Science.gov

Sample records for administration significantly inhibited

  1. A chimeric peptide of intestinal trefoil factor containing cholesteryl ester transfer protein B cell epitope significantly inhibits atherosclerosis in rabbits after oral administration.

    PubMed

    Qi, Gaofu; Li, Jingjing; Wang, Shengying; Xin, Shanshan; Du, Peng; Zhang, Qingye; Zhao, Xiuyun

    2011-04-01

    Vaccination against cholesteryl ester transfer protein (CETP) is proven to be effective for inhibiting atherosclerosis in animal models. In this study, the proteases-resistant intestinal trefoil factor (TFF3) was used as a molecular vehicle to construct chimeric TFF3 (cTFF3) containing CETP B cell epitope and tetanus toxin helper T cell epitope. It was found that cTFF3 still preserved a trefoil structure, and can resist proteases digestion in vitro. After oral immunization with cTFF3, the CETP-specific IgA and IgG could be found in intestine lavage fluid and serum, and the anti-CETP antibodies could inhibit partial CETP activity to increase high-density lipoprotein cholesterol, decrease low-density lipoprotein cholesterol, and inhibit atherosclerosis in animals. Therefore, TFF3 is a potential molecular vehicle for developing oral peptide vaccines. Our research highlights a novel strategy for developing oral peptide vaccines in the future.

  2. Inhibition of nociceptive responses after systemic administration of amidated kyotorphin

    PubMed Central

    Ribeiro, MMB; Pinto, A; Pinto, M; Heras, M; Martins, I; Correia, A; Bardaji, E; Tavares, I; Castanho, M

    2011-01-01

    BACKGROUND AND PURPOSE Kyotorphin (KTP; L-Tyr-L-Arg), an endogenous neuropeptide, is potently analgesic when delivered directly to the central nervous system. Its weak analgesic effects after systemic administration have been explained by inability to cross the blood–brain barrier (BBB) and detract from the possible clinical use of KTP as an analgesic. In this study, we aimed to increase the lipophilicity of KTP by amidation and to evaluate the analgesic efficacy of a new KTP derivative (KTP-amide – KTP-NH2). EXPERIMENTAL APPROACH We synthesized KTP-NH2. This peptide was given systemically to assess its ability to cross the BBB. A wide range of pain models, including acute, sustained and chronic inflammatory and neuropathic pain, were used to characterize analgesic efficacies of KTP-NH2. Binding to opioid receptors and toxicity were also measured. KEY RESULTS KTP-NH2, unlike its precursor KTP, was lipophilic and highly analgesic following systemic administration in several acute and chronic pain models, without inducing toxic effects or affecting motor responses and blood pressure. Binding to opioid receptors was minimal. KTP-NH2 inhibited nociceptive responses of spinal neurons. Its analgesic effects were prevented by intrathecal or i.p. administration of naloxone. CONCLUSIONS AND IMPLICATIONS Amidation allowed KTP to show good analgesic ability after systemic delivery in acute and chronic pain models. The indirect opioid-mediated actions of KTP-NH2 may explain why this compound retained its analgesic effects although the usual side effects of opioids were absent, which is a desired feature in next-generation pain medications. PMID:21366550

  3. Intranasal oxytocin administration is associated with enhanced endogenous pain inhibition and reduced negative mood states

    PubMed Central

    Goodin, Burel R.; Anderson, Austen J. B.; Freeman, Emily L.; Bulls, Hailey W.; Robbins, Meredith T.; Ness, Timothy J.

    2014-01-01

    Objectives This study examined whether the administration of intranasal oxytocin was associated with pain sensitivity, endogenous pain inhibitory capacity, and negative mood states. Methods A total of 30 pain-free, young adults each completed three laboratory sessions on consecutive days. The first session (baseline) assessed ischemic pain sensitivity, endogenous pain inhibition via conditioned pain modulation (CPM), and negative mood using the Profile of Mood States (POMS). CPM was tested on the dominant forearm and ipsilateral masseter muscle using algometry (test stimulus) and the cold pressor task (conditioning stimulus; non-dominant hand). For the second and third sessions, participants initially completed the State-Trait Anxiety Inventory (STAI) and then self-administered a single (40IU/1mL) dose of intranasal oxytocin or placebo in a randomized counter-balanced order. Thirty minutes post-administration, participants again completed the STAI and repeated assessments of ischemic pain sensitivity and CPM followed by the POMS. Results Findings demonstrated that ischemic pain sensitivity did not significantly differ across the three study sessions. CPM at the masseter, but not the forearm, was significantly greater following administration of oxytocin compared to placebo. Negative mood was also significantly lower following administration of oxytocin compared to placebo. Similarly, anxiety significantly decreased following administration of oxytocin but not placebo. Discussion This study incorporated a placebo-controlled, double-blind, within-subjects crossover design with randomized administration of intranasal oxytocin and placebo. The data suggest that the administration of intranasal oxytocin may augment endogenous pain inhibitory capacity and reduce negative mood states including anxiety. PMID:25370147

  4. Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.

    PubMed

    Rojewska, Ewelina; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy.

  5. Inhibition of arthritis by systemic administration of endostatin in passive murine collagen induced arthritis

    PubMed Central

    Kurosaka, D; Yoshida, K; Yasuda, J; Yokoyama, T; Kingetsu, I; Yamaguchi, N; Joh, K; Matsushima, M; Saito, S; Yamada, A

    2003-01-01

    Methods: Four kinds of monoclonal anti-type II collagen antibody followed by lipopolysaccharide (LPS) three days later were given to 6 week old, female Balb/c mice to induce arthritis. Three groups of mice received 0.2 mg/kg/day, 2 mg/kg/day, and 10 mg/kg/day of endostatin, respectively, whereas a control group received phosphate buffered saline (PBS). Endostatin or PBS was given for 13 days, starting before the development of arthritis. Arthritis was evaluated by arthritis scores and hind paw thicknesses. Mice were killed for histological examination on the 22nd day after the administration of monoclonal anti-type II collagen antibody. Results: Arthritis developed within three days after LPS administration in both the control and endostatin treatment groups. No difference in the development rate of arthritis was noted between the control and endostatin treatment groups. Arthritis scores remained significantly lower in the endostatin 10 mg/kg/day group than in the control group. Hind paw thicknesses also remained significantly smaller in the endostatin 10 mg/kg/day group than in the control group. Histopathological examination showed that synovial thickening and subchondral bone erosion improved more in the endostatin treatment groups than in the control group. Conclusion: The systemic administration of endostatin had an arthritis inhibiting effect in RA animal models. Endostatin inhibited, in particular, pannus formation and bone destruction. PMID:12810435

  6. A systemic administration of liposomal curcumin inhibits radiation pneumonitis and sensitizes lung carcinoma to radiation

    PubMed Central

    Shi, Hua-shan; Gao, Xiang; Li, Dan; Zhang, Qiong-wen; Wang, Yong-sheng; Zheng, Yu; Cai, Lu-Lu; Zhong, Ren-ming; Rui, Ao; Li, Zhi-yong; Zheng, Hao; Chen, Xian-cheng; Chen, Li-juan

    2012-01-01

    Radiation pneumonitis (RP) is an important dose-limiting toxicity during thoracic radiotherapy. Previous investigations have shown that curcumin is used for the treatment of inflammatory conditions and cancer, suggesting that curcumin may prevent RP and sensitize cancer cells to irradiation. However, the clinical advancement of curcumin is limited by its poor water solubility and low bioavailability after oral administration. Here, a water-soluble liposomal curcumin system was developed to investigate its prevention and sensitizing effects by an intravenous administration manner in mice models. The results showed that liposomal curcumin inhibited nuclear factor-κB pathway and downregulated inflammatory factors including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and transforming growth factor-β induced by thoracic irradiation. Furthermore, the combined treatment with liposomal curcumin and radiotherapy increased intratumoral apoptosis and microvessel responses to irradiation in vivo. The significantly enhanced inhibition of tumor growth also was observed in a murine lung carcinoma (LL/2) model. There were no obvious toxicities observed in mice. The current results indicate that liposomal curcumin can effectively mitigate RP, reduce the fibrosis of lung, and sensitize LL/2 cells to irradiation. This study also suggests that the systemic administration of liposomal curcumin is safe and deserves to be investigated for further clinical application. PMID:22679371

  7. Social isolation stress significantly enhanced the disruption of prepulse inhibition in mice repeatedly treated with methamphetamine.

    PubMed

    Dai, Hongmei; Okuda, Hirotomo; Iwabuchi, Kentaro; Sakurai, Eiko; Chen, Zhong; Kato, Motohisa; Iinuma, Kazuie; Yanai, Kazuhiko

    2004-10-01

    Repeated administration of methamphetamine (METH) causes reverse tolerance or behavioral sensitization in mice. However, the effects of social isolation stress on the METH-caused reverse tolerance have not been studied until now. The aim of this study was to investigate the effects of social isolation stress on METH-caused reverse tolerance by examining the prepulse inhibition of startle response (PPI). PPI was tested in socially isolated and grouped mice after repeated METH injections. Locomotor activity and PPI were also examined just after a four-week isolation rearing period as a control experiment. After completing behavioral experiments, the mice were sacrificed, and the contents of monoamines, including histamine in the brain, were measured. Social isolation stress significantly lowered the locomotion and disrupted PPI. Repeated injections of METH enhanced the effects of social isolation on PPI. The content of dopamine and histamine significantly increased in the cortex, and the turnover rate of dopamine decreased significantly. These findings demonstrate that social isolation stress significantly enhances METH-induced behavioral sensitization and that the altered histaminergic neuron system might play an important role in METH-induced behavioral sensitization in addition to dopaminergic and serotoninergic neurotransmission. Our data suggest that social isolation is involved in the development of METH-induced psychosis, schizophrenia, and other related psychiatric disorders.

