Early Endosomal Escape of a Cyclic Cell-Penetrating Peptide Allows Effective Cytosolic Cargo Delivery

PubMed Central

2015-01-01

Cyclic heptapeptide cyclo(FΦRRRRQ) (cFΦR4, where Φ is l-2-naphthylalanine) was recently found to be efficiently internalized by mammalian cells. In this study, its mechanism of internalization was investigated by perturbing various endocytic events through the introduction of pharmacologic agents and genetic mutations. The results show that cFΦR4 binds directly to membrane phospholipids, is internalized into human cancer cells through endocytosis, and escapes from early endosomes into the cytoplasm. Its cargo capacity was examined with a wide variety of molecules, including small-molecule dyes, linear and cyclic peptides of various charged states, and proteins. Depending on the nature of the cargos, they may be delivered by endocyclic (insertion of cargo into the cFΦR4 ring), exocyclic (attachment of cargo to the Gln side chain), or bicyclic approaches (fusion of cFΦR4 and cyclic cargo rings). The overall delivery efficiency (i.e., delivery of cargo into the cytoplasm and nucleus) of cFΦR4 was 4–12-fold higher than those of nonaarginine, HIV Tat-derived peptide, or penetratin. The higher delivery efficiency, coupled with superior serum stability, minimal toxicity, and synthetic accessibility, renders cFΦR4 a useful transporter for intracellular cargo delivery and a suitable system for investigating the mechanism of endosomal escape. PMID:24896852

Adrenergic modulation of hepatotoxicity.

PubMed

Roberts, S M; DeMott, R P; James, R C

1997-01-01

Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for

Herbal hepatotoxicity: a tabular compilation of reported cases.

PubMed

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.

In vitro transcriptomic prediction of hepatotoxicity for early drug discovery

PubMed Central

Cheng, Feng; Theodorescu, Dan; Schulman, Ira G.; Lee, Jae K.

2012-01-01

Liver toxicity (hepatotoxicity) is a critical issue in drug discovery and development. Standard preclinical evaluation of drug hepatotoxicity is generally performed using in vivo animal systems. However, only a small number of preselected compounds can be examined in vivo due to high experimental costs. A more efficient yet accurate screening technique which can identify potentially hepatotoxic compounds in the early stages of drug development would thus be valuable. Here, we develop and apply a novel genomic prediction technique for screening hepatotoxic compounds based on in vitro human liver cell tests. Using a training set of in vivo rodent experiments for drug hepatotoxicity evaluation, we discovered common biomarkers of drug-induced liver toxicity among six heterogeneous compounds. This gene set was further triaged to a subset of 32 genes that can be used as a multi-gene expression signature to predict hepatotoxicity. This multi-gene predictor was independently validated and showed consistently high prediction performance on five test sets of in vitro human liver cell and in vivo animal toxicity experiments. The predictor also demonstrated utility in evaluating different degrees of toxicity in response to drug concentrations which may be useful not only for discerning a compound’s general hepatotoxicity but also for determining its toxic concentration. PMID:21884709

Hepatotoxicity during Treatment for Tuberculosis in People Living with HIV/AIDS.

PubMed

Araújo-Mariz, Carolline; Lopes, Edmundo Pessoa; Acioli-Santos, Bartolomeu; Maruza, Magda; Montarroyos, Ulisses Ramos; Ximenes, Ricardo Arraes de Alencar; Lacerda, Heloísa Ramos; Miranda-Filho, Demócrito de Barros; Albuquerque, Maria de Fátima P Militão de

2016-01-01

Hepatotoxicity is frequently reported as an adverse reaction during the treatment of tuberculosis. The aim of this study was to determine the incidence of hepatotoxicity and to identify predictive factors for developing hepatotoxicity after people living with HIV/AIDS (PLWHA) start treatment for tuberculosis. This was a prospective cohort study with PLWHA who were monitored during the first 60 days of tuberculosis treatment in Pernambuco, Brazil. Hepatotoxicity was considered increased levels of aminotransferase, namely those that rose to three times higher than the level before initiating tuberculosis treatment, these levels being associated with symptoms of hepatitis. We conducted a multivariate logistic regression analysis and the magnitude of the associations was expressed by the odds ratio with a confidence interval of 95%. Hepatotoxicity was observed in 53 (30.6%) of the 173 patients who started tuberculosis treatment. The final multivariate logistic regression model demonstrated that the use of fluconazole, malnutrition and the subject being classified as a phenotypically slow acetylator increased the risk of hepatotoxicity significantly. The incidence of hepatotoxicity during treatment for tuberculosis in PLWHA was high. Those classified as phenotypically slow acetylators and as malnourished should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis. The use of fluconazole should be avoided during tuberculosis treatment in PLWHA.

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

PubMed Central

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

Inhibition of Insulin Amyloid Fibrillation by a Novel Amphipathic Heptapeptide

PubMed Central

Ratha, Bhisma N.; Ghosh, Anirban; Brender, Jeffrey R.; Gayen, Nilanjan; Ilyas, Humaira; Neeraja, Chilukoti; Das, Kali P.; Mandal, Atin K.; Bhunia, Anirban

2016-01-01

The aggregation of insulin into amyloid fibers has been a limiting factor in the development of fast acting insulin analogues, creating a demand for excipients that limit aggregation. Despite the potential demand, inhibitors specifically targeting insulin have been few in number. Here we report a non-toxic and serum stable-designed heptapeptide, KR7 (KPWWPRR-NH2), that differs significantly from the primarily hydrophobic sequences that have been previously used to interfere with insulin amyloid fibrillation. Thioflavin T fluorescence assays, circular dichroism spectroscopy, and one-dimensional proton NMR experiments suggest KR7 primarily targets the fiber elongation step with little effect on the early oligomerization steps in the lag time period. From confocal fluorescence and atomic force microscopy experiments, the net result appears to be the arrest of aggregation in an early, non-fibrillar aggregation stage. This mechanism is noticeably different from previous peptide-based inhibitors, which have primarily shifted the lag time with little effect on later stages of aggregation. As insulin is an important model system for understanding protein aggregation, the new peptide may be an important tool for understanding peptide-based inhibition of amyloid formation. PMID:27679488

Paracetamol poisoning in children and hepatotoxicity.

PubMed Central

Penna, A; Buchanan, N

1991-01-01

1. Paracetamol is one of the most common drugs that children accidentally ingest. Unlike the situation in adults, death and hepatotoxicity in children from paracetamol poisoning are exceedingly uncommon events. A review of the literature has revealed only seven deaths and fourteen cases of hepatotoxicity in children, with most of the cases resulting from chronic poisoning and not acute poisoning. 2. Children may be less prone to paracetamol hepatotoxicity because of developmental differences in the drug's metabolism and its pathways of detoxification. In the therapeutic setting of treatment of fever and pain in children, paracetamol is regarded as a drug with a higher therapeutic index, and as such, there seems to be little concern with strict adherence to dosage regimes. 3. Scrutiny of the above paediatric cases associated with chronic paracetamol poisoning suggests that the margin of safety of frequent therapeutic doses of paracetamol in infants and young children to be a lot lower than previously appreciated. This review highlights the need to re-evaluate the safety of paracetamol in the context of chronic therapy in infants and young children. PMID:1931463

Research Advances on Hepatotoxicity of Herbal Medicines in China.

PubMed

Liu, Changxiao; Fan, Huirong; Li, Yazhuo; Xiao, Xiaohe

2016-01-01

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.

Research Advances on Hepatotoxicity of Herbal Medicines in China

PubMed Central

Fan, Huirong; Li, Yazhuo; Xiao, Xiaohe

2016-01-01

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. PMID:28078299

Cherimolacyclopeptide D, a novel cycloheptapeptide from the seeds of Annona cherimola.

PubMed

Wélé, Alassane; Ndoye, Idrissa; Zhang, Yanjun; Brouard, Jean-Paul; Bodo, Bernard

2005-03-01

In a chemical investigation of the seeds of Annona cherimola, a natural cyclic heptapeptide, cherimolacyclopeptide D, were isolated and purified by HPLC with three known cyclic peptides, cherimolacyclopeptides A, B and C. The structure was established by various analyses including MS/MS fragmentation, spectroscopic and chemical evidences.

Role of metabolism in drug-induced idiosyncratic hepatotoxicity.

PubMed

Walgren, Jennie L; Mitchell, Michael D; Thompson, David C

2005-01-01

Rare adverse reactions to drugs that are of unknown etiology, or idiosyncratic reactions, can produce severe medical complications or even death in patients. Current hypotheses suggest that metabolic activation of a drug to a reactive intermediate is a necessary, yet insufficient, step in the generation of an idiosyncratic reaction. We review evidence for this hypothesis with drugs that are associated with hepatotoxicity, one of the most common types of idiosyncratic reactions in humans. We identified 21 drugs that have either been withdrawn from the U.S. market due to hepatotoxicity or have a black box warning for hepatotoxicity. Evidence for the formation of reactive metabolites was found for 5 out of 6 drugs that were withdrawn, and 8 out of 15 drugs that have black box warnings. For the other drugs, either evidence was not available or suitable studies have not been carried out. We also review evidence for reactive intermediate formation from a number of additional drugs that have been associated with idiosyncratic hepatotoxicity but do not have black box warnings. Finally, we consider the potential role that high dosages may play in these adverse reactions.

Synthesis and contractile activity of the C-terminal heptapeptide of substance P with N5-dimethyl glutamine in the 6-position. Active site studies.

PubMed

Poulos, C P; Pinas, N; Theodoropoulos, D

1980-09-15

The synthesis and testing of [N5-dimethyl-Gln6]-SP5-11 showed 37 +/- 12% contractile activity relative to SP, and intrinsic efficacy 98 +/- 4%. This finding indicates that the carboxamide groups of the dual Gln5-Cln6 moiety are not equally related with the contractile response of the C-terminal heptapeptide of SP.

Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease.

PubMed

Wong, D R; Coenen, M J H; Derijks, L J J; Vermeulen, S H; van Marrewijk, C J; Klungel, O H; Scheffer, H; Franke, B; Guchelaar, H-J; de Jong, D J; Engels, L G J B; Verbeek, A L M; Hooymans, P M

2017-02-01

Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations. To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5. Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 × 10 8 erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7). In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure. © 2016 John Wiley & Sons Ltd.

Microbiota transplantation reveals beneficial impact of berberine on hepatotoxicity by improving gut homeostasis.

PubMed

Qin, Chenjie; Zhang, Huilu; Zhao, Linghao; Zeng, Min; Huang, Weijian; Fu, Gongbo; Zhou, Weiping; Wang, Hongyang; Yan, Hexin

2017-11-29

Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products and metabolites. In this study, we showed that berberine has beneficial effects on both hepatotoxicity and intestinal damage in a rat model of chronic or acute liver injury. Microbiota transplantation from the rats with chronic hepatotoxicity could aggravate acute hepatotoxicity in mice treated with diethylnitrosamine (DEN). In rat models with gut homeostasis disruption induced by penicillin or dextran sulfate sodium (DSS), their fecal microbiota could also cause an enhanced hepatotoxicity of recipient mice. When treated with berberine, the DSS-induced enteric dysbacteriosis could be mitigated and their fecal bacteria were able to reduce acute hepatotoxicity in recipient mice. This study indicates that berberine could improve intestinal dysbacteriosis, which reduces the hepatotoxicity caused by pathological or pharmacological intervention. Fecal microbiota transplantation might be a useful method to directly explore homeostatic alteration in gut microbiota.

IL-1RN and IL-1β Polymorphism and ARV-Associated Hepatotoxicity

PubMed Central

Samani, Dharmesh; Nema, Vijay; Gangakhedkar, R. R.

2018-01-01

The severity of hepatic injury depends upon cytokines. Previous studies associated IL-1RN allele 2 with IL-1β production. Hence, we examined the association of IL-1 RN and IL-1β polymorphisms with ARV-associated hepatotoxicity. Genotyping of IL-1RN (VNTR), IL-1β (-511C/T) polymorphisms was done in 162 HIV-infected patients, 34 with ARV hepatotoxicity, 128 without hepatotoxicity, and 152 healthy controls using PCR and PCR-RFLP method. The haplotypes 1T and 2C enhanced the risk for severe hepatotoxicity (OR = 1.41, P = 0.25; OR = 1.67, P = 0.31). IL-1β-511TT genotype significantly represented among tobacco using HIV-infected individuals compared to nonusers (OR = 3.74, P = 0.05). IL-1β-511TT genotype among alcohol users increased the risk for hepatotoxicity (OR = 1.80, P = 0.90). IL-1β-511CT and -511TT genotypes overrepresented in alcohol using HIV-infected individuals (OR = 2.29, P = 0.27; OR = 2.64, P = 0.19). IL-RN 2/2 and 1/3 genotypes represented higher in nevirapine using hepatotoxicity patients (OR = 1.42, P = 0.64, OR = 8.79, P = 0.09). IL-1β-511CT and -511 TT genotypes among nevirapine users enhanced the risk for severe hepatotoxicity (OR = 4.29, P = 0.20; OR = 1.95, P = 0.56). IL-1β-511CT and -511TT genotypes were overrepresented in combined nevirapine and alcohol using HIV-infected individuals as compared to nevirapine users and alcohol nonusers (OR = 2.56, P = 0.26; OR = 2.84, P = 0.24). IL-1β-511TT genotype with tobacco, alcohol, and nevirapine usage revealed a trend of risk for the development of ARV-associated hepatotoxicity and its severity.

A case of lacosamide-induced hepatotoxicity.

PubMed

Sunwoo, Jun-Sang; Byun, Jung-Ick; Lee, Sang Kun

2015-06-01

Lacosamide is a novel antiepileptic drug that acts mainly via the selective enhancement of slow inactivation of voltage-gated sodium channels. It has been reported that lacosamide is effective and generally tolerable as an adjuvant treatment in patients with partial seizures. There are few reports regarding liver damage caused by lacosamide. We describe a case of a patient with drug-resistant epilepsy who developed symptomatic hepatotoxicity after lacosamide administration. A 22-year-old female with a 2-year history of temporal lobe epilepsy was admitted to our hospital because of nausea, dizziness, and abnormal liver function tests. Lacosamide was added for further seizure control 9 days before the current presentation. Her liver enzymes were markedly increased: aspartate aminotransferase, 635 U/L; alanine aminotransferase, 697 U/L. Lacosamide was ceased immediately, whereas other medications (zonisamide, clobazam, and tianeptine) were not withdrawn. The level of liver enzymes improved significantly within a few days, and a diagnosis of lacosamide-induced hepatitis was made based on the obvious temporal relationship. This case report demonstrates that hepatotoxicity may develop in association with lacosamide therapy. Liver function tests should be prompted in patients with symptoms suggestive of adverse effects after the initiation of lacosamide. Further research is required to identify predisposing factors of lacosamideinduced hepatotoxicity.

[Hepatotoxicity associated with the use of Herbalife].

PubMed

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. < 20 micromol/L), ALP 407 U/L (range: 149-712; ref. 35-105 U/L) and ALT 24 87 U/L (range: 456-2637; ref. 70 and 45 U/L for males and females, respectively). Liver biopsy was performed in 2 patients and was consistent with toxic hepatitis in both cases. Other causes of hepatitis were excluded by appropriate serological testing and ultrasound. Causality assessment according to RUCAM was probable in three cases and possible in two. Using the WHO-UMC criteria causality was certain in one case, probable in two and possible in two cases. Hepatotoxicity is probably associated with the use of Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury.

Hepatotoxic constituents and toxicological mechanism of Xanthium strumarium L. fruits.

PubMed

Xue, Li-Ming; Zhang, Qiao-Yan; Han, Ping; Jiang, Yi-Ping; Yan, Rong-Di; Wang, Yang; Rahman, Khalid; Jia, Min; Han, Ting; Qin, Lu-Ping

2014-03-14

In the recent years, the international community has attached increasing importance to possible toxicity associated with Traditional Chinese Medicine (TCM). And hepatotoxicity is one of the major concerns, a fundamental pathological process induced by toxicant. This paper is in an attempt to identify the hepatotoxic components in Xanthium strumarium L. fruits (XSF) and interpret the toxicological mechanism induced by XSF. XSF extract was prepared and seven characteristic components were isolated and identified in XSF water extracts. We evaluated their hepatotoxicity effect on cell proliferation and lactate dehydrogenase (LDH) activity in L-02 and BRL liver cell line. An integrated metabonomics study using high-resolution (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy combined with multivariate statistical analysis was undertake to elucidate the hepatotoxicity mechanism induced in rats by XSF. The urine and serum metabolites were measured after treatment of rats with XSF (7.5, 15.0 and 30.0 g/kg/day) for 5 days. The results showed that atractyloside, carboxyatractyloside, 4'-desulphate-atractyloside and XSF induced significant cytotoxic effects in both L-02 and BRL liver cell lines, indicating that atractyloside, carboxyatractyloside, and 4'-desulphate-atractyloside were the toxic components of XSF. When rats were treated with XSF at 30.0 g/kg the hepatotoxicity was reflected in the changes observed in serum biochemical profiles and by the histopathological examination of the liver. The levels of VLDL/LDL, 3-HB, lactate, acetate, acetone and glutamate in serum were increased in this group, while d-glucose, choline and valine were decreased. The elevation in the levels of succinate, citrate, 2-oxo-glutamate, glycine, 3-HB, acetate, lactate, hippurate, dimethylglycine, methylamine, dimethylamine, phenylalanine and tryptophan was observed in urine, in contrast a reduction in the intensities of taurine, d-glucose, N-acetyl-glucoprotein and trimethylamine

Hepatotoxicity of NONI juice: Report of two cases

PubMed Central

Stadlbauer, Vanessa; Fickert, Peter; Lackner, Carolin; Schmerlaib, Jutta; Krisper, Peter; Trauner, Michael; Stauber, Rudolf E

2005-01-01

AIM: NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses. No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed. The first patient underwent successful liver transplantation while the second patient recovered spontaneously after cessation of NONI juice. A 29-year-old man with previous toxic hepatitis associated with small doses of paracetamol developed sub-acute hepatic failure following consumption of 1.5 L NONI juice over 3 wk necessitating urgent liver transplantation. A 62-year-old woman without evidence of previous liver disease developed an episode of self-limited acute hepatitis following consumption of 2 L NONI juice for over 3 mo. The most likely hepatotoxic components of Morinda citrifolia were anthraquinones. Physicians should be aware of potential hepatotoxicity of NONI juice. PMID:16094725

Expansion and diversification of the MSDIN family of cyclic peptide genes in the poisonous agarics Amanita phalloides and A. bisporigera

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pulman, Jane A.; Childs, Kevin L.; Sgambelluri, R. Michael

Here, the cyclic peptide toxins of Amanita mushrooms, such as α-amanitin and phalloidin, are encoded by the “MSDIN” gene family and ribosomally biosynthesized. Based on partial genome sequence and PCR analysis, some members of the MSDIN family were previously identified in Amanita bisporigera, and several other members are known from other species of Amanita. However, the complete complement in any one species, and hence the genetic capacity for these fungi to make cyclic peptides, remains unknown. As a result, draft genome sequences of two cyclic peptide-producing mushrooms, the “Death Cap” A. phalloides and the “Destroying Angel” A. bisporigera, were obtained.more » Each species has ~30 MSDIN genes, most of which are predicted to encode unknown cyclic peptides. Some MSDIN genes were duplicated in one or the other species, but only three were common to both species. A gene encoding cycloamanide B, a previously described nontoxic cyclic heptapeptide, was also present in A. phalloides, but genes for antamanide and cycloamanides A, C, and D were not. In A. bisporigera, RNA expression was observed for 20 of the MSDIN family members. Based on their predicted sequences, novel cyclic peptides were searched for by LC/MS/MS in extracts of A. phalloides. The presence of two cyclic peptides, named cycloamanides E and F with structures cyclo(SFFFPVP) and cyclo(IVGILGLP), was thereby demonstrated. Of the MSDIN genes reported earlier from another specimen of A. bisporigera, 9 of 14 were not found in the current genome assembly. Differences between previous and current results for the complement of MSDIN genes and cyclic peptides in the two fungi probably represents natural variation among geographically dispersed isolates of A. phalloides and among the members of the poorly defined A. bisporigera species complex. Both A. phalloides and A. bisporigera contain two prolyl oligopeptidase genes, one of which (POPB) is probably dedicated to cyclic peptide biosynthesis

Expansion and diversification of the MSDIN family of cyclic peptide genes in the poisonous agarics Amanita phalloides and A. bisporigera

DOE PAGES

Pulman, Jane A.; Childs, Kevin L.; Sgambelluri, R. Michael; ...

2016-12-15

Here, the cyclic peptide toxins of Amanita mushrooms, such as α-amanitin and phalloidin, are encoded by the “MSDIN” gene family and ribosomally biosynthesized. Based on partial genome sequence and PCR analysis, some members of the MSDIN family were previously identified in Amanita bisporigera, and several other members are known from other species of Amanita. However, the complete complement in any one species, and hence the genetic capacity for these fungi to make cyclic peptides, remains unknown. As a result, draft genome sequences of two cyclic peptide-producing mushrooms, the “Death Cap” A. phalloides and the “Destroying Angel” A. bisporigera, were obtained.more » Each species has ~30 MSDIN genes, most of which are predicted to encode unknown cyclic peptides. Some MSDIN genes were duplicated in one or the other species, but only three were common to both species. A gene encoding cycloamanide B, a previously described nontoxic cyclic heptapeptide, was also present in A. phalloides, but genes for antamanide and cycloamanides A, C, and D were not. In A. bisporigera, RNA expression was observed for 20 of the MSDIN family members. Based on their predicted sequences, novel cyclic peptides were searched for by LC/MS/MS in extracts of A. phalloides. The presence of two cyclic peptides, named cycloamanides E and F with structures cyclo(SFFFPVP) and cyclo(IVGILGLP), was thereby demonstrated. Of the MSDIN genes reported earlier from another specimen of A. bisporigera, 9 of 14 were not found in the current genome assembly. Differences between previous and current results for the complement of MSDIN genes and cyclic peptides in the two fungi probably represents natural variation among geographically dispersed isolates of A. phalloides and among the members of the poorly defined A. bisporigera species complex. Both A. phalloides and A. bisporigera contain two prolyl oligopeptidase genes, one of which (POPB) is probably dedicated to cyclic peptide biosynthesis

Evidence for dimer formation by an amphiphilic heptapeptide that mediates chloride and carboxyfluorescein release from liposomes

PubMed Central

Pajewski, Robert; Ferdani, Riccardo; Pajewska, Jolanta; Djedovič, Natasha; Schlesinger, Paul H.; Gokel, George W.

2008-01-01

Heptapeptides having dioctadecyl, N-terminal hydrocarbon chains insert in phospholipid bilayer membranes and form pores through which at least chloride ions pass. Although amphiphilic, these compounds do not typically form vesicles themselves. They insert in the bilayers of phospholipid vesicles and mediate the release of carboxyfluorescein. Hill analysis indicates that at least two molecules of the amphiphile are involved in pore formation. In CD2Cl2, dimer formation is detected by NMR chemical shift changes. The anion release activity of individual anion transporters is increased by linking them covalently at the C-terminus or, even more, by linking them at the N-terminus. Evidence is presented that either linked molecule releases chloride from liposomes more effectively and rapidly than the individual transporter molecule at a comparable concentration. PMID:15703797

Neonicotinoid formaldehyde generators: possible mechanism of mouse-specific hepatotoxicity/hepatocarcinogenicity of thiamethoxam.

PubMed

Swenson, Tami L; Casida, John E

2013-02-04

Thiamethoxam (TMX), an important insecticide, is hepatotoxic and hepatocarcinogenic in mice but not rats. Studies of Syngenta Central Toxicology Laboratory on species specificity in metabolism established that TMX is a much better substrate for mouse liver microsomal CYPs than the corresponding rat or human enzymes in forming desmethyl-TMX (dm-TMX), which is also hepatotoxic, and clothianidin (CLO), which is not hepatotoxic or hepatocarcinogenic. They proposed that TMX hepatotoxicity/hepatocarcinogencity is due to dm-TMX and a further metabolite desmethyl-CLO (dm-CLO) (structurally analogous to a standard inducible nitric oxide synthase inhibitor) acting synergistically. The present study considers formation of formaldehyde (HCHO) and N-methylol intermediates as an alternative mechanism of TMX hepatotoxicity/hepatocarcinogenicity. Comparison of neonicotinoid metabolism by mouse, rat and human microsomes with NADPH showed two important points. First, TMX and dm-TMX yield more HCHO than any other commercial neonicotinoid. Second, mouse microsomes give much higher conversion than rat or human microsomes. These observations provide an alternative hypothesis of HCHO and N-methylol intermediates from CYP-mediated oxidative oxadiazinane ring cleavage as the bioactivated hepatotoxicants. However, the proposed mono-N-methylol CYP metabolites are not observed, possibly further reacting in situ. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre.

PubMed

Shu, C-C; Lee, C-H; Lee, M-C; Wang, J-Y; Yu, C-J; Lee, L-N

2013-07-01

Hepatotoxicity with first-line drugs, a major complication of anti-tuberculosis treatment, has not been studied by time-dependent analysis. Adult patients diagnosed with pulmonary tuberculosis (PTB) from 2005 to 2009 were reviewed retrospectively. Hepatotoxicity during anti-tuberculosis treatment was defined by symptomatic elevation of liver transaminases ≥3 times the upper limit of normal, or ≥5 times if asymptomatic. Risk factors for hepatotoxicity were investigated using time-dependent Cox regression analysis. Of 926 patients identified and followed for 4122.9 person-months (pm), 111 (12.0%) developed hepatotoxicity after a median 38.0 days from start of treatment. Around 3.5% had severe hepatotoxicity. The most common symptoms were general malaise and poor appetite. The incidence rate of hepatotoxicity was 0.59, 0.69 and 3.71/100 pm for isoniazid, rifampicin (RMP) and pyrazinamide (PZA), respectively. Old age, female sex, autoimmune disease, human immunodeficiency virus infection, more days with PZA in the last 8-14 days, and fewer days with RMP in the last 15-21 days before hepatotoxicity were independent risk factors for hepatotoxicity during treatment. A significant number of adult patients on first-line treatment experience hepatotoxicity. PZA is the most common causative drug. For high-risk patients, careful adjustment of the anti-tuberculosis regimen and regular monitoring of liver transaminases are necessary.

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

PubMed

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.

Levofloxacin-induced hepatotoxicity and death.

PubMed

Gulen, Muge; Ay, Mehmet Oguzhan; Avci, Akkan; Acikalin, Ayca; Icme, Ferhat

2015-01-01

Drug-induced hepatotoxicity is a major cause of hepatocellular injury in patients admitting to emergency services with acute liver failure. Hepatic necrosis may be at varying degrees from mild elevations in transaminases to fulminant hepatitis, and even death. The case of a 53-year-old female patient with toxic hepatitis due to levofloxacin and multiple organ failure secondary to toxic hepatitis is presented. Patient suffered itching, redness, and rash after receiving a single dose of 750 mg of levofloxacin tablets for pulmonary infection 10 days ago. Skin lesions had regressed within 3 days, but desquamation formed all over the body. After the fifth day of drug intake, complaints of abdominal pain, vomiting, and yellowing in skin color had started. The patient was referred to our emergency department with these complaints 10 days after drug intake. Patient was thought as a candidate for liver transplant, but cardiopulmonary arrest occurred, and the patient died before she could be referred to a transplant center. This case is important because hepatotoxicity and death due to levofloxacin is uncommon in the literature.

Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats.

PubMed

Jiang, Peng; Zhang, Xiuwen; Huang, Yutong; Cheng, Nengneng; Ma, Yueming

2017-10-25

Our previous study showed that kurarinone was the main hepatotoxic ingredient of Sophora flavescens , accumulating in the liver. This study characterized the mechanism of Sophora flavescens extract (ESF) hepatotoxicity and hepatic accumulation of kurarinone. ESF impaired hepatic function and caused fat accumulation in the liver after oral administration (1.25 and 2.5 g/kg for 14 days in rats). Serum metabolomics evaluation based on high-resolution mass spectrometry was conducted and real-time PCR was used to determine the expression levels of CPT-1, CPT-2, PPAR-α, and LCAD genes. Effects of kurarinone on triglyceride levels were evaluated in HL-7702 cells. Tissue distribution of kurarinone and kurarinone glucuronides was analyzed in rats receiving ESF (2.5 g/kg). Active uptake of kurarinone and kurarinone glucuronides was studied in OAT2-, OATP1B1-, OATP2B1-, and OATP1B3-transfected HEK293 cells. Our results revealed that after oral administration of ESF in rats, kurarinone glucuronides were actively transported into hepatocytes by OATP1B3 and hydrolyzed into kurarinone, which inhibited fatty acid β-oxidation through the reduction of l-carnitine and the inhibition of PPAR-α pathway, ultimately leading to lipid accumulation and liver injury. These findings contribute to understanding hepatotoxicity of kurarinone after oral administration of ESF.

Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China.

PubMed

Yang, Jun; Li, Lin-Fa; Xu, Qin; Zhang, Jun; Weng, Wan-Wen; Zhu, Yang-Jun; Dong, Meng-Jie

2015-03-01

Antithyroid drug (ATD)-induced severe hepatotoxicity is a rare but serious complication of ATD therapy. The characteristics of severe hepatotoxicity have been reported in only a small number of patients. Ninety patients with ATD-induced severe hepatotoxicity presenting during a 13 year period (2000-2013) who were about to undergo nuclear medicine therapy with (131)I from a sample of 8864 patients with hyperthyroidism were studied, and the outcomes were evaluated. The mean age of the patients with ATD-induced severe hepatotoxicity was 41.6±12.5 years (mean±standard deviation), and the female to male ratio was 2.2:1. The methimazole (MMI) dose given at the onset was 19.1±7.4 mg/day. The propylthiouracil (PTU) dose given at the onset was 212.8±105.0 mg/day. ATD-induced severe hepatotoxicity occurred in 63.3%, 75.6%, and 81.1% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. The types of severe hepatotoxicity did not differ significantly between the MMI and PTU groups (p=0.188). The frequency of the cholestatic type in the MMI group (35.3%, 18/51) was higher than that in the PTU group (17.9%, 7/39), but these frequencies were not significantly different (p=0.069). The patients who were treated with (131)I received an average dose of 279.1±86.1 MBq (n=84). Therapy was successful in 60 of the 67 patients (89.6%). The success rate was equivalent (p=0.696) between the groups receiving MMI (91.7%, 33/36) and PTU (87.1%, 27/31). Severe hepatotoxicity tends to occur within the first three months after the onset of ATD therapy. The type of ATD-induced severe hepatotoxicity did not differ between the MMI and PTU groups. (131)I therapy is an effective treatment approach for patients with ATD-induced severe hepatotoxicity.

Hepatotoxicity induced by methimazole in a previously healthy patient.

PubMed

Gallelli, Luca; Staltari, Orietta; Palleria, Caterina; De Sarro, Giovambattista; Ferraro, Maria

2009-09-01

We report a case of hepatotoxicity induced by methimazole treatment in a patient affected by hyperthyroidism. A 54-year-old man, presented to our observation for palpitations, excessive sweating, weakness, heat intolerance and weight loss. On physical examination, his blood pressure was 140/90 mmHg and heart beat was 100/min regular. He had mild tremors and left exophthalmos. Laboratory test revealed a significant increase in serum thyroid hormone levels with a decrease in thyroid stimulating hormone levels. A diagnosis of hyperthyroidism was made and he began treatment with methimazole (30 mg/day). Fourteen days later, he returned for the development of scleral icterus, followed by dark urine, and abdominal pain in the right upper quadrant. Laboratory examinations and liver biopsy performed a diagnosis of cholestatic hepatitis, secondary to methimazole usage. Methimazole was promptly withdrawn and cholestyramine, ursodeoxycholic acid, and chlorpheniramine were given. After five days, abdominal pain resolved and laboratory parameters returned to normal. Naranjo probability scale indicated a probable relationship between hepatotoxicity and methimazole therapy. In conclusion physicians should be aware the risk of hepatotoxicity related with methimazole.

Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI.

PubMed

Bliven-Sizemore, E E; Sterling, T R; Shang, N; Benator, D; Schwartzman, K; Reves, R; Drobeniuc, J; Bock, N; Villarino, M E

2015-09-01

Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear. To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity. Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV. Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors. The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.

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

PubMed

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.

A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity

PubMed Central

Patel, Suraj J; Luther, Jay; Bohr, Stefan; Iracheta-Vellve, Arvin; Li, Matthew; King, Kevin R; Chung, Raymond T; Yarmush, Martin L

2016-01-01

Objectives: Acetaminophen (APAP)-induced hepatotoxicity is a major cause of morbidity and mortality. The current pharmacologic treatment for APAP hepatotoxicity, N-acetyl cysteine (NAC), targets the initial metabolite-driven injury but does not directly affect the host inflammatory response. Because of this, NAC is less effective if given at later stages in the disease course. Resolvins, a novel group of lipid mediators shown to attenuate host inflammation, may be a therapeutic intervention for APAP hepatotoxicity. Methods: The temporal patterns of liver injury and neutrophil activation were investigated in a murine model of APAP hepatotoxicity. In addition, the effect of neutrophil depletion and resolvin administration on the severity of liver injury induced by APAP was studied. In vitro studies to investigate the mechanism of resolvin effect on hepatocyte injury and neutrophil adhesion were performed. Results: We demonstrate that hepatic neutrophil activation occurs secondary to the initial liver injury induced directly by APAP. We also show that neutrophil depletion attenuates APAP-induced liver injury, and administration of resolvins hours after APAP challenge not only attenuates liver injury, but also extends the therapeutic window eightfold compared to NAC. Mechanistic in vitro analysis highlights resolvins' ability to inhibit neutrophil attachment to endothelial cells in the presence of the reactive metabolite of APAP. Conclusions: This study highlights the ability of resolvins to protect against APAP-induced liver injury and extend the therapeutic window compared to NAC. Although the mechanism for resolvin-mediated hepatoprotection is likely multifactorial, inhibition of neutrophil infiltration and activation appears to play an important role. PMID:26986653

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

PubMed

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.

IDENTIFICATION OF MICROCYSTIN TOXINS FROM A STRAIN OF MICROCYSTIS AERUGINOSA

EPA Science Inventory

Microcystin toxins are cyclic heptapeptides produced by several genera and species of cyanobacteria that are responsible for the "green scum" frequently observed on eutrophic surface waters. These toxins, which are a million times more toxic than cyanide ion, have caused deaths o...

The role of chronic hepatitis in isoniazid hepatotoxicity during treatment for latent tuberculosis infection.

PubMed

Bliven, E E; Podewils, L J

2009-09-01

To examine chronic viral hepatitis (CVH) as a risk factor for hepatotoxicity during isoniazid (INH) treatment for latent tuberculosis infection (LTBI). A search of MEDLINE (1966-May 2008) was conducted using the terms 'tuberculosis', 'antitubercular', 'therapeutics', 'treatment', 'prevention', 'prophylaxis', 'hepatitis', 'toxic hepatitis', 'hepatotoxic', 'liver' and 'injury'. Peer-reviewed, English-language articles describing the relationship between a history of CVH and occurrence of hepatotoxicity during LTBI treatment were selected. We limited CVH diagnoses to reports with positive serological test or biopsy for hepatitis B or C. Risk ratios and 95% confidence intervals were abstracted or derived. We reviewed 486 abstracts, and 11 studies met the selection criteria. Populations included in the studies were the general population (n = 6) and transplant recipients (n = 5). The variability in study designs and case finding practices precluded performing a quantitative meta-analysis. Two studies of former or current drug users reported a consistent, positive association between chronic hepatitis C infection and INH hepatotoxicity. Other risk ratios did not significantly or consistently show any association between CVH in patients treated for LTBI and the development of INH hepatotoxicity. Owing to the limited number of published papers, CVH was not established as a risk factor for INH hepatotoxicity during LTBI treatment. Controlled studies are needed to define the safety and tolerability of LTBI treatment in those with CVH and to provide an evidence base for recommendations for LTBI treatment in persons with CVH.

Identifying 2 prenylflavanones as potential hepatotoxic compounds in the ethanol extract of Sophora flavescens.

PubMed

Yu, Qianqian; Cheng, Nengneng; Ni, Xiaojun

2013-11-01

Zhixue capsule is a prescription for hemorrhoid commonly used in traditional Chinese medicine. This drug was recalled by the State Food and Drug Administration in 2008 because of severe adverse hepatic reactions. Zhixue capsule is composed of ethanol extracts of Cortex Dictamni (ECD) and Sophora flavescens (ESF). In our preliminary study, we observed the hepatotoxic effects of ESF on rat primary hepatocytes. However, ECD did not exhibit hepatotoxicity at the same concentration range. In this study, ESF was evaluated for its potential hepatotoxic effects on rats. Bioassay-guided isolation was used to identify the material basis for hepatotoxicity. Treatment with 1.25 g/kg and 2.5 g/kg ESF significantly elevated the alanine aminotransferase and aspartate aminotransferase levels in the serum. The changes in the levels of transaminases were supported by the remarkable fatty degeneration of liver histopathology. Further investigations using bioassay-guided isolation and analysis indicated that prenylated flavanones accounted for the positive hepatotoxic results. Two isolated compounds were identified, kurarinone and sophoraflavanone G, using nuclear magnetic resonance and mass spectrometry techniques. These compounds have potent toxic effects on primary rat hepatocytes (with IC50 values of 29.9 μM and 16.5 μM) and human HL-7702 liver cells (with IC50 values of 48.2 μM and 40.3 μM), respectively. Consequently, the hepatotoxic constituents of S. flavescens were determined to be prenylated flavanones, kurarinone, and sophoraflavanone G. © 2013 Institute of Food Technologists®

ANTAGONISM OF CHLOROBENZENE-INDUCED HEPATOTOXICITY BY LINDANE

EPA Science Inventory

In a 2x2 factorial designed experiment involving chlorobenzene and gamma-hexachlorocyclohexane (lindane), the hepatotoxicity induced by a challenge dose of chlorobenzene was altered by the pretreatments due to selective changes in various metabolic pathways. These changes resulte...

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

PubMed

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 <10,000 mg/L × IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L × IU/L. When calculated within eight hours of ingestion, mild elevations of the 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

Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity.

PubMed

Giamanco, Nicole M; Cunningham, Bethany S; Klein, Laura S; Parekh, Dina S; Warwick, Anne B; Lieuw, Kenneth

2016-03-01

6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels. We suggest that this combination therapy can be used safely to change the metabolite production in patients who develop excessive hepatotoxicity.

Hepatotoxicity of illegal home-made alcohols.

PubMed

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 (<10%), mild = 1 (10%-40%), moderate = 2 (40%-70%), severe = 3 (above 70%). Chemical composition of illegally produced raki sample (%v/v) was as follows: trans-anethole %1

Molindone and hepatotoxicity.

PubMed

Bhatia, S C; Banta, L E; Ehrlich, D W

1985-10-01

An adolescent male with chronic schizophrenic disorder, paranoid type, was treated with molindone. He developed hepatotoxicity in the early treatment phase as evidenced by flu-like symptoms and laboratory abnormalities of liver functions. These symptoms and his hepatic functions improved on discontinuing molindone. Similar liver function trends were seen on reintroduction and subsequent withdrawal of the drug. Hepatic hypersensitivity has not been reported previously with the use of this drug. It is suggested that clinicians should be aware of this association and should assess hepatic functions in patients who develop a prodromal flu-like syndrome with this drug, especially in the early treatment phase.

IDENTIFICATION OF MICROCYSTIN TOXINS FROM A STRAIN OF MICROCYSTIS AERUGINOSA BY LIQUID CHROMATOGRAPHY INTRODUCTION INTO A HYBRID LINEAR ION TRAP-FOURIER TRANSFORM ION CYCLOTRON RESONANCE MASS SPECTROMETER

EPA Science Inventory

The cyclic heptapeptide microcystin toxins produced by a strain of Microcystis aeruginosa that has not been investigated previously were separated by liquid chromatography and identified by high-accuracy m/z measurements of their [M + H]+ ions and the fragment i...

Rocuronium is more hepatotoxic than succinylcholine in vitro.

PubMed

Sauer, Martin; Piel, Ines; Haubner, Cristof; Richter, Georg; Mann, Miriam; Nöldge-Schomburg, Gabriele; Mencke, Thomas

2017-09-01

The development of liver failure is a major problem in critically ill patients. The hepatotoxicity of many drugs, as one important reason for liver failure, is poorly screened for in human models. Rocuronium and succinylcholine are neuromuscular blocking agents used for tracheal intubation and for rapid-sequence induction. We used an in-vitro test with a permanent cell line and compared rocuronium and succinylcholine for hepatotoxicity. In-vitro study. A basic science laboratory, University Hospital Rostock, Germany. The basic test compound is the permanent human liver cell line HepG2/C3A. In a standardised microtitre plate assay the toxicity of different concentrations of rocuronium, succinylcholine and plasma control was tested. After two incubation periods of 3 days, the viability of cells (XTT test, lactate dehydrogenase release and trypan blue staining), micro-albumin synthesis and the cytochrome 1A2 activity (metabolism of ethoxyresorufin) were measured. Differences between rocuronium and succinylcholine were assessed using the Kruskal-Wallis one-way test and two-tailed Mann-Whitney U test. Rocuronium, but not succinylcholine, led to a significant dose-dependent decrease of viability, albumin synthesis and cytochrome 1A2 activity of test cells. An in-vitro test with a cell line showed hepatotoxicity of rocuronium that was dose-dependent. Further studies are needed to investigate the underlying mechanisms of the effects of rocuronium on hepatic cellular integrity. Not suitable.

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

PubMed

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.

Hepatotoxicity due to red bush tea consumption: a case report.

PubMed

Reddy, Shamantha; Mishra, Pragnyadipta; Qureshi, Sana; Nair, Singh; Straker, Tracey

2016-12-01

Many conventional drugs used today, including isoniazid, dapsone, and acetaminophen, are well recognized culprits of hepatotoxicity. With increasing use of complementary and alternative medical therapies, several herbal medicines, such as Ma-Huang, kava, and chaparral leaf, have been implicated as hepatotoxins. Hepatotoxicity may be the most frequent adverse reaction to these herbal remedies when taken in excessive quantities. A myriad of liver dysfunctions may occur including transient liver enzyme abnormalities due to acute and chronic hepatitis. These herbal products are often overlooked as the causal etiologic agent during the evaluation of a patient with elevated liver function tests. We describe a case of hepatotoxicity due to ingestion of red bush tea diagnosed during preoperative assessment of a patient scheduled for laparoscopic appendectomy. Elevated liver enzymes and thrombocytopenia detected in the patient's laboratory work up confounded the initial diagnosis of acute appendicitis and additional investigations were required to rule out cholecystitis and other causes of hepatitis. Open appendectomy was done uneventfully under spinal anesthesia without any further deterioration of hepatic function. Copyright © 2016. Published by Elsevier Inc.

Hepatotoxicity by Drugs: The Most Common Implicated Agents

PubMed Central

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

Predicting Drug-induced Hepatotoxicity Using QSAR and Toxicogenomics Approaches

PubMed Central

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

Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole

PubMed Central

Gardner, Carol R.; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

2012-01-01

Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8–12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole. PMID

Exacerbation of acetaminophen hepatotoxicity by the anthelmentic drug fenbendazole.

PubMed

Gardner, Carol R; Mishin, Vladimir; Laskin, Jeffrey D; Laskin, Debra L

2012-02-01

Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8-12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole.

In silico models for the prediction of dose-dependent human hepatotoxicity

NASA Astrophysics Data System (ADS)

Cheng, Ailan; Dixon, Steven L.

2003-12-01

The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-limiting considerations in the drug development cycle, yet there remains a serious shortage of methods to predict hepatotoxicity from chemical structure. We discuss our latest findings in this area and present a new, fully general in silico model which is able to predict the occurrence of dose-dependent human hepatotoxicity with greater than 80% accuracy. Utilizing an ensemble recursive partitioning approach, the model classifies compounds as toxic or non-toxic and provides a confidence level to indicate which predictions are most likely to be correct. Only 2D structural information is required and predictions can be made quite rapidly, so this approach is entirely appropriate for data mining applications and for profiling large synthetic and/or virtual libraries.

[Nevirapine related hepatotoxicity: the prevalence and risk factors in a cohort of ART naive Han Chinese with AIDS].

PubMed

Gao, Shi-cheng; Gui, Xi-en; Deng, Li-ping; Zhang, Yong-xi; Yan, Ya-jun; Rong, Yu-ping; Liang, Ke; Yang, Rong-rong

2010-09-01

To investigate the incidence of hepatotoxicity in acquired immunodeficiency syndrome (AIDS) patients on combined anti-retroviral therapy (cART) containing nevirapine (NVP) and to assess the risk factors and its impact on cART. 330 AIDS patients from March 2003 to June 2008 at local county were enrolled and a retrospective study using Kaplan-meier survival and Multivariate logistic regression modeling was conducted. 267 out of 330 patients received NVP based cART and 63 cases received EFV-based cART. The deference of prevalences of hepatotoxicity between the two groups is statistically significant (Chi2 = 6.691, P = 0.01). 133 out of 267 (49.8%) patients on NVP based cART had at least one episode of ALT elevation during a median 21 months (interquartile ranges, IQR 6, 37) follow-up time, amounts for 28.5 cases per 100 person-years. Baseline ALT elevation (OR = 14.368, P = 0.017)and HCV co-infection (OR = 3.009, P = 0.000) were risk factors for cART related hepatotoxicity, while greatly increased CD4+ T(CD4) cell count was protective against hepatotoxicity development (OR = 0.996, P = 0.000). Patients co-infected with HCV received NVP-based cART had the higher probability of hepatotoxicity than those without HCV co-infection (Log rank: Chi2 = 16.764, P = 0.000). 23 out of the 133 subjects (17.3%) with NVP related hepatotoxicity discontinued cART temporarily or shifted NVP to efavirenz. NVP related hepatotoxicity was common among ARV naive HIV infected subjects in our cohort. Baseline ALT elevation and HCV co-infection were associated statistically with the development of hepatotoxicity. Hepatotoxicity led to discontinuing cART temporarily or switching to other regimens in some subjects. It suggested that NVP should be used with caution in patients co-infected with HCV among whom anti-HCV therapy before cART initiation may contribute to minimizing the probability of NVP associated hepatotoxicity.

Are Reactive Oxygen Species Involved in Microcystin-LR Intoxication?

DTIC Science & Technology

1988-05-12

peroxidation in paracetamol intoxication, did not alter the effect of BHA pretreatment., -- 2-A 4" 4 2 - INTRODUCTION The toxic cyclic heptapeptide...that paracetamol induces dose-dependant lipid peroxidation in starved, but not in fed mice (WENDEL et a’.., 1979). This fact, and the trends

Experimental models of hepatotoxicity related to acute liver failure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maes, Michaël; Vinken, Mathieu, E-mail: mvinken@vub.ac.be; Jaeschke, Hartmut

Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposuremore » or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. - Highlights: • The murine APAP model is very close to what is observed in patients. • The Gal/ET model is useful to study TNFα-mediated apoptotic signaling mechanisms. • Fas receptor activation is an effective model of apoptosis and secondary necrosis. • The ConA model is a relevant model of auto-immune hepatitis and viral hepatitis. • Multiple time point evaluation needed in experimental models of acute liver injury.« less

Herbal hepatotoxicity: suspected cases assessed for alternative causes.

PubMed

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.

Establishment of a methodology for investigating protectants against ethanol-induced hepatotoxicity.

PubMed

Ruan, Xueqing; Shen, Chong; Meng, Qin

2010-05-01

Ethanol-induced liver injury has been extensively reported in clinic, but still lacks an efficient in vitro platform for investigating its hepatotoxicity and protectants. This study aimed to establish a methodology on the culture conditions regarding the sealability against evaporation of ethanol, culture medium and 2D/3D culture of hepatocytes. Based on the experimental findings, it was indicated that the ethanol evaporation from culture plates was a severe problem reducing its toxicity in hepatocyte. According to the detected ethanol toxic response marked by reduced cell viability, 3D cultured hepatocytes in gel entrapment were suggested to be better than 2D hepatocyte in monolayer, but the cultures in either William's Medium E or DMEM exhibited comparable sensitivity to ethanol toxicity. Subsequently, 3D cultured hepatocytes with Parafilm sealing were systematically illustrated to well reflect the ethanol-induced lipid accumulation, reactive oxygen species/malondialdehyde generation, glutathione depletion and cytochrome 2E1 induction. Finally, such hepatocyte models were proposed as a platform for screening of herbal component against ethanol hepatotoxicity. Nano-silibinin, for the first time, found to perform significant protection against ethanol-induced hepatotoxicity while silibinin in normal particles could not inhibit such toxicity. This protection of nano-silibinin might relate to its improved bioavailability compared to normal insoluble silibinin and could act as an anti-oxidative and anti-steatosis agent against ethanol-induced hepatotoxicity. Copyright (c) 2010. Published by Elsevier Ltd.

Membrane-associated precursor to poliovirus VPg identified by immunoprecipitation with antibodies directed against a synthetic heptapeptide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Semelr, B.L.; Anderson, C.W.; Hanecak, R.

1982-02-01

A synthetic heptapeptide corresponding to the C-terminal sequence of the poliovirus genome protein (VPg) has been linked to bovine serum albumin and used to raise antibodies in rabbits. These antibodies precipitate not only VPg but also at least two more virus-specific polypeptides. The smaller polypeptide, denoted P3-9 (12,000 daltons), has been mapped by Edman degradation and by fragmentation with cyanogen bromide and determined to be the N-terminal cleavage product of polypeptide P3-1b, a precursor to the RNA polymerase. P3-9 contains the sequence of the basic protein VPg (22 amino acids) at its C terminus. As predicted by the known RNAmore » sequence of poliovirus, P3-9 also contains a hydrophobic region of 22 amino acids preceding VPg, an observation suggesting that P3-9 may be membrane-associated. This was confirmed by fractionation of infected cells in the presence or absence of detergent. We speculate that P3-9 may be the donor of VPg to RNA chains in the membrane-bound RNA replication complex.« less

Effects of ebselen on radiocontrast media-induced hepatotoxicity in rats.

PubMed

Basarslan, Fatmagul; Yilmaz, Nigar; Davarci, Isil; Akin, Mustafa; Ozgur, Mustafa; Yilmaz, Cahide; Ulutas, Kemal Turker

2013-09-01

Oxidative stress is accepted as a potential responsible mechanism in the pathogenesis of radiocontrast media (RCM)-induced hepatotoxicity. Therefore, we aimed to investigate the protective effects of ebselen against RCM-induced hepatotoxicity by measuring tissue oxidant/antioxidant parameters and histological changes in rats. Wistar albino rats were randomly separated into four groups consisting of eight rats per group. Normal saline was given to the rats in control group (group 1). RCM was given to the rats in group 2, and both RCM and ebselen were given to the rats in group 3. Only ebselen was given to the rats in group 4. Liver sections of the killed animals were analyzed to measure the levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as histopathological changes. In RCM group, SOD and CAT levels were found increased. In RCM-ebselen group, MDA, SOD and CAT levels were found decreased. In RCM-ebselen group, however, GSH-Px activities of liver tissue increased. All these results indicated that ebselen produced a protective mechanism against RCM-induced hepatotoxicity and took part in oxidative stress.

Toxicogenomic analysis identifies the apoptotic pathway as the main cause of hepatotoxicity induced by tributyltin.

PubMed

Zhou, Mi; Feng, Mei; Fu, Ling-Ling; Ji, Lin-Dan; Zhao, Jin-Shun; Xu, Jin

2016-11-01

Tributyltin (TBT) is one of the most widely used organotin biocides, which has severe endocrine-disrupting effects on marine species and mammals. Given that TBT accumulates at higher levels in the liver than in any other organ, and it acts mainly as a hepatotoxic agent, it is important to clearly delineate the hepatotoxicity of TBT. However, most of the available studies on TBT have focused on observations at the cellular level, while studies at the level of genes and proteins are limited; therefore, the molecular mechanisms of TBT-induced hepatotoxicity remains largely unclear. In the present study, we applied a toxicogenomic approach to investigate the effects of TBT on gene expression in the human normal liver cell line HL7702. Gene expression profiling identified the apoptotic pathway as the major cause of hepatotoxicity induced by TBT. Flow cytometry assays confirmed that medium- and high-dose TBT treatments significantly increased the number of apoptotic cells, and more cells underwent late apoptosis in the high-dose TBT group. The genes encoding heat shock proteins (HSPs), kinases and tumor necrosis factor receptors mediated TBT-induced apoptosis. These findings revealed novel molecular mechanisms of TBT-induced hepatotoxicity, and the current microarray data may also provide clues for future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Side Effects of HIV Medicines: HIV and Hepatotoxicity

MedlinePlus

... provider tells you to. How is hepatotoxicity detected? Liver function tests (LFTs) are a group of blood tests ... Laboratory Testing From the Department of Veterans Affairs: Primary Care of Veterans with HIV: Liver Disease and Cirrhosis From the National Institutes of ...

Hepatotoxic microcystin removal using pumice embedded monolithic composite cryogel as an alternative water treatment method.

PubMed

Gurbuz, Fatma; Ceylan, Şeyda; Odabaşı, Mehmet; Codd, Geoffrey A

2016-03-01

Microcystins are the most commonly encountered water-borne cyanotoxins which present short- and long-term risks to human health. Guidelines at international and national level, and legislation in some countries, have been introduced for the effective health risk management of these potent hepatotoxic, tumour-promoters. The stable cyclic structure of microcystins and their common production by cyanobacteria in waterbodies at times of high total dissolved organic carbon content presents challenges to drinking water treatment facilities, with conventional, advanced and novel strategies under evaluation. Here, we have studied the removal of microcystins using three different forms of pumice particles (PPs), which are embedded into macroporous cryogel columns. Macroporous composite cryogel columns (MCCs) are a new generation of separation media designed to face this challenging task. Three different MCCs were prepared by adding plain PPs, Cu(2+)-attached PPs and Fe(3+)-attached PPs to reaction media before the cryogelation step. Column studies showed that MCCs could be successfully used as an alternative water treatment method for successful microcystin removal. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ginger for Prevention of Antituberculosis-induced Gastrointestinal Adverse Reactions Including Hepatotoxicity: A Randomized Pilot Clinical Trial.

PubMed

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.

Predicting hepatotoxicity using ToxCast in vitro bioactivity and ...

EPA Pesticide Factsheets

Background: The U.S. EPA ToxCastTM program is screening thousands of environmental chemicals for bioactivity using hundreds of high-throughput in vitro assays to build predictive models of toxicity. We represented chemicals based on bioactivity and chemical structure descriptors then used supervised machine learning to predict their hepatotoxic effects.Results: A set of 677 chemicals were represented by 711 in vitro bioactivity descriptors (from ToxCast assays), 4,376 chemical structure descriptors (from QikProp, OpenBabel, PADEL, and PubChem), and three hepatotoxicity categories (from animal studies). Hepatotoxicants were defined by rat liver histopathology observed after chronic chemical testing and grouped into hypertrophy (161), injury (101) and proliferative lesions (99). Classifiers were built using six machine learning algorithms: linear discriminant analysis (LDA), Naïve Bayes (NB), support vector classification (SVM), classification and regression trees (CART), k-nearest neighbors (KNN) and an ensemble of classifiers (ENSMB). Classifiers of hepatotoxicity were built using chemical structure, ToxCast bioactivity, and a hybrid representation. Predictive performance was evaluated using 10-fold cross-validation testing and in-loop, filter-based, feature subset selection. Hybrid classifiers had the best balanced accuracy for predicting hypertrophy (0.78±0.08), injury (0.73±0.10) and proliferative lesions (0.72±0.09). Though chemical and bioactivity class

p-Aminophenol-induced hepatotoxicity in hamsters: role of glutathione.

PubMed

Fu, Xin; Chen, Theresa S; Ray, Mukunda B; Nagasawa, Herbert T; Williams, Walter M

2004-01-01

p-Aminophenol (PAP) is a widely used industrial chemical and a known nephrotoxin. Recently, it was found to also cause hepatotoxicity and glutathione (GSH) depletion in mice. The exact mechanism of liver toxicity is not known. The aims of this study were to determine whether PAP can cause acute hepatotoxicity in hamsters and to further investigate the role of GSH in PAP-induced toxicity. PAP was administered ip to hamsters in doses of 200-800 mg/kg. Liver damage at 24 h after PAP administration was assessed by elevations in plasma enzyme activities and histopathologic examination. GSH and cysteine (Cys) levels in liver at 4 h were determined by HPLC. PAP decreased hepatic GSH concentration to 8% and Cys to 30% of vehicle control values. It increased plasma glutamic pyruvic transaminase (GPT) activity by 47-fold and sorbitol dehydrogenase (SDH) activity by 113-fold. PAP also caused severe centrilobular hepatocellular necrosis. 2(RS)-n-Propylthiazolidine-4(R)-carboxylic acid (PTCA), a Cys precursor, attenuated the PAP-induced decreases in hepatic sulfhydryl levels; GSH and Cys were 39% and 78% of vehicle controls, respectively. PTCA also attenuated the PAP-induced elevations in plasma enzyme activities and hepatic necrosis. It was concluded that PAP hepatotoxicity is associated with depletion of hepatic GSH and can be prevented by PTCA. Copyright 2004 Wiley Periodicals, Inc.

Investigation of the Hepatotoxic and Immunotoxic Effects of the Peroxisome Proliferator Perfluorodecanoic Acid

DTIC Science & Technology

1991-04-30

np. A #127 6Investigation of the Hepatotoxic and OHIO Immunotoxic Effects of the Peroxisome AJE Proliferator Perfluorodecanoic Acid Donald E. Frazier...Investigation of the Hepatotoxic and Immunotoxic Effects G-AFOSR 90-0371 of the Peroxisome Proliferator Perfluorodecanoic Acid TA - 2312/A5 L AUTMOS) Donald E...involved evaluation of the immunotoxic and toxic effects of perfluorodecanoic acid (PFDA). Eight day exposure to PFDA caused thymic atrophy with marked

Protective effect of the edible brown alga Ecklonia stolonifera on doxorubicin-induced hepatotoxicity in primary rat hepatocytes.

PubMed

Jung, Hyun Ah; Kim, Jae-I; Choung, Se Young; Choi, Jae Sue

2014-08-01

As part of our efforts to isolate anti-hepatotoxic agents from marine natural products, we screened the ability of 14 edible varieties of Korean seaweed to protect against doxorubicin-induced hepatotoxicity in primary rat hepatocytes. Among the crude extracts of two Chlorophyta (Codium fragile and Capsosiphon fulvescens), seven Phaeophyta (Undaria pinnatifida, Sargassum thunbergii, Pelvetia siliquosa, Ishige okamurae, Ecklonia cava, Ecklonia stolonifera and Eisenia bicyclis), five Rhodophyta (Chondrus ocellatus, Gelidium amansii, Gracilaria verrucosa, Symphycladia latiuscula and Porphyra tenera), and the extracts of Ecklonia stolonifera, Ecklonia cava, Eisenia bicyclis and Pelvetia siliquosa exhibited significant protective effects on doxorubicin-induced hepatotoxicity, with half maximal effective concentration (EC50) values of 2.0, 2.5, 3.0 and 15.0 μg/ml, respectively. Since Ecklonia stolonifera exhibits a significant protective potential and is frequently used as foodstuff, we isolated six phlorotannins, including phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofucofuroeckol A (4), dieckol (5) and triphloroethol-A (6). Phlorotannins 2 ∼ 6 exhibited potential protective effects on doxorubicin-induced hepatotoxicity, with corresponding EC50 values of 3.4, 8.3, 4.4, 5.5 and 11.5 μg/ml, respectively. The results clearly demonstrated that the anti-hepatotoxic effects of Ecklonia stolonifera and its isolated phlorotannins are useful for further exploration and development of therapeutic modalities for treatment of hepatotoxicity. © 2014 Royal Pharmaceutical Society.

Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests.

PubMed

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) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding

Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

PubMed Central

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

2013-01-01

AIM: To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. METHODS: 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) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. RESULTS: Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n

Acetaminophen hepatotoxicity and sterile inflammation: The mechanism of protection of Chlorogenic acid.

PubMed

Jaeschke, Hartmut

2016-01-05

Acetaminophen hepatotoxicity is characterized by extensive necrotic cell death and a sterile inflammatory response. A recent report suggested that a therapeutic intervention with chlorogenic acid, a dietary polyphenolic compound, protects against acetaminophen-induced liver injury by inhibiting the inflammatory injury. The purpose of this letter is to discuss a number of reasons why the protective mechanism of chlorogenic acid against acetaminophen hepatotoxicity does not involve an anti-inflammatory effect and provides an alternative explanation for the observed protection. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Advancing Predictive Hepatotoxicity at the Intersection of Experimental, in Silico, and Artificial Intelligence Technologies.

PubMed

Fraser, Keith; Bruckner, Dylan M; Dordick, Jonathan S

2018-06-18

Adverse drug reactions, particularly those that result in drug-induced liver injury (DILI), are a major cause of drug failure in clinical trials and drug withdrawals. Hepatotoxicity-mediated drug attrition occurs despite substantial investments of time and money in developing cellular assays, animal models, and computational models to predict its occurrence in humans. Underperformance in predicting hepatotoxicity associated with drugs and drug candidates has been attributed to existing gaps in our understanding of the mechanisms involved in driving hepatic injury after these compounds perfuse and are metabolized by the liver. Herein we assess in vitro, in vivo (animal), and in silico strategies used to develop predictive DILI models. We address the effectiveness of several two- and three-dimensional in vitro cellular methods that are frequently employed in hepatotoxicity screens and how they can be used to predict DILI in humans. We also explore how humanized animal models can recapitulate human drug metabolic profiles and associated liver injury. Finally, we highlight the maturation of computational methods for predicting hepatotoxicity, the untapped potential of artificial intelligence for improving in silico DILI screens, and how knowledge acquired from these predictions can shape the refinement of experimental methods.

