Prognostic significance of pre-treatment ALBI grade in advanced non-small cell lung cancer receiving immune checkpoint therapy.

The liver is an essential organ for regulating innate and acquired immunity. We hypothesized that the pre-treatment hepatic function affects the clinical outcome of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). We analyzed 140 patients with NSCLC who received ICIs. We investigated the association between pre-treatment liver function, assessed using the albumin-bilirubin (ALBI) grade, and clinical outcomes in univariate, multivariate, and propensity score matching analyses. Patients were divided into four grades according to pre-treatment liver function. Eighty-eight patients had good hepatic reserve (ALBI grade 1 or 2a), whereas 52 patients had poor hepatic reserve (ALBI grade 2b or 3). In the univariate Kaplan-Meier analysis, the ALBI grade 1, 2a group had a significantly prolonged progression-free survival (PFS, 5.3 versus 2.5 months, p = 0.0019) and overall survival (OS, 19.6 vs. 6.2 months, p = 0.0002). These results were consistent, regardless of whether the analysis was performed in patients with a performance status of 0 or 1 at pre-treatment (N = 124) or in those selected using propensity score matching (N = 76). In the multivariate analysis, pre-treatment ALBI grade was an independent prognostic factor for both PFS (hazard ratio [HR] 0.57, 95% confidence interval [95% CI] 0.38-0.86, p = 0.007) and OS (HR 0.45, 95% CI 0.29-0.72, p = 0.001). Our results suggest that pre-treatment hepatic function assessed by ALBI grade could be an essential biomarker for predicting the efficacy of treatment with ICIs in NSCLC.

UGT1A1 dysfunction increases liver burden and aggravates hepatocyte damage caused by long-term bilirubin metabolism disorder.

UGT1A1 is the only enzyme that can metabolize bilirubin, and its encoding gene is frequently mutated. UGT1A1*6 (G71R) is a common mutant in Asia which leads to the decrease of UGT1A1 activity and abnormal bilirubin metabolism. However, it is not clear whether low UGT1A1 activity-induced bilirubin metabolism disorder increases hepatocyte fragility. ugt1a+/- mice were used to simulate the UGT1A1*6 (G71R) population. Under the same CCl4 induction condition, ugt1a+/- mice showed severer liver damage and fibrosis, indicating that ugt1a1 dysfunction increased liver burden and aggravated hepatocyte damage. In the animal experiment with a continuous intraperitoneal injection of bilirubin, the ugt1a+/- mice livers had more serious unconjugated bilirubin accumulation. The accumulated bilirubin leads to hyperphosphorylation of IκB-α, Ikk-ß, and p65 and a significant increase of inflammatory factor. The α-SMA and Collagen I proteins markedly up-regulated in the ugt1a+/- mice livers. Immunofluorescence and confocal microscopy showed that hepatic stellate cells and Kupffer cells were activated in ugt1a+/- mice. Comprehensive results show that there was a crosstalk relationship between low UGT1A1 activity-bilirubin-liver damage. Furthermore, cell experiments confirmed that unconjugated bilirubin activated the NF-κB pathway and induced DNA damage in hepatocytes, leading to the significant increase of inflammatory factors. UGT1A1 knockdown in hepatocytes aggravated the toxicity of unconjugated bilirubin. Conversely, overexpression of UGT1A1 had a protective effect on hepatocytes. Finally, Schisandrin B, an active ingredient with hepatoprotective effects, extracted from a traditional Chinese medicinal herb, which could protect the liver from bilirubin metabolism disorders caused by ugt1a1 deficiency by downregulating p65 phosphorylation, inhibiting Kupffer cells, reducing inflammation levels. Our data clarified the mechanism of liver vulnerability caused by cross-talk between low UGT1A1 activity bilirubin, and provided a reference for individualized prevention of liver fragility in Gilbert's syndrome.

Molecular Pathways and Pigments Underlying the Colors of the Pearl Oyster Pinctada margaritifera var. cumingii (Linnaeus 1758).

