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Sample records for hepatotoxic biomarker alanine

  1. Influence of Moxifloxacin on Hepatic Redox Status and Plasma Biomarkers of Hepatotoxicity and Nephrotoxicity in Rat

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    Ayokanmi Ore

    2015-01-01

    Full Text Available Moxifloxacin is a broad spectrum fluoroquinolone antibacterial agent. We examined the hepatic redox status and plasma biomarkers of nephrotoxicity and hepatotoxicity in rat following administration of moxifloxacin (MXF. Twenty-four Wistar rats, 180–200 g, were randomized into four groups (I–IV. Animals in group I (control received 1 mL of distilled water, while animals in groups II, III, and IV received 1 mL each of MXF equivalent to 4 mg/kg b.w., 8 mg/kg b.w., and 16 mg/kg b.w., respectively. After seven days, plasma urea, bilirubin, and creatinine were significantly (P<0.05 elevated in the MXF-treated animals. Activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase were significantly increased in the plasma of MXF-treated animals compared to control. Also plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides increased significantly in the MXF-treated groups relative to control. Moreover, MXF triggered a significant decrease in hepatic catalase, superoxide dismutase, and glutathione-S transferase activities. Likewise, MXF caused a decrease in the hepatic levels of glutathione and vitamin C. A significant increase in hepatic MDA content was also observed in the MXF-treated animals relative to control. Overall, our data suggest that the half-therapeutic, therapeutic, and twice the therapeutic dose of MXF induced nephrotoxicity, hepatotoxicity, and altered hepatic redox balance in rats.

  2. Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies.

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    Sharapova, T; Devanarayan, V; LeRoy, B; Liguori, M J; Blomme, E; Buck, W; Maher, J

    2016-01-01

    MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases. © The Author(s) 2015.

  3. Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

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    Jinchun Sun

    2014-07-01

    Full Text Available It has been estimated that 10% of acute liver failure is due to “idiosyncratic hepatotoxicity”. The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride, two idiosyncratic hepatotoxicants (felbamate and dantrolene, and three non-hepatotoxicants (meloxicam, penicillin and metformin. Male Sprague–Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h, 7 (24 h and 20 (6 h and 24 h metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting.

  4. Dynamic and accurate assessment of acetaminophen-induced hepatotoxicity by integrated photoacoustic imaging and mechanistic biomarkers in vivo.

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    Brillant, Nathalie; Elmasry, Mohamed; Burton, Neal C; Rodriguez, Josep Monne; Sharkey, Jack W; Fenwick, Stephen; Poptani, Harish; Kitteringham, Neil R; Goldring, Christopher E; Kipar, Anja; Park, B Kevin; Antoine, Daniel J

    2017-10-01

    The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention. Perturbation of liver function and cellular viability was assessed in C57BL/6J male mice by Indocyanine green (ICG) clearance (Multispectral Optoacoustic Tomography (MSOT)) and by measurement of mechanistic (miR-122, HMGB1) and established (ALT, bilirubin) circulating biomarkers in response to the acetaminophen and its treatment with acetylcysteine (NAC) in vivo. We utilised a 60% partial hepatectomy model as a situation of defined hepatic functional mass loss to compared acetaminophen-induced changes to. Integration of these mechanistic markers correlated with histological features of APAP hepatotoxicity in a time-dependent manner. They accurately reflected the onset and recovery from hepatotoxicity compared to traditional biomarkers and also reported the efficacy of NAC with high sensitivity. ICG clearance kinetics correlated with histological scores for acute liver damage for APAP (i.e. 3h timepoint; r=0.90, P<0.0001) and elevations in both of the mechanistic biomarkers, miR-122 (e.g. 6h timepoint; r=0.70, P=0.005) and HMGB1 (e.g. 6h timepoint; r=0.56, P=0.04). For the first time we report the utility of this non-invasive longitudinal imaging approach to provide direct visualisation of the liver function coupled with mechanistic biomarkers, in the same animal, allowing the investigation of the toxicological and pharmacological aspects of APAP-ILI and hepatic regeneration. Copyright © 2017

  5. Protective Effect of Cornus mas Fruits Extract on Serum Biomarkers in CCl4-Induced Hepatotoxicity in Male Rats.

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    Alavian, Seyed Moayed; Banihabib, Nafiseh; Es Haghi, Masoud; Panahi, Farid

    2014-04-01

    Nowadays attention to use herbs such as cornelian cherry (Cornus mas) is increasing, which contains high levels of antioxidants and anthocyanins. Cornus mas fruits have been used for gastrointestinal and excretory disorders for many years in traditional medicine, also may improve liver and kidney functions, and have protective effects such as anti-allergic, antidiabetic, antibacterial, antimicrobial, antihistamine and antimalarial properties. The aim of this study was to investigate protective effects of Cornus mas fruits extract on serum biomarkers in CCl4-induced hepatotoxicity in male rats. Hepatotoxicity was induced by administration of carbon tetrachloride (1 mL/kg i.p.) in 1:1 dilution with olive oil. To evaluate the effect of Cornus mas fruits extract on disease progression, serum marker enzymes, serum total protein and albumin and liver lipid peroxidation were determined in CCl4-induced hepatotoxicity. Oral administration of Cornus mas fruits extract to rats for 14 days provided a significant (P mas fruit extract effect may be due to including some antioxidant components, which caused membrane stabilizing and normalization of fluctuated biochemical profiles induced by CCl4 exposure. Our results validated the traditional use of Cornus mas in the treatment of liver disorders.

  6. Risk prediction of hepatotoxicity in paracetamol poisoning.

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    Wong, Anselm; Graudins, Andis

    2017-09-01

    Paracetamol (acetaminophen) poisoning is the most common cause of acute liver failure in the developed world. A paracetamol treatment nomogram has been used for over four decades to help determine whether patients will develop hepatotoxicity without acetylcysteine treatment, and thus indicates those needing treatment. Despite this, a small proportion of patients still develop hepatotoxicity. More accurate risk predictors would be useful to increase the early detection of patients with the potential to develop hepatotoxicity despite acetylcysteine treatment. Similarly, there would be benefit in early identification of those with a low likelihood of developing hepatotoxicity, as this group may be safely treated with an abbreviated acetylcysteine regimen. To review the current literature related to risk prediction tools that can be used to identify patients at increased risk of hepatotoxicity. A systematic literature review was conducted using the search terms: "paracetamol" OR "acetaminophen" AND "overdose" OR "toxicity" OR "risk prediction rules" OR "hepatotoxicity" OR "psi parameter" OR "multiplication product" OR "half-life" OR "prothrombin time" OR "AST/ALT (aspartate transaminase/alanine transaminase)" OR "dose" OR "biomarkers" OR "nomogram". The search was limited to human studies without language restrictions, of Medline (1946 to May 2016), PubMed and EMBASE. Original articles pertaining to the theme were identified from January 1974 to May 2016. Of the 13,975 articles identified, 60 were relevant to the review. Paracetamol treatment nomograms: Paracetamol treatment nomograms have been used for decades to help decide the need for acetylcysteine, but rarely used to determine the risk of hepatotoxicity with treatment. Reported paracetamol dose and concentration: A dose ingestion >12 g or serum paracetamol concentration above the treatment thresholds on the paracetamol nomogram are associated with a greater risk of hepatotoxicity. Paracetamol elimination half

  7. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity.

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    Andreas Buness

    Full Text Available Early and accurate pre-clinical and clinical biomarkers of hepatotoxicity facilitate the drug development process and the safety monitoring in clinical studies. We selected eight known model compounds to be administered to male Wistar rats to identify biomarkers of drug induced liver injury (DILI using transcriptomics, metabolite profiling (metabolomics and conventional endpoints. We specifically explored early biomarkers in serum and liver tissue associated with histopathologically evident acute hepatotoxicity. A tailored data analysis strategy was implemented to better differentiate animals with no treatment-related findings in the liver from animals showing evident hepatotoxicity as assessed by histopathological analysis. From the large number of assessed parameters, our data analysis strategy allowed us to identify five metabolites in serum and five in liver tissue, 58 transcripts in liver tissue and seven clinical chemistry markers in serum that were significantly associated with acute hepatotoxicity. The identified markers comprised metabolites such as taurocholic acid and putrescine (measured as sum parameter together with agmatine, classical clinical chemistry markers like AST (aspartate aminotransferase, ALT (alanine aminotransferase, and bilirubin, as well as gene transcripts like Igfbp1 (insulin-like growth factor-binding protein 1 and Egr1 (early growth response protein 1. The response pattern of the identified biomarkers was concordant across all types of parameters and sample matrices. Our results suggest that a combination of several of these biomarkers could significantly improve the robustness and accuracy of an early diagnosis of hepatotoxicity.

  8. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity.

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    Buness, Andreas; Roth, Adrian; Herrmann, Annika; Schmitz, Oliver; Kamp, Hennicke; Busch, Kristina; Suter, Laura

    2014-01-01

    Early and accurate pre-clinical and clinical biomarkers of hepatotoxicity facilitate the drug development process and the safety monitoring in clinical studies. We selected eight known model compounds to be administered to male Wistar rats to identify biomarkers of drug induced liver injury (DILI) using transcriptomics, metabolite profiling (metabolomics) and conventional endpoints. We specifically explored early biomarkers in serum and liver tissue associated with histopathologically evident acute hepatotoxicity. A tailored data analysis strategy was implemented to better differentiate animals with no treatment-related findings in the liver from animals showing evident hepatotoxicity as assessed by histopathological analysis. From the large number of assessed parameters, our data analysis strategy allowed us to identify five metabolites in serum and five in liver tissue, 58 transcripts in liver tissue and seven clinical chemistry markers in serum that were significantly associated with acute hepatotoxicity. The identified markers comprised metabolites such as taurocholic acid and putrescine (measured as sum parameter together with agmatine), classical clinical chemistry markers like AST (aspartate aminotransferase), ALT (alanine aminotransferase), and bilirubin, as well as gene transcripts like Igfbp1 (insulin-like growth factor-binding protein 1) and Egr1 (early growth response protein 1). The response pattern of the identified biomarkers was concordant across all types of parameters and sample matrices. Our results suggest that a combination of several of these biomarkers could significantly improve the robustness and accuracy of an early diagnosis of hepatotoxicity.

  9. Traditional Chinese Medicine (TCM) and Herbal Hepatotoxicity: RUCAM and the Role of Novel Diagnostic Biomarkers Such as MicroRNAs.

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    Teschke, Rolf; Larrey, Dominique; Melchart, Dieter; Danan, Gaby

    2016-07-19

    Background : Traditional Chinese Medicine (TCM) with its focus on herbal use is popular and appreciated worldwide with increased tendency, although its therapeutic efficacy is poorly established for most herbal TCM products. Treatment was perceived as fairly safe but discussions emerged more recently as to whether herb induced liver injury (HILI) from herbal TCM is a major issue; Methods : To analyze clinical and case characteristics of HILI caused by herbal TCM, we undertook a selective literature search in the PubMed database with the search items Traditional Chinese Medicine, TCM, alone and combined with the terms herbal hepatotoxicity or herb induced liver injury; Results : HILI caused by herbal TCM is rare and similarly to drugs can be caused by an unpredictable idiosyncratic or a predictable intrinsic reaction. Clinical features of liver injury from herbal TCM products are variable, and specific diagnostic biomarkers such as microsomal epoxide hydrolase, pyrrole-protein adducts, metabolomics, and microRNAs are available for only a few TCM herbs. The diagnosis is ascertained if alternative causes are validly excluded and causality levels of probable or highly probable are achieved applying the liver specific RUCAM (Roussel Uclaf Causality Assessment Method) as the most commonly used diagnostic tool worldwide. Case evaluation may be confounded by inappropriate or lacking causality assessment, poor herbal product quality, insufficiently documented cases, and failing to exclude alternative causes such as infections by hepatotropic viruses including hepatitis E virus infections; Conclusion : Suspected cases of liver injury from herbal TCM represent major challenges that deserve special clinical and regulatory attention to improve the quality of case evaluations and ascertain patients' safety and benefit.

  10. Traditional Chinese Medicine (TCM and Herbal Hepatotoxicity: RUCAM and the Role of Novel Diagnostic Biomarkers Such as MicroRNAs

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    Rolf Teschke

    2016-07-01

    Full Text Available Background: Traditional Chinese Medicine (TCM with its focus on herbal use is popular and appreciated worldwide with increased tendency, although its therapeutic efficacy is poorly established for most herbal TCM products. Treatment was perceived as fairly safe but discussions emerged more recently as to whether herb induced liver injury (HILI from herbal TCM is a major issue; Methods: To analyze clinical and case characteristics of HILI caused by herbal TCM, we undertook a selective literature search in the PubMed database with the search items Traditional Chinese Medicine, TCM, alone and combined with the terms herbal hepatotoxicity or herb induced liver injury; Results: HILI caused by herbal TCM is rare and similarly to drugs can be caused by an unpredictable idiosyncratic or a predictable intrinsic reaction. Clinical features of liver injury from herbal TCM products are variable, and specific diagnostic biomarkers such as microsomal epoxide hydrolase, pyrrole-protein adducts, metabolomics, and microRNAs are available for only a few TCM herbs. The diagnosis is ascertained if alternative causes are validly excluded and causality levels of probable or highly probable are achieved applying the liver specific RUCAM (Roussel Uclaf Causality Assessment Method as the most commonly used diagnostic tool worldwide. Case evaluation may be confounded by inappropriate or lacking causality assessment, poor herbal product quality, insufficiently documented cases, and failing to exclude alternative causes such as infections by hepatotropic viruses including hepatitis E virus infections; Conclusion: Suspected cases of liver injury from herbal TCM represent major challenges that deserve special clinical and regulatory attention to improve the quality of case evaluations and ascertain patients’ safety and benefit.

  11. Enhancement of acetaminophen overdosage-induced hepatotoxicity ...

    African Journals Online (AJOL)

    paracetamol) overdosage-induced hepatotoxicity in three groups of albino Wistar rats. Administration of the minimum toxic dose of paracetamol (150mg/kg body weight) to animals (group II) produced significantly (P≤0.05) higher levels of alanine ...

  12. Potential protective effect of honey against paracetamol-induced hepatotoxicity.

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    Galal, Reem M; Zaki, Hala F; Seif El-Nasr, Mona M; Agha, Azza M

    2012-11-01

    Paracetamol overdose causes severe hepatotoxicity that leads to liver failure in both humans and experimental animals. The present study investigates the protective effect of honey against paracetamol-induced hepatotoxicity in Wistar albino rats. We have used silymarin as a standard reference hepatoprotective drug. Hepatoprotective activity was assessed by measuring biochemical parameters such as the liver function enzymes, serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST). Equally, comparative effects of honey on oxidative stress biomarkers such as malondialdyhyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx) were also evaluated in the rat liver homogenates.  We estimated the effect of honey on serum levels and hepatic content of interleukin-1beta (IL-1β) because the initial event in paracetamol-induced hepatotoxicity has been shown to be a toxic-metabolic injury that leads to hepatocyte death, activation of the innate immune response and upregulation of inflammatory cytokines. Paracetamol caused marked liver damage as noted by significant increased activities of serum AST and ALT as well as the level of Il-1β. Paracetamol also resulted in a significant decrease in liver GSH content and GPx activity which paralleled an increase in Il-1β and MDA levels. Pretreatment with honey and silymarin prior to the administration of paracetamol significantly prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines. Histopathological evaluation of the livers also revealed that honey reduced the incidence of paracetamol-induced liver lesions. Honey can be used as an effective hepatoprotective agent against paracetamol-induced liver damage.

  13. Ameliorative effect of gallic acid on methotrexate-induced hepatotoxicity and nephrotoxicity in rat

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    Ebenezer Tunde Olayinka

    2016-08-01

    Full Text Available We investigated the protective effect of gallic acid (GA against methotrexate (MTX-induced hepatotoxicity and nephrotoxicity. Male Wistar rats were randomized into five groups (n = 6/group: I, control; II, MTX-treated for seven days; III, pre-treated with GA for seven days, followed by MTX for seven days; IV, co-treated with MTX and GA for seven days and V, GA for seven days. MTX caused a significant increase (P<0.05 in plasma biomarkers of nephrotoxicity (urea, creatinine and hepatotoxicity (Bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase when compared with control. Furthermore, MTX caused a significant decrease in the activities of hepatic enzymic antioxidants (superoxide dismutase, catalase, glutathione S-transferase and nonenzymic antioxidants (Vitamin C and glutathione, followed by a significant increase in hepatic malondialdehyde content. However, pretreatment and co-treatment with gallic acid ameliorated the MTX-induced biochemical changes observed. Taken together, GA protected against MTX-induced hepatotoxicity and nephrotoxicity in rats, by reducing the impact of oxidative damage to tissues.

  14. Thalidomide-induced severe hepatotoxicity.

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    Hanje, A James; Shamp, Jennifer L; Thomas, Fred B; Meis, Greg M

    2006-07-01

    Thalidomide is a relatively safe and efficacious form of therapy in the treatment of advanced, refractory multiple myeloma. Hepatotoxicity is listed as an extremely rare adverse effect associated with its use. We describe a 76-year-old woman with multiple myeloma who was treated with dexamethasone and thalidomide. By week 6 of therapy, she had developed acute increases in her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to more than 50 times the upper limit of normal. Her liver function test results had been within the normal ranges before and immediately after the start of therapy, and the patient had no known history of underlying liver disease. A liver biopsy specimen demonstrated evidence of acute injury with chronic changes of underlying steatosis and bridging fibrosis due to previously undiagnosed nonalcoholic steatohepatitis. Immediately after discontinuing thalidomide, her liver function test results began trending downward. Seven days later, her AST and ALT levels had improved to 86 and 165 U/L, respectively. This case and a limited number of other reports demonstrate severe hepatotoxicity as a rare but potentially serious adverse effect of thalidomide therapy. With the expanding use of thalidomide as a therapeutic agent, clinicians must recognize severe hepatotoxicity as a potential complication. Whether patients with preexisting liver disease are at increased risk when receiving thalidomide remains to be seen.

  15. Curcumin Attenuates Hepatotoxicity Induced by Zinc Oxide Nanoparticles in Rats

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    Layasadat Khorsandi

    2016-06-01

    Full Text Available Background: Zinc oxide nanoparticles (NZnO are increasingly used in modern life. Most metal nanoparticles have adverse effects on the liver. Aims: To explore the protective action of curcumin (Cur against hepatotoxicity induced by NZnO in rats. Study Design: Animal experimentation. Methods: Control group animals received normal saline, while the Cur group animals were treated with 200 mg/kg of Cur orally for 21 days. NZnO-intoxicated rats received 50 mg/kg of NZnO for 14 days by gavage method. In the NZnO+Cur group, rats were pretreated with Cur for 7 days before NZnO administration. Plasma activities of Alanine aminotransferase (ALT, aspartate aminotransferase (AST and alkaline phosphatase (ALP were measured as biomarkers of hepatotoxicity. Hepatic levels of malondialdehyde (MDA and superoxide dismutase (SOD and glutathione peroxidase (GPx activities were measured for detection of oxidative stress in liver tissue. Histological changes and apoptosis in liver tissue were studied by using Hematoxylin-eosin staining and the transferase dUTP nick end labeling (TUNEL method. Results: NZnO induced a significant increase in plasma AST (2.8-fold, ALT (2.7-fold and ALP (1.97-fold activity in comparison to the control group (p<0.01. NZnO increased MDA content and reduced SOD and GPx activities. NZnO caused liver damage including centrilobular necrosis and microvesicular steatosis. The percentage of apoptosis in hepatocytes was increased in NZnO-treated rats (p<0.01. Pre-treatment of Cur significantly reduced lipid peroxidation (39%, increased SOD (156% and GPx (26% activities, and attenuated ALT (47%, AST (41% and ALP (30% activities. Pre-treatment with Cur also decreased the histology changes and apoptotic index of hepatocytes (p<0.05. Conclusion: These findings indicate that Cur effectively protects against NZnO-induced hepatotoxicity in rats. However, future studies are required to propose Cur as a potential protective agent against hepatotoxicity

  16. Stem cell intervention ameliorates epigallocatechin-3-gallate/lipopolysaccharide-induced hepatotoxicity in mice.

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    Saleh, I G; Ali, Z; Hammad, M A; Wilson, F D; Hamada, F M; Abd-Ellah, M F; Walker, L A; Khan, I A; Ashfaq, M K

    2015-11-01

    Stem cells are identified as a novel cell therapy for regenerative medicine because of their ability to differentiate into many functional cell types. We have shown earlier a new model of hepatotoxicity in mice by administering (1500 mg/kg) epigallocatechin-3-gallate (EGCG) intragastric (IG) for 5 days after a single intraperitoneal dose (6 mg/kg) of lipopolysaccharide (LPS). In this study, we aimed to study the effect of intrahepatic (IH) injection of mouse embryonic stem cells (MESCs) on the hepatotoxicity induced by EGCG/LPS in mice. Mice were administered EGCG/LPS and rested for 3 days. MESCs were obtained from American Type Culture Collection and cultured in vitro for 4 days. Stem cells were injected IH. Seven days later, a single dose of LPS (6 mg/kg) followed by daily doses of IG administration of EGCG were re-administered for 5 days. At the end of the experiment, blood samples were collected for analysis of biochemical parameters associated with liver. Results showed that the group of mice that were administered MESCs prior to EGCG/LPS showed lower levels of alanine amino transferase, alkaline phosphatase, and bilirubin, higher albumin/globulin ratio, and less remarkable histopathological lesions. Also, that group of mice showed less expression of oxidative stress biomarkers (oxidized low-density lipoprotein Ox.LDL and chemokine CXCL16), less expression of nuclear protein receptors (retinoic acid receptor and retinoid X receptor), and less expression of inflammatory biomarkers (tumor necrosis factor α and transforming growth factor β1) compared with other groups of mice that were not given MESCs. In conclusion, MESCs can ameliorate EGCG/LPS-induced hepatotoxicity in mice. © The Author(s) 2015.

  17. Diagnostic accuracy of serum alanine aminotransferase as biomarker for nonalcoholic fatty liver disease and insulin resistance in healthy subjects, using 3T MR spectroscopy.

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    Martin-Rodriguez, Jose Luis; Gonzalez-Cantero, Jorge; Gonzalez-Cantero, Alvaro; Arrebola, Juan Pedro; Gonzalez-Calvin, Jorge Luis

    2017-04-01

    Recognition of the close relationship of nonalcoholic fatty liver disease (NAFLD) with diabetes mellitus 2, obesity, metabolic syndrome, and cardiovascular disease has stimulated growing interest in NAFLD as a public health problem. Serum alanine aminotransferase (ALT) has been proposed as a marker of NAFLD, but levels are within the range currently considered "normal" in a large proportion of NAFLD subjects.The aim of the study was to determine the diagnostic accuracy of serum ALT for identifying individuals with NAFLD, using 3-Tesla (T) magnetic resonance spectroscopy (H-MRS).A cross-sectional study was conducted in 129 healthy subjects. Liver triglyceride content was quantified by H-MRS. NAFLD was defined as liver triglyceride content greater than 5.56%.Liver triglyceride content was >5.56% in 79 participants (NAFLD) and lower in the remaining 50 (normal). Serum ALT levels correlated positively with liver triglyceride content (r = 0.58, P liver triglyceride quantification.

  18. Anti-hepatotoxic and synergistic effects of sesame oil with ...

    African Journals Online (AJOL)

    Biomarkers of cartilage degeneration (MMP-3) and synthesis, (IGF-1), inflammatory mediators (TNF-α, IL-6, NO), anti-inflammatory mediators(IL-10) and oxidative stress were estimated. MTX mono-therapy were enhanced hepatotoxicity but concomitant administration with sesame oil was able to ameliorating RA biomarker ...

  19. A lab-on-a-chip system integrating tissue sample preparation and multiplex RT-qPCR for gene expression analysis in point-of-care hepatotoxicity assessment.

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    Lim, Geok Soon; Chang, Joseph S; Lei, Zhang; Wu, Ruige; Wang, Zhiping; Cui, Kemi; Wong, Stephen

    2015-10-21

    A truly practical lab-on-a-chip (LOC) system for point-of-care testing (POCT) hepatotoxicity assessment necessitates the embodiment of full-automation, ease-of-use and "sample-in-answer-out" diagnostic capabilities. To date, the reported microfluidic devices for POCT hepatotoxicity assessment remain rudimentary as they largely embody only semi-quantitative or single sample/gene detection capabilities. In this paper, we describe, for the first time, an integrated LOC system that is somewhat close to a practical POCT hepatotoxicity assessment device - it embodies both tissue sample preparation and multiplex real-time RT-PCR. It features semi-automation, is relatively easy to use, and has "sample-in-answer-out" capabilities for multiplex gene expression analysis. Our tissue sample preparation module incorporating both a microhomogenizer and surface-treated paramagnetic microbeads yielded high purity mRNA extracts, considerably better than manual means of extraction. A primer preloading surface treatment procedure and the single-loading inlet on our multiplex real-time RT-PCR module simplify off-chip handling procedures for ease-of-use. To demonstrate the efficacy of our LOC system for POCT hepatotoxicity assessment, we perform a preclinical animal study with the administration of cyclophosphamide, followed by gene expression analysis of two critical protein biomarkers for liver function tests, aspartate transaminase (AST) and alanine transaminase (ALT). Our experimental results depict normalized fold changes of 1.62 and 1.31 for AST and ALT, respectively, illustrating up-regulations in their expression levels and hence validating their selection as critical genes of interest. In short, we illustrate the feasibility of multiplex gene expression analysis in an integrated LOC system as a viable POCT means for hepatotoxicity assessment.

  20. Cannabidiol Treatment Ameliorates Acetaminophen-Induced Hepatotoxicity in Mice

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    Amr A. Fouad; Waleed H. Albuali; Iyad Jresat

    2013-01-01

    The possible therapeutic effect of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated against acute hepatotoxicity induced by a single oral dose of acetaminophen (500mg/kg) in mice. Cannabidiol (two intraperitoneal injections, 5mg/kg, each) was given 1 hour and 12 hours following acetaminophen administration. Acetaminophen administration caused significant elevations of serum alanine aminotransferase, and hepatic malondialdehyde, and nitric oxide levels, and a sign...

  1. Alanine transaminase (ALT) blood test

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    ... gov/ency/article/003473.htm Alanine transaminase (ALT) blood test To use the sharing features on this page, please enable JavaScript. The alanine transaminase (ALT) blood test measures the level of the enzyme ALT in ...

  2. Hepatotoxicity of botanicals.

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    Stickel, F; Egerer, G; Seitz, H K

    2000-06-01

    Hepatic impairment resulting from the use of conventional drugs is widely acknowledged, but there is less awareness of the potential hepatotoxicity of herbal preparations and other botanicals, many of which are believed to be harmless and are commonly used for self-medication without supervision. The aim of this paper is to examine the evidence for hepatotoxicity of botanicals and draw conclusions regarding their pathology, safety and applications. Current literature on the hepatotoxicity of herbal drugs and other botanicals is reviewed. The aetiology, clinical picture and treatment of mushroom (Amanita) poisoning are described. Hepatotoxic effects have been reported for some Chinese herbal medicines (such as Jin Bu Huan, Ma-Huang and Sho-saiko-to), pyrrolizidine alkaloid-containing plants, germander (Teucrium chamaedrys), chaparral (Larrea tridentata), Atractylis gummifera, Callilepsis laureola, and others. The frequency with which botanicals cause hepatic damage is unclear. There is a lack of controlled treatment trials and the few studies published to date do not clarify the incidence of adverse effects. Many plant products do not seem to lead to toxic effects in everyone taking them, and they commonly lack a strict dose-dependency. For some products, such as Sho-saiko-to, the picture is confused further by demonstrations of hepatoprotective properties for some components. Mushroom poisoning is mostly due to the accidental consumption of Amanita species. Treatment with silymarin, thioctic acid, penicillin and liver transplantation have been shown to be effective but require early diagnosis. Severe liver injury, including acute and chronic abnormalities and even cirrhotic transformation and liver failure, has been described after the ingestion of a wide range of herbal products and other botanical ingredients, such as mushrooms. It is concluded that in certain situations herbal products may be just as harmful as conventional drugs.

  3. Effect of methylxanthines on acetaminophen hepatotoxicity in various induction states.

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    Kalhorn, T F; Lee, C A; Slattery, J T; Nelson, S D

    1990-01-01

    The effect of caffeine, theophylline and theobromine on acetaminophen-induced hepatotoxicity was evaluated in uninduced, 3-methylcholanthrene- and phenobarbital-induced adult male Sprague-Dawley rats. The methylxanthines themselves did not cause hepatotoxicity in any induction state. In 3-methylcholanthrene-induced rats, each methylxanthine afforded protection (in varying degrees) against acetaminophen-induced hepatotoxicity as reflected by serum alanine aminotransferase and liver histopathology determined 24 hr after acetaminophen administration. However, in phenobarbital-induced rats, caffeine and theophylline substantially potentiated the hepatotoxicity of acetaminophen whereas theobromine had no effect. Hepatic glutathione (GSH) was determined in rats that received caffeine 4 hr after acetaminophen or vehicle. Acetaminophen alone substantially depleted hepatic GSH in each induction state, whereas caffeine depleted hepatic GSH in uninduced and phenobarbital-induced, but not in 3-methylcholanthrene-induced rats. In rats that received both caffeine and acetaminophen together, hepatic GSH depletion was greater than in rats that received acetaminophen only. The effect of caffeine on hepatic GSH is most likely due to a decrease in core body temperature. The most likely mechanisms for the effects observed are 1) inhibition of acetaminophen reactive metabolite formation in 3-methylcholanthrene-induced animals by each of the methylxanthines, and 2) activation of the phenobarbital-inducible forms of cytochrome(s) P-450 toward formation of acetaminophen reactive metabolites by caffeine and theophylline, but not theobromine.

  4. Protective effect of artichoke leaf extract against paracetamol-induced hepatotoxicity in rats.

    Science.gov (United States)

    El Morsy, Engy M; Kamel, Rehab

    2015-02-01

    Paracetamol overdose is a predominant cause of hepatotoxicity in both humans and experimental animals. In this study, we investigated the protective effect of aqueous artichoke leaf extract (ALE) against paracetamol-induced liver injury in rats using N-acetylcysteine (NAC) as a reference drug. Rats were divided into five groups: negative control, paracetamol (2 g/kg, single oral dose), ALE (1.5 g/kg, orally for 14 d), ALE + paracetamol, and NAC (100 mg/kg) + paracetamol. Indices of liver damage (serum alanine aminotransferase and aspartate aminotransferase) were measured. Liver homogenates were analyzed for oxidative stress biomarkers (MDA, malondialdehyde; SOD activity, superoxide dismutase activity; NO, nitric oxide; GSH content, reduced glutathione), glutathione cycling (GR, glutathione reductase), and utilization (GST, glutathione-S-transferase). Apoptosis was assessed using the comet assay. Paracetamol caused marked liver damage as noted by significant increased activities of serum aminotransferases (p hepatic MDA and NO levels (p hepatic GSH, reversed oxidative stress parameters, DNA damage, and necrosis induced by paracetamol. These results suggest that ALE may protect from paracetamol-induced liver toxicity via its antioxidant and anti-apoptotic properties.

  5. The Possible Efficacy of Artichoke in Fluconazole Related Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Hüseyin Kurt

    2014-01-01

    Full Text Available Although fluconazole related hepatotoxicity (FRH is rare, mortal acute hepatic necrosis and jaundice were reported in immunocompromised states such as acquired immunodeficiency syndrome (AIDS and bone marrow transplant (BMT. We present a case of a patient with multiple sclerosis who developed hepatotoxicity with the use of a single 150 mg fluconazole tablet for fungal vaginitis, 10 days after methylprednisolone pulse treatment. Our patient’s alanine aminotransferase (ALT and aspartate aminotransferase (AST levels were decreased, 1200 U/L and 800 U/L, respectively, and bilirubin levels were consistent at 37 mg/dL. Artichoke which has anticholestatic and antioxidant properties was used by our patient. She consumed a 30 mg artichoke leaf extract tea 3 times a day. The bilirubin levels significantly declined at the end of the first week and all liver function tests were normalized within 2 months.

  6. Hepatotoxicity of amiodarone

    DEFF Research Database (Denmark)

    Rumessen, J J

    1986-01-01

    Amiodarone has proved very effective in the treatment of otherwise resistant cardiac tachyarrhythmias. The use of amiodarone has, however, been limited due to its serious side-effects. A patient with cholestatic hepatitis due to amiodarone treatment is presented below and a review...... of the hepatotoxicity of amiodarone is given. It is concluded that solid evidence exists of hepatic injury due to amiodarone treatment, including steatosis, alterations resembling alcoholic hepatitis, cholestatic hepatitis and micronodular cirrhosis of the liver. Patients receiving amiodarone should be regularly...

  7. Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model.

    Science.gov (United States)

    Shimizu, Shinji; Atsumi, Ryo; Nakazawa, Tsunenori; Izumi, Takashi; Sudo, Kenichi; Okazaki, Osamu; Saji, Hideo

    2011-04-01

    We investigated hepatotoxicity induced by ticlopidine (TIC) in glutathione (GSH)-depleted rats by pre-treatment of a well-known GSH synthesis inhibitor, L-buthionine-S,R-sulfoxinine (BSO). Although sole administration of either TIC or BSO showed no signs of hepatotoxicity, combined administration of TIC with BSO induced hepatotoxicity, which was characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Administration of radio-labeled TIC in combination with BSO resulted in significantly higher covalent binding to rat liver proteins than that observed after sole dosing of radio-labeled TIC. Pre-treatment of 1-aminobenzotriazole, a non-specific inhibitor of P450s, completely suppressed both hepatotoxicity and the increased hepatic covalent binding caused by TIC co-treatment with BSO. The results obtained in this animal model suggest that GSH depletion and covalent binding may be involved in hepatotoxicity induced by TIC. These observations may help to understand the risk factors and the mechanism of hepatotoxicity of TIC in humans.

  8. Possible hepatotoxicity of chronic marijuana usage

    Directory of Open Access Journals (Sweden)

    Paulo Borini

    Full Text Available CONTEXT: Hepatotoxicity is a potential complication from the usage of various illicit drugs, possibly consequent to their liver metabolism, but information on this is scarce in the medical literature. OBJECTIVE: To study the occurrence of clinical and laboratory hepatic alterations in chronic marijuana users, from the use of marijuana on its own or in association with other legal or illicit drugs. TYPE OF STUDY: transversal study SETTING: Hospital Espírita de Marília, Marília, São Paulo, Brazil PARTICIPANTS: The study was made among 123 patients interned in the Hospital Espírita de Marília from October 1996 to December 1998, divided into 3 groups: 26 (21% using only marijuana, 83 (67.5% using marijuana and crack, and 14 (11.4% consuming marijuana and alcohol. PROCEDURES AND MAIN MEASUREMENTS: Patients were examined clinically with special emphasis on types of drugs used, drug intake route, age when consumption began, length and pattern of usage, presence of tattooing, jaundice, hepatomegaly and splenomegaly. Serum determinations of total proteins, albumin, globulin, total and fractions of bilirubin, aspartate (AST and alanine (ALT aminotransferases, alkaline phosphatase (AP, gamma-glutamyltransferase and prothrombin activity were performed. RESULTS: Among users of only marijuana, hepatomegaly was observed in 57.7% and splenomegaly in 73.1%, and slightly elevated AST (42.3%, ALT (34.6% and AP (53.8%. The three groups did not differ significantly in the prevalence of hepatomegaly, splenomegaly and hepatosplenomegaly. The group using both marijuana and alcohol showed the highest prevalence of alterations and highest levels of aminotransferases. Mean AP levels were above normal in all groups. CONCLUSIONS: Chronic marijuana usage, on its own or in association with other drugs, was associated with hepatic morphologic and enzymatic alterations. This indicates that cannabinoids are possible hepatotoxic substances.

  9. Systems toxicology used in nanotoxicology: mechanistic insights into the hepatotoxicity of nano-copper particles from toxicogenomics.

    Science.gov (United States)

    Yang, BaoHua; Wang, Quanjun; Lei, RongHui; Wu, ChunQi; Shi, Chang; Wang, QingXiu; Yuan, Ye; Wang, Ying; Luo, YongWei; Hu, ZhongHui; Ma, Huazhi; Liao, MingYang

    2010-12-01

    In some studies, nano-copper particles have been found to be acutely toxic to exposed mice, with the liver and kidney being the target tissues. However, the characteristics of subacute toxicity from repeated nano-copper exposure in rats and the molecular mechanism of its hepatotoxicity at the genomic level remain unclear. We investigated the mechanisms of nano-copper-induced hepatotoxicity, which were identified from hepatic gene expression profiles that were phenotypically anchored to conventional toxicological outcomes, and identified biomarkers of nanotoxicity caused by nano-copper. Male Wistar rats were administered nano-copper or micro-copper at different doses for five days. Subsequently, we examined conventional toxicological parameters including body weight, clinical chemistry, and histopathology, and also used microarrays to identify gene expression changes in rat liver. High dose nano-copper induced increases in alanine aminotransferase, aspartate aminotransferase, triglyceride, total bilirubin, total bile acid levels, and a decrease in body weight. Histopathological studies of the liver indicated scattered, dotted hepatocytic necrosis in all rats in the high dose nano-copper group. Identified genes from the group receiving the high dose were functionally categorized, and results showed that genes related to oxidoreductase activity, metabolism, and signal transduction were involved in the development of the observed phenotypes. The results also suggest that altered gene expression patterns induced by exposure to a low, subtoxic dose of nano-copper may reveal signs of cell stress or subtle cell injury indicative of overt toxicity at higher doses. Results in this study provide new insights into the toxicology of nano-copper particles and illustrate how toxicogenomic approaches are providing an unprecedented amount of mechanistic information on molecular responses to nano-copper, as well as how they are likely to impact hazard and risk assessment. Gene

  10. Relationship of hepatotoxicity and the target tissue dose of decabrominated diphenyl ether in subacutely exposed Wistar rats

    Directory of Open Access Journals (Sweden)

    Ćurčić Marijana

    2015-01-01

    Full Text Available Background/Aim. Based on numerous studies in animals, the most prominent toxic effects of decabrominated diphenyl ether (BDE-209 are observed in the liver, thyroid hormone homeostasis, reproductive and nervous systems. BDE-209 exhibits its toxic effects partly through the aryl hydrocarbon (Ah receptor and consequent induction of hepatic microsomal enzymes. The aim of this study was to assess the hepatotoxic effect vs target tissue dose of BDE-209 in the subacutely orally exposed Wistar rats. Methods. Effects were examined on male Wistar rats, weighing 200-240 g, exposed to doses of 1,000, 2,000 or 4,000 mg BDE-209/kg body weight (bw/day by gavage during 28 days. Animals were treated according to the decision of the Ethics Committee of the Military Medical Academy, No 9667-1/2011. Evaluation of the hepatotoxic effect was based on: relative liver weight water and food intake, biochemical parameters of liver function [aspartate amino transferase (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP, gama glutamyl transferase (γ-GT], and oxidative stress parameters in liver homogenates [malondialdehiyde (MDA, superoxide dismutase (SOD, -SH] and morphological and pathohistological changes in the liver. For the assessment of internal dose - response relationship, lower confidence limit of Benchmark dose (BMDL of 5% or 10% i.e. BMDL5 or BMDL10, were calculated using PROAST software. Results. After the application of 1,000, 2,000 or 4,000 mg BDE-209/kg bw/day, the concentrations of BDE-209 measured in liver were 0.269, 0.569 and 0.859 mg/kg of liver wet weight, (ww respectively. Internal doses correlated with external (r = 0.972; p < 0.05 according to equation: internal dose (mg BDE-209/kg of liver ww = 0.0002 x external dose (mg/kg bw/day + 0.0622. Hepato-toxicity was demonstrated based on significant increase in AST and γ-GT activities and the degree of histopathological changes. The lowest BMDL5 of 0.07228 mg BDE-209/kg of liver ww

  11. Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests.

    Science.gov (United States)

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel

    2013-07-27

    To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables included low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Shortcomings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis E virus infection was considered in one single patient and found positive, infections by herpes simplex virus and varicella zoster virus were excluded in none. Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed.

  12. [Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy].

    Science.gov (United States)

    Iveli, Pablo; Noguera-Julian, Antoni; Soler-Palacín, Pere; Martín-Nalda, Andrea; Rovira-Girabal, Núria; Fortuny-Guasch, Clàudia; Figueras-Nadal, Concepció

    2016-01-01

    The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585). The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  13. Hepatotoxicity associated with the use of Herbalife

    National Research Council Canada - National Science Library

    Jóhannsson, Magnús; Ormarsdóttir, Sif; Olafsson, Sigurdur

    2010-01-01

    Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity...

  14. Chaparral-associated hepatotoxicity.

    Science.gov (United States)

    Sheikh, N M; Philen, R M; Love, L A

    1997-04-28

    Personal health care practices that may include the use of dietary supplements are common in the United States. Products marketed as dietary supplements are diverse and may include botanicals, vitamins, and/or minerals. Chaparral (Larrea tridentata) is a botanical dietary supplement made from a desert shrub and used for its antioxidant properties. Several reports of chaparral-associated hepatitis have been published since 1990, but a complete picture of the clinical presentation is still unclear. We reviewed the 18 case reports of adverse events associated with the ingestion of chaparral reported to the Food and Drug Administration between 1992 and 1994. These reports were from health care professionals, state health departments, and individual consumers. Of 18 reports of illnesses associated with the ingestion of chaparral, there was evidence of hepatotoxicity in 13 cases. Clinical presentation, characterized as jaundice with a marked increase in serum liver chemistry values, occurred 3 to 52 weeks after the ingestion of chaparral, and it resolved 1 to 17 weeks after most individuals stopped their intake of chaparral. The predominant pattern of liver injury was characterized as toxic or drug-induced cholestatic hepatitis; in 4 individuals, there was progression to cirrhosis; and in 2 individuals, there was acute fulminant liver failure that required liver transplants. These data indicate that the use of chaparral may be associated with acute to chronic irreversible liver damage with fulminant hepatic failure, and they underscore the potential for certain dietary supplement ingredients to cause toxic effects on the liver. Health professionals should be encouraged to inquire routinely about the use of dietary supplements and other products, to be alert to potential adverse effects that may be associated with these products, and, finally, to report any serious adverse events associated with these products through the MEDWatch Program of the Food and Drug

  15. Relationship of fetal alanine uptake and placental alanine metabolism to maternal plasma alanine concentration

    NARCIS (Netherlands)

    M. Timmerman (Michelle); M. Chung; R.B. Wilkening; P.V. Fennessey (Paul); F.C. Battaglia (Frederick); G. Meschia

    1998-01-01

    textabstractUterine and umbilical uptakes of alanine (Ala) were measured in 10 ewes before (control) and during intravenous infusion of Ala, which increased maternal arterial Ala concentration from 115 +/- 14 to 629 +/- 78 microM (P < 0.001). In 8 of these ewes,

  16. [The idiosyncratic hepatotoxicity of Polygonum multiflorum based on endotoxin model].

    Science.gov (United States)

    Li, Chun-yu; Li, Xiao-fei; Tu, Can; Li, Na; Ma, Zhi-jie; Pang, Jing-yao; Jia, Ge-liu-chang; Cui, He-rong; You, Yun; Song, Hai-bo; Du, Xiao-xi; Zhao, Yan-ling; Wang, Jia-bo; Xiao, Xiao-he

    2015-01-01

    The liver injury induced by Polygonum multiflorum Thunb. (PM) was investigated based on idiosyncratic hepatotoxicity model co-treated with lipopolysaccharide (LPS) at a non-hepatotoxic dose. Sprague-Dawley (SD) rats were intragastrically administered with three doses (18.9, 37.8, 75.6 g crude drug per kg body weight) of 50% alcohol extracts of PM alone or co-treated with non-toxic dose of LPS (2.8 mg·kg(-1)) via tail vein injection. The plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were assayed and the isolated livers were evaluated for histopathological changes. The dose-toxicity relationships of single treatment of PM or co-treatment of LPS were investigated comparatively to elucidate the idiosyncratic hepatotoxicity of PM. The results showed that no significant alterations of plasma ALT and AST activities were observed in the groups of solo-administration of LPS (2.8 mg·kg(-1), i.v.) or different dosage (18.9, 37.8 and 75.6 g·kg(-1), i.g.) of PM, compared to normal control group (P > 0.05); while significant elevations were observed in the co-administration groups of PM and LPS. Treatment with LPS alone caused slight infiltration of inflammatory cells in portal area but no evident hepatocytes injury. Co-treatment with LPS and PM (75.6 g·kg(-1), i.g.) caused hepatocyte focal necrosis, loss of central vein intima and a large number of inflammatory cell infiltration in portal areas. When further reduce the dosage of PM, significant increases of plasma ALT and AST activities (P < 0.05) were still observed in co-administration groups of LPS and PM (1.08 or 2.16 g·kg(-1)), but not in LPS or PM solo-administration groups. Nevertheless, the co-treatment of low dosage of PM (0.54 g·kg(-1)) with LPS did not induce any alteration of plasma ALT and AST. In conclusion, intragastric administration with 75.6 g·kg(-1) of PM did not induce liver injury in normal rats model; while the 2 folds of clinical equivalent dose of PM (1.08 g

  17. Pattern recognition analysis for hepatotoxicity induced by acetaminophen using plasma and urinary 1H NMR-based metabolomics in humans.

    Science.gov (United States)

    Kim, Ji Won; Ryu, Sung Ha; Kim, Siwon; Lee, Hae Won; Lim, Mi-sun; Seong, Sook Jin; Kim, Suhkmann; Yoon, Young-Ran; Kim, Kyu-Bong

    2013-12-03

    Drug-induced liver injury (DILI) is currently an increasingly relevant health issue. However, available biomarkers do not reliably detect or quantify DILI risk. Therefore, the purpose of this study was to comparatively evaluate plasma and urinary biomarkers obtained from humans treated with acetaminophen (APAP) using a metabolomics approach and a proton nuclear magnetic resonance (NMR) platform. APAP (3 g/day, two 500 mg tablets every 8 h) was administered to 20 healthy Korean males (age, 20-29 years) for 7 days. Urine was collected daily before and during dosing and 6 days after the final dose. NMR spectra of these urine samples were analyzed using principal component analysis (PCA) and partial least-squares-discrimination analysis. Although the activities of aspartate aminotransferase and lactate dehydrogenase were significantly increased 7 days post-APAP treatment, serum biochemical parameters of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, γ-glutamyl transpeptidase, and lactate dehydrogenase were within normal range of hepatic function. However, urine and plasma (1)H NMR spectroscopy revealed different clustering between predosing and after APAP treatment for global metabolomic profiling through PCA. Urinary endogenous metabolites of trimethylamine-N-oxide, citrate, 3-chlorotyrosine, phenylalanine, glycine, hippurate, and glutarate as well as plasma endogenous metabolites such as lactate, glucose, 3-hydroxyisovalerate, isoleucine, acetylglycine, acetone, acetate, glutamine, ethanol, and isobutyrate responded significantly to APAP dosing in humans. Urinary and plasma endogenous metabolites were more sensitive than serum biochemical parameters. These results might be applied to predict or screen potential hepatotoxicity caused by other drugs using urinary and plasma (1)H NMR analyses.

  18. Hepatoprotective effect of ethanolic extract of Crocus sativus L. (Saffron stigma in comparison with silymarin against rifampin induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Daryoush Mohajeri

    2011-01-01

    Full Text Available Background: Anti-tuberculous drug Rifampin is a potent hepatotoxicant. The aim of the present study was to evaluate the protective effect of ethanolic extract of Crocus sativus L. stigma (EECSL.S in comparison with standard drug silimarin against rifampin-induced hepatotoxicity in the rats. Materials and Method: 40 male Wistar rats with the mean body weight of 200±20 gr and age of 10 weeks were randomly assigned into 5 groups of 8 animals and kept in specific cages with 12/12 h light/dark cycle at 21±2οC. Group I as normal control received normal saline (10 ml/kg and group II as toxicant control received rifampin (500 mg/kg. Group Ш as positive control received silymarin plus rifampin (500 mg/kg and groups IV and V (50 mg/kg received EECSL.S at 40 mg/kg and 80 mg/kg plus rifampin, respectively. All the treatments were carried out through the gavage dissolving in 10 ml/kg normal saline daily for 1 month. At the end of experiment, levels of liver function marker enzymes (Aspartate aminotransferase, Alanine aminotransferase and Alkaline Phosphatase, total bilirubin, albumin and total proteins were assessed in serum of the rats. Moreover, histopathological observation was assayed at the degree of hepatic injury. Results: In rifampin-treated rats, silymarin and EECSL.S (40 and 80 mg/kg significantly decreased the levels of serum biomarker of hepathic injury and total bilirubin and elevated the levels of albumin and total proteins. Histopathologically, silymarin and EECSL.S ameliorated rifampin induced hepatic injury. Histopathological changes were in agreement with biochemical findings.Conclusion: Results indicated that EECSL.S (80 mg/kg equals with silymarin as standard drug, point of view hepatoprotective effects against rifampin-induced hepatotoxicity

  19. Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose.

    Science.gov (United States)

    Wong, Anselm; Sivilotti, Marco L A; Graudins, Andis

    2017-06-01

    The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity. In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500 mg/L × IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the

  20. Biochemical effects of Calotropis procera on hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Ali Ismaiel Ali Abd Alrheam

    2015-12-01

    Full Text Available Introduction: Calotropis procera commonly known as Sodom apple is a 6-meter high shrub that belongs to the Aclepiadaceae plant family and is commonly found in West Africa and other tropical places. In Saudi Arabia the plant is commonly used in traditional medicine for the treatment of variety of diseases including fever, constipation, muscular spasm and joint pain. Aim: In the present study C. procera were investigated for the hepatoprotective activity. Material and Methods: Carbon tetrachloride is used to produce hepatotoxicity. Forty two male albino rats, weighting 150-200 gm divided into seven groups, each consisted of 6 rats. Carbon tetrachloride 2ml/kg was administered twice a week to all of the groups of animals except group I, which served as control and given the normal saline. Group II served as Carbon tetrachloirde control. Group III received Silymarin at 100 mg/kg/day dose, Group IV received aqueous leaves extracts C. procera 200mg/kg, Group V received chloroform leaves extracts C. procera 200mg/kg, Group VI received ethanol leaves extracts C. procera 200 mg/kg, Group VII received latex of C. procera 200mg/kg. The effect of aqueous, chloroform, ethanol leaves extract and latex C. procera on biochemical parameters of liver was measured. Results: The results showed that the aqueous, chloroform, ethanol leaves extract and latex C. procera produced significant decrease in Acid phosphatase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Total protein, Albumin and total bilirubin levels compared to the CCL4 treated group II. Conclusion: Calotropis procera appears to to have hepatoprotective activity and these may be due to enrich of the plant by phytoconstituents that activate and in hence a pharmacological response of different parts of the body and this study need further studies to shows the complete properties of the plant. [Biomed Res Ther 2015; 2(12.000: 446-453

  1. Protective effect of chitosan treatment against acetaminophen-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Eda Ozcelik

    2014-06-01

    Full Text Available Acetaminophen (APAP is the most commonly reported toxic ingestion in the world. Severe liver injury resulting from overdose or chronic use of APAP remains a significant clinical problem. In recent years, the mechanisms underlying liver injury caused by APAP have become much better understood. We have studied the protective effect of chitosan supplementation against APAP-induced hepatotoxicity with respect to changes in the levels of total and lipid-bound sialic acid in the serum and in the liver tissue and changes in the activity of diagnostic marker enzymes, lipid peroxidation, and ceruloplasmin oxidase enzyme in normal and experimental groups of rats. During the experimental period, chitosan (200 mg/kg body weight per day was administered to APAP + chitosan-treated rats by oral gavage. Results showed that treatment with APAP induced a significant increase in the serum alanine aminotransferase and alkaline phosphatase activities, in total and lipid-bound sialic acids levels, and in the liver lipid peroxide content. The administration of chitosan significantly prevented APAP-induced alterations in the levels of diagnostic marker enzymes, total sialic acid, lipid-bound sialic acid, and malondialdehyde in the experimental groups of rats. Furthermore, chitosan administration increased the activity of ceruloplasmin oxidase. In conclusion, our results suggest that chitosan has a protective effect on APAP-induced hepatic injury in rats. The study sheds light on the therapeutic potential of chitosan in an APAP-induced hepatotoxicity model.

  2. Methoxyflurane enhances allyl alcohol hepatotoxicity in rats. Possible involvement of increased acrolein formation.

    Science.gov (United States)

    Kershaw, W C; Barsotti, D A; Leonard, T B; Dent, J G; Lage, G L

    1989-01-01

    The effect of methoxyflurane anesthesia on allyl alcohol-induced hepatotoxicity and the metabolism of allyl alcohol was studied in male rats. Hepatotoxicity was assessed by the measurement of serum alanine aminotransferase activity and histopathological examination. Allyl alcohol-induced hepatotoxicity was enhanced when allyl alcohol (32 mg/kg) was administered 4 hr before or up to 8 days after a single 10-min exposure to methoxyflurane vapors. The possibility that methoxyflurane increases alcohol dehydrogenase-dependent oxidation of allyl alcohol to acrolein, the proposed toxic metabolite, was evaluated by measuring the rate of acrolein formation in the presence of allyl alcohol and liver cytosol. The effect of methoxyflurane on alcohol dehydrogenase activity in liver cytosol was also assessed by measuring the rate of NAD+ utilization in the presence of ethyl alcohol or allyl alcohol. Alcohol dehydrogenase activity and rate of acrolein formation were elevated in methoxyflurane-pretreated rats. The results suggest that a modest increase in alcohol dehydrogenase activity and rate of acrolein formation markedly enhances allyl alcohol-induced hepatotoxicity.

  3. Low body surface area predicts hepatotoxicity of nintedanib in patients with idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Ikeda, Satoshi; Sekine, Akimasa; Baba, Tomohisa; Yamanaka, Yumie; Sadoyama, Shinko; Yamakawa, Hideaki; Oda, Tsuneyuki; Okuda, Ryo; Kitamura, Hideya; Okudela, Koji; Iwasawa, Tae; Ohashi, Kenichi; Takemura, Tamiko; Ogura, Takashi

    2017-09-07

    After the commercialization of nintedanib in Japan, a high incidence of hepatotoxicity resulting in treatment interruption was noted in idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib in our hospital. This study aimed to clarify the risk factors for hepatotoxicity of nintedanib. Sixty-eight consecutive cases of IPF newly treated with nintedanib at a dose of 150 mg twice daily from September 2015 to September 2016 were enrolled: 46 patients (67.6%) exhibited aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) elevation and 16 patients (23.5%) also had a Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2. Body surface area (BSA) was significantly lower in the CTCAE grade ≥2 group than in another group. A multivariate logistic regression analysis showed that the association between BSA and AST/ALT elevation with CTCAE grade ≥2 was statistically significant. Eight of 10 patients who resumed nintedanib at a reduced dose of 100 mg twice daily after interruption due to hepatotoxicity did not again develop AST/ALT elevation. In conclusion, a low BSA was associated with hepatotoxicity of nintedanib at a dose of 150 mg twice daily. It would be a good option for patients with a small physique to start nintedanib at a dose of 100 mg twice daily and then increase if possible after confirming its safety.

  4. Protective role of food supplement Spirulina fusiformis in chemical induced hepatotoxicity: A Bromobenzene model in rats

    Directory of Open Access Journals (Sweden)

    Evan Prince Sabina

    2014-03-01

    Full Text Available The present study evaluated the efficacy of Spirulina fusiformis in protecting against chemical induced hepatotoxicity in rats using Bromobenzene as the candidate toxin. A single oral dose of bromobenzene (BB (10mmol/kg b.w. resulted in significant (p< 0.05 decrease in antioxidant levels (catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidese, total reduced glutathione and total protein, and significant (p< 0.05 increase in the levels of serum bilirubin, liver enzymes (alanine transaminase, aspartate transaminase and alkaline phosphatase indicating the induction of hepatotoxicity. Spirulina fusiformis (400 mg/kg b.w was orally administered for 8 days prior to the administration of BB and was seen to protect the above parameters from significant changes upon challenge with bromobenzene. This was also confirmed by the histological examination of liver tissues after sacrifice. The protective effect of Spirulina fusiformis was comparable to that of the standard hepatoprotective drug sylimarin.

  5. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.

  6. Vibrational dynamics of crystalline L-alanine

    Energy Technology Data Exchange (ETDEWEB)

    Bordallo, H.N.; Eckert, J. [Los Alamos National Lab., NM (United States); Barthes, M. [Univ. Montpellier II (France)

    1997-11-01

    The authors report a new, complete vibrational analysis of L-alanine and L-alanine-d{sub 4} which utilizes IINS intensities in addition to frequency information. The use of both isotopomers resulted in a self-consistent force field for and assignment of the molecular vibrations in L-alanine. Some details of the calculation as well as a comparison of calculated and observed IINS spectra are presented. The study clarifies a number of important issues on the vibrational dynamics of this molecule and presents a self-consistent force field for the molecular vibrations in crystalline L-alanine.

  7. Isoniazid-induced hepatotoxicity in children with latent tuberculosis infection.

    Science.gov (United States)

    Devrim, I; Devrim, F; Aktürk, H; Kara, A; Bayram, N; Can, D; Apa, H

    2015-09-17

    We aimed to determine overall incidence of severe and mild isoniazid (INH) hepatotoxicity and outcome of hepatotoxicity in children who were receiving INH for latent tuberculosis. Patients who had received isoniazid for treatment of latent tuberculosis were included in the study. Hepatotoxicity was classified according to the World Health Organization Toxicity Classification Standards. Among 1038 patients, overall hepatotoxicity was observed in 23 patients (2.2 %), while 5 patients (0.48 %) had moderate - severe hepatotoxicity; while other 18 patients had grade I - II hepatotoxicity (1.73%). Age and gender did not appear to be risk factors for hepatotoxicity. The median time for therapy rechallenge in patients with grade III - IV hepatotoxicity was 21 days (ranging from 14 to 25 days). Isoniazid hepatotoxicity is lower and generally reversible after cessation of INH in children. The grade of hepatotoxicity affects the duration for recovery of hepatotoxicity and restarting of INH therapy.

  8. GC-MS analysis and hepatoprotective activity of the n-hexane extract of Acrocarpus fraxinifolius leaves against paracetamol-induced hepatotoxicity in male albino rats.

    Science.gov (United States)

    Abd El-Ghffar, Eman A; El-Nashar, Heba A S; Eldahshan, Omayma A; Singab, Abdel Nasser B

    2017-12-01

    In Egypt, the burden of liver diseases is exceptionally high. To investigate the components of the n-hexane extract of Acrocarpus fraxinifolius Arn. (Leguminosae) and its hepatoprotective activity against paracetamol (APAP)-induced hepatotoxicity in rats. TRACE GC ultra gas chromatogaphic spectrometry was used for extract analysis. Thirty albino rats were divided into six groups (five rats in each). Group 1 was the healthy control; Groups 2 and 3 were healthy treated groups (250 and 500 mg/kg b.w. of the extract, respectively) for seven days. Group 4 was hepatotoxicity control (APAP intoxicated group). Groups 5 and 6 received APAP + extract 250 and APAP + extract 500, respectively. Chromatographic analysis revealed the presence of 36 components. Major compounds were α-tocopherol (18.23%), labda-8 (20)-13-dien-15-oic acid (13.15%), lupeol (11.93%), phytol (10.95%) and squalene (7.19%). In the acute oral toxicity study, the mortality rates and behavioural signs of toxicity were zero in all groups (doses from 0 to 5 g/kg b.w. of A. fraxinifolius). LD50 was found to be greater than 5 g/kg of the extract. Only the high dose (500 mg/kg b.w.) of extract significantly alleviated the liver relative weight (4.01 ± 0.06) and biomarkers, as serum aspartate aminotransferase (62.87 ± 1.41), alanine aminotransferase (46.74 ± 1.45), alkaline phosphatase (65.96 ± 0.74), lipid profiles (180.39 ± 3.51), bilirubin profiles (2.30 ± 0.06) and hepatic lipid peroxidation (114.20 ± 2.06), and increased body weight (11.58 ± 0.20), serum protein profile (11.09 ± 0.46) and hepatic total antioxidant capacity (23.78 ± 0.66) in APAP-induced hepatotoxicity in rats. Our study proves the antihepatotoxic/antioxidant efficacies of A. fraxinifolius hexane extract.

  9. ALANINE - VALINE DYNAMICS IN PREGNANT RABBITS

    African Journals Online (AJOL)

    USER

    [15N]-alanine and [15N]–valine dynamics were studied in 29 -30 days pregnant New-Zealand rabbits. Over the experimental period, there was no detectable significant difference of mean ± SD of alanine concentrations within the sampling intervals in maternal, umbilical venous and arterial blood samples suggesting that ...

  10. Review article: herbal and dietary supplement hepatotoxicity.

    Science.gov (United States)

    Bunchorntavakul, C; Reddy, K R

    2013-01-01

    Herbal and dietary supplements are commonly used throughout the World. There is a tendency for underreporting their ingestion by patients and the magnitude of their use is underrecognised by Physicians. Herbal hepatotoxicity is not uncommonly encountered, but the precise incidence and manifestations have not been well characterised. To review the epidemiology, presentation and diagnosis of herbal hepatotoxicity. This review will mainly discuss single ingredients and complex mixtures of herbs marketed under a single label. A Medline search was undertaken to identify relevant literature using search terms including 'herbal', 'herbs', 'dietary supplement', 'liver injury', 'hepatitis' and 'hepatotoxicity'. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. The incidence rates of herbal hepatotoxicity are largely unknown. The clinical presentation and severity can be highly variable, ranging from mild hepatitis to acute hepatic failure requiring transplantation. Scoring systems for the causality assessment of drug-induced liver injury may be helpful, but have not been validated for herbal hepatotoxicity. Hepatotoxicity features of commonly used herbal products, such as Ayurvedic and Chinese herbs, black cohosh, chaparral, germander, greater celandine, green tea, Herbalife, Hydroxycut, kava, pennyroyal, pyrrolizidine alkaloids, skullcap, and usnic acid, have been individually reviewed. Furthermore, clinically significant herb-drug interactions are also discussed. A number of herbal medicinal products are associated with a spectrum of hepatotoxicity events. Advances in the understanding of the pathogenesis and the risks involved are needed to improve herbal medicine safety. © 2012 Blackwell Publishing Ltd.

  11. An official ATS statement: hepatotoxicity of antituberculosis therapy.

    Science.gov (United States)

    Saukkonen, Jussi J; Cohn, David L; Jasmer, Robert M; Schenker, Steven; Jereb, John A; Nolan, Charles M; Peloquin, Charles A; Gordin, Fred M; Nunes, David; Strader, Dorothy B; Bernardo, John; Venkataramanan, Raman; Sterling, Timothy R

    2006-10-15

    Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop

  12. Anabolic androgenic steroid-induced hepatotoxicity.

    Science.gov (United States)

    Bond, Peter; Llewellyn, William; Van Mol, Peter

    2016-08-01

    Anabolic androgenic steroids (AAS) have been abused for decades by both professional and amateur athletes in order to improve physical performance or muscle mass. AAS abuse can cause adverse effects, among which are hepatotoxic effects. These effects include cholestatic icterus and possibly peliosis hepatis and hepatocellular carcinoma or adenoma. In particular, 17α-alkylated AAS appear to be hepatotoxic, whereas nonalkylated AAS appear not to be. The 17α-alkyl substitution retards hepatic metabolism of the AAS rendering it orally bioavailable. The mechanism responsible for the hepatotoxicity induced by 17α-alkylated AAS remains poorly understood. However, oxidative stress has been repeatedly shown to be associated with it. In this manuscript we present a hypothesis which describes a potential mechanism responsible for AAS-induced hepatotoxicity, based on several observations from the literature which suggest oxidative stress being a causal factor. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Catechins in dietary supplements and hepatotoxicity.

    Science.gov (United States)

    Navarro, Victor J; Bonkovsky, Herbert L; Hwang, Sun-Il; Vega, Maricruz; Barnhart, Huiman; Serrano, Jose

    2013-09-01

    Many herbal dietary supplements (HDS) contain green tea extract (GTE) and its component catechins, although their presence may not always be indicated on the product label. Because GTE and catechins have been implicated in human hepatotoxicity in several case reports, our objective was to determine whether catechins were present in HDS that were implicated in hepatotoxicity, even if not identified among the labeled ingredients, and whether these compounds could be associated with liver injury. We assayed 97 HDS implicated in human hepatotoxicity for catechins. We found that 29 of 73 HDS (39.7%) that did not identify GTE or any of its component catechins on their label contained catechins. Among patients with confirmed hepatotoxicity, there was no statistically significant association between the presence of catechin or the dose consumed and liver injury causality score, severity, or pattern of liver injury. Catechin levels tended to be highest in products used for weight loss, although catechin concentrations were low in most products. Many HDS commonly contain catechins that are implicated in hepatotoxicity, although their presence may not be indicated on the product label. Although our results did not establish an association between GTE or catechins with hepatotoxicity, they highlight some of the many complexities and uncertainties that surround the attribution of drug-induced liver injury (DILI) to HDS.

  14. Attenuation of anti-tuberculosis therapy induced hepatotoxicity by Spirulina fusiformis, a candidate food supplement.

    Science.gov (United States)

    Martin, Sherry Joseph; Baskaran, Udhaya Lavinya; Vedi, Mahima; Sabina, Evan Prince

    2014-12-01

    Therapy using Isoniazid (INH) and Rifampicin (RIF) leads to induction of hepatotoxicity in some individuals undergoing anti-tuberculosis treatment. In this study, we assessed the effect of Spirulina fusiformis on INH and RIF induced hepatotoxicity in rats compared with hepatoprotective drug Silymarin. Induction of hepatotoxicity was measured by changes in the liver marker enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase). The antioxidant status was also analyzed in liver tissue homogenate and plasma by measurement of superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, and lipid peroxidation levels. We also aimed to study the binding and interactions of the transcription factors Pregnane X Receptor (PXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of Spirulina fusiformis by in silico methods. The administration of INH and RIF resulted in significant (p Spirulina fusiformis was seen to protect the parameters from significant changes upon challenge with INH and RIF in a dose-dependent manner. This was corroborated by histological examination of the liver. The results of the in silico analyses further support the wet lab results.

  15. Therapeutic potential of carfilzomib, an irreversible proteasome inhibitor, against acetaminophen-induced hepatotoxicity in mice.

    Science.gov (United States)

    Alanazi, Abdulrazaq; Algfeley, Saleh G; Al-Hosaini, Khaled A; Korashy, Hesham M; Imam, Faisal; Nagi, Mahmoud N

    2017-04-01

    Overdose of acetaminophen (APAP) is often associated with hepatotoxicity. Carfilzomib (CFZ) shows multiple pharmacological activities including anti-inflammatory potential. Therefore, this study was undertaken to evaluate the possible therapeutic effects of CFZ against APAP-induced hepatotoxicity. Hepatotoxicity was induced by administration of APAP (350 mg/kg, intraperitoneal). Mice were given CFZ (0.125, 0.25, or 0.5 mg/kg, intraperitoneal) 1.5 h after APAP administration. Animals were sacrificed on 6 h and blood and liver tissue samples were collected for analysis. In CFZ-post-treated group, there was significant and dose-dependent decrease in serum alanine aminotransferase levels. The level of tumor necrosis factor-α (TNF-α), reactive oxygen species, and NO decreased, whereas glutathione increased significantly by CFZ post-treatment. Upregulated mRNA expression of COX-II and iNOS were significantly downregulated by CFZ post-treatment. CFZ may exert its hepatoprotective action by alleviating inflammatory, oxidative, and nitrosative stress via inhibition of TNF-α, COX-II, and iNOS. © 2016 Wiley Periodicals, Inc.

  16. The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Jun Ho Shin

    2013-03-01

    Full Text Available The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC on acetaminophen (APAP-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH production and glutathione peroxidase (GSH-px activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

  17. Hepatoprotective activity of quercetin against acrylonitrile-induced hepatotoxicity in rats.

    Science.gov (United States)

    Abo-Salem, Osama M; Abd-Ellah, Mohamed F; Ghonaim, Mabrouk M

    2011-01-01

    Acrylonitrile is a potent hepatotoxic, mutagen, and carcinogen. A role for free radical-mediated lipid peroxidation in the toxicity of acrylonitrile has been suggested. The present study was designed to assess the hepatoprotective effect of quercetin against acrylonitrile-induced hepatotoxicity in rats. Liver damage was induced by oral administration of acrylonitrile (50 mg/kg/day/5 weeks). Acrylonitrile produced a significant elevation of malondialdehyde (138.9%) with a marked decrease in reduced glutathione (72.4%), and enzymatic antioxidants; superoxide dismutase (81%), and glutathione peroxidase (53.2%) in the liver. Serum aspartate aminotransferase, alanine aminotransferases, direct bilirubin, and total bilirubin showed a significant increase in acrylonitrile alone treated rats (115.5%, 110.8%, 1006.8%, and 1000.8%, respectively). Pretreatment with quercetin (70 mg/kg/day/6 weeks) and its coadministration with acrylonitrile prevented acrylonitrile-induced alterations in hepatic lipid peroxides and enzymatic antioxidants as well as serum aminotransferases and bilirubin. Histopathological findings supported the biochemical results. We suggest that querectin possess hepatoprotective effect against acrylonitrile-induced hepatotoxicity through its antioxidant activity. Copyright © 2011 Wiley Periodicals, Inc.

  18. Sorghum [Sorghum bicolor (L.) Moench] leaf sheath dye protects against cisplatin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Agbebi, Oluwaseun J; Boligon, Aline A; Athayde, Margareth L

    2014-12-01

    This study sought to determine the protective effect of dietary inclusion of sorghum leaf sheath dye on cisplatin-induced hepatotoxicity and oxidative stress in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups I and II were fed a basal diet, while groups III and IV were fed diets containing 0.5% and 1% sorghum leaf sheath dye, respectively, for 20 days before cisplatin administration. Hepatotoxicity was induced by a single dose of cisplatin (7 mg/kg body weight, i.p.), and the experiment was terminated at 3 days after cisplatin injection. The liver and plasma were studied for hepatotoxicity and antioxidant capacity. Cisplatin caused a significant (Psorghum leaf sheath dye. Furthermore, dietary inclusion of sorghum leaf sheath dye caused a marked reduction in the activities of alanine aminotransferase and aspartate aminotransferase after cisplatin administration. However, the ability of the dye to prevent significant cisplatin-induced alteration of both plasma and liver antioxidant indices suggests an antioxidant mechanism of action. Hence, this protective effect of Sorghum bicolor leaf sheath dye against cisplatin-induced hepatotoxicity in rats reflects its potential and beneficial role in the prevention of liver damage associated with cisplatin administration.