  8. Intraventricular administration of isoproterenol inhibits both heat production and heat loss mechanisms in rats.

    PubMed

    Lin, M T; Chandra, A; Fan, Y C; Sun, R

    1980-07-15

    At an ambient temperature (Ta) of 8 degrees C, intraventricular administration of isoproterenol inhibited metabolic heat production and led to hypothermia in rats. In contrast, at a Ta of 22 degrees C and of 30 degrees C, isoproterenol decreased cutaneous circulation and led to hyperthermia. The data indicate that isoproterenol inhibits both heat production and heat loss mechanisms in rats.

  9. The monoamine oxidase (MAO) inhibitor tranylcypromine enhances nicotine self-administration in rats through a mechanism independent of MAO inhibition.

    PubMed

    Lotfipour, Shahrdad; Arnold, Monica M; Hogenkamp, Derk J; Gee, Kelvin W; Belluzzi, James D; Leslie, Frances M

    2011-01-01

    Our current study aims to evaluate the mechanisms of tranylcypromine (TCP)-mediated enhancement of nicotine self-administration. We replicated our previous findings which demonstrate that 1 h pretreatment with TCP (3 mg/kg, i.p.) enhances nicotine self-administration (7.5 μg/kg/inj, i.v.) when compared with vehicle-treated rodents. We tested whether TCP-mediated enhancement of nicotine self-administration was due to MAO inhibition or off-target effects by (i) extending the TCP pretreatment time from 1 to 20 h, and (ii) evaluating the role of the individual TCP stereoisomers in nicotine self-administration studies. While 20 h and (-)TCP pretreatment induced significant inhibition of MAO (60-90%), animals found nicotine only weakly reinforcing. Furthermore, while both (+) and (±)TCP treatment induced nearly 100% MAO inhibition, (+)TCP pretreated animals took longer to acquire nicotine self-administration compared to (±)TCP pretreated animals. Stable nicotine self-administration in (+)TCP pretreated animals was influenced by nicotinic receptor activation but not nicotine-paired cues. The opposite was found in (±)TCP pretreated animals. Treatment with (-) or (±)TCP increased dopamine and serotonin overflow, while the (+) and (±)TCP treatment enhanced monoamine overflow subsequent to nicotine. Together, our data suggests TCP enhancement of nicotine self-administration are mediated through mechanisms independent of MAO inhibition, including nicotine-paired cues and monoamine uptake inhibition.

  10. Annual committee reports on significant legislative, judicial, and administrative developments in 1981: Environmental-Quality Committee

    SciTech Connect

    Not Available

    1982-01-01

    The committee found significant developments under the National Environmental Policy Act (NEPA). There were no amendments to NEPA, but there were new rules affecting DOE defense-related nuclear facilities. Judicial developments continued a deference to agency discretion in environmental impact statement issues and conflicts with other laws. The administration's budget cuts effectively disabled the Council on Environmental Quality (CEQ). The report also outlines significant legislative, judicial, and administrative developments for the Federal Insecticide, Fungicide, and Rodenticide Act, the Endangered Species Act, and the Toxic Substances Act. 188 references. (DCK)

  11. Epinephrine inhibits analgesic tolerance to intrathecal administrated morphine and increases the expression of calcium-calmodulin-dependent protein kinase IIalpha.

    PubMed

    Satarian, Leila; Javan, Mohammad; Fathollahi, Yaghoub

    2008-01-17

    Activation of hypothalamic-pituitary-adrenal (HPA) axis inhibits development of morphine tolerance. Also, the expression of CaMKIIalpha is increased following chronic administration of morphine. In the current study, we tried to examine the effect of epinephrine, on the development of morphine tolerance; and also evaluate the expression of CaMKIIalpha as a molecular index for tolerance development. Analgesic tolerance was induced by intrathecal (i.t.) injection of morphine 15 microg/rat, twice a day for 5 days. To study the effect of epinephrine on development or reversal of morphine tolerance, epinephrine was administrated 20 min before morphine injections. Analgesia was assessed using tail flick test. Gene expression assays were done using RT-PCR. Following 5 days of combined administration of morphine and epinephrine (2, 5 or 10 microg/rat), in day 6, morphine produced potent analgesia. Administration of saline and morphine during days 1-5, caused reduced analgesic effect of morphine on day 6. After tolerance induction during 5 days, co-administration of epinephrine and morphine for another 5 days, significantly reversed the tolerance. Both morphine and epinephrine increased the expression of CaMKIIalpha. The expression of CaMKIIalpha was highly increased following combined administration of epinephrine and morphine. Our results showed the inhibition and reversal of analgesic tolerance to local administrated morphine by epinephrine. We observed the increased expression of CaMKIIalpha without development of morphine tolerance in animals treated with combined epinephrine and morphine.

  12. Biotransformation of baicalin to baicalein significantly strengthens the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms.

    PubMed

    Teng, Yanjie; Nian, Hong; Zhao, Hongtao; Chen, Pei; Wang, Guan

    2013-09-01

    The aim of the present study was to investigate the influence of biotransformation of baicalin into baicalein towards the inhibition potential towards one of the most important drug-metabolizing enzymes (DMEs) UDP-glucuronosyltransferases (UGTs). in vitro incubation method using recombinant UGTs-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used to evaluate the inhibition towards important UGT isoforms in the liver, including UGT1A1, 1A3, 1A6, 1A9, and 2B7. At the same concentration (100 microM), baicalein showed stronger inhibition potential than baicalin towards all the tested UGT isoforms. Data fitting using Dixon plot and Lineweaver-Burk plot was carried out to determine the inhibition type, and the second plot with the slopes from Lineweaver-Burk plot towards baicalein's concentrations was used to calculate the inhibition kinetic parameters (K(i)). Competitive inhibition type was observed for UGT1A1, 1A6, 1A9 and 2B7, and noncompetitive inhibition was detected for UGT1A3. The inhibition kinetic parameters (K(i)) were calculated to be 1.2, 5.1, 15.3, 26.3, and 48.9 microM for UGT1A1, 1A3, 1A6, 1A9, and 2B7, respectively. All these information reminds us of the necessary monitoring when oral administration of baicalin or baicalin-containing herbs.

  13. Oral Administration of Probiotics Inhibits Absorption of the Heavy Metal Cadmium by Protecting the Intestinal Barrier

    PubMed Central

    Zhai, Qixiao; Tian, Fengwei; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan

    2016-01-01

    ABSTRACT The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. Our previous work demonstrated that oral administration of probiotics can significantly inhibit Cd absorption in the intestines of mice, but further evidence is needed to gain insights into the related protection mode. The goal of this study was to evaluate whether probiotics can inhibit Cd absorption through routes other than the Cd binding, with a focus on gut barrier protection. In the in vitro assay, both the intervention and therapy treatments of Lactobacillus plantarum CCFM8610 alleviated Cd-induced cytotoxicity in the human intestinal cell line HT-29 and protected the disruption of tight junctions in the cell monolayers. In a mouse model, probiotics with either good Cd-binding or antioxidative ability increased fecal Cd levels and decreased Cd accumulation in the tissue of Cd-exposed mice. Compared with the Cd-only group, cotreatment with probiotics also reversed the disruption of tight junctions, alleviated inflammation, and decreased the intestinal permeability of mice. L. plantarum CCFM8610, a strain with both good Cd binding and antioxidative abilities, exhibited significantly better protection than the other two strains. These results suggest that along with initial intestinal Cd sequestration, probiotics can inhibit Cd absorption by protecting the intestinal barrier, and the protection is related to the alleviation of Cd-induced oxidative stress. A probiotic with both good Cd-binding and antioxidative capacities can be used as a daily supplement for the prevention of oral Cd exposure. IMPORTANCE The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. For the general population, food and drinking water are the main sources of Cd exposure due to the biomagnification of Cd within the food chain; therefore, the intestinal tract is the first organ that is susceptible to Cd

  14. Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer

    SciTech Connect

    Hao, Hui-fang; Takaoka, Munenori; Bao, Xiao-hong; Wang, Zhi-gang; Tomono, Yasuko; Sakurama, Kazufumi; Ohara, Toshiaki; Fukazawa, Takuya; Yamatsuji, Tomoki; Fujiwara, Toshiyoshi; Naomoto, Yoshio

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer A novel FAK inhibitor TAE226 suppressed FAK activity in HCT116 colon cancer cells. Black-Right-Pointing-Pointer TAE226 suppressed proliferation and migration, with a modest effect on adhesion. Black-Right-Pointing-Pointer Silencing of FAK by siRNA made no obvious difference on cancer cell attachment. Black-Right-Pointing-Pointer TAE226 treatment suppressed the progression of peritoneal dissemination. Black-Right-Pointing-Pointer Oral administration of TAE226 prolonged the survival of tumor-bearing mice. -- Abstract: Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken

  15. Exogenous NAD+ administration significantly protects against myocardial ischemia/reperfusion injury in rat model

    PubMed Central

    Zhang, Youjun; Wang, Ban; Fu, Xingli; Guan, Shaofeng; Han, Wenzheng; Zhang, Jie; Gan, Qian; Fang, Weiyi; Ying, Weihai; Qu, Xinkai

    2016-01-01

    Acute myocardial infarction is one of the leading causes for death around the world. Although essential for successful interventional therapy, it is inevitably complicated by reperfusion injury. Thus effective approaches to reduce ischemia/reperfusion (I/R) injury are still critically needed. To test our hypothesis that intravenous administration of NAD+ can attenuate I/R injury by reducing apoptotic damage and enhancing antioxidant capacity, we used a rat mode of myocardial I/R. Our study found that administration of 10-20 mg/kg NAD+ can dose dependently reduce myocardial infarct induced by I/R, with an approximately 85% reduction of the infarct at the dosage of 20 mg/kg NAD+. We further found that the injection of NAD+ can significantly decrease I/R-induced apoptotic damage in the heart: NAD+ administration can both decrease the TUNEL signals, Bax, cleaved caspase-3 levels and increase the Bcl-XL levels in the rats that are subjected to myocardial I/R injury. NAD+ administration can also significantly attenuate I/R-induced decreases in SOD activity and SOD-2 protein levels in the hearts. NAD+ can profoundly decrease myocardial I/R injury at least partially by attenuating apoptotic damage and enhancing the antioxidant capacity, thus suggesting that NAD+ may become a promising therapeutic agent for myocardial I/R injury. PMID:27648125

