European Journal of Pharmacology (v.661, #1-3)

Induction of G1 cell cycle arrest and apoptosis by berberine in bladder cancer cells by Keqiang Yan; Cheng Zhang; Jinbo Feng; Lifang Hou; Lei Yan; Zunlin Zhou; Zhaoxu Liu; Cheng Liu; Yidon Fan; Baozhong Zheng; Zhonghua Xu (1-7).
Bladder cancer is the ninth most common type of cancer, and its surgery is always followed by chemotherapy to prevent recurrence. Berberine is non-toxic to normal cells but has anti-cancer effects in many cancer cell lines. This study was aimed to determine whether berberine inhibits the cell proliferation and induces cell cycle arrest and apoptosis in BIU-87 and T24 bladder cancer cell line. The superficial bladder cancer cell line BIU-87 and invasive T24 bladder cancer cells were treated with different concentrations of berberine. MTT assay was used to determine the effects of berberine on the viability of these cells. The cell cycle arrest was detected through propidium iodide (PI) staining. The induction of apoptosis was determined through Annexin V-conjugated Alexa Fluor 488 (Alexa488) staining. Berberine inhibited the viability of BIU-87 and T24 cells in a dose- and time-dependent manner. It also promoted cell cycle arrest at G0/G1 in a dose-dependent manner and induced apoptosis. We observed that H-Ras and c-fos mRNA and protein expressionswere dose-dependently and time-dependently decreased by berberine treatment. Also, we investigated the cleaved caspase-3 and caspase-9 protein expressions increased in a dose-dependent manner. Berberine inhibits the cell proliferation and induces cell cycle arrest and apoptosis in BIU-87, bladder cancer cell line and T24, invasive bladder cancer cell line. Berberine can inhibit the oncogentic H-Ras and c-fos in T24 cells, and can induce the activation of the caspase-3 and caspase-9 apoptosis. Therefore, berberine has the potential to be a novel chemotherapy drug to treat the bladder cancer by suppressing tumor growth.
Keywords: Bladder cancer; Berberine; BIU-87; T24; Cell cycle arrest; Apoptosis;

ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors by Teresa Riccioni; Fabio Bordi; Patrizia Minetti; Gilberto Spadoni; Hyung-Mun Yun; Bo-Hye Im; Giorgio Tarzia; Hyewhon Rhim; Franco Borsini (8-14).
5-HT6 receptor is one of the most recently cloned serotonin receptors, and it might play important roles in Alzheimer's disease, depression, and learning and memory disorders. Availability of only very few 5-HT6 receptor agonists, however, does not allow examining their contribution in psychopharmacological processes. Therefore, a new 5-HT6 receptor agonist, ST1936, was synthesized. ST1936 binds to human 5-HT6 receptors with good affinity (Ki  = 28.8 nM). ST1936 also exhibited some moderate binding affinity for 5HT2B, 5HT1A, 5HT7 receptors and adrenergic α receptors. ST1936 behaved as a full 5-HT6 agonist on cloned cells and was able to increase Ca2+ concentration, phosphorylation of Fyn kinase, and regulate the activation of ERK1/2 that is a downstream target of Fyn kinase. These effects were completely antagonized by two 5-HT6 receptor antagonists, SB271046 and SB258585. The other 5-HT6 receptor agonist, WAY181187 also increased Fyn kinase activity. These results suggest that both ST1936 and WAY181187 mediate 5-HT6 receptor-dependent signal pathways, such as cAMP, Fyn and ERK1/2 kinase, as specific agonists.Display Omitted
Keywords: ST1936; Biochemistry; 5-HT6 receptor; cAMP; Fyn kinase; (Rat);