  19. Modulatory effects of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Owoloye, Tosin R; Agbebi, Oluwaseun J

    2013-06-01

    To investigate the ameliorative effect of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups 1 and 2 were fed basal diet while Groups 3 and 4 were fed diets containing 2% and 4% garlic respectively for 27 d prior to gentamycin administration. Hepatotoxicity was induced by the intraperitoneal administration of gentamycin (100 mg/kg body weight) for 3 d. The liver and plasma were studied for hepatotoxicity and antioxidant indices. Gentamycin induces hepatic damage as revealed by significant (P<0.05) elevation of liver damage marker enzymes (aspartate transaminase and alanine aminotransferase) and reduction in plasma albumin level. Gentamycin also caused a significant (P<0.05) alteration in plasma and liver enzymatic (catalase, glutathione and super oxygen dehydrogenises) and non-enzymatic (glutathione and vitamin C) antioxidant indices with concomitant increase in the malondialdehyde content; however, there was a significant (P<0.05) restoration of the antioxidant status coupled with significant (P<0.05) decrease in the tissues' malondialdehyde content, following consumption of diets containing garlic. These results suggest that dietary inclusion of garlic powder could protect against gentamycin-induced hepatotoxicity, improve antioxidant status and modulate oxidative stress; a function attributed to their phenolic constituents.

  20. [Hepatotoxicity in patients treated with endothelin receptor antagonists: systematic review and meta-analysis of randomized clinical trials].

    Science.gov (United States)

    Macías Saint-Gerons, Diego; de la Fuente Honrubia, César; Montero Corominas, Dolores; Catalá-López, Ferrán

    2014-04-22

    We evaluated the risk of hepatotoxicity associated to endothelin receptor antagonists. Systematic searches in PubMed/MEDLINE, the Cochrane Library as well as regulatory agencies websites were performed. Randomized controlled trials in patients receiving endothelin receptor antagonists (bosentan, sitaxentan or ambrisentan) in at least one treatment group were included. Prior to data extraction, definitions of hepatotoxicity were established. Effect sizes with 95% confidence intervals were calculated using random effects models. Heterogeneity was analysed using Cochran's Q and I(2) tests. Publication bias was assessed using Egger's method and funnel plots were generated. Twenty-one trials met the inclusion criteria (3,644 patients). Bosentan was the evaluated drug in 1,689 (74%) patients who received endothelin receptor antagonists. Compared with controls, relative risk for any hepatic adverse reaction was 2.92 (1.85-4.62; I(2)=30.6%). When hepatotoxicity was defined as elevations of liver alanine or aspartate aminotransferases equal or greater than 3 times the upper limit of normal, relative risk was 2.98 (1.69-5.25; I(2) = 40.9%). No evidence of publication bias was found (Egger's method: p = 0.68). Our results suggest an increased risk of hepatotoxicity in patients receiving endothelin receptor antagonists. Given the limited data available for endothelin receptor antagonists other than bosentan, it is not possible to draw firm conclusions about the individual risk associated for the remaining endothelin receptor antagonists. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  1. Hepatotoxicity of germander (Teucrium chamaedrys L.) and one of its constituent neoclerodane diterpenes teucrin A in the mouse.

    Science.gov (United States)

    Kouzi, S A; McMurtry, R J; Nelson, S D

    1994-01-01

    The hepatotoxicity of the herbal plant germander and that of one of its major furanoneoclerodane diterpenes, teucrin A, were investigated in mice. Teucrin A was found to cause the same midzonal hepatic necrosis as observed with extracts of the powedered plant material. Evidence that bioactivation of teucrin A by cytochromes P450 (P450) to a reactive metabolite(s) is required for initiation of the hepatocellular damage is provided by results of experiments on the induction and inhibition of P450 and from studies on the effects of glutathione depletion. Pretreatment of mice with the P450 inducer phenobarbital enhanced the hepatotoxic response, as indicated by an increase in plasma alanine aminotransferase (ALT) levels and hepatic necrosis, while pretreatment with the P450 inhibitor piperonyl butoxide markedly attenuated the toxic response. Hepatotoxicity of teucrin A also was increased following pretreatment with the inhibitor of glutathione synthesis buthionine sulfoximine. Most importantly, the tetrahydrofuran analog of teucrin A, obtained by selective chemical reduction of the furan ring, was not hepatotoxic, a result that provides strong evidence that oxidation of the furan ring moiety of the neoclerodane diterpenes is involved in the initiation of hepatocellular injury caused by germander.

  2. Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum.

    Science.gov (United States)

    Li, Chunyu; Niu, Ming; Bai, Zhaofang; Zhang, Congen; Zhao, Yanling; Li, Ruiyu; Tu, Can; Li, Huifang; Jing, Jing; Meng, Yakun; Ma, Zhijie; Feng, Wuwen; Tang, Jinfa; Zhu, Yun; Li, Jinjie; Shang, Xiaoya; Zou, Zhengsheng; Xiao, Xiaohe; Wang, Jiabo

    2017-06-01

    The main constituents of a typical medicinal herb, Polygonum multiflorum (Heshouwu in Chinese), that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide (LPS) and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent "knock-out" and "knock-in" strategy, we found that the ethyl acetate (EA) extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-β-glucoside (trans-SG) and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization of trans-SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.

  3. An Evaluation of Hepatotoxicity in Breast Cancer Patients Receiving ...

    African Journals Online (AJOL)

    Conclusion: There exist a strong correlation between the use of Inj. Doxorubicin and risk for developing hepatotoxicity. The health‑care professionals dealing with breast cancer patients need to have awareness for hepatotoxicity with the use of Inj. Doxorubicin therapy. Keywords: Breast cancer, Doxorubicin, Hepatotoxicity, ...

  4. Dietary pretreatment with green tea polyphenol, (-)-epigallocatechin-3-gallate reduces the bioavailability and hepatotoxicity of subsequent oral bolus doses of (-)-epigallocatechin-3-gallate.

    Science.gov (United States)

    James, Karma D; Forester, Sarah C; Lambert, Joshua D

    2015-02-01

    Human case-studies have reported an association between green tea-based dietary supplements and hepatotoxicity. Studies have demonstrated the hepatotoxicity of high-dose oral bolus dosing with the tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in mice and dogs. We examined the effect of pretreatment with dietary EGCG on the hepatotoxicity and bioavailability of acute oral bolus dosing with EGCG in CF-1 mice. EGCG (750 mg/kg, i.g., once daily for 3 days) increased plasma alanine aminotransferase by 80-fold, decreased both reduced (by 59%) and total (by 33%) hepatic glutathione, and increased hepatic levels of phosphorylated histone 2AX. Pretreatment with dietary EGCG (3.2 mg/g diet) for 2 weeks mitigated hepatotoxicity. Acute oral EGCG also decreased mRNA expression of glutathione reductase. Dietary pretreatment prevented these decreased and increased glutathione peroxidase (Gpx)2, Gpx3, Gpx5, and Gpx7 expression. We found that dietary EGCG reduced the plasma (57% reduction) and hepatic (71% reduction) EGCG exposure following oral bolus dosing compared to mice that were not pre-treated. Overall, it appears that EGCG can modulate its own bioavailability and that dietary treatment may reduce the toxic potential of acute high oral bolus doses of EGCG. These data may partly explain the observed variation in hepatotoxic response to green tea-containing dietary supplements. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. [Hepatotoxicity associated with the use of Herbalife].

    Science.gov (United States)

    Jóhannsson, Magnús; Ormarsdóttir, Sif; Olafsson, Sigurdur

    2010-03-01

    Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity. The clinical presentations of five cases of Herbalife related liver injury during the period of 1999-2008 are analysed. Causality was assessed by using the WHO-UMC system for causality assessment and the RUCAM method. Of the five cases there were four females and one male; median age was 46 years (range 29-78). Herbalife had been used for 1 to 7 months prior to presentation. Four patients presented with a hepatocellular and one with a cholestatic reaction. Median values were for bilirubin 190 micromol/L (range: 26-311; ref. Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury.

  6. 21 CFR 582.5118 - Alanine.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Alanine. 582.5118 Section 582.5118 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1...

  7. Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry

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    Emilia V. Perdices

    2014-04-01

    Full Text Available Objectives: The hepatotoxic potential of statins is controversial. The objectives of this study were to describe the relative frequency of hepatotoxicity caused by statins and the phenotypes found in Spain. Patients and methods: The incidence of hepatotoxicity attributed to statins in the Spanish Hepatotoxicity Registry (REH were studied and compared with those attributed to other drugs. Results: Between April 1994 and August 2012, the REH included a total of 858 cases of which 47 (5.5 % were attributed to statins. Of these, 16 were due to atorvastatin (34 %; 13 to simvastatin (27.7 %; 12 to fluvastatin (25.5 %; 4 to lovastatin (8.5 % and 2 to pravastatin (4.3 %. Statins represented approximately half of the cardiovascular group which occupied 3.er place (10 %, after anti-infectious agents (37 % and central nervous system drugs (14 %. The hepatocellular pattern was predominant, especially in the simvastatin group (85%, the cholestatic/mixed pattern was more frequent with fluvastatin (66 % and had a similar distribution to atorvastatin. Patients with statin-induced toxicity were older (62 years versus 53 years, p < 0.001 and more often demonstrated an autoimmune hepatitis phenotype (8.5 % versus 1.4 %, p < 0.003. Conclusions: Statins are not a common cause of hepatotoxicity in Spain. Atorvastatin is the statin involved in the greatest number of incidents. The liver injury pattern varies among the different statins. The hepatitis phenotype with autoimmune features appears to be a characteristic signature of statin-induced hepatotoxicity.

  8. Herbal hepatotoxicity: current status, examples, and challenges.

    Science.gov (United States)

    Calitz, Carlemi; du Plessis, Lissinda; Gouws, Chrisna; Steyn, Dewald; Steenekamp, Jan; Muller, Christo; Hamman, Sias

    2015-01-01

    Herbal medicines have commonly been considered safe by the general public due to their natural origin and long history of traditional uses. In contrast to this belief, many plants produce toxic substances as secondary metabolites that are sometimes not easily distinguishable from the pharmacological active compounds. Some herbal medicines have been associated with adverse effects and toxic effects, including hepatotoxicity, which have been reversed upon discontinuation of the herbal medicine by the patient. This review reflects on selected herbal medicines that are associated with hepatotoxic effects including a description of the phytochemicals that have been linked to liver injury where available. Although case studies are discussed where patients presented with hepatotoxicity due to use of herbal medicines, results from both in vitro and in vivo studies that have been undertaken to confirm liver injury are also included. Increasing evidence of herbal hepatotoxicity has become available through case reports; however, several factors contribute to challenges associated with causality assessment and pre-emptive testing as well as diagnosis of herb-induced liver injury.

  9. Investigation of Hepatotoxicity of Antituberculosis Medications in ...

    African Journals Online (AJOL)

    Objectives: This study was designed to investigate rifampicin, isoniazid and pyrazinamide induced-hepatotoxicity among TB patients in Sudan. Methods: Sudanese in-patients (n=57) their ages ranged between 15 to 76 years, with active pulmonary tuberculosis and normal pretreatment liver function, received rifampicin (10 ...

  10. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate.

    Science.gov (United States)

    Humphreys, Jenny H; Warner, Alexander; Costello, Ruth; Lunt, Mark; Verstappen, Suzanne M M; Dixon, William G

    2017-09-01

    Patients with rheumatoid arthritis (RA) who take methotrexate (MTX) are advised to limit their alcohol intake due to potential combined hepatotoxicity. However, data are limited to support this. The aim of this study was to quantify the risk of developing abnormal liver blood tests at different levels of alcohol consumption, using routinely collected data from primary care. Patients with RA in the Clinical Practice Research Datalink starting MTX between 1987 and 2016 were included. Hepatotoxicity was defined as transaminitis: alanine transaminase or aspartate aminotransferase more than three times the upper limit of normal. Crude rates of transaminitis were calculated per 1000 person-years, categorised by weekly alcohol consumption in units. Cox proportional hazard models tested the association between alcohol consumption and transaminitis univariately, then age and gender adjusted. 11 839 patients were included, with 530 episodes of transaminitis occurring in 47 090 person-years follow-up. Increased weekly alcohol consumption as a continuous variable was associated with increased risk of transaminitis, adjusted HR (95% CI) per unit consumed 1.01 (1.00 to 1.02); consuming between 15 and 21 units was associated with a possible increased risk of hepatotoxicity, while drinking >21 units per week significantly increased rates of transaminitis, adjusted HR (95% CI) 1.85 (1.17 to 2.93). Weekly alcohol consumption of Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  11. Effects of phoxim-induced hepatotoxicity on SD rats and the protection of vitamin E.

    Science.gov (United States)

    Zhang, Jing; Song, Wentao; Sun, Yuecheng; Shan, Anshan

    2017-11-01

    Currently, public pay more attention to the adverse effect of organophosphate pesticides on human and animal health and on the environment in developing nations. Vitamin E may protect the hepatocyte and increase the function of liver. The study was to investigate the effects of phoxim-induced hepatotoxicity on Sprague Dawley (SD) rats and the protection of vitamin E. SD rats received by gavage 180 mg kg-1 (per body weight) of phoxim, 200 mg kg-1 (per body weight) of vitamin E, and phoxim + vitamin E. The results showed that exposure to phoxim elevated liver coefficient; glutamyl transpeptidase (GGT), aspartate aminotransferase, alkaline phosphatase, total bilirubin, total bile acid, and alanine aminotransferase in the serum; ROS in the liver; and the expression of p53, Bax, CYP2E1, ROS, caspase-9, caspase-8, and caspase-3, while phoxim caused a reduction of total protein, albumin, and cholinesterase in the serum; acetylcholinesterase, total antioxidant capacity, glutathione peroxidase, and glutathione in the liver; and the expression of Bcl-2. Vitamin E modified the phoxim-induced hepatotoxicity by reducing the GGT in the serum, malondialdehyde in the liver, and the expression of CYP2E1 significantly. There were no significant changes of globulin in the serum, the activity of catalase in the liver, as well as expression levels of Fas and Bad in the liver. Overall, subacute exposure to phoxim induced hepatic injury, oxidative stress damage, and cell apoptosis. Vitamin E modified phoxim-induced hepatotoxicity slightly. And, vitamin E minimized oxidative stress damage and ultrastructural changes in rat hepatocytes notably.

  12. Effects of platelet-rich plasma on liver regeneration in CCl4-induced hepatotoxicity model.

    Science.gov (United States)

    Mafi, Afsaneh; Dehghani, Farzaneh; Moghadam, Abbas; Noorafshan, Ali; Vojdani, Zahra; Talaei-Khozani, Tahereh

    2016-12-01

    Numerous bioactive growth factors and cytokines in platelet-rich plasma (PRP) have recently made it an attractive biomaterial for therapeutic purposes. These growth factors have the potential to regenerate the injured tissues. The aim of this study was to investigate the therapeutic effects of PRP in hepatotoxic animal model. Hepatotoxicity was induced in rats by oral administration of 4 mL/kg/week of CCl4 diluted 1:1 in corn oil for 10 weeks. To confirm the hepatotoxicity, 24 h after the last CCl4 administration, blood samples were collected via cardiac puncture to assess the serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total protein, and total bilirubin. Twenty-four hours after blood collection, the experimental animals received a single injection of PRP (1 mL) via the anterior mesenteric vein. One week later, all biochemical tests were performed again, and the rats were scarified and their livers were removed, prepared histologically, and stained. The stereological analyses were performed to evaluate the effects of PRP on histopathological features of CCl4-treated livers. The results were compared statistically with the corresponding control and CCl4+normal saline (NS)-treated animals. A significant decrease in the number and volume of hepatocytes (p = 0.01), and also a reduction in the volume of sinusoids (p = 0.001) and connective tissue (p = 0.04), were observed in the PRP-treated animals compared with the CCl4+NS-treated ones. Our findings demonstrated that application of PRP had beneficial effects on CCl4-induced fibrosis; however, it had detrimental effects on the total number of hepatocytes and the volume of hepatocytes and sinusoidal spaces.

  13. Hepatotoxicity and oxidative stress induced by Naja haje crude venom.

    Science.gov (United States)

    Al-Quraishy, Saleh; Dkhil, Mahamed A; Abdel Moneim, Ahmed Esmat

    2014-01-01

    Snake venoms are synthesized and stored in venom glands. Most venoms are complex mixtures of several proteins, peptides, enzymes, toxins and non-protein components. In the present study, we investigated the oxidative stress and apoptosis in rat liver cells provoked by Naja haje crude injection (LD50) after four hours. Wistar rats were randomly divided into two groups, the control group was intraperitoneally injected with saline solution while LD50-dose envenomed group was intraperitoneally injected with venom at a dose of 0.025 μg/kg of body weight. Animals were killed four hours after the injection. Lipid peroxidation, nitric oxide and glutathione levels were measured as oxidative markers in serum and liver homogenate. In addition, liver function parameters and activities of antioxidant enzymes were determined. N. haje crude venom (0.025 μg/kg of body weight) enhanced lipid peroxidation and nitric oxide production in both serum and liver with concomitant reduction in glutathione, catalase, glutathione reductase and glutathione-S-transferase activities. Superoxide dismutase and glutathione peroxidase activities were significantly increased in liver of envenomed rats. These findings were associated with apoptosis induction in the liver. In addition, N. haje crude venom caused hepatic injury as indicated by histopathological changes in the liver tissue with an elevation in total bilirubin, serum alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, and alkaline phosphatase. Based on the present results, it can hypothesized that N. haje crude venom is a potent inducer of toxin-mediated hepatotoxicity associated with apoptosis in the liver.

  14. [Exploration research on hepatotoxic constituents from Polygonum multiflorum root].

    Science.gov (United States)

    Yang, Min; Liu, Ting; Feng, Wei-Hong; Hui, Lian-Qiang; Li, Rao-Rao; Liu, Xiao-Qian; Chen, An-Jia; Li, Chun; Wang, Zhi-Min

    2016-04-01

    By observing the cytotoxic effects of anthraquinones on HepG2 cell and using the precision-cut liver slices technique to authenticate the cytotoxic constituents, the paper aims to explore the material basis of Polygonum multiflorum root to cause liver toxicity. Firstly, MTT method was used to detect the effect of 11 anthraquinone derivatives on HepG2 cell. Then, the clear cytotoxic ingredients were co-cultured with rat liver slices for 6h respectively, and the liver tissue homogenate was prepared. BCA method was used to determine the content of protein in the homogenate and continuous monitoring method was used to monitor the leakage of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamine amino transpeptidase (GGT) and lactate dehydrogenase (LDH). The toxic effect of these ingredients on liver tissue was tested by calculating the leakage rate of the monitored enzymes. As a result, rhein, emodin, physcion-8-O-β-D-glucopyranoside and physcion-8-O-(6'-O-acetyl)-β-D-glucopyranoside showed cytotoxic effects on HepG2 cell and their IC₅₀ values were 71.07, 125.62, 242.27, 402.32 μmol•L⁻¹ respectively, but the other 7 compounds are less toxic and their IC₅₀ values can not be calculated. The precision-cut liver slices tests showed that rhein group of 400 μmol•L⁻¹ concentration significantly increased the leakage rate of ALT, AST and LDH (Pmultiflorum root respectively, which is far from the statutory dose of crude P. multiflorum root (3-6 g) or its processed product (6-12 g). Therefore, the conclusion that anthraquinones are the prime constituents of the hepatotoxicity of P. multiflorum root are still not be proved. Copyright© by the Chinese Pharmaceutical Association.

  15. Sonographic assessment of petroleum-induced hepatotoxicity in Nigerians: does biochemical assessment underestimate liver damage?

    Science.gov (United States)

    Anakwue, Angel-Mary; Anakwue, Raphael; Okeji, Mark; Idigo, Felicitas; Agwu, Kenneth; Nwogu, Uloma

    2017-03-01

    Exposure to petroleum products has been shown to have significant adverse effects on the liver which can manifest either as morphological or physiological changes. The aim of the study was to assess the effects of chronic exposure to some petroleum products on the liver of exposed workers using sonography and to determine whether biochemical assessments underestimated hepatotoxicity. Abdominal ultrasound was performed on 415 exposed workers in order to evaluate liver echogenicity and size. Also, biochemical assessment of the liver was done to evaluate its function. Statistically significant increase in the liver parenchymal echogenicity and the liver size was seen in the exposed workers compared with control (p ≤ 0.05). These increased as the exposure duration increased. It was also noted that out of 16.87% (N=70) exposed workers with abnormal liver echopattern, only 2.65% (N=11) had alanine aminotransferase above the reference range. The study revealed evidence of ultrasound detectable hepatotoxicity among the exposed subjects. Sonography appeared to detect petroleum products-induced hepatic toxicity more than biochemical assays suggesting that biochemical assessment may have underestimated toxicity.

  16. The effects of Artemisia aucheri extract on hepatotoxicity induced by thioacetamide in male rats

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    Azam Rezaei

    2013-07-01

    Full Text Available Objective: Liver is an important organ that is exposed to many oxidant and carcinogenic agents, thus antioxidant compounds are beneficial for liver health. Artemisia contains flavonoid compounds and anti-diabetic, antioxidant, and anti-inflammatory properties. Due to possessing terpene and sesquiterpene compounds, this plant has antioxidant properties. This study was done to investigate the effects of Artemisia plant extract on thioacetamide-induced hepatotoxicity in Wistar rats. Materials and Methods: For induction of hepatotoxicity, 50 mg/kg thioacetamide was injected intraperitoneally (i.p.After extraction and purification, the hydroalcoholicextract was injected i.p. at 100, 200, and 300 mg/kg doses for 21 days together with thioacetamide at 50 mg/kg dose in the last 3 days. After blood sampling and separation of serum, alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, albumin, and total protein concentrations were measured. Results: Significant decreases in aminotransferase and alkaline phosphatase activities and significant increases in the concentration of albumin and total protein in groups treated with the extract compared with thioacetamide-treated group were observed (p

  17. Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.

    Science.gov (United States)

    Yu, Hong; Barrass, Nigel; Gales, Sonya; Lenz, Eva; Parry, Tony; Powell, Helen; Thurman, Dale; Hutchison, Michael; Wilson, Ian D; Bi, Luke; Qiao, Junwen; Qin, Qiuping; Ren, Jin

    2015-03-01

    1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.

  18. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-12-01

    Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. The treatment with Arctium lappa extract reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in the acetaminophen group when compared with the control group. DNA fragments in the acetaminophen-injected group were also significantly increased (P Arctium lappa treatment (12.97±0.89 nmol/mg) when compared with the acetaminophen-treated-only group (12.97±0.89 nmol/mg). Histopathologic examination revealed that acetaminophen administration produced hepatic cell necrosis, infiltrate of lymphocytes, and vacuolation that were associated with the acetaminophen-treated animal group, but the degree of acetaminophen-induced hepatotoxicity was mediated by treatment with Arctium lappa extract. Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats.

  19. Moringa oleifera-based diet protects against nickel-induced hepatotoxicity in rats

    Science.gov (United States)

    Stephen Adeyemi, Oluyomi; Sokolayemji Aroge, Cincin; Adewumi Akanji, Musbau

    2017-01-01

    Multiple health-promoting effects have been attributed to the consumption of Moringa oleifera leaves, as part of diet without adequate scientific credence. This study evaluated the effect of M. oleifera-based diets on nickel (Ni) - induced hepatotoxicity in rats. Male rats assigned into six groups were given oral administration of 20 mg/kg body weight nickel sulfate in normal saline and either fed normal diet orM. oleifera-based diets for 21 days. All animals were sacrificed under anesthesia 24 hours after the last treatment. Ni exposure elevated the rat plasma activities of alanine transaminase, aspartate transaminase and alkaline phosphatase significantly. Ni exposure also raised the levels of triglyceride, total cholesterol and low-density lipoprotein cholesterol while depleting the high-density lipoprotein cholesterol concentration. Further, Ni exposure raised rat plasma malondialdehyde but depleted reduced glutathione concentrations. The histopathological presentations revealed inflammation and cellular degeneration caused by Ni exposure. We show evidence thatM. oleifera-based diets protected against Ni-induced hepatotoxicity by improving the rat liver function indices, lipid profile as well as restoring cellular architecture and integrity. Study lends credence to the health-promoting value ofM. oleifera as well as underscores its potential to attenuate hepatic injury. PMID:28808207

  20. Hepatoprotective effect of Rosa canina fruit extract against carbon tetrachloride induced hepatotoxicity in rat

    Directory of Open Access Journals (Sweden)

    Heibatollah Sadeghi

    2016-03-01

    Full Text Available Objective: The present study was conducted to investigate the hepatoprotective activity of hydro-ethanolic fruit extract of Rosa canina (R. canina against carbon tetrachloride (CCl4-induced hepatotoxicity in rats. Methods: Male Wistar albino rats were randomly divided into six groups of 8 animals of each, including control, toxic (CCl4, R. canina 250, 500, and 750 mg/kg + CCl4 and R. canina 750 mg/kg alone. R. canina (p.o., daily and CCl4 (1 ml/kg twice a week, 50% v/v in olive oil, i.p. were administered to animals for six weeks. Serum analysis was performed to assay the levels of aspartate aminotransferase (AST, alanine amino transaminase (ALT, alkaline phosphatase (ALP, albumin (ALB, total protein (TP and malondialdehyde (MDA. Biochemical observations were also supplemented with histopathological examination (haematoxylin and eosin staining of liver section.Results: Hepatotoxicity was evidenced by considerable increase in serum levels of AST, ALT, ALP, and lipid peroxidation (MDA and decrease in levels of ALB and TP. Injection of CCL4 also induced congestion in central vein, and lymphocyte infiltration. Treatment with hydro-alcoholic fruit extract of R. canina at doses of 500 and 750 mg/kg significantly reduced CCl4-elevated levels of ALT, AST, ALP and MDA (p

  1. Hepatotoxicity and genotoxicity of patulin in mice, and its modulation by green tea polyphenols administration.

    Science.gov (United States)

    Song, Erqun; Xia, Xiaomin; Su, Chuanyang; Dong, Wenjing; Xian, Yaping; Wang, Wei; Song, Yang

    2014-09-01

    Patulin (PAT) is a mycotoxin produced by certain species of Penicillium, Aspergillus, and Byssochlamys. Previous studies demonstrated its cytotoxic, genotoxic, and mutagenic effects in different cell lines. However, there is little information available concerning its toxic behavior in vivo. In the present study, we investigated PAT-induced hepatotoxicity and genotoxicity in mice. We also investigated the antioxidant and anti-genotoxicity efficiency of green tea polyphenols (GTP) against PAT-induced toxicity. We found that PAT-treatment induced serum alanine transaminase (ALT) and aspartate transaminase (AST) activities significantly. PAT-induced lipid peroxidation was confirmed with the elevation of thiobarbituric acid-reactive substances (TBARS). Moreover, the increasing of reactive oxygen species (ROS) and decreasing of GSH level implied its oxidative damage mechanism. In bone marrow cell, PAT was found to induce micronucleus and chromosomal aberration formation. In addition, our result suggested that GTP administration has dose-dependent antioxidative and antigenotoxic effect in against PAT-induced hepatotoxicity and genotoxicity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Clinical and Laboratory Findings of Lead Hepatotoxicity in the Workers of a Car Battery Manufacturing Factory

    Directory of Open Access Journals (Sweden)

    Bita Dadpour

    2016-02-01

    Full Text Available Background: Occupational lead poisoning is common in workers of some industries, but lead hepatotoxicity has rarely been reported. Several animal studies have revealed lead induced liver damage but clinical studies concerning the manifestations of lead induced liver toxicity in humans are scares. This study was designed to investigate the clinical manifestations and pathological parameters of hepatic dysfunction and its relationship with blood and urine lead concentrations in a car battery-manufacturing workers. Methods: This cross sectional study was carried out in Mashhad, Iran, during April-June 2011. One hundred and twelve workers underwent blood and urine sampling for determination of lead concentrations and liver function tests. Clinical signs and symptoms of possible lead hepatotoxicity were investigated. Results: Mean (±SD age of the workers was 28.78 (±5.17 yr with a daytime work of 8.67 (±1.41 h and mean work duration of 3.89 (±2.40 yr. Mean blood lead concentration (BLC and urine lead concentration (ULC were 398.95 (±177.41 µg/l and 83.67(±50 μg/l, respectively. We found no correlation between the clinical findings and BLC or ULC. A weak correlation (R: 0.27, P=0.087 between serum alkaline phosphatase concentration and BLC was obtained. No significant relationship was found between other liver function tests and BLC or ULC. Conclusion: We found no specific clinical and laboratory abnormalities of liver in the workers of car battery manufacturer who had chronic lead toxicity. Further investigations with more specific laboratory tests such as LDH5 and gamma glutamyl transferase (GGT as well as novel biomarkers of metal induced hepatotoxicity might be helpful in evaluating lead hepatotoxicity.

  3. Hepatotoxicity Induced by "the 3Ks": Kava, Kratom and Khat.

    Science.gov (United States)

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Zaami, Simona; Ricci, Serafino; Giorgetti, Raffaele; Terranova, Daniela; Busardò, Francesco P; Marinelli, Enrico

    2016-04-16

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by "the 3Ks", while trying to clarify the numerous aspects that still need to be addressed.

  4. The combination of atorvastatin and ethanol is not more hepatotoxic to rats than the administration of each drug alone

    Directory of Open Access Journals (Sweden)

    D.T. Ito

    2007-03-01

    Full Text Available Animal studies and premarketing clinical trials have revealed hepatotoxicity of statins, primarily minor elevations in serum alanine aminotransferase levels. The combined chronic use of medicines and eventual ethanol abuse are common and may present a synergistic action regarding liver injury. Our objective was to study the effect of the chronic use of atorvastatin associated with acute ethanol administration on the liver in a rat model. One group of rats was treated daily for 5 days a week for 2 months with 0.8 mg/kg atorvastatin by gavage. At the end of the treatment the livers were perfused with 72 mM ethanol for 60 min. Control groups (at least 4 animals in each group consisted of a group of 2-month-old male Wistar EPM-1 rats exposed to 10% ethanol (v/v ad libitum replacing water for 2 months, followed by perfusion of the liver with 61 nM atorvastatin for 60 min, and a group of animals without chronic ethanol treatment whose livers were perfused with atorvastatin and/or ethanol. The combination of atorvastatin with ethanol did not increase the release of injury marker enzymes (alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase from the liver and no change in liver function markers (bromosulfophthalein clearance, and oxygen consumption was observed. Our results suggest that the combination of atorvastatin with ethanol is not more hepatotoxic than the separate use of each substance.

  5. Herbal Supplements and Hepatotoxicity: A Short Review.

    Science.gov (United States)

    Haslan, Haszianaliza; Suhaimi, Farihah Haji; Das, Srijit

    2015-10-01

    Herbal products have gained popularity over the past few decades. The reasons attributed to the rise in popularity are cheaper costs, easy availability, patient compliance and fewer side effects. However, liver toxicity following consumption of herbal remedies is on the increase. Thus, there is an urgent need to understand the mechanism of action of the herbal supplements on the liver. Occasionally, herbal supplements may also interact with conventional drugs. The present review focusses on a few herbs such as Aloe barbadensis, Atractylis gummifera, Centella asiatica, Mitragyna speciosa, Morinda citrifolia, Larea tridentata, Symphytum officinale, Teucrium chamaedrys and Xanthium strumarium, which are reported to cause hepatotoxicity in humans and animals. Prior knowledge on hepatotoxicity caused by herbs may be beneficial for clinicians and medical practitioners.

  6. Hepatotoxic slimming aids and other herbal hepatotoxins.

    Science.gov (United States)

    Chitturi, Shivakumar; Farrell, Geoffrey C

    2008-03-01

    Perceptions of safety and/or cultural mores prompt individuals to seek herbal slimming aids in preference to conventional dietary, physical activity and medication-based protocols. In recent years, terpenoid-containing dietary supplements have been implicated in causing severe and sometimes fatal hepatotoxicity. Teucrium polium (germander) was the first of these herbal products to be clearly linked to cases of acute liver failure. Subsequently, similar hepatotoxicity has been observed with other members of the Teucrium genus. While diterpenoid-derived reactive metabolites are central to germander hepatotoxicity, it may also be that the hepatic effects of compounds such as Sho-saiko-to, Centella asiatica and Black cohosh are linked to their triterpenoid content. Other non-terpenoid-containing herbal remedies marketed for weight reduction have been causally associated with significant liver injury. Important among these are preparations containing N-nitrosofenfluramine, usnic acid and ephedra alkaloids. Finally, we review recent data on known and emerging hepatotoxins such as Boh-Gol-Zhee, Kava, pyrrolizidine alkaloids and Shou-Wu-Pian. Better public and physician awareness through health education, early recognition and management of herbal toxicity and tighter regulation of complementary/alternative medicine systems are required to minimize the dangers of herbal product use.

  7. Green reduction of graphene oxide using alanine.

    Science.gov (United States)

    Wang, Jiabin; Salihi, Elif Caliskan; Šiller, Lidija

    2017-03-01

    There remains a real need for the easy, eco-friendly and scalable preparation method of graphene due to various potential applications. Chemical reduction is the most versatile method for the large scale production of graphene. Here we report the operating conditions for a one-step, economical and green synthesis method for the reduction of graphene oxide using a biomolecule (alanine). Graphene oxide was produced by the oxidation and exfoliation of natural graphite flake with strong oxidants using Hummers method (Hummers and Offeman, 1958), but the method was revised in our laboratory to set up a safe and environmentally friendly route. The reduction of graphene oxide was investigated using alanine at various operating conditions in order to set up optimum conditions (treatment time, temperature and concentration of the reagent). Samples have been characterized by using UV-Visible spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, Raman spectroscopy and X-ray diffraction analysis. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  8. ALT1-encoded alanine aminotransferase plays a central role in the metabolism of alanine in Saccharomyces cerevisiae.

    Science.gov (United States)

    García-Campusano, Florencia; Anaya, Víctor-Hugo; Robledo-Arratia, Luis; Quezada, Héctor; Hernández, Hugo; Riego, Lina; González, Alicia

    2009-04-01

    In the yeast Saccharomyces cerevisiae, the paralogous genes ALT1 and ALT2 have been proposed to encode alanine aminotransferase isozymes. Although in other microorganisms this enzyme constitutes the main pathway for alanine biosynthesis, its role in S. cerevisiae had remained unclear. Results presented in this paper show that under respiratory conditions, Alt1p constitutes the sole pathway for alanine biosynthesis and catabolism, constituting the first example of an alanine aminotransferase that simultaneously carries out both functions. Conversely, under fermentative conditions, it plays a catabolic role and alanine is mainly synthesized through an alternative pathway. It can thus be concluded that ALT1 has functions in alanine biosynthesis and utilization or only alanine utilization under respiratory and fermentative conditions, respectively. ALT2 expression was repressed under all tested conditions, suggesting that Alt2p biosynthesis is strictly controlled and only allowed to express under peculiar physiological conditions.

  9. Crystallization and preliminary crystallographic analysis of d-alanine-d-alanine ligase from Streptococcus mutans

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Yong-Zhi; Sheng, Yu [Institute for Nanobiomedical Technology and Membrane Biology, West China Hospital, Sichuan University, Chengdu 610065, Sichuan (China); Li, Lan-Fen [National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing 100871 (China); Tang, De-Wei [Institute for Nanobiomedical Technology and Membrane Biology, West China Hospital, Sichuan University, Chengdu 610065, Sichuan (China); Liu, Xiang-Yu [National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing 100871 (China); Zhao, Xiaojun, E-mail: zhaoxj@scu.edu.cn [Institute for Nanobiomedical Technology and Membrane Biology, West China Hospital, Sichuan University, Chengdu 610065, Sichuan (China); Liang, Yu-He, E-mail: zhaoxj@scu.edu.cn; Su, Xiao-Dong [National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing 100871 (China); Institute for Nanobiomedical Technology and Membrane Biology, West China Hospital, Sichuan University, Chengdu 610065, Sichuan (China)

    2007-09-01

    A potential target for antibiotic drug design, d-alanine-d-alanine ligase from S. mutans, was expressed in E. coli, purified and crystallized. Diffraction data were collected to 2.4 Å resolution. d-Alanine-d-alanine ligase is encoded by the gene ddl (SMU-599) in Streptococcus mutans. This ligase plays a very important role in cell-wall biosynthesis and may be a potential target for drug design. To study the structure and function of this ligase, the gene ddl was amplified from S. mutans genomic DNA and cloned into the expression vector pET28a. The protein was expressed in soluble form in Escherichia coli strain BL21 (DE3). Homogeneous protein was obtained using a two-step procedure consisting of Ni{sup 2+}-chelating and size-exclusion chromatography. Purified protein was crystallized and the cube-shaped crystal diffracted to 2.4 Å. The crystal belongs to space group P3{sub 1}21 or P3{sub 2}21, with unit-cell parameters a = b = 79.50, c = 108.97 Å. There is one molecule per asymmetric unit.

  10. 3,5,5-Trimethyl-Hexanoyl-Ferrocene Diet Protects Mice from Moderate Transient Acetaminophen-Induced Hepatotoxicity

    Science.gov (United States)

    Moon, Mi Sun; Kang, Boo-Hyon; Krzeminski, Jacek; Amin, Shantu; Aliaga, Cesar; Zhu, Junjia; McDevitt, Emily I.; Kocher, Susan; Richie, John P.; Isom, Harriet C.

    2011-01-01

    Acetaminophen (APAP) overdose is the most frequent cause of adult acute liver failure. Susceptibility or resistance to APAP toxicity is most likely accounted for by the interplay of several factors. One factor important in multiple different chronic liver diseases that may play a role in APAP toxicity is elevated hepatic iron. Hereditary hemochromatosis is traditionally associated with hepatic iron overload. However, varying degrees of elevated hepatic iron stores observed in chronic hepatitis C and B, alcoholic liver disease and nonalcoholic fatty liver disease also have clinical relevance. We employed an animal model in which mice are fed a 3,5,5-trimethyl-hexanoyl-ferrocene (TMHF)-supplemented diet to evaluate the effect of elevated hepatic iron on APAP hepatotoxicity. Three hundred milligrams per kilogram APAP was chosen because this dosage induces hepatotoxicity but is not lethal. Since both excess iron and APAP induce oxidative stress and mitochondrial dysfunction, we hypothesized that the TMHF diet would enhance APAP hepatotoxicity. The results were the opposite. Centrilobular vacuolation/necrosis, APAP adducts, nitrotyrosine adducts, and a spike in serum alanine aminotransferase, which were observed in control mice treated with APAP, were not observed in TMHF-fed mice treated with APAP. Further analysis showed that the levels of CYP2E1 and CYP1A2 were not significantly different in TMHF-treated compared with control mice. However, the magnitude of depletion of glutathione following APAP treatment was considerably less in TMHF-treated mice than in mice fed a control diet. We conclude that a TMHF diet protects mice from moderate transient APAP-induced hepatotoxicity prior to the formation of APAP adducts, and one contributing mechanism is reduction in glutathione depletion. PMID:21908766

  11. External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose.

    Science.gov (United States)

    Wong, Anselm; Sivilotti, Marco L A; Dargan, Paul I; Wood, David M; Greene, Shaun L

    2015-01-01

    Risk prediction in paracetamol (acetaminophen, or APAP) poisoning treated with acetylcysteine helps guide initial patient management and disposition. The paracetamol-aminotransferase multiplication product may be a useful and less time-sensitive risk predictor. The aim of this study was to validate this multiplication product in an independent cohort of patients with paracetamol overdose. Using an existing toxicology dataset of poisoned patients from two large inner-city United Kingdom teaching hospitals, we retrospectively identified by electronic search all paracetamol overdoses from February 2005 to March 2013. We assessed the diagnostic accuracy of the multiplication product (serum APAP concentration × alanine transaminase [ALT] activity), especially at the pre-specified cut-off points of 1 500 mg/L × IU/L (10 000 micromol/L × IU/L) and 10 000 mg/L × IU/L (66 000 micromol/L × IU/L). The primary outcome was hepatotoxicity defined by a peak ALT > 1000 IU/L. Of 3823 total paracetamol overdose presentations, there were 2743 acute single, 452 delayed single (> 24 h post overdose), 426 staggered (ingestion over > 1 h), and 202 supratherapeutic ingestions. Altogether, 34 patients developed hepatotoxicity. Among the acute single-ingestion patients, a multiplication product > 10 000 mg/L × IU/L had a sensitivity of 80% (95% confidence interval [CI]: 44%, 96%) and specificity of 99.6% [99.3%, 99.8%], while a product > 1 500 mg/L × IU/L had a sensitivity of 100% [66%, 100%] and specificity of 92% [91%, 93%]. Overall, 16 patients with a multiplication product > 10 000 mg/L × IU/L developed hepatotoxicity (likelihood ratio: 250, 95% CI: 130, 480), and 4 patients with a multiplication product between 1 500 and 10 000 (likelihood ratio: 2.5, 95% CI: 1.0, 6.0). No patient with a product 10 000 mg/L × IU/L was associated with a very high likelihood, and < 1 500 mg/L × IU/L with a very low likelihood, of developing hepatotoxicity in patients treated with acetylcysteine.

  12. Cyfluthrin-induced hepatotoxicity in rats | Omotuyi | African Journal ...

    African Journals Online (AJOL)

    The hepatotoxic effect of continous administration of cyfluthrin was investigated in rats. Rats (Rattus norvegicus) were grouped into A (0 ppm) control, B (100 ppm) and C (200 ppm) with the indicated amount of cyfluthrin administered orally for 15 weeks.The hepatotoxicity level was assessed by monitoring the changes in the ...

  13. Antituberculosis drugs and hepatotoxicity among hospitalized patients in Jos, Nigeria

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    Samson E Isa

    2016-01-01

    Conclusion: Hepatotoxicity due to first-line anti-TBs, whether based on clinical features alone or backed by liver chemistry, is common among hospitalized patients in our environment. Studies to determine the predictors of hepatotoxicity to guide clinical interventions aimed at the prevention or timely identification of cases are needed.

  14. The prevalence of drug induced hepatotoxicity among HIV positive ...

    African Journals Online (AJOL)

    Introduction: Drug induced hepatotoxicity is a recognized problem associated with the anti-tuberculosis (anti-TB) chemotherapy and is of great concern especially in this era of HIV infection. Objectives: To obtain the prevalence of hepatotoxicity due to anti-TB medications in HIV positive and negative patients with pulmonary ...

  15. Lead hepatotoxicity: Selected aspects of pathobiochemistry

    Directory of Open Access Journals (Sweden)

    Mateusz Labudda

    2013-08-01

    Full Text Available Lead (Pb that belongs to heavy metals is one of the major pollution components of the environment. Occupational and environmental exposure to lead can cause its absorption by the body and consequently exert toxic effects in the liver. In this paper biochemical determinants of hepatotoxicity caused by lead are presented. Generation of reactive oxygen species, disturbances in the cellular antioxidant system, lipid peroxidation, inhibition of enzymatic proteins and intercellular signaling are also discussed. Med Pr 2013;64(4:565–568

  16. Retinoids modulate thioacetamide-induced acute hepatotoxicity.

    Science.gov (United States)

    Shmarakov, Igor O; Borschovetska, Vira L; Marchenko, Mykhailo M; Blaner, William S

    2014-06-01

    The literature indicates that retinoids can influence the metabolism and actions of xenobiotics and conversely that xenobiotics can influence the metabolism and actions of retinoids. We were interested in understanding the degree to which hepatic retinoid stores, accumulated over a lifetime, affect xenobiotic metabolism, and actions. To investigate this, we induced liver injury through administration of the hepatotoxin thioacetamide (TAA) to chow fed wild type (WT) mice and lecithin:retinol acyltransferase-deficient (Lrat(-/-)) mice that are genetically unable to accumulate hepatic retinoid stores. Within 48 h of TAA-treatment, WT mice develop liver injury as evidenced by focal necrotic areas and increases in serum ALT activity and myeloperoxidase activity in hepatic parenchyma. Simultaneously, features of hepatic encephalopathy develop, as evidenced by a 25% increase in blood ammonia and a threefold reduction of blood glucose levels. This is accompanied by reduced hepatic glutathione, and increased thiobarbituric acid reactive substances, protein carbonyl and sulfhydryl groups, and increased cytochrome P450-catalyzed hydroxylation activity and flavin-containing monooxygenase activity in microsomes prepared from WT liver. Strikingly, none of these TAA-induced effects were observed for matched Lrat(-/-) mice. To confirm that TAA hepatotoxicity depends on retinoid availability, we administered, over 48 h, four oral doses of 3000 IU retinyl acetate each to the mice. This led to the development of hepatotoxicity in Lrat(-/-) mice that was similar in extent to that observed in WT mice. Our findings establish that endogenous hepatic retinoid stores can modulate the toxicity of TAA in mice.

  17. Hepatotoxicity of illegal home-made alcohols.

    Science.gov (United States)

    Gökce, Hasan; Akcan, Ramazan; Celikel, Adnan; Zeren, Cem; Ortanca, Ibrahim; Demirkiran, Sumeyra

    2016-10-01

    Alcohol-related hepatotoxicity is not only caused by excessive alcohol consumption but also caused and even accelerated by hepatotoxic ingredients other than ethanol. Concentrations of hepatotoxic substances might be significantly high, particularly in illegally produced home-made alcohols. In this study we aim to analyze the hepatotoxic effects of a home-made alcohol traditionally called "bogma raki" in Turkey. Fifty Wistar albino male rats were used. Five groups were randomly formed with ten animals in each. Besides laboratory diets, groups were fed as follows: Group 1 (control group) distilled water; Group 2 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day); Group 3 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day)+walnut (10 g/kg/day); Group 4 whisky with distilled water (%40 (v/v), 9.2 ml/kg/day); Group 5 distilled water + walnut (10 g/kg/day), for 28 days. The toxicological analysis of The spirits were analyzed using Hewlett-Packard (Palo Alto, CA) GC/MS system with HP 6890 gas chromatograph, an HP 5972 mass selective detector (MSD) and an HP 6890 automatic liquid sampler GC/MS; the pressure of the carrier gas helium was 6.0 bar and the split value with a ratio of 1:100. The injection unit temperature set to 250 °C and MS quadrupole temperature set to 280 °C. The MS quadrupole detector ionization energy set to 70 eV. The initial column temperature was 60 °C (for 4 min) programmed by 6 °C/min to final temperature 160 °C and kept for 8 min at 160 °C. Utilized whisky and bogma raki samples were analyzed for the amounts of trans-anethole, ethanol, methanol, 1-propanolol, butanol, 2-butanol, 2-methyl-1-propanolol (isobutanol) and 3-methylbutanol (isoamyl alcohol). Histopathological changes in liver tissues were graded as follows; normal = 0 (moderate = 2 (40%-70%), severe = 3 (above 70%). Chemical composition of illegally produced raki sample (%v/v) was as follows: trans-anethole %1.93, ethanol %95.70, 2-methyl-1

  18. STUDY OF LYSINE AND ALANINE DELIVERANCE THROUGH POLYPYRROLE MEMBRANE

    Directory of Open Access Journals (Sweden)

    Adhitasari Suratman

    2010-06-01

    Full Text Available Electropolymerization processes of pyrrole and the usage of polypyrrole membrane as lysine and alanine deliverance have been studied by cyclic voltammetry technique. Polypyrrole membrane was prepared by electropolymerization processes of pyrrole in water based solvent containing sodium perchlorate as supporting electrolyte. Electropolymerization processes were carried out within potential range of 0-1100 mV vs Ag/AgCl reference electrode and at the scanning rate of 100 mV/s. In this study, lysine and alanine have been used as molecules which could easily be loaded on and released from polypyrrole membrane. The presence of lysine or alanine during electropolymerization process reduced the rate of electropolymerization of polypyrrole. In lysine or alanine transfer processes into polypyrrole membrane, the interaction between polypyrrole and lysine or alanine showed by the curve of E½ oxidation in respect of - log C. It proved that the E½ oxidation shifted to more positive potential showed by the increasing of concentration of lysine or alanine. Beside that, voltammetric responses of lysine and alanine transfered into polypyrrole membrane were found to be Nernstian. The results indicated that polypyrrole could be used as a sensor of lysine and alanine.   Keywords: Electropolymerization, polypyrrole membrane, voltammetry technique

  19. Earthworms accumulate alanine in response to drought.

    Science.gov (United States)

    Holmstrup, Martin; Slotsbo, Stine; Henriksen, Per G; Bayley, Mark

    2016-09-01

    Earthworms have ecologically significant functions in tropical and temperate ecosystems and it is therefore important to understand how these animals survive during drought. In order to explore the physiological responses to dry conditions, we simulated a natural drought incident in a laboratory trial exposing worms in slowly drying soil for about one month, and then analyzed the whole-body contents of free amino acids (FAAs). We investigated three species forming estivation chambers when soils dry out (Aporrectodea tuberculata, Aporrectodea icterica and Aporrectodea longa) and one species that does not estivate during drought (Lumbricus rubellus). Worms subjected to drought conditions (Aporrectodea species and 300μmolg(-1) dry weight in L. rubellus. Proline was only weakly upregulated in some species as were a few other FAAs. Species forming estivation chambers (Aporrectodea spp.) did not show a better ability to conserve body water than the non-estivating species (L. rubellus) at the same drought level. These results suggest that the accumulation of alanine is an important adaptive trait in drought tolerance of earthworms in general. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Comparison of EPR response of alanine and Gd₂O₃-alanine dosimeters exposed to TRIGA Mainz reactor.

    Science.gov (United States)

    Marrale, M; Schmitz, T; Gallo, S; Hampel, G; Longo, A; Panzeca, S; Tranchina, L

    2015-12-01

    In this work we report some preliminary results regarding the analysis of electron paramagnetic resonance (EPR) response of alanine pellets and alanine pellets added with gadolinium used for dosimetry at the TRIGA research reactor in Mainz, Germany. Two set-ups were evaluated: irradiation inside PMMA phantom and irradiation inside boric acid phantom. We observed that the presence of Gd2O3 inside alanine pellets increases the EPR signal by a factor of 3.45 and 1.24 in case of PMMA and boric acid phantoms, respectively. We can conclude that in the case of neutron beam with a predominant thermal neutron component the addition of gadolinium oxide can significantly improve neutron sensitivity of alanine pellets. Monte Carlo (MC) simulations of both response of alanine and Gd-added alanine pellets with FLUKA code were performed and a good agreement was achieved for pure alanine dosimeters. For Gd2O3-alanine deviations between MC simulations and experimental data were observed and discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Quercetin and beta-sitosterol prevent high fat diet induced dyslipidemia and hepatotoxicity in Swiss albino mice.

    Science.gov (United States)

    Sikder, Kunal; Das, Nilanjan; Kesh, Swaraj Bandhu; Dey, Sanjit

    2014-01-01

    High fat diet group showed a significant rise in serum and hepatic total cholesterol, triglyceride and atherogenic index which are major biomarkers of dyslipidemia and cardiovascular risk. The liver function markers, lipid peroxidation and proinflammatory cytokine levels were elevated in high fat diet group whereas antioxidant levels significantly reduced. These findings manifest hepatic damage which was further confirmed by histological findings. Quercetin and beta-sitosterol though structurally different yet both ameliorate the sickening changes in different mechanism. The current investigation is perhaps the first report of the mechanistic role of two polyphenols over dyslipidemia and subsequent hepatotoxicity.

  2. Overexpression of Nrf2 protects against microcystin-induced hepatotoxicity in mice.

    Directory of Open Access Journals (Sweden)

    Yuan-Fu Lu

    Full Text Available Oxidative stress and glutathione (GSH depletion are implicated in mycocystin hepatotoxicity. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2 in microcystin-induced liver injury, Nrf2-null, wild-type, and Keap1-hepatocyte knockout (Keap1-HKO mice were treated with microcystin (50 μg/kg, i.p.. Blood and liver samples were collected 8 h thereafter. Microcystin increased serum alanine aminotransferase and aspartate aminotransferase activities, and caused extensive inflammation and necrosis in Nrf2-null and wild-type mice, but not in Keap1-HKO mice. Oxidative stress and inflammation are implicated in microcystin-induced hepatotoxicity, as evidenced by increased lipid peroxidation and increased expression of pro-inflammatory genes, such as neutrophil-specific chemokines mKC and MIP-2, and pro-inflammatory cytokines IL-1β and IL-6. The increased expression of these pro-inflammatory genes was attenuated in Keap1-HKO mice. Nrf2 and Nqo1 mRNA and protein were higher in Keap1-HKO mice at constitutive levels and after microcystin. To further investigate the mechanism of the protection, hepatic GSH and the mRNA of GSH-related enzymes were determined. Microcystin markedly depleted liver GSH by 60-70% in Nrf2 and WT mice but only 35% in Keap1-HKO mice. The mRNAs of GSH conjugation and peroxide reduction enzymes, such as Gstα1, Gstα4, Gstμ, and Gpx2 were higher in livers of Keap1-HKO mice, together with higher expression of the rate-limiting enzyme for GSH synthesis (Gclc. Organic anion transport polypeptides were increased by microcystin with the most increase in Keap1-HKO mice. In conclusion, this study demonstrates that higher basal levels of Nrf2 and GSH-related genes in Keap1-HKO mice prevented microcystin-induced oxidative stress and liver injury.

  3. Protective role of licochalcone B against ethanol-induced hepatotoxicity through regulation of Erk signaling

    Directory of Open Access Journals (Sweden)

    Xiao-peng Gao

    2017-02-01

    Full Text Available Objective(s: Oxidative stress has been established as a key cause of alcohol-induced hepatotoxicity. Licochalcone B, an extract of licorice root, has shown antioxidative properties. This study was to investigate the effects and mechanisms of licochalcone B in ethanol-induced hepatic injury in an in vitro study. Materials and Methods: An in vitro model of Ethanol-induced cytotoxicity in BRL cells was used in this study. Cell injury was assessed using WST-1 assay and lactate dehydrogenase, alanine transaminase, and aspartate aminotransferase release assay. Cell apoptosis were quantified by flow cytometric analysis. The intracellular oxidative level was evaluated by reactive oxidative species, malondialdehyde and glutathione detection. Furthermore, the expression level of Erk, p-Erk, Nrf-2 were assessed using Western blot. Results: Treatment with ethanol induced marked cell injury and cell apoptosis in BRL cells. Licochalcone B significantly attenuated ethanol-induced cell injury, and inhibited cell apoptosis. Furthermore, licochalcone B significantly inhibited ethanol-induced intracellular oxidative level, upregulated the expression of p-Erk, and promoted nuclear localization of Nrf2. Additionally, this hepatoprotective role was significantly abolished by inhibition of Erk signaling. However, no apparent effects of Erk inhibition were observed on ethanol-induced hepatotoxicity. Conclusion: This study demonstrates that licochalcone B protects hepatocyte from alcohol-induced cell injury, and this hepatoprotective role might be attributable to apoptosis reduction, inhibition of oxidative stress, and upregulation of Erk–Nrf2. Therefore, licochalcone B might possess potential as a novel therapeutic drug candidate for alcohol-related liver disorders.

  4. Utility of human hepatocyte spheroids without feeder cells for evaluation of hepatotoxicity.

    Science.gov (United States)

    Ogihara, Takuo; Arakawa, Hiroshi; Jomura, Tomoko; Idota, Yoko; Koyama, Satoshi; Yano, Kentaro; Kojima, Hajime

    2017-01-01

    We investigated the utility of three-dimensionally cultured hepatocytes (spheroids) without feeder cells (Sph(f-)) for the prediction of drug-induced liver injury (DILI) in humans. Sph(f-) and spheroids cultured on feeder cells (Sph(f+)) were exposed to the hepatotoxic drugs flutamide, diclofenac, isoniazid and chlorpromazine at various concentrations for 14 days, and albumin secretion and cumulative leakages of toxicity marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and γ-glutamyl transpeptidase (γ-GTP), were measured. The cumulative AST, LDH or γ-GTP leakages from Sph(f-) were similar to or greater than those from Sph(f+) for all drugs tested, although ALT leakages showed no consistent difference between Sph(f+) and Sph(f-). In the case of Sph(f-), significant correlations among all the toxicity markers except for γ-GTP were observed. As regards the drug concentrations causing 1.2-fold elevation of enzyme leakage (F1.2), no consistent difference between Sph(f+) and Sph(f-) was found, although several F1.2 values were undetermined, especially in Sph(f+). The IC50 of albumin secretion and F1.2 of AST leakage from Sph(f-) were equal to or lower than those of Sph(f+) for all the tested drugs. These results indicate that feeder cells might contribute to resistance to hepatotoxicity, suggesting DILI could be evaluated more accurately by using Sph(f-). We suggest that long-term exposure of Sph(f-) to drugs might be a versatile method to predict and reproduce clinical chronic toxicity, especially in response to repeated drug administration.

  5. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Ruibing [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Lihui [Shandong Normal University, Jinan, Shandong Province 250012 (China); Luo, Zheng; Guo, Xiaolan [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Ming, E-mail: ymylh@163.com [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  6. A Case of Supplement-Induced Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Fong-Kuei Frank Cheng

    2010-01-01

    Full Text Available A 45-year-old Caucasian male presented with a two-week history of jaundice and right-upper quadrant (RUQ abdominal pain. Transaminases and biliary enzymes were markedly elevated with hyperferritinemia and mildly elevated INR. Imaging tests showed no significant abnormality. He denied prescription or over-the-counter (OTC medication use, but he had been taking at least 9 dietary supplements for 12 months. Other causes of liver disease were excluded. His supplements were discontinued, and his liver-associated enzymes significantly markedly improved over the next 6 weeks and remained normal after one year suggesting supplement-induced hepatotoxicity. Due to the number of supplements, no specific agent could be identified as the primary cause of his liver injury. This case illustrates the importance of inquiring and educating patients of the potential harmful risks of over-the-counter medications and supplements.

  7. Kava hepatotoxicity: pathogenetic aspects and prospective considerations.

    Science.gov (United States)

    Teschke, Rolf

    2010-10-01

    Kava hepatotoxicity is a well-defined herb-induced liver injury, caused by the use of commercial anxyolytic ethanolic and acetonic kava extracts, and of traditional recreational aqueous kava extracts. The aim of this review is to elucidate possible pathogenetic factors for the development of kava-induced liver injury, considering also confounding variables. In patients with liver disease in a causal relation to kava ± comedication, confounding factors include non-adherence to therapy recommendations and comedication consisting of synthetic and herbal drugs and dietary supplements including herbal ones and herbs-kava mixtures. Various possible pathogenetic factors have to be discussed and comprise metabolic interactions with exogenous compounds at the hepatic microsomal cytochrome P450 level; genetic enzyme deficiencies; toxic constituents and metabolites derived from the kava extract including impurities and adulterations; cyclooxygenase inhibition; P-glycoprotein alterations; hepatic glutathione depletion; solvents and solubilizers of the extracts; and kava raw material of poor quality. In particular, inappropriate kava plant parts and unsuitable kava cultivars may have been used sometimes for manufacturing the kava extracts instead of the rhizome of a noble cultivar of the kava plant (Piper methysticum G. Forster). In conclusion, kava hepatotoxicity occurred independently of the extraction medium used for the kava extracts and may primarily be attributed to daily overdose, prolonged treatment and to a few kava extract batches of poor quality; by improving kava quality and adherence to therapy recommendation under avoidance of comedication, liver injury by kava should be a preventable disease, at least to a major extent. © 2010 John Wiley & Sons A/S.

  8. A Rare Side Effect of Metformin: Metformin-Induced Hepatotoxicity

    OpenAIRE

    Aksay, Ersin

    2007-01-01

    Metformin is an oral hypoglycemic agent that is commonly used in the treatment of type 2 diabetes mellitus. While metformin-associated metabolic acidosis is a widely recognized side effect of this drug, metformin-induced hepatotoxicity has been rarely reported in the literature. We present herein the case of a 52-year-old male in whom metformin-associated lactic acidosis and metformin-induced hepatotoxicity developed.

  9. The antiproton depth–dose curve measured with alanine detectors

    CERN Document Server

    Bassler, Niels; Palmans, Hugo; Holzscheiter, Michael H; Kovacevic, Sandra

    2008-01-01

    n this paper we report on the measurement of the antiproton depth–dose curve, with alanine detectors. The results are compared with simulations using the particle energy spectrum calculated by FLUKA, and using the track structure model of Hansen and Olsen for conversion of calculated dose into response. A good agreement is observed between the measured and calculated relative effectiveness although an underestimation of the measured values beyond the Bragg-peak remains unexplained. The model prediction of response of alanine towards heavy charged particles encourages future use of the alanine detectors for dosimetry of mixed radiation fields.

  10. Medical reference dosimetry using EPR measurements of alanine

    DEFF Research Database (Denmark)

    Helt-Hansen, Jakob; Rosendal, F.; Kofoed, I.M.

    2009-01-01

    Background. Electron spin resonance (EPR) is used to determine the absorbed dose of alanine dosimeters exposed to clinical photon beams in a solid-water phantom. Alanine is potentially suitable for medical reference dosimetry, because of its near water equivalence over a wide energy spectrum, low...... methods the proposed algorithm can be applied without normalisation of phase shifts caused by changes in the g-value of the cavity. The study shows that alanine dosimetry is a suitable candidate for medical reference dosimetry especially for quality control applications....

  11. Herbal hepatotoxicity: a tabular compilation of reported cases.

    Science.gov (United States)

    Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2012-11-01

    Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide. To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity. A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity. A total of 185 publications were identified and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specific ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan(®). In many other publications, however, causality was not properly evaluated by a liver-specific and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences). This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future. © 2012 John Wiley & Sons A/S.

  12. Calcium-deficient diet attenuates carbon tetrachloride-induced hepatotoxicity in mice through suppression of lipid peroxidation and inflammatory response

    Directory of Open Access Journals (Sweden)

    Hiroki Yoshioka

    2016-06-01

    Full Text Available The aim of this study is to investigate whether a Ca-deficient diet has an attenuating effect on carbon tetrachloride (CCl4-induced hepatotoxicity. Four-week-old male ddY mice were fed a Ca-deficient diet for 4 weeks as a part of the experimental protocol. While hypocalcemia was observed, there was no significant change in body weight. The CCl4-exposed hypocalcemic mice exhibited a significant decrease in alanine aminotransferase and aspartate aminotransferase activities at both 6 h and 24 h even though markers of renal function remained unchanged. Moreover, lipid peroxidation was impaired and total antioxidant power was partially recovered in the liver. Studies conducted in parallel with the biochemical analysis revealed that hepatic histopathological damage was attenuated 24 h post CCl4 injection in hypocalcemic mice fed the Ca-deficient diet. Finally, this diet impaired CCl4-induced inflammatory responses. Although upregulation of Ca concentration is a known indicator of terminal progression to cell death in the liver, these results suggest that Ca is also involved in other phases of CCl4-induced hepatotoxicity, via regulation of oxidative stress and inflammatory responses.

  13. ANTIHEPATOTOXIC EFFECT OF MARRUBIUM VULGARE AND WITHANIA SOMNIFERA EXTRACTS ON CARBON TETRACHLORIDE-INDUCED HEPATOTOXICITY IN RATS

    Science.gov (United States)

    Elberry, Ahmed A.; Harraz, Fathalla M.; Ghareib, Salah A.; Nagy, Ayman A.; Gabr, Salah A.; Suliaman, Mansour I.; Abdel-Sattar, Essam

    2010-01-01

    Marrubium vulgare and Withania somnifera are used in folk medicine of several countries. Many researches showed that they are used for the treatment of variety of diseases due to their antioxidant effects. The present aim of this study was to evaluate the antihepatotoxic and antioxidant activities of the both extracts against carbon tetrachloride (CCl4)-induced hepatic damage in rats. Both extracts were given orally in a dose of 500 mg/kg/day for 4 weeks along with CCl4 started at the 7th week of induction of hepatotoxicity. The antihepatotoxic activity was assessed by measuring aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), reduced glutathione (GSH), tissue content and malondialdehyde (MDA) as well as histopathological examination. Both extracts showed a significant antihepatotoxic effect by reducing significantly the levels of AST, ALT and LDH. However, ALP levels were decreased non-significantly. Regarding the antioxidant activity, they exhibited significant effects by increasing the GPx, GR and GST activities with increased GSH tissue contents and decreased production of MDA level. Furthermore, both extracts alleviated histopathological changes in rats’ liver treated with CCl4. M. vulgare and W. somnifera protect the rats’ liver against CCl4-induced hepatotoxicity. This effect may be attributed, at least in part, to the antioxidant activities of these extracts. PMID:24825994

  14. Protective effect of curcumin on experimentally induced inflammation, hepatotoxicity and cardiotoxicity in rats: evidence of its antioxidant property.

    Science.gov (United States)

    Naik, Suresh R; Thakare, Vishnu N; Patil, Snehal R

    2011-07-01

    The present study investigates the protective effects of curcumin on experimentally induced inflammation, hepatotoxicity, and cardiotoxicity using various animal models with biochemical parameters like serum marker enzymes and antioxidants in target tissues. In addition, liver and cardiac histoarchitecture changes were also studied. Curcumin treatment inhibited carrageenin and albumin induced edema, cotton pellet granuloma formation. The increased relative weight of liver and heart in CCl(4) induced liver injury and isoproterenol induced cardiac necrosis were also reduced by curcumin treatment. Elevated serum marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) increased lipid peroxidation, decreased gluthione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) in edematous, granulomatus, liver and heart tissues during inflammation, liver injury and cardiac necrosis, respectively. Curcumin treatment reversed all these above mentioned biochemical changes significantly in all animal models studied. Even histoarchitecture alterations observed in liver injury and cardiac necrosis observed were partially reversed (improved) by curcumin treatments. In in vitro experiments too curcumin inhibited iron catalyzed lipid peroxidation in liver homogenates, scavenged nitric oxide spontaneously generated from nitroprusside and inhibited heat induced hemolysis of rat erythrocytes. The present in vitro and in vivo experimental findings suggest the protective effect of curcumin on experimentally induced inflammation, hepatotoxicity, and cardiotoxicity in rats. Copyright © 2010 Elsevier GmbH. All rights reserved.

  15. Camellia sinensis L. Extract and Its Potential Beneficial Effects in Antioxidant, Anti-Inflammatory, Anti-Hepatotoxic, and Anti-Tyrosinase Activities

    Directory of Open Access Journals (Sweden)

    Surached Thitimuta

    2017-03-01

    Full Text Available The aims of this study were to investigate the potential benefits of antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities of a methanolic extract of fresh tea leaves (FTE (Camellia sinensis L.. The antioxidant capacity was investigated using three different methods at different temperatures. The anti-inflammatory activity was studied in vitro by the inhibition of 5-lipoxygenase assay. The anti-hepatotoxic effect was investigated in CCl4-induced liver injury in rats. The anti-tyrosinase activities of the FTE and its principal phenolic compounds were investigated in l-3,4-dihydroxyphenylalanine (l-DOPA oxidation by a mushroom tyrosinase. A molecular docking study was conducted to determine how the FTE’s principal catechins interact with the tyrosinase. The FTE exhibited the best shelf life at low temperatures and demonstrated concentration-dependent antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase effects compared to positive references. Treatment of rats with the FTE at 2000 mg/kg/day for 28 consecutive days reversed CCl4-induced oxidative damage in hepatic tissues by lowering the levels of alanine aminotransferase by 69% and malondialdehyde by 90%. Our findings suggest that the FTE has the capacity to scavenge free radicals and can protect against oxidative stress induced by CCl4 intoxication. The docking results were consistent with our in vitro data, indicating the anti-tyrosinase potency of the principal catechins.

  16. Camellia sinensis L. Extract and Its Potential Beneficial Effects in Antioxidant, Anti-Inflammatory, Anti-Hepatotoxic, and Anti-Tyrosinase Activities.

    Science.gov (United States)

    Thitimuta, Surached; Pithayanukul, Pimolpan; Nithitanakool, Saruth; Bavovada, Rapepol; Leanpolchareanchai, Jiraporn; Saparpakorn, Patchreenart

    2017-03-04

    The aims of this study were to investigate the potential benefits of antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities of a methanolic extract of fresh tea leaves (FTE) ( Camellia sinensis L.). The antioxidant capacity was investigated using three different methods at different temperatures. The anti-inflammatory activity was studied in vitro by the inhibition of 5-lipoxygenase assay. The anti-hepatotoxic effect was investigated in CCl₄-induced liver injury in rats. The anti-tyrosinase activities of the FTE and its principal phenolic compounds were investigated in l-3,4-dihydroxyphenylalanine (l-DOPA) oxidation by a mushroom tyrosinase. A molecular docking study was conducted to determine how the FTE's principal catechins interact with the tyrosinase. The FTE exhibited the best shelf life at low temperatures and demonstrated concentration-dependent antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase effects compared to positive references. Treatment of rats with the FTE at 2000 mg/kg/day for 28 consecutive days reversed CCl₄-induced oxidative damage in hepatic tissues by lowering the levels of alanine aminotransferase by 69% and malondialdehyde by 90%. Our findings suggest that the FTE has the capacity to scavenge free radicals and can protect against oxidative stress induced by CCl₄ intoxication. The docking results were consistent with our in vitro data, indicating the anti-tyrosinase potency of the principal catechins.

  17. Combination of LC/MS and GC/MS based metabolomics to study the hepatotoxic effect of realgar nanoparticles in rats.

    Science.gov (United States)

    Zhang, Mo-Han; Chen, Jia-Qing; Guo, Hui-Min; Li, Rui-Ting; Gao, Yi-Qiao; Tian, Yuan; Zhang, Zun-Jian; Huang, Yin

    2017-09-01

    Realgar nanoparticles (NPs) are increasingly used as therapeutic agents for their enhanced anti-proliferation effect and cytotoxicity on cancer cells. However, the alteration of particle size may enhance biological reactivity as well as toxicity. A LC/MS and GC/MS based metabolomics approach was employed to explore the mechanism of realgar NPs-induced hepatotoxicity and identify potential biomarkers. Male Sprague-Dawley rats were administrated intragastrically with realgar or realgar NPs at a dose of 1.0 g·kg -1 ·d -1 for 28 days and toxic effects of realgar NPs on liver tissues were examined by biochemical indicator analysis and histopathologic examination. Increased levels of serum enzymes and high hepatic steatosis were discovered in the realgar NPs treated group. Multivariate data analysis revealed that rats with realgar NPs-induced hepatotoxicity could be distinctively differentiated from the animals in the control and realgar treated groups. In addition, 21 and 32 endogenous metabolites were apparently changed in the serum and live extracts, respectively. Realgar NPs might induce free fatty acid and triglyceride accumulation, resulting in hepatotoxicity. In conclusion, the present study represents the first comprehensive LC/MS- and GC/MS-based metabolomics analysis of realgar NPs-induced hepatotoxicity, which may help further research of nanotoxicity. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  18. Alanine administration does not stimulate gluconeogenesis in preterm infants

    NARCIS (Netherlands)

    van Kempen, Anne A. M. W.; Romijn, Johannes A.; Ruiter, An F. C.; Endert, Erik; Weverling, Gerrit Jan; Kok, Johanna H.; Sauerwein, Hans P.