  16. Diuresis by intravenous administration of xanthurenic acid in rats, and inhibition by probenecid.

    PubMed

    Uwai, Yuichi; Nakashima, Yuta; Honjo, Emi; Kawasaki, Tatsuya; Nabekura, Tomohiro

    2014-01-01

    The conjugates with sulfate and glucoside of xanthurenic acid, a tryptophan metabolite, were reported to show natriuresis. Sulfotransferase for xanthurenic acid works in the renal proximal tubule to produce the sulfate of xanthurenic acid as well as the liver, and we recently found that xanthurenic acid is a substrate of renal organic anion transporter OAT1. The purpose of this study was to examine relationship between the transport by OAT1 and diuresis related with xanthurenic acid. Drug transport experiment using Xenopus laevis oocytes represented that probenecid inhibited xanthurenic acid uptake by rat OAT1 (rOAT1). Although no diuresis was recognized by the intravenous injection of xanthurenic acid as a bolus in rats, the addition of its infusion exhibited natriuresis. Simultaneous administration of probenecid significantly decreased the urine volume and excreted amounts of sodium into urine. These findings showed the diuresis by the xanthurenic acid administration, and it was probenecid-sensitive. The rOAT1-mediated transport of xanthurenic acid might, at least in part, contribute to its diuretic effect.

  17. Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats.

    PubMed

    Castino, Matthew R; Cornish, Jennifer L; Clemens, Kelly J

    2015-01-01

    Chromatin remodelling is integral to the formation of long-term memories. Recent evidence suggests that histone modification may play a role in the persistence of memories associated with drug use. The present series of experiments aimed to examine the effect of histone deacetylase (HDAC) inhibition on the extinction and reinstatement of nicotine self-administration. Rats were trained to intravenously self-administer nicotine for 12 days on a fixed-ratio 1 schedule. In Experiment 1, responding was then extinguished through removal of nicotine and response-contingent cues. After each extinction session, the HDAC inhibitor, sodium butyrate (NaB), was administered immediately, or six hours after each session. In Experiment 2, response-contingent cues remained available across extinction to increase rates of responding during this phase, and NaB was administered immediately after the session. Finally, in Experiment 3, the effect of NaB treatment on extinction of responding for sucrose pellets was assessed. Across all experiments reinstatement to the cue and/or the reward itself was then tested. In the first experiment, treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately, but not six hours after each extinction session. When administered after cue-extinction (Expt. 2), NaB treatment specifically facilitated the rate of extinction across sessions, indicating that HDAC inhibition enhanced consolidation of the extinction memory. In contrast, there was no effect of NaB on the extinction and reinstatement of sucrose-seeking (Expt. 3), indicating that the observed effects are specific to a drug context. These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.

  18. Microencapsulation of tannic acid for oral administration to inhibit carbohydrate digestion in the gastrointestinal tract.

    PubMed

    Zhao, Wei; Iyer, Vidya; Flores, Floirendo P; Donhowe, Erik; Kong, Fanbin

    2013-06-01

    The prevalence of diabetes mellitus and obesity is rapidly rising worldwide. Recently, there is increasing evidence that phytochemicals such as polyphenols in our diet could directly inhibit the activities of key digestive enzymes, representing a novel method of controlling and preventing diabetes mellitus and obesity. More research is required to determine how to effectively utilize phytochemicals within the gastrointestinal (GI) tract to obtain maximum inhibition of digestive enzymes. This study investigated the inhibition efficiency of tannic acid (TA) on α-amylase as compared with other potential inhibitors using an in vitro method. The inhibition mode and kinetics were studied. The results showed that tannic acid (TA) is more effective in inhibiting α-amylase than a commercial starch blocker (Phase 2 Starch Blocker), and some selected flavonoids and polyphenols including quercetin, rutin, and polyphenon from green tea. It is also found that inhibition of α-amylase by TA in the GI tract is difficult if administered orally due to the non-specific and reversible noncompetitive interaction between tannic acid and α-amylase or other proteins. Accordingly, a pH-sensitive delivery system using calcium-alginate microspheres encapsulating tannic acid was successfully developed for oral administration to inhibit carbohydrate digestion in the GI tract. The encapsulated TA in calcium-alginate microspheres could be protected from the proteins in the stomach, and sustain release and inhibit α-amylase activity in the small intestine.

  19. Antibiotic administration routes significantly influence the levels of antibiotic resistance in gut microbiota.

    PubMed

    Zhang, Lu; Huang, Ying; Zhou, Yang; Buckley, Timothy; Wang, Hua H

    2013-08-01

    This study examined the impact of oral exposure to antibiotic-resistant bacteria and antibiotic administration methods on antibiotic resistance (AR) gene pools and the profile of resistant bacteria in host gastrointestinal (GI) tracts using C57BL/6J mice with natural gut microbiota. Mice inoculated with a mixture of tet(M)-carrying Enterococcus spp. or blaCMY-2-carrying Escherichia coli were treated with different doses of tetracycline hydrochloride (Tet) or ampicillin sodium (Amp) and delivered via either feed or intravenous (i.v.) injection. Quantitative PCR assessment of mouse fecal samples revealed that (i) AR gene pools were below the detection limit in mice without prior inoculation of AR gene carriers regardless of subsequent exposure to corresponding antibiotics; (ii) oral exposure to high doses of Tet and Amp in mice inoculated with AR gene carriers led to rapid enrichment of corresponding AR gene pools in feces; (iii) significantly less or delayed development of AR in the GI tract of the AR carrier-inoculated mice was observed when the same doses of antibiotics were administered via i.v. injection rather than oral administration; and (iv) antibiotic dosage, and maybe the excretion route, affected AR in the GI tract. The shift of dominant AR bacterial populations in the gut microbiota was consistent with the dynamics of AR gene pools. The emergence of endogenous resistant bacteria in the gut microbiota corresponding to drug exposure was also observed. Together, these data suggest that oral administration of antibiotics has a prominent effect on AR amplification and development in gut microbiota, which may be minimized by alternative drug administration approaches, as illustrated by i.v. injection in this study and proper drug selection.

  20. Alteration of aluminium inhibition of synaptosomal (Na(+)/K(+))ATPase by colestipol administration.

    PubMed

    Silva, V S; Oliveira, L; Gonçalves, P P

    2013-11-01

    The ability of aluminium to inhibit the (Na(+)/K(+))ATPase activity has been observed by several authors. During chronic dietary exposure to AlCl3, brain (Na(+)/K(+))ATPase activity drops, even if no alterations of catalytic subunit protein expression and of energy charge potential are observed. The aluminium effect on (Na(+)/K(+))ATPase activity seems to implicate the reduction of interacting protomers within the oligomeric ensemble of the membrane-bound (Na(+)/K(+))ATPase. The activity of (Na(+)/K(+))ATPase is altered by the microviscosity of lipid environment. We studied if aluminium inhibitory effect on (Na(+)/K(+))ATPase is modified by alterations in synaptosomal membrane cholesterol content. Adult male Wistar rats were submitted to chronic dietary AlCl3 exposure (0.03 g/day of AlCl3) and/or to colestipol, a hypolidaemic drug (0.31 g/day) during 4 months. The activity of (Na(+)/K(+))ATPase was studied in brain cortex synaptosomes with different cholesterol contents. Additionally, we incubate synaptosomes with methyl-β-cyclodextrin for both enrichment and depletion of membrane cholesterol content, with or without 300 μM AlCl3. This enzyme activity was significantly reduced by micromolar AlCl3 added in vitro and when aluminium was orally administered to rats. The oral administration of colestipol reduced the cholesterol content and concomitantly inhibited the (Na(+)/K(+))ATPase. The aluminium inhibitory effect on synaptosomal (Na(+)/K(+))ATPase was reduced by cholesterol depletion both in vitro and in vivo.

  1. Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing

    PubMed Central

    Modi, Meera E.; Majchrzak, Mark J.; Fonseca, Kari R.; Doran, Angela; Osgood, Sarah; Vanase-Frawley, Michelle; Feyfant, Eric; McInnes, Heather; Darvari, Ramin; Buhl, Derek L.

    2016-01-01

    Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non–brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response. PMID:27217590

  2. fMRI of Cocaine Self-Administration in Macaques Reveals Functional Inhibition of Basal Ganglia

    PubMed Central

    Mandeville, Joseph B; Choi, Ji-Kyung; Jarraya, Bechir; Rosen, Bruce R; Jenkins, Bruce G; Vanduffel, Wim

    2011-01-01

    Disparities in cocaine-induced neurochemical and metabolic responses between human beings and rodents motivate the use of non-human primates (NHP) to model consequences of repeated cocaine exposure in human subjects. To characterize the functional response to cocaine infusion in NHP brain, we employed contrast-enhanced fMRI during both non-contingent injection of drug and self-administration of cocaine in the magnet. Cocaine robustly decreased cerebral blood volume (CBV) throughout basal ganglia and motor/pre-motor cortex and produced subtle functional inhibition of prefrontal cortex. No brain regions exhibited significant elevation of CBV in response to cocaine challenge. Theses effects in NHP brain are opposite in sign to the cocaine-induced fMRI response in rats, but consistent with previous measurements in NHP based on glucose metabolism. Because the striatal ratio of D2 to D1 receptors is larger in human beings and NHP than rats, we hypothesize that the inhibitory effects of D2 receptor binding dominate the functional response in primates, whereas excitatory D1 receptor stimulation predominates in the rat. If the NHP accurately models the human response to cocaine, downregulation of D2 receptors in human cocaine-abusing populations can be expected to blunt cocaine-induced functional responses, contributing to the weak and variable fMRI responses reported in human basal ganglia following cocaine infusion. PMID:21307843