The shell color of the Mollusca has attracted naturalists and collectors for hundreds of years, while the molecular pathways regulating pigment production and the pigments themselves remain poorly described. In this study, our aim was to identify the main pigments and their molecular pathways in the pearl oyster Pinctada margaritifera-the species displaying the broadest range of colors. Three inner shell colors were investigated-red, yellow, and green. To maximize phenotypic homogeneity, a controlled population approach combined with common garden conditioning was used. Comparative analysis of transcriptomes (RNA-seq) of P. margaritifera with different shell colors revealed the central role of the heme pathway, which is involved in the production of red (uroporphyrin and derivates), yellow (bilirubin), and green (biliverdin and cobalamin forms) pigments. In addition, the Raper-Mason, and purine metabolism pathways were shown to produce yellow pigments (pheomelanin and xanthine) and the black pigment eumelanin. The presence of these pigments in pigmented shell was validated by Raman spectroscopy. This method also highlighted that all the identified pathways and pigments are expressed ubiquitously and that the dominant color of the shell is due to the preferential expression of one pathway compared with another. These pathways could likely be extrapolated to many other organisms presenting broad chromatic variation.

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study.

Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin's lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin's lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p < 5 × 10-8) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) gene explained 16.9% and the remaining 114 SNPs (non-UGT1A1 SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin's lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73-0.99, P 0.04 and OR 0.64, 95% CI 0.42-0.99, p 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04-1.20, p 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin's lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers.

Liver Growth Factor "LGF" as a Therapeutic Agent for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive degenerative disorder and the most common cause of dementia in aging populations. Although the pathological hallmarks of AD are well defined, currently no effective therapy exists. Liver growth factor (LGF) is a hepatic albumin-bilirubin complex with activity as a tissue regenerating factor in several neurodegenerative disorders such as Parkinson's disease and Friedreich's ataxia. Our aim here was to analyze the potential therapeutic effect of LGF on the APPswe mouse model of AD. Twenty-month-old mice received intraperitoneal (i.p.) injections of 1.6 µg LGF or saline, twice a week during three weeks. Mice were sacrificed one week later, and the hippocampus and dorsal cortex were prepared for immunohistochemical and biochemical studies. LGF treatment reduced amyloid-ß (Aß) content, phospho-Tau/Tau ratio and the number of Aß plaques with diameter larger than 25 µm. LGF administration also modulated protein ubiquitination and HSP70 protein levels, reduced glial reactivity and inflammation, and the expression of the pro-apoptotic protein Bax. Because the administration of this factor also restored cognitive damage in APPswe mice, we propose LGF as a novel therapeutic tool that may be useful for the treatment of AD.

Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank.

BACKGROUND: Moderately raised serum bilirubin levels are associated with lower rates of lung cancer, particularly among smokers. It is not known whether these relationships reflect antioxidant properties or residual confounding. OBJECTIVE: This study aimed to investigate potential causal relationships between serum total bilirubin and lung cancer incidence using one-sample Mendelian randomisation (MR) and UK Biobank. METHODS: We instrumented serum total bilirubin level using two variants (rs887829 and rs4149056) that together explain ~40% of population-level variability and are linked to mild hereditary hyperbilirubinaemia. Lung cancer events occurring after recruitment were identified from national cancer registries. Observational and genetically instrumented incidence rate ratios (IRRs) and rate differences per 10 000 person-years (PYs) by smoking status were estimated. RESULTS: We included 377 294 participants (median bilirubin 8.1 µmol/L (IQR 6.4-10.4)) and 2002 lung cancer events in the MR analysis. Each 5 µmol/L increase in observed bilirubin levels was associated with 1.2/10 000 PY decrease (95% CI 0.7 to 1.8) in lung cancer incidence. The corresponding MR estimate was a decrease of 0.8/10 000 PY (95% CI 0.1 to 1.4). The strongest associations were in current smokers where a 5 µmol/L increase in observed bilirubin levels was associated with a decrease in lung cancer incidence of 10.2/10 000 PY (95% CI 5.5 to 15.0) and an MR estimate of 6.4/10 000 PY (95% CI 1.4 to 11.5). For heavy smokers (≥20/day), the MR estimate was an incidence decrease of 23.1/10 000 PY (95% CI 7.3 to 38.9). There was no association in never smokers and no mediation by respiratory function. CONCLUSION: Genetically raised serum bilirubin, common across human populations, may protect people exposed to high levels of smoke oxidants against lung cancers.