    2003-01-01

    Gluconeogenesis partially depends on sufficient precursor supply, and plasma alanine concentrations are generally low in preterm infants. Stimulation of gluconeogenesis may contribute to the prevention of hypoglycemia, an important clinical problem in these infants. In this study we evaluated the

  19. Mecanismos de hepatotoxicidade Mechanisms of hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Marcelo Chiara Bertolami

    2005-10-01

    Full Text Available Hepatopatia relacionada ao uso de drogas hipolipemiantes tem sido definida como um dano celular (aumento das enzimas AST e ALT sem alterações colestáticas (aumento de bilirrubinas e/ou fosfatase alcalina. Seis mecanismos são propostos para a hepatopatia: 1. Reações de alta energia no citocromo P450 comprometendo a homeostase do cálcio com a ruptura de fibrilas intracelulares e lise de hepatócitos. 2. Disfunção de proteínas transportadoras relacionadas com o fluxo de ácidos biliares (mecanismo proposto para a toxicidade hepática dos fibratos. 3. Reações imunes geradas pela formação de metabólitos das drogas hipolipemiantes formados no fígado. 4. Hepatoxicidade promovida por células T com inflamação adicional mediada por neutrófilos. 5. Apoptose mediada por TNF e Fas (imune-mediada. 6. Estresse oxidativo gerado por dano a organelas intracelulares. Ainda, idade avançada, consumo excessivo de álcool, altas doses de drogas hipolipemiantes, interação com outros fármacos, e doença hepática ativa prévia podem aumentar a hepatotoxidade.Liver disease following the use of hypolipidemic drugs has been reported as a cellular damage (increases in AST or ALT enzymes without cholestatic alterations (bilirubin and or alkaline phosphatase increases. Six mechanisms were proposed for hepatotoxicity : 1. High energy reactions on P450 cytochrome impairing calcium homestasis with rupture of intracellular fibrils and hepatocyte lysis. 2. Impairment of transporter proteins related to the bile acids flux (mechanism proposed for fibrate liver toxicity. 3. Immune reactions due to the formation of metabolites linked to enzymes following liver metabolism of hypolipidemic drugs. 4. Hepatotoxicity by T cells with additional inflammation mediated by neutrophils. 5. Apoptosis mediated by TNF and Fas (immune mediated. 6. Oxidative stress due to damage of intracellular organelles. In addition, advanced age, alcohol in excess, high doses of

  20. Determination of Alanine concentration in Alanine-supercritical water mixture, using UNIQUAC methods and density functional theory

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    Vahid mohammadrezaee

    2016-12-01

    Full Text Available In the following paper, density functional method and Universal QUAsi-chemical (UNIQUA activity index model were applied to calculate the concentration of Alanine I supercritical water. B3LYB method and 6-311G+ (2D, 2P basic function were used to optimize the molecular structure of Alanine, water and Alanine water complex. Then, reaction parameters of UNIQUAC model were calculated, using formation energy values. PCM method and zeropoint energy were utilized to include solvent effect and BSSE effect respectively. The resulted errors indicate that the method in a fairly good agreement with the experimental data. Including SSE in the interaction parameter calculations reduces the total error significantly. According to our calculations theAlanine- water complex showed a negative deviation from Raoul’s law.

  1. Modifiable clinical and lifestyle factors are associated with elevated alanine aminotransferase levels in newly diagnosed type 2 diabetes patients

    DEFF Research Database (Denmark)

    Mor, Anil; Svensson, Elisabeth; Rungby, Jørgen

    2014-01-01

    BACKGROUND: Current literature lacks data on markers of non-alcoholic fatty liver disease (NAFLD) in newly diagnosed type 2 diabetes mellitus (T2DM) patients. We therefore, conducted a cross-sectional study to examine modifiable clinical and lifestyle factors associated with elevated alanine...... aminotransferase (ALT) levels as a marker of NAFLD in new T2DM patients. METHODS: Alanine aminotransferase levels were measured in 1026 incident T2DM patients enrolled in the nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. We examined prevalence of elevated ALT (>38 IU/L for women...... and >50 IU/L for men) and calculated prevalence ratios associated with clinical and lifestyle factors using Poisson regression. We examined the association with other biomarkers by linear regression. RESULTS: The median value of ALT was 24 IU/L (interquartile range: 18-32 IU/L) in women and 30 IU...

  2. Silymarin nanoparticle prevents paracetamol-induced hepatotoxicity.

    Science.gov (United States)

    Das, Suvadra; Roy, Partha; Auddy, Runa Ghosh; Mukherjee, Arup

    2011-01-01

    Silymarin (Sm) is a polyphenolic component extracted from Silybum marianum. It is an antioxidant, traditionally used as an immunostimulant, hepatoprotectant, and dietary supplement. Relatively recently, Sm has proved to be a valuable chemopreventive and a useful antineoplastic agent. Medical success for Sm is, however, constrained by very low aqueous solubility and associated biopharmaceutical limitations. Sm flavonolignans are also susceptible to ion-catalyzed degradation in the gut. Proven antihepatotoxic activity of Sm cannot therefore be fully exploited in acute chemical poisoning conditions like that in paracetamol overdose. Moreover, a synchronous delivery that is required for hepatic regeneration is difficult to achieve by itself. This work is meant to circumvent the inherent limitations of Sm through the use of nanotechnology. Sm nanoparticles (Smnps) were prepared by nanoprecipitation in polyvinyl alcohol stabilized Eudragit RS100(®) polymer (Rohm Pharma GmbH, Darmstadt, Germany). Process parameter optimization provided 67.39% entrapment efficiency and a Gaussian particle distribution of average size 120.37 nm. Sm release from the nanoparticles was considerably sustained for all formulations. Smnps were strongly protective against hepatic damage when tested in a paracetamol overdose hepatotoxicity model. Nanoparticles recorded no animal death even when administered after an established paracetamol-induced hepatic necrosis. Preventing progress of paracetamol hepatic damage was traced for an efficient glutathione regeneration to a level of 11.3 μmol/g in hepatic tissue due to Smnps.

  3. Hepatotoxicity evaluation of dextran stabilized iron oxide nanoparticles in Wistar rats.

    Science.gov (United States)

    Easo, Sheeja Liza; Mohanan, P V

    2016-07-25

    Cellular and organ responses to nanoparticles are relevant in the context of use of nanoparticles for biomedical applications. The purpose of the present study was to determine the potential of dextran stabilized iron oxide nanoparticles (DIONPs) to influence hepatic uptake and consequently induce hepatotoxic response in rats following intravenous administration. Inductively coupled plasma atomic emission spectroscopy analysis revealed that DIONPs are rapidly taken up into the liver, progressively broken down to iron constituents and exported into blood, with a part of it being retained in the liver. The potential of DIONPs to induce oxidative stress response was determined by evaluating the time-dependent redox defense status. Maximum alterations in antioxidant activities were observed to occur within a period of 7days. However, this effect was not followed by significant increase in lipid peroxidation or modulation of hepatic enzymes such as alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and bilirubin levels. Overall, these data imply that the liver retains functional integrity with a dose of 10mg/kg DIONPs, although with brief activation of redox defenses. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Calotropis procera latex affords protection against carbon tetrachloride induced hepatotoxicity in rats.

    Science.gov (United States)

    Padhy, B M; Srivastava, A; Kumar, V L

    2007-09-25

    In the present study, latex of Calotropis procera possessing potent antioxidant and anti-inflammatory properties was evaluated for its hepatoprotective effect against carbon tetrachloride (CCl(4)) induced hepatotoxicity in rats. Subcutaneous injection of CCl(4,) administered twice a week, produced a marked elevation in the serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and tumor necrosis factor alpha (TNF-alpha). Histological analysis of the liver of these rats revealed marked necro-inflammatory changes that were associated with increase in the levels of TBARS, PGE(2) and catalase and decrease in the levels of glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Daily oral administration of aqueous suspension of dried latex (DL) of Calotropis procera at 5, 50 and 100mg/kg doses produced a dose-dependent reduction in the serum levels of liver enzymes and inflammatory mediators and attenuated the necro-inflammatory changes in the liver. The DL treatment also normalized various biochemical parameters of oxidative stress. Our study shows that the antioxidant and anti-inflammatory effects of DL and silymarin were comparable and suggests that DL could be used as a hepatoprotective agent.

  5. Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity

    Science.gov (United States)

    Craig, Darren G N; Bates, Caroline M; Davidson, Janice S; Martin, Kirsty G; Hayes, Peter C; Simpson, Kenneth J

    2011-01-01

    AIMS Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported. METHODS Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses. PMID:21219409

  6. Protective effect of Coleus aromaticus Benth (Lamiaceae) against naphthalene-induced hepatotoxicity.

    Science.gov (United States)

    Vijayavel, K; Anbuselvam, C; Ashokkumar, B

    2013-04-01

    To investigate protective effect of Coleus aromaticus leaf extract against naphthalene induced hepatotoxicity in rats. Eighteen male rats were divided into three groups. Group I rats were treated as control. Group II rats were intraperitoneally administered with naphthalene (435 mg/kg b.wt) dissolved in corn oil once a day for a period of 30 days. Group III rats were treated with leaf extract (100 mg/kg b.wt) dissolved in 0.9% saline and naphthalene (435 mg/kg b.wt) dissolved in corn oil once a day for a period of 30 days. Significant protective effect was observed against naphthalene induced liver damage, which appeared evident from the response levels of marker enzymes (aspartate transaminase, alanine transaminase, acid phosphatase, alkaline phosphatase and lactate dehydrogenase). The biochemical components viz. triglycerides, free fatty acids, cholesterol acyl transferase, high-density lipoprotein, low-density lipoprotein, cholesterol and bilirubin were found to be increased in liver and serum of naphthalene stressed rats when compared to control. Treatment of naphthalene intoxicated rats with plant extract reversed these distorted parameters to near normal levels. Liver histology showed supportive evidence regarding the protective nature of plant extract against fatty changes induced by naphthalene. The present study provides a scientific rationale for using C. aromaticus in the management of liver disorders. Copyright © 2013 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  7. Amelioration of lead-induced hepatotoxicity by Allium sativum extracts in Swiss albino mice

    Science.gov (United States)

    Sharma, Arti; Sharma, Veena; Kansal, Leena

    2010-01-01

    Lead is a blue–gray and highly toxic divalent metal that occurs naturally in the earth's crust and is spread throughout the environment by various human activities. The efficacy of garlic (Allium sativum) to reduce hepatotoxicity induced by lead nitrate was evaluated experimentally in male mice. Oral treatment with lead nitrate at a dose of 50 mg/kg body weight daily for 40 days (1/45 of LD50) induced a significant increase in the levels of hepatic aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acid phosphatase, cholesterol, lipid peroxidation, and lead nitrate. In parallel, hepatic protein levels in lead-exposed mice were significantly depleted. Lead nitrate exposure also produced detrimental effects on the redox status of the liver indicated by a significant decline in the levels of liver antioxidants such as superoxide dismutase, catalase, and glutathione. After exposure to lead nitrate (50 mg/kg body weight for 10 days), the animals received aqueous garlic extract (250 mg/kg body weight and 500 mg/kg body weight) and ethanolic garlic extract (100 mg/kg body weight and 250 mg/kg body weight), and partially restored the deranged parameters significantly. Histological examination of the liver also revealed pathophysiological changes in lead nitrate-exposed group and treatment with garlic improved liver histology. Our data suggest that garlic is a phytoantioxidant that can counteract the deleterious effects of lead nitrate. PMID:21483544

  8. Protective effects of vitamins C and E against hepatotoxicity induced by methyl parathion in rats.

    Science.gov (United States)

    Uzunhisarcikli, Meltem; Kalender, Yusuf

    2011-10-01

    Male rats were given vitamins C+E, methyl parathion, or both daily via gavage for seven weeks. Body weight was decreased while liver weight increased significantly at the end of fourth and seventh weeks in the methyl parathion- and methyl parathion plus vitamin-treated groups. Serum total protein, albumin, triglyceride, low density lipoprotein-cholesterol (VLDL-cholesterol) levels decreased, and serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl-transferase (GGT), lactate dehydrogenase (LDH), and total cholesterol levels increased significantly in the methyl parathion- and the methyl parathion plus vitamin-treated rats. There was a statistically significant difference for all biochemical parameters when the methyl parathion plus vitamin-treated group was compared with methyl parathion-treated group. In electron microscopic investigation, cytopathological alterations were observed in hepatocytes of the methyl parathion- and the methyl parathion plus vitamin-treated rats. As a result, methyl parathion-induced hepatotoxicity is reduced by vitamins C+E, but vitamins C+E did not provide complete protection. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Amelioration of carbon tetrachloride-induced hepatotoxicity by terpenoid extract from leaves of Vernonia amydgalina.

    Science.gov (United States)

    Babalola, O O; Anetor, J I; Adeniyi, F A

    2001-01-01

    Sesquiterpene lactone extract from the leaves of Vernonia amygdalina was tested for antihepatotoxic activity. Adult male rats were selected for the study. One group of rats was treated with toxic doses of carbon tetrachloride (CCl4) the second group was pretreated with known concentration of terpenoid extract from leaves of V. amygdalina. One hour prior to receiving toxic doses of CCl4, Kolaviron, a biflavonoid extract of the seeds of Garcina kola was used as a positive control. Serum enzymes, alanine amino transferase (ALT), ornithine carbamoyl transferase (OCT) that are known to be very sensitive to cytotoxic hepatic injury, and aspertate amino transferase (AST) that is particularly sensitive to carbon tetrachloride poisoning, were measured as indices of hepatotoxicity. The results obtained showed that there were reduction in the activities of serum ALT, AST and OCT from 20.57 +/- 5.59, 10.46 +/- 6.71 and 184.8 +/- 10.45 in animals treated with toxic doses of CCl4 to 3.40 +/- 0.10, 3.95 +/- 0.15 and 1293 +/- 12.10 in animal pretreated with terpenoid extract before CCl4 intoxication, representing 83.5%, 62.3%, and 30% decrease respectively. These decreases were statistically significant (P sesquiterpene lactone extract from the leaves of V. amygdalina like kolaviron, a biflavonoid extract from the seeds of G. kola has antihepatotoxic activity in CCl4-induced hepatic damage in rats.

  10. Amelioration of acetaminophen induced hepatotoxicity by methanolic extract of pomegranate peels in rats.

    Science.gov (United States)

    Ahmad, Nadia; Tahir, Mohammad; Lone, Khalid Perwez

    2016-07-01

    To observe the ameliorating effect by methanolic extract of pomegranate peel in acetaminophen-induced hepatotoxicity. The randomised controlled study was conducted from July 2013 to June 2014 at the University of Health Sciences, Lahore, Pakistan, and comprised rats that were randomly divided into three equal groups. Control group A was given normal saline (5ml/kg), whereas group B and C were given 750mg/kg acetaminophen intraperitoneally dissolved in normal saline (5ml/kg) on 1st day of experiment. From Day 2 till day 14, group A and B were given distilled water (5ml/kg), while group C was given 50mg/kg methanolic extract of pomegranate peel dissolved in distilled water (5ml/kg) orally. On day 15, blood was collected through cardiac puncture, and livers were removed and processed for histological examination. There were 24 rats weighing 175±25gm each. Each group had 8(33.3%) rats. Mean liver aspartate aminotransferase at the end of the experiment in groups A, B and C were 97.88±19.45, 148.25±16.48 and 96.13±17.95U/L, while alanine transaminase levels were 51.50±15.38, 96.75±10.91 and 49.63±12.08 U/L (ppomegranate peel ameliorated the hepatic picture probably because of its antioxidant properties.

  11. Effect of indigestible oligosaccharides on the hepatotoxic action of D-galactosamine in rats.

    Science.gov (United States)

    Wang, B; Egashira, Y; Ohta, T; Sanada, H

    1998-08-01

    The effects of dietary oligosaccharides on the hepatotoxic action of D-galactosamine (GalN) were investigated in this study. Male Wistar rats fed with 20% casein diets containing 10% oligosaccharide or D-galactose (Gal) for 2 weeks were injected with GalN (1,900 mg/kg of body weight), and the plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the hepatic glycogen concentration were examined 20 hours after the injection. The plasma AST and ALT activities in experiment 1 for the Gal + neomycin (NEO) group were significantly lower than those for the control (C), NEO, raffinose (RAF) + NEO and galacto-oligosaccharide (GA-LO) + NEO groups. In experiment 2, these activities were significantly lower in the Gal, Gal + NEO and RAF groups than in the RAF + NEO group when the groups were treated with GalN. On the other hand, in respect of the hepatic glycogen concentration in experiment 1, that of the Gal + NEO group was higher than that of the C, NEO, RAF + NEO or GALO + NEO groups. In experiment 2, this parameter was significantly higher in the Gal, Gal + NEO and RAF groups than in the RAF + NEO group after the GalN treatment. As a result, it is suggested that the GalN-hepatitis-suppressive effects of indigestible oligosaccharides such as RAF or GALO is mediated by the action of intestinal bacteria.

  12. Protective effect of boric acid against carbon tetrachloride-induced hepatotoxicity in mice.

    Science.gov (United States)

    Ince, Sinan; Keles, Hikmet; Erdogan, Metin; Hazman, Omer; Kucukkurt, Ismail

    2012-07-01

    The protective effect of boric acid against liver damage was evaluated by its attenuation of carbon tetrachloride (CCl(4))-induced hepatotoxicity in mice. Male albino mice were treated intraperitoneally (i.p.) with boric acid (50, 100, and 200 mg/kg) or silymarin daily for 7 days and received 0.2% CCl(4) in olive oil (10 mL/kg, i.p.) on day 7. Results showed that administration of boric acid significantly reduced the elevation in serum levels of aspartate aminotransferase, alkaline phosphatase, alanine aminotransferase, and the level of malondialdehyde in the liver that were induced by CCl(4) in mice. Boric acid treatment significantly increased glutathione content, as well as the activities of superoxide dismutase and catalase in the liver. Boric acid treatment improved the catalytic activity of cytochrome P450 2E1 and maintained activation of nuclear factor kappa light-chain enhancer of activated B cell gene expression, with no effect on inducible nitric oxide synthase gene expression in the livers of mice. Histopathologically, clear decreases in the severity of CCl(4)-induced lesions were observed, particularly at high boric acid concentrations. Results suggest that boric acid exhibits potent hepatoprotective effects on CCl(4)-induced liver damage in mice, likely the result of both the increase in antioxidant-defense system activity and the inhibition of lipid peroxidation.

  13. Research Advances on Hepatotoxicity of Herbal Medicines in China

    Directory of Open Access Journals (Sweden)

    Changxiao Liu

    2016-01-01

    Full Text Available In general, herbal medicines have been considered as safe by the general public, since they are naturally occurring and have been applied in treatment for over thousands of years. As the use of herbal medicine is rapidly increasing globally, the potential toxicity of herbal drugs, in particular drug-induced liver injury (DILI, has now become a serious medical issue. According to the literature, the authors analyzed and discussed the hepatotoxicity problem of Chinese herbal medicines (CHM, including global overview on herbal-induced liver injury (HILI, current research progress on toxic CHM, diagnosis and treatment of HILI, and modern approaches and technologies of study of hepatotoxicity. As to promote the recognition of HILI and tackle the issue, a guideline for the diagnosis and treatment of HILI has recently been drafted by Chinese scientists. As suggested by the guideline, the hepatotoxicity issue of CHM, as a matter of fact, is overestimated. Up to date, the investigation of hepatotoxicity of CHM is now booming with worldwide application of CHM. This review therefore provides useful information for investigating hepatotoxicity of herbal medicine and characterizing DILI caused by CHM. In addition, authors describe in which way further efforts should be made to study the rationale of CHM and liver injury.

  14. Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice.

    Directory of Open Access Journals (Sweden)

    Jing-Dun Xie

    Full Text Available Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC. Aspartate transaminase (AST, alanine aminotransferase (ALT, and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl-3,5-diphenylformazan (MTT, and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2 of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided.

  15. Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice

    Science.gov (United States)

    Pan, Jia-Hao; Bi, Bing-Tian; Feng, Kun-Yao; Huang, Wan; Zeng, Wei-An

    2015-01-01

    Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided. PMID:26633878

  16. Caramelization of maltose solution in presence of alanine.

    Science.gov (United States)

    Fadel, H H M; Farouk, A

    2002-01-01

    Two solutions of maltose in water were used to prepare caramels. Alanine as a catalyst was added to one of these solutions. The caramelization was conducted at 130 degrees C for total time period 90 minutes. Convenient samples were taken of each caramel solution every 30 min and subjected to sensory analysis and isolation of volatile components. The odour and colour sensory tests were evaluated according to the international standard methods (ISO). The results showed that, the presence of alanine gave rise to a high significant (P caramel attributes, which are the most important caramel notes. On the other hand the increase in heating time in presence of alanine as a catalyst resulted in a high significant (P caramel solution. The new technique Solid Phase Micro Extraction (SPME) was used for trapping the volatile components in the headspace of each caramel samples followed by thermal desorption and GC and GC - MS analysis. The 5-hydroxymethyl-2-furfural (HMF), the main characteristic caramel product, showed its highest value in sample containing alanine after heating for 60 minutes. The best sensory results of the sample contains alanine were confirmed by the presence of high concentrations of the most potent odorants of caramel besides to the formation of some volatile compounds have caramel like flavours such as 2-acetyl pyrrole, 2-furanones and 1-(2-furanyl)1,2-propandione.

  17. EPR structure of the gamma irradiated alanine spectrum

    Energy Technology Data Exchange (ETDEWEB)

    Cabral P, A.; Jimenez D, H.; Urena N, F.; Galindo, S.; Bosch, P

    1992-03-15

    In this study is shown that the broadened five-line EPR pattern of the gamma irradiated alanine possibly decomposes into a more complex pattern when the recorded spectrum is subject to an operation of deconvolution. The EPR powder spectra of gamma irradiated DL- and L-alanine with and without binders are analysed. In all recorded spectra, each observed line is resolved into an asymmetrical triplet when a Gaussian distribution of 8.2 gauss width is removed, by deconvolution, from the observed spectrum. On the other hand, from a simple fitting analysis carried out on the original data, one encounters that some calculated relations between characteristic parameters, such as intensity ratios, deviate consistently from assumed height ratios. Both, from deconvolution and fitting results, a different structure is suggested for the observed broadened five-line EPR pattern of {gamma}-irradiated powder DL- and L-alanine. (Author)

  18. Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice.

    Science.gov (United States)

    Sheweita, Salah A; El-Hosseiny, Lobna S; Nashashibi, Munther A

    2016-01-01

    Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn't change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared

  19. Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice

    Science.gov (United States)

    Sheweita, Salah A.; El-Hosseiny, Lobna S.; Nashashibi, Munther A.

    2016-01-01

    Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn’t change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared

  20. Inhibition of hepatobiliary transporters by a novel kinase inhibitor contributes to hepatotoxicity in beagle dogs.

    Science.gov (United States)

    Daniels, John Scott; Lai, Yurong; South, Sarah; Chiang, Po-Chang; Walker, Daniel; Feng, Bo; Mireles, Rouchelle; Whiteley, Laurence O; McKenzie, Jeremy W; Stevens, Jeffrey; Mourey, Robert; Anderson, David; Davis Ii, John W

    2013-03-01

    PF-022 (1) is a novel polycyclic benzothiophene kinase inhibitor selective for mitogen-activated protein kinase-activated protein kinase 2 (MK2). Compound 1 emerged as an inhibitor bearing submicromolar potency against MK2 (IC50 5 nM) and demonstrated projected human pharmacokinetics sufficient for oral dosing. However, following a single, oral administration of 1 to beagle dogs, animals experienced an acute liver injury characterized by increases in biomarkers associated with hepatotoxicity; particularly noteworthy was the reversible elevation in bile salts and total bilirubin. Accompanying this observation was an ADME appraisal which included hepatic bioactivation of 1 in multiple species and the in vitro inhibition of P-glycoprotein (P-gp; IC50 21 μM). Simply attenuating the bioactivation via structural modification proved ineffective in improving the in vivo tolerability of this polycyclic scaffold. Hence, disruption of hepatobiliary transporters by the compound series was hypothesized as the likely mechanism contributing to the acute hepatotoxicity. Indeed, closer in vitro examination employing transporter gene overexpressing MDCK cell lines and membrane vesicles revealed potent compound-dependent inhibition of human multi-drug resistance-associated protein 2 (MRP2/ABCC2; IC50 38 μM) and bile salt export pump (BSEP/ABCB11; IC50 10 μM), two crucial hepatobiliary transport proteins accountable for bilirubin and bile salt homeostasis, respectively. Subsequent introduction of pKa-altering modifications to a second generation compound PF029 proved successful in reducing its affinity for these key efflux transporters (MRP2 IC50 >80 μM; BSEP IC50 > 70 μM; P-gp > 90 μM), consequently mitigating this overt organ toxicity in dogs.

  1. Microhardness studies on nonlinear optical L-alanine single crystals

    Indian Academy of Sciences (India)

    alanine single crystals by slow evaporation technique over a load range of 10–50 g on selected broad (2 0 3) plane. Vickers (Hv) and Knoop (Hk) microhardness for the above loads were found to be in the range of 60–71 kg/mm2 and 35–47 ...

  2. Impact of weight reduction program on serum alanine ...

    African Journals Online (AJOL)

    Impact of weight reduction program on serum alanine aminotransferase activity and immunologic response in obese hepatitis B patients. Shehab Mahmoud Abd El- Kader1, Mohammed H Saiem Al-Dahr2. 1. Department of Physical Therapy, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi.

  3. Pressure-induced phase transformations in L-alanine crystals

    DEFF Research Database (Denmark)

    Olsen, J. Staun; Gerward, Leif; Freire, P.T.C.

    2008-01-01

    Raman scattering and synchrotron X-ray diffraction have been used to investigate the high-pressure behavior of L-alanine. This study has confirmed a structural phase transition observed by Raman scattering at 2.3 GPa and identified it as a change from orthorhombic to tetragonal structure. Another...

  4. Impact of weight reduction program on serum alanine ...

    African Journals Online (AJOL)

    In addition, there were significant differences between mean levels of the investigated parameters in groups. Conclusion: Based on our findings, weight loss modulates serum alanine aminotransferase and immune system parameters of patients with hepatitis B virus infection. Keywords: Hepatitis B virus, obesity, immune ...

  5. The Antiproton Depth Dose Curve Measured with Alanine Detectors

    DEFF Research Database (Denmark)

    Bassler, Niels; Hansen, Johnny Witterseh; Palmans, Hugo

    2008-01-01

    In this paper we report on the measurement of the antiproton depth dose curve, with alanine detectors. The results are compared with simulations using the particle energy spectrum calculated by FLUKA, and using the track structure model of Hansen et Olsen for conversion of calculated dose...

  6. The Response of Alanine Dosimeters in Thermal Neutron Fields

    DEFF Research Database (Denmark)

    Schmitz, T.; Bassler, Niels; Sharpe, P.

    component. All alanine pellets irradiated are manufactured and read out at the National Physical Laboratory (NPL), United Kingdom [4]. To predict the dose and its components for each pellet, the Hansen & Olsen detector response model [5] is applied along together with FLUKA [6]. Results: The measured dose...

  7. Correlation between alanine aminotransferase level, HCV-RNA titer ...

    African Journals Online (AJOL)

    Reham Al Swaff

    2012-04-04

    Apr 4, 2012 ... Abstract The relationship of serum alanine aminotransferase (ALT) level and viral replication to liver damage in chronic hepatitis C virus (HCV) patients remains unclear. The aim of the present study was to determine whether the stage of fibrosis correlates with HCV-. RNA titer and/or serum ALT level in ...

  8. Hepatotoxic and Nephrotoxic Effects of Petroleum Fumes on Petrol ...

    African Journals Online (AJOL)

    The present study was conducted to evaluate the hepatotoxic and nephrotoxic effects of petroleum fumes on male and female petrol attendants. Investigations had been carried out on thirty (30) adult petrol attendants from different filling stations in Ibadan metropolis of Nigeria with ten (10) healthy adults as control. All the ...

  9. Activation of Nrf2 protects against triptolide-induced hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Jia Li

    Full Text Available Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF, has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2 in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN, attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.

  10. The Effects of Bitter Kola Supplemented Diet on Hepatotoxicity of ...

    African Journals Online (AJOL)

    MICHAEL

    ABSTRACT: The effect of bitter kola on the hepatotoxicity following mercury poisoning (mercuric chloride solution of 10ppm) was investigated in rats for a duration of six weeks. Thirty (30) acclimatized Wistar rats were divided into five groups(n=6).Group I served as control and were fed on normal rat chow and clean.

  11. Inhibition of autophagy protects against PAMAM dendrimers-induced hepatotoxicity.

    Science.gov (United States)

    Li, Yubin; Zeng, Xian; Wang, Shaofei; Sun, Yun; Wang, Ziyu; Fan, Jiajun; Song, Ping; Ju, Dianwen

    2015-05-01

    Toxicity of nanomaterials is one of the biggest challenges in their medicinal applications. Although toxicities of nanomaterials have been widely reported, the exact mechanisms of toxicities are still not well elucidated. Consequently, the exploration of approaches to attenuate toxicities of nanomaterials is limited. In this study, we reported that poly-amidoamine (PAMAM) dendrimers, a widely used nanomaterial in the pharmaceutical industry, caused toxicity of human liver cells by inducing cell growth inhibition, mitochondria damage, and apoptosis. Meanwhile, autophagy was activated in PAMAM dendrimers-induced toxicity and inhibition of autophagy-rescued viability of hepatic cells, indicating that autophagy played a key role in PAMAM dendriemrs-induced hepatotoxicity. To further explore approaches to attenuate PAMAM dendrimers-induced liver injury, effects of autophagic inhibitors on PAMAM dendrimers' hepatotoxicity were investigated in an in vivo model. Autophagy blockage in PAMAM dendrimers-administered mice led to weight restoration, damage reversion of liver tissue, and protection against changes of serum biochemistry parameters. Moreover, inhibition of Akt/mTOR and activation of Erk1/2 signaling pathways were involved in PAMAM dendrimers-induced autophagy. Collectively, these findings indicated that autophagy was associated with PAMAM dendrimers-induced hepatotoxicity, and supported the possibility that autophagy inhibitors could be used to reduce hepatotoxicity of PAMAM dendrimers.

  12. Effect of propolis consumption on hepatotoxicity and brain damage ...

    African Journals Online (AJOL)

    This study was undertaken to determine the protective effect of propolis against the hepatotoxicity and brain damage of chlorpyrifos (CPF) in male rats. Animals were assigned to one of four groups. The first group was used as control. Groups 2, 3 and 4 were treated with 6.8 mg CPF /kg BW (1/20 LD50); 50 mg propolis/kg ...

  13. Hepatotoxicity and Associated Risk Factors in Hiv-Infected Patients ...

    African Journals Online (AJOL)

    Hepatotoxicity and Associated Risk Factors in Hiv-Infected Patients Receiving Antiretroviral Therapy at Felege Hiwot Referral Hospital, Bahirdar, Ethiopia. ... over use (P=0.014; AOR = 1.23; CI: 1.36- 3.29) and detectable HIV-1 RNA copies (P=0.015; AOR=2.07; CI: 1.15-3.74) independently predicts the elevation of ALT.

  14. Hepatotoxic effects of low dose oral administration of monosodium ...

    African Journals Online (AJOL)

    The present study is aimed at investigating the potentials of low concentration administration of monosodium glutamate in inducing hepatotoxic effects in male albino rats. Thus, monosodium glutamate at a dose of 5 mg/kg of body weight was administered to adult male albino rats by oral intubation. Treatment was daily for ...

  15. Sub-acute hepatotoxicity of Pausinystalia yohimbe bark extract ...

    African Journals Online (AJOL)

    It increases blood flow to erectile tissues and exerts its erectogenic effects through a central action and peripheral autonomic nervous system effects. Aim: This study was carried out to examine the hepatotoxicity and cellular deleterious effects of Pausinystalia yohimbe bark ethanolic extract used as burantashi at varying ...

  16. Anti-hepatotoxic effect of Casuarina stricta and Casuarina suberosa ...

    African Journals Online (AJOL)

    The aim of the present study was to investigate the protective and antioxidant effects of methanolic extract of Casuarina stricta and Casuarina suberosa leaves on ethanol induced hepatotoxicity in rats. The ethanol intoxication (1 ml of 40 % ethanol for 100 gm body weight for 6 weeks) to rats resulted in a significant increase ...

  17. ideal hepatotoxicity model in rats using carbon tetrachloride (ccl4)

    African Journals Online (AJOL)

    DR. AMINU

    ABSTRACT. A study to produce ideal Hepatotoxicity rats' models using varying concentrations of carbon tetrachloride (CCl4) was carried out. A total of seventy five rats were divided into five (5) groups of twenty five (25) rats each; rats in group I are negative control, were not induced with lipid peroxidation. Rats in groups II, ...

  18. Amelioration of carbon tetrachloride-induced hepatotoxicity and ...

    African Journals Online (AJOL)

    This study was conducted to explore possible protective effect of Cnidoscolus aconitifolius (CA) leaf extract on carbon tetrachloride (CCl4)-induced hepatotoxicity and haemotoxicity in experimental animal models. Thirty six rats of six per group were used in this study. Group I received 10ml/kg normal saline as control.

  19. Influence of extraction methods on the hepatotoxicity of Azadirachta ...

    African Journals Online (AJOL)

    The influence of extraction methods: Cold aqueous (CA) hot aqueous (HA) and alcoholic extraction (AE) methods on the hepatotoxic effect of Azadirachta indica bark extract (ABC) was investigated using albino rats. A total of forty eight rats were divided into three groups of sixteen rats equally for the extraction methods.

  20. CCl 4 -Induced Hepatotoxicity: Protective Effects of Carnosine on ...

    African Journals Online (AJOL)

    CCl4) induced oxidative stress and hepatotoxicity in rats was investigated. Liver toxicity was induced in rat model at which four experimental groups of 20 rats each were constructed: group (1) the control group in which rats were not ...

  1. Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice

    Energy Technology Data Exchange (ETDEWEB)

    Hagiya, Yoshifumi; Kamata, Shotaro; Mitsuoka, Saya; Okada, Norihiko; Yoshida, Saori; Yamamoto, Junya; Ohkubo, Rika [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Abiko, Yumi [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Yamada, Hidenori [Jobu Hospital for Respiratory Diseases, Maebashi 371-0048 (Japan); Akahoshi, Noriyuki [Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543 (Japan); Kasahara, Tadashi [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Kumagai, Yoshito [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Ishii, Isao, E-mail: isao-ishii@umin.ac.jp [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan)

    2015-01-15

    The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs{sup +/−} or Cth{sup +/−}) and homozygous (Cth{sup −/−}) knockout mice. At 4 h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth{sup −/−} mice at 150 mg/kg dose, and also in Cbs{sup +/−} or Cth{sup +/−} mice at 250 mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth{sup −/−} mice but not wild-type mice, although glutamate–cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth{sup −/−} mice with lower K{sub m} values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150 mg acetaminophen/kg into Cth{sup −/−} mice; the profiles were similar to 1000 mg acetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200–300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities. - Highlights: • Cbs{sup +/−}, Cth{sup +/−}, and

  2. Crystal structures of d-alanine-d-alanine ligase from Xanthomonas oryzae pv. oryzae alone and in complex with nucleotides.

    Science.gov (United States)

    Doan, Thanh Thi Ngoc; Kim, Jin-Kwang; Ngo, Ho-Phuong-Thuy; Tran, Huyen-Thi; Cha, Sun-Shin; Min Chung, Kyung; Huynh, Kim-Hung; Ahn, Yeh-Jin; Kang, Lin-Woo

    2014-03-01

    D-Alanine-D-alanine ligase (DDL) catalyzes the biosynthesis of d-alanyl-d-alanine, an essential bacterial peptidoglycan precursor, and is an important drug target for the development of antibacterials. We determined four different crystal structures of DDL from Xanthomonas oryzae pv. oryzae (Xoo) causing Bacteria Blight (BB), which include apo, ADP-bound, ATP-bound, and AMPPNP-bound structures at the resolution between 2.3 and 2.0 Å. Similarly with other DDLs, the active site of XoDDL is formed by three loops from three domains at the center of enzyme. Compared with d-alanyl-d-alanine and ATP-bound TtDDL structure, the γ-phosphate of ATP in XoDDL structure was shifted outside toward solution. We swapped the ω-loop (loop3) of XoDDL with those of Escherichia coli and Helicobacter pylori DDLs, and measured the enzymatic kinetics of wild-type XoDDL and two mutant XoDDLs with the swapped ω-loops. Results showed that the direct interactions between ω-loop and other two loops are essential for the active ATP conformation for D-ala-phosphate formation. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Structure of the Mycobacterium tuberculosis D-Alanine:D-Alanine Ligase, a Target of the Antituberculosis Drug D-Cycloserine

    Energy Technology Data Exchange (ETDEWEB)

    Bruning, John B.; Murillo, Ana C.; Chacon, Ofelia; Barletta, Raúl G.; Sacchettini, James C. (TAM); (UNL)

    2011-09-28

    D-Alanine:D-alanine ligase (EC 6.3.2.4; Ddl) catalyzes the ATP-driven ligation of two D-alanine (D-Ala) molecules to form the D-alanyl:D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development. D-Cycloserine (DCS), an analog of D-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure of Mycobacterium tuberculosis Ddl at a resolution of 2.1 {angstrom}. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoined by several loop regions. The M. tuberculosis apo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide and D-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP and D-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed for D-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC{sub 50}) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors.

  4. Semiprotective Effects of Hempseed Oil on Carbon Tetrachloride-induced Hepatotoxicity in Male Rats: An Ultra-short Toxicological Intervention

    Directory of Open Access Journals (Sweden)

    Mona Hashemzadeh

    2017-12-01

    Full Text Available This study was designed to investigate the protective activity of hempseed oil on carbon tetrachloride (CCl4 hepatotoxicity in male rats at Islamic Azad University, Saveh Branch, Saveh, Iran in 2015. Normal control (NC group was injected intraperitoneally (i.p. with distilled water (0.5 ml/kg; CCl4-intoxicated group (TCC injected CCl4; hempseed oil treated group (HSO gavaged hempseed oil; TCC-HSO group was injected CCl4 prior to intake of hempseed oil and HSO-TCC group was gavaged hempseed oil prior to being injected with CCl4. In all treated groups, toxicity was induced by i.p. injection of CCl4 (0.5 ml/kg for two consecutive days and hemp seed, oil was gavaged at 8 ml/kg in respective group once daily for one week. Plasma alanine aminotransferase (ALT and aspartate transaminase (AST levels increased in TCC. Protection against toxicity in HSO-TCC and TCC-HSO reduced AST and ALT activities compared to TCC. Plasma alkaline phosphatase activity in TCC-HSO and HSO-TCC increased as compared with other groups. CCl4 decreased plasma high-density lipoprotein cholesterol (HDL-C in TCC. Hempseed oil decreased total cholesterol (TC, low-density lipoprotein cholesterol (LDL-C, very low-density lipoprotein cholesterol, and triacylglycerols in HSO compared to NC. Hempseed oil in TCC-HSO and HSO-TCC restored TC, HDL-C, and LDL-C levels to those of NC. Atherogenic index was lower in HSO in comparison to TCC. Based on histopathology, hempseed oil improved CCl4-induced-cardio- and hepatotoxicity in TCC-HSO and HSO-TCC; however, hempseed oil did not prevent CCl4-induced nephrotoxicity. To sum up, hempseed oil has mild protective effects against CCl4 toxicity in male rats.

  5. Anti-hepatotoxic activities of Hibiscus sabdariffa L. in animal model of streptozotocin diabetes-induced liver damage.

    Science.gov (United States)

    Adeyemi, David O; Ukwenya, Victor O; Obuotor, Efere M; Adewole, Stephen O

    2014-07-30

    Flavonoid-rich aqueous fraction of methanolic extract of Hibiscus sabdariffa calyx was evaluated for its anti-hepatotoxic activities in streptozotocin-induced diabetic Wistar rats. Diabetes Mellitus was induced in Wistar rats by a single i.p injection of 80 mg/kg b.w. streptozotocin (STZ) dissolved in 0.1 M citrate buffer (pH 6.3). The ameliorative effects of the extract on STZ-diabetes induced liver damage was evident from the histopathological analysis and the biochemical parameters evaluated in the serum and liver homogenates. Reduced levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) (3.76 ± 0.38 μM, 0.42 ± 0.04 U/L, 41.08 ± 3.04 U/ml, 0.82 ± 0.04 U/L respectively) in the liver of diabetic rats were restored to a near normal level in the Hibiscus sabdariffa-treated rats (6.87 ± 0.51 μM, 0.72 ± 0.06 U/L, 87.92 ± 5.26 U/ml, 1.37 ± 0.06 U/L respectively). Elevated levels of aspartate amino transferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) in the serum of diabetic rats were also restored in Hibiscus sabdariffa -treated rats. Examination of stained liver sections revealed hepatic fibrosis and excessive glycogen deposition in the diabetic rats. These pathological changes were ameliorated in the extract-treated rats. The anti-hepatotoxic activity of Hibiscus sabdariffa extract in STZ diabetic rats could be partly related to its antioxidant activity and the presence of flavonnoids.

  6. The potential protective effect of α-lipoic acid against nanocopper particle-induced hepatotoxicity in male rats.

    Science.gov (United States)

    Khalaf, A A; Zaki, A R; Galal, M K; Ogaly, H A; Ibrahim, M A; Hassan, A

    2017-09-01

    The present research task is aimed to evaluate the role of exogenous α-lipoic acid (ALA) (100 mg/kg body weight) as hepatoprotective and potent antioxidant in amelioration of copper nanoparticle (CNP)-induced hepatotoxicity. Forty male rats were randomly assigned into four equal groups: group I (control), group II received CNPs, group III received CNPs + ALA, and finally group IV received ALA for 2 months. At the end of the experimental period, the rats were decapitated, and blood and liver tissue samples were collected for measurement of liver function tests, antioxidant status, lipid peroxidation (LPO), copper content, expression of some apoptotic genes, and histopathological analysis. CNPs induced marked hepatic damages as evident by severe alteration in hepatic biomarkers. This was accompanied by a significant elevation in hepatic LPO and induced nitric oxide, copper content, and expression level of apoptotic genes (C-myc and C-jun). In contrast, marked depletion for antioxidant parameters was detected. These findings were confirmed with severe pathological alterations. Coadministration of ALA as a powerful antioxidant attenuates the hepatotoxic effects of CNPs through improvement of liver parameters, oxidative status, genetic changes, and preservation of liver integrity through histopathological analysis. These results suggest that consumed ALA could be used as an applicable hepatoprotective agent against oxidative damage mediated by nanoparticles intoxication.

  7. Degradation of glycine and alanine on irradiated quartz.

    Science.gov (United States)

    Pawlikowski, Maciej; Benko, Aleksandra; Wróbel, Tomasz P

    2013-04-01

    Recent researches suggest participation of minerals in the formation of life under primordial conditions. Among all of the minerals, quartz seems to be one of the most probable to take part in such processes. However, an external source of energy is needed, e.g. electric discharge. A device simulating the proposed conditions was designed and was used to simulate prebiotic conditions. Investigation of processes occurring during the stimulation of quartz with electric discharge was studied by means of Ultraviolet-visible (UV-VIS) spectroscopy, in order to monitor the generation kinetics of free radicals. Additionally, infrared spectroscopy was applied to identify chemical reaction products created in a solution of alanine or glycine, in the presence of quartz treated with electric discharge. Formation of increased amounts of free radicals, compared to experiments performed without quartz and/or amino acid, is reported, along with identification of possible degradation products of alanine. No synthetic reactions were observed.

  8. A Comparative Study on the Effects of Glutathione and Green Tea Extract (Camellia sinensis L. on Thioacetamide-induced Hepatotoxicity in Male Adult Wistar Rats

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    Shahnaz Shekarforoush

    2014-12-01

    Full Text Available Background: Flavonoids play significant role in the treatment of many diseases. Green tea (Camellia Sinensis L. is a common beverage all over the world with antioxidant and detoxification effects related to the presence of flavonoids and catchins. This study aimed to investigate the protective effect of green tea on thioacetamide-induced hepatotoxicity. Materials and Methods: In this experimental study, 64 male Wistar rats were allocated to eight groups. The control group received a normal diet alone, sham group received normal saline, hepatotoxic group received thioacetamide (50 mg/kg thioacetamide for three days, other groups received a thioacetamide for three days and the alcoholic extract of bgreen tea, at minimum (50 mg/kg, moderate (100 mg/kg, and maximum (200 mg/kg doses, glutathione (250 mg/kg, green tea (200 mg/kg with glutathione (250 mg/kg for 21 days (i.p.. After that, blood samples were drawn and the levels of serum alanine aminotransferase, aspartate aminotransferase, Alkaline phosphatase, total protein and albumin, as liver injury indices, were measured. Results: The decrease of aminotransferase and alkaline phosphatase activity in the receptors of different dosages of green tea and glutathione was significant compared with the group treated by thioacetamide. Also, a significant increase was observed in total protein and albumin of serum in green tea receptors compared with thioacetamide group. Conclusion: The study results show the protective effect of green tea on thioacetamide-induced hepatotoxicity which is likely caused by the antioxidant effect of polyphenol compounds controlling thioacetamide activity which in turn controls the cytochrome P450 activity and neutralization of free radicals.

  9. Pretreatment of chronic active hepatitis C in patients coinfected with HIV and hepatitis C virus reduces the hepatotoxicity associated with subsequent antiretroviral therapy.

    Science.gov (United States)

    Uberti-Foppa, Caterina; De Bona, Anna; Morsica, Giulia; Galli, Laura; Gallotta, Giulia; Boeri, Enzo; Lazzarin, Adriano

    2003-06-01

    Chronic hepatitis C virus (HCV) is an independent risk factor for antiretroviral-related hepatotoxicity, but little is known about the frequency of severe liver toxicity in patients with HIV-HCV coinfection first treated for HCV (pretreated). The aim of this prospective study of 105 patients was to compare the incidence of progression to severe antiretroviral-related liver toxicity in 66 patients pretreated (36 with interferon-alpha [IFNalpha], 30 with IFNalpha plus ribavirin), and 39 patients not pretreated. The subjects could choose whether to receive anti-HCV therapy. Severe liver toxicity was defined as alanine aminotransferase (ALT) level > or =5-times the upper limit of normal in patients with normal baseline levels and > or =3.5-times in those with increased baseline levels. The authors also estimated the hepatotoxicity-related risk of discontinuing antiretroviral therapy. During antiretroviral therapy, 10 subjects (9.5%) experienced severe hepatotoxicity: 4 of 66 pretreated patients and 6 of 39 untreated patients (24-month survival: 94% +/- 2.9% vs. 85% +/- 5.8%). After adjusting for baseline CD4 cell counts, ALT levels, histologic scores, HCV and HIV viremia, HCV genotype (genotype 1 in 29% of pretreated patients and 20% of patients not pretreated), and previous anti-HCV therapy, the risk of discontinuing anti-HIV treatment was significantly higher in the anti-HCV untreated patients (RR = 10.4; 95% CI: 1.6-66; p =.0127) and in those with increased baseline ALT levels (RR = 1.014; 95% CI: 1.006-1.021; p =.0005). The authors' data suggest that previous treatment of chronic active HCV is an independent factor associated with a decrease of severe liver toxicity as the result of a subsequent antiretroviral regimen. The authors also confirm that the baseline level of ALT is an important prognostic factor for increased liver damage during antiretroviral therapy.

  10. Role of saffron (Crocus sativus L.) and honey syrup on aluminum-induced hepatotoxicity.

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    Shati, Ali A; Alamri, Saad A

    2010-10-01

    To study the biochemical and molecular hepatotoxicity induced by aluminium chloride (AlCl3) and the protective role of saffron and honey against such toxicity. This study was performed in the Department of Biology, College of Science, King Khalid University, Abha, Kingdom of Saudi Arabia between July and August 2009. Two mice strains, BALB/c and C57BL/6 (20 animals from each strain), were used and randomly divided into 4 groups: control group; AlCl3 group; AlCl3+saffron group; and AlCl3+honey group. Changes in liver biochemical markers such as gamma-glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin and lipid peroxidation levels were estimated. Induced and suppressed mRNA in the liver homogenate was scanned followed by up- and down- regulated genes were isolated, cloned, and sequenced. There was a significant increase in the cholesterol levels, triglycerides, GGT, ALT, AST, ALP, lipid peroxidation, and presence of hyperglycemia in the AlCl3 group compared to the control. However, treating those animals exposed to AlCl3 by saffron and honey improved the disrupted liver biochemical markers and alleviated the increase of lipid peroxidation. Seven down-regulated genes (3 BALB/c and 4 C57BL/6) and 5 up-regulated genes (2 BALB/c and 3 C57BL/6) were observed. Aa2-245 gene was observed as being up-regulated in AlCl3+ saffron and AlCl3+honey groups in the BALB/c strain. The use of saffron and honey minimized the toxic effect of AlCl3 in the liver by alleviating its disruptive effect on the biochemical and molecular levels.

  11. Liver function tests as a measure of hepatotoxicity in areca nut chewers

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    Kanika Singroha

    2016-01-01

    Full Text Available Background: Areca nut has been listed as a carcinogenic agent in humans and is linked to cancers of oral cavity, gastrointestinal tract, and hepatobiliary system. Liver function tests (LFTs, the estimation of enzymes specific to the hepatic system, give an assessment of its cellular integrity, and functionality. Aim and Objectives: This study aimed to evaluate the state of the liver in patients consuming areca nut and its products over a period. Materials and Methods: LFTs were carried out on 10 nonareca nut chewers and thirty patients with a history of areca nut, quid or a combination of tobacco and areca nut chewing, extending from 6 months to 30 years. The LFTs included estimation of aspartate transaminase (AST, alanine transaminase, alkaline phosphatase (ALP, direct bilirubin, albumin, and total protein content. A comparative analysis was done for each biochemical marker with duration, form (betel nut alone, quid, and betel nut with tobacco, and frequency of chewing areca nut. Results: A mild increment in AST was seen in 33.3% cases. Statistically significant association (P < 0.05 was observed between the control and cases for AST, ALP, and total protein content. A significant positive Pearson's correlation (+0.417 was obtained for a form of areca nut chewing (areca nut and tobacco and AST. A significant negative Pearson's correlation (−0.05 was observed between total protein content and form of chewing (areca nut and tobacco. Conclusion: The results of the study seem to indicate that even long-term chewing of areca nut is not hepatotoxic. Minor alterations in LFTs were well within limits.

  12. Pyrene is a Novel Constitutive Androstane Receptor (CAR) Activator and Causes Hepatotoxicity by CAR.

    Science.gov (United States)

    Zhang, Xiao-Jie; Shi, Zhe; Lyv, Jing-Xi; He, Xuyan; Englert, Neal A; Zhang, Shu-Yun

    2015-10-01

    Polycyclic aromatic hydrocarbons (PAHs) are a class of ubiquitous persistent environmental pollutants which are primarily formed from the incomplete combustion of organic materials. Many potential sources of human exposure to PAHs exist, including daily exposures from the ambient environment or occupational settings. PAHs have been found to cause harmful effects on human health. Here, we evaluated the adverse effects of pyrene, a common PAH, on the liver. The present study demonstrates that pyrene is able to activate mouse constitutive androstane receptor (CAR). CAR protein, as measured by Western blot analysis, was observed to translocate into the nucleus from the cytoplasm in mouse liver after exposure to pyrene. Utilizing CAR null mice, we identified that CAR mediates pyrene-induced hepatotoxicity. Increased relative liver weight, hepatocellular hypertrophy, and elevated serum alanine aminotransferase levels were found in wild-type but not CAR null mice after orally administered pyrene. We further show that pyrene induced the expression of mouse liver metabolism enzymes including CYP2B10, CYP3A11, GSTm1, GSTm3, and SULT1A1, and caused hepatic glutathione depletion in wild-type but not CAR null mice. Moreover, by luciferase reporter assay and quantitative real-time PCR analysis, pyrene was found to be a potential inducer of CYP2B6 expression via activation of human CAR in HepG2 cells and human primary hepatocytes. Our observations suggest that pyrene is a novel CAR activator and that CAR is essential for mediating pyrene-induced liver injury. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Hepatotoxicity associated with overexposure to 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123).

    Science.gov (United States)

    Boucher, Raymond; Hanna, Constance; Rusch, George M; Stidham, Danny; Swan, Ellen; Vazquez, Manny

    2003-01-01

    1,1-Dichloro-2,2,2-trifluoroethane (HCFC-123) was evaluated as a substitute for trichlorofluoromethane (CFC-11), and it appeared that a permissible exposure limit of 50 ppm was justified. When HCFC-123 was introduced as a precision cleaning agent in a controlled operation, marked elevations in serum alanine transaminase and serum aspartase transaminase were noted in exposed workers. Sampling taken during start-up documented personal samples from 24-480 ppm (375 and 21 min, respectively) and area samples of 18-180 ppm (375 and 21 min, respectively). Personal and area samples collected after the liver abnormalities were identified ranged from 5-12 ppm. Exposure data were not available for the period when the abnormalities are suspected to have developed. Two models were developed to estimate exposure during the unmonitored period: (1) the entire plant as a homogenous box and (2) evaporation into smaller work zones. Modeling using the entire building estimated 8-hour time-weighted average (TWA) exposures of 10-35 ppm. Modeled estimates of work area and air exchange rates indicated that degreaser exposed workers could have experienced peak levels of 280-2,100 ppm (8-hour TWAs 252-1,630 ppm). Modeling of the work environment, estimated to be one-third of the volume of the entire open building, indicated peak exposures of 28-210 ppm (8-hour TWAs 25-163 ppm). These ranges estimate the minimum and maximum exposure levels. The best estimates, using 12 air changes per day, suggest peak levels around the degreaser of 635-2,100 ppm (8-hour TWA 499-1,630 ppm) and 63-207 ppm (8-hour TWAs 50-163 ppm) in the work area. These are the first estimates of exposure level associated with these hepatotoxic effects; all are significantly higher than personal and area samples collected for HCFC-123 after the liver abnormalities were identified.

  14. Dietary Coleus forskohlii extract generates dose-related hepatotoxicity in mice.

    Science.gov (United States)

    Virgona, Nantiga; Taki, Yuko; Yamada, Shizuo; Umegaki, Keizo

    2013-09-01

    Coleus forskohlii root extract (CFE) represented by its bioactive constituent 'forskolin' is popularly used as a natural weight-lowering product, but the association of its use with liver-related risks is very limited. In the present study, the effect of standardized CFE with 10% forskolin on liver function of mice was examined. Mice were given 0-5% CFE in an AIN93G-based diet for 3-5 weeks. Food intake, body weights, relative organ weights and liver marker enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)] combined with histophatological analysis were assessed. CFE (0-0.5%) only had minimal effects on food intake and body weight whereas a significant difference was observed in mice receiving the highest dose (5% CFE). The extract 0.05-5% dose-dependently decreased visceral fat weight by between 16% and 63%, and a dose-dependent several folds increase was observed in liver weights and plasma AST, ALT and ALP activities with quick onset apparent after only 1 week of 0.5% CFE intake. The hepatic effect persisted throughout the 3-weeks course but was restored towards normalization within 1 week after withdrawal of treatment. Liver histology of mice fed 0.5% CFE for 3 weeks showed hepatocyte hypertrophy and fat deposition. In contrast, none of the hepatic responses measured were altered when mice were given a diet containing pure forskolin alone at the dose corresponding to its content in 0.5% CFE. The present study clearly indicated that forskolin was not involved in the CFE-induced hepatotoxicity and was caused by other unidentified constituents in CFE which warrants further studies. Copyright © 2012 John Wiley & Sons, Ltd.

  15. Hesperidin alleviates cisplatin-induced hepatotoxicity in rats without inhibiting its antitumor activity.

    Science.gov (United States)

    Omar, Hany A; Mohamed, Wafaa R; Arafa, El-Shaimaa A; Shehata, Basim A; El Sherbiny, Gamal A; Arab, Hany H; Elgendy, Abdel Nasser A M

    2016-04-01

    Hesperidin, a naturally occurring flavonoid, exerts many clinically appreciable effects such as anti-oxidant, anti-allergic and anti-inflammatory actions. The present study aimed to investigate the possible protective effects of multiple doses of hesperidin against cisplatin-induced acute hepatotoxicity in rats. Hesperidin (100 or 200mg/kg po) was given to rats one day before cisplatin (7.5mg/kg, ip) injection. All animals were sacrificed 5 days after cisplatin injection and blood samples were collected for determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, triglycerides (TG) and total cholesterol levels. Liver samples were used for the determination of malondialdehyde (MDA), glutathione (GSH), total nitrate and nitrite contents. Western blot analysis was used for the assessment of NF-κB and p-Akt expression and histopathological examination was also performed. Results showed that hesperidin significantly reduced cisplatin-induced elevations in serum ALT and AST activities, TG and total cholesterol levels. It also reduced cisplatin-induced oxidative stress by significant reduction in liver MDA and NO content and elevation of GSH content. In addition, hesperidin significantly counteracted cisplatin-induced increased NF-κB expression and decreased p-Akt expression. Histopathological examination revealed that hesperidin greatly protected liver against cisplatin-induced injury. Moreover hesperidin did not inhibit the cytotoxic effect of cisplatin on cancer cells as determined by MTT assay. Hesperidin decreased cisplatin-induced functional and histopathological liver damage in a dose-dependent manner without affecting its potential cytotoxic effect. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  16. Antioxidant and hepatoprotective effects of Artemisia dracunculus against CCl4-induced hepatotoxicity in rats

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    Vahid Zarezade

    2017-12-01

    Full Text Available Objective: The present study was conducted to investigate the antioxidant and hepatoprotective activity of the hydro-alcoholic extract of aerial parts of Artemisia dracunculus (HAAD against CCl4-induced hepatotoxicity in rats. Materials and Methods: The antioxidant activity was evaluated by reducing power, 2, 2-diphenyl-1-picrylhydrazyl (DPPH and 2, 20-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS assays. Rats were pre-treated with either 50, 100, and 200 mg/kg of HAAD or silymarin (100 mg/kg; served as the positive control group for 15 days and they received a single dose of CCl4 on the last day. Hepatoprotective effects were investigated by assessment of serum biochemical enzymes such as alanine transaminase (ALT, aspartate transaminase (AST, alkaline phosphatase (ALP, total protein (TP, total bilirubin (TB, malondialdehyde (MDA, and antioxidant enzymes (SOD, CAT, GST and GSH, along with histopathological studies. Results: Total phenolic content was 197.22±3.73 mg gallic acid equivalent/g HAAD dry weight. HAAD indicated powerful activity in FRAP, DPPH and ABTS tests. Acute toxicity study showed that the extract had an LD50 of >5000 mg/kg. Oral treatment with HAAD exhibited a significant decrease in the levels of AST, ALT, ALP and TB and an increase in the level of TP. The extract significantly diminished MDA levels. The activities of the antioxidant enzymes were significantly augmented in rats pretreated with HAAD 200 mg/kg. Histopathological examination demonstrated lower liver damage in HAAD-treated groups as compared to CCl4 groups. Conclusion: Our findings indicated hepatoprotective effects of the hydro-alcoholic extract of A. dracunculus on CCl4-induced hepatic damage in rats and suggested that these effects may be produced by reducing oxidative stress.

  17. Effects of S-Adenosylmethionine and Its Combinations With Taurine and/or Betaine on Glutathione Homeostasis in Ethanol-induced Acute Hepatotoxicity.

    Science.gov (United States)

    Lee, Seo Yeon; Ko, Kwang Suk

    2016-09-01

    Exposure to ethanol abuse and severe oxidative stress are risk factors for hepatocarcinoma. The aim of this study was to evaluate the effects of S-adenosylmethionine (SAMe) and its combinations with taurine and/or betaine on the level of glutathione (GSH), a powerful antioxidant in the liver, in acute hepatotoxicity induced by ethanol. To examine the effects of SAMe and its combinations with taurine and/or betaine on ethanol-induced hepatotoxicity, AML12 cells and C57BL/6 mice were pretreated with SAMe, taurine, and/or betaine, followed by ethanol challenge. Cell viability was detected with an MTT assay. GSH concentration and mRNA levels of GSH synthetic enzymes were measured using GSH reductase and quantitative real-time reverse transcriptase-PCR. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured with commercially available kits. Pretreatment of SAMe, with or without taurine and/or betaine, attenuated decreases in GSH levels and mRNA expression of the catalytic subunit of glutamate-cysteine ligase (GCL), the rate-limiting enzyme for GSH synthesis, in ethanol-treated cells and mice. mRNA levels of the modifier subunit of GCL and glutathione synthetase were increased in mice treated with SAMe combinations. SAMe, taurine, and/or betaine pretreatment restored serum ALT and AST levels to control levels in the ethanol-treated group. Combinations of SAMe with taurine and/or betaine have a hepatoprotective effect against ethanol-induced liver injury by maintaining GSH homeostasis.

  18. Protective Effects of Rooibos (Aspalathus linearis and/or Red Palm Oil (Elaeis guineensis Supplementation on tert-Butyl Hydroperoxide-Induced Oxidative Hepatotoxicity in Wistar Rats

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    Olawale R. Ajuwon

    2013-01-01

    Full Text Available The possible protective effects of an aqueous rooibos extract (Aspalathus linearis, red palm oil (RPO (Elaeis guineensis, or their combination on tert-butyl-hydroperoxide-(t-BHP-induced oxidative hepatotoxicity in Wistar rats were investigated. tert-butyl hydroperoxide caused a significant (P<0.05 elevation in conjugated dienes (CD and malondialdehyde (MDA levels, significantly (P<0.05 decreased reduced glutathione (GSH and GSH : GSSG ratio, and induced varying changes in activities of catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase in the blood and liver. This apparent oxidative injury was associated with histopathological changes in liver architecture and elevated levels of serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, and lactate dehydrogenase (LDH. Supplementation with rooibos, RPO, or their combination significantly (P<0.05 decreased CD and MDA levels in the liver and reduced serum level of ALT, AST, and LDH. Likewise, changes observed in the activities of antioxidant enzymes and impairment in redox status in the erythrocytes and liver were reversed. The observed protective effects when rooibos and RPO were supplemented concomitantly were neither additive nor synergistic. Our results suggested that rooibos and RPO, either supplemented alone or combined, are capable of alleviating t-BHP-induced oxidative hepatotoxicity, and the mechanism of this protection may involve inhibition of lipid peroxidation and modulation of antioxidants enzymes and glutathione status.

  19. Protective Effects of Rooibos (Aspalathus linearis) and/or Red Palm Oil (Elaeis guineensis) Supplementation on tert-Butyl Hydroperoxide-Induced Oxidative Hepatotoxicity in Wistar Rats.

    Science.gov (United States)

    Ajuwon, Olawale R; Katengua-Thamahane, Emma; Van Rooyen, Jacques; Oguntibeju, Oluwafemi O; Marnewick, Jeanine L

    2013-01-01

    The possible protective effects of an aqueous rooibos extract (Aspalathus linearis), red palm oil (RPO) (Elaeis guineensis), or their combination on tert-butyl-hydroperoxide-(t-BHP-)induced oxidative hepatotoxicity in Wistar rats were investigated. tert-butyl hydroperoxide caused a significant (P < 0.05) elevation in conjugated dienes (CD) and malondialdehyde (MDA) levels, significantly (P < 0.05) decreased reduced glutathione (GSH) and GSH : GSSG ratio, and induced varying changes in activities of catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase in the blood and liver. This apparent oxidative injury was associated with histopathological changes in liver architecture and elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). Supplementation with rooibos, RPO, or their combination significantly (P < 0.05) decreased CD and MDA levels in the liver and reduced serum level of ALT, AST, and LDH. Likewise, changes observed in the activities of antioxidant enzymes and impairment in redox status in the erythrocytes and liver were reversed. The observed protective effects when rooibos and RPO were supplemented concomitantly were neither additive nor synergistic. Our results suggested that rooibos and RPO, either supplemented alone or combined, are capable of alleviating t-BHP-induced oxidative hepatotoxicity, and the mechanism of this protection may involve inhibition of lipid peroxidation and modulation of antioxidants enzymes and glutathione status.

  20. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

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    Flaminia Pantano

    2016-04-01

    Full Text Available The 3Ks (kava, kratom and khat are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed.

  1. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

    Science.gov (United States)

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Zaami, Simona; Ricci, Serafino; Giorgetti, Raffaele; Terranova, Daniela; Busardò, Francesco P.; Marinelli, Enrico

    2016-01-01

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed. PMID:27092496

  2. Hepatotoxicity by Drugs: The Most Common Implicated Agents

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    Einar S. Björnsson

    2016-02-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov. According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab.

  3. Hepatotoxicity of atenolol therapy - A report of 2 cases

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    Somnath Mondal

    2013-01-01

    Full Text Available This case report highlights atenolol induced episodes of chronic and acute hepatotoxicities in 2 elderly hypertensive patients. The 1st patient manifested liver dysfunction after 8 months of 50 mg daily atenolol therapy and in the 2nd patient liver dysfunction was revealed within 3 weeks of 100 mg daily atenolol intake. There was no evidence of any other possible hereditary, traumatic, surgical, metabolic, infective, organic, or pathologic causes giving rise to these conditions. Possibilities of drug interactions were carefully ruled out and these episodes of hepatotoxicities were ‘probably’ drug (atenolol induced, as depicted by CIOMS/RUCAM scale. Withdrawal of the offending drug resulted in reversal of the diseased states. Routine liver function tests may be warranted in patients on atenolol therapy.

  4. Xenobiotics-induced hepatotoxicity and an influence of HLA typisation

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    Žunić Miodrag

    2014-01-01

    Full Text Available Introduction: The increased reporting of cases of drug-induced liver injuries, reflects the growing number of new agents introduced into clinical practice in the last decades. It should be added to the modernization of industries, and new chemicals which it applied. Drug-induced liver injuries make up a persisting and challenging problem for physicians, health agencies and pharmaceutical firms. Research objectives: The aim of the study is the determination of the most common causes of drug-induced liver injury in our surroundings. We compared the importance of hepatotoxic action of drugs in relation to other noxa in human environment. We determinated the importance of the body sensitivity on the acting agents. We also examined the importance of different drugs in the development of hepatotoxicity, regardless the dose. Materials and methods: We analyzed 52 patients with a diagnosis of hepa-totoxic liver injury (medical history, detailed clinical evaluation of patients, histopathological analysis of the liver, abdominal ultra sound, laboratory determination of standard liver function tests and followed up for 12 months. In the period from 01.04. 2005 to 01.04.2009, in these patients of the Institute of Gastroenterology and Hepatology, Clinical Center of Serbia in Belgrade, we monitored liver functional tests and morphological findings. We used biological markers relevant for the differential diagnosis, monitoring of disease progression and response to therapy. The results of the patients with hepatotoxic liver injury were compared with the values of the findings of the 52 patients in the control group, with the diagnosis of chronic viral hepatitis, hospitalized in the same institution during the same time. Results: The causes of toxic liver damage in our study were following agents, classified into groups: Industrial toxins (8 patients, Food and beverages (9 pts, Antirheumatics and analgesics (6 pts, Antiarrhythmic drugs (4 pts Antilipemic (4 pts

  5. Hepatotoxicity by Drugs: The Most Common Implicated Agents

    Science.gov (United States)

    Björnsson, Einar S.

    2016-01-01

    Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab. PMID:26861310

  6. Role of reactive metabolites in drug-induced hepatotoxicity.

    Science.gov (United States)

    Srivastava, A; Maggs, J L; Antoine, D J; Williams, D P; Smith, D A; Park, B K

    2010-01-01

    Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism. However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now a great deal of evidence which shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, such as acetaminophen, tamoxifen, isoniazid, and amodiaquine. The main theme of this article is to review the evidence for chemically reactive metabolites being initiating factors for the multiple downstream biological events culminating in toxicity. The major objectives are to understand those idiosyncratic hepatotoxicities thought to be caused by chemically reactive metabolites and to define the role of toxic metabolites.

  7. A gene encoding alanine racemase is involved in spore germination in Bacillus thuringiensis.

    Science.gov (United States)

    Yan, Xiaohua; Gai, Yuling; Liang, Liang; Liu, Gang; Tan, Huarong

    2007-05-01

    Alanine racemase is a major component of the exosporium of Bacillus cereus spores. A gene homologous to that of alanine racemase (alrA) was cloned from Bacillus thuringiensis subsp. kurstaki, and RT-PCR showed that alrA was transcribed only in the sporulating cells. Disruption of alrA did not affect the growth and sporulation of B. thuringiensis, but promoted L-alanine-induced spore germination. When the spore germination rate was measured by monitoring DPA release, complementation of the alrA disruptant reduced the rate of L-alanine-induced spore germination below that of even wild-type spores. As previously reported for spores of other Bacillus species, D-alanine was an effective and competitive inhibitor of L-alanine-induced germination of B. thuringiensis spores. D-cycloserine alone stimulated inosine-induced germination of B. thuringiensis spores in addition to increasing L-alanine-induced germination by inhibiting alanine racemase. D-alanine also increased the rate of inosine-induced germination of wild-type spores. However, D-alanine inhibited inosine-induced germination of the alrA disruptant spores. It is possible that AlrA converted D-alanine to L-alanine, and this in turn, stimulated spore germination in B. thuringiensis. These results suggest that alrA plays a crucial role in moderating the germination rate of B. thuringiensis spores.

  8. Period of onset and lack of clinical manifestation of hepatotoxicity ...

    African Journals Online (AJOL)

    2011-06-25

    Jun 25, 2011 ... Martín‑Carbonero L, Núñez M, González‑Lahoz J, Soriano V. Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. HIV. Clin Trials 2003;4:115‑20. 9. Sanne I, Mommeja‑Marin H, Hinkle J, Bartlett JA, Lederman MM, Maartens G, et al. Severe hepatotoxicity associated with ...

  9. Predicting Drug-induced Hepatotoxicity Using QSAR and Toxicogenomics Approaches

    Science.gov (United States)

    Low, Yen; Uehara, Takeki; Minowa, Yohsuke; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro; Sedykh, Alexander; Muratov, Eugene; Fourches, Denis; Zhu, Hao; Rusyn, Ivan; Tropsha, Alexander

    2014-01-01

    Quantitative Structure-Activity Relationship (QSAR) modeling and toxicogenomics are used independently as predictive tools in toxicology. In this study, we evaluated the power of several statistical models for predicting drug hepatotoxicity in rats using different descriptors of drug molecules, namely their chemical descriptors and toxicogenomic profiles. The records were taken from the Toxicogenomics Project rat liver microarray database containing information on 127 drugs (http://toxico.nibio.go.jp/datalist.html). The model endpoint was hepatotoxicity in the rat following 28 days of exposure, established by liver histopathology and serum chemistry. First, we developed multiple conventional QSAR classification models using a comprehensive set of chemical descriptors and several classification methods (k nearest neighbor, support vector machines, random forests, and distance weighted discrimination). With chemical descriptors alone, external predictivity (Correct Classification Rate, CCR) from 5-fold external cross-validation was 61%. Next, the same classification methods were employed to build models using only toxicogenomic data (24h after a single exposure) treated as biological descriptors. The optimized models used only 85 selected toxicogenomic descriptors and had CCR as high as 76%. Finally, hybrid models combining both chemical descriptors and transcripts were developed; their CCRs were between 68 and 77%. Although the accuracy of hybrid models did not exceed that of the models based on toxicogenomic data alone, the use of both chemical and biological descriptors enriched the interpretation of the models. In addition to finding 85 transcripts that were predictive and highly relevant to the mechanisms of drug-induced liver injury, chemical structural alerts for hepatotoxicity were also identified. These results suggest that concurrent exploration of the chemical features and acute treatment-induced changes in transcript levels will both enrich the

  10. Protective activity of kudzu (Pueraria thunbergiana) vine on chemically-induced hepatotoxicity: in vitro and in vivo studies.