  3. Oral Administration of Escin Inhibits Acute Inflammation and Reduces Intestinal Mucosal Injury in Animal Models

    PubMed Central

    Li, Minmin; Lu, Chengwen; Zhang, Leiming; Zhang, Jianqiao; Du, Yuan; Duan, Sijin; Wang, Tian; Fu, Fenghua

    2015-01-01

    The present study aimed to investigate the effects of oral administration of escin on acute inflammation and intestinal mucosal injury in animal models. The effects of escin on carrageenan-induced paw edema in a rat model of acute inflammation, cecal ligation and puncture (CLP) induced intestinal mucosal injury in a mouse model, were observed. It was shown that oral administration of escin inhibits carrageenan-induced paw edema and decreases the production of prostaglandin E2 (PGE2) and cyclooxygenase- (COX-) 2. In CLP model, low dose of escin ameliorates endotoxin induced liver injury and intestinal mucosal injury and increases the expression of tight junction protein claudin-5 in mice. These findings suggest that escin effectively inhibits acute inflammation and reduces intestinal mucosal injury in animal models. PMID:26199634

  4. Annual committee reports on significant legislative, judicial and administrative developments in 1983: Air-Quality Committee

    SciTech Connect

    Not Available

    1984-01-01

    Congress passed no significant amendments to the Clean Air Act (CAA) in 1983. Under judicial developments, the committee describes seven categories of cases concerning: nonattainment areas under CAA section 107, the adequacy and appropriateness of state implementation plans and regulation of interstate air pollution, new source-permitting cases, regulation of hazardous air pollutants, enforcement and attorneys fees and the scope of section 304 and 307 of the CAA, sections 120 and 123 of the CAA, and 1983 Title II cases. Administration developments included new steps under Titles I and II of the CAA taken by the Environmental Protection Agency to promulgate final regulation on nonattainment sanctions and new source standards and to revise hydrocarbon and carbon monoxide standards for heavy-duty engines and for vehicles at high altitudes. 264 references.

  5. Clinically significant CYP2C inhibition by noscapine but not by glucosamine.

    PubMed

    Rosenborg, S; Stenberg, M; Otto, S; Ostervall, J; Masquelier, M; Yue, Q-Y; Bertilsson, L; Eliasson, E

    2010-09-01

    Noscapine and glucosamine reportedly interact with warfarin. We investigated the effects of these drugs on various cytochrome P450 (CYP) activity markers. Twelve healthy subjects were phenotyped at baseline and during separate treatments with noscapine and glucosamine. Whereas glucosamine had no significant effect on CYP activity, noscapine caused marked inhibition of CYP2C9 (4.9-fold increase in urinary losartan/E3174 ratio) and CYP2C19 (3.6-fold increase in the plasma omeprazole/5-hydroxyomeprazole ratio). Noscapine-dependent inhibition of CYP2C9 may explain the interaction with warfarin.

  6. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

    NASA Astrophysics Data System (ADS)

    Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L.; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

    2015-12-01

    Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

  7. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.

    PubMed

    Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

    2015-12-01

    Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

  8. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

    PubMed Central

    Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L.; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

    2016-01-01

    Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies. PMID:26587712

  9. Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine-seeking

    PubMed Central

    Knackstedt, Lori A.; Moussawi, Khaled; Lalumiere, Ryan; Schwendt, Marek; Klugmann, Matthias; Kalivas, Peter W.

    2010-01-01

    Learning to inhibit drug-seeking can be an important strategy for inhibiting relapse, and this can be modeled by extinguishing drug-seeking in response to a drug-paired context. Rats were either extinguished or withdrawn without extinction training (abstinence) from cocaine self-administration and measurements of postsynaptic density proteins in the core and shell subcompartments of the nucleus accumbens were compared to yoked-saline controls. Only extinguished rats had elevations of PSD-95, Homer1b/c, and Narp in the postsynaptic density of the core, while no proteins measured were altered in the postsynaptic density of the shell in either extinguished or abstinent rats. Using a biotinylation strategy, it was found that surface expression of mGluR5 was reduced only in the core of extinguished animals. While both extinguished and abstinent animals showed a reduction in long-term potentiation elicited in the core by stimulating prefrontal cortex, blunted long-term depression was observed only in extinguished rats. These data indicate that the elevation in Homer1b/c in the core may have sequestered mGluR5 away from the membrane surface, and that the loss of surface mGluR5 inhibits long-term depression. Accordingly, when Homer1c was over-expressed in the core of cocaine naïve rats with an adeno-associated virus, long-term depression was inhibited. This mechanism may contribute to the inhibition of cocaine seeking by extinction training because over-expression Homer1c in the core also inhibited cue-induced reinstatement of cocaine seeking. These data identify a cellular mechanism that may contribute to extinction-induced inhibition of cocaine seeking. PMID:20534846

  10. Behaviorally inhibited individuals demonstrate significantly enhanced conditioned response acquisition under non-optimal learning conditions.

    PubMed

    Holloway, J L; Allen, M T; Myers, C E; Servatius, R J

    2014-03-15

    Behavioral inhibition (BI) is an anxiety vulnerability factor associated with hypervigilance to novel stimuli, threat, and ambiguous cues. The progression from anxiety risk to a clinical disorder is unknown, although the acquisition of defensive learning and avoidance may be a critical feature. As the expression of avoidance is also central to anxiety development, the present study examined avoidance acquisition as a function of inhibited temperament using classical eyeblink conditioning. Individuals were classified as behaviorally inhibited (BI) or non-inhibited (NI) based on combined scores from the Adult and Retrospective Measures of Behavioural Inhibition (AMBI and RMBI, respectively). Acquisition was assessed using delay, omission, or yoked conditioning schedules of reinforcement. Omission training was identical to delay, except that the emission of an eyeblink conditioned response (CR) resulted in omission of the unconditioned airpuff stimulus (US) on that trial. Each subject in the yoked group was matched on total BI score to a subject in the omission group, and received the same schedule of CS and US delivery, resulting in a partial reinforcement training schedule. Delay conditioning elicited significantly more CRs compared to the omission and yoked contingencies, the latter two of which did not differ from each other. Thus, acquisition of an avoidance response was not apparent. BI individuals demonstrated enhanced acquisition overall, while partial reinforcement training significantly distinguished between BI and NI groups. Enhanced learning in BI may be a function of an increased defensive learning capacity, or sensitivity to uncertainty. Further work examining the influence of BI on learning acquisition is important for understanding individual differences in disorder etiology in anxiety vulnerable cohorts.

  11. Hydroxytyrosyl alkyl ether derivatives inhibit platelet activation after oral administration to rats.

    PubMed

    Muñoz-Marín, Javier; De la Cruz, José Pedro; Reyes, José Julio; López-Villodres, Juan Antonio; Guerrero, Ana; López-Leiva, Inmaculada; Espartero, José Luis; Labajos, María Teresa; González-Correa, José Antonio

    2013-08-01

    The low lipophilicity of hydroxytyrosol (HT) has motivated efforts to synthesize homologous series with better lipid solubility, such as the ethers, which are more lipophilic than HT. Because HT inhibits platelet aggregation, the aim of the study was to assess the possible anti-platelet effect of five HT ether derivatives (ethyl, butyl, hexyl, octyl and dodecyl) after oral administration to rats. Whole blood collagen-induced platelet aggregation and calcium-induced thromboxane B2 (TxB2), aortic 6-keto-prostaglandin F1α (6-keto-PGF1α) and nitrites+nitrates, plasma concentration of lipid peroxides (TBARS) and red blood cell content of reduced glutathione (GSH) were measured. The administration of 20 mg/kg/day inhibited platelet aggregation, TxB2 and TBARS in a non-linear manner related to the length of the carbon chain, with a cut-off effect in the hexyl derivative. Aortic nitrite and red blood cell GSH production were also increased. The aortic production of 6-keto-PGF1α was unaltered except in the group treated with the dodecyl derivative. The administration of 50 mg/kg/day showed a similar pharmacodynamic profile but without the non-linear effect. In conclusion, HT ethers, especially the hexyl derivative, are a potential alternative to hydroxytyrosol, and their effect merits additional research to determine their role in the prophylaxis of vascular disease.

  12. Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model

    PubMed Central

    Suman, Suman; Das, Trinath P.; Moselhy, Jim; Pal, Deeksha; Kolluru, Venkatesh; Alatassi, Houda; Ankem, Murali K.; Damodaran, Chendil

    2016-01-01

    We previously reported that withaferin A (WA), a natural compound, deters prostate cancer by inhibiting AKT while inducing apoptosis. In the current study, we examined its chemopreventive efficacy against carcinogenesis in the prostate using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Two distinct sets of experiments were conducted. To determine whether WA delays tumor progression, it was given before cancer onset, at week 6, and until week 44. To determine its effect after the onset of prostate cancer, it was given from weeks 12 to 35. In both strategies, oral administration of WA effectively suppressed tumor burden when compared to vehicle-treated animals. No toxicity was seen in treated animals at gross pathological examination. Western blot analysis and immunohistochemistry of tumor sections revealed that in TRAMP controls, AKT and pAKT were highly expressed while nuclear FOXO3a and Par-4 were downregulated. On the contrary, treated mice showed inhibition of AKT signaling and activation of FOX03a-Par-4-induced cell death. They also displayed inhibition of mesenchymal markers such as β-catenin, vimentin, and snail as well as upregulation of E-cadherin. Because expressions of the angiogenic markers factor VIII and retic were downregulated, an anti-angiogenic role of WA is suggested. Overall, our results suggest that WA could be a promising anti-cancer agent that effectively inhibits carcinogenesis of the prostate. PMID:27447565

  13. Intracerebral Stem Cell Administration Inhibits Relapse-like Alcohol Drinking in Rats.

    PubMed

    Israel, Yedy; Ezquer, Fernando; Quintanilla, María Elena; Morales, Paola; Ezquer, Marcelo; Herrera-Marschitz, Mario

    2017-01-01

    Study describes the blockade of relapse-like alcohol drinking by mesenchymal stem cells (MSCs). High alcohol-intake bred rats consumed alcohol for 3 months and were subjected to repeated alcohol deprivations for 7-14 days, followed by alcohol reaccess. Upon reaccess, animals consumed 2.2 g alcohol/kg in 60 minutes. A single intra-cerebroventricular MSC administration inhibited relapse-like drinking up to 80-85% for 40 days (P < 0.001). An alcohol-use-disorder was prevented.