The protective role of quercetin and arginine on gold nanoparticles induced hepatotoxicity in rats.

PubMed

Abdelhalim, Mohamed Anwar K; Moussa, Sherif A Abdelmottaleb; Qaid, Huda Abdo Yahya

2018-01-01

The aim of the study was to confirm the hepatotoxicity induced by small-sized gold nanoparticles (GNPs) and evaluate the role of quercetin (Qur) and arginine (Arg) against hepatotoxicity caused by GNPs. Twenty-five healthy male Wistar-Kyoto rats were used. GNPs were administered intraperitoneally to these rats at the dose of 50 μL for seven consecutive days. The role of Qur and Arg antioxidants against toxicity induced by GNPs was detected through the measurement of serum liver function and oxidative stress biomarkers in the liver tissues. Coadministration of Qur and Arg along with GNPs significantly induced dramatic alterations in the biochemical parameters. Levels of malondialdehyde, gamma-glutamyl transferase, alanine aminotransferase, alkaline phosphatase, and total protein increased significantly in the GNPs injected group than in the control group, while reduced glutathione was greatly reduced in the GNPs group than in the control group. It also significantly decreased liver enzymes and the oxidative stress, therefore improving the liver damage and hepatotoxicity induced by GNPs. This study demonstrated that Qur and Arg antioxidants effectively improved the hepatic oxidative damage induced by GNPs. It also substantiates the application of Qur and Arg as protecting stand-in against GNPs' hepatotoxicity.

Acute hepatotoxicity after ingestion of Morinda citrifolia (Noni Berry) juice in a 14-year-old boy.

PubMed

Yu, Elizabeth L; Sivagnanam, Mamata; Ellis, Linda; Huang, Jeannie S

2011-02-01

We present a case of a 14-year-old previously healthy boy with acute hepatotoxicity after noni berry juice consumption. As the popularity of noni berry consumption continues to increase, heightened awareness of the relation between noni berry consumption and acute hepatotoxicity is important.

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

PubMed

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.

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

PubMed Central

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. PMID:25954198

Heptapeptide-loaded solid lipid nanoparticles for cosmetic anti-aging applications.

PubMed

Suter, Franz; Schmid, Daniel; Wandrey, Franziska; Zülli, Fred

2016-11-01

The cosmetic industry requires more and more expensive actives and ingredients such as retinol, coenzyme Q10, proteins, peptides and biotechnologically produced molecules. In this study, we demonstrate the development of a cost effective formulation of a nanostructured lipid carrier (NLC) or solid lipid nanoparticles (SLN) improving peptide delivery into skin. NLC or SLN are very suitable vehicles for the delivery of active ingredients into skin. The SLN, produced by using hot high pressure homogenization method combine advantages such as physical stability, protection of incorporated labile actives and controlled release. By the used method we dispersed the amorphous heptapeptide DEETGEF in shea butter and homogenized this pre-dispersion at 60°C together with the water phase using a Microfluidizer at 1000bar. The analysis of the obtained SLN-P7 showed a particle size of 173nm, incorporated peptide of 0.014%, entrapment efficiency of 90.8%, melting peak (DSC) of the core lipid of 27°C and a zeta potential of -54mV. By an ex vivo study with skin explants we could stimulate NQO1 (NAD(P)H quinone oxidoreductase), HMOX1 (Heme oxygenase-1) and PRDX1 (Peroxiredoxin-1) genes all of which are cell protecting enzymes. In a multicellular protection against UV induced stress study with skin explants we detected the formation of sun burn cells and the number and morphology of Langerhans cells. The application of our SLN-P7 formulation on skin explants led to a significant and dose dependent protection against UV irradiation. In the clinical suction blister study, irradiation with UVA light for two hours after final product application led to a statistically significant increase of the 8-OhdG (8-hydroxy-2'-deoxyguanosine) concentration in the human epidermis. The skin treated with our verum formulation showed a statistically significant 20% decrease in DNA damage compared to placebo. In conclusion, it was demonstrated that SLN technology enabled peptide delivery into skin

Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type

PubMed Central

Kane, Alice E.; Mitchell, Sarah J.; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; de Cabo, Rafael; Hilmer, Sarah N.

2018-01-01

Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID:26615879

Upgrading cytochrome P450 activity in HepG2 cells co-transfected with adenoviral vectors for drug hepatotoxicity assessment.

PubMed

Tolosa, Laia; Donato, M Teresa; Pérez-Cataldo, Gabriela; Castell, José Vicente; Gómez-Lechón, M José

2012-12-01

In a number of adverse drug reactions leading to hepatotoxicity, drug metabolism is thought to be involved by the generation of reactive metabolites from non-toxic drugs. The use of hepatoma cell lines, such as HepG2 cell line, for the evaluation of drug-induced hepatotoxicity is hampered by their low cytochrome P450 expression which makes impossible the study of the toxicity produced by bioactivable compounds. Genetically manipulated cells constitute promising tools for hepatotoxicity applications. HepG2 cells were simultaneously transfected with recombinant adenoviruses encoding CYP1A2, CYP2C9 and CYP3A4 to confer them drug-metabolic competence. Upgraded cells (Adv-HepG2) were highly able to metabolize the toxin studied in contrast to the reduced metabolic capacity of HepG2 cells. Aflatoxin B1-induced hepatotoxicity was studied as a proof of concept in metabolically competent and non-competent HepG2 cells by using high content screening technology. Significant differences in mitochondrial membrane potential, intracellular calcium concentration, nuclear morphology and cell viability after treatment with aflatoxin B1 were observed in Adv-HepG2 when compared to HepG2 cells. Rotenone (non bioactivable) and citrate (non hepatotoxic) were analysed as negative controls. This cell model showed to be a suitable hepatic model to test hepatotoxicity of bioactivable drugs and constitutes a valuable alternative for hepatotoxicity testing. Copyright © 2011 Elsevier Ltd. All rights reserved.

Rofecoxib-induced hepatotoxicity: A forgotten complication of the coxibs

PubMed Central

Yan, Brian; Leung, Yvette; Urbanski, Stefan J; Myers, Robert P

2006-01-01

Rofecoxib is a member of the coxib family of nonsteroidal anti-inflammatory drugs that selectively inhibit cyclooxygenase-2. Although the coxibs are generally well-tolerated, rofecoxib was recently withdrawn from the market due to concerns regarding cardiovascular safety. Rare cases of hepatic injury attributable to the coxibs have been reported. In the present study, two additional cases of severe hepatotoxicity are described in patients with cholestatic symptoms and abnormal liver biochemistry, shortly following the initiation of rofecoxib for arthritic complaints. In both cases, liver histology was compatible with drug-induced hepatotoxicity, and rapid clinical and biochemical improvements were observed following rofecoxib discontinuation. With new coxibs and expanding indications on the horizon, physicians in all areas of practice must be aware of this disorder and consider it in any patient who develops hepatic dysfunction after taking a coxib. PMID:16691302

Protective effect of rutin in comparison to silymarin against induced hepatotoxicity in rats.

PubMed

Reddy, M Kasi; Reddy, A Gopala; Kumar, B Kala; Madhuri, D; Boobalan, G; Reddy, M Anudeep

2017-01-01

The aim of this study is to evaluate the hepatoprotective effect of rutin (RTN) in comparison to silymarin (SLM) against acetaminophen (APAP)-induced hepatotoxicity in rats. Male Wistar albino rats (n=24) of 3 months age were equally divided into four groups. Group 1 served as normal control. Hepatotoxicity was induced in the remaining three groups with administration of 500 mg/kg po APAP from day 1-3. Groups 2, 3, and 4 were subsequently administered orally with distilled water, 25 mg/kg of SLM, and 20 mg/kg of RTN, respectively, for 11 days. The mean body weights and biomarkers of hepatotoxicity were estimated on day 0, 4 (confirmation of toxicity), and 15 (at the end of treatment). Hematological parameters were evaluated on day 4 and 15. Antioxidant profile and adenosine triphosphatases (ATPases) were assessed at the end of the experiment. Liver tissues were subjected to histopathology and transmission electron microscopy after the sacrifice on day 15. Antioxidant profile, ATPases, and hematological and sero-biochemical parameters were significantly altered, and histopathological changes were noticed in the liver of toxic control group. These changes were reversed in groups 3 and 4 that were administered with SLM and RTN, respectively. The results of the present investigation enunciated that SLM has potent hepatoprotective activity though the RTN was found superior in restoring the pathological alterations in paracetamol-induced hepatotoxicity in Wistar albino rats.

Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity.

PubMed

McEneny-King, Alanna; Osman, Wesseem; Edginton, Andrea N; Rao, Praveen P N

2017-06-01

The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC 50 =33.0µM; 2, IC 50 =8.5µM) compared to tacrine (CYP1A2 IC 50 =1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Hepatotoxicity induced by acute and chronic paracetamol overdose in children: Where do we stand?

PubMed

Tong, Hoi Yan; Medrano, Nicolás; Borobia, Alberto Manuel; Ruiz, José Antonio; Martínez, Ana María; Martín, Julia; Quintana, Manuel; García, Santos; Carcas, Antonio José; Ramírez, Elena

2017-02-01

There are few data on hepatotoxicity induced by acute or chronic paracetamol poisoning in the pediatric population. Paracetamol poisoning data can reveal the weaknesses of paracetamol poisoning management guidelines. We retrospectively studied the patients of less than 18 years old with measurable paracetamol levels, who were brought to the emergency department (ED) of La Paz University Hospital, Madrid, Spain, for suspected paracetamol overdoses between 2005 and 2010. Ninety-two patients with suspected paracetamol poisoning were identified. In 2007, the incidence of paracetamol poisoning in the pediatric population was 0.8 [Poisson-95% confidence interval (CI): 0.03-3.69] per 10 000 inhabitants aged less than 18 years. The incidence in the same year was 1.53 (Poisson-95% CI: 0.24-5.57) per 10 000 patients in the pediatric ED. The most common cause of poisoning was attempted suicide (47.8%) in teenagers with a median age of 15 years, followed by accidental poisoning (42.2%) in babies with a median age of 2.65 years. Difference was seen in the frequency of hepatotoxicity between acute and chronic poisoning cases. Only 1 of 49 patients with acute poisoning showed hepatotoxicity [acute liver failure (ALF)], whereas 7 of 8 patients with chronic poisoning showed hepatotoxicity (3 cases of ALF). The average time to medical care was 6.83 hours for acute poisoning and 52.3 hours for chronic poisoning (P<0.001). Chronic paracetamol poisoning is a potential risk factor for hepatotoxicity and acute liver failure. Delays in seeking medical help might be a contributing factor. Clinicians should have a higher index of clinical suspicion for this entity.

Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts

PubMed Central

Burel, Sebastien A.; Hart, Christopher E.; Cauntay, Patrick; Hsiao, Jill; Machemer, Todd; Katz, Melanie; Watt, Andy; Bui, Huynh-hoa; Younis, Husam; Sabripour, Mahyar; Freier, Susan M.; Hung, Gene; Dan, Amy; Prakash, T.P.; Seth, Punit P.; Swayze, Eric E.; Bennett, C. Frank; Crooke, Stanley T.; Henry, Scott P.

2016-01-01

High affinity antisense oligonucleotides (ASOs) containing bicylic modifications (BNA) such as locked nucleic acid (LNA) designed to induce target RNA cleavage have been shown to have enhanced potency along with a higher propensity to cause hepatotoxicity. In order to understand the mechanism of this hepatotoxicity, transcriptional profiles were collected from the livers of mice treated with a panel of highly efficacious hepatotoxic or non-hepatotoxic LNA ASOs. We observed highly selective transcript knockdown in mice treated with non-hepatotoxic LNA ASOs, while the levels of many unintended transcripts were reduced in mice treated with hepatotoxic LNA ASOs. This transcriptional signature was concurrent with on-target RNA reduction and preceded transaminitis. Remarkably, the mRNA transcripts commonly reduced by toxic LNA ASOs were generally not strongly associated with any particular biological process, cellular component or functional group. However, they tended to have much longer pre-mRNA transcripts. We also demonstrate that the off-target RNA knockdown and hepatotoxicity is attenuated by RNase H1 knockdown, and that this effect can be generalized to high affinity modifications beyond LNA. This suggests that for a certain set of ASOs containing high affinity modifications such as LNA, hepatotoxicity can occur as a result of unintended off-target RNase H1 dependent RNA degradation. PMID:26553810

Long-enduring primary hepatocyte-based co-cultures improve prediction of hepatotoxicity.

PubMed

Novik, Eric I; Dwyer, Jacquelyn; Morelli, James K; Parekh, Amit; Cho, Cheul; Pludwinski, Eitan; Shrirao, Anil; Freedman, Robert M; MacDonald, James S; Jayyosi, Zaid

2017-12-01

The failure of drug candidates during clinical trials and post-marketing withdrawal due to Drug Induced Liver Injury (DILI), results in significant late-stage attrition in the pharmaceutical industry. Animal studies have proven insufficient to definitively predict DILI in the clinic, therefore a variety of in vitro models are being tested in an effort to improve prediction of human hepatotoxicity. The model system described here consists of cryopreserved primary rat, dog or human hepatocytes co-cultured together with a fibroblast cell line, which aids in the hepatocytes' maintenance of more in vivo-like characteristics compared to traditional hepatic mono-cultures, including long term viability and retention of activity of cytochrome P450 isozymes. Cell viability was assessed by measurement of ATP following treatment with 29 compounds having known hepatotoxic liabilities. Hμrelrat™, Hμreldog™, and Hμrelhuman™ hepatic co-cultures were treated for 24h, or under repeat-dosing for 7 or 13days, and compared to rat and human hepatic mono-cultures following single-dose exposure for 24h. The results allowed for a comparison of cytotoxicity, species-specific responses and the effect of repeat compound exposure on the prediction of hepatotoxic potential in each model. Results show that the co-culture model had greater sensitivity compared to that of the hepatic mono-cultures. In addition, "time-based ratios" were determined by dividing the compounds' 24-hour TC 50 /C max values by TC 50 /C max values measured after dosing for either 7 or 13days. The results suggest that this approach may serve as a useful adjunct to traditional measurements of hepatotoxicity, improving the predictive value of early screening studies. Copyright © 2017 Elsevier Inc. All rights reserved.

The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Henninger, Christian; Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf; Huelsenbeck, Johannes

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 anmore » 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

Multicenter study of trimethoprim/sulfamethoxazole-related hepatotoxicity: incidence and associated factors among HIV-infected patients treated for Pneumocystis jirovecii pneumonia.

PubMed

Yang, Jen-Jia; Huang, Chung-Hao; Liu, Chun-Eng; Tang, Hung-Jen; Yang, Chia-Jui; Lee, Yi-Chien; Lee, Kuan-Yeh; Tsai, Mao-Song; Lin, Shu-Wen; Chen, Yen-Hsu; Lu, Po-Liang; Hung, Chien-Ching

2014-01-01

The incidence of hepatotoxicity related to trimethoprim/sulfamethoxazole (TMP/SMX) administered at a therapeutic dose may vary among study populations of different ethnicities and hepatotoxic metabolites of TMP/SMX may be decreased by drug-drug interaction with fluconazole. We aimed to investigate the incidence of hepatotoxicity and the role of concomitant use of fluconazole in HIV-infected patients receiving TMP/SMX for Pneumocystis jirovecii pneumonia. We reviewed medical records to collect clinical characteristics and laboratory data of HIV-infected patients who received TMP/SMX for treatment of P. jirovecii pneumonia at 6 hospitals around Taiwan between September 2009 and February 2013. Hepatotoxicity was defined as 2-fold or greater increase of aminotransferase or total bilirubin level from baselines. Roussel UCLAF Causality Assessment Method (RUCAM) was used to analyze the causality of drug-induced liver injuries. NAT1 and NAT2 acetylator types were determined with the use of polymerase-chain-reaction (PCR) restriction fragment length polymorphism to differentiate common single-nucleotide polymorphisms (SNPs) predictive of the acetylator phenotypes in a subgroup of patients. During the study period, 286 courses of TMP/SMX treatment administered to 284 patients were analyzed. One hundred and fifty-two patients (53.1%) developed hepatotoxicity, and TMP/SMX was considered causative in 47 (16.4%) who had a RUCAM score of 6 or greater. In multivariate analysis, concomitant use of fluconazole for candidiasis was the only factor associated with reduced risk for hepatotoxicity (adjusted odds ratio, 0.372; 95% confidence interval, 0.145-0.957), while serostatus of hepatitis B or C virus, NAT1 and NAT2 acetylator types, or receipt of combination antiretroviral therapy was not. The incidence of hepatotoxicity decreased with an increasing daily dose of fluconazole up to 4.0 mg/kg. We conclude that the incidence of TMP/SMX-related hepatotoxicity was 16.4% in HIV

Potential protective effect of honey against paracetamol-induced hepatotoxicity.

PubMed

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.

Hepatoprotective and antioxidant effects of Cuscuta chinensis against acetaminophen-induced hepatotoxicity in rats.

PubMed

Yen, Feng-Lin; Wu, Tzu-Hui; Lin, Liang-Tzung; Lin, Chun-Ching

2007-04-20

Tu-Si-Zi, the seeds of Cuscuta chinensis Lam. (Convolvulaceae), is a traditional Chinese medicine that is commonly used to nourish and improve the liver and kidney conditions in China and other Asian countries. As oxidative stress promotes the development of acetaminophen (APAP)-induced hepatotoxicity, the aim of the present study was to evaluate and compare the hepatoprotective effect and antioxidant activities of the aqueous and ethanolic extracts of C chinensis on APAP-induced hepatotoxicity in rats. The C chinensis ethanolic extract at an oral dose of both 125 and 250mg/kg showed a significant hepatoprotective effect relatively to the same extent (P<0.05) by reducing levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and alkaline phosphatase (ALP). In addition, the same ethanolic extract prevented the hepatotoxicity induced by APAP-intoxicated treatment as observed when assessing the liver histopathology. Regarding the antioxidant activity, C chinensis ethanolic extract exhibited a significant effect (P<0.05) by increasing levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and by reducing malondialdehyde (MDA) levels. In contrast, the same doses of the aqueous extract of C chinensis did not present any hepatoprotective effect as seen in the ethanolic extract, and resulted in further liver deterioration. In conclusion, these data suggest that the ethanolic extract of Cuscuta chinensis can prevent hepatic injuries from APAP-induced hepatotoxicity in rats and this is likely mediated through its antioxidant activities.

Bee sting therapy-induced hepatotoxicity: A case report.

PubMed

Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

2011-10-27

The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo.

Bee sting therapy-induced hepatotoxicity: A case report

PubMed Central

Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

2011-01-01

The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo. PMID:22059110

Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats.

PubMed

Khoza, Star; Moyo, Ishmael; Ncube, Denver

2017-01-01

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.

Severe hepatotoxic reaction with progression to cirrhosis after use of a novel retinoid (acitretin).

PubMed

van Ditzhuijsen, T J; van Haelst, U J; van Dooren-Greebe, R J; van de Kerkhof, P C; Yap, S H

1990-09-01

We report the case of a 50-year-old female who suffered from severe palmar and plantar pustulosis. During treatment with acitretin, a novel oral retinoid, which is the main derivative of etretinate, the patient developed a severe hepatotoxic reaction. Subsequent histological studies strongly suggested the development of liver cirrhosis. Reversible elevation of serum aminotransferase values during treatment with acitretin has been reported. However, the present observation indicates that severe hepatotoxic injury may also follow treatment with this agent.

Altered Protein S-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

PubMed Central

McGarry, David J.; Chakravarty, Probir; Wolf, C. Roland

2015-01-01

Acetaminophen (APAP) is the most commonly used over-the-counter analgesic. However, hepatotoxicity induced by APAP is a major clinical issue, and the factors that define sensitivity to APAP remain unclear. We have previously demonstrated that mice nulled for glutathione S-transferase Pi (GSTP) are resistant to APAP-induced hepatotoxicity. This study aims to exploit this difference to delineate pathways of importance in APAP toxicity. We used mice nulled for GSTP and heme oxygenase-1 oxidative stress reporter mice, together with a novel nanoflow liquid chromatography–tandem mass spectrometry methodology to investigate the role of oxidative stress, cell signaling, and protein S-glutathionylation in APAP hepatotoxicity. We provide evidence that the sensitivity difference between wild-type and Gstp1/2−/− mice is unrelated to the ability of APAP to induce oxidative stress, despite observing significant increases in c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation in wild-type mice. The major difference in response to APAP was in the levels of protein S-glutathionylation: Gstp1/2−/− mice exhibited a significant increase in the number of S-glutathionylated proteins compared with wild-type animals. Remarkably, these S-glutathionylated proteins are involved in oxidative phosphorylation, respiratory complexes, drug metabolism, and mitochondrial apoptosis. Furthermore, we found that S-glutathionylation of the rate-limiting glutathione-synthesizing enzyme, glutamate cysteine ligase, was markedly increased in Gstp1/2−/− mice in response to APAP. The data demonstrate that S-glutathionylation provides an adaptive response to APAP and, as a consequence, suggest that this is an important determinant in APAP hepatotoxicity. This work identifies potential novel avenues associated with cell survival for the treatment of chemical-induced hepatotoxicity. PMID:26311813

Role of the Sympathetic Nervous System in Carbon Tetrachloride-Induced Hepatotoxicity and Systemic Inflammation

PubMed Central

Lin, Jung-Chun; Peng, Yi-Jen; Wang, Shih-Yu; Young, Ton-Ho; Salter, Donald M.; Lee, Herng-Sheng

2015-01-01

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. PMID:25799095

Factors associated with anti-TB drug-induced hepatotoxicity and genetic polymorphisms in indigenous and non-indigenous populations in Brazil.

PubMed

Heinrich, Melissa M; Zembrzuski, Verônica M; Ota, Marcos M; Sacchi, Flavia P; Teixeira, Raquel L F; Cabello Acero, Pedro H; Cunha, Geraldo Marcelo; Souza-Santos, Reinaldo; Croda, Julio; Basta, Paulo C

2016-12-01

Anti-tuberculosis (TB) drugs are responsible for the occurrence of several adverse drug reactions (ADRs), including hepatotoxicity. The aim was to estimate the incidence of hepatotoxicity and its association with genetic polymorphisms and clinical-epidemiological factors by comparing indigenous and non-indigenous TB patients. We investigated clinical-epidemiological variables, serum levels of liver enzymes and NAT2, CYP2E1 and GSTM1 polymorphisms. A non-conditional logistic regression was used to identify the factors associated with hepatotoxicity. Odds ratios were used as the association measures. The incidence of hepatotoxicity was 19.7% for all patients. The risk of hepatotoxicity was almost four times higher in indigenous patients, comparing to non-indigenous. We identified a new nonsynonymous single nucleotide polymorphism of NAT2 in indigenous patients. In total, 54.6% of the patients expressed a slow acetylation phenotype profile. The frequency of the null genotype of GSTM1 was higher in non-indigenous patients (p = 0.002), whereas no significant differences in relation to polymorphisms of CYP2E1 were observed between the groups. Hepatotoxicity was associated with patients older than 60 and indigenous (OR = 26.0; 95%CI:3.1-217.6; OR = 3.8; 95%CI:1.3-11.1, respectively). Furthermore, hepatotoxicity was associated with a slow acetylation profile in indigenous patients (OR = 10.7; 95%CI:1.2-97.2). Our findings suggest that there are distinct acetylation profiles in the Brazilian population, emphasizing the importance of pharmacogenetic analyses for achieving personalized therapeutic schemes and better outcomes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cosgrove, Benjamin D.; Cell Decision Processes Center, Massachusetts Institute of Technology, Cambridge, MA; Biotechnology Process Engineering Center, Massachusetts Institute of Technology, Cambridge, MA

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF,more » IFN{gamma}, IL-1{alpha}, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1{alpha}, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.« less

Mechanistic Biomarkers in Acetaminophen-induced Hepatotoxicity and Acute Liver Failure: From Preclinical Models to Patients

PubMed Central

McGill, Mitchell R.; Jaeschke, Hartmut

2015-01-01

SUMMARY Introduction Drug hepatotoxicity is a major clinical issue. Acetaminophen (APAP) overdose is especially common. Serum biomarkers used to follow patient progress reflect either liver injury or function, but focus on biomarkers that can provide insight into the basic mechanisms of hepatotoxicity is increasing and enabling us to translate mechanisms of toxicity from animal models to humans. Areas covered We review recent advances in mechanistic serum biomarker research in drug hepatotoxicity. Specifically, biomarkers for reactive drug intermdiates, mitochondrial dysfunction, nuclear DNA damage, mode of cell death and inflammation are discussed, as well as microRNAs. Emphasis is placed on APAP-induced liver injury. Expert Opinion Several serum biomarkers of reactive drug intermediates, mitochondrial damage, nuclear DNA damage, apoptosis and necrosis, and inflammation have been described. These studies have provided evidence that mitochondrial damage is critical in APAP hepatotoxicity in humans, while apoptosis has only a minor role, and inflammation is important for recovery and regeneration after APAP overdose. Additionally, mechanistic serum biomarkers have been shown to predict outcome as well as, or better than, some clinical scores. In the future, such biomarkers will help determine the need for liver transplantation and, with improved understanding of the human pathophysiology, identify novel therapeutic targets. PMID:24836926

Drug induced hepatotoxicity: data from the Serbian pharmacovigilance database.

PubMed

Petronijevic, Marija; Ilic, Katarina; Suzuki, Ayako

2011-04-01

The main aim of this study was to determine the most frequently reported drugs to the Serbian Pharmacovigilance Database (SPD) with suspected induced hepatotoxicity. Additionally, reasons for the low reporting rate of adverse drug reactions (ADRs) in Serbia were identified. Retrospective observational study of spontaneously reported ADRs recorded in the SPD from January 1995 to December 2008 was performed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify cases of hepatobiliary disorders (HD). Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification. Medline and WHO-UMC databases were used to address specific queries suggested by our results. The questionnaire was used to investigate the health care professionals' knowledge and practice related to spontaneous reporting. Among the 1804 reports of ADRs recorded in the SPD between 1995 and 2008, 70 (3.9%) cases of HD were identified. Drugs most frequently associated with hepatotoxicity were anti-infectives for systemic use, drugs affecting the nervous system, herbal products, hypolipemics, and anticoagulant drugs (26.83, 24.39, 12.20, 9.76, and 8.54% cases, respectively). Four cases (5.71%) of liver injury resulted in death, which accounted for 10.26% of all ADR fatalities reported to the SPD. The main reasons for not reporting ADRs were lack of reporting knowledge (30.26%), well-known ADRs (29.89%), and insecurity about causality relationship (15.50%). Anti-infectives, nervous system drugs, and herbal products were the most common drug classes reported for hepatotoxicity in Serbia. There is a need for additional education about ADRs, and enhanced reporting by health care professionals. Copyright © 2011 John Wiley & Sons, Ltd.

Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

PubMed Central

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

2013-01-01

The diagnosis of herbal hepatotoxicity or herb induced liver injury (HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation. At the day HILI is suspected in a patient, physicians should start assessing the quality of the used herbal product, optimizing the clinical data for completeness, and applying the Council for International Organizations of Medical Sciences (CIOMS) scale for initial causality assessment. This scale is structured, quantitative, liver specific, and validated for hepatotoxicity cases. Its items provide individual scores, which together yield causality levels of highly probable, probable, possible, unlikely, and excluded. After completion by additional information including raw data, this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation. The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases, compared to numerous other causality assessment methods, which are inferior on various grounds. Among these disputed methods are the Maria and Victorino scale, an insufficiently qualified, shortened version of the CIOMS scale, as well as various liver unspecific methods such as the ad hoc causality approach, the Naranjo scale, the World Health Organization (WHO) method, and the Karch and Lasagna method. An expert panel is required for the Drug Induced Liver Injury Network method, the WHO method, and other approaches based on expert opinion, which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician. In conclusion, HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale, avoiding pitfalls commonly observed with other approaches. PMID:23704820

Acute Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCIPP) Causes Hepatic Inflammation and Leads to Hepatotoxicity in Zebrafish

NASA Astrophysics Data System (ADS)

Liu, Chunsheng; Su, Guanyong; Giesy, John P.; Letcher, Robert J.; Li, Guangyu; Agrawal, Ira; Li, Jing; Yu, Liqin; Wang, Jianghua; Gong, Zhiyuan

2016-01-01

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been frequently detected in environmental media and has adverse health effect on wildlife and humans. It has been implicated to have hepatotoxicity, but its molecular mechanisms remain unclear. In the present study, adult male zebrafish were exposed to TDCIPP and global hepatic gene expression was examined by RNA-Seq and RT-qPCR in order to understand the molecular mechanisms of TDCIPP-induced hepatotoxicity. Our results indicated that TDCIPP exposure significantly up-regulated the expression of genes involved in endoplasmic reticulum stress and Toll-like receptor (TLR) pathway, implying an inflammatory response, which was supported by up-regulation of inflammation-related biomaker genes. Hepatic inflammation was further confirmed by histological observation of increase of infiltrated neutrophils and direct observation of liver recruitment of neutrophils labeled with Ds-Red fluorescent protein of Tg(lysC:DsRed) zebrafish upon TDCIPP exposure. To further characterize the hepatotoxicity of TDCIPP, the expression of hepatotoxicity biomarker genes, liver histopathology and morphology were examined. The exposure to TDCIPP significantly up-regulated the expression of several biomarker genes for hepatotoxicity (gck, gsr and nqo1) and caused hepatic vacuolization and apoptosis as well as increase of the liver size. Collectively, our results suggest that exposure to TDCIPP induces hepatic inflammation and leads to hepatotoxicity in zebrafish.

The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishiya, Takayoshi; Mori, Kazuhiko; Hattori, Chiharu

2008-10-15

To investigate the hepatotoxic potential of tienilic acid in vivo, we administered a single oral dose of tienilic acid to Sprague-Dawley rats and performed general clinicopathological examinations and hepatic gene expression analysis using Affymetrix microarrays. No change in the serum transaminases was noted at up to 1000 mg/kg, although slight elevation of the serum bile acid and bilirubin, and very mild hepatotoxic changes in morphology were observed. In contrast to the marginal clinicopathological changes, marked upregulation of the genes involved in glutathione biosynthesis [glutathione synthetase and glutamate-cysteine ligase (Gcl)], oxidative stress response [heme oxygenase-1 and NAD(P)H dehydrogenase quinone 1] andmore » phase II drug metabolism (glutathione S-transferase and UDP glycosyltransferase 1A6) were noted after 3 or 6 h post-dosing. The hepatic reduced glutathione level decreased at 3-6 h, and then increased at 24 or 48 h, indicating that the upregulation of NF-E2-related factor 2 (Nrf2)-regulated gene and the late increase in hepatic glutathione are protective responses against the oxidative and/or electrophilic stresses caused by tienilic acid. In a subsequent experiment, tienilic acid in combination with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of Gcl caused marked elevation of serum alanine aminotransferase (ALT) with extensive centrilobular hepatocyte necrosis, whereas BSO alone showed no hepatotoxicity. The elevation of ALT by this combination was observed at the same dose levels of tienilic acid as the upregulation of the Nrf2-regulated genes by tienilic acid alone. In conclusion, these results suggest that the impairment of glutathione biosynthesis may play a critical role in the development of tienilic acid hepatotoxicity through extensive oxidative and/or electrophilic stresses.« less

Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study

PubMed Central

Wang, Meng-Ting; Lee, Wan-Ju; Huang, Tien-Yu; Chu, Che-Li; Hsieh, Chang-Hsun

2014-01-01

Aims The evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population-based manner. Methods We conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non-infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively. Results The study cohort comprised 71 379 ATD initiators, with a median follow-up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person-years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person-years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89-fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08-fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22). Conclusions MMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose-dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis. PMID:25279406

Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi

PubMed Central

Henderson, Colin J.; Wolf, C. Roland; Kitteringham, Neil; Powell, Helen; Otto, Diana; Park, B. Kevin

2000-01-01

Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S-transferases (GST), such as GST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP (GstP1/P2(−/−)). Contrary to our expectations, instead of being more sensitive, GstP null mice were highly resistant to the hepatotoxic effects of this compound. No significant differences between wild-type (GstP1/P2(+/+)) mice and GstP1/P2(−/−) nulls in either the rate or route of metabolism, particularly to glutathione conjugates, or in the levels of covalent binding of acetaminophen-reactive metabolites to cellular protein were observed. However, although a similar rapid depletion of hepatic reduced glutathione (GSH) was found in both GstP1/P2(+/+) and GstP1/P2(−/−) mice, GSH levels only recovered in the GstP1/P2(−/−) mice. These data demonstrate that GstP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound. This study identifies new ways in which GST can modulate cellular sensitivity to toxic effects and suggests that the level of GST Pi may be an important and contributing factor in the sensitivity of patients with acetaminophen-induced hepatotoxicity. PMID:11058152

Quercetin attenuates toosendanin-induced hepatotoxicity through inducing the Nrf2/GCL/GSH antioxidant signaling pathway.

PubMed

Jin, Yao; Huang, Zhen-Lin; Li, Li; Yang, Yang; Wang, Chang-Hong; Wang, Zheng-Tao; Ji, Li-Li

2018-06-19

Toosendanin (TSN) is the main active compound in Toosendan Fructus and Meliae Cortex, two commonly used traditional Chinese medicines. TSN has been reported to induce hepatotoxicity, but its mechanism remains unclear. In this study, we demonstrated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2) in protecting against TSN-induced hepatotoxicity in mice and human normal liver L-02 cells. In mice, administration of TSN (10 mg/kg)-induced acute liver injury evidenced by increased serum alanine/aspartate aminotransferase (ALT/AST) and alkaline phosphatase (ALP) activities, and total bilirubin (TBiL) content as well as the histological changes. Furthermore, TSN markedly increased liver reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and decreased liver glutathione (GSH) content and Nrf2 expression. In L-02 cells, TSN (2 μM) time-dependently reduced glutamate-cysteine ligase (GCL) activity and cellular expression of the catalytic/modify subunit of GCL (GCLC/GCLM). Moreover, TSN reduced cellular GSH content and the increased ROS formation, and time-dependently decreased Nrf2 expression and increased the expression of the Nrf2 inhibitor protein kelch-like ECH-associated protein-1 (Keap1). Pre-administration of quercetin (40, 80 mg/kg) effectively inhibited TSN-induced liver oxidative injury and reversed the decreased expression of Nrf2 and GCLC/GCLM in vivo and in vitro. In addition, the quercetin-provided protection against TSN-induced hepatotoxicity was diminished in Nrf2 knock-out mice. In conclusion, TSN decreases cellular GSH content by reducing Nrf2-mediated GCLC/GCLM expression via decreasing Nrf2 expression. Quercetin attenuates TSN-induced hepatotoxicity by inducing the Nrf2/GCL/GSH antioxidant signaling pathway. This study implies that inducing Nrf2 activation may be an effective strategy to prevent TSN-induced hepatotoxicity.

Hepatotoxicity of Microcystin-LR in Fed and Fasted Rats

DTIC Science & Technology

1990-04-20

a free radical scavenger, silymarin , prot’cted mice against MCYST-LR (MEREISH et al., 1989). One of the more dramatic changes in liver after exposure...Microcystin-LR hepatotoxicity by silymarin in mice and rats. The FASEB J. 3, A1190. MERILUOTO, J. A. 0., SANDSTROM, A., ERIKSSON, J. E., REMAUD, G

Comparison of mouse strains for susceptibility to styrene-induced hepatotoxicity and pneumotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carlson, G.P.

1997-10-01

Styrene is known to cause both hepatotoxicity and pneumotoxicity in mice. Strain differences have been reported by other investigators suggesting that Swiss mice are less susceptible than non-Swiss mice to styrene-induced liver damage. In this study, All and C57BL16 mice were found to be similar to non-Swiss albino (NSA) mice in susceptibility whereas CD-1 (Swiss) mice were more resistant to hepatotoxicity as assessed by serum sorbitol dehydrogenase levels and pneumotoxicity as determined by gamma-glutamyltranspeptidase and lactate dehydrogenase measurements in bronchoalveolar ravage fluid. Styrene was hepatotoxic in CD-1 mice treated with pyridine to induce CYP2E1. CYP2E1 apoprotein levels and p-nitrophenol hydroxylasemore » activities in control and pyridine-induced mice were similar in the two strains. Hepatic and pulmonary microsomal preparations from both strains metabolized styrene to styrene oxide at similar rates. CD-1 mice were as susceptible as the NSA mice to the effects of styrene oxide. The data suggest that there are no differences in the bioactivation of styrene to styrene oxide or innate susceptibility to the active metabolite that would account for the differences between the CD-1 and NSA mice. 26 refs., 6 tabs.« less

The liver-gut microbiota axis modulates hepatotoxicity of tacrine in the rat.

PubMed

Yip, Lian Yee; Aw, Chiu Cheong; Lee, Sze Han; Hong, Yi Shuen; Ku, Han Chen; Xu, Winston Hecheng; Chan, Jessalyn Mei Xuan; Cheong, Eleanor Jing Yi; Chng, Kern Rei; Ng, Amanda Hui Qi; Nagarajan, Niranjan; Mahendran, Ratha; Lee, Yuan Kun; Browne, Edward R; Chan, Eric Chun Yong

2018-01-01

The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher β-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral β-glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo. This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (Hepatology 2018;67:282-295). © 2017 by the American Association for the Study of Liver Diseases.

Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity.

PubMed

Hayashi, Paul H; Fontana, Robert J; Chalasani, Naga P; Stolz, Andrew A; Talwalkar, Jay A; Navarro, Victor J; Lee, William M; Davern, Timothy J; Kleiner, David E; Gu, Jiezhun; Hoofnagle, Jay H

2015-09-01

Isoniazid is a leading cause of liver injury but it is not clear how many cases are reported or how many clinicians and patients adhere to American Thoracic Society (ATS) guidelines. We collected data on cases of isoniazid hepatotoxicity and assessed adherence to ATS guidelines and reports to the Centers for Disease Control's (CDC) isoniazid severe adverse events program. We analyzed Drug-Induced Liver Injury Network (DILIN) cases considered definite, highly likely, or probable for isoniazid injury from 2004 through 2013. We assessed the delays in isoniazid discontinuance according to ATS criteria and hepatotoxicity severity by Severity Index Score. We checked reporting to the CDC by matching cases based on age, latency, indication, reporting period, and comorbidities. Isoniazid was the second most commonly reported agent in the DILIN, with 69 cases; 60 of these met inclusion criteria. The median age of cases was 49 years (range, 4-68 y), 70% were female, 97% had latent tuberculosis, and 62% were hospitalized. Patients took a median of 9 days to stop taking isoniazid (range, 0-99 days). Thirty-three cases (55%) continued taking isoniazid for more than 7 days after the ATS criteria for stopping were met. Twenty-four cases (40%) continued isoniazid for more than 14 days after meeting criteria for stopping. A delay in stopping was associated with more severe injury (P < .05). Of 13 patients who died or underwent liver transplantation, 9 (70%) continued taking isoniazid for more than 7 days after meeting criteria for stopping. Only 1 of 25 cases of isoniazid hepatotoxicity eligible for reporting to the CDC was reported. Poor adherence to ATS guidelines is common in cases of hepatotoxicity and is associated with more severe outcomes including hospitalization, death, and liver transplantation. Isoniazid continues to be a leading cause of DILI in the United States, and its hepatotoxicity is under-reported significantly. Copyright © 2015 AGA Institute. Published by

[Hepatotoxicity of emodin based on UGT1A1 enzyme-mediated bilirubin in liver microsomes].

PubMed

Wang, Qi; Dai, Zhong; Zhang, Yu-Jie; Ma, Shuang-Cheng

2016-12-01

To study the hepatotoxicity of emodin based on bilirubin metabolism mediated by glucuronidation of UGT1A1 enzyme. In this study, three different incubation systems were established by using RLM, HLM, and rUGT1A1, with bilirubin as the substrate. Different concentrations of bilirubin and emodin were added in the incubation systems. The double reciprocal Michaelis equation was drawn based on the total amount of bilirubin glucuronidation. The apparent inhibition constant Ki was then calculated with the slope curve to predict the hepatotoxicity. The results indicated that emodin had a significant inhibition to the UGT1A1 enzyme in all of the three systems, with Ki=5.400±0.956(P<0.05) in HLM system, Ki =10.020±0.611(P<0.05) in RLM system, Ki=4.850±0.528(P<0.05) in rUGT1A1 system. Meanwhile, emodin had no significant difference between rat and human in terms of inhibition of UGT1A1 enzyme. Emodin had a potential risk of the hepatotoxicity by inhibiting the UGT1A1 enzyme activity. And the method established in this study provides a new thought and new method to evaluate hepatotoxicity and safety of traditional Chinese medicines. Copyright© by the Chinese Pharmaceutical Association.

6-gingerol, an active ingredient of ginger, protects acetaminophen-induced hepatotoxicity in mice.

PubMed

Sabina, Evan Prince; Pragasam, Samuel Joshua; Kumar, Suresh; Rasool, Mahaboobkhan

2011-11-01

To investigate the hepatoprotective efficacy of 6-gingerol against acetaminophen-induced hepatotoxicity in mice. Mice were injected with a single dose of acetaminophen (900 mg/kg) to induce hepatotoxicity, while 6-gingerol (30 mg/kg) or the standard drug silymarin (25 mg/kg) was given 30 min after the acetaminophen administration. The mice were sacrificed 4 h after acetaminophen injection to determine the activities of liver marker enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), total bilirubin in serum, and lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione transferase and glutathione) in liver homogenate. The treatment of 6-gingerol and silymarin to acetaminophen-induced hepatotoxicity showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, and ALP) and total bilirubin in serum (P<0.05). In addition, 6-gingerol and silymarin treatment prevented the elevation of hepatic malondialdehyde formation and the depletion of antioxidant status in the liver of acetaminophen-intoxicated mice (P<0.05). The results evidently demonstrate that 6-gingerol has promising hepatoprotective effect which is comparable to the standard drug silymarin.

A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience.

PubMed

Goldkind, Lawrence; Laine, Loren

2006-04-01

Drug-induced hepatotoxicity is the leading cause of acute liver failure (ALF) in the US and the most common adverse event causing drug non-approval and drug withdrawal by the U.S. Food and Drug Administration (FDA). Three different nonsteroidal anti-inflammatory drugs (NSAIDs) have been withdrawn in the UK and/or the US due to hepatotoxicity (bromfenac, ibufenac, and benoxaprofen). A systematic review of clinical trials data for these drugs was performed in an effort to identify possible early signals that could have predicted post-marketing serious hepatoxicity. There were very limited published data on benoxaprofen and none on ibufenac or bromfenac. The publicly accessible archives of the FDA provided information on bromfenac. Flu-like symptoms associated with hepatic enzyme elevation and a case of possible drug-related hepatocellular jaundice may in retrospect have been signals for serious hepatotoxicity in the database of 1195 subjects reviewed by the FDA. Following approval, rates of acute liver failure for bromfenac were estimated to be in the range of 1:10 000. In addition, the safety databases of several drugs also accessed through FDA archives have been reviewed (simvastatin, tacrine, troglitazone, and ximelagatran). These data suggest that while ALT elevations alone do not reliably signal serious hepatotoxicity, elevated transaminases in association with symptomatic hepatitis or jaundice may be predictors of an increased risk of ALF. At present, however, pre-approval databases are generally not large enough to rule out low rates of serious hepatotoxicity. Therefore, it remains critical that clinicians report such cases to the FDA through the MEDWATCH system and that active post-marketing monitoring studies be used to identify potential rare cases of hepatotoxicity. Copyright (c) 2006 John Wiley & Sons, Ltd.

A single acute hepatotoxic dose of CCl4 causes oxidative stress in the rat brain.

PubMed

Ritesh, K R; Suganya, A; Dileepkumar, H V; Rajashekar, Y; Shivanandappa, T

2015-01-01

Carbon tetrachloride (CCl 4 ), a hepatotoxic agent is widely used to study the toxic mechanisms in experimental animals. We have investigated whether oxidative stress is induced in the brain at a single hepatotoxic dosage (1 ml/kg bw) of CCl 4 . Increased lipid peroxidation (LPO), protein carbonyls (PC) content and glutathione (GSH) depletion were observed in the brain regions of rats treated with CCl 4 which was higher than that of liver. A drastic reduction in the activity of glutathione- S -transferase (GST) was seen in the brain regions which was higher than that of liver. Similarly, activities of glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), NADH- and NADPH-dehydrogenase were reduced in the brain regions similar to that of liver. Higher induction of oxidative stress in the brain compared to that of liver implies vulnerability of the brain for CCl 4 neurotoxicity. Our study shows that a single hepatotoxic dose of CCl 4 is equally neurotoxic to rats.

Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen.

PubMed

Wong, Anselm; Sivilotti, Marco L A; Gunja, Naren; McNulty, Richard; Graudins, Andis

2018-03-01

Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol-aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen. We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L). Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500 mg/L × IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000 mg/L × IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase. The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.

The altered liver microRNA profile in hepatotoxicity induced by rhizome Dioscorea bulbifera in mice.

PubMed

Yang, Rui; Bai, Qingyun; Zhang, Jiaqi; Sheng, Yuchen; Ji, Lili

2017-08-01

MicroRNA (miRNA) has been reported to play important roles in regulating drug-induced liver injury. Ethyl acetate extract isolated from rhizoma Dioscoreae bulbifera (EF) has been reported to induce hepatotoxicity in our previous studies. This study aims to observe the altered liver miRNA profile and its related signalling pathway involved in EF-induced hepatotoxicity. Serum alanine/aspartate aminotransferase assay showed that EF (450 mg/kg)-induced hepatotoxicity in mice. Results of miRNA chip analysis showed that the expression of eight miRNAs was up-regulated and of other nine miRNAs was down-regulated in livers from EF-treated mice. Further, the altered expression of miR-200a-3p, miR-5132-5p and miR-5130 was validated using real-time polymerase chain reaction (PCR) assay. There were total seven predicted target genes of miR-200a-3p, miR-5132-5p and miR-5130. Only one kyoto encyclopedia genes and genomes pathway was annotated using those target genes, which is protein processing in endoplasmic reticulum (ER). Furthermore, liver expression of DnaJ subfamily A member 1, a key gene involved in protein processing in ER based on the altered miRNAs, was increased in EF-treated mice. In conclusion, the results demonstrated that EF altered the expression of liver miRNA profile and its related signalling pathway, which may be involved in EF-induced hepatotoxicity.

Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

PubMed Central

Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

2017-01-01

Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

The protective effect of vildagliptin in chronic experimental cyclosporine A-induced hepatotoxicity.

PubMed

El-Sherbeeny, Nagla A; Nader, Manar A

2016-03-01

The study examined the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin, in cyclosporine (CsA)-induced hepatotoxicity. Rats were divided into 4 groups treated for 28 days: control (vehicle), vildagliptin (10 mg/kg, orally), CsA (20 mg/kg, s.c.), and CsA-vildagliptin group. Liver function was assessed by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (γGT), lactate dehydrogenase (LDH), and albumin, and histopathological changes of liver were examined. Oxidative stress markers were evaluated. Assessment of nuclear factor-kappa B (NF-κB) activity in hepatic nuclear extract, serum DPP-4, and expression of Bax and Bcl2 were also done. CsA-induced hepatotoxicity was evidenced by increase in serum levels of AST, ALT, and γGT; a decrease in serum albumin; and a significant alteration in hepatic architecture. Also, significant increase in thiobarbituric acid reactive substance (TBARS) and decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) levels, increased expression Bax proteins with deceased expression of Bcl2, and increased hepatic activity of NF-κB and serum DPP-4 level were observed upon CsA treatment. Vildagliptin significantly improved all altered parameters induced by CsA administration. Vildagliptin has the potential to protect the liver against CsA-induced hepatotoxicity by reducing oxidative stress, DPP-4 activity, apoptosis, and inflammation.

Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice.

PubMed

Pan, Qiong; Sun, Yiming; Jin, Qili; Li, Qixiang; Wang, Qing; Liu, Hao; Zhao, Surong

2016-11-01

To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

Unusual Synchronous Methimazole-Induced Agranulocytosis and Severe Hepatotoxicity in Patient with Hyperthyroidism: A Case Report and Review of the Literature

PubMed Central

Yang, Jun; Zhang, Jun; Xu, Qin; Sheng, Guo-ping; Weng, Wan-wen; Dong, Meng-jie

2015-01-01

Context. To report a patient with hyperthyroidism who developed concurrent occurrence of agranulocytosis and severe hepatotoxicity after taking methimazole (MMI). Case. A 51-year-old Chinese male was diagnosed as hyperthyroidism with normal white blood count and liver function. After 4 weeks' treatment with MMI 20 mg/d, it developed to agranulocytosis and severe cholestatic hepatotoxicity. The patient's symptoms and laboratory abnormalities disappeared after the withdrawal of MMI; his white blood count and liver function recover to normal in 2 weeks and 5 weeks, respectively. 296 MBq dose of 131I was given to the patient 3 weeks after the withdrawal of MMI and his thyroid function was back to normal in 6 months. As we know through literature review, only 5 previous cases reported the synchronous ATD-induced agranulocytosis and severe hepatotoxicity in patients with hyperthyroidism. Methods. Review of the patient's clinical course. Literature review of cases of hyperthyroidism with agranulocytosis and severe hepatotoxicity demonstrated that these complications occurred after taking antithyroid drug (ATD). Conclusions. Patient with hyperthyroidism can have synchronous ATD-induced agranulocytosis and severe hepatotoxicity. This case is extremely rare, but the adverse effects with ATDs is clinically significant. The clinicians need to be careful about this and monitor biochemical of patients who take ATDs. PMID:26060496

Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer's Disease.

PubMed

Dgachi, Youssef; Bautista-Aguilera, Oscar M; Benchekroun, Mohamed; Martin, Hélène; Bonet, Alexandre; Knez, Damijan; Godyń, Justyna; Malawska, Barbara; Gobec, Stanislav; Chioua, Mourad; Janockova, Jana; Soukup, Ondrej; Chabchoub, Fakher; Marco-Contelles, José; Ismaili, Lhassane

2016-05-14

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

NMR-based metabonomic analysis of the hepatotoxicity induced by combined exposure to PCBs and TCDD in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu Chunfeng; Department of Pharmacology, Basic Medical College, Jiamusi University, Jiamusi 154007; Wang Yimei

2010-11-01

A metabonomic approach using {sup 1}H NMR spectroscopy was adopted to investigate the metabonomic pattern of rat urine after oral administration of environmental endocrine disruptors (EDs) polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) alone or in combination and to explore the possible hepatotoxic mechanisms of combined exposure to PCBs and TCDD. {sup 1}H NMR spectra of urines collected 24 h before and after exposure were analyzed via pattern recognition by using principal component analysis (PCA). Serum biochemistry and liver histopathology indicated significant hepatotoxicity in the rats of the combined group. The PCA scores plots of urinary {sup 1}H NMR datamore » showed that all the treatment groups could be easily distinguished from the control group, so could the PCBs or TCDD group and the combined group. The loadings plots of the PCA revealed remarkable increases in the levels of lactate, glucose, taurine, creatine, and 2-hydroxy-isovaleric acid and reductions in the levels of 2-oxoglutarate, citrate, succinate, hippurate, and trimethylamine-N-oxide in rat urine after exposure. These changes were more striking in the combined group. The changed metabolites may be considered possible biomarker for the hepatotoxicity. The present study demonstrates that combined exposure to PCBs and TCDD induced significant hepatotoxicity in rats, and mitochondrial dysfunction and fatty acid metabolism perturbations might contribute to the hepatotoxicity. There was good conformity between changes in the urine metabonomic pattern and those in serum biochemistry and liver histopathology. These results showed that the NMR-based metabonomic approach may provide a promising technique for the evaluation of the combined toxicity of EDs.« less

Protective effect of ALDH2 against cyclophosphamide-induced acute hepatotoxicity via attenuating oxidative stress and reactive aldehydes.

PubMed

Zhai, Xiaoxuan; Zhang, Zhenxiao; Liu, Wenwen; Liu, Baoshan; Zhang, Rui; Wang, Wenjun; Zheng, Wen; Xu, Feng; Wang, Jiali; Chen, Yuguo

2018-04-30

Cyclophosphamide (CY) is a widely used chemotherapeutic agent that is associated with severe side effects, such as hepatotoxicity and nephrotoxicity. However, the extent, mechanisms and potential prevention and treatment strategies of CY-induced acute hepatotoxicity and nephrotoxicity are largely unknown. In this study, we determined the existence and extent of CY-induced acute hepatotoxicity and nephrotoxicity, and demonstrated the effect of ALDH2 on CY-induced acute tissue toxicity and related mechanisms. Adult male C57BL/6J (wide-type, WT) and ALDH2 -/- (KO) mice were divided into four groups: WT, WT + CY, KO + CY and WT + CY + Alda-1. Biochemical analysis showed that plasma ALT was increased by 35.8% in KO + CY group and decreased by 21.1% in WT + CY + Alda-1 group compared to WT + CY group (P < 0.05, respectively). However, there was no significant difference among WT, WT + CY and KO + CY groups regarding plasma renal marker enzymes, including blood urea nitrogen (BUN), creatinine and cystatin C (CysC). Levels of reactive oxygen species (ROS) and toxic aldehydes (acrolein, 4-hydroxynonenol and malondialdehyde) were increased significantly in KO + CY group and decreased significantly in WT + CY + Alda-1 group compared to WT + CY group (P < 0.05, respectively). These findings demonstrate that CY could induce acute hepatotoxicity without nephrotoxicity, and ALDH2 plays a protective role in CY-induced acute hepatotoxicity. The underlying mechanisms are associated with attenuating oxidative stress and detoxifying reactive aldehydes. Copyright © 2018 Elsevier Inc. All rights reserved.

Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARγ and abrogation of oxidative stress and inflammation.

PubMed

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.

Successful oral desensitization with osimertinib following osimertinib-induced fever and hepatotoxicity: a case report.

PubMed

Hirabayashi, Ryosuke; Fujimoto, Daichi; Satsuma, Yukari; Hirabatake, Masaki; Tomii, Keisuke

2018-05-02

Osimertinib is a standard second-line therapy for patients who develop EGFR Thr790Met resistance mutation after treatment with first-line epidermal growth factor receptor tyrosine kinase inhibitors. Although no other effective targeted treatment option exists for these patients, osimertinib might be permanently discontinued owing to the onset of severe drug-induced toxicities like hepatotoxicity. Herein, we report a case of successful oral desensitization with osimertinib after the patient developed osimertinib-induced fever and hepatotoxicity. In the present case report, a 62-year-old Japanese woman received osimertinib as the sixth-line therapy for non-small cell lung carcinoma harboring EGFR Thr790Met-mutation. After 15 days of treatment, she developed general malaise. Although we reduced the drug at a lower dose, she again presented with high fever and elevated serum AST/ALT levels three days after re-initiating treatment. We then attempted oral desensitization with osimertinib over a two-week period. Thereafter, the patient continued osimertinib treatment for 6 months without the recurrence of side effects. In conclusion, oral desensitization may be a useful method in treating hepatotoxicity and drug fever caused by osimertinib.

Review article: Herbal hepatotoxicity--an update on traditional Chinese medicine preparations.

PubMed

Teschke, R; Wolff, A; Frenzel, C; Schulze, J

2014-07-01

Although evidence for their therapeutic efficacy is limited, herbal traditional Chinese medicine (TCM) preparations increasingly gain popularity. In contrast to other herbal products, adverse effects by herbal TCM including liver toxicity were rarely reported. In recent years, more cases were published, providing new clinical challenges. To summarise comprehensively the literature on herbal TCM hepatotoxicity since 2011. PubMed was searched using key words related to TCM, the results were restricted to full English-language publications and abstracts published since 2011. In addition, the database of the National Institutes of Health (NIH) and LiverTox was accessed under the topic 'Drug record: Chinese and other Asian herbal medicines'. Since 2011, new case reports and case series provided evidence for herbal hepatotoxicity by TCM, focusing on nine TCM herbal mixtures and four individual TCM herbs with potential health hazards. These were the TCM products Ban Tu Wan, Chai Hu, Du Huo, Huang Qin, Jia Wei Xia Yao San, Jiguja, Kamishoyosan, Long Dan Xie Gan Tang, Lu Cha, Polygonum multiflorum products, Shan Chi, 'White flood' containing the herbal TCM Wu Zhu Yu and Qian Ceng Ta, and Xiao Chai Hu Tang. Other developments include the establishment of a new and early diagnostic serum marker for hepatotoxicity caused by pyrrolizidine alkaloids, assessed using ultra performance liquid chromatography-mass spectrometry analysis, and new regulatory details to improve herbal TCM product quality and safety. Stringent evaluation of the risk/benefit ratio is essential to protect traditional Chinese medicines users from health hazards including liver injury. © 2014 John Wiley & Sons Ltd.

[Constitutional syndrome associated to metformin induced hepatotoxicity].

PubMed

de la Poza Gómez, Gema; Rivero Fernández, Miguel; Vázquez Romero, Manuel; Angueira Lapeña, Teresa; Arranz de la Mata, Gemma; Boixeda de Miquel, Daniel

2008-12-01

Metformin is an oral antidiabetic agent frequently used to manage type II diabetes. This drug produces nonspecific gastrointestinal symptoms in 5-20% of patients and, more rarely, has also been associated with severe adverse effects such as lactic acidosis. Only a few isolated cases of hepatotoxicity due to this drug have been documented. We report the case of an 83-year-old man with constitutional syndrome and hepatic biochemical alterations, which were attributed to metformin after ruling out an oncologic etiology and observing complete clinical and biochemical resolution after withdrawal of the drug.

Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements

PubMed Central

Dara, Lily; Hewett, Jennifer; Lim, Joseph Kartaik

2008-01-01

Dietary supplements represent an increasingly common source of drug-induced liver injury. Hydroxycut is a popular weight loss supplement which has previously been linked to hepatotoxicity, although the individual chemical components underlying liver injury remain poorly understood. We report two cases of acute hepatitis in the setting of Hydroxycut exposure and describe possible mechanisms of liver injury. We also comprehensively review and summarize the existing literature on commonly used weight loss supplements, and their individual components which have demonstrated potential for liver toxicity. An increased effort to screen for and educate patients and physicians about supplement-associated hepatotoxicity is warranted. PMID:19058338

Assessment of hepatotoxicity of first-line anti-tuberculosis drugs on Wistar rats.

PubMed

Sharma, Radhika; Kaur, Ramneek; Mukesh, Manishi; Sharma, Vijay L

2018-01-01

Adverse drug reactions are inevitable risk factors associated with use of modern medicines. First-line anti-tuberculosis drugs contribute to diverse pathological complications, and hepatotoxicity is one of them. This study investigated the effects of anti-TB drugs in combination (rifampicin [RIF] + isoniazid [INH] + pyrazinamide [PZA]) on Wistar rats. Rats were grouped as control group (saline), toxicant group that was given (30.85 mg/kg b.wt., INH + 61.7 mg/kg b.wt., RIF + 132.65 mg/kg b.wt. PZA in dosage extrapolated from dose that is used in human). Different anti-oxidant enzymes were measured in the liver along with histopathology, hematology, genotoxic effect on bone marrow chromosomes, and DNA fragmentation. In addition, gene and protein expression of CYP2E1, NR1I2, NAT, and CYP7A1 was measured by qPCR and western blot. After administration of anti-TB drugs to Wistar rats for 28 days, there was an increase in thiobarbituric acid reactive substances and a decrease in anti-oxidant enzymes. Marked changes in histopathology, hematology, DNA fragmentation, chromosomes, and in gene expression were observed. Results of the study proved increased hepatotoxicity due to combinational treatment of anti-TB drugs and also that CYP2E1, NR1I2, NAT, and CYP7A1 genes play a vital role in anti-TB drug-induced hepatotoxicity.

VIRTUAL LIVER: AN IN SILICO FRAMEWORK FOR ANALYZING CHEMICAL-INDUCED HEPATOTOXICITY

EPA Science Inventory

The US EPA Virtual Liver (v-LiverTM) is an in silico framework for the dose-dependent perturbation of normal hepatic functions by chemicals using in vitro data. The framework consists of a computable knowledge-base (KB) to infer putative pathways in hepatotoxicity and a cellular...

Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats.

PubMed

Tan, Gang; Pan, Shangha; Li, Jie; Dong, Xuesong; Kang, Kai; Zhao, Mingyan; Jiang, Xian; Kanwar, Jagat R; Qiao, Haiquan; Jiang, Hongchi; Sun, Xueying

2011-01-01

Hydrogen sulfide (H(2)S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2)S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2)S in carbon tetrachloride (CCl(4))-induced hepatotoxicity, cirrhosis and portal hypertension. Sodium hydrosulfide (NaHS), a donor of H(2)S, and DL-propargylglycine (PAG), an irreversible inhibitor of cystathionine γ-lyase (CSE), were applied to the rats to investigate the effects of H(2)S on CCl(4)-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2)S, hepatic H(2)S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP) 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4) significantly reduced serum levels of H(2)S, hepatic H(2)S production and CSE expression. NaHS attenuated CCl(4)-induced acute hepatotoxicity by supplementing exogenous H(2)S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), albumin, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and soluble intercellular adhesion molecule (ICAM)-1, liver histology, hepatic hydroxyproline content and α-smooth muscle actin (SMA) expression. PAG showed opposing effects to NaHS on most of the above parameters. Exogenous H(2)S attenuates CCl(4)-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H(2)S may present a promising approach, particularly for its prophylactic effects, against liver cirrhosis and portal hypertension.

Protective effects of phenolics rich extract of ginger against Aflatoxin B1-induced oxidative stress and hepatotoxicity.

PubMed

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.

A Systematic Strategy for Screening and Application of Specific Biomarkers in Hepatotoxicity Using Metabolomics Combined With ROC Curves and SVMs.