    Science.gov (United States)

    Chang, Bo Yoon; Lee, Dong-Sung; Lee, Jun-Kyoung; Kim, Youn-Chul; Cho, Hyoung-Kwon; Kim, Sung Yeon

    2016-01-29

    Kudzu (Pueraria thunbergiana) root has long been used in Traditional Chinese Medicine. However, the vine of the kudzu plant has been considered waste material. This study aimed to investigate the hepatoprotective properties of the kudzu vine. We created 0 %, 30 %, 70 %, and 95 % ethanolic kudzu vine extracts. The isoflavone contents of kudzu vine extract were quantified by high-performance liquid chromatography. Tertiary-butylhydroperoxide (t-BHP) was added to human liver-derived HepG2 cells, and the production of reactive oxygen species was measured in the presence and absence of kudzu vine extract. Antioxidant activity was evaluated in all kudzu vine extracts using a hydroxyradical scavenging assay. Thirty-five male Sprague-Dawley rats were divided into seven groups (n = 5); two groups were not given any extract or drug, one group was treated with 50 mg/kg silymarin orally for 5 days, and the remaining four groups were respectively treated with 100 mg/kg of 0%, 30%, 70%, or 95% ethanolic extract of kudzu vine orally once daily for 5 days. On day 5 the treatment groups and one untreated group were fed 0.75 ml/kg carbon tetrachloride (CCl4) to induce liver damage. Blood and liver tissue samples were collected 24 h after CCl4 administration for measurement of plasma alanine aminotransferase and aspartate aminotransferase, and concentration of malondialdehyde and glutathione in liver tissue. Puerarin was the most abundant isoflavone in kudzu vine extract. Kudzu vine extract significantly reduced the cytotoxicity and production of reactive oxygen species induced by t-BHP in a dose-dependent manner. Treatment with 0 % and 30 % ethanolic extracts of kudzu vine significantly lowered the plasma levels of alanine aminotransferase and aspartate aminotransferase in a CCl4-induced hepatotoxicity rat model (P vine is potentially highly beneficial in treating liver damage, as it scavenges reactive free radicals and boosts the endogenous antioxidant system.

  11. Hepatotoxic potential of asarones: In vitro evaluation of hepatotoxicity and quantitative determination in herbal products

    Directory of Open Access Journals (Sweden)

    Dhavalkumar Narendrabha Patel

    2015-02-01

    Full Text Available α and β asarones are natural constituents of some aromatic plants, especially species of the genus Acorus. In addition to beneficial properties of asarones, genotoxicity and carcinogenicity are also reported. Due to potential toxic effects of β-asarone, a limit of exposure from herbal products of approximately 2 μg/kg body weight/day has been set temporarily until a full benefit/risk assessment has been carried out by the European Medicines Agency. Therefore, it is important to monitor levels of β-asarone in herbal products. In this study, we developed a simple, rapid and validated GC-MS method for quantitative determination of asarones and applied it in 20 pediatric herbal products after detecting high concentrations of β-asarone in a product suspected to be implicated in hepatotoxicity in a 3 month old infant. Furthermore, targeted toxicological effects were further investigated in human hepatocytes (THLE-2 cells by employing various in vitro assays, with the goal of elucidating possible mechanisms for the observed toxicity. Results showed that some of the products contained as much as 4 to 25 times greater amounts of β-asarone than the recommended levels. In 4 of 10 samples found to contain asarones, the presence of asarones could not be linked to the labeled ingredients, possibly due to poor quality control. Cell-based investigations in THLE2 cells confirmed the cytotoxicity of -asarone (IC50 = 40.0 ± 2.0 µg/mL which was associated with significant lipid peroxidation and glutathione depletion. This observed cytotoxicity effect is likely due to induction of oxidative stress by asarones. Overall, the results of this study ascertained the usability of this GC-MS method for the quantitative determination of asarones from herbal products, and shed light on the importance of controlling the concentration of potentially toxic asarones in herbal products to safeguard consumer safety. Further investigations of the toxicity of asarones are

  12. Short-Term Feeding of Fibre-Enriched Biscuits: Protective Effect against Hepatotoxicity in Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Ochuko L. Erukainure

    2015-01-01

    Full Text Available The effects of fibre-enriched biscuit on biomarkers associated with hepatotoxicity in diabetic rats were investigated. Diabetes was induced by single intraperitoneal injection of alloxan monohydrate. Treatment lasted for 14 days after which the rats were sacrificed by cervical dislocation. Blood serum was analyzed to determine hepatic function enzymes. The liver was also analyzed to determine hepatic lipid profile and antioxidant enzymes. Induction of diabetes led to elevated levels of ALP, AST, and ALT. These were, however, significantly (p<0.05 reduced in the fibre-enriched biscuit fed (treated group. There was no significant difference in the serum bilirubin and total protein levels of the studied groups. Reduced albumin level was observed in the diabetic group; this was further lowered on feeding with fibre-enriched biscuits. Induction of diabetes led to increased hepatic level of cholesterol, triglyceride (TG, low density lipoprotein (LDL, and lipid peroxidation and decreased activities of glutathione (GSH, catalase (CAT, and superoxide dismutase (SOD and HDL level. These were significantly (p<0.05 reversed on feeding with fibre-enriched biscuit. This study portrays the protective effect of fibre-enriched biscuit on increased oxidative stress and hyperlipidemia in hepatic tissues of alloxan-induced diabetic rats.

  13. Moyamoya Biomarkers

    Science.gov (United States)

    2015-01-01

    Moyamoya disease (MMD) is an arteriopathy of the intracranial circulation predominantly affecting the branches of the internal carotid arteries. Heterogeneity in presentation, progression and response to therapy has prompted intense study to improve the diagnosis and prognosis of this disease. Recent progress in the development of moyamoya-related biomarkers has stimulated marked interest in this field. Biomarkers can be defined as biologically derived agents-such as specific molecules or unique patterns on imaging-that can identify the presence of disease or help to predict its course. This article reviews the current categories of biomarkers relevant to MMD-including proteins, cells and genes-along with potential limitations and applications for their use. PMID:26180608

  14. Plasma metabolomics study of the hepatoprotective effect of glycyrrhetinic acid on realgar-induced sub-chronic hepatotoxicity in mice via1H NMR analysis.

    Science.gov (United States)

    Huo, Taoguang; Fang, Ying; Zhang, Yinghua; Wang, Yanlei; Feng, Cong; Yuan, Mingmei; Wang, Shouyun; Chen, Mo; Jiang, Hong

    2017-08-17

    Realgar, a type of mineral drug that contains arsenic, is concurrently used with Glycyrrhizae Radx et Rhizoma to reduce its toxicity in many Chinese herbal formulations. Glycyrrhetinic acid (GA) is the bioactive ingredient in Glycyrrhizae Radx et Rhizoma. In this study, the protective effects of GA on realgar-induced hepatotoxicity was investigated using 1 H nuclear magnetic resonance ( 1 H NMR)-based metabolomic approaches. Mice were divided into control, GA, realgar, and GA and realgar co-administration groups. Their plasma samples were used for a metabolomics study. GA can protect the mice against realgar-induced hepatotoxicity to some extent by relieving alterations in the clinical biochemical parameters and the damage to hepatocytes. Metabolic profiling via principal components analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) indicated that the metabolic perturbation caused by realgar was reduced by GA. Six metabolites, including 3-hydroxybutyrate (3-HB), very low density/low density lipoprotein (VLDL/LDL), N-acetylglycoprotein (NAc), lactate, choline and D-glucose, were considered as potential biomarkers that are involved in the toxicity reduction effect of GA on realgar-induced hepatotoxicity. The correlation analysis showed that these potential biomarkers were all positively correlated with ALT and AST activities (correlation coefficient > 0.5). Lipid and energy metabolism pathways were found to be primarily associated with the hepatoprotective effect of GA. GA has an effective protection function by regulating the lipid and energy metabolism to liver injuries that are induced by realgar. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  15. Analysis of an Alanine/Arginine Mixture by Using TLC/FTIR Technique

    Directory of Open Access Journals (Sweden)

    Jun Liu

    2014-01-01

    Full Text Available We applied TLC/FTIR coupled with mapping technique to analyze an alanine/arginine mixture. Narrow band TLC plates prepared by using AgI as a stationary phase were used to separate alanine and arginine. The distribution of alanine and arginine spots was manifested by a 3D chromatogram. Alanine and arginine can be successfully separated by the narrow band TLC plate. In addition, the FTIR spectra of the separated alanine and arginine spots on the narrow band TLC plate are roughly the same as the corresponding reference IR spectra.

  16. Acetaminophen: Dose-Dependent Drug Hepatotoxicity and Acute Liver Failure in Patients.

    Science.gov (United States)

    Jaeschke, Hartmut

    2015-01-01

    Drug-induced liver injury is a rare but serious clinical problem. A number of drugs can cause severe liver injury and acute liver failure at therapeutic doses in a very limited number of patients (liver injury, which is currently not predictable in preclinical safety studies, appears to depend on individual susceptibility and the inability to adapt to the cellular stress caused by a particular drug. In striking contrast to idiosyncratic drug-induced liver injury, drugs with dose-dependent hepatotoxicity are mostly detected during preclinical studies and do not reach the market. One notable exception is acetaminophen (APAP, paracetamol), which is a safe drug at therapeutic doses but can cause severe liver injury and acute liver failure after intentional and unintentional overdoses. Key Messages: APAP overdose is responsible for more acute liver failure cases in the USA or UK than all other etiologies combined. Since APAP overdose in the mouse represents a model for the human pathophysiology, substantial progress has been made during the last decade in understanding the mechanisms of cell death, liver injury and recovery. More recently, emerging evidence based on mechanistic biomarker analysis in patients and studies of cell death in human hepatocytes suggests that most of the mechanisms discovered in mice also apply to patients. The rapid development of N-acetylcysteine as an antidote against APAP overdose was based on the early understanding of APAP toxicity in mice. However, despite the efficacy of N-acetylcysteine in patients who present early after APAP overdose, there is a need to develop intervention strategies for late-presenting patients. The challenges related to APAP toxicity are to better understand the mechanisms of cell death in order to limit liver injury and prevent acute liver failure, and also to develop biomarkers that better predict as early as possible who is at risk for developing acute liver failure with poor outcome. © 2015 S. Karger AG

  17. Alanine Radiation Detectors in Therapeutic Carbon Ion Beams

    DEFF Research Database (Denmark)

    Herrmann, Rochus; Jäkel, Oliver; Palmans, Hugo

    at energies below 20 MeV/u. We implemented this model in the Monte Carlo code FLUKA. At the GSI heavy ion facility in Darmstadt, Germany, alanine has been irradiated with carbon ions at energies between 88 an 400 MeV/u, which is the energy range used for therapy. The irradiation and the detector response have...... been simulated with FLUKA. We found an agreement between measured values of the relative efficiency with values predicted by the Hansen and Olsen model with divergence less than 4%. With the implementation in FLUKA we are able to simulate the detector response in the depth dose curves with precisions...

  18. Moringa oleifera hydroethanolic extracts effectively alleviate acetaminophen-induced hepatotoxicity in experimental rats through their antioxidant nature.

    Science.gov (United States)

    Fakurazi, Sharida; Sharifudin, Syazana Akmal; Arulselvan, Palanisamy

    2012-07-10

    The aim of the study was to investigate the in vitro antioxidant properties Moringa oleifera Lam. (MO) extracts and its curative role in acetaminophen (APAP)-induced toxic liver injury in rats caused by oxidative damage. The total phenolic content and antioxidant properties of hydroethanolic extracts of different MO edible parts were investigated by employing an established in vitro biological assay. In the antihepatotoxic study, either flowers or leaves extract (200 mg/kg or 400 mg/kg, i.p) were administered an hour after APAP administration, respectively. N-Acetylcysteine was used as the positive control against APAP-induced hepatotoxicity. The levels of liver markers such as alanine aminotransferase (ALT) and the levels of oxidative damage markers including malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) protein adduct, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were analysed and compared between experimental groups. Among MO edible parts the flower extracts contain the highest total phenolic content and antioxidant capacity, followed by leaves extract. The oxidative marker MDA, as well as 4-HNE protein adduct levels were elevated and GSH, SOD and CAT were significantly decreased in groups treated with hepatotoxin. The biochemical liver tissue oxidative markers measured in the rats treated with MO flowers and leaves hydroethanolic extracts showed a significant (p < 0.05) reduction in the severity of the liver damage. The results of this study strongly indicate the therapeutic properties of MO hydroethanolic extracts against acute liver injury and thereby scientifically support its traditional use.

  19. Efficacy of Lepidium sativum against carbon tetra chloride induced hepatotoxicity and determination of its bioactive compounds by GC–MS

    Directory of Open Access Journals (Sweden)

    Abdulrahman Khazim Al-Asmari

    2015-01-01

    To evaluate the hepatoprotective activity, six groups (n = 6 of rats were taken. First group was control, second was toxic and other groups received oral test solutions: 100 mg/kg silymarin, or LSS (100, 200, and 400 mg/kg, once daily for 7 consecutive days, followed by hepatotoxicity induction with CCl4. Blood and liver tissues were collected for biochemical, antioxidant and microscopic analyses. The bioactive constituents present in the extract were analyzed by GC–MS. Results showed that pretreatment with LSS and silymarin significantly reduced the level of serum alanine transaminase (ALT, aspartate transaminase (AST, alkaline phosphatase (ALP and bilirubin (BIL, which was increased significantly in toxic group treated with only CCl4. Histological analysis of liver tissues in groups pretreated with LSS and silymarin showed mild necrosis and inflammation of the hepatocytes compared to the toxic group. GC–MS analysis of LSS showed the presence of twelve major fatty acids including alpha-linolenic acid as a major constituent. These results indicated that LSS exerts enhance hepatoprotective activity that could be attributed towards its antioxidant activity, coupled together with the presence of anti-inflammatory compounds in LSS extract.

  20. Antitumor activity, pharmacokinetics, tumor-homing effect, and hepatotoxicity of a species cross-reactive c-Met antibody.

    Science.gov (United States)

    Park, Hyunkyu; Kim, Donggeon; Son, Eunju; Shin, Sunhwa; Sa, Jason K; Kim, Seok-Hyung; Yoon, Yeup; Nam, Do-Hyun

    2017-12-09

    The receptor tyrosine kinase c-Met plays critical roles in promoting tumor growth, invasion, metastasis, and angiogenesis in various types of cancer and is a promising therapeutic target. The development of a species cross-reactive therapeutic antibody could provide useful to comprehensive preclinical assessment in animal models. Towards this goal, we developed human/mouse cross-reactive c-Met antibodies using an antibody phage library. IRCR201, a c-Met antibody with species cross-reactivity, successfully inhibited the HGF/c-Met signaling pathway via degradation of c-Met and disruption of the binding with its partners, and demonstrated strong in vivo antitumor activity. In pharmacokinetic analysis, IRCR201 exhibited a nonlinear pharmacokinetic profile and showed rapid serum clearance at low dosage. Ex vivo fluorescence imaging and immunohistochemistry demonstrated strong tumor accumulation of IRCR201. Hepatotoxicity analysis revealed that IRCR201 does not significantly affect primary human and mouse hepatocytes. Serum chemistry analysis demonstrated that the alanine aminotransferase serum level was elevated in mice treated with 30 mg/kg IRCR201 than in PBS-treated mice, whereas the levels of aspartate aminotransferase and blood urea nitrogen did not significantly differ. Thus, IRCR201 is a potent therapeutic antibody that can disrupt the HGF/c-Met signaling axis and its species cross-reactivity would enable to evaluate precise biological activity in animal models. Copyright © 2017. Published by Elsevier Inc.

  1. Protective effect of binaphthyl diselenide, a synthetic organoselenium compound, on 2-nitropropane-induced hepatotoxicity in rats.

    Science.gov (United States)

    Ibrahim, Mohammad; Prigol, Marina; Hassan, Waseem; Nogueira, Cristina W; Rocha, Joao B T

    2010-06-01

    Organoselenides have been documented as promising pharmacological agents against a number of diseases associated with oxidative stress. Here we have investigated, for the first time, the potential antioxidant activity of binaphthyl diselenide ((NapSe)(2); 50 mg kg(-1), p.o.) against the 2-nitropropane (2-NP)-induced hepatoxicity in rats, using different end points of toxicity (liver histopathology, plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatinine). In addition, in view of the association of oxidative stress with 2-NP exposure, hepatic lipid peroxidation, ascorbic acid levels, delta-aminolevulinate dehydratase (delta-ALA-D) and catalase (CAT) activities were evaluated. 2-NP caused an increase of AST, ALT and hepatic lipid peroxidation. 2-NP also caused hepatic histopathological alterations and delta-ALA-D inhibition. (NapSe)(2) (50 mg kg(-1)) prevented 2-NP-induced changes in plasmatic ALT and AST activities and also prevented changes in hepatic histology, delta-ALA-D and lipid peroxidation. Results presented here indicate that the protective mechanism of (NapSe)(2) against 2-NP hepatotoxicity is possibly linked to its antioxidant activity. 2010 John Wiley & Sons, Ltd.

  2. Hypericum perforatum Reduces Paracetamol-Induced Hepatotoxicity and Lethality in Mice by Modulating Inflammation and Oxidative Stress.

    Science.gov (United States)

    Hohmann, Miriam S N; Cardoso, Renato D R; Fattori, Victor; Arakawa, Nilton S; Tomaz, José C; Lopes, Norberto P; Casagrande, Rubia; Verri, Waldiceu A

    2015-07-01

    Hypericum perforatum is a medicinal plant with anti-inflammatory and antioxidant properties, which is commercially available for therapeutic use in Brazil. Herein the effect of H. perforatum extract on paracetamol (acetaminophen)-induced hepatotoxicity, lethality, inflammation, and oxidative stress in male swiss mice were investigated. HPLC analysis demonstrated the presence of rutin, quercetin, hypericin, pseudohypericin, and hyperforin in H. perforatum extract. Paracetamol (0.15-3.0 g/kg, p.o.) induced dose-dependent mortality. The sub-maximal lethal dose of paracetamol (1.5 g/kg, p.o.) was chosen for the experiments in the study. H. perforatum (30-300 mg/kg, i.p.) dose-dependently reduced paracetamol-induced lethality. Paracetamol-induced increase in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, and hepatic myeloperoxidase activity, IL-1β, TNF-α, and IFN-γ concentrations as well as decreased reduced glutathione (GSH) concentrations and capacity to reduce 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate radical cation; ABTS˙(+) ) were inhibited by H. perforatum (300 mg/kg, i.p.) treatment. Therefore, H. perforatum protects mice against paracetamol-induced lethality and liver damage. This effect seems to be related to the reduction of paracetamol-induced cytokine production, neutrophil recruitment, and oxidative stress. Copyright © 2015 John Wiley & Sons, Ltd.

  3. The effect of immunonutrition (glutamine, alanine on fracture healing

    Directory of Open Access Journals (Sweden)

    Abdullah Küçükalp

    2014-11-01

    Full Text Available Background: There have been various studies related to fracture healing. Glutamine is an amino acid with an important role in many cell and organ functions. This study aimed to make a clinical, radiological, and histopathological evaluation of the effects of glutamine on fracture healing. Methods: Twenty rabbits were randomly allocated into two groups of control and immunonutrition. A fracture of the fibula was made to the right hind leg. All rabbits received standard food and water. From post-operative first day for 30 days, the study group received an additional 2 ml/kg/day 20% L-alanine L-glutamine solution via a gastric catheter, and the control group received 2 ml/kg/day isotonic via gastric catheter. At the end of 30 days, the rabbits were sacrificed and the fractures were examined clinically, radiologically, and histopathologically in respect to the degree of union. Results: Radiological evaluation of the control group determined a mean score of 2.5 according to the orthopaedists and 2.65 according to the radiologists. In the clinical evaluation, the mean score was 1.875 for the control group and 2.0 for the study group. Histopathological evaluation determined a mean score of 8.5 for the control group and 9.0 for the study group. Conclusion: One month after orally administered glutamine–alanine, positive effects were observed on fracture healing radiologically, clinically, and histopathologically, although no statistically significant difference was determined.

  4. Vibrational analysis of L-alanine and deuterated analogs

    Science.gov (United States)

    Susi, Heino; Byler, D. Michael

    1980-05-01

    Raman spectra of the polycrystalline L-alanine analogs CH 3CH(NH +3)COO -, CH 3CH(ND +3)-COO -, CD 3CD(NH +3)COO -, and CD 3CD(ND +3)COO - have been obtained. A normal coordinate analysis is carried out based on the experimental frequencies of the four isotopic analogs and a 34 parameter valence-type force field defined in terms of local symmetry coordinates. The final refinement, in which five stretching force constants are constrained to fixed values obtained from bond length data, results in an average error of 7 cm -1 (0.9%) for the observed frequencies of the four isotopically substituted molecules. Band assignments are given in terms of the potential energy distribution for local symmetry coordinates. For non-deuterated L-alanine, the vibrations above 1420 cm -1 and below 950 cm -1 may be described as localized group vibrations. By contrast, the eight modes in the middle frequency range, viz. the three skeletal stretching, the COO - symmetric stretching, one NH +3 rocking, the symmetric CH 3 deformation, and the two methyne CH deformation vibrations, are very strongly coupled to one another. Some decoupling appears to take place in the perdeutero molecule, and all but five modes can be described as localized group vibrations.

  5. Alanine racemase mutants of Burkholderia pseudomallei and Burkholderia mallei and use of alanine racemase as a non-antibiotic-based selectable marker.

    Directory of Open Access Journals (Sweden)

    Sheryl L W Zajdowicz

    Full Text Available Burkholderia pseudomallei and Burkholderia mallei are category B select agents and must be studied under BSL3 containment in the United States. They are typically resistant to multiple antibiotics, and the antibiotics used to treat B. pseudomallei or B. mallei infections may not be used as selective agents with the corresponding Burkholderia species. Here, we investigated alanine racemase deficient mutants of B. pseudomallei and B. mallei for development of non-antibiotic-based genetic selection methods and for attenuation of virulence. The genome of B. pseudomallei K96243 has two annotated alanine racemase genes (bpsl2179 and bpss0711, and B. mallei ATCC 23344 has one (bma1575. Each of these genes encodes a functional enzyme that can complement the alanine racemase deficiency of Escherichia coli strain ALA1. Herein, we show that B. pseudomallei with in-frame deletions in both bpsl2179 and bpss0711, or B. mallei with an in-frame deletion in bma1575, requires exogenous D-alanine for growth. Introduction of bpsl2179 on a multicopy plasmid into alanine racemase deficient variants of either Burkholderia species eliminated the requirement for D-alanine. During log phase growth without D-alanine, the viable counts of alanine racemase deficient mutants of B. pseudomallei and B. mallei decreased within 2 hours by about 1000-fold and 10-fold, respectively, and no viable bacteria were present at 24 hours. We constructed several genetic tools with bpsl2179 as a selectable genetic marker, and we used them without any antibiotic selection to construct an in-frame ΔflgK mutant in the alanine racemase deficient variant of B. pseudomallei K96243. In murine peritoneal macrophages, wild type B. mallei ATCC 23344 was killed much more rapidly than wild type B. pseudomallei K96243. In addition, the alanine racemase deficient mutant of B. pseudomallei K96243 exhibited attenuation versus its isogenic parental strain with respect to growth and survival in murine

  6. Alanine racemase mutants of Burkholderia pseudomallei and Burkholderia mallei and use of alanine racemase as a non-antibiotic-based selectable marker.

    Science.gov (United States)

    Zajdowicz, Sheryl L W; Jones-Carson, Jessica; Vazquez-Torres, Andres; Jobling, Michael G; Gill, Ronald E; Holmes, Randall K

    2011-01-01

    Burkholderia pseudomallei and Burkholderia mallei are category B select agents and must be studied under BSL3 containment in the United States. They are typically resistant to multiple antibiotics, and the antibiotics used to treat B. pseudomallei or B. mallei infections may not be used as selective agents with the corresponding Burkholderia species. Here, we investigated alanine racemase deficient mutants of B. pseudomallei and B. mallei for development of non-antibiotic-based genetic selection methods and for attenuation of virulence. The genome of B. pseudomallei K96243 has two annotated alanine racemase genes (bpsl2179 and bpss0711), and B. mallei ATCC 23344 has one (bma1575). Each of these genes encodes a functional enzyme that can complement the alanine racemase deficiency of Escherichia coli strain ALA1. Herein, we show that B. pseudomallei with in-frame deletions in both bpsl2179 and bpss0711, or B. mallei with an in-frame deletion in bma1575, requires exogenous D-alanine for growth. Introduction of bpsl2179 on a multicopy plasmid into alanine racemase deficient variants of either Burkholderia species eliminated the requirement for D-alanine. During log phase growth without D-alanine, the viable counts of alanine racemase deficient mutants of B. pseudomallei and B. mallei decreased within 2 hours by about 1000-fold and 10-fold, respectively, and no viable bacteria were present at 24 hours. We constructed several genetic tools with bpsl2179 as a selectable genetic marker, and we used them without any antibiotic selection to construct an in-frame ΔflgK mutant in the alanine racemase deficient variant of B. pseudomallei K96243. In murine peritoneal macrophages, wild type B. mallei ATCC 23344 was killed much more rapidly than wild type B. pseudomallei K96243. In addition, the alanine racemase deficient mutant of B. pseudomallei K96243 exhibited attenuation versus its isogenic parental strain with respect to growth and survival in murine peritoneal macrophages.

  7. Effect of anemia on hepatotoxicity of HAART in HIV patients in Benin ...

    African Journals Online (AJOL)

    Background: Hepatotoxicity is a relevant adverse effect of highly active antiretroviral Treatment owing to its frequency, and it can cause interruption of therapy, hepatitis, and death. There is dearth of information on hepatotoxicity arising from highly active antiretroviral therapy (HAART) in anemic patients. Anemia is the most ...

  8. Prevalence, knowledge and attitudes relating to β-alanine use among professional footballers.

    Science.gov (United States)

    Kelly, Vincent G; Leveritt, Michael D; Brennan, Christopher T; Slater, Gary J; Jenkins, David G

    2017-01-01

    To investigate β-alanine supplementation use and level of knowledge amongst professional footballers. Cross-sectional survey of Australian professional football players. Questionnaires assessing β-alanine supplementation behaviours, level of knowledge and sources of information were completed by professional rugby union (RU) (n=87), rugby league (RL) (n=180) and Australian Rules Football (ARF) (n=303) players. Approximately 61% of athletes reported β-alanine use, however use by ARF football players (44%) was lower than that of RU (80%) and RL players (80%). The majority of respondents were not using β-alanine in accordance with recommendations. Only 35% of the participants were able to correctly identify the potential benefits of β-alanine supplementation. The main information sources that influenced players' decision to use β-alanine were strength and conditioning coach (71%) and dietitian (52%). Forty-eight per cent of athletes never read labels prior to supplementing and only 11% completed their own research on β-alanine. Compared to RL and ARF players, RU players had both a greater knowledge of β-alanine supplementation and better supplementation practices. Despite over half the surveyed professional footballers using β-alanine, the majority of athletes used β-alanine in a manner inconsistent with recommendations. A better understanding of the environment and culture within professional football codes is required before supplement use becomes consistent with evidence based supplement recommendations. Copyright © 2016 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  9. Regulation of Bacillus subtilis macrofiber twist development by D-alanine.

    Science.gov (United States)

    Surana, U; Wolfe, A J; Mendelson, N H

    1988-01-01

    Twist states of Bacillus subtilis macrofibers were found to vary as a function of the concentration of D-alanine in the medium during growth. L-Alanine in the same concentration range had no effect. Increasing concentrations of D-alanine resulted in structures progressively more right-handed (or less left-handed). All strains examined in this study, including mutants fixed in the left-hand domain as a function of temperature, responded to D-alanine in the same way. All twist states from tight left- to tight right-handedness could be achieved solely by varying the D-alanine concentration. The D-alanine-requiring macrofiber strain 2C8, which carries a genetic defect (dal-1) in the alanine racemase, behaved in a similar fashion. The combined effects of D-alanine and ammonium sulfate (a factor known to influence macrofiber twist development in the leftward direction) were examined by using both strains able to undergo temperature-induced helix hand inversion and others incapable of doing so. In all cases, the effects of D-alanine predominated. A synergism was found in which increasing the concentration of ammonium sulfate in the presence of D-alanine enhanced the right-factor activity of the latter. A D-alanine pulse protocol provided evidence that structures undergo a transient inversion indicative of "memory." Chloramphenicol treatment inhibited the establishment of memory in the D-alanine-induced right to left inversion, supporting the existence of a "left twist protein(s)" that is required for the attainment of left-handed twist states. Chemical analysis of cell walls obtained from right- and left-handed macrofibers produced in the presence and absence of D-alanine, respectively, failed to reveal twist state-specific differences in the overall composition of either peptidoglycan or wall teichoic acids. PMID:3129406

  10. Herbal hepatotoxicity: suspected cases assessed for alternative causes.

    Science.gov (United States)

    Teschke, Rolf; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel; Frenzel, Christian

    2013-09-01

    Alternative explanations are common in suspected drug-induced liver injury (DILI) and account for up to 47.1% of analyzed cases. This raised the question of whether a similar frequency may prevail in cases of assumed herb-induced liver injury (HILI). We searched the Medline database for the following terms: herbs, herbal drugs, herbal dietary supplements, hepatotoxic herbs, herbal hepatotoxicity, and herb-induced liver injury. Additional terms specifically addressed single herbs and herbal products: black cohosh, Greater Celandine, green tea, Herbalife products, Hydroxycut, kava, and Pelargonium sidoides. We retrieved 23 published case series and regulatory assessments related to hepatotoxicity by herbs and herbal dietary supplements with alternative causes. The 23 publications comprised 573 cases of initially suspected HILI; alternative causes were evident in 278/573 cases (48.5%). Among them were hepatitis by various viruses (9.7%), autoimmune diseases (10.4%), nonalcoholic and alcoholic liver diseases (5.4%), liver injury by comedication (DILI and other HILI) (43.9%), and liver involvement in infectious diseases (4.7%). Biliary and pancreatic diseases were frequent alternative diagnoses (11.5%), raising therapeutic problems if specific treatment is withheld; pre-existing liver diseases including cirrhosis (9.7%) were additional confounding variables. Other diagnoses were rare, but possibly relevant for the individual patient. In 573 cases of initially assumed HILI, 48.5% showed alternative causes unrelated to the initially incriminated herb, herbal drug, or herbal dietary supplement, calling for thorough clinical evaluations and appropriate causality assessments in future cases of suspected HILI.

  11. Hepatotoxicity of anti-inflammatory and analgesic drugs: ultrastructural aspects.

    Science.gov (United States)

    Manov, Irena; Motanis, Helen; Frumin, Idan; Iancu, Theodore C

    2006-03-01

    With the increasing incidence of drug-induced liver disease, attempts are being made to better understand the mechanisms behind these frequently life-endangering reactions. Analgesics and anti-inflammatory drugs are a major group exhibiting hepatotoxicity. We review research relating to these reactions, focusing on ultrastructural findings, which may contribute to the comprehension and possible avoidance of drug-induced liver disease. We also present some original observations on clinical material and cultured cells exposed to acetaminophen alone or in combination with the antioxidant N-acetylcysteine or the P-glycoprotein inhibitor verapamil.

  12. Increased liver-specific proteins in circulating extracellular vesicles as potential biomarkers for drug- and alcohol-induced liver injury.

    Directory of Open Access Journals (Sweden)

    Young-Eun Cho

    Full Text Available Drug- and alcohol-induced liver injury are a leading cause of liver failure and transplantation. Emerging evidence suggests that extracellular vesicles (EVs are a source of biomarkers because they contain unique proteins reflecting the identity and tissue-specific origin of the EV proteins. This study aimed to determine whether potentially hepatotoxic agents, such as acetaminophen (APAP and binge alcohol, can increase the amounts of circulating EVs and evaluate liver-specific EV proteins as potential biomarkers for liver injury. The circulating EVs, isolated from plasma of APAP-exposed, ethanol-fed mice, or alcoholic hepatitis patients versus normal control counterparts, were characterized by proteomics and biochemical methods. Liver specific EV proteins were analyzed by immunoblots and ELISA. The amounts of total and liver-specific proteins in circulating EVs from APAP-treated mice significantly increased in a dose- and time-dependent manner. Proteomic analysis of EVs from APAP-exposed mice revealed that the amounts of liver-specific and/or hepatotoxic proteins were increased compared to those of controls. Additionally, the increased protein amounts in EVs following APAP exposure returned to basal levels when mice were treated with N-acetylcysteine or glutathione. Similar results of increased amounts and liver-specific proteins in circulating EVs were also observed in mice exposed to hepatotoxic doses of thioacetamide or d-galactosamine but not by non-hepatotoxic penicillin or myotoxic bupivacaine. Additionally, binge ethanol exposure significantly elevated liver-specific proteins in circulating EVs from mice and alcoholics with alcoholic hepatitis, compared to control counterparts. These results indicate that circulating EVs in drug- and alcohol-mediated hepatic injury contain liver-specific proteins that could serve as specific biomarkers for hepatotoxicity.

  13. Radiolysis of alanine adsorbed in a clay mineral

    Energy Technology Data Exchange (ETDEWEB)

    Aguilar-Ovando, Ellen Y.; Negron-Mendoza, Alicia [Instituto de Ciencias Nucleares, Universidad Nacional Autonoma de Mexico (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Apartado Postal 70-543, Deleg. Coyoacan, C.P. 04510 (Mexico)

    2013-07-03

    Optical activity in molecules is a chemical characteristic of living beings. In this work, we examine the hypothesis of the influence of different mineral surfaces on the development of a specific chirality in organic molecules when subjected to conditions simulating the primitive Earth during the period of chemical evolution. By using X-ray diffraction techniques and HPLC/ELSD to analyze aqueous suspensions of amino acids adsorbed on minerals irradiated in different doses with a cobalt-60 gamma source, the experiments attempt to prove the hypothesis that some solid surfaces (like clays and meteorite rocks) may have a concentration capacity and protective role against external sources of ionizing radiation (specifically {gamma}-ray) for some organic compounds (like some amino acids) adsorbed on them. Preliminary results show a slight difference in the adsorption and radiolysis of the D-and L-alanine.

  14. Hepatotoxicity in hyperthyroid patient after consecutive methimazole and propylthiouracil therapies

    Directory of Open Access Journals (Sweden)

    Fernando Gomez-Peralta

    2018-01-01

    Full Text Available Methimazole (MMI and propylthiouracil (PTU are widely used antithyroid drugs (ATD that have been approved for the treatment of hyperthyroidism. Hepatotoxicity may be induced by these drugs, though they exert dissimilar incidence rates of hepatotoxicity and, possibly, with different underlying pathogenic mechanisms. We report the case of a 55-year-old woman with no relevant medical history diagnosed with hyperthyroidism due to Graves’ disease, who developed two episodes of acute hepatitis concurrent with the consecutive administration of two different ATDs, first MMI and then PTU. Given the impossibility of administering ATDs, it was decided to perform a total thyroidectomy because the patient was found to be euthyroid at that point. Pathological anatomy showed diffuse hyperplasia and a papillary thyroid microcarcinoma of 2 mm in diameter. Subsequent clinical check-ups were normal. This case suggests the importance of regular monitoring of liver function for hyperthyroid patients. Due to the potential severity of this side effect, it is recommended to determine baseline liver function prior to initiation of treatment.

  15. Mixed learning algorithms and features ensemble in hepatotoxicity prediction.

    Science.gov (United States)

    Liew, Chin Yee; Lim, Yen Ching; Yap, Chun Wei

    2011-09-01

    Drug-induced liver injury, although infrequent, is an important safety concern that can lead to fatality in patients and failure in drug developments. In this study, we have used an ensemble of mixed learning algorithms and mixed features for the development of a model to predict hepatic effects. This robust method is based on the premise that no single learning algorithm is optimum for all modelling problems. An ensemble model of 617 base classifiers was built from a diverse set of 1,087 compounds. The ensemble model was validated internally with five-fold cross-validation and 25 rounds of y-randomization. In the external validation of 120 compounds, the ensemble model had achieved an accuracy of 75.0%, sensitivity of 81.9% and specificity of 64.6%. The model was also able to identify 22 of 23 withdrawn drugs or drugs with black box warning against hepatotoxicity. Dronedarone which is associated with severe liver injuries, announced in a recent FDA drug safety communication, was predicted as hepatotoxic by the ensemble model. It was found that the ensemble model was capable of classifying positive compounds (with hepatic effects) well, but less so on negatives compounds when they were structurally similar. The ensemble model built in this study is made available for public use. © Springer Science+Business Media B.V. 2011

  16. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics.

    Science.gov (United States)

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J

    2016-04-09

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  17. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus

    Science.gov (United States)

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Objective: Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Materials and Methods: Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were administered with 25, 50 and 75 mg/kg body weight blend of sunset yellow, metanil yellow and tartrazine for 30 days. Hepatotoxicity in rats treated with a blend of these food colors was studied by assessing parameters such as serum total protein, serum albumin, serum alkaline phosphatase (ALP) as well as hepatic malondialdehyde (MDA). The activity of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were assessed. Results: Significantly increased concentrations of serum total protein, serum albumin, serum ALP and hepatic MDA and significantly lowered levels of SOD, reduced GSH and CAT in the liver tissue of treated animals were observed when compared with control animals. The alteration in the liver includes necrosis of hepatocytes, infiltration and vacuolation. Conclusion: The result indicates that consumption of food color in diet induces liver tissue damage. The used doses of food color were mostly attributable to hepatocellular damage and drastic alteration in antioxidant defense system. PMID:26862277

  18. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

    Science.gov (United States)

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J.

    2016-01-01

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs. PMID:27070596

  19. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

    Directory of Open Access Journals (Sweden)

    Miren García-Cortés

    2016-04-01

    Full Text Available Dietary supplements (DS are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™ while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang. Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  20. A review of the hepatotoxic plant Lantana camara.

    Science.gov (United States)

    Sharma, Om P; Sharma, Sarita; Pattabhi, Vasantha; Mahato, Shashi B; Sharma, Pritam D

    2007-05-01

    Lantana (Lantana camara Linn) is a noxious weed that grows in many tropical and subtropical parts of the world. Ingestion of lantana foliage by grazing animals causes cholestasis and hepatotoxicity. Both ruminants and nonruminant animals such as guinea pigs, rabbits, and female rats are susceptible to the hepatotoxic action of lantana toxins. The hepatotoxins are pentacyclic triterpenoids called lantadenes. Molecular structure of lantadenes has been determined. Green unripe fruits of the plant are toxic to humans. Lantana spp. exert allelopathic action on the neighboring vegetation. The allelochemicals have been identified as phenolics, with umbelliferone, methylcoumarin, and salicylic acid being the most phytotoxic. In addition to phenolics, a recent report indicates lantadene A and B as more potent allelochemicals. Management of lantana toxicosis in animals is achieved by drenching with activated charcoal and supportive therapy. Recent reports on the bilirubin clearance effect of Chinese herbal tea Yin Zhi Huang (decoction of the plant Yin Chin, Artemisia capillaries, and three other herbs) or its active ingredient 6,7-dimethylesculetin, in jaundice are very exciting and warrant investigations on its, possible, ameliorative effects in lantana intoxicated animals. Research is being conducted on new drug discovery based on natural products in different parts of the lantana plant.

  1. Zinc modulates lithium-induced hepatotoxicity in rats.

    Science.gov (United States)

    Chadha, Vijayta Dani; Bhalla, Punita; Dhawan, Devinder Kumar

    2008-04-01

    The present study explored the hepatoprotective role of zinc in lithium-induced hepatotoxicity. Rats received either lithium treatment in diet at a dose level of 1.1 g/kg diet, zinc alone at a dose level of 227 mg/L in drinking water, and combined lithium plus zinc or drinking water alone for different time durations of 1, 2 and 4 months. This study explored the hepatic marker enzymes, antioxidant status and histopathological investigations in the liver of rats following different treatments. The activities of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and alkaline phosphatase were found to be elevated significantly following 2 and 4 months of lithium treatment. Lithium-treated rats showed a significant increase in the levels of lipid peroxidation and superoxide dismutase and a significant inhibition in the levels of reduced glutathione, catalase and glutathione-S-transferase, following 2 and 4 months of treatment. However, zinc co-administration revealed significant improvement in the altered activities of hepatic marker and antioxidant enzymes in comparison with lithium-treated animals. Lithium-treated rats also indicated drastic alterations in hepatic histoarchitecture and zinc co-administration resulted in improvement in the structure of hepatocytes. The present study suggests the protective potential of zinc in lithium-induced hepatotoxicity.

  2. Virgin coconut oil supplementation attenuates acute chemotherapy hepatotoxicity induced by anticancer drug methotrexate via inhibition of oxidative stress in rats.

    Science.gov (United States)

    Famurewa, Ademola C; Ufebe, Odomero G; Egedigwe, Chima A; Nwankwo, Onyebuchi E; Obaje, Godwin S

    2017-03-01

    The emerging health benefit of virgin coconut oil (VCO) has been associated with its potent natural antioxidants; however, the antioxidant and hepatoprotective effect of VCO against methotrexate-induced liver damage and oxidative stress remains unexplored. The study explored the antioxidant and hepatoprotective effects of VCO against oxidative stress and liver damage induced by anticancer drug methotrexate (MTX) in rats. Liver damage was induced in Wistar rats pretreated with dietary supplementation of VCO (5% and 15%) by intraperitoneal administration of MTX (20mg/kg bw) on day 10 only. After 12days of treatment, assays for serum liver biomarkers (aminotransferases), alkaline phosphatase, albumin and total protein as well as hepatic content of malondialdehyde, reduced glutathione and antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were carried out. Liver was used to examine histopathological changes. MTX administration induced significant increase in serum liver enzymes along with marked decrease in albumin and total protein compared to control group. Hepatic activities of antioxidant enzymes were significantly decreased, while malondialdehyde increased significantly. Treatment with VCO supplemented diet prior to MTX administration attenuated MTX-induced liver injury and oxidative stress evidenced by significant improvements in serum liver markers, hepatic antioxidant enzymes and malondialdehyde comparable to control group. Histopathological alterations were prevented and correlated well with the biochemical indices. The study suggests antioxidant and hepatoprotective effects of VCO supplementation against hepatotoxicity and oxidative damage via improving antioxidant defense system in rats. Our findings may have beneficial application in the management of hepatotoxicity associated with MTX cancer chemotherapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  3. Effect of β-alanine supplementation on high-intensity exercise performance.

    Science.gov (United States)

    Harris, Roger C; Stellingwerff, Trent

    2013-01-01

    Carnosine is a dipeptide of β-alanine and L-histidine found in high concentrations in skeletal muscle. Combined with β-alanine, the pKa of the histidine imidazole ring is raised to ∼6.8, placing it within the muscle intracellular pH high-intensity exercise transit range. Combination with β-alanine renders the dipeptide inert to intracellular enzymic hydrolysis and blocks the histidinyl residue from participation in proteogenesis, thus making it an ideal, stable intracellular buffer. For vegetarians, synthesis is limited by β-alanine availability; for meat-eaters, hepatic synthesis is supplemented with β-alanine from the hydrolysis of dietary carnosine. Direct oral β-alanine supplementation will compensate for low meat and fish intake, significantly raising the muscle carnosine concentration. This is best achieved with a sustained-release formulation of β-alanine to avoid paresthesia symptoms and decreasing urinary spillover. In humans, increased levels of carnosine through β-alanine supplementation have been shown to increase exercise capacity and performance of several types, particularly where the high-intensity exercise range is 1-4 min. β-Alanine supplementation is used by athletes competing in high-intensity track and field cycling, rowing, swimming events and other competitions. Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel.

  4. Evolutionary Diversification of Alanine Transaminases in Yeast: Catabolic Specialization and Biosynthetic Redundancy

    Directory of Open Access Journals (Sweden)

    Ximena Escalera-Fanjul

    2017-06-01

    Full Text Available Gene duplication is one of the major evolutionary mechanisms providing raw material for the generation of genes with new or modified functions. The yeast Saccharomyces cerevisiae originated after an allopolyploidization event, which involved mating between two different ancestral yeast species. ScALT1 and ScALT2 codify proteins with 65% identity, which were proposed to be paralogous alanine transaminases. Further analysis of their physiological role showed that while ScALT1 encodes an alanine transaminase which constitutes the main pathway for alanine biosynthesis and the sole pathway for alanine catabolism, ScAlt2 does not display alanine transaminase activity and is not involved in alanine metabolism. Moreover, phylogenetic studies have suggested that ScALT1 and ScALT2 come from each one of the two parental strains which gave rise to the ancestral hybrid. The present work has been aimed to the understanding of the properties of the ancestral type Lacchancea kluyveri LkALT1 and Kluyveromyces lactis KlALT1, alanine transaminases in order to better understand the ScALT1 and ScALT2 evolutionary history. These ancestral -type species were chosen since they harbor ALT1 genes, which are related to ScALT2. Presented results show that, although LkALT1 and KlALT1 constitute ScALT1 orthologous genes, encoding alanine transaminases, both yeasts display LkAlt1 and KlAlt1 independent alanine transaminase activity and additional unidentified alanine biosynthetic and catabolic pathway(s. Furthermore, phenotypic analysis of null mutants uncovered the fact that KlAlt1 and LkAlt1 have an additional role, not related to alanine metabolism but is necessary to achieve wild type growth rate. Our study shows that the ancestral alanine transaminase function has been retained by the ScALT1 encoded enzyme, which has specialized its catabolic character, while losing the alanine independent role observed in the ancestral type enzymes. The fact that ScAlt2 conserves 64

  5. β-Alanine Dose for Maintaining Moderately Elevated Muscle Carnosine Levels

    National Research Council Canada - National Science Library

    STEGEN, SANNE; BEX, TINE; VERVAET, CHRIS; VANHEE, LANDER; ACHTEN, ERIC; DERAVE, WIM

    2014-01-01

    INTRODUCTIONChronic β-alanine (BA) supplementation is an increasingly popular nutritional strategy, because it can elevate muscle carnosine content and thereby enhance high-intensity exercise performance...

  6. Effects of rosmarinic acid on acetaminophen-induced hepatotoxicity in male Wistar rats.

    Science.gov (United States)

    Hasanein, Parisa; Sharifi, Maryam

    2017-12-01

    Drug-induced liver injury is a significant worldwide clinical problem. Rosmarinic acid (RA), a natural phenol, has antioxidant effects. The effects of RA against acetaminophen (N-acetyl-p-amino-phenol (APAP))-induced oxidative damage and hepatotoxicity in rats were investigated. Male Wistar rats were pretreated with RA (10, 50 and 100 mg/kg, i.g.) for one week. On day 7, rats received APAP (500 mg/kg, i.p.). Then aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein, malondialdehyde (MDA), glutathione (GSH), total antioxidant capacity (TAC), glutathione S-transferase (GST), cytochrome CYP450 and histopathological changes were determined. APAP-induced oxidative stress in liver by a significant increase in the level of MDA (7.6 ± 0.21 nmol/mg) as well as a decrease in the contents of TAC (1.75 ± 0.14 μmol/g), GSH (1.9 ± 0.22 μmol/g) and GST) 3.2 ± 0.28 U/mg). RA treatment decreased MDA (4.32 ± 0.35 nmol/mg) but increased the contents of TAC (3.51 ± 0.34 μmol/g), GSH (3.42 ± 0.16 μmol/g) and GST (5.71 ± 0.71 μmol/g) in APAP group. RA 100 mg/kg decreased ALT (91.5 ± 1.5 U/L), AST (169 ± 8.8 U/L) and CYP450 (3 ± 0.2 nmol/min/mg) in APAP group. Histologically RA attenuated hepatic damage by decreasing necrosis, inflammation, and haemorrhage in liver sections of APAP group. This is the first report that oral administration of RA dose-dependently elicited significant hepatoprotective effects in rats through inhibition of hepatic CYP2E1 activity and lipid peroxidation. RA-protected hepatic GSH and GST reserves and total tissue antioxidant capacity.

  7. Hepatotoxicity and P-4502E1-dependent metabolic oxidation of N,N-dimethylformamide in rats and mice.

    Science.gov (United States)

    Chieli, E; Saviozzi, M; Menicagli, S; Branca, T; Gervasi, P G

    1995-01-01

    A comparative biochemical and histological study on the hepatotoxicity of a single dose of N,N-dimethylformamide (DMF) and N-methylformamide (NMF) in control and acetone-treated SD male rats and CD-1 male mice was performed. In control and acetone-pretreated rats, neither DMF nor NMF caused hepatic damage or elevation of plasma transaminases. In contrast, in acetonized but not in control mice, DMF administration yielded some evidence of liver necrosis and elevation of ALAT (alanine-amino transferase) activity. After a DMF dose of 1000 mg/kg, ALAT activity was found 1215 +/- 832 mU/ml and 47 +/- 18 mU/ml in acetonized and control mice, respectively. NMF treatment was hepatotoxic in control mice and lethal in acetonized mice. In control mice, an NMF dose of 600 mg/kg increased ALAT activity from a basal value of 35 +/- 5 to 2210 +/- 1898 mU/ml. When the oxidative metabolism of DMF was investigated, microsomes from both rats and mice preinduced by acetone increased the demethylation rate of DMF 7 to 10-fold compared to that (about 0.25 nmol/min per mg protein) of the corresponding control microsomes. The enzymatic affinities for DMF oxidation, however, were different: in mice the Km (0.05 mM) was one order of magnitude lower than that (0.56 mM) found in rats. The experiments performed with purified rat and mouse P-450 2E1 in a reconstituted system confirmed that the P-450 2E1 isoforms are very active catalysts towards DMF oxidation (the turnover was about 10 nmol/min per nmol P-450 for both enzymes) but with a strikingly different affinity. Whereas the Km for mouse P-450 2E1 was 0.08 +/- 0.03 mM, that for rat P-450 2E1 was 1.1 +/- 0.2 mM.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Protective Effect of Hesperidin against Cyclophosphamide Hepatotoxicity in Rats

    OpenAIRE

    Amr A. Fouad; Waleed H. Albuali; Iyad Jresat

    2014-01-01

    The protective effect of hesperidin was investigated in rats exposed to liver injury induced by a single intraperitoneal injection of cyclophosphamide (CYP) at a dose of 150 mg kg-1. Hesperidin treatment (100 mg kg-1/day, orally) was applied for seven days, starting five days before CYP administration. Hesperidin significantly decreased the CYP-induced elevations of serum alanine aminotransferase, and hepatic malondialdehyde and myeloperoxidase activity, significantly pre...

  9. Hepatotoxicity in mice of a novel anti-parasite drug candidate hydroxymethylnitrofurazone: a comparison with Benznidazole.

    Directory of Open Access Journals (Sweden)

    Carolina Davies

    2014-10-01

    Full Text Available Treatment of Chagas disease, caused by Trypanosoma cruzi, relies on nifurtimox and benznidazole (BZL, which present side effects in adult patients, and natural resistance in some parasite strains. Hydroxymethylnitrofurazone (NFOH is a new drug candidate with demonstrated trypanocidal activity; however, its safety is not known.HepG2 cells dose response to NFOH and BZL (5-100 µM was assessed by measurement of ROS, DNA damage and survival. Swiss mice were treated with NFOH or BZL for short-term (ST, 21 d or long-term (LT, 60 d periods. Sera levels of cellular injury markers, liver inflammatory and oxidative stress, and fibrotic remodeling were monitored.HepG2 cells exhibited mild stress, evidenced by increased ROS and DNA damage, in response to NFOH, while BZL at 100 µM concentration induced >33% cell death in 24 h. In mice, NFOH ST treatment resulted in mild-to-no increase in the liver injury biomarkers (GOT, GPT, and liver levels of inflammatory (myeloperoxidase, TNF-α, oxidative (lipid peroxides and nitrosative (3-nitrotyrosine stress. These stress responses in NFOH LT treated mice were normalized to control levels. BZL-treated mice exhibited a >5-fold increase in GOT, GPT and TNF-α (LT and a 20-40% increase in liver levels of MPO activity (ST and LT in comparison with NFOH-treated mice. The liver inflammatory infiltrate was noted in the order of BZL>vehicle≥NFOH and BZL>NFOH≥vehicle, respectively, after ST and LT treatments. Liver fibrotic remodeling, identified after ST treatment, was in the order of BZL>vehicle>NFOH; lipid deposits, indicative of mitochondrial dysfunction and in the order of NFOH>vehicle>BZL were evidenced after LT treatment.NFOH induces mild ST hepatotoxicity that is normalized during LT treatment in mice. Our results suggest that additional studies to determine the efficacy and toxicity of NFOH are warranted.

  10. Hepatotoxicity in Mice of a Novel Anti-parasite Drug Candidate Hydroxymethylnitrofurazone: A Comparison with Benznidazole

    Science.gov (United States)

    Davies, Carolina; Dey, Nilay; Negrette, Olga Sanchez; Parada, Luis Antonio; Basombrio, Miguel A.; Garg, Nisha Jain

    2014-01-01

    Background Treatment of Chagas disease, caused by Trypanosoma cruzi, relies on nifurtimox and benznidazole (BZL), which present side effects in adult patients, and natural resistance in some parasite strains. Hydroxymethylnitrofurazone (NFOH) is a new drug candidate with demonstrated trypanocidal activity; however, its safety is not known. Methods HepG2 cells dose response to NFOH and BZL (5–100 µM) was assessed by measurement of ROS, DNA damage and survival. Swiss mice were treated with NFOH or BZL for short-term (ST, 21 d) or long-term (LT, 60 d) periods. Sera levels of cellular injury markers, liver inflammatory and oxidative stress, and fibrotic remodeling were monitored. Results HepG2 cells exhibited mild stress, evidenced by increased ROS and DNA damage, in response to NFOH, while BZL at 100 µM concentration induced >33% cell death in 24 h. In mice, NFOH ST treatment resulted in mild-to-no increase in the liver injury biomarkers (GOT, GPT), and liver levels of inflammatory (myeloperoxidase, TNF-α), oxidative (lipid peroxides) and nitrosative (3-nitrotyrosine) stress. These stress responses in NFOH LT treated mice were normalized to control levels. BZL-treated mice exhibited a >5-fold increase in GOT, GPT and TNF-α (LT) and a 20–40% increase in liver levels of MPO activity (ST and LT) in comparison with NFOH-treated mice. The liver inflammatory infiltrate was noted in the order of BZL>vehicle≥NFOH and BZL>NFOH≥vehicle, respectively, after ST and LT treatments. Liver fibrotic remodeling, identified after ST treatment, was in the order of BZL>vehicle>NFOH; lipid deposits, indicative of mitochondrial dysfunction and in the order of NFOH>vehicle>BZL were evidenced after LT treatment. Conclusions NFOH induces mild ST hepatotoxicity that is normalized during LT treatment in mice. Our results suggest that additional studies to determine the efficacy and toxicity of NFOH are warranted. PMID:25329323

  11. Eukaryotic beta-alanine synthases are functionally related but have a high degree of structural diversity.

    Science.gov (United States)

    Gojković, Z; Sandrini, M P; Piskur, J

    2001-01-01

    beta-Alanine synthase (EC 3.5.1.6), which catalyzes the final step of pyrimidine catabolism, has only been characterized in mammals. A Saccharomyces kluyveri pyd3 mutant that is unable to grow on N-carbamyl-beta-alanine as the sole nitrogen source and exhibits diminished beta-alanine synthase activity was used to clone analogous genes from different eukaryotes. Putative PYD3 sequences from the yeast S. kluyveri, the slime mold Dictyostelium discoideum, and the fruit fly Drosophila melanogaster complemented the pyd3 defect. When the S. kluyveri PYD3 gene was expressed in S. cerevisiae, which has no pyrimidine catabolic pathway, it enabled growth on N-carbamyl-beta-alanine as the sole nitrogen source. The D. discoideum and D. melanogaster PYD3 gene products are similar to mammalian beta-alanine synthases. In contrast, the S. kluyveri protein is quite different from these and more similar to bacterial N-carbamyl amidohydrolases. All three beta-alanine synthases are to some degree related to various aspartate transcarbamylases, which catalyze the second step of the de novo pyrimidine biosynthetic pathway. PYD3 expression in yeast seems to be inducible by dihydrouracil and N-carbamyl-beta-alanine, but not by uracil. This work establishes S. kluyveri as a model organism for studying pyrimidine degradation and beta-alanine production in eukaryotes. PMID:11454750

  12. Degradation of pyrimidines in Saccharomyces kluyveri: transamination of beta-alanine

    DEFF Research Database (Denmark)

    Schnackerz, K D; Andersen, G; Dobritzsch, D

    2008-01-01

    Beta-alanine is an intermediate in the reductive degradation of uracil. Recently we have identified and characterized the Saccharomyces kluyveri PYD4 gene and the corresponding enzyme beta -alanine aminotransferase ((Sk)Pyd4p), highly homologous to eukaryotic gamma-aminobutyrate aminotransferase ...

  13. No effect of β-alanine on muscle function and kayak performance

    DEFF Research Database (Denmark)

    Bech, Signe Refsgaard; Nielsen, Tobias Schmidt; Hald, Martin

    2018-01-01

    PURPOSE: It was investigated if β-alanine supplementation counteracts muscular fatigue development or improves athletic performance. METHODS: Elite kayak rowers (10 males and 7 females) were supplemented with either 80 mg/kg body mass/day β-alanine or placebo for 8 weeks. Muscular fatigue...

  14. Energy landscapes and global thermodynamics for alanine peptides

    Science.gov (United States)

    Somani, Sandeep; Wales, David J.

    2013-09-01

    We compare different approaches for computing the thermodynamics of biomolecular systems. Techniques based on parallel replicas evolving via molecular dynamics or Monte Carlo simulations produce overlapping histograms for the densities of states. In contrast, energy landscape methods employ a superposition partition function constructed from local minima of the potential energy surface. The latter approach is particularly powerful for systems exhibiting broken ergodicity, and it is usually implemented using a harmonic normal mode approximation, which has not been extensively tested for biomolecules. The present contribution compares these alternative approaches for small alanine peptides modelled using the CHARMM and AMBER force fields. Densities of states produced from canonical sampling using multiple temperature replicas provide accurate reference data to evaluate the effect of the harmonic normal mode approximation in the superposition calculations. This benchmarking lays foundations for the application of energy landscape methods to larger biomolecules. It will also provide well characterised model systems for developing enhanced sampling methods, and for the treatment of anharmonicity corresponding to individual local minima.

  15. [Relationship between alanine aminotransferase and overweight or obesity in children].

    Science.gov (United States)

    Fan, Xin; Chen, Shao-Ke; Tang, Qing; Luo, Jing-Si; Feng, Ying

    2011-12-01

    To study the association of alanine aminotransferase (ALT) with overweight or obesity in children. A total of 2889 healthy children and 702 overweight or obese children aged from 7 to 18 years who had received a physical examination were enrolled. Height, body weight, waist circumference, and blood pressure were measured, and the biochemical indicators including blood glucose, blood lipids, ALT, and insulin were detected. The insulin resistance index were calculated. The ALT level was significantly higher in boys than in girls. Along with the increase of BMI, the ALT level increased in the normal, overweight, and obese groups in both boys and girls. ALT was correlated with BMI, waist circumference, triglyceride, and insulin resistance index. Among the overweight or obese children, the boys with the increased ALT level had higher BMI, waist circumference, blood pressure, triglyceride, low density lipoprotein and insulin resistance index than the boys with normal ALT level (Pobesity and metabolic disorders caused by overweight and obesity such as dyslipidemia and insulin resistance.

  16. Impact of charged amino acid substitution in the transmembrane domain of L-alanine exporter, AlaE, of Escherichia coli on the L-alanine export.

    Science.gov (United States)

    Kim, Seryoung; Ihara, Kohei; Katsube, Satoshi; Ando, Tasuke; Isogai, Emiko; Yoneyama, Hiroshi

    2017-01-01

    The Escherichia coli alaE gene encodes the L-alanine exporter, AlaE, that catalyzes active export of L-alanine using proton electrochemical potential. The transporter comprises only 149 amino acid residues and four predicted transmembrane domains (TMs), which contain three charged amino acid residues. The AlaE-deficient L-alanine non-metabolizing cells (ΔalaE cells) appeared hypersusceptible to L-alanyl-L-alanine showing a minimum inhibitory concentration (MIC) of 2.5 µg/ml for the dipeptide due to a toxic accumulation of L-alanine. To elucidate the mechanism by which AlaE exports L-alanine, we replaced charged amino acid residues in the TMs, glutamic acid-30 (TM-I), arginine-45 (TM-II), and aspartic acid-84 (TM-III) with their respective charge-conserved amino acid or a net neutral cysteine. The ΔalaE cells producing R45K or R45C appeared hypersusceptible to the dipeptide, indicating that arginine-45 is essential for AlaE activity. MIC of the dipeptide in the ΔalaE cells expressing E30D and E30C was 156 µg/ml and >10,000 µg/ml, respectively, thereby suggesting that a negative charge at this position is not essential. The ΔalaE cells expressing D84E or D84C showed an MIC >10,000 and 78 µg/ml, respectively, implying that a negative charge is required at this position. These results were generally consistent with that of the L-alanine accumulation experiments in intact cells. We therefore concluded that charged amino acid residues (R45 and D84) in the AlaE transmembrane domain play a pivotal role in L-alanine export. Replacement of three cysteine residues at C22, C28 (both in TM-I), and C135 (C-terminal region) with alanine showed only a marginal effect on L-alanine export.

  17. Early predictors of severe acetaminophen-induced hepatotoxicity in a paediatric population referred to a tertiary paediatric department

    DEFF Research Database (Denmark)

    Hedeland, Rikke Lindgaard; Andersen, Jesper; Askbo, Natasha Louise Friis

    2014-01-01

    AIM: The data on severe acetaminophen-induced hepatotoxicity in children are very limited. This study explored the dose-response relationship between ingested acetaminophen and hepatotoxicity, the early biochemical and clinical predictors of hepatotoxicity, the impact of early N-acetylcysteine tr......AIM: The data on severe acetaminophen-induced hepatotoxicity in children are very limited. This study explored the dose-response relationship between ingested acetaminophen and hepatotoxicity, the early biochemical and clinical predictors of hepatotoxicity, the impact of early N......-acetylcysteine treatment on hepatotoxicity and the incidence of nephrotoxicity. METHODS: We carried out a retrospective case study on 25 children aged 11-16 years with severe acetaminophen poisoning. RESULTS: Initial biochemical parameters predicted hepatotoxicity, defined as the maximum levels of the international...... of nephrotoxicity was 12%. There was no significant relationship between the amount of ingested acetaminophen and the degree of hepatotoxicity. CONCLUSION: Paediatric patients at increased risk of severe hepatotoxicity were identified by early biochemical parameters, prehospital vomiting episodes and latency time...

  18. Folic acid protects against lead acetate-induced hepatotoxicity by decreasing NF-κB, IL-1β production and lipid peroxidation mediataed cell injury.

    Science.gov (United States)

    Abd Allah, Eman S H; Badary, Dalia M

    2017-03-01

    Folic acid plays an important role in cellular metabolic activities. The present study was designed to investigate the protective effect of folic acid against lead acetate-induced hepatotoxicity. Twenty four male Wistar albino rats were randomly divided into four groups, six animals each. Negative control group received the vehicle, positive control group received 1mg/kg folic acid for five consecutive days/week for 4 weeks orally, lead-exposed group received 10mg/kg lead acetate intraperitoneally (IP) for five consecutive days/week for 4 weeks, and lead-treated group received 10mg/kg lead acetate IP and 1mg/kg folic acid orally for five consecutive days/week for 4 weeks concurrently. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ- glutamyltransferase (GGT) were measured. Hepatic total peroxide and interleukin-1β (IL-1β) were also investigated. Histopathological studies using hematoxylin-eosin (H&E) and periodic acid shiff's (PAS) were carried out. The expression of nuclear factor kappa B (NF-κB) was evaluated using immunohistochemistry. Serum AST, ALT and GGT and hepatic total peroxide and IL-1β were significantly increased in lead-exposed group and were positively correlated with hepatic lead level. Moreover, lead-exposed rats showed hydropic degeneration, nuclear vesiculation, high lymphocytic infiltration, depletion of glycogen content and NF-κB expression. Concomitant folic acid administration resulted in a significant alleviation of biochemical and structural alteration-induced by lead. This was associated with reduction of hepatic total peroxide and IL-1β and reduction of NF-κB expression. In conclusion, folic acid protects against lead acetate-induced hepatotoxicity by decreasing NF-κB, IL-1β production and lipid peroxidation mediataed cell injury. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats.

    Science.gov (United States)

    Rajan, Balan; Sathish, Shanmugam; Balakumar, Subramanian; Devaki, Thiruvengadam

    2015-03-01

    Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Fructose diet alleviates acetaminophen-induced hepatotoxicity in mice.

    Directory of Open Access Journals (Sweden)

    Sungjoon Cho

    Full Text Available Acetaminophen (APAP is a commonly used analgesic and antipyretic that can cause hepatotoxicity due to production of toxic metabolites via cytochrome P450 (Cyp 1a2 and Cyp2e1. Previous studies have shown conflicting effects of fructose (the major component in Western diet on the susceptibility to APAP-induced hepatotoxicity. To evaluate the role of fructose-supplemented diet in modulating the extent of APAP-induced liver injury, male C57BL/6J mice were given 30% (w/v fructose in water (or regular water for 8 weeks, followed by oral administration of APAP. APAP-induced liver injury (determined by serum levels of liver enzymes was decreased by two-fold in mice pretreated with fructose. Fructose-treated mice exhibited (~1.5 fold higher basal glutathione levels and (~2 fold lower basal (mRNA and activity levels of Cyp1a2 and Cyp2e1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose-fed mice. Hepatic mRNA expression of heat shock protein 70 was also found increased in fructose-fed mice. Analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle groups showed that the fructose diet altered gut bacterial community, leading to increased α-diversity. The abundance of several bacterial taxa including the genus Anaerostipes was found to be significantly correlated with the levels of hepatic Cyp2e1, Cyp1a2 mRNA, and glutathione. Together, these results suggest that the fructose-supplemented diet decreases APAP-induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification of toxic metabolites, potentially through altered composition of gut microbiota.

  1. Nonalcoholic fatty liver sensitizes rats to carbon tetrachloride hepatotoxicity.

    Science.gov (United States)

    Donthamsetty, Shashikiran; Bhave, Vishakha S; Mitra, Mayurranjan S; Latendresse, John R; Mehendale, Harihara M

    2007-02-01

    This study tested whether hepatic steatosis sensitizes liver to toxicant-induced injury and investigated the potential mechanisms of hepatotoxic sensitivity. Male Sprague-Dawley rats were fed a methionine- and choline-deficient diet for 31 days to induce steatosis. On the 32nd day, administration of a nonlethal dose of CCl4 (2 mL/kg, intraperitoneally) yielded 70% mortality in steatotic rats 12-72 hours after CCl4 administration, whereas all nonsteatotic rats survived. Neither CYP2E1 levels nor covalent binding of [14C] CCl4-derived radio-label differed between the groups, suggesting that increased bioactivation is not the mechanism for this amplified toxicity. Cell division and tissue repair, assessed by [3H]thymidine incorporation and proliferative cell nuclear antigen assay, were inhibited in the steatotic livers after CCl4 administration and led to progressive expansion of liver injury culminating in mortality. The hypothesis that fatty hepatocytes undergo cell cycle arrest due to (1) an inability to replenish ATP due to overexpressed uncoupling protein-2 (UCP-2) or (2) induction of growth inhibitor p21 leading to G1/S phase arrest was tested. Steatotic livers showed 10-fold lower ATP levels due to upregulated UCP-2 throughout the time course after CCl4 administration, leading to sustained inhibition of cell division. Western blot analysis revealed an up-regulation of p21 due to overexpression of TGF beta1 and p53 and down-regulation of transcription factor Foxm 1b in steatotic livers leading to lower phosphorylated retinoblastoma protein. Thus, fatty hepatocytes fail to undergo compensatory cell division, rendering the liver susceptible to progression of liver injury. Impaired tissue repair sensitizes the steatotic livers to hepatotoxicity.

  2. Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats.

    Science.gov (United States)

    Jacevic, Vesna; Djordjevic, Aleksandar; Srdjenovic, Branislava; Milic-Tores, Vukosava; Segrt, Zoran; Dragojevic-Simic, Viktorija; Kuca, Kamil

    2017-04-01

    Doxorubicin (DOX), commonly used antineoplastic agent, affects bone marrow, intestinal tract and heart, but it also has some hepatotoxic effects. Main mechanism of its toxicity is the production of free reactive oxygen species. Polyhidroxilated C 60 fullerene derivatives, fullerenol nanoparticles (FNP), act as free radical scavengers in in vitro systems. The aim of the study was to investigate potential FNP protective role against DOX-induced hepatotoxicity in rats. Experiments were performed on adult male Wistar rats. Animals were divided into five groups: (1) 0.9% NaCl (control), (2) 100mg/kg ip FNP, (3) 10mg/kg DOX iv, (4) 50mg/kg ip FNP 30min before 10mg/kg iv DOX, (5) 100mg/kg ip FNP 30min before 10mg/kg iv DOX. A general health condition, body and liver weight, TBARS level and antioxidative enzyme activity, as well as pathohistological examination of the liver tissue were conducted on days 2 and 14 of the study. FNP, applied alone, did not alter any examinated parameters. However, when used as a pretreatment it significantly increased survival rate, body and liver weight, and decreased TBARS level, antioxidative enzyme activity and hepatic damage score in DOX-treated rats. FNP administered at a dose of 100mg/kg significantly attenuated effects of doxorubicin administered in a single high dose in rats, concerning general condition, body and liver weight, lipid peroxidation level and antioxidative enzyme activity as well as structural alterations of the hepatic tissue. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Nrf2 protects against furosemide-induced hepatotoxicity.