  14. Cholinesterase inhibition and acetylcholine accumulation following intracerebral administration of paraoxon in rats

    SciTech Connect

    Ray, A.; Liu, J.; Karanth, S.; Gao, Y.; Brimijoin, S.; Pope, C.

    2009-05-01

    We evaluated the inhibition of striatal cholinesterase activity following intracerebral administration of paraoxon assaying activity either in tissue homogenates ex vivo or by substrate hydrolysis in situ. Artificial cerebrospinal fluid (aCSF) or paraoxon in aCSF was infused unilaterally (0.5 {mu}l/min for 2 h) and ipsilateral and contralateral striata were harvested for ChE assay ex vivo. High paraoxon concentrations were needed to inhibit ipsilateral striatal cholinesterase activity (no inhibition at < 0.1 mM; 27% at 0.1 mM; 79% at 1 mM paraoxon). With 3 mM paraoxon infusion, substantial ChE inhibition was also noted in contralateral striatum. ChE histochemistry generally confirmed these concentration- and side-dependent effects. Microdialysates collected for up to 4 h after paraoxon infusion inhibited ChE activity when added to striatal homogenate, suggesting prolonged efflux of paraoxon. Since paraoxon efflux could complicate acetylcholine analysis, we evaluated the effects of paraoxon (0, 0.03, 0.1, 1, 10 or 100 {mu}M, 1.5 {mu}l/min for 45 min) administered by reverse dialysis through a microdialysis probe. ChE activity was then monitored in situ by perfusing the colorimetric substrate acetylthiocholine through the same probe and measuring product (thiocholine) in dialysates. Concentration-dependent inhibition was noted but reached a plateau of about 70% at 1 {mu}M and higher concentrations. Striatal acetylcholine was below the detection limit at all times with 0.1 {mu}M paraoxon but was transiently elevated (0.5-1.5 h) with 10 {mu}M paraoxon. In vivo paraoxon (0.4 mg/kg, sc) in adult rats elicited about 90% striatal ChE inhibition measured ex vivo, but only about 10% inhibition measured in situ. Histochemical analyses revealed intense AChE and glial fibrillary acidic protein staining near the cannula track, suggesting proliferation of inflammatory cells/glia. The findings suggest that ex vivo and in situ cholinesterase assays can provide very different views

  15. Oral Administration of Blueberry Inhibits Angiogenic Tumor Growth and Enhances Survival of Mice with Endothelial Cell Neoplasm

    PubMed Central

    Fang, Huiqing; Khanna, Savita; Harper, Justin; Phillips, Gary; Sen, Chandan K.

    2009-01-01

    Abstract Endothelial cell neoplasms are the most common soft tissue tumor in infants. Subcutaneous injection of spontaneously transformed murine endothelial (EOMA) cells results in development of hemangioendothelioma (HE). We have previously shown that blueberry extract (BBE) treatment of EOMA cells in vitro prior to injection in vivo can significantly inhibit the incidence and size of developing HE. In this study, we sought to determine whether oral BBE could be effective in managing HE and to investigate the mechanisms through which BBE exerts its effects on endothelial cells. A dose-dependent decrease in HE tumor size was observed in mice receiving daily oral gavage feeds of BBE. Kaplan-Meier survival curve showed significantly enhanced survival for mice with HE tumors given BBE, compared to control. BBE treatment of EOMA cells inhibited both c-Jun N-terminal kinase (JNK) and NF-κB signaling pathways that culminate in monocyte chemoattractant protein-1 (MCP-1) expression required for HE development. Antiangiogenic effects of BBE on EOMA cells included decreased proliferation by BrdU assay, decreased sprouting on Matrigel, and decreased transwell migration. Thus, this work provides first evidence demonstrating that BBE can limit tumor formation through antiangiogenic effects and inhibition of JNK and NF-κB signaling pathways. Oral administration of BBE represents a potential therapeutic antiangiogenic strategy for treating endothelial cell neoplasms in children. Antioxid Redox Signal 11, 47–58. PMID:18817478

  16. Oral administration of protease inhibits enterotoxigenic Escherichia coli receptor activity in piglet small intestine.

    PubMed Central

    Mynott, T L; Luke, R K; Chandler, D S

    1996-01-01

    The virulence of enterotoxigenic Escherichia coli (ETEC) is attributed to their ability to adhere via fimbrial adhesins to specific receptors located on the intestinal mucosa. A novel approach to preventing ETEC induced diarrhoea would be to prevent attachment of ETEC to intestine by proteolytically modifying the receptor attachment sites. This study aimed to examine the effect of bromelain, a proteolytic extract obtained from pineapple stems, on ETEC receptor activity in porcine small intestine. Bromelain was administered orally to piglets and K88+ ETEC attachment to small intestine was measured at 50 cm intervals using an enzyme immunoassay. K88+ ETEC attachment to intestinal sections that were not treated with bromelain varied appreciably between sampling sites. Variability in receptor activity along the intestinal surface is though to be caused by the localised effects of endogenous proteases. Oral administration of exogenous protease inhibited K88+ ETEC attachment to pig small intestine in a dose dependent manner (p < 0.05). Attachment of K88+ ETEC was negligible after treatment, resembling the levels of attachment of K88 to piglets of the genetically determined non-adhesive phenotype, which are resistant to K88+ ETEC infection. Serum biochemical analysis and histopathological examination of treated piglets showed no adverse effects of the bromelain treatment. It is concluded that administration of bromelain can inhibit ETEC receptor activity in vivo and may therefore be useful for prevention of K88+ ETEC induced diarrhoea. PMID:8566855

  17. Acupuncture-mediated inhibition of inflammation facilitates significant functional recovery after spinal cord injury.

    PubMed

    Choi, Doo C; Lee, Jee Y; Moon, Youn J; Kim, Shin W; Oh, Tae H; Yune, Tae Y

    2010-09-01

    Here, we first demonstrated the neuroprotective effect of acupuncture after SCI. Acupuncture applied at two specific acupoints, Shuigou (GV26) and Yanglingquan (GB34) significantly alleviated apoptotic cell death of neurons and oligodendrocytes, thereby leading to improved functional recovery after SCI. Acupuncture also inhibited caspase-3 activation and reduced the size of lesion cavity and extent of loss of axons. We also found that the activation of both p38 mitogen-activated protein kinase and resident microglia after injury are significantly attenuated by acupuncture. In addition, acupuncture significantly reduced the expression or activation of pro-nerve growth factor, proinflammatory factors such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, nitric oxide synthase, cycloxygenase-2, and matrix metalloprotease-9 after SCI. Thus, our results suggest that the neuroprotection by acupuncture may be partly mediated via inhibition of inflammation and microglial activation after SCI and acupuncture can be used as a potential therapeutic tool for treating acute spinal injury in human.

  18. 21 CFR 10.70 - Documentation of significant decisions in administrative file.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... decision on any matter under the laws administered by the Commissioner, whether it is raised formally, for... handling a matter are responsible for insuring the completeness of the administrative file relating to it... supervisory personnel, responsible for handling the matter. (i) The recommendations and decisions are...

  19. 21 CFR 10.70 - Documentation of significant decisions in administrative file.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... decision on any matter under the laws administered by the Commissioner, whether it is raised formally, for... handling a matter are responsible for insuring the completeness of the administrative file relating to it... supervisory personnel, responsible for handling the matter. (i) The recommendations and decisions are...

  20. Inhibition of class IIb histone deacetylase significantly improves cloning efficiency in mice.

    PubMed

    Ono, Tetsuo; Li, Chong; Mizutani, Eiji; Terashita, Yukari; Yamagata, Kazuo; Wakayama, Teruhiko

    2010-12-01

    Since the first mouse clone was produced by somatic cell nuclear transfer, the success rate of cloning in mice has been extremely low. Some histone deacetylase inhibitors, such as trichostatin A and scriptaid, have improved the full-term development of mouse clones significantly, but the mechanisms allowing for this are unclear. Here, we found that two other specific inhibitors, suberoylanilide hydroxamic acid and oxamflatin, could also reduce the rate of apoptosis in blastocysts, improve the full-term development of cloned mice, and increase establishment of nuclear transfer-generated embryonic stem cell lines significantly without leading to obvious abnormalities. However, another inhibitor, valproic acid, could not improve cloning efficiency. Suberoylanilide hydroxamic acid, oxamflatin, trichostatin A, and scriptaid are inhibitors for classes I and IIa/b histone deacetylase, whereas valproic acid is an inhibitor for classes I and IIa, suggesting that inhibiting class IIb histone deacetylase is an important step for reprogramming mouse cloning efficiency.

  1. The CO2 inhibition of terrestrial isoprene emission significantly affects future ozone projections

    NASA Astrophysics Data System (ADS)

    Young, P. J.; Arneth, A.; Schurgers, G.; Zeng, G.; Pyle, J. A.

    2008-11-01

    Simulations of future tropospheric composition often include substantial increases in biogenic isoprene emissions arising from the Arrhenius-like leaf emission response and warmer surface temperatures, and from enhanced vegetation productivity in response to temperature and atmospheric CO2 concentration. However, a number of recent laboratory and field data have suggested a direct inhibition of leaf isoprene production by increasing atmospheric CO2 concentration, notwithstanding isoprene being produced from precursor molecules that include some of the primary products of carbon assimilation. The cellular mechanism that underlies the decoupling of leaf photosynthesis and isoprene production still awaits a full explanation but accounting for this observation in a dynamic vegetation model that contains a semi-mechanistic treatment of isoprene emissions has been shown to change future global isoprene emission estimates notably. Here we use these estimates in conjunction with a chemistry-climate model to compare the effects of isoprene simulations without and with a direct CO2-inhibition on late 21st century O3 and OH levels. The impact on surface O3 was significant. Including the CO2-inhibition of isoprene resulted in opposing responses in polluted (O3 decreases of up to 10 ppbv) vs. less polluted (O3 increases of up to 10 ppbv) source regions, due to isoprene nitrate and peroxy acetyl nitrate (PAN) chemistry. OH concentration increased with relatively lower future isoprene emissions, decreasing methane lifetime by ~7 months. Our simulations underline the large uncertainties in future chemistry and climate studies due to biogenic emission patterns and emphasize the problems of using globally averaged climate metrics to quantify the atmospheric impact of reactive, heterogeneously distributed substances.

