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- Methylglyoxal induces mitochondrial dysfunction and cell death in liver. [Journal Article]
- Toxicol Res 2014 Sep; 30(3):193-8.
Degradation of glucose is aberrantly increased in hyperglycemia, which causes various harmful effects on the liver. Methylglyoxal is produced during glucose degradation and the levels of methylglyoxal are increased in diabetes patients. In this study we investigated whether methylglyoxal induces mitochondrial impairment and apoptosis in HepG2 cells and induces liver toxicity in vivo. Methylglyoxal caused apoptotic cell death in HepG2 cells. Moreover, methylglyoxal significantly promoted the production of reactive oxygen species (ROS) and depleted glutathione (GSH) content. Pretreatment with antioxidants caused a marked decrease in methylglyoxal-induced apoptosis, indicating that oxidant species are involved in the apoptotic process. Methylglyoxal treatment induced mitochondrial permeability transition, which represents mitochondrial impairment. However, pretreatment with cyclosporin A, an inhibitor of the formation of the permeability transition pore, partially inhibited methylglyoxal-induced cell death. Furthermore, acute treatment of mice with methylglyoxal increased the plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indicating liver toxicity. Collectively, our results showed that methylglyoxal increases cell death and induces liver toxicity, which results from ROS-mediated mitochondrial dysfunction and oxidative stress.
- Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors. [JOURNAL ARTICLE]
- Cell Death Differ 2014 Oct 24.
Apoptosis signaling is involved in both physiological tissue homeostasis and acute and chronic diseases. The role of regulatory apoptosis signaling molecules and their organ-specific functions are less defined. Therefore, we investigated the loss of the anti-apoptotic cellular FLICE-inhibitory protein (cFLIP) and the mechanisms of the resulting lethal organ failure in vivo using inducible knockout mice. These were generated by crossing floxed cFLIP mice to a tamoxifen inducible Rosa26-creERT2 mouse strain. Death following global loss of cFLIP resulted from liver failure, accumulation of M1-polarized macrophages and accompanying hepatic cell death and inflammation. Apoptosis was also prominent in immune cells, the kidney and intestinal epithelial cells (IECs) but not in cardiomyocytes. Cellular injury led to the release of damage-associated molecular patterns (DAMPs) and the induction of innate immune receptors including toll-like receptors (TLRs) 4 and 9, and stimulator of interferon genes (STING). Transplantation of bone marrow with intact cFLIP or depletion of macrophages prevented the phenotype of acute liver failure. Interestingly, compound deletion of cFLIP in bone marrow-derived cells and hepatocytes did not promote organ failure. Thus, cFLIP exerts a critical role in tissue homeostasis by preventing the activation of monocytic cells and innate immunity, which causes cell death and inflammation in susceptible tissues. These results encourage the development of organ-specific anti-apoptotic and anti-inflammatory therapies in acute organ failure.Cell Death and Differentiation advance online publication, 24 October 2014; doi:10.1038/cdd.2014.178.
- Leptin-to-adiponectin ratio in obese adolescents with nonalcoholic fatty liver disease. [JOURNAL ARTICLE]
- Turk J Pediatr 2014 May-June; 56(3):259-266.
The leptin-to-adiponectin (L/A) ratio has been used to show insulin resistance (IR) in recent years. The aim of this study was to investigate the L/A ratio in obese adolescents and compare this ratio in patients with and without nonalcoholic fatty liver disease (NAFLD) and also with healthy controls. The second aim was to search the possible correlations between the L/A ratio with the markers of IR and inflammation. A total of 47 obese (mean age: 13.1±2.1 years) and 19 healthy children (mean age: 13.8±0.3 years) were included in the study. The presence of fatty liver was identified by ultrasonography. Cases were divided into three groups as NAFLD (+) and NAFLD (-) obese patients and controls. Liver biochemistries, insulin and serum lipids, C-reactive protein, tumor necrosis factor-alpha (TNF-alpha), interleukin-6, adiponectin, and leptin were determined. The L/A ratio was calculated. IR was estimated according to the homeostasis model assessment of insulin resistance (HOMA-IR). The L/A ratio was significantly higher in NAFLD (+) patients than in the other two groups, and in NAFLD (-) patients than the healthy peers. Moreover, L/A ratio correlated more strongly with weight for height (r: 0.528, p<0.0001), alanine aminotransferase (ALT) (r: 0.499, p<0.0001), triglyceride (r: 0.591, p<0.0001), and HOMA-IR (r: 0.574, p<0.0001) than did either leptin and adiponectin alone. This study shows that the L/A ratio is a noninvasive predictor of NAFLD in obese children and correlates with weight for height, ALT, triglyceride, and HOMA-IR better than each single adipokine.
