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- Artemisia pallens alleviates acetaminophen induced toxicity via modulation of endogenous biomarkers. [JOURNAL ARTICLE]
- Pharm Biol 2014 Oct 23.:1-11.
Abstract Context: Acetaminophen (APAP) leads to severe hepatic and renal necrosis and thus causes significant clinical problems. Artemisia pallens Walls ex D.C. (Asteraceae) possesses various pharmacological properties such as antidiabetic, antioxidant, analgesic, and anti-inflammatory activity. Objective: The objective was to evaluate the protective effects of Artemisia pallens methanol extract (APME) in APAP-induced hepatic and nephro-toxicity. Materials and methods: The methanolic extract of aerial parts of Artemisia pallens (APME) was prepared. Toxicity was induced in male Wistar rats (180-220 g) by administration of APAP (700 mg/kg, p.o., 14 d). APME (100, 200, and 400 mg/kg, p.o.) was administered to rats 2 h before APAP oral administration. Various biochemical and molecular parameters along with histopathological aberration were studied in the kidney and liver of rats. Results: Pretreatment with APME (200 and 400 mg/kg, p.o.) significantly (p < 0.01 and p < 0.001) decreased aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, blood urea nitrogen (BUN), and serum creatinine as compared with APAP-treated rat. Decreased level of serum albumin, serum uric acid, and HDL were significantly (p < 0.01 and p < 0.001) restored by APME (200 and 400 mg/kg, p.o.) pre-treatment. Administration of APME (200 and 400 mg/kg, p.o.) significantly (p < 0.01 and p < 0.001) reduced the elevated level of cholesterol, LDL, LDH, triglyceride, and VLDL. It also significantly (p < 0.01 and p < 0.001) restored the altered level of hepatic and renal antioxidant enzymes (superoxide dismutase (SOD) and glutathione (GSH)). The increased level of malondialdehyde (MDA) and nitric oxide (NO) in hepatic as well as renal tissue was significantly (p < 0.01 and p < 0.001) decreased by APME (200 and 400 mg/kg, p.o.) administration. Histological alternation induced by APAP in liver and kidney was also reduced by the APME (200 and 400 mg/kg, p.o.) pre-treatment. Conclusion: It is concluded that the methanol extract of Artemisia pallens alleviates APAP induced in rats toxicity through its antioxidative and anti-inflammatory actions.
- Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression. [JOURNAL ARTICLE]
- Mol Med Rep 2014 Oct 22.
The aim of the present study was to investigate the effects of octreotide treatment on hepatic heme oxygenase‑1 (HO‑1) expression, together with the influence of altered hepatic HO‑1 expression levels on hepatic function and fibrosis in bile duct‑ligated rats. The rats were divided randomly into sham, cirrhotic, cobalt protoporphyrin and octreotide treatment groups. The expression levels of hepatic HO‑1 mRNA were measured by reverse‑transcription polymerase chain reaction, while the protein expression was determined by western blotting and immunohistochemical analysis. Hematoxylin and eosin, and Van Gieson's staining, along with determination of the hydroxyproline content in the liver, were performed to determine the degree of liver fibrosis. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in arterial blood, and the mean arterial pressure and portal vein pressure were also measured. As compared with the sham group, hepatic HO‑1 mRNA and protein expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood, hydroxyproline and collagen type I content were all significantly increased in the cirrhotic group. As compared with the cirrhotic group, the octreotide‑treated group exhibited significantly reduced hepatic HO‑1 expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood and the extent of hepatic fibrosis, whereas the cobalt protoporphyrin group exhibited significantly increased hepatic HO‑1 expression levels, as well as aggravated hepatic function and fibrosis (P<0.05). In conclusion, octreotide inhibited hepatic HO‑1 overexpression in cirrhotic rats, reduced hepatic HO‑1 expression levels to relieve liver injury and attenuated liver fibrosis.
- Protective Role of Cupressuflavone from Cupressus macrocarpa against Carbon Tetrachloride-Induced Hepato- and Nephrotoxicity in Mice. [JOURNAL ARTICLE]
- Planta Med 2014 Oct 22.