    Science.gov (United States)

    Qu, Qiang; Liu, Jie; Zhou, Hong-Hao; Klaassen, Curtis D

    2014-10-03

    Furosemide is a diuretic drug, but its reactive intermediates lead to acute liver injury in mice. Given the essential role of Nrf2 as a cellular defense regulator, we investigated whether Nrf2 would protect against furosemide-induced liver injury using the Nrf2 "gene-dose response" mouse model (Nrf2-null with Nrf2 knock-out, wild-type with normal expression of Nrf2, Keap1-KD with enhanced Nrf2 activation and Keap1-HKO mice with maximum Nrf2 activation). Twenty-four hours after furosemide administration (250mg/kg, i.p.), serum ALT activities and histopathological analysis indicated severe hepatotoxicity in Nrf2-null and WT mice, but significantly less in the Nrf2-overexpressing Keap1-KD and Keap1-HKO mice. Furosemide increased the mRNA of genes involved in the acute phase response (hemeoxygenase-1 and metallothionein-1), ER stress (C/Ebp-homologous protein and Growth arrest and DNA-damage-inducible protein), inflammatory cytokine (interleukin 1 beta), chemokines (macrophage inflammatory protein 2 and mouse keratinocyte-derived chemokine), as well as apoptosis (early growth response factor and BCL2-associated X protein) in livers of Nrf2-null and wild-type mice, but these genes increased less in mice with more Nrf2. The two genotypes of over-expressed Nrf2 mice had increased expression of the Nrf2 target genes Gclm, Gclc and Nqo1 prior to furosemide administration, and the expressions of these genes were increased further after furosemide administration. Thus, our findings provide strong evidence that over-expression of Nrf2 in Keap1-KD and Keap1-HKO mice and the increases in mRNA of a number of genes involved in anti-oxidative stress, anti-inflammation, anti-ER stress and anti-apoptosis protect against furosemide-induced hepatotoxicity. Copyright © 2014. Published by Elsevier Ireland Ltd.

  4. SlimQuick™ - associated hepatotoxicity in a woman with alpha-1 antitrypsin heterozygosity.

    Science.gov (United States)

    Weinstein, Douglas H; Twaddell, William S; Raufman, Jean-Pierre; Philosophe, Benjamin; Mindikoglu, Ayse L

    2012-04-27

    Green tea (Camellia sinensis)-associated hepatotoxicity is reported. However, the presence of alpha-1 antitrypsin MZ phenotype as a predisposing factor to green tea-associated drug-induced liver injury (DILI) is unknown. A previously healthy woman with alpha-1 antitrypsin MZ phenotype who took SlimQuick™, an herbal supplement containing green tea extract, developed severe hepatotoxicity requiring corticosteroid treatment. Green tea-associated hepatotoxicity is reviewed and alpha-1 antitrypsin MZ phenotype as a predisposing factor to green tea-associated DILI is discussed. Liver biopsy demonstrated marked inflammation with necrosis suggestive of toxic injury with diffuse alpha-1 antitrypsin globule deposition on immunostaining. Corticosteroid therapy resulted in rapid clinical improvement. Alpha-1 antitrypsin MZ phenotype may increase vulnerability to herbal hepatotoxicity.

  5. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs

    National Research Council Canada - National Science Library

    Sewing, Sabine; Boess, Franziska; Moisan, Annie; Bertinetti-Lapatki, Cristina; Minz, Tanja; Hedtjaern, Maj; Tessier, Yann; Schuler, Franz; Singer, Thomas; Roth, Adrian B

    2016-01-01

    .... The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO...

  6. Ergogenic Effects of β-Alanine and Carnosine: Proposed Future Research to Quantify Their Efficacy

    Science.gov (United States)

    Caruso, John; Charles, Jessica; Unruh, Kayla; Giebel, Rachel; Learmonth, Lexis; Potter, William

    2012-01-01

    β-alanine is an amino acid that, when combined with histidine, forms the dipeptide carnosine within skeletal muscle. Carnosine and β-alanine each have multiple purposes within the human body; this review focuses on their roles as ergogenic aids to exercise performance and suggests how to best quantify the former’s merits as a buffer. Carnosine normally makes a small contribution to a cell’s total buffer capacity; yet β-alanine supplementation raises intracellular carnosine concentrations that in turn improve a muscle’s ability to buffer protons. Numerous studies assessed the impact of oral β-alanine intake on muscle carnosine levels and exercise performance. β-alanine may best act as an ergogenic aid when metabolic acidosis is the primary factor for compromised exercise performance. Blood lactate kinetics, whereby the concentration of the metabolite is measured as it enters and leaves the vasculature over time, affords the best opportunity to assess the merits of β-alanine supplementation’s ergogenic effect. Optimal β-alanine dosages have not been determined for persons of different ages, genders and nutritional/health conditions. Doses as high as 6.4 g day−1, for ten weeks have been administered to healthy subjects. Paraesthesia is to date the only side effect from oral β-alanine ingestion. The severity and duration of paraesthesia episodes are dose-dependent. It may be unwise for persons with a history of paraesthesia to ingest β-alanine. As for any supplement, caution should be exercised with β-alanine supplementation. PMID:22852051

  7. Ergogenic Effects of β-Alanine and Carnosine: Proposed Future Research to Quantify Their Efficacy

    Directory of Open Access Journals (Sweden)

    John Caruso

    2012-06-01

    Full Text Available β-alanine is an amino acid that, when combined with histidine, forms the dipeptide carnosine within skeletal muscle. Carnosine and β-alanine each have multiple purposes within the human body; this review focuses on their roles as ergogenic aids to exercise performance and suggests how to best quantify the former’s merits as a buffer. Carnosine normally makes a small contribution to a cell’s total buffer capacity; yet β-alanine supplementation raises intracellular carnosine concentrations that in turn improve a muscle’s ability to buffer protons. Numerous studies assessed the impact of oral β-alanine intake on muscle carnosine levels and exercise performance. β-alanine may best act as an ergogenic aid when metabolic acidosis is the primary factor for compromised exercise performance. Blood lactate kinetics, whereby the concentration of the metabolite is measured as it enters and leaves the vasculature over time, affords the best opportunity to assess the merits of β-alanine supplementation’s ergogenic effect. Optimal β-alanine dosages have not been determined for persons of different ages, genders and nutritional/health conditions. Doses as high as 6.4 g day−1, for ten weeks have been administered to healthy subjects. Paraesthesia is to date the only side effect from oral β-alanine ingestion. The severity and duration of paraesthesia episodes are dose-dependent. It may be unwise for persons with a history of paraesthesia to ingest β-alanine. As for any supplement, caution should be exercised with β-alanine supplementation.

  8. Effect of beta-alanine, with and without sodium bicarbonate, on 2000-m rowing performance.

    Science.gov (United States)

    Hobson, Ruth M; Harris, Roger C; Martin, Dan; Smith, Perry; Macklin, Ben; Gualano, Bruno; Sale, Craig

    2013-10-01

    To examine the effect of beta-alanine only and beta-alanine with sodium bicarbonate supplementation on 2,000-m rowing performance. Twenty well-trained rowers (age 23 ± 4 y; height 1.85 ± 0.08 m; body mass 82.5 ± 8.9 kg) were assigned to either a placebo or beta-alanine (6.4 g · d(-1) for 4 weeks) group. A 2,000-m rowing time trial (TT) was performed before supplementation (Baseline) and after 28 and 30 days of supplementation. The post supplementation trials involved supplementation with either maltodextrin or sodium bicarbonate in a double-blind, crossover design, creating four study conditions (placebo with maltodextrin; placebo with sodium bicarbonate; beta-alanine with maltodextrin; beta-alanine with sodium bicarbonate). Blood lactate, pH, bicarbonate, and base excess were measured pre-TT, immediately post-TT and at TT+5 min. Performance data were analyzed using magnitude based inferences. Beta-alanine supplementation was very likely to be beneficial to 2,000-m rowing performance (6.4 ± 8.1 s effect compared with placebo), with the effect of sodium bicarbonate having a likely benefit (3.2 ± 8.8 s). There was a small (1.1 ± 5.6 s) but possibly beneficial additional effect when combining chronic beta-alanine supplementation with acute sodium bicarbonate supplementation compared with chronic beta-alanine supplementation alone. Sodium bicarbonate ingestion led to increases in plasma pH, base excess, bicarbonate, and lactate concentrations. Both chronic beta-alanine and acute sodium bicarbonate supplementation alone had positive effects on 2,000-m rowing performance. The addition of acute sodium bicarbonate to chronic beta-alanine supplementation may further enhance rowing performance.

  9. Risk Factors for Voriconazole-Associated Hepatotoxicity in Patients in the Intensive Care Unit.

    Science.gov (United States)

    Wang, Yan; Wang, Taotao; Xie, Jiao; Yang, Qianting; Zheng, Xiaowei; Dong, Weihua; Xing, Jianfeng; Wang, Xue; Dong, Yalin

    2016-07-01

    To determine the incidence of hepatotoxicity in critically ill patients who were treated with voriconazole and to identify potential risk factors for voriconazole-associated hepatotoxicity in these patients. Single-center prospective observational study. Intensive care unit (ICU) in a university-affiliated hospital in Xi'an, China. Sixty-three adults, admitted to the ICU between January 2010 and July 2015, who had an ICU length of stay longer than 3 days, had received voriconazole treatment for at least 3 days, and had at least one trough voriconazole plasma concentration (VPC) measurement. All patients received CYP2C19 genotyping and were evaluated for the development of hepatotoxicity by assessing liver function tests performed before, during, and after voriconazole therapy. Hepatotoxicity was classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade scores and was defined as a CTCAE grade score that had increased by at least 2 grade scores over the baseline score. Hepatotoxicity occurred in 12 (19%) of the 63 patients. Characteristics of the patients who developed hepatotoxicity were compared with those of the patients who did not develop hepatotoxicity by univariate and multivariate Cox regression analyses. In the univariate analysis, Acute Physiology and Chronic Health Evaluation II score, invasive fungal infection classification, CYP2C19 genotype, and trough VPC were identified as the variables, and they were subsequently combined in the multivariate regression analysis. Multivariate Cox regression analysis revealed that hepatotoxicity was independently associated with trough VPC (hazard ratio 1.76, p<0.001). The relationships between trough VPCs and probability of hepatotoxicity were explored by using logistic regression analysis, and a target VPC upper limit of 4 mg/L was identified. The Kaplan-Meier method for the cumulative incidence of hepatotoxicity showed a significant difference between patients

  10. A Rare Outcome Induced by Metformin Intoxication: Severe Lactic Acidosis and Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Elyigit Faruk

    2016-06-01

    Full Text Available Metformin is a widely used oral anti-diabetic agent that decreases insulin resistance. Lactic acidosis rarely develops with this medication. Metformin-induced hepatotoxicity has been rarely reported in the literature. We describe a patient, who presented with lactic acidosis and hepatotoxicity after ingestion of 40 pills of metformin in order to commit suicide. The most important treatment step in patients with metformin-associated lactic acidosis (MALA is high-volume hemodialysis and hemofiltration.

  11. Predicting Hepatotoxicity of Drug Metabolites via an Ensemble Approach Based on Support Cector Machine.

    Science.gov (United States)

    Lu, Yin; Liu, Lili; Lu, Dong; Cai, Yudong; Zheng, Mingyue; Luo, Xiaomin; Jiang, Hualiang; Chen, Kaixian

    2017-11-20

    Drug-induced liver injury (DILI) is a major cause of drug withdrawal. The chemical properties of the drug, especially drug metabolites, play key roles in DILI. Our goal is to construct a QSAR model to predict drug hepatotoxicity based on drug metabolites. 64 hepatotoxic drug metabolites and 3,339 non-hepatotoxic drug metabolites were gathered from MDL Metabolite Database. Considering the imbalance of the dataset, we randomly split the negative samples and combined each portion with all the positive samples to construct individually balanced datasets for constructing independent classifiers. Then, we adopted an ensemble approach to make prediction based on the results of all individual classifiers and applied the minimum Redundancy Maximum Relevance (mRMR) feature selection method to select the molecular descriptors. Eventually, for the drugs in the external test set, a Bayesian inference method was used to predict the hepatotoxicity of a drug based on its metabolites. The model showed the average balanced accuracy=78.47%, sensitivity =74.17%, and specificity=82.77%. Five molecular descriptors characterizing molecular polarity, intramolecular bonding strength, and molecular frontier orbital energy were obtained. When predicting the hepatotoxicity of a drug based on all its metabolites, the sensitivity, specificity and balanced accuracy were 60.38%, 70.00%, and 65.19%, respectively, indicating that this method is useful for identifying the hepatotoxicity of drugs. We developed an in silico model to predict hepatotoxicity of drug metabolites. Moreover, Bayesian inference was applied to predict the hepatotoxicity of a drug based on its metabolites which brought out valuable high sensitivity and specificity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Risk of hepatotoxicity associated with the use of telithromycin: a signal detection using data mining algorithms.

    Science.gov (United States)

    Chen, Yan; Guo, Jeff J; Healy, Daniel P; Lin, Xiaodong; Patel, Nick C

    2008-12-01

    With the exception of case reports, limited data are available regarding the risk of hepatotoxicity associated with the use of telithromycin. To detect the safety signal regarding the reporting of hepatotoxicity associated with the use of telithromycin using 4 commonly employed data mining algorithms (DMAs). Based on the Adverse Events Reporting System (AERS) database of the Food and Drug Administration, 4 DMAs, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the Gamma Poisson Shrinker (GPS), were applied to examine the association between the reporting of hepatotoxicity and the use of telithromycin. The study period was from the first quarter of 2004 to the second quarter of 2006. The reporting of hepatotoxicity was identified using the preferred terms indexed in the Medical Dictionary for Regulatory Activities. The drug name was used to identify reports regarding the use of telithromycin. A total of 226 reports describing hepatotoxicity associated with the use of telithromycin were recorded in the AERS. A safety problem of telithromycin associated with increased reporting of hepatotoxicity was clearly detected by 4 algorithms as early as 2005, signaling the problem in the first quarter by the ROR and the IC, in the second quarter by the PRR, and in the fourth quarter by the GPS. A safety signal was indicated by the 4 DMAs suggesting an association between the reporting of hepatotoxicity and the use of telithromycin. Given the wide use of telithromycin and serious consequences of hepatotoxicity, clinicians should be cautious when selecting telithromycin for treatment of an infection. In addition, further observational studies are required to evaluate the utility of signal detection systems for early recognition of serious, life-threatening, low-frequency drug-induced adverse events.

  13. Aqueous extract of Monodora myristica ameliorates cadmium-induced hepatotoxicity in male rats

    OpenAIRE

    Oyinloye, Babatunji Emmanuel; Adenowo, Abiola Fatimah; Osunsanmi, Foluso Oluwagbemiga; Ogunyinka, Bolajoko Idiat; Nwozo, Sarah Onyenibe; Kappo,Abidemi Paul

    2016-01-01

    In recent years, indigenous medicinal plants exhibiting diverse biological activities have been explored in the amelioration of hepatotoxicity. This study investigates the protective effect of Monodora myristica (MM) on cadmium-induced liver damage in experimental animals. Male Wistar albino rats were maintained on 200?mg/L cadmium: Cd (Cd as CdCl2) in the animals? main drinking water to induce hepatotoxicity. Added to this, the animals received aqueous extracts of MM at a dose of 200 or 400 ...

  14. Incidence of Severe Hepatotoxicity Related to Antiretroviral Therapy in HIV/HCV Coinfected Patients

    Directory of Open Access Journals (Sweden)

    Emily L. Heil

    2010-01-01

    Full Text Available Introduction. Hepatotoxicity is a concern in HIV/hepatitis C virus (HCV coinfected patients due to their underlying liver disease. This study assessed the incidence of hepatotoxicity in HIV/HCV co-infected patients in two outpatient infectious diseases clinics. Methods. HIV/HCV co-infected adults were included in this retrospective study if they were PI or NNRTI naïve at their first clinic visit and were initiated on an NNRTI- and/or PI-based antiretroviral regimen. Patients were excluded if they had active or chronic hepatitis B virus (HBV. The primary objective was to determine the overall incidence of severe hepatotoxicity. Results. Fifty-six of the 544 patients identified met inclusion criteria. The incidence of severe hepatotoxicity was 10.7% (6/56 patients. Severe hepatotoxicity occurred with efavirenz (=2, nevirapine (=1, indinavir (=1, nelfinavir (=1, and saquinavir/ritonavir (=1. Conclusion. The incidence of severe hepatotoxicity appears to be low in this retrospective analysis of HIV/HCV co-infected patients receiving a PI-and/or NNRTI-based regimen.

  15. Hepatotoxicity and hepatic metabolism of available drugs: current problems and possible solutions in preclinical stages.

    Science.gov (United States)

    Giri, Shibashish; Nieber, Karen; Bader, Augustinus

    2010-08-01

    IMPORTANCE OF THE FILED: According to a 2006 survey report of pharmaceutical companies, hepatotoxicity was ranked first in terms of adverse events and it remains the most common reason for restriction or withdrawal of a drug from the market by the FDA. Although there are many reasons underlying drug-induced hepatotoxicity, one of the most important is hepatotoxicity induced by drug metabolites. This review highlights the unexpected evidence showing that > 64 allopathic drugs out of 900 can induce potentially life-threatening hepatotoxicity with diverse clinical features. In parallel, we demonstrate the use of a two-compartment organotypical model for monitoring drug biotransformation and the status of parent drugs or drug metabolites (reactive or stable metabolites). The reader will gain knowledge of the importance of the two-compartment model with special reference to drug metabolites and become aware of the hepatotoxicity of a list of allopathic drugs, many of which are presently used without prescription. A central challenge regarding drug-induced hepatotoxicity is to understand drug metabolite formation because, although many parent drugs are not toxic, their metabolites can be toxic to liver cells following biotransformation.

  16. Solvation Free Energies of Alanine Peptides: The Effect of Flexibility

    Energy Technology Data Exchange (ETDEWEB)

    Kokubo, Hironori; Harris, Robert C.; Asthagiri, Dilip; Pettitt, Bernard M.

    2013-12-03

    The electrostatic (?Gel), cavity-formation (?Gvdw), and total (?G) solvation free energies for 10 alanine peptides ranging in length (n) from 1 to 10 monomers were calculated. The free energies were computed both with xed, extended conformations of the peptides and again for some of the peptides without constraints. The solvation free energies, ?Gel, ?Gvdw, and ?G, were found to be linear in n, with the slopes of the best-fit lines being gamma_el, gamma_vdw, and gamma, respectively. Both gamma_el and gamma were negative for fixed and flexible peptides, and gamma_vdw was negative for fixed peptides. That gamma_vdw was negative was surprising, as experimental data on alkanes, theoretical models, and MD computations on small molecules and model systems generally suggest that gamma_vdw should be positive. A negative gamma_vdw seemingly contradicts the notion that ?Gvdw drives the initial collapse of the protein when it folds by favoring conformations with small surface areas, but when we computed ?Gvdw for the flexible peptides, thereby allowing the peptides to assume natural ensembles of more compact conformations, gamma-vdw was positive. Because most proteins do not assume extended conformations, a ?Gvdw that increases with increasing surface area may be typical for globular proteins. An alternative hypothesis is that the collapse is driven by intramolecular interactions. We show that the intramolecular van der Waal's interaction energy is more favorable for the flexible than for the extended peptides, seemingly favoring this hypothesis, but the large fluctuations in this energy may make attributing the collapse of the peptide to this intramolecular energy difficult.

  17. Exercise training and beta-alanine-induced muscle carnosine loading.

    Directory of Open Access Journals (Sweden)

    Tine eBex

    2015-05-01

    Full Text Available Purpose. Beta-alanine (BA supplementation has been shown to augment muscle carnosine concentration, thereby promoting high-intensity exercise performance. Trained muscles of athletes have a higher increase in carnosine concentration after BA supplementation compared to untrained muscles, but it remains to be determined whether this is due to an accumulation of acute exercise effects or to chronic adaptations from prior training. The aim of the present study was to investigate whether high-volume (HV and/or high-intensity (HI exercise can improve BA-induced carnosine loading in untrained subjects.Methods. All participants (n=28 were supplemented with 6.4 g/day of BA for 23 days. The subjects were allocated to a control group, HV or HI training group. During the BA supplementation period, the training groups performed 9 exercise sessions consisting of either 75–90 min continuous cycling at 35–45% Wmax (HV or 3 to 5 repeats of 30s cycling at 165% Wmax with 4 min recovery (HI. Carnosine content was measured in soleus and gastrocnemius medialis by proton magnetic resonance spectroscopy.Results. There was no difference in absolute increase in carnosine content between the groups in soleus and gastrocnemius muscle. For the average muscle carnosine content, a higher absolute increase was found in HV (+ 2.95 mM; P = 0.046 and HI (+ 3.26 mM; P = 0.028 group compared to the control group (+ 1.91 mM. However, there was no additional difference between the HV and HI training group.Conclusions. HV and HI exercise training showed no significant difference on BA-induced muscle carnosine loading in soleus and gastrocnemius muscle. It can be suggested that there can be a small cumulative effect of exercise on BA supplementation efficiency, although differences did not reach significance on individual muscle level.

  18. In vivo dosimetry with L-alpha-alanine

    Energy Technology Data Exchange (ETDEWEB)

    Boey, R.; Van Der Velden, K. [Industriele Hogeschool van het Gemeenschapsonderwijs Limburg, Hasselt (Belgium); Schaeken, B. [Algemeen Ziekenhuis Middelheim, Antwerp (Belgium). Dept. of Radiotherapy

    1995-12-01

    When organic substances are irradiated, stable electrons can be formed. The concentration of these electrons is detected via electron paramagnetic resonance (EPR), a non-destructive form of dosimetry. L-alpha-alanine is extremely suited as a detector because of its high stability and high yield of unpaired electrons. With an EMS 104 spectrometer, we measure the peak-to-peak value of the first derivate of the resonance-spectrum. This value is proportional to the concentration of unpaired electrons and therefore with the absorbed dose. Prior to the in vivo measurements in teletherapy, a calibration curve had to be established. This clearly showed a linear relationship between the EPR-signal and the absorbed dose, except for very low dose where precision was low (20% 1 sd). This indicates that the background signal of the dosimeter is strongly orientation dependent. For this reason it was decided to use pre-irradiated detectors. A number of in vivo measurements has been performed. It was found that the error propagation plays a major role in the calculation of the measured absorbed dose, in the range 1 Gy-6 Gy. Contrary to in vivo measurements in brachytherapy, where higher doses are measured, large uncertainties (30% 1 sd) on the entry dose calculations were observed. For this reason, it is recommended to use a statistical method of reducing this standard deviation to an acceptable level. The proposed method, consisting of 2 detectors and the usage of weight coefficients on our standard deviations, gave promising results. However, theoretical calculations and in vivo measurements show that this method is still not satisfactory to reduce the uncertainty to an acceptable standard in clinical situations.

  19. Barium chloride induces redox status unbalance, upregulates cytokine genes expression and confers hepatotoxicity in rats-alleviation by pomegranate peel.

    Science.gov (United States)

    Elwej, Awatef; Grojja, Yousri; Ghorbel, Imen; Boudawara, Ons; Jarraya, Raoudha; Boudawara, Tahia; Zeghal, Najiba

    2016-04-01

    The present study was performed to establish the therapeutic efficacy of pomegranate peel against barium chloride induced liver injury. Adult rats were divided into four groups of six animals each: group I, serving as controls, received distilled water; group II received by their drinking water 67 ppm of BaCl2; group III received both 67 ppm of BaCl2 by the same way than group II and 5 % of pomegranate peel (PP) via diet; group IV received 5 % of PP. Analysis by HPLC/MS of PP showed its rich composition in flavonoids such as gallic acid, castalin, hyperin, quercitrin, syringic acid, and quercetin. The protective effects of pomegranate peel against hepatotoxicity induced by barium chloride were assessed using biochemical parameters and histological studies. Exposure of rats to barium caused oxidative stress in the liver as evidenced by an increase in malondialdehyde (MDA), lipid hydroperoxides (LOOHs), H2O2 and advanced oxidation protein product (AOPP) levels, and lactate dehydrogenase (LDH), gamma glutamyl transpeptidase (GGT), alanine aminotransferase (AST) and aspartate aminotransferase (ALT) activities, a decrease in catalase (CAT) and glutathione peroxidase (GPx) activities, glutathion (GSH), non-protein thiol (NPSH), vitamin C levels, and Mn-SOD gene expression. Liver total MT levels, MT-1, and MT-2 and pro-inflammatory cytokine genes expression like TNF-α, IL-1β and IL-6 were increased. Pomegranate peel, supplemented in the diet of barium-treated rats, showed an improvement of all the parameters indicated above.The present work provided ethnopharmacological relevance of pomegranate peel against the toxic effects of barium, suggesting its beneficial role as a potential antioxidant.

  20. Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity

    Science.gov (United States)

    Craig, Darren G N; Bates, Caroline M; Davidson, Janice S; Martin, Kirsty G; Hayes, Peter C; Simpson, Kenneth J

    2012-01-01

    AIMS Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P = 0.025), although this overdose pattern did not independently predict death. The King's College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P = 0.009). CONCLUSIONS Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi-organ failure and should be considered for early transfer to specialist liver centres. PMID:22106945

  1. d-Alanine metabolism is essential for growth and biofilm formation of Streptococcus mutans.

    Science.gov (United States)

    Qiu, W; Zheng, X; Wei, Y; Zhou, X; Zhang, K; Wang, S; Cheng, L; Li, Y; Ren, B; Xu, X; Li, Y; Li, M

    2016-10-01

    Part of the d-alanine (d-Ala) metabolic pathway in bacteria involves the conversion of l-alanine to d-Ala by alanine racemase and the formation of d-alanyl-d-alanine by d-alanine-d-alanine ligase, the product of which is involved in cell wall peptidoglycan synthesis. At present, drugs that target the metabolic pathway of d-Ala are already in clinical use - e.g. d-cycloserine (DCS) is used as an antibiotic against Mycobacterium tuberculosis. Streptococcus mutans is the main cariogenic bacterium in the oral cavity. Its d-Ala metabolism-associated enzymes alanine racemase and d-alanine-d-alanine ligase are encoded by the genes smu.1834 and smu.599, respectively, which may be potential targets for inhibitors. In this study, the addition of DCS blocked the d-Ala metabolic pathway in S. mutans, leading to bacterial cell wall defects, significant inhibition of bacterial growth and biofilm formation, and reductions in extracellular polysaccharide production and bacterial adhesion. However, the exogenous addition of d-Ala could reverse the inhibitory effect of DCS. Through the means of drug regulation, our study demonstrated, for the first time, the importance of d-Ala metabolism in the survival and biofilm formation of S. mutans. If the growth of S. mutans can be specifically inhibited by designing drugs that target d-Ala metabolism, then this may serve as a potential new treatment for dental caries. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. β-alanine supplementation improves YoYo intermittent recovery test performance

    OpenAIRE

    Saunders Bryan; Sunderland Caroline; Harris Roger C; Sale Craig

    2012-01-01

    Abstract Background β-alanine supplementation has been shown to improve high-intensity exercise performance and capacity. However, the effects on intermittent exercise are less clear, with no effect shown on repeated sprint activity. The aim of this study was to investigate the effects of β-alanine supplementation on YoYo Intermittent Recovery Test Level 2 (YoYo IR2) performance. Methods Seventeen amateur footballers were allocated to either a placebo (PLA; N = 8) or β-alanine (BA; N = 9) sup...

  3. Fluoropolymer coated alanine films treated by atmospheric pressure plasmas − In comparison with gamma irradiation

    DEFF Research Database (Denmark)

    Kusano, Yukihiro; Bardenshtein, Alexander; Morgen, Per

    2017-01-01

    Fluoropolymer coated alanine films are treated by a dielectric barrier discharge and a gliding arc at atmospheric pressure as well as with gamma irradiation. The film surfaces and the underlying bulk materials are characterized before and after each treatment. The fluorine content decreases...... and the oxygen content increases at the fluoropolymer surfaces, while deposition of specific plasma energies in the alanine films is detected by electron paramagnetic resonance spectroscopy, indicating that not only the fluoropolymer surfaces but also the bulk alanine materials are modified. Differences...... of surface and bulk modification effects between the two plasma treatments are discussed in detail....

  4. Trihalomethane exposure and biomonitoring for the liver injury indicator, alanine aminotransferase, in the United States population (NHANES 1999–2006)

    Science.gov (United States)

    Burch, James B.; Everson, Todd M.; Seth, Ratanesh K.; Wirth, Michael D.; Chatterjee, Saurabh

    2015-01-01

    Exposure to trihalomethanes (or THMs: chloroform, bromoform, bromodichloromethane, and dibromochloromethane [DBCM]) formed via drinking water disinfection has been associated with adverse reproductive outcomes and cancers of the digestive or genitourinary organs. However, few studies have examined potential associations between THMs and liver injury in humans, even though experimental studies suggest that these agents exert hepatotoxic effects, particularly among obese individuals. This study examined participants in the National Health and Nutrition Examination Survey (1999–2006, N = 2781) to test the hypothesis that THMs are associated with liver injury as assessed by alanine aminotransferase (ALT) activity in circulation. Effect modification by body mass index (BMI) or alcohol consumption also was examined. Associations between blood THM concentrations and ALT activity were assessed using unconditional multiple logistic regression to calculate prevalence odds ratios (ORs) with 95% confidence intervals (CIs) for exposure among cases with elevated ALT activity (men: >40 IU/L, women: >30 IU/L) relative to those with normal ALT, after adjustment for variables that may confound the relationship between ALT and THMs. Compared to controls, cases were 1.35 times more likely (95% CI: 1.02, 1.79) to have circulating DBCM concentrations exceeding median values in the population. There was little evidence for effect modification by BMI, although the association varied by alcohol consumption. Among non-drinkers, cases were more likely than controls to be exposed to DBCM (OR: 3.30, 95% CI: 1.37–7.90), bromoform (OR: 2.88, 95% CI: 1.21–6.81), or brominated THMs (OR: 4.00, 95% CI: 1.31–12.1), but no association was observed among participants with low, or moderate to heavy alcohol consumption. Total THM levels exceeding benchmark exposure limits continue to be reported both in the United States and globally. Results from this study suggest a need for further

  5. Determination of the carbon, hydrogen and nitrogen contents of alanine and their uncertainties using the certified reference material L-alanine (NMIJ CRM 6011-a).

    Science.gov (United States)

    Itoh, Nobuyasu; Sato, Ayako; Yamazaki, Taichi; Numata, Masahiko; Takatsu, Akiko

    2013-01-01

    The carbon, hydrogen, and nitrogen (CHN) contents of alanine and their uncertainties were estimated using a CHN analyzer and the certified reference material (CRM) L-alanine. The CHN contents and their uncertainties, as measured using the single-point calibration method, were 40.36 ± 0.20% for C, 7.86 ± 0.13% for H, and 15.66 ± 0.09% for N; the results obtained using the bracket calibration method were also comparable. The method described in this study is reasonable, convenient, and meets the general requirement of having uncertainties ≤ 0.4%.

  6. Potentiation of carbon tetrachloride hepatotoxicity by pentosan polysulfate in rats

    Directory of Open Access Journals (Sweden)

    Zim M.C.A.

    2002-01-01

    Full Text Available Few data are available in the literature regarding the effect of pentosan polysulfate (PPS on normal and fibrotic rat livers. In addition, the combination of PPS and carbon tetrachloride (CCl4 has not been studied so far. The objective of this study was to assess the effect of PPS on rat livers treated or not with CCl4 for the induction of liver fibrosis. The study consisted of four stages: 1 hepatic fibrosis induction with CCl4 (N = 36 rats; 2 evaluation of the effect of PPS on CCl4-induced hepatic fibrosis (N = 36 rats; 3 evaluation of the effect of higher doses of PPS in combination with CCl4 (N = 50 rats; 4 evaluation of the presence of an enzymatic inductor effect by PPS (N = 18 rats using the sodium pentobarbital test which indirectly evaluates hepatic microsomal enzyme activity in vivo. Adult (60 to 70 days male Wistar rats weighing 180 to 220 g were used. All animals receiving 0.5 ml 8% CCl4 (N = 36 developed hepatic fibrosis, and after 8 weeks they also developed cirrhosis. No delay or prevention of hepatic fibrosis was observed with the administration of 5 mg/kg PPS (N = 8 and 1 mg/kg PPS (N = 8 1 h after the administration of CCl4, but the increased hepatotoxicity resulting from the combination of the two substances caused massive hepatic necrosis in most rats (N = 45. PPS (40 mg/kg alone caused hepatic congestion only after 8 weeks, but massive hepatic necrosis was again observed in association with 0.5 ml CCl4 after 1 to 4 weeks of treatment. Unexpectedly, sleeping time increased with time of PPS administration (1, 2, or 3 weeks. This suggests that PPS does not function as an activator of the hepatic microsomal enzymatic system. Further studies are necessary in order to clarify the unexpected increase in hepatotoxicity caused by the combination of CCl4 and high doses of PPS, which results in massive hepatic necrosis.

  7. Chicory (Cichorium intybus L. root extract regulates the oxidative status and antioxidant gene transcripts in CCl4-induced hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Yasser S El-Sayed

    Full Text Available The ability of Cichorium intybus root extract (chicory extract to protect against carbon tetrachloride (CCl4-induced oxidative stress and hepatotoxicity was evaluated in male rats. The rats were divided into four groups according to treatment: saline (control; chicory extract (100 mg/kg body weight daily, given orally for 2 weeks; CCl4 (1 ml/kg body weight by intraperitoneal injection for 2 consecutive days only; or chicory extract (100 mg/kg body weight daily for 2 weeks + CCl4 injection on days 16 and 17. The levels of hepatic lipid peroxidation, antioxidants, and molecular biomarkers were estimated twenty-four hours after the last CCl4 injection. Pretreatment with chicory extract significantly reduced CCl4-induced elevation of malondialdehyde levels and nearly normalized levels of glutathione and activity of glutathione S-transferase, glutathione peroxidase (GPx, glutathione reductase, catalase (CAT, paraoxonase-1 (PON1, and arylesterase in the liver. Chicory extract also attenuated CCl4-induced downregulation of hepatic mRNA expression levels of GPx1, CAT and PON1 genes. Results of DNA fragmentation support the ability of chicory extract to ameliorate CCl4-induced liver toxicity. Taken together, our results demonstrate that chicory extract is rich in natural antioxidants and able to attenuate CCl4-induced hepatocellular injury, likely by scavenging reactive free radicals, boosting the endogenous antioxidant defense system, and overexpressing genes encoding antioxidant enzymes.

  8. Implementation of an alanine dosimetry service; Puesta en marcha de un servicio de dosimetria de alanima

    Energy Technology Data Exchange (ETDEWEB)

    Gago Arias, A.; Nunez Pelaez, N.; Peteiro Vilaseco, E.; Gomez Rodriguez, F.; Gonzalez Castano, D. M.

    2011-07-01

    This work facing the implementation of an alanine dosimetry service, linked to the installation of Co{sub 6}0 Radio physics Laboratory (LP) and Paramagnetic Resonance Service of the University of Santiago de Compostela (USC).

  9. Second harmonic generation studies in L-alanine single crystals grown from solution

    Energy Technology Data Exchange (ETDEWEB)

    Boomadevi, Shanmugam, E-mail: sboomi@gmail.com [Department of Physics, Periyar Maniammai University, Thanjavur-613 403, Tamil Nadu (India); Pandiyan, Krishnamoorthy [School of Electrical and Electronics Engineering, SASTRA University, Thanjavur-613 401, Tamil Nadu (India)

    2014-01-01

    Single crystals of L-alanine of dimensions 2×1.1×0.5 cm{sup 3} were grown by evaporation method using deionised water as a solvent. The morphology of the grown crystals had (1 2 0) and (0 1 1) as their prominent faces. UV–vis-near IR spectrum shows the transparency range of L-alanine crystal available for frequency doubling from 250 to 1400 nm. Phase-matched second harmonic generation was observed in L-alanine sample by using 7 ns Q-switched Nd:YAG laser with OPO set up. In the present work, phase matching was achieved by angle and wavelength tuning. The angular and spectral phase-matching bandwidths were determined experimentally for a 1.5 mm thick L-alanine crystal and the results have been compared with their theoretical results. Further the possible reasons for the broadening of SHG spectrum have been discussed.

  10. Titration of Alanine Monitored by NMR Spectroscopy: A Biochemistry Laboratory Experiment

    Science.gov (United States)

    Waller, Francis J.; And Others

    1977-01-01

    The experiment described here involves simultaneous monitoring of pH and NMR chemical shifts during an aqueous titration of alpha- and beta-alanine. This experiment is designed for use in an undergraduate biochemistry course. (MR)

  11. A novel low molecular weight alanine aminotransferase from fasted rat liver.

    Science.gov (United States)

    Vedavathi, M; Girish, K S; Kumar, M Karuna

    2006-01-01

    Alanine is the most effective precursor for gluconeogenesis among amino acids, and the initial reaction is catalyzed by alanine aminotransferase (AlaAT). Although the enzyme activity increases during fasting, this effect has not been studied extensively. The present study describes the purification and characterization of an isoform of AlaAT from rat liver under fasting. The molecular mass of the enzyme is 17.7 kD with an isoelectric point of 4.2; glutamine is the N-terminal residue. The enzyme showed narrow substrate specificity for L-alanine with Km values for alanine of 0.51 mM and for 2-oxoglutarate of 0.12 mM. The enzyme is a glycoprotein. Spectroscopic and inhibition studies showed that pyridoxal phosphate (PLP) and free -SH groups are involved in the enzymatic catalysis. PLP activated the enzyme with a Km of 0.057 mM.

  12. Role of L-alanine for redox self-sufficient amination of alcohols.

    Science.gov (United States)

    Klatte, Stephanie; Wendisch, Volker F

    2015-01-23

    In white biotechnology biocatalysis represents a key technology for chemical functionalization of non-natural compounds. The plasmid-born overproduction of an alcohol dehydrogenase, an L-alanine-dependent transaminase and an alanine dehydrogenase allows for redox self-sufficient amination of alcohols in whole cell biotransformation. Here, conditions to optimize the whole cell biocatalyst presented in (Bioorg Med Chem 22:5578-5585, 2014), and the role of L-alanine for efficient amine functionalization of 1,10-decanediol to 1,10-diaminodecane were analyzed. The enzymes of the cascade for amine functionalization of alcohols were characterized in vitro to find optimal conditions for an efficient process. Transaminase from Chromobacterium violaceum, TaCv, showed three-fold higher catalytic efficiency than transaminase from Vibrio fluvialis, TaVf, and improved production at 37°C. At 42°C, TaCv was more active, which matched thermostable alcohol dehydrogenase and alanine dehydrogenase and improved the 1,10-diaminodecane production rate four-fold. To study the role of L-alanine in the whole cell biotransformation, the L-alanine concentration was varied and 1,10.diaminodecane formation tested with constant 10 mM 1,10- decanediol and 100 mM NH4Cl. Only 5.6% diamine product were observed without added L-alanine. L-alanine concentrations equimolar to that of the alcohol enabled for 94% product formation but higher L-alanine concentrations allowed for 100% product formation. L-alanine was consumed by the E. coli biocatalyst, presumably due to pyruvate catabolism since up to 16 mM acetate accumulated. Biotransformation employing E. coli strain YYC202/pTrc99a-ald-adh-ta Cv, which is unable to catabolize pyruvate, resulted in conversion with a selectivity of 42 mol-%. Biotransformation with E. coli strains only lacking pyruvate oxidase PoxB showed similar reduced amination of 1,10-decanediol indicating that oxidative decarboxylation of pyruvate to acetate by PoxB is primarily

  13. Differential Effects of Sodium Acetoacetate and Acetoacetic Acid Infusions on Alanine and Glutamine Metabolism in Man

    OpenAIRE

    Féry, Françoise; Balasse, Edmond O.

    1980-01-01

    It has been suggested that ketone bodies might participate in the nitrogen-sparing process occurring during prolonged starvation by inhibiting the muscular production of alanine and glutamine, which are the main gluconeogenic amino acids. The results of the ketone infusion studies on which this theory is based have been reevaluated in this study by following the plasma levels of ketone bodies, alanine, glutamine, and other substrates during 11.5 h in five groups of normal overnight-fasted sub...

  14. No Effect of β-alanine on Muscle Function and Kayak Performance.

    Science.gov (United States)

    Bech, Signe Refsgaard; Nielsen, Tobias Schmidt; Hald, Martin; Jakobsen, Jarl Pors; Nordsborg, Nikolai Baastrup

    2017-10-05

    It was investigated if β-alanine supplementation counteracts muscular fatigue development or improves athletic performance. Elite kayak rowers (10 males and 7 females) were supplemented with either 80 mg/kg body mass/day β-alanine or placebo for 8 weeks. Muscular fatigue development was investigated by applying a 2 min elbow flexor maximal voluntary contraction (MVC). Electromyography (EMG) was recorded continuously and voluntary activation (VA) was determined 30, 60, 90 and 115 s into the 2 min MVC. Additionally, performance was evaluated as 1000 m and 5 × 250 m kayak ergometer rowing. Force reduction during the 2 min MVC was similar before and after supplementation with β-alanine (30.9 ± 10.3 % vs 36.0 ± 14.1 %) and placebo (35.5 ± 7.7 % vs 35.1 ± 8.0 %). No time-effect was apparent in VA during the 2 min MVC. Additionally, there was no detectable effect of β-alanine supplementation on 1000 m kayak ergometer performance (β-alanine: 0.26 ± 0.02 % vs placebo: -0.18 ± 0.02 %) or accumulated 5 × 250 m time (β-alanine: -1.0 ± 0.3 % vs placebo: -1.0 ± 0.2 %). In 5 × 250 m, mean power output (MPO) was reduced to a similar extend from 1st to 5th interval before and after supplementation with β-alanine (23 ± 11 % vs 22 ± 10 %) and placebo (26 ± 13 % vs 20 ± 5 %). 2 min MVC characteristics are unaffected by β-alanine supplementation in elite kayakers and likewise both a 1000 m kayak ergometer time trial lasting 4-5 min as well as 5 × 250 m repeated sprint ability was unaltered by supplementation.

  15. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity.

    Science.gov (United States)

    Elinav, Eran; Pinsker, Galia; Safadi, Rifaat; Pappo, Orit; Bromberg, Michal; Anis, Emilia; Keinan-Boker, Lital; Broide, Efrat; Ackerman, Zvi; Kaluski, Dorit Nitzan; Lev, Boaz; Shouval, Daniel

    2007-10-01

    Nutritional supplements are frequently considered to be harmless but indiscriminate use of unlabelled ingredients may lead to significant adverse reactions. In 2004, identification of four index cases of acute hepatitis associated with Herbalife intake led to a ministry of health investigation in all Israeli hospitals. Twelve patients with acute idiopathic liver injury in association with consumption of Herbalife products were investigated. Eleven of the patients were females, aged 49.5+/-13.4 y. One patient had stage I primary biliary cirrhosis and another had hepatitis B. Acute liver injury was diagnosed after 11.9+/-11.1 months of initiation of Herbalife consumption. Liver biopsies demonstrated active hepatitis, portal inflammation rich with eosinophils, ductular reaction and parenchymal inflammation with peri-central accentuation. One patient developed sub-fulminant and two fulminant episodes of hepatic failure. Hepatitis resolved in eleven patients, while one patient succumbed to complications following liver transplantation. Three patients resumed consumption of Herbalife products following normalization of liver enzymes, resulting in a second bout of hepatitis. An association between intake of Herbalife products and acute hepatitis was identified in Israel. We call for prospective evaluation of Herbalife products for possible hepatotoxicity. Until then, caution should be exercised by consumers, especially among individuals suffering from underlying liver disease.

  16. Engineered andrographolide nanosystems for smart recovery in hepatotoxic conditions

    Science.gov (United States)

    Roy, Partha; Das, Suvadra; Auddy, Runa Ghosh; Mukherjee, Arup

    2014-01-01

    Andrographolide (AG) is one of the most potent labdane diterpenoid-type free radical scavengers available from plant sources. The compound is the principal bioactive component in Andrographis paniculata leaf extracts, and is responsible for anti-inflammatory, anticancer, and immunomodulatory activity. The application of AG in therapeutics, however, is severely constrained, due to its low aqueous solubility, short biological half-life, and poor cellular permeability. Engineered nanoparticles in biodegradable polymer systems were therefore conceived as one solution to aid in further drug-like applications of AG. In this study, a cationic modified poly(lactic-co-glycolic) acid nanosystem was applied for evaluation against experimental mouse hepatotoxic conditions. Biopolymeric nanoparticles of hydrodynamic size of 229.7±17.17 nm and ζ-potential +34.4±1.87 mV facilitated marked restoration in liver functions and oxidative stress markers. Superior dissolution for bioactive AG, hepatic residence, and favorable cytokine regulation in the liver tissues are some of the factors responsible for the newer nanosystem-assisted rapid recovery. PMID:25336950

  17. Zinc oxide nanoparticles hepatotoxicity: Histological and histochemical study.

    Science.gov (United States)

    Almansour, Mansour I; Alferah, Mosaid A; Shraideh, Ziad A; Jarrar, Bashir M

    2017-04-01

    Zinc oxide nanoparticles (ZnO NPs) are widely used in industry and cosmetic products with promising investment in medical diagnosis and treatment. However, these particles may reveal a high potential risk for human health with no information about hepatotoxicity that might be associated with their exposure. The present work was carried out to investigate the histological and histochemical alterations induced in the hepatic tissues by naked 35nm ZnO NPs. Male Wistar albino rats were exposed to ZnO NPs at a daily dose of 2mg/kg for 21days. Liver biopsies from all rats under study were subjected to histopathological examinations. In comparison with the control rats, the following histological and histochemical alterations were demonstrated in the hepatic tissues of rats exposed to ZnO NPs: sinusoidal dilatation, Kupffer cells hyperplasia, lobular and portal triads inflammatory cells infiltration, necrosis, hydropic degeneration, hepatocytes apoptosis, anisokaryosis, karyolysis, nuclear membrane irregularity, glycogen content depletion and hemosidrosis. The findings of the present work might indicate that ZnO NPs have potential oxidative stress in the hepatic tissues that may affect the function of the liver. More work is needed to elucidate the toxicity and pathogenesis of zinc oxide nanoparticles on the vital organs. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Decomposition study of the electron paramagnetic resonance spectrum of irradiated alanine.

    Science.gov (United States)

    Vanhaelewyn, G C; Amira, S A; Mondelaers, W K; Callens, F J

    2000-02-01

    Recent Electron Paramagnetic Resonance (EPR) studies on alanine powders as a function of irradiation dose and temperature on the one hand and single crystal Electron Nuclear DOuble Resonance (ENDOR) studies on the other hand, showed the presence of at least three radicals contributing to the total alanine EPR spectrum. The latter spectrum obtained after irradiation at room temperature (RT), is dominated by the well-known stable-alanine-radical (SAR) CH3C*HCOO-, also denoted R1. Appropriate heating of irradiated alanine causes the relative contribution of R1 to decrease, resulting in a spectrum mainly caused by the H-abstraction radical CH3C*(NH3)COO-, denoted R2. Although the EPR spectrum of these two radicals could be satisfactorily simulated, their influence on dose reconstruction has not been reported yet. Therefore, a detailed Maximum Likelihood Common Factor Analysis (MLCFA) study has been performed on EPR spectra from polycrystalline alanine samples, after irradiation and heat treatments. Conclusions concerning the number of contributing radicals and their influence on the RT irradiated alanine EPR spectrum will be made.

  19. Accurate measurement of the optical activity of alanine crystals and the determination of their absolute chirality

    Science.gov (United States)

    Ishikawa, Kazuhiko; Terasawa, Yukana; Tanaka, Masahito; Asahi, Toru

    2017-05-01

    Wavelength dependence measurements of the chiroptical properties in alanine crystals have so far been unsuccessful using conventional spectroscopic techniques. We describe our attempts to measure the wavelength dependence of the optical activity in L- and D-alanine crystals along each crystallographic axis, and to determine the absolute chirality of alanine crystals by correlating the absolute structure to the optical activity using an x-ray diffractometer and a generalized high accuracy universal polarimeter. We have succeeded in accurately measuring the optical rotatory dispersion in the direction, which shows that the optical rotation of the D-alanine crystal is dextrorotatory and that of the L-alanine crystal is laevorotatory, thereby determining the absolute chirality. Furthermore, comparison with the optical activity in solution shows that the optical activity in alanine crystals is different not only in value, but also in the sign. These results have led us to conclude that the optical rotatory power in the crystalline state should not be simply the summation of molecular optical rotatory power values. We propose the necessity of a theory, which contains the contribution of molecular interactions within the crystal, in order to calculate the optical rotatory power of the crystalline state.

  20. Studies of single-walled carbon nanotubes-induced hepatotoxicity by NMR-based metabonomics of rat blood plasma and liver extracts

    Science.gov (United States)

    Lin, Bencheng; Zhang, Huashan; Lin, Zhiqing; Fang, Yanjun; Tian, Lei; Yang, Honglian; Yan, Jun; Liu, Huanliang; Zhang, Wei; Xi, Zhuge

    2013-05-01

    The toxicological effects of single-walled carbon nanotubes (SWCNTs) were investigated after intratracheal instillation in male Wistar rats over a 15-day period using metabonomic analysis of 1H (nuclear magnetic resonance) NMR spectra of blood plasma and liver tissue extracts. Concurrent liver histopathology examinations and plasma clinical chemistry analyses were also performed. Significant changes were observed in clinical chemistry features, including alkaline phosphatase, total protein, and total cholesterol, and in liver pathology, suggesting that SWCNTs clearly have hepatotoxicity in the rat. 1H NMR spectra and pattern recognition analyses from nanomaterial-treated rats showed remarkable differences in the excretion of lactate, trimethylamine oxide, bilineurin, phosphocholine, amylaceum, and glycogen. Indications of amino acid metabolism impairment were supported by increased lactate concentrations and decreased alanine concentrations in plasma. The rise in plasma and liver tissue extract concentrations of choline and phosphocholine, together with decreased lipids and lipoproteins, after SWCNTs treatment indicated a disruption of membrane fluidity caused by lipid peroxidation. Energy, amino acid, and fat metabolism appeared to be affected by SWCNTs exposure. Clinical chemistry and metabonomic approaches clearly indicated liver injury, which might have been associated with an indirect mechanism involving nanomaterial-induced oxidative stress.

  1. Anti-Glycemic and Anti-Hepatotoxic Effects of Mangosteen Vinegar Rind from Garcinia mangostana Against HFD/STZ-Induced Type II Diabetes in Mice

    Directory of Open Access Journals (Sweden)

    Karim Naymul

    2018-06-01

    Full Text Available This study focuses on anti-glycemic and anti-hepatotoxic effects of mangosteen vinegar rind (MVR on five weeks high-fat diet (HFD / single dose streptozotocin (STZ 30 mg/kg BW induced male ICR diabetic mice. Mice were randomly divided into five groups (n=6, normal control, diabetic control, and diabetic groups treated with MVR 100, 200 mg/kg BW and glibenclamide 60 mg/kg BW for one week. After the treatment, lipid profile, glycogen and bilirubin contents, oxidative damage (malondialdehyde, MDA, aspartate aminotransferase (AST and alanine aminotransferase (ALT activities, antioxidant enzymes: superoxide dismutase (SOD, catalase (CAT were measured in plasma and/or liver tissues. MVR and glibenclamide treatment to HFD/STZ-induced diabetic mice significantly reduced their plasma glucose, plasma lipid profile, and hepatic lipid profile (P<0.05. Increased hepatic glycogen content indicates improvement of insulin sensitivity. Moreover, oxidative damage markers were ameliorated in MVR- and glibenclamide-treated groups compared to the diabetic control group. MVR with phenolic compounds content of 75 mg GAE/g dry weight and antioxidant potential of 303 mmol/L Trolox/g dry weight acted as a hepatoprotective agent against oxidative damage.

  2. First identification of the hepatotoxic microcystins in the serum of a chronically exposed human population together with indication of hepatocellular damage.

    Science.gov (United States)

    Chen, Jun; Xie, Ping; Li, Li; Xu, Jun

    2009-03-01

    Hepatotoxic microcystins (MCs) are the most commonly reported cyanotoxins in eutrophic freshwaters. In 1996, human intoxications by MCs caused deaths of 76 patients at Caruaru dialysis centers in Brazil. So far, there have been no direct evidences of MC occurrence in human tissue in consequence of exposure to MC. In this study, we improved cleanup procedures for detecting MCs in serum sample using liquid chromatography-mass spectrometry, and confirmed for the first time the presence of MCs in serum samples (average 0.39 ng/ml, which amounts to ca. 1/87 of the concentrations found in tissue samples of the Caruaru victims) of fishermen at Lake Chaohu. Daily intake by the fishermen was estimated to be in the range of 2.2-3.9 microg MC-LReq, whereas the provisional World Health Organization tolerable daily intake (TDI) for daily lifetime exposure is 0.04 microg/kg or 2-3 microg per person. Moreover, statistical analysis showed closer positive relationships between MC serum concentrations and concentrations of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase than between the MC concentrations and other biochemical indicators. Thus, the data raise the question whether extended exposure in the range of the TDI or up to a factor of 10 above it may already lead to indication of liver damage. The results also demonstrate a risk of health effects from chronic exposure to MCs at least for populations with high levels of exposure, like these fishermen.

  3. A novel method to analyze hepatotoxic components in Polygonum multiflorum using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry.

    Science.gov (United States)

    Lin, Longfei; Lin, Hongmei; Zhang, Miao; Ni, Boran; Yin, Xingbin; Qu, Changhai; Ni, Jian

    2015-12-15

    Polygonum multiflorum, called Heshouwu in China, is a traditional Chinese medicine used to treat various diseases. However, the administration of P. multiflorum (PM) and P. multiflorum Praeparata (PMP) causes numerous adverse effects. This study sought to analyze the toxic components of PM using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), and their hepatotoxicity in L02 human liver cells. Toxicity was evaluated by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) leakage, and liver enzyme secretion (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) assays. Furthermore, UPLC-Q-TOF/MS, Progenesis QI, and Makerlynx XS software analyses were used to differentiate extracts and analyze the toxic components. The order of toxicity was P. multiflorum ethanol extract (PME)>P. multiflorum water extract (PMW)>P. multiflorum Praeparata ethanol extract (PMPE)>P. multiflorum Praeparata water extract (PMPW), which was determined by MTT assay, LDH leakage, and liver enzyme secretion levels. The analysis methods suggest that PM toxicity may be associated with anthraquinone, emodin-O-(malonyl)-hex, emodin-O-glc, emodin, emodin-8-O-glc, emodin-O-(acetyl)-hex, and emodin-O-hex-sulphate. The toxic mechanisms of these components require further study. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Kava hepatotoxicity: comparison of aqueous, ethanolic, acetonic kava extracts and kava-herbs mixtures.

    Science.gov (United States)

    Teschke, Rolf; Genthner, Alexander; Wolff, Albrecht

    2009-06-25

    Ethanolic and acetonic kava extracts have previously been causally related to rare hepatotoxicity observed in patients from Germany and Switzerland, but causality assessment was not performed in cases of patients having taken the traditional aqueous kava extracts of South Pacific islands or kava-herbs mixtures. To study the possible hepatotoxicity of aqueous kava extracts of the South Pacific Islands. Causality of hepatotoxicity by aqueous kava extracts and kava-herbs mixtures was assessed, using the updated score of the quantitative CIOMS (Council for the International Organizations of Medical Sciences). Causality was established in five patients from New Caledonia, Australia, the United States and Germany for aqueous kava extracts and kava-herbs mixtures. A comparison with 9 patients from Germany and Switzerland with established causality of hepatotoxicity by ethanolic and acetonic kava extracts reveals that the clinical picture in all 14 patients is similar, independently whether aqueous, ethanolic and acetonic kava extracts or kava-herbs mixtures were used. Kava hepatotoxicity occurs also with traditional aqueous kava extracts of the South Pacific islands and thereby independently from ethanol or acetone as chemical solvents, suggesting that the toxicity is linked to the kava plant itself with a possibly low quality of the used kava cultivar or kava plant part rather than to chemical solvents.

  5. NAT2 Genotypes in Moroccan Patients with Hepatotoxicity Due to Antituberculosis Drugs.

    Science.gov (United States)

    Guaoua, Soukaina; Ratbi, Ilham; El Bouazzi, Omaima; Hammi, Sanaa; Tebaa, Amina; Bourkadi, Jamal Eddine; Bencheikh, Rachida Soulaymani; Sefiani, Abdelaziz

    2016-11-01

    Isoniazid (INH) is the most effective drug used as a first-line tuberculosis (TB) treatment besides rifampicin, pyrazinamide, and ethambutol. It is also the most commonly associated with hepatotoxicity. Differences of toxicity induced by INH have been attributed to genetic variability of the N-acetyltransferase 2 (NAT2) gene which encodes a drug-metabolizing enzyme. The aim of this study was to characterize the acetylation profile of patients who developed hepatotoxicity after TB treatment by genotyping NAT2 polymorphisms. This study included 42 Moroccan patients who developed hepatotoxicity after TB treatment and 163 Moroccan controls without TB. We genotyped four selected variants of the NAT2 gene (NAT2*5, NAT2*6, NAT2*7, and NAT2*14) by Sanger sequencing for patients and real-time polymerase chain reaction for controls. The majority of patients had NAT2 genotypes previously described as slow acetylators including NAT2*5/*5, NAT2*5/*6, NAT2*6/*6, and NAT2*6/*14 (78%) and none were genotyped as rapid acetylators. Controls were slow, intermediate, and rapid acetylators with frequencies of 72.39%, 21.48%, and 6.13%, respectively. There were no fast acetylator genotypes found among the patients having INH-hepatotoxicity. This finding suggests that the slow acetylator phenotype may contribute to the development of TB treatment hepatotoxicity.

  6. Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide.

    Science.gov (United States)

    Fouad, Amr A; Qutub, Hatem O; Al-Melhim, Walid N

    2016-07-01

    This study investigated the possible hepatoprotection of punicalagin in rats received cyclophosphamide (20mg/kg/day, i.p., for 7 days). Punicalagin given at two doses, 15 and 30mg/kg/day, p.o., for 7 days, starting the same day of cyclophosphamide administration. Punicalagin significantly and dose-dependently reduced the elevations of serum alanine aminotransferase, and liver nuclear factor-κB p65, tumor necrosis factor-α, interleukin-1β, malondialdehyde, nitric oxide, Bax/Bcl-2 ratio, inducible nitric oxide synthase, caspases 3 and 9 activities, and prevented the decrease of hepatic total antioxidant capacity. Punicalagin also attenuated the histopathological liver tissue damage, and decreased cyclooxygenase-2 expression in liver of rats received cyclophosphamide in a dose-dependent manner. It was concluded that punicalagin protected rat liver against cyclophosphamide toxicity by inhibiting oxidative/nitrosative stress, inflammation, and apoptosis. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Defining Pesticide Biomarkers

    Science.gov (United States)

    Biomarkers are measurable substances or characteristics in the human body that can be used to monitor the presence of a chemical in the body, biological responses or harm to health. This Web page describes categories of biomarkers and provides examples.

  8. Glial cells transform glucose to alanine, which fuels the neurons in the honeybee retina.

    Science.gov (United States)

    Tsacopoulos, M; Veuthey, A L; Saravelos, S G; Perrottet, P; Tsoupras, G

    1994-03-01

    The retina of honeybee drone is a nervous tissue with a crystal-like structure in which glial cells and photoreceptor neurons constitute two distinct metabolic compartments. The phosphorylation of glucose and its subsequent incorporation into glycogen occur in glia, whereas O2 consumption (QO2) occurs in the photoreceptors. Experimental evidence showed that glia phosphorylate glucose and supply the photoreceptors with metabolic substrates. We aimed to identify these transferred substrates. Using ion-exchange and reversed-phase HPLC and gas chromatography-mass spectrometry, we demonstrated that more than 50% of 14C(U)-glucose entering the glia is transformed to alanine by transamination of pyruvate with glutamate. In the absence of extracellular glucose, glycogen is used to make alanine; thus, its pool size in isolated retinas is maintained stable or even increased. Our model proposes that the formation of alanine occurs in the glia, thereby maintaining the redox potential of this cell and contributing to NH3 homeostasis. Alanine is released into the extracellular space and is then transported into photoreceptors using an Na(+)-dependent transport system. Purified suspensions of photoreceptors have similar alanine aminotransferase activity as glial cells and transform 14C-alanine to glutamate, aspartate, and CO2. Therefore, the alanine entering photoreceptors is transaminated to pyruvate, which in turn enters the Krebs cycle. Proline also supplies the Krebs cycle by making glutamate and, in turn, the intermediate alpha-ketoglutarate. Light stimulation caused a 200% increase of QO2 and a 50% decrease of proline and of glutamate. Also, the production of 14CO2 from 14C-proline was increased. The use of these amino acids would sustain about half of the light-induced delta QO2, the other half being sustained by glycogen via alanine formation. The use of proline meets a necessary anaplerotic function in the Krebs cycle, but implies high NH3 production. The results showed

  9. Treatment of Non-Small-Cell Lung Cancer with Erlotinib following Gefitinib-Induced Hepatotoxicity: Review of 8 Clinical Cases

    Directory of Open Access Journals (Sweden)

    Yukihiro Yano

    2012-01-01

    Full Text Available Objective. Gefitinib often induces liver damage. A few reports have described that the subsequent administration of erlotinib was associated with less hepatotoxicity, but the safety and efficacy of this treatment are still not fully investigated. Therefore, we evaluated retrospectively the patients with erlotinib following gefitinib-induced hepatotoxicity. Methods and Patients. We retrospectively reviewed the medical records between December 2007 and March 2010. The patients were evaluated including the following information: age, gender, histology of lung cancer, performance status, smoking status, epidermal growth factor receptor (EGFR mutation status, liver metastasis, viral hepatitis, alcoholic liver injury, clinical response, and hepatotoxicity due to EGFR tyrosine kinase inhibitors. Results. We identified 8 patients with erlotinib following gefitinib-induced hepatotoxicity. All achieved disease control by gefitinib. Hepatotoxicity was grades 2 and 3 in 3 and 5 patients, respectively. The median duration of treatment with gefitinib was 112.5 days and the median time to gefitinib-induced hepatotoxicity was 51.5 days. The median duration of treatment with erlotinib was 171.5 days. Grade 1 and 2 erlotinib-induced hepatotoxicity was observed in 2 and 1 patient, respectively. Conclusions. Erlotinib administration with careful monitoring is thought to be a good alternative strategy for patients who respond well to gefitinib treatment but experience hepatotoxicity.

  10. Combination of biomarkers

    DEFF Research Database (Denmark)

    Thurfjell, Lennart; Lötjönen, Jyrki; Lundqvist, Roger

    2012-01-01

    The New National Institute on Aging-Alzheimer's Association diagnostic guidelines for Alzheimer's disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury.......The New National Institute on Aging-Alzheimer's Association diagnostic guidelines for Alzheimer's disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury....

  11. Biomarkers in Veterinary Medicine.

    Science.gov (United States)

    Myers, Michael J; Smith, Emily R; Turfle, Phillip G

    2017-02-08

    This article summarizes the relevant definitions related to biomarkers; reviews the general processes related to biomarker discovery and ultimate acceptance and use; and finally summarizes and reviews, to the extent possible, examples of the types of biomarkers used in animal species within veterinary clinical practice and human and veterinary drug development. We highlight opportunities for collaboration and coordination of research within the veterinary community and leveraging of resources from human medicine to support biomarker discovery and validation efforts for veterinary medicine.

  12. Ochratoxin A exposure biomarkers in the Czech Republic and comparison with foreign countries.

    Science.gov (United States)

    Malir, Frantisek; Ostry, Vladimir; Pfohl-Leszkowicz, Annie; Roubal, Tomas

    2012-11-01

    Among ochratoxins, ochratoxin A (OTA) occupies a dominant place and represents significant risk for human and animal health which also implies economic losses around the world. OTA is nephrotoxic, hepatotoxic, teratogenic and immunotoxic mycotoxin. OTA exposure may lead to formation of DNA adducts resulting to genotoxicity and carcinogenicity (human carcinogen of 2B group). Now it seems that OTA could be "a complete carcinogen" which obliges to monitor its presence in biological materials, especially using the suitable biomarkers. In this article, OTA findings in urine, blood, serum, plasma and human kidneys (target dose) in the Czech Republic and comparison with foreign countries are presented.

  13. Hepatotoxicity after continuous amiodarone infusion in a postoperative cardiac infant.

    Science.gov (United States)

    Kicker, Jennifer S; Haizlip, Julie A; Buck, Marcia L

    2012-04-01

    A former 34-week-old female infant with Down syndrome underwent surgical correction of a congenital heart defect at 5 months of age. Her postoperative course was complicated by severe pulmonary hypertension and junctional ectopic tachycardia. Following treatment with amiodarone infusion, she developed laboratory indices of acute liver injury. At their peak, liver transaminase levels were 19 to 35 times greater than the upper limit of normal. Transaminitis was accompanied by coagulopathy, hyperammonemia, and high serum lactate and lipid levels. Hepatic laboratory abnormalities began to resolve within 48 hr of stopping amiodarone infusion. Heart rate control was achieved concurrently with discovery of laboratory test result abnormalities, and no further antiarrhythmic therapy was required. The intravenous formulation of amiodarone contains the diluent polysorbate 80, which may have hepatotoxic effects. Specifically, animal studies suggest that polysorbate 80 may destabilize cell membranes and predispose to fatty change within liver architecture. Polysorbate was implicated in infant fatalities from E-ferol use in the 1980s. This case illustrates a possible adverse event by the Naranjo probability scale. Given the extent of clinically apparent hepatic injury, this patient was not rechallenged with amiodarone during the remainder of her hospitalization. With amiodarone now used as first-line pharmacologic therapy for critical tachyarrhythmia in this population, the number of children exposed to this drug should be expected to increase. Laboratory indices of liver function should be evaluated at initiation of amiodarone therapy, as well as frequently throughout duration of therapy. Consideration should be given to polysorbate-free formulation of intravenous amiodarone for use in the cohort with congenital cardiac disease.

  14. Vitamin A modulation of xenobiotic-induced hepatotoxicity in rodents.

    Science.gov (United States)

    Hooser, S B; Rosengren, R J; Hill, D A; Mobley, S A; Sipes, I G

    1994-01-01

    Vitamin A (VA, retinol) has been shown to modulate cells of the immune system. When rats are pretreated with VA (75 mg/kg/day) for 7 days, there is greatly potentiated liver damage upon subsequent exposure to hepatotoxicants such as CCl4. This potentiated damage can be blocked by superoxide dismutase or catalase, suggesting that reactive oxygen species are playing a major role in the increased liver injury. The studies reported here examined VA-induced modulation of CCl4 hepatotoxicity in different strains of male rats, female rats, and different strains of male mice. Also, the role of VA-induced weight loss on potentiation of CCl4 injury was investigated. Rats or mice were dosed with VA (retinol) at 75 mg/kg/day, po, for 7 days. In an additional VA dose-response study, mice were given VA at 18.8, 37.5, or 75 mg/kg/day, po, for 7 days. On day 8 they were given a dose of CCl4 which elicited mild hepatic damage. On day 9 they were necropsied. Male and female Sprague-Dawley rats, and male Fischer-344 and athymic nude rats pretreated with VA had an approximately 10-fold increase in liver damage as compared to vehicle controls. Pretreatment of male Balb/C, C3H/HeJ, Swiss-Webster, or athymic nude mice resulted in a marked reduction of CCl4-induced hepatic damage. In the dose-response study in mice, increasing doses of VA elicited increasing amounts of protection from CCl4-induced liver injury. Paired feeding studies revealed that VA-induced weight loss (or decreased weight gain) had no effect on subsequent VA-induced potentiation (rats) or protection (mice) from hepatic damage caused by CCl4.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1. A Figure 1. B Figure 3. A Figure 3. B Figure 3. C Figure 3. D Figure 3. E Figure 3. F PMID:7698082

  15. New sepsis biomarkers

    Directory of Open Access Journals (Sweden)

    Dolores Limongi

    2016-06-01

    Full Text Available Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes. Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity, specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis, timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  16. Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors.

    Science.gov (United States)

    Rodrigues, Robim M; Sachinidis, Agapios; De Boe, Veerle; Rogiers, Vera; Vanhaecke, Tamara; De Kock, Joery

    2015-09-01

    Besides their role in the elucidation of pathogenic processes of medical and pharmacological nature, biomarkers can also be used to document specific toxicological events. Hepatic cells generated from human skin-derived precursors (hSKP-HPC) were previously shown to be a promising in vitro tool for the evaluation of drug-induced hepatotoxicity. In this study, their capacity to identify potential liver-specific biomarkers at the gene expression level was investigated with particular emphasis on acute liver failure (ALF). To this end, a set of potential ALF-specific biomarkers was established using clinically relevant liver samples obtained from patients suffering from hepatitis B-associated ALF. Subsequently, this data was compared to data obtained from primary human hepatocyte cultures and hSKP-HPC, both exposed to the ALF-inducing reference compound acetaminophen. It was found that both in vitro systems revealed a set of molecules that was previously identified in the ALF liver samples. Yet, only a limited number of molecules was common between both in vitro systems and the ALF liver samples. Each of the in vitro systems could be used independently to identify potential toxicity biomarkers related to ALF. It seems therefore more appropriate to combine primary human hepatocyte cultures with complementary in vitro models to efficiently screen out potential hepatotoxic compounds. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Isolation and characterization of cytosolic alanine aminotransferase isoforms from starved rat liver.

    Science.gov (United States)

    Vedavathi, M; Girish, K S; Kumar, M Karuna

    2004-12-01

    Alanine is the most effective precursor for gluconeogenesis among amino acids and the initial reaction is catalyzed by alanine aminotransferases (AlaATs). It is a less extensively studied enzyme under starvation and known to that the enzyme activity increases in liver under starvation. The present study describes the purification and characterization of two isoforms of alanine aminotransferases from starved male rat liver under starvation. The molecular mass of isoforms was found to be 17.7 and 112.2 kDa with isoelectric points of 4.2 and 5.3 respectively for AlaAT I and AlaAT II. Both the enzymes showed narrow substrate specificity for L-alanine with different Km for alanine and 2-oxoglutarate. Both the enzymes were glycoprotein in nature. Inhibition, modification and spectroscopic studies showed that both PLP and free-SH groups are directly involved in the enzymatic catalysis. PLP activated both the enzymes with a Km 0.057 mM and 0.2 mM for AlaAT I and II respectively.

  18. Effect of 10 Week Beta-Alanine Supplementation on Competition and Training Performance in Elite Swimmers

    Directory of Open Access Journals (Sweden)

    Louise M. Burke

    2012-10-01

    Full Text Available Although some laboratory-based studies show an ergogenic effect with beta-alanine supplementation, there is a lack of field-based research in training and competition settings. Elite/Sub-elite swimmers (n = 23 males and 18 females, age = 21.7 ± 2.8 years; mean ± SD were supplemented with either beta-alanine (4 weeks loading phase of 4.8 g/day and 3.2 g/day thereafter or placebo for 10 weeks. Competition performance times were log-transformed, then evaluated before (National Championships and after (international or national selection meet supplementation. Swimmers also completed three standardized training sets at baseline, 4 and 10 weeks of supplementation. Capillary blood was analyzed for pH, bicarbonate and lactate concentration in both competition and training. There was an unclear effect (0.4%; ±0.8%, mean, ±90% confidence limits of beta-alanine on competition performance compared to placebo with no meaningful changes in blood chemistry. While there was a transient improvement on training performance after 4 weeks with beta-alanine (−1.3%; ±1.0%, there was an unclear effect at ten weeks (−0.2%; ±1.5% and no meaningful changes in blood chemistry. Beta-alanine supplementation appears to have minimal effect on swimming performance in non-laboratory controlled real-world training and competition settings.

