- Hepatic metabolomics reveals that liver injury increases PCB 126-induced oxidative stress and metabolic dysfunction. [Journal Article]
- CChemosphere 2018 Oct 30; 217:140-149
- The deleterious effects of PCB 126 are complex, and the role of the liver in modifying toxic insult is not well understood. We utilized metabolomics approaches to compare liver metabolites significan...
The deleterious effects of PCB 126 are complex, and the role of the liver in modifying toxic insult is not well understood. We utilized metabolomics approaches to compare liver metabolites significantly affected by PCB 126 in control mice and a diet induced liver injury mouse model. In this 14-week study, mice were fed either an amino acid supplemented control diet (CD) or a methionine-choline deficient diet (MCD) which promoted nonalcoholic steatohepatitis (NASH) and were subsequently exposed to PCB 126. The liver metabolome was profiled by a global metabolomic analysis using LC-MS. There were clear differences between PCB 126 exposed and control mice in the hepatic metabolomic profiles (216 and 266 metabolites were altered in CD-fed and MCD-fed mice respectively after PCB 126 exposure). PCB 126 modulated glycerophospholipid metabolism, glutathione metabolism, and CoA biosynthesis pathways irrespective of diet; indicating that the disturbance in lipid metabolism and thiol metabolites are general markers of PCB 126 exposure irrespective of liver health. Additionally, metabolites associated with oxidative stress and mitochondrial dysfunction were greatly elevated in PCB 126 exposed mice with compromised livers (e.g., 4-hydroxy-nonenal glutathione, oxylipids, uric acid, and acylcarnitines). Moreover, PCB 126 exposure downregulated redox genes, and the effect was more pronounced in liver injury mice. In conclusion, this study demonstrates that PCB 126 could induce oxidative stress and metabolic dysfunction, and pre-existing liver injury can markedly modify PCB 126-induced metabolic changes. Using metabolic profiling, this study suggests mechanism of enhanced PCB 126 toxicity under liver injury settings.
- Added value of plasma metabolomics to describe maternal effects in rat maternal and prenatal toxicity studies. [Journal Article]
- TLToxicol Lett 2018 Nov 08
- For regulatory purposes prenatal developmental toxicity (OECD 414) studies are routinely performed in our laboratories. The suitability of metabolomics as technology to identify maternal toxicity in ...
For regulatory purposes prenatal developmental toxicity (OECD 414) studies are routinely performed in our laboratories. The suitability of metabolomics as technology to identify maternal toxicity in such studies was investigated. Plasma was sampled from pregnant, non-fasted rats on gestation day 20 before cesarean section. Metabolite profiling was performed by gas- and liquid-chromatography-tandem mass spectrometry techniques. The sensitivity of routinely examined maternal toxicity parameters (OECD No. 414) was compared to those of metabolome analysis. Evaluating 44 studies, the metabolome-derived NOEL was more sensitive in 45% of the cases in detecting maternal toxicity than the maternal NOAEL. Metabolome patterns indicative for liver effects and 4-hydroxyphenylpyruvate dioxygenase (HPPD) enzyme-inhibition were established in pregnant rats based on regulated metabolites using reference compounds. The HPPD inhibition and liver toxicity patterns in pregnant rats were reasonably comparable to the ones established in non-pregnant, fasted rats. Metabolomics is a useful tool for an improved and mechanism-based identification of maternal toxicity in maternal and prenatal toxicity studies. The data suggest that the current classical maternal toxicity parameters may underestimate the extent of effects of compounds on the dams.
- Meroterpenoids isolated from Arnebia euchroma (Royle) Johnst. And their cytotoxic activity in human hepatocellular carcinoma cells. [Journal Article]
- FFitoterapia 2018 Nov 08
- Six previously undescribed naturally occurring meroterpenoids (2, 5-9) together with seven known meroterpenoids (1, 3, 4, 10-13) were isolated from the root plant of Arnebia euchroma. Their structure...
Six previously undescribed naturally occurring meroterpenoids (2, 5-9) together with seven known meroterpenoids (1, 3, 4, 10-13) were isolated from the root plant of Arnebia euchroma. Their structures and absolute configurations were determined by extensive 1D (1H NMR, 13C NMR) and 2D NMR (1H1H COSY, DEPT, HMQC, HMBC, NOESY) spectroscopic methods, spectroscopy high resolution mass spectrometry, as well as DFT and MM2 force-field calculations. Meroterpenoids 1-13 were evaluated for their cytotoxicities against human liver cancer cell lines SMMC-7721, HepG2, QGY-7703 and HepG2/ADM. Meroterpenoid 5 exhibited the most potent activity with IC50 values of 6.40 ± 0.51, 3.86 ± 0.28, 3.43 ± 0.27 and 11.31 ± 0.67 μM, respectively. Meroterpenoid 4 exhibited significant growth inhibitory effects against HepG2/ADM with IC50 at 18.77 ± 1.23 μM, and meroterpenoid 8 with IC50 at 5.41 ± 0.51 and 6.18 ± 0.47 μM against HepG2 and QGY-7703, respectively. These were more potent than the positive drug, Cisplatin.