Initial Experience of Ramucirumab Treatment After Lenvatinib Failure for Patients With Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: The outcomes of ramucirumab after lenvatinib failure for hepatocellular carcinoma (HCC) patients with alpha fetoprotein (AFP) levels of ≥400 ng/ml are unknown. PATIENTS AND METHODS: Of 12 patients treated with ramucirumab after lenvatinib failure, 10 patients were enrolled in this retrospective study. RESULTS: The disease control rate of 80% at 6 weeks and the median time to progression of 3.1 months were the same by both the Response Evaluation Criteria in Solid Tumors (RECIST) and the modified RECIST. AFP reduction was seen in 5 patients at 2 weeks and in 3 patients at 6 weeks. The incidence of grade 3 adverse events was low at 10%. The albumin-bilirubin scores within 6 weeks did not worsen. CONCLUSION: Ramucirumab might have potential therapeutic efficacy and safety in advanced HCC patients after lenvatinib failure. Further studies are needed to confirm the outcomes of ramucirumab after lenvatinib failure.

Combined albumin-bilirubin grade and Mac-2 binding protein glycosylation isomer as a useful predictor in compensated liver cirrhosis.

We aimed to compare the impact on survival among albumin-bilirubin (ALBI) grade, modified ALBI (mALBI) and our proposed combined ALBI grade and Mac-2 binding protein glycosylation isomer (M2BPGi) or FIB4 index grading system in chronic hepatitis C (CHC) related compensated liver cirrhosis (n = 165, 93 men and 72 women, median age = 67 years). Patients with ALBI grade 1, 2, and 3 were allocated a score of 1, 2, and 3 points, respectively. Patients with mALBI grade 1, 2A, and 2B were allocated a score of 1, 2, and 3 points, respectively. Patients with a high or low M2BPGi were allocated a score of 1 and 0 point. Patients with a high or low FIB4 index were allocated a score of 1 and 0 point. Sum of the point of ALBI (1, 2, or 3) and M2BPGi (0 or 1) or FIB4 index (0 or 1) was defined as ALBI-M2BPGi grade or ALBI-FIB4 grade. Prognostic accuracy was compared using the Akaike information criterion (AIC) value and time dependent receiver operating characteristics (ROC) curve analysis. The median follow-up duration was 5.422 years. AIC value for survival by ALBI-M2BPGi grade was the lowest among 4 prognostic models (AIC: 205.731 in ALBI grade, 200.913 in mALBI grade, 189.816 in ALBI-M2BPGi grade, and 204.671 in ALBI-FIB4 grade). All area under the ROC curves of ALBI-M2BPGi grade in each time point were higher than those of ALBI grade, mALBI grade, and ALBI-FIB4 grade. In conclusion, our proposed ALBI-M2BPGi grading system seems to be helpful for estimating prognosis in patients with CHC related compensated LC.

Analysis of the UGT1A1 Genotype in Hyperbilirubinemia Patients: Differences in Allele Frequency and Distribution.

OBJECTIVE: The spectrum of UDP-glucuronyl transferase A1 (UGT1A1) variants in hereditary unconjugated hyperbilirubinemia varies markedly between different ethnic populations. This study evaluated the UGT1A1 genotypes in hyperbilirubinemia patients from southeastern China. METHODS: We enrolled 60 patients from southeastern China (44 men and 16 women; age range: 3-76 years) with unconjugated hyperbilirubinemia and performed genetic analysis of the UGT1A1 gene by direct sequencing. RESULTS: For patients with Gilbert syndrome, 85% (47/55) harbored pathogenic variants of UGT1A1⁎60. Both UGT1A1⁎28 and UGT1A1⁎81 were detected in the promoter region of UGT1A1. Additionally, 83% (20/24) of patients with Gilbert syndrome heterozygous for UGT1A1⁎60 had an association with heterozygous variation of UGT1A1⁎28 or UGT1A1⁎81, while 91% (21/23) of Gilbert syndrome patients homozygous for UGT1A1⁎60 had biallelic variations of UGT1A1⁎28 and UGT1A1⁎81. We detected 213 UGT1A1 allelic variants, including six novel variations, with the most frequent allele being the UGT1A1⁎60, followed by UGT1A1⁎28 and UGT1A1⁎6. All of the patients showed multiple sites of variants in UGT1A1; however, variation number was not associated with bilirubin levels (P>0.05). CONCLUSIONS: The spectrum of UGT1A1 variants in southeastern Chinese patients was distinct from other ethnic populations. Our findings broaden the knowledge concerning traits associated with UGT1A1 variants and help profile genotype-phenotype correlations in hyperbilirubinemia patients.