  19. Effect of β-alanine supplementation on 20 km cycling time trial performance

    Directory of Open Access Journals (Sweden)

    Ruth Margaret JAMES

    2014-09-01

    Full Text Available The effects of β-alanine supplementation on high-intensity cycling performance and capacity have been evaluated, although the effects on longer duration cycling performance are unclear. Nineteen UK category 1 male cyclists completed four 20 km cycling time trials, two before and two after supplementation with either 6.4 g•d-1 β-alanine (n = 10; BA or a matched placebo (n = 9; P. Performance time for the 20 km time trial and 1 km split times were recorded. There was no significant effect of β-alanine supplementation on 20 km time trial performance (BA-pre 1943 ± 129 s; BA-post 1950 ± 147 s; P-pre 1989 ± 106 s; P-post 1986 ± 115 s or on the performance of each 1 km split. The effect of β-alanine on 20 km time trial performance was deemed unclear as determined by magnitude based inferences. Supplementation with 6.4 g•d-1 of β-alanine for 4 weeks did not affect 20 km cycling time trial performance in well trained male cyclists.

  20. Beta-alanine supplementation enhances judo-related performance in highly-trained athletes.

    Science.gov (United States)

    de Andrade Kratz, Caroline; de Salles Painelli, Vitor; de Andrade Nemezio, Kleiner Márcio; da Silva, Rafael Pires; Franchini, Emerson; Zagatto, Alessandro Moura; Gualano, Bruno; Artioli, Guilherme Giannini

    2017-04-01

    In official judo competitions, athletes usually engage in 5-7 matches in the same day, performing numerous high-intensity efforts interspersed by short recovery intervals. Thus, glycolytic demand in judo is high and acidosis may limit performance. Carnosine is a relevant intracellular acid buffer whose content is increased with beta-alanine supplementation. Thus, we hypothesized that beta-alanine supplementation could attenuate acidosis and improve judo performance. Twenty-three highly-trained judo athletes were randomly assigned to receive either beta-alanine (6.4gday-1) or placebo (dextrose, same dosage) for 4 weeks. Performance was assessed before (PRE) and after (POST) supplementation through a 5-min simulated fight (randori) followed by 3 bouts of the Special Judo Fitness Test (SJFT). Blood samples were collected for blood pH, bicarbonate (HCO3-) and lactate determination. Beta-alanine supplementation improved the number of throws per set and the total number of throws (both p0.05). Blood pH and HCO3- reduced after exercise (all p0.05). However, the lactate response to exercise increased in the beta-alanine group as compared to placebo (pjudo-related performance in highly-trained athletes. Copyright © 2016 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  1. Metabolomic approaches in the discovery of potential urinary biomarkers of drug-induced liver injury (DILI).

    Science.gov (United States)

    Araújo, Ana Margarida; Carvalho, Márcia; Carvalho, Félix; Bastos, Maria de Lourdes; Guedes de Pinho, Paula

    2017-09-01

    Drug-induced liver injury (DILI) is a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. The identification of DILI biomarkers is a labor-intensive area. Conventional biomarkers are not specific and often only appear at significant levels when liver damage is substantial. Therefore, new biomarkers for early identification of hepatotoxicity during the drug discovery process are needed, thus resulting in lower development costs and safer drugs. In this sense, metabolomics has been increasingly playing an important role in the discovery of biomarkers of liver damage, although the characterization of the mechanisms of toxicity induced by xenobiotics remains a huge challenge. These new-generation biomarkers will offer obvious benefits for the pharmaceutical industry, regulatory agencies, as well as a personalized clinical follow-up of patients, upon validation and translation into clinical practice or approval for routine use. This review describes the current status of the metabolomics applied to the early diagnosis and prognosis of DILI and in the discovery of new potential urinary biomarkers of liver injury.

  2. Degradation of pyrimidines in Saccharomyces kluyveri: transamination of beta-alanine.

    Science.gov (United States)

    Schnackerz, K D; Andersen, G; Dobritzsch, D; Piskur, J

    2008-06-01

    Beta-alanine is an intermediate in the reductive degradation of uracil. Recently we have identified and characterized the Saccharomyces kluyveri PYD4 gene and the corresponding enzyme beta -alanine aminotransferase ((Sk)Pyd4p), highly homologous to eukaryotic gamma-aminobutyrate aminotransferase (GABA-AT). S. kluyveri has two aminotransferases, GABA aminotransferase ((Sk)Uga1p) with 80% and (Sk)Pyd4p with 55% identity to S. cerevisiae GABA-AT. (Sk)Pyd4p is a typical pyridoxal phosphate-dependent aminotransferase, specific for alpha-ketoglutarate (alpha KG), beta-alanine (BAL) and gamma-aminobutyrate (GABA), showing a ping-pong kinetic mechanism involving two half-reactions and substrate inhibition. (Sk)Uga1p accepts only alpha KG and GABA but not BAL, thus only (Sk)Pydy4p belongs to the uracil degradative pathway.

  3. Use of commercial alanine and TL dosemeters for dosimetry intercomparisons among Italian radiotherapy centres.

    Science.gov (United States)

    Onori, S; Bortolin, E; Calicchia, A; Carosi, A; De Angelis, C; Grande, S

    2006-01-01

    In the implementation of a large-scale dosimetry intercomparison one of the main constraints is the availability of large number of dosemeters of the highest quality. Therefore, ISS tested the possibility of using commercially available dosemeters, alanine pellets and thermoluminescence (TL) dosimetry chips, for transfer dosimetry within the Italian intercomparison programme. In this work the characterisation of commercial alanine and TL dosemeters along with the ISS dose assessment procedure used in the Italian intercomparison are reported. Results demonstrate the feasibility of the ISS approach to transfer dosimetry since it is possible to measure 10 Gy with a combined uncertainty of 1% (1sigma) and 1 Gy with a combined uncertainty of 1.7% (1sigma) with alanine and TL dosemeters, respectively.

  4. Protective effect of cannabidiol against cadmium hepatotoxicity in rats.

    Science.gov (United States)

    Fouad, Amr A; Al-Mulhim, Abdulruhman S; Gomaa, Wafaey

    2013-10-01

    The protective effect of cannabidiol, the non-psychoactive component of Cannabis sativa, against liver toxicity induced by a single dose of cadmium chloride (6.5 mgkg(-1) i.p.) was investigated in rats. Cannabidiol treatment (5 mgkg(-1)/day, i.p.) was applied for five days starting three days before cadmium administration. Cannabidiol significantly reduced serum alanine aminotransferase, and suppressed hepatic lipid peroxidation, prevented the depletion of reduced glutathione and nitric oxide, and catalase activity, and attenuated the elevation of cadmium level in the liver tissue resulted from cadmium administration. Histopathological examination showed that cadmium-induced liver tissue injury was ameliorated by cannabidiol treatment. Immunohistochemical analysis revealed that cannabidiol significantly decreased the cadmium-induced expression of tumor necrosis factor-α, cyclooxygenase-2, nuclear factor-κB, caspase-3, and caspase-9, and increased the expression of endothelial nitric oxide synthase in liver tissue. It was concluded that cannabidiol may represent a potential option to protect the liver tissue from the detrimental effects of cadmium toxicity. Copyright © 2013 Elsevier GmbH. All rights reserved.

  5. Hepatotoxicity effect of some Iranian medicinal herbal formulation on rats

    Directory of Open Access Journals (Sweden)

    Ahmad Movahedian

    2014-01-01

    Full Text Available Background: The public conviction that ′herbal remedies are safe′ has led to an increased consumption of these products. This study was performed in view of the wide distribution of herbal remedies, the risks posed by self-treatment with these products, and the existing reports about the toxic effects of some medicinal herbs. Materials and Methods: In this study the effect of some of the most used herbal drops of A, B, C, and D on the liver function of rats was examined at different doses, namely minimum dose, maximum dose, and 2.5 times the maximum dose indicated in the brochures. The rats were administered the said doses via a feeding tube for 50 days. The liver function parameters including aspartate aminotransferase (AST, alanine aminotransferase (ALT, lactate dehydrogenase (LDH, alkaline phosphatase (ALP, total serum protein, albumin, and urea were measured using the spectrophotometric method. Results: The animals′ liver tissues were examined pathologically. The A drop did not change the liver function parameters significantly. The B drop increased the LDH by 34% compared to the controls, at the maximum administered dose. The C and D drops increased the ALT, AST, and LDH significantly compared to the controls. The histological findings suggest the possible effect of C and D drops on the function of hepatocytes. Conclusions: We recommend that the herbal formulations available in pharmaceutical markets be more closely controlled in terms of quality, as well as toxicity, especially with regard to the possible effects on the hepatic function.

  6. Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions

    Directory of Open Access Journals (Sweden)

    Mahamid M

    2011-10-01

    Full Text Available Mahmud Mahamid1,3, Reuven Mader4, Rifaat Safadi1,2 1Liver Unit, Holy Family Hospital, Nazareth, Israel; 2Hadassah Medical Center, Jerusalem, Israel; 3Shaare Zedek Medical Center, Jerusalem, Israel; 4Rheumatology Unit, Ha’emek Medical Center, Afula, Israel Background: Elevation of liver enzymes in rheumatoid arthritis patients treated with tocilizumab (Actemra® or anakinra (Kineret® is a well-documented phenomenon. However, characterization of liver histology has not been defined in most cases. Similarly, the factors involved in decisions regarding discontinuation of treatment and outcome have not been discussed in the literature to any significant extent. Cases: Two women with rheumatoid arthritis refractory to standard therapies are reported here. One was treated with tocilizumab and the other with anakinra, and both developed toxic liver effects. Liver biopsy in both cases showed focal necrosis of hepatocytes – a hallmark of drug toxicity – with steatosis and early fibrosis. Inflammatory infiltrates were prominent in the patient treated with anakinra but not in the tocilizumab-treated patient. However, FibroTest (Assistance publique – Hôpitaux de Paris, Paris, France in the latter patient showed an inflammatory activity of A2 and was staged as F2, and the histology also showed hemorrhagic areas. Although both patients were overweight and both had been exposed to steroids, the steatosis and steatohepatitis were considered to be related to drug hepatotoxicity. Other possible etiologies for liver injury were excluded. Discontinuation of anakinra led to rapid normalization of liver enzymes. The patient receiving tocilizumab developed hepatosplenomegaly but had normal liver enzymes. In spite of the hepatosplenomegaly, the tocilizumab treatment was continued since the patient had not responded to other drugs. There was a good response to the tocilizumab treatment and the liver biopsy showed only insignificant, reversible liver injury. At

  7. Oxidation of phenyl alanine by pyridinium chlorochromate in acidic DMF–water medium: A kinetic study

    Directory of Open Access Journals (Sweden)

    B.L. Hiran

    2016-11-01

    Full Text Available The kinetics of oxidation of phenyl alanine by pyridinium chlorochromate in DMF–water (70:30% mixture in presence of perchloric acid leads to the formation of corresponding aldehyde. The reaction is of first order each in [PCC], [HClO4] and [AA]. Michaelis–Menten type kinetics was observed with phenyl alanine. The reaction rates were determined at different temperatures [25, 30, 35, 40, 45, 50 °C] and the activation parameters were calculated. The reaction does not induce polymerization of acrylonitrile. With an increase in the amount of DMF in its aqueous mixture, the rate increases. A suitable mechanism for the reaction was postulated.

  8. Eksplorativ analyse av EPR-spektre av alanin og Gorilla® Glass

    OpenAIRE

    Jåstad, Eirik Ogner

    2016-01-01

    Elektron Paramagnetisk Resonans (EPR) spektroskopi er en måleteknikk som tar opp spektre som kan brukes til å estimere absorbert stråledose, såkalt EPR-dosimetri. EPR-dosimetri måler mengden frie radikaler i et materiale, som er proporsjonalt med den absorberte dosen. De fleste frie radikaler er kortlivede ved romtemperatur, dette er en utfordring ved EPR-dosimetri. Et materiale som ofte brukes i dosimetri er aminosyren L-α-alanin. Alanin egner seg for planlagte eksponeringer, men ikke nødven...

  9. Synthesis, Characterization and Metal Ion Detection of Novel Fluoroionophores Based on Heterocyclic Substituted Alanines

    Directory of Open Access Journals (Sweden)

    M. Manuela M Raposo

    2007-10-01

    Full Text Available The synthesis of new fluorescent probes containing the thiophene andbenzoxazole moieties combined with an alanine residue is described. The resulting highlyfluorescent heterocyclic alanine derivatives respond via a quenching effect, withparamagnetic Cu(II and Ni(II metal ions and with diamagnetic Hg(II, as shown by theabsorption and steady-state fluorescence spectroscopy studies. The formation ofmononuclear or dinuclear metal complexes was postulated based on the presence of thefree carboxylic acid as binding site and also with the interaction with the donor atoms inthe chromophore. Interaction with other important biological metal ions such as Zn(II,Ca(II and Na(I was also explored.

  10. EFV/FTC/TDF-associated hepatotoxicity: a case report and review.

    Science.gov (United States)

    Echenique, Ignacio A; Rich, Josiah D

    2013-09-01

    The fixed-dose combination efavirenz, emtricitabine, and tenofovir (EFV/FTC/TDF) is a first-line agent for the treatment of HIV. We report the case of a 40-year-old female with a history of HIV acquired through heterosexual contact who initiated EFV/FTC/TDF. Hepatitis B and C serologies were negative, CD4 cell count was 253 cells per cubic millimeter (15.8%), and HIV viral load was 67,373 copies per milliliter. Eight months later she developed transaminitis and severe right upper quadrant pain. Neither illicit drug abuse nor hepatotoxic medication such as acetaminophen was reported. After evaluation including negative acute viral hepatitis studies, EFV/FTC/TDF was discontinued; both her transaminitis and pain resolved. Hepatotoxicity is most often associated with efavirenz. Rarely, fulminant hepatic failure occurs. Efavirenz-related hepatotoxicity is thought to result from a cellular self-digestion process known as autophagy. This is the first report to our knowledge of EFV/FTC/TDF-related hepatotoxicity.

  11. Hcv coinfection, an important risk factor for hepatotoxicity in pregnant women starting antiretroviral therapy

    NARCIS (Netherlands)

    I.J.M. Snijdewind (Ingrid); C. Smit (Colette); M.H. Godfried; J.F.J.B. Nellen (Jeannine); F. de Wolf (Frank); K. Boer (Kees); M.E. van der Ende (Marchina)

    2012-01-01

    textabstractObjectives: This retrospective cohort study evaluated the risk of hepatotoxicity in HIV-1 positive pregnant and non-pregnant women starting combined ART. Methods: Data were used from the ATHENA observational cohort. The study population consisted of HIV-1 infected, therapy naïve,

  12. Hepatotoxic effects of fenofibrate in spontaneously hypertensive rats expressing human C-reactive protein

    Czech Academy of Sciences Publication Activity Database

    Škop, V.; Trnovská, J.; Oliyarnyk, O.; Marková, I.; Malínská, H.; Kazdová, L.; Zídek, Václav; Landa, Vladimír; Mlejnek, Petr; Šimáková, Miroslava; Kůdela, M.; Pravenec, Michal; Šilhavý, Jan

    2016-01-01

    Roč. 65, č. 6 (2016), s. 891-899 ISSN 0862-8408 R&D Projects: GA MZd(CZ) NT14325 Institutional support: RVO:67985823 Keywords : fenofibrate * rosuvastatin * C-reactive protein * transgenic * spontaneously hypertensive rat * inflammation * hepatotoxic Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.461, year: 2016

  13. Paracetamol, 3-monoalkyl- and 3,5-dialkyl derivatives : comparison of their hepatotoxicity in mice

    NARCIS (Netherlands)

    Van de Straat, R; de Vries, J; Groot, E J; Zijl, R; Vermeulen, N P

    1987-01-01

    The effect of 3-monoalkyl and 3,5-dialkyl substitution (R = CH3, C2H5, and i-C3H7) on hepatotoxicity of the analgesic paracetamol was studied in vivo. To that purpose, varying doses of paracetamol and six alkyl-substituted derivatives were orally administered to male DAP mice. Paracetamol caused

  14. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats

    Science.gov (United States)

    Ko, Je-Won; Lee, In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho

    2014-01-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological alterations, including degeneration/necrosis of hepatocytes, vacuolation, and sinusoidal dilation. In addition, an increase in the malondialdehyde (MDA) concentration and a decrease in the reduced glutathione (GSH) content and catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) activities were observed in the cisplatin-treated rat hepatic tissues. In contrast, PYC treatment effectively prevented cisplatin-induced hepatotoxicity, including the elevation of aminotransferase and histopathological lesions, in a dosedependent manner. Moreover, PYC treatment also induced antioxidant activity by decreasing MDA level and increasing GSH content and SOD and GST activities in liver tissues. These results indicate that PYC has a protective effect against acute hepatotoxicity induced by cisplatin in rats, and that the protective effects of PYC may be due to inhibiting lipid peroxidation and increasing antioxidant activity. PMID:25628728

  15. Acute Hepatotoxicity of Intravenous Amiodarone: Case Report and Review of the Literature.

    Science.gov (United States)

    Chen, Chia-Chi; Wu, Chien-Chih

    2016-01-01

    Amiodarone is a class III antiarrhythmic drug widely used for the treatment of both supraventricular and ventricular arrhythmias in intensive care unit. Hepatotoxicity of amiodarone is usually mild and delayed onset. Acute hepatotoxicity is a rare side effect and usually correlated to intravenous form use. In this case, acute hepatocellular injury occurred within 24 hours after the administration of intravenous amiodarone. Liver enzyme significantly improved after holding intravenous amiodarone use. Because ventricular arrhythmia persisted and side effects occurred to alternative therapy, low dose of oral amiodarone was resumed and hepatotoxicity did not occur afterward. Acute hepatotoxicity of intravenous amiodarone is possibly related to polysorbate 80, the solubilizer of amiodarone infusion or higher dose. As a result, when intravenous amiodarone is prescribed, closely monitoring liver enzyme is highly suggested. If acute hepatitis takes place secondary to intravenous amiodarone, oral therapy should not be resumed afterward. If there is no alternative treatment, lower dose of oral amiodarone (≤200 mg/d) could be tried and should monitor liver function regularly.

  16. Amiodarone hepatotoxicity in the context of the metabolic syndrome and right-sided heart failure.

    Science.gov (United States)

    Mattar, Wissam; Juliar, Beth; Gradus-Pizlo, Irmina; Kwo, Paul Y

    2009-12-01

    Amiodarone is associated with varying degrees of hepatotoxicity. to study the association between the presence of the metabolic syndrome or right-sided heart failure and the prevalence of amiodarone induced liver disease. Retrospective chart review of patients who received amiodarone for > or =60 days at a university affiliated community hospital. We collected information about clinical progression and liver chemistries on 409 included patients. Subgroup analysis was based on the presence or absence of right-sided heart failure and the metabolic syndrome. The 409 patients (58% male, 55% Caucasian) had a mean age of 62 years, mean follow up of 37.6 months and mean cumulative amiodarone dose of 295+/-404 grams. No subjects developed clinical hepatitis, cirrhosis or death related to amiodarone. Eight patients developed amiodarone hepatotoxicity, 5 required discontinuation and 3 required dose reduction of the medication with resolution of the transaminitis in all. No differences in liver chemistries at follow up between patients with or without the metabolic syndrome and with or without right cardiac dysfunction were noted. Administration of amiodarone was associated with a low incidence of hepatotoxicity without relationship to cumulative dose. The presence of the metabolic syndrome or right-sided heart failure does not increase the incidence of amiodarone hepatotoxicity.

  17. Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment

    NARCIS (Netherlands)

    van Hest, Rob; Baars, Hennie; Kik, Sandra; van Gerven, Paul; Trompenaars, Marie-Christine; Kalisvaart, Nico; Keizer, Sytze; Borgdorff, Martien; Mensen, Marlies; Cobelens, Frank

    2004-01-01

    Severe liver injury has been attributed to preventive treatment of latent tuberculosis infection with a 2-month course of rifampin-pyrazinamide. A retrospective cohort study in The Netherlands compared the hepatotoxicity of preventive treatment with rifampin-pyrazinamide with that of preventive

  18. Hcv coinfection, an important risk factor for hepatotoxicity in pregnant women starting antiretroviral therapy

    NARCIS (Netherlands)

    Snijdewind, Ingrid J. M.; Smit, Colette; Godfried, Mieke H.; Nellen, Jeannine F. J. B.; de Wolf, Frank; Boer, Kees; van der Ende, Marchina E.

    2012-01-01

    Objectives: This retrospective cohort study evaluated the risk of hepatotoxicity in HIV-1 positive pregnant and non-pregnant women starting combined ART. Methods: Data were used from the ATHENA observational cohort. The study population consisted of HIV-1 infected, therapy naive, pregnant and

  19. A 1H NMR-based metabolomics approach for mechanistic insight into acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    Fukuhara, Kiyoshi; Ohno, Akiko; Ando, Yosuke; Yamoto, Takashi; Okuda, Haruhiro

    2011-01-01

    The widely used analgesic-antipyretic drug acetaminophen (APAP) is known to cause serious liver necrosis at high doses in man and experimental animals. For studies of toxic processes, 1H NMR spectroscopy of biofluids allows monitoring of endogenous metabolite profiles that alter characteristically in response to changes in physiological status. Herein, a 1H NMR metabolomics approach was applied to the investigation of APAP toxicity in rats and the effect of phenobarbital (PB) on APAP-induced hepatotoxicity. Metabolite differences due to hepatotoxicity were observed in 1H NMR spectra of serum and urine, and enhanced APAP hepatotoxicity by pretreatment with PB was clearly shown by a principal components analysis of the spectral data. NMR spectra of APAP-dosed rat urine provided profiles of APAP-related compounds together with endogenous metabolites. By comparison of endogenous and APAP-related metabolite spectra with those from rats pretreated with PB, it was possible to show the importance of oxidative metabolism of APAP to N-acetyl-p-benzoquinone, an essential step in APAP hepatotoxicity.

  20. Cytokine genes as potential biomarkers for muscle weakness in OPMD

    DEFF Research Database (Denmark)

    Riaz, Muhammad; Raz, Yotam; van der Slujis, Barbara

    2016-01-01

    Molecular biomarkers emerge as an accurate diagnostic tool, but are scarce for myopathies. Lack of outcome measures sensitive to disease onset and symptom severity hamper evaluation of therapeutic developments. Cytokines are circulating immunogenic molecules, and their potential as biomarkers has...... been exploited in the last decade. Cytokines are released from many tissues, including skeletal muscles, but their application to monitor muscle pathology is sparse. We report that the cytokine functional group is altered in the transcriptome of oculopharyngeal muscular dystrophy (OPMD). OPMD...... is a dominant, late-onset myopathy, caused by an alanine-expansion mutation in the gene encoding for poly(A) binding protein nuclear 1 (expPABPN1). Here, we investigated the hypothesis that cytokines could mark OPMD disease state. We determined cytokines levels the vastus lateralis muscle from genetically...

  1. Simultaneous determination of β-alanine betaine and trimethylamine in bacterial culture and plant samples by capillary electrophoresis

    National Research Council Canada - National Science Library

    Mohamed Ahmed, Isam A; Maimaiti, Ailijiang; Mori, Nobuhiro; Yamanaka, Norikazu; Taniguchi, Takeshi

    2014-01-01

    3-N-trimethylaminopropionic acid (β-alanine betaine) and trimethylamine (TMA) are important nitrogenous compounds that perform fundamental roles in biological pathways throughout all kingdoms of life...

  2. Engineering of sugar metabolism of Corynebacterium glutamicum for production of amino acid L-alanine under oxygen deprivation.

    Science.gov (United States)

    Jojima, Toru; Fujii, Miho; Mori, Eiji; Inui, Masayuki; Yukawa, Hideaki

    2010-06-01

    Corynebacterium glutamicum was genetically engineered to produce L-alanine from sugar under oxygen deprivation. The genes associated with production of organic acids in C. glutamicum were inactivated and the alanine dehydrogenase gene (alaD) from Lysinibacillus sphaericus was overexpressed to direct carbon flux from organic acids to alanine. Although the alaD-expressing strain produced alanine from glucose under oxygen deprivation, its productivity was relatively low due to retarded glucose consumption. Homologous overexpression of the gapA gene encoding glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the alaD-expressing strain stimulated glucose consumption and consequently improved alanine productivity. In contrast gapA overexpression did not affect glucose consumption under aerobic conditions, indicating that oxygen deprivation engendered inefficient regeneration of NAD+ resulting in impaired GAPDH activity and reduced glucose consumption in the alanine-producing strains. Inactivation of the alanine racemase gene allowed production of L-alanine with optical purity greater than 99.5%. The resulting strain produced 98 g l(-1) of L-alanine after 32 h in mineral salts medium. Our results show promise for amino acid production under oxygen deprivation.

  3. Luminescent probing of the simplest chiral α-amino acid-alanine in an enantiopure and racemic state.

    Science.gov (United States)

    Tarasevych, Arkadii V; Kostyukov, Anton I; Baronskiy, Mark G; Rastorguev, Alexander A; Guillemin, Jean-Claude; Snytnikov, Valeriy N

    2017-07-01

    Luminescent spectroscopy combined with the technique of luminescent probing with rare earth ions (europium, gadolinium, terbium) and an actinide ion (uranyl) was used to differentiate enantiopure and racemic alanine, the simplest chiral proteinogenic amino acid. Using the achiral luminescent probes, small differences between pure L and DL alanine in the solid state were strongly amplified. Based on the observed electronic transitions of the probes, the position of the triplet level of the coordinated alanine was estimated. Formation of homo- and heterochiral complexes between enantiomers of alanine and the metal ions is discussed as a possible mechanism of chiral self-discrimination. © 2017 Wiley Periodicals, Inc.

  4. Biomarkers in sarcoidosis.

    Science.gov (United States)

    Chopra, Amit; Kalkanis, Alexandros; Judson, Marc A

    2016-11-01

    Numerous biomarkers have been evaluated for the diagnosis, assessment of disease activity, prognosis, and response to treatment in sarcoidosis. In this report, we discuss the clinical and research utility of several biomarkers used to evaluate sarcoidosis. Areas covered: The sarcoidosis biomarkers discussed include serologic tests, imaging studies, identification of inflammatory cells and genetic analyses. Literature was obtained from medical databases including PubMed and Web of Science. Expert commentary: Most of the biomarkers examined in sarcoidosis are not adequately specific or sensitive to be used in isolation to make clinical decisions. However, several sarcoidosis biomarkers have an important role in the clinical management of sarcoidosis when they are coupled with clinical data including the results of other biomarkers.

  5. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps.

    Science.gov (United States)

    Teschke, Rolf; Eickhoff, Axel

    2015-01-01

    Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.

  6. Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists

    Science.gov (United States)

    Andrade, Raúl J; Robles, Mercedes; Fernández-Castañer, Alejandra; López-Ortega, Susana; López-Vega, M Carmen; Lucena, M Isabel

    2007-01-01

    Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected. PMID:17230599

  7. Herbal hepatotoxicity in traditional and modern medicine: Actual key issues and new encouraging steps

    Directory of Open Access Journals (Sweden)

    Rolf eTeschke

    2015-04-01

    Full Text Available Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.

  8. Efficacy of Rosmarinus officinalis leaves extract against cyclophosphamide-induced hepatotoxicity.

    Science.gov (United States)

    El-Naggar, Sabry A; Abdel-Farid, Ibrahim B; Germoush, Mousa O; Elgebaly, Hassan A; Alm-Eldeen, Abeer A

    2016-10-01

    Context Cyclophosphamide (CTX) is used to treat different cancer types, although it causes severe hepatotoxicity due to its oxidative stress effect. Rosmarinus officinalis, L. (Lamiaceae) has a therapeutic potential against hepatotoxicity due to its antioxidant activity. Objective The objective of this study is to investigate the phytochemical analysis of the methanol extract of Rosmarinus officianalis leaves (MEROL) and its efficacy against CTX-induced hepatotoxicity. Materials and methods The phytochemical analyses were assessed spectrophotometericaly. To assess the MEROL efficacy, 72 Swiss albino mice were divided into six groups. Group 1 was control, groups 2 and 3 included mice which were injected intraperitoneally (i.p.) with 100 or 200 mg/kg of MEROL at days 1, 4, 7, 10, 13 and 16; group 4 was injected (i.p.) with CTX (200 mg/kg) at day 17, groups 5 and 6 were injected (i.p.) with MEROL as groups 3 and 4 followed by 200 mg/kg CTX at day 17, respectively. At day 22, six mice from each group were sacrificed and the others were sacrificed at day 37. Results MEROL has a high content of total phenolics, saponins, total antioxidant capacity and DPPH radical scavenging activity. The median lethal dose (LD50) value of MEROL was 4.125 g/kg b.w. The inhibitory concentration 50 (IC50) value for DPPH radical scavenging was 55 μg/mL. Pretreatment with 100 mg/kg MEROL for 16 d ameliorated CTX-induced hepatotoxicity represented in lowering the levels of the aspartate aminotransferase (AST) and lipid profile and minimizing the histological damage. Conclusions Pretreatment with 100 mg/kg b.w. MEROL mitigated CTX-induced hepatotoxicity due to its antioxidant activity.

  9. alpha(1)-Adrenoceptor antagonists prevent paracetamol-induced hepatotoxicity in mice.

    Science.gov (United States)

    Randle, L E; Sathish, J G; Kitteringham, N R; Macdonald, I; Williams, D P; Park, B K

    2008-02-01

    Paracetamol, a major cause of acute liver failure (ALF) represents a significant clinical problem. Adrenoceptor stimulation or antagonism can modulate chemical-induced hepatotoxicity. We investigated the role of endogenous catecholamines and alpha(1)-adrenoceptors in the development of paracetamol- induced hepatotoxicity. Paracetamol (3.5 mmol kg(-1)) was administered to male CD-1 mice, with and without alpha(1)-adrenoceptor antagonists (prazosin, doxazosin, terazosin and tamsulosin; 35.7 micromol kg(-1)). Serum transaminases and hepatic glutathione (GSH) levels were assessed as markers of hepatic damage. Paracetamol bioactivation was assessed by covalent binding, hepatic and urinary conjugate formation and uridine glucuronosyltransferase activity. Plasma catecholamines levels and hepatic congestion were also analysed. Plasma catecholamine levels were significantly elevated 5 h post paracetamol administration. Prazosin prevented hepatotoxicity when administered 1 h before a toxic paracetamol insult and importantly, when administered up to 1 h post paracetamol injection. Prazosin had no effect on paracetamol-induced depletion of hepatic GSH, paracetamol bioactivation or paracetamol-induced transcription of defence genes. Paracetamol toxicity is associated with marked accumulation of erythrocytes within hepatic sinusoids and prazosin completely prevented this accumulation. Paracetamol-induced hepatocellular damage is associated with increased circulating catecholamines. alpha(1)-Adrenoceptor antagonists conferred complete protection from paracetamol -induced hepatotoxicity. Protection was associated with absence of hepatic erythrocyte accumulation. Increased catecholamine levels may contribute to the pathophysiology of paracetamol-induced hepatotoxicity by compromising hepatic perfusion. Protection against paracetamol toxicity by alpha(1) antagonists in mice has implications for therapeutic management of patients presenting with paracetamol overdose and ALF.

  10. Role of the sympathetic nervous system in carbon tetrachloride-induced hepatotoxicity and systemic inflammation.

    Directory of Open Access Journals (Sweden)

    Jung-Chun Lin

    Full Text Available Carbon tetrachloride (CCl4 is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA in a mouse model of CCl4-induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL-1α, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2, and tumor necrosis factor-α (TNF-α], as well as decreased expression of granulocyte colony-stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1α, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-α were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response.

  11. Metabolomics Toward Biomarker Discovery.

    Science.gov (United States)

    Yin, Peiyuan; Xu, Guowang

    2017-01-01

    Metabolomics has been used as practical tool in the discovery of novel biomarkers in a broad area in the clinic. The analytical platforms including nuclear magnetic resonance (NMR) and mass spectrometry (MS) can cover thousands of metabolites. With the help of multivariate data analysis, many potential biomarkers can be defined in the studies. Since metabolites stand at the end point of metabolism, it remains difficult to find novel biomarkers with good diagnostic or prognostic performance. In this chapter, we will introduce a general protocol for biomarker discovery within the scope of metabolomics using MS.

  12. Is ketogenic diet treatment hepatotoxic for children with intractable epilepsy?

    Science.gov (United States)

    Arslan, Nur; Guzel, Orkide; Kose, Engin; Yılmaz, Unsal; Kuyum, Pınar; Aksoy, Betül; Çalık, Tansel

    2016-12-01

    Long-term ketogenic diet (KD) treatment has been shown to induce liver steatosis and gallstone formation in some in vivo and clinical studies. The aim of this retrospective study was to evaluate the hepatic side effects of KD in epileptic children. A total of 141 patients (mean age: 7.1±4.1years [2-18 years], 45.4% girls), receiving KD at least one year for intractable epilepsy due to different diagnoses (congenital brain defects, GLUT-1 deficiency, West syndrome, tuberous sclerosis, hypoxic brain injury, etc.) were included in the study. Serum triglyceride, cholesterol, aminotransferase, bilirubin, protein and albumin levels and abdominal ultrasonography were recorded before and at 1, 3, 6, and 12 months following after diet initiation. The mean duration of KD was 15.9±4.3months. At one month of therapy, three patients had elevated alanine and aspartate aminotransferase levels. These patients were receiving ketogenic diet for Doose syndrome, idiopathic epilepsy and GLUT-1 deficiency. Hepatosteatosis was detected in three patients at 6 months of treatment. Two of these patients were treated with KD for the primary diagnosis of tuberous sclerosis and one for Landau Kleffner syndrome. Cholelithiasis was detected in two patients at 12 months of treatment. They were receiving treatment for West syndrome and hypoxic brain injury sequelae. Long-term ketogenic diet treatment stimulates liver parenchymal injury, hepatic steatosis and gallstone formation. Patients should be monitored by screening liver enzymes and abdominal ultrasonography in order to detect these side effects. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  13. Role of the gerA operon in L-alanine germination of Bacillus licheniformis spores

    Directory of Open Access Journals (Sweden)

    Løvdal Irene S

    2012-03-01

    Full Text Available Abstract Background The genome of Bacillus licheniformis DSM 13 harbours three neighbouring open reading frames showing protein sequence similarities to the proteins encoded from the Bacillus subtilis subsp. subtilis 168 gerA operon, GerAA, GerAB and GerAC. In B. subtilis, these proteins are assumed to form a germinant receptor involved in spore germination induced by the amino acid L-alanine. Results In this study we show that disruption of the gerAA gene in B. licheniformis MW3 hamper L-alanine and casein hydrolysate-triggered spore germination, measured by absorbance at 600 nm and confirmed by phase contrast microscopy. This ability was restored by complementation with a plasmid-borne copy of the gerA locus. Addition of D-alanine in the casein hydrolysate germination assay abolished germination of both B. licheniformis MW3 and the complementation mutant. Germination of both B. licheniformis MW3 and the gerA disruption mutant was induced by the non-nutrient germinant Ca2+-Dipicolinic acid. Conclusions These results demonstrate that the B. licheniformis MW3 gerA locus is involved in germination induced by L-alanine and potentially other components present in casein hydrolysate.

  14. Isomeric effects in ion-induced fragmentation of alpha- and beta-alanine

    NARCIS (Netherlands)

    Sobocinski, P.; Bari, S.; Postma, J.; Alvarado, F.; Hoekstra, R.; Manil, B.; Rangama, J.; Bernigaud, V.; Huber, B. A.; Schlatholter, T.; McGuigan, KG; Tokesi, K; Sulik, B

    2008-01-01

    We have investigated the dissociation of alpha- and beta- alanine following impact of slow multicharged ions, namely He(+), He(2+), O(5+) and Xe(20+) at 10 keV per charge unit. The collision products were analyzed using a reflectron-type time-of-flight mass spectrometer. In general, for a given

  15. On the fragmentation of biomolecules: fragmentation of alanine dipeptide along the polypeptide chain

    DEFF Research Database (Denmark)

    Solov'yov, Ilia; Yakubovich, Alexander; Solov'yov, Andrey

    2006-01-01

    The interaction potential between amino acids in alanine dipeptide has been studied for the first time taking into account exact molecular geometry. Ab initio calculation has been performed in the framework of density functional theory taking into account all electrons in the system. The fragment...

  16. Solid phase extraction of β-N-methylamino-L-alanine (BMAA) from ...

    African Journals Online (AJOL)

    2011-01-25

    Jan 25, 2011 ... β-N-methylamino-L-alanine (BMAA) has been implicated in amyotrophic lateral sclerosis/parkinsonism dementia complex ... Current analytical techniques are, however, insufficiently sensitive to detect the molecule at concentrations of less than 250 .... was detected from flow through or wash fractions.

  17. Inhibitory effect of different product analogues on {beta}-alanine synthase: A thermodynamic and fluorescence analysis

    Energy Technology Data Exchange (ETDEWEB)

    Andujar-Sanchez, Montserrat; Martinez-Gomez, Ana Isabel; Martinez-Rodriguez, Sergio; Clemente-Jimenez, Josefa Maria; Heras-Vazquez, Francisco Javier Las; Rodriguez-Vico, Felipe [Departamento de Quimica Fisica, Bioquimica y Quimica Inorganica, Facultad de Ciencias Experimentales, Universidad de Almeria, Carretera de Sacramento s/n, La Canada de San Urbano, Almeria 04120 (Spain); Jara-Perez, Vicente [Departamento de Quimica Fisica, Bioquimica y Quimica Inorganica, Facultad de Ciencias Experimentales, Universidad de Almeria, Carretera de Sacramento s/n, La Canada de San Urbano, Almeria 04120 (Spain)], E-mail: vjara@ual.es

    2009-02-15

    The enzyme N-carbamoyl-{beta}-alanine amidohydrolase catalyse the hydrolysis of N-carbamoyl-{beta}-alanine or N-carbamoyl-{beta}-aminoisobutyric acid to {beta}-alanine or 3-aminoisobutyric acid, under the release of carbon-dioxide and ammonia. This work studies the inhibition of N-carbamoyl-{beta}-alanine amidohydrolase from Agrobacterium tumefaciens C58 (At{beta}car) by different carboxylic acid compounds that differ in number of carbons, and position and size of ramification, while the binding thermodynamics of the inhibitors are studied by isothermal titration calorimetry (ITC) and fluorescence. From the binding constants and inhibition studies, we conclude that propionate is the most efficient inhibitor among those tested. Substitution of the linear alkyl acids in positions 2 and 3 resulted in a drastic decrease of the affinity. The thermodynamic parameters show that a conformational change is triggered upon ligand binding. Binding enthalpy {delta}H{sub b} is negative in all cases for all ligands, and thus, Van der Waals interactions and hydrogen bonding are most probably the major sources for this term. The process is entropically favoured at all temperatures and pH studied, most probably due to the liberation of water molecules accompanying the conformational change of the enzyme.

  18. High-pressure X-ray diffraction of L-ALANINE crystal

    DEFF Research Database (Denmark)

    Olsen, J.S.; Gerward, Leif; Souza, A.G.

    2006-01-01

    L-ALANINE has been studied by X-ray diffraction at ambient temperature and pressure up to 10.3 GPa. The material is found to transform to a tetragonal structure between 2 and 3 GPa. and to a monoclinic structure between 8 and 10 GPa. The experimental bulk modulus is 25(5) GPa for the orthorhombic...

  19. Electronic structure and first hyperpolarizability of poly (μ2-L-alanine ...

    Indian Academy of Sciences (India)

    Poly(2-L-alanine-3-sodium nitrate (I)), -LASN, crystals have been grown by slow evaporation at room temperature. The nominal size of the crystals obtained by the method was of 500 nm. The UV–Vis spectrum shows a wide range, where absorption is lacking around 532 nm, which is required in order to have the ...

  20. Yeast beta-alanine synthase shares a structural scaffold and origin with dizinc-dependent exopeptidases

    DEFF Research Database (Denmark)

    Lundgren, S.; Gojkovic, Zoran; Piskur, Jure

    2003-01-01

    beta-Alanine synthase (betaAS) is the final enzyme of the reductive pyrimidine catabolic pathway, which is responsible for the breakdown of pyrimidine bases, including several anticancer drugs. In eukaryotes, betaASs belong to two subfamilies, which exhibit a low degree of sequence similarity. We...

  1. A gene duplication led to specialized gamma-aminobutyrate and beta-alanine aminotransferase in yeast

    DEFF Research Database (Denmark)

    Andersen, Gorm; Andersen, Birgit; Dobritzsch, D.

    2007-01-01

    In humans, beta-alanine (BAL) and the neurotransmitter gamma-aminobutyrate (GABA) are transaminated by a single aminotransferase enzyme. Apparently, yeast originally also had a single enzyme, but the corresponding gene was duplicated in the Saccharomyces kluyveri lineage. SkUGA1 encodes a homolog...

  2. AlaScan: A Graphical User Interface for Alanine Scanning Free-Energy Calculations.

    Science.gov (United States)

    Ramadoss, Vijayaraj; Dehez, François; Chipot, Christophe

    2016-06-27

    Computation of the free-energy changes that underlie molecular recognition and association has gained significant importance due to its considerable potential in drug discovery. The massive increase of computational power in recent years substantiates the application of more accurate theoretical methods for the calculation of binding free energies. The impact of such advances is the application of parent approaches, like computational alanine scanning, to investigate in silico the effect of amino-acid replacement in protein-ligand and protein-protein complexes, or probe the thermostability of individual proteins. Because human effort represents a significant cost that precludes the routine use of this form of free-energy calculations, minimizing manual intervention constitutes a stringent prerequisite for any such systematic computation. With this objective in mind, we propose a new plug-in, referred to as AlaScan, developed within the popular visualization program VMD to automate the major steps in alanine-scanning calculations, employing free-energy perturbation as implemented in the widely used molecular dynamics code NAMD. The AlaScan plug-in can be utilized upstream, to prepare input files for selected alanine mutations. It can also be utilized downstream to perform the analysis of different alanine-scanning calculations and to report the free-energy estimates in a user-friendly graphical user interface, allowing favorable mutations to be identified at a glance. The plug-in also assists the end-user in assessing the reliability of the calculation through rapid visual inspection.

  3. Effects of ethanol on alanine metabolism in perfused mouse liver studied by /sup 13/C NMR

    Energy Technology Data Exchange (ETDEWEB)

    Cohen, S.M. (Bell Laboratories, Murray Hill, NJ); Shulman, R.G.; McLaughlin, A.C.

    1979-10-01

    Time courses of /sup 13/C labeling from alanine and ethanol in perfused mouse livers have been followed by NMR. The enrichment at specific carbons of glucose, glutamate, glutamine, aspartate, acetate, acetoacetate, ..beta..-hydroxybutyrate, and lactate has been measured. The specific labeling of glutamate in the presence of labeled alanine and labeled or unlabeled ethanol shows that, under these conditions, alanine enters the tricarboxylic acid cycle almost exclusively through pyruvate carboxylation, whereas ethanol is the exclusive source of acetyl-CoA. In the absence of ethanol, the alanine label flows through both paths. By comparing the scrambling of /sup 13/C between C3 and C2 of glutamate it is possible to estimate the mitochondrial fumarase activity; the C6-to-C5 ratios in glucose give the additional scrambling by cytosolic fumarase activity. In addition, the C6-to-C1 and C5-to-C2 ratios in glucose show that there is about 15% flux through the pentose cycle. Finally, the C4-to-C2 ratios in glutamine and glutamate are unequal at any time (the glutamine labels reflect the label distribution in glutamate measured 1 hr earlier), providing a method for studying flow through glutamine synthetase in situ.

  4. Electronic structure and first hyperpolarizability of poly(μ2-L-alanine ...

    Indian Academy of Sciences (India)

    Administrator

    poly(μ2-L-alanine-μ3-sodium nitrate (I)) crystals. A DUARTE MOLLER. Centro de Investigación en Materiales Avanzados, SC, Miguel de Cervantes 120, Complejo Industrial Chihuahua,. Chihuahua 31109, México. Present address: Universidad Tecnológica de Querétaro, Avenida Pie de la Cuesta 2501, Unidad Nacional,.

  5. Liver alanine aminotransferase, insulin resistance and endothelial dysfunction in normotriglyceridaemic subjects with type 2 diabetes mellitus

    NARCIS (Netherlands)

    Schindhelm, RK; Diamant, M; Bakker, SJL; van Dijk, RAJM; Scheffer, PG; Teerlink, T; Kostense, PJ; Heine, RJ

    Background Plasma levels of liver transaminases, including alanine aminotransferase (ALT), are elevated in most cases of nonalcoholic fatty liver disease (NAFLD). Elevated ALT levels are associated with insulin resistance, and subjects with NAFLD have features of the metabolic syndrome that confer

  6. Alanine racemase is essential for the growth and interspecies competitiveness of Streptococcus mutans

    Science.gov (United States)

    Wei, Yuan; Qiu, Wei; Zhou, Xue-Dong; Zheng, Xin; Zhang, Ke-Ke; Wang, Shi-Da; Li, Yu-Qing; Cheng, Lei; Li, Ji-Yao; Xu, Xin; Li, Ming-Yun

    2016-01-01

    D-alanine (D-Ala) is an essential amino acid that has a key role in bacterial cell wall synthesis. Alanine racemase (Alr) is a unique enzyme that interconverts L-alanine and D-alanine in most bacteria, making this enzyme a potential target for antimicrobial drug development. Streptococcus mutans is a major causative factor of dental caries. The factors involved in the survival, virulence and interspecies interactions of S. mutans could be exploited as potential targets for caries control. The current study aimed to investigate the physiological role of Alr in S. mutans. We constructed alr mutant strain of S. mutans and evaluated its phenotypic traits and interspecies competitiveness compared with the wild-type strain. We found that alr deletion was lethal to S. mutans. A minimal supplement of D-Ala (150 μg·mL−1) was required for the optimal growth of the alr mutant. The depletion of D-alanine in the growth medium resulted in cell wall perforation and cell lysis in the alr mutant strain. We also determined the compromised competitiveness of the alr mutant strain relative to the wild-type S. mutans against other oral streptococci (S. sanguinis or S. gordonii), demonstrated using either conditioned medium assays or dual-species fluorescent in situ hybridization analysis. Given the importance and necessity of alr to the growth and competitiveness of S. mutans, Alr may represent a promising target to modulate the cariogenicity of oral biofilms and to benefit the management of dental caries. PMID:27740612

  7. Biomarkers of Diabetic Retinopathy.

    Science.gov (United States)

    Ting, Daniel Shu Wei; Tan, Kara-Anne; Phua, Val; Tan, Gavin Siew Wei; Wong, Chee Wai; Wong, Tien Yin

    2016-12-01

    Diabetic retinopathy (DR), a leading cause of acquired vision loss, is a microvascular complication of diabetes. While traditional risk factors for diabetic retinopathy including longer duration of diabetes, poor blood glucose control, and dyslipidemia are helpful in stratifying patient's risk for developing retinopathy, many patients without these traditional risk factors develop DR; furthermore, there are persons with long diabetes duration who do not develop DR. Thus, identifying biomarkers to predict DR or to determine therapeutic response is important. A biomarker can be defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Incorporation of biomarkers into risk stratification of persons with diabetes would likely aid in early diagnosis and guide treatment methods for those with DR or with worsening DR. Systemic biomarkers of DR include serum measures including genomic, proteomic, and metabolomics biomarkers. Ocular biomarkers including tears and vitreous and retinal vascular structural changes have also been studied extensively to prognosticate the risk of DR development. The current studies on biomarkers are limited by the need for larger sample sizes, cross-validation in different populations and ethnic groups, and time-efficient and cost-effective analytical techniques. Future research is important to explore novel DR biomarkers that are non-invasive, rapid, economical, and accurate to help reduce the incidence and progression of DR in people with diabetes.

  8. Respiratory Toxicity Biomarkers

    Science.gov (United States)

    The advancement in high throughput genomic, proteomic and metabolomic techniques have accelerated pace of lung biomarker discovery. A recent growth in the discovery of new lung toxicity/disease biomarkers have led to significant advances in our understanding of pathological proce...

  9. Novel biomarkers for sepsis

    DEFF Research Database (Denmark)

    Larsen, Frederik Fruergaard; Petersen, J Asger

    2017-01-01

    biomarkers to discriminate between patients with and without infection, as the cause of deterioration. METHOD: Narrative review of current literature. RESULTS: A number of the most promising biomarkers for diagnoses and prognostication of sepsis are presented. CONCLUSION: Procalcitonin, presepsin, CD64, su...

  10. Unexpected paracetamol (acetaminophen) hepatotoxicity at standard dosage in two older patients: time to rethink 1 g four times daily?

    Science.gov (United States)

    Ging, Patricia; Mikulich, Olga; O'Reilly, Katherine M A

    2016-07-01

    We present two cases of acute hepatotoxicity associated with elevated paracetamol (acetaminophen) levels in older patients. Both patients were receiving a standard European dose of oral paracetamol (2 × 500 mg QDS) with no risk factors for slowed metabolism (weight paracetamol can be hepatotoxic. © The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Modulatory effects of dietary inclusion of garlic (Allium sativum) on gentamycin–induced hepatotoxicity and oxidative stress in rats

    OpenAIRE

    Ademiluyi, Adedayo O.; Ganiyu Oboh; Owoloye, Tosin R; Agbebi, Oluwaseun J.

    2013-01-01

    Objective: To investigate the ameliorative effect of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity in rats. Methods: Adult male rats were randomly divided into four groups with six animals in each group. Groups 1 and 2 were fed basal diet while Groups 3 and 4 were fed diets containing 2% and 4% garlic respectively for 27 d prior to gentamycin administration. Hepatotoxicity was induced by the intraperitoneal administration of gentamycin (100 mg/kg body we...

  12. Preclinical biomarker qualification.

    Science.gov (United States)

    Sauer, John-Michael; Porter, Amy C

    2017-01-01

    Biomarkers are ubiquitously used within drug development programs in both nonclinical species and in humans to assess safety and efficacy of novel compounds. To routinely apply such novel biomarkers with certainty, a well-defined data package is necessary for review and endorsement by regulatory agencies including the US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. This type of endorsement is known as regulatory qualification. Novel approaches are being applied to speed the process, lower the resource intensity, and increase the accessibility of biomarker qualification data and it is likely that consortia will continue to play a fundamental role in the qualification process by bringing together like-minded stakeholders focused on specific tools to accelerate drug development. This article will focus on learnings from the previous three nonclinical biomarker qualification projects, as well as discuss the progression of preclinical biomarker projects into the clinical qualification space and the current strategy for the use of nonclinical biomarker data in the translational qualification of clinical biomarkers; much like nonclinical information is used in the approval of drug development candidates. Impact statement This minireview provides an overview of the history of preclinical biomarker qualification by summarizing the three examples of this type of qualification with US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. In addition, an overview of the biomarker qualification process is included to educate key stakeholders with links to relevant white papers that provide information on current evidentiary considerations. The manuscript also provides new information on the evolution of the role that preclinical qualification plays in clinical qualification of biomarkers and the novel approaches that are being utilized to improve the

  13. Glycolysis and the tricarboxylic acid cycle are linked by alanine aminotransferase during hypoxia induced by waterlogging of Lotus japonicus.

    Science.gov (United States)

    Rocha, Marcio; Licausi, Francesco; Araújo, Wagner L; Nunes-Nesi, Adriano; Sodek, Ladaslav; Fernie, Alisdair R; van Dongen, Joost T

    2010-03-01

    The role of nitrogen metabolism in the survival of prolonged periods of waterlogging was investigated in highly flood-tolerant, nodulated Lotus japonicus plants. Alanine production revealed to be a critical hypoxic pathway. Alanine is the only amino acid whose biosynthesis is not inhibited by nitrogen deficiency resulting from RNA interference silencing of nodular leghemoglobin. The metabolic changes that were induced following waterlogging can be best explained by the activation of alanine metabolism in combination with the modular operation of a split tricarboxylic acid pathway. The sum result of this metabolic scenario is the accumulation of alanine and succinate and the production of extra ATP under hypoxia. The importance of alanine metabolism is discussed with respect to its ability to regulate the level of pyruvate, and this and all other changes are discussed in the context of current models concerning the regulation of plant metabolism.

  14. CCl4-induced hepatotoxicity: protective effect of rutin on p53, CYP2E1 and the antioxidative status in rat

    Directory of Open Access Journals (Sweden)

    Khan Rahmat A

    2012-10-01

    Full Text Available Abstract Background Rutin is a polyphenolic natural flavonoid which possesses antioxidant and anticancer activity. In the present study the hepatoprotective effect of rutin was evaluated against carbon tetrachloride (CCl4-induced liver injuries in rats. Methods and materials 24 Sprague–Dawley male rats were equally divided into 4 groups for the assessment of hepatoprotective potential of rutin. Rats of group I (control received only vehicles; 1 ml/kg bw of saline (0.85% and olive oil (3 ml/kg and had free access to food and water. Rats of group II, III and IV were treated with CCl4 (30% in olive oil, 3 ml/kg bw via the intraperitoneal route twice a week for four weeks. The rutin at the doses of 50 and 70 mg/kg were administered intragastrically after 48 h of CCl4 treatment to group III and IV, respectively. Protective effect of rutin on serum enzyme level, lipid profile, activities of antioxidant enzymes and molecular markers were calculated in CCl4-induced hepatotoxicity in rat. Results Rutin showed significant protection with the depletion of alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, gamma glutamyl transpeptidase (γ-GT in serum as was raised by the induction of CCl4. Concentration of serum triglycerides, total cholesterol and low density lipoproteins was increased while high-density lipoprotein was decreased with rutin in a dose dependent manner. Activity level of endogenous liver antioxidant enzymes; catalase (CAT, superoxide dismutase (SOD, glutathione peroxidase (GSHpx, glutathione-S-transferase (GST and glutathione reductase (GSR and glutathione (GSH contents were increased while lipid peroxidation (TBARS was decreased dose dependently with rutin. Moreover, increase in DNA fragmentation and oxo8dG damages while decrease in p53 and CYP 2E1 expression induced with CCl4 was restored with the treatment of rutin. Conclusion From these results, it is suggested that rutin possesses

  15. In vitro metabolism of isoline, a pyrrolizidine alkaloid from Ligularia duciformis, by rodent liver microsomal esterase and enhanced hepatotoxicity by esterase inhibitors.

    Science.gov (United States)

    Tang, Jun; Akao, Teruaki; Nakamura, Norio; Wang, Zheng-Tao; Takagawa, Kiyoshi; Sasahara, Masakiyo; Hattori, Masao

    2007-10-01

    Isoline, a major retronecine-type pyrrolizidine alkaloid (PA) from the Chinese medicinal herb Ligularia duciformis, was suggested to be the most toxic known PA. Its in vitro metabolism was thus examined in rat and mouse liver microsomes, and its toxicity was compared with that of clivorine and monocrotaline after i.p. injection in mice. Isoline was more rapidly metabolized by both microsomes than clivorine and monocrotaline and converted to two polar metabolites M1 and M2, which were spectroscopically determined to be bisline (a deacetylated metabolite of isoline) and bisline lactone, respectively. Both metabolites were formed in the presence or absence of an NADPH-generating system with liver microsomes but not cytosol. Their formation was completely inhibited by the esterase inhibitors, triorthocresyl phosphate (TOCP) and phenylmethylsulfonyl fluoride, but not at all or partially by cytochrome P450 (P450) inhibitors, alpha-naphthoflavone and proadifen (SKF 525A), respectively. These results demonstrated that both metabolites were produced by microsomal esterase(s) but not P450 isozymes. The esterase(s) involved showed not only quite different activities but also responses to different inhibitors in rat and mouse liver microsomes, suggesting that different key isozyme(s) or combinations might be responsible for the deacetylation of isoline. Isoline injected i.p. into mice induced liver-specific toxicity that was much greater than that with either clivorine or monocrotaline, as judged by histopathology as well as serum alanine aminotransferase and aspartate aminotransferase levels. Isoline-induced hepatotoxicity was remarkably enhanced by the esterase inhibitor TOCP but was reduced by the P450 inhibitor SKF 525A, indicating that rodent hepatic esterase(s) played a principal role in the detoxification of isoline via rapid deacetylation in vivo.

  16. Moringa oleifera Hydroethanolic Extracts Effectively Alleviate Acetaminophen-Induced Hepatotoxicity in Experimental Rats through Their Antioxidant Nature

    Directory of Open Access Journals (Sweden)

    Sharida Fakurazi

    2012-07-01

    Full Text Available The aim of the study was to investigate the in vitro antioxidant properties Moringa oleifera Lam. (MO extracts and its curative role in acetaminophen (APAP- induced toxic liver injury in rats caused by oxidative damage. The total phenolic content and antioxidant properties of hydroethanolic extracts of different MO edible parts were investigated by employing an established in vitro biological assay. In the antihepatotoxic study, either flowers or leaves extract (200 mg/kg or 400 mg/kg, i.p were administered an hour after APAP administration, respectively. N-Acetylcysteine was used as the positive control against APAP-induced hepatotoxicity. The levels of liver markers such as alanine aminotransferase (ALT and the levels of oxidative damage markers including malondialdehyde (MDA, 4-hydroxynonenal (4-HNE protein adduct, reduced glutathione (GSH, superoxide dismutase (SOD and catalase (CAT were analysed and compared between experimental groups. Among MO edible parts the flower extracts contain the highest total phenolic content and antioxidant capacity, followed by leaves extract. The oxidative marker MDA, as well as 4-HNE protein adduct levels were elevated and GSH, SOD and CAT were significantly decreased in groups treated with hepatotoxin. The biochemical liver tissue oxidative markers measured in the rats treated with MO flowers and leaves hydroethanolic extracts showed a significant (p < 0.05 reduction in the severity of the liver damage. The results of this study strongly indicate the therapeutic properties of MO hydroethanolic extracts against acute liver injury and thereby scientifically support its traditional use.

  17. Protective Effects of Tormentic Acid, a Major Component of Suspension Cultures of Eriobotrya japonica Cells, on Acetaminophen-Induced Hepatotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Wen-Ping Jiang

    2017-05-01

    Full Text Available An acetaminophen (APAP overdose can cause hepatotoxicity and lead to fatal liver damage. The hepatoprotective effects of tormentic acid (TA on acetaminophen (APAP-induced liver damage were investigated in mice. TA was intraperitoneally (i.p. administered for six days prior to APAP administration. Pretreatment with TA prevented the elevation of serum aspartate aminotransferase (AST, alanine aminotransferase (ALT, total bilirubin (T-Bil, total cholesterol (TC, triacylglycerol (TG, and liver lipid peroxide levels in APAP-treated mice and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, TA attenuated the APAP-induced production of nitric oxide (NO, reactive oxygen species (ROS, tumor necrosis factor-alpha (TNF-α, interleukin-1beta (IL-1β, and IL-6. Furthermore, the Western blot analysis showed that TA blocked the protein expression of inducible NO synthase (iNOS and cyclooxygenase-2 (COX-2, as well as the inhibition of nuclear factor-kappa B (NF-κB and mitogen-activated protein kinases (MAPKs activation in APAP-injured liver tissues. TA also retained the superoxidase dismutase (SOD, glutathione peroxidase (GPx, and catalase (CAT in the liver. These results suggest that the hepatoprotective effects of TA may be related to its anti-inflammatory effect by decreasing thiobarbituric acid reactive substances (TBARS, iNOS, COX-2, TNF-α, IL-1β, and IL-6, and inhibiting NF-κB and MAPK activation. Antioxidative properties were also observed, as shown by heme oxygenase-1 (HO-1 induction in the liver, and decreases in lipid peroxides and ROS. Therefore, TA may be a potential therapeutic candidate for the prevention of APAP-induced liver injury by inhibiting oxidative stress and inflammation.

  18. Biochemical characterization and kinetic properties of alanine aminotransferase homologues partially purified from wheat (Triticum aestivum L.).

    Science.gov (United States)

    Kendziorek, Maria; Paszkowski, Andrzej; Zagdańska, Barbara

    2012-10-01

    Four homologues of alanine aminotransferase have been isolated from shoots of wheat seedlings and purified by saline precipitation, gel filtration, preparative electrophoresis and anion exchange chromatography on Protein-Pak Q 8HR column attached to HPLC. Alanine aminotransferase 1 (AlaAT1) and 2 (AlaAT2) were purified 303- and 452-fold, respectively, whereas l-glutamate: glyoxylate aminotransferase 1 (GGAT1) and 2 (GGAT2) were purified 485- and 440-fold, respectively. Consistent inhibition of AlaAT (EC 2.6.1.2) and GGAT (EC 2.6.1.4) activities by p-hydroxymercuribenzoate points on participation of cysteine residues in the enzyme activity. The molecular weight of AlaAT1 and AlaAT2 was estimated to be 65kDa and both of them are monomers in native state. Nonsignificant differences between K(m) using alanine as substrate and catalytic efficiency (k(cat)/K(m)) for l-alanine in reaction with 2-oxoglutarate indicate comparable kinetic constants for AlaAT1 and AlaAT2. Similar kinetic constants for l-alanine in reaction with 2-oxoglutarate and for l-glutamate in reaction with pyruvate for all four homologues suggest equally efficient reaction in both forward and reverse directions. GGAT1 and GGAT2 were able to catalyze transamination between l-glutamate and glyoxylate, l-alanine and glyoxylate and reverse reactions between glycine and 2-oxoglutarate or pyruvate. Both GGATs also consisted of a single subunit with molecular weight of about 50kDa. The estimated K(m) for GGAT1 (3.22M) and GGAT2 (1.27M) using l-glutamate as substrate was lower in transamination with glyoxylate than with pyruvate (9.52 and 9.09mM, respectively). Moreover, distinctively higher values of catalytic efficiency for l-glutamate in reaction with glyoxylate than for l-glutamate in reaction with pyruvate confirm involvement of these homologues into photorespiratory metabolism. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. The alanine detector in BNCT dosimetry: Dose response in thermal and epithermal neutron fields

    Energy Technology Data Exchange (ETDEWEB)

    Schmitz, T., E-mail: schmito@uni-mainz.de [Institute for nuclear chemistry, Johannes Gutenberg-University, Mainz D-55128 (Germany); Bassler, N. [Department of Physics and Astronomy, Aarhus University, Ny Munkegade 120, Aarhus C, Aarhus 8000 (Denmark); Blaickner, M. [AIT Austrian Institute of Technology GmbH, Vienna A-1220 (Austria); Ziegner, M. [AIT Austrian Institute of Technology GmbH, Vienna A-1220, Austria and TU Wien, Vienna University of Technology, Vienna A-1020 (Austria); Hsiao, M. C. [Insitute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Liu, Y. H. [Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Koivunoro, H. [Department of Physics, University of Helsinki, POB 64, FI-00014, Finland and HUS Medical Imaging Center, Helsinki University Central Hospital, FI-00029 HUS (Finland); Auterinen, I.; Serén, T.; Kotiluoto, P. [VTT Technical Research Centre of Finland, Espoo (Finland); Palmans, H. [National Physical Laboratory, Acoustics and Ionising Radiation Division, Teddington TW11 0LW, United Kingdom and Medical Physics Group, EBG MedAustron GmbH, Wiener Neustadt A-2700 (Austria); Sharpe, P. [National Physical Laboratory, Acoustics and Ionising Radiation Division, Teddington TW11 0LW (United Kingdom); Langguth, P. [Department of Pharmacy and Toxicology, University of Mainz, Mainz D-55128 (Germany); Hampel, G. [Institut für Kernchemie, Johannes Gutenberg-Universität, Mainz D-55128 (Germany)

    2015-01-15

    Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a {sup 60}Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. Conclusions: The

  20. Prognostic biomarkers in osteoarthritis

    Science.gov (United States)

    Attur, Mukundan; Krasnokutsky-Samuels, Svetlana; Samuels, Jonathan; Abramson, Steven B.

    2013-01-01

    Purpose of review Identification of patients at risk for incident disease or disease progression in osteoarthritis remains challenging, as radiography is an insensitive reflection of molecular changes that presage cartilage and bone abnormalities. Thus there is a widely appreciated need for biochemical and imaging biomarkers. We describe recent developments with such biomarkers to identify osteoarthritis patients who are at risk for disease progression. Recent findings The biochemical markers currently under evaluation include anabolic, catabolic, and inflammatory molecules representing diverse biological pathways. A few promising cartilage and bone degradation and synthesis biomarkers are in various stages of development, awaiting further validation in larger populations. A number of studies have shown elevated expression levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma). These chemical biomarkers are under evaluation in combination with imaging biomarkers to predict early onset and the burden of disease. Summary Prognostic biomarkers may be used in clinical knee osteoarthritis to identify subgroups in whom the disease progresses at different rates. This could facilitate our understanding of the pathogenesis and allow us to differentiate phenotypes within a heterogeneous knee osteoarthritis population. Ultimately, such findings may help facilitate the development of disease-modifying osteoarthritis drugs (DMOADs). PMID:23169101

  1. Hepatotoxicity associated with microcystin/ Hepatotoxicidade associada à microcistina

    Directory of Open Access Journals (Sweden)

    Ana Paula Frederico Rodrigues Loureiro Bracarense

    2008-08-01

    Full Text Available Urban and industrial discharges, intense agricultural exploitation and fisheries have been causing the eutrophication in both drinking and recreational waters. A frequent consequence of eutrophication in waters is the massive development of cyanobacteria. The occurrence of these blooms induces a severe problem, as Microcystis aeruginosa, the most widespread distributed cyanobacteria, can produce microcystins (MC. Toxic effects of MC have been described in liver, lungs, stomach, and intestine. Deaths in wildlife, livestock and human beings were also associated with MC exposition. MC exposition can occurs directly by ingestion, inhalation, contact, intravenous inoculation of contaminated water (hemodialysis or indirectly, by the consumption of animals, as fish and mollusks, the majors ingestors of cyanobacteria and its toxins. The most toxic MC, an also the most common is microcystin-LR (MC-LR, that has the liver as the main target organ. Microcystin is taken up specifically into the liver by bile acid transporters and, after entering the cytoplasm, inhibit protein phosphatases 1 and 2A, which leads to the increase in protein phosphorylation. This effect has two main consequences: the destruction of cytoskeleton directly causing cytotoxic effects, and deregulation of cell division, leading to tumor-promoting activity. Acute exposition to MC induces severe intrahepatic hemorrhage, necrosis and apoptosis, while chronic exposure can cause hepatic or intestinal neoplasia. It has been documented that MC hepatotoxicity is closely associated with intracellular reactive oxygen species formation. Natural degradation of microcystins depends on the solar radiation and bacteria. If degradation is insufficient, MC will persist in the freshwater food chain. Microcystin contamination of waters is therefore a hazard to human and animal health, so efforts to avoid eutrophication of waters sources are essential, in order to minimize the risks to public health

  2. Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States

    Science.gov (United States)

    Avigan, Mark I.; Mozersky, Robert P.; Seeff, Leonard B.

    2016-01-01

    In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized. PMID:26950122

  3. Hepatotoxicity associated with illicit use of anabolic androgenic steroids in doping.

    Science.gov (United States)

    Solimini, R; Rotolo, M C; Mastrobattista, L; Mortali, C; Minutillo, A; Pichini, S; Pacifici, R; Palmi, I

    2017-03-01

    Anabolic Androgenic Steroids (AAS) abuse and misuse is nowadays a harmful habit involving both professional or recreational athletes, as well as general population. AAS are also frequently present in over-the-counter dietary supplements without being declared in the list of ingredients, leaving consumers unaware of the risks of adverse effects. Indeed, health risks of AAS consumption in pharmaceutical preparations or dietary complements seem still underestimated and under-reported. The variety of complications due to AAS misuse involves cardiovascular, central nervous, musculoskeletal and genitourinary systems of both males and females; psychiatric and behavioral effects, damages to metabolic system, skin and mainly liver. For instance, relevant concern has been raised by the AAS hepatotoxicity including adenoma, hepatocellular carcinoma, cholestasis, and peliosis hepatis. The present review reports the information available on the hepatotoxic effects of AAS use in professional and amateur athletes.

  4. Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States

    Directory of Open Access Journals (Sweden)

    Mark I. Avigan

    2016-03-01

    Full Text Available In the United States (US, the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized.

  5. Hepatoprotective effect of leaves of aqueous ethanol extract of Cestrum nocturnum against paracetamol-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    M. Imran Qadir

    2014-06-01

    Full Text Available The hepatoprotective activities of Cestrum nocturnum (Queen of Night was evaluated against the paracetamol induced hepatotoxicity in the mice. Aqueous ethanol (30:70 extract of plant was obtained by maceration. Results showed that aqueous ethanol extract of C. nocturnum (250 mg/kg and 500 mg/kg produced significant (p<0.05 hepatoprotective activities against paracetamol induced liver injury in Swiss albino mice. Histopathalogical studied of liver further supported the hepatoprotective effects of C. notrunum. Phyto-chemical screening showed the presence of alkaloids, flavonoids, saponins, terpenes, phenolic compounds, carbohydrates and volatile oils. Most of the flavonoids have hepatoprotective activity. Therefore, the hepatoprotective activity of C. nocturnum may be due to the presence of flavonoids and phenolic components. It was concluded from the present study that aqueous ethanol extract of leaves of C. nocturnum has hepatoprotective activity against the paracetamol-induced hepatotoxicity in albino mice.

  6. Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity.

    Science.gov (United States)

    Larrey, D; Vial, T; Pauwels, A; Castot, A; Biour, M; David, M; Michel, H

    1992-07-15

    To show that germander (Teucrium chamaedrys), an herbal medicine used to facilitate weight loss, may be hepatotoxic and to delineate the nature of the injury. Retrospective study. Liver units of several centers in the French Network of Pharmacovigilance. Seven patients who developed hepatitis after germander administration and who had no other cause of liver injury. Clinical examination, liver function tests, various serologic tests, ultrasonography, and histologic study. Hepatitis characterized by jaundice and a marked increase in serum aminotransferase levels occurred 3 to 18 weeks after germander administration. Liver biopsy specimens in three patients showed hepatocyte necrosis. After discontinuing treatment with germander, jaundice disappeared within 8 weeks and recovery was complete in 1.5 to 6 months. In three cases, germander readministration was followed by the prompt recurrence of hepatitis. Germander may be hepatotoxic, which supports the view that herbal medicines are not always as safe as generally assumed.