  2. The CO2 inhibition of terrestrial isoprene emission significantly affects future ozone projections

    NASA Astrophysics Data System (ADS)

    Young, P. J.; Arneth, A.; Schurgers, G.; Zeng, G.; Pyle, J. A.

    2009-04-01

    Simulations of future tropospheric composition often include substantial increases in biogenic isoprene emissions arising from the Arrhenius-like leaf emission response and warmer surface temperatures, and from enhanced vegetation productivity in response to temperature and atmospheric CO2 concentration. However, a number of recent laboratory and field data have suggested a direct inhibition of leaf isoprene production by increasing atmospheric CO2 concentration, notwithstanding isoprene being produced from precursor molecules that include some of the primary products of carbon assimilation. The cellular mechanism that underlies the decoupling of leaf photosynthesis and isoprene production still awaits a full explanation but accounting for this observation in a dynamic vegetation model that contains a semi-mechanistic treatment of isoprene emissions has been shown to change future global isoprene emission estimates notably. Here we use these estimates in conjunction with a chemistry-climate model to compare the effects of isoprene simulations without and with a direct CO2-inhibition on late 21st century O3 and OH levels. The impact on surface O3 was significant. Including the CO2-inhibition of isoprene resulted in opposing responses in polluted (O3 decreases of up to 10 ppbv) vs. less polluted (O3 increases of up to 10 ppbv) source regions, due to isoprene nitrate and peroxy acetyl nitrate (PAN) chemistry. OH concentration increased with relatively lower future isoprene emissions, decreasing methane lifetime by ~7 months (6.6%). Our simulations underline the large uncertainties in future chemistry and climate studies due to biogenic emission patterns and emphasize the problems of using globally averaged climate metrics (such as global radiative forcing) to quantify the atmospheric impact of reactive, heterogeneously distributed substances.

  3. Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice

    PubMed Central

    Agrawal, Vijayendra; Maharjan, Sony; Kim, Kyeojin; Kim, Nam-Jung; Son, Jimin; Lee, Keunho; Choi, Hyun-Jung; Rho, Seung-Sik; Ahn, Sunjoo; Won, Moo-Ho; Ha, Sang-Jun; Koh, Gou Young; Kim, Young-Myeong; Suh, Young-Ger; Kwon, Young-Guen

    2014-01-01

    Tumor blood vessels are leaky and immature, which causes inadequate blood supply to tumor tissues resulting in hypoxic microenvironment and promotes metastasis. Here we have explored tumor vessel modulating activity of Sac-1004, a recently developed molecule in our lab, which directly potentiates VE-cadherin-mediated endothelial cell junction. Sac-1004 could enhance vascular junction integrity in tumor vessels and thereby inhibit vascular leakage and enhance vascular perfusion. Improved perfusion enabled Sac-1004 to have synergistic anti-tumor effect on cisplatin-mediated apoptosis of tumor cells. Interestingly, characteristics of normalized blood vessels namely reduced hypoxia, improved pericyte coverage and decreased basement membrane thickness were readily observed in tumors treated with Sac-1004. Remarkably, Sac-1004 was also able to inhibit lung and lymph node metastasis in MMTV and B16BL6 tumor models. This was in correlation with a reduction in epithelial-to-mesenchymal transition of tumor cells with considerable diminution in expression of related transcription factors. Moreover, cancer stem cell population dropped substantially in Sac-1004 treated tumor tissues. Taken together, our results showed that direct restoration of vascular junction could be a significant strategy to induce normalization of tumor blood vessels and reduce metastasis. PMID:24811731

  4. Inhibition of stress induced hyperglucagonemia by administration of glucose in normal and alloxan-diabetic rat.

    PubMed

    Klimes, I; Jurcovicová, J; Németh, S; Jezová, D; Vigas, M

    1981-01-01

    The increase in plasma pancreatic glucagon which is known to occur under several stress conditions was confirmed in fed and 18 h prefasted rats subjected to a low, "stress producing" dose of the Noble-collip drum procedure (400 revolutions per 400 s). A single dose of exogenous glucose ( 1 g kg-1) injected 3 min and 20 s before stress into the jugular vein of intact fasted or fed animals anesthetized with pentobarbital 930 mg kg-1) completely abolished their hyperglucagonemic response in stress. In alloxan-diabetic hyperglycemic rats the stress-hyperglucagonemia was exaggerated, but was also suppressible by exogenous glucose. It was concluded that: 1. the stress induced hyperglucagonemic response of both intact and alloxan-diabetic rats was completely suppressible by administration of i.v. bolus of exogenous glucose; 2. the site inhibiting effect of glucose might be located either at the level of A cell or at the level of "'glucoreceptors" in hypothalamus.

  5. Glutathione deficiency in Gclm null mice results in complex I inhibition and dopamine depletion following paraquat administration.

    PubMed

    Liang, Li-Ping; Kavanagh, Terrance J; Patel, Manisha

    2013-08-01

    Depletion of glutathione has been shown to occur in autopsied brains of patients with Parkinson's disease (PD) and in animal models of PD. The goal of this study was to determine whether chronic glutathione (GSH) deficiency per se resulted in complex I inhibition and/or dopamine depletion and whether these indices were further potentiated by aging or administration of paraquat, a redox-cycling herbicide that produces a PD-like neurodegeneration model in rodents (Brooks, A. I., Chadwick, C. A., Gelbard, H. A., Cory-Slechta, D. A., and Federoff, H. J. [1999]. Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res. 823, 1-10; McCormack, A. L., Thiruchelvam, M., Manning-Bog, A. B., Thiffault, C., Langston, J. W., Cory-Slechta, D. A., and Di Monte, D. A. [2002]. Environmental risk factors and Parkinson's disease: Selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol. Dis. 10, 119-127.) Deletion of the rate-limiting GSH synthesis gene, glutamate-cysteine ligase modifier subunit (Gclm), leads to significantly lower GSH concentrations in all tissues including brain. Gclm null (Gclm (-/-)) mice provide a model of prolonged GSH depletion to explore the relationship between GSH, complex I inhibition, and dopamine loss in vivo. Despite ~60% depletion of brain GSH in Gclm (-/-) mice of ages 3-5 or 14-16 months, striatal complex I activity, dopamine levels, 3-nitrotyroine/tyrosine ratios, aconitase activity, and CoASH remained unchanged. Administration of paraquat (10mg/kg, twice/week, 3 weeks) to 3- to 5-month-old Gclm (-/-) mice resulted in significantly decreased aconitase activity, complex I activity, and dopamine levels but not in 3- to 5-month-old Gclm (+/+) mice. Furthermore, paraquat-induced inhibition of complex I and aconitase activities in Gclm (-/-) mice was observed in the striatum but not in the cortex. The results suggest that chronic deficiency of GSH in Gclm (-/-) mice was not

  6. Long-term administration of inulin-type fructans has no significant lipid-lowering effect in normolipidemic humans.

    PubMed

    Forcheron, Fabien; Beylot, Michel

    2007-08-01

    Short-term studies have shown that the addition to diet of inulin-type fructans, a nondigestible carbohydrate, may have a plasma lipid-lowering effect in humans. Whether this beneficial effect persists during long-term administration has not been determined. The study was aimed at determining whether a prolonged (6 months) administration of inulin-type fructans to healthy subjects has a lipid-lowering action. In a double-blind, randomized, placebo-controlled study, 17 healthy subjects were studied before and after 6 months of daily administration of placebo (8 subjects) or 10 g of a mix of inulin and oligofructose (9 subjects). During this 6-month period, they consumed their usual diet and did not modify their everyday way of life. We measured plasma lipid concentrations; cholesterol synthesis and hepatic lipogenesis; and adipose tissue and circulating mononuclear cell messenger RNA concentrations of key regulatory genes of cholesterol metabolism. Compared with the administration of placebo, the administration of inulin-type fructans had no effect on plasma triacylglycerol concentrations and hepatic lipogenesis and induced only a nonsignificant trend for decreased plasma total and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol concentration. Cholesterol synthesis was not significantly modified. Of all the messenger RNA concentrations measured, none was significantly modified by the administration of inulin-type fructans. In conclusion, contrary to what was observed in short-term studies, we observed no significant beneficial effect of a long-term (6-month) administration of inulin-type fructans on plasma lipids in healthy human subjects.

  7. Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro.

    PubMed

    Kato, Takahiro; Monji, Akira; Hashioka, Sadayuki; Kanba, Shigenobu

    2007-05-01

    Microglia has recently been regarded to be a mediator of neuroinflammation via the release of proinflammatory cytokines, nitric oxide (NO) and reactive oxygen species (ROS) in the central nervous system (CNS). Microglia has thus been reported to play an important role in the pathology of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The pathological mechanisms of schizophrenia remain unclear while some recent neuroimaging studies suggest even schizophrenia may be a kind of neurodegenerative disease. Risperidone has been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia. Many recent studies have demonstrated that immunological mechanisms via such as interferon (IFN)-gamma and cytokines might be relevant to the pathophysiology of schizophrenia. In the present study, we thus investigated the effects of risperidone on the generation of nitric oxide, inducible NO synthase (iNOS) expression and inflammatory cytokines: interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha by IFN-gamma-activated microglia by using Griess assay, Western blotting and ELISA, respectively. In comparison with haloperidol, risperidone significantly inhibited the production of NO and proinflammatory cytokines by activated microglia. The iNOS levels of risperidone-treated cells were much lower than those of the haloperidol-treated cells. Antipsychotics, especially risperidone may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia.