Minocycline attenuates the development of diabetic neuropathic pain: Possible anti-inflammatory and anti-oxidant mechanisms by Kavita Pabreja; Kamal Dua; Saurabh Sharma; Satyanarayana S.V. Padi; Shrinivas K. Kulkarni (15-21).
Painful neuropathy, a common complication of diabetes mellitus is characterized by allodynia and hyperalgesia. Recent studies emphasized on the role of non-neuronal cells, particularly microglia in the development of neuronal hypersensitivity. The purpose of the present study is to evaluate the effect of minocyline, a selective inhibitor of microglial activation to define the role of neuroimmune activation in experimental diabetic neuropathy. Cold allodynia and thermal and chemical hyperalgesia were assessed and the markers of inflammation and oxidative and nitrosative stress were estimated in streptozotocin-induced diabetic rats. Chronic administration of minocycline (40 and 80 mg/kg, i.p.) for 2 weeks started 2 weeks after diabetes induction attenuated the development of diabetic neuropathy as compared to diabetic control animals. In addition, minocyline treatment reduced the levels of interleukin-1β and tumor necrosis factor-α, lipid peroxidation, nitrite and also improved antioxidant defense in spinal cords of diabetic rats as compared to diabetic control animals. In contrast, minocycline (80 mg/kg, per se) had no effect on any of these behavioral and biochemical parameters assessed in age-matched control animals. The results of the present study strongly suggest that activated microglia are involved in the development of experimental diabetic neuropathy and minocycline exerted its effect probably by inhibition of neuroimmune activation of microglia. In addition, the beneficial effects of minocycline are partly mediated by its anti-inflammatory effect by reducing the levels of proinflammatory cytokines and in part by modulating oxidative and nitrosative stress in the spinal cord that might be involved in attenuating the development of behavioral hypersensitivity in diabetic rats.
Keywords: Allodynia; Diabetic neuropathy; Hyperalgesia; Microglia;

Eszopiclone stimulates the hypothalamo-pituitary-adrenal axis in the rat by Robert N. Pechnick; Liliana M. Lacayo; Charlene M. Manalo; Yasmin Bholat; Inna Spivak (22-26).
Eszopiclone (Lunesta®) is used for the treatment of insomnia. It is the S (+)-enantiomer of racemic zopiclone, a cyclopyrrolone with no structural similarity to the hypnotic drugs zolpidem and zaleplon or to the benzodiazepines and barbiturates. Although eszopiclone interacts with the gamma-aminobutyric acid A-type (GABAA) receptor complex, it has a different binding profile than other sedative/hypnotic agents and modulates the receptor complex in a unique manner. Thus, eszopiclone might produce different pharmacological effects compared to other sedative/hypnotic agents. Beside their behavioral properties, sedative/hypnotic drugs affect the hypothalamo-pituitary-adrenal (HPA) axis. In general, low doses of benzodiazepine-type drugs decrease, whereas high doses increase the activity of the HPA axis. Furthermore, benzodiazepines reduce stress-induced increases in HPA axis activity. The goal of the present study was to characterize the effects of eszopiclone on the HPA axis in the rat. Male rats were injected with saline or eszopiclone and trunk blood was collected for the measurement of plasma levels of adrenocorticotropin (ACTH) and corticosterone by radioimmunoassay. The acute administration of eszopiclone produced dose-dependent increases in plasma levels of ACTH and corticosterone, and tolerance developed to these effects after repeated drug administration. Pretreatment with eszopiclone did not affect stress-induced stimulation of the HPA axis. These results show that eszopiclone and the benzodiazepine-type drugs differentially affect the HPA axis.
Keywords: Eszopiclone; Benzodiazepine; GABA receptor; Hormone; ACTH; Corticosterone; Sedative/hypnotic; Tolerance; Stress; Pituitary; Adrenal gland;