  7. Development of Antibody-Coated Magnetite Nanoparticles for Biomarker Immobilization

    Directory of Open Access Journals (Sweden)

    Christian Chapa Gonzalez

    2014-01-01

    Full Text Available Magnetic nanoparticles (MNPs have great potential in biomedical applications because of their magnetic response offers the possibility to direct them to specific areas and target biological entities. Magnetic separation of biomolecules is one of the most important applications of MNPs because their versatility in detecting cancer biomarkers. However, the effectiveness of this method depends on many factors, including the type of functionalization onto MNPs. Therefore, in this study, magnetite nanoparticles have been developed in order to separate the 5′-nucleotidase enzyme (5eNT. The 5eNT is used as a bio-indicator for diagnosing diseases such as hepatic ischaemia, liver tumor, and hepatotoxic drugs damage. Magnetic nanoparticles were covered in a core/shell type with silica, aminosilane, and a double shell of silica-aminosilane. A ScFv (fragment antibody and anti-CD73 antibody were attached to the coated nanoparticles in order to separate the enzyme. The magnetic separation of this enzyme with fragment antibody was found to be 28% higher than anti-CD73 antibody and the enzyme adsorption was improved with the double shell due to the increased length of the polymeric chain. Magnetite nanoparticles with a double shell (silica-aminosilane were also found to be more sensitive than magnetite with a single shell in the detection of biomarkers.

  8. Circulating RNA Molecules as Biomarkers in Liver Disease

    Directory of Open Access Journals (Sweden)

    Liviu S. Enache

    2014-09-01

    Full Text Available Liver disease is a major cause of morbidity and mortality worldwide. As in other fields of medicine, there is a stringent need for non-invasive markers to improve patient diagnostics, monitoring and prognostic ability in liver pathology. Cell-free circulating RNA molecules have been recently acknowledged as an important source of potential medical biomarkers. However, many aspects related to the biology of these molecules remain to be elucidated. In this review, we summarize current concepts related to the origin, transportation and possible functions of cell-free RNA. We outline current development of extracellular RNA-based biomarkers in the main forms of non-inherited liver disease: chronic viral hepatitis, hepatocellular carcinoma, non-alcoholic fatty liver, hepato-toxicity, and liver transplantation. Despite recent technological advances, the lack of standardization in the assessment of these markers makes their adoption into clinical practice difficult. We thus finally review the main factors influencing quantification of circulating RNA. These factors should be considered in the reporting and interpretation of current findings, as well as in the proper planning of future studies, to improve reliability and reproducibility of results.

  9. Metabolic products as biomarkers

    Science.gov (United States)

    Melancon, M.J.; Alscher, R.; Benson, W.; Kruzynski, G.; Lee, R.F.; Sikka, H.C.; Spies, R.B.; Huggett, Robert J.; Kimerle, Richard A.; Mehrle, Paul M.=; Bergman, Harold L.

    1992-01-01

    Ideally, endogenous biomarkers would indicate both exposure and environmental effects of toxic chemicals; however, such comprehensive biochemical and physiological indices are currently being developed and, at the present time, are unavailable for use in environmental monitoring programs. Continued work is required to validate the use of biochemical and physiological stress indices as useful components of monitoring programs. Of the compounds discussed only phytochelatins and porphyrins are currently in biomarkers in a useful state; however, glutathione,metallothioneins, stress ethylene, and polyamines are promising as biomarkers in environmental monitoring.

  10. Effect of imidacloprid on hepatotoxicity and nephrotoxicity in male albino mice

    OpenAIRE

    Arfat, Yasir; Mahmood, Nasir; Tahir, Muhammad Usman; Rashid, Maryam; Anjum, Sameer; Zhao, Fan; Li, Di-Jie; Sun, Yu-Long; Hu, Lifang; Zhihao, Chen; Yin, Chong; Shang, Peng; Qian, Ai-Rong

    2014-01-01

    Imidacloprid (IC) is a systemic insecticide related to the tobacco toxin nicotine. IC is a toxic substance frequently used into combat insects, rodents and plants pests and other creatures that can pose problems for agriculture. We, therefore, planned this study to assess risk factors, biochemical and histological alterations associated with hepatotoxicity and nephrotoxicity. Forty-eight adult male albino mice were divided into four groups of 12 animals each. All the animals were given standa...

  11. Cholestatic Hepatocellular Injury with Azathioprine: A Case Report and Review of the Mechanisms of Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Joseph Romagnuolo

    1998-01-01

    Full Text Available Azathioprine is a drug commonly used for the treatment of inflammatory bowel disease, organ transplantation and various autoimmune diseases. Hepatotoxicity is a rare, but important complication of this drug. The cases reported to date can be grouped into three syndromes: hypersensitivity; idiosyncratic cholestatic reaction; and presumed endothelial cell injury with resultant raised portal pressures, veno-occlusive disease or peliosis hepatis. The components of azathioprine, 6-mercaptopurine and the imidazole group, may play different roles in the pathogenesis of hepatotoxicity. The strong association with male sex, and perhaps with human leukocyte antigen type, suggests a genetic predisposition of unknown type. Many of the symptoms of hepatotoxicity, such as nausea, abdominal pain and diarrhea, can be nonspecific and can be confused with a flare-up of inflammatory bowel disease. As well, the subtype resulting in portal hypertension can occur without biochemical abnormalities. A 63-year-old man with Crohn's disease who is presented developed the rare idiosyncratic form of azathioprine hepatotoxicity, but also had a severe disabling steroid myopathy, peripheral neuropathy, resultant deep venous thrombosis and pulmonary embolism related to immobility, and a nosocomial pneumonia. His jaundice and liver enzyme levels improved markedly on withdrawal of the drug, returning to almost normal in five weeks. Treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle. Understanding the risks of treatment is the first important step. There must be a low threshold for obtaining liver function tests, especially in men, and alertness to the need to discontinue the drug or perform a liver biopsy should patients on azathioprine develop liver biochemical abnormalities, unexplained hepatomegaly or signs of portal hypertension.

  12. The Potential Protective and Therapeutic Effects of Aloe Vera Juice on Malathion Induced Hepatotoxicity in Rabbits

    OpenAIRE

    Mohamed S. Al-Shinnawy, Ahmed R. Hassan, Dalia A. Ismail and Mohamed A. Shahin

    2014-01-01

    Background: the potential protective and therapeutic effects of Aloe vera juice against malathion induced hepatotoxicity were evaluated in this study. Material and methods: one hundred twelve young male rabbits were used ; they were allocated into two sets of experiments included rabbits treated for short (7 days) and long (21 days) periods. Animals of the first set (short period of treatment) were divided into eight groups; each consisted of four treated groups and four control groups (e...

  13. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps

    OpenAIRE

    Rolf eTeschke; Alex eEickhoff

    2015-01-01

    Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and...

  14. Lactobacillus fermentum Postbiotic-induced Autophagy as Potential Approach for Treatment of Acetaminophen Hepatotoxicity

    OpenAIRE

    Dinić, Miroslav; Lukić, Jovanka; Djokić, Jelena; Milenković, Marina; Strahinić, Ivana; Golić, Nataša; Begović, Jelena

    2017-01-01

    The aim of this study was to investigate the potential of postbiotics originated from Lactobacillus fermentum BGHV110 strain (HV110) to counteract acetaminophen (APAP)-induced hepatotoxicity in HepG2 cells. This strain was selected according to its autophagy inducing potential, based on previous studies reporting protective role of autophagy in APAP caused cellular damage. Cell viability was assessed using MTT and LDH assays, while autophagy was monitored by qPCR analysis of BECN1, Atg5, p62/...

  15. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats

    OpenAIRE

    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-01-01

    Background: Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. Objective: To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Methods: Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. Results: The treatment with Arctium lappa extract reduc...

  16. The Molecular Anatomy of PFDA Hepatotoxicity as Studied by Two-Dimensional Electrophoresis

    Science.gov (United States)

    1993-02-26

    MOLECULAR ANATOMY OF PFDA HEPATOTOXICITY AS STUDIED BY TWO- DIMENSIONAL ELECTROPHORESIS Frank A. Witzmann, Ph.D. Department of Biology Indiana...last 10 of those years, two- dimensional (2-D) protein electrophoresis has become a powerful tool in molecular biology and has found increasing...application in pharmacologic and toxicologic investigations (5-15). The primary motivation behind developing this technique in toxicology has been the

  17. Reactive oxygen and nitrogen species generation features under conditions of acute hepatotoxicity

    Directory of Open Access Journals (Sweden)

    I. О. Shmarakov

    2014-02-01

    Full Text Available Development of the most of pathological conditions occurs by free radical mechanism which is characterized by increased free radical production at the cellular level, especially reactive oxygen and nitrogen species (ROS/RNS. The main producers of reactive oxygen species are, first of all, membrane bound NADH-dependent mitochondrial and NADPH-dependent endoplasmic reticulum electron transport systems, cytosolic oxidoreductase enzymes and multienzyme complexes. The aim of the study was to determine the features of generation of superoxide anion radical (O2· as the primary reactive oxygen species, and nitric oxide (NO· under conditions of thioacetamide-induced hepatotoxicity. The features of NAD(PH-dependent gen-eration of superoxide anion radical (O2· as the primary reactive oxygen species, and nitric oxide (NO· in subcellular (mitochondrial, microsomal and post-microsomal fractions of C57BL/6J mouse liver cells isolated by the method of differential centrifugation were determined under conditions of thioacetamide-induced hepatotoxicity and supplementation with pharma-cological doses of vitamin A. It was found that the development of acute hepatotoxicity induced by single intraperitoneal ad-ministration of 500 mg/kg of thioacetamide was accompanied by increased intensity of superoxide anion radical and nitric oxide production in microsomal and cytosolic fractions of liver cells, but not in mitochondrial fraction. Consumption of the pharmacological doses of vitamin A (3000 IU has no hepatoprotective effect, however, it enhances the production of reactive oxygen and nitrogen species in the liver during acute hepatotoxicity.

  18. Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways

    Science.gov (United States)

    Han, Tao; Hu, Di; Wang, Yi; Yuan, Yan; Gu, Jianhong; Bian, Jianchun; Zhu, Jiaqiao; Liu, Zong-ping

    2015-01-01

    It is known that cadmium (Cd) induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A) and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI) of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC) and activation of mitogen-activated protein kinase (MAPK) pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA), administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK) inhibitor (U0126) and a p38 inhibitor (SB202190) but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways. PMID:26070151

  19. Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways.

    Directory of Open Access Journals (Sweden)

    Hui Zou

    Full Text Available It is known that cadmium (Cd induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC and activation of mitogen-activated protein kinase (MAPK pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA, administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK inhibitor (U0126 and a p38 inhibitor (SB202190 but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK inhibitor (SP600125. These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways.

  20. Small-Field Dosimetry in A 6 MV Photon Beam Using Alanine and Liquid Ionisation Chamber

    DEFF Research Database (Denmark)

    Zimmermann, S.; Riis, H. L.; Hjelm-Hansen, M.

    2012-01-01

    , 2 times 4 sweeps with a 90° turn in between, total measurement time was 3 minutes per dosimeter. The alanine dosimetry system was calibrated using a Co60 gamma cell ensuring traceability to a national standard. Results: The results are summarized in Table 1. At depths below 2 mm, we noted......Purpose/Objective: Dosimetry of small field sizes in MV photon beams is an increasingly important subject, and a generally accepted guideline for clinical measurements is still lacking. The present comparative study was carried out to further investigate the use of alanine and the PTW micro.......9 mm× 88 mm. The stick was held vertically in a PTW MP3 water tank. A latex sleeve of Ø5 mm was used to protect the dosimeter from the water. Measurements were carried of at four depths, 0.2, 15, 100 and 200 mm. The distance from the target to the water surface was 100 cm in all experiments...

  1. A fatal case of bupropion (Zyban hepatotoxicity with autoimmune features: Case report

    Directory of Open Access Journals (Sweden)

    Humayun Fawwaz

    2007-09-01

    Full Text Available Abstract Background Bupropion is approved for the treatment of mood disorders and as an adjuvant medication for smoking cessation. Bupropion is generally well tolerated and considered safe. Two randomized controlled trials of bupropion therapy for smoking cessation did not report any hepatic adverse events. However, there are three reports of severe but non-fatal bupropion hepatotoxicity published in the literature. Case Presentation We present the case of a 55-year old man who presented with jaundice and severe hepatic injury approximately 6 months after starting bupropion for smoking cessation. Laboratory evaluation demonstrated a mixed picture of hepatocellular injury and cholestasis. Liver biopsy demonstrated findings consistent with severe hepatotoxic injury due to drug induced liver injury. Laboratory testing was also notable for positive autoimmune markers. The patient initially had clinical improvement with steroid therapy but eventually died of infectious complications. Conclusion This report represents the first fatal report of bupropion related hepatotoxicity and the second case of bupropion related liver injury demonstrating autoimmune features. The common use of this medication for multiple indications makes it important for physicians to consider this medication as an etiologic agent in patients with otherwise unexplained hepatocellular jaundice.

  2. Beneficial effects of rosmarinic acid against alcohol-induced hepatotoxicity in rats.

    Science.gov (United States)

    Hasanein, Parisa; Seifi, Rosa

    2017-07-04

    Alcohol is a severe hepatotoxicant that causes a variety of liver disorders. Rosmarinic acid (RA), a natural phenol, shows some biological activities, including antioxidant and anti-inflammatory effects. We investigated the effects of RA (10 mg/kg) against ethanol-induced oxidative damage and hepatotoxicity in rats. Animals received ethanol (4 g/kg, i.g.) and (or) RA (10 mg/kg, i.g.) daily for 4 weeks. At the end of the treatment period, rats were weighed and use for biochemical, molecular, and histopathological examinations. Ethanol increased hepatic lipid peroxidation (P < 0.001) and decreased hepatic levels of reduced glutathione (P < 0.01), catalase (P < 0.05), and superoxide dismutase (P < 0.001) compared with control group. RA prevented the prooxidant and antioxidant imbalance induced by ethanol in liver. Furthermore, RA ameliorated the increased liver mass, serum levels of ALT, AST, LDH, TNF-α, and IL-6 in ethanol group. Necrosis and infiltration of inflammatory cells in liver parenchyma were attenuated by RA treatment. Our findings showed that RA prevents ethanol-induced oxidant/antioxidant imbalance and liver injury in an experimental model of ethanol-induced hepatotoxicity. Therefore, RA may be a good candidate to protect against ethanol-induced hepatotoxicity; this deserves consideration and further examination.

  3. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats

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    Star Khoza

    2017-01-01

    Full Text Available Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels (p=0.0017 and AST levels (p=0.0008 than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment (p<0.0001. The liver enzyme levels suggested that ketoconazole had the highest risk in causing liver injury followed by itraconazole, fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

  4. The Postulated Hepatotoxic Metabolite of Methimazole Causes Mitochondrial Dysfunction and Energy Metabolism Disturbances in Liver

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    Hossein Niknahad 1,2, Akram Jamshidzadeh 1,2, Reza Heidari 1 * , Narges Abdoli 3, Mohammad Mehdi Ommati 4, Faezeh Jafari 2, Mahdi Zarei 2, Behnam Asadi 2

    2016-12-01

    Full Text Available Background: Although several cases of methimazole-induced liver injury are reported, but there is no clear idea on the mechanism of methimazole hepatotoxicity. N-methyl thiourea (NMT is a postulated hepatotoxic metabolite for methimazole. The current investigation was designed to evaluate the effect of NMT on hepatocyte mitochondria as a target of xenobiotics-induced cellular injury. Methods: Isolated liver mitochondria from healthy mice were incubated with NMT (10 µM-160 mM (in vitro. Furthermore, mice received NMT (10, 20, 40 and 80 mg/kg, i.p then, their liver mitochondria were isolated and assessed (in vivo. Several mitochondrial indices including mitochondrial succinate dehydrogenase activity, mitochondrial membrane potential, mitochondrial swelling, reactive oxygen species, lipid peroxidation, and mitochondrial glutathione and ATP content were assessed. Results: NMT caused a decrease in succinate dehydrogenase activity, an increase in mitochondrial ROS formation, lipid peroxidation, and swelling along with the collapse of mitochondrial membrane potential in both in vitro and in vivo experiments. Moreover, the level of glutathione and ATP was lower in NMT-exposed mitochondria. Conclusion: Our data indicate that mitochondrial dysfunction might play a major role in the mechanism of liver injury induced by the methimazole hepatotoxic metabolite.

  5. Sirolimus-associated hepatotoxicity: case report and review of the literature

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    Macdonald B

    2012-01-01

    Full Text Available Brock Macdonald1, Evi Vakiani2, Rhonda K Yantiss3, Jun Lee4, Robert S Brown Jr5, Samuel H Sigal61Division of Gastroenterology, Department of Medicine, University of California-San Francisco, San Francisco, CA, 2Department of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY, 3Department of Pathology and Laboratory Medicine, New York Weill Cornell Medical College, New York, NY, 4Division of Nephrology, Department of Medicine, Weill Cornell Medical College, New York, NY, 5Division of Gastroenterology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 6Division of Gastroenterology and Hepatology, Department of Medicine, New York University, New York, NY, USAAbstract: The use of sirolimus as an alternative to calcineurin inhibitors for posttransplant immunosuppression is associated with a variety of inflammatory conditions. In this report, we describe the case of a 34-year-old man who developed abnormal liver tests 6 years after live-donor kidney transplantation and 5 years after initiation of sirolimus-based immunosuppression. Elevated aminotransferase levels persisted after withdrawal of potentially hepatotoxic medications, and serologic evaluation for viral hepatitis, autoimmune disease, and genetic disorders was unrevealing. Liver biopsy revealed prominent hepatocellular injury associated with a mixed inflammatory infiltrate and liver tests normalized within 2 weeks of discontinuation of sirolimus. In this report, we review previous reports of sirolimus hepatotoxicity and propose a unifying hypothesis for the various inflammatory conditions that have been attributed to sirolimus.Keywords: sirolimus, immunosuppression, transplant, inflammatory conditions, hepatotoxicity

  6. A critical analysis of the hepatotoxicity cases described in the literature related to Herbalife (r products

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    Flávio Ailton Duque Zambrone

    2015-12-01

    Full Text Available Abstract The aim of this study was to assess the hepatotoxicity cases described in the literature, attributed to the consumption of Herbalife(r products, and to determine whether a causal relationship exists between the reported cases of liver injury and the use of these products. A literature search was performed on the PubMed, LILACS and PAHO databases. Seven publications reporting a total of 53 cases of hepatotoxicity linked to the use of Herbalife(r products were retrieved. All of the studies lacked sufficient information to some degree, whether related to patients' history, concomitant use of medication and/or other compounds (including alcohol, observations on interrupted use (dechallenge, results found with markers, viral serology and autoantibodies or observations concerning re-exposure to the products. In addition to these items, the lack of clear information on the type of products evaluated and their respective composition is an important factor to be considered. Furthermore, data quality was also questionable due to the presence of confounding factors, absence of proper exclusion of alternative explanations, and the use of questionable methods for attributing causality. Hence, an association between hepatotoxicity and consumption of these products cannot be proven based on the data collected and rigorous scientific analysis.

  7. β-alanine supplementation improves YoYo intermittent recovery test performance.

    Science.gov (United States)

    Saunders, Bryan; Sunderland, Caroline; Harris, Roger C; Sale, Craig

    2012-08-28

    β-alanine supplementation has been shown to improve high-intensity exercise performance and capacity. However, the effects on intermittent exercise are less clear, with no effect shown on repeated sprint activity. The aim of this study was to investigate the effects of β-alanine supplementation on YoYo Intermittent Recovery Test Level 2 (YoYo IR2) performance. Seventeen amateur footballers were allocated to either a placebo (PLA; N = 8) or β-alanine (BA; N = 9) supplementation group, and performed the YoYo IR2 on two separate occasions, pre and post 12 weeks of supplementation during a competitive season. Specifically, players were supplemented from early to mid-season (PLA: N = 5; BA: N = 6) or mid- to the end of the season (PLA: N = 3; BA: N = 3). Data were analysed using a two factor ANOVA with Tukey post-hoc analyses. Pre supplementation scores were 1185 ± 216 and 1093 ± 148 m for PLA and BA, with no differences between groups (P = 0.41). YoYo performance was significantly improved for BA (+34.3%, P ≤ 0.001) but not PLA (-7.3%, P = 0.24) following supplementation. 2 of 8 (Early - Mid: 2 of 5; Mid - End: 0 of 3) players improved their YoYo scores in PLA (Range: -37.5 to + 14.7%) and 8 of 9 (Early - Mid: 6 of 6; Mid - End: 2 of 3) improved for BA (Range: +0.0 to +72.7%). 12 weeks of β-alanine supplementation improved YoYo IR2 performance, likely due to an increased muscle buffering capacity resulting in an attenuation of the reduction in intracellular pH during high-intensity intermittent exercise.

  8. β-alanine supplementation improves YoYo intermittent recovery test performance

    Directory of Open Access Journals (Sweden)

    Saunders Bryan

    2012-08-01

    Full Text Available Abstract Background β-alanine supplementation has been shown to improve high-intensity exercise performance and capacity. However, the effects on intermittent exercise are less clear, with no effect shown on repeated sprint activity. The aim of this study was to investigate the effects of β-alanine supplementation on YoYo Intermittent Recovery Test Level 2 (YoYo IR2 performance. Methods Seventeen amateur footballers were allocated to either a placebo (PLA; N = 8 or β-alanine (BA; N = 9 supplementation group, and performed the YoYo IR2 on two separate occasions, pre and post 12 weeks of supplementation during a competitive season. Specifically, players were supplemented from early to mid-season (PLA: N = 5; BA: N = 6 or mid- to the end of the season (PLA: N = 3; BA: N = 3. Data were analysed using a two factor ANOVA with Tukey post-hoc analyses. Results Pre supplementation scores were 1185 ± 216 and 1093 ± 148 m for PLA and BA, with no differences between groups (P = 0.41. YoYo performance was significantly improved for BA (+34.3%, P ≤ 0.001 but not PLA (−7.3%, P = 0.24 following supplementation. 2 of 8 (Early – Mid: 2 of 5; Mid – End: 0 of 3 players improved their YoYo scores in PLA (Range: -37.5 to + 14.7% and 8 of 9 (Early – Mid: 6 of 6; Mid – End: 2 of 3 improved for BA (Range: +0.0 to +72.7%. Conclusions 12 weeks of β-alanine supplementation improved YoYo IR2 performance, likely due to an increased muscle buffering capacity resulting in an attenuation of the reduction in intracellular pH during high-intensity intermittent exercise.

  9. β-alanine supplementation improves isometric endurance of the knee extensor muscles.

    Science.gov (United States)

    Sale, Craig; Hill, Chester A; Ponte, James; Harris, Roger C

    2012-06-14

    We examined the effect of four weeks of β-alanine supplementation on isometric endurance of the knee extensors at 45% maximal voluntary isometric contraction (MVIC). Thirteen males (age 23 ± 6 y; height 1.80 ± 0.05 m; body mass 81.0 ± 10.5 kg), matched for pre-supplementation isometric endurance, were allocated to either a placebo (n = 6) or β-alanine (n = 7; 6.4 g·d-1 over 4 weeks) supplementation group. Participants completed an isometric knee extension test (IKET) to fatigue, at an intensity of 45% MVIC, before and after supplementation. In addition, two habituation tests were completed in the week prior to the pre-supplementation test and a further practice test was completed in the week prior to the post-supplementation test. MVIC force, IKET hold-time, and impulse generated were recorded. IKET hold-time increased by 9.7 ± 9.4 s (13.2%) and impulse by 3.7 ± 1.3 kN·s-1 (13.9%) following β-alanine supplementation. These changes were significantly greater than those in the placebo group (IKET: t(11) = 2.9, p ≤0.05; impulse: t(11) = 3.1, p ≤ 0.05). There were no significant changes in MVIC force in either group. Four weeks of β-alanine supplementation at 6.4 g·d-1 improved endurance capacity of the knee extensors at 45% MVIC, which most likely results from improved pH regulation within the muscle cell as a result of elevated muscle carnosine levels.

  10. A COMPARATIVE STUDY ON THE ACTIVITY OF ALANIN-AMINOTRANSFERASE IN HYPOPHTHALMICHTHYS MOLITRIX AND ARISTICHTHYS NOBILIS

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    Gabriela Vasile

    2006-08-01

    Full Text Available The present paper represents a comparative study on the activity of one aminotransferase - alaninaminotransferase, in the digestive tube of Hypophthalmichthys molitrix (silver carp and Aristichthys nobilis (bighead carp. The enzymatic activity has been determined colorimetrically, with 2, 4 - dinitrophenyl hydrazine, the results obtained being expressed as UE / g / min. It was observed that, comparatively with the alanin-aminotransferase activity recorded in silver carp, in the case of bighead carp, the values recorded are much lower.

  11. Comparative characterization of Aedes 3-hydroxykynurenine transaminase/alanine glyoxylate transaminase and Drosophila serine pyruvate aminotransferase

    OpenAIRE

    Han, Qian; Li, Jianyong

    2002-01-01

    This study describes the comparative analysis of two insect recombinant aminotransferases, Aedes aegypti 3-hy-droxykynurenine (3-HK) transaminase/alanine glyoxylate aminotransferase (Ae-HKT/AGT) and Drosophila melanogaster serine pyruvate aminotransferase (Dm-Spat), which share 52% identity in their amino acid sequences. Both enzymes showed AGT activity. In addition, Ae-HKT/AGT is also able to catalyze the transamination of 3-HK or kynurenine with glyoxylate, pyruvate or oxaloacetate as the a...

  12. β-alanine supplementation improves isometric endurance of the knee extensor muscles

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    Sale Craig

    2012-06-01

    Full Text Available Abstract Background We examined the effect of four weeks of β-alanine supplementation on isometric endurance of the knee extensors at 45% maximal voluntary isometric contraction (MVIC. Methods Thirteen males (age 23 ± 6 y; height 1.80 ± 0.05 m; body mass 81.0 ± 10.5 kg, matched for pre-supplementation isometric endurance, were allocated to either a placebo (n = 6 or β-alanine (n = 7; 6.4 g·d-1 over 4 weeks supplementation group. Participants completed an isometric knee extension test (IKET to fatigue, at an intensity of 45% MVIC, before and after supplementation. In addition, two habituation tests were completed in the week prior to the pre-supplementation test and a further practice test was completed in the week prior to the post-supplementation test. MVIC force, IKET hold-time, and impulse generated were recorded. Results IKET hold-time increased by 9.7 ± 9.4 s (13.2% and impulse by 3.7 ± 1.3 kN·s-1 (13.9% following β-alanine supplementation. These changes were significantly greater than those in the placebo group (IKET: t(11 = 2.9, p ≤0.05; impulse: t(11 = 3.1, p ≤ 0.05. There were no significant changes in MVIC force in either group. Conclusion Four weeks of β-alanine supplementation at 6.4 g·d-1 improved endurance capacity of the knee extensors at 45% MVIC, which most likely results from improved pH regulation within the muscle cell as a result of elevated muscle carnosine levels.

  13. Muscle carnosine metabolism and beta-alanine supplementation in relation to exercise and training.

    Science.gov (United States)

    Derave, Wim; Everaert, Inge; Beeckman, Sam; Baguet, Audrey

    2010-03-01

    Carnosine is a dipeptide with a high concentration in mammalian skeletal muscle. It is synthesized by carnosine synthase from the amino acids L-histidine and beta-alanine, of which the latter is the rate-limiting precursor, and degraded by carnosinase. Recent studies have shown that the chronic oral ingestion of beta-alanine can substantially elevate (up to 80%) the carnosine content of human skeletal muscle. Interestingly, muscle carnosine loading leads to improved performance in high-intensity exercise in both untrained and trained individuals. Although carnosine is not involved in the classic adenosine triphosphate-generating metabolic pathways, this suggests an important role of the dipeptide in the homeostasis of contracting muscle cells, especially during high rates of anaerobic energy delivery. Carnosine may attenuate acidosis by acting as a pH buffer, but improved contractile performance may also be obtained by improved excitation-contraction coupling and defence against reactive oxygen species. High carnosine concentrations are found in individuals with a high proportion of fast-twitch fibres, because these fibres are enriched with the dipeptide. Muscle carnosine content is lower in women, declines with age and is probably lower in vegetarians, whose diets are deprived of beta-alanine. Sprint-trained athletes display markedly high muscular carnosine, but the acute effect of several weeks of training on muscle carnosine is limited. High carnosine levels in elite sprinters are therefore either an important genetically determined talent selection criterion or a result of slow adaptation to years of training. beta-Alanine is rapidly developing as a popular ergogenic nutritional supplement for athletes worldwide, and the currently available scientific literature suggests that its use is evidence based. However, many aspects of the supplement, such as the potential side effects and the mechanism of action, require additional and thorough investigation by the

  14. Partial alanine scan of mast cell degranulating peptide (MCD): importance of the histidine- and arginine residues.

    Science.gov (United States)

    Buku, Angeliki; Mendlowitz, Milton; Condie, Barry A; Price, Joseph A

    2004-06-01

    The influence of the two histidine and two arginine residues of mast cell degranulating peptide (MCD) in activity and binding was studied by replacing these amino acids in the MCD sequence with L-alanine. Their histamine releasing activity was determined on rat peritoneal mast cells. Their binding affinity to the FcepsilonRIalpha binding subunit of the human mast cell receptor protein, was carried out using fluorescence polarization. The histamine assay showed that replacement of His13 by Ala o ccurred without loss of activity compared with the activity of MCD. Alanine substitutions for Arg7 and His8 resulted in an approximately 40 fold increase, and for Arg16 in a 14-fold increase in histamine-releasing activity of MCD. The binding affinities of the analogs were tested by competitive displacement of bound fluorescent MCD peptide from the FcepsilonRIalpha binding protein of the mast cell receptor by the Ala analogs using fluorescence polarization. The analogs Ala8 (for His) and Ala16 (for Arg) showed the same binding affinities as MCD, whereas analog Ala7 (for Arg) and analog Ala13 (for His) showed slightly better binding affinity than the parent compound. This study showed that the introduction of alanine residues in these positions resulted in MCD agonists of diverse potency. These findings will be useful in further MCD structure-activity studies.

  15. Biomarkers in Airway Diseases

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    Janice M Leung

    2013-01-01

    Full Text Available The inherent limitations of spirometry and clinical history have prompted clinicians and scientists to search for surrogate markers of airway diseases. Although few biomarkers have been widely accepted into the clinical armamentarium, the authors explore three sources of biomarkers that have shown promise as indicators of disease severity and treatment response. In asthma, exhaled nitric oxide measurements can predict steroid responsiveness and sputum eosinophil counts have been used to titrate anti-inflammatory therapies. In chronic obstructive pulmonary disease, inflammatory plasma biomarkers, such as fibrinogen, club cell secretory protein-16 and surfactant protein D, can denote greater severity and predict the risk of exacerbations. While the multitude of disease phenotypes in respiratory medicine make biomarker development especially challenging, these three may soon play key roles in the diagnosis and management of airway diseases.

  16. amphibian_biomarker_data

    Data.gov (United States)

    U.S. Environmental Protection Agency — Amphibian metabolite data used in Snyder, M.N., Henderson, W.M., Glinski, D.G., Purucker, S. T., 2017. Biomarker analysis of american toad (Anaxyrus americanus) and...

  17. Acetaminophen Induced Hepatotoxicity in Wistar Rats—A Proteomic Approach

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    Soundharrajan Ilavenil

    2016-01-01

    Full Text Available Understanding the mechanism of chemical toxicity, which is essential for cross-species and dose extrapolations, is a major challenge for toxicologists. Standard mechanistic studies in animals for examining the toxic and pathological changes associated with the chemical exposure have often been limited to the single end point or pathways. Toxicoproteomics represents a potential aid to the toxicologist to understand the multiple pathways involved in the mechanism of toxicity and also determine the biomarkers that are possible to predictive the toxicological response. We performed an acute toxicity study in Wistar rats with the prototype liver toxin; the acetaminophen (APAP effects on protein profiles in the liver and its correlation with the plasma biochemical markers for liver injury were analyzed. Three separate groups—control, nontoxic (150 mg/kg and toxic dose (1500 mg/kg of APAP—were studied. The proteins extracted from the liver were separated by 2-DE and analyzed by MALDI-TOF. The differential proteins in the gels were analyzed by BIORAD’s PDQuest software and identified by feeding the peptide mass fingerprint data to various public domain programs like Mascot and MS-Fit. The identified proteins in toxicity-induced rats were classified based on their putative protein functions, which are oxidative stress (31%, immunity (14%, neurological related (12% and transporter proteins (2%, whereas in non-toxic dose-induced rats they were  oxidative stress (9%, immunity (6%, neurological (14% and transporter proteins (9%. It is evident that the percentages of oxidative stress and immunity-related proteins were up-regulated in toxicity-induced rats as compared with nontoxic and control rats. Some of the liver drug metabolizing and detoxifying enzymes were depleted under toxic conditions compared with non-toxic rats. Several other proteins were identified as a first step in developing an in-house rodent liver toxicoproteomics database.

  18. Theranostic Biomarkers for Schizophrenia

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    Matea Nikolac Perkovic

    2017-03-01

    Full Text Available Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.

  19. Theranostic Biomarkers for Schizophrenia

    Science.gov (United States)

    Nikolac Perkovic, Matea; Nedic Erjavec, Gordana; Svob Strac, Dubravka; Uzun, Suzana; Kozumplik, Oliver; Pivac, Nela

    2017-01-01

    Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide. PMID:28358316

  20. Luminally expressed gastrointestinal biomarkers.

    Science.gov (United States)

    Cummins, Gerard; Yung, Diana E; Cox, Ben F; Koulaouzidis, Anastasios; Desmulliez, Marc P Y; Cochran, Sandy

    2017-12-01

    A biomarker is a measurable indicator of normal biologic processes, pathogenic processes or pharmacological responses. The identification of a useful biomarker is challenging, with several hurdles to overcome before clinical adoption. This review gives a general overview of a range of biomarkers associated with inflammatory bowel disease or colorectal cancer along the gastrointestinal tract. Areas covered: These markers include those that are already clinically accepted, such as inflammatory markers such as faecal calprotectin, S100A12 (Calgranulin C), Fatty Acid Binding Proteins (FABP), malignancy markers such as Faecal Occult Blood, Mucins, Stool DNA, Faecal microRNA (miRNA), other markers such as Faecal Elastase, Faecal alpha-1-antitrypsin, Alpha2-macroglobulin and possible future markers such as microbiota, volatile organic compounds and pH. Expert commentary: There are currently a few biomarkers that have been sufficiently validated for routine clinical use at present such as FC. However, many of these biomarkers continue to be limited in sensitivity and specificity for various GI diseases. Emerging biomarkers have the potential to improve diagnosis and monitoring but further study is required to determine efficacy and validate clinical utility.

  1. Theranostic Biomarkers for Schizophrenia.

    Science.gov (United States)

    Perkovic, Matea Nikolac; Erjavec, Gordana Nedic; Strac, Dubravka Svob; Uzun, Suzana; Kozumplik, Oliver; Pivac, Nela

    2017-03-30

    Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.

  2. Alanine aminotransferase, gamma-glutamyltransferase (GGT) and all-cause mortality: results from a population-based Danish twins study alanine aminotransferase, GGT and mortality in elderly twins

    DEFF Research Database (Denmark)

    Fraser, Abigail; Thinggaard, Mikael; Christensen, Kaare

    2009-01-01

    Abstract Background/Aims: Alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) are widely used markers of liver disease. Several population-based cohort studies have found associations of these liver enzymes with all-cause mortality. None of these studies controlled for genetic...... variation as well as fetal and early life exposure, whether environmental or genetic. Methods: We studied the associations of ALT and GGT with all-cause mortality using data for 686 twins (73-94 years old) included in the Longitudinal Study of Aging Danish Twins. Results: An increase in 1 logged U/L of GGT...... was associated with a 15% increase in the hazard ratio (HR) for mortality [95% confidence interval (CI) 0.99, 1.32] but there was no strong evidence of an association of ALT with all-cause mortality (HR=1.07, 95% CI 0.82, 1.40) when controlling for potential confounders. In this analysis, the study population...

  3. Integrative assessment of biomarker responses in teleostean fishes exposed to glyphosate-based herbicide (Excel Mera 71)

    OpenAIRE

    Dey, Sukhendu; Samanta, Palas; Pal, Sandipan; Mukherjee, Aloke Kumar; Kole, Debraj; Ghosh, Apurba Ratan

    2016-01-01

    Present study deals with the effects of glyphosate-based herbicide, Excel Mera 71 on Anabas testudineus, Heteropnestes fossilis and Oreochromis niloticus in field conditions (1.85 kg/ha) based on anti-oxidative, metabolic and digestive responses. For this study following biomarkers viz., acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, l...

  4. The Relation between Hepatotoxicity and the Total Coumarin Intake from Traditional Japanese Medicines Containing Cinnamon Bark

    Science.gov (United States)

    Iwata, Naohiro; Kainuma, Mosaburo; Kobayashi, Daisuke; Kubota, Toshio; Sugawara, Naoko; Uchida, Aiko; Ozono, Sahoko; Yamamuro, Yuki; Furusyo, Norihiro; Ueda, Koso; Tahara, Eiichi; Shimazoe, Takao

    2016-01-01

    Cinnamon bark is commonly used in traditional Japanese herbal medicines (Kampo medicines). The coumarin contained in cinnamon is known to be hepatotoxic, and a tolerable daily intake (TDI) of 0.1 mg/kg/day, has been quantified and used in Europe to insure safety. Risk assessments for hepatotoxicity by the cinnamon contained in foods have been reported. However, no such assessment of cinnamon bark has been reported and the coumarin content of Kampo medicines derived from cinnamon bark is not yet known. To assess the risk for hepatotoxicity by Kampo medicines, we evaluated the daily coumarin intake of patients who were prescribed Kampo medicines and investigated the relation between hepatotoxicity and the coumarin intake. The clinical data of 129 outpatients (18 male and 111 female, median age 58 years) who had been prescribed keishibukuryogankayokuinin (TJ-125) between April 2008 and March 2013 was retrospectively investigated. Concurrent Kampo medicines and liver function were also surveyed. In addition to TJ-125, the patients took some of the other 32 Kampo preparations and 22 decoctions that include cinnamon bark. The coumarin content of these Kampo medicines was determined by high performance liquid chromatography (HPLC). TJ-125 had the highest daily content of coumarin (5.63 mg/day), calculated from the daily cinnamon bark dosage reported in the information leaflet inserted in each package of Kampo medicine. The coumarin content in 1g cinnamon bark decoction was 3.0 mg. The daily coumarin intake of the patients was 0.113 (0.049–0.541) mg/kg/day, with 98 patients (76.0%) exceeding the TDI. Twenty-three patients had an abnormal change in liver function test value, but no significant difference was found in the incidence of abnormal change between the group consuming less than the TDI value (6/31, 19.4%) and the group consuming equal to or greater than the TDI value (17/98, 17.3%). In addition, no abnormal change related to cinnamon bark was found for individual

  5. Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

    Energy Technology Data Exchange (ETDEWEB)

    Gandhi, Adarsh, E-mail: adarsh.gandhi@nih.gov [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Guo, Tao, E-mail: tguo4@jhu.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Shah, Pranav [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Moorthy, Bhagavatula [Baylor College of Medicine, Department of Pediatrics, 1102 Bates Avenue, Suite 530, Houston, TX 77030 (United States); Ghose, Romi, E-mail: rghose@uh.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States)

    2013-02-01

    Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP{sup +/+} and TIRAP{sup −/−} mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP{sup +/+} mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP{sup −/−} mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies

  6. A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose

    Directory of Open Access Journals (Sweden)

    Kalsi SS

    2011-12-01

    Full Text Available Sarbjeet S Kalsi1,2, Paul I Dargan2–4, W Stephen Waring5, David M Wood2–41Emergency Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3King’s Health Partners, London, UK; 4King’s College London, London, UK; 5York Teaching Hospital NHS Foundation Trust, York, UKAbstract: Paracetamol (acetaminophen poisoning is common throughout the world. The management of nonstaggered (acute paracetamol overdose is based on the plasma paracetamol concentration plotted on a treatment nomogram. In the UK there are two treatment lines on this nomogram, with the lower treatment line used for individuals felt to be at ‘high risk’ of paracetamol-related hepatotoxicity either as a result of induction of cytochrome P450 isoenzymes or reduction of intrahepatic glutathione. In this article we review the risk factors that, in current guidelines, are felt to increase risk due to a reduction in intrahepatic glutathione concentrations. Based on our review of the published literature, we feel that cystic fibrosis, acute viral illness, malnutrition, and eating disorders such as anorexia nervosa are likely to be associated with reduction in intrahepatic glutathione concentrations, and that this risk is likely to be related to malnutrition secondary to the disease. Chronic hepatitis C infection is also associated with reduced glutathione concentrations, although this appears to be independent of any associated malnutrition. Ageing and acute fasting are not associated with an increased risk of paracetamol-related hepatotoxicity due to reductions in glutathione concentrations. Finally, the evidence for HIV infection is inconclusive, particularly as the majority of studies were conducted in the pre-anti-viral treatment (HAART era; however it is likely that patients with symptomatic HIV/AIDS have reduced glutathione concentrations due to associated malnutrition. Although

  7. Differential effects of sodium acetoacetate and acetoacetic acid infusions on alanine and glutamine metabolism in man.

    Science.gov (United States)

    Féry, F; Balasse, E O

    1980-08-01

    It has been suggested that ketone bodies might participate in the nitrogen-sparing process occurring during prolonged starvation by inhibiting the muscular production of alanine and glutamine, which are the main gluconeogenic amino acids. The results of the ketone infusion studies on which this theory is based have been reevaluated in this study by following the plasma levels of ketone bodies, alanine, glutamine, and other substrates during 11.5 h in five groups of normal overnight-fasted subjects. Subjects of groups I, II, and III were infused for 3 h, respectively, with Na acetoacetate, Na bicarbonate, or free acetoacetic acid administered in comparable amounts (about 20 mumol/kg per min), whereas group IV was infused with hydrochloric acid (7.0 mumol/kg per min). A control group (V) received no infusion. Na acetoacetate induced a rise in blood pH (+0.1+/-0.003) and a fall in the plasma levels of alanine (-41.8+/-4.6%) and glutamine (-10.6+/-1.4%), whereas free acetoacetic acid had a barely detectable lowering effect on blood pH and induced a rise in alanine (+22.5+/-8.0%) and glutamine (+14.6+/-3.2%) levels. Both infusions were associated with a lowering of plasma glucose, which therefore seems independent of the changes in alanine and glutamine concentrations. Sodium bicarbonate reproduced the alkalinizing effect and the hypoalaninemic action of Na acetoacetate, which seems thus unrelated to hyperketonemia. On the other hand, acidification of blood with hydrochloric acid did not mimic the effects of acetoacetic acid. If the hyperalaninemic and hyperglutaminemic effects of ketone bodies infused in their physiological form (free acids) reflect a stimulation of the muscular output of these amino acids, the participation of ketone bodies in the nitrogen-sparing process of prolonged fasting seems very unlikely. On the other hand, during brief starvation, when both ketogenesis and gluconeogenesis are markedly stimulated, ketone bodies might indirectly contribute in

  8. Histological and biochemical markers of the liver of male Wistar rats ...

    African Journals Online (AJOL)

    Background: Mechanism of action of nevirapine in the prophylaxis treatment and treatment of HIV-1 may involve elevations in levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and other biomarkers of liver function. This study presents the hepatotoxic effect of nevirapine suspension ...

  9. Effect of antiretroviral therapy on some liver enzymes in HIV/AIDS ...

    African Journals Online (AJOL)

    The relationship and effect of antiretroviral therapy with associated hepatotoxicity were investigated in different paediatric age groups using serum alanine and aspartate transaminases (ALT and AST) and alkaline phosphates (ALP) biomarkers. The study consisted of a total of one hundred and twenty (120) participants; ...

  10. Alanine with the Precipitate of Tomato Juice Administered to Rats Enhances the Reduction in Blood Ethanol Levels

    Directory of Open Access Journals (Sweden)

    Shunji Oshima

    2015-01-01

    Full Text Available Delay in gastric emptying (GE lowers the blood ethanol concentration (BEC after alcohol administration. We previously demonstrated that water-insoluble fractions, mainly comprising dietary fiber derived from many types of botanical foods, possessed the ability to absorb ethanol-containing aqueous solutions. Furthermore, there was a significant correlation between the absorption of ethanol and lowering of BEC because of delay in GE. Here we identified dietary nutrients that synergize with the water-insoluble fraction of tomatoes to lower BEC in rats. Consequently, unlike tomato juice without alanine, tomato juice with 5.0% alanine decreased BEC depending on the delay in GE and mediated the ethanol-induced decrease in the spontaneous motor activity (an indicator of drunkenness. Our findings indicate that the synergism between tomato juice and alanine to reduce the absorption of ethanol was attributable to the effect of alanine on precipitates such as the water-insoluble fraction of tomatoes.

  11. Volatile components formed from reaction of sugar and beta-alanine as a model system of cookie processing.

    Science.gov (United States)

    Nishibori, S; Berhnard, R A; Osawa, T; Kawakishi, S

    1998-01-01

    Volatile components formed from the reaction of monosaccharides or disaccharides with beta-alanine were investigated in a dry condition as a model system of cookie processing. Maltol is a common compound formed in the Maillard reaction, but it was very difficult to detect it in previous experiments using actual cookie materials. In this work, we investigated the principal compounds and maltol formation from the reaction of monosaccharides or disaccharides with beta-alanine at 150 degrees C for 10 min. Neither the reaction of monosaccharides nor the disaccharides with beta-alanine resulted in the formation of maltol. 2,3-Dihydro-3,5-dihydroxy-6-methyl-4(H)-pyran-4-one (DDMP) was detected as a principal product from the reaction of monosaccharides with beta-alanine. 5-Hydroxymethyl-2-furfural was also confirmed as being a major product in both reactions.

  12. Ginger for Prevention of Antituberculosis-induced Gastrointestinal Adverse Reactions Including Hepatotoxicity: A Randomized Pilot Clinical Trial.

    Science.gov (United States)

    Emrani, Zahra; Shojaei, Esphandiar; Khalili, Hossein

    2016-06-01

    In this study, the potential benefits of ginger in preventing antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity have been evaluated in patients with tuberculosis. Patients in the ginger and placebo groups (30 patients in each group) received either 500 mg ginger (Zintoma)(®) or placebo one-half hour before each daily dose of antituberculosis drugs for 4 weeks. Patients' gastrointestinal complaints (nausea, vomiting, dyspepsia, and abdominal pain) and antituberculosis drug-induced hepatotoxicity were recorded during the study period. In this cohort, nausea was the most common antituberculosis drug-induced gastrointestinal adverse reactions. Forty eight (80%) patients experienced nausea. Nausea was more common in the placebo than the ginger group [27 (90%) vs 21 (70%), respectively, p = 0.05]. During the study period, 16 (26.7%) patients experienced antituberculosis drug-induced hepatotoxicity. Patients in the ginger group experienced less, but not statistically significant, antituberculosis drug-induced hepatotoxicity than the placebo group (16.7% vs 36.7%, respectively, p = 0.07). In conclusion, ginger may be a potential option for prevention of antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  13. Inhibiting Inosine Hydrolase and Alanine Racemase to Enhance the Germination of Bacillus anthracis Sterne Spores: Potential Spore Decontamination Strategies

    Science.gov (United States)

    2015-06-19

    2015): << Inhibiting inosine hydrolase and alanine racemase to enhance the germination of Bacillus anthracis Sterne spores: potential spore...display a currently valid OMB control number. 1. REPORT DATE 02 OCT 2015 2. REPORT TYPE N/A 3. DATES COVERED 4. TITLE AND SUBTITLE Inhibiting...inosine hydrolase and alanine racemase to enhance the germination of Bacillus anthracis Sterne spores potential spore decontamination strategies 5a

  14. Biomarkers of sepsis

    Science.gov (United States)

    2013-01-01

    Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate’s effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high. PMID:23480440

  15. Biomarkers intersect with the exposome.

    Science.gov (United States)

    Rappaport, Stephen M

    2012-09-01

    The exposome concept promotes use of omic tools for discovering biomarkers of exposure and biomarkers of disease in studies of diseased and healthy populations. A two-stage scheme is presented for profiling omic features in serum to discover molecular biomarkers and then for applying these biomarkers in follow-up studies. The initial component, referred to as an exposome-wide-association study (EWAS), employs metabolomics and proteomics to interrogate the serum exposome and, ultimately, to identify, validate and differentiate biomarkers of exposure and biomarkers of disease. Follow-up studies employ knowledge-driven designs to explore disease causality, prevention, diagnosis, prognosis and treatment.

  16. Oxygen radical-mediated oxidation reactions of an alanine peptide motif - density functional theory and transition state theory study.

    Science.gov (United States)

    Chen, Hsing-Yu; Jang, Soonmin; Jinn, Tzyy-Rong; Chang, Jia-Yaw; Lu, Hsiu-Feng; Li, Feng-Yin

    2012-04-24

    Oxygen-base (O-base) oxidation in protein backbone is important in the protein backbone fragmentation due to the attack from reactive oxygen species (ROS). In this study, an alanine peptide was used model system to investigate this O-base oxidation by employing density functional theory (DFT) calculations combining with continuum solvent model. Detailed reaction steps were analyzed along with their reaction rate constants. Most of the O-base oxidation reactions for this alanine peptide are exothermic except for the bond-breakage of the Cα-N bond to form hydroperoxy alanine radical. Among the reactions investigated in this study, the activated energy of OH α-H abstraction is the lowest one, while the generation of alkylperoxy peptide radical must overcome the highest energy barrier. The aqueous situation facilitates the oxidation reactions to generate hydroxyl alanine peptide derivatives except for the fragmentations of alkoxyl alanine peptide radical. The Cα-Cβ bond of the alkoxyl alanine peptide radical is more labile than the peptide bond. the rate-determining step of oxidation in protein backbone is the generation of hydroperoxy peptide radical via the reaction of alkylperoxy peptide radical with HO2. The stabilities of alkylperoxy peptide radical and complex of alkylperoxy peptide radical with HO2 are crucial in this O-base oxidation reaction.

  17. Oxygen radical-mediated oxidation reactions of an alanine peptide motif - density functional theory and transition state theory study

    Directory of Open Access Journals (Sweden)

    Chen Hsing-Yu

    2012-04-01

    Full Text Available Abstract Background Oxygen-base (O-base oxidation in protein backbone is important in the protein backbone fragmentation due to the attack from reactive oxygen species (ROS. In this study, an alanine peptide was used model system to investigate this O-base oxidation by employing density functional theory (DFT calculations combining with continuum solvent model. Detailed reaction steps were analyzed along with their reaction rate constants. Results Most of the O-base oxidation reactions for this alanine peptide are exothermic except for the bond-breakage of the Cα-N bond to form hydroperoxy alanine radical. Among the reactions investigated in this study, the activated energy of OH α-H abstraction is the lowest one, while the generation of alkylperoxy peptide radical must overcome the highest energy barrier. The aqueous situation facilitates the oxidation reactions to generate hydroxyl alanine peptide derivatives except for the fragmentations of alkoxyl alanine peptide radical. The Cα-Cβ bond of the alkoxyl alanine peptide radical is more labile than the peptide bond. Conclusion the rate-determining step of oxidation in protein backbone is the generation of hydroperoxy peptide radical via the reaction of alkylperoxy peptide radical with HO2. The stabilities of alkylperoxy peptide radical and complex of alkylperoxy peptide radical with HO2 are crucial in this O-base oxidation reaction.

  18. Alanine scan of core positions in ubiquitin reveals links between dynamics, stability, and function.

    Science.gov (United States)

    Lee, Shirley Y; Pullen, Lester; Virgil, Daniel J; Castañeda, Carlos A; Abeykoon, Dulith; Bolon, Daniel N A; Fushman, David

    2014-04-03

    Mutations at solvent-inaccessible core positions in proteins can impact function through many biophysical mechanisms including alterations to thermodynamic stability and protein dynamics. As these properties of proteins are difficult to investigate, the impacts of core mutations on protein function are poorly understood for most systems. Here, we determined the effects of alanine mutations at all 15 core positions in ubiquitin on function in yeast. The majority (13 of 15) of alanine substitutions supported yeast growth as the sole ubiquitin. Both the two null mutants (I30A and L43A) were less stable to temperature-induced unfolding in vitro than wild type (WT) but were well folded at physiological temperatures. Heteronuclear NMR studies indicated that the L43A mutation reduces temperature stability while retaining a ground-state structure similar to WT. This structure enables L43A to bind to common ubiquitin receptors in vitro. Many of the core alanine ubiquitin mutants, including one of the null variants (I30A), exhibited an increased accumulation of high-molecular-weight species, suggesting that these mutants caused a defect in the processing of ubiquitin-substrate conjugates. In contrast, L43A exhibited a unique accumulation pattern with reduced levels of high-molecular-weight species and undetectable levels of free ubiquitin. When conjugation to other proteins was blocked, L43A ubiquitin accumulated as free ubiquitin in yeast. Based on these findings, we speculate that ubiquitin's stability to unfolding may be required for efficient recycling during proteasome-mediated substrate degradation. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. 3-Hydroxykynurenine transaminase identity with alanine glyoxylate transaminase. A probable detoxification protein in Aedes aegypti.

    Science.gov (United States)

    Han, Qian; Fang, Jianmin; Li, Jianyong

    2002-05-03

    This study describes the functional characterization of a specific mosquito transaminase responsible for catalyzing the transamination of 3-hydroxykynurenine (3-HK) to xanthurenic acid (XA). The enzyme was purified from Aedes aegypti larvae by ammonium sulfate fractionation, heat treatment, and various chromatographic techniques, plus non-denaturing electrophoresis. The purified transaminase has a relative molecular mass of 42,500 by SDS-PAGE. N-terminal and internal sequencing of the purified protein and its tryptic fragments resolved a partial N-terminal sequence of 19 amino acid residues and 3 partial internal peptide sequences with 7, 10, and 7 amino acid residues. Using degenerate primers based on the partial internal sequences for PCR amplification and cDNA library screening, a full-length cDNA clone with a 1,167-bp open reading frame was isolated. Its deduced amino acid sequence consists of 389 amino acid residues with a predicted molecular mass of 43,239 and shares 45-46% sequence identity with mammalian alanine glyoxylate transaminases. Northern analysis shows the active transcription of the enzyme in larvae and developing eggs. Substrate specificity analysis of this mosquito transaminase demonstrates that the enzyme is active with 3-HK, kynurenine, or alanine substrates. The enzyme has greater affinity and catalytic efficiency for 3-HK than for kynurenine and alanine. The biochemical characteristics of the enzyme in conjunction with the profiles of 3-HK transaminase activity and XA accumulation during mosquito development clearly point out its physiological function in the 3-HK to XA pathway. Our data suggest that the mosquito transaminase was evolved in a manner precisely reflecting the physiological requirement of detoxifying 3-HK produced in the tryptophan oxidation pathway in the mosquito.

  20. Inflammatory biomarkers and cancer

    DEFF Research Database (Denmark)

    Rasmussen, Line Jee Hartmann; Schultz, Martin; Gaardsting, Anne

    2017-01-01

    soluble urokinase plasminogen activator receptor (suPAR) and the pattern recognition receptors (PRRs) pentraxin-3, mannose-binding lectin, ficolin-1, ficolin-2 and ficolin-3. We aimed to evaluate these biomarkers and compare their diagnostic ability to classical biomarkers for diagnosing cancer......In Denmark, patients with serious nonspecific symptoms and signs of cancer (NSSC) are referred to the diagnostic outpatient clinics (DOCs) where an accelerated cancer diagnostic program is initiated. Various immunological and inflammatory biomarkers have been associated with cancer, including...... in patients with NSSC. Patients were included from the DOC, Department of Infectious Diseases, Copenhagen University Hospital Hvidovre. Patients were given a final diagnosis based on the combined results from scans, blood work and physical examination. Weight loss, Charlson score and previous cancer were...

  1. Biomarkers of the Dementia

    Directory of Open Access Journals (Sweden)

    Mikio Shoji

    2011-01-01

    Full Text Available Recent advances in biomarker studies on dementia are summarized here. CSF Aβ40, Aβ42, total tau, and phosphorylated tau are the most sensitive biomarkers for diagnosis of Alzheimer's disease (AD and prediction of onset of AD from mild cognitive impairment (MCI. Based on this progress, new diagnostic criteria for AD, MCI, and preclinical AD were proposed by National Institute of Aging (NIA and Alzheimer's Association in August 2010. In these new criteria, progress in biomarker identification and amyloid imaging studies in the past 10 years have added critical information. Huge contributions of basic and clinical studies have established clinical evidence supporting these markers. Based on this progress, essential therapy for cure of AD is urgently expected.

  2. Towards Improved Biomarker Research

    DEFF Research Database (Denmark)

    Kjeldahl, Karin

    This thesis takes a look at the data analytical challenges associated with the search for biomarkers in large-scale biological data such as transcriptomics, proteomics and metabolomics data. These studies aim to identify genes, proteins or metabolites which can be associated with e.g. a diet...... to actually identify strong biomarkers when strict validation is applied; the latter phenomenon is to some extentmasked by a publication bias, but has been widely observed among researchers working with omics data. In this thesis, the background of this apparent small effect size of the biomarkers...... is investigated and followed by some suggestions which can potentially improve the chances of a successful outcome of an omics study. A method widely applied in the analysis of omics studies is Partial Least Squares (PLS) regression which is one of the work horses within the chemometrics tool box; a method which...

  3. β-N-methylamino-L-alanine enhances neurotoxicity through multiple mechanisms

    OpenAIRE

    Lobner, Doug; Piana, Peachy Mae T.; Salous, Abed K.; Peoples, Robert W.

    2006-01-01

    The idea that the environmental toxin β-N-methylamino-L-alanine (BMAA) is involved in neurodegenerative diseases on Guam has risen and fallen over the years. The theory has gained greater interest with recent reports that BMAA is biomagnified, is widely distributed around the planet, and is present in the brains of Alzheimer’s patients in Canada. We provide two important new findings. First, we show that BMAA at concentrations as low as 10 µM can potentiate neuronal injury induced by other in...

  4. A Novel Synthetic Approach to C-Glycosyl-D- and L-Alanines

    Directory of Open Access Journals (Sweden)

    Miroslava Martinková

    2008-12-01

    Full Text Available C-Glycosyl-(S- and (R-alanines 12a and 12b were synthesized from the known β-C-glycoside 1. The nitrogen function was introduced by aza-Claisen rearrangement of the allylic thiocyanate 7, derived from the corresponding alcohol 6. The absolute configuration of the newly created chiral carbon center (C-3 was assigned by X-ray diffraction analysis of the intermediate 3(S-isothiocyanato-D-glycero-D-galacto-decose 8a.

  5. Crystallization and preliminary X-ray data analysis of beta-alanine synthase from Drosophila melanogaster.

    Science.gov (United States)

    Lundgren, Stina; Andersen, Birgit; Piskur, Jure; Dobritzsch, Doreen

    2007-10-01

    Beta-alanine synthase catalyzes the last step in the reductive degradation pathway for uracil and thymine, which represents the main clearance route for the widely used anticancer drug 5-fluorouracil. Crystals of the recombinant enzyme from Drosophila melanogaster, which is closely related to the human enzyme, were obtained by the hanging-drop vapour-diffusion method. They diffracted to 3.3 A at a synchrotron-radiation source, belong to space group C2 (unit-cell parameters a = 278.9, b = 95.0, c = 199.3 A, beta = 125.8 degrees) and contain 8-10 molecules per asymmetric unit.

  6. Comparative characterization of Aedes 3-hydroxykynurenine transaminase/alanine glyoxylate transaminase and Drosophila serine pyruvate aminotransferase.

    Science.gov (United States)

    Han, Qian; Li, Jianyong

    2002-09-11

    This study describes the comparative analysis of two insect recombinant aminotransferases, Aedes aegypti 3-hydroxykynurenine (3-HK) transaminase/alanine glyoxylate aminotransferase (Ae-HKT/AGT) and Drosophila melanogaster serine pyruvate aminotransferase (Dm-Spat), which share 52% identity in their amino acid sequences. Both enzymes showed AGT activity. In addition, Ae-HKT/AGT is also able to catalyze the transamination of 3-HK or kynurenine with glyoxylate, pyruvate or oxaloacetate as the amino acceptor. Kinetic analysis and other data suggest that Ae-HKT/AGT plays a critical role in mosquito tryptophan catabolism by detoxifying 3-HK and that Dm-Spat is primarily involved in glyoxylate detoxification.

  7. Volume dose ratios relevant for alanine dosimetry in small, 6 MV photon beams

    DEFF Research Database (Denmark)

    Cronholm, Rickard O.; Andersen, Claus Erik; Behrens, Claus F.

    2012-01-01

    The overall objective of this work is to establish alanine dosimetry for traceable measurements in clinical radiotherapy beams, in particular for non-reference situations such as small field sizes and composite beam delivery (e.g. intensity modulated radiotherapy and volumetric modulated arc...... therapy). To this end, we here present the results of a Monte Carlo simulation study with DOSRZnrc that investigated the influence of field and detector size for small 6 MV photon beams. The study focusses on doses averaged over the volume of the detector rather than point doses.The ratio of volume...

  8. Biomarkers of kidney injury.

    Science.gov (United States)

    Urbschat, Anja; Obermüller, Nicholas; Haferkamp, Axel

    2011-07-01

    Acute kidney injury (AKI) represents a common serious clinical problem. Up to date mortality due to AKI, especially in intensive care units, has not been changed significantly over the past 50 years. This is partly due to a delay in initiating renal protective and appropriate therapeutic measures since until now there are no reliable early-detecting biomarkers. The gold standard, serum creatinine, displays poor specificity and sensitivity with regard to recognition of the early period of AKI. Our objective was to review established markers versus novel urine and serum biomarkers of AKI in humans, which have progressed to clinical phase with regard to their diagnostic and prognostic value. A review was performed on the basis of literature search of renal failure, acute kidney injury, and biomarkers in Pubmed. Next to established biomarkers as creatinine and cystatin C, other molecules such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), monocyte chemotactic peptide (MCP-1), Netrin-1, and interleukin (IL)-18 are available and represent promising new markers that, however, need to be further evaluated in the clinical setting for suitability. In clinical settings with incipient AKI, not only the development and the implementation of more sensitive biomarkers are required for earlier treatment initiation in order to attenuate the severity of kidney injury, but also equally important remains the substantial improvement and application of refined and prophylactic therapeutic options in these situations. Adequately powered clinical trials testing a row of biomarkers are warranted before they may qualify for full adoption in clinical practice.

  9. Amelioration of Prallethrin-Induced Oxidative Stress and Hepatotoxicity in Rat by the Administration of Origanum majorana Essential Oil

    Directory of Open Access Journals (Sweden)

    Abdel-Tawab H. Mossa

    2013-01-01

    Full Text Available This study was carried out to evaluate the adverse effects of exposure to prallethrin on oxidant/antioxidant status and liver dysfunction biomarkers and the protective role of Origanum majorana essential oil (EO in rat. Male rats were divided into 4 groups: (i received only olive oil (ii treated with 64.0 mg/kg body weight prallethrin (1/10 LD50 in olive oil via oral route daily for 28 days, (iii treated with 64.0 mg/kg body weight prallethrin (1/10 LD50 and EO (160 μL/kg b.wt. in olive oil and (iv received EO (160 μL/kg b.wt. in olive oil via oral route twice daily for 28 days. Prallethrin treatment caused decrease in body weight gain and increase in relative liver weight. There was a significant increase in the activity of serum marker enzymes, aspartate transaminase, alanine transaminase, and alkaline phosphatase. It caused increase in thiobarbituric acid reactive substances and reduction in the activities of superoxide dismutase, catalase, and glutathione-S-transferase in liver. Consistent histological changes were found in the liver of prallethrin treatment. EO showed significant protection with the depletion of serum marker enzymes and replenishment of antioxidant status and brought all the values to near normal, indicating the protective effect of EO. We can conclude that prallethrin caused oxidative damage and liver injury in male rat and co-administration of EO attenuated the toxic effect of prallethrin. These results demonstrate that administration of EO may be useful, easy, and economical to protect human against pyrethroids toxic effects.

  10. Amelioration of Prallethrin-Induced Oxidative Stress and Hepatotoxicity in Rat by the Administration of Origanum majorana Essential Oil

    Science.gov (United States)

    Mossa, Abdel-Tawab H.; Refaie, Amel A.; Ramadan, Amal; Bouajila, Jalloul

    2013-01-01

    This study was carried out to evaluate the adverse effects of exposure to prallethrin on oxidant/antioxidant status and liver dysfunction biomarkers and the protective role of Origanum majorana essential oil (EO) in rat. Male rats were divided into 4 groups: (i) received only olive oil (ii) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) in olive oil via oral route daily for 28 days, (iii) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) and EO (160 μL/kg b.wt.) in olive oil and (iv) received EO (160 μL/kg b.wt.) in olive oil via oral route twice daily for 28 days. Prallethrin treatment caused decrease in body weight gain and increase in relative liver weight. There was a significant increase in the activity of serum marker enzymes, aspartate transaminase, alanine transaminase, and alkaline phosphatase. It caused increase in thiobarbituric acid reactive substances and reduction in the activities of superoxide dismutase, catalase, and glutathione-S-transferase in liver. Consistent histological changes were found in the liver of prallethrin treatment. EO showed significant protection with the depletion of serum marker enzymes and replenishment of antioxidant status and brought all the values to near normal, indicating the protective effect of EO. We can conclude that prallethrin caused oxidative damage and liver injury in male rat and co-administration of EO attenuated the toxic effect of prallethrin. These results demonstrate that administration of EO may be useful, easy, and economical to protect human against pyrethroids toxic effects. PMID:24381944

  11. Effect of imidacloprid on hepatotoxicity and nephrotoxicity in male albino mice

    Directory of Open Access Journals (Sweden)

    Yasir Arfat

    2014-01-01

    Full Text Available Imidacloprid (IC is a systemic insecticide related to the tobacco toxin nicotine. IC is a toxic substance frequently used into combat insects, rodents and plants pests and other creatures that can pose problems for agriculture. We, therefore, planned this study to assess risk factors, biochemical and histological alterations associated with hepatotoxicity and nephrotoxicity. Forty-eight adult male albino mice were divided into four groups of 12 animals each. All the animals were given standard synthetic pellet diet. One group served as control, and the other three were served as experimental groups. Decrease in the body weight of the high dose group was observed at 15 mg/kg/day, and no mortality occurred during the treatment period. High dose of imidacloprid caused a significant elevation of serum clinical chemistry parameters, serum glutamic oxaloacetic transaminase (SGOT, serum glutamic pyruvate kinase (SGPT, alkaline phosphatase (ALP and total bilirubin (TBIL. Histology of liver and kidney indicates hepatotoxicity and nephrotoxicity at a high dose of imidacloprid. Based on the morphological, biochemical and histopathological analysis, it is evident that imidacloprid induced toxicological effects at 15 mg/kg/day to mice. The results of the present study demonstrate that IC had significant effects on body weight, liver functions and kidney (p < 0.05 at a dose of 15 mg/kg body weight. IC treatment 5 and 10 mg/kg/day may be considered as no observed adverse effect level (NOAEL for mice. It was concluded that IC can cause hepatotoxicity and nephrotoxicity at a dose much lower than the LD50 (131 mg/kg body weight in mice.

  12. Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Chun-Hung Chiu

    2016-07-01

    Full Text Available Lipopolysaccharide (LPS-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST, a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10 for seven days and then were LPS-challenged (i.p., 5 mg/kg. The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT, glutamic oxaloacetic transaminase (GOT, blood urea nitrogen (BUN, creatinine (CRE, hepatic malondialdehyde (MDA and glutathione peroxidase (GSH-Px, IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS, suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day. Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.

  13. The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    Possamai, Lucia A; McPhail, Mark Jw; Khamri, Wafa; Wu, Bishan; Concas, Danilo; Harrison, Mark; Williams, Roger; Cox, Roger D; Cox, I Jane; Anstee, Quentin M; Thursz, Mark R

    2015-03-01

    Variations in intestinal microbiota may influence acetaminophen metabolism. This study aimed to determine whether intestinal microbiota are a source of differential susceptibility to acetaminophen-induced hepatotoxicity. Conventionally housed C3H/HeH (CH) and C3H/HeH germ-free (GF) mice were administered a 200 mg/kg IP dose of acetaminophen. The severity of hepatotoxicity at 8 h was assessed by histology and biochemical indices. A urinary metabolic profile was obtained using (1) H-NMR. Baseline hepatic glutathione content and CYP2E1 expression were quantified. An additional group of C3H/HeJ (LPS-r) mice were assessed to determine the contribution of LPS/TLR4 signalling. Baseline glutathione levels were significantly reduced (P = 0.03) in GF mice. CYP2E1 mRNA expression and protein levels were not altered. Interindividual variability did not differ between GF and CH groups. No significant differences in the extent of hepatocellular injury (ALT or percentage necrosis) were demonstrated. However, a milder acute liver failure (ALF) phenotype was shown in GF compared with CH mice, with reduced plasma bilirubin and creatinine and increased blood glucose. Differential acetaminophen metabolism was demonstrated. GF mice displayed a higher urinary acetaminophen-sulphate:glucuronide ratio compared with CH (P = 0.01). Urinary analysis showed metabolic differentiation of GF and CH groups at baseline and 8 h (cross-validated anova P = 1 × 10(-22) ). Interruption of TLR4 signalling in LPS-r mice had additional protective effects. Variations in intestinal microbiota do not fully explain differential susceptibility to acetaminophen-induced hepatotoxicity. GF mice experienced some protection from secondary complications following acetaminophen overdose and this may be mediated through reduced TLR4/LPS signalling. © 2014 The Authors. Liver International Published by John Wiley & Sons Ltd.

  14. The effect of essential oil of Achillea wilhelmsii flowers on cisplatin-induced hepatotoxicity

    OpenAIRE

    Sahar Ghanbari; Leila Amjad; Kahin Shahanipur

    2017-01-01

    Background: The essential oil of Achillea wilhelmsii has‎ anti-inflammatory and antioxidant properties. Cisplatin is one of the most important anticancer drugs that are widely used to treat various types of cancers. This study aimed at examining the effects of the essential oil of A. wilhelmsii flowers on cisplatin-induced hepatotoxicity in rats. Materials and Methods: In this study, 36 male Wistar rats weighing 200-250 g were divided into 6 groups: 1) control, 2) cisplatin (0.4 mg/kg), ...

  15. Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis

    Energy Technology Data Exchange (ETDEWEB)

    Brusko, C.S.; Marten, J.T. (Purdue University School of Pharmacy and Pharmacal Sciences, Lafayette, IN (United States))

    1991-12-01

    Environmental illness, a hypothesized disease caused by exposure to substances such as combustion products, pesticides, food additives, and Candida albicans, is discussed. The case of a patient with environmental illness and systemic candidiasis for six weeks with ketoconazole, liver enzyme concentrations increased. One month after discontinuation of ketoconazole, the liver enzyme concentrations decreased; however, over the next five months, liver enzymes and bilirubin increased. The patient developed encephalopathy and eventually was transferred to a medical center for possible liver transplant. A review of the literature pertaining to ketoconazole hepatotoxicity is also presented.16 references.