The hepatoprotective and nephroprotective activity of cupressuflavone isolated from Cupressus macrocarpa was investigated against CCl4-induced toxicity in mice. Cupressuflavone was administered (40, 80, and 160 mg/kg/day) for five days. CCl4 was administered (0.5 mL/kg intraperitoneally) at the end of the experiment. A substantial increase (p < 0.001) in the levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, total bilirubin, cholesterol, creatinine, uric acid, urea, and malondialdehyde was observed in the CCl4-treated group compared to the normal control group. In contrast, a significant reduction (p < 0.001) in glutathione and superoxide dismutase contents as well as the total protein level was evident in the CCl4-intoxicated mice. Cupressuflavone pretreatment markedly inhibited the CCl4-induced increase in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, cholesterol, creatinine, uric acid, urea, and malondialdehyde levels in a dose-dependent manner (p < 0.001 at all the tested doses). In addition, a significant (p < 0.001) and dose-dependent decrease in the total bilirubin levels was evident by cupressuflavone pretreatment (80 and 160 mg/kg/day) when compared to the CCl4-intoxicated group. Furthermore, cupressuflavone administration significantly increased the activity of antioxidant parameters glutathione and superoxide dismutase as well as the serum protein levels (p < 0.001 at all the tested doses) in a dose-dependent manner. Histological observations confirmed the strong hepato- and nephroprotective activity. These findings suggest that cupressuflavone could exert a beneficial effect against oxidative stress by enhancing the antioxidant defense status, reducing lipid peroxidation, and protecting against the pathological changes induced by CCl4 in the liver and kidney tissues. The structure of cupressuflavone was identified by NMR, UV, and HRESI-MS/MS spectral data.
- Field's Massage with Oil Decreases Bilirubin Levels in Healthy Fullterm Newborns. [Journal Article]
- J Clin Neonatol 2014 Jul; 3(3):142-3.
- The ability of bilirubin in identifying smokers with higher risk of lung cancer: a large cohort study in conjunction with global metabolomic profiling. [JOURNAL ARTICLE]
- Clin Cancer Res 2014 Oct 21.
Purpose: We aimed to identify serum metabolites as potential valuable biomarkers for lung cancer and to improve risk stratification in smokers. Experimental Design: We performed global metabolomic profiling followed by targeted validation of individual metabolites in a case-control design of 386 lung cancer cases and 193 matched controls. We then validated the most significant metabolite bilirubin as a risk marker for lung cancer incidence and mortality in a large prospective cohort comprised of 425,660 participants. Results: Through global metabolomic profiling and following targeted validation, bilirubin levels consistently showed a statistically significant difference among healthy controls and lung cancer cases. In the prospective cohort, the inverse association was only seen in male smokers, regardless of smoking pack-years and intensity. Compared with male smokers in the highest bilirubin group (>1 mg/dL), those in the lowest bilirubin group (<0.75 mg/dL) had 55% and 66% increase in risks of lung cancer incidence and mortality, respectively. For every 0.1 mg/dL decrease of bilirubin, the risks for lung cancer incidence and mortality increased by 5% and 6% in male smokers, respectively (both P < 0.001). There was a significant interaction between low serum bilirubin level and smoking on lung cancer risk (P for interaction = 0.001). Conclusions: Low levels of serum bilirubin are associated with higher risks of lung cancer incidence and mortality in male smokers and can be used to identify higher risk smokers for lung cancer.
- Transcriptional regulation of human UDP-glucuronosyltransferase genes. [JOURNAL ARTICLE]
- Drug Metab Rev 2014 Oct 22.:1-38.
Abstract Glucuronidation is an important metabolic pathway for many small endogenous and exogenous lipophilic compounds, including bilirubin, steroid hormones, bile acids, carcinogens and therapeutic drugs. Glucuronidation is primarily catalyzed by the UDP-glucuronosyltransferase (UGT) 1A and two subfamilies, including nine functional UGT1A enzymes (1A1, 1A3-1A10) and 10 functional UGT2 enzymes (2A1, 2A2, 2A3, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28). Most UGTs are expressed in the liver and this expression relates to the major role of hepatic glucuronidation in systemic clearance of toxic lipophilic compounds. Hepatic glucuronidation activity protects the body from chemical insults and governs the therapeutic efficacy of drugs that are inactivated by UGTs. UGT mRNAs have also been detected in over 20 extrahepatic tissues with a unique complement of UGT mRNAs seen in almost every tissue. This extrahepatic glucuronidation activity helps to maintain homeostasis and hence regulates biological activity of endogenous molecules that are primarily inactivated by UGTs. Deciphering the molecular mechanisms underlying tissue-specific UGT expression has been the subject of a large number of studies over the last two decades. These studies have shown that the constitutive and inducible expression of UGTs is primarily regulated by tissue-specific and ligand-activated transcription factors (TFs) via their binding to cis-regulatory elements (CREs) in UGT promoters and enhancers. This review first briefly summarizes published UGT gene transcriptional studies and the experimental models and tools utilized in these studies, and then describes in detail the TFs and their respective CREs that have been identified in the promoters and/or enhancers of individual UGT genes.
- Neonatal Dubin-Johnson syndrome: Novel compound heterozygous mutation in the ABCC2 gene. [Journal Article]
- Pediatr Int 2014 Oct; 56(5):e62-4.