Identification of short-acting κ-opioid receptor antagonists with anxiolytic-like activity by Matthew F. Peters; Anna Zacco; John Gordon; Carla M. Maciag; Linda C. Litwin; Carolann Thompson; Patricia Schroeder; Linda A. Sygowski; Timothy M. Piser; Todd A. Brugel (27-34).
The κ-opioid receptor plays a central role in mediating the response to stressful life events. Inhibiting κ-opioid receptor signaling is proposed as a mechanism for treating stress-related conditions such as depression and anxiety. Preclinical testing consistently confirms that disruption of κ-opioid signaling is efficacious in animal models of mood disorders. However, concerns about the feasibility of developing antagonists into drugs stem from an unusual pharmacodynamic property of prototypic κ-opioid receptor-selective antagonists; they inhibit receptor signaling for weeks to months after a single dose. Several fundamental questions include — is it possible to identify short-acting antagonists; is long-lasting inhibition necessary for efficacy; and is it safe to develop long-acting antagonists in the clinic. Here, we test representative compounds (AZ-ECPC, AZ-MTAB, and LY-DMPF) from three new chemical series of κ-opioid receptor ligands for long-lasting inhibition. Each compound dose-dependently reversed κ-opioid agonist-induced diuresis. However, unlike the prototypic antagonist, nBNI, which fully inhibited evoked diuresis for at least four weeks, the new compounds showed no inhibition after one week. The two compounds with greater potency and selectivity were tested in prenatally-stressed rats on the elevated plus maze, an exploration-based model of anxiety. Spontaneous exploration of open arms in the elevated plus maze was suppressed by prenatal stress and restored with both compounds. These findings indicate that persistent inhibition is not an inherent property of κ-opioid-selective antagonists and that post-stress dosing with transient inhibitors can be effective in a mood disorder model. This further supports κ-opioid receptor as a promising target for developing novel psychiatric medications.
Keywords: κ-Opioid receptor; Long-lasting antagonism; Depression; Anxiety; Diuresis;

Long-lasting, distinct changes in central opioid receptor and urinary bladder functions in models of schizophrenia in rats by Orsolya Kekesi; Gabor Tuboly; Maria Szucs; Erika Birkas; Zita Morvay; Gyorgy Benedek; Gyongyi Horvath (35-41).
Ketamine treatments and social isolation of rats reflect certain features of schizophrenia, among them altered pain sensitivity. To study the underlying mechanisms of these phenomena, rats were either housed individually or grouped for 33 days after weaning, and treated with either ketamine or saline for 14 days. After one month re-socialization, the urinary bladder capacity by ultrasound examination in the anesthetized animals, and changes of μ-opioid receptors by saturation binding experiments using a specific μ-opioid agonist [3H]DAMGO were determined. G-protein signaling was investigated in DAMGO-stimulated [35S]GTPγS functional assays. Ketamine treatment significantly decreased the bladder volume and isolation decreased the receptor density in cortical membranes. Among all groups, the only change in binding affinity was an increase induced by social isolation in the cortex. G-protein signaling was significantly decreased by either ketamine or social isolation in this tissue. Ketamine treatment, but not housing, significantly increased μ-opioid receptor densities in hippocampal membranes. Both ketamine and isolation increased the efficacy, while the potency of signaling was decreased by any treatment. Ketamine increased the receptor density and G-protein activation; while isolation decreased the efficacy of G-protein signaling in hippocampal membranes. The changes in the co-treated group were similar to those of the isolated animals in most tests. The distinct changes of opioid receptor functioning in different areas of the CNS may, at least partially, explain the augmented nociceptive threshold and morphine potency observed in these animals. Changes in the relative urinary bladder suggest a detrusor hyperreflexia, another sign of schizophrenia.
Keywords: Opioid; Receptor binding; Schizophrenia; Social isolation; Urinary bladder;