- Membrane topologies of PEX13 and PEX14 provide new insights on the mechanism of protein import into peroxisomes. [Journal Article]
- FJFEBS J 2018 Nov 10
- PEX13 and PEX14 are two core components of the so-called peroxisomal docking/translocation module, the transmembrane hydrophilic channel through which newly synthesized peroxisomal proteins are trans...
PEX13 and PEX14 are two core components of the so-called peroxisomal docking/translocation module, the transmembrane hydrophilic channel through which newly synthesized peroxisomal proteins are translocated into the organelle matrix. The two proteins interact with each other and with PEX5, the peroxisomal matrix protein shuttling receptor, through relatively well characterized domains. However, the topologies of these membrane proteins are still poorly defined. Here, we subjected proteoliposomes containing PEX13 or PEX14 and purified rat liver peroxisomes to protease-protection assays and analyzed the protected protein fragments by mass spectrometry, Edman degradation and Western blotting using antibodies directed to specific domains of the proteins. Our results indicate that PEX14 is a bona fide intrinsic membrane protein with a Nin -Cout topology, and that PEX13 adopts a Nout -Cin topology, thus exposing its carboxy-terminal Src homology 3 [SH3] domain into the organelle matrix. These results reconcile several enigmatic findings previously reported on PEX13 and PEX14 and provide new insights into the organization of the peroxisomal protein import machinery. This article is protected by copyright. All rights reserved.
- Total Bioavailable Organic Selenium in Fishmeal-Based Diet Influences Growth and Physiology of Juvenile Cobia Rachycentron canadum (Linnaeus, 1766). [Journal Article]
- BTBiol Trace Elem Res 2018 Nov 09
- The study examined the effects of supplemental organic selenium (Se) extracted from selenoyeast on the growth performance, glutathione peroxidase (GPx) activity, biochemical status and liver histoche...
The study examined the effects of supplemental organic selenium (Se) extracted from selenoyeast on the growth performance, glutathione peroxidase (GPx) activity, biochemical status and liver histochemistry of juvenile cobia Rachycentron canadum. Six experimental diets were prepared supplemented with Se with total concentration of 1.52 (Se-1.52), 1.93 (Se-1.93), 2.29 (Se-2.29), 2.71 (Se-2.71) and 3.14 (Se-3.14) mg/kg of total Se in the diets and a fishmeal-based control diet without Se supplementation containing 1.15 (Se-1.15) mg/kg of Se was used as control. Experimental diets were fed to the fish of six treatment groups in triplicate twice daily for 8 weeks. Juvenile cobia fed dietary Se of 1.93, 2.29 and 2.71 mg/kg showed increased final body weight (FBW), specific growth rate (SGR) and feed intake (FI) than the fish fed the control diet. Se accumulations in the muscle and liver tissue displayed a positive linear relationship with dietary Se levels. Se deficiency was apparent in fish fed the control diet and displayed reduced growth and feed efficiency. Red blood cell (RBC) counts were significantly (P < 0.05) higher in cobia fed dietary Se between 1.52 to 2.71 mg/kg than the fish fed 3.14-mg/kg Se diet. Glutathione peroxidase activity significantly (P < 0.05) declined in the group fed with control diet compared to fish fed Se-supplemental diet. Juvenile cobia fed the highest Se level (Se-3.14 mg/kg) showed toxic effects in the liver, including histopathological lesions in the liver. Based on the results obtained for FBW, SGR, tissue Se retention and haematological parameters, we conclude that optimal dietary Se requirement for juvenile cobia fed commercial diets is 2.32 mg/kg.
- Comparative effects of dietary n-3 docosapentaenoic acid (DPA), DHA and EPA on plasma lipid parameters, oxidative status and fatty acid tissue composition. [Journal Article]
- JNJ Nutr Biochem 2018 Oct 12; 63:186-196
- The specific and shared physiologic and metabolic effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and even more of n-3 docosapentaenoic acid (DPA) are poorly known. We investigated...