PubMed

Li, Yubo; Wang, Lei; Ju, Liang; Deng, Haoyue; Zhang, Zhenzhu; Hou, Zhiguo; Xie, Jiabin; Wang, Yuming; Zhang, Yanjun

2016-04-01

Current studies that evaluate toxicity based on metabolomics have primarily focused on the screening of biomarkers while largely neglecting further verification and biomarker applications. For this reason, we used drug-induced hepatotoxicity as an example to establish a systematic strategy for screening specific biomarkers and applied these biomarkers to evaluate whether the drugs have potential hepatotoxicity toxicity. Carbon tetrachloride (5 ml/kg), acetaminophen (1500 mg/kg), and atorvastatin (5 mg/kg) are established as rat hepatotoxicity models. Fifteen common biomarkers were screened by multivariate statistical analysis and integration analysis-based metabolomics data. The receiver operating characteristic curve was used to evaluate the sensitivity and specificity of the biomarkers. We obtained 10 specific biomarker candidates with an area under the curve greater than 0.7. Then, a support vector machine model was established by extracting specific biomarker candidate data from the hepatotoxic drugs and nonhepatotoxic drugs; the accuracy of the model was 94.90% (92.86% sensitivity and 92.59% specificity) and the results demonstrated that those ten biomarkers are specific. 6 drugs were used to predict the hepatotoxicity by the support vector machines model; the prediction results were consistent with the biochemical and histopathological results, demonstrating that the model was reliable. Thus, this support vector machine model can be applied to discriminate the between the hepatic or nonhepatic toxicity of drugs. This approach not only presents a new strategy for screening-specific biomarkers with greater diagnostic significance but also provides a new evaluation pattern for hepatotoxicity, and it will be a highly useful tool in toxicity estimation and disease diagnoses. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Reparation of Isoniazid and Rifampicin Combinatorial Therapy-Induced Hepatotoxic Effects by Bacopa monnieri.

PubMed

Evan Prince, Sabina; Udhaya, Lavinya B; Sunitha, Priyadharshini S; Arumugam, Geetha

2016-01-01

Drug-induced liver injury is a major challenge in treating tuberculosis with isoniazid (INH) and rifampicin (RIF). This study was aimed at evaluating the protective effects of Bacopamonnieri (Brahmi) against INH and RIF-induced hepatotoxicity in a rat model and also to study the patterns of interaction between pregnane X receptor (PXR) and chosen active compounds of B. monnieri. Hepatotoxicity was induced in the experimental animals by the oral administration of INH and RIF (50 mg/kg b.w. each/day) for 28 days. The effects of co-administration of B. monnieri (500 mg/kg b.w./day) in INH- and RIF-induced rats were studied by the estimation of biochemical analyses. The standard hepatoprotective drug silymarin (25 mg/kg b.w./day) was used for the purpose of comparison. In silico docking experiments were carried out using the PatchDock server and the results were analysed on the PyMol molecular viewer. There was significant reduction in the antioxidant status of INH and RIF-induced rats. Also, there was significant elevation in the levels of serum liver function markers in the INH- and RIF-induced rats. B. monnieri was able to normalise the tested parameters. In silico studies reveal significant interaction between PXR and bacopaside I. B. monnieri exerts significant protective effects against INH and RIF-induced hepatotoxicity in rats. © 2016 S. Karger AG, Basel.

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

PubMed

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.

Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid.

PubMed

Zhu, He; Long, Min-Hui; Wu, Jie; Wang, Meng-Meng; Li, Xiu-Yang; Shen, Hong; Xu, Jin-Di; Zhou, Li; Fang, Zhi-Jun; Luo, Yi; Li, Song-Lin

2015-12-02

Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes' activities and GSH's level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co-administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver.

Hepatotoxicity associated with 6-methyl mercaptopurine formation during azathioprine and 6-mercaptopurine therapy does not occur on the short-term during 6-thioguanine therapy in IBD treatment.

PubMed

van Asseldonk, Dirk P; Seinen, Margien L; de Boer, Nanne K H; van Bodegraven, Ad A; Mulder, Chris J

2012-02-01

High concentrations of methylated thiopurine metabolites, such as 6-methyl mercaptopurine, are associated with hepatotoxicity during administration of the conventional thiopurines azathioprine or 6-mercaptopurine in IBD patients. Metabolization of the non-conventional thiopurine 6-thioguanine does not generate 6-methyl mercaptopurine. Hence, the aim of our study was to evaluate hepatotoxicity during 6-thioguanine in IBD patients who previously failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. A retrospective single center intercept cohort study was performed of IBD patients using 6-thioguanine between January 2006 and July 2010 after failing conventional thiopurine therapy due to 6-methyl mercaptopurine associated hepatotoxicity. The primary outcome was the occurrence of 6-thioguanine induced hepatotoxicity, scaled according to the Common Terminology Criteria for Adverse Events. Nineteen patients were included. Median duration of 6-thioguanine therapy (median daily dosage 21 mg (9-24)) was 23 weeks (6-96). Hepatotoxicity did not reoccur in 15 out of 19, whereas grade 1 toxicity persisted in 4 patients (p<0.001). Median aspartate aminotransferase and alanine aminotransferase concentrations decreased from 34 U/l (20-59) and 64 U/l (15-175) to 23 U/l (18-40; p=0.003) and 20 U/l (14-48; p=0.019), respectively. Hepatotoxicity does not reoccur during 6-thioguanine treatment in most IBD patients who failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. Hence, at least at short-term, 6-thioguanine appears a justifiable alternative thiopurine for these IBD patients. Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

PubMed Central

Chiu, Chun-Hung; Chang, Chun-Chao; Lin, Shiang-Ting; Chyau, Charng-Cherng; Peng, Robert Y.

2016-01-01

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. PMID:27428953

Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia

PubMed Central

Alachkar, Houda; Fulton, Noreen; Sanford, Ben; Malnassy, Greg; Mutonga, Martin; Larson, Richard A.; Bloomfield, Clara D.; Marcucci, Guido; Nakamura, Yusuke; Stock, Wendy

2016-01-01

Asparaginase, which depletes asparagine and glutamine, activates amino acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this SNP are needed to develop therapeutic approaches that mitigate this toxicity. PMID:27019981

Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

PubMed Central

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

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

PubMed

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.

Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity.

PubMed

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.

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

PubMed

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.

Phenotypic and biomarker evaluation of zebrafish larvae as an alternative model to predict mammalian hepatotoxicity.

PubMed

Verstraelen, Sandra; Peers, Bernard; Maho, Walid; Hollanders, Karen; Remy, Sylvie; Berckmans, Pascale; Covaci, Adrian; Witters, Hilda

2016-09-01

Zebrafish phenotypic assays have shown promise to assess human hepatotoxicity, though scoring of liver morphology remains subjective and difficult to standardize. Liver toxicity in zebrafish larvae at 5 days was assessed using gene expression as the biomarker approach, complementary to phenotypic analysis and analytical data on compound uptake. This approach aimed to contribute to improved hepatotoxicity prediction, with the goal of identifying biomarker(s) as a step towards the development of transgenic models for prioritization. Morphological effects of hepatotoxic compounds (acetaminophen, amiodarone, coumarin, methapyrilene and myclobutanil) and saccharin as the negative control were assessed after exposure in zebrafish larvae. The hepatotoxic compounds induced the expected zebrafish liver degeneration or changes in size, whereas saccharin did not have any phenotypic adverse effect. Analytical methods based on liquid chromatography-mass spectrometry were optimized to measure stability of selected compounds in exposure medium and internal concentration in larvae. All compounds were stable, except amiodarone for which precipitation was observed. There was a wide variation between the levels of compound in the zebrafish larvae with a higher uptake of amiodarone, methapyrilene and myclobutanil. Detection of hepatocyte markers (CP, CYP3A65, GC and TF) was accomplished by in situ hybridization of larvae to coumarin and myclobutanil and confirmed by real-time reverse transcription-quantitative polymerase chain reaction. Experiments showed decreased expression of all markers. Next, other liver-specific biomarkers (i.e. FABP10a and NR1H4) and apoptosis (i.e. CASP-3 A and TP53) or cytochrome P450-related (CYP2K19) and oxidoreductase activity-related (ZGC163022) genes, were screened. Links between basic mechanisms of liver injury and results of biomarker responses are described. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

In vivo assessment of the hepatotoxicity of a new Nostoc isolate from the Nile River: Nostoc sp. strain NRI.

PubMed

Abu-Serie, Marwa M; Nasser, Nermine; Abd El-Wahab, Abeer; Shehawy, Rehab; Pienaar, Harrison; Baddour, Nahed; Amer, Ranya

2018-03-01

Nostoc sp. is one of the most widely distributed cyanobacterial genera that produce potentially protein phosphatase (PP) inhibitor; microcystins (MCs). MCs have posed a worldwide concern due to predominant hepatotoxicity to human health. We have previously isolated a Nostoc strain (NR1) from the Nile River (the main water supply in Egypt) and this strain exerted production of rare and highly toxic MC; demethylated microcystin-LR. There is no data concerning risk factors of liver diseases for human and animal exposure to NR1-contaminated drinking water yet. It is thus important to evaluate acute (LD 50 dose), subacute (0.01% and 10% of LD 50 dose) and subchronic (0.01% and 10% of LD 50 dose) hepatotoxicity's NR1 extract using experimental mice. Mice groups, who orally received 0.01% LD 50 , represented a permissible concentration of the World Health Organization (WHO) for MC in drinking water. Several parameters were detected, including hepatotoxicity (i.e. PP activity, liver function, oxidative stress markers and DNA fragmentation), pro-inflammatory cytokine (TNF-α) and liver histopathology. Our results demonstrated LD 50 of NR1 extract was at 15,350 mg/kg body weight and caused hepatotoxicity that attributed to PP inhibition and a significant increase of hepatic damage biomarkers with lipid accumulation. Moreover, NR1 extract induced hepatic oxidative damage that may have led to DNA fragmentation and production of TNF-α. As demonstrated from the histopathological study, NR1 extract caused a severe collapse of cytoskeleton with subsequent focal degeneration of hepatocytes, necroinflammation and steatosis. The grade of hepatotoxicity in subacute (10% of LD 50 ) group was higher than that in the subchronic (10% of LD 50 and 0.01% of LD 50 , WHOch, respectively) groups. No significant hepatotoxicity was detectable for subacute (0.01% of LD 50 , WHOac) group. NR1 is therefore considered as one of the harmful and life-threatening cyanobacteria for Egyptian people

Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes.

PubMed

Cheng, Dan; Xu, Wang; Yuan, Lin; Zhang, Xiaobing

2017-07-18

Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO - ) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO - and Rhod-ONOO - ) for ONOO - through a novel and universally applicable mechanism: ONOO - -mediated deprotection of α-keto caged fluorophores. Among them, Rhod-ONOO - can selectively accumulate and react in mitochondria, one of the main sources of ONOO - , with a substantial lower nanomolar sensitivity of 43 nM. The superior selectivity and sensitivity of two probes enable real-time imaging of peroxynitrite generation in lipopolysaccharide-stimulated live cells, with a remarkable difference from cells doped with other interfering reactive oxygen species, in either one- or two-photon imaging modes. More importantly, we elucidated the drug-induced hepatotoxicity pathway with Rhod-ONOO - and revealed that CYP450/CYP2E1-mediated enzymatic metabolism of acetaminophen leads to ONOO - generation in liver cells. This is the first time to showcase the drug-induced hepatotoxicity pathways by use of a small-molecule fluorescent probe. We hence conclude that fluorescent probes can engender a deeper understanding of reactive species and their pathological revelations. The reaction-based fluorescent probes will be a potentially useful chemical tool to assay drug-induced hepatotoxicity.

Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States

PubMed Central

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

Trifluoperazine inhibits acetaminophen-induced hepatotoxicity and hepatic reactive nitrogen formation in mice and in freshly isolated hepatocytes.

PubMed

Banerjee, Sudip; Melnyk, Stepan B; Krager, Kimberly J; Aykin-Burns, Nukhet; McCullough, Sandra S; James, Laura P; Hinson, Jack A

2017-01-01

The hepatotoxicity of acetaminophen (APAP) occurs by initial metabolism to N-acetyl-p-benzoquinone imine which depletes GSH and forms APAP-protein adducts. Subsequently, the reactive nitrogen species peroxynitrite is formed from nitric oxide (NO) and superoxide leading to 3-nitrotyrosine in proteins. Toxicity occurs with inhibited mitochondrial function. We previously reported that in hepatocytes the nNOS (NOS1) inhibitor NANT inhibited APAP toxicity, reactive nitrogen and oxygen species formation, and mitochondrial dysfunction. In this work we examined the effect of trifluoperazine (TFP), a calmodulin antagonist that inhibits calcium induced nNOS activation, on APAP hepatotoxicity and reactive nitrogen formation in murine hepatocytes and in vivo . In freshly isolated hepatocytes TFP inhibited APAP induced toxicity, reactive nitrogen formation (NO, GSNO, and 3-nitrotyrosine in protein), reactive oxygen formation (superoxide), loss of mitochondrial membrane potential, decreased ATP production, decreased oxygen consumption rate, and increased NADH accumulation. TFP did not alter APAP induced GSH depletion in the hepatocytes or the formation of APAP protein adducts which indicated that reactive metabolite formation was not inhibited. Since we previously reported that TFP inhibits the hepatotoxicity of APAP in mice without altering hepatic APAP-protein adduct formation, we examined the APAP treated mouse livers for evidence of reactive nitrogen formation. 3-Nitrotyrosine in hepatic proteins and GSNO were significantly increased in APAP treated mouse livers and decreased in the livers of mice treated with APAP plus TFP. These data are consistent with a hypothesis that APAP hepatotoxicity occurs with altered calcium metabolism, activation of nNOS leading to increased reactive nitrogen formation, and mitochondrial dysfunction.

Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data.

PubMed

Kim, Marlene Thai; Huang, Ruili; Sedykh, Alexander; Wang, Wenyi; Xia, Menghang; Zhu, Hao

2016-05-01

Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Quantitative structure-activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro-in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and big data. Environ Health Perspect 124:634-641;�

Ameliorative effect of vitamin C against hepatotoxicity induced by emamectin benzoate in rats.

PubMed

Khaldoun Oularbi, H; Richeval, C; Lebaili, N; Zerrouki-Daoudi, N; Baha, M; Djennas, N; Allorge, D

2017-07-01

In the present study, we aimed to assess the potential protective effect of ascorbic acid (AA) against emamectin benzoate (EMB)-induced hepatotoxicity. For this purpose, biochemical, histopathological and analytical investigations were performed. Male Wistar rats were distributed into three groups, that is, a control group, an EMB group given 10 mg EMB/kg body weight (BW) by gavage and an EMB + AA group given 10 mg EMB/kg BW and vitamin C intraperitoneally (200 mg/kg). The duration of the treatment was 28 days and the duration of the study was 42 days. There was a statistically significant increase of all hepatic biomarkers, that is, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase activities, and glycemia, in EMB-treated group when compared with the control group. Light microscopic observations revealed variable signs of hepatotoxicity in the EMB group, which were represented by alteration of normal hepatic architecture, inflammatory cell infiltration, hepatocellular steatosis and foci of necrosis at 28 and 42 days post-treatment. However, co-treatment with vitamin C reduced EMB-related liver toxicity and diminished the abnormal biochemical and architectural damage. Emamectin B1a and B1b residues were detectable in all plasma samples of treated rats at 14, 21 and 28 days of treatment. The drug liver tissue concentration was significantly lower in EMB + AA group compared with EMB group at 28 and 42 days. In conclusion, the findings of the present study clearly indicate a significant protective action of vitamin C against EMB hepatotoxicity.

Zingiber officinale Roscoe prevents acetaminophen-induced acute hepatotoxicity by enhancing hepatic antioxidant status.

PubMed

Ajith, T A; Hema, U; Aswathy, M S

2007-11-01

A large number of xenobiotics are reported to be potentially hepatotoxic. Free radicals generated from the xenobiotic metabolism can induce lesions of the liver and react with the basic cellular constituents - proteins, lipids, RNA and DNA. Hepatoprotective activity of aqueous ethanol extract of Zingiber officinale was evaluated against single dose of acetaminophen-induced (3g/kg, p.o.) acute hepatotoxicity in rat. Aqueous extract of Z. officinale significantly protected the hepatotoxicity as evident from the activities of serum transaminase and alkaline phosphatase (ALP). Serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT) and ALP activities were significantly (p<0.01) elevated in the acetaminophen alone treated animals. Antioxidant status in liver such as activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase and glutathione-S-transferase (GST), a phase II enzyme, and levels of reduced glutathione (GSH) were declined significantly (p<0.01) in the acetaminophen alone treated animals (control group). Hepatic lipid peroxidation was enhanced significantly (p<0.01) in the control group. Administration of single dose of aqueous extract of Z. officinale (200 and 400mg/kg, p.o.) prior to acetaminophen significantly declines the activities of serum transaminases and ALP. Further the hepatic antioxidant status was enhanced in the Z. officinale plus acetaminophen treated group than the control group. The results of the present study concluded that the hepatoprotective effect of aqueous ethanol extract of Z. officinale against acetaminophen-induced acute toxicity is mediated either by preventing the decline of hepatic antioxidant status or due to its direct radical scavenging capacity.

Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy.

PubMed

Dgachi, Youssef; Sokolov, Olga; Luzet, Vincent; Godyń, Justyna; Panek, Dawid; Bonet, Alexandre; Martin, Hélène; Iriepa, Isabel; Moraleda, Ignacio; García-Iriepa, Cristina; Janockova, Jana; Richert, Lysiane; Soukup, Ondrej; Malawska, Barbara; Chabchoub, Fakher; Marco-Contelles, José; Ismaili, Lhassane

2017-01-27

Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC 50  = 0.75 ± 0.01 μM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Hepatotoxicity and subchronic toxicity tests of Morinda citrifolia (noni) fruit.

PubMed

West, Brett J; Su, Chen X; Jensen, C Jarakae

2009-10-01

Morinda citrifolia (noni) fruit juice has been approved as a safe food in many nations. A few cases of hepatitis in people who had been drinking noni juice have been reported, even though no causal link could be established between the liver injury and ingestion of the juice. To more fully evaluate the hepatotoxic potential of noni fruit juice, in vitro hepatotoxicity tests were conducted in human liver cells, HepG2 cell line. A subchronic oral toxicity test of noni fruit was also performed in Sprague-Dawley (SD) rats to provide benchmark data for understanding the safety of noni juice, without the potential confounding variables associated with many commercial noni juice products. Freeze-dried filtered noni fruit puree did not decrease HepG2 cell viability or induce neutral lipid accumulation and phospholipidosis. There were no histopathological changes or evidence of dose-responses in hematological and clinical chemistry measurements, including liver function tests. The no-observed-adverse-effect level (NOAEL) for freeze-dried noni fruit puree is greater than 6.86 g/kg body weight, equivalent to approximately 90 ml of noni fruit juice/kg. These findings corroborate previous conclusions that consumption of noni fruit juice is unlikely to induce adverse liver effects.

Protective Effect of Korean Red Ginseng against Aflatoxin B1-Induced Hepatotoxicity in Rat

PubMed Central

Kim, Yong-Seong; Kim, Yong-Hoon; Noh, Jung-Ran; Cho, Eun-Sang; Park, Jong-Ho; Son, Hwa-Young

2011-01-01

Korean red ginseng (KRG), the steamed root of Panax ginseng Meyer, has a variety of biological properties, including anti-inflammatory, antioxidant and anticancer effects. Aflatoxin B1 (AFB1) produced by the Aspergillus spp. causes acute hepatotoxicity by lipid peroxidation and oxidative DNA damage, and induces liver carcinoma in humans and laboratory animals. This study was performed to examine the protective effects of KRG against hepatotoxicity induced by AFB1 using liver-specific serum marker analysis, histopathology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. In addition, to elucidate the possible mechanism of hepatoprotective effects, superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde were analyzed. Rats were treated with 250 mg/kg of KRG (KRG group) or saline (AFB1 group) for 4 weeks and then received 150 μg/kg of AFB1 intraperitoneally for 3 days. Rats were sacrificed at 12 h, 24 h, 48 h, 72 h, or 1 wk after AFB1 treatment. In the KRG pre-treatment group, serum alanine aminotransferase, aspartate aminotransferase, and malondialdehyde levels were low, but superoxide dismutase, catalase, and glutathione peroxidase activities were high as compared to the AFB1 alone group. Histopathologically, AFB1 treatment induced necrosis and apoptosis in hepatocytes, and led to inflammatory cells infiltration in the liver. KRG pre-treatment ameliorated these changes. These results indicate that KRG may have protective effects against hepatotoxicity induced by AFB1 that involve the antioxidant properties of KRG. PMID:23717067

[Hepatox: database on hepatotoxic drugs].

PubMed

Quinton, A; Latry, P; Biour, M

1993-01-01

Hepatox is a data base on the hepatotoxic drugs file published every year in Gastroentérologie Clinique et Biologique. The program was developed under Omnis 7 for Apple computers, and under Visual Basic Professional Toolkit and Code Base for IBM PC and compatibles computers. The data base includes forms of 866 drugs identified by their approved name and those of their 1,300 corresponding proprietary names in France; drugs are distributed among 104 pharmacological classes. It is possible to have instantaneously access to the card of a drug identified by its approved name. Acceding to a drug identified by its proprietary name gives a list of the approved name of its components; going from a name of this list to the correspondent card of hepatoxicity is immediate. It is easy to extract lists of drugs responsible of a type of hepatic injury, and a table of types of hepatic injuries induced by the drugs of a pharmacological class.

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

PubMed

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

2017-07-13

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.

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

PubMed

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 < 0.05). The comet assay revealed increased detaching tail length and DNA concentration during the hepatic toxicity in the acetaminophen group. The malondialdehyde content was inhibited by 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.

Active uptake system for substance P carboxy-terminal heptapeptide (5-11) into a fraction from rabbit enriched in glial cells.

PubMed

Inoue, A; Nakata, Y; Yajima, H; Segawa, T

1984-10-01

In the present study, we demonstrated the existence of an active uptake system for substance P carboxy-terminal heptapeptide, (5-11)SP. When a fraction from rabbit brain enriched in glial cells was incubated with [3H] (5-11)SP, an uptake of [3H](5-11)SP was observed. The uptake system has the properties of an active transport mechanism. Kinetic analysis indicated two components of [3H](5-11)SP uptake, one representing a high and the other a low affinity transport system. After unilateral ablation of the striatum, approximately 30% of the high affinity [3H](5-11)SP uptake capacity of substantia nigra slices disappeared. The subcellular distribution of the high affinity uptake indicated that [3H] 5-hydroxytryptamine was taken up mostly into the P2B fraction (synaptosomal fraction), whereas [3H](5-11)SP was taken up into the P2A fraction (myelin fraction) to the same extent as into the P2B fraction. These results suggest that when SP is released from nerve terminals, it is hydrolysed into (5-11)SP, which is in turn accumulated into glial cells as well as nerve terminals and that this high affinity uptake mechanism may play an important role in terminating the synaptic action of SP.

POTENTIATION OF CARBON TETRACHLORIDE HEPATOTOXICITY BY INHALED METHANOL:TIME COURSE INJURY AND RECOVERY

EPA Science Inventory

Increases in the use of methanol (MeOH) as a transportation fuel would result in greater potential for inhalation exposure. ecause oral exposure to MeOH potentates the hepatotoxicity of carbon tetrachloride (CCl4), we examined the ability of inhaled MeOH to potentiate CCl4 hepato...

Liver steatosis is a risk factor for hepatotoxicity in patients with inflammatory bowel disease under immunosuppressive treatment.

PubMed

Schröder, Torsten; Schmidt, Klaus J; Olsen, Vera; Möller, Steffen; Mackenroth, Tilo; Sina, Christian; Lehnert, Hendrik; Fellermann, Klaus; Büning, Jürgen

2015-06-01

In inflammatory bowel disease (IBD), hepatic disorders are frequently due to nonalcoholic fatty liver disease and drug-induced hepatotoxicity. Immunosuppressive treatment is known to exert hepatotoxic side effects by a still unknown mode. The relevance of liver steatosis for the development of drug-related hepatotoxicity in IBD is unknown. The charts of 259 patients with IBD under immunosuppression with either azathioprine, 6-mercaptopurine, or methotrexate were reviewed. The prevalence of liver steatosis was assessed by means of ultrasound reports. Aspartate transaminase and alanine transaminase above the normal range were used to indicate liver abnormalities. Liver steatosis on the basis of ultrasound criteria was observed in 73 patients (28.2%). In patients with liver steatosis, the presence of elevated liver enzymes (ELE) was found to be significantly more prevalent (28.8 vs. 14.5%, P=0.0095). The finding of liver steatosis was associated with higher age (44.1 vs. 34.5 years, P<0.0001) and body weight (BMI 26.7 vs. 23.4 kg/m, P<0.0001). Development of ELE under immunosuppression was seen in 50 patients (19.3%). Of the patients who developed ELE, 44.0% (vs. 24.4%, P=0.0095) showed liver steatosis. Logistic regression analysis revealed that male individuals showed an increased likelihood of developing ELE associated with steatosis (P=0.0118, odds ratio=3.93) and that patients who received steroids less often developed ELE in association with liver steatosis (P=0.0414, odds ratio=0.31). This study suggests that fatty liver represents a risk factor for hepatotoxicity in patients with IBD under immunosuppressive treatment and should be routinely considered in treatment strategies.

Protective effects of silymarin against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice.

PubMed

Bektur, Nuriye Ezgi; Sahin, Erhan; Baycu, Cengiz; Unver, Gonul

2016-04-01

This study was designed to estimate protective effects of silymarin on acetaminophen (N-acetyl-p-aminophenol, paracetamol; APAP)-induced hepatotoxicity and nephrotoxicity in mice. Treatment of mice with overdose of APAP resulted in the elevation of aspartate aminotransferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), and serum creatinine (SCr) levels in serum, liver, and kidney nitric oxide (NO) levels and significant histological changes including decreased body weight, swelling of hepatocytes, cell infiltration, dilatation and congestion, necrosis and apoptosis in liver, and dilatation of Bowman's capsular space and glomerular capillaries, pale-stained tubules epithelium, cell infiltration, and apoptosis in kidney. Posttreatment with silymarin 1 h after APAP injection for 7 days, however, significantly normalized the body weight, histological damage, serum ALT, AST, BUN, SCr, and tissue NO levels. Our observation suggested that silymarin ameliorated the toxic effects of APAP-induced hepatotoxicity and nephrotoxicity in mice. The protective role of silymarin against APAP-induced damages might result from its antioxidative and anti-inflammatory effects. © The Author(s) 2013.

Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats

PubMed Central

Akbulut, Sami; Elbe, Hulya; Eris, Cengiz; Dogan, Zumrut; Toprak, Gulten; Otan, Emrah; Erdemli, Erman; Turkoz, Yusuf

2014-01-01

AIM: To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity. METHODS: An MTX-induced hepatotoxicity model was established in 44 male Sprague Dawley rats by administration of a single intraperitoneal injection of 20 mg/kg MTX. Eleven of the rats were left untreated (Model group; n = 11), and the remaining rats were treated with a 7-d course of 50 mg/kg per day NAC (MTX + NAC group; n = 11), 50 mg/kg per single dose AMF (MTX + AMF group; n = 11), or 10 mg/kg per day ASC (MTX + ASC group; n = 11). Eleven rats that received no MTX and no treatments served as the negative control group. Structural and functional changes related to MTX- and the various treatments were assessed by histopathological analysis of liver tissues and biochemical assays of malondialdehyde (MDA), superoxide dismutase (SOD), catalase, glutathione (GSH) and xanthine oxidase activities and of serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin. RESULTS: Exposure to MTX caused structural and functional hepatotoxicity, as evidenced by significantly worse histopathological scores [median (range) injury score: control group: 1 (0-3) vs 7 (6-9), P = 0.001] and significantly higher MDA activity [409 (352-466) nmol/g vs 455.5 (419-516) nmol/g, P < 0.05]. The extent of MTX-induced perturbation of both parameters was reduced by all three cytoprotective agents, but only the reduction in hepatotoxicity scores reached statistical significance [4 (3-6) for NAC, 4.5 (3-5) for AMF and 6 (5-6) for ASC; P = 0.001, P = 0.001 and P < 0.005 vs model group respectively]. Exposure to MTX also caused a significant reduction in the activities of GSH and SOD antioxidants in liver tissues [control group: 3.02 (2.85-3.43) μmol/g and 71.78 (61.88-97.81) U/g vs model group: 2.52 (2.07-3.34) μmol/g and 61.46 (58

The enhanced atorvastatin hepatotoxicity in diabetic rats was partly attributed to the upregulated hepatic Cyp3a and SLCO1B1

PubMed Central

Shu, Nan; Hu, Mengyue; Ling, Zhaoli; Liu, Peihua; Wang, Fan; Xu, Ping; Zhong, Zeyu; Sun, Binbin; Zhang, Mian; Li, Feng; Xie, Qiushi; Liu, Xiaodong; Liu, Li

2016-01-01

Liver injury is a common adverse effect of atorvastatin. This study aimed to investigate atorvastatin-induced hepatotoxicity in diabetic rats induced by high-fat diet combined with streptozotocin. The results showed that 40 mg/kg atorvastatin was lethal to diabetic rats, whose mean survival time was 6.2 days. Severe liver injury also occurred in diabetic rats treated with 10 mg/kg and 20 mg/kg atorvastatin. The in vitro results indicated that atorvastatin cytotoxicity in hepatocytes of diabetic rats was more severe than normal and high-fat diet feeding rats. Expressions and activities of hepatic Cyp3a and SLCO1B1 were increased in diabetic rats, which were highly correlated with hepatotoxicity. Antioxidants (glutathione and N-Acetylcysteine), Cyp3a inhibitor ketoconazole and SLCO1B1 inhibitor gemfibrozil suppressed cytotoxicity and ROS formation in primary hepatocytes of diabetic rats. In HepG2 cells, up-regulations of CYP3A4 and SLCO1B1 potentiated hepatotoxicity and ROS generation, whereas knockdowns of CYP3A4 and SLCO1B1 as well as CYP3A4/SLCO1B1 inhibitions showed the opposite effects. Phenobarbital pretreatment was used to induce hepatic Cyp3a and SLCO1B1 in rats. Phenobarbital aggravated atorvastatin-induced hepatotoxicity, while decreased plasma exposure of atorvastatin. All these findings demonstrated that the upregulations of hepatic Cyp3a and SLCO1B1 in diabetic rats potentiated atorvastatin-induced hepatotoxicity via increasing ROS formation. PMID:27624558

Grey-scale ultrasonography for monitoring industrial exposure to hepatotoxic agents.

PubMed

Taylor, K J; Williams, D M; Smith, P M; Duck, B W

1975-05-31

Industrial exposure to several potentially hepatotoxic agents, such as vinyl-chloride monomer may occur, and there is a need for non-vasive, diagnostic techniques to detect and monitor progressive pathological processes in liver or spleen. Grey-scale ultrasonography permits display of detailed anatomy and pathology in the liver, portal veins, and spleen. The combination of fine resolution, non-invasiveness, absence of ionising radiation hazard, and portable equipment makes the technique ideal for screening populations at risk.

Hepatotoxicity of nucleoside reverse transcriptase inhibitors.

PubMed

Montessori, Valentina; Harris, Marianne; Montaner, Julio S G

2003-05-01

Hepatotoxicity is an adverse effect of all available classes of antiretrovirals, including nucleoside reverse transcriptase inhibitors (NRTI). A syndrome of hepatic steatosis and lactic acidosis has been recognized as a rare, potentially fatal complication since the advent of NRTI monotherapy in the early 1990s. Today, NRTI remain the backbone of antiretroviral combination regimens, and, with the success of current treatment strategies, exposure to two or more of these agents may occur over a number of years. Hepatic steatosis and lactic acidosis are accordingly being observed more frequently, along with a more recently recognized syndrome of chronic hyperlactatemia. These as well as other adverse effects of NRTI are mediated by inhibition of human DNA polymerase gamma, resulting in mitochondrial dysfunction in the liver and other tissues. Early recognition and intervention are essential to avert serious outcomes.

Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data

PubMed Central

Kim, Marlene Thai; Huang, Ruili; Sedykh, Alexander; Wang, Wenyi; Xia, Menghang; Zhu, Hao

2015-01-01

Background: Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. Objective: The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Methods: Quantitative structure–activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro–in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. Results: The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Conclusion: Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Citation: Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and

HEPATOTOXIC EVALUATION OF THE BINARY INTERACTIONS OF BROMODICHLOROMETHANE WITH CHLOROFORM, CHLORODIBROMOMETHANE AND BROMOFORM

EPA Science Inventory

HEPATOTOXIC EVALUATION OF THE BINARY INTERACTIONS OF BROMODICHLOROMETHANE (BDCM) WITH CHLOROFORM (CHC13), CHLORODIBROMOMETHANE (CDBM) AND BROMOFORM (CHBr3). Y M Se'', C Gennings2, A McDonald', L K Teuschler3, A Hamm2and J E Simmons .'NHEERL, ORD, U.S. EPA, RTP, NC; 2MCV, VCU, Ric...

In vivo investigation on the chronic hepatotoxicity induced by sertraline.

PubMed

Almansour, Mansour I; Jarrar, Yazun B; Jarrar, Bashir M

2018-05-30

Although sertraline is widely prescribed as relatively safe antidepressant drug, hepatic toxicity was reported in some patients with sertraline treatment. The present study was conducted to investigate the morphometric, hepatotoxicity, and change in gene expression of drug metabolizing enzymes. Male healthy adult rabbits (Oryctolagus cuniculus) ranging from 1050 to 1100 g were exposed to oral daily doses of sertraline (0, 1, 2, 4, 8 mg/kg) for 9 weeks. The animals were subjected to morphometric, hepatohistological, histochemical and quantitative real-time polymerase chain reaction analyses. Sertraline chronic exposure induced morphometric changes and provoked histological and histochemical alterations including: hepatocytes hydropic degeneration, necrosis, nuclear alteration, sinusoidal dilation, bile duct hyperplasia, inflammatory cells infiltration, portal vessel congestion, Kupffer cells hyperplasia, portal fibrosis and glycogen depletion. In addition, the gene expression of drug and arachidonic acid metabolizing enzymes were reduced significantly (p value <0.05). The most affected genes were cyp4a12, ephx2, cyp2d9 and cyp1a2, demonstrating 5 folds or more down-regulation. These findings suggest that chronic sertraline treatment induced toxic histological alterations in the hepatic tissues and reduced the gene expression of drug metabolizing enzymes. Patients on chronic sertraline treatment may be on risk of hepatotoxicity with reduced capacity to metabolize drugs and fatty acids. Copyright © 2018 Elsevier B.V. All rights reserved.

Cyclic control stick

DOEpatents

Whitaker, Charles N.; Zimmermann, Richard E.

1989-01-01

A cyclic control stick of the type used in helicopters for reducing the safety hazards associated with such a mechanism in the event of a crewman being thrown violently into contact with the cyclic control stick resulting from a crash or the like. The cyclic control stick is configured to break away upon the exertion of an impact force which exceeds a predetermined value and/or is exerted for more than a momentary time duration. The cyclic control stick is also configured to be adjustable so as to locate the grip thereof as far away from the crewman as possible for safety reasons without comprising the comfort of the crewman or the use of the control stick, and a crushable pad is provided on the top of the grip for impact energy absorbing purposes.

Compressed sensing with cyclic-S Hadamard matrix for terahertz imaging applications

NASA Astrophysics Data System (ADS)

Ermeydan, Esra Şengün; ćankaya, Ilyas

2018-01-01

Compressed Sensing (CS) with Cyclic-S Hadamard matrix is proposed for single pixel imaging applications in this study. In single pixel imaging scheme, N = r . c samples should be taken for r×c pixel image where . denotes multiplication. CS is a popular technique claiming that the sparse signals can be reconstructed with samples under Nyquist rate. Therefore to solve the slow data acquisition problem in Terahertz (THz) single pixel imaging, CS is a good candidate. However, changing mask for each measurement is a challenging problem since there is no commercial Spatial Light Modulators (SLM) for THz band yet, therefore circular masks are suggested so that for each measurement one or two column shifting will be enough to change the mask. The CS masks are designed using cyclic-S matrices based on Hadamard transform for 9 × 7 and 15 × 17 pixel images within the framework of this study. The %50 compressed images are reconstructed using total variation based TVAL3 algorithm. Matlab simulations demonstrates that cyclic-S matrices can be used for single pixel imaging based on CS. The circular masks have the advantage to reduce the mechanical SLMs to a single sliding strip, whereas the CS helps to reduce acquisition time and energy since it allows to reconstruct the image from fewer samples.

A retrospective review of methotrexate-induced hepatotoxicity among patients with psoriasis in a tertiary dermatology center in Malaysia.

PubMed

Ng, Lim Chui; Lee, Yin Yin; Lee, Chew Kek; Wong, Su-Ming

2013-01-01

Methotrexate (MTX) is a common and efficacious systemic agent used for the treatment of moderate to severe psoriasis. Nevertheless, its use is associated with the risk of hepatotoxicity. This study was performed to study the association of MTX dose with regards to hepatotoxicity as evidenced by deranged transaminases. This was a retrospective review of patients with psoriasis on MTX from 2000 to 2009 at the outpatient dermatology clinic, University Malaya Medical Centre (UMMC). We analyzed patients' demography, serial laboratory investigations, liver ultrasounds, and liver biopsies of patients on MTX. Sixty-six of 710 (9.30%) patients with psoriasis were prescribed MTX throughout the 10-year period. Among them 57.6% developed deranged transaminases, with six requiring MTX withdrawal due to hepatotoxicity. The mean cumulative dose of MTX at the detection of liver enzyme derangement was 552.3 ± 596.1 mg. A high proportion of patients on MTX had deranged transaminases. However, the number of serious events was low. We concluded from this study that the use of MTX is relatively safe in patients with moderate to severe psoriasis. © 2013 The International Society of Dermatology.

Vitamin E and selenium treatment of monocrotaline induced hepatotoxicity in rats.

PubMed

Cuce, G; Canbaz, H T; Sozen, M E; Yerlikaya, F H; Kalkan, S

2017-01-01

Monocrotaline (MCT) is a hepatotoxic pyrrolizidine alkaloid that is derived from plants; exposure may occur by consumption of contaminated grains, herbal teas and medicines. MCT can cause liver damage. We investigated the antioxidant effects of selenium (Se) and vitamin E against the toxic effects of MCT. Female Wistar albino rats were divided into four groups: a control group, an MCT group, an MCT + Se group, and an MCT + vitamin E group. Liver tissues were harvested, fixed, processed to paraffin and sections were cut. Anti-von Willebrand factor (vWF) immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL), and hematoxylin and eosin staining were performed. Serum and liver tissue glutathione (GSH), catalase (CAT), and glutathione peroxidase (GPx) levels were measured. Histopathological and TUNEL data showed significantly increased liver damage in the MCT group compared to controls. Histopathological and TUNEL staining indicated significant improvements in the MCT + vitamin E and MCT + Se groups compared to the MCT group. MCT significantly reduced the serum GSH level and GPx activity, and liver GPx activity. Biochemical data indicated a significant improvement in serum GSH level in the MCT + vitamin E group compared to the MCT group. We suggest that vitamin E and Se afford limited protection against MCT hepatotoxicity.

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

PubMed Central

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 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 < 0.05). The comet assay revealed increased detaching tail length and DNA concentration during the hepatic toxicity in the acetaminophen group. The malondialdehyde content was inhibited by 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. Conclusions Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats. PMID:26543508

Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits.

PubMed

Zubairi, Maysaa B; Ahmed, Jawad H; Al-Haroon, Sawsan S

2014-01-01

To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally), group 3, 4,5 and 6 were treated at a dose in (mg/kg/day) of the following: Carvedilol (10 mg), prazosin (0.5 mg), metoprolol (10 mg), and a combination of metoprolol (10 mg) and prazosin (0.5 mg) respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA) and glutathione (GSH) in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection.

Acetaminophen-induced hepatotoxicity is associated with early changes in NF-kB and NF-IL6 DNA binding activity.

PubMed

Blazka, M E; Germolec, D R; Simeonova, P; Bruccoleri, A; Pennypacker, K R; Luster, M I

Nuclear transcription factors, such as NF-kB and NF-IL6, are believed to play an important role in regulating the expression of genes that encode for products involved in tissue damage and inflammation and, thus, may represent early biomarkers for chemical toxicities. In the present study changes in DNA binding activity of these factors were examined in livers of mice administered hepatotoxic doses of acetaminophen (APAP). NF-kB and NF-IL6 DNA binding occurred constitutively in control mouse liver. However, within 4 hr following administration of hepatotoxic doses of APAP, their binding activities were transiently lost and is in contrast to AP-1 transcription factor where activation occurs under similar conditions. These changes corresponded with increased release of inflammatory mediators (IL-6, serum amyloid A) and increased levels of enzymatic markers of hepatocyte damage. Similarly, treatment of mice with gadolinium chloride, an inhibitor of Kupffer cell activation and known to protect against APAP-induced hepatotoxicity, reduced the observed pathophysiological response in the liver while altering the APAP-associated changes in NF-kB DNA binding activity. NF-kB was found predominantly in parenchymal and endothelial cells and was composed primarily of relatively inactive p50 homodimer subunits in control liver. Taken together, these studies suggest that hepatotoxicity is associated with early and complex changes in DNA binding activities of specific transcription factors. In particular, NF-kB and NF-IL6 may serve as negative regulators of hepatocyte-derived inflammatory mediators and is analogous to that previously observed in certain other cell systems such as B lymphocytes.

Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity.

PubMed

Maes, Michaël; McGill, Mitchell R; da Silva, Tereza Cristina; Abels, Chloé; Lebofsky, Margitta; Weemhoff, James L; Tiburcio, Taynã; Veloso Alves Pereira, Isabel; Willebrords, Joost; Crespo Yanguas, Sara; Farhood, Anwar; Beschin, Alain; Van Ginderachter, Jo A; Penuela, Silvia; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

2017-05-01

Pannexins constitute a relatively new family of transmembrane proteins that form channels linking the cytoplasmic compartment with the extracellular environment. The presence of pannexin1 in the liver has been documented previously, where it underlies inflammatory responses, such as those occurring upon ischemia-reperfusion injury. In the present study, we investigated whether pannexin1 plays a role in acute drug-induced liver toxicity. Hepatic expression of pannexin1 was characterized in a mouse model of acetaminophen-induced hepatotoxicity. Subsequently, mice were overdosed with acetaminophen followed by treatment with the pannexin1 channel inhibitor 10 Panx1. Sampling was performed 1, 3, 6, 24 and 48 h after acetaminophen administration. Evaluation of the effects of pannexin1 channel inhibition was based on a number of clinically relevant readouts, including protein adduct formation, measurement of aminotransferase activity and histopathological examination of liver tissue as well as on a series of markers of inflammation, oxidative stress and regeneration. Although no significant differences were found in histopathological analysis, pannexin1 channel inhibition reduced serum levels of alanine and aspartate aminotransferase. This was paralleled by a reduced amount of neutrophils recruited to the liver. Furthermore, alterations in the oxidized status were noticed with upregulation of glutathione levels upon suppression of pannexin1 channel opening. Concomitant promotion of regenerative activity was detected as judged on increased proliferating cell nuclear antigen protein quantities in 10 Panx1-treated mice. Pannexin1 channels are important actors in liver injury triggered by acetaminophen. Inhibition of pannexin1 channel opening could represent a novel approach for the treatment of drug-induced hepatotoxicity.

Activation of Sirt1/FXR Signaling Pathway Attenuates Triptolide-Induced Hepatotoxicity in Rats.

PubMed

Yang, Jing; Sun, Lixin; Wang, Lu; Hassan, Hozeifa M; Wang, Xuan; Hylemon, Phillip B; Wang, Tao; Zhou, Huiping; Zhang, Luyong; Jiang, Zhenzhou

2017-01-01

Triptolide (TP), a diterpenoid isolated from Tripterygium wilfordii Hook F, has an excellent pharmacological profile of immunosuppression and anti-tumor activities, but its clinical applications are severely restricted due to its severe and cumulative toxicities. The farnesoid X receptor (FXR) is the master bile acid nuclear receptor and plays an important role in maintaining hepatic metabolism homeostasis. Hepatic Sirtuin (Sirt1) is a key regulator of the FXR signaling pathway and hepatic metabolism homeostasis. The aims of this study were to determine whether Sirt1/FXR signaling pathway plays a critical role in TP-induced hepatotoxicity. Our study revealed that the intragastric administration of TP (400 μg/kg body weight) for 28 consecutive days increased bile acid accumulation, suppressed hepatic gluconeogenesis in rats. The expression of bile acid transporter BSEP was significantly reduced and cholesterol 7α-hydroxylase (CYP7A1) was markedly increased in the TP-treated group, whereas the genes responsible for hepatic gluconeogenesis were suppressed in the TP-treated group. TP also modulated the FXR and Sirt1 by decreasing its expression both in vitro and in vivo . The Sirt1 agonist SRT1720 and the FXR agonist obeticholic acid (OCA) were used both in vivo and in vitro . The remarkable liver damage induced by TP was attenuated by treatment with either SRT1720 or OCA, as reflected by decreased levels of serum total bile acids and alkaline phosphatase and increased glucose levels. Meanwhile, SRT1720 significantly alleviated TP-induced FXR suppression and FXR-targets involved in hepatic lipid and glucose metabolism. Based on these results, we conclude that Sirt1/FXR inactivation plays a critical role in TP-induced hepatotoxicity. Moreover, Sirt1/FXR axis represents a novel therapeutic target that could potentially ameliorate TP-induced hepatotoxicity.

Discovery of Rare and Highly Toxic Microcystins from Lichen-Associated Cyanobacterium Nostoc sp. Strain IO-102-I

PubMed Central

Oksanen, Ilona; Jokela, Jouni; Fewer, David P.; Wahlsten, Matti; Rikkinen, Jouko; Sivonen, Kaarina

2004-01-01

The production of hepatotoxic cyclic heptapeptides, microcystins, is almost exclusively reported from planktonic cyanobacteria. Here we show that a terrestrial cyanobacterium Nostoc sp. strain IO-102-I isolated from a lichen association produces six different microcystins. Microcystins were identified with liquid chromatography-UV mass spectrometry by their retention times, UV spectra, mass fragmentation, and comparison to microcystins from the aquatic Nostoc sp. strain 152. The dominant microcystin produced by Nostoc sp. strain IO-102-I was the highly toxic [ADMAdda5]microcystin-LR, which accounted for ca. 80% of the total microcystins. We assigned a structure of [DMAdda5]microcystin-LR and [d-Asp3,ADMAdda5]microcystin-LR and a partial structure of three new [ADMAdda5]-XR type of microcystin variants. Interestingly, Nostoc spp. strains IO-102-I and 152 synthesized only the rare ADMAdda and DMAdda subfamilies of microcystin variants. Phylogenetic analyses demonstrated congruence between genes involved directly in microcystin biosynthesis and the 16S rRNA and rpoC1 genes of Nostoc sp. strain IO-102-I. Nostoc sp. strain 152 and the Nostoc sp. strain IO-102-I are distantly related, revealing a sporadic distribution of toxin production in the genus Nostoc. Nostoc sp. strain IO-102-I is closely related to Nostoc punctiforme PCC 73102 and other symbiotic Nostoc strains and most likely belongs to this species. Together, this suggests that other terrestrial and aquatic strains of the genus Nostoc may have retained the genes necessary for microcystin biosynthesis. PMID:15466511

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

PubMed Central

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

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

PubMed

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

Fructose diet alleviates acetaminophen-induced hepatotoxicity in mice.

PubMed

Cho, Sungjoon; Tripathi, Ashutosh; Chlipala, George; Green, Stefan; Lee, Hyunwoo; Chang, Eugene B; Jeong, Hyunyoung

2017-01-01

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.

Genetics Home Reference: cyclic neutropenia

MedlinePlus

... Facebook Twitter Home Health Conditions Cyclic neutropenia Cyclic neutropenia Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Cyclic neutropenia is a disorder that causes frequent infections and ...

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

PubMed

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 <14 units per week does not appear to be associated with an increased risk of transaminitis. Published by the BMJ Publishing Group 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/.

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

PubMed

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 CCl 4 diluted 1:1 in corn oil for 10 weeks. To confirm the hepatotoxicity, 24 h after the last CCl 4 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 CCl 4 -treated livers. The results were compared statistically with the corresponding control and CCl 4 +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 CCl 4 +NS-treated ones. Our findings demonstrated that application of PRP had beneficial effects on CCl 4 -induced fibrosis; however, it had detrimental effects on the total number of hepatocytes and the volume of hepatocytes and sinusoidal spaces.

Active uptake of substance P carboxy-terminal heptapeptide (5-11) into rat brain and rabbit spinal cord slices.

PubMed

Nakata, Y; Kusaka, Y; Yajima, H; Segawa, T

1981-12-01

We previously reported that nerve terminals and glial cells lack an active uptake system capable of terminating transmitter action of substance P (SP). In the present study, we demonstrated the existence of an active uptake system for SP carboxy-terminal heptapeptide, (5-11)SP. When the slices from either rat brain or rabbit spinal cord were incubated with [3H](5-11)SP, the uptake of (5-11)SP into slices was observed. The uptake system has the properties of an active transport mechanism: it is dependent on temperature and sensitive to hypoosmotic treatment and is inhibited by ouabain and dinitrophenol (DNP). In the brain, (5-11)SP was accumulated by means of a high-affinity and a low-affinity uptake system. The Km and the Vmax values for the high-affinity system were 4.20 x 10(-8) M and 7.59 fmol/10 mg wet weight/min, respectively, whereas these values for the low-affinity system were 1.00 x 10(-6) M and 100 fmol/10 mg wet weight/min, respectively. In the spinal cord, there was only one uptake system, with a Km value of 2.16 x 10(-7) M and Vmax value of 26.2 fmol/10 mg wet weight/min. These results suggest that when SP is released from nerve terminals, it is hydrolysed into (5-11)SP before or after acting as a neurotransmitter, which is in turn accumulated into nerve terminals. Therefore, the uptake system may represent a possible mechanism for the inactivation of SP.

Affordable Cyclic Voltammetry

ERIC Educational Resources Information Center

Stewart, Greg; Kuntzleman, Thomas S.; Amend, John R.; Collins, Michael J.

2009-01-01

Cyclic voltammetry is an important component of the undergraduate chemical curriculum. Unfortunately, undergraduate students rarely have the opportunity to conduct experiments in cyclic voltammetry owing to the high cost of potentiostats, which are required to control these experiments. By using MicroLab data acquisition interfaces in conjunction…

Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Atienzar, Franck A., E-mail: franck.atienzar@ucb.com; Novik, Eric I.; Gerets, Helga H.

Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro primary hepatocyte models from different species for predicting hepatotoxicity in both animals and humans early in drug development. Dog is often chosen as the non-rodent species for toxicology studies. Unfortunately, dog in vitro models allowing long term cultures are not available. The objective of the present manuscript is to describe the development of a co-culture dog model for predicting hepatotoxic drugs in humans and to compare the predictivity of the canine modelmore » along with primary human hepatocytes and HepG2 cells. After rigorous optimization, the dog co-culture model displayed metabolic capacities that were maintained up to 2 weeks which indicates that such model could be also used for long term metabolism studies. Most of the human hepatotoxic drugs were detected with a sensitivity of approximately 80% (n = 40) for the three cellular models. Nevertheless, the specificity was low approximately 40% for the HepG2 cells and hepatocytes compared to 72.7% for the canine model (n = 11). Furthermore, the dog co-culture model showed a higher superiority for the classification of 5 pairs of close structural analogs with different DILI concerns in comparison to both human cellular models. Finally, the reproducibility of the canine system was also satisfactory with a coefficient of correlation of 75.2% (n = 14). Overall, the present manuscript indicates that the dog co-culture model may represent a relevant tool to perform chronic hepatotoxicity and metabolism studies. - Highlights: • Importance of species differences in drug development. • Relevance of dog co-culture model for metabolism and toxicology studies. • Hepatotoxicity: higher predictivity of dog co-culture vs HepG2 and human hepatocytes.« less

Lipoic acid attenuates Aroclor 1260-induced hepatotoxicity in adult rats.

PubMed

Aly, Hamdy A A; Mansour, Ahmed M; Hassan, Memy H; Abd-Ellah, Mohamed F

2016-08-01

The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase-3 & -9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260-induced liver injury. Lipoic acid could protect rats against Aroclor 1260-induced hepatotoxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913-922, 2016. © 2014 Wiley Periodicals, Inc.

High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort

PubMed Central

Clarke, Alan T.; Johnson, Paul C. D.; Hall, Gillian C.; Ford, Ian; Mills, Peter R.

2016-01-01

Background & Aims Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. Methods The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. Results Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4–2.6]. High dose was classified as 40–80mg daily and low dose 10–20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2–12.7] for HDA, 1.4 [0.9–2.0] for LDA and 1.5 [1.0–2.2] for HDS. Conclusions The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small. PMID:26983033

Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPAR{alpha} with clofibrate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donthamsetty, Shashikiran; Bhave, Vishakha S.; Mitra, Mayurranjan S.

2008-08-01

The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPAR{alpha} via lower cell division and tissue repair. Male Swiss Webster mice fed methionine and choline deficient diet for 31 days exhibited NASH. On the 32nd day, a marginally toxic dose of APAP (360 mg/kg, ip) yielded 70% mortality in steatohepatitic mice, while all non steatohepatitic mice receiving the same dose survived. {sup 14}C-APAP covalent binding, CYP2E1 protein, and enzyme activity did not differ from the controls, obviating increased APAP bioactivation as the cause of amplified APAPmore » hepatotoxicity. Liver injury progressed only in steatohepatitic livers between 6 and 24 h. Cell division and tissue repair assessed by {sup 3}H-thymidine incorporation and PCNA were inhibited only in the steatohepatitic mice given APAP suggesting that higher sensitivity of NASH liver to APAP-induced hepatotoxicity was due to lower tissue repair. The hypothesis that impeded liver tissue repair in steatohepatitic mice was due to downregulation of PPAR{alpha} was tested. PPAR{alpha} was downregulated in NASH. To investigate whether downregulation of PPAR{alpha} in NASH is the critical mechanism of compromised liver tissue repair, PPAR{alpha} was induced in steatohepatitic mice with clofibrate (250 mg/kg for 3 days, ip) before injecting APAP. All clofibrate pretreated steatohepatitic mice receiving APAP exhibited lower liver injury, which did not progress and the mice survived. The protection was not due to lower bioactivation of APAP but due to higher liver tissue repair. These findings suggest that inadequate PPAR{alpha} expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity.« less

Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits

PubMed Central

Zubairi, Maysaa B.; Ahmed, Jawad H.; Al-Haroon, Sawsan S.

2014-01-01

Objectives: To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. Materials and Methods: Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally), group 3, 4,5 and 6 were treated at a dose in (mg/kg/day) of the following: Carvedilol (10 mg), prazosin (0.5 mg), metoprolol (10 mg), and a combination of metoprolol (10 mg) and prazosin (0.5 mg) respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA) and glutathione (GSH) in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. Results: Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. Conclusion: Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection. PMID:25538338

Alcohol-induced S-adenosylhomocysteine accumulation in the liver sensitizes to TNF hepatotoxicity: possible involvement of mitochondrial S-adenosylmethionine transport.

PubMed

Song, Zhenyuan; Zhou, Zhanxiang; Song, Ming; Uriarte, Silvia; Chen, Theresa; Deaciuc, Ion; McClain, Craig J

2007-08-01

Hepatocytes are resistant to tumor necrosis factor-alpha- (TNF) induced killing/apoptosis under normal circumstances, but primary hepatocytes from rats chronically fed alcohol have increased TNF cytotoxicity. Therefore, there must be mechanism(s) by which alcohol exposure "sensitizes" to TNF hepatotoxicity. Abnormal metabolism of methionine and S-adenosylmethionine (SAM) are well-documented acquired metabolic abnormalities in ALD. S-adenosylhomocysteine (SAH) is the product of SAM in hepatic transmethylation reactions, and SAH hydrolase (SAHH) is the only enzyme to metabolize SAH to homocysteine and adenosine. Our previous studies demonstrated that chronic intracellular accumulation of SAH sensitized hepatocytes to TNF cytotoxicity in vitro. In the current study, we extended our previous observations by further characterizing the effects of chronic alcohol intake on mitochondrial SAM levels in liver and examining its possible involvement in SAH sensitization to TNF hepatotoxicity. Chronic alcohol consumption in mice not only increased cytosolic SAH levels, but also decreased mitochondrial SAM concentration, leading to decreased mitochondrial SAM to SAH ratio. Moreover, accumulation of hepatic SAH induced by administration of 3-deaza-adenosine (DZA-a potent inhibitor of SAHH) enhanced lipopolysaccharide (LPS)/TNF hepatotoxicity in mice in vivo. Inhibition of SAHH by DZA resulted not only in accumulation of cytoplasmic SAH, but also in depletion of the mitochondrial SAM pool. Further studies using mitochondrial SAM transporter inhibitors showed that inhibition of SAM transport into mitochondria sensitized HepG2 cells to TNF cytotoxicity. In conclusion, our results demonstrate that depletion of the mitochondrial SAM pool by SAH, which is elevated during chronic alcohol consumption, plays a critical role in SAH induced sensitization to TNF hepatotoxicity.

[3D evaluation model for drug hepatotoxicity testing on HepG2 cells and its application in drug safety evaluation].

PubMed

Li, Dan-Dan; Tang, Xiang-Lin; Tan, Hong-Ling; Liang, Qian-de; Wang, Yu-Guang; Ma, Zeng-Chun; Xiao, Cheng-Rong; Gao, Yue

2016-04-01

3D in vitro toxicity testing model was developed by magnetic levitation method for culture of the human hepatoma cell line HepG2 and applied to evaluate the drug hepatotoxicity. After formation of stable 3D structure for HepG2 cells, their glycogen storage capacity under 2D and 3D culture conditions were detected by immunohistochemistry technology, and the mRNA expression levels of phase Ⅰ and Ⅱ drug metabolism enzymes, drug transporters, nuclear receptors and liver-specific marker albumin(ALB) were compared between 2D and 3D culture conditions by using RT-PCR method. Immunohistochemistry results showed that HepG2 cells had abundant glycogen storage capacity under 3D culture conditions, which was similar to human liver tissues. The mRNA expression levels of major drug metabolism enzymes, drug transporters, nuclear receptors and ALB in HepG2 cells under 3D culture conditions were up-regulated as compared with 2D culture conditions. For drug hepatotoxicity evaluation, the typical hepatotoxic drug acetaminophen(APAP), and most reported drugs Polygonum multiflorum Thunb.(Chinese name He-shou-wu) and Psoraleae corylifolia L.(Chinese name Bu-gu-zhi) were selected for single dose and repeated dose(7 d) exposure. In the repeated dose exposure test, 3D HepG2 cells showed higher sensitivity. This established 3D HepG2 cells model with magnetic levitation 3D culture techniques was more close to the human liver tissues both in morphology and functions, so it was a better 3D hepatotoxicity evaluation model. Copyright© by the Chinese Pharmaceutical Association.

The involvement of Nrf2 in the protective effects of (-)-Epigallocatechin-3-gallate (EGCG) on NaAsO2-induced hepatotoxicity.

PubMed

Han, Xiao-Dong; Zhang, Yan-Yan; Wang, Ke-Lei; Huang, Yong-Pan; Yang, Zhong-Bao; Liu, Zhi

2017-09-12

Arsenic exposure produces hepatotoxicity. The common mechanism determining its toxicity is the generation of oxidative stress. Oxidative stress induced by arsenic leads to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. (-)-Epigallocatechin-3-gallate (EGCG) possesses a potent antioxidant capacity and exhibits extensive pharmacological activities. This study aims to evaluate effects of EGCG on arsenic-induced hepatotoxicity and activation of Nrf2 pathway. Plasma activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase were measured; Histological analyses were conducted to observe morphological changes; Biochemical indexes such as oxidative stress (Catalase (CAT), malonyldialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), reactive oxygen species (ROS)), Nrf2 signaling related genes ( Nrf2, Nqo1, and Ho-1 ) were assessed. The results showed that EGCG inhibited arsenic-induced hepatic pathological damage, liver ROS level and MDA level. Arsenic decreases the antioxidant enzymes SOD, GPX, and CAT activity and the decrease was inhibited by treatment of EGCG. Furthermore, EGCG attenuated the retention of arsenic in liver tissues and improved the expressions of Nrf2 signaling related genes ( Nrf2, Nqo1, and Ho-1 ). These findings provide evidences that EGCG may be useful for reducing hepatotoxicity associated with oxidative stress by the activation of Nrf2 signaling pathway. Our findings suggest a possible mechanism of antioxidant EGCG in preventing hepatotoxicity, which implicate that EGCG may be a potential treatment for arsenicosis therapy.

Switching Cyclic Nucleotide-Selective Activation of Cyclic Adenosine Monophosphate-Dependent Protein Kinase Holoenzyme Reveals Distinct Roles of Tandem Cyclic Nucleotide-Binding Domains.

PubMed

He, Daniel; Lorenz, Robin; Kim, Choel; Herberg, Friedrich W; Lim, Chinten James

2017-12-15

The cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-dependent protein kinases (PKA and PKG) are key effectors of cyclic nucleotide signaling. Both share structural features that include tandem cyclic nucleotide-binding (CNB) domains, CNB-A and CNB-B, yet their functions are separated through preferential activation by either cAMP or cGMP. Based on structural studies and modeling, key CNB contact residues have been identified for both kinases. In this study, we explored the requirements for conversion of PKA activation from cAMP-dependent to cGMP-dependent. The consequences of the residue substitutions T192R/A212T within CNB-A or G316R/A336T within CNB-B of PKA-RIα on cyclic nucleotide binding and holoenzyme activation were assessed in vitro using purified recombinant proteins, and ex vivo using RIα-deficient mouse embryonic fibroblasts genetically reconstituted with wild-type or mutant PKA-RIα. In vitro, a loss of binding and activation selectivity was observed when residues in either one of the CNB domains were mutated, while mutations in both CNB domains resulted in a complete switch of selectivity from cAMP to cGMP. The switch in selectivity was also recapitulated ex vivo, confirming their functional roles in cells. Our results highlight the importance of key cyclic nucleotide contacts within each CNB domain and suggest that these domains may have evolved from an ancestral gene product to yield two distinct cyclic nucleotide-dependent protein kinases.