- Symptom Progression in Acute Mountain Sickness During a 12-Hour Exposure to Normobaric Hypoxia Equivalent to 4500 M. [JOURNAL ARTICLE]
- High Alt Med Biol 2014 Oct 23.
Abstract Burtscher, Martin, Maria Wille, Verena Menz, Martin Faulhaber, and Hannes Gatterer. Symptom progression in acute mountain sickness (AMS) during a 12-hour exposure to normobaric hypoxia equivalent to 4500 m. High Alt Med Biol. 00:000-000, 2014.-The diagnosis and quantification of severity of acute mountain sickness (AMS) continue to be problematic. What symptoms should be included in a score and how to weigh any given symptom in the total score remain matter of debate. Seventy seven healthy male (n=43) and female (n=34) volunteers, aged between 18 and 42 years, were exposed to normobaric hypoxia (Fio2=12.6%≙4500 m) for 12 hours. Symptoms of AMS according to the Lake Louise Scoring system (LLS) were recorded before and after 30 min, 3, 6, 9, and 12 hours in hypoxia. AMS scores continued to increase steeply during the entire hypoxia exposure in subjects suffering from AMS (LLS>2). Headache was the predominant symptom and the severity of nausea progressed faster in subjects who left the hypoxia room prematurely (severely affected by AMS) compared to those moderately affected (LLS>2 but completing the 12-h hypoxia exposure). Whereas headache scores up to 6 hours in hypoxia were not correlated with other AMS symptoms, nausea was correlated with dizziness and fatigue (r=0.45 and 0.56, p<0.01). Cluster analysis identified three different distributions of symptom severity compatible with being very likely free of AMS (cluster 1), compatible with very likely suffering from AMS (cluster 3), and compatible with ambiguous allocation (cluster 2). In conclusion, our findings confirm that headache plus one or more of the symptoms nausea, dizziness, and fatigue of at least mild to moderate severity are required for diagnosis of AMS. The inter-relationship between nausea, dizziness, and fatigue, however, raises the question whether each of these symptoms should be given equal diagnostic weighting. The time course of symptom progression within the first hours at altitude may provide clinically important information on the severity of subsequent AMS development and will support the decision to start therapeutic intervention.
- Effects of Traditional Flood Irrigation on Invertebrates in Lowland Meadows. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e110854.
Lowland meadow irrigation used to be widespread in Central Europe, but has largely been abandoned during the 20th century. As a result of agri-environment schemes and nature conservation efforts, meadow irrigation is now being re-established in some European regions. In the absence of natural flood events, irrigation is expected to favour fauna typical of lowland wet meadows. We analysed the effects of traditional flood irrigation on diversity, densities and species composition of three invertebrate indicator taxa in lowland meadows in Germany. Unexpectedly, alpha diversity (species richness and Simpson diversity) and beta diversity (multivariate homogeneity of group dispersions) of orthopterans, carabids, and spiders were not significantly different between irrigated and non-irrigated meadows. However, spider densities were significantly higher in irrigated meadows. Furthermore, irrigation and elevated humidity affected species composition and shifted assemblages towards moisture-dependent species. The number of species of conservation concern, however, did not differ between irrigated and non-irrigated meadows. More variable and intensive (higher duration and/or frequency) flooding regimes might provide stronger conservation benefits, additional species and enhance habitat heterogeneity on a landscape scale.
- Intracellular proliferation of S. aureus in osteoblasts and effects of rifampicin and gentamicin on S. aureus intracellular proliferation and survival. [JOURNAL ARTICLE]
- Eur Cell Mater 2014.:258-268.