The specific and shared physiologic and metabolic effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and even more of n-3 docosapentaenoic acid (DPA) are poorly known. We investigated the physiological effects and the overall fatty acid tissue composition of a nutritional supplementation of DPA compared both to EPA and DHA in healthy adult rats. Rats (n=32) were fed with semisynthetic diets supplemented or not with 1% of total lipids as EPA, DPA or DHA in ethyl esters form from weaning for 6 weeks. Fatty acid tissue composition was determined by gas chromatography-mass spectrometry, and blood assays were performed. The DPA supplementation was the only one that led to a decrease in plasma triglycerides, total cholesterol, non-high-density lipoprotein (HDL)-cholesterol, cholesterol esters and total cholesterol/HDL-cholesterol ratio compared to the nonsupplemented control group. The three supplemented groups had increased plasma total antioxidant status and superoxide dismutase activity. In all supplemented groups, the n-3 polyunsaturated fatty acid level increased in all studied tissues (liver, heart, lung, spleen, kidney, red blood cells, splenocytes, peripheral mononucleated cells) except in the brain. We showed that the DPA supplementation affected the overall fatty acid composition and increased DPA, EPA and DHA tissue contents in a similar way than with EPA. However, liver and heart DHA contents increased in DPA-fed rats at the same levels than in DHA-fed rats. Moreover, a large part of DPA seemed to be retroconverted into EPA in the liver (38.5%) and in the kidney (68.6%). In addition, the digestibility of DPA was lower than that of DHA and EPA.
- In vitroand in vivo investigation of metabolic fate of riociguat by HPLC-Q-TOF/MS/MS and in silico evaluation of the metabolites by ADMET predictor™. [Journal Article]
- JPJ Pharm Biomed Anal 2018 Nov 01; 164:326-336
- Riociguat, a guanyl cyclase inhibitor, is one of its kind drug regimen approved for management of pulmonary arterial hypertension and chronic thromboembolism pulmonary hypertension. Extensive literat...
Riociguat, a guanyl cyclase inhibitor, is one of its kind drug regimen approved for management of pulmonary arterial hypertension and chronic thromboembolism pulmonary hypertension. Extensive literature review indicates lack of comprehensive reports on its metabolic fate. The present study reports the in vivo and in vitro identification and characterization of metabolites of riociguat, using high-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry. In vitro studies were conducted by incubating the drug in human and rat liver microsomes in presence of respective cofactors. In vivo studies were undertaken by oral administration of suspension of drug to male Sprague-Dawley rats followed by collection of urine, feces and blood at specific intervals. A total of 18 metabolites were observed in in vivo and in vitro matrices which includes hydroxyl, N-oxide, desmethyl, defluorinated hydroxyl, glucuronides and N-acetyl cysteine conjugates. Presence of N-acetyl cysteine conjugates strongly points towards the formation of a reactive metabolite intermediate trapped through N-acetyl cysteine and can be considered a matter of concern as the reactive metabolites have been known to manifest toxicities. Their presence was mimicked in in vitro samples as well. The toxicological properties of drug and metabolites were evaluated by using ADMET Predictor ™ software.
- Immune checkpoint inhibitors of CTLA4 and PD-1 for malignant melanoma arising in ovarian cystic teratoma: A case report. [Journal Article]
- MMedicine (Baltimore) 2018; 97(43):e12937
- CONCLUSIONS: This is the first case of MM arising in OCT treated by immune checkpoint inhibitors, with information of PD-L1 immunohistochemical expression and adverse events. The present case is the longest survivor following the detection of recurrence among all the previous reports. The long survival and slow-growing tumor in the present case may be associated with no PD-L1 expressions.
- Screening for hepatic fibrosis and steatosis in Turkish patients with type 2 diabetes mellitus: A transient elastography study. [Journal Article]
- TJTurk J Gastroenterol 2018 Nov 09
- CONCLUSIONS: TE is a useful non-invasive imaging modality to screen for liver involvement in Turkish patients with T2DM. High rates of TE-defined fibrosis and steatosis in our sample reflect the presence of an elevated mean BMI.
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- The application of capillary electrophoresis, mass spectrometry and Brdicka reaction in human and rabbit metallothioneins analysis. [Journal Article]
- ACAdv Clin Exp Med 2018 Oct 31
- CONCLUSIONS: The applied methods allowed for the characterization of MTs and gave complementary information about MT isoforms. Altered electrochemical activity of human and rabbit MTs, despite the same number of -sulfhydryl (-SH) groups, was observed, which may be due to different availability of MT cysteinyl groups.