Isolated cells from adult rat dorsal root ganglia (DRG) are frequently used as a model system to study responses of primary sensory neurons to nociceptor sensitizing agents such as prostaglandin E2 and prostacyclin, which are presumed to act only on the neurons in typical mixed cell cultures. In the present study, we evaluated the expression of prostaglandin E2 (EP4) and prostacyclin (IP) receptors in cultures of mixed DRG cells and in purified DRG glia. We show here that EP4 and IP receptor agonists stimulated adenylyl cyclase activity in both mixed DRG cells and in purified DRG glia, and that these responses were specifically inhibited by EP4 and IP receptor antagonists, respectively. The presence of EP4 and IP receptors in DRG glia was further confirmed by the expression of EP4 and IP receptor immunoreactivity and mRNA. With the increasing awareness of neuron-glial interactions within intact DRG and the use of isolated DRG cells in the study of mechanisms underlying nociception, it will be essential to consider the role played by EP4 and IP receptor-expressing glial cells when evaluating prostanoid-induced sensitization of DRG neurons.
Keywords: cAMP; Dorsal root ganglia; EP4 receptors; IP receptors; Prostaglandin E2; Satellite glial cells;

Effect of the p38 MAPK inhibitor SB-239063 on Lipopolysaccharide-induced psychomotor retardation and peripheral biomarker alterations in rats by Silvia Bison; Maria Razzoli; Roberto Arban; Francesca Michielin; Simone Bertani; Lucia Carboni (49-56).
Lipopolysaccharide (LPS) administration in rats induces a characteristic syndrome termed ‘sickness behavior’, including profound changes on locomotor activity and circulating stress and inflammatory mediators. The aim of the present investigation was to evaluate whether the behavioral and the peripheral biomarker responses induced by LPS could be modified by acute treatment with the p38 mitogen-activated protein kinase inhibitor SB-239063. Male Sprague–Dawley rats were treated orally either with vehicle or SB-239063 (3, 10 and 30 mg/kg) 1 h before an intraperitoneal injection of either saline or LPS 125 μg/kg. Two hours after LPS injection, rats were placed in a novel open field arena for locomotion assessment during both the light and dark periods. Inflammation and stress mediators were evaluated in plasma 2, 3, 5 or 14 h into the dark phase. Pre-treatment with SB-239063 significantly reversed the locomotor deficits induced by LPS injection. Interleukin (IL)-1β, IL-6, IL-10, Granulocyte-Macrophage-Colony Stimulating Factor, Interferon-γ, and C-reactive-protein levels were increased significantly by LPS, but not when LPS was preceded by SB-239063 treatment. LPS significantly decreased growth-hormone and Prolactin, and this effect was attenuated by SB-239063. Tumor Necrosis Factor-α, Adrenocorticotropic Hormone and Corticosterone levels were significantly higher in LPS-treated rats and were not normalized by SB-239063. Thus, we demonstrate that acute treatment with SB-239063 may have ameliorating effects in early changes of LPS-induced sickness behavior and alteration in the peripheral cytokines/hormones. As such, our procedure may offer an opportunity to test the activity of novel anti-inflammatory compounds on specific symptoms of sickness associated with neuroimmune dysfunctions.
Keywords: Lipopolysaccharide; Sickness behavior; Locomotor activity; Cytokine; Stress hormone; p38 MAPK inhibitor;

Pemirolast reduces cisplatin-induced kaolin intake in rats by Yoko Tatsushima; Nobuaki Egashira; Naohiro Matsushita; Kentaro Kurobe; Takehiro Kawashiri; Takahisa Yano; Ryozo Oishi (57-62).
Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK1 receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT3 receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK1 receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release.
Keywords: Substance P; Pemirolast; Tachykinin NK1 receptor; Cisplatin; Emesis;

The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxamide (SCH 655842): Comparison of efficacy and side effects across rodent species by Sherry X. Lu; Guy A. Higgins; Robert A. Hodgson; Lynn A. Hyde; Robert A. Del Vecchio; Donald H. Guthrie; Tatiana Kazdoba; Martha F. McCool; Cynthia A. Morgan; Ana Bercovici; Ginny D. Ho; Deen Tulshian; Eric M. Parker; John C. Hunter; Geoffrey B. Varty (63-71).
The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3–10 mg/kg) and fear-potentiated startle (3–10 mg/kg) tests, a guinea pig pup vocalization test (1–3 mg/kg), as well as in mouse Geller–Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70–100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.
Keywords: ORL opioid receptor; Anxiety; (Rat); (Mouse); (Guinea pig);