Potential Role of Activated Nonparenchymal Cells in Acetaminophen-Induced Potentiation of Hepatotoxicity

DTIC Science & Technology

1991-06-14

ALT is either being degraded or the activity is inhibited by something in the 133 media. AST activity in cocultures of NPCs and hepatocytes was... Paracetamol Hepatotoxicity: IN VITRO Studies in Isolated Mouse Hepatocytes. Toxicology Letters. 2229: 37-48. Casini, A. M., P. A. Ferrali and M...Acute Liver Necrosis Following Overdose of Paracetamol . British Medical Journal. 2: 497-499. Decker, T., M. L. Lohmann-Matthes, U. Karck, T. Peters

Analysis of changes in hepatic gene expression in a murine model of tolerance to acetaminophen hepatotoxicity (autoprotection)

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Connor, Meeghan A., E-mail: meeghan.oconnor@boehringer-ingelheim.com; Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368; Koza-Taylor, Petra, E-mail: petra.h.koza-taylor@pfizer.com

Pretreatment of mice with a low hepatotoxic dose of acetaminophen (APAP) results in resistance to a subsequent, higher dose of APAP. This mouse model, termed APAP autoprotection was used here to identify differentially expressed genes and cellular pathways that could contribute to this development of resistance to hepatotoxicity. Male C57BL/6J mice were pretreated with APAP (400 mg/kg) and then challenged 48 h later with 600 mg APAP/kg. Livers were obtained 4 or 24 h later and total hepatic RNA was isolated and hybridized to Affymetrix Mouse Genome MU430{sub 2} GeneChip. Statistically significant genes were determined and gene expression changes weremore » also interrogated using the Causal Reasoning Engine (CRE). Extensive literature review narrowed our focus to methionine adenosyl transferase-1 alpha (MAT1A), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), flavin-containing monooxygenase 3 (Fmo3) and galectin-3 (Lgals3). Down-regulation of MAT1A could lead to decreases in S-adenosylmethionine (SAMe), which is known to protect against APAP toxicity. Nrf2 activation is expected to play a role in protective adaptation. Up-regulation of Lgals3, one of the genes supporting the Nrf2 hypothesis, can lead to suppression of apoptosis and reduced mitochondrial dysfunction. Fmo3 induction suggests the involvement of an enzyme not known to metabolize APAP in the development of tolerance to APAP toxicity. Subsequent quantitative RT-PCR and immunochemical analysis confirmed the differential expression of some of these genes in the APAP autoprotection model. In conclusion, our genomics strategy identified cellular pathways that might further explain the molecular basis for APAP autoprotection. - Highlights: • Differential expression of genes in mice resistant to acetaminophen hepatotoxicity. • Increased gene expression of Flavin-containing monooxygenase 3 and Galectin-3. • Decrease in MAT1A expression and compensatory hepatocellular regeneration. • Two distinct

Severe hepatotoxicity following ingestion of Herbalife nutritional supplements contaminated with Bacillus subtilis.

PubMed

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.

Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice.

PubMed

Yan, Sheng-Lei; Wang, Zhi-Hong; Yen, Hsiu-Fang; Lee, Yi-Ju; Yin, Mei-Chin

2016-12-01

Ethanol was used to induce acute hepatotoxicity in mice. Effects of cinnamic acid (CA) and syringic acid (SA) post-intake for hepatic recovery from alcoholic injury was investigated. Ethanol treated mice were supplied by CA or SA at 40 or 80 mg/kg BW/day for 5 days. Results showed that ethanol stimulated protein expression of CYP2E1, p47 phox , gp91 phox , cyclooxygenase-2 and nuclear factor kappa B in liver. CA or SA post-intake restricted hepatic expression of these molecules. Ethanol suppressed nuclear factor erythroid 2-related factor (Nrf2) expression, and CA or SA enhanced Nrf2 expression in cytosolic and nuclear fractions. Ethanol increased the release of reactive oxygen species, oxidized glutathione, interleukin-6, tumor necrosis factor-alpha, nitric acid and prostaglandin E 2 . CA or SA lowered hepatic production of these oxidative and inflammatory factors. Histological data revealed that ethanol administration caused obvious foci of inflammatory cell infiltration, and CA or SA post-intake improved hepatic inflammatory infiltration. These findings support that cinnamic acid and syringic acid are potent nutraceutical agents for acute alcoholic liver disease therapy. However, potential additive or synergistic benefits of cinnamic and syringic acids against ethanol-induced hepatotoxicity need to be investigated. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Role of RAAS Inhibition by Aliskiren on Paracetamol-Induced Hepatotoxicity Model in Rats.

PubMed

Karcioglu, Saliha Sena; Palabiyik, Saziye Sezin; Bayir, Yasin; Karakus, Emre; Mercantepe, Tolga; Halici, Zekai; Albayrak, Abdulmecit

2016-03-01

Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS. © 2015 Wiley Periodicals

Visual search of cyclic spatio-temporal events

NASA Astrophysics Data System (ADS)

Gautier, Jacques; Davoine, Paule-Annick; Cunty, Claire

2018-05-01

The analysis of spatio-temporal events, and especially of relationships between their different dimensions (space-time-thematic attributes), can be done with geovisualization interfaces. But few geovisualization tools integrate the cyclic dimension of spatio-temporal event series (natural events or social events). Time Coil and Time Wave diagrams represent both the linear time and the cyclic time. By introducing a cyclic temporal scale, these diagrams may highlight the cyclic characteristics of spatio-temporal events. However, the settable cyclic temporal scales are limited to usual durations like days or months. Because of that, these diagrams cannot be used to visualize cyclic events, which reappear with an unusual period, and don't allow to make a visual search of cyclic events. Also, they don't give the possibility to identify the relationships between the cyclic behavior of the events and their spatial features, and more especially to identify localised cyclic events. The lack of possibilities to represent the cyclic time, outside of the temporal diagram of multi-view geovisualization interfaces, limits the analysis of relationships between the cyclic reappearance of events and their other dimensions. In this paper, we propose a method and a geovisualization tool, based on the extension of Time Coil and Time Wave, to provide a visual search of cyclic events, by allowing to set any possible duration to the diagram's cyclic temporal scale. We also propose a symbology approach to push the representation of the cyclic time into the map, in order to improve the analysis of relationships between space and the cyclic behavior of events.

Hypericum perforatum-induced hepatotoxicity with possible association with copaiba (Copaifera langsdorffii Desf):case report

PubMed Central

Agollo, Marjorie Costa; Miszputen, Sender Jankiel; Diament, Jayme

2014-01-01

We report a case of liver damage in an elderly patient after the use of herbal products of Hypericum perforatum and copaiba (Copaifera langsdorffii Desf). Hepatotoxicity related to Hypericum perforatum is anecdotally known, but for copaiba, widely used as anti-inflammatory, there is just experimental data in the national literature. This report aimed to draw attention to the possible toxic effects of this association as well as to the clinical recovery of the patient after discontinuing their use. There is a tendency to suspect of the action of drugs to justify a non-viral acute liver injury, because of the large number of drugs responsible for hepatotoxicity. There are experiments and clinical reports in the literature describing some herbal products, including Hypericum perforatum, as the causative agents of this aggression, and are considered innocuous and used with no restrictions. We must remember that adverse reactions also occur with these substances; hence, they should be investigated when collecting the patient´s history, for leading to severe liver failure. PMID:25167337

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

PubMed

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.

Protective effects of an ethanol extract of Angelica keiskei against acetaminophen-induced hepatotoxicity in HepG2 and HepaRG cells

PubMed Central

Choi, Yoon-Hee; Lee, Hyun Sook; Chung, Cha-Kwon

2017-01-01

BACKGROUND/OBJECTIVE Although Angelica keiskei (AK) has widely been utilized for the purpose of general health improvement among Asian, its functionality and mechanism of action. The aim of this study was to determine the protective effect of ethanol extract of AK (AK-Ex) on acute hepatotoxicity induced by acetaminophen (AAP) in HepG2 human hepatocellular liver carcinoma cells and HepaRG human hepatic progenitor cells. MATERIALS/METHODS AK-Ex was prepared HepG2 and HepaRG cells were cultured with various concentrations and 30 mM AAP. The protective effects of AK-Ex against AAP-induced hepatotoxicity in HepG2 and HepaRG cells were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, lactate dehydrogenase (LDH) assay, flow cytometry, and Western blotting. RESULTS AK-Ex, when administered prior to AAP, increased cell growth and decreased leakage of LDH in a dose-dependent manner in HepG2 and HepaRG cells against AAP-induced hepatotoxicity. AK-Ex increased the level of Bcl-2 and decreased the levels of Bax, Bok and Bik decreased the permeability of the mitochondrial membrane in HepG2 cells intoxicated with AAP. AK-Ex decreased the cleavage of poly (ADP-ribose) polymerase (PARP) and the activation of caspase-9, -7, and -3. CONCLUSIONS These results demonstrate that AK-Ex downregulates apoptosis via intrinsic and extrinsic pathways against AAP-induced hepatotoxicity. We suggest that AK could be a useful preventive agent against AAP-induced apoptosis in hepatocytes. PMID:28386382

Cyclic nucleotide content of tobacco BY-2 cells.

PubMed

Richards, Helen; Das, Swadipa; Smith, Christopher J; Pereira, Louisa; Geisbrecht, Alan; Devitt, Nicola J; Games, David E; van Geyschem, Jan; Gareth Brenton, A; Newton, Russell P

2002-11-01

The cyclic nucleotide content of cultured tobacco bright yellow-2 (BY-2) cells was determined, after freeze-killing, perchlorate extraction and sequential chromatography, by radioimmunoassay. The identities of the putative cyclic nucleotides, adenosine 3',5'-cyclic monophosphate (cyclic AMP), guanosine 3',5'-cyclic monophosphate (cyclic GMP) and cytidine 3',5'-cyclic monophosphate (cyclic CMP) were unambiguously confirmed by tandem mass spectrometry. The potential of BY-2 cell cultures as a model system for future investigations of cyclic nucleotide function in higher plants is discussed.

Inhibition of acetaminophen-induced hepatotoxicity in mice by exogenous thymosinβ4 treatment.

PubMed

Wang, Lei; Li, Xiankui; Chen, Cai

2018-05-21

To study the effects of exogenous thymosinβ4 (Tβ4) treatment in acetaminophen (APAP)-induced hepatotoxicity. Liver injury was induced in mice by a single intraperitoneal injection of APAP (500 mg/kg). Exogenous Tβ4 was intraperitoneally administrated at 0 h, 2 h and 4 h after APAP injection. Chloroquine (CQ) (60 mg/kg) was intraperitoneally injected 2 h before APAP administration to inhibit autophagy. Six hours after APAP injection liver injury was evaluated by histological examinations, biochemical measurements and enzyme linked immunosorbent assay (ELISAs). Western blots were performed to detect proteins expression. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were significantly increased 6 h after APAP administration, but were significantly reduced by co-administration of Tβ4. Histological examinations demonstrated that Tβ4 reduced necrosis and inflammation induced by APAP. Immunofluorescence showed that Tβ4 suppressed APAP-induced translocation of high mobility group box-1 protein (HMGB1) from the nucleus to cytosol and intercellular space. Hepatic glutathione (GSH) depletion, malondialdehyde (MDA) formation and decreased superoxide dismutase (SOD) activities induced by APAP were all attenuated by Tβ4. APAP-induced increases in hepatic nuclear factor-κB (NF-κB) p65 protein expression and inflammatory cytokines production including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were reduced by Tβ4 treatment. Increased LC3 and p62 proteins in the liver tissues of APAP-treated mice were decreased by Tβ4 treatment, which indicated the enhancement of autophagy flux by Tβ4. Furthermore, inhibiting autophagy by CQ abrogated the protective effects of Tβ4 against APAP hepatotoxicity. Exogenous Tβ4 treatment exerts protective effects against APAP-induced hepatotoxicity in mice. The underneath molecular mechanisms may involve autophagy enhancement and inhibition of oxidative stress by Tβ4

Toxicokinetics of Microcystin and Dihydro-Microcystin in Swine

DTIC Science & Technology

1994-05-14

cyanobacteria (blue-green algae) including, Nicrocystis, Anabaena, Nostoc , and Oscillatoria, produce cyclic heptapeptida hepatotoxins that have been termed...1990) describe three hepatotoxic MCs from Nostoc spp. which retained toxicity similar to MCLR despite the fact that they contained an acetoxyl group...W. W. (1990) Structures of three new cyclic hepatapeptide hepatotoxins produced by the cyanobacterium (blue-green algae) Nostoc sp. Strain 152. J

Advances in targeting cyclic nucleotide phosphodiesterases

PubMed Central

Maurice, Donald H.; Ke, Hengming; Ahmad, Faiyaz; Wang, Yousheng; Chung, Jay; Manganiello, Vincent C.

2014-01-01

Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants. PMID:24687066

In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System.

PubMed

Knöspel, Fanny; Jacobs, Frank; Freyer, Nora; Damm, Georg; De Bondt, An; van den Wyngaert, Ilse; Snoeys, Jan; Monshouwer, Mario; Richter, Marco; Strahl, Nadja; Seehofer, Daniel; Zeilinger, Katrin

2016-04-16

Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.

In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System

PubMed Central

Knöspel, Fanny; Jacobs, Frank; Freyer, Nora; Damm, Georg; De Bondt, An; van den Wyngaert, Ilse; Snoeys, Jan; Monshouwer, Mario; Richter, Marco; Strahl, Nadja; Seehofer, Daniel; Zeilinger, Katrin

2016-01-01

Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro. PMID:27092500

Upgrading HepG2 cells with adenoviral vectors that encode drug-metabolizing enzymes: application for drug hepatotoxicity testing.

PubMed

Gómez-Lechón, M José; Tolosa, Laia; Donato, M Teresa

2017-02-01

Drug attrition rates due to hepatotoxicity are an important safety issue considered in drug development. The HepG2 hepatoma cell line is currently being used for drug-induced hepatotoxicity evaluations, but its expression of drug-metabolizing enzymes is poor compared with hepatocytes. Different approaches have been proposed to upgrade HepG2 cells for more reliable drug-induced liver injury predictions. Areas covered: We describe the advantages and limitations of HepG2 cells transduced with adenoviral vectors that encode drug-metabolizing enzymes for safety risk assessments of bioactivable compounds. Adenoviral transduction facilitates efficient and controlled delivery of multiple drug-metabolizing activities to HepG2 cells at comparable levels to primary human hepatocytes by generating an 'artificial hepatocyte'. Furthermore, adenoviral transduction enables the design of tailored cells expressing particular metabolic capacities. Expert opinion: Upgraded HepG2 cells that recreate known inter-individual variations in hepatic CYP and conjugating activities due to both genetic (e.g., polymorphisms) or environmental (e.g., induction, inhibition) factors seems a suitable model to identify bioactivable drug and conduct hepatotoxicity risk assessments. This strategy should enable the generation of customized cells by reproducing human pheno- and genotypic CYP variability to represent a valuable human hepatic cell model to develop new safer drugs and to improve existing predictive toxicity assays.

GENE EXPRESSION PROFILING IN THE LIVER OF CD-1 MICE TO CHARACTERIZE THE HEPATOTOXICITY OF TRIAZOLE FUNGICIDES.

EPA Science Inventory

Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and ...

GENE EXPRESSION PROFILING IN THE LIVER OF CD-1 MICE TO CHARACTERIZE THE HEPATOTOXICITY OF TRIAZOLE FUNGICIDES

EPA Science Inventory

Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and ...

Use of the HepaRG Cell Line to Assess Potential Human Hepatotoxicity of ToxCast™ Chemicals

EPA Science Inventory

The HepaRG cell line is a promising model system for predicting human hepatotoxicity in part because of the greater capacity to metabolize chemicals than other cell models. We hypothesized that this cell line would be a relevant model for toxicity testing of industrial chemicals....

Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity.

PubMed

Cen, Juan; Guo, Huiyan; Hong, Chen; Lv, Jianwu; Yang, Yacheng; Wang, Ting; Fang, Dong; Luo, Wen; Wang, Chaojie

2018-01-20

A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced β-amyloid (Aβ) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Unexpected paracetamol (acetaminophen) hepatotoxicity at standard dosage in two older patients: time to rethink 1 g four times daily?

PubMed

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 <50 kg, interacting medications, hepatic enzyme inducers, history of liver disease). Significantly, both patients had recently had a dose escalation from 'as needed' dosing to 4 g daily, and the medication was being administered by nursing staff. Our experience shows that even when prescribed appropriately at the usual therapeutic dosage, 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.

Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions.

PubMed

Freyer, Nora; Greuel, Selina; Knöspel, Fanny; Gerstmann, Florian; Storch, Lisa; Damm, Georg; Seehofer, Daniel; Foster Harris, Jennifer; Iyer, Rashi; Schubert, Frank; Zeilinger, Katrin

2018-03-15

The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP ( p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP ( p < 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP ( p < 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions.

Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

PubMed Central

Freyer, Nora; Greuel, Selina; Knöspel, Fanny; Gerstmann, Florian; Storch, Lisa; Damm, Georg; Seehofer, Daniel; Foster Harris, Jennifer; Iyer, Rashi; Schubert, Frank; Zeilinger, Katrin

2018-01-01

The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP (p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP (p < 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP (p < 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions. PMID:29543727

Ameliorative Influence of Green Tea Extract on Copper Nanoparticle-Induced Hepatotoxicity in Rats

NASA Astrophysics Data System (ADS)

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.

Sequencing Cyclic Peptides by Multistage Mass Spectrometry

PubMed Central

Mohimani, Hosein; Yang, Yu-Liang; Liu, Wei-Ting; Hsieh, Pei-Wen; Dorrestein, Pieter C.; Pevzner, Pavel A.

2012-01-01

Some of the most effective antibiotics (e.g., Vancomycin and Daptomycin) are cyclic peptides produced by non-ribosomal biosynthetic pathways. While hundreds of biomedically important cyclic peptides have been sequenced, the computational techniques for sequencing cyclic peptides are still in their infancy. Previous methods for sequencing peptide antibiotics and other cyclic peptides are based on Nuclear Magnetic Resonance spectroscopy, and require large amount (miligrams) of purified materials that, for most compounds, are not possible to obtain. Recently, development of mass spectrometry based methods has provided some hope for accurate sequencing of cyclic peptides using picograms of materials. In this paper we develop a method for sequencing of cyclic peptides by multistage mass spectrometry, and show its advantages over single stage mass spectrometry. The method is tested on known and new cyclic peptides from Bacillus brevis, Dianthus superbus and Streptomyces griseus, as well as a new family of cyclic peptides produced by marine bacteria. PMID:21751357

[Individualized clinical treatment from the prospective of hepatotoxicity of non-toxic traditional Chinese medicine].

PubMed

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.

Inhibition of Carbamyl Phosphate Synthetase-I and Glutamine Synthetase by Hepatotoxic Doses of Acetaminophen in Mice

PubMed Central

Gupta, Sanjiv; Rogers, Lynette K.; Taylor, Sarah K.; Smith, Charles V.

2016-01-01

The primary mechanisms proposed for acetaminophen-induced hepatic necrosis should deplete protein thiols, either by covalent binding and thioether formation or by oxidative reactions such as S-thiolations. However, in previous studies we did not detect significant losses of protein thiol contents in response to administration of hepatotoxic doses of acetaminophen in vivo. In the present study we employed derivatization with the thiol-specific agent monobromobimane and separation of proteins by SDS–PAGE to investigate the possible loss of specific protein thiols during the course of acetaminophen-induced hepatic necrosis. Fasted adult male mice were given acetaminophen, and protein thiol status was examined subsequently in subcellular fractions isolated by differential centrifugation. No decreases in protein thiol contents were indicated, with the exception of a marked decrease in the fluorescent intensity, but not of protein content, as indicated by staining with Coomassie blue, of a single band of approximately 130 kDa in the mitochondrial fractions of acetaminophen-treated mice. This protein was identified by isolation and N-terminal sequence analysis as carbamyl phosphate synthetase-I (CPS-I) (EC 6.3.4.16). Hepatic CPS-I activities were decreased in mice given hepatotoxic doses of acetaminophen. In addition, hepatic glutamine synthetase activities were lower, and plasma ammonia levels were elevated in mice given hepatotoxic doses of acetaminophen. The observed hyperammonemia may contribute to the adverse effects of toxic doses of acetaminophen, and elucidation of the specific mechanisms responsible for the hyperammonemia may prove to be useful clinically. However, the preferential depletion of protein thiol content of a mitochondrial protein by chemically reactive metabolites generated in the endoplasmic reticulum presents a challenging and potentially informative mechanistic question. PMID:9344900

The effect of natural antioxidants in cyclophosphamide-induced hepatotoxicity: Role of Nrf2/HO-1 pathway.

PubMed

Sherif, Iman O

2018-05-22

Hepatotoxicity induced by cyclophosphamide (Cyclo) is a major concern in clinical practice. This study was designed to investigate the possible cytoprotective effect of natural antioxidants as oleuropein and quercetin against Cyclo induced hepatotoxicity via the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Male Wistar rats were randomly divided into six groups and treated for 10 days as follow: Group I (Normal control) received saline, group II (Oleu control): received orally oleuropein 30 mg/kg/day, group III (Quer control): administered orally quercetin 50 mg/kg/day, group IV (Cyclo): received saline and injected with single intraperitoneal (i.p) dose of Cyclo 200 mg/kg at day 5, group V (Oleu ttt): treated with oleuropein plus Cyclo i.p. injection at day 5, and group VI (Quer ttt): treated with quercetin plus Cyclo i.p. injection at day 5. Injection of Cyclo showed marked increase in serum transaminases and alkaline phosphatase, hepatic malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-⍺) levels along with significant reduction in hepatic reduced glutathione (GSH), superoxide dismutase (SOD), and catalase levels in addition to downregulation of hepatic Nrf2 and HO-1 expressions and reduction in hepatic nuclear Nrf2 binding activity when compared with normal group. Histopathological examination of Cyclo treated rats revealed hepatic damage. Both oleuropein and quercetin exhibited an improvement in the biochemical and histopathological findings. In conclusion, the natural antioxidants oleuropein and quercetin counteract the Cyclo induced hepatotoxicity through activation of Nrf2/HO-1 signaling pathway with subsequent suppression of oxidative stress and inflammation. Copyright © 2018 Elsevier B.V. All rights reserved.

Hepatotoxicity associated with metformin therapy in treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease.

PubMed

Cone, Catherine J; Bachyrycz, Amy M; Murata, Glen H

2010-10-01

To report a case of idiosyncratic hepatotoxicity associated with metformin in the treatment of type 2 diabetes with nonalcoholic fatty liver disease (NAFLD). A 61-year-old obese man presented with jaundice, nausea, fatigue, and an unintentional weight loss 2 weeks following initiation of metformin. Laboratory findings revealed aminotransferase values 10-15 times the upper limit of normal. Potential causative agents, including metformin, simvastatin, and Niaspan (extended-release niacin), were discontinued. Two months later, the patient's signs and symptoms had resolved and aminotransferase values returned to normal. An objective causality assessment revealed that the adverse reaction was probably associated with metformin. Since numerous medications and disease states can cause abnormalities in liver enzymes, it is important for providers to be able to distinguish the cause(s) and take appropriate actions. This can take a great deal of time and effort in patients with multiple medications and comorbidities. In this patient's case, viral hepatitis, worsening NAFLD, and the concomitant drugs were highly suspected. As hydroxymethylglutaryl coenzyme A reductase inhibitors offer substantial cardiovascular benefits and as metformin is a first-line agent in helping to lower blood glucose concentrations and to normalize the metabolic profile in type 2 diabetes, reintroduction of metformin and simvastatin would likely be beneficial. This is a case report of metformin-induced hepatotoxicity. As the prevalence of type 2 diabetes and subsequent metabolic effects increases in the US, metformin use will likewise increase. As potential for increased idiosyncratic hepatotoxicity associated with metformin use is likely to occur, clinicians should be vigilant.

A natural antioxidant, tannic acid mitigates iron-overload induced hepatotoxicity in Swiss albino mice through ROS regulation.

PubMed

Basu, Tapasree; Panja, Sourav; Shendge, Anil Khushalrao; Das, Abhishek; Mandal, Nripendranath

2018-05-01

Tannic acid (TA), a water soluble natural polyphenol with 8 gallic acids groups, is abundantly present in various medicinal plants. Previously TA has been investigated for its antimicrobial and antifungal properties. Being a large polyphenol, TA chelates more than 1 metal. Hence TA has been explored for potent antioxidant activities against reactive oxygen species (ROS), reactive nitrogen species (RNS) and as iron chelator in vitro thereby mitigating iron-overload induced hepatotoxicity in vivo. Iron dextran was injected intraperitoneally in Swiss albino mice to induce iron-overload triggered hepatotoxicity, followed by oral administration of TA for remediation. After treatment, liver, spleen, and blood samples were processed from sacrificed animals. The liver iron, serum ferritin, serum markers, ROS, liver antioxidant status, and liver damage parameters were assessed, followed by histopathology and protein expression studies. Our results show that TA is a prominent ROS and RNS scavenger as well as iron chelator in vitro. It also reversed the ROS levels in vivo and restricted the liver damage parameters as compared to the standard drug, desirox. Moreover, this natural polyphenol exclusively ameliorates the histopathological and fibrotic changes in liver sections reducing the iron-overload, along with chelation of liver iron and normalization of serum ferritin. The protective role of TA against iron-overload induced apoptosis in liver was further supported by changed levels of caspase 3, PARP as well as Bax/BCl-2 ratio. Thus, TA can be envisaged as a better orally administrable iron chelator to reduce iron-overload induced hepatotoxicity through ROS regulation. © 2018 Wiley Periodicals, Inc.

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

PubMed

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.

Risk assessment of hepatotoxicity among tuberculosis and human immunodeficiency virus/AIDS-coinfected patients under tuberculosis treatment.

PubMed

Ngouleun, Williams; Biapa Nya, Prosper Cabral; Pieme, Anatole Constant; Telefo, Phelix Bruno

2016-12-01

Tuberculosis (TB) is a worldwide public health problem. It is a contagious and grave disease caused by Mycobacterium tuberculosis. Current drugs such as isoniazid, pyrazinamide, and rifampicin used for the treatment of tuberculosis are potentially hepatotoxic and can lead to drug hepatitis. In order to improve the follow-up of TB patients in Cameroon, we carried out a study which aimed to evaluate the hepatotoxicity risk factors associated with anti-TB drugs. The studies were performed on 75 participants who had visited the Loum District Hospital located in the littoral region of Cameroon for their routine consultation. Participants have been selected based on pre-established criteria of inclusion and exclusion. Prior to the informed consent signature, patients were given compelling information about the objective and the result output of the study. They were questioned about antioxidant food and alcohol consumption as well as some clinical signs of hepatotoxicity such as fever, nausea, vomiting, and tiredness. The collected blood was tested for the determination of biochemical markers (transaminases and C-reactive protein) using standard spectrophotometric methods. Biochemical analysis of samples showed a significant increase (p<.05) of aspartate aminotransferase and alanine aminotransferase values in TB patients coinfected with human immunodeficiency virus/AIDS (33.28±16.58UI/L and 30.84±17.17UI/L, respectively) compared with the respective values of the controls (16.35±5.31UI/L and 16.45±4.83UI/L). Taking individually, the liver injury patient percentage of TB patients was significant compared to TBC when considering alanine aminotransferase and aspartate aminotransferase parameters. When considering risk factors, antioxidant food consumption significantly reduced the liver injury patient percentage for the above parameters, whereas an opposite situation was observed with alcohol consumption between TB-coinfection and TB patients. Regarding the C

Characterization of a microcystin and detection of microcystin synthetase genes from a Brazilian isolate of Nostoc.

PubMed

Genuário, Diego Bonaldo; Silva-Stenico, Maria Estela; Welker, Martin; Beraldo Moraes, Luiz Alberto; Fiore, Marli Fátima

2010-04-01

A nostocalean nitrogen-fixing cyanobacterium isolated from an eutrophic freshwater reservoir located in Piracicaba, São Paulo, Brazil, was evaluated for the production of hepatotoxic cyclic heptapeptides, microcystins. Morphologically this new cyanobacterium strain appears closest to Nostoc, however, in the phylogenetic analysis of 16S rRNA gene it falls into a highly stable cluster distantly only related to the typical Nostoc cluster. Extracts of Nostoc sp. CENA88 cultured cells, investigated using ELISA assay, gave positive results and the microcystin profile revealed by ESI-Q-TOF/MS/MS analysis confirmed the production of [Dha(7)]MCYST-YR. Further, Nostoc sp. CENA88 genomic DNA was analyzed by PCR for sequences of mcyD, mcyE and mcyG genes of microcystin synthetase (mcy) cluster. The result revealed the presence of mcyD, mcyE and mcyG genes with similarities to those from mcy of Nostoc sp. strains 152 and IO-102-I and other cyanobacterial genera. The phylogenetic tree based on concatenated McyG, McyD and McyE amino acids clustered the sequences according to cyanobacterial genera, with exception of the Nostoc sp. CENA88 sequence, which was placed in a clade distantly related from other Nostoc strains, as previously observed also in the 16S rRNA phylogenetic analysis. The present study describes for the first time a Brazilian Nostoc microcystin producer and also the occurrence of demethyl MCYST-YR variant in this genus. The sequenced Nostoc genes involved in the microcystin synthesis can contribute to a better understanding of the toxigenicity and evolution of this cyanotoxin. Copyright 2009 Elsevier Ltd. All rights reserved.

A peptidomic approach for monitoring and characterising peptide cyanotoxins produced in Italian lakes by matrix-assisted laser desorption/ionisation and quadrupole time-of-flight mass spectrometry.

PubMed

Ferranti, Pasquale; Nasi, Antonella; Bruno, Milena; Basile, Adriana; Serpe, Luigi; Gallo, Pasquale

2011-05-15

In recent years, the occurrence of cyanobacterial blooms in eutrophic freshwaters has been described all over the world, including most European countries. Blooms of cyanobacteria may produce mixtures of toxic secondary metabolites, called cyanotoxins. Among these, the most studied are microcystins, a group of cyclic heptapeptides, because of their potent hepatotoxicity and activity as tumour promoters. Other peptide cyanotoxins have been described whose structure and toxicity have not been thoroughly studied. Herein we present a peptidomic approach aimed to characterise and quantify the peptide cyanotoxins produced in two Italian lakes, Averno and Albano. The procedure was based on matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry mass spectrometry (MALDI-TOF-MS) analysis for rapid detection and profiling of the peptide mixture complexity, combined with liquid chromatography/electrospray ionisation quadrupole time-of- flight tandem mass spectrometry (LC/ESI-Q-TOF-MS/MS) which provided unambiguous structural identification of the main compounds, as well as accurate quantitative analysis of microcystins. In the case of Lake Averno, a novel variant of microcystin-RR and two novel anabaenopeptin variants (Anabaenopeptins B(1) and Anabaenopeptin F(1)), presenting homoarginine in place of the commonly found arginine, were detected and characterised. In Lake Albano, the peculiar peptide patterns in different years were compared, as an example of the potentiality of the peptidomic approach for fast screening analysis, prior to fine structural analysis and determination of cyanotoxins, which included six novel aeruginosin variants. This approach allows for wide range monitoring of cyanobacteria blooms, and to collect data for evaluating possible health risks to consumers, through the panel of the compounds produced along different years. Copyright © 2011 John Wiley & Sons, Ltd.

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

PubMed Central

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

Distinct roles of NF-{kappa}B p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dambach, Donna M.; Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ 08543; Durham, Stephen K.

2006-03-01

Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. In addition to inducing direct cellular damage, oxidants can activate transcription factors including NF-{kappa}B, which regulate the production of inflammatory mediators implicated in hepatotoxicity. Here, we investigated the role of APAP-induced oxidative stress and NF-{kappa}B in inflammatory mediator production. Treatment of mice with APAP (300 mg/kg, i.p.) resulted in centrilobular hepatic necrosis and increased serum aminotransferase levels. This was correlated with depletion of hepatic glutathione and CuZn superoxide dismutase (SOD). APAP administration also increased expression of the proinflammatory mediators, interleukin-1{beta} (IL-1{beta}), tumor necrosis factor-{alpha} (TNF{alpha}), macrophage chemotactic protein-1 (MCP-1), andmore » KC/gro, and the anti-inflammatory cytokine, interleukin-10 (IL-10). Pretreatment of mice with the antioxidant, N-acetylcysteine (NAC) prevented APAP-induced depletion of glutathione and CuZnSOD, as well as hepatotoxicity. NAC also abrogated APAP-induced increases in TNF{alpha}, KC/gro, and IL-10, but augmented expression of the anti-inflammatory cytokines interleukin-4 (IL-4) and transforming growth factor-{beta} (TGF{beta}). No effects were observed on IL-1{beta} or MCP-1 expression. To determine if NF-{kappa}B plays a role in regulating mediator production, we used transgenic mice with a targeted disruption of the gene for NF-{kappa}B p50. As observed with NAC pretreatment, the loss of NF-{kappa}B p50 was associated with decreased ability of APAP to upregulate TNF{alpha}, KC/gro, and IL-10 expression and increased expression of IL-4 and TGF{beta}. However, in contrast to NAC pretreatment, the loss of p50 had no effect on APAP-induced hepatotoxicity. These data demonstrate that APAP-induced cytokine expression in the liver is influenced by oxidative stress and that this is dependent, in part, on NF-{kappa}B. However, NF-{kappa}B p50

Are Math Grades Cyclical?

ERIC Educational Resources Information Center

Adams, Gerald J.; Dial, Micah

1998-01-01

The cyclical nature of mathematics grades was studied for a cohort of elementary school students from a large metropolitan school district in Texas over six years (average cohort size of 8495). The study used an autoregressive integrated moving average (ARIMA) model. Results indicate that grades do exhibit a significant cyclical pattern. (SLD)

40 CFR 721.2120 - Cyclic amide.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Cyclic amide. 721.2120 Section 721... Cyclic amide. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a cyclic amide (PMN P-92-131) is subject to reporting under this section for the...

Cyclic completion of the anamorphic universe

NASA Astrophysics Data System (ADS)

Ijjas, Anna

2018-04-01

Cyclic models of the universe have the advantage of avoiding initial conditions problems related to postulating any sort of beginning in time. To date, the best known viable examples of cyclic models have been ekpyrotic. In this paper, we show that the recently proposed anamorphic scenario can also be made cyclic. The key to the cyclic completion is a classically stable, non-singular bounce. Remarkably, even though the bounce construction was originally developed to connect a period of contraction with a period of expansion both described by Einstein gravity, we show here that it can naturally be modified to connect an ordinary contracting phase described by Einstein gravity with a phase of anamorphic smoothing. The paper will present the basic principles and steps in constructing cyclic anamorphic models.

Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: A case report and review of the literature.

PubMed

Blackman, Alison; Boutin, Alyssa; Shimanovsky, Alexei; Baker, William J; Forcello, Nicholas

2018-07-01

Asparaginase is a chemotherapeutic agent that is commonly used in combination with other medications for the treatment of acute lymphoblastic leukemia. An adverse effect of asparaginase includes hepatotoxicity, which can lead to severe liver failure and death. Several reports have documented successful treatment of asparaginase-induced hepatotoxicity using levocarnitine (l-carnitine) and vitamin B complex. Herein, we report a patient with acute lymphoblastic leukemia that experienced acute liver injury following pegaspargase administration. Our patient was successfully treated with l-carnitine and vitamin B complex for 8 days and achieved recovery of hepatic function. Furthermore, we review the current literature and provide a recommendation on a regimen that can be used as an option for the treatment of asparaginase-induced hepatic injury.

Effect of goat milk on hepatotoxicity induced by antitubercular drugs in rats.

PubMed

Miglani, Sonam; Patyar, Rakesh Raman; Patyar, Sazal; Reshi, Mohammad Rafi

2016-10-01

Aim of the present study was to assess the hepatoprotective activity of goat milk on antitubercular drug-induced hepatotoxicity in rats. Hepatotoxicity was induced in rats using a combination of isoniazid, rifampicin, and pyrazinamide given orally as a suspension for 30 days. Treatment groups received goat milk along with antitubercular drugs. Liver damage was assessed using biochemical and histological parameters. Administration of goat milk (20 mL/kg) along with antitubercular drugs (Group III) reversed the levels of serum alanine aminotransferase (82 ± 25.1 vs. 128.8 ± 8.9 units/L) and aspartate aminotransferase (174.7 ± 31.5 vs. 296.4 ± 56.4 units/L, p<0.01) compared with antitubercular drug treatment Group II. There was a significant decrease in serum alanine aminotransferase (41.8 ± 4.1 vs. 128.8 ± 8.9 ​ units/L, p<0.01) and aspartate aminotransferase (128.8 ± 8.54 vs. 296.4 ± 56.4 units/L, p<0.001) levels in Group IV (goat milk 40 mL/kg) compared with antitubercular drug treatment Group II. Goat milk (20 mL/kg and 40 mL/kg) was effective in reversing the rise in malondialdehyde level compared with the antitubercular drug suspension groups (58.5 ± 2 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001 and 69.7 ± 0.78 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001, respectively). Similarly, both doses of milk significantly prevented a fall in superoxide dismutase level (6.23 ± 0.29 vs. 3.1 ± 0.288 units/mL, p<0.001 and 7.8 ± 0.392 vs. 3.1 ± 0.288 units/mL, p<0.001) compared with the group receiving antitubercular drugs alone. Histological examination indicated that goat milk reduced inflammation and necrotic changes in hepatocytes in the treatment groups. The results indicated that goat milk prevented the antitubercular drug-induced hepatotoxicity and is an effective hepatoprotective agent. Copyright © 2016. Published by Elsevier B.V.

History-independent cyclic response of nanotwinned metals

NASA Astrophysics Data System (ADS)

Pan, Qingsong; Zhou, Haofei; Lu, Qiuhong; Gao, Huajian; Lu, Lei

2017-11-01

Nearly 90 per cent of service failures of metallic components and structures are caused by fatigue at cyclic stress amplitudes much lower than the tensile strength of the materials involved. Metals typically suffer from large amounts of cumulative, irreversible damage to microstructure during cyclic deformation, leading to cyclic responses that are unstable (hardening or softening) and history-dependent. Existing rules for fatigue life prediction, such as the linear cumulative damage rule, cannot account for the effect of loading history, and engineering components are often loaded by complex cyclic stresses with variable amplitudes, mean values and frequencies, such as aircraft wings in turbulent air. It is therefore usually extremely challenging to predict cyclic behaviour and fatigue life under a realistic load spectrum. Here, through both atomistic simulations and variable-strain-amplitude cyclic loading experiments at stress amplitudes lower than the tensile strength of the metal, we report a history-independent and stable cyclic response in bulk copper samples that contain highly oriented nanoscale twins. We demonstrate that this unusual cyclic behaviour is governed by a type of correlated ‘necklace’ dislocation consisting of multiple short component dislocations in adjacent twins, connected like the links of a necklace. Such dislocations are formed in the highly oriented nanotwinned structure under cyclic loading and help to maintain the stability of twin boundaries and the reversible damage, provided that the nanotwins are tilted within about 15 degrees of the loading axis. This cyclic deformation mechanism is distinct from the conventional strain localizing mechanisms associated with irreversible microstructural damage in single-crystal, coarse-grained, ultrafine-grained and nanograined metals.

A cup product structure for cyclic cohomology

NASA Astrophysics Data System (ADS)

Espinosa Tintos, Jose Eduardo

In this work we construct a cup product structure for cyclic cohomology of a cyclic set X. introduced by Comics. We make use of a categorical construction of cyclic homology by Fiedorowicz and Loday to define our cup product structure by using a large resolution of the cyclic category. We also provide a way to construct a chain map from a smaller resolution where the action of the finite groups is clear. and in the process of constructing this map we learn the large complex can be viewed as all factorizations in the category DeltaC using the cyclic structure of X.

The C- and N-Terminal Residues of Synthetic Heptapeptide Ion Channels Influence Transport Efficacy Through Phospholipid Bilayers

PubMed Central

Djedovič, Natasha; Ferdani, Riccardo; Harder, Egan; Pajewska, Jolanta; Pajewski, Robert; Weber, Michelle E.; Schlesinger, Paul H.; Gokel, George W.

2008-01-01

The synthetic peptide, R2N-COCH2OCH2CO-Gly-Gly-Gly-Pro-Gly-Gly-Gly-OR’, was shown to be selective for Cl- over K+ when R is n-octadecyl and R’ is benzyl. Nineteen heptapeptides have now been prepared in which the N-terminal and C-terminal residues have been varied. All of the N-terminal residues are dialkyl but the C-terminal chains are esters, 2° amides, or 3° amides. The compounds having varied N-terminal anchors and C-terminal benzyl groups are as follows: 1, R = n-propyl; 2, R = n-hexyl; 3, R = n-octyl; 4, R = n-decyl; 5, R = n-dodecyl; 6, R = n-tetradecyl; 7, R = n-hexadecyl; 8, R = n-octadecyl. Compounds 9-19 have R = n-octadecyl and C-terminal residues as follows: 9, OR’ = OCH2CH3; 10, OR’ = OCH(CH3)2; 11, OR’ = O(CH2)6CH3; 12, OR’ = OCH2-c-C6H11; 13, OR’ = O(CH2)9CH3; 14, OR’ = O (CH2)17CH3; 15, NR’2 = N[(CH2)6CH3]2; 16, NHR’ = NH(CH2)9CH3; 17, NR’2 = N[(CH2)9CH3]2; 18, NHR’ = NH(CH2)17CH3; 19, NR’2 = N[(CH2)17CH3]2. The highest anion transport activities were observed as follows. For the benzyl esters whose N-terminal residues were varied, i.e. 1-8, compound 3 was most active. For the C18 anchored esters 10-14, n-heptyl ester 11 was most active. For the C18 anchored, C-terminal amides 15-19, di-n-decylamide 17 was most active. It was concluded that both the C- and N-terminal anchors were important for channel function in the bilayer but that activity was lost unless only one of the two anchoring groups was dominant. PMID:19633728

Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brusko, C.S.; Marten, J.T.

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.

Human hepatocytes derived from pluripotent stem cells: a promising cell model for drug hepatotoxicity screening.

PubMed

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.

Acute hepatotoxicity induced by hepatotoxins in Suncus murinus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, S.; Saito, H.; Yohro, T.

A comparative study was conducted to contrast the hepatotoxicity of several chemicals in the musk shrew (Suncus murinus) versus other common laboratory species (mouse or rat), and the following results were obtained from serum enzymes (SGOT and SGPT) and histopathological findings of liver specimens. (1) The sensitivity of Suncus liver to CCl/sub 4/ was different from that of mouse liver. (2) The sensitivity of Suncus liver to ..beta..-D-galactosamine was weaker than that of rat liver. (3) The sensitivity of Suncus liver to ethanol was stronger than that of mouse liver. After a single oral administration of ethanol (99.5% v/v, 0.1more » ml/50 g body weight), the gallbladder of Suncus became enlarged and dark blue in color. (4) A striking fatty degeneration was seen 24 h after a single ip administration of amethopterin at 50 mg/kg in Suncus liver.« less

Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity.

PubMed

Liu, Aiming; Krausz, Kristopher W; Fang, Zhong-Ze; Brocker, Chad; Qu, Aijuan; Gonzalez, Frank J

2014-04-01

Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis.

Protective Effects of Caffeic Acid Phenethyl Ester on Fluoxetine-Induced Hepatotoxicity: An Experimental Study.

PubMed

Yılmaz, Ahmet; Elbey, Bilal; Yazgan, Ümit Can; Dönder, Ahmet; Arslan, Necmi; Arslan, Serkan; Alabalık, Ulaş; Aslanhan, Hamza

2016-01-01

Background. The aim of the study was to analyse the effect of caffeic acid phenethyl ester (CAPE) on fluoxetine-induced hepatotoxicity in rats. Materials and Methods. Group I served as control. Group II received CAPE intraperitoneally. Group III received fluoxetine per orally. Group IV received fluoxetine and CAPE. The total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and liver enzymes including paraoxonase-1 (PON-1), aspartate transaminase, and alanine transaminase levels were measured. Liver tissues were processed histopathologically for evaluation of liver injury and to validate the serum enzyme levels. Results. An increase in TOS and OSI and a decrease in TAC and PON-1 levels in serum and liver tissues of Group III were observed compared to Groups I and II. After treatment with CAPE, the level of TOS and OSI decreased while TAC and PON-1 increased in serum and liver in Group IV. Histopathological examination of the liver revealed hepatic injury after fluoxetine treatment and reduction of injury with CAPE treatment. Conclusion. Our results suggested that CAPE treatment provided protection against fluoxetine toxicity. Following CAPE treatment with fluoxetine-induced hepatotoxicity, TOS and OSI levels decreased, whereas PON-1 and TAC increased in the serum and liver.

Toward structure prediction of cyclic peptides.

PubMed

Yu, Hongtao; Lin, Yu-Shan

2015-02-14

Cyclic peptides are a promising class of molecules that can be used to target specific protein-protein interactions. A computational method to accurately predict their structures would substantially advance the development of cyclic peptides as modulators of protein-protein interactions. Here, we develop a computational method that integrates bias-exchange metadynamics simulations, a Boltzmann reweighting scheme, dihedral principal component analysis and a modified density peak-based cluster analysis to provide a converged structural description for cyclic peptides. Using this method, we evaluate the performance of a number of popular protein force fields on a model cyclic peptide. All the tested force fields seem to over-stabilize the α-helix and PPII/β regions in the Ramachandran plot, commonly populated by linear peptides and proteins. Our findings suggest that re-parameterization of a force field that well describes the full Ramachandran plot is necessary to accurately model cyclic peptides.

Hepatotoxicity of kaurene glycosides from Xanthium strumarium L. fruits in mice.

PubMed

Wang, Yang; Han, Ting; Xue, Li-Ming; Han, Ping; Zhang, Qiao-Yan; Huang, Bao-Kang; Zhang, Hong; Ming, Qian-Liang; Peng, Wei; Qin, Lu-Ping

2011-06-01

The fruit of Xanthium strumarium L. (Cang-Er-Zi) is a traditional Chinese medicine that is used in curing nasal diseases and headache according to the Chinese Pharmacopoeia. However, clinical utilization of Xanthium strumarium is relatively limited because of its toxicity. The present investigation was carried out to evaluate the toxic effects on acute liver injury in mice of the two kaurene glycosides (atractyloside and carbxyatractyloside), which are main toxic constituents isolated from Fructus Xanthii on acute liver injury in mice. Histopathological examinations revealed that there were not obviously visible injury in lungs, heart, spleen, and the central nervous system in the mice by intraperitoneal injection of atractyloside (ATR, at the doses 50,125 and 200 mg/kg) and carbxyatractyloside (CATR, at the doses 50,100 and 150 mg/kg) for 5 days. However, it revealed extensive liver injuries compared with the normal group. In the determination of enzyme levels in serum, intraperitoneal injection of ATR and CATR resulted in significantly elevated serum alanine aminotransferase (ALT), asparate aminotransferase (AST), alkaline phosphatase (ALP) activities compared to controls. In the hepatic oxidative stress level, antioxidant-related enzyme activity assays showed that ATR and CATR administration significantly increased hepatic malondialdehyde (MDA) concentration, as well as decreased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) concentration, and this was in good agreement with the results of serum aminotransferase activity and histopathological examinations. Taken together, our results demonstrate that kaurene glycosides induce hepatotoxicity in mice by way of its induction of oxidative stress as lipid peroxidation in liver, which merited further studies. Therefore, these toxic constituents explain, at least in part, the hepatotoxicity of X. strumarium L. in traditional medicine.

Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ - Hawaii, 2013.

PubMed

Johnston, David I; Chang, Arthur; Viray, Melissa; Chatham-Stephens, Kevin; He, Hua; Taylor, Ethel; Wong, Linda L; Schier, Joshua; Martin, Colleen; Fabricant, Daniel; Salter, Monique; Lewis, Lauren; Park, Sarah Y

2016-01-01

Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases' medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and traceback, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Heat Shock Protein 27-Targeted Heptapeptide of the PKC{Delta} Catalytic V5 Region Sensitizes Tumors With Radio- and Chemoresistance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Hae-June; Kim, Eun-Ho; School of Life Sciences and Biotechnology, Korea University, Seoul

Purpose: Previous data suggest that the PKC{delta} catalytic V5 (PKC{delta}-V5) heptapeptide (HEPT) (FEQFLDI) binds HSP27 and blocks HSP27-mediated radio- or chemoresistance. Here we investigated further the in vivo function of the PKC{delta}-V5 HEPT. Methods and Materials: Labeling of HEPT with Cy5.5 or fluorescein isothiocyanate was performed to evaluate in vitro or in vivo distribution of HEPT. A clonogenic survival assay, flow cytometry, and Western blotting of cleaved caspase-3 were performed to determine in vitro sensitization effects of HEPT plus ionizing radiation (IR) versus IR alone or those of HEPT plus cisplatin(Cis) versus Cis alone. A nude mouse xenografting system wasmore » also applied to detect in vivo sensitizing effects of HEPT. Results: HEPT efficiently bound to HSP27 and showed sensitization after combined treatment with IR versus treatment with Cis alone in NCI-H1299 lung carcinoma cells, with higher HSP27 expression, which was similar to that of combined treatment with IR or with Cis alone in NCI-H460 lung carcinoma cells with lower HSP27 expression. In vivo image analysis using Cy5.5-labeled HEPT showed that HEPT was retained in HSP27-overexpressing cancer cells after xenografting to nude mice. Combined treatment of HEPT with IR versus that with Cis alone in xenografted mice showed that HEPT increased radio- or chemosensitization in NCI-H1299 cells compared to that in mice xenografted with NCI-H460 cells. Conclusions: The novel PKC{delta}-V5 HEPT may help overcome HSP27-mediated radio- or chemoresistance.« less

THE DIFFERENTIAL HEPATOTOXICITY AND CYTOCHROME P450 RESPONSE OF F344 RATS TO THE THREE ISOMERS OF DICHLOROBENZENE

EPA Science Inventory

The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate toxic thresholds and to further e1ucidate the role of cytochrome P450 in the metabolism and toxici...

Virtual screening using combinatorial cyclic peptide libraries reveals protein interfaces readily targetable by cyclic peptides.

PubMed

Duffy, Fergal J; O'Donovan, Darragh; Devocelle, Marc; Moran, Niamh; O'Connell, David J; Shields, Denis C

2015-03-23

Protein-protein and protein-peptide interactions are responsible for the vast majority of biological functions in vivo, but targeting these interactions with small molecules has historically been difficult. What is required are efficient combined computational and experimental screening methods to choose among a number of potential protein interfaces worthy of targeting lead macrocyclic compounds for further investigation. To achieve this, we have generated combinatorial 3D virtual libraries of short disulfide-bonded peptides and compared them to pharmacophore models of important protein-protein and protein-peptide structures, including short linear motifs (SLiMs), protein-binding peptides, and turn structures at protein-protein interfaces, built from 3D models available in the Protein Data Bank. We prepared a total of 372 reference pharmacophores, which were matched against 108,659 multiconformer cyclic peptides. After normalization to exclude nonspecific cyclic peptides, the top hits notably are enriched for mimetics of turn structures, including a turn at the interaction surface of human α thrombin, and also feature several protein-binding peptides. The top cyclic peptide hits also cover the critical "hot spot" interaction sites predicted from the interaction crystal structure. We have validated our method by testing cyclic peptides predicted to inhibit thrombin, a key protein in the blood coagulation pathway of important therapeutic interest, identifying a cyclic peptide inhibitor with lead-like activity. We conclude that protein interfaces most readily targetable by cyclic peptides and related macrocyclic drugs may be identified computationally among a set of candidate interfaces, accelerating the choice of interfaces against which lead compounds may be screened.

Influence of caffeine on allyl alcohol-induced hepatotoxicity in rats. I. In vivo study.

PubMed

Karas, M; Chakrabarti, S K

2001-01-01

Cotreatment of rats with a low hepatotoxic dose (30.7 mg/kg, i.p.) of allyl alcohol (AA) and a higher, but nontoxic, dose (150 mg/kg, oral) of caffeine (CF) potentiated the hepatotoxicity of AA. This was verified by significantly higher levels of plasma alanine aminotransferase (ALT) activity and histopathologically greater severity of lesions in the periportal hepatocytes than those due to AA alone. Treatment of rats with 4-methylpyrazole (4-MP) (0.5 mmol/kg, i.p.) (an inhibitor liver alcohol dehydrogenase) for 30 minutes, followed by similar cotreatment with AA and CF, completely prevented the elevation of plasma levels of ALT and histological damage induced by cotreatment with CF and AA 24 hours following their administration. Severe liver damage induced by cotreatment with CF and AA was further, markedly enhanced by phenobarbital pretreatment (80 mg/kg, i.p., 3 days). Thus, extensive necrosis of periportal hepatocytes was noted, as well as edema and accumulation of inflammatory cells in the necrotic foci caused by such pretreatment. The depression of hepatic nonprotein sulfhydryls resulting from CF plus AA was much more severe than that caused by AA or CF alone and appeared as early as 30 minutes after administration. However, much less marked depletion of protein thiols was observed following similar treatments. Significant increase in lipid peroxidation (as measured by melondialdehyde [MDA] formation) was also observed in rat liver but only 24 hours after administration. The production ofMDA in the rat liver was significantly higher after administration of AA plus CF than after administration of AA alone. Pretreatment of rats with phenobarbital further significantly enhanced the formation of 2,4-dinitrophenylhydrazine (DNP)-reactive metabolite(s) (measured as DNP-acrolein adduct equivalents) in rat liver induced by AA (30.7 mg/kg) plus CF (150 mg/kg) within 1 hour following such treatment. Cotreatment with AA and a higher dose of CF resulted in significantly

Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ — Hawaii, 2013

PubMed Central

Johnston, David I.; Chang, Arthur; Viray, Melissa; Chatham-Stephens, Kevin; He, Hua; Taylor, Ethel; Wong, Linda L.; Schier, Joshua; Martin, Colleen; Fabricant, Daniel; Salter, Monique; Lewis, Lauren; Park, Sarah Y.

2015-01-01

Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases’ medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and trace back, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events. PMID:26538199

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

PubMed

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 (F 1.2 ), no consistent difference between Sph(f+) and Sph(f-) was found, although several F 1.2 values were undetermined, especially in Sph(f+). The IC 50 of albumin secretion and F 1.2 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.

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

PubMed

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

Alpha-lipoic acid-stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study.

PubMed

Dhaundiyal, Ankit; Jena, Sunil K; Samal, Sanjaya K; Sonvane, Bhavin; Chand, Mahesh; Sangamwar, Abhay T

2016-12-01

This study was designed to demonstrate the potential of novel α-lipoic acid-stearylamine (ALA-SA) conjugate-based solid lipid nanoparticles in modulating the pharmacokinetics and hepatotoxicity of tamoxifen (TMX). α-lipoic acid-stearylamine bioconjugate was synthesized via carbodiimide chemistry and used as a lipid moiety for the generation of TMX-loaded solid lipid nanoparticles (TMX-SLNs). TMX-SLNs were prepared by solvent emulsification-diffusion method and optimized for maximum drug loading using rotatable central composite design. The optimized TMX-SLNs were stabilized using 10% w/w trehalose as cryoprotectant. In addition, pharmacokinetics and hepatotoxicity of freeze-dried TMX-SLNs were also evaluated in Sprague Dawley rats. Initial characterization with transmission electron microscopy revealed spherical morphology with smooth surface having an average particle size of 261.08 ± 2.13 nm. The observed entrapment efficiency was 40.73 ± 2.83%. In-vitro release study showed TMX release was slow and pH dependent. Pharmacokinetic study revealed a 1.59-fold increase in relative bioavailability as compared to TMX suspension. A decrease in hepatotoxicity of TMX is evidenced by the histopathological evaluation of liver tissues. α-lipoic acid-stearylamine conjugate-based SLNs have a great potential in enhancing the oral bioavailability of poorly soluble drugs like TMX. Moreover, this ALA-SA nanoparticulate system could be of significant value in long-term anticancer therapy with least side effects. © 2016 Royal Pharmaceutical Society.

Synergistic activity of curcumin with methotrexate in ameliorating Freund's Complete Adjuvant induced arthritis with reduced hepatotoxicity in experimental animals.

PubMed

Banji, David; Pinnapureddy, Jyothi; Banji, Otilia J F; Saidulu, A; Hayath, Md Sikinder

2011-10-01

Methotrexate is employed in low doses for the treatment of rheumatoid arthritis. One of the major drawbacks with methotrexate is hepatotoxicity resulting in poor compliance of therapy. Curcumin is an extensively used spice possessing both anti-arthritic and hepatoprotective potential. The present study was aimed at investigating the effect of curcumin (30 and 100 mg/kg) in combination with subtherapeutic dose of methotrexate (1 mg/kg) is salvaging hepatotoxicity, oxidative stress and producing synergistic anti-arthritic action with methotrexate. Wistar albino rats were induced with arthritis by subplantar injection of Freund's Complete Adjuvant and pronounced arthritis was seen after 9 days of injection. Groups of animals were treated with subtherapeutic dose of methotrexate followed half an hour later with 30 and 100mg/kg of curcumin from day 9 up to days 45 by intraperitoneal route. Methotrexate treatment in Freund's Complete Adjuvant induced arthritic animals produced elevation in the levels of aminotransferases, alkaline phosphatase, total and direct bilirubin. Enhanced oxidative stress in terms of measured lipid peroxides was observed in the methotrexate treated group. Curcumin significantly circumvented hepatotoxicity induced by methotrexate as evidenced by a change in biochemical markers possibly due to its strong anti-oxidant action. Hepatoprotective potential of curcumin was also confirmed from histological evaluation. Sub-therapeutic dose of methotrexate elicited substantial anti-arthritic action when used in combination with curcumin implying that the latter potentiated its action. Concomitant administration of curcumin with methotrexate was also found to minimize liver damage. Copyright © 2011 Elsevier B.V. All rights reserved.

Hepatoprotective activity of Leptadenia reticulata stems against carbon tetrachloride-induced hepatotoxicity in rats

PubMed Central

Nema, Amit Kumar; Agarwal, Abhinav; Kashaw, Varsha

2011-01-01

Objective: To evaluate the hepatoprotective activity of ethanolic and aqueous extract of stems of Leptadenia reticulata (Retz.) Wight. and Arn. in carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Materials and Methods: The toxicant CCl4 was used to induce hepatotoxicity at a dose of 1.25 ml/kg as 1 : 1 mixture with olive oil. Ethanolic and aqueous extracts of L. reticulata stems were administered in the doses of 250 and 500 mg/kg/day orally for 7 days. Silymarin (50 mg/kg) was used as standard drug. The hepatoprotective effect of these extracts was evaluated by the assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, total bilirubin, serum protein, and histopathological studies of the liver. Results: Treatment of animals with ethanolic and aqueous extracts significantly reduced the liver damage and the symptoms of liver injury by restoration of architecture of liver as indicated by lower levels of serum bilirubin and protein as compared with the normal and silymarin-treated groups. Histology of the liver sections confirmed that the extracts prevented hepatic damage induced by CCl4 showing the presence of normal hepatic cords, absence of necrosis, and fatty infiltration. Conclusion: The ethanolic and aqueous extracts of stems of L. reticulata showed significant hepatoprotective activity. The ethanolic extract is more potent in hepatoprotection in CCl4-indiced liver injury model as compared with aqueous extract. PMID:21713086

Herbal hepatotoxicity: a critical review

PubMed Central

Teschke, Rolf; Frenzel, Christian; Glass, Xaver; Schulze, Johannes; Eickhoff, Axel

2013-01-01

This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumed HILI cases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using the Council for International Organizations of Medical Sciences scale ( CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements. PMID:22831551

Strategies for In Vivo Screening and Mitigation of Hepatotoxicity Associated with Antisense Drugs.

PubMed

Kamola, Piotr J; Maratou, Klio; Wilson, Paul A; Rush, Kay; Mullaney, Tanya; McKevitt, Tom; Evans, Paula; Ridings, Jim; Chowdhury, Probash; Roulois, Aude; Fairchild, Ann; McCawley, Sean; Cartwright, Karen; Gooderham, Nigel J; Gant, Timothy W; Moores, Kitty; Hughes, Stephen A; Edbrooke, Mark R; Clark, Kenneth; Parry, Joel D

2017-09-15

Antisense oligonucleotide (ASO) gapmers downregulate gene expression by inducing enzyme-dependent degradation of targeted RNA and represent a promising therapeutic platform for addressing previously undruggable genes. Unfortunately, their therapeutic application, particularly that of the more potent chemistries (e.g., locked-nucleic-acid-containing gapmers), has been hampered by their frequent hepatoxicity, which could be driven by hybridization-mediated interactions. An early de-risking of this liability is a crucial component of developing safe, ASO-based drugs. To rank ASOs based on their effect on the liver, we have developed an acute screen in the mouse that can be applied early in the drug development cycle. A single-dose (3-day) screen with streamlined endpoints (i.e., plasma transaminase levels and liver weights) was observed to be predictive of ASO hepatotoxicity ranking established based on a repeat-dose (15 day) study. Furthermore, to study the underlying mechanisms of liver toxicity, we applied transcriptome profiling and pathway analyses and show that adverse in vivo liver phenotypes correlate with the number of potent, hybridization-mediated off-target effects (OTEs). We propose that a combination of in silico OTE predictions, streamlined in vivo hepatotoxicity screening, and a transcriptome-wide selectivity screen is a valid approach to identifying and progressing safer compounds. Copyright © 2017 GSK R&D. Published by Elsevier Inc. All rights reserved.

Paracetamol causes endocrine disruption and hepatotoxicity in male fish Rhamdia quelen after subchronic exposure.