Serum Albumin, but not Bilirubin, is Associated with Diabetic Chronic Vascular Complications in a Chinese Type 2 Diabetic Population.

To identify the factors associated with serum total bilirubin (STB) and determine whether STB is independently associated with diabetic retinopathy (DR) or diabetic kidney disease (DKD), 1,665 Chinese patients with type 2 diabetes (T2DM) (248 outpatients newly diagnosed with T2DM [NDM] and 1,417 inpatients previously diagnosed with T2DM [PDM]) were studied. Clinical and biochemical information was collected, and a single nucleotide polymorphism (rs6704078) of the UGT1A1 gene was genotyped in 1,059 individuals. Multiple linear regression showed that STB was associated with haemoglobin concentration, platelet count, and serum triglyceride concentration in NDM and PDM patients, and with serum albumin, duration of diabetes, and smoking in PDM patients. In patients with PDM, multiple logistic regression revealed that serum albumin was associated with DR (odds ratio [OR] = 0.92, 95% confidence interval [CI]: 0.87-0.96, p = 0.001) and DKD (OR = 0.93, 95% CI: 0.88-0.98, p = 0.005) after adjustment for STB, STB-related factors, and risk factors for DR and DKD. In addition, patients with the T allele of rs6704078 had higher STB (13.2 [10.4-17.9] µmol/L versus 11.8 (9.4-14.8) µmol/L; p < 0.001) and similar risks of DR or DKD to those without the T allele. Thus, serum albumin, but not STB, is associated with DR and DKD.

RNA sequencing in human HepG2 hepatocytes reveals PPAR-α mediates transcriptome responsiveness of bilirubin.

Bilirubin is a potent antioxidant that reduces inflammation and the accumulation of fat. There have been reports of gene responses to bilirubin, which was mostly attributed to its antioxidant function. Using RNA sequencing, we found that biliverdin, which is rapidly reduced to bilirubin, induced transcriptome responses in human HepG2 hepatocytes in a peroxisome proliferator-activated receptor (PPAR)-α-dependent fashion (398 genes with >2-fold change; false discovery rate P < 0.05). For comparison, a much narrower set of genes demonstrated differential expression when PPAR-α was suppressed via lentiviral shRNA knockdown (23 genes). Gene set enrichment analysis revealed the bilirubin-PPAR-α transcriptome mediates pathways for oxidation-reduction processes, mitochondrial function, response to nutrients, fatty acid oxidation, and lipid homeostasis. Together, these findings suggest that transcriptome responses from the generation of bilirubin are mostly PPAR-α dependent, and its antioxidant function regulates a smaller set of genes.

The Neonatal Acute Bilirubin Encephalopathy Registry (NABER): Background, Aims, and Protocol.

BACKGROUND: Acute bilirubin encephalopathy (ABE) is a potentially devastating condition that can lead to death or life-long neurodevelopmental handicaps. ABE is particularly tragic because it is, in theory, completely preventable. Progress toward its prevention has been hampered by the perception that the extreme hyperbilirubinemia giving rise to ABE typically has no clear causation, with the majority of previous cases being labeled as "idiopathic" neonatal jaundice. OBJECTIVES: This research briefing is intended to inform readers of a new prospective study aimed at clarifying the causes of ABE. This is accomplished by identifying qualifying patients with ABE anywhere in the USA and then documenting their clinical characteristics and the results of testing 28 specific genetic associations in a web-based, institutional review board-approved, REDCap (research electronic data capture) deidentified registry. METHODS: In this research briefing, we present an overview of ABE and discuss the problem that most patients in the past have been labeled as having "idiopathic" hyperbilirubinemia. We also present data supporting a new theory that most (perhaps all) ABE patients have mutations or polymorphisms in genes involved in bilirubin production or metabolism. We introduce a new registry seeking to enroll 100 neonates with ABE as a voluntary, deidentified database, with next generation sequencing of 28 genes involved in bilirubin production/metabolism provided to enrollees at no cost. RESULTS AND CONCLUSIONS: The Neonatal Acute Bilirubin Encephalopathy Registry (NABER) study will correlate deidentified clinical and genetic data in order to clarify the underlying causes of hyperbilirubinemia in current ABE patients. We maintain that the improved understanding this study produces will constitute a needed step toward devising new clinical pathways and strategies for preventing ABE in neonates.