The psychostimulants amphetamine and methylphenidate (MPD/Ritalin) are the drugs most often used to treat attention deficit hyperactivity disorder (ADHD). In addition, students of all ages take these drugs to improve academic performance but also abuse them for pleasurable enhancement. In addition, other psychostimulants such as 3,4-methylenedioxymethamphetamine (MDMA/ecstasy) are used/abused for similar objectives. One of the experimental markers for the potential of a drug to produce dependence is its ability to induce behavioral sensitization and cross sensitization with other drugs of abuse. The objective of this study is to use identical experimental protocols and behavioral assays to compare in female rats the effects of amphetamine, MPD and MDMA on locomotor activity and to determine if they induce behavioral sensitization and/or cross sensitization with each other. The main findings of this study are as follows: (1) acute amphetamine, MPD and MDMA all elicited increases in locomotor activity; (2) chronic administration of an intermediate dose of amphetamine or MPD elicited behavioral sensitization; (3) chronic administration of MDMA elicited behavioral sensitization in some animals and behavioral tolerance in others; (4) cross sensitization between MPD and amphetamine was observed; and (5) MDMA did not show either cross sensitization or cross tolerance with amphetamine. In conclusion, these results suggest that MDMA acts by different mechanisms compared to MPD and amphetamine.
Keywords: Ritalin; Amphetamine; Ecstasy; Locomotor; Cross-sensitization; (Female rat);

Down-regulation of DDAH2 and eNOS induces endothelial dysfunction in sinoaortic-denervated rats by Jinzhong Feng; Hede Luo; Yihua Qiu; Wei Zhou; Feng Yu; Feng Wu (86-91).
The aim of present study was to investigate whether downregulation of dimethylarginine dimethylaminohydrolase (DDAH2) and endothelial nitric oxide synthase (eNOS) induced endothelial dysfunction in sinoaortic-denervated (SAD) rats. SAD rats exhibited significantly higher blood pressure (BP) variability and markedly lower baroreflex sensitivity. However, there was no significant difference in BP between SAD rats and sham-operated rats. In SAD rats, ultrastructural analysis revealed that endothelial cells were degenerated and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) study showed that apoptotic aortic endothelial cells increased. Circulating angiotensinII (AngII), asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) levels in SAD rats were similar to sham-operated rats, but aortic AngII and MDA levels locally increased. Endothelium-mediated relaxation of thoracic aorta isolated from SAD rats was impaired compared to sham-operated rats, whereas the sodium nitroprusside-induced relaxation was quite similar. Western blotting results showed that DDAH2 and eNOS expressions decreased significantly in the aortae of SAD rats. Treatment of primary cultured rat aortic endothelial cells with AngII (1 μM) resulted in a marked reduction of DDAH2 and eNOS expressions, and coadministration of losartan (1 μM), an AT1 receptor antagonist, abolished the effect. In conclusion, downregulation of DDAH2 and eNOS induced endothelial dysfunction in SAD rats. DDAH2 and eNOS may be the potential targets for treatment of endothelial dysfunction.
Keywords: dimethylarginine dimethylaminohydrolase 2; Nitric oxide; Endothelial nitric oxide synthase; Endothelial dysfunction; Sinoartic-denervation; AngiotensinII;