Dubin-Johnson syndrome (DJS) is an autosomal recessive inherited disorder characterized by conjugated hyperbilirubinemia. Neonatal-onset DJS is rare. It is caused by dysfunction of adenosine triphosphate-binding cassette, sub-family C, member 2 (ABCC2). We found a novel compound heterozygous mutation of DJS-related gene: W709R (T2145C): a missense mutation in exon 17, and R768W (C2302T), a missense mutation in exon 18. Serum diglucuronosyl bilirubin/monoglucuronosyl bilirubin ratio was high. ABCC2 may excrete diglucuronosyl bilirubin preferentially over monoglucuronosyl bilirubin.
- Liver failure after hepatocellular carcinoma surgery. [JOURNAL ARTICLE]
- Langenbecks Arch Surg 2014 Oct 22.
The aim of this study was to construct a prediction model for posthepatectomy liver failure (PHLF), as defined by the International Study Group of Liver Surgery, and evaluate its accuracy in hepatocellular carcinoma (HCC) patients with cirrhosis or chronic hepatitis.A total of 277 consecutive hepatectomies for HCC between 2005 and 2013 were analyzed retrospectively. Multivariate logistic regression analysis was used to develop a predictive model for PHLF. The sensitivity, specificity, and area under the receiver operating characteristic (AUROC) curve were evaluated. The Hosmer-Lemeshow goodness-of-fit test was used to assess the model calibration. The constructed model was internally validated by k-fold cross-validation (k = 5).PHLF developed in 12.6 % of hepatectomies. Multivariate analysis identified the following variables as predictors of PHLF: elevated preoperative serum bilirubin level, elevated preoperative international normalized ratio, and intraoperative packed red blood cell transfusion. The predictive model allowed discrimination between patients who developed PHLF and those who did not, with a sensitivity of 82.9 %, specificity of 72.3 %, and AUROC curve of 0.81 (95 % CI, 0.74 to 0.89). The Hosmer-Lemeshow test indicated a good fit (P = 0.545). The AUROC curve of the developed model was significantly greater than that of the model for end-stage liver disease (MELD) score (P = 0.014), suggesting that the former model is better at predicting the PHLF than the latter one.The developed model could be useful for predicting the occurrence of PHLF in HCC patients with underlying liver disease.
- [The dynamics of biochemical blood indicators in patients with hemophilia and posttransfusion hepatitis receiving hepatotropic therapy]. [English Abstract, Journal Article]
- Klin Lab Diagn 2014 Jun; (6):4-6.
The sample of 128 patients with hemophilia aged from 1 to 71 years (Me 32) was examined. The study established that 109 patients (85.2%) had hemophilia A and 19 patients (14.8%) had hemophilia B. In 77 adult patients (60%) markers of viruses of hepatitis C and B were detected and the signs of disorders of liver functions were established in 64% out of them. These signs included reliable increasing of levels of AST and ALT, total and conjugated bilirubin, urea and creatinine and absence of any clinical manifestations. The detected alterations served as a background for implementation of hepatotropic therapy with pharmaceutical Heptral. The ademetionin is the reactant of preparation. After two weeks of intravenous application of Heptal the tendency to normalization of content of bilirubin was established. The significant decrease of activity of aminotransferases was detected, nevertheless their levels still overridden physiological standard. This situation required to prescribe pharmaceutical and to continue treatment in out-patient conditions. The continuous repair of functional activity of hepatic cells requires further search of more effective schemes of therapy.
- Transcutaneous Bilirubin After Phototherapy in Term and Preterm Infants. [JOURNAL ARTICLE]
- Pediatrics 2014 Oct 20.
To compare transcutaneous bilirubin (TcB) readings with total serum bilirubin (TSB) after phototherapy, estimating the range of TcB where confirmation through blood sampling can be avoided.Preterm and term neonates receiving in-hospital phototherapy underwent TcB measurements (device JM-103, TcB) alongside routine TSB before and after treatment. We calculated time-dependent safety margins for transcutaneous readings to correctly assign 99% of infants not to receive phototherapy.Between August 2011 and December 2012, 86 newborn infants (47 preterm, 39 term) underwent a total of 189 parallel measurements. Mean difference (TcB - TSB) before treatment was -0.6 mg/dL (SD, 1.9 mg/dL). Within the first 8 hours after phototherapy, TcB levels were -2.4 mg/dL (SD, 2.1 mg/dL) below TSB. Thereafter the difference gradually returned to pretreatment values (-1.8 mg/dL in 8-16 hours, -1.1 mg/dL in 16-24 hours, and -0.8 mg/dL after 24 hours), while variations remained stable over time (SD, 1.4-1.8 mg/dL). In the first 8 hours after treatment, TcB levels of -7.3 mg/dL below the individual phototherapy threshold allowed safe rejection of confirmatory blood sampling. After 8 hours, that safety margin was reduced to approximately -5.0 mg/dL.TcB measurements remain a valuable tool after phototherapy when time-dependent underestimation of TcB is being accounted for.