Hypoxia occurs in chronic and acute vascular diseases and tumor formation. The ability of tumor cells to maintain a balance between an adaptation to hypoxia and cell death is regulated by a family of transcription factors called hypoxia-inducible factor 1 (HIF-1). Tumor hypoxia mediated by HIF-1 would facilitate the likelihood of resistance to chemotherapy and radiotherapy, proliferation, metastasis and the invasive potential; all of which culminate in a decrease in patient survival. And HIF-1 alpha subunit decides the activity of HIF-1, which is regulated by oxygen. So understanding the role of HIF in signal pathway, drug resistance mechanism and its feature is crucial for developing novel anticancer therapies. In recent years, more attentions have focused on HIF-1 alpha inhibitors. It is expected that development of more potent and selective HIF inhibitors will provide an effective treatment of cancer and other HIF-related diseases. So we will focus on the biological characteristics and mechanism of HIF-1 to review currently studied HIF-1 inhibitors.
Cell Death ; Humans ; Hypoxia-Inducible Factor 1 ; antagonists & inhibitors ; metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit ; antagonists & inhibitors ; metabolism ; Neoplasms ; drug therapy ; Oxygen ; metabolism ; Signal Transduction

Brain is a logical target of free radical damage, considering the large lipid content of myelin sheaths and the high rate of brain oxidative metabolism. Thus, the hypothesis that free radicals may be involved in the pathogenesis of certain CNS diseases has gained increasing popularity in recent years. In CNS ischemia-reperfusion injury, the role of free radicals appears to be well established, however, involvement of other factors, such as excitatory amino acids and prostaglandins, may also contribute to the production of neuronal necrosis following ischemia. Liberation of free iron appears to play a crucial role in the generation of reactive oxygen species in posttraumatic epilepsy. Although there is no direct evidence to indicate free radical involvement in the pathogenesis of Alzheimer's disease, brain trauma with release of iron, amyloid angiopathy and disturbances in blood-brain barrier function all appear to contribute to the development of ischemic episodes with free radical generation and neuronal degeneration. In Parkinson's disease, the substantia nigra appears to be under oxidative stress as evidenced by the findings of increased lipid peroxidation, reduced GSH levels, high concentration of iron and free radical generation via autocatalytic mechanisms within neuromelanin-containing catecholaminergic neurons. Regardless of the initial insult, a cascade of events involving both reactive oxygen radicals and mitochondrial metabolism is likely to contribute to cell injury.
Brain Diseases/*chemically induced ; Enzymes/physiology ; Free Radical Scavengers ; Human ; Iron/physiology ; Oxygen/*antagonists & inhibitors ; *Reactive Oxygen Species ; Support, U.S. Gov't, P.H.S.

In the late 1950, Greifenstein and associates have studied the properties of phenylcyelohexylamine derivatives and reported that these chemicals produced amnesia, analgesia, catatonia and catalepsy. Phencyclidine was the first of these drugs used in clinical anesthesia, but convulsive movement as well as excitatory behavior discouraged the use of the agent in human beings. Continued research for a more suitable derivative of phencyclidine with similar analgesic action, but shorter duratoin and lesser psychotomimetic action led McCarthy and Chen to investigate the pharmacologic properties of a large series of compounds. One of these, 2-ochlorophenylcyclohexylamine, was shown to have some advantages. Ketamine hydrochloride, chemically related to both phencyclidine and cyclohexylamine, proved to be more satisfactory for clinical anesthesia. Clinical investigations were begun in 1965 by Dominos group who first termed it dissociative anesthesia. As noted by Pender, the clinical signs of anesthesia with ketamine are completely different from those seen with conventional intravenous agents and gaseous compounds. Ketamine acts rapidly on intravenous or intramuscular administration to produce a state chracterized by catalepsy, analgesia and amnesia. It is devoid of sedation, hypnotic or convulsive properties. Normal pharyngeal-laryngeal reflexes are maintained and skeletal tone remains normal or increased. Since the introduction of ketamine by Domino's group, numerous reports have appeared to explain various aspects of the cardiovascular response(increased cardiac output, hypertention, little or no change in peripheral resistance) and respiratory response. However there are few reports on the effect of ketamine on intestinal motility. Thus we have made a study to observe the effect of ketamine on the intestinal motility of chickens. Strips of isolated muscle, 1 cm long, from adult fowl weighing l.2-1.5 kg and isolated smooth muscle of a patient with stomach cancer, were suspended in a muscle chamber containing Tyrode's solution into which was bubbled oxygen gas. The solution was. kept constant at 38 degrees C and contraction of the preparations was recorded on a polygraph. After being washed several times with fresh solution, the muscle strips attained constant motility and tonus. Ketamine and other drugs were added in various concentrations to the chamber. The results are as follows: 1) Ketamine did not exert any effect on human intestinal motility. It relaxed fowl intestinal muscle strips and potentiated the effect of epinephrine, norepinephrine, and isoproterenol. 2) The relaxing effects of ketamine on fowl intestinal muscle strips were not abolished by adrenergic blocking agents. 3) Ketamine demonstrated anticholinergic effect on the intestinal motility of the human and fowl. From the above results, it may be concluded that ketamine exerts a anticholinergic effect and depressant effect on intestinal motility of fowl without relation to adrenergic receptors.
Adrenergic Antagonists ; Adult ; Amnesia ; Analgesia ; Anesthesia ; Cardiac Output ; Catalepsy ; Catatonia ; Chickens* ; Cyclohexylamines ; Epinephrine ; Gastrointestinal Motility* ; Humans ; Isoproterenol ; Ketamine* ; Muscle, Smooth ; Norepinephrine ; Oxygen ; Phencyclidine ; Receptors, Adrenergic ; Reflex ; Stomach Neoplasms