Staphylococcus aureus is the most clinically relevant pathogen regarding implant-associated bone infection and its capability to invade osteoblasts is well known. The aim of this study was to investigate firstly whether S. aureus is not only able to invade but also to proliferate within osteoblasts, secondly to delineate the mechanism of invasion and thirdly to clarify whether rifampicin or gentamicin can inhibit intracellular proliferation and survival of S. aureus. The SAOS-2 osteoblast-like cell line and human primary osteoblasts were infected with S. aureus EDCC5055 and S. aureus Rosenbach 1884. Both S. aureus strains were able to invade efficiently and to proliferate within human osteoblasts. Immunofluorescence microscopy showed intracellular invasion of S. aureus and transmission electron microscopy images could demonstrate bacterial division as a sign of intracellular proliferation as well as cytosolic bacterial persistence. Cytochalasin D, the major actin depolymerisation agent, was able to significantly reduce S. aureus invasion, suggesting that invasion was enabled by promoting actin rearrangement at the cell surface. 7.5 μg/mL of rifampicin was able to inhibit bacterial survival in SAOS-2 cells with almost complete elimination of bacteria after 4 h. Gentamicin could also kill intracellular S. aureus in a dose-dependent manner, an effect that was significantly lower than that observed using rifampicin. In conclusion, S. aureus is not only able to invade but also to proliferate in osteoblasts. Invasion seems to be associated with actin rearrangement at the cell surface. Rifampicin is effective in intracellular eradication of S. aureus whereas gentamicin only poorly eliminates intracellularly replicating bacteria.
- Effect of intra-arterial infusion with triolein emulsion on rabbit liver. [Journal Article]
- World J Gastroenterol 2014 Oct 21; 20(39):14442-9.
To determine whether intra-arterial infusion of triolein emulsion has biochemical and histopathologic effect on rabbit liver.An emulsion of 0.2 mL triolein in 20 mL of saline was infused into either the hepatic arteries of nine rabbits (group 1) or the superior mesenteric arteries of 12 rabbits (group 2). Five rabbits infused with 20 mL of normal saline were used as a control group (group 3). The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured to evaluate liver function in each group just before the infusion, at 2 h, day 1, day 4, and day 7 following infusion. Each rabbit in all of the groups was infused with Evans blue on day 7 to evaluate changes in vascular permeability, and obtain the stained area of the hepatic surface. If the stained area was not available, the anteroinferior portion of the right hepatic lobe was selected. The obtained tissues were examined by light, electron and confocal microscopy. The changes in AST and ALT levels at each time point were calculated and statistically analyzed using a mixed linear model. A P value < 0.05 was regarded as statistically significant.In group 1 (hepatic artery group), both the AST and ALT serum levels increased significantly on day 1 (P = 0.0016 and P < 0.0001, respectively) compared with the control group, followed by a decrease thereafter. In group 2 (portal vein group), the AST level increased on day 4 (P = 0.0095), while the ALT level increased significantly on day 1 (P < 0.0001), and decreased thereafter, as compared with the control. For the remainder of the examination days, there were no significant changes in the AST and ALT levels (P > 0.05). Only three rabbits in each group showed hepatic surface staining with the Evans blue dye. Light and electron microscopic findings showed no specific changes in the selected hepatic tissues. Confocal microscopic examination with transferase-mediated dUTP nick-end labeling stain revealed lack of hepatocyte apoptosis in any of the groups. There were no differences in the results between group 1 and group 2.Infusion of triolein emulsion into rabbit livers revealed a minimal transient decrease of liver function, and no specific histopathologic changes.
- Artemisia pallens alleviates acetaminophen induced toxicity via modulation of endogenous biomarkers. [JOURNAL ARTICLE]
- Pharm Biol 2014 Oct 23.:1-11.