Genetic lesions in the UGT1A1 genes among Gilbert's syndrome patients from India.

The present study was undertaken to investigate genetic variations present in the coding regions of the UGT1A1 gene among the Gilbert's syndrome patients. Analysis of genetic variations was performed by direct DNA sequencing among the patients that do not have any polymorphic variations in the promoter regions of the UGT1A1 gene. We identified seven different sequence variations among Gilbert's Syndrome patients, of which four were novel. Out of seven variants, six missense and one silent single nucleotide substitutions were present in the UGT1A1 gene. In addition, molecular modeling of UGT1A1 (H55R, P152S and N212H) variants suggested a reduced activity of the enzyme. This study demonstrates that different variations present in the UGT1A1 gene and specifically, the H55R variation had a significant effect on bilirubin levels and could be genetic risk factors for hyperbilirubinemia.

Acute neonatal bilirubin encephalopathy in the State of Utah 2009-2018.

Herein we report a case series of seven newborn infants, all apparently well at birth, who in the period since 2009 were cared for in the State of Utah with acute bilirubin encephalopathy (ABE). This report summarizes our attempts to define common features of these seven through a state-wide voluntary registry, as a step toward devising new means of preventing such cases in the future. In previous reports of ABE, many of the affected neonates had no clearly defined explanation for their progressive hyperbilirubinemia. Our efforts to identify clear explanations in all seven cases included next generation DNA sequencing, testing a panel of 28 genes involved in bilirubin production and metabolism. We found that hemolytic disease was a unifying feature of these seven; two had DAT (+) Anti-D or anti-c hemolysis, while five had confirmed mutations in genes involved in bilirubin production and or metabolism that were previously unrecognized in these families.

The UGT1A1*28 gene variant predicts long-term mortality in patients undergoing coronary angiography.

BACKGROUND: Uridine diphosphate glycosyltransferases 1A1 (UGT1A1) plays an essential role in detoxification and excretion of several endogenous and exogenous compounds. A functional polymorphism in the promoter of the UGT1A1 gene (TA repeat insertion, UGT1A1*28, rs3064744) has been associated with reduced UGT1A1 enzyme activity. The purpose of the present study was to investigate the role of UGT1A1 genotypes in mortality. METHODS: UGT1A1 genotypes as well as baseline plasma bilirubin levels were analyzed in participants of the Ludwigshafen Risk and Cardiovascular Health study (n=3316). UGT1A1*28 genotypes were determined on an ABI PRISM 3730 genetic analyzer. RESULTS: As expected, UGT1A1 genotypes were associated with baseline bilirubin levels (*1/*1 genotype: 9.1±4.6 µmol/L; *1/*28 genotype: 10.8±5.3; *28/*28: 16.9±9.2; p<0.001). During a median follow-up of 10.4 years, 995 subjects (30.0%) died. In a multivariate regression analysis adjusting for age, sex, smoking, type 2 diabetes, dyslipidemia, alanine aminotransferase (ALT) levels and bilirubin levels, the UGT1A1*28 variant predicted lower overall mortality (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.78-0.95; p=0.003). Contrary to expected, higher baseline bilirubin levels predicted increased mortality (HR, 1.014; 95% CI, 1.002-1.025; p=0.019). CONCLUSIONS: The UGT1A1*28 gene variant is associated with lower mortality rates. The protective effect of the UGT1A1*28 variant likely includes mechanism other than bilirubin metabolism.

Bilirubin and Stroke Risk Using a Mendelian Randomization Design.

BACKGROUND AND PURPOSE: Circulating bilirubin, a natural antioxidant, is associated with decreased risk of stroke. However, the nature of the relationship between the two remains unknown. We used a Mendelian randomization analysis to assess the causal effect of serum bilirubin on stroke risk in Koreans. METHODS: The 14 single-nucleotide polymorphisms (SNPs) (<10-7) including rs6742078 of uridine diphosphoglucuronyl-transferase were selected from genome-wide association study of bilirubin level in the KCPS-II (Korean Cancer Prevention Study-II) Biobank subcohort consisting of 4793 healthy Korean and 806 stroke cases. Weighted genetic risk score was calculated using 14 SNPs selected from the top SNPs. RESULTS: Both rs6742078 (F statistics=138) and weighted genetic risk score with 14 SNPs (F statistics=187) were strongly associated with bilirubin levels. Simultaneously, serum bilirubin level was associated with decreased risk of stroke in an ordinary least-squares analysis. However, in 2-stage least-squares Mendelian randomization analysis, no causal relationship between serum bilirubin and stroke risk was found. CONCLUSIONS: There is no evidence that bilirubin level is causally associated with risk of stroke in Koreans. Therefore, bilirubin level is not a risk determinant of stroke.