Hepatoprotective activity of a vinylic telluride against acute exposure to acetaminophen by Daiana Silva Ávila; Aline Schwertner Palma; Dirleise Colle; Rogério Scolari; Flávia Manarin; Aron Ferreira da Silveira; Cristina Wayne Nogueira; João Batista Teixeira Rocha; Félix Alexandre Antunes Soares (92-101).
Acetaminophen (APAP) hepatotoxicity has been related with several cases of cirrhosis, hepatitis and suicides attempts. Notably, oxidative stress plays a central role in the hepatic damage caused by APAP and antioxidants have been tested as alternative treatment against APAP toxicity. In the present study, we observed the hepatoprotector activity of the diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP), an organotellurium compound with low toxicity and high antioxidant potential. When the dose of 200 mg/kg of APAP was used, we observed that all used doses of DPTVP were able to restore the –SH levels that were depleted by APAP. Furthermore, the increase in thiobarbituric acid reactive substances levels and in the seric alanine aminotransferase (ALT) activity and the histopathological alterations caused by APAP were restored to control levels by DPTVP (30, 50 and 100 μmol/kg). On the other hand, when the 300 mg/kg dose of APAP was used, DPTVP restored the non-proteic –SH levels and repaired the normal liver morphology of the intoxicated mice only at 50 μmol/kg. Our in vitro results point out to a scavenging activity of DPTVP against several reactive species, action that is attributed to its chemical structure. Taken together, our results demonstrate that the pharmacological action of DPTVP as a hepatoprotector is probably due to its scavenging activity related to its chemical structure.
Keywords: Tellurium; Acetaminophen; Oxidative stress; Hepatoprotection; –SH levels; Histopathological analysis;

Protective effects of hemin in an experimental model of ventilator-induced lung injury by Li An; Chang-Ting Liu; Xue-Bing Qin; Qing-Hui Liu; Yan Liu; Sen-Yang Yu (102-108).
Mechanical ventilation is an indispensable life-support modality for critically ill patients with acute lung injury or acute respiratory distress syndrome. Unfortunately, mechanical ventilation even the protective ventilation strategies may evoke ventilator-induced lung injury. Heme oxygenase-1 (HO-1) has recently exhibited anti-inflammatory and anti-oxidative properties in vitro and in vivo. The effect of HO-1 in ventilator-induced lung injury has not been fully characterized. In this study, rabbits were subjected to high tidal volume ventilation to induce ventilator-induced lung injury, which was confirmed by histopathological alterations, increased bronchoalveolar lavage fluid protein content and lung wet-to-dry ratio. In contrast to the level of HO-1 expression in high tidal volume group, pretreatment with hemin, an inducer of HO-1, further up-regulated HO-1 expression. At the same time, these lung injury indexes were attenuated markedly. This pulmonary protection was accompanied by a decrease in bronchoalveolar lavage fluid neutrophil count and in lung myeloperoxidase activity. Besides, pretreatment with hemin prohibited the production of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-8, and up-regulated the level of anti-inflammatory cytokine interleukin (IL)-10 in bronchoalveolar lavage fluid. Furthermore, a decreased malondialdehyde activity, a marker of oxidative stress and a robust increase in total antioxidant capacity were observed in hemin-treated animals. Our findings suggest that HO-1 up-regulation by hemin plays a protective role in ventilator-induced lung injury by suppression inflammatory process and oxidative stress.
Keywords: Ventilator-induced lung injury; Mechanical ventilation; Heme oxygenase-1; Oxidative stress; Inflammation;