  8. Annual committee reports on significant legislative, judicial, and administrative developments in 1980: Environmental Quality Committee

    SciTech Connect

    Not Available

    1981-01-01

    The reporting responsibilities of the Environmental Quality Committee cover those major federal environmental statutes not covered by the Air Quality, Water Quality, Urban Environment, or Public Lands and Land Use Committees. The 1980 report includes significant developments under the National Environmental Policy Act, the Federal Insecticide, Fungicide and Rodenticide Act, the Toxic Substances Control Act, the Endangered Species Act, the Resource Conservation and Recovery Act, and the Comprehensive Environmental Response, Compensation, and Liability Act (Superfund). The dates of publication and page references in the Federal Register list the final procedures by agency in the appendix. 392 references.

  9. Central administration of methamphetamine synergizes with metabolic inhibition to deplete striatal monoamines.

    PubMed

    Burrows, K B; Nixdorf, W L; Yamamoto, B K

    2000-03-01

    These studies examined, in vivo, the effect of local intrastriatal perfusion of methamphetamine (MA) on dopamine (DA) and glutamate release in relation to changes in striatal DA and serotonin (5-HT) content measured 1 week after treatment. Interactions between the inhibition of energy metabolism and the direct perfusion of MA on long-term decreases in DA and 5-HT content also were investigated. MA (100 microM), the succinate dehydrogenase inhibitor malonate, or the combination of MA and malonate was reverse-dialyzed into the striatum for 8 h. The continuous local perfusion of MA alone increased DA release by 30-fold, similar to that seen after systemic administration, but did not increase glutamate or body temperature, and did not deplete neurotransmitter content. Malonate perfusion increased both DA and glutamate overflow, and dose dependently decreased DA content. 5-HT content was not as affected by malonate perfusions (200 mM malonate depleted DA by 66% and 5-HT by 40%). When MA was coperfused with 200 mM malonate, DA content was reduced by 80% and to a greater extent compared with malonate alone. Coperfusion of MA and 200 mM malonate did not enhance 5-HT loss. Overall, the present findings provide evidence that energy metabolism plays an important role in MA toxicity and that striatal dopaminergic terminals are more vulnerable than 5-HT terminals to damage after metabolic stress.

  10. Inhibition of cocaine self-administration by fluoxetine or D-fenfluramine combined with phentermine.

    PubMed

    Glatz, Andrew C; Ehrlich, Michelle; Bae, Richard S; Clarke, Michelle J; Quinlan, Patricia A; Brown, Emily C; Rada, Pedro; Hoebel, Bartley G

    2002-01-01

    Instrumental responding for intravenous cocaine in rats at 85% of free-feeding weight was significantly decreased 50% by D-fenfluramine plus phentermine (D-Fen/Phen, 5 mg/kg of each for 1 day). A similar effect was obtained in normal-weight rats self-administering a cocaine-heroin mixture. Treating normal-weight animals with fluoxetine (5 mg/kg) for 4 days also significantly decreased cocaine self-administration by half, and then adding phentermine caused an additional decrease in cocaine intake. Animals that were well trained to self-administer drug did not self-administer intravenous D-Fen/Phen or Flu/Phen. The present results confirm that serotonergic drugs can decrease cocaine, or cocaine/heroin, self-administration in rats, and that phentermine adds to the effect. Based on related research with the same dose of D-Fen/Phen, it is suggested that effectiveness in reducing cocaine reinforcement is due in part to a satiating effect in which dopamine and acetylcholine are released in the nucleus accumbens.

  11. [Diagnostic significance of the spinal-brain stem polysynaptic reflex and the period of inhibition].

    PubMed

    Ivanichev, G A

    1985-01-01

    Electrical stimulation of the radial nerve associated with voluntary contraction of the shoulder girdle inhibited bioelectrical activity not only in the muscles of the hypothenar but also in the proximal muscles. In resting muscles, such stimulation elicited a reflex response with a large latent period. With weak voluntary tension stimulation elicited a reflex response while in the presence of considerable contraction the reflex response merged with bioelectrical activity, with a clearly demonstrable subsequent period of inhibition. The current viewpoint about the antidromal blockade of the segmental motoneurons is debated. It is suggested that the polysynaptic reflex and the inhibition period are connected with the same level of realization -- the oral portions of the brain stem.

  12. Maternal Intravenous Administration of Azithromycin Results in Significant Fetal Uptake in a Sheep Model of Second Trimester Pregnancy

    PubMed Central

    Miura, Yuichiro; Payne, Matthew S.; Jobe, Alan H.; Kallapur, Suhas G.; Saito, Masatoshi; Stock, Sarah J.; Spiller, O. Brad; Ireland, Demelza J.; Yaegashi, Nobuo; Clarke, Michael; Hahne, Dorothee; Rodger, Jennifer; Keelan, Jeffrey A.; Newnham, John P.

    2014-01-01

    Treatment of intrauterine infection is likely key to preventing a significant proportion of preterm deliveries before 32 weeks of gestation. Azithromycin (AZ) may be an effective antimicrobial in pregnancy; however, few gestation age-approriate data are available to inform the design of AZ-based treatment regimens in early pregnancy. We aimed to determine whether a single intra-amniotic AZ dose or repeated maternal intravenous (i.v.) AZ doses would safely yield therapeutic levels of AZ in an 80-day-gestation (term is 150 days) ovine fetus. Fifty sheep carrying single pregnancies at 80 days gestation were randomized to receive either: (i) a single intra-amniotic AZ administration or (ii) maternal intravenous AZ administration every 12 h. Amniotic fluid, maternal plasma, and fetal AZ concentrations were determined over a 5-day treatment regimen. Markers of liver injury and amniotic fluid inflammation were measured to assess fetal injury in response to drug exposure. A single intra-amniotic administration yielded significant AZ accumulation in the amniotic fluid and fetal lung. In contrast, repeated maternal intravenous administrations achieved high levels of AZ accumulation in the fetal lung and liver and a statistically significant increase in the fetal plasma drug concentration at 120 h. There was no evidence of fetal injury in response to drug exposure. These data suggest that (i) repeated maternal i.v. AZ dosing yields substantial fetal tissue uptake, although fetal plasma drug levels remain low; (ii) transfer of AZ from the amniotic fluid is less than transplacental transfer; and (iii) exposure to high concentrations of AZ did not elicit overt changes in fetal white blood cell counts, amniotic fluid monocyte chemoattractant protein 1 concentrations, or hepatotoxicity, all consistent with an absence of fetal injury. PMID:25155606

  13. Finasteride administration potentiates the disruption of prepulse inhibition induced by forced swim stress.

    PubMed

    Pallarès, M; Llidó, A; Mòdol, L; Vallée, M; Darbra, S

    2015-08-01

    Acute stress has been demonstrated to alter sensory gating processes, measured by the prepulse inhibition of the startle response (PPI). It is well known that brain and plasma levels of the neurosteroid allopregnanolone (ALLO) increase after acute environmental stress, fact that has been considered a homeostatic mechanism in restoring normal function following stress. Thus, it is of great interest to study the contribution of stress-altered plasma ALLO levels on PPI function. For this purpose, animals were injected with finasteride, an ALLO synthesis inhibitor, and submitted to swim stress before PPI testing. In order to obtain ALLO plasma levels, a separate set of animals that followed the same experimental procedure was used. We hypothesize that the blockade of ALLO production in response to stress can increase the stress-induced PPI disruption. In accordance with other authors, our results indicate that acute swim stress disrupted the normal PPI evolution (increase) related to the increase in prepulse intensities, and also decreased PPI at the highest prepulse intensity level (15 db above background). Finasteride potentiated the PPI decrease induced by swim stress in the intermediate prepulse intensity (10 db above background). As expected, plasma ALLO levels were increased in stressed animals and this increase was neutralized by prior finasteride administration. These results indicate that the neutralization of the physiological plasma ALLO levels increase after acute stress potentiates stress-induced PPI disruption. This data suggests that alterations in homeostatic ALLO synthesis mechanism may be linked to some neuropsychiatric disorders related to stress, such as anxiety/depression disorders.

  14. CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation

    PubMed Central

    Xu, Yang; Dong, Hongxia; Ge, Changhui; Gao, Yan; Liu, Haifeng

    2016-01-01

    Background Ulcerative colitis (UC) is a nonspecific inflammatory disease for which medications and therapeutic strategies have only been moderately successful. CBLB502, a toll-like receptor 5 (TLR5) agonist derived from Salmonella flagellin, exhibits anticancer and radioprotective activities via modulation of TLRs and the nuclear factor kappa B (NF-κB) signaling pathway and can protect against acute renal ischemic failure. In this study, we intend to examine the effects of CBLB502 on both TLR responses and the interleukin (IL) and NF-κB signaling pathways in UC treatment. Methods The UC mouse model was prepared in BALB/c mice by administering 2,4,6-trinitrobenzene sulfonic acid (TNBS). CBLB502 was used as the therapeutic drug. After CBLB502 therapy, the IL and tumor necrosis factor-α (TNF-α) levels were measured by ELISA. Total RNA and protein of colon samples was extracted. Results We found that CBLB502 had a distinctive therapeutic effect in the UC model. In control group animals, IL-10 expression in serum was 91.48±24.38 ng/mL; this was higher than in the model group (59.36±14.46 ng/mL, P<0.05) or the treatment group (54.29±5.83 ng/mL, P<0.05). In model group animals, the concentration of TNF-α in serum was 140.11±12.70 ng/mL, which was lower than protein levels in the control group (173.86±29.26 ng/mL, P<0.05). The mRNA levels of TLR1, 2, 3, 4, 6, 7, 8, and 9 in the CBLB502 treatment group were significantly lower than in the model group (P<0.05). Western blot revealed that CBLB502 also reduced NF-κB expression in the mouse colon, but that NF-κB expression was not significantly lower than the model group. Conclusions CBLB502 can reduce mucosal damage induced by TNBS and inhibit inflammation and TLR expression. The inhibition of UC by CBLB502 is strictly TLR-IL-dependent and is dose-dependent within the efficacious dose range. Therefore, our results suggested that CBLB502 might be a candidate drug for the treatment of UC. PMID:27668221

  15. Annual committee reports on significant legislative, judicial and administrative developments in 1983: Solid and Hazardous Waste Committee

    SciTech Connect

    Not Available

    1984-01-01

    There were several significant developments under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA or Superfund), the Resource Conservation and Recovery Act (RCRA), and the Toxic Substance Act (TSCA). Court cases on CERCLA involved basic liability issues, prerequisites to actions, and several miscellaneous issues, while adminstrative developments included issuing the national priorities list and amendments to the National Contingency Plan. Court decisions under RCRA addressed liability of those accepting wastes. The Environmental Protection Agency issued a new definition of solid waste and new regulations. Administrative developments under TSCA covered integrated control programs for new and existing chemicals, the collection of information on existing chemicals, and enforcement and inspection activities. 228 references.