PubMed

Guiloski, Izonete Cristina; Ribas, João Luiz Coelho; Piancini, Laercio Dante Stein; Dagostim, Ana Carolina; Cirio, Silvana Maris; Fávaro, Luis Fernando; Boschen, Suelen Lúcio; Cestari, Marta Margarete; da Cunha, Cláudio; Silva de Assis, Helena Cristina

2017-07-01

Paracetamol is one of the most widely sold non-prescription drugs. This study aimed to evaluate the effects of the paracetamol on reproductive, biochemical, genetic, histopathological and hematogical biomarkers by waterborne exposure. Male fish of Rhamdia quelen were exposed to environmental concentrations of paracetamol (0, 0.25, 2.5μg/L) in a semi-static bioassay for 21days. Hemoglobin and hematocrit were reduced upon exposure to 0.25μg/L of paracetamol. Leukocytes and thrombocytes increased after paracetamol exposure. Paracetamol reduced testosterone levels in all exposed groups and increased estradiol levels at higher concentration. Serotonin and dopamine levels increased at exposure to 0.25μg/L. Paracetamol also caused protein carbonyls and increased SOD activity in fish exposed to 2.5μg/L and in addition led to an inhibition of EROD and GST activities in both concentrations. Hepatic genotoxicity occurred at the 0.25μg/L concentration. Hepatic tissues of exposed fish showed mild blood congestion and leucocytes infiltration. The results showed that paracetamol disrupted the hypothalamic-pituitary-gonadal axis, changed hematological parameters and caused hepatotoxicity in Rhamdia quelen. The findings suggest that this drug merits attention relative to its potential endocrine disrupter effect and hepatotoxicity, even at concentrations found in the aquatic environment. Copyright © 2017 Elsevier B.V. All rights reserved.

Dietary protocatechuic acid ameliorates dextran sulphate sodium-induced ulcerative colitis and hepatotoxicity in rats.

PubMed

Farombi, Ebenezer O; Adedara, Isaac A; Awoyemi, Omolola V; Njoku, Chinonye R; Micah, Gabriel O; Esogwa, Cynthia U; Owumi, Solomon E; Olopade, James O

2016-02-01

The present study investigated the antioxidant and anti-inflammatory effects of dietary protocatechuic acid (PCA), a simple hydrophilic phenolic compound commonly found in many edible vegetables, on dextran sulphate sodium (DSS)-induced ulcerative colitis and its associated hepatotoxicity in rats. PCA was administered orally at 10 mg kg(-1) to dextran sulphate sodium exposed rats for five days. The result revealed that administration of PCA significantly (p < 0.05) prevented the incidence of diarrhea and bleeding, the decrease in the body weight gain, shortening of colon length and the increase in colon mass index in DSS-treated rats. Furthermore, PCA prevented the increase in the plasma levels of pro-inflammatory cytokines, markers of liver toxicity and markedly suppressed the DSS-mediated elevation in colonic nitric oxide concentration and myeloperoxidase activity in the treated rats. Administration of PCA significantly protected against colonic and hepatic oxidative damage by increasing the antioxidant status and concomitantly decreased hydrogen peroxide and lipid peroxidation levels in the DSS-treated rats. Moreover, histological examinations confirmed PCA chemoprotection against colon and liver damage. Immunohistochemical analysis showed that PCA significantly inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression in the colon of DSS-treated rats. In conclusion, the effective chemoprotective role of PCA in colitis and the associated hepatotoxicity is related to its intrinsic anti-inflammatory and anti-oxidative properties.

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

PubMed

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.

A Case of Hepatotoxicity Induced by Adulterated "Tiger King", a Chinese Herbal Medicine Containing Sildenafil.

PubMed

Nissan, Ran; Poperno, Alina; Stein, Gideon Y; Shapira, Barak; Fuchs, Shmuel; Berkovitz, Ronny; Hess, Zipora; Arieli, Mickey

2016-01-01

Detection of Phosphodiesterase Type 5 (PDE-5) inhibitors and their analogues in "100% natural" or "herbal" supplements have been described in numerous reports. However, few reports have been published in relation to actual harm caused by counterfeit erectile dysfunction herbal supplements. We describe a case of a 65-year old male admitted to a tertiary hospital with acute liver toxicity, possibly induced by adulterated "Chinese herbal" supplement "Tiger King" for sexual enhancement. Chemical analysis of the tablets discovered the presence of therapeutic doses of sildenafil with no other herbal components. Other medications were excluded as potential causes of the hepatic impairment. According to the Naranjo adverse drug reaction scale and the Roussel Uclaf Causality Assessment Method (RUCAM) the probability of association of Hepatotoxicity with Sildenafil was "possible" and "probable" respectively (Naranjo score of 4, RUCAM score of 7). Within three days of admission, the patient's clinical status and liver function improved without any specific treatment. His liver function tests normalized 30 days post discharge. Further pharmacovigilance actions should be taken by regulatory authorities and pharmaceutical companies in order to determine the relation between sildenafil and hepatotoxicity. This case emphasizes the importance of raising public awareness on the potential dangers of "Tiger king" in particular, and other counterfeit medications or herbal supplements of unknown origin.

Deltamethrin-Induced Hepatotoxicity and Virgin Olive Oil Consumption: An Experimental Study.

PubMed

Khalatbary, Ali Reza; Ghabaee, Davood Nasiry Zarrin; Ahmadvand, Hassan; Amiri, Fereshteh Talebpour; Lehi, Somaieh Tadayoni

2017-11-01

Deltamethrin (DM) is a synthetic pyrethroid insecticide which can lead to pathological effects in mammals through oxidative stress. On the other hand, virgin olive oil (VOO) is a rich source of phenolic compounds with antioxidants. The aim of the present study was to determine the protective effects of VOO against DM-induced hepatotoxicity. Thirty-six mice were randomly separated into 4 groups: vehicle group, VOO group, DM group, and DM plus VOO group. Immunohistochemistry of PARP, COX-2, and caspase-3 with the biochemical analysis of malondialdehyde and total antioxidant capacity levels were performed in the liver samples 5 weeks after gavaging. Statistical analysis was performed using SPSS, version 15. The data were compared between the groups using the Tukey multiple comparison tests and the analysis of the variance. A P value <0.05 was considered significant. The malondialdehyde level in the liver was increased in the DM group (71.18±0.01), whereas it was significantly (P=0.001) decreased after VOO administration in the DM plus VOO group (39.59±2.43). While the total antioxidant capacity level in the liver was decreased in the DM group (3.05±0.05), it was significantly increased (P=0.03) after VOO administration in the DM plus VOO group (3.95±0.04). A greater expression of caspase-3 (P=0.008), COX-2 (P =0.004), and PARP (P 0.006) could be detected in the DM group, while it was significantly (P=0.009) attenuated in the DM plus VOO group. Also, the degeneration of hepatocytes, which was detected in the DM group, was attenuated after VOO consumption. VOO exerted protective effects against DM-induced hepatotoxicity, which might be associated with its anti-apoptotic, anti-inflammatory, and antioxidative properties.

Cyclic steady state stress-strain behavior of UHMW polyethylene.

PubMed

Krzypow, D J; Rimnac, C M

2000-10-01

To increase the long-term performance of total joint replacements, finite element analyses of ultra high molecular weight polyethylene (UHMWPE) components have been conducted to predict the effect of load on the stress and strain distributions occurring on and within these components. Early models incorporated the monotonic behavior of UHMWPE without considering the unloading and cyclic loading behavior. However, UHMWPE components undergo cyclic loading during use and at least two wear damage modes (pitting and delamination) are thought to be associated with the fatigue fracture properties of UHMWPE. The objective of this study was to examine the fully reversed uniaxial tension/compression cyclic steady state stress-strain behavior of UHMWPE as a first step towards developing a cyclic constitutive relationship for UHMWPE. The hypothesis that cycling results in a permanent change in the stress-strain relationship, that is, that the cyclic steady state represents a new cyclically stabilized state, was examined. It was found that, like other ductile polymers, UHMWPE substantially cyclically softens under fully reversed uniaxial straining. More cyclic softening occurred in tension than in compression. Furthermore, cyclic steady state was attained, but not cyclic stability. It is suggested that it may be more appropriate to base a material constitutive relationship for UHMWPE for finite element analyses of components upon a cyclically modified stress-strain relationship.

Cyclic tensile strain and cyclic hydrostatic pressure differentially regulate expression of hypertrophic markers in primary chondrocytes.

PubMed

Wong, Marcy; Siegrist, Mark; Goodwin, Kelly

2003-10-01

Endochondral ossification is regulated by many factors, including mechanical stimuli, which can suppress or accelerate chondrocyte maturation. Mathematical models of endochondral ossification have suggested that tension (or shear stress) can accelerate the formation of endochondral bone, while hydrostatic stress preserves the cartilage phenotype. The goal of this study was to test this hypothesis by examining the expression of hypertrophic chondrocyte markers (transcription factor Cbfa1, MMP-13, type X collagen, VEGF, CTGF) and cartilage matrix proteins under cyclic tension and cyclic hydrostatic pressure. Chondrocyte-seeded alginate constructs were exposed to one of the two loading modes for a period of 3 h per day for 3 days. Gene expression was analyzed using real-time RT-PCR. Cyclic tension upregulated the expression of Cbfa1, MMP-13, CTGF, type X collagen and VEGF and downregulated the expression of TIMP-1. Cyclic tension also upregulated the expression of type 2 collagen, COMP and lubricin, but did not change the expression of SOX9 and aggrecan. Cyclic hydrostatic pressure downregulated the expression of MMP-13 and type I collagen and upregulated expression of TIMP-1 compared to the unloaded controls. Hydrostatic pressure may slow chondrocyte differentiation and have a chondroprotective, anti-angiogenic influence on cartilage tissue. Our results suggest that cyclic tension activates the Cbfa1/MMP-13 pathway and increases the expression of terminal differentiation hypertrophic markers. Mammalian chondrocytes appear to have evolved complex mechanoresponsive mechanisms, the effects of which can be observed in the histomorphologic establishment of the cartilaginous skeleton during development and maturation.

Statistical damage constitutive model for rocks subjected to cyclic stress and cyclic temperature

NASA Astrophysics Data System (ADS)

Zhou, Shu-Wei; Xia, Cai-Chu; Zhao, Hai-Bin; Mei, Song-Hua; Zhou, Yu

2017-10-01

A constitutive model of rocks subjected to cyclic stress-temperature was proposed. Based on statistical damage theory, the damage constitutive model with Weibull distribution was extended. Influence of model parameters on the stress-strain curve for rock reloading after stress-temperature cycling was then discussed. The proposed model was initially validated by rock tests for cyclic stress-temperature and only cyclic stress. Finally, the total damage evolution induced by stress-temperature cycling and reloading after cycling was explored and discussed. The proposed constitutive model is reasonable and applicable, describing well the stress-strain relationship during stress-temperature cycles and providing a good fit to the test results. Elastic modulus in the reference state and the damage induced by cycling affect the shape of reloading stress-strain curve. Total damage induced by cycling and reloading after cycling exhibits three stages: initial slow increase, mid-term accelerated increase, and final slow increase.

HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity.

PubMed

Stephens, Camilla; López-Nevot, Miguel-Ángel; Ruiz-Cabello, Francisco; Ulzurrun, Eugenia; Soriano, Germán; Romero-Gómez, Manuel; Moreno-Casares, Antonia; Lucena, M Isabel; Andrade, Raúl J

2013-01-01

The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity

PubMed Central

Stephens, Camilla; López-Nevot, Miguel-Ángel; Ruiz-Cabello, Francisco; Ulzurrun, Eugenia; Soriano, Germán; Romero-Gómez, Manuel; Moreno-Casares, Antonia; Lucena, M. Isabel; Andrade, Raúl J.

2013-01-01

Background and Aim The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. Methods High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. Results The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). Conclusions HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients. PMID:23874514

BENZYL ALCOHOL PROTECTS AGAINST ACETAMINOPHEN HEPATOTOXICITY BY INHIBITING CYTOCHROME P450 ENZYMES BUT CAUSES MITOCHONDRIAL DYSFUNCTION AND CELL DEATH AT HIGHER DOSES

PubMed Central

Du, Kuo; McGill, Mitchell R.; Xie, Yuchao; Jaeschke, Hartmut

2015-01-01

Acetaminophen (APAP) hepatotoxicity is a serious public health problem in western countries. Current treatment options for APAP poisoning are limited and novel therapeutic intervention strategies are needed. A recent publication suggested that benzyl alcohol (BA) protects against APAP hepatotoxicity and could serve as a promising antidote for APAP poisoning. To assess the protective mechanisms of BA, C56Bl/6J mice were treated with 400mg/kg APAP and/or 270mg/kg BA. APAP alone caused extensive liver injury at 6h and 24h post-APAP. This injury was attenuated by BA co-treatment. Assessment of protein adduct formation demonstrated that BA inhibits APAP metabolic activation. In support of this, in vitro experiments also showed that BA dose-dependently inhibits cytochrome P450 activities. Correlating with the hepatoprotection of BA, APAP-induced oxidant stress and mitochondrial dysfunction were reduced. Similar results were obtained in primary mouse hepatocytes. Interestingly, BA alone caused mitochondrial membrane potential loss and cell toxicity at high doses, and its protective effect could not be reproduced in primary human hepatocytes (PHH). We conclude that BA protects against APAP hepatotoxicity mainly by inhibiting cytochrome P450 enzymes in mice. Considering its toxic effect and the loss of protection in PHH, BA is not a clinically useful treatment option for APAP overdose patient. PMID:26522885

[Erythromycin in therapy of cyclic vomiting syndrome].

PubMed

Pavlović, Momcilo; Radlović, Nedeljko; Leković, Zoran; Berenji, Karolina

2007-01-01

Cyclic vomiting syndrome is an insufficiently understood disorder which manifests itself in stereotypical episodes of vomiting with no detectable organic cause. Considering its unknown aetiology, drugs borrowed from various medication classes are applied in the therapy of this disorder, with variable success. Among other medicaments, erythromycin is also used in treatment of cyclic vomiting syndrome. This is a case study in which the application of erythromycin led to the prevention of attacks of cyclic vomiting syndrome. Our case report presents how periodical erythromycin therapy in two-week intervals at expected attack periods in a girl led to disappearance of cyclic vomiting. Adverse effects of erythromycin did not show up.

[Cyclic Cushing's Syndrome - rare or rarely recognized].

PubMed

Kiałka, Marta; Doroszewska, Katarzyna; Mrozińska, Sandra; Milewicz, Tomasz; Stochmal, Ewa

2015-01-01

Cyclic Cushing's syndrome is a type of Cushing's disease which is characterized by alternating periods of increasing and decreasing levels of cortisol in the blood. The diagnostic criteria for cyclic Cushing's syndrome are at least three periods of hypercortisolism alternating with at least two episodes of normal levels of serum cortisol concentration. The epidemiology, signs, symptoms, pathogenesis and treatment of cyclic Cushing's syndrome have been discussed.

The role of peel stresses in cyclic debonding

NASA Technical Reports Server (NTRS)

Everett, R. A., Jr.

1982-01-01

When an adhesively bonded joint is undergoing cyclic loading, one of the possible damage modes that occurs is called cyclic debonding - progressive separation of the adherends by failure of the adhesive bond under cyclic loading. In most practical structures, both peel and shear stresses exist in the adhesive bonding during cyclic loading. The results of an experimental and analytical study to determine the role of peel stresses on cyclic debonding in a mixed mode specimen are presented. Experimentally, this was done by controlling the forces that create the peel stresses by applying a clamping force to oppose the peel stresses. Cracked lap shear joints were chosen for this study. A finite element analysis was developed to assess the effect of the clamping force on the strain energy release rates due to shear and peel stresses. The results imply that the peel stress is the principal stress causing cyclic debonding.

An assessment of the potential of protopine to inhibit microsomal drug metabolising enzymes and prevent chemical-induced hepatotoxicity in rodents.

PubMed

Janbaz, K H; Saeed, S A; Gilani, A H

1998-09-01

The potential of protopine to inhibit microsomal drug metabolising enzymes (MDM E) and prevent paracetamol- and CCl4-induced hepatotoxicity was studied in rats. Paracetamol at the dose of 640 mg kg-1 produced hepatic damage in rats as manifested by the rise in serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) to 972+/-186 and 624+/-131 IU (mean+/-sem; n=10), respectively, compared to respective control values of 101+/-29 and 64+/-18 IU. Pretreatment of rats with protopine (11 mg kg-1, orally twice daily for 2 days) lowered significantly the respective serum AST and ALT levels (P<0.05) to 289+/-52 and 178+/-43 IU. The hepatotoxic dose of CCl4 (1.5 ml kg-1; orally) raised serum AST and ALT levels to 543+/-89 and 387+/-69 IU (mean+/-sem; n=10), respectively, compared to respective control values of 98+/-28 and 56+/-17 IU. The same dose of protopine (11 mg kg-1) was able to prevent significantly (P<0.05), the CCl4-induced rise in serum enzymes and the estimated values of AST and ALT were 168+/-36 and 93+/-28 IU, respectively. Protopine caused prolongation (P<0.05) in pentobarbital (55 mg kg-1)-induced sleep as well as potentiated strychnine-induced toxicity in rats, suggestive of an inhibitory effect on MDME. These results indicate that protopine exhibits anti-hepatotoxic action which may be mediated through inhibition of MDME. Copyright 1998 The Italian Pharmacological Society

Enniatin B and beauvericin are common in Danish cereals and show high hepatotoxicity on a high-content imaging platform.

PubMed

Svingen, Terje; Lund Hansen, Niels; Taxvig, Camilla; Vinggaard, Anne Marie; Jensen, Udo; Have Rasmussen, Peter

2017-05-01

Mycotoxins are fungi-born metabolites that can contaminate foods through mould-infected crops. They are a significant food/feed-safety issue across the globe and represent a substantial financial burden for the world economy. Moreover, with a changing climate and fungal biota, there is now much discussion about emerging mycotoxins that are measurable at significant levels in crops world-wide. Unfortunately, we still know very little about the bioavailability and toxic potentials of many of these less characterized mycotoxins, including the large family of enniatins. In this study, we present new occurrence data for enniatin A, A1, B, B1 and beauvericin in four Danish crops: oat, wheat, and barley from the 2010 harvest, and rye from 2011 harvest. The occurrence of the four enniatins were B > B1 > A1 > A. Enniatin B was detected in 100% of tested samples regardless of crop type. In addition to occurrence data, we report a proof-of-concept study using a human-relevant high-content hepatotoxicity, or "quadroprobe," assay to screen mycotoxins for their cytotoxic potential. The assay was sensitive for most cytotoxic compounds in the 0.009-100 µM range. Among eight tested mycotoxins (enniatin B, beauvericin, altenariol, deoxynivalenol, aflatoxin B1, andrastin A, citrinin, and penicillic acid), enniatin B and beauvericin showed significant cytotoxicity at a concentration lower than that for aflatoxin B1, which is the archetypal acute hepatotoxic and liver-carcinogenic mycotoxin. Hence, the quadroprobe hepatotoxicity assay may become a valuable assessment tool for toxicity assessment of mycotoxins in the future. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1658-1664, 2017. © 2016 Wiley Periodicals, Inc.

Nephrotoxicity and hepatotoxicity evaluation of Crocus sativus stigmas in neonates of nursing mice

PubMed Central

Bahmani, Mahmoud; Rafieian, Mortaza; Baradaran, Azar; Rafieian, Samira; Rafieian-kopaei, Mahmoud

2014-01-01

Background: Crocus sativus, known as saffron crocus, is best known for the spice saffron. Saffron use spans more than 3500 years, however, its toxicity on neonates during lactation has not yet evaluated. Objectives: This study was aimed to examine the acute toxicity of saffron on adult mice and its nephrotoxicity and hepatotoxicity on neonates of lactating mothers that used saffron during lactation. Materials and Methods: In this experimental study, following acute toxicity evaluation, 32 pregnant mice were randomly designated into four equal groups. Following delivery, the mothers of groups 1 to 4 were administered orally (by gavage) normal saline (control group), 500, 1000 or 2000 mg/kg/day of saffron for three weeks, respectively. The newborn’s kidney and liver parameters were assessed at the end of the study for possible nephrotoxicity and hepatotoxicity evaluation. The kidney and liver tissue samples of newborns were histopathologically studied after staining with Hematoxylin & Eosin. Data were analyzed using ANOVA and Scheffe’s tests Results: The LD50 value of saffron was calculated to be 4120±556 mg/kg in mice. To evaluate lactating toxicity, saffron was administered orally to the mothers once daily for 21 days, after delivery, during lactating period. Saffron increased serum urea nitrogen (p< 0.05). Histological studies indicated that saffron did not have any toxic effect on liver, however, histopathology changes were seen in the kidney of neonates. Conclusions: From the results of present study, it might be concluded that saffron is a nearly safe spice, however, nursing mothers should avoid high doses of this spice. PMID:24772401

Synthesis of potent agonists of substance P by replacement of Met11 with Glu(OBzl) and N-terminal glutamine with Glp of the C-terminal hexapeptide and heptapeptide of substance P.

PubMed

Stavropoulos, G; Karagiannis, K; Anagnostides, S; Ministrouski, I; Selinger, Z; Chorev, M

1995-06-01

The analogues [Glp6,Glu(OBzl)11]SP(6-11) and [Glp5,Glu(OBzl)11]SP(5-11) of the C-terminal hexapeptide and heptapeptide of Substance P have been synthesized by conventional solution methods. In each analogue the N-terminal glutamine has been replaced by pyroglutamic acid, while the COOCH2C6H5 ester group has replaced the SCH3 group of the Met11 side chain. The in vitro activity of both analogues has been determined on three biological preparations: guinea pig ileum (GPI), rat vas deferens (RVD) and rat portal vein (RPV). The results showed that both analogues are highly potent and selective agonists on GPI through the NK-1 receptor. They are more potent than SP itself, with 1.54 and 1.25 respective values of relative potency on GPI. Their selectivity has been studied by utilizing atropine-treated guinea pig ileum (GPI+At). The analogues showed low activity on RVD and RPV tissues, which represent NK-2 and NK-3 monoreceptor assay, respectively.

Silymarin nanoparticle prevents paracetamol-induced hepatotoxicity

PubMed Central

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. PMID:21753880

Cyclic membrane separation process

DOEpatents

Bowser, John

2004-04-13

A cyclic process for controlling environmental emissions of volatile organic compounds (VOC) from vapor recovery in storage and dispensing operations of liquids maintains a vacuum in the storage tank ullage. In one of a two-part cyclic process ullage vapor is discharged through a vapor recovery system in which VOC are stripped from vented gas with a selectively gas permeable membrane. In the other part, the membrane is inoperative while gas pressure rises in the ullage. Ambient air is charged to the membrane separation unit during the latter part of the cycle.

Down-regulation of angiotensin II receptor subtypes and desensitization of cyclic GMP production in neuroblastoma N1E-115 cells.

PubMed

Reagan, L P; Ye, X; Maretzski, C H; Fluharty, S J

1993-01-01

Murine neuroblastoma N1E-115 cells possess membranous receptors for the octapeptide angiotensin II (AngII) whose density is substantially increased by in vitro differentiation. Incubation of differentiated N1E-115 cells with AngII produced a rapid decrease in receptor density, but did not alter the affinity of these receptors for either 125I-AngII or the high-affinity antagonist 125I-[Sarc1,Ile8]-AngII. This apparent down-regulation was dose related with an ED50 of 1 nM, and maximal decreases of approximately 90% were obtained with 100 nM AngII. Receptor loss from differentiated cell membranes was unaffected by incubations of membranes obtained from agonist-exposed cells with non-hydrolyzable analogues of GTP for 60 min at 37 degrees C to ensure dissociation of the ligand. Partial loss of AngII receptors was apparent within 5 min of agonist exposure, whereas maximal declines were not observed until 30 min. This temporal pattern resulted from a preferential decrease in the AT1 receptor subtype during the first 5 min, followed by a decline in both AT1 and AT2 receptors with longer periods of agonist exposure. The loss of membranous receptors was reversible with partial recovery observed after 4 h, and with nearly full recovery observed 18 h after exposure of the cells to AngII. However, the long-term recovery of receptor density was blocked by the protein synthesis inhibitor, cycloheximide. The heptapeptide angiotensin III produced a similar down-regulation of receptors, and the high-affinity antagonist [Sarc1,Thr8]-AngII blocked agonist-induced down-regulation. Finally, the apparent loss of cell surface AngII receptors decreased the ability of AngII to stimulate cyclic GMP production within intact N1E-115 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclic Voltammetry.

ERIC Educational Resources Information Center

Evans, Dennis H.; And Others

1983-01-01

Cyclic voltammetry is a simple experiment that has become popular in chemical research because it can provide useful information about redox reactions in a form which is easily obtained and interpreted. Discusses principles of the method and illustrates its use in the study of four electrode reactions. (Author/JN)

Toxins produced in cyanobacterial water blooms – toxicity and risks

PubMed Central

Bláha, Luděk; Babica, Pavel; Maršálek, Blahoslav

2009-01-01

Cyanobacterial blooms in freshwaters represent a major ecological and human health problem worldwide. This paper briefly summarizes information on major cyanobacterial toxins (hepatotoxins, neurotoxins etc.) with special attention to microcystins-cyclic heptapeptides with high acute and chronic toxicities. Besides discussion of human health risks, microcystin ecotoxicology and consequent ecological risks are also highlighted. Although significant research attention has been paid to microcystins, cyanobacteria produce a wide range of currently unknown toxins, which will require research attention. Further research should also address possible additive, synergistic or antagonistic effects among different classes of cyanobacterial metabolites, as well as interactions with other toxic stressors such as metals or persistent organic pollutants. PMID:21217843

Theoretical Studies of Some HEDM Species: Cyclic O4, Cyclic O3 and Cubane

NASA Technical Reports Server (NTRS)

Walch, Stephen P.; Langhoff, Steve R. (Technical Monitor)

1996-01-01

Calculations have been carried out for the HEDM species (cyclic O4, cyclic O3, and cubane) using CASSCF/derivative and CASSCF/ICCI methods. Cyclic O4 is of interest both as a potential HEDM species and because of its possible role in the ozone deficit problem in atmospheric chemistry. We have studied the pathway for decomposition from the D(2d) minimum and also have found the approximate location of the singlet triplet crossing. The barrier to decomposition is found to be about 9 kcal/mol and is not limited by the singlet triplet crossing. For cyclic O3 we have focused on the crossings between the lowest five surfaces (X(1)A(1), s(1)A(1), (1)A(2), (1)B(1), and (1)B(2)) to provide some insight into ways to form cyclic O3 photochemically. The crossing region between the X(1)A(1) and 2(1)A(1) surfaces is in agreement with the work of Xantheas et al. The calculations show that vertical excitation from the ground state to the (1)A(2) state leads to a crossing with the (1)A(1) manifold near the crossing region of the X(1)A(1) and 2(1)A(1) surfaces. We have studied the decomposition pathways for cubane to benzene plus acetylene and to cyclooctatetraene. We have also studied the ground and excited states for the photochemical ring closure step. The state which closes to cubane can be described as a double triplet pi to pi* excitation with respect to the ground state. Thus, this state has only a small oscillator strength with respect to the ground state. However, there is a singlet pi to pi* state at nearly the same energy and excitation to this state followed by intersystem crossing could lead to the triplet pi to pi* state.

Functionalized linear and cyclic polyolefins

DOEpatents

Tuba, Robert; Grubbs, Robert H.

2018-02-13

This invention relates to methods and compositions for preparing linear and cyclic polyolefins. More particularly, the invention relates to methods and compositions for preparing functionalized linear and cyclic polyolefins via olefin metathesis reactions. Polymer products produced via the olefin metathesis reactions of the invention may be utilized for a wide range of materials applications. The invention has utility in the fields of polymer and materials chemistry and manufacture.

Computer Simulation Of Cyclic Oxidation

NASA Technical Reports Server (NTRS)

Probst, H. B.; Lowell, C. E.

1990-01-01

Computer model developed to simulate cyclic oxidation of metals. With relatively few input parameters, kinetics of cyclic oxidation simulated for wide variety of temperatures, durations of cycles, and total numbers of cycles. Program written in BASICA and run on any IBM-compatible microcomputer. Used in variety of ways to aid experimental research. In minutes, effects of duration of cycle and/or number of cycles on oxidation kinetics of material surveyed.

Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1)by bosentan: a mechanism for species differences in hepatotoxicity.

PubMed

Leslie, Elaine M; Watkins, Paul B; Kim, Richard B; Brouwer, Kim L R

2007-06-01

Bile acid accumulation in hepatocytes due to inhibition of the canalicular bile salt export pump (BSEP/ABCB11) has been proposed as a mechanism for bosentan-induced hepatotoxicity. The observation that bosentan does not induce hepatotoxicity in rats, although bosentan has been reported to inhibit rat Bsep and cause elevated serum bile acids, challenges this mechanism. The lack of hepatotoxicity could be explained if bosentan inhibited hepatocyte uptake as well as canalicular efflux of bile acids. In the current study, bosentan was found to be a more potent inhibitor of Na(+)-dependent taurocholate uptake in rat (IC(50) 5.4 microM) than human (IC(50) 30 microM) suspended hepatocytes. In addition, bosentan was a more potent inhibitor of taurocholate uptake by rat Na(+)-dependent taurocholate co-transporting polypeptide (Ntcp/Slc10a1) (IC(50) 0.71 microM) than human NTCP (SLC10A1) (IC(50) 24 microM) expressed in HEK293 cells. Thus, bosentan is a more potent inhibitor of Ntcp than NTCP, and this should result in less intrahepatocyte accumulation of bile acids in rats during bosentan treatment. To begin characterization of this species difference, two chimeric molecules were generated and expressed in HEK293 cells; NTCP(1-140)/Ntcp(141-362) and Ntcp(1-140)/NTCP(141-349). The mode of bosentan inhibition was noncompetitive for Ntcp, and competitive for NTCP (K(i) 18 microM) and NTCP(1-140)/Ntcp(141-362) (K(i) 1.7 microM); bosentan affected both the K(m) and V(max) of Ntcp(1-140)/NTCP(141-349) (K(i) 7.0 microM). The carboxyl portions of NTCP and Ntcp were found to confer species differences in basal taurocholate transport V(max). In conclusion, differential inhibition of Ntcp and NTCP may represent a novel mechanism for species differences in bosentan-induced hepatotoxicity.

Protective effect of ganodermanondiol isolated from the Lingzhi mushroom against tert-butyl hydroperoxide-induced hepatotoxicity through Nrf2-mediated antioxidant enzymes.

PubMed

Li, Bin; Lee, Dong-Sung; Kang, Yue; Yao, Nai-Qi; An, Ren-Bo; Kim, Youn-Chul

2013-03-01

Ganodermanondiol, a biologically active compound, was isolated from the Lingzhi mushroom (Ganoderma lucidum). The present study examined the protective effects of ganodermanondiol against tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity. Ganodermanondiol protected human liver-derived HepG2 cells through nuclear factor-E2-related factor 2 (Nrf2) pathway-dependent heme oxygenase-1 expressions. Moreover, ganodermanondiol increased cellular glutathione levels and the expression of the glutamine-cysteine ligase gene in a dose-dependent manner. Furthermore, ganodermanondiol exposure enhanced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its upstream kinase activators, LKB1 and Ca(2+)/calmodulin-dependent protein kinase-II (CaMKII). This study indicates that ganodermanondiol exhibits potent cytoprotective effects on t-BHP-induced hepatotoxicity in human liver-derived HepG2 cells, presumably through Nrf2-mediated antioxidant enzymes and AMPK. Copyright © 2012 Elsevier Ltd. All rights reserved.

Color visualization of cyclic magnitudes

NASA Astrophysics Data System (ADS)

Restrepo, Alfredo; Estupiñán, Viviana

2014-02-01

We exploit the perceptual, circular ordering of the hues in a technique for the visualization of cyclic variables. The hue is thus meaningfully used for the indication of variables such as the azimuth and the units of the measurement of time. The cyclic (or circular) variables may be both of the continuous type or the discrete type; among the first there is azimuth and among the last you find the musical notes and the days of the week. A correspondence between the values of a cyclic variable and the chromatic hues, where the natural circular ordering of the variable is respected, is called a color code for the variable. We base such a choice of hues on an assignment of of the unique hues red, yellow, green and blue, or one of the 8 even permutations of this ordered list, to 4 cardinal values of the cyclic variable, suitably ordered; color codes based on only 3 cardinal points are also possible. Color codes, being intuitive, are easy to remember. A possible low accuracy when reading instruments that use this technique is compensated by fast, ludic and intuitive readings; also, the use of a referential frame makes readings precise. An achromatic version of the technique, that can be used by dichromatic people, is proposed.

Cyclic membrane separation process

DOEpatents

Nemser, Stuart M.

2005-05-03

A cyclic process for controlling environmental emissions of volatile organic compounds (VOC) from vapor recovery in storage and dispensing operations of liquids maintains a vacuum in the storage tank ullage. In the first part of a two-part cyclic process ullage vapor is discharged through a vapor recovery system in which VOC are stripped from vented gas with a selectively gas permeable membrane. In the second part, the membrane is inoperative while gas pressure rises in the ullage. In one aspect of this invention, a vacuum is drawn in the membrane separation unit thus reducing overall VOC emissions.

Measuring Cyclic Error in Laser Heterodyne Interferometers

NASA Technical Reports Server (NTRS)

Ryan, Daniel; Abramovici, Alexander; Zhao, Feng; Dekens, Frank; An, Xin; Azizi, Alireza; Chapsky, Jacob; Halverson, Peter

2010-01-01

An improved method and apparatus have been devised for measuring cyclic errors in the readouts of laser heterodyne interferometers that are configured and operated as displacement gauges. The cyclic errors arise as a consequence of mixing of spurious optical and electrical signals in beam launchers that are subsystems of such interferometers. The conventional approach to measurement of cyclic error involves phase measurements and yields values precise to within about 10 pm over air optical paths at laser wavelengths in the visible and near infrared. The present approach, which involves amplitude measurements instead of phase measurements, yields values precise to about .0.1 microns . about 100 times the precision of the conventional approach. In a displacement gauge of the type of interest here, the laser heterodyne interferometer is used to measure any change in distance along an optical axis between two corner-cube retroreflectors. One of the corner-cube retroreflectors is mounted on a piezoelectric transducer (see figure), which is used to introduce a low-frequency periodic displacement that can be measured by the gauges. The transducer is excited at a frequency of 9 Hz by a triangular waveform to generate a 9-Hz triangular-wave displacement having an amplitude of 25 microns. The displacement gives rise to both amplitude and phase modulation of the heterodyne signals in the gauges. The modulation includes cyclic error components, and the magnitude of the cyclic-error component of the phase modulation is what one needs to measure in order to determine the magnitude of the cyclic displacement error. The precision attainable in the conventional (phase measurement) approach to measuring cyclic error is limited because the phase measurements are af-

Tropical green leafy vegetables prevent garlic-induced hepatotoxicity in the rat.

PubMed

Oboh, Ganiyu

2006-01-01

Garlic (Allium sativum) is popularly consumed because of its role in the treatment and management of several diseases. However, unregulated and chronic intake of garlic can cause damage to cells through the production of free radicals. This study was carried out in order to assess the ability of some tropical green leafy vegetables (Telfairia occidentalis, Solanum macrocapon, Corchorus olitorius, Baselia alba, Cnidoscolus acontifolus, Amarantus cruentus, and Ocimum gratissimum) to prevent garlic-induced hepatotoxicity in rats. Wistar strain albino rats were fed diet containing 4% garlic along with or without 40% green leafy vegetable supplement for 14 days. Thereafter, the feeding trial was terminated, the serum of the blood was prepared, and the liver, spleen, intestine, and organ were isolated for gross pathological investigation. The results of the study revealed that there was a significant increase (P < .05) in serum glutamate-oxaloacetate transaminase (SGOT) and glutamate-pyruvate transaminase (SGPT) of the albino rats fed diet containing 4% garlic supplement when compared with the rats fed the basal diet without garlic and vegetable (40%) supplement. However, there was a significant decrease (P < .05) in the serum total protein and albumin levels in those rats. Conversely, there was a consistent significant decrease (P < .05) in the SGOT and SGPT of the rats fed diet containing garlic (4%) and T. occidentalis (40%) and C. acontifolus (40%) supplement compared with those rats fed diet containing garlic (4%) supplement, while there were no consistent significant decrease in those rats fed diet with garlic (4%) alongside with 40% of other leafy vegetables (S. macrocanum, C. olitorius, B. alba, A. cruentus, and O. gratissimum). An increase in serum level of total protein and albumin was also observed in the rats fed T. occidentalis and C. acontifolus. Thus, T. occidentalis and C. acontifolus proved to be better vegetables in preventing garlic

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cui, Ruibing; Yan, Lihui; Luo, Zheng

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 hmore » 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.« less

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

PubMed

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 (p<0.05 each) On histological examination of group B, the normal hepatic architecture was distorted with loss of classically arranged hepatic cords. Vascular congestion was present with centrilobular necrosis, marked by pyknotic nuclei and vacuoles. Acetaminophen is hepatotoxic and methanolic extract of pomegranate peel ameliorated the hepatic picture probably because of its antioxidant properties.

Rhodium-Catalyzed Dehydrogenative Borylation of Cyclic Alkenes

PubMed Central

Kondoh, Azusa; Jamison, Timothy F.

2010-01-01

A rhodium-catalyzed dehydrogenative borylation of cyclic alkenes is described. This reaction provides direct access to cyclic 1-alkenylboronic acid pinacol esters, useful intermediates in organic synthesis. Suzuki-Miyaura cross-coupling applications are also presented. PMID:20107646

Modulatory effects of some natural products on hepatotoxicity induced by combination of sodium valproate and paracetamol in rats.

PubMed

Zaky, Hanan S; Gad, Amany M; Nemr, Ekram; Hassan, Wedad; Abd El-Raouf, Ola M; Ali, Aza A

2018-05-25

Possible hepatoprotective effect of Curcuma longa and/or Nigella sativa against hepatotoxicity induced by coadministration of sodium valproate (SV) and paracetamol was studied. Rats were divided into 10 groups, control groups 1, 2, 3, and 4 received vehicles, C. longa (200 mg/kg, p.o.), N. sativa (250 mg/kg, p.o.), or both herbs for 21 days, respectively. Toxicity groups 5, 6, and 7 received SV (300 mg/kg, i.p.), paracetamol (1000 mg/kg, p.o.) for the last 4 days or both for 21 days, respectively. Protection groups 8, 9, and 10 received C. longa, N. sativa, or both, respectively, 1 h before the administration of both the drugs for 21 days. SV and/or paracetamol significantly increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, relative liver/body weight ratio, malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), and caspase-3 (Casp-3) while significantly decreased albumin, total protein, glutathione (GSH) reduced, GSH peroxidase, and superoxide dismutase (SOD). Preadministration of C. longa and/or N. sativa caused protective effect against the hepatotoxicity induced by both drugs. © 2018 Wiley Periodicals, Inc.

Cyclically optimized electrochemical processes

NASA Astrophysics Data System (ADS)

Ruedisueli, Robert Louis

It has been frequently observed in experiment and industry practice that electrochemical processes (deposition, dissolution, fuel cells) operated in an intermittent or cyclic (AC) mode show improvements in efficiency and/or quality and yield over their steady (DC) mode of operation. Whether rationally invoked by design or empirically tuned-in, the optimal operating frequency and duty cycle is dependent upon the dominant relaxation time constant for the process in question. The electrochemical relaxation time constant is a function of: double-layer and reaction intermediary pseudo-capacitances, ion (charge) transport via electrical migration (mobility), and diffusion across a concentration gradient to electrode surface reaction sites where charge transfer and species incorporation or elimination occurs. The rate determining step dominates the time constant for the reaction or process. Electrochemical impedance spectroscopy (EIS) and piezoelectric crystal electrode (PCE) response analysis have proven to be useful tools in the study and identification of reaction mechanisms. This work explains and demonstrates with the electro-deposition of copper the application of EIS and PCE measurement and analysis to the selection of an optimum cyclic operating schedule, an optimum driving frequency for efficient, sustained cyclic (pulsed) operation.

Protective Effect of Boiled and Freeze-dried Mature Silkworm Larval Powder Against Diethylnitrosamine-induced Hepatotoxicity in Mice.

PubMed

Cho, Jae-Min; Kim, Kee-Young; Ji, Sang-Deok; Kim, Eun-Hee

2016-09-01

Hepatocellular carcinoma (HCC) is a representative inflammation-associated cancer and known to be the most frequent tumors. HCC may also induce important pro- and anti-tumor immune reactions. However, the underlying mechanisms are unsatisfactorily identified. We investigated the protective effect of boiled and freeze-dried mature silkworm larval powder (BMSP) on diethylnitrosamine (DEN)-induced hepatotoxicity in mice. Mice were fed with diet containing BMSP (0.1, 1, and 10 g/kg) for two weeks and DEN (100 mg/kg, intraperitoneally) was injected 18 hours before the end of this experiment. Liver toxicity was determined in serum and histopathological examination was assessed in the liver tissues. Infiltration of immune cells and expressions of inflammatory cytokines and chemokines were also examined. Pretreatment with BMSP reduced necrotic and histopathological changes induced by DEN in the liver. Measurement of serum biochemical indicators, the levels of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase, showed that pretreatment with BMSP also decreased DEN-induced hepatotoxicity. In addition, BMSP inhibited the macrophage and CD31 infiltration in a dose-dependent manner. The expressions of interleukin-1β, IFN-γ and chemokines for T cell activation were decreased in BMSP pretreatment groups. BMSP may have a protective effect against acute liver injury by inhibiting necrosis and inflammatory response in DEN-treated mice.

New perspectives in cyclic nucleotide-mediated functions in the CNS: the emerging role of cyclic nucleotide-gated (CNG) channels.

PubMed

Podda, Maria Vittoria; Grassi, Claudio

2014-07-01

Cyclic nucleotides play fundamental roles in the central nervous system (CNS) under both physiological and pathological conditions. The impact of cAMP and cGMP signaling on neuronal and glial cell functions has been thoroughly characterized. Most of their effects have been related to cyclic nucleotide-dependent protein kinase activity. However, cyclic nucleotide-gated (CNG) channels, first described as key mediators of sensory transduction in retinal and olfactory receptors, have been receiving increasing attention as possible targets of cyclic nucleotides in the CNS. In the last 15 years, consistent evidence has emerged for their expression in neurons and astrocytes of the rodent brain. Far less is known, however, about the functional role of CNG channels in these cells, although several of their features, such as Ca(2+) permeability and prolonged activation in the presence of cyclic nucleotides, make them ideal candidates for mediators of physiological functions in the CNS. Here, we review literature suggesting the involvement of CNG channels in a number of CNS cellular functions (e.g., regulation of membrane potential, neuronal excitability, and neurotransmitter release) as well as in more complex phenomena, like brain plasticity, adult neurogenesis, and pain sensitivity. The emerging picture is that functional and dysfunctional cyclic nucleotide signaling in the CNS has to be reconsidered including CNG channels among possible targets. However, concerted efforts and multidisciplinary approaches are still needed to get more in-depth knowledge in this field.

Modulatory Effect of Methanol Extract of Piper guineense in CCl₄-Induced Hepatotoxicity in Male Rats.

PubMed

Oyinloye, Babatunji Emmanuel; Osunsanmi, Foluso Oluwagbemiga; Ajiboye, Basiru Olaitan; Ojo, Oluwafemi Adeleke; Kappo, Abidemi Paul

2017-08-24

This study seeks to investigate the possible protective role of the methanol extract of Piper guineense seeds against CCl₄-induced hepatotoxicity in an animal model. Hepatotoxicity was induced by administering oral doses of CCl₄ (1.2 g/kg bw) three times a week for three weeks. Group 1 (Control) and Group 2 (CCl₄) were left untreated; Piper guineense (PG; 400 mg/kg bw) was administered to Group 3 (T₁) by oral gavage for 14 days prior to the administration of CCl₄ and simultaneously with CCl₄; PG (400 mg/kg bw) was administered simultaneously with CCl₄ in Group 4 (T₂); and Livolin forte (20 mg/kg bw) was administered simultaneously with CCl₄ in Group 5 (T₃), the standard drug group. The administration of CCl₄ induces histopathological alteration in the liver, with concomitant increased activities of serum hepatic marker enzymes associated with increased levels of lipid peroxidation. Similarly, there was decrease in non-enzymatic (reduced glutathione) and enzymatic antioxidants (glutathione S-transferase), superoxide dismutase, and catalase. An elevation in serum triglyceride and total cholesterol levels was noticed along with decreased levels of serum total protein. Treatment with PG 400 mg/kg bw exhibited excellent modulatory activity with respect to the different parameters studied by reversing all the above-mentioned biochemical changes significantly in the experimental animals. These results suggest that PG offered protection comparable to that of Livolin forte with better efficacy when pre-treated with 400 mg/kg bw 14 days prior to CCl₄-exposure.

Evaluation of a High-Throughput Peptide Reactivity Format Assay for Assessment of the Skin Sensitization Potential of Chemicals

PubMed Central

Wong, Chin Lin; Lam, Ai-Leen; Smith, Maree T.; Ghassabian, Sussan

2016-01-01

The direct peptide reactivity assay (DPRA) is a validated method for in vitro assessment of the skin sensitization potential of chemicals. In the present work, we describe a peptide reactivity assay using 96-well plate format and systematically identified the optimal assay conditions for accurate and reproducible classification of chemicals with known sensitizing capacity. The aim of the research is to ensure that the analytical component of the peptide reactivity assay is robust, accurate, and reproducible in accordance with criteria that are used for the validation of bioanalytical methods. Analytical performance was evaluated using quality control samples (QCs; heptapeptides at low, medium, and high concentrations) and incubation of control chemicals (chemicals with known sensitization capacity, weak, moderate, strong, extreme, and non-sensitizers) with each of three synthetic heptapeptides, viz Cor1-C420 (Ac-NKKCDLF), cysteine- (Ac-RFAACAA), and lysine- (Ac-RFAAKAA) containing heptapeptides. The optimal incubation temperature for all three heptapeptides was 25°C. Apparent heptapeptide depletion was affected by vial material composition. Incubation of test chemicals with Cor1-C420, showed that peptide depletion was unchanged in polypropylene vials over 3-days storage in an autosampler but this was not the case for borosilicate glass vials. For cysteine-containing heptapeptide, the concentration was not stable by day 3 post-incubation in borosilicate glass vials. Although the lysine-containing heptapeptide concentration was unchanged in both polypropylene and borosilicate glass vials, the apparent extent of lysine-containing heptapeptide depletion by ethyl acrylate, differed between polypropylene (24.7%) and glass (47.3%) vials. Additionally, the peptide-chemical complexes for Cor1-C420-cinnamaldehyde and cysteine-containing heptapeptide-2, 4-dinitrochlorobenzene were partially reversible during 3-days of autosampler storage. These observations further highlight

Protective and prophylactic effects of chlorogenic acid on aluminum-induced acute hepatotoxicity and hematotoxicity in mice.

PubMed

Cheng, Dai; Zhang, Xinyu; Xu, Lihan; Li, Xiang; Hou, Lihua; Wang, Chunling

2017-08-01

The possible health impact of the exposures to Al from environment would be inevitable for humans. Using chelating agents and natural antioxidants against Al-induced biotoxicity become a natural and modern way to prevent the adverse effects of Al in people. This study was undertaken to determine the effectiveness of chlorogenic acid (CGA, 5-O-caffeoylquinic acid) in preventing aluminum chloride (AlCl 3 ) induced hepatotoxicity and hematotoxicity in mice. Control, Al-treated (a single injection of 25 mg Al 3+ /kg, i.p.), Al + CGA (2 h after, a single dose of 100 mg/kg, i.p.), CGA + Al (administered to mice daily for 5 days at 30 mg/kg before Al-treatment) and group of CGA per se (administered to mice daily for 5 days at 30 mg/kg) were used. The levels of Al in liver and blood, the activities of transaminases in serum and osmotic fragility were increased by comparison with the control, while the activities of superoxide dismutase and catalase decreased significantly in the Al-treated group. However, treating mice with CGA at either dosing regimens, post- or pre- Al administration alleviate Al oxidative damaging effects, stabilize cell membrane, prevent hepatocyte apoptosis. CGA supplementation may be favorable to avoid Al-induced hematotoxicity and hepatotoxicity for humans. Copyright © 2017 Elsevier B.V. All rights reserved.

Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-κB and STAT3 signaling.

PubMed

Liu, Aiming; Tanaka, Naoki; Sun, Lu; Guo, Bin; Kim, Jung-Hwan; Krausz, Kristopher W; Fang, Zhongze; Jiang, Changtao; Yang, Julin; Gonzalez, Frank J

2014-11-05

Overdose of acetaminophen (APAP) can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. The traditional Chinese herb Bupleurum falcatum has been widely used for the treatment of several liver diseases in eastern Asian countries, and saikosaponin d (SSd) is one of its major pharmacologically-active components. However, the efficacy of Bupleurum falcatum or SSd on APAP toxicity remains unclear. C57/BL6 mice were administered SSd intraperitoneally once daily for 5days, followed by APAP challenge. Biochemical and pathological analysis revealed that mice treated with SSd were protected against APAP-induced hepatotoxicity. SSd markedly suppressed phosphorylation of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) and reversed the APAP-induced increases in the target genes of NF-κB, such as pro-inflammatory cytokine Il6 and Ccl2, and those of STAT3, such as Socs3, Fga, Fgb and Fgg. SSd also enhanced the expression of the anti-inflammatory cytokine Il10 mRNA. Collectively, these results demonstrate that SSd protects mice from APAP-induced hepatotoxicity mainly through down-regulating NF-κB- and STAT3-mediated inflammatory signaling. This study unveils one of the possible mechanisms of hepatoprotection caused by Bupleurum falcatum and/or SSd. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The use of cultured hepatocytes to investigate the metabolism of drugs and mechanisms of drug hepatotoxicity.

PubMed

Gómez-Lechón, M J; Ponsoda, X; Bort, R; Castell, J V

2001-01-01

Hepatotoxins can be classified as intrinsic when they exert their effects on all individuals in a dose-dependent manner, and as idiosyncratic when their effects are the consequence of an abnormal metabolism of the drug by susceptible individuals (metabolic idiosyncrasy) or of an immune-mediated injury to hepatocytes (allergic hepatitis). Some xenobiotics are electrophilic, and others are biotransformed by the liver into highly reactive metabolites that are usually more toxic than the parent compound. This activation process is the key to many hepatotoxic phenomena. Mitochondria are a frequent target of hepatotoxic drugs, and the alteration of their function has immediate effects on the energy balance of cells (depletion of ATP). Lipid peroxidation, oxidative stress, alteration of Ca(2+) homeostasis, and covalent binding to cell macromolecules are the molecular mechanisms that are frequently involved in the toxicity of xenobiotics. Against these potential hazards, cells have their own defence mechanisms (for example, glutathione, DNA repair, suicide inactivation). Ultimately, toxicity is the balance between bioactivation and detoxification, which determines whether a reactive metabolite elicits a toxic effect. The ultimate goal of in vitro experiments is to generate the type of scientific information needed to identify compounds that are potentially toxic to man. For this purpose, both the design of the experiments and the interpretation of the results are critical.

The protective effect of Capparis ovata on 6-mercaptopurine-induced hepatotoxicity and oxidative stress in rats.

PubMed

Tülümen, Tuğçe; Ayata, Ali; Özen, Metehan; Sütçü, Recep; Canatan, Duran

2015-05-01

Capparis ovata is a member of Capparidacaeae family has been used in phytomedicine with a lot of positive effects such as an antioxidative, antihyperlipidemic, anti-inflammatory, and antihepatotoxic agent. The aim of this study was to research the protective effect of C. ovata on 6-mercaptopurine (6-MP) induced to hepatotoxicity and oxidative stress in rats. The rats were divided into 4 groups: control, 6-MP, C. ovataovate, and 6-MP + C. ovata. A complete blood count was performed, liver function test and antioxidant enzymes levels such as superoxide dismutase, glutathione peroxidase, catalase, and malondialdehyde were measured in blood before and after a 14-day test period. White blood cell and platelet counts were lower in the 6-MP group than other 3 groups (P < 0.005). Hepatic transaminase levels were higher in 6-MP group than the 3 groups (P < 0.05). Superoxide dismutase, glutathione peroxidase, and CAT levels were lower and malondialdehyde was higher in blood samples in 6-MP group than other 3 groups (P < 0.005). In conclusion, our tests were showed that C. ovata may be useful in patients receiving 6-MP therapy to prevent hepatotoxicity and in order to maintain uninterrupted therapy possibly reducing the risk of relapse. Although additional studies ensure that Capparis does not affect 6-MP antileukemic activity. We believe these results are important contribution to the literature.

Structure of a eukaryotic cyclic nucleotide-gated channel

PubMed Central

Li, Minghui; Zhou, Xiaoyuan; Wang, Shu; Michailidis, Ioannis; Gong, Ye; Su, Deyuan; Li, Huan; Li, Xueming; Yang, Jian

2018-01-01

Summary Cyclic nucleotide-gated (CNG) channels are essential for vision and olfaction. They belong to the voltage-gated ion channel superfamily but their activities are controlled by intracellular cyclic nucleotides instead of transmembrane voltage. Here we report a 3.5 Å-resolution single-particle electron cryomicroscopy structure of a CNG channel from C. elegans in the cGMP-bound open state. The channel has an unusual voltage-sensor-like domain (VSLD), accounting for its deficient voltage dependence. A C-terminal linker connecting S6 and the cyclic nucleotide-binding domain interacts directly with both the VSLD and pore domain, forming a gating ring that couples conformational changes triggered by cyclic nucleotide binding to the gate. The selectivity filter is lined by the carboxylate side chains of a functionally important glutamate and three rings of backbone carbonyls. This structure provides a new framework for understanding mechanisms of ion permeation, gating and channelopathy of CNG channels and cyclic nucleotide modulation of related channels. PMID:28099415

Dietary α-Mangostin Provides Protective Effects against Acetaminophen-Induced Hepatotoxicity in Mice via Akt/mTOR-Mediated Inhibition of Autophagy and Apoptosis.

PubMed

Yan, Xiao-Tong; Sun, Yin-Shi; Ren, Shen; Zhao, Li-Chun; Liu, Wen-Cong; Chen, Chen; Wang, Zi; Li, Wei

2018-05-01

Acetaminophen overdose-induced hepatotoxicity is the most common cause of acute liver failure in many countries. Previously, alpha-mangostin (α-MG) has been confirmed to exert protective effects on a variety of liver injuries, but the protective effect on acetaminophen-induced acute liver injury (ALI) remains largely unknown. This work investigated the regulatory effect and underlying cellular mechanisms of α-MG action to attenuate acetaminophen-induced hepatotoxicity in mice. The increased serum aminotransferase levels and glutathione (GSH) content and reduced malondialdehyde (MDA) demonstrated the protective effect of α-MG against acetaminophen-induced hepatotoxicity. In addition, α-MG pretreatment inhibited increases in tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) caused by exposure of mice to acetaminophen. In liver tissues, α-MG inhibited the protein expression of autophagy-related microtubule-associated protein light chain 3 (LC3) and BCL2/adenovirus E1B protein-interacting protein 3 (BNIP3). Western blotting analysis of liver tissues also proved evidence that α-MG partially inhibited the activation of apoptotic signaling pathways via increasing the expression of Bcl-2 and decreasing Bax and cleaved caspase 3 proteins. In addition, α-MG could in part downregulate the increase in p62 level and upregulate the decrease in p-mTOR, p-AKT and LC3 II /LC3 I ratio in autophagy signaling pathways in the mouse liver. Taken together, our findings proved novel perspectives that detoxification effect of α-MG on acetaminophen-induced ALI might be due to the alterations in Akt/mTOR pathway in the liver.

Cyclic Voltammetry Experiment.

ERIC Educational Resources Information Center

Van Benschoten, James J.; And Others

1983-01-01

Describes a three-part experiment designed to introduce cyclic voltammetry to graduate/undergraduate students. Part 1 demonstrates formal reduction potential, redox electron transfer, diffusion coefficient, and electrochemical reversibility. Part 2 investigates electrochemical behavior of acetaminophen. Part 3 examines such experimental variables…

Strain controlled cyclic tests on miniaturized specimens

NASA Astrophysics Data System (ADS)

Procházka, R.; Džugan, J.

2017-02-01

The paper is dealing with strain controlled cyclic tests using a non-contact strain measurement based on digital image correlation techniques on proportional sizes of conventional specimens. The cyclic behaviour of 34CrNiMo6 high-strength steel was investigated on miniaturized round specimens with diameter of 2mm that were compared with specimens in accordance with ASTM E606 standards. The cycle asymmetry coefficient was R= -1. This application is intended to be used for life time assessment of in service components in future work which enables to carried out a group of mechanical tests from a limited amount of the experimental material. The attention was paid to confirm the suitability of the proposed size miniaturization geometry, testing set up and procedure. The test results obtained enabled to construct Manson-Coffin curves and assess fatigue parameters. The purpose of this study is to present differences between cyclic curves and cyclic parameters which have been evaluated based on conventional and miniaturized specimens.

Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Dan; Wu, Chun-qi; Li, Ze-jun

Objective: To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. Methods: Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50 μM) for 48 h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrialmore » respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p < 0.05. Results: Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. Conclusion: All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles. - Highlights: • We compared three TZD mitochondrial toxicity characteristics in HepaRG cells. • TZD induced respiratory disorders and mitochondrial structural damage. • Mitochondrial toxicity evaluation presents guidance value for

Urate synthesis and oxidative stress in phenytoin hepatotoxicity: the role of antioxidant vitamins.

PubMed

Ekaidem, Itemobong S; Usoh, Itoro F; Akpanabiatu, Monday I; Uboh, Friday E; Akpan, Henry D

2014-11-01

Phenytoin is known to induce microsomal enzymes including xanthine oxidase which catalyzes uric acid synthesis with superoxides as byproducts, thus contributing to the oxidative stress of phenytoin hepatotoxicity. To investigate the role of antioxidant vitamins in ameliorating phenytoin induced hepatic changes through possible actions on xanthine oxidase activities as measured by urate concentration. Growing albino rats of Wistar strain were randomly divided into 8 groups of 7 rats each. Group 2, 3, 4, 5, 6, 7 and 8 were treated with phenytoin alone, phenytoin + folic acid, phenytoin + vitamin E, phenytoin + vitamin E + vitamin C, phenytoin + vitamin C, phenytoin + folic acid + vitamin E and phenytoin + vitamin E + vitamin C + folic acid respectively while animals in group 1 were given normal saline to serve as control. Serum concentrations of uric acid, albumin, total protein and the activities of aspartate and alanine aminotransferases (AST and ALT) and catalase were measured spectrophotometrically using appropriate commercial reagent kits. Result showed that administration of phenytoin alone caused significant (p < 0.05) increase in serum levels of globulin, uric acid, AST and ALT activities while the levels of albumin and catalase were reduced significantly (p < 0.05). Supplementation of phenytoin treatment with vitamins resulted in various degrees of protection. However, the elevated level of uric acid in serum was not significantly (p < 0.05) affected by any of the vitamins used and there was no significant correlation between the activities of aminotransferases and uric acid concentration in the vitamin treated animals as was observed between aminotransferases and catalase. The findings in this study suggest that antioxidant vitamins were able to ameliorate phenytoin hepatotoxic effects by improving oxidant radicals removal in the animals but would not inhibit further generation of the superoxides by xanthine oxidase activity and that xanthine oxidase may

Cyclic multiverses

NASA Astrophysics Data System (ADS)

Marosek, Konrad; Dąbrowski, Mariusz P.; Balcerzak, Adam

2016-09-01

Using the idea of regularization of singularities due to the variability of the fundamental constants in cosmology we study the cyclic universe models. We find two models of oscillating and non-singular mass density and pressure (`non-singular' bounce) regularized by varying gravitational constant G despite the scale factor evolution is oscillating and having sharp turning points (`singular' bounce). Both violating (big-bang) and non-violating (phantom) null energy condition models appear. Then, we extend this idea on to the multiverse containing cyclic individual universes with either growing or decreasing entropy though leaving the net entropy constant. In order to get an insight into the key idea, we consider the doubleverse with the same geometrical evolution of the two `parallel' universes with their physical evolution [physical coupling constants c(t) and G(t)] being different. An interesting point is that there is a possibility to exchange the universes at the point of maximum expansion - the fact which was already noticed in quantum cosmology. Similar scenario is also possible within the framework of Brans-Dicke theory where varying G(t) is replaced by the dynamical Brans-Dicke field φ(t) though these theories are slightly different.

Estimation of Cyclic Shift with Delayed Correlation and Matched Filtering in Time Domain Cyclic-SLM for PAPR Reduction

PubMed Central

2016-01-01

Time domain cyclic-selective mapping (TDC-SLM) reduces the peak-to-average power ratio (PAPR) in OFDM systems while the amounts of cyclic shifts are required to recover the transmitted signal in a receiver. One of the critical issues of the SLM scheme is sending the side information (SI) which reduces the throughputs in wireless OFDM systems. The proposed scheme implements delayed correlation and matched filtering (DC-MF) to estimate the amounts of the cyclic shifts in the receiver. In the proposed scheme, the DC-MF is placed after the frequency domain equalization (FDE) to improve the accuracy of cyclic shift estimation. The accuracy rate of the propose scheme reaches 100% at E b/N 0 = 5 dB and the bit error rate (BER) improves by 0.2 dB as compared with the conventional TDC-SLM. The BER performance of the proposed scheme is also better than that of the conventional TDC-SLM even though a nonlinear high power amplifier is assumed. PMID:27752539

Cyclic behavior at quasi-parallel collisionless shocks

NASA Technical Reports Server (NTRS)

Burgess, D.