A potential for granulocyte-colony stimulating factor for use as a prophylactic agent for heatstroke in rats by Ming-Chi Yung; Chuan-Chih Hsu; Chieh-Yi Kang; Chia-Li Lin; Shu-Ling Chang; Jhi-Joung Wang; Mao-Tsun Lin; Pei-Jarn Chen; Sheng-Hsien Chen (109-117).
Heatstroke is a form of excessive hyperthermia associated with a systemic inflammatory response that leads to multi-organ dysfunction in which central nervous system disorders predominate. Herein we determined to ascertain whether heat-induced multi-organ dysfunction in rats could be attenuated by granulocyte-colony stimulating factor (G-CSF) preconditioning. Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline, 0.3 ml, subcutaneously) or G-CSF (50–200 μg/kg body weight in 0.3 ml normal saline, subcutaneously) daily and consecutively for 5 days before the start of thermal experiments. They were exposed to an ambient temperature of 43 °C for 68 min to induce heatstroke. G-CSF preconditioning significantly prolonged the survival time in heatstroke rats in a dose-related way (82–98 min vs 127–243 min). The non-preconditioning heatstroke animals showed hyperthermia, arterial hypotension, increased serum levels of systemic inflammatory response molecules, increased hypothalamic apoptotic cell numbers as well as neuronal damage scores, and increased serum levels of renal and hepatic dysfunction indicators. These heatstroke syndromes could be significantly reduced by G-CSF preconditioning. Thus our results revealed a potential for G-CSF used as a prophylactic agent for heatstroke in rats.
Keywords: Granulocyte-colony stimulating factor; Heat stroke; Hypothalamus; Cytokine;

Effect of compound IMMLG5521, a novel coumarin derivative, on carrageenan-induced pleurisy in rats by Zhi-Peng Li; Jin-Feng Hu; Ming-Na Sun; Hai-Jie Ji; Ming Zhao; Dong-Hui Wu; Guang-Yan Li; Gang Liu; Nai-Hong Chen (118-123).
Accumulative evidences have showed that some coumarin derivatives have significantly anti-inflammatory effects. To investigate the potential anti-inflammatory effect of compound IMMLG5521, a novel coumarin derivative, carrageenan-induced pleurisy model in rats was employed. The results showed that IMMLG5521 (5, 10 and 20 mg/kg) exhibited anti-inflammatory effects, reducing pleural exudate formation, decreasing total number of inflammation cells and polymorphonuclear leukocytes infiltration, attenuating histological injury and reducing TNF-α, IL-1β, MIP-2 and IL-8 release. Further investigation revealed that the compound may exert its anti-inflammatory effect via inhibiting nuclear translocation of NF-кB in inflammatory cells collected from pleural exudates. Taken together, the present results suggested that IMMLG5521 inhibited acute inflammation in carrageenan-induced pleurisy model that could be, in part, related to a reduction of release of inflammatory factors, another part may be related to an inhibition of NF-кB activation.
Keywords: Coumarin derivative; Pleurisy; Inflammation; NF-кB;

Solar ultraviolet (UV) radiation causes skin damage including increases in skin thickness, edema, and flush. In this study, we examined the effects of two main flavonoids (wogonin and baicalein) isolated from the roots of Scutellaria baicalensis, a traditional remedy for allergic inflammatory diseases long used in China and Japan, on acute UVB irradiation-induced skin damage in hairless mice. Baicalein and wogonin (10 or 50 mg/kg) were administered orally twice daily for 14 consecutive days. The UVB irradiation was performed at a dose of 200 mJ/cm2 on days 7 and 8 of the treatment with the two main flavonoids. Baicalein, and wogonin prevented the increases in skin thickness and the levels of matrix metalloproteinase (MMP)-9, and vascular endothelial growth factor (VEGF) induced by the irradiation. Wogonin reduced the levels of cyclooxygenase (COX)-2 and hypoxia inducible factor (HIF)-1α in UVB-treated HaCaT cells. These findings suggest that wogonin inhibits irradiation-induced skin damage by suppressing increases in the levels of MMP-9, and VEGF through the inhibition of COX-2 and HIF-1α expression. Baicalein inhibited COX-2 and NF-κB/p65 expression, but stimulated HIF-1α expression. Therefore, its inhibitory action is likely due to the expression of MMP-9 and VEGF through the suppression of COX-2 and NF-κB/p65 expression. Furthermore, the inhibitory effects of baicalein on UVB-irradiated hyperplasia of skin epidermis may be due to the stimulation of HIF-1α expression.
Keywords: Ultraviolet B; MMP-9; VEGF; COX-2; Wogonin; Baicalein;