Ketamine hydrochlaride, chemically related to both pencyclidine and cyclohexamine, is a new nonbarbiturate intravenous anesthetic agent. Clinical investigations were begun in 1965 by Domino and associates, who first used the term "dissociative anesthesia" . Anesthesia induced by ketamine dissimilar to that resulting from the more widely used intravenous or gaseous componds. Because of its minimal depressant effect on the cardiovascular and respiratory systems as well as its dissociative effect on the central nervous system ketamne bas achieved widespread use. However there have been few reports on its effect an intestinal motility. The present study was undertaken to determine the effect of ketamine on doudenal motility and on other smooth muscles of the rabbit. Strips of various isolated smooth muscle, 2 cm long from adult rabbits weighing about 2 kg, were suspended in a muscle chamber containing Tyrode's solution, which was bubbled with oxygen gas, and the solution was kept constant at 38C. Contraction of the preparations was recorded on polygraph (Grass, mode17). After being washed several times with fresh solution, the smooth muscle strips attained constant motility and tonus. Ketamine and other drugs were added in various concentrations to the chamber. The results areas follows: 1) Ketamine relaxed the isolated rabbit duodenag strip and potentiated the relaxing effect of epinephrine, norepinephrine and isoproterenol. 2) The relaxing effect of ketamine on isolated duodenal strip of rabbits was not abolished by the adrenergic blocking agents, but ketamine antagonized histamine or serotonin-induced contra ction. 3) Ketamine did not exert any effect on the isolated auricle, aorta, trachea, trigone and detrusor muscle strips of rabbit. From the results described above, it may be concluded that ketamine exerts a depressant effect on the isolated duodenal smooth muscle of rabbits without relation to adrenergic receptors.
Adrenergic Antagonists ; Adult ; Anesthesia ; Aorta ; Central Nervous System ; Epinephrine ; Gastrointestinal Motility ; Histamine ; Humans ; Isoproterenol ; Ketamine* ; Muscle, Smooth* ; Norepinephrine ; Oxygen ; Rabbits ; Receptors, Adrenergic ; Respiratory System ; Trachea

Animals ; Chronic Disease ; Febuxostat ; Heart Failure ; drug therapy ; metabolism ; Humans ; Reactive Oxygen Species ; Thiazoles ; pharmacology ; therapeutic use ; Xanthine Oxidase ; antagonists & inhibitors

OBJECTIVETo investigate the molecular mechanisms involved in anti-apoptotic effects of epicathechin in liver cells.

METHODHuman hepatoma cell line (Huh7) was treated with 400 miromol x L(-1) taurodeoxycholic acid (TDCA) for 48 hours to induce apoptosis. Intracellular generation of reactive oxygen species (ROS) was detected with DCFH-DA assay. Caspase-3/7 activity was analyzed with EnzoLyte Homogeneous AMC kit. Cell proliferation was measured by MTT assay. The expression of Bax, Phospho-p38 MAPK and the levels of cytochrome C were assessed by Western-blot analysis.

RESULTTDCA-dependent intracellular ROS production was 8-fold higher as compared to untreated cells, consequently resulting in 45% reduction of cell viability. Interestingly, pretreatment of cells with epicatechin resulted in a dose-dependent inhibition of TDCA-induced ROS generation and reduced cell apoptosis by threefold as compared to TDCA treatment alone. In addition epicatechin reduced Bax expression with consequential inhibition of cytochrome C release from mitochondria, inhibition of caspase 3/7 activation and p38 MAPK phosphorylation.

CONCLUSIONEpicatechin protects Huh7 cells from oxidative stress and mitochondria-induced apoptosis. The molecular mechanisms of anti-apoptotic effects of epicatechin were associated with inhibition of p38 MAPK phosphorylation and Bax expression, and reduction of ROS production. These findings implicate epicathechin might have potential as protective agent against a variety of oxidative stress-mediated liver conditions.