1989-01-01

Large scale one-dimensional hybrid simulations with resistive electrons have been carried out of a quasi-parallel high-Mach-number collisionless shock. The shock initially appears stable, but then exhibits cyclic behavior. For the magnetic field, the cycle consists of a period when the transition from upstream to downstream is steep and well defined, followed by a period when the shock transition is extended and perturbed. This cyclic shock solution results from upstream perturbations caused by backstreaming gyrating ions convecting into the shock. The cyclic reformation of a sharp shock transition can allow ions, at one time upstream because of reflection or leakage, to contribute to the shock thermalization.

Chloroform ingestion causing severe gastrointestinal injury, hepatotoxicity and dermatitis confirmed with plasma chloroform concentrations.

PubMed

Jayaweera, Dushan; Islam, Shawkat; Gunja, Naren; Cowie, Chris; Broska, James; Poojara, Latesh; Roberts, Michael S; Isbister, Geoffrey K

2017-02-01

Poisoning due to chloroform ingestion is rare. The classic features of acute chloroform toxicity include central nervous system (CNS) and respiratory depression, and delayed hepatotoxicity. A 30-year-old female ingested 20-30 mL of 99% chloroform solution, which caused rapid loss of consciousness, transient hypotension and severe respiratory depression requiring endotracheal intubation and ventilation. She was alert by 12 h and extubated 16 h post-overdose. At 38-h post-ingestion, her liver function tests started to rise and she was commenced on intravenous acetylcysteine. Her alanine transaminase (1283 U/L), aspartate transaminase (734 U/L) and international normalized ratio (2.3) peaked 67- to 72-h post-ingestion. She also developed severe abdominal pain, vomiting and diarrhoea. An abdominal CT scan was consistent with severe enterocolitis, and an upper gastrointestinal endoscopy showed erosive oesophagitis, severe erosive gastritis and ulceration. She was treated with opioid analgesia, proton pump inhibitors, sucralfate and total parenteral nutrition. Secretions caused a contact dermatitis of her face and back. Nine days post-ingestion she was able to tolerate food. Her liver function tests normalized and the dermatitis resolved. Chloroform was measured using headspace gas chromatograph mass spectrometry, with a peak concentration of 2.00 μg/mL, 4 h 20 min post-ingestion. The concentration-time data fitted a 1-compartment model with elimination half-life 6.5 h. In addition to early CNS depression and delayed hepatotoxicity, we report severe gastrointestinal injury and dermatitis with chloroform ingestion. Recovery occurred with good supportive care, acetylcysteine and management of gastrointestinal complications.

Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats

PubMed Central

El-Hosseiny, L. S.; Alqurashy, N. N.; Sheweita, S. A.

2016-01-01

Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats’ liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes’ activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition. PMID:27493593

The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats.

PubMed

Gelen, Volkan; Şengül, Emin; Yıldırım, Serkan; Atila, Gözde

2018-04-01

5-fluorouracil-induced (5-FU), an anticarcinogenic agent, is reported to have side-effects that include hepatotoxicity and nephrotoxicity. The study objective was to investigate the protective effects of naringin on 5-FU-induced hepatotoxicity and nephrotoxicity. Thirty rodents were assigned to three groups. The control group received 1 ml of intragastric distilled water for 14 days. The 5-FU group received 1 ml of distilled water for 14 days as a placebo. On day 9, this same group received a 20 mg/kg dose of 5-FU administered intraperitoneally(IP) for a further five days. The naringin+5-FU group received a 100 mg/kg dose of naringin (IP) for 14 days. On day 9, 20 mg/kg of 5-FU was administered (IP) to this group for a further five days. On day 15, the rats were decapitated, and blood and renal and hepatic tissues were taken. It was determined that serum creatinine, BUN, AST, ALT, ALP, and LDH levels, as well as cytokine levels in the liver and kidney tissues were significantly elevated in the 5-FU group, compared to the control group. The comparative values were similar in the control and naringin+5-FU groups. When the liver tissue was examined histopathologically, in the control group it was found to be normal in structure. However, necrosis was observed in the hepatocytes of the pericentric region in the 5-FU group. 8-OHdG cell density was significantly elevated in the 5-FU group, compared to the control and naringin+5-FU groups. Naringin was observed to have a protective effect on 5-FU-induced liver and kidney damage.

Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats.

PubMed

El-Hosseiny, L S; Alqurashy, N N; Sheweita, S A

2016-06-01

Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats' liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes' activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition.

Plasma metabolomics study of the hepatoprotective effect of glycyrrhetinic acid on realgar-induced sub-chronic hepatotoxicity in mice via 1H NMR analysis.

PubMed

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.

Microcystins from tap water could be a risk factor for liver and colorectal cancer: a risk intensified by global change.

PubMed

Martínez Hernández, Juan; López-Rodas, V; Costas, E

2009-05-01

An increasing number of people drink water from fresh water supply reservoirs. However, with the global change a lot of reservoirs become eutrophic, which facilitates the occurrence of toxin-producing cyanobacterial blooms. Microcystins (powerful hepatotoxic water-soluble heptapeptides) are the most important cyanobacterial toxins affecting humans. High doses of microcystins produce hepatic necrosis. Consequently, WHO Guidelines limit microcystins to 1 ppb in drinking waters. However, microcystins are present frequently in tap water at lower doses. Here, we hypothesized that chronic consume of tap water containing low doses of microcystins may be a risk factor for liver and colorectal cancer. Two kinds of evidences support this hypothesis. On one hand some epidemiological data (mainly in China). On the other hand, the molecular mechanism of microcystins toxicity (inhibition of protein phosphatases PP1 and PP2) is just like okadaic acid (a potent tumor promoter). Cancer risk from drinking water is certainly less than smoking, occupational exposures or some foods. But it is significant and with a rapid increase of toxic cyanobacterial blooms by eutrophycation, become more frequent.

Caspase-Mediated Anti-Apoptotic Effect of Ginsenoside Rg5, a Main Rare Ginsenoside, on Acetaminophen-Induced Hepatotoxicity in Mice.

PubMed

Wang, Zi; Hu, Jun-Nan; Yan, Meng-Han; Xing, Jing-Jing; Liu, Wen-Cong; Li, Wei

2017-10-25

Frequent overdose of acetaminophen (APAP) is one of the most common and important incentives of acute hepatotoxicity. Prior to this work, our research group confirmed that black ginseng (Panax ginseng, BG) showed powerful protective effects on APAP-induced ALI. However, it is not clear which kind of individual ginsenoside from BG plays such a liver protection effect. The objective of the current investigation was to evaluate whether ginsenoside Rg5 (G-Rg5) protected against APAP-induced hepatotoxicity and the involved action mechanisms. Mice were administrated with G-Rg5 at two dosages of 10 or 20 mg/kg for 7 consecutive days. After the last treatment, all of the animals that received a single intraperitoneal injection of APAP (250 mg/kg) showed severe liver toxicity after 24 h, and the liver protection effects of G-Rg5 were examined. The results clearly indicated that pretreatment with G-Rg5 remarkably inhibited the production of serum tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) compared with the APAP group. Meanwhile, G-Rg5 decreased the hepatic malondialdehyde (MDA) content, the protein expression levels of 4-hydroxynonenal (4-HNE) and cytochrome P450 2E1 (CYP2E1) in the liver tissues. G-Rg5 decreased APAP caused the hepatic overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Furthermore, analysis of immunohistochemistry and Western blotting also indicated that G-Rg5 pretreatment inhibited activation of apoptotic pathways mainly via increasing the expression of Bcl-2 protein, decreasing the expression of Bax protein, proliferating cell nuclear antigen (PCNA), cytochrome c, caspase-3, caspase-8, and caspase-9. Liver histopathological observation provided further evidence that pretreatment with G-Rg5 could significantly inhibit hepatocyte necrosis, inflammatory cell infiltration, and apoptosis caused by APAP. In conclusion, the present study clearly demonstrates that G-Rg5 exerts a liver protection effect against

Protective Effect of Propolis in Proteinuria, Crystaluria, Nephrotoxicity and Hepatotoxicity Induced by Ethylene Glycol Ingestion.

PubMed

El Menyiy, Nawal; Al Waili, Noori; Bakour, Meryem; Al-Waili, Hamza; Lyoussi, Badiaa

2016-10-01

Propolis is a natural honeybee product with wide biological activities and potential therapeutic properties. The aim of the study is to evaluate the protective effect of propolis extract on nephrotoxicity and hepatotoxicity induced by ethylene glycol in rats. Five groups of rats were used. Group 1 received drinking water, group 2 received 0.75% ethylene-glycol in drinking water, group 3 received 0.75% ethylene-glycol in drinking water along with cystone 500 mg/kg/body weight (bw) daily, group 4 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 100 mg/kg/bw daily, and group 5 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 250 mg/kg/bw daily. The treatment continued for a total of 30 d. Urinalyses for pH, crystals, protein, creatinine, uric acid and electrolytes, and renal and liver function tests were performed. Ethylene-glycol increased urinary pH, urinary volume, and urinary calcium, phosphorus, uric acid and protein excretion. It decreased creatinine clearance and magnesium and caused crystaluria. Treatment with propolis extract or cystone normalized the level of magnesium, creatinine, sodium, potassium and chloride. Propolis is more potent than cystone. Propolis extract alleviates urinary protein excretion and ameliorates the deterioration of liver and kidney function caused by ethylene glycol. Propolis extract has a potential protective effect against ethylene glycol induced hepatotoxicity and nephrotoxicity and has a potential to treat and prevent urinary calculus, crystaluria and proteinuria. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection is Associated with Induction of Flavin-containing Monooxygenase-3 (FMO3) in Hepatocytes

EPA Science Inventory

Acetaminophen (APAP) pretreatment with a low hepatotoxic dose in mice results in resistance to a second, higher dose of APAP (APAP autoprotection). Recent microarray work by our group showed a drastic induction of liver flavin containing monooxygenase-3 (Fmo3) mRNA expression in...

Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia.

PubMed

Ramachandran, Balaji; Jayavelu, Subramani; Murhekar, Kanchan; Rajkumar, Thangarajan

2016-01-01

EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

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

PubMed Central

Olayinka, Ebenezer Tunde

2015-01-01

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. PMID:26550491

High-Temperature Cyclic Oxidation Data, Volume 1

NASA Technical Reports Server (NTRS)

Barrett, C. A.; Garlick, R. G.; Lowell, C. E.

1984-01-01

This first in a series of cyclic oxidation handbooks contains specific-weight-change-versus-time data and X-ray diffraction results derived from high-temperature cyclic tests on high-temperature, high-strength nickel-base gamma/gamma' and cobalt-base turbine alloys. Each page of data summarizes a complete test on a given alloy sample.

Safety Discrete Event Models for Holonic Cyclic Manufacturing Systems

NASA Astrophysics Data System (ADS)

Ciufudean, Calin; Filote, Constantin

In this paper the expression “holonic cyclic manufacturing systems” refers to complex assembly/disassembly systems or fork/join systems, kanban systems, and in general, to any discrete event system that transforms raw material and/or components into products. Such a system is said to be cyclic if it provides the same sequence of products indefinitely. This paper considers the scheduling of holonic cyclic manufacturing systems and describes a new approach using Petri nets formalism. We propose an approach to frame the optimum schedule of holonic cyclic manufacturing systems in order to maximize the throughput while minimize the work in process. We also propose an algorithm to verify the optimum schedule.

Distribution in Rats Internal Organs of Intraperitoneally Given 125I-Labeled Heptapeptide [2-8]-Leucopyrokinin ([2-8]-LPK), a Truncated Analog of Insect Neuropeptide Leucopyrokinin.

PubMed

Ryszka, Florian; Dolińska, Barbara; Suszka-Świtek, Aleksandra; Rykaczewska-Czerwińska, Monika; Konopińska, Danuta; Kuczer, Mariola; Plech, Andrzej

2015-01-01

It was previously found that synthetic, insect-derived octapeptide leucopyrokinin (LPK) applied directly into the lateral brain ventricle induced a significant antinociceptive effect in rats. Its synthetic truncated analog heptapeptide [2-8]-leucopyrokinin displayed a stronger antinociceptive effect in comparison to native LPK. Moreover it was previously found a high accumulation of these both 125I-labeled peptides in adrenals, as well as in hypothalamus and in hippocampus of rats brain. The aim of the present study was to assess the distribution of 125I-labeled [2-8]-leucopyrokinin in rats' internal organs an in several parts of the brain after peripheral - intraperitoneal (i.p.) administration. The study was performed on male Wistar rats. A synthetic [2-8]-leucopyrokinin ([2-8]-LPK) was iodinated with Na125I. On the day of experiment a solution of 125I-[2-8]-LPK was i.p. injected and the next after 1 and 24 h animals were sacrificed by decapitation. Radioactivity levels in samples of parts of the brain and of internal organs were determined by counter Gamma Auto Count. A uniform, low accumulation 125I-[2-8]-LPK was found in evaluated samples of the brain and in internal organs. The results of the present study indicate a weak penetration into the brain and internal organs of intraperitoneally applied 125I-[2-8]-LPK in rats and correspond with previously determined weak biological effects of i.p. injected LPK and [2-8]-LPK.

Acute Hepatotoxicity After Ingestion of Morinda citrifolia (Noni Berry) Juice in a 14-year-old Boy

PubMed Central

Yu, Elizabeth L.; Sivagnanam, Mamata; Ellis, Linda; Huang, Jeannie S.

2017-01-01

Morinda citrifolia, commonly known as the noni berry, is a tropical fruit that has been used for more than 2000 years as a Polynesian herbal remedy (1). Since 1996, it has been sold widely in the United States as a general remedy for a wide array of health problems including cancer, diabetes, HIV/AIDS, gastric ulcers, hypertension, infections, depression, and chronic fatigue (2,3). We report a case of acute hepatotoxicity after ingestion of an energy drink containing noni berries in a previously healthy 14-year-old boy. PMID:21119544

Subchronic hepatotoxicity of selenomethionine ingestion in mallard ducks

USGS Publications Warehouse

Hoffman, D.J.; Heinz, G.H.; LeCaptain, L.J.; Bunck, C.M.; Green, D.E.

1991-01-01

Twoyearold male mallards (Anas platyrhynchos) received a control diet (0.2 ppm Se) or diets containing 1, 2, 4, 8, 16, or 32 ppm Se as selenomethionine for 14 wk. Se accumulated readily in the liver in a dosedependent manner, reaching a mean concentration of 29 ppm (wet weight) in the 32 ppm group. Dietary Se of 2 ppm or greater increased plasma glutathione peroxidase activity. Mortality (10%) and histopathological effects, including bile duct hyperplasia and hemosiderin pigmentation of the liver and spleen, occurred in the 32 ppm group. These histopathological effects were accompanied by lower hemoglobin concentrations (16 and 32 ppm groups) and hematocrit (32 ppm group), and elevated plasma alkaline phosphatase activity (32 ppm group) indicative of cholestatic liver inJury. Other manifestations of hepatotoxicity included significant linear dose responses for hepatic oxidized glutathione (GSSG) concentrations and ratio of GSSG to reduced glutathione (GSH). Means for both of these responses differed from controls in groups receiving 832 ppm Se. Mean hepatic GSH and malondialdehyde (a measure of lipid peroxidation) concentrations were significantly elevated in the 16 and 32 ppm groups. Subchronic effects of selenomethionine, which occurs in vegetation, are of particular interest with respect to the health of wild aquatic birds in seleniferous locations.

Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury

PubMed Central

Gao, Yuan; Cao, Zhijun; Yang, Xi; Abdelmegeed, Mohamed A.; Sun, Jinchun; Chen, Si; Beger, Richard D.; Davis, Kelly; Salminen, William F.; Song, Byoung-Joon; Mendrick, Donna L.; Yu, Li-Rong

2017-01-01

Purpose Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury. Experimental design Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS. Results Molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose- and time-dependent manner upon APAP treatment. Imbalanced expression of hemeoxygenase 1 (HMOX1) and biliverdin reductase A (BLVRA) was associated with hepatotoxicity. Protein abundance changes of a total of 31 proteins were uniquely correlated to liver damage, among which a dramatic increase of HMOX1 levels in plasma was observed. Liver injury-associated significant elevation of plasma HMOX1 was further validated in mice treated with APAP. Conclusions and clinical relevance This study unveiled molecular changes associated with APAP-induced liver toxicity at the pathway levels and identified HMOX1 as a potential plasma biomarker of liver injury. PMID:27634590

Cyclic nucleotide binding proteins in the Arabidopsis thaliana and Oryza sativa genomes

PubMed Central

Bridges, Dave; Fraser, Marie E; Moorhead, Greg BG

2005-01-01

Background Cyclic nucleotides are ubiquitous intracellular messengers. Until recently, the roles of cyclic nucleotides in plant cells have proven difficult to uncover. With an understanding of the protein domains which can bind cyclic nucleotides (CNB and GAF domains) we scanned the completed genomes of the higher plants Arabidopsis thaliana (mustard weed) and Oryza sativa (rice) for the effectors of these signalling molecules. Results Our analysis found that several ion channels and a class of thioesterases constitute the possible cyclic nucleotide binding proteins in plants. Contrary to some reports, we found no biochemical or bioinformatic evidence for a plant cyclic nucleotide regulated protein kinase, suggesting that cyclic nucleotide functions in plants have evolved differently than in mammals. Conclusion This paper provides a molecular framework for the discussion of cyclic nucleotide function in plants, and resolves a longstanding debate about the presence of a cyclic nucleotide dependent kinase in plants. PMID:15644130

Gonadotropin level abnormalities in women with cyclic mastalgia.

PubMed

Ecochard, R; Marret, H; Rabilloud, M; Boehringer, H; Mathieu, C; Guerin, J F

2001-01-01

Women with cyclic mastalgia seem to be at risk of fibrocystic breast disease and/or breast cancer. We studied the relationships between mastalgia and hormone levels throughout the menstrual cycle. Ostensibly healthy women were monitored during a sum of 326 cycles. A case-control study compared personal and hormonal variables of 30 women experiencing cyclic mastalgia with those of 77 women without this symptom. Except sleeping times, no significant differences were found in personal variables. Cyclic mastalgia and symptoms of fluid retention were slightly associated. Menses and the luteal phase were significantly longer in cases than in controls. Gonadotropin but not ovarian hormone levels were also significantly higher in cases throughout the cycle. Cyclic mastalgia is less related to symptoms of fluid retention or to ovarian hormone levels than to regularly high gonadotropin levels, specific inhibitors might thus be used to alleviate the symptom.

Can mixtures of cyanotoxins represent a risk to the zooplankton? The case study of Daphnia magna Straus exposed to hepatotoxic and neurotoxic cyanobacterial extracts.

PubMed

Freitas, Emanuela Cristina; Pinheiro, Carlos; Rocha, Odete; Loureiro, Susana

2014-01-01

Worldwide, cyanobacterial blooms have been increasing in intensity and frequency, with toxic cyanobacteria sometimes dominant throughout the year in many freshwater bodies. Since the coexistence of more than one type of cyanotoxins in freshwater environments is a common phenomenon, studies on the joint effects of these toxins would be very useful. In this study, the single and combined effects of two cyanotoxins with different modes of action (hepatotoxic and neurotoxic) on the survival (lethal exposure) and feeding (sublethal exposure) of the cladoceran Daphnia magna were investigated. With the single exposures, it was observed that both the survival and feeding activity of the daphnids were impaired by the hepatotoxic and neurotoxic extracts at environmentally relevant concentrations. In the combined exposures, both survival and feeding rate endpoints showed a good fit to the independent action model. For the acute assay and 24h exposure period in the feeding inhibition test, there was no interaction between components of the hepatotoxic and neurotoxic extracts, although a slight tendency to a synergistic deviation could be seen in the feeding rates. On the other hand, for the 4h post-exposure period, a synergistic deviation was found in feeding rates at all mixture concentrations tested. Hence, the combined exposure of hepatotoxins and neurotoxins should also be taken into account in risk assessments of freshwater bodies, since the mixture of these toxins can result in more severe post-exposure effects on the feeding of daphnids than the sum of those expected for single exposures. Copyright © 2013 Elsevier B.V. All rights reserved.

Elevational gradient in the cyclicity of a forest-defoliating insect

Treesearch

Kyle J. Haynes; Andrew M. Liebhold; Derek M. Johnson

2012-01-01

Observed changes in the cyclicity of herbivore populations along latitudinal gradients and the hypothesis that shifts in the importance of generalist versus specialist predators explain such gradients has long been a matter of intense interest. In contrast, elevational gradients in population cyclicity are largely unexplored. We quantified the cyclicity of gypsy moth...

MICROWAVE-ASSISTED PREPARATION OF CYCLIC UREAS FROM DIAMINES

EPA Science Inventory

Rajender S. Varma* and Yong-Jin Kim
Cyclic ureas are useful intermediates for a variety of pharmaceuticals and pesticides. One of the attractive approaches for the synthesis of cyclic ureas uses condensation of diamines with urea as a carbonyl source under dynamic evacuation. ...

Pregnane X Receptor-Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity.

PubMed

Spruiell, Krisstonia; Gyamfi, Afua A; Yeyeodu, Susan T; Richardson, Ricardo M; Gonzalez, Frank J; Gyamfi, Maxwell A

2015-09-01

Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXR-humanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor α, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females. U.S. Government work not protected by U.S. copyright.

The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats

PubMed Central

Gelen, Volkan; Şengül, Emin; Yıldırım, Serkan; Atila, Gözde

2018-01-01

Objective(s): 5-fluorouracil-induced (5-FU), an anticarcinogenic agent, is reported to have side-effects that include hepatotoxicity and nephrotoxicity. The study objective was to investigate the protective effects of naringin on 5-FU-induced hepatotoxicity and nephrotoxicity. Materials and Methods: Thirty rodents were assigned to three groups. The control group received 1 ml of intragastric distilled water for 14 days. The 5-FU group received 1 ml of distilled water for 14 days as a placebo. On day 9, this same group received a 20 mg/kg dose of 5-FU administered intraperitoneally(IP) for a further five days. The naringin+5-FU group received a 100 mg/kg dose of naringin (IP) for 14 days. On day 9, 20 mg/kg of 5-FU was administered (IP) to this group for a further five days. On day 15, the rats were decapitated, and blood and renal and hepatic tissues were taken. Results: It was determined that serum creatinine, BUN, AST, ALT, ALP, and LDH levels, as well as cytokine levels in the liver and kidney tissues were significantly elevated in the 5-FU group, compared to the control group. The comparative values were similar in the control and naringin+5-FU groups. When the liver tissue was examined histopathologically, in the control group it was found to be normal in structure. However, necrosis was observed in the hepatocytes of the pericentric region in the 5-FU group. 8-OHdG cell density was significantly elevated in the 5-FU group, compared to the control and naringin+5-FU groups. Conclusion: Naringin was observed to have a protective effect on 5-FU-induced liver and kidney damage. PMID:29796225

Design, synthesis and biological evaluation of (S)-valine thiazole-derived cyclic and non-cyclic peptidomimetic oligomers as modulators of human P-glycoprotein (ABCB1)

PubMed Central

Singh, Satyakam; Prasad, Nagarajan Rajendra; Kapoor, Khyati; Chufan, Eduardo E.; Patel, Bhargav A.; Ambudkar, Suresh V.; Talele, Tanaji T.

2014-01-01

Multidrug resistance (MDR) caused by ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) through extrusion of anticancer drugs from the cells is a major cause of failure to cancer chemotherapy. Previously, selenazole containing cyclic peptides were reported as P-gp inhibitors and these were also used for co-crystallization with mouse P-gp, which has 87% homology to human P-gp. It has been reported that human P-gp, can simultaneously accommodate 2-3 moderate size molecules at the drug binding pocket. Our in-silico analysis based on the homology model of human P-gp spurred our efforts to investigate the optimal size of (S)-valine-derived thiazole units that can be accommodated at drug-binding pocket. Towards this goal, we synthesized varying lengths of linear and cyclic derivatives of (S)-valine-derived thiazole units to investigate the optimal size, lipophilicity and the structural form (linear and cyclic) of valine-derived thiazole peptides that can accommodate well in the P-gp binding pocket and affects its activity, previously an unexplored concept. Among these oligomers, lipophilic linear- (13) and cyclic-trimer (17) derivatives of QZ59S-SSS were found to be the most and equally potent inhibitors of human P-gp (IC50 = 1.5 μM). Cyclic trimer and linear trimer being equipotent, future studies can be focused on non-cyclic counterparts of cyclic peptides maintaining linear trimer length. Binding model of the linear trimer (13) within the drug-binding site on the homology model of human P-gp represents an opportunity for future optimization, specifically replacing valine and thiazole groups in the non-cyclic form. PMID:24288265

Transplantation of allogenic bone marrow in canine cyclic neutropenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dale, D.C.; Graw, R.G. Jr.

Transplantation of normal bone marrow cells to a gray collie dog with cyclic neutropenia resulted in normal granulocytopoiesis. The finding suggests that cyclic neutropenia occurs because the hematopoietic stem cells are defective. Because of the similarity of human and canine cyclic neutropenia, it also suggests that the human disease may be curable by marrow transplantation. One day before transplantation, the recipient received 1000 rads gamma irradiation from opposing /sup 60/Co sources at 9 rad/min. (CH)

Colour cyclic code for Brillouin distributed sensors

NASA Astrophysics Data System (ADS)

Le Floch, Sébastien; Sauser, Florian; Llera, Miguel; Rochat, Etienne

2015-09-01

For the first time, a colour cyclic coding (CCC) is theoretically and experimentally demonstrated for Brillouin optical time-domain analysis (BOTDA) distributed sensors. Compared to traditional intensity-modulated cyclic codes, the code presents an additional gain of √2 while keeping the same number of sequences as for a colour coding. A comparison with a standard BOTDA sensor is realized and validates the theoretical coding gain.

Protective effect of Selenium nanoparticle against cyclophosphamide induced hepatotoxicity and genotoxicity in Swiss albino mice.

PubMed

Bhattacharjee, Arin; Basu, Abhishek; Ghosh, Prosenjit; Biswas, Jaydip; Bhattacharya, Sudin

2014-08-01

Cyclophosphamide (CP) is the most commonly used chemotherapeutic drug for various types of cancer. However, its use causes severe cytotoxicity to normal cells in human. It is well known that the undesirable side effects are caused due to the formation of reactive oxygen species. Selenium is an essential micronutrient for both animals and humans and has antioxidant and membrane stabilizing property, but selenium is also toxic above certain level. Nano selenium has been well proved to be less toxic than inorganic selenium as well as certain organoselenium compounds. The objective of the study is to evaluate the protective role of Nano-Se against CP-induced hepatotoxicity and genotoxicity in Swiss albino mice. CP was administered intraperitoneally (25 mg/kg b.w.) and Nano-Se was given by oral gavages (2 mg Se/kg b.w.) in concomitant and pretreatment scheme. Intraperitoneal administration of CP induced hepatic damage as indicated by the serum marker enzymes aspartate and alanine transaminases and increased the malonaldehyde level, depleted the glutathione content and antioxidant enzyme activity (glutathione peroxidase, glutathione-s-transferase, superoxide dismutase and catalase), and induced DNA damage and chromosomal aberration. Oral administration of Nano-Se caused a significant reduction in malonaldehyde, ROS level and glutathione levels, restoration of antioxidant enzyme activity, reduction in chromosomal aberration in bone marrow, and DNA damage in lymphocytes and also in bone marrow. Moreover, the chemoprotective efficiency of Nano-Se against CP induced toxicity was confirmed by histopathological evaluation. The results support the protective effect of Nano-Se against CP-induced hepatotoxicity and genotoxicity. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Cyclic Dinucleotides in Oral Bacteria and in Oral Biofilms.

PubMed

Gürsoy, Ulvi K; Gürsoy, Mervi; Könönen, Eija; Sintim, Herman O

2017-01-01

Oral cavity acts as a reservoir of bacterial pathogens for systemic infections and several oral microorganisms have been linked to systemic diseases. Quorum sensing and cyclic dinucleotides, two "decision-making" signaling systems, communicate to regulate physiological process in bacteria. Discovery of cyclic dinucleotides has a long history, but the progress in our understanding of how cyclic dinucleotides regulate bacterial lifestyle is relatively new. Oral microorganisms form some of the most intricate biofilms, yet c-di-GMP, and c-di-AMP signaling have been rarely studied in oral biofilms. Recent studies demonstrated that, with the aid of bacterial messenger molecules and their analogs, it is possible to activate host innate and adaptive immune responses and epithelial integrity with a dose that is relevant to inhibit bacterial virulence mechanisms, such as fimbriae and exopolysaccharide production, biofilm formation, and host cell invasion. The aim of this perspective article is to present available information on cyclic dinucleotides in oral bacteria and in oral biofilms. Moreover, technologies that can be used to detect cyclic dinucleotides in oral biofilms are described. Finally, directions for future research are highlighted.

Amelioration of Paracetamol-Induced Hepatotoxicity in Rat by the Administration of Methanol Extract of Muntingia calabura L. Leaves

PubMed Central

Mahmood, N. D.; Mamat, S. S.; Kamisan, F. H.; Yahya, F.; Kamarolzaman, M. F. F.; Nasir, N.; Mohtarrudin, N.; Tohid, S. F. Md.; Zakaria, Z. A.

2014-01-01

Muntingia calabura L. is a tropical plant species that belongs to the Elaeocarpaceae family. The present study is aimed at determining the hepatoprotective activity of methanol extract of M. calabura leaves (MEMC) using two models of liver injury in rats. Rats were divided into five groups (n = 6) and received 10% DMSO (negative control), 50 mg/kg N-acetylcysteine (NAC; positive control), or MEMC (50, 250, and 500 mg/kg) orally once daily for 7 days and on the 8th day were subjected to the hepatotoxic induction using paracetamol (PCM). The blood and liver tissues were collected and subjected to biochemical and microscopical analysis. The extract was also subjected to antioxidant study using the 2,2-diphenyl-1-picrylhydrazyl-(DPPH) and superoxide anion-radical scavenging assays. At the same time, oxygen radical antioxidant capacity (ORAC) and total phenolic content were also determined. From the histological observation, lymphocyte infiltration and marked necrosis were observed in PCM-treated groups (negative control), whereas maintenance of hepatic structure was observed in group pretreated with N-acetylcysteine and MEMC. Hepatotoxic rats pretreated with NAC or MEMC exhibited significant decrease (P < 0.05) in ALT and AST enzymes level. Moreover, the extract also exhibited good antioxidant activity. In conclusion, MEMC exerts potential hepatoprotective activity that could be partly attributed to its antioxidant activity and, thus warrants further investigations. PMID:24868543

Cyclic and low temperature effects on microcircuits

NASA Technical Reports Server (NTRS)

Weissflug, V. A.; Sisul, E. V.

1977-01-01

Cyclic temperature and low temperature operating life tests, and pre-/post-life device evaluations were used to determine the degrading effects of thermal environments on microcircuit reliability. Low power transistor-transistor-logic gates and linear devices were included in each test group. Device metallization systems included aluminum metallization/aluminum wire, aluminum metallization/gold wire, and gold metallization/gold wire. Fewer than 2% electrical failures were observed during the cyclic and low temperature life tests and the post-life evaluations revealed approximately 2% bond pull failures. Reconstruction of aluminum die metallization was observed in all devices and the severity of the reconstruction appeared to be directly related to the magnitude of the temperature excursion. All types of bonds except the gold/gold bonds were weakened by exposure to repeated cyclic temperature stress.

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

PubMed

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.

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

PubMed Central

Antoine, Daniel James; Williams, Dominic P; Kipar, Anja; Laverty, Hugh; Park, B Kevin

2010-01-01

Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP. We also investigated in fasted mice the critical role played by inhibition of caspase-dependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology. PMID:20811657

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

PubMed

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.

Morphological, biochemical, histological, and ultrastructural protective effects of misoprostol on cisplatin induced-hepatotoxicity in adult male rats.

PubMed

Nasr, Ashraf Y

2013-12-01

To investigate the possible protective effect of misoprostol on cisplatin-induced hepatotoxicity. Four-equal sized groups (control, cisplatin-treated, misoprostol-treated, combined misoprostol, and cisplatin-treated) adult male Wistar rats (6 each) were used in this study. Body weight, liver weight, and liver weight/body weight ratio was calculated. Blood samples were obtained from the hearts of rats to determine the levels of total serum bilirubin (TSB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin. Liver specimens were prepared for both light and electron microscopes. The study was carried out between June 2012 and April 2013 at the Anatomy Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt, and the Department of Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. A single cisplatin dose (7.5 mg/kg intraperitoneally) resulted in significant elevation of AST, ALT, and TSB serum levels, and a significant reduction of serum albumin level, body weight, liver weight, and liver weight/body weight ratio. A combination of misoprostol (200 ug/kg/day) with cisplatin improved most of the previous parameters. Examination of specimens by both light and electron microscopes revealed pericentral hepatic necrosis, periportal fibrosis, dilatation, and congestion of central vein and blood sinusoids, diminished glycogen content, degenerated mitochondria, vesicular dilated rough endoplasmic reticulum, and nuclear changes in cisplatin-treated rats. Oral intake of misoprostol with cisplatin improved many of these changes. The results indicate that misoprostol may have a protective effect on cisplatin-induced hepatotoxicity.

cGMP and cyclic nucleotide-gated channels participate in mouse sperm capacitation.

PubMed

Cisneros-Mejorado, Abraham; Sánchez Herrera, Daniel P

2012-01-20

During capacitation of mammalian sperm intracellular [Ca(2+)] and cyclic nucleotides increase, suggesting that CNG channels play a role in the physiology of sperm. Here we study the effect of capacitation, 8Br-cAMP (8-bromoadenosine 3',5'-cyclic monophosphate) and 8Br-cGMP (8-bromoguanosine 3',5'-cyclic monophosphate) on the macroscopic ionic currents of mouse sperm, finding the existence of different populations of sperm, in terms of the recorded current and its response to cyclic nucleotides. Our results show that capacitation and cyclic nucleotides increase the ionic current, having a differential sensitivity to cGMP (cyclic guanosine monophosphate) and cAMP (cyclic adenosine monophosphate). Using a specific inhibitor we determine the contribution of CNG channels to macroscopic current and capacitation. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Cyclic plasticity models and application in fatigue analysis

NASA Technical Reports Server (NTRS)

Kalev, I.

1981-01-01

An analytical procedure for prediction of the cyclic plasticity effects on both the structural fatigue life to crack initiation and the rate of crack growth is presented. The crack initiation criterion is based on the Coffin-Manson formulae extended for multiaxial stress state and for inclusion of the mean stress effect. This criterion is also applied for the accumulated damage ahead of the existing crack tip which is assumed to be related to the crack growth rate. Three cyclic plasticity models, based on the concept of combination of several yield surfaces, are employed for computing the crack growth rate of a crack plane stress panel under several cyclic loading conditions.

The mycotoxin definition reconsidered towards fungal cyclic depsipeptides.

PubMed

Taevernier, Lien; Wynendaele, Evelien; De Vreese, Leen; Burvenich, Christian; De Spiegeleer, Bart

2016-04-02

Currently, next to the major classes, cyclic depsipeptides beauvericin and enniatins are also positioned as mycotoxins. However, as there are hundreds more fungal cyclic depsipeptides already identified, should these not be considered as mycotoxins as well? The current status of the mycotoxin definition revealed a lack of consistency, leading to confusion about what compounds should be called mycotoxins. Because this is of pivotal importance in risk assessment prioritization, a clear and quantitatively expressed mycotoxin definition is proposed, based on data of widely accepted mycotoxins. Finally, this definition is applied to a set of fungal cyclic depsipeptides, revealing that some of these should indeed be considered as mycotoxins.

Holographic entanglement entropy and cyclic cosmology

NASA Astrophysics Data System (ADS)

Frampton, Paul H.

2018-06-01

We discuss a cyclic cosmology in which the visible universe, or introverse, is all that is accessible to an observer while the extroverse represents the total spacetime originating from the time when the dark energy began to dominate. It is argued that entanglement entropy of the introverse is the more appropriate quantity to render infinitely cyclic, rather than the entropy of the total universe. Since vanishing entanglement entropy implies disconnected spacetimes, at the turnaround when the introverse entropy is zero the disconnected extroverse can be jettisoned with impunity.

More Cyclic-Oxidation Data For Turbine Alloys

NASA Technical Reports Server (NTRS)

Barrett, Charles A.; Garlick, Ralph G.

1993-01-01

Document presents data on cyclic oxidation of high-temperature, high-strength, nickel-base and cobalt-base alloys for turbines. Completes presentation of data begun in NASA Technical Memorandum 83665 (Revised 1989), "High-Temperature Cyclic Oxidation Data, Turbine Alloys, Part 1." Data consist of plots and tabulations of changes in specific weight as function of time, and lists of surface and spalled material phases identified by x-ray diffraction measurements.

Contribution of Cyclic and Pseudo-cyclic Electron Transport to the Formation of Proton Motive Force in Chloroplasts.

PubMed

Shikanai, Toshiharu; Yamamoto, Hiroshi

2017-01-09

Photosynthetic electron transport is coupled to proton translocation across the thylakoid membrane, resulting in the formation of a trans-thylakoid proton gradient (ΔpH) and membrane potential (Δψ). Ion transporters and channels localized to the thylakoid membrane regulate the contribution of each component to the proton motive force (pmf). Although both ΔpH and Δψ contribute to ATP synthesis as pmf, only ΔpH downregulates photosynthetic electron transport via the acidification of the thylakoid lumen by inducing thermal dissipation of excessive absorbed light energy from photosystem II antennae and slowing down of the electron transport through the cytochrome b 6 f complex. To optimize the tradeoff between efficient light energy utilization and protection of both photosystems against photodamage, plants have to regulate the pmf amplitude and its components, ΔpH and Δψ. Cyclic electron transport around photosystem I (PSI) is a major regulator of the pmf amplitude by generating pmf independently of the net production of NADPH by linear electron transport. Chloroplast ATP synthase relaxes pmf for ATP synthesis, and its activity should be finely tuned for maintaining the size of the pmf during steady-state photosynthesis. Pseudo-cyclic electron transport mediated by flavodiiron protein (Flv) forms a large electron sink, which is essential for PSI photoprotection in fluctuating light in cyanobacteria. Flv is conserved from cyanobacteria to gymnosperms but not in angiosperms. The Arabidopsis proton gradient regulation 5 (pgr5) mutant is defective in the main pathway of PSI cyclic electron transport. By introducing Physcomitrella patens genes encoding Flvs, the function of PSI cyclic electron transport was substituted by that of Flv-dependent pseudo-cyclic electron transport. In transgenic plants, the size of the pmf was complemented to the wild-type level but the contribution of ΔpH to the total pmf was lower than that in the wild type. In the pgr5 mutant, the

Evaluating cyclic fatigue of sealants during outdoor testing

Treesearch

R. Sam Williams; Steven Lacher; Corey Halpin; Christopher White

2009-01-01

A computer-controlled test apparatus (CCTA) and other instrumentation for subjecting sealant specimens to cyclic fatigue during outdoor exposure was developed. The CCTA enables us to use weather-induced conditions to cyclic fatigue specimens and to conduct controlled tests in-situ during the outdoor exposure. Thermally induced dimensional changes of an aluminum bar...

Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis.

PubMed

Ward, Jeanine; Kanchagar, Chitra; Veksler-Lublinsky, Isana; Lee, Rosalind C; McGill, Mitchell R; Jaeschke, Hartmut; Curry, Steven C; Ambros, Victor R

2014-08-19

We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as sensitive diagnostic and prognostic clinical tools for severe liver injury and could be useful for monitoring drug-induced liver injury during drug discovery.

Cyclic steaming in heavy oil diatomite

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, M.; Beatty, F.D.

1995-12-31

Chevron currently uses cyclic steaming as a recovery method to produce economically its heavy oil diatomite resource in the Cymric field, San Joaquin Valley, California. A highly instrumented, cyclically steaming well from this field was simulated in this study to delineate important production mechanisms, to optimize operations, and to improve reservoir management. The model was constrained, as much as possible, by the available measured data. Results show that fluid flow from the well to the reservoir is primarily through the hydraulic fracture induced by the injected steam. Parameters with unique importance to modeling cyclic steaming in diatomites are: (1) inducedmore » fracture dimension (length and height), (2) matrix permeability, (3) oil/water capillary pressure, (4) grid size perpendicular to fracture face, and (5) producing bottomhole pressures. Additionally, parameters important for conventional steam injection processes, such as relative permeabilities and injected steam volume, quality, and rate, are important for diatomites also. Oil production rates and steam/oil ratios calculated by this model compare reasonably with field data.« less

Sources of Water to Wells for Transient Cyclic Systems

USGS Publications Warehouse

Reilly, T.E.; Pollock, D.W.

1996-01-01

Many state agencies are currently (1995) developing wellhead protection programs. The thrust of some of these programs is to protect water supplies by determining the areas contributing recharge to water-supply wells and by specifying regulations to minimize the opportunity for contamination of the recharge water by activities at the land surface. The area contributing recharge to a discharging well is the surface area at the water table through which the water flowing to the well entered the ground-water system. In the analyses of ground-water flow systems, steady-state average conditions are commonly used to simplify the problem and make a solution tractable. However, recharge is usually cyclic in nature, with seasonal cycles and longer term climatic cycles. The effect of these cyclic stresses on the area contributing recharge to wells is quantitatively analyzed for a hypothetical alluvial valley aquifer system that is representative of a large class of ground-water systems that are extensively developed for water supply. The analysis shows that, in many cases, these cyclic changes in the recharge rates do not significantly affect the location and size of the areas contributing recharge to wells. The ratio of the mean travel time to the length of the cyclic stress period appears to be an indicator of whether the transient effects of the cyclic stress must be explicitly represented in the analysis of contributing areas to wells. For the cases examined, if the ratio of the mean travel time to the period of the cyclic stress was much greater than one, then the transient area contributing recharge to wells was similar to the area calculated using an average steady-state condition. However, cyclic stresses on systems with ratios less than one do have an effect on the location and size of the areas contributing recharge to wells.

A Material Model for the Cyclic Behavior of Nitinol

NASA Astrophysics Data System (ADS)

Rebelo, Nuno; Zipse, Achim; Schlun, Martin; Dreher, Gael

2011-07-01

The uniaxial behavior of Nitinol in different forms and at different temperatures has been well documented in the literature. Mathematical models for the three-dimensional behavior of this class of materials, covering superelasticity, plasticity, and shape memory effects have been previously developed. Phenomenological models embedded in FEA analysis are part of common practice today in the development of devices made out of Nitinol. In vivo loading of medical devices has cyclic characteristics. There have been some indications in the literature that cyclic loading of Nitinol modifies substantially its behavior. A consortium of several stent manufacturers, Safe Technology and Dassault Systèmes Simulia Corp., dedicated to the development of fatigue laws suitable for life prediction of Nitinol devices, has conducted an extensive experimental study of the modifications in uniaxial behavior of both Nitinol wire and tubing due to cyclic loading. The Abaqus Nitinol material model has been extended to capture some of the phenomena observed and is described in this article. Namely, a preload beyond 6% strain alters the transformation plateaus; if the cyclic load amplitude is large enough, permanent deformations (residual martensite) are observed; the lower plateau increases; and the upper plateau changes. The modifications to the upper plateau are very interesting in the sense that it appears broken: its start stress gets lowered creating a new plateau up to the highest level of cyclic strain, followed by resuming the original plateau until full transformation. Since quite often the geometry of a device at the point at which it is subjected to cyclic loading is very much dependent on the manufacturing, deployment, and preloading sequence, it is important that analyses be conducted with the original material behavior up to that point, and then with the cyclic behavior thereafter.

Probabilistic Simulation of Combined Thermo-Mechanical Cyclic Fatigue in Composites

NASA Technical Reports Server (NTRS)

Chamis, Christos C.

2011-01-01

A methodology to compute probabilistically-combined thermo-mechanical fatigue life of polymer matrix laminated composites has been developed and is demonstrated. Matrix degradation effects caused by long-term environmental exposure and mechanical/thermal cyclic loads are accounted for in the simulation process. A unified time-temperature-stress-dependent multifactor-interaction relationship developed at NASA Glenn Research Center has been used to model the degradation/aging of material properties due to cyclic loads. The fast probability-integration method is used to compute probabilistic distribution of response. Sensitivities of fatigue life reliability to uncertainties in the primitive random variables (e.g., constituent properties, fiber volume ratio, void volume ratio, ply thickness, etc.) computed and their significance in the reliability-based design for maximum life is discussed. The effect of variation in the thermal cyclic loads on the fatigue reliability for a (0/+/-45/90)s graphite/epoxy laminate with a ply thickness of 0.127 mm, with respect to impending failure modes has been studied. The results show that, at low mechanical-cyclic loads and low thermal-cyclic amplitudes, fatigue life for 0.999 reliability is most sensitive to matrix compressive strength, matrix modulus, thermal expansion coefficient, and ply thickness. Whereas at high mechanical-cyclic loads and high thermal-cyclic amplitudes, fatigue life at 0.999 reliability is more sensitive to the shear strength of matrix, longitudinal fiber modulus, matrix modulus, and ply thickness.

Probabilistic Simulation of Combined Thermo-Mechanical Cyclic Fatigue in Composites

NASA Technical Reports Server (NTRS)

Chamis, Christos C.

2010-01-01

A methodology to compute probabilistically-combined thermo-mechanical fatigue life of polymer matrix laminated composites has been developed and is demonstrated. Matrix degradation effects caused by long-term environmental exposure and mechanical/thermal cyclic loads are accounted for in the simulation process. A unified time-temperature-stress-dependent multifactor-interaction relationship developed at NASA Glenn Research Center has been used to model the degradation/aging of material properties due to cyclic loads. The fast probability-integration method is used to compute probabilistic distribution of response. Sensitivities of fatigue life reliability to uncertainties in the primitive random variables (e.g., constituent properties, fiber volume ratio, void volume ratio, ply thickness, etc.) computed and their significance in the reliability-based design for maximum life is discussed. The effect of variation in the thermal cyclic loads on the fatigue reliability for a (0/+/-45/90)s graphite/epoxy laminate with a ply thickness of 0.127 mm, with respect to impending failure modes has been studied. The results show that, at low mechanical-cyclic loads and low thermal-cyclic amplitudes, fatigue life for 0.999 reliability is most sensitive to matrix compressive strength, matrix modulus, thermal expansion coefficient, and ply thickness. Whereas at high mechanical-cyclic loads and high thermal-cyclic amplitudes, fatigue life at 0.999 reliability is more sensitive to the shear strength of matrix, longitudinal fiber modulus, matrix modulus, and ply thickness.

Mechanical annealing under low-amplitude cyclic loading in micropillars

NASA Astrophysics Data System (ADS)

Cui, Yi-nan; Liu, Zhan-li; Wang, Zhang-jie; Zhuang, Zhuo

2016-04-01

Mechanical annealing has been demonstrated to be an effective method for decreasing the overall dislocation density in submicron single crystal. However, simultaneously significant shape change always unexpectedly happens under extremely high monotonic loading to drive the pre-existing dislocations out of the free surfaces. In the present work, through in situ TEM experiments it is found that cyclic loading with low stress amplitude can drive most dislocations out of the submicron sample with virtually little change of the shape. The underlying dislocation mechanism is revealed by carrying out discrete dislocation dynamic (DDD) simulations. The simulation results indicate that the dislocation density decreases within cycles, while the accumulated plastic strain is small. By comparing the evolution of dislocation junction under monotonic, cyclic and relaxation deformation, the cumulative irreversible slip is found to be the key factor of promoting junction destruction and dislocation annihilation at free surface under low-amplitude cyclic loading condition. By introducing this mechanics into dislocation density evolution equations, the critical conditions for mechanical annealing under cyclic and monotonic loadings are discussed. Low-amplitude cyclic loading which strengthens the single crystal without seriously disturbing the structure has the potential applications in the manufacture of defect-free nano-devices.

Bicalutamide-induced hepatotoxicity: A rare adverse effect.

PubMed

Hussain, Salwa; Haidar, Abdallah; Bloom, Robert E; Zayouna, Nafea; Piper, Michael H; Jafri, Syed-Mohammed R

2014-01-01

Male, 81 FINAL DIAGNOSIS: Prostate cancer Symptoms: Anorexia • dark urine • joundice • letargy Casodex Clinical Procedure: - Specialty: Oncology. Adverse events of drug therapy. Bicalutamide is a nonsteroidal anti-androgen used extensively during the initiation of androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) agonist to reduce the symptoms of tumor flare in patients with metastatic prostate neoplasm. It can cause gynecomastia, hot flashes, fatigue, and decreased libido through competitive androgen receptor blockade. Although not as common, acute drug-induced liver injury is also possible with bicalutamide therapy. Typically, this results in transient derangement of liver function and patients remain asymptomatic. We share our experience with a case of symptomatic acute hepatotoxicity secondary to the use of bicalutamide and use this opportunity to present a brief review of existing literature. An 81-year-old African American male with metastatic prostate neoplasm presented with nonspecific symptoms along with jaundice of 1-day duration. He was started on a trial of bicalutamide 3 weeks prior to presentation. On physical examination, scleral icterus was noted. Workup revealed acutely elevated liver transaminases (>5 times the upper limit of normal), alkaline phosphatase, conjugated hyperbilirubinemia, and coagulopathy. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were considered. Bicalutamide was discontinued and the patient was managed with supportive care. He showed improvement of clinical and laboratory abnormalities within days. While rare, clinically significant and potentially life-threatening liver injury can result from use of bicalutamide. Prompt recognition and discontinuation of bicalutamide is necessary to avoid serious complications from this adverse reaction.

Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury.

PubMed

Gao, Yuan; Cao, Zhijun; Yang, Xi; Abdelmegeed, Mohamed A; Sun, Jinchun; Chen, Si; Beger, Richard D; Davis, Kelly; Salminen, William F; Song, Byoung-Joon; Mendrick, Donna L; Yu, Li-Rong

2017-01-01

Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury. Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS. Molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose- and time-dependent manner upon APAP treatment. Imbalanced expression of hemeoxygenase 1 (HMOX1) and biliverdin reductase A (BLVRA) was associated with hepatotoxicity. Protein abundance changes of a total of 31 proteins were uniquely correlated to liver damage, among which a dramatic increase of HMOX1 levels in plasma was observed. Liver injury-associated significant elevation of plasma HMOX1 was further validated in mice treated with APAP. This study unveiled molecular changes associated with APAP-induced liver toxicity at the pathway levels and identified HMOX1 as a potential plasma biomarker of liver injury. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Flexural creep of structural flakeboards under cyclic humidity

Treesearch

M.C. Yeh; R.C. Tang; Chung-Yun Hse

1990-01-01

Flexural creep behavior of randomly oriented structural flakeboards under cyclic humidity is presented. Specimens fabricated with 5 and 7 percent phenol-formaldehyde resin were subjected to constant concentrated load in bending under slow and fast cyclic relative humidity (RH) between 65 and 95 percent for 100 days. The temperature was set at a constant 75°F through...

Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides

NASA Astrophysics Data System (ADS)

Zorzi, Alessandro; Middendorp, Simon J.; Wilbs, Jonas; Deyle, Kaycie; Heinis, Christian

2017-07-01

The rapid renal clearance of peptides in vivo limits this attractive platform for the treatment of a broad range of diseases that require prolonged drug half-lives. An intriguing approach for extending peptide circulation times works through a `piggy-back' strategy in which peptides bind via a ligand to the long-lived serum protein albumin. In accordance with this strategy, we developed an easily synthesized albumin-binding ligand based on a peptide-fatty acid chimera that has a high affinity for human albumin (Kd=39 nM). This ligand prolongs the elimination half-life of cyclic peptides in rats 25-fold to over seven hours. Conjugation to a peptide factor XII inhibitor developed for anti-thrombotic therapy extends the half-life from 13 minutes to over five hours, inhibiting coagulation for eight hours in rabbits. This high-affinity albumin ligand could potentially extend the half-life of peptides in human to several days, substantially broadening the application range of peptides as therapeutics.

Evaluation of homogeneous electrocatalysts by cyclic voltammetry.

PubMed

Rountree, Eric S; McCarthy, Brian D; Eisenhart, Thomas T; Dempsey, Jillian L

2014-10-06

The pursuit of solar fuels has motivated extensive research on molecular electrocatalysts capable of evolving hydrogen from protic solutions, reducing CO2, and oxidizing water. Determining accurate figures of merit for these catalysts requires the careful and appropriate application of electroanalytical techniques. This Viewpoint first briefly presents the fundamentals of cyclic voltammetry and highlights practical experimental considerations before focusing on the application of cyclic voltammetry for the characterization of electrocatalysts. Key metrics for comparing catalysts, including the overpotential (η), potential for catalysis (E(cat)), observed rate constant (k(obs)), and potential-dependent turnover frequency, are discussed. The cyclic voltammetric responses for a general electrocatalytic one-electron reduction of a substrate are presented along with methods to extract figures of merit from these data. The extension of this analysis to more complex electrocatalytic schemes, such as those responsible for H2 evolution and CO2 reduction, is then discussed.

Hibiscus vitifolius (Linn.) root extracts shows potent protective action against anti-tubercular drug induced hepatotoxicity.

PubMed

Samuel, Anbu Jeba Sunilson John; Mohan, Syam; Chellappan, Dinesh Kumar; Kalusalingam, Anandarajagopal; Ariamuthu, Saraswathi

2012-05-07

The roots of Hibiscus vitifolius Linn. (Malvaceae) is used for the treatment of jaundice in the folklore system of medicine in India. This study is an attempt to evaluate the hepatoprotective activity of the roots of Hibiscus vitifolius against anti-tubercular drug induced hepatotoxicity. Hepatotoxicity was induced in albino rats of either sex by oral administration of a combination of three anti-tubercular drugs. Petroleum ether, chloroform, methanol and aqueous extracts of roots of Hibiscus vitifolius (400mg/kg/day) were evaluated for their possible hepatoprotective potential. All the extracts were found to be safe up to a dose of 2000mg/kg. Among the four extracts studied, oral administration of methanol extract of Hibiscus vitifolius at 400mg/kg showed significant difference in all the parameters when compared to control. There was a significant (P<0.001) reduction in the levels of serum aspartate amino transaminase, alanine amino transferase, alkaline phosphatase, lactate dehydrogenase, total and direct bilirubin, where as an increase was found in the levels of total cholesterol, total protein and albumin. Liver homogenate studies showed a significant increase in the levels of total protein, phospholipids and glycogen, and a reduction in the levels of total lipids, triglycerides, and cholesterol against control animals. In the tissue anti-oxidant studies, we found a significant increase in the levels of catalase and superoxide dismutase, whereas there was marked reduction in the levels of thiobarbituric acid reactive substances, as compared to control. Histology of liver sections of the animals treated with the extracts showed significant reduction of necrosis and fatty formation when compared with control specimens. These findings suggest that the root extracts of Hibiscus vitifolius have potent hepatoprotective activity, thereby justifying its ethnopharmacological claim. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Properties of Tangential and Cyclic Polygons: An Application of Circulant Matrices

ERIC Educational Resources Information Center

Leung, Allen; Lopez-Real, Francis

2003-01-01

In this paper, the properties of tangential and cyclic polygons proposed by Lopez-Real are proved rigorously using the theory of circulant matrices. In particular, the concepts of slippable tangential polygons and conformable cyclic polygons are defined. It is shown that an n-sided tangential (or cyclic) polygon P[subscript n] with n even is…

Ribosomal Biosynthesis of the Cyclic Peptide Toxins of Amanita Mushrooms

PubMed Central

Walton, Jonathan D.; Hallen-Adams, Heather E.; Luo, Hong

2014-01-01

Some species of mushrooms in the genus Amanita are extremely poisonous and frequently fatal to mammals including humans and dogs. Their extreme toxicity is due to amatoxins such as α- and β-amanitin. Amanita mushrooms also biosynthesize a chemically related group of toxins, the phallotoxins, such as phalloidin. The amatoxins and phallotoxins (collectively known as the Amanita toxins) are bicyclic octa- and heptapeptides, respectively. Both contain an unusual Trp-Cys cross-bridge known as tryptathionine. We have shown that, in Amanita bisporigera, the amatoxins and phallotoxins are synthesized as proproteins on ribosomes and not by nonribosomal peptide synthetases. The proproteins are 34–35 amino acids in length and have no predicted signal peptides. The genes for α-amanitin (AMA1) and phallacidin (PHA1) are members of a large family of related genes, characterized by highly conserved amino acid sequences flanking a hypervariable “toxin” region. The toxin regions are flanked by invariant proline (Pro) residues. An enzyme that could cleave the proprotein of phalloidin was purified from the phalloidin-producing lawn mushroom Conocybe apala. The enzyme is a serine protease in the prolyl oligopeptidase (POP) subfamily. The same enzyme cuts at both Pro residues to release the linear hepta- or octapeptide. PMID:20564017

Fatigue crack growth under general-yielding cyclic-loading

NASA Technical Reports Server (NTRS)

Minzhong, Z.; Liu, H. W.

1986-01-01

In low cycle fatigue, cracks are initiated and propagated under general yielding cyclic loading. For general yielding cyclic loading, Dowling and Begley have shown that fatigue crack growth rate correlates well with the measured delta J. The correlation of da/dN with delta J was also studied by a number of other investigators. However, none of thse studies have correlated da/dN with delta J calculated specifically for the test specimens. Solomon measured fatigue crack growth in specimens in general yielding cyclic loading. The crack tips fields for Solomon's specimens are calculated using the finite element method and the J values of Solomon's tests are evaluated. The measured crack growth rate in Solomon's specimens correlates very well with the calculated delta J.

Degradation forecast for PEMFC cathode-catalysts under cyclic loads

NASA Astrophysics Data System (ADS)

Moein-Jahromi, M.; Kermani, M. J.; Movahed, S.

2017-08-01

Degradation of Fuel Cell (FC) components under cyclic loads is one of the biggest bottlenecks in FC commercialization. In this paper, a novel experimental based algorithm is presented to predict the Catalyst Layer (CL) performance loss during cyclic load. The algorithm consists of two models namely Models 1 and 2. The Model 1 calculates the Electro-Chemical Surface Area (ECSA) and agglomerate size (e.g. agglomerate radius, rt,agg) for the catalyst layer under cyclic load. The Model 2 is the already-existing model from our earlier studies that computes catalyst performance with fixed structural parameters. Combinations of these two Models predict the CL performance under an arbitrary cyclic load. A set of parametric/sensitivity studies is performed to investigate the effects of operating parameters on the percentage of Voltage Degradation Rate (VDR%) with rank 1 for the most influential one. Amongst the considered parameters (such as: temperature, relative humidity, pressure, minimum and maximum voltage of the cyclic load), the results show that temperature and pressure have the most and the least influences on the VDR%, respectively. So that, increase of temperature from 60 °C to 80 °C leads to over 20% VDR intensification, the VDR will also reduce 1.41% by increasing pressure from 2 atm to 4 atm.

Identification of potential genomic biomarkers of hepatotoxicity caused by reactive metabolites of N-methylformamide: Application of stable isotope labeled compounds in toxicogenomic studies.

PubMed

Mutlib, Abdul; Jiang, Ping; Atherton, Jim; Obert, Leslie; Kostrubsky, Seva; Madore, Steven; Nelson, Sidney

2006-10-01

The inability to predict if a metabolically bioactivated compound will cause toxicity in later stages of drug development or post-marketing is of serious concern. One approach for improving the predictive success of compound toxicity has been to compare the gene expression profile in preclinical models dosed with novel compounds to a gene expression database generated from compounds with known toxicity. While this guilt-by-association approach can be useful, it is often difficult to elucidate gene expression changes that may be related to the generation of reactive metabolites. In an effort to address this issue, we compared the gene expression profiles obtained from animals treated with a soft-electrophile-producing hepatotoxic compound against corresponding deuterium labeled analogues resistant to metabolic processing. Our aim was to identify a subset of potential biomarker genes for hepatotoxicity caused by soft-electrophile-producing compounds. The current study utilized a known hepatotoxic compound N-methylformamide (NMF) and its two analogues labeled with deuterium at different positions to block metabolic oxidation at the formyl (d(1)) and methyl (d(3)) moieties. Groups of mice were dosed with each compound, and their livers were harvested at different time intervals. RNA was prepared and analyzed on Affymetrix GeneChip arrays. RNA transcripts showing statistically significant changes were identified, and selected changes were confirmed using TaqMan RT-PCR. Serum clinical chemistry and histopathologic evaluations were performed on selected samples as well. The data set generated from the different groups of animals enabled us to determine which gene expression changes were attributed to the bioactivating pathway. We were able to selectively modulate the metabolism of NMF by labeling various positions of the molecule with a stable isotope, allowing us to monitor gene changes specifically due to a particular metabolic pathway. Two groups of genes were

[Cyclic fatigue of Vita mark II machinable ceramics under Hertzian's contact].

PubMed

Liu, Wei-Cai; Zhang, Zhi-Shen; Huang, Cheng-Min; Chao, Yong-Lie; Wan, Qian-Bing

2006-08-01

To investigate the cyclic fatigue modes of Vita mark II machinable ceramics under Hertzian's contact. Hertzian's contact technique (WC spheres r = 3.18 mm) was used to investigate the cyclic fatigue of Vita mark II machinable ceramic. All specimens were fatigued by cyclic loading in moist environment, furthermore, surviving strength was examined by three point test and morphology damage observation. In homogeneous Vita mark II machinable ceramics, two fatigue damage modes existed after cyclic loading with spheres under moist environment, including conventional tensile-driven cone cracking (brittle mode) and shear-driven microdamage accumulation (quasi-plastic mode). The latter generated radial cracks and deeply penetrating secondary cone crack. Initial strength degradation were caused by the cone cracks, subsequent and much more deleterious loss was caused by radial cracks. Cyclic fatigue modes of Vita mark II machinable ceramics includes brittle and quasi-plastic mode.

Behavior of nonplastic silty soils under cyclic loading.

