meconium microscopically contained mucus glycoprotein, cellular debris, and bile pigments. Meconium fragments released pigments with maximal absorption at 405 nm after submersion in saline over approximately 8 h. Pancreatic enzymes significantly increased pigment release and decreased residual meconium solids. DTT did not improve meconium digestion and the acidic reducing agent NAC worsened digestion. Pancreatic enzymes digested CF meconium best at neutral pH in isotonic saline. We conclude that pancreatic enzymes digest obstructive meconium from CF pigs, while hydrating or reducing agents alone were less effective. This work suggests a potential role for pancreatic enzymes in relieving obstruction due to MI in newborns with CF.
PubMed: 38665380
DOI: 10.3389/fped.2024.1387171 -
Zhongguo Dang Dai Er Ke Za Zhi =... Apr 2024To investigate the effect of chaperone-mediated autophagy (CMA) on the damage of mouse microglial BV2 cells induce by unconjugated bilirubin (UCB).
OBJECTIVES
To investigate the effect of chaperone-mediated autophagy (CMA) on the damage of mouse microglial BV2 cells induce by unconjugated bilirubin (UCB).
METHODS
The BV2 cell experiments were divided into two parts. (1) For the CMA activation experiment: control group (treated with an equal volume of dimethyl sulfoxide), QX77 group (treated with 20 μmol/L QX77 for 24 hours), UCB group (treated with 40 μmol/L UCB for 24 hours), and UCB+QX77 group (treated with both 20 μmol/L QX77 and 40 μmol/L UCB for 24 hours). (2) For the cell transfection experiment: silencing control group (treated with an equal volume of dimethyl sulfoxide), silencing control+UCB group (treated with 40 μmol/L UCB for 24 hours), silencing group (treated with an equal volume of dimethyl sulfoxide), and silencing+UCB group (treated with 40 μmol/L UCB for 24 hours). The cell viability was assessed using the modified MTT method. The expression levels of p65, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), and cysteinyl aspartate specific proteinase-1 (caspase-1) were detected by Western blot. The relative mRNA expression levels of the inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were determined by real-time quantitative polymerase chain reaction. Levels of IL-6 and TNF-α in the cell culture supernatant were measured using ELISA. The co-localization of heat shock cognate protein 70 with p65 and NLRP3 was detected by immunofluorescence.
RESULTS
Compared to the UCB group, the cell viability in the UCB+QX77 group increased, and the expression levels of inflammation-related proteins p65, NLRP3, and caspase-1, as well as the mRNA relative expression levels of IL-1β, IL-6, and TNF-α and levels of IL-6 and TNF-α decreased (<0.05). Compared to the control group, there was co-localization of heat shock cognate protein 70 with p65 and NLRP3 in both the UCB and UCB+QX77 groups. After silencing the gene, compared to the silencing control+UCB group, the silencing+UCB group showed increased expression levels of inflammation-related proteins p65, NLRP3, and caspase-1, as well as increased mRNA relative expression levels of IL-1β, IL-6, and TNF-α and levels of IL-6 and TNF-α (<0.05).
CONCLUSIONS
CMA is inhibited in UCB-induced BV2 cell damage, and activating CMA may reduce p65 and NLRP3 protein levels, suppress inflammatory responses, and counteract bilirubin neurotoxicity.
Topics: Animals; Mice; Microglia; Bilirubin; Chaperone-Mediated Autophagy; NLR Family, Pyrin Domain-Containing 3 Protein; Lysosomal-Associated Membrane Protein 2; Caspase 1; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Interleukin-1beta; Interleukin-6; Cells, Cultured; Cell Survival
PubMed: 38660903
DOI: 10.7499/j.issn.1008-8830.2312014 -
Bioresources and Bioprocessing Feb 2024Biliverdin, a bile pigment hydrolyzed from heme by heme oxygenase (HO), serves multiple functions in the human body, including antioxidant, anti-inflammatory, and immune...
Biliverdin, a bile pigment hydrolyzed from heme by heme oxygenase (HO), serves multiple functions in the human body, including antioxidant, anti-inflammatory, and immune response inhibitory activities. Biliverdin has great potential as a clinical drug; however, no economic and efficient production method is available currently. Therefore, the production of biliverdin by the biotransformation of exogenous heme using recombinant HO-expressing yeast cells was studied in this research. First, the heme oxygenase-1 gene (HO1) encoding the inducible plastidic isozyme from Arabidopsis thaliana, with the plastid transport peptide sequence removed, was recombined into Pichia pastoris GS115 cells. This resulted in the construction of a recombinant P. pastoris GS115-HO1 strain that expressed active HO1 in the cytoplasm. After that, the concentration of the inducer methanol, the induction culture time, the pH of the medium, and the concentration of sorbitol supplied in the medium were optimized, resulting in a significant improvement in the yield of HO1. Subsequently, the whole cells of GS115-HO1 were employed as catalysts to convert heme chloride (hemin) into biliverdin. The results showed that the yield of biliverdin was 132 mg/L when hemin was added to the culture of GS115-HO1 and incubated for 4 h at 30 °C. The findings of this study have laid a good foundation for future applications of this method for the economical production of biliverdin.
PubMed: 38647967
DOI: 10.1186/s40643-024-00736-w