Apoptosis ; drug effects ; physiology ; Carcinoma, Hepatocellular ; pathology ; Catechin ; pharmacology ; Cell Proliferation ; drug effects ; Cytochromes c ; antagonists & inhibitors ; Drug Interactions ; Humans ; MAP Kinase Kinase Kinases ; antagonists & inhibitors ; Membrane Potential, Mitochondrial ; drug effects ; Mitochondria ; drug effects ; Phosphorylation ; drug effects ; Proto-Oncogene Proteins ; antagonists & inhibitors ; Reactive Oxygen Species ; metabolism ; Taurodeoxycholic Acid ; pharmacology ; Tumor Cells, Cultured ; bcl-2-Associated X Protein ; antagonists & inhibitors ; p38 Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; metabolism

In vascular smooth muscle cells, reactive oxygen species (ROS) were known to mediate platelet-derived growth factor (PDGF)-induced cell proliferation and NADH/NADPH oxidase is the major source of ROS. NADH/NADPH oxidase is controlled by rac1 in non-phagocytic cells. In this study, we examined whether the inhibition of rac1 by adenoviral-mediated gene transfer of a dominant negative rac1 gene product (Ad.N17rac1) could reduce the proliferation of rat aortic vascular smooth muscle cells (RASMC) stimulated by PDGF via decreasing intracellular ROS. RASMC were stimulated by PDGF (80 ng/mL) with or without N-acetylcysteine 1 mM or infected with 100 mutiplicity of infection of Ad.N17rac1. Intracellular ROS levels were measured at 12 hr using carboxyl-2', 7'-dichlorodi-hydrofluorescein diacetate confocal microscopy. At 72 hr, cellular proliferation was evaluated by cell number counting and XTT assay. Compared with control, ROS levels were increased by 2-folds by PDGF. NAC and Ad.N17rac1 inhibited PDGF-induced increase of ROS by 77% and 65%, respectively. Cell number was increased by PDGF by 1.6-folds compared with control. NAC and Ad.N17rac1 inhibited PDGF-induced cellular growth by 45% and 87%, respectively. XTT assay also showed similar results. We concluded that inhibition of rac1 in RASMCs could reduce intracellular ROS levels and cellular proliferation induced by PDGF.
Adenoviridae/genetics ; Animal ; Aorta, Thoracic/cytology ; Cell Division/drug effects/physiology ; Cells, Cultured ; Gene Expression/physiology ; Gene Transfer Techniques ; Multienzyme Complexes/antagonists & inhibitors ; Muscle, Smooth, Vascular/*cytology/*metabolism ; NADH, NADPH Oxidoreductases/antagonists & inhibitors ; NADPH Oxidase/antagonists & inhibitors ; Platelet-Derived Growth Factor/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; rac1 GTP-Binding Protein/*genetics/metabolism

The incidence rates of urinary bladder cancer continue to rise yearly, and thus new therapeutic approaches and early diagnostic markers for bladder cancer are urgently needed. Thus, identifying the key mediators and molecular mechanisms responsible for the survival of bladder cancer has valuable implications for the development of therapy. In this study, the role of BLT2, a receptor for leukotriene B4 (LTB4) and 12(S)-hydroxyeicosatetraenoic acid (HETE), in the survival of bladder cancer 253J-BV cells was investigated. We found that the expression of BLT2 is highly elevated in bladder cancer cells. Also, we observed that blockade of BLT2 with an antagonist or BLT2 siRNA resulted in cell cycle arrest and apoptotic cell death, suggesting a role of BLT2 in the survival of human bladder cancer 253J-BV cells. Further experiments aimed at elucidating the mechanism by which BLT2 mediates survival revealed that enhanced level of reactive oxygen species (ROS) are generated via a BLT2-dependent up-regulation of NADPH oxidase members NOX1 and NOX4. Additionally, we observed that inhibition of ROS generation by either NOX1/4 siRNAs or treatment with an ROS-scavenging agent results in apoptotic cell death in 253J-BV bladder cancer cells. These results demonstrated that a 'BLT2-NOX1/4-ROS' cascade plays a role in the survival of this aggressive bladder cancer cells, thus pointing to BLT2 as a potential target for anti-bladder cancer therapy.
*Apoptosis ; Blotting, Western ; Cell Proliferation ; Cells, Cultured ; Gene Expression Regulation, Neoplastic/*physiology ; Humans ; Leukotriene Antagonists/pharmacology ; NADPH Oxidase/antagonists & inhibitors/genetics/metabolism ; Phosphorylation ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Receptors, Leukotriene B4/antagonists & inhibitors/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Tetrazoles/pharmacology ; Up-Regulation ; Urinary Bladder Neoplasms/*genetics/mortality