PubMed

Ural, Nazile; Gunduz, Zeki

2014-01-01

The engineering behavior of nonplastic silts is more difficult to characterize than is the behavior of clay or sand. Especially, behavior of silty soils is important in view of the seismicity of several regions of alluvial deposits in the world, such as the United States, China, and Turkey. In several hazards substantial ground deformation, reduced bearing capacity, and liquefaction of silty soils have been attributed to excess pore pressure generation during dynamic loading. In this paper, an experimental study of the pore water pressure generation of silty soils was conducted by cyclic triaxial tests on samples of reconstituted soils by the slurry deposition method. In all tests silty samples which have different clay percentages were studied under different cyclic stress ratios. The results have showed that in soils having clay content equal to and less than 10%, the excess pore pressure ratio buildup was quicker with an increase in different cyclic stress ratios. When fine and clay content increases, excess pore water pressure decreases constant cyclic stress ratio in nonplastic silty soils. In addition, the applicability of the used criteria for the assessment of liquefaction susceptibility of fine grained soils is examined using laboratory test results.

Behavior of Nonplastic Silty Soils under Cyclic Loading

PubMed Central

Ural, Nazile; Gunduz, Zeki

2014-01-01

The engineering behavior of nonplastic silts is more difficult to characterize than is the behavior of clay or sand. Especially, behavior of silty soils is important in view of the seismicity of several regions of alluvial deposits in the world, such as the United States, China, and Turkey. In several hazards substantial ground deformation, reduced bearing capacity, and liquefaction of silty soils have been attributed to excess pore pressure generation during dynamic loading. In this paper, an experimental study of the pore water pressure generation of silty soils was conducted by cyclic triaxial tests on samples of reconstituted soils by the slurry deposition method. In all tests silty samples which have different clay percentages were studied under different cyclic stress ratios. The results have showed that in soils having clay content equal to and less than 10%, the excess pore pressure ratio buildup was quicker with an increase in different cyclic stress ratios. When fine and clay content increases, excess pore water pressure decreases constant cyclic stress ratio in nonplastic silty soils. In addition, the applicability of the used criteria for the assessment of liquefaction susceptibility of fine grained soils is examined using laboratory test results. PMID:24672343

Activation of the Nrf2 Signaling Pathway Involving KLF9 Plays a Critical Role in Allicin Resisting Against Arsenic Trioxide-Induced Hepatotoxicity in Rats.

PubMed

Yang, Daqian; Lv, Zhanjun; Zhang, Haili; Liu, Biying; Jiang, Huijie; Tan, Xiao; Lu, Jingjing; Baiyun, Ruiqi; Zhang, Zhigang

2017-03-01

Arsenic trioxide (As 2 O 3 ) is both the most prevalent, naturally occurring inorganic arsenical threatening human health and an efficient therapeutic for acute promyelocytic leukemia. Regretfully, As 2 O 3 -treated cancer patients often suffer from hepatotoxicity. While effective antioxidant and anticarcinogenic actions of allicin have previously been demonstrated, studies indicating how allicin affects As 2 O 3 -induced hepatotoxicity and arsenic accumulation are lacking. Our study, for the first time, elaborates potential details of the hepatoprotective mechanisms of allicin against As 2 O 3 -induced liver injury. Wistar rats were administrated allicin (30 mg/kg) 1 h before As 2 O 3 (3 mg/kg) by daily gavage for 2 weeks. Our results indicate that allicin ameliorated As 2 O 3 -induced liver dysfunction, oxidative stress, and arsenic accumulation in the liver. Meanwhile, allicin decreased NF-κB level and upregulated expression of proteins reduced by As 2 O 3 including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1, nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1, and Krüppel-like factor 9 (KLF9). In addition, allicin promoted B cell lymphoma-extra large expression and suppressed B cell lymphoma-2-associated X protein levels regulated by As 2 O 3 . However, neither allicin nor As 2 O 3 affected cytochrome P450 2E1 mRNA expression. In conclusion, allicin attenuated As 2 O 3 -induced hepatotoxicity by activating the Nrf2 signaling pathway involving KLF9 to inhibit oxidative stress and apoptosis. Our findings elucidate a detailed mechanism by which allicin provides protection against As 2 O 3 -induced liver injury and support its potential role as an adjunctive therapy for patients suffering from chronic arsenic exposure.

Cyclic Oxidation Modeling Program Rewritten for MS Windows

NASA Technical Reports Server (NTRS)

Smialek, James L.; Auping, Judith V.

2002-01-01

Turbine superalloy components are subject to high-temperature oxidation during operation. Protection is often conferred by coatings designed to form slow-growing, adherent oxide scales. Degradation by oxidation is exacerbated by the thermal cycling encountered during normal aircraft operations. Cooling has been identified as the major contributor to stresses in the oxidation scales, and it may often cause some oxide scale spallation with a proportional loss of protective behavior. Overall oxidation resistance is, thus, studied by the weight change behavior of alloy coupons during high-temperature cyclic oxidation in furnace or burner rig tests. The various characteristics of this behavior are crucial in understanding the performance of alloys at high temperatures. This new modeling effort helps in the understanding of the major factors involved in the cyclic oxidation process. Weight change behavior in cyclic oxidation is typified by an initial parabolic weight gain response curve that eventually exhibits a maximum, then transitions into a linear rate of weight loss due to spalling. The overall shape and magnitude of the curve are determined by the parabolic growth rate, kp, the cycle duration, the type of oxide scale, and the regular, repetitive spalling process. This entire process was modeled by a computer program called the Cyclic Oxidation Spalling Program (COSP) previously developed at the NASA Glenn Research Center. Thus, by supplying appropriate oxidation input parameters, one can determine the best fit to the actual data. These parameters describe real behavior and can be used to compare alloys and project cyclic oxidation behavior for longer times or under different cycle frequencies.

Cyclic Axial-Torsional Deformation Behavior of a Cobalt-Base Superalloy

NASA Technical Reports Server (NTRS)

Bonacuse, Peter J.; Kalluri, Sreeramesh

1995-01-01

The cyclic, high-temperature deformation behavior of a wrought cobalt-base super-alloy, Haynes 188, is investigated under combined axial and torsional loads. This is accomplished through the examination of hysteresis loops generated from a biaxial fatigue test program. A high-temperature axial, torsional, and combined axial-torsional fatigue database has been generated on Haynes 188 at 760 C. Cyclic loading tests have been conducted on uniform gage section tubular specimens in a servohydraulic axial-torsional test rig. Test control and data acquisition were accomplished with a minicomputer. The fatigue behavior of Haynes 188 at 760 C under axial, torsional, and combined axial-torsional loads and the monotonic and cyclic deformation behaviors under axial and torsional loads have been previously reported. In this paper, the cyclic hardening characteristics and typical hysteresis loops in the axial stress versus axial strain, shear stress ,versus engineering shear strain, axial strain versus engineering shear strain. and axial stress versus shear stress spaces are presented for cyclic in-phase and out-of-phase axial-torsional tests. For in-phase tests, three different values of the proportionality constant lambda (the ratio of engineering shear strain amplitude to axial strain amplitude, are examined, viz. 0.86, 1.73, and 3.46. In the out-of-phase tests, three different values of the phase angle, phi (between the axial and engineering shear strain waveforms), are studied, viz., 30, 60, and 90 degrees with lambda equals 1.73. The cyclic hardening behaviors of all the tests conducted on Haynes 188 at 760 C are evaluated using the von Mises equivalent stress-strain and the maximum shear stress-maximum engineering shear strain (Tresca) curves. Comparisons are also made between the hardening behaviors of cyclic axial, torsional, and combined in-phase (lambda = 1.73 and phi = 0) and out-of-phase (lambda = 1.73 and phi = 90') axial-torsional fatigue tests. These comparisons

Curcuma longa Linn. extract and curcumin protect CYP 2E1 enzymatic activity against mercuric chloride-induced hepatotoxicity and oxidative stress: A protective approach.

PubMed

Joshi, Deepmala; Mittal, Deepak Kumar; Shukla, Sangeeta; Srivastav, Sunil Kumar; Dixit, Vaibhav A

2017-07-05

The present investigation has been conducted to evaluate the therapeutic potential of Curcuma longa (200mgkg -1 , po) and curcumin (80mgkg -1 , po) for their hepatoprotective efficacy against mercuric chloride (HgCl 2 : 12μmolkg -1 , ip; once only) hepatotoxicity. The HgCl 2 administration altered various biochemical parameters, including transaminases, alkaline phosphatase, lactate dehydrogenase, bilirubin, gamma-glutamyl transferase, triglycerides and cholesterol contents with a concomitant decline in protein and albumin concentration in serum which were restored towards control by therapy of Curcuma longa or curcumin. On the other hand, both treatments showed a protective effect on drug metabolizing enzymes viz. aniline hydroxylase (AH) and amidopyrine-N-demethylase (AND), hexobarbitone induced sleep time and BSP retention. Choleretic, 1,1-diphenyl-2-picryl-hydrazil (DPPH)-free radical scavenging activities and histological studies also supported the biochemical findings. The present study concludes that Curcuma longa extract or curcumin has the ability to alleviate the hepatotoxic effects caused by HgCl 2 in rats. Copyright © 2017 Elsevier GmbH. All rights reserved.

Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity.

PubMed

Sharma, Surendra K; Jha, Brajesh Kumar; Sharma, Abhishek; Sreenivas, V; Upadhyay, Vishwanath; Jaisinghani, Chandrita; Singla, Rohit; Mishra, Hemant Kumar; Soneja, Manish

2016-12-01

The N-acetyltransferase 2 (NAT2) gene encodes an enzyme which both activates and deactivates arylamine and other drugs and carcinogens. This study was aimed to investigate the role of NAT2 gene polymorphism in anti-tuberculosis drug-induced hepatotoxicity (DIH). In this prospective study, polymerase chain reaction-restriction fragment length polymorphism results for NAT2 gene were compared between 185 tuberculosis patients who did not develop DIH and 105 tuberculosis patients who developed DIH while on anti-tuberculosis drugs. Frequency of slow-acetylator genotype was commonly encountered and was not significantly different between DIH (82.8%) and non-DIH (77.2%) patients. However, the genotypic distribution of variant NAT2FNx015/FNx017 amongst slow-acetylator genotypes was significantly higher in DIH (56%) group as compared to non-DIH (39%) group (odds ratio 2.02; P=0.006). The present study demonstrated no association between NAT2 genotype and DIH in the north Indian patients with tuberculosis.

Recent Updates on Acetaminophen Hepatotoxicity: The Role of Nrf2 in Hepatoprotection

PubMed Central

Gum, Sang Il

2013-01-01

Acetaminophen (APAP) known as paracetamol is the main ingredient in Tylenol, which has analgesic and anti-pyretic properties. Inappropriate use of APAP causes major morbidity and mortality secondary to hepatic failure. Overdose of APAP depletes the hepatic glutathione (GSH) rapidly, and the metabolic intermediate leads to hepatocellular death. This article reviews the mechanisms of hepatotoxicity and provides an overview of current research studies. Pharmacokinetics including metabolism (activation and detoxification), subsequent transport (efflux)-facilitating excretion, and some other aspects related to toxicity are discussed. Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene battery plays a critical role in the multiple steps associated with the mitigation of APAP toxicity. The role of Nrf2 as a protective target is described, and potential natural products inhibiting APAP toxicity are outlined. This review provides an update on the mechanism of APAP toxicity and highlights the beneficial role of Nrf2 and specific natural products in hepatoprotection. PMID:24386516

Halothane hepatotoxicity and the reduced derivative, 1,1,1-trifluoro-2-chloroethane.

PubMed Central

Brown, B R; Sipes, I G; Baker, R K

1977-01-01

Halothane (1,1,1-trifluoro-2-bromo-2-chloroethane) is a safe, clinically useful inhalation anesthetic. Rare, unpredictable cases of liver necrosis have been reported following its use. Although the mechanism of this reaction in man is unknown the most plausible is biotransformation to reactive intermediates compounds. The oxidative metabolism of halothane appears to be benign. There is early evidence that reductive (nonoxygen dependent) may be harmful. Since the bromine atom of halothane appears to possess weak bond energy, the reduced, debrominated derivative of halothane, 1,1,1-trifluoro-2-chloroethane, was synthesized and tested for hepatotoxicity in the rat. The derivative is unstable and thus was prepared anaerobically and trapped in propylene glycol solvent. Injection of small amounts of this compound into the portal vein of rats produces extensive liver necrosis. It is postulated that biotransformation of halothane via a reductive pathway could produce this reactive intermediate metabolite. Images FIGURE 1. PMID:612444

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans.

PubMed

Yu, Dianke; Wu, Leihong; Gill, Pritmohinder; Tolleson, William H; Chen, Si; Sun, Jinchun; Knox, Bridgett; Jin, Yaqiong; Xiao, Wenming; Hong, Huixiao; Wang, Yong; Ren, Zhen; Guo, Lei; Mei, Nan; Guo, Yongli; Yang, Xi; Shi, Leming; Chen, Yinting; Zeng, Linjuan; Dreval, Kostiantyn; Tryndyak, Volodymyr; Pogribny, Igor; Fang, Hong; Shi, Tieliu; McCullough, Sandra; Bhattacharyya, Sudeepa; Schnackenberg, Laura; Mattes, William; Beger, Richard D; James, Laura; Tong, Weida; Ning, Baitang

2018-02-01

Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) HepaRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6-559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes.

Molecular forms of HMGB1 and Keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity

PubMed Central

Antoine, Daniel J; Jenkins, Rosalind E; Dear, James W; Williams, Dominic P; McGill, Mitchell R; Sharpe, Matthew R; Craig, Darren G; Simpson, Kenneth J; Jaeschke, Hartmut; Park, B. Kevin

2014-01-01

Background & Aims Full length keratin-18 (FL-K18) and High Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during acetaminophen (APAP) hepatotoxicity in vivo. In addition, the caspase-cleaved fragment of K18 (cK18) and hyper-acetylated HMGB1 represent serum indicators of apoptosis and immune cell activation respectively. The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis and immune cell activation throughout the time course of clinical APAP hepatotoxicity. Methods HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC-MS/MS assays in APAP overdose patients (n=78). Results HMGB1 (total; 15.4±1.9ng/ml, p<0.01, acetylated; 5.4±2.6ng/ml, p<0.001), cK18 (5649.8±721.0U/l, p<0.01) and FL-K18 (54770.2±6717.0U/l, p<0.005) were elevated in the sera of APAP overdose patients with liver injury compared to overdose patients without liver injury and healthy volunteers. HMGB1 and FL-K18 correlated with alanine aminotransferase (ALT) activity (R2=0.60 and 0.58 respectively, p<0.0001) and prothrombin time (R2=0.62 and 0.71 respectively, p<0.0001). Increased total and acetylated HMGB1 and FL-K18 were associated with worse prognosis (King’s College Criteria) or patients that died/required liver transplant compared to spontaneous survivors (all p<0.05-0.001), a finding not reflected by ALT and supported by ROC analysis. Acetylated HMGB1 was a better predictor of outcome than the other markers of cell death. Conclusion K18 and HMGB1 represent blood-based tools to investigate the cell death balance clinical APAP hepatotoxicity. Activation of the immune response was seen later in the time course as shown by the distinct profile of acetylated HMGB1 and was associated with worse outcome. PMID:22266604

Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450

PubMed Central

Chen, Taosheng

2017-01-01

Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s. Induction of the expression or inhibition of the activity of CYP450s can result in DDIs and toxicity. Currently, the United States (US) Food and Drug Administration does not require the investigation of the interactions of herbal supplements and CYP450s. This review provides a summary of herbal supplements that inhibit CYP450s, induce the expression of CYP450s, and/or whose toxicity is mediated by CYP450s. PMID:29117101

A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations

PubMed Central

Thiel, Christoph; Cordes, Henrik; Fabbri, Lorenzo; Aschmann, Hélène Eloise; Baier, Vanessa; Atkinson, Francis; Blank, Lars Mathias; Kuepfer, Lars

2017-01-01

Drug-induced toxicity is a significant problem in clinical care. A key problem here is a general understanding of the molecular mechanisms accompanying the transition from desired drug effects to adverse events following administration of either therapeutic or toxic doses, in particular within a patient context. Here, a comparative toxicity analysis was performed for fifteen hepatotoxic drugs by evaluating toxic changes reflecting the transition from therapeutic drug responses to toxic reactions at the cellular level. By use of physiologically-based pharmacokinetic modeling, in vitro toxicity data were first contextualized to quantitatively describe time-resolved drug responses within a patient context. Comparatively studying toxic changes across the considered hepatotoxicants allowed the identification of subsets of drugs sharing similar perturbations on key cellular processes, functional classes of genes, and individual genes. The identified subsets of drugs were next analyzed with regard to drug-related characteristics and their physicochemical properties. Toxic changes were finally evaluated to predict both molecular biomarkers and potential drug-drug interactions. The results may facilitate the early diagnosis of adverse drug events in clinical application. PMID:28151932

Pharmacological evaluation of a novel cyclic phosphatidic acid derivative 3-S-cyclic phosphatidic acid (3-S-cPA).

PubMed

Nozaki, Emi; Gotoh, Mari; Tanaka, Ryo; Kato, Masaru; Suzuki, Takahiro; Nakazaki, Atsuo; Hotta, Harumi; Kobayashi, Susumu; Murakami-Murofushi, Kimiko

2012-05-15

Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator possessing cyclic phosphate ring, which is necessary for its specific biological activities. To stabilize cyclic phosphate ring of cPA, we synthesized a series of cPA derivatives. We have shown that racemic 3-S-cPA, with a phosphate oxygen atom replaced with a sulfur atom at the sn-3, was a more effective autotaxin (ATX) inhibitor than cPA. In this study, we showed that racemic 3-S-cPA also had potent biological activities such as inhibition of cancer cell migration, suppression of the nociceptive reflex, and attenuation of ischemia-induced delayed neuronal cell death in the hippocampal CA1. Moreover, we synthesized both enantiomers of palmitoleoyl derivative of 3-S-cPA, and found that the chirality of 3-S-cPA is not involved in ATX inhibition. Based on these findings, racemic 3-S-cPA is suggested as an effective therapeutic compound like cPA. Copyright © 2012 Elsevier Ltd. All rights reserved.

Review fantastic medical implications of 3D-printing in liver surgeries, liver regeneration, liver transplantation and drug hepatotoxicity testing: A review.

PubMed

Wang, Jing-Zhang; Xiong, Nan-Yan; Zhao, Li-Zhen; Hu, Jin-Tian; Kong, De-Cheng; Yuan, Jiang-Yong

2018-06-07

The epidemiological trend in liver diseases becomes more serious worldwide. Several recent articles published by International Journal of Surgery in 2018 particularly emphasized the encouraging clinical benefits of hepatectomy, liver regeneration and liver transplantation, however, there are still many technical bottlenecks underlying these therapeutic approaches. Remarkably, a few preliminary studies have shown some clues to the role of three-dimensional (3D) printing in improving traditional therapy for liver diseases. Here, we concisely elucidated the curative applications of 3D-printing (no cells) and 3D Bio-printing (with hepatic cells), such as 3D-printed patient-specific liver models and devices for medical education, surgical simulation, hepatectomy and liver transplantation, 3D Bio-printed hepatic constructs for liver regeneration and artificial liver, 3D-printed liver tissues for evaluating drug's hepatotoxicity, and so on. Briefly, 3D-printed liver models and bioactive tissues may facilitate a lot of key steps to cure liver disorders, predictably bringing promising clinical benefits. This work further provides novel insights into facilitating treatment of hepatic carcinoma, promoting liver regeneration both in vivo and in vitro, expanding transplantable liver resources, maximizing therapeutic efficacy as well as minimizing surgical complications, medical hepatotoxicity, operational time, economic costs, etc. Copyright © 2018. Published by Elsevier Ltd.

Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats.

PubMed

Hwang, Jinah; Chang, Yun-Hee; Park, Jung Hwa; Kim, Soo Yeon; Chung, Haeyon; Shim, Eugene; Hwang, Hye Jin

2011-10-20

Dietary polyunsaturated fats increase liver injury in response to ethanol feeding. We evaluated the effect of dietary corn oil (CO), olive oil (OO), and beef tallow (BT) on fatty acid composition of liver microsomal membrane and acute acetaminophen hepatotoxicity. Male Sprague-Dawley rats were fed 15% (wt/wt) CO, OO or BT for 6 weeks. After treatment with acetaminophen (600 mg/kg), samples of plasma and liver were taken for analyses of the fatty acid composition and toxicity. Treatment with acetaminophen significantly elevated levels of plasma GOT and GPT as well as hepatic TBARS but reduced hepatic GSH levels in CO compared to OO and BT groups. Acetaminophen significantly induced protein expression of cytochrome P450 2E1 in the CO group. In comparison with the CO diet, lower levels of linoleic acid, higher levels of oleic acids and therefore much lower ratios of linoleic to oleic acid were detected in rats fed OO and BT diets. Dietary OO and BT produces similar liver microsomal fatty acid composition and may account for less severe liver injury after acetaminophen treatment compared to animals fed diets with CO rich in linoleic acid. These findings imply that types of dietary fat may be important in the nutritional management of drug-induced hepatotoxicity.

A Practical Beginner's Guide to Cyclic Voltammetry

ERIC Educational Resources Information Center

Elgrishi, Noémie; Rountree, Kelley J.; McCarthy, Brian D.; Rountree, Eric S.; Eisenhart, Thomas T.; Dempsey, Jillian L.

2018-01-01

Despite the growing popularity of cyclic voltammetry, many students do not receive formalized training in this technique as part of their coursework. Confronted with self-instruction, students can be left wondering where to start. Here, a short introduction to cyclic voltammetry is provided to help the reader with data acquisition and…

Biosynthesis of cyclic 2,3-diphosphoglycerate. Isolation and characterization of 2-phosphoglycerate kinase and cyclic 2,3-diphosphoglycerate synthetase from Methanothermus fervidus.

PubMed

Lehmacher, A; Vogt, A B; Hensel, R

1990-10-15

Starting from 2-phosphoglycerate the biosynthesis of cDPG comprises two steps: (i) the phosphorylation of 2-phosphoglycerate to 2,3-diphosphoglycerate and (ii) the intramolecular cyclization to cyclic 2,3-diphosphoglycerate. The involved enzymes, 2-phosphoglycerate kinase and cyclic 2,3-diphosphoglycerate synthetase, were purified form Methanothermus fervidus. Their molecular and catalytic properties were characterized.

Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation

PubMed Central

Frenzel, Christian; Teschke, Rolf

2016-01-01

Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance. PMID:27128912

Topological chaos, braiding and bifurcation of almost-cyclic sets.

PubMed

Grover, Piyush; Ross, Shane D; Stremler, Mark A; Kumar, Pankaj

2012-12-01

In certain two-dimensional time-dependent flows, the braiding of periodic orbits provides a way to analyze chaos in the system through application of the Thurston-Nielsen classification theorem (TNCT). We expand upon earlier work that introduced the application of the TNCT to braiding of almost-cyclic sets, which are individual components of almost-invariant sets [Stremler et al., "Topological chaos and periodic braiding of almost-cyclic sets," Phys. Rev. Lett. 106, 114101 (2011)]. In this context, almost-cyclic sets are periodic regions in the flow with high local residence time that act as stirrers or "ghost rods" around which the surrounding fluid appears to be stretched and folded. In the present work, we discuss the bifurcation of the almost-cyclic sets as a system parameter is varied, which results in a sequence of topologically distinct braids. We show that, for Stokes' flow in a lid-driven cavity, these various braids give good lower bounds on the topological entropy over the respective parameter regimes in which they exist. We make the case that a topological analysis based on spatiotemporal braiding of almost-cyclic sets can be used for analyzing chaos in fluid flows. Hence, we further develop a connection between set-oriented statistical methods and topological methods, which promises to be an important analysis tool in the study of complex systems.

Micromechanics of soil responses in cyclic simple shear tests

NASA Astrophysics Data System (ADS)

Cui, Liang; Bhattacharya, Subhamoy; Nikitas, George

2017-06-01

Offshore wind turbine (OWT) foundations are subjected to a combination of cyclic and dynamic loading arising from wind, wave, rotor and blade shadowing. Under cyclic loading, most soils change their characteristics including stiffness, which may cause the system natural frequency to approach the loading frequency and lead to unplanned resonance and system damage or even collapse. To investigate such changes and the underlying micromechanics, a series of cyclic simple shear tests were performed on the RedHill 110 sand with different shear strain amplitudes, vertical stresses and initial relative densities of soil. The test results showed that: (a) Vertical accumulated strain is proportional to the shear strain amplitude but inversely proportional to relative density of soil; (b) Shear modulus increases rapidly in the initial loading cycles and then the rate of increase diminishes and the shear modulus remains below an asymptote; (c) Shear modulus increases with increasing vertical stress and relative density, but decreasing with increasing strain amplitude. Coupled DEM simulations were performed using PFC2D to analyse the micromechanics underlying the cyclic behaviour of soils. Micromechanical parameters (e.g. fabric tensor, coordination number) were examined to explore the reasons for the various cyclic responses to different shear strain amplitudes or vertical stresses. Both coordination number and magnitude of fabric anisotropy contribute to the increasing shear modulus.

Cyclic strain increases protease-activated receptor-1 expression in vascular smooth muscle cells

NASA Technical Reports Server (NTRS)

Nguyen, K. T.; Frye, S. R.; Eskin, S. G.; Patterson, C.; Runge, M. S.; McIntire, L. V.

2001-01-01

Cyclic strain regulates many vascular smooth muscle cell (VSMC) functions through changing gene expression. This study investigated the effects of cyclic strain on protease-activated receptor-1 (PAR-1) expression in VSMCs and the possible signaling pathways involved, on the basis of the hypothesis that cyclic strain would enhance PAR-1 expression, reflecting increased thrombin activity. Uniaxial cyclic strain (1 Hz, 20%) of cells cultured on elastic membranes induced a 2-fold increase in both PAR-1 mRNA and protein levels. Functional activity of PAR-1, as assessed by cell proliferation in response to thrombin, was also increased by cyclic strain. In addition, treatment of cells with antioxidants or an NADPH oxidase inhibitor blocked strain-induced PAR-1 expression. Preincubation of cells with protein kinase inhibitors (staurosporine or Ro 31-8220) enhanced strain-increased PAR-1 expression, whereas inhibitors of NO synthase, tyrosine kinase, and mitogen-activated protein kinases had no effect. Cyclic strain in the presence of basic fibroblast growth factor induced PAR-1 mRNA levels beyond the effect of cyclic strain alone, whereas no additive effect was observed between cyclic strain and platelet-derived growth factor-AB. Our findings that cyclic strain upregulates PAR-1 mRNA expression but that shear stress downregulates this gene in VSMCs provide an opportunity to elucidate signaling differences by which VSMCs respond to different mechanical forces.

Synthesis and screening of one-bead-one-compound cyclic peptide libraries.

PubMed

Qian, Ziqing; Upadhyaya, Punit; Pei, Dehua

2015-01-01

Cyclic peptides have been a rich source of biologically active molecules. Herein we present a method for the combinatorial synthesis and screening of large one-bead-one-compound (OBOC) libraries of cyclic peptides against biological targets such as proteins. Up to ten million different cyclic peptides are rapidly synthesized on TentaGel microbeads by the split-and-pool synthesis method and subjected to a multistage screening protocol which includes magnetic sorting, on-bead enzyme-linked and fluorescence-based assays, and in-solution binding analysis of cyclic peptides selectively released from single beads by fluorescence anisotropy. Finally, the most active hit(s) is identified by the partial Edman degradation-mass spectrometry (PED-MS) method. This method allows a single researcher to synthesize and screen up to ten million cyclic peptides and identify the most active ligand(s) in ~1 month, without the time-consuming and expensive hit resynthesis or the use of any special equipment.

Cyclic Boronates Inhibit All Classes of β-Lactamases

PubMed Central

Cain, Ricky; Wang, David Y.; Lohans, Christopher T.; Wareham, David W.; Oswin, Henry P.; Mohammed, Jabril; Spencer, James; Fishwick, Colin W. G.; McDonough, Michael A.

2017-01-01

ABSTRACT β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyze their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Coproduction of MBLs and SBLs in resistant infections is thus of major clinical concern. The development of “dual-action” inhibitors, targeting both SBLs and MBLs, is of interest, but this is considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactamases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase CTX-M-15, the class C enzyme AmpC from Pseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolyzing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small-molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis. PMID:28115348

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hagiya, Yoshifumi; Kamata, Shotaro; Mitsuoka, Saya

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 alaninemore » 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 +/�

Cyclic debonding of adhesively bonded composites

NASA Technical Reports Server (NTRS)

Mall, S.; Johnson, W. S.; Everett, R. A., Jr.

1982-01-01

The fatigue behavior of a simple composite to composite bonded joint was analyzed. The cracked lap shear specimen subjected to constant amplitude cyclic loading was studied. Two specimen geometries were tested for each bonded system: (1) a strap adherend of 16 plies bonded to a lap adherend of 8 plies; and (2) a strap adherend of 8 plies bonded to a lap adherend of 16 plies. In all specimens the fatigue failure was in the form of cyclic debonding with some 0 deg fiber pull off from the strap adherend. The debond always grew in the region of adhesive that had the highest mode (peel) loading and that region was close to the adhesive strap interface.

Separation of isotopes by cyclical processes

DOEpatents

Hamrin, Jr., Charles E.; Weaver, Kenny

1976-11-02

Various isotopes of hydrogen are separated by a cyclic sorption process in which a gas stream containing the isotopes is periodically passed through a high pressure column containing a palladium sorbent. A portion of the product from the high pressure column is passed through a second column at lower pressure to act as a purge. Before the sorbent in the high pressure column becomes saturated, the sequence is reversed with the stream flowing through the former low-pressure column now at high pressure, and a portion of the product purging the former high pressure column now at low pressure. The sequence is continued in cyclic manner with the product being enriched in a particular isotope.

On the connection between multigrid and cyclic reduction

NASA Technical Reports Server (NTRS)

Merriam, M. L.

1984-01-01

A technique is shown whereby it is possible to relate a particular multigrid process to cyclic reduction using purely mathematical arguments. This technique suggest methods for solving Poisson's equation in 1-, 2-, or 3-dimensions with Dirichlet or Neumann boundary conditions. In one dimension the method is exact and, in fact, reduces to cyclic reduction. This provides a valuable reference point for understanding multigrid techniques. The particular multigrid process analyzed is referred to here as Approximate Cyclic Reduction (ACR) and is one of a class known as Multigrid Reduction methods in the literature. It involves one approximation with a known error term. It is possible to relate the error term in this approximation with certain eigenvector components of the error. These are sharply reduced in amplitude by classical relaxation techniques. The approximation can thus be made a very good one.

The effects of cyclical axial motion on rotary endodontic instrument fatigue.

PubMed

Dederich, D N; Zakariasen, K L

1986-02-01

A potential problem with the use of rotary engine-driven files to flare canals is metal fatigue and subsequent breakage. This study analyzes the effects of cyclical axial motion on instrument failure by fatigue testing of endodontic files with and without cyclical axial motion. Eighteen new instruments, sizes 15 to 45, were mounted in a lathe and turned at 1650 rpm in the lubricated lumen of a curved Pyrex capillary tube until failure occurred. Nine instruments of each size were turned with cyclical axial motion and nine were turned without it. The results indicated that cyclical axial motion can significantly extend the life span of rotary engine files. Torsional forces were not considered in this study.

Cyclic peptides as potential therapeutic agents for skin disorders.

PubMed

Namjoshi, Sarika; Benson, Heather A E

2010-01-01

There is an increasing understanding of the role of peptides in normal skin function and skin disease. With this knowledge, there is significant interest in the application of peptides as therapeutics in skin disease or as cosmeceuticals to enhance skin appearance. In particular, antimicrobial peptides and those involved in inflammatory processes provide options for the development of new therapeutic directions in chronic skin conditions such as psoriasis and dermatitis. To exploit their potential, it is essential that these peptides are delivered to their site of action in active form and in sufficient quantity to provide the desired effect. Many polymers permeate the skin poorly and are vulnerable to enzymatic degradation. Synthesis of cyclic peptide derivatives can substantially alter the physicochemical characteristics of the peptide with the potential to improve its skin permeation. In addition, cyclization can stabilize the peptide structure and thereby increase its stability. This review describes the role of cyclic peptides in the skin, examples of current cyclic peptide therapeutic products, and the potential for cyclic peptides as dermatological therapeutics and cosmeceuticals.

Computational Design of Self-Assembling Cyclic Protein Homo-oligomers

PubMed Central

Fallas, Jorge A.; Ueda, George; Sheffler, William; Nguyen, Vanessa; McNamara, Dan E.; Sankaran, Banumathi; Pereira, Jose Henrique; Parmeggiani, Fabio; Brunette, TJ; Cascio, Duilio; Yeates, Todd R.; Zwart, Peter; Baker, David

2016-01-01

Self-assembling cyclic protein homo-oligomers play important roles in biology and the ability to generate custom homo-oligomeric structures could enable new approaches to probe biological function. Here we report a general approach to design cyclic homo-oligomers that employs a new residue pair transform method for assessing the design ability of a protein-protein interface. This method is sufficiently rapid to enable systematic enumeration of cyclically docked arrangements of a monomer followed by sequence design of the newly formed interfaces. We use this method to design interfaces onto idealized repeat proteins that direct their assembly into complexes that possess cyclic symmetry. Of 96 designs that were experimentally characterized, 21 were found to form stable monodisperse homo-oligomers in solution, and 15 (4 homodimers, 6 homotrimers, 6 homotetramers and 1 homopentamer) had solution small angle X-ray scattering data consistent with the design models. X-ray crystal structures were obtained for five of the designs and each of these were shown to be very close to their design model. PMID:28338692

Analysis and optimization of cyclic methods in orbit computation

NASA Technical Reports Server (NTRS)

Pierce, S.

1973-01-01

The mathematical analysis and computation of the K=3, order 4; K=4, order 6; and K=5, order 7 cyclic methods and the K=5, order 6 Cowell method and some results of optimizing the 3 backpoint cyclic multistep methods for solving ordinary differential equations are presented. Cyclic methods have the advantage over traditional methods of having higher order for a given number of backpoints while at the same time having more free parameters. After considering several error sources the primary source for the cyclic methods has been isolated. The free parameters for three backpoint methods were used to minimize the effects of some of these error sources. They now yield more accuracy with the same computing time as Cowell's method on selected problems. This work is being extended to the five backpoint methods. The analysis and optimization are more difficult here since the matrices are larger and the dimension of the optimizing space is larger. Indications are that the primary error source can be reduced. This will still leave several parameters free to minimize other sources.

Influence of cyclic torsional preloading on cyclic fatigue resistance of nickel - titanium instruments.

PubMed

Pedullà, E; Lo Savio, F; Boninelli, S; Plotino, G; Grande, N M; Rapisarda, E; La Rosa, G

2015-11-01

To evaluate the effect of different torsional preloads on cyclic fatigue resistance of endodontic rotary instruments constructed from conventional nickel-titanium (NiTi), M-Wire or CM-Wire. Eighty new size 25, 0.06 taper Mtwo instruments (Sweden & Martina), size 25, 0.06 taper HyFlex CM (Coltene/Whaledent, Inc) and X2 ProTaper Next (Dentsply Maillefer) were used. The Torque and distortion angles at failure of new instruments (n = 10) were measured, and 0% (n = 10), 25%, 50% and 75% (n = 20) of the mean ultimate torsional strength as preloading condition were applied according to ISO 3630-1 for each brand. The twenty files tested for every extent of preload were subjected to 20 or 40 torsional cycles (n = 10). After torsional preloading, the number of cycles to failure was evaluated in a simulated canal with 60° angle of curvature and 5 mm of radius of curvature. Data were analysed using two-way analysis of variance. The fracture surface of each fragment was examined with a scanning electron microscope (SEM). Data were analysed by two-way analyses of variance. Preload repetitions did not influence the cyclic fatigue of the three brands; however, the 25%, 50% and 75% torsional preloading significantly reduced the fatigue resistance of all instruments tested (P < 0.01, P < 0.001 and P < 0.0001, respectively) except for the HyFlex CM preloaded with 25% of the maximum torsional strength (P > 0.05). Torsional preloads reduced the cyclic fatigue resistance of conventional and treated (M-wire and CM-wire) NiTi rotary instruments except for size 25, 0.06 taper HyFlex CM instruments with a 25% of torsional preloading. © 2014 International Endodontic Journal. Published by John Wiley & Sons Ltd.

Cyclic degassing of Erebus volcano, Antarctica

NASA Astrophysics Data System (ADS)

Ilanko, Tehnuka; Oppenheimer, Clive; Burgisser, Alain; Kyle, Philip

2015-06-01

Field observations have previously identified rapid cyclic changes in the behaviour of the lava lake of Erebus volcano. In order to understand more fully the nature and origins of these cycles, we present here a wavelet-based frequency analysis of time series measurements of gas emissions from the lava lake, obtained by open-path Fourier transform infrared spectroscopy. This reveals (i) a cyclic change in total gas column amount, a likely proxy for gas flux, with a period of about 10 min, and (ii) a similarly phased cyclic change in proportions of volcanic gases, which can be explained in terms of chemical equilibria and pressure-dependent solubilities. Notably, the wavelet analysis shows a persistent periodicity in the CO2/CO ratio and strong periodicity in H2O and SO2 degassing. The `peaks' of the cycles, defined by maxima in H2O and SO2 column amounts, coincide with high CO2/CO ratios and proportionally smaller increases in column amounts of CO2, CO, and OCS. We interpret the cycles to arise from recharge of the lake by intermittent pulses of magma from shallow depths, which degas H2O at low pressure, combined with a background gas flux that is decoupled from this very shallow magma degassing.

EFFICIENCY OF BORAGE SEEDS OIL AGAINST GAMMA IRRADIATION-INDUCED HEPATOTOXICITY IN MALE RATS: POSSIBLE ANTIOXIDANT ACTIVITY.

PubMed

Khattab, Hala A H; Abdallah, Inas Z A; Yousef, Fatimah M; Huwait, Etimad A

2017-01-01

Borage ( Borago officinal L.) is an annual herbaceous plant of great interest because its oil contains a high percentage of γ-linolenic acid (GLA). The present work was carried out to detect fatty acids composition of the oil extracted from borage seeds (BO) and its potential effectiveness against γ-irradiation- induced hepatotoxicity in male rats. GC-MS analysis of fatty acids methyl esters of BO was performed to identify fatty acids composition. Sixty rats were divided into five groups (12 rats each): Control, irradiated; rats were exposed to (6.5 Gy) of whole body γ-radiation, BO (50 mg/kg b.wt), irradiated BO post-treated and irradiated BO prepost-treated. Six rats from each group were sacrificed at two time intervals 7 and 15 days post-irradiation. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT) levels, lipids profile, as well as serum and hepatic reduced glutathione (GSH) and lipid peroxide (malondialdehyde) (MDA) levels were assessed. Histopathological examination of liver sections were also carried out. The results showed that the high contents of BO extracted by cold pressing, were linoleic acid (34.23%) and GLA (24.79%). Also, oral administration of BO significantly improved serum levels of liver enzymes, lipids profile, as well as serum and hepatic GSH and MDA levels (p<0.001) as compared with irradiated rats after 15 days post irradiation. Moreover, it exerted marked amelioration against irradiation-induced histopathological changes in liver tissues. The improvement was more pronounced in irradiated BO prepost-treated group than irradiated BO post-treated. BO has a beneficial role in reducing hepatotoxicity and oxidative stress induced by radiation exposure. Therefore, BO may be used as a beneficial supplement for patients during radiotherapy treatment.

Cyclic AMP system in muscle tissue during prolonged hypokinesia

NASA Technical Reports Server (NTRS)

Antipenko, Y. A.; Bubeyev, Y. A.; Korovkin, B. F.; Mikhaleva, N. P.

1980-01-01

Components of the cyclic Adenosine-cyclic-35-monophosphate (AMP) system in the muscle tissue of white rats were studied during 70-75 days of hypokinesia, created by placing the animals in small booths which restricted their movements, and during the readaptation period. In the initial period, cyclic AMP levels and the activities of phosphodiesterase and adenylate cyclase in muscle tissue were increased. The values for these indices were roughly equal for controls and experimental animals during the adaptation period, but on the 70th day of the experiment cAMP levels dropped, phosphodiesterase activity increased, and the stimulative effect of epinephrine on the activity of adenylate cyclase decreased. The indices under study normalized during the readaptation period.

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

PubMed Central

Zhang, Li-fang; Liu, Ling-sheng; Chu, Xiao-man; Xie, Hao; Cao, Li-juan; Guo, Cen; A, Ji-ye; Cao, Bei; Li, Meng-jie; Wang, Guang-ji; Hao, Hai-ping

2014-01-01

Aim: To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. Methods: Male SD rats were orally administered VPA (100 or 500 mg·kg−1·d−1) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low-molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. Results: HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. Conclusion: HFD magnifies VPA-induced impairment of mitochondrial β-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD. PMID:24442146

The antitumor effect and hepatotoxicity of a hexokinase II inhibitor 3-bromopyruvate: in vivo investigation of intraarterial administration in a rabbit VX2 hepatoma model.

PubMed

Jae, Hwan Jun; Chung, Jin Wook; Park, Hee Sun; Lee, Min Jong; Lee, Ki Chang; Kim, Hyo-Cheol; Yoon, Jung Hwan; Chung, Hesson; Park, Jae Hyung

2009-01-01

The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3-BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/ 0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. The tumor necrosis rate was significantly higher in the high dose group (93% +/- 7.6 [mean +/- SD]) than that in the control group (48% +/- 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% +/- 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% +/- 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method.

The Antitumor Effect and Hepatotoxicity of a Hexokinase II Inhibitor 3-Bromopyruvate: In Vivo Investigation of Intraarterial Administration in a Rabbit VX2 Hepatoma Model

PubMed Central

Jae, Hwan Jun; Park, Hee Sun; Lee, Min Jong; Lee, Ki Chang; Kim, Hyo-Cheol; Yoon, Jung Hwan; Chung, Hesson; Park, Jae Hyung

2009-01-01

Objective The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. Materials and Methods This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3-BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/ 0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. Results The tumor necrosis rate was significantly higher in the high dose group (93% ± 7.6 [mean ± SD]) than that in the control group (48% ± 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% ± 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% ± 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. Conclusion Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method. PMID:19885316

Melatonin-mediated upregulation of Sirt3 attenuates sodium fluoride-induced hepatotoxicity by activating the MT1-PI3K/AKT-PGC-1α signaling pathway.

PubMed

Song, Chao; Zhao, Jiamin; Fu, Beibei; Li, Dan; Mao, Tingchao; Peng, Wei; Wu, Haibo; Zhang, Yong

2017-11-01

Mitochondrial reactive oxygen species (ROS) production has been implicated in the pathogenesis of fluoride toxicity in liver. Melatonin, an indolamine synthesized in the pineal gland, was previously shown to protect against sodium fluoride (NaF)-induced hepatotoxicity. This study investigated the protective effects of melatonin pretreatment on NaF-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. Reducing mitochondrial ROS by melatonin substantially attenuated NaF-induced NADPH oxidase 4 (Nox4) upregulation and cytotoxicity in L-02 cells. Melatonin exerted its hepatoprotective effects by upregulating Sirtuin 3 (Sirt3) expression level and its activity. Melatonin increased the activity of manganese superoxide dismutase (SOD2) by promoting Sirt3-mediated deacetylation and promoted SOD2 expression through Sirt3-regulated DNA-binding activity of forkhead box O3 (FoxO3a), thus inhibiting the production of mitochondrial ROS induced by NaF. Notably, increased peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) by melatonin activated the Sirt3 expression, which was regulated by an estrogen-related receptor (ERR) binding element (ERRE) mapped to Sirt3 promoter region. Analysis of the cell signaling pathway profiling systems and specific pathway inhibition indicated that melatonin enhances PGC-1α expression by activating the PI3K/AKT signaling pathway. Importantly, inhibition of melatonin receptor (MT)-1 blocked the melatonin-activated PI3K/AKT-PGC-1α-Sirt3 signaling. Mechanistic study revealed that the protective effects of melatonin were associated with down-regulation of JNK1/2 phosphorylation. Our findings provided a theoretical basis that melatonin mitigated NaF-induced hepatotoxicity, which, in part, was mediated through the activation of the Sirt3 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Probing the Reactivity of Cyclic "N,O"-Acetals versus Cyclic "O,O"-Acetals with NaBH[subscript 4] and CH[subscript 3]MgI

ERIC Educational Resources Information Center

Ciaccio, James A.; Saba, Shahrokh; Bruno, Samantha M.; Bruppacher, John H.; McKnight, Alexa G.

2018-01-01

An operationally straightforward, project-like laboratory experiment has been developed in which students directly compare the reactivity of two heterocycles, a cyclic "O,O"-acetal (standard C-O protecting group) and a cyclic "N,O"-acetal (oxazolidine), toward sodium borohydride and methylmagnesium iodide. Students synthesize a…

Scale factor duality for conformal cyclic cosmologies

NASA Astrophysics Data System (ADS)

Camara da Silva, U.; Alves Lima, A. L.; Sotkov, G. M.

2016-11-01

The scale factor duality is a symmetry of dilaton gravity which is known to lead to pre-big-bang cosmologies. A conformal time version of the scale factor duality (SFD) was recently implemented as a UV/IR symmetry between decelerated and accelerated phases of the post-big-bang evolution within Einstein gravity coupled to a scalar field. The problem investigated in the present paper concerns the employment of the conformal time SFD methods to the construction of pre-big-bang and cyclic extensions of these models. We demonstrate that each big-bang model gives rise to two qualitatively different pre-big-bang evolutions: a contraction/expansion SFD model and Penrose's Conformal Cyclic Cosmology (CCC). A few examples of SFD symmetric cyclic universes involving certain gauged Kähler sigma models minimally coupled to Einstein gravity are studied. We also describe the specific SFD features of the thermodynamics and the conditions for validity of the generalized second law in the case of Gauss-Bonnet (GB) extension of these selected CCC models.

Acetaminophen-Induced Hepatotoxicity in Mice Occurs with Inhibition of Activity and Nitration of Mitochondrial Manganese Superoxide Dismutase

PubMed Central

Agarwal, Rakhee; MacMillan-Crow, Lee Ann; Rafferty, Tonya M.; Saba, Hamida; Roberts, Dean W.; Fifer, E. Kim; James, Laura P.

2011-01-01

In overdose the analgesic/antipyretic acetaminophen (APAP) is hepatotoxic. Toxicity is mediated by initial hepatic metabolism to N-acetyl-p-benzoquinone imine (NAPQI). After low doses NAPQI is efficiently detoxified by GSH. However, in overdose GSH is depleted, NAPQI covalently binds to proteins as APAP adducts, and oxygen/nitrogen stress occurs. Toxicity is believed to occur by mitochondrial dysfunction. Manganese superoxide dismutase (MnSOD) inactivation by protein nitration has been reported to occur during other oxidant stress-mediated diseases. MnSOD is a critical mitochondrial antioxidant enzyme that prevents peroxynitrite formation within the mitochondria. To examine the role of MnSOD in APAP toxicity, mice were treated with 300 mg/kg APAP. GSH was significantly reduced by 65% at 0.5 h and remained reduced from 1 to 4 h. Serum alanine aminotransferase did not significantly increase until 4 h and was 2290 IU/liter at 6 h. MnSOD activity was significantly reduced by 50% at 1 and 2 h. At 1 h, GSH was significantly depleted by 62 and 80% at nontoxic doses of 50 and 100 mg/kg, respectively. No further GSH depletion occurred with hepatotoxic doses of 200 and 300 mg/kg APAP. A dose response decrease in MnSOD activity was observed for APAP at 100, 200, and 300 mg/kg. Immunoprecipitation of MnSOD from livers of APAP-treated mice followed by Western blot analysis revealed nitrated MnSOD. APAP-MnSOD adducts were not detected. Treatment of recombinant MnSOD with NAPQI did not produce APAP protein adducts. The data indicate that MnSOD inactivation by nitration is an early event in APAP-induced hepatic toxicity. PMID:21205919

On the no-boundary proposal for ekpyrotic and cyclic cosmologies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Battarra, Lorenzo; Lehners, Jean-Luc, E-mail: lorenzo.battarra@aei.mpg.de, E-mail: jlehners@aei.mpg.de

2014-12-01

The no-boundary proposal provides a compelling theory for the initial conditions of our universe. We study the implications of such initial conditions for ekpyrotic and cyclic cosmologies. These cosmologies allow for the existence of a new type of ''ekpyrotic instanton'', which describes the creation of a universe in the ekpyrotic contraction phase. Remarkably, we find that the ekpyrotic attractor can explain how the universe became classical. In a cyclic context, in addition to the ekpyrotic instantons there exist de Sitter-like instantons describing the emergence of the universe in the dark energy phase. Our results show that typically the ekpyrotic instantonsmore » yield a higher probability. In fact, in a potential energy landscape allowing both inflationary and cyclic cosmologies, the no-boundary proposal implies that the probability for ekpyrotic and cyclic initial conditions is vastly higher than that for inflationary ones.« less

Activation of the adenylyl cyclase/cyclic AMP/protein kinase A pathway in endothelial cells exposed to cyclic strain

NASA Technical Reports Server (NTRS)

Cohen, C. R.; Mills, I.; Du, W.; Kamal, K.; Sumpio, B. E.

1997-01-01

The aim of this study was to assess the involvement of the adenylyl cyclase/cyclic AMP/protein kinase A pathway (AC) in endothelial cells (EC) exposed to different levels of mechanical strain. Bovine aortic EC were seeded to confluence on flexible membrane-bottom wells. The membranes were deformed with either 150 mm Hg (average 10% strain) or 37.5 mm Hg (average 6% strain) vacuum at 60 cycles per minute (0.5 s strain; 0.5 s relaxation) for 0-60 min. The results demonstrate that at 10% average strain (but not 6% average strain) there was a 1.5- to 2.2-fold increase in AC, cAMP, and PKA activity by 15 min when compared to unstretched controls. Further studies revealed an increase in cAMP response element binding protein in EC subjected to the 10% average strain (but not 6% average strain). These data support the hypothesis that cyclic strain activates the AC/cAMP/PKA signal transduction pathway in EC which may occur by exceeding a strain threshold and suggest that cyclic strain may stimulate the expression of genes containing cAMP-responsive promoter elements.

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

PubMed

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). LD 50 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.

Characterization of an antibiotic produced by Bacillus subtilis JW-1 that suppresses Ralstonia solanacearum.

PubMed

Kwon, Jae Won; Kim, Shin Duk

2014-01-01

Bacillus subtilis JW-1 was isolated from rhizosphere soil as a potential biocontrol agent of bacterial wilt caused by Ralstonia solanacearum. Seed treatment followed by a soil drench application with this strain resulted in >80% reduction in bacterial wilt disease compared with that in the untreated control under greenhouse conditions. The antibacterial compound produced by strain JW-1 was purified by bioactivity-guided fractionation. Based on mass spectroscopy and nuclear magnetic resonance spectral data ((1)H, (13)C, (1)H-(1)H correlation spectroscopies, rotating frame nuclear Overhauser effect spectroscopy, and heteronuclear multiple-bond correlation spectroscopy), the structure of this compound was elucidated as a cyclic lipopeptide composed of a heptapeptide (Gln-Leu-Leu-Val-Asp-Leu-Leu) bonded to a β-hydroxy-iso-hexadecanoic acid arranged in a lactone ring system.

Cyclic Deformation of Ultra-Fine Grained Commercial Purity Aluminum Processed by Accumulative Roll-Bonding.

PubMed

Kwan, Charles C F; Wang, Zhirui

2013-08-13

Accumulative Roll-Bonding (ARB) is one of the more recently developed techniques capable of producing bulk ultra-fine grained (ufg) metals. There are still many aspects of the behavior of ufg metals that lacks an in-depth understanding, such as a generalized view of the factors that govern the cyclic deformation mechanism(s). This study aims to advance the understanding of the cyclic deformation behavior of ufg metals through the systematic investigation of ARB processed aluminum upon cyclic loading. It was found that the cyclic softening response often reported for ufg metals is largely influenced by the microstructure stability as the cyclic softening response is facilitated by grain coarsening which becomes inhibited with highly stable microstructure. On one hand, shear bands resembling braids of dislocations trespassing multiple grains have been observed to operate for the accommodation of the imposed cyclic strain in cases where grain coarsening is largely restricted. On the other hand, it was found that the microstructure stability can be overcome at higher applied cyclic plastic strain levels, leading to grain coarsening and thus a cyclic softening response. The findings in this study have further confirmed that the cyclic softening behavior found in many ufg metals, which may be detrimental in practical applications, can be inhibited by improvements in the microstructure stability.

Lanthanum inhibition of Vibrio cholerae and Escherichia coli enterotoxin-induced enterosorption and its effects on intestinal mucosa cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate levels.

PubMed Central

Leitch, G J; Amer, M S

1975-01-01

Several trivalent cations, including lanthanum (La3+), inhibited the secretion (enterosorption) induced by the enterotoxins of Vibrio cholerae and Escherichia coli in the rabbit ileum in vivo. High concentrations (greater than 10 mM) of La3+ were required to inhibit cholera enterotoxin (CE)-induced enterosorption, probably because of the adsorption of the La3+ often potentiated the CE-induced enterosorption. If luminal La3+ exposure followed CE exposure, some recovery of the enterosorptive response was observed. The longer the lag between the CE exposure and the La3+ exposure, the greater was the recovery of the enterosorptive response. Lanthanum inhibited HCO3- secretion more than Cl- secretion. By altering the luminal fluid pH at the time of La3+ exposure, it was found that La3+ was adsorbed to negatively charged luminal sites, having an apparent pK between 2.5 and 3.0. Although La3+ antagonized the enterosorptive response to CE, it mimicked rather than antagonized the cyclic adenosine 3',5'-monophosphate elevation and cyclic guanosine 3',5'-monophosphate depression induced by the toxin. It is therefore concluded that the La3+ inhibition of the CE-induced enterosorption must have occurred at a site following the generation of the cyclic nucleotides. Cholera enterotoxin caused complex time-dependent changes in the mucosal cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate levels, as revealed by studying tissue cyclic adenosine 3',5'-monophosphate/cyclic guanosine 3',5'-monophosphate ratios. The possible roles these two cyclic nucleotides may play in the pathogenesis of the cholera diarrhea are discussed. PMID:164410

Levels of cyclic-2,3-diphosphoglycerate in Methanobacterium thermoautotrophicum during phosphate limitation.

PubMed Central

Seely, R J; Fahrney, D E

1984-01-01

Batch-grown Methanobacterium thermoautotrophicum cells grew nonexponentially in the absence of exogenous Pi until intracellular cyclic-2,3-diphosphoglycerate (cyclic DPG) had fallen below 2 mumol/g (dry weight), the limit of detection. Growth resumed immediately upon transfer to medium containing Pi Cyclic DPG levels were also below detection in Pi-limited chemostat cultures operating at a dilution rate of 0.173 h-1 (4-h doubling time), with reservoir Pi concentrations below 200 microM. At this dilution rate, the Pi concentration in the culture was 4 microM. An H2-limited steady state was achieved with 400 microM Pi in the inflowing medium (67 microM in the culture). The cyclic DPG content of these cells was 72 to 74 mumol/g, about one-third the amount in batch-grown cells. The specific growth rate accelerated immediately to 0.36 h-1 (1.9-h doubling time) under washout conditions at high dilution rate. The cellular content of cyclic DPG declined over a 2-h period, and then increased rapidly as the Pi level in the medium approached 200 microM. Expansion of the cyclic DPG pool coincided with a marked increase in Pi assimilation. These results indicated that M. thermoautotrophicum accumulated cyclic DPG only when Pi and H2 were readily available. PMID:6480564

Levels of cyclic-2,3-diphosphoglycerate in Methanobacterium thermoautotrophicum during phosphate limitation.

PubMed

Seely, R J; Fahrney, D E

1984-10-01

Batch-grown Methanobacterium thermoautotrophicum cells grew nonexponentially in the absence of exogenous Pi until intracellular cyclic-2,3-diphosphoglycerate (cyclic DPG) had fallen below 2 mumol/g (dry weight), the limit of detection. Growth resumed immediately upon transfer to medium containing Pi Cyclic DPG levels were also below detection in Pi-limited chemostat cultures operating at a dilution rate of 0.173 h-1 (4-h doubling time), with reservoir Pi concentrations below 200 microM. At this dilution rate, the Pi concentration in the culture was 4 microM. An H2-limited steady state was achieved with 400 microM Pi in the inflowing medium (67 microM in the culture). The cyclic DPG content of these cells was 72 to 74 mumol/g, about one-third the amount in batch-grown cells. The specific growth rate accelerated immediately to 0.36 h-1 (1.9-h doubling time) under washout conditions at high dilution rate. The cellular content of cyclic DPG declined over a 2-h period, and then increased rapidly as the Pi level in the medium approached 200 microM. Expansion of the cyclic DPG pool coincided with a marked increase in Pi assimilation. These results indicated that M. thermoautotrophicum accumulated cyclic DPG only when Pi and H2 were readily available.

Earl Sutherland (1915-1974) [corrected] and the discovery of cyclic AMP.

PubMed

Blumenthal, Stanley A

2012-01-01

In 1945, Earl Sutherland (1915-1974) [corrected] and associates began studies of the mechanism of hormone-induced glycogen breakdown in the liver. In 1956, their efforts culminated in the identification of cyclic AMP, an ancient molecule generated in many cell types in response to hormonal and other extracellular signals. Cyclic AMP, the original "second messenger," transmits such signals through pathways that regulate a diversity of cellular functions and capabilities: metabolic processes such as lipolysis and glycogenolysis; hormone secretion; the permeability of ion channels; gene expression; cell proliferation and survival. Indeed, it can be argued that the discovery of cyclic AMP initiated the study of intracellular signaling pathways, a major focus of contemporary biomedical inquiry. This review presents relevant details of Sutherland's career; summarizes key contributions of his mentors, Carl and Gerti Cori, to the knowledge of glycogen metabolism (contributions that were the foundation for his own research); describes the experiments that led to his identification, isolation, and characterization of cyclic AMP; assesses the significance of his work; and considers some aspects of the impact of cyclic nucleotide research on clinical medicine.

Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity.

PubMed

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.

Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy.

PubMed

Michalakis, Stylianos; Becirovic, Elvir; Biel, Martin

2018-03-07

The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG) channels. CNG channels are ligand-gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP). Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca 2+ concentration. Structurally, the CNG channels belong to the superfamily of pore-loop cation channels and share a common gross structure with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and voltage-gated potassium channels (KCN). In this review, we provide an overview on the molecular properties of CNG channels and describe their physiological role in the phototransduction pathways. We also discuss insights into the pathophysiological role of CNG channel proteins that have emerged from the analysis of CNG channel-deficient animal models and human CNG channelopathies. Finally, we summarize recent gene therapy activities and provide an outlook for future clinical application.

Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy

PubMed Central

Biel, Martin

2018-01-01

The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG) channels. CNG channels are ligand-gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP). Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca2+ concentration. Structurally, the CNG channels belong to the superfamily of pore-loop cation channels and share a common gross structure with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and voltage-gated potassium channels (KCN). In this review, we provide an overview on the molecular properties of CNG channels and describe their physiological role in the phototransduction pathways. We also discuss insights into the pathophysiological role of CNG channel proteins that have emerged from the analysis of CNG channel-deficient animal models and human CNG channelopathies. Finally, we summarize recent gene therapy activities and provide an outlook for future clinical application. PMID:29518895

Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats

PubMed Central

2011-01-01

Background Dietary polyunsaturated fats increase liver injury in response to ethanol feeding. We evaluated the effect of dietary corn oil (CO), olive oil (OO), and beef tallow (BT) on fatty acid composition of liver microsomal membrane and acute acetaminophen hepatotoxicity. Methods Male Sprague-Dawley rats were fed 15% (wt/wt) CO, OO or BT for 6 weeks. After treatment with acetaminophen (600 mg/kg), samples of plasma and liver were taken for analyses of the fatty acid composition and toxicity. Results Treatment with acetaminophen significantly elevated levels of plasma GOT and GPT as well as hepatic TBARS but reduced hepatic GSH levels in CO compared to OO and BT groups. Acetaminophen significantly induced protein expression of cytochrome P450 2E1 in the CO group. In comparison with the CO diet, lower levels of linoleic acid, higher levels of oleic acids and therefore much lower ratios of linoleic to oleic acid were detected in rats fed OO and BT diets. Conclusions Dietary OO and BT produces similar liver microsomal fatty acid composition and may account for less severe liver injury after acetaminophen treatment compared to animals fed diets with CO rich in linoleic acid. These findings imply that types of dietary fat may be important in the nutritional management of drug-induced hepatotoxicity. PMID:22011590

Cyclic Deformation of Ultra-Fine Grained Commercial Purity Aluminum Processed by Accumulative Roll-Bonding

PubMed Central

Kwan, Charles C.F.; Wang, Zhirui

2013-01-01

Accumulative Roll-Bonding (ARB) is one of the more recently developed techniques capable of producing bulk ultra-fine grained (ufg) metals. There are still many aspects of the behavior of ufg metals that lacks an in-depth understanding, such as a generalized view of the factors that govern the cyclic deformation mechanism(s). This study aims to advance the understanding of the cyclic deformation behavior of ufg metals through the systematic investigation of ARB processed aluminum upon cyclic loading. It was found that the cyclic softening response often reported for ufg metals is largely influenced by the microstructure stability as the cyclic softening response is facilitated by grain coarsening which becomes inhibited with highly stable microstructure. On one hand, shear bands resembling braids of dislocations trespassing multiple grains have been observed to operate for the accommodation of the imposed cyclic strain in cases where grain coarsening is largely restricted. On the other hand, it was found that the microstructure stability can be overcome at higher applied cyclic plastic strain levels, leading to grain coarsening and thus a cyclic softening response. The findings in this study have further confirmed that the cyclic softening behavior found in many ufg metals, which may be detrimental in practical applications, can be inhibited by improvements in the microstructure stability. PMID:28811446

cap alpha. /sub 2/-Adrenergic receptor-mediated sensitization of forskolin-stimulated cyclic AMP production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, S.B.; Toews, M.L.; Turner, J.T.