  16. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Henninger, Christian [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany); Huelsenbeck, Johannes; Huelsenbeck, Stefanie [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Grösch, Sabine [Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main (Germany); Schad, Arno [Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Lackner, Karl J. [Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Kaina, Bernd [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Fritz, Gerhard, E-mail: fritz@uni-duesseldorf.de [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany)

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  17. Amiodarone-induced exudative bullous lesion and hepatotoxicity in a patient with ventricular tachycardia

    Directory of Open Access Journals (Sweden)

    Ahmet Karakurt

    2015-09-01

    Full Text Available Amiodarone is a potent, iodine rich, highly lipophilic class III antiarrhythmic drug widely used for the management of both supraventricular and ventricular arrhythmias. It tends to concentrate in tissues including fat, lung, liver cornea and skin. Several side effects have been reported in patients taking amiodarone. The mechanisms of amiodarone-induced side effects are poorly understood. Accumulation of amiodarone in tissues and organs has been suggested as a possible mechanism. The most frequent dermatologic side effects are photosensitivity, skin discoloration and erythema. This article presents the case of a patient who developed amiodarone-induced bullous skin lesions and hepatotoxicity.

  18. Mineralization of alanine enantiomers in soil treated with heavy metals and nutrients

    Directory of Open Access Journals (Sweden)

    Pavel Formánek

    2011-01-01

    Full Text Available This work deals with the determination of the effect of heavy metals and nutrients applied to the soil on alanine enatiomers mineralization with the main focus on evaluating the effect on L/D alanine respiration rate ratio. This study was initiated because previous research works revealed a change in L/D amino acid respiration under acid- or heavy metal-stress in soil. Generally, D-amino acids artificially supplied to soil are less utilized by microorganisms compared with their L-enantiomers. Stress of soil microorganisms cause decreased discrimination of D-amino acids utilization. Also, previous research showed that an application of fertilizers or combinations of fertilizers may affect the mineralization rate of L-amino acids differently, compared with their D-enantiomers. The results of this study show, that the effect of both heavy metals and nutrients on the L/D ratio was not clear, increasing or decreasing this ratio. Further research is necessary to broaden this study.

  19. Elevated alanine aminotransferase levels in HIV-infected persons without hepatitis B or C virus coinfection.

    Science.gov (United States)

    Alghamdi, Saad; Alrbiaan, Abdullah; Alaraj, Ali; Alhuraiji, Ahmad; Alghamdi, Mohammad; Alrajhi, Abdulrahman

    2016-01-01

    Mortality related to human immunodeficiency (HIV) has improved with the use of antiretroviral therapy; however, liver disease-related mortality remains a major concern for the HIV population. Elevation of alanine aminotransferase (ALT) has been noted in HIV-infected persons even without viral hepatitis infection. The objective of this study was to determine the incidence and prevalence of chronic alanine ALT elevation among patients infected with HIV who are negative for hepatitis B or C infection. Retrospective chart review. We reviewed the medical records of all patients infected with HIV who had been treated from November 2002 to December 2010. Patients with an unknown or positive HBV or HCV infection status were excluded. We identified patient demographics, route of transmission, peak viral load, and nadir CD4 count. We followed 440 patients for up to 2265 person-years. A total of 123 patients developed chronically elevated ALT levels, with an incidence of 5.8 cases per 100 person-years. Chronically elevated ALT levels were associated with high HIV viral load, mean body mass index, and diabetes mellitus. We found exposure to lamivudine in 58% of the patients, efavirenz in 41%, and zidovudine in 38%. Abdominal ultrasounds revealed fatty liver in 20 of 39 (51%) of the patients. Among patients without viral hepatitis coinfection, the prevalence and incidence of chronic elevated ALT levels were high and accompanied by high HIV RNA levels and increased BMI. The limitations of this report are its retrospective nature and lack of a control group.

  20. Enhanced poly(3-hydroxypropionate production via β-alanine pathway in recombinant Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Stephen Tamekou Lacmata

    Full Text Available Poly(3-hydroxypropionate (P3HP is a thermoplastic with great compostability and biocompatibility, and can be produced through several biosynthetic pathways, in which the glycerol pathway achieved the highest P3HP production. However, exogenous supply of vitamin B12 was required to maintain the activity of glycerol dehydratase, resulting in high production cost. To avoid the addition of VB12, we have previously constructed a P3HP biosynthetic route with β-alanine as intermediate, and the present study aimed to improve the P3HP production of this pathway. L-aspartate decarboxylase PanD was found to be the rate-limiting enzyme in the β-alanine pathway firstly. To improve the pathway efficiency, PanD was screened from four different sources (Escherichia coli, Bacillus subtilis, Pseudomonas fluorescens, and Corynebacterium glutamicum. And PanD from C. glutamicum was found to have the highest activity, the P3HP production was improved in flask cultivation with this enzyme. To further improve the production, the host strain was screened and the culture condition was optimized. Under optimal conditions, production and content of P3HP reached to 10.2 g/L and 39.1% (wt/wt [cell dry weight] in an aerobic fed-batch fermentation. To date, this is the highest P3HP production without VB12.

  1. First Calibrations of Alanine and Radio-Photo-Luminescence Dosemeters to a Hadronic Radiation Environment

    CERN Document Server

    Fürstner, Markus; Floret, Idelette; Forkel-Wirth, Doris; Mayer, Sabine; Menzel, Hans Gregor; Vincke, Helmut H

    2005-01-01

    Alanine and Radio-Photo-Luminescence (RPL) dosimeters are used to monitor radiation doses occurring inside the tunnels of all CERN accelerators including the Large Hadron Collider (LHC). They are placed close to radiation sensitive machine components like cables or insulation of magnet coils to predict their remaining lifetime. The dosimeters are exposed to mixed high-energy radiation fields. However, up to now both dosimeter types are calibrated to 60Co-photons only. In order to study the response of RPL and alanine dosimeters to mixed particle fields like those occurring at CERN's accelerators, an irradiation campaign at the CERN-EC High-Energy Reference field Facility (CERF-field) was performed. Moreover, the dosimeters were first time calibrated to a proton radiation field of a constant momentum of 24 GeV/c. In addition to the experiment FLUKA Monte Carlo simulations were carried out, which provide information concerning the energy deposition and the radiation field at the dosimeter locations.

  2. Characterization of lithium formate EPR dosimeters for high dose applications – comparison with alanine

    DEFF Research Database (Denmark)

    Waldeland, Einar; Helt-Hansen, Jakob; Malinen, Eirik

    2011-01-01

    Lithium formate and l-α-alanine (alanine) EPR dosimeters were irradiated to doses from 100 Gy to 100 kGy. The irradiations were mainly performed at a Gammacell irradiator with dose rate of approximately 5.5 kGy h−1. Both the peak-to-peak amplitude of the first derivative EPR spectrum and the area...... under the EPR absorption spectrum were extracted, and the resulting dose dependence of these EPR signal intensity parameters were analyzed. The dependence of the peak-to-peak width of the central resonance in the first derivative EPR spectrum on the dose was also elucidated. In addition, the dependence...... on dose rate and irradiation temperature for the two materials was measured. Dosimeters were given doses from 100 Gy to 10 kGy at two different Gammacells with dose rates of 5.5 kGy h−1 and 0.6 kGy h−1, respectively, and the results were compared. Furthermore, the EPR signal intensities for dosimeters...

  3. A single glycine-alanine exchange directs ligand specificity of the elephant progestin receptor.

    Directory of Open Access Journals (Sweden)

    Michael Wierer

    Full Text Available The primary gestagen of elephants is 5α-dihydroprogesterone (DHP, which is unlike all other mammals studied until now. The level of DHP in elephants equals that of progesterone in other mammals, and elephants are able to bind DHP with similar affinity to progesterone indicating a unique ligand-binding specificity of the elephant progestin receptor (PR. Using site-directed mutagenesis in combination with in vitro binding studies we here report that this change in specificity is due to a single glycine to alanine exchange at position 722 (G722A of PR, which specifically increases DHP affinity while not affecting binding of progesterone. By conducting molecular dynamics simulations comparing human and elephant PR ligand-binding domains (LBD, we observed that the alanine methyl group at position 722 is able to push the DHP A-ring into a position similar to progesterone. In the human PR, the DHP A-ring position is twisted towards helix 3 of PR thereby disturbing the hydrogen bond pattern around the C3-keto group, resulting in a lower binding affinity. Furthermore, we observed that the elephant PR ligand-binding pocket is more rigid than the human analogue, which probably explains the higher affinity towards both progesterone and DHP. Interestingly, the G722A substitution is not elephant-specific, rather it is also present in five independent lineages of mammalian evolution, suggesting a special role of the substitution for the development of distinct mammalian gestagen systems.

  4. Role of tRNAPro in pretransfer editing of alanine by prolyl-tRNA synthetase

    Directory of Open Access Journals (Sweden)

    Boyarshin K. S.

    2013-09-01

    Full Text Available Aim. To characterize the process of tRNA-dependent pretransfer edi- ting of alanine by prolyl-tRNA synthetase of bacteria Enterococcus faecalis (ProRSEf. Methods. Velocity of the editing processes in vitro was determined by ATP hydrolysis by ProRSEf. Pretransfer and posttransfer editing were experimentally separated by site-directed mutagenesis. Results. tRNA-dependent pretransfer editing is characterized by three-fold larger velocity then tRNA-independent editing. Effectivity of the process depends on the presence of 2'-hydroxyle group of A76 tRNAPro. In the absence of tRNAPro selective release of alanyl-AMP occurs simultaneously with tRNA-independent pretransfer editing. Released alanyl-AMP can be re-bound and hydrolyzed. Conclusions. tRNA-dependent pretransfer editing of alanine by ProRSEf is the catalytic mechanism, mediated by 2'-hydroxyl group of A76 tRNAPro. In the absence of tRNAPro tRNA-independent pretransfer editing and selective release of alanyl-AMP occur.

  5. Validation of New Cancer Biomarkers

    DEFF Research Database (Denmark)

    Duffy, Michael J; Sturgeon, Catherine M; Söletormos, Georg

    2015-01-01

    BACKGROUND: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. CONTENT: In this review, we discuss the key steps in ad...

  6. Emerging Biomarkers in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Warren P. Mason

    2013-08-01

    Full Text Available Glioblastoma, the most common primary brain tumor, has few available therapies providing significant improvement in survival. Molecular signatures associated with tumor aggressiveness as well as with disease progression and their relation to differences in signaling pathways implicated in gliomagenesis have recently been described. A number of biomarkers which have potential in diagnosis, prognosis and prediction of response to therapy have been identified and along with imaging modalities could contribute to the clinical management of GBM. Molecular biomarkers including O(6-methlyguanine-DNA-methyltransferase (MGMT promoter and deoxyribonucleic acid (DNA methylation, loss of heterozygosity (LOH of chromosomes 1p and 19q, loss of heterozygosity 10q, isocitrate dehydrogenase (IDH mutations, epidermal growth factor receptor (EGFR, epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1 (ELTD1, vascular endothelial growth factor (VEGF, tumor suppressor protein p53, phosphatase and tensin homolog (PTEN, p16INK4a gene, cytochrome c oxidase (CcO, phospholipid metabolites, telomerase messenger expression (hTERT messenger ribonucleic acid [mRNA], microRNAs (miRNAs, cancer stem cell markers and imaging modalities as potential biomarkers are discussed. Inclusion of emerging biomarkers in prospective clinical trials is warranted in an effort for more effective personalized therapy in the future.

  7. Emerging Biomarkers in Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    McNamara, Mairéad G.; Sahebjam, Solmaz; Mason, Warren P., E-mail: warren.mason@uhn.ca [Pencer Brain Tumor Centre, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9 (Canada)

    2013-08-22

    Glioblastoma, the most common primary brain tumor, has few available therapies providing significant improvement in survival. Molecular signatures associated with tumor aggressiveness as well as with disease progression and their relation to differences in signaling pathways implicated in gliomagenesis have recently been described. A number of biomarkers which have potential in diagnosis, prognosis and prediction of response to therapy have been identified and along with imaging modalities could contribute to the clinical management of GBM. Molecular biomarkers including O(6)-methlyguanine-DNA-methyltransferase (MGMT) promoter and deoxyribonucleic acid (DNA) methylation, loss of heterozygosity (LOH) of chromosomes 1p and 19q, loss of heterozygosity 10q, isocitrate dehydrogenase (IDH) mutations, epidermal growth factor receptor (EGFR), epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, phosphatase and tensin homolog (PTEN), p16INK4a gene, cytochrome c oxidase (CcO), phospholipid metabolites, telomerase messenger expression (hTERT messenger ribonucleic acid [mRNA]), microRNAs (miRNAs), cancer stem cell markers and imaging modalities as potential biomarkers are discussed. Inclusion of emerging biomarkers in prospective clinical trials is warranted in an effort for more effective personalized therapy in the future.

  8. Emerging Biomarkers in Cognition

    Science.gov (United States)

    Wicklund, Meredith; Petersen, Ronald C.

    2014-01-01

    Synopsis The field of aging and dementia is rapidly evolving with the aim of identifying individuals in the earliest stages of disease processes. Biomarkers allow the clinician to demonstrate the presence of an underlying pathologic process and resultant synapse dysfunction and neurodegeneration, even in those earliest stages. For example, PET amyloid imaging and CSF Aβ42 provide direct evidence of amyloid deposition and structural MRI, FDG-PET or SPECT and CSF tau provide indirect evidence of synapse dysfunction and neurodegeneration when the pathologic process is due to Alzheimer's disease (AD). While this review will focus on biomarkers for mild cognitive impairment (MCI) due to AD, structural MRI, FDG-PET or SPECT, and PET with dopamine ligands are also valuable in suggesting non-AD pathologic processes. While these biomarkers are very useful and can even be applied to diagnostic criteria in MCI, several limitations exist. As the field continues to grow, several new biomarkers are emerging and ultimately, a more biological characterization of subjects’ underlying pathophysiologic spectra will be possible. PMID:24094298

  9. Biomarkers of cell senescence

    Science.gov (United States)

    Dirmi, Goberdhan P.; Campisi, Judith; Peacocke, Monica

    1996-01-01

    The present invention provides a biomarker system for the in vivo and in vitro assessment of cell senescence. In the method of the present invention, .beta.-galactosidase activity is utilized as a means by which cell senescence may be assessed either in in vitro cell cultures or in vivo.

  10. Biomarkers for anorexia nervosa

    DEFF Research Database (Denmark)

    Sjøgren, Jan Magnus

    2017-01-01

    Biomarkers for anorexia nervosa (AN) which reflect the pathophysiology and relate to the aetiology of the disease, are warranted and could bring us one step closer to targeted treatment of AN. Some leads may be found in the biochemistry which often is found disturbed in AN, although normalization...

  11. Muscle Carnosine Concentration with the Co-Ingestion of Carbohydrate with β-alanine in Male Rats.

    Science.gov (United States)

    Naderi, Alireza; Sadeghi, Mehdi; Sarshin, Amir; Imanipour, Vahid; Nazeri, Seyed Ali; Farkhayi, Fatemeh; Willems, Mark E T

    2017-07-04

    Muscle carnosine is an intracellular buffer. The intake of β-alanine, combined with carbohydrate and protein, enhanced carnosine loading in human muscle. The aim of the present study was to examine if muscle carnosine loading was enhanced by β-alanine intake and co-ingestion of glucose in male rats. Thirty-six male rats were divided into three groups and supplemented for four weeks: β-alanine (βA group, 1.8% β-alanine in drinking water), β-alanine and glucose (βAGL group, 1.8% β-alanine and 5% glucose in drinking water), and control (C group, drinking water). During the supplementation period, rats were exercised (20 m·min-1, 10 min·day-1, 4 days·week-1 for 4 weeks). Muscle carnosine concentration was quantified in soleus (n = 12) and rectus femoris (n = 6) muscles using high-performance liquid chromatography. In soleus muscle, carnosine concentration was 2.24 ± 1.10, 6.12 ± 1.08, and 6.93 ± 2.56 mmol/kg dw for control, βA, and βAGL, respectively. In rectus femoris, carnosine concentration was 2.26 ± 1.31, 7.90 ± 1.66, and 8.59 ± 2.33 mmol/kg dw for control, βA, and βAGL respectively. In each muscle, βA and βAGL resulted in similar carnosine increases compared to the control. In conclusion, β-alanine intake for four weeks, either alone or with glucose co-ingestion, equally increased muscle carnosine content. It appears that the potential insulin response to fluid glucose intake does not affect muscle carnosine loading in male rats.

  12. Asthma outcomes: Biomarkers

    Science.gov (United States)

    Szefler, Stanley J.; Wenzel, Sally; Brown, Robert; Erzurum, Serpil C.; Fahy, John V.; Hamilton, Robert G.; Hunt, John F.; Kita, Hirohito; Liu, Andrew H.; Panettieri, Reynold A.; Schleimer, Robert P.; Minnicozzi, Michael

    2012-01-01

    Background Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects. Objective National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies. Methods We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health–organized workshop convened in March 2010 and finalized in September 2011. Results Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (Feno), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures. Conclusion The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories. PMID:22386512

  13. Biomarkers of cancer cachexia.

    Science.gov (United States)

    Loumaye, Audrey; Thissen, Jean-Paul

    2017-12-01

    Cachexia is a complex multifactorial syndrome, characterized by loss of skeletal muscle and fat mass, which affects the majority of advanced cancer patients and is associated with poor prognosis. Interestingly, reversing muscle loss in animal models of cancer cachexia leads to prolong survival. Therefore, detecting cachexia and maintaining muscle mass represent a major goal in the care of cancer patients. However, early diagnosis of cancer cachexia is currently limited for several reasons. Indeed, cachexia development is variable according to tumor and host characteristics. In addition, safe, accessible and non-invasive tools to detect skeletal muscle atrophy are desperately lacking in clinical practice. Finally, the precise molecular mechanisms and the key players involved in cancer cachexia remain poorly characterized. The need for an early diagnosis of cancer cachexia supports therefore the quest for a biomarker that might reflect skeletal muscle atrophy process. Current research offers different promising ways to identify such a biomarker. Initially, the quest for a biomarker of cancer cachexia has mostly focused on mediators of muscle atrophy, produced by both tumor and host, in an attempt to define new therapeutic approaches. In another hand, molecules released by the muscle into the circulation during the atrophy process have been also considered as potential biomarkers. More recently, several "omics" studies are emerging to identify new muscular or circulating markers of cancer cachexia. Some genetic markers could also contribute to identify patients more susceptible to develop cachexia. This article reviews our current knowledge regarding potential biomarkers of cancer cachexia. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  14. The effects of beta alanine plus creatine administration on performance during repeated bouts of supramaximal exercise in sedentary men.

    Science.gov (United States)

    Okudan, N; Belviranli, M; Pepe, H; Gökbel, H

    2015-11-01

    The aim of this study was to investigate the effects of beta alanine and/or creatine supplementation on performance during repeated bouts of supramaximal exercise in sedentary men. Forty-four untrained healthy men (aged 20-22 years, weight: 68-72 kg, height: 174-178 cm) participated in the present study. After performing the Wingate Test (WAnT) for three times in the baseline exercise session, the subjects were assigned to one of four treatment groups randomly: 1) placebo (P; 10 g maltodextrose); 2) creatine (Cr; 5 g creatine plus 5 g maltodextrose); 3) beta-alanine (β-ALA; 1,6 g beta alanine plus 8,4 g maltodextrose); and 4) beta-alanine plus creatine (β-ALA+Cr; 1,6 g beta alanine plus 5 g creatine plus 3,4 g maltodextrose). Participants were given the supplements orally twice a day for 22 consecutive days, then four times a day for the following 6 days. After 28 days, the second exercise session was applied during which peak power (PP) and mean power (MP) were measured and fatigue index (FI) was calculated. PP and MP decreased and FI increased in all groups during exercise before and after the treatment. During the postsupplementation session PP2 and PP3 increased in creatine supplemented group (from 642.7±148.6 to 825.1±205.2 in PP2 and from 522.9±117.5 to 683.0±148.0 in PP3, respectively). However, MP increased in β-ALA+Cr during the postsupplementation compared to presupplementation in all exercise sessions (from 586.2±55.4 to 620.6±49.6 in MP1, from 418.1±37.2 to 478.3±30.3 in MP2 and from 362.0±41.3 to 399.1±3 in MP3, respectively). FI did not change with beta alanine and beta alanine plus creatine supplementation during the postsupplementation exercise session. Beta-alanine and beta alanine plus creatine supplementations have strong performance enhancing effect by increasing mean power and delaying fatigue Index during the repeated WAnT.

  15. Rescue therapy with sirolimus in a renal transplant recipient with tacrolimus-induced hepatotoxicity.

    Science.gov (United States)

    Mesar, Ines; Kes, Petar; Hudolin, Tvrtko; Basic-Jukic, Nikolina

    2013-01-01

    Calcineurin inhibitors at elevated serum concentrations frequently cause mild elevation of the liver chemistries. Although rare, severe hepatotoxicity is their serious complication. A 54-year-old man with end-stage renal disease due to chronic glomerulonephritis without biopsy received a renal allograft from the deceased donor. Eleven days after transplantation severe liver injury (AST up to 421 IU/L, ALT 1242  IU/L, and GGT 212 IU/L) with the serum bilirubin within the normal range was recorded. Tacrolimus trough level was 5.5 ng/mL. Liver ultrasound and color-Doppler of the portal system were normal. Liver failure completely resolved after withdrawal of the calcineurin inhibitor and switch to sirolimus. After 9 months of follow-up our patient has excellent graft and liver function. Awareness of the possible association of tacrolimus use with hepatotoxicity is important to timely discontinuation of the causative agent, and to introduce sirolimus as the rescue therapy.

  16. Traditional Chinese Medicine and herbal hepatotoxicity: a tabular compilation of reported cases.

    Science.gov (United States)

    Teschke, Rolf; Zhang, Li; Long, Hongzhu; Schwarzenboeck, Alexander; Schmidt-Taenzer, Wolfgang; Genthner, Alexander; Wolff, Albrecht; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2015-01-01

    Traditional Chinese Medicine (TCM) with its focus on herbal use became popular worldwide. Treatment was perceived as safe, with neglect of rare adverse reactions including liver injury. To compile worldwide cases of liver injury by herbal TCM, we undertook a selective literature search in the PubMed database and searched for the items Traditional Chinese Medicine, TCM, Traditional Asian Medicine, and Traditional Oriental Medicine, also combined with the terms herbal hepatotoxicity or herb induced liver injury. The search focused primarily on English-language case reports, case series, and clinical reviews. We identified reported hepatotoxicity cases in 77 relevant publications with 57 different herbs and herbal mixtures of TCM, which were further analyzed for causality by the Council for International Organizations of Medical Sciences (CIOMS) scale, positive reexposure test results, or both. Causality was established for 28/57 different herbs or herbal mixtures, Bai Xian Pi, Bo He, Ci Wu Jia, Chuan Lian Zi, Da Huang, Gan Cao, Ge Gen, Ho Shou Wu, Huang Qin, Hwang Geun Cho, Ji Gu Cao, Ji Xue Cao, Jin Bu Huan, Jue Ming Zi, Jiguja, Kudzu, Ling Yang Qing Fei Keli, Lu Cha, Rhen Shen, Ma Huang, Shou Wu Pian, Shan Chi, Shen Min, Syo Saiko To, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, and Zhen Chu Cao. In conclusion, this compilation of liver injury cases establishes causality for 28/57 different TCM herbs and herbal mixtures, aiding diagnosis for physicians who care for patients with liver disease possibly related to herbal TCM.

  17. Metallothionein’s role in PCB126 induced hepatotoxicity and hepatic micronutrient disruption

    Directory of Open Access Journals (Sweden)

    W.D Klaren

    2016-01-01

    Full Text Available Polychlorinated biphenyls (PCBs, industrial chemicals and persistent environmental pollutants, are found in rural and urban settings. Rodent studies have shown that exposure to PCB126, a dioxin-like PCB, causes a significant disruption of hepatic micronutrient homeostasis and an increase in metallothionein (MT, an antioxidant protein and metal carrier. A MT knockout mouse strain was used to assess metallothionein’s role in micronutrient disruption and overall hepatotoxicity. Twenty four 129S male mice (12 wild type (WT and 12 MT knockout (MTKO were placed on a purified diet (AIN-93G for 3 weeks to achieve hepatic metal equilibrium. Mice were then given a single IP injection of either vehicle or 150 μmol/kg PCB126 in vehicle. The animals were sacrificed 2 weeks later and organs processed for analysis. Liver histology, hepatic lipids, gene expression, micronutrient and ROS status were investigated. Liver weights, liver lipids, ROS, and hepatocyte vacuolation were increased with PCB126 exposure along with AhR responsive genes. The MTKO animals had more severe histological changes in the liver and elevated liver lipids than their wild type counterparts. Hepatic and renal metals levels (Cu, Zn, Se and Mn were mostly reduced by PCB126 treatment. Renal micronutrients were more affected by PCB126 treatment in the MTKO animals. This research suggests that MT may not be the sole/primary cause of the metal disruption caused by PCB126 exposure in mice, but may provide protection against overall hepatotoxicity.

  18. Carbon tetrachloride-induced hepatotoxicity: studies in developing rats and protection by zinc.

    Science.gov (United States)

    Cagen, S Z; Klaasen, C D

    1980-11-01

    This investigation was designed to evaluate carbon tetrachlorid (CCl4)-induced hepatotoxicity in developing rats and in adult rats pretreated with zinc. Hepatotoxicity of CCl4 in rats as young as 4 days of age was similar to that in adults. However, CCl4 metabolism, measured by in vitro binding of 14CCl4 to hepatic microsomal protein and lipid, was significantly lower in 4- and 14-day old rats than in adults. The sensitivity of young animals to CCl4 toxicity may be due to metabolic ketosis since blood concentrations of acetoacetate were 3-5 times higher in young rats than in adult animals. It has previously been shown that adult rats are more sensitive to CCl4 toxicity when they are in the ketonic state. The protection from CCl4 toxicity that was afforded adult rats pretreated with zinc was determined to be independent of the effect of zinc on CCl4 metabolism. Since treatment with zinc results in a large increase in hepatic concentration of metallothionein and that some product of 14CCl4 appeared to bind to zinc-induced metallothionein, it was suggested that metallothionein may protect against CCl4-induced liver damage by sequestering reactive metabolites of CCl4. These studies represent two examples of how the toxicity of a chemical whose toxicity is mediated via a metabolite can be modified by factors independent of metabolic activation.

  19. The protective effects of vitamin C on hepatotoxicity induced by radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Ki Jung; Park, Sung Kwang; Cho, Heung Lae [Pusan Paik Hospital, Inje University, Busan (Korea, Republic of); Kang, Ki Mun; Chai, Gyu Young; Chung, Duck Wha [Gyungsang National University, Jinju (Korea, Republic of); Kang, Jin Soon [Jinju International University, Jinju (Korea, Republic of)

    2004-12-15

    This study was carried out to determine the protective effects of vitamin C on the hepatotoxicity induced by radiation. The Spraque Dawley rats were randomly divided into 3 groups; the control group, the radiation exposed group, and the radiation and vitamin C-treated group. SOD activity catalase, malondialdehyde and liver enzymes were analyzed to assess the antioxidant effects of vitamin C. The increased level of malondialdehyde and the decreased catalase activity that were induced by radiation were improved after vitamin C but were was no statistical significance among three groups. The superoxide dismutase activity of the liver was increased by vitamin C, but there were no statistically significant differences between the vitamin C-treated group and the non vitamin C-treated group. The level of liver enzymes in sera such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactate dehyrogenase and alkaline phosphatase were remarkably elevated by radiation. The levels of those enzymes were decreased in the vitamin C-treated group and statistical significance was noted for the GPT level ({rho} < 0.01). On the electromicrographic findings, the hepatic cell destruction was considerably decreased in the vitamin C-treated group. Vitamin C is thought to be an effective antioxidant against the hepatotoxicity induced by radiation.

  20. Ameliorative Influence of Green Tea Extract on Copper Nanoparticle-Induced Hepatotoxicity in Rats

    Science.gov (United States)

    Ibrahim, Marwa A.; Khalaf, A. A.; Galal, Mona K.; Ogaly, Hanan A.; H. M. Hassan, Azza

    2015-09-01

    The potential toxicity of copper nanoparticles (CNPs) to the human health and environment remains a critical issue. In the present study, we investigated the protective influence of an aqueous extract of green tea leaves (GTE) against CNPs-induced (20-30 nm) hepatotoxicity. Four different groups of rats were used: group I was the control, group II received CNPs (40 mg/kg BW), group III received CNPs plus GTE, and group IV received GTE alone. We highlighted the hepatoprotective effect of GTE against CNPs toxicity through monitoring the alteration of liver enzyme activity, antioxidant defense mechanism, histopathological alterations, and DNA damage evaluation. The rats that were given CNPs only had a highly significant elevation in liver enzymes, alteration in oxidant-antioxidant balance, and severe pathological changes. In addition, we detected a significant elevation of DNA fragmentation percentage, marked DNA laddering, and significance over expression of both caspase-3 and Bax proteins. The findings for group III clarify the efficacy of GTE as a hepatoprotectant on CNPs through improving the liver enzyme activity, antioxidant status, as well as suppressing DNA fragmentation and the expression of the caspase-3 and Bax proteins. In conclusion, GTE was proved to be a potential hepatoprotective additive as it significantly ameliorates the hepatotoxicity and apoptosis induced by CNPs.

  1. Lactobacillus fermentum Postbiotic-induced Autophagy as Potential Approach for Treatment of Acetaminophen Hepatotoxicity.

    Science.gov (United States)

    Dinić, Miroslav; Lukić, Jovanka; Djokić, Jelena; Milenković, Marina; Strahinić, Ivana; Golić, Nataša; Begović, Jelena

    2017-01-01

    The aim of this study was to investigate the potential of postbiotics originated from Lactobacillus fermentum BGHV110 strain (HV110) to counteract acetaminophen (APAP)-induced hepatotoxicity in HepG2 cells. This strain was selected according to its autophagy inducing potential, based on previous studies reporting protective role of autophagy in APAP caused cellular damage. Cell viability was assessed using MTT and LDH assays, while autophagy was monitored by qPCR analysis of BECN1, Atg5, p62/SQSTM1, and PINK1 mRNA expression and by Western blot analysis of p62/SQSTM1 and lipidated LC3 accumulation. Our results showed that detrimental effect of APAP on cell viability was suppressed in the presence of HV110 which was linked with increased conversion of LC3 protein and p62/SQSTM1 protein degradation. Additionally, higher p62/SQSTM1 and PINK1 mRNA transcription were noticed in cells co-treated with APAP/HV110, simultaneously. In conclusion, this study suggests that HV110 enhances activation of PINK1-dependent autophagy in HepG2 cells and its eventual co-supplementation with APAP could be potentially used for alleviation of hepatotoxic side effects caused by APAP overdose.

  2. Therapeutic potential of Moringa oleifera extracts against acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Sharifudin, Syazana Akmal; Fakurazi, Sharida; Hidayat, Mohamad Taufik; Hairuszah, Ithnin; Moklas, Mohamad Aris Mohd; Arulselvan, Palanisamy

    2013-03-01

    Moringa oleifera Lam. (Moringaceae) is a rich source of essential minerals and antioxidants; it has been used in human and animal nutrition. The leaves and flowers are being used by the population with great dietary importance. The present study was to investigate the therapeutic effects of the hydroethanolic extract of Moringa oleifera (MO) leaves and flowers against hepatotoxicity induced by acetaminophen (APAP) in rats. In the hepatoprotective study, either flowers or leaves of hydroethanolic extract (200 or 400 mg/kg bw through IP injection) were administered an hour after APAP administration. N-Acetylcysteine (NAC) was used as the positive control for this study. Liver and kidney function tests including lipid peroxidation levels were analyzed and histopathological changes of liver and kidney were also observed. Acetaminophen-induced hepatotoxicity increased the activities of liver marker enzymes. Histologically, the liver was observed to have inflammation and bridging necrosis. Liver marker enzymes were significantly reduced when treated with flower and leaf extracts of MO in animals with APAP induced toxicity. In addition, there were no significant changes observed in clinical markers of kidney function. Histological observation on liver tissue from the rats treated with MO flower and leaf extract showed reduction in the severity of the liver damage. These results indicated the possible therapeutic action of flower and leaf extract from MO in protecting liver damage in rats given an over dosage of APAP.

  3. Severe hepatotoxicity following ingestion of Herbalife nutritional supplements contaminated with Bacillus subtilis.

    Science.gov (United States)

    Stickel, Felix; Droz, Sara; Patsenker, Eleonora; Bögli-Stuber, Katja; Aebi, Beat; Leib, Stephen L

    2009-01-01

    Nutritional supplements are widely used. Recently, liver injury after consumption of Herbalife preparations was reported but the underlying pathogenesis remained cryptic. Two patients presented with cholestatic hepatitis and pruritus, and cirrhosis, respectively. Viral, alcoholic, metabolic, autoimmune, neoplastic, vascular liver diseases and synthetic drugs as the precipitating causes of liver injury were excluded. However, both patients reported long-term consumption of Herbalife products. All Herbalife products were tested for contamination with drugs, pesticides, heavy metals, and softeners, and examined for microbial contamination according to standard laboratory procedures. Bacteria isolated from the samples were identified as Bacillus subtilis by sequencing the 16S rRNA and gyrB genes. Causality between consumption of Herbalife products and disease according to CIOMS was scored "probable" in both cases. Histology showed cholestatic and lobular/portal hepatitis with cirrhosis in one patient, and biliary fibrosis with ductopenia in the other. No contamination with chemicals or heavy metals was detected, and immunological testing showed no drug hypersensitivity. However, samples of Herbalife products ingested by both patients showed growth of Bacillus subtilis of which culture supernatants showed dose- and time-dependent hepatotoxicity. Two novel incidents of severe hepatic injury following intake of Herbalife products contaminated with Bacillus subtilis emphasize its potential hepatotoxicity.

  4. Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity

    Science.gov (United States)

    Jaeschke, Hartmut; Williams, C. David; Ramachandran, Anup; Bajt, Mary L.

    2013-01-01

    Acetaminophen (APAP) hepatotoxicity because of overdose is the most frequent cause of acute liver failure in the western world. Metabolic activation of APAP and protein adduct formation, mitochondrial dysfunction, oxidant stress, peroxynitrite formation and nuclear DNA fragmentation are critical intracellular events in hepatocytes. However, the early cell necrosis causes the release of a number of mediators such as high-mobility group box 1 protein, DNA fragments, heat shock proteins (HSPs) and others (collectively named damage-associated molecular patterns), which can be recognized by toll-like receptors on macrophages, and leads to their activation with cytokine and chemokine formation. Although pro-inflammatory mediators recruit inflammatory cells (neutrophils, monocytes) into the liver, neither the infiltrating cells nor the activated resident macrophages cause any direct cytotoxicity. In contrast, pro- and anti-inflammatory cytokines and chemokines can directly promote intracellular injury mechanisms by inducing nitric oxide synthase or inhibit cell death mechanisms by the expression of acute-phase proteins (HSPs, heme oxygenase-1) and promote hepatocyte proliferation. In addition, the newly recruited macrophages (M2) and potentially neutrophils are involved in the removal of necrotic cell debris in preparation for tissue repair and resolution of the inflammatory response. Thus, as discussed in detail in this review, the preponderance of experimental evidence suggests that the extensive sterile inflammatory response during APAP hepatotoxicity is predominantly beneficial by limiting the formation and the impact of pro-inflammatory mediators and by promoting tissue repair. PMID:21745276

  5. Hepatotoxicity prediction by systems biology modeling of disturbed metabolic pathways using gene expression data.

    Science.gov (United States)

    Carbonell, Pablo; Lopez, Oriol; Amberg, Alexander; Pastor, Manuel; Sanz, Ferran

    2017-01-01

    The present study applies a systems biology approach for the in silico predictive modeling of drug toxicity on the basis of high-quality preclinical drug toxicity data with the aim of increasing the mechanistic understanding of toxic effects of compounds at different levels (pathway, cell, tissue, organ). The model development was carried out using 77 compounds for which gene expression data for treated primary human hepatocytes is available in the LINCS database and for which rodent in vivo hepatotoxicity information is available in the eTOX database. The data from LINCS were used to determine the type and number of pathways disturbed by each compound and to estimate the extent of disturbance (network perturbation elasticity), and were used to analyze the correspondence with the in vivo information from eTOX. Predictive models were developed through this integrative analysis, and their specificity and sensitivity were assessed. The quality of the predictions was determined on the basis of the area under the curve (AUC) of plots of true positive vs. false positive rates (ROC curves). The ROC AUC reached values of up to 0.9 (out of 1.0) for some hepatotoxicity endpoints. Moreover, the most frequently disturbed metabolic pathways were determined across the studied toxicants. They included, e.g., mitochondrial beta-oxidation of fatty acids and amino acid metabolism. The process was exemplified by successful predictions on various statins. In conclusion, an entirely new approach linking gene expression alterations to the prediction of complex organ toxicity was developed and evaluated.

  6. Protective effects of metallothionein on isoniazid and rifampicin-induced hepatotoxicity in mice.

    Directory of Open Access Journals (Sweden)

    Yong Lian

    Full Text Available Isoniazid (INH and Rifampicin (RFP are widely used in the world for the treatment of tuberculosis, but the hepatotoxicity is a major concern during clinical therapy. Previous studies showed that these drugs induced oxidative stress in liver, and several antioxidants abated this effect. Metallothionein (MT, a member of cysteine-rich protein, has been proposed as a potent antioxidant. This study attempts to determine whether endogenous expression of MT protects against INH and RFP-induced hepatic oxidative stress in mice. Wild type (MT+/+ and MT-null (MT-/- mice were treated intragastrically with INH (150 mg/kg, RFP (300 mg/kg, or the combination (150 mg/kg INH +300 mg/kg RFP for 21 days. The results showed that MT-/- mice were more sensitive than MT+/+ mice to INH and RFP-induced hepatic injuries as evidenced by hepatic histopathological alterations, increased serum AST levels and liver index, and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status. Furthermore, INH increased the protein expression of hepatic CYP2E1 and INH/RFP (alone or in combination decreased the expression of hepatic CYP1A2. These findings clearly demonstrate that basal MT provides protection against INH and RFP-induced toxicity in hepatocytes. The CYP2E1 and CYP1A2 were involved in the pathogenesis of INH and RFP-induced hepatotoxicity.

  7. Lutein Has a Protective Effect on Hepatotoxicity Induced by Arsenic via Nrf2 Signaling

    Science.gov (United States)

    Li, Shugang; Ding, Yusong; Niu, Qiang; Xu, Shangzhi; Pang, Lijuan; Ma, Rulin; Jing, Mingxia; Feng, Gangling; Tang, Jing Xia; Zhang, Qian; Ma, Xiaomei; Yan, Yizhong; Wang, Hai Xia; Li, Feng; Guo, Shuxia

    2015-01-01

    Arsenic produces liver disease through the oxidative stress. While lutein can alleviate cytotoxic and oxidative injury, nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a critical role in defending oxidative species. However, the mechanisms by which lutein protects the liver against the effect of arsenic are not known. Therefore, this study aims to investigate the mechanisms involved in the action of lutein using mice model in which hepatotoxicity was induced by arsenic. We found that mice treatment with lutein could reverse changes in morphological and liver indexes and result in a significant improvement in hepatic function comparing with arsenic trioxide group. Lutein treatment improved the activities of antioxidant enzymes and attenuated increasing of ROS and MDA induced by arsenic trioxide. Lutein could increase the mRNA and protein expression of Nrf2 signaling related genes (Nrf2, Nqo1, Ho-1, and Gst). These findings provide additional evidence that lutein may be useful for reducing reproductive injury associated with oxidative stress by the activation of Nrf2 signaling. Our findings suggest a possible mechanism of antioxidant lutein in preventing the hepatotoxicity, which implicate that a dietary lutein may be a potential treatment for liver diseases, especially for arsenicosis therapy. PMID:25815309

  8. Effect of Smilax zeylanica roots and rhizomes in paracetamol induced hepatotoxicity.

    Science.gov (United States)

    Murali, Anita; Ashok, Purnima; Madhavan, V

    2012-11-09

    Smilax zeylanica L.(Smilacaceae) is a climbing shrub with woody prickly stems. This study evaluated the hepatoprotective effect of S. zeylanica against paracetamol induced hepatotoxicity in Wistar rats. The protective effects of the methanol extract (200 and 400 mg/kg) of root and rhizome of S. zeylanica were studied on paracetamol induced (1 g/kg) hepatic damage in Wistar rats by estimating the serum levels of AST, ALT, alkaline phosphatase (ALP), total proteins, total bilirubin and albumin. Sections of liver were observed for histopathological changes in liver architecture. Rats were protected from the hepatotoxic action of paracetamol as evidenced by the significant reduction in the elevated serum levels of ALT (Pparacetamol control. Silymarin (100 mg/kg) was used as the standard. The biochemical observations were supplemented by the histopathological studies on the liver sections of different groups. The methanol extract of S. zeylanica was found to alter the damage caused to hepatocytes by paracetamol and prevent the leakage of vital serum markers, which confirmed the hepatoprotective effect of this plant.

  9. Human hepatocytes derived from pluripotent stem cells: a promising cell model for drug hepatotoxicity screening.

    Science.gov (United States)

    Gómez-Lechón, María José; Tolosa, Laia

    2016-09-01

    Drug-induced liver injury (DILI) is a frequent cause of failure in both clinical and post-approval stages of drug development, and poses a key challenge to the pharmaceutical industry. Current animal models offer poor prediction of human DILI. Although several human cell-based models have been proposed for the detection of human DILI, human primary hepatocytes remain the gold standard for preclinical toxicological screening. However, their use is hindered by their limited availability, variability and phenotypic instability. In contrast, pluripotent stem cells, which include embryonic and induced pluripotent stem cells (iPSCs), proliferate extensively in vitro and can be differentiated into hepatocytes by the addition of soluble factors. This provides a stable source of hepatocytes for multiple applications, including early preclinical hepatotoxicity screening. In addition, iPSCs also have the potential to establish genotype-specific cells from different individuals, which would increase the predictivity of toxicity assays allowing more successful clinical trials. Therefore, the generation of human hepatocyte-like cells derived from pluripotent stem cells seems to be promising for overcoming limitations of hepatocyte preparations, and it is expected to have a substantial repercussion in preclinical hepatotoxicity risk assessment in early drug development stages.

  10. [Individualized clinical treatment from the prospective of hepatotoxicity of non-toxic traditional Chinese medicine].

    Science.gov (United States)

    Yang, Nan; Chen, Juan; Hou, Xue-Feng; Song, Jie; Feng, Liang; Jia, Xiao-Bin

    2017-04-01

    Traditional Chinese medicine has a long history in clinical application, and been proved to be safe and effective. In recent years, the toxicity and side-effects caused by the western medicine have been attracted much attention. As a result, increasing people have shifted their attention to traditional Chinese medicine. Nonetheless, due to the natural origin of traditional Chinese medicine and the lack of basic knowledge about them, many people mistakenly consider the absolute safety of traditional Chinese medicine, except for well-known toxic ones, such as arsenic. However, according to the clinical practices and recent studies, great importance shall be attached to the toxicity of non-toxic traditional Chinese medicine, in particular the hepatotoxicity. Relevant studies indicated that the toxicity of non-toxic traditional Chinese medicine is closely correlated with individual gene polymorphism and constitution. By discussing the causes and mechanisms of the hepatotoxicity induced by non-toxic traditional Chinese medicine in clinical practices, we wrote this article with the aim to provide new ideas for individualized clinical therapy of traditional Chinese medicine and give guidance for rational and safe use of traditional Chinese medicine. Copyright© by the Chinese Pharmaceutical Association.

  11. Hematological, antioxidant and protective performance of Usnea longissima on chemical induced hepatotoxicity in experimental animals

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    Pritt Verma

    2017-05-01

    Full Text Available Objective: To investigated the hematological, antioxidant and protective performance of Usnea longissima (U. longissima on CCl4 induced hepatotoxicity in experimental animals. Methods: Hepatotoxicity was induced by CCl4 (1 mL/kg body weigt 1:1 CCl4 i.p., ethanolic U. longissima extracts at a doses (200 and 400 mg/kg body weigt were administered to and compared with Silymarin (25 mg/kg body weigt and hematological, antioxidant and enzymatic, non-enzymatic parameters were assessed through the liver functions test. All the observation was also supplemented with histopathological examination of liver sections. Results: Phytochemical investigation showed that ethanolic extract contains poly phenolic compounds tannins, flavonoids, alkaloids and saponins and acute toxicity study shows that ethanolic extract was safe up to 2 000 mg/kg body weight. The toxicant induced a rise in the plasma enzyme levels of ALT, AST, ALP and total bilirubin level. This increased level was significantly decreased by the extract at 400 mg/kg body weight than 200 mg/kg body weight. The animals were prevented (partly or fully which was showed in the histopathological changes using ethonolic U. longissima extract. Conclusions: The outcome of this study reveals that, there is a powerful antioxidant and hepatoprotective activity of U. longissima. It is believed that the present constituents are responsible for courting the hepatic disease and alternative components have the power to act as free radical scavenging properties.

  12. Risk assessment of hepatotoxicity among tuberculosis and human immunodeficiency virus/AIDS-coinfected patients under tuberculosis treatment

    Directory of Open Access Journals (Sweden)

    Williams Ngouleun

    2016-01-01

    Conclusion: The results showed that human immunodeficiency virus status and alcohol consumption constitutes aggravating factors for the occurrence of hepatic toxicity. In addition, the consumption of antioxidant foods simultaneously with TB drugs help in reducing the hepatotoxic effects of these drugs.

  13. Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity.

    Science.gov (United States)

    El-Mansy, A A; Mazroa, S A; Hamed, W S; Yaseen, A H; El-Mohandes, E A

    2016-01-01

    The liver is a target for toxic chemicals such as cadmium (Cd). When the liver is damaged, hepatic stellate cells (HSC) are activated and transformed into myofibroblast-like cells, which are responsible for liver fibrosis. Curcuma longa has been reported to exert a hepato-protective effect under various pathological conditions. We investigated the effects of C. longa administration on HSC activation in response to Cd induced hepatotoxicity. Forty adult male albino rats were divided into: group 1 (control), group 2 (Cd treated), group 3 (C. longa treated) and group 4 (Cd and C. longa treated). After 6 weeks, liver specimens were prepared for light and electron microscopy examination of histological changes and immunohistochemical localization of alpha smooth muscle actin (αSMA) as a specific marker for activated HSC. Activated HSC with a positive αSMA immune reaction were not detected in groups 1 and 3. Large numbers of activated HSC with αSMA immune reactions were observed in group 2 in addition to Cd induced hepatotoxic changes including excess collagen deposition in thickened portal triads, interlobular septa with hepatic lobulation, inflammatory cell infiltration, a significant increase in Kupffer cells and degenerated hepatocytes. In group 4, we observed a significant decrease in HSC that expressed αSMA with amelioration of the hepatotoxic changes. C. longa administration decreased HSC activation and ameliorated hepatotoxic changes caused by Cd in adult rats.

  14. Protective effects of phenolics rich extract of ginger against Aflatoxin B1-induced oxidative stress and hepatotoxicity.

    Science.gov (United States)

    A V, Vipin; K, Raksha Rao; Kurrey, Nawneet Kumar; K A, Anu Appaiah; G, Venkateswaran

    2017-07-01

    Aflatoxin B 1 (AFB 1 ) is one of the predominant mycotoxin contaminant in food and feed, causing oxidative stress and hepatotoxicity. Ginger phenolics have been reported for its antioxidant potential and hepatoprotective activity. The present study investigated the protective effects of phenolics rich ginger extract (GE) against AFB 1 induced oxidative stress and hepatotoxicity, in vitro and in vivo. The phenolic acid profiles of GE showed 6-gingerol and 6-shogaol as predominant components. Pretreatment of HepG2 cells with GE significantly inhibited the production of intracellular reactive oxygen species (ROS), DNA strand break, and cytotoxicity induced by AFB 1 . A comparable effect was observed in in vivo. Male Wistar rats were orally treated with GE (100 and 250mg/kg) daily, with the administration of AFB 1 (200μg/kg) every alternative day for 28days. Treatment with GE significantly reduced AFB 1 induced toxicity on the serum markers of liver damage. In addition, GE also showed significant hepatoprotective effect by reducing the lipid peroxidation and by enhancing the antioxidant enzymes activities. These results combined with liver histopathological observations indicated that GE has potential protective effect against AFB 1 induced hepatotoxicity. Additionally, administration of GE up-regulated Nrf2/HO-1 pathway, which further proved the efficiency of GE to inhibit AFB 1 induced hepatotoxicity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. DILI (drug induced liver injury in a 9-month-old infant: a rare case of phenobarbital-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Anna Paola Pinna

    2013-04-01

    Full Text Available Phenobarbital is one of the most commonly prescribed antiepileptic drugs in childhood, but it can rarely cause serious adverse effects, such as hepatotoxicity that includes a broad clinical spectrum (from isolate hypertransaminasemia to acute liver failure. We describe a case of DILI in a 9-month-old infant caused by chronic therapy with phenobarbital.

  16. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.

    Science.gov (United States)

    Janas, Maja M; Schlegel, Mark K; Harbison, Carole E; Yilmaz, Vedat O; Jiang, Yongfeng; Parmar, Rubina; Zlatev, Ivan; Castoreno, Adam; Xu, Huilei; Shulga-Morskaya, Svetlana; Rajeev, Kallanthottathil G; Manoharan, Muthiah; Keirstead, Natalie D; Maier, Martin A; Jadhav, Vasant

    2018-02-19

    Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity can be associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.

  17. Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARγ and abrogation of oxidative stress and inflammation.

    Science.gov (United States)

    Mahmoud, Ayman M

    2014-09-01

    The most important reason for the non-approval and withdrawal of drugs by the Food and Drug Administration is hepatotoxicity. Therefore, this study was undertaken to evaluate the protective effects of hesperidin against cyclophosphamide (CYP)-induced hepatotoxicity in Wistar rats. The rats received a single intraperitoneal dose of CYP of 200 mg/kg body mass, followed by treatment with hesperidin, orally, at doses of 25 and 50 mg/kg for 11 consecutive days. CYP induced hepatic damage, as evidenced by the significantly elevated levels of serum pro-inflammatory cytokines, serum transaminases, liver lipid peroxidation, and nitric oxide. As a consequence, there was reduced glutathione content, and the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, were markedly reduced. In addition, CYP administration induced a considerable downregulation of peroxisome proliferator activated receptor gamma (PPARγ) and upregulation of nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) mRNA expression. Hesperidin, in a dose-dependent manner, rejuvenated the altered markers to an almost normal state. In conclusion, hesperidin showed a potent protective effect against CYP-induced oxidative stress and inflammation leading to hepatotoxicity. The study suggests that hesperidin exerts its protective effect against CYP-induced hepatotoxicity through upregulation of hepatic PPARγ expression and abrogation of inflammation and oxidative stress.

  18. Relationship Between Structural Alerts in NSAIDs and Idiosyncratic Hepatotoxicity : An Analysis of Spontaneous Report Data from the WHO Database

    NARCIS (Netherlands)

    Jessurun, Naomi; van Puijenbroek, Eugene

    2015-01-01

    BACKGROUND: Idiosyncratic drug reactions such as hepatotoxicity and blood dyscrasias represent one of the major causes of drug withdrawal from the market. According to the reactive metabolite (RM) concept, this may be due to the metabolic activation of structural alerts (SAs), functionalities in the

  19. Biomarker evaluation of skeletal muscle toxicity following clofibrate administration in rats.

    Science.gov (United States)

    Bodié, Karen; Buck, Wayne R; Pieh, Julia; Liguori, Michael J; Popp, Andreas

    2016-05-01

    The use of sensitive biomarkers to monitor skeletal muscle toxicity in preclinical toxicity studies is important for the risk assessment in humans during the development of a novel compound. Skeletal muscle toxicity in Sprague Dawley Rats was induced with clofibrate at different dose levels for 7 days to compare standard clinical pathology assays with novel skeletal muscle and cardiac muscle biomarkers, gene expression and histopathological changes. The standard clinical pathology assays aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) enzyme activity were compared to novel biomarkers fatty acid binding protein 3 (Fabp3), myosin light chain 3 (Myl3), muscular isoform of CK immunoreactivity (three isoforms CKBB, CKMM, CKMB), parvalbumin (Prv), skeletal troponin I (sTnI), cardiac troponin T (cTnT), cardiac troponin I (cTnI), CKMM, and myoglobin (Myo). The biomarker elevations were correlated to histopathological findings detected in several muscles and gene expression changes. Clofibrate predominantly induced skeletal muscle toxicity of type I fibers of low magnitude. Useful biomarkers for skeletal muscle toxicity were AST, Fabp3, Myl3, (CKMB) and sTnI. Measurements of CK enzyme activity by a standard clinical assay were not useful for monitoring clofibrate-induced skeletal muscle toxicity in the rat at the doses used in this study. Copyright © 2016 The Authors. Published by Elsevier GmbH.. All rights reserved.

  20. Averaged electron collision cross sections for thermal mixtures of β-alanine conformers in the gas phase

    Science.gov (United States)

    Fujimoto, Milton M.; de Lima, Erik V. R.; Tennyson, Jonathan

    2017-10-01

    A theoretical study of elastic electron scattering by gas-phase amino acid molecule β-alanine (NH2-CH2-CH2-COOH) is presented. R-matrix calculations are performed for each of the ten lowest-lying, thermally-accessible conformers of β-alanine. Eigenphase sums, resonance features, differential and integral cross sections are computed for each conformer. The positions of the low-energy shape resonance associated with the unoccupied {π }* orbital of the -COOH group are found to vary from 2.5 to 3.3 eV and the resonance widths from 0.2 to 0.5 eV depending on the conformation. The temperature-dependent population ratios are derived, based on temperature-corrected Gibbs free energies. Averaged cross sections for thermal mixtures of the 10 conformers are presented. A comparison with previous results for the α-alanine isomer is also presented.

  1. Global Transcriptional and Physiological Responses of Saccharomyces cerevisiae to Ammonium, L-Alanine, or L-Glutamine Limitation

    DEFF Research Database (Denmark)

    Usaite, Renata; Patil, Kiran Raosaheb; Grotkjær, Thomas

    2006-01-01

    The yeast Saccharomyces cerevisiae encounters a range of nitrogen sources at various concentrations in its environment. The impact of these two parameters on transcription and metabolism was studied by growing S. cerevisiae in chemostat cultures with L-glutamine, L-alanine, or L-ammonium in limit......The yeast Saccharomyces cerevisiae encounters a range of nitrogen sources at various concentrations in its environment. The impact of these two parameters on transcription and metabolism was studied by growing S. cerevisiae in chemostat cultures with L-glutamine, L-alanine, or L...... repression (NCR) may be responsible for this regulation. Ninety-one genes had transcript levels on both L-glutamine and ammonium that were decreased compared to those on L-alanine, independent of the concentration. The GATAAG element in these genes suggests two groups of NCR-responsive genes, those...

  2. Establishing a synthetic pathway for high-level production of 3-hydroxypropionic acid in Saccharomyces cerevisiae via β-alanine

    DEFF Research Database (Denmark)

    Borodina, Irina; Kildegaard, Kanchana Rueksomtawin; Jensen, Niels Bjerg

    2015-01-01

    . With the objective of developing Saccharomyces cerevisiae as an efficient cell factory for highlevel production of 3HP, we identified the ß-alanine biosynthetic route as the most economically attractive according to the metabolic modeling. We engineered and optimized a synthetic pathway for de novo biosynthesis of ß......-alanine and its subsequent conversion into 3HP using a novel ß-alanine-pyruvate aminotransferase discovered in Bacillus cereus. The final strain produced 3HP at a titer of 13.7±0.3 g・L-1 with a 0.14±0.0 C-mol・C-mol-1 yield on glucose in 80 hours in controlled fed-batch fermentation in mineral medium at pH 5...

  3. The effect of irradiation temperatures between ambient and 80 deg. C on the response of alanine dosimeters

    DEFF Research Database (Denmark)

    Sharpe, P.H.G.; Miller, Arne; Sephton, J.P.

    2009-01-01

    Published data on the effect of irradiation temperature on the response of alanine dosimeters does not extend to the temperatures that may be experienced in high-dose industrial irradiations, particularly in the case of electron beams. We describe here results of the irradiation of alanine...... dosimeters at temperatures up to 80 °C and doses up to 70 kGy. Data have been obtained for both 60Co and electron beam irradiations and the effect of temperature on the stability of the radiation-induced signal has also been investigated. At temperatures above 50 °C the irradiation temperature coefficient...... begins to deviate significantly from linearity and shows marked dose dependence. The effect of this behaviour under conditions typically experienced in industrial processing is evaluated and recommendations made concerning the use of alanine dosimeters at high doses and temperatures....

  4. Biomarkers in Neurocritical Care

    OpenAIRE

    Kimberly, W. Taylor

    2011-01-01

    The gold standard for assessing neurological function is the bedside clinical examination. However, in neurocritical patients, the signs and symptoms related to the severity of illness can often be ambiguous. It can be hard to distinguish between a severe but stable disease state and one that is dynamic and in a critical decline. Clinicians and family members alike may struggle with the uncertainty of functional outcome prediction. Intermediate biomarkers of brain injury can assist with ongoi...

  5. Biomarkers of Selenium Status

    Directory of Open Access Journals (Sweden)

    Gerald F. Combs, Jr.

    2015-03-01

    Full Text Available The essential trace element, selenium (Se, has multiple biological activities, which depend on the level of Se intake. Relatively low Se intakes determine the expression of selenoenzymes in which it serves as an essential constituent. Higher intakes have been shown to have anti-tumorigenic potential; and very high Se intakes can produce adverse effects. This hierarchy of biological activities calls for biomarkers informative at different levels of Se exposure. Some Se-biomarkers, such as the selenoproteins and particularly GPX3 and SEPP1, provide information about function directly and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se-treatment. They are useful under conditions of Se intake within the range of regulated selenoprotein expression, e.g., for humans <55 μg/day and for animals <20 μg/kg diet. Other Se-biomarkers provide information indirectly through inferences based on Se levels of foods, tissues, urine or feces. They can indicate the likelihood of deficiency or adverse effects, but they do not provide direct evidence of either condition. Their value is in providing information about Se status over a wide range of Se intake, particularly from food forms. There is need for additional Se biomarkers particularly for assessing Se status in non-deficient individuals for whom the prospects of cancer risk reduction and adverse effects risk are the primary health considerations. This would include determining whether supranutritional intakes of Se may be required for maximal selenoprotein expression in immune surveillance cells. It would also include developing methods to determine low molecular weight Se-metabolites, i.e., selenoamino acids and methylated Se-metabolites, which to date have not been detectable in biological specimens. Recent analytical advances using tandem liquid chromatography-mass spectrometry suggest prospects for detecting these metabolites.

  6. The VA and VCD spectra of various isotopomers of L-alanine in aqueous solution

    DEFF Research Database (Denmark)

    Abdali, Salim; Jalkanen, Karl J.; Bohr, Henrik

    2002-01-01

    Density functional theory (DFT) at the Becke 3LYP level has been used to calculate the vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra of various deuterated species Of L-alanine. The effect of replacing the methine hydrogen, CH1, the methyl group, CH3, and both...... changes in the VA and VCD spectra are used as a check of the Becke 3LYP hybrid model to successfully reproduce these fine features in the VA and VCD intensities. Furthermore, several aspects of the isotopomers and the isotope effects on vibrational spectra are discussed in the light of the approximation......, i.e., validity of Born-Oppenheimer approximation. (C) 2002 Elsevier Science B.V. All rights reserved....

  7. Densities and solubilities of Glycylglycine and Glycyl-L-Alanine in Aqueous Electrolyte Solutions

    DEFF Research Database (Denmark)

    Breil, Martin Peter; Mollerup, Jørgen; Rudolph, E. Susanne J.

    2004-01-01

    is 1.74 and 4.78 mol/kg of water, respectively. The solubility of glycylglycine in salt solutions of NaCl, Na2SO4, and (NH4)(2)SO4 show a moderate salting-in effect. The solubility of glycyl-L-alanine show a minor or no salting-in effect at low salt concentrations and a moderate salting-out effect...... at higher salt concentrations in NaCl and Na2SO4, and in (NH4)(2)SO4 the solubility is almost constant. The densities of the solutions have been determined experimentally, and the volume expansions by dissolving salt and dipeptide in water have been calculated. (C) 2003 Elsevier B.V. All rights reserved....

  8. Excitatory amino acid b-N-methylamino-L-alanine is a putative environmental neurotoxin

    Directory of Open Access Journals (Sweden)

    VLADIMIR NEDELJKOV

    2011-04-01

    Full Text Available The amino acid b-N-methylamino-L-alanine (L-BMAA has been associated with the amyotrophic lateral sclerosis/parkinsonism-dementia complex in three distinct western Pacific populations. The putative neurotoxin is produced by cyanobacteria, which live symbiotically in the roots of cycad trees. L-BMAA was thought to be a threat only to those few populations whose diet and medicines rely heavily on cycad seeds. However, the recent discovery that cyanobacteria from diverse terrestrial, freshwater, and saltwater ecosystems around the world produce the toxin requires a reassessment of whether it poses a larger health threat. Therefore, it is proposed that monitoring L-BMAA levels in cyanobacteria-contaminated water supplies might be prudent.

  9. Dosimetry auditing procedure with alanine dosimeters for light ion beam therapy

    DEFF Research Database (Denmark)

    Ableitinger, Alexander; Vatnitsky, Stanislav; Herrmann, Rochus

    2013-01-01

    Background and purpose In the next few years the number of facilities providing ion beam therapy with scanning beams will increase. An auditing process based on an end-to-end test (including CT imaging, planning and dose delivery) could help new ion therapy centres to validate their entire logistic...... chain of radiation delivery. An end-to-end procedure was designed and tested in both scanned proton and carbon ion beams, which may also serve as a dosimetric credentialing procedure for clinical trials in the future. The developed procedure is focused only on physical dose delivery and the validation...... of the biological dose is out of scope of the current work. Materials and methods The audit procedure was based on a homogeneous phantom that mimics the dimension of a head (20 × 20 × 21 cm3). The phantom can be loaded either with an ionisation chamber or 20 alanine dosimeters plus 2 radiochromic EBT films. Dose...

  10. Assessment of an alanine EPR dosimetry technique with enhanced precision and accuracy

    CERN Document Server

    Hayes, R B; Wieser, A; Romanyukha, A A; Hardy, B L; Barrus, J K

    2000-01-01

    Dose reconstruction in the course of a series of blind tests demonstrated that an accuracy of 10 mGy for low doses and 1% for high doses can be achieved using EPR spectroscopy. This was accomplished using a combination of methodologies including polynomial filtration of the EPR spectrum, dosimeter rotation during scanning, use of an EPR standard fixed into the resonator and subtraction of all nonradiogenic signals. Doses were reconstructed over the range of 0.01-1000 Gy using this compound spectral EPR analysis. This EPR technique, being equally applicable to fractionated doses (such as those delivered during multiple radiotherapy treatments), was verified to exhibit dose reciprocity. Irradiated alanine dosimeters which were stored exhibited compound spectral EPR signal fading of ca 3% over 9 months. All error estimates given in this paper are given at the 1 standard deviation level and unless otherwise specified do not account for uncertainties in source calibration.

  11. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats Transplante de hepatócitos recém-isolados em um modelo de hepatotoxicidade induzida por acetaminofeno em ratos

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.CONTEXTO: O transplante de hepatócitos é uma modalidade terapêutica atrativa para doenças hepáticas como alternativa ao transplante hepático ortotópico. OBJETIVO: Investigar a factibilidade do uso de hepatócitos frescos isolados de ratos em um modelo de hepatotoxicidade induzida por paracetamol. MÉTODOS: Hepatócitos foram isolados de ratos Wistar machos e transplantados 24 horas após a administração de paracetamol em receptores fêmeas. As ratas receberam 1x10(7 hepatócitos ou tampão salina fosfato pela veia porta ou no baço e foram sacrificadas após 48 horas. RESULTADOS: Os níveis de alanina aminotransferase medidos durante o experimento não diferiram entre os grupos em nenhum momento. Análises moleculares e histológicas demonstraram a presença de hepatócitos no fígado dos animais transplantados pelo baço ou pela veia porta. CONCLUSÃO: Os dados indicam a factibilidade e eficácia do

  12. [Biomarkers of cardiorenal syndrome].

    Science.gov (United States)

    Kuster, Nils; Moréna, Marion; Bargnoux, Anne-Sophie; Leray, Hélène; Chenine, Leila; Dupuy, Anne-Marie; Canaud, Bernard; Cristol, Jean-Paul

    2013-01-01

    Complex interactions existing between cardiac and renal diseases led to define 5 types of so-called cardiorenal syndromes. This classification is based on the organ primarily involved and the acute or chronic failure. The mutual impact of renal and cardiac functions makes it difficult to evaluate and manage patients with cardiorenal syndromes and worsen morbidity and mortality. This review seeks to discuss the place of biomarkers in diagnosis, management and follow-up of patients with cardiorenal syndromes. Biomarkers can be classified as functional (creatinine, cystatin C…) or lesional (neutrophil gelatinase-associated lipocalin, urinary cystatin C…) renal markers and functional (natriuretic peptides…) or lesional (troponin, fatty acid binding protein) cardiac markers. A last kind of biomarkers reflects the dialogue between heart and kidney (renin-angiotensin-aldosteron-system, indicators of activation of arginine vasopressin system) or the systemic impact (inflammation, oxidative stress…). In order to evaluate accurately the complex interactions that are the basis of cardiorenal syndromes, a multi-marker approach seems nowadays necessary.

  13. Alanine and proline content modulate global sensitivity to discrete perturbations in disordered proteins.

    Science.gov (United States)

    Perez, Romel B; Tischer, Alexander; Auton, Matthew; Whitten, Steven T

    2014-12-01

    Molecular transduction of biological signals is understood primarily in terms of the cooperative structural transitions of protein macromolecules, providing a mechanism through which discrete local structure perturbations affect global macromolecular properties. The recognition that proteins lacking tertiary stability, commonly referred to as intrinsically disordered proteins (IDPs), mediate key signaling pathways suggests that protein structures without cooperative intramolecular interactions may also have the ability to couple local and global structure changes. Presented here are results from experiments that measured and tested the ability of disordered proteins to couple local changes in structure to global changes in structure. Using the intrinsically disordered N-terminal region of the p53 protein as an experimental model, a set of proline (PRO) and alanine (ALA) to glycine (GLY) substitution variants were designed to modulate backbone conformational propensities without introducing non-native intramolecular interactions. The hydrodynamic radius (R(h)) was used to monitor changes in global structure. Circular dichroism spectroscopy showed that the GLY substitutions decreased polyproline II (PP(II)) propensities relative to the wild type, as expected, and fluorescence methods indicated that substitution-induced changes in R(h) were not associated with folding. The experiments showed that changes in local PP(II) structure cause changes in R(h) that are variable and that depend on the intrinsic chain propensities of PRO and ALA residues, demonstrating a mechanism for coupling local and global structure changes. Molecular simulations that model our results were used to extend the analysis to other proteins and illustrate the generality of the observed PRO and alanine effects on the structures of IDPs. © 2014 Wiley Periodicals, Inc.

  14. Chiral selectivity of amino acid adsorption on chiral surfaces—The case of alanine on Pt

    Energy Technology Data Exchange (ETDEWEB)

    Franke, J.-H.; Kosov, D. S. [Department of Physics, Campus Plaine - CP 231, Université Libre de Bruxelles, 1050 Brussels (Belgium)

    2015-02-07

    We study the binding pattern of the amino acid alanine on the naturally chiral Pt surfaces Pt(531), Pt(321), and Pt(643). These surfaces are all vicinal to the (111) direction but have different local environments of their kink sites and are thus a model for realistic roughened Pt surfaces. Alanine has only a single methyl group attached to its chiral center, which makes the number of possible binding conformations computationally tractable. Additionally, only the amine and carboxyl group are expected to interact strongly with the Pt substrate. On Pt(531), we study the molecule in its pristine as well as its deprotonated form and find that the deprotonated one is more stable by 0.47 eV. Therefore, we study the molecule in its deprotonated form on Pt(321) and Pt(643). As expected, the oxygen and nitrogen atoms of the deprotonated molecule provide a local binding “tripod” and the most stable adsorption configurations optimize the interaction of this “tripod” with undercoordinated surface atoms. However, the interaction of the methyl group plays an important role: it induces significant chiral selectivity of about 60 meV on all surfaces. Hereby, the L-enantiomer adsorbs preferentially to the Pt(321){sup S} and Pt(643){sup S} surfaces, while the D-enantiomer is more stable on Pt(531){sup S}. The binding energies increase with increasing surface density of kink sites, i.e., they are largest for Pt(531){sup S} and smallest for Pt(643){sup S}.

  15. Overexpression of genes encoding glycolytic enzymes in Corynebacterium glutamicum enhances glucose metabolism and alanine production under oxygen deprivation conditions.

    Science.gov (United States)

    Yamamoto, Shogo; Gunji, Wataru; Suzuki, Hiroaki; Toda, Hiroshi; Suda, Masako; Jojima, Toru; Inui, Masayuki; Yukawa, Hideaki

    2012-06-01

    We previously reported that Corynebacterium glutamicum strain ΔldhAΔppc+alaD+gapA, overexpressing glyceraldehyde-3-phosphate dehydrogenase-encoding gapA, shows significantly improved glucose consumption and alanine formation under oxygen deprivation conditions (T. Jojima, M. Fujii, E. Mori, M. Inui, and H. Yukawa, Appl. Microbiol. Biotechnol. 87:159-165, 2010). In this study, we employ stepwise overexpression and chromosomal integration of a total of four genes encoding glycolytic enzymes (herein referred to as glycolytic genes) to demonstrate further successive improvements in C. glutamicum glucose metabolism under oxygen deprivation. In addition to gapA, overexpressing pyruvate kinase-encoding pyk and phosphofructokinase-encoding pfk enabled strain GLY2/pCRD500 to realize respective 13% and 20% improved rates of glucose consumption and alanine formation compared to GLY1/pCRD500. Subsequent overexpression of glucose-6-phosphate isomerase-encoding gpi in strain GLY3/pCRD500 further improved its glucose metabolism. Notably, both alanine productivity and yield increased after each overexpression step. After 48 h of incubation, GLY3/pCRD500 produced 2,430 mM alanine at a yield of 91.8%. This was 6.4-fold higher productivity than that of the wild-type strain. Intracellular metabolite analysis showed that gapA overexpression led to a decreased concentration of metabolites upstream of glyceraldehyde-3-phosphate dehydrogenase, suggesting that the overexpression resolved a bottleneck in glycolysis. Changing ratios of the extracellular metabolites by overexpression of glycolytic genes resulted in reduction of the intracellular NADH/NAD(+) rat