OBJECTIVE: To explore the role of mitochondrial permeability transition pore (mPTP) in mediating the protective effect of gastrodin against oxidative stress damage in H9c2 cardiac myocytes. METHODS: H9c2 cardiac myocytes were treated with HO, gastrodin, gastrodin+HO, cyclosporin A (CsA), or CsA+gas+HO group. MTT assay was used to detect the survival ratio of H9c2 cells, and flow cytometry with Annexin V-FITC/PI double staining was used to analyze the early apoptosis rate after the treatments. The concentration of ATP and level of reactive oxygen species (ROS) in the cells were detected using commercial kits. The mitochondrial membrane potential of the cells was detected with laser confocal microscopy. The expression of cytochrome C was detected with Western blotting, and the activity of caspase-3 was also assessed in the cells. RESULTS: Gastrodin pretreatment could prevent oxidative stress-induced reduction of mitochondrial membrane potential, and this effect was inhibited by the application of CsA. Gastrodin significantly lowered the levels of ROS and apoptosis-related factors in HO-exposed cells, and such effects were reversed by CsA. CsA significantly antagonized the protective effect of gastrodin against apoptosis in HO-exposed cells. CONCLUSIONS Gastrodin prevents oxidative stress-induced injury in H9c2 cells by inhibiting mPTP opening to reduce the cell apoptosis.
Adenosine Triphosphate ; analysis ; Apoptosis ; drug effects ; Benzyl Alcohols ; antagonists & inhibitors ; pharmacology ; Caspase 3 ; analysis ; Cell Line ; Cell Survival ; drug effects ; Cyclosporine ; pharmacology ; Cytochromes c ; analysis ; Glucosides ; antagonists & inhibitors ; pharmacology ; Humans ; Hydrogen Peroxide ; antagonists & inhibitors ; pharmacology ; Membrane Potential, Mitochondrial ; drug effects ; Mitochondrial Membrane Transport Proteins ; physiology ; Myocytes, Cardiac ; drug effects ; metabolism ; Oxidative Stress ; Reactive Oxygen Species ; analysis

Induction of general anesthesia with direct laryngoscopy and tracheal intubation is a routine procedure. However, it is accompanied by varying degree of sympathetic stimulation as reflected by significant hypertension, tachycardia, and arrhythmia. These transient hemodynamic responses are undesirable, especially in patients with cardiovascular or intracranial diseases. Many approaches have been tried to attenuate these potentially adverse circulatory responses (topical or i.v. lidocaine, deep anesthesia with inhalation anesthetics, opioids, adrenergic blockers, calcium channel blockers, sedatives, etc), and several trials reduced the hemodynamic effects. This study was done to examine blunting effect of verapamil, labetalol, and fentanyl on the adverse hemodynamic changes following direct laryngoscopy and tracheal intubation. Eighty patients, ASA Physical Status I II, scheduled for elective surgery, were selected randomly. These were divided into four groups. Group 1: Control (saline) (n = 20) Group 2: Verapamil 100 ug/kg (n = 20) Group 3: Labetalol 0.25 mg/kg (n = 20) Group 4: Fentanyl 3 ug/kg (n = 20) These were injected 3 minutes before induction with thiopental sodium (5mg/kg) and succinylcholine (1 mg/kg) i.v. in alI groups. Laryngoscopy and endotracheal intubation were performed 5 minutes after study drugs injection. After the completion of intubation, 50% nitrous oxide in oxygen and 1.5 Vol% halothane were inhaled. The blood pressure and heart rate were measured with automatic noninvasive blood pressure device and E.C.G monitoring every minutes for 10 minutes. The data were analyzed with Student's paired t-test within the groups and unpaired t-test between the groups. Results were considered statistically significant if p < 0.05. All study drugs, verapamil, labetalol, or fentanyl significantly blunted the increase in heart rate, arterial blood pressure, and rate pressure product caused by direct laryngoscopy and endotracheal intubation. There was no significant difference between verapamil and labetalol, but the blunting effects on hemodynamic changes were very significant in fentanyl group. So, verapamil, labetalol, and fentanyl may offer on important role in patients in whom an inaease in blood pressure, heart rate, and/or rate pressure product should be avoided during the endotracheal intubation.
Adrenergic Antagonists ; Analgesics, Opioid ; Anesthesia ; Anesthesia, General ; Anesthetics, Inhalation ; Arrhythmias, Cardiac ; Arterial Pressure ; Blood Pressure ; Calcium Channel Blockers ; Fentanyl* ; Halothane ; Heart Rate ; Hemodynamics* ; Humans ; Hypertension ; Hypnotics and Sedatives ; Intubation ; Intubation, Intratracheal* ; Labetalol* ; Laryngoscopy ; Lidocaine ; Nitrous Oxide ; Oxygen ; Succinylcholine ; Tachycardia ; Thiopental ; Verapamil*