Abstract Context: Acetaminophen (APAP) leads to severe hepatic and renal necrosis and thus causes significant clinical problems. Artemisia pallens Walls ex D.C. (Asteraceae) possesses various pharmacological properties such as antidiabetic, antioxidant, analgesic, and anti-inflammatory activity. Objective: The objective was to evaluate the protective effects of Artemisia pallens methanol extract (APME) in APAP-induced hepatic and nephro-toxicity. Materials and methods: The methanolic extract of aerial parts of Artemisia pallens (APME) was prepared. Toxicity was induced in male Wistar rats (180-220 g) by administration of APAP (700 mg/kg, p.o., 14 d). APME (100, 200, and 400 mg/kg, p.o.) was administered to rats 2 h before APAP oral administration. Various biochemical and molecular parameters along with histopathological aberration were studied in the kidney and liver of rats. Results: Pretreatment with APME (200 and 400 mg/kg, p.o.) significantly (p < 0.01 and p < 0.001) decreased aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, blood urea nitrogen (BUN), and serum creatinine as compared with APAP-treated rat. Decreased level of serum albumin, serum uric acid, and HDL were significantly (p < 0.01 and p < 0.001) restored by APME (200 and 400 mg/kg, p.o.) pre-treatment. Administration of APME (200 and 400 mg/kg, p.o.) significantly (p < 0.01 and p < 0.001) reduced the elevated level of cholesterol, LDL, LDH, triglyceride, and VLDL. It also significantly (p < 0.01 and p < 0.001) restored the altered level of hepatic and renal antioxidant enzymes (superoxide dismutase (SOD) and glutathione (GSH)). The increased level of malondialdehyde (MDA) and nitric oxide (NO) in hepatic as well as renal tissue was significantly (p < 0.01 and p < 0.001) decreased by APME (200 and 400 mg/kg, p.o.) administration. Histological alternation induced by APAP in liver and kidney was also reduced by the APME (200 and 400 mg/kg, p.o.) pre-treatment. Conclusion: It is concluded that the methanol extract of Artemisia pallens alleviates APAP induced in rats toxicity through its antioxidative and anti-inflammatory actions.
- Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression. [JOURNAL ARTICLE]
- Mol Med Rep 2014 Oct 22.
The aim of the present study was to investigate the effects of octreotide treatment on hepatic heme oxygenase‑1 (HO‑1) expression, together with the influence of altered hepatic HO‑1 expression levels on hepatic function and fibrosis in bile duct‑ligated rats. The rats were divided randomly into sham, cirrhotic, cobalt protoporphyrin and octreotide treatment groups. The expression levels of hepatic HO‑1 mRNA were measured by reverse‑transcription polymerase chain reaction, while the protein expression was determined by western blotting and immunohistochemical analysis. Hematoxylin and eosin, and Van Gieson's staining, along with determination of the hydroxyproline content in the liver, were performed to determine the degree of liver fibrosis. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in arterial blood, and the mean arterial pressure and portal vein pressure were also measured. As compared with the sham group, hepatic HO‑1 mRNA and protein expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood, hydroxyproline and collagen type I content were all significantly increased in the cirrhotic group. As compared with the cirrhotic group, the octreotide‑treated group exhibited significantly reduced hepatic HO‑1 expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood and the extent of hepatic fibrosis, whereas the cobalt protoporphyrin group exhibited significantly increased hepatic HO‑1 expression levels, as well as aggravated hepatic function and fibrosis (P<0.05). In conclusion, octreotide inhibited hepatic HO‑1 overexpression in cirrhotic rats, reduced hepatic HO‑1 expression levels to relieve liver injury and attenuated liver fibrosis.
- Evaluation of bacterial translocation in patients with chronic HCV infection. [Journal Article]
- Rom J Intern Med 2014 Apr-Jun; 52(2):91-6.
The factors involved in the progression of liver disease towards decompensated cirrhosis are not completely elucidated. It seems that bacterial translocation (BT) from the gut to the systemic blood flow has an important role in the disease progression, but literature data are controversial. Our objectives were to evaluate the presence of BT in patients with chronic HCV infection and to assess the correlation between BT and liver fibrosis stages and inflammatory state.We conducted a cross-sectional study on patients with chronic HCV infection in a tertiary care hospital between January and July 2013. Blood samples were collected for aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), total cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, platelets, lipopolysaccharide (LPS) and tumor necrosis-alpha (TNFα). Plasma LPS were measured by ELISA (Kamiya Biomedical Company Seattle, SUA) and TNFα by DIAsource ImmunoAssay (Louvain-la-Neuve, Belgium) kits. Liver fibrosis was evaluated by means of FibroMax (BioPredictive, Paris, France) in all patients.We enrolled 116 patients with CHC, with a sex ratio M/F of 0.55 and a median age of 54 (45-61) years. Most of the patients (32) had compensated cirrhosis (F4). LPS levels were higher in patients with mild fibrosis--median value of 60.34 (32-91.7) ng/mL, than in cirrhotic patients--median value 40.39 (20.2-74.4) ng/mL (p = 0.051). We found no statistical correlation between LPS levels and fibrosis (p = 0.068) or TNFα levels (p = 0.097) CONCLUSIONS: There was BT in patients with CHC but it was not correlated with liver fibrosis stages or systemic inflammation. This may suggest that LPS evaluation may not be the best technique to assess baterial translocation, but further studies are needed.