The impact of the UGT1A1*60 allele on bilirubin serum concentrations.

AIM: Identify the functional status of the uridine-diphosphate glucuronyl transferase 1A1 (UGT1A1) -3279T>G (*60) variant. MATERIALS & METHODS: Retrospective review of clinically obtained serum bilirubin concentrations in pediatric patients to evaluate the association of the UGT1A1 -3279T>G (*60) variant with bilirubin concentrations and assessed linkage disequilibrium of the UGT1A1 -3279T>G (*60) and A(TA)7TAA (*28) variants. RESULTS: Total bilirubin concentration did not differ between patients who had a UGT1A1*1/*1 diplotype and patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant. Total bilirubin concentration was lower in patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant than in patients homozygous for the UGT1A1 A(TA)7TAA (*28/*28) variant (p < 0.01). The -3279T>G (*60) and A(TA)7TAA (*28) variants were in strong incomplete linkage disequilibrium in both black and white patients. CONCLUSION: The presence of the UGT1A1 -3279T>G (*60) variant is not associated with increased bilirubin concentrations.

[Study on effect of scutellarin in resisting liver fibrosis in rats].

Totally 80 rats were randomly divided into the control group, the model group, low, middle and high dose (25, 50, 100 mg x kg(-1)) scutellarin( SC) groups and the colchicine ( Col) group. Apart from the blank group, all of the remaining groups were intraperitoneally injected with 0.5 mL pig serum twice every week for consecutively 13 weeks and orally administered with the corresponding drugs since the 9th week. The blank group and the model group were orally given equal volume of normal saline once every for consecutively four weeks. After the experiment, efforts were made to detect the contents of alanine aminotransferase (ALT), aspertate aminotransferase (AST), albumin (ALB), total protein (TP), total bilirubin (TBIL), hyaluronic acid (HA), laminin (LN) and collagen type IV (CIV), collect liver tissues of fixed positions, observe the pathological changes through hematoxylin-eosin (HE) staining, conduct the pathological grading for liver fibrosis, determine the expressions of hepatic collagen type I and III (C I, C III) and calculate their color rendering index. Compared with the model group, low, middle and high dose (25, 50, 100 mg x kg(-1)) SC groups could decrease the contents of ALT, AST, TBIL, HA, LN, CIV, increase the contents of ALB, TP in serum and reduce the contents of C I, C III in liver tissues. In conclusion, scutellarin has a certain therapeutic effect on immune liver fibrosis in rats induced by pig serum.

Association of neonatal hyperbilirubinemia in breast-fed infants with UGT1A1 or SLCOs polymorphisms.

Neonates have physiologically increased bilirubin production and immature bilirubin metabolism, and present hyperbilirubinemia in association with genetic and or epigenetic factors. We previously reported that maximal body weight loss (inadequate feeding) is an independent risk factor for the development of hyperbilirubinemia in breast-fed Japanese neonates, and the UGT1A1 211G>A genotype becomes a risk factor under conditions of inadequate feeding. We extended the study to the association of other genetic factors, the UGT1A1 (TA)7 and solute-carrier organic anion transporters (SLCOs) polymorphisms with neonatal hyperbilirubinemia. We enrolled 401 full-term Japanese infants who were exclusively breastfeeding and classified them into two groups based on the degree of maximal body weight loss. We analyzed the clinical characteristics and UGT1A1 and SLCOs genotypes. Statistical analysis revealed that maximal body weight loss is the only independent risk factor for the development of neonatal hyperbilirubinemia. UGT1A1, SLCO1B1 and SLCO1B3 polymorphisms become risk factors in neonates showing 10% or greater body weight loss during the neonatal period. Inadequate feeding may increase the bilirubin burden and cause apparent hyperbilirubinemia in neonates, who have a polymorphic change in the genes involved in the transport and/or metabolism of bilirubin.