1987-03-01

Preincubation of HT29 human colonic adenocarcinoma cells with ..cap alpha../sub 2/-adrenergic agonists resulted in a 10- to 20-fold increase in forskolin-stimulated cyclic AMP production as compared to cells preincubated without agonist. Similar results were obtained using either a (/sup 3/H)adenine prelabeling assay or a cyclic AMP radioimmunoassay to measure cyclic AMP levels. This phenomenon, which is termed sensitization, is ..cap alpha../sub 2/-adrenergic receptor-mediated and rapid in onset and reversal. Yohimbine, an ..cap alpha../sub 2/-adrenergic receptor-selective antagonist, blocked norepinephrine-induced sensitization, whereas prazosin (..cap alpha../sub 1/-adrenergic) and sotalol (..beta..-adrenergic) did not. The time for half-maximal sensitization was 5 min and the half-timemore » for reversal was 10 min. Only a 2-fold sensitization of cyclic AMP production stimulated by vasoactive intestinal peptide was observed, indicating that sensitization is relatively selective for forskolin. Sensitization reflects an increased production of cyclic AMP and not a decreased degradation of cyclic AMP, since incubation with a phosphodiesterase inhibitor and forskolin did not mimic sensitization. Increasing the levels of cyclic AMP during the preincubation had no effect on sensitization, indicating that sensitization is not caused by decreased cyclic AMP levels during the preincubation. This rapid and dramatic sensitization of forskolin-stimulated cyclic AMP production is a previously unreported effect that can be added to the growing list of ..cap alpha../sub 2/-adrenergic responses that are not mediated by a decrease in cyclic AMP.« less

Cyclical vomiting syndrome secondary to a Chiari I malformation-a case report.

PubMed

White, William L; Bagga, Veejay; Campbell, David I; Hart, Anthony R; Ushewokunze, Shungu

2017-12-01

Cyclical vomiting syndrome is a disorder characterised by recurrent episodes of profuse vomiting. There are no cases in the literature on the management of children with presenting with cyclical vomiting syndrome and a Chiari malformation type I. We report the case of a 12-year-old child diagnosed with cyclical vomiting syndrome and a Chiari malformation type I. The patient received symptomatic relief following a craniocervical decompression.

Windows(Registered Trademark)-Based Software Models Cyclic Oxidation Behavior

NASA Technical Reports Server (NTRS)

Smialek, J. L.; Auping, J. V.

2004-01-01

Oxidation of high-temperature aerospace materials is a universal issue for combustion-path components in turbine or rocket engines. In addition to the question of the consumption of material due to growth of protective scale at use temperatures, there is also the question of cyclic effects and spallation of scale on cooldown. The spallation results in the removal of part of the protective oxide in a discontinuous step and thereby opens the way for more rapid oxidation upon reheating. In experiments, cyclic oxidation behavior is most commonly characterized by measuring changes in weight during extended time intervals that include hundreds or thousands of heating and cooling cycles. Weight gains occurring during isothermal scale-growth processes have been well characterized as being parabolic or nearly parabolic functions of time because diffusion controls reaction rates. In contrast, the net weight change in cyclic oxidation is the sum of the effects of the growth and spallation of scale. Typically, the net weight gain in cyclic oxidation is determined only empirically (that is, by measurement), with no unique or straightforward mathematical connection to either the rate of growth or the amount of metal consumed. Thus, there is a need for mathematical modeling to infer spallation mechanisms. COSP is a computer program that models the growth and spallation processes of cyclic oxidation on the basis of a few elementary assumptions that were discussed in COSP: A Computer Model of Cyclic Oxidation, Oxidation of Metals, vol. 36, numbers 1 and 2, 1991, pages 81-112. Inputs to the model include the selection of an oxidation-growth law and a spalling geometry, plus oxide-phase, growth-rate, cycle-duration, and spall-constant parameters. (The spalling fraction is often shown to be a constant factor times the existing amount of scale.) The output of COSP includes the net change in weight, the amounts of retained and spalled oxide, the total amounts of oxygen and metal

Cyclic dominance in evolutionary games: a review

PubMed Central

Szolnoki, Attila; Mobilia, Mauro; Jiang, Luo-Luo; Szczesny, Bartosz; Rucklidge, Alastair M.; Perc, Matjaž

2014-01-01

Rock is wrapped by paper, paper is cut by scissors and scissors are crushed by rock. This simple game is popular among children and adults to decide on trivial disputes that have no obvious winner, but cyclic dominance is also at the heart of predator–prey interactions, the mating strategy of side-blotched lizards, the overgrowth of marine sessile organisms and competition in microbial populations. Cyclical interactions also emerge spontaneously in evolutionary games entailing volunteering, reward, punishment, and in fact are common when the competing strategies are three or more, regardless of the particularities of the game. Here, we review recent advances on the rock–paper–scissors (RPS) and related evolutionary games, focusing, in particular, on pattern formation, the impact of mobility and the spontaneous emergence of cyclic dominance. We also review mean-field and zero-dimensional RPS models and the application of the complex Ginzburg–Landau equation, and we highlight the importance and usefulness of statistical physics for the successful study of large-scale ecological systems. Directions for future research, related, for example, to dynamical effects of coevolutionary rules and invasion reversals owing to multi-point interactions, are also outlined. PMID:25232048

Factors associated with early cyclicity in postpartum dairy cows.

PubMed

Vercouteren, M M A A; Bittar, J H J; Pinedo, P J; Risco, C A; Santos, J E P; Vieira-Neto, A; Galvão, K N

2015-01-01

The objective of this study was to evaluate factors associated with resumption of ovarian cyclicity within 21 days in milk (DIM) in dairy cows. Cows (n=768) from 2 herds in north Florida had their ovaries scanned at 17±3, 21±3, and 24±3 DIM. Cows that had a corpus luteum ≥20mm at 17±3 or at 21±3 DIM or that had a corpus luteum <20mm in 2 consecutive examinations were determined to be cyclic by 21±3 DIM. The following information was collected for up to 14 DIM: calving season, parity, calving problems, metabolic problems, metritis, mastitis, digestive problems, lameness, body weight loss, dry period length, and average daily milk yield. Body condition was scored at 17±3 DIM. Multivariable mixed logistic regression analysis was performed using the GLIMMIX procedure of SAS. Variables with P≤0.2 were considered in each model. Herd was included as a random variable. Three models were constructed: model 1 included all cows, model 2 included only cows from dairy 1 that had daily body weights available, and model 3 included only multiparous cows with a previous dry period length recorded. In model 1, variables associated with greater cyclicity by 21±3 DIM were calving in the summer and fall rather than in the winter or spring, being multiparous rather than primiparous, and not having metabolic or digestive problems. In model 2, variables associated with greater cyclicity by 21±3 DIM were calving in the summer and fall, not having metritis or digestive problems and not losing >28 kg of BW within 14 DIM. In model 3, variables associated with greater cyclicity by 21±3 DIM were absence of metabolic problems and dry period ≤76 d. In summary, cyclicity by 21±3 DIM was negatively associated with calving in winter or spring, primiparity, metritis, metabolic or digestive problems, loss of >28 kg of body weight, and a dry period >76d. Strategies preventing extended dry period length and loss of BW, together with reductions in the incidence of metritis as well as

Oxidation of Alkyl-substituted Cyclic Hydrocarbons by a Nocardia during Growth on n-Alkanes

PubMed Central

Davis, J. B.; Raymond, R. L.

1961-01-01

Nocardia 107-332, a soil isolate, oxidizes short-chain alkyl-substituted cyclic hydrocarbons to cyclic acids while growing on n-alkanes. Cyclic acids are produced also from relatively long-chain alkyl-substituted cyclics such as n-nonylbenzene or n-dodecylbenzene which alone support growth in a mineral-salts medium. ω-Oxidation of the alkyl substituents is followed by β-oxidation. It is of particular interest that cyclic acids such as cyclohexaneacetic and phenylacetic with C2 residual carboxylic acid substituents are resistant to further oxidation by the nocardia but cyclic acids with C1 or C3 substituents are readily oxidized and utilized for growth. The specificity of microbial oxidations is demonstrated by the conversion of p-isopropyltoluene (p-cymene) to p-isopropylbenzoic acid in n-alkane, growth-supported nocardia cultures. PMID:13720182

On Fitts's and Hooke's laws: simple harmonic movement in upper-limb cyclical aiming.

PubMed

Guiard, Y

1993-03-01

Can discrete, single-shot movements and continuous, cyclical movements be reduced to a single concept? In the classical, computational approach to human motor behaviour, cyclical aimed movement has generally been considered to derive from discrete primitives through a concatenation mechanism. Much importance, accordingly, has been attached to discrete-movement paradigms and to techniques allowing the segmentation of continuous data. An alternative approach, suggested by the nonlinear dynamical systems theory, views discreteness as a limiting case of cyclicity. Although attempts have been made recently to account for discrete movements in dynamical terms, cyclical paradigms have been favoured. The concatenation interpretation of cyclical aimed movement is criticized on the ground that it implies a complete waste of mechanical energy once in every half-cycle. Some kinematic data from a one-dimensional reciprocal (i.e., cyclical) aiming experiment are reported, suggesting that human subjects do save muscular efforts from one movement to the next in upper-limb cyclical aiming. The experiment demonstrated convergence on simple harmonic motion as aiming tolerance was increased, an outcome interpreted with reference to Hooke's law, in terms of the muscles' capability of storing potential, elastic energy across movement reversals. Not only is the concatenation concept problematic for understanding cyclical aimed movements, but the very reality of discrete movements is questionable too. It is pointed out that discrete motor acts of real life are composed of complete cycles, rather than half-cycles.

Severe congenital cyclic neutropenia: A case report

PubMed Central

Patil, Vidyavathi H; Hugar, Shivayogi M; Balikai, Girish; Patil, Sudha

2016-01-01

Congenital cyclic neutropenia syndrome is a constitutional genetic disorder which is characterized by very low number of neutrophils (neutropenia). Patients suffering from this disorder clinically present with neutropenia at early age, history of recurrent fever, ulcerations in the oral cavity, gingivitis, and other recurrent infections. This paper describes a case report of a child with recurrent mouth ulcers, fever, and later diagnosed with severe congenital cyclic neutropenia. This also emphasizes the importance of identification of rare causes of immunosuppressive conditions in children presenting with recurrent oral ulcers and poor dental hygiene, to prevent long-term complications of oral cavity and also morbidity and mortality secondary to neutropenic sepsis. PMID:27857902

Impact of glutathione S-transferase M1 and T1 on anti-tuberculosis drug-induced hepatotoxicity in Chinese pediatric patients.

PubMed

Liu, Fang; Jiao, An-xia; Wu, Xi-rong; Zhao, Wei; Yin, Qing-qin; Qi, Hui; Jiao, Wei-wei; Xiao, Jing; Sun, Lin; Shen, Chen; Tian, Jian-ling; Shen, Dan; Jacqz-Aigrain, Evelyne; Shen, A-dong

2014-01-01

Anti-tuberculosis drug induced hepatotoxicity (ATDH) is a major adverse drug reaction associated for anti-tuberculosis therapy. The glutathione S-transferases (GST) plays a crucial role in the detoxification of hepatotoxic metabolites of anti-tuberculosis drugs.An association between GSTM1/GSTT1 null mutations and increased risk of ATDH has been demonstrated in adults. Given the ethnic differences and developmental changes, our study aims to investigate the potential impacts of GSTM1/GSTT1 genotypes on the development of ATDH in Han Chinese children treated with anti-tuberculosis therapy. Children receiving anti-tuberculosis therapy with or without evidence of ATDH were considered as the cases or controls, respectively. The GSTM1 and GSTT1 genotyping were performed using the polymerase chain reaction. One hundred sixty-three children (20 cases and 143 controls) with a mean age of 4.7 years (range: 2 months-14.1 years) were included. For the GSTM1, 14 (70.0%) cases and 96 (67.1%) controls had homozygous null mutations. For the GSTT1, 13 (65.0%) cases and 97 (67.8%) controls had homozygous null mutations. Neither the GSTM1, nor the GSTT1 polymorphism was significantly correlated with the occurrence of ATHD. Our results did not support the GSTM1 and GSTT1 polymorphisms as the predictors of ADTH in Chinese Han children treated with anti-tuberculosis drugs. An age-related association between pharmacogenetics and ATHD need to be confirmed in the further study.

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

PubMed Central

Lee, Seo Yeon; Ko, Kwang Suk

2016-01-01

Background 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. Methods 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. Results 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. Conclusions Combinations of SAMe with taurine and/or betaine have a hepatoprotective effect against ethanol-induced liver injury by maintaining GSH homeostasis. PMID:27722142

Prediction of elemental creep. [steady state and cyclic data from regression analysis

NASA Technical Reports Server (NTRS)

Davis, J. W.; Rummler, D. R.

1975-01-01

Cyclic and steady-state creep tests were performed to provide data which were used to develop predictive equations. These equations, describing creep as a function of stress, temperature, and time, were developed through the use of a least squares regression analyses computer program for both the steady-state and cyclic data sets. Comparison of the data from the two types of tests, revealed that there was no significant difference between the cyclic and steady-state creep strains for the L-605 sheet under the experimental conditions investigated (for the same total time at load). Attempts to develop a single linear equation describing the combined steady-state and cyclic creep data resulted in standard errors of estimates higher than obtained for the individual data sets. A proposed approach to predict elemental creep in metals uses the cyclic creep equation and a computer program which applies strain and time hardening theories of creep accumulation.

Cyclic Load Effects on Long Term Behavior of Polymer Matrix Composites

NASA Technical Reports Server (NTRS)

Shah, A. R.; Chamis, C. C.

1996-01-01

A methodology to compute the fatigue life for different ratios, r, of applied stress to the laminate strength based on first ply failure criteria combined with thermal cyclic loads has been developed and demonstrated. Degradation effects resulting from long term environmental exposure and thermo-mechanical cyclic loads are considered in the simulation process. A unified time-stress dependent multi-factor interaction equation model developed at NASA Lewis Research Center has been used to account for the degradation of material properties caused by cyclic and aging loads. Effect of variation in the thermal cyclic load amplitude on a quasi-symmetric graphite/epoxy laminate has been studied with respect to the impending failure modes. The results show that, for the laminate under consideration, the fatigue life under combined mechanical and low thermal amplitude cyclic loads is higher than that due to mechanical loads only. However, as the thermal amplitude increases, the life also decreases. The failure mode changes from tensile under mechanical loads only to the compressive and shear at high mechanical and thermal loads. Also, implementation of the developed methodology in the design process has been discussed.

Alleviative effects of s-allyl cysteine and s-ethyl cysteine on MCD diet-induced hepatotoxicity in mice.

PubMed

Lin, Chun-che; Yin, Mei-chin; Liu, Wen-hu

2008-11-01

Alleviative effects of s-allyl cysteine (SAC) and s-ethyl cysteine (SEC) upon methionine and choline deficient (MCD) diet-induced hepatotoxicity in mice were examined. SAC or SEC at 1g/L was added into drinking water for 7 weeks with MCD diet. MCD feeding significantly increased hepatic triglyceride and cholesterol levels, and elevated the activity of glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme, fatty acid synthase (FAS) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (P < 0.05). However, the intake of SAC or SEC significantly decreased hepatic triglyceride accumulation, and reduced G6PDH and FAS activities (P < 0.05). MCD feeding significantly lowered serum and hepatic glutathione (GSH) levels, increased malondialdehyde (MDA) and oxidized glutathione (GSSG) formation, and suppressed the activity and mRNA expression of glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (P < 0.05). The intake of SAC or SEC significantly increased serum and hepatic GSH levels, decreased MDA and GSSG formation, restored the activity and mRNA expression of GPX, SOD and catalase (P < 0.05). MCD feeding significantly enhanced the mRNA expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, matrix metalloproteinases-9 (MMP-9) and collagen-alpha1 (P < 0.05). The intake of SAC and SEC significantly blunted the mRNA expression of IL-1beta, IL-6, TNF-alpha, TGF-beta1 and collagen-alpha1 (P < 0.05). SEC was greater than SAC in suppressing IL-6 and TNF-alpha expression (P < 0.05), but SAC was greater than SEC in suppressing collagen-alpha1 and TGF-beta1 expression (P < 0.05). These data suggest that SAC and SEC are potent agents against MCD-induced hepatotoxicity.

Cyclic adenosine 3′,5′-monophosphate in human lymphocytes. Alterations after phytohemagglutinin stimulation

PubMed Central

Smith, Jay W.; Steiner, Alton L.; Newberry, W. Marcus; Parker, Charles W.

1971-01-01

We have studied cyclic adenosine 3′,5′-monophosphate (cyclic AMP) concentrations in human peripheral blood lymphocytes after stimulation with phytohemagglutinin (PHA), isoproterenol, prostaglandins, and aminophylline. Purified lymphocytes were obtained by nylon fiber chromatography, and low speed centrifugation to remove platelets. Cyclic AMP levels were determined by a highly sensitive radioimmunoassay. At concentrations of 0.1-1.0 mmoles/liter isoproterenol and aminophylline produced moderate increases in cyclic AMP concentrations, whereas prostaglandins produced marked elevations. High concentrations of PHA produced 25-300% increases in cyclic AMP levels, alterations being demonstrated within 1-2 min. The early changes in cyclic AMP concentration appear to precede previously reported metabolic changes in PHA-stimulated cells. After 6 hr cyclic AMP levels in PHA-stimulated cells had usually fallen to the levels of control cells. After 24 hr the level in PHA-stimulated cells was characteristically below that of the control cells. Adenyl cyclase, the enzyme which converts ATP to cyclic AMP, was measured in lymphocyte homogenates. Adenyl cyclase activity was rapidly stimulated by fluoride, isoproterenol, prostaglandins, and PHA. Since adenyl cyclase is characteristically localized in external cell membranes, our results are consistent with an initial action of PHA at this level. PMID:4395563

Protection of rats against 3-butene-1,2-diol-induced hepatotoxicity and hypoglycemia by N-acetyl-L-cysteine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sprague, Christopher L.; Elfarra, Adnan A.

2005-09-15

3-Butene-1,2-diol (BDD), an allylic alcohol and major metabolite of 1,3-butadiene, has previously been shown to cause hepatotoxicity and hypoglycemia in male Sprague-Dawley rats, but the mechanisms of toxicity were unclear. In this study, rats were administered BDD (250 mg/kg) or saline, ip, and serum insulin levels, hepatic lactate levels, and hepatic cellular and mitochondrial GSH, GSSG, ATP, and ADP levels were measured 1 or 4 h after treatment. The results show that serum insulin levels were not causing the hypoglycemia and that the hypoglycemia was not caused by an enhancement of the metabolism of pyruvate to lactate because hepatic lactatemore » levels were either similar (1 h) or lower (4 h) than controls. However, both hepatic cellular and mitochondrial GSH and GSSG levels were severely depleted 1 and 4 h after treatment and the mitochondrial ATP/ADP ratio was also lowered 4 h after treatment relative to controls. Because these results suggested a role for hepatic cellular and mitochondrial GSH in BDD toxicity, additional rats were administered N-acetyl-L-cysteine (NAC; 200 mg/kg) 15 min after BDD administration. NAC treatment partially prevented depletion of hepatic cellular and mitochondrial GSH and preserved the mitochondrial ATP/ADP ratio. NAC also prevented the severe depletion of serum glucose concentration and the elevation of serum alanine aminotransferase activity after BDD treatment without affecting the plasma concentration of BDD. Thus, depletion of hepatic cellular and mitochondrial GSH followed by the decrease in the mitochondrial ATP/ADP ratio was likely contributing to the mechanisms of hepatotoxicity and hypoglycemia in the rat.« less

On cyclic yield strength in definition of limits for characterisation of fatigue and creep behaviour

NASA Astrophysics Data System (ADS)

Gorash, Yevgen; MacKenzie, Donald

2017-06-01

This study proposes cyclic yield strength as a potential characteristic of safe design for structures operating under fatigue and creep conditions. Cyclic yield strength is defined on a cyclic stress-strain curve, while monotonic yield strength is defined on a monotonic curve. Both values of strengths are identified using a two-step procedure of the experimental stress-strain curves fitting with application of Ramberg-Osgood and Chaboche material models. A typical S-N curve in stress-life approach for fatigue analysis has a distinctive minimum stress lower bound, the fatigue endurance limit. Comparison of cyclic strength and fatigue limit reveals that they are approximately equal. Thus, safe fatigue design is guaranteed in the purely elastic domain defined by the cyclic yielding. A typical long-term strength curve in time-to-failure approach for creep analysis has two inflections corresponding to the cyclic and monotonic strengths. These inflections separate three domains on the long-term strength curve, which are characterised by different creep fracture modes and creep deformation mechanisms. Therefore, safe creep design is guaranteed in the linear creep domain with brittle failure mode defined by the cyclic yielding. These assumptions are confirmed using three structural steels for normal and high-temperature applications. The advantage of using cyclic yield strength for characterisation of fatigue and creep strength is a relatively quick experimental identification. The total duration of cyclic tests for a cyclic stress-strain curve identification is much less than the typical durations of fatigue and creep rupture tests at the stress levels around the cyclic yield strength.

Hierarchical assembly of branched supramolecular polymers from (cyclic Peptide)-polymer conjugates.

PubMed

Koh, Ming Liang; Jolliffe, Katrina A; Perrier, Sébastien

2014-11-10

We report the synthesis and assembly of (N-methylated cyclic peptide)-polymer conjugates for which the cyclic peptide is attached to either the α- or both α- and ω- end groups of a polymer. A combination of chromatographic, spectroscopic, and scattering techniques reveals that the assembly of the conjugates follows a two-level hierarchy, initially driven by H-bond formation between two N-methylated cyclic peptides, followed by unspecific, noncovalent aggregation of this peptide into small domains that behave as branching points and lead to the formation of branched supramolecular polymers.

Identification of cytidine 2',3'-cyclic monophosphate and uridine 2',3'-cyclic monophosphate in Pseudomonas fluorescens pfo-1 culture.

PubMed

Bordeleau, Emily; Oberc, Christopher; Ameen, Eve; da Silva, Amanda Mendes; Yan, Hongbin

2014-09-15

Cytidine 2',3'-cyclic monophosphate (2',3'-cCMP) and uridine 2',3'-cyclic monophosphate (2',3'-cUMP) were isolated from Pseudomonas fluorescens pfo-1 cell extracts by semi-preparative reverse phase HPLC. The structures of the two compounds were confirmed by NMR and mass spectroscopy against commercially available authentic samples. Concentrations of both intracellular and extracellular 2',3'-cCMP and 2',3'-cUMP were determined. Addition of 2',3'-cCMP and 2',3'-cUMP to P. fluorescens pfo-1 culture did not significantly affect the level of biofilm formation in static liquid cultures. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of Ranitidine on Acetaminophen-Induced Hepatotoxicity in Dogs

PubMed Central

Panella, C.; Makowka, L.; Barone, M.; Polimeno, L.; Rizzi, S.; Demetris, J.; Bell, S.; Guglielmi, F. W.; Prelich, J. G.; Van Thiel, D. H.; Starzl, T. E.; Francavilla, A.

2010-01-01

The effect of ranitidine administration upon the hepatotoxic effect produced by a multidose acetaminophen administration regimen was examined. Seventy-two dogs received three subcutaneous injections of acetaminophen (750, 200, 200 mg/kg body wt) in DMSO (600 mg/ml) at time zero, 9 hr later, and 24 hr after the first dose. Ten control animals (group I) were not given ranitidine, the remaining 62 dogs received an intramuscular injection of ranitidine 30 min before each acetaminophen dose. Three different doses of ranitidine were used (mg/kg body wt): 50 mg, group II (33 dogs); 75 mg, group III (14 dogs); 120 mg, group IV (15 dogs). Ranitidine reduced the expected acetaminophen-induced hepatoxicity in a dose–response manner. Moreover, a significant correlation was found between the ranitidine dose and the survival rate, as evidenced by transaminase levels in the serum and histology of the liver. This model of fulminant hepatic failure induced by acetaminophen and its modulation with ranitidine provides clinical investigators with a research tool that will be useful in the future investigation of putative medical and surgical therapies being investigated for use in the clinical management of fulminant hepatic failure. Because of the size of the animal used in this model, frequent and serial analyses of blood and liver were available for study to determine the effect of therapy within a given animal as opposed to within groups of animals. PMID:2307085

Topology and symmetry of surface Majorana arcs in cyclic superconductors

NASA Astrophysics Data System (ADS)

Mizushima, Takeshi; Nitta, Muneto

2018-01-01

We study the topology and symmetry of surface Majorana arcs in superconductors with nonunitary "cyclic" pairing. Cyclic p -wave pairing may be realized in a cubic or tetrahedral crystal, while it is a candidate for the interior P32 superfluids of neutron stars. The cyclic state is an admixture of full gap and nodal gap with eight Weyl points and the low-energy physics is governed by itinerant Majorana fermions. We here show the evolution of surface states from Majorana cone to Majorana arcs under rotation of surface orientation. The Majorana cone is protected solely by an accidental spin rotation symmetry and fragile against spin-orbit coupling, while the arcs are attributed to two topological invariants: the first Chern number and one-dimensional winding number. Lastly, we discuss how topologically protected surface states inherent to the nonunitary cyclic pairing can be captured from surface probes in candidate compounds, such as U1 -xThxBe13 . We examine tunneling conductance spectra for two competitive scenarios in U1 -xThxBe13 —the degenerate Eu scenario and the accidental scenario.

Revisiting the formation of cyclic clusters in liquid ethanol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balanay, Mannix P.; Fan, Haiyan, E-mail: haiyan.fan@nu.edu.kz; Kim, Dong Hee

2016-04-21

The liquid phase of ethanol in pure and in non-polar solvents was studied at room temperature using Fourier transform infrared (FT-IR) and {sup 1}H nuclear magnetic resonance (NMR) spectroscopies together with theoretical approach. The FT-IR spectra for pure ethanol and solution in cyclohexane at different dilution stages are consistent with {sup 1}H NMR results. The results from both methods were best explained by the results of the density functional theory based on a multimeric model. It is suggested that cyclic trimers and tetramers are dominated in the solution of cyclohexane/hexane with the concentration greater than 0.5M at room temperature. Inmore » liquid ethanol, while the primary components at room temperature are cyclic trimers and tetramers, there is a certain amount (∼14%) of open hydroxide group representing the existence of chain like structures in the equilibria. The cyclic cluster model in the liquid and concentrated solution phase (>0.5M) can be used to explain the anomalously lower freezing point of ethanol (159 K) than that of water (273 K) at ambient conditions. In addition, {sup 1}H NMR at various dilution stages reveals the dynamics for the formation of cyclic clusters.« less

Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model

PubMed Central

Takuma, K; Lee, E; Enomoto, R; Mori, K; Baba, A; Matsuda, T

2001-01-01

We examined the effect of 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (ibudilast), which has been clinically used for bronchial asthma and cerebrovascular disorders, on cell viability induced in a model of reperfusion injury. Ibudilast at 10 – 100 μM significantly attenuated the H2O2-induced decrease in cell viability. Ibudilast inhibited the H2O2-induced cytochrome c release, caspase-3 activation, DNA ladder formation and nuclear condensation, suggesting its anti-apoptotic effect. Phosphodiesterase inhibitors such as theophylline, pentoxyfylline, vinpocetine, dipyridamole and zaprinast, which increased the guanosine-3′,5′-cyclic monophosphate (cyclic GMP) level, and dibutyryl cyclic GMP attenuated the H2O2-induced injury in astrocytes. Ibudilast increased the cyclic GMP level in astrocytes. The cyclic GMP-dependent protein kinase inhibitor KT5823 blocked the protective effects of ibudilast and dipyridamole on the H2O2-induced decrease in cell viability, while the cyclic AMP-dependent protein kinase inhibitor KT5720, the cyclic AMP antagonist Rp-cyclic AMPS, the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD98059 and the leukotriene D4 antagonist LY 171883 did not. KT5823 also blocked the effect of ibudilast on the H2O2-induced cytochrome c release and caspase-3-like protease activation. These findings suggest that ibudilast prevents the H2O2-induced delayed apoptosis of astrocytes via a cyclic GMP, but not cyclic AMP, signalling pathway. PMID:11454657

Cyclic axial-torsional deformation behavior of a cobalt-base superalloy

NASA Technical Reports Server (NTRS)

Bonacuse, Peter J.; Kalluri, Sreeramesh

1992-01-01

Multiaxial loading, especially at elevated temperature, can cause the inelastic response of a material to differ significantly from that predicted by simple flow rules, i.e., von Mises or Tresca. To quantify some of these differences, the cyclic high-temperature, deformation behavior of a wrought cobalt-based superalloy, Haynes 188, is investigated under combined axial and torsional loads. Haynes 188 is currently used in many aerospace gas turbine and rocket engine applications, e.g., the combustor liner for the T800 turboshaft engine for the RAH-66 Comanche helicopter and the liquid oxygen posts in the main injector of the space shuttle main engine. The deformation behavior of this material is assessed through the examination of hysteresis loops generated from a biaxial fatigue test program. A high-temperature axial, torsional, and combined axial-torsional fatigue data base has been generated on Haynes 188 at 760 C. Cyclic loading tests have been conducted on uniform gauge section tubular specimens in a servohydraulic axial-torsional test rig. Test control and data acquisition were accomplished with a minicomputer. In this paper, the cyclic hardening characteristics and typical hysteresis loops in the axial stress versus axial strain, shear stress versus engineering shear strain, axial strain versus engineering shear strain, and axial stress versus shear stress spaces are presented for cyclic, in-phase and out-of-phase, axial torsional tests. For in-phase tests three different values of the proportionality constant, lambda (ratio of engineering shear strain amplitude to axial strain amplitude), are examined, viz., 0.86, 1.73, and 3.46. In the out-of-phase tests, three different values of the phase angle, phi (between the axial and engineering shear strain waveforms), are studied, viz., 30, 60, and 90 deg with lambda = 1.73. The cyclic hardening behaviors of all the tests conducted on Haynes 188 at 760 C are evaluated using the von Mises equivalent stress

Cyclic hardening behavior of extruded ZK60 magnesium alloy with different grain sizes

NASA Astrophysics Data System (ADS)

Zhang, Lixin; Zhang, Wencong; Chen, Wenzhen; Wang, Wenke

2018-04-01

Montonic and fully reversed strain-controlled cyclic deformation experiments were conducted on extruded ZK60 magnesium alloy with two different grain sizes in ambient air. Results revealed that the hardening rates of the ZK60 magnesium alloy rods with fine grain and coarse grain in the monotonic deformation and the fully reversed strain-controlled cyclic deformation were opposite along the extrusion direction. Electron Backscatter Diffration analysis revealed that fine grains were more easily rotated than coarse grains under the cyclic deformation. Under the twinning and detwinning process of the cyclic deformation at a large strain amplitude, the coarse grained ZK60 magnesium alloys were more prone to tension twinning {10-12}<10-11> and more residual twins were observed. Texture hardening of coarse grained magnesium alloy was more obvious in cyclic defromation than fine-grained magnesium alloy.

Silybum marianum (milk thistle) in the management and prevention of hepatotoxicity in a patient undergoing reinduction therapy for acute myelogenous leukemia.

PubMed

McBride, Ali; Augustin, Kristan M; Nobbe, Julie; Westervelt, Peter

2012-09-01

Hepatotoxicity has been observed with several chemotherapy agents and combination regimens. Conventional treatment methods often include supportive care or observation. We report a case of a patient with noted transaminitis presumed secondary to chemotherapy, which did not resolve with supportive care but was shown to respond to milk thistle. The patient had an immediate decrease in liver function tests and showed decreased elevation in levels upon treatment with subsequent chemotherapy regimens. This case demonstrates the potential efficacy of milk thistle as a unique hepatoprotective agent.

Cyclic Oxidation and Hot Corrosion of NiCrY-Coated Disk Superalloy

NASA Technical Reports Server (NTRS)

Gabb, Tim; Miller, R. A.; Sudbrack, C. K.; Draper, S. L.; Nesbitt, J.; Telesman, J.; Ngo, V.; Healy, J.

2015-01-01

Powder metallurgy disk superalloys have been designed for higher engine operating temperatures through improvement of their strength and creep resistance. Yet, increasing disk application temperatures to 704 C and higher could enhance oxidation and activate hot corrosion in harmful environments. Protective coatings could be necessary to mitigate such attack. Cylindrical coated specimens of disk superalloys LSHR and ME3 were subjected to thermal cycling to produce cyclic oxidation in air at a maximum temperature of 760 C. The effects of substrate roughness and coating thickness on coating integrity after cyclic oxidation were considered. Selected coated samples that had cyclic oxidation were then subjected to accelerated hot corrosion tests. The effects of this cyclic oxidation on resistance to subsequent hot corrosion attack were examined.

Cyclic Oxidation and Hot Corrosion of NiCrY-Coated Disk Superalloys

NASA Technical Reports Server (NTRS)

Gabb, Timothy P.; Miller, Robert A.; Sudbrack, Chantal K.; Draper, Susan L.; Nesbitt, James A.; Rogers, Richard B.; Telesman, Ignacy; Ngo, Vanda; Healy, Jonathan

2016-01-01

Powder metallurgy disk superalloys have been designed for higher engine operating temperatures through improvement of their strength and creep resistance. Yet, increasing disk application temperatures to 704 degrees Centigrade and higher could enhance oxidation and activate hot corrosion in harmful environments. Protective coatings could be necessary to mitigate such attack. Cylindrical coated specimens of disk superalloys LSHR and ME3 were subjected to thermal cycling to produce cyclic oxidation in air at a maximum temperature of 760 degrees Centigrade. The effects of substrate roughness and coating thickness on coating integrity after cyclic oxidation were considered. Selected coated samples that had cyclic oxidation were then subjected to accelerated hot corrosion tests. This cyclic oxidation did not impair the coating's resistance to subsequent hot corrosion pitting attack.

On the energy efficiency of cyclic mechanisms

NASA Astrophysics Data System (ADS)

Briskin, E. S.; Kalinin, Ya. V.; Maloletov, A. V.; Chernyshev, V. V.

2014-01-01

We consider cyclic mechanisms with one degree of freedom driven by engines of various types such as alternating and direct current motors, internal combustion engines, etc. We pose the problem of modifying the mechanism structure by joining additional links or by varying the parameters or operation mode of the original mechanism so as to minimize the thermal losses in the driving motor. The solution is based on the minimization of the functional determining the irreversible power losses. We show that, for the engines considered, all cyclic mechanisms with one degree of freedom should satisfy a fundamental condition ensuring the minimum of losses. We consider two examples, one of which corresponds to actually existing mechanisms.

Effect of Cyclic Thermo-Mechanical Loads on Fatigue Reliability in Polymer Matrix Composites

NASA Technical Reports Server (NTRS)

Shah, A. R.; Murthy, P. L. N.; Chamis, C. C.

1996-01-01

A methodology to compute probabilistic fatigue life of polymer matrix laminated composites has been developed and demonstrated. Matrix degradation effects caused by long term environmental exposure and mechanical/thermal cyclic loads are accounted for in the simulation process. A unified time-temperature-stress dependent multi-factor interaction relationship developed at NASA Lewis Research Center has been used to model the degradation/aging of material properties due to cyclic loads. The fast probability integration method is used to compute probabilistic distribution of response. Sensitivities of fatigue life reliability to uncertainties in the primitive random variables (e.g., constituent properties, fiber volume ratio, void volume ratio, ply thickness, etc.) computed and their significance in the reliability- based design for maximum life is discussed. The effect of variation in the thermal cyclic loads on the fatigue reliability for a (0/+/- 45/90)(sub s) graphite/epoxy laminate with a ply thickness of 0.127 mm, with respect to impending failure modes has been studied. The results show that, at low mechanical cyclic loads and low thermal cyclic amplitudes, fatigue life for 0.999 reliability is most sensitive to matrix compressive strength, matrix modulus, thermal expansion coefficient, and ply thickness. Whereas at high mechanical cyclic loads and high thermal cyclic amplitudes, fatigue life at 0.999 reliability is more sensitive to the shear strength of matrix, longitudinal fiber modulus, matrix modulus, and ply thickness.

Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI

PubMed Central

Kegel, Victoria; Pfeiffer, Elisa; Burkhardt, Britta; Liu, Jia L.; Zeilinger, Katrin; Nüssler, Andreas K.; Seehofer, Daniel; Damm, Georg

2015-01-01

Drug induced liver injury (DILI) is an idiosyncratic adverse drug reaction leading to severe liver damage. Kupffer cells (KC) sense hepatic tissue stress/damage and therefore could be a tool for the estimation of consequent effects associated with DILI. Aim of the present study was to establish a human in vitro liver model for the investigation of immune-mediated signaling in the pathogenesis of DILI. Hepatocytes and KC were isolated from human liver specimens. The isolated KC yield was 1.2 ± 0.9 × 106 cells/g liver tissue with a purity of >80%. KC activation was investigated by the measurement of reactive oxygen intermediates (ROI, DCF assay) and cell activity (XTT assay). The initial KC activation levels showed broad donor variability. Additional activation of KC using supernatants of hepatocytes treated with hepatotoxic drugs increased KC activity and led to donor-dependent changes in the formation of ROI compared to KC incubated with supernatants from untreated hepatocytes. Additionally, a compound- and donor-dependent increase in proinflammatory cytokines or in anti-inflammatory cytokines was detected. In conclusion, KC related immune signaling in hepatotoxicity was successfully determined in a newly established in vitro liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production. PMID:26491234

Cyclic dominance in evolutionary games: a review.

PubMed

Szolnoki, Attila; Mobilia, Mauro; Jiang, Luo-Luo; Szczesny, Bartosz; Rucklidge, Alastair M; Perc, Matjaž

2014-11-06

Rock is wrapped by paper, paper is cut by scissors and scissors are crushed by rock. This simple game is popular among children and adults to decide on trivial disputes that have no obvious winner, but cyclic dominance is also at the heart of predator-prey interactions, the mating strategy of side-blotched lizards, the overgrowth of marine sessile organisms and competition in microbial populations. Cyclical interactions also emerge spontaneously in evolutionary games entailing volunteering, reward, punishment, and in fact are common when the competing strategies are three or more, regardless of the particularities of the game. Here, we review recent advances on the rock-paper-scissors (RPS) and related evolutionary games, focusing, in particular, on pattern formation, the impact of mobility and the spontaneous emergence of cyclic dominance. We also review mean-field and zero-dimensional RPS models and the application of the complex Ginzburg-Landau equation, and we highlight the importance and usefulness of statistical physics for the successful study of large-scale ecological systems. Directions for future research, related, for example, to dynamical effects of coevolutionary rules and invasion reversals owing to multi-point interactions, are also outlined. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Microgravity changes in heart structure and cyclic-AMP metabolism

NASA Technical Reports Server (NTRS)

Philpott, D. E.; Fine, A.; Kato, K.; Egnor, R.; Cheng, L.

1985-01-01

The effects of microgravity on cardiac ultrastructure and cyclic AMP metabolism in tissues of rats flown on Spacelab 3 are reported. Light and electron microscope studies of cell structure, measurements of low and high Km phosphodiesterase activity, cyclic AMP-dependent protein kinase activity, and regulatory subunit compartmentation show significant deviations in flight animals when compared to ground controls. The results indicate that some changes have occurred in cellular responses associated with catecholamine receptor interactions and intracellular signal processing.

Cyclic Peptides Arising by Evolutionary Parallelism via Asparaginyl-Endopeptidase–Mediated Biosynthesis[C][W

PubMed Central

Mylne, Joshua S.; Chan, Lai Yue; Chanson, Aurelie H.; Daly, Norelle L.; Schaefer, Hanno; Bailey, Timothy L.; Nguyencong, Philip; Cascales, Laura; Craik, David J.

2012-01-01

The cyclic miniprotein Momordica cochinchinensis Trypsin Inhibitor II (MCoTI-II) (34 amino acids) is a potent trypsin inhibitor (TI) and a favored scaffold for drug design. We have cloned the corresponding genes and determined that each precursor protein contains a tandem series of cyclic TIs terminating with the more commonly known, and potentially ancestral, acyclic TI. Expression of the precursor protein in Arabidopsis thaliana showed that production of the cyclic TIs, but not the terminal acyclic TI, depends on asparaginyl endopeptidase (AEP) for maturation. The nature of their repetitive sequences and the almost identical structures of emerging TIs suggest these cyclic peptides evolved by internal gene amplification associated with recruitment of AEP for processing between domain repeats. This is the third example of similar AEP-mediated processing of a class of cyclic peptides from unrelated precursor proteins in phylogenetically distant plant families. This suggests that production of cyclic peptides in angiosperms has evolved in parallel using AEP as a constraining evolutionary channel. We believe this is evolutionary evidence that, in addition to its known roles in proteolysis, AEP is especially suited to performing protein cyclization. PMID:22822203

Comparison of cyclic fatigue resistance of original and counterfeit rotary instruments.

PubMed

Ertas, Huseyin; Capar, Ismail Davut; Arslan, Hakan; Akan, Ender

2014-05-31

In recent years, with the advances in counterfeiting methods, counterfeit products have reached the dental market. The purpose of this study was to compare the cyclic fatigue resistance of original and counterfeit rotary root canal instruments. The cyclic fatigue of original and counterfeit ProTaper F2 endodontic instruments was tested (n = 20) in 3 mm radius steel canals with a 60° angle of curvature. The number of cycles to fracture (NCF) was calculated, and the data were subjected to the Student's t-test (α = 0.05). The original instruments showed better cyclic fatigue resistance than the counterfeit ones (p < .001). The mean NCF was 483 ± 84 for the original files and 186 ± 86 for the counterfeit files. The cyclic fatigue resistance of the counterfeit instruments was very low. As a result, clinicians should be careful not to purchase counterfeit products.

Experimental investigation of steel fiber-reinforced concrete beams under cyclic loading

NASA Astrophysics Data System (ADS)

Ranjbaran, Fariman; Rezayfar, Omid; Mirzababai, Rahmatollah

2018-03-01

An experimental study has been conducted to study the cyclic behavior of reinforced concrete beams in which steel fibers were added to the concrete mix. Seven similar geometrically specimens in full scale were studied under four- point bending test in the form of slow cyclic loading. One sample as a control specimen was made without steel fibers or 0% volume fraction (vf) and six other samples with 1, 2 and 4% vf of steel fibers in twin models. The maximum and ultimate resistance, ductility, degradation of loading and unloading stiffness, absorption and dissipation of energy and equivalent viscous damping were studied in this investigation and the effect of steel fibers on the cyclic behavior was compared with each other. Generally, the addition of steel fibers up to a certain limit value (vf = 2%) improves the cyclic behavior of reinforced concrete beams and results in the increase of maximum strength and ultimate displacement.

Cyclic electron flow is redox-controlled but independent of state transition.

PubMed

Takahashi, Hiroko; Clowez, Sophie; Wollman, Francis-André; Vallon, Olivier; Rappaport, Fabrice

2013-01-01

Photosynthesis is the biological process that feeds the biosphere with reduced carbon. The assimilation of CO2 requires the fine tuning of two co-existing functional modes: linear electron flow, which provides NADPH and ATP, and cyclic electron flow, which only sustains ATP synthesis. Although the importance of this fine tuning is appreciated, its mechanism remains equivocal. Here we show that cyclic electron flow as well as formation of supercomplexes, thought to contribute to the enhancement of cyclic electron flow, are promoted in reducing conditions with no correlation with the reorganization of the thylakoid membranes associated with the migration of antenna proteins towards Photosystems I or II, a process known as state transition. We show that cyclic electron flow is tuned by the redox power and this provides a mechanistic model applying to the entire green lineage including the vast majority of the cases in which state transition only involves a moderate fraction of the antenna.

Comparison of CYP2D metabolism and hepatotoxicity of the myocardial metabolic agent perhexiline in Sprague-Dawley and Dark Agouti rats.

PubMed

Licari, Giovanni; Somogyi, Andrew A; Milne, Robert W; Sallustio, Benedetta C

2015-01-01

1. Perhexiline, a chiral anti-anginal agent, may be useful to develop new cardiovascular therapies, despite its potential hepatotoxicity. 2. This study compared Dark Agouti (DA) and Sprague-Dawley (SD) rats, as models of perhexiline's metabolism and hepatotoxicity in humans. Rats (n = 4/group) received vehicle or 200 mg/kg/d of racemic perhexiline maleate for 8 weeks. Plasma and liver samples were collected to determine concentrations of perhexiline and its metabolites, hepatic function and histology. 3. Median (range) plasma and liver perhexiline concentrations in SD rats were 0.09 (0.04-0.13) mg/L and 5.42 (0.92-8.22) ng/mg, respectively. In comparison, DA rats showed higher (p < 0.05) plasma 0.50 (0.16-1.13) mg/L and liver 24.5 (9.40-54.7) ng/mg perhexiline concentrations, respectively, 2.5- and 3.7-fold higher cis-OH-perhexiline concentrations, respectively (p < 0.05), and lower plasma metabolic ratio (0.89 versus 1.55, p < 0.05). In both strains, the (+):(-) enantiomer ratio was 2:1. Perhexiline increased plasma LDH concentrations in DA rats (p < 0.05), but had no effect on plasma biochemistry in SD rats. Liver histology revealed lower glycogen content in perhexiline-treated SD rats (p < 0.05), but no effects on lipid content in either strain. 4. DA rats appeared more similar to humans with respect to plasma perhexiline concentrations, metabolic ratio, enantioselective disposition and biochemical changes suggestive of perhexiline-induced toxicity.

Physiological cyclic strain promotes endothelial cell survival via the induction of heme oxygenase-1

PubMed Central

Liu, Xiao-ming; Peyton, Kelly J.

2013-01-01

Endothelial cells (ECs) are constantly subjected to cyclic strain that arises from periodic change in vessel wall diameter as a result of pulsatile blood flow. Application of physiological levels of cyclic strain inhibits EC apoptosis; however, the underlying mechanism is not known. Since heme oxygenase-1 (HO-1) is a potent inhibitor of apoptosis, the present study investigated whether HO-1 contributes to the antiapoptotic action of cyclic strain. Administration of physiological cyclic strain (6% at 1 Hz) to human aortic ECs stimulated an increase in HO-1 activity, protein, and mRNA expression. The induction of HO-1 was preceded by a rise in reactive oxygen species (ROS) and Nrf2 protein expression. Cyclic strain also stimulated an increase in HO-1 promoter activity that was prevented by mutating the antioxidant responsive element in the promoter or by overexpressing dominant-negative Nrf2. In addition, the strain-mediated induction of HO-1 and activation of Nrf2 was abolished by the antioxidant N-acetyl-l-cysteine. Finally, application of cyclic strain blocked inflammatory cytokine-mediated EC death and apoptosis. However, the protective action of cyclic strain was reversed by the HO inhibitor tin protoporphyrin-IX and was absent in ECs isolated from HO-1-deficient mice. In conclusion, the present study demonstrates that a hemodynamically relevant level of cyclic strain stimulates HO-1 gene expression in ECs via the ROS-Nrf2 signaling pathway to inhibit EC death. The ability of cyclic strain to induce HO-1 expression may provide an important mechanism by which hemodynamic forces promote EC survival and vascular homeostasis. PMID:23604711

Mixed-mode cyclic debonding of adhesively bonded composite joints. M.S. Thesis

NASA Technical Reports Server (NTRS)

Rezaizadeh, M. A.; Mall, S.

1985-01-01

A combined experimental-analytical investigation to characterize the cyclic failure mechanism of a simple composite-to-composite bonded joint is conducted. The cracked lap shear (CLS) specimens of graphite/epoxy adherend bonded with EC-3445 adhesive are tested under combined mode 1 and 2 loading. In all specimens tested, fatigue failure occurs in the form of cyclic debonding. The cyclic debond growth rates are measured. The finite element analysis is employed to compute the mode 1, mode 2, and total strain energy release rates (i.e., GI, GII, and GT). A wide range of mixed-mode loading, i.e., GI/GII ranging from 0.03 to 0.38, is obtained. The total strain energy release rate, G sub T, appeared to be the driving parameter for cyclic debonding in the tested composite bonded system.

Effects of fenspiride on human bronchial cyclic nucleotide phosphodiesterase isoenzymes: functional and biochemical study.

PubMed

Cortijo, J; Naline, E; Ortiz, J L; Berto, L; Girard, V; Malbezin, M; Advenier, C; Morcillo, E J

1998-01-02

We have investigated the role of human bronchial cyclic nucleotide phosphodiesterases in the effects of fenspiride, a drug endowed with bronchodilator and anti-inflammatory properties. Functional studies on human isolated bronchi showed that fenspiride (10(-6)-3 x 10(-3) M, 30 min) induced a shift to the left of the concentration-response curves for isoprenaline and sodium nitroprusside with -logEC50 values of 4.1+/-0.1 (n = 7) and 3.5+/-0.2 (n = 8), respectively. Biochemical studies were carried out on three human bronchi in which separation of cyclic nucleotide phosphodiesterase isoenzymes was performed by ion exchange chromatography followed by determination of phosphodiesterase activity with a radioisotopic method. Phosphodiesterase 4 (cyclic AMP-specific) and phosphodiesterase 5 (cyclic GMP-specific) were the major phosphodiesterase isoforms present in the human bronchial tissue. The presence of phosphodiesterase 1 (Ca2+/calmodulin-stimulated), phosphodiesterase 2 (cyclic GMP-stimulated) and, in two cases, phosphodiesterase 3 (cyclic GMP-inhibited) was also identified. Fenspiride inhibited phosphodiesterase 4 and phosphodiesterase 3 activities with -logIC50 values of 4.16+/-0.09 and 3.44+/-0.12, respectively. Phosphodiesterase 5 activity was also inhibited with a -logIC50 value of approximately 3.8. Fenspiride (< or = 10(-3) M) produced less than 25% inhibition of phosphodiesterase 1 and phosphodiesterase 2 activities. In conclusion, fenspiride is an effective inhibitor of both cyclic AMP and cyclic GMP hydrolytic activity in human bronchial tissues and this action may contribute to its airway effects.

A Geometric Construction of Cyclic Cocycles on Twisted Convolution Algebras

NASA Astrophysics Data System (ADS)

Angel, Eitan

2010-09-01

In this thesis we give a construction of cyclic cocycles on convolution algebras twisted by gerbes over discrete translation groupoids. In his seminal book, Connes constructs a map from the equivariant cohomology of a manifold carrying the action of a discrete group into the periodic cyclic cohomology of the associated convolution algebra. Furthermore, for proper étale groupoids, J.-L. Tu and P. Xu provide a map between the periodic cyclic cohomology of a gerbe twisted convolution algebra and twisted cohomology groups. Our focus will be the convolution algebra with a product defined by a gerbe over a discrete translation groupoid. When the action is not proper, we cannot construct an invariant connection on the gerbe; therefore to study this algebra, we instead develop simplicial notions related to ideas of J. Dupont to construct a simplicial form representing the Dixmier-Douady class of the gerbe. Then by using a JLO formula we define a morphism from a simplicial complex twisted by this simplicial Dixmier-Douady form to the mixed bicomplex of certain matrix algebras. Finally, we define a morphism from this complex to the mixed bicomplex computing the periodic cyclic cohomology of the twisted convolution algebras.

SYNERGISTIC DEGRADATION OF DENTIN BY CYCLIC STRESS AND BUFFER AGITATION

PubMed Central

Orrego, Santiago; Romberg, Elaine; Arola, Dwayne

2015-01-01

Secondary caries and non-carious lesions develop in regions of stress concentrations and oral fluid movement. The objective of this study was to evaluate the influence of cyclic stress and fluid movement on material loss and subsurface degradation of dentin within an acidic environment. Rectangular specimens of radicular dentin were prepared from caries-free unrestored 3rd molars. Two groups were subjected to cyclic cantilever loading within a lactic acid solution (pH=5) to achieve compressive stresses on the inner (pulpal) or outer sides of the specimens. Two additional groups were evaluated in the same solution, one subjected to movement only (no stress) and the second held stagnant (control: no stress or movement). Exterior material loss profiles and subsurface degradation were quantified on the two sides of the specimens. Results showed that under cyclic stress material loss was significantly greater (p≤0.0005) on the pulpal side than on the outer side and significantly greater (p≤0.05) under compression than tension. However, movement only caused significantly greater material loss (p≤0.0005) than cyclic stress. Subsurface degradation was greatest at the location of highest stress, but was not influenced by stress state or movement. PMID:25637823

[Assessment of sulfasalazine and hydroxichloroqine hepatotoxicity in patients with rheumatic arthritis and isolated HBS-antigen positivity].

PubMed

Petrov, A V

2004-01-01

Findings were based on long-period survey (12-16 month) of 39 patients with rheumatoid arthritis (RA) and isolated persistent HBS-antigen. The patients were prescribed Hydroxichloroqine (H) and Sulfasolin (SF). Clinical data, laboratory tests, ultrasonic diagnostics to evaluate liver condition have been analyzed. HBs, Hbe-antigenes, DNA-virus B hepatitis blood test, nucleus dimensions, proliferative FGA response test and immune CD 8+, CD 14+ and CD 16+ cells to Fas-induced apoptosis were taken. SF therapy was found to be more hepatotoxic and likely to activate a latent virus B hepatitis as compared with Hydroxichloroqine and combine H and SF therapies. Triggering replication of virus B hepatitis occurs against a background of decreasing in functional activity of CD 14+ and CD 16+ cells. The immune critical level needed to activate VHB was determined.

Structural diversity of marine cyclic peptides and their molecular mechanisms for anticancer, antibacterial, antifungal, and other clinical applications.

PubMed

Lee, Yeji; Phat, Chanvorleak; Hong, Soon-Cheol

2017-09-01

Many cyclic peptides and analogues derived from marine sources are known to possess biological properties, including anticancer, antitumor, antibacterial, antifungal, antiparasitic, anti-inflammation, anti-proliferative, anti-hypertensive, cytotoxic, and antibiotic properties. These compounds demonstrate different activities and modes of action according to their structure such as cyclic oligopeptide, cyclic lipopeptide, cyclic glycopeptide and cyclic depsipeptide. The recent advances in application of the above-mentioned cyclic peptides were reported in dolastatins, soblidotin, didemnin B, aplidine, salinosporamide A, kahalalide F and bryostatin 1 and they are currently in clinical trials. These cyclic peptides are possible novel drugs discovered and developed from marine origin. Literature data concerning the potential properties of marine cyclic peptides were reviewed here, and the structural diversity and biological activities of marine cyclic peptides are discussed in relation to the molecular mechanisms of these marine cyclic peptides. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed

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.

Antifungal activity of the lipopeptides produced by Bacillus amyloliquefaciens anti-CA against Candida albicans isolated from clinic.

PubMed

Song, Bo; Rong, Yan-Jun; Zhao, Ming-Xin; Chi, Zhen-Ming

2013-08-01

The bacterium Bacillus amyloliquefaciens anti-CA isolated from mangrove system was found to be able to actively kill Candida albicans isolated from clinic. The bacterial strain anti-CA could produce high level of bioactive substance, amylase and protease in the cheap medium containing 2.0 % soybean meal, 2.0 % wheat flour, pH 6.5 within 26 h. After purification, the main bioactive substance was confirmed to be a cyclic lipopeptide containing a heptapeptide, L-Asp→L-Leu→L-Leu→L-Val→L-Val→L-Glu→L-Leu and a 3-OH fatty acid (15 carbons). In addition to C. albicans, the purified lipopeptide can also kill many yeast strains including Metschnikowia bicuspidata, Candida tropicalis, Yarrowia lipolytica and Saccharomyces cerevisiae. After treated by the purified lipopeptide, both the whole cells and protoplasts of C. albicans were destroyed.

A computer program for cyclic plasticity and structural fatigue analysis

NASA Technical Reports Server (NTRS)

Kalev, I.

1980-01-01

A computerized tool for the analysis of time independent cyclic plasticity structural response, life to crack initiation prediction, and crack growth rate prediction for metallic materials is described. Three analytical items are combined: the finite element method with its associated numerical techniques for idealization of the structural component, cyclic plasticity models for idealization of the material behavior, and damage accumulation criteria for the fatigue failure.

Theory of chromatography of partially cyclic polymers: Tadpole-type and manacle-type macromolecules.

PubMed

Vakhrushev, Andrey V; Gorbunov, Alexei A

2016-02-12

A theory of chromatography is developed for partially cyclic polymers of tadpole- and manacle-shaped topological structures. We present exact equations for the distribution coefficient K at different adsorption interactions; simpler approximate formulae are also derived, relevant to the conditions of size-exclusion, adsorption, and critical chromatography. Theoretical chromatograms of heterogeneous partially cyclic polymers are simulated, and conditions for good separation by topology are predicted. According to the theory, an effective SEC-radius of tadpoles and manacles is mostly determined by the molar mass M, and by the linear-cyclic composition. In the interactive chromatography, the effect of molecular topology on the retention becomes significant. At the critical interaction point, partial dependences K(Mlin) and K(Mring) are qualitatively different: while being almost independent of Mlin, K increases with Mring. This behavior could be realized in critical chromatography-for separation of partially cyclic polymers by the number and molar mass of cyclic elements. Copyright © 2015 Elsevier B.V. All rights reserved.

Brucella β 1,2 Cyclic Glucan Is an Activator of Human and Mouse Dendritic Cells

PubMed Central

Martirosyan, Anna; Pérez-Gutierrez, Camino; Banchereau, Romain; Dutartre, Hélène; Lecine, Patrick; Dullaers, Melissa; Mello, Marielle; Pinto Salcedo, Suzana; Muller, Alexandre; Leserman, Lee; Levy, Yves; Zurawski, Gerard; Zurawski, Sandy; Moreno, Edgardo; Moriyón, Ignacio; Klechevsky, Eynav; Banchereau, Jacques; Oh, SangKon; Gorvel, Jean-Pierre

2012-01-01

Bacterial cyclic glucans are glucose polymers that concentrate within the periplasm of alpha-proteobacteria. These molecules are necessary to maintain the homeostasis of the cell envelope by contributing to the osmolarity of Gram negative bacteria. Here, we demonstrate that Brucella β 1,2 cyclic glucans are potent activators of human and mouse dendritic cells. Dendritic cells activation by Brucella β 1,2 cyclic glucans requires TLR4, MyD88 and TRIF, but not CD14. The Brucella cyclic glucans showed neither toxicity nor immunogenicity compared to LPS and triggered antigen-specific CD8+ T cell responses in vivo. These cyclic glucans also enhanced antigen-specific CD4+ and CD8+ T cell responses including cross-presentation by different human DC subsets. Brucella β 1,2 cyclic glucans increased the memory CD4+ T cell responses of blood mononuclear cells exposed to recombinant fusion proteins composed of anti-CD40 antibody and antigens from both hepatitis C virus and Mycobacterium tuberculosis. Thus cyclic glucans represent a new class of adjuvants, which might contribute to the development of effective antimicrobial therapies. PMID:23166489

Emergence of unusual coexistence states in cyclic game systems.

PubMed

Park, Junpyo; Do, Younghae; Jang, Bongsoo; Lai, Ying-Cheng

2017-08-07

Evolutionary games of cyclic competitions have been extensively studied to gain insights into one of the most fundamental phenomena in nature: biodiversity that seems to be excluded by the principle of natural selection. The Rock-Paper-Scissors (RPS) game of three species and its extensions [e.g., the Rock-Paper-Scissors-Lizard-Spock (RPSLS) game] are paradigmatic models in this field. In all previous studies, the intrinsic symmetry associated with cyclic competitions imposes a limitation on the resulting coexistence states, leading to only selective types of such states. We investigate the effect of nonuniform intraspecific competitions on coexistence and find that a wider spectrum of coexistence states can emerge and persist. This surprising finding is substantiated using three classes of cyclic game models through stability analysis, Monte Carlo simulations and continuous spatiotemporal dynamical evolution from partial differential equations. Our finding indicates that intraspecific competitions or alternative symmetry-breaking mechanisms can promote biodiversity to a broader extent than previously thought.

Cyclic Tetrapyrrole Sulfonation, Metals, and Oligomerization in Antiprion Activity▿

PubMed Central

Caughey, Winslow S.; Priola, Suzette A.; Kocisko, David A.; Raymond, Lynne D.; Ward, Anne; Caughey, Byron

2007-01-01

Cyclic tetrapyrroles are among the most potent compounds with activity against transmissible spongiform encephalopathies (TSEs; or prion diseases). Here the effects of differential sulfonation and metal binding to cyclic tetrapyrroles were investigated. Their potencies in inhibiting disease-associated protease-resistant prion protein were compared in several types of TSE-infected cell cultures. In addition, prophylactic antiscrapie activities were determined in scrapie-infected mice. The activity of phthalocyanine was relatively insensitive to the number of peripheral sulfonate groups but varied with the type of metal bound at the center of the molecule. The tendency of the various phthalocyanine sulfonates to oligomerize (i.e., stack) correlated with anti-TSE activity. Notably, aluminum(III) phthalocyanine tetrasulfonate was both the poorest anti-TSE compound and the least prone to oligomerization in aqueous media. Similar comparisons of iron- and manganese-bound porphyrin sulfonates confirmed that stacking ability correlates with anti-TSE activity among cyclic tetrapyrroles. PMID:17709470

Improving oral bioavailability of cyclic peptides by N-methylation.

PubMed

Räder, Andreas F B; Reichart, Florian; Weinmüller, Michael; Kessler, Horst

2018-06-01

The renaissance of peptides in pharmaceutical industry results from their importance in many biological functions. However, low metabolic stability and the lack of oral availability of most peptides is a certain limitation. Whereas metabolic instability may be often overcome by development of small cyclic peptides containing d-amino acids, the very low oral availability of most peptides is a serious limitation for some medicinal applications. The situation is complicated because a twofold optimization - biological activity and oral availability - is required to overcome this problem. Moreover, most simple "rules" for achieving oral availability are not general and are applicable only to limited cases. Many structural modifications for increasing biological activities and metabolic stabilities of cyclic peptides have been described, of which N-alkylation is probably the most common. This mini-review focuses on the effects of N-methylation of cyclic peptides in strategies to optimize bioavailabilities. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.