Zhong Z, Ramshesh VK, Rehman H, Currin RT, Sridharan V, Theruvath TP, Kim I, Wright GL, Lemasters JJ. Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 295: G823-G832, 2008. First published September 4, 2008 doi:10.1152/ajpgi.90287.2008.-The mitochondrial permeability transition (MPT) plays an important role in hepatocyte death caused by ischemia-reperfusion (IR). This study investigated whether activation of the cellular oxygen-sensing signal cascade by prolyl hydroxylase inhibitors (PHI) protects against the MPT after hepatic IR. Ethyl 3,4-dihyroxybenzoate (EDHB, 100 mg/kg ip), a PHI, increased mouse hepatic hypoxia-inducible factor-1␣ and heme oxygenase-1 (HO-1). EDHB-treated and untreated mice were subjected to 1 h of warm ischemia to ϳ70% of the liver followed by reperfusion. Mitochondrial polarization, cell death, and the MPT were assessed by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. EDHB largely blunted alanine aminotransferase (ALT) release and necrosis after reperfusion. In vehicle-treated mice at 2 h after reperfusion, viable cells with depolarized mitochondria were 72%, and dead cells were 2%, indicating that depolarization preceded necrosis. Mitochondrial voids excluding calcein disappeared, indicating MPT onset in vivo. NIM811, a specific inhibitor of the MPT, blocked mitochondrial depolarization after IR, further confirming that mitochondrial depolarization was due to MPT onset. EDHB decreased mitochondrial depolarization to 16% and prevented the MPT. Tin protoporphyrin (10 mol/kg sc), an HO-1 inhibitor, partially abrogated protection by EDHB against ALT release, necrosis, and mitochondrial depolarization. In conclusion, IR causes the MPT and mitochondrial dysfunction, leading to hepatocellular death. PHI prevents MPT onset and liver damage through an effect mediated partially by HO-1. ethyl 3,4-dihyroxybenzoate; heme oxygenase; hepatic ischemia-reperfusion; mitochondrial permeability transition; prolyl hydroxylase inhibitor ISCHEMIA-REPERFUSION (IR) injury to the liver occurs in trauma, hemorrhagic and cardiac shock, vascular diseases, and hepatic surgery, including tumor resection and liver transplantation. A variety of pathophysiological processes likely contribute to development of IR injury. Reactive oxygen species (ROS) play a critical role in the injury caused by IR (18,36,57). ROS not only directly damage cell membranes, DNA, and protein; they also trigger formation of toxic cytokines and increase adhesion molecules leading to inflammatory responses, tissue damage, and multiple organ failure (1,10,17,41). Recently, growing evidence supports an important role of the mitochondrial permeability transition (MPT) in cell injury after IR (24,25,45,58). The mitochondrial membrane potential collapses when the MPT occurs, leading to failure of ATP synthesis, release of cytochrome c, and cell death (24,25,55). ROS cause opening of MPT pores (22...

The phytochemical, antioxidant and mineral composition of hydroalcoholic extract of leaves of Cichorium intybus L., was determined. The leaves were found to possess comparatively higher values of total flavonoids, total phenolic acids. The phytochemical screening confirmed the presence of tannins, saponins, flavonoids, in the leaves of the plant. The leaf extract was found to show comparatively low value of IC50 for 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition. The IC50 value of chicory leaves extract was found to be 67.2 ± 2.6 μg/ml. The extracts were found to contain high amount of mineral elements especially Mg and Zn. Due to good phytochemical and antioxidant composition, C. intybus L., leaves would be an important candidate in pharmaceutical formulations and play an important role in improving the human health by participating in the antioxidant defense system against free radical generation.

Background/AimsAn increase of ethanol metabolism and hepatic mitochondrial respiration occurs in vivo after a single binge of alcohol. Here, our aim was to determine how ethanol intake affects hepatic mitochondrial polarization status in vivo in relation to ethanol metabolism and steatosis.MethodsHepatic mitochondrial polarization, permeability transition (MPT), and reduce pyridine nucleotides, and steatosis in mice were monitored by intravital confocal/multiphoton microscopy of the fluorescence of rhodamine 123 (Rh123), calcein, NAD(P)H, and BODIPY493/503, respectively, after gavage with ethanol (1–6 g/kg).ResultsMitochondria depolarized in an all-or-nothing fashion in individual hepatocytes as early as 1 h after alcohol. Depolarization was dose- and time-dependent, peaked after 6 to 12 h and maximally affected 94% of hepatocytes. This mitochondrial depolarization was not due to onset of the MPT. After 24 h, mitochondria of most hepatocytes recovered normal polarization and were indistinguishable from untreated after 7 days. Cell death monitored by propidium iodide staining, histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was low throughout. After alcohol, mitochondrial NAD(P)H autofluorescence increased and decreased, respectively, in hepatocytes with polarized and depolarized mitochondria. Ethanol also caused steatosis mainly in hepatocytes with depolarized mitochondria. Depolarization was linked to ethanol metabolism, since deficiency of alcohol dehydrogenase and cytochrome-P450 2E1 (CYP2E1), the major ethanol-metabolizing enzymes, decreased mitochondrial depolarization by ∼70% and ∼20%, respectively. Activation of aldehyde dehydrogenase decreased depolarization, whereas inhibition of aldehyde dehydrogenase enhanced depolarization. Activation of aldehyde dehydrogenase also markedly decreased steatosis.ConclusionsAcute ethanol causes reversible hepatic mitochondrial depolarization in vivo that may contribute to steatosis and increased mitochondrial respiration. Onset of this mitochondrial depolarization is linked, at least in part, to metabolism of ethanol to acetaldehyde.

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Objectives:To review and analyze the pattern of breast cancer (BC) in the Kingdom of Saudi Arabia (KSA).Methods:A retrospective descriptive epidemiological review of BC of all diagnosed Saudi female cases from January 1990 to December 2014 was conducted at the Faculty of Sciences, Department of Biology, University of Tabuk, Tabuk, KSA. This report contains information obtained from the Saudi Cancer Registry and from King Faisal Specialist Hospital and Research Center.Results:The number of women with BC increased steadily from 1990-2010. On the basis of the number of cases, the percentage distribution of BC appears to be increasing. There were 1152 female BC cases in 2008 in comparison with 1308 in 2009, and 1473 in 2010. Breast cancer ranked first among females accounting for 27.4% of all newly diagnosed female cancers (5378) in the year 2010. The average age at the diagnosis of BC was 48; weighted average was 49.8, and range 43-52.Conclusion:Among Saudi patients, there was a significant increase in the number of cases of BC, which occurs at an earlier age than in Western countries. Continued vigilance, mammographic screening, and patient education are needed to establish early diagnosis and perform optimal treatment.