  16. Reversible and persistent decreases in cocaine self-administration after cholinesterase inhibition: different effects of donepezil and rivastigmine.

    PubMed

    Grasing, Kenneth; Yang, Yungao; He, Shuangteng

    2011-02-01

    We recently observed that pretreatment with the cholinesterase inhibitor, tacrine can produce long-lasting reductions in cocaine-reinforced behavior, described as persistent attenuation. In addition to inhibiting both acetylcholinesterase (AChE) and butyrylcholinesterase, tacrine can potentiate actions of dopamine. This study was carried out to evaluate the effects of donepezil (which selectively inhibits AChE) and rivastigmine (which inhibits both AChE and butyrylcholinesterase) on cocaine self-administration. High self-administration rats self-administered different doses of cocaine under a fixed ratio-5 schedule. Over a 4-day period, vehicle, donepezil, or rivastigmine was infused as animals were maintained in home cages (21 h per day), with signs of cholinergic stimulation (fasciculation, vacuous jaw movements, yawning, and diarrhea) scored by a blinded observer. Both compounds dose-dependently decreased cocaine self-administration, but differed in the potency and temporal pattern of their effects. Self-administration of low-dose cocaine was decreased to a greater degree by rivastigmine than donepezil (50% effective doses of 2.33 and 6.21 mg/kg/day, respectively), but this early effect did not continue beyond sessions immediately after treatment with rivastigmine. Group means for cocaine self-administration were decreased at some time points occurring between 1 and 3 days after the treatment with 10 mg/kg/day of donepezil (late effects), with decreases of more than 80% observed in some individual rats that persisted for 1 week or longer. Early, but not late, effects were correlated with signs of cholinergic stimulation. In summary, pretreatment with donepezil, but not rivastigmine produced persistent reductions in cocaine-reinforced behavior, which were not associated with signs of cholinergic stimulation.

  17. Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

    PubMed Central

    Shedlofsky, S I; Israel, B C; McClain, C J; Hill, D B; Blouin, R A

    1994-01-01

    In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNF alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism. PMID:7989576

  18. In vivo administration of a JAK3 inhibitor during acute SIV infection leads to significant increases in viral load during chronic infection.

    PubMed

    Takahashi, Yoshiaki; Byrareddy, Siddappa N; Albrecht, Christina; Brameier, Markus; Walter, Lutz; Mayne, Ann E; Dunbar, Paul; Russo, Robert; Little, Dawn M; Villinger, Tara; Khowawisetsut, Ladawan; Pattanapanyasat, Kovit; Villinger, Francois; Ansari, Aftab A

    2014-03-01

    The studies reported herein are the first to document the effect of the in vivo administration of a JAK3 inhibitor for defining the potential role of NK cells during acute SIV infection of a group of 15 rhesus macaques (RM). An additional group of 16 MHC/KIR typed RM was included as controls. The previously optimized in vivo dose regimen (20 mg/kg daily for 35 days) led to a marked depletion of each of the major NK cell subsets both in the blood and gastro-intestinal tissues (GIT) during acute infection. While such depletion had no detectable effects on plasma viral loads during acute infection, there was a significant sustained increase in plasma viral loads during chronic infection. While the potential mechanisms that lead to such increased plasma viral loads during chronic infection remain unclear, several correlates were documented. Thus, during acute infection, the administration of the JAK3 inhibitor besides depleting all NK cell subsets also decreased some CD8⁺ T cells and inhibited the mobilization of the plasmacytoid dendritic cells in the blood and their localization to the GIT. Of interest is the finding that the administration of the JAK3 inhibitor during acute infection also resulted in the sustained maintenance during chronic infection of a high number of naïve and central memory CD4⁺ T cells, increases in B cells in the blood, but decreases in the frequencies and function of NKG2a⁺ NK cells within the GIT and blood, respectively. These data identify a unique role for JAK3 inhibitor sensitive cells, that includes NK cells during acute infection that in concert lead to high viral loads in SIV infected RM during chronic infection without affecting detectable changes in antiviral humoral/cellular responses. Identifying the precise mechanisms by which JAK3 sensitive cells exert their influence is critical with important implications for vaccine design against lentiviruses.

  19. Acute ethanol administration inhibits Toll-like receptor 4 signaling pathway in rat intestinal epithelia.

    PubMed

    Zhou, Chao; Zhao, Ji; Li, Jing; Wang, Haiying; Tang, Chengwei

    2013-05-01

    Excess alcohol intake, as in binge drinking, increases susceptibility to microbial pathogens. Alcohol impairs macrophage function by suppression of the Toll-like receptor 4 (TLR4) pathway. This study investigated the effects of acute ethanol intake on the TLR4 pathway in rat intestinal epithelia, which usually encounters luminal antigens at first and participates in the development of intestinal immunity. Twenty Wistar rats were randomly assigned to an ethanol group given ethanol as a 25% (v/v) solution in water at 7.5 g/kg, or a control group given saline, by oral gavage daily for 3 days. The epithelial histology and ultrastructure, the intestinal microflora, peripheral and portal venous plasma lipopolysaccharide (LPS) levels, and somatostatin (SST) levels in the peripheral plasma and small intestine were evaluated. Somatostatin receptor 2 (SSTR2), TLR4, TANK binding kinase-1 (TBK1), activated nuclear factor-κB (NF-κB), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in the intestinal mucosa were assayed. LPS responsiveness with or without SST pretreatment was assayed in vitro by quantification of TLR4, TBK1, activated NF-κB, IFN-γ and TNF-α in isolated intestinal epithelia. Mucosal damage was observed in the ethanol group by light and electron microscopy. Escherichia coli cultures were unchanged in rat intestine of the ethanol group compared with controls, but lactobacilli cultures were reduced (p < 0.05). LPS levels increased in peripheral and portal venous plasma (p < 0.05), but mucosal TLR4, TBK1, nuclear NF-κB, IFN-γ and TNF-α were unchanged in the ethanol group. LPS treatment in vitro up-regulated the level of TLR4, TBK1 and nuclear NF-κB as well as the production of IFN-γ and TNF-α in isolated intestinal epithelia in the control (p < 0.05), but not the ethanol group. The stimulatory effects of LPS on intestinal epithelia isolated from the control group were significantly inhibited by SST pretreatment (p < 0.05). The

  20. Sublingual administration of Lactobacillus paracasei KW3110 inhibits Th2-dependent allergic responses via upregulation of PD-L2 on dendritic cells.

    PubMed

    Inamine, Ayako; Sakurai, Daijyu; Horiguchi, Shigetoshi; Yonekura, Syuji; Hanazawa, Toyoyuki; Hosokawa, Hiroyuki; Matuura-Suzuki, Asaka; Nakayama, Toshinori; Okamoto, Yoshitaka

    2012-05-01

    Lactic acid bacteria have potential in immunomodulation therapy, but their clinical efficacy and underlying mechanisms are unclear. We aimed to clarify the anti-allergic immune responses induced by intragastric and sublingual administration of heat-killed Lactobacillus paracasei KW3110 and Lactobacillus acidophilus L-92. The KW3110 strain (but not the L-92 strain) enhanced ovalbumin (OVA)-induced expression of CCR-7 and PD-L2 in murine dendritic cells (DCs), and strongly inhibited IL-5 and IL-13 production in vitro in co-cultures with Th2-skewed CD4(+) T cells from DO11.10 transgenic mice. Sublingual administration of low-dose KW3110 (but not L-92) to OVA-sensitized mice selectively suppressed serum IgE production and Th2 cytokine expression in cervical lymph nodes, and significantly improved symptoms after OVA provocation in vivo. KW3110 probably accelerates DC migration into the regional lymph nodes and inhibits Th2 cytokine production through enhanced CCR-7 and PD-L2 expression. Thus, sublingual KW3110 administration may be effective in reducing allergic inflammation.

  1. Oral administration of the extract from Hatakeshimeji (Lyophyllum decastes sing.) mushroom inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice.

    PubMed

    Ukawa, Yuuichi; Izumi, Yoshiya; Ohbuchi, Takayuki; Takahashi, Tetsunari; Ikemizu, Shoichi; Kojima, Yasushi

    2007-06-01

    We examined whether the extract from Hatakeshimeji (Lyophyllum decastes, LD) mushrooms suppresses the development of atopic dermatitis (AD)-like skin lesions induced by repeated application of picryl chloride (PiCl) in NC/Nga mice. Oral administration of LD extract to NC/Nga mice inhibited the development of AD-like skin lesions based on lower total skin severity scores and serum immunoglobulin E (IgE) levels. Splenic lymphocytes were stimulated with the T cell mitogen concanavalin A, and secretion of a Th1 cytokine (IFN-gamma) and a Th2 cytokine (IL-4) was determined by ELISA. IFN-gamma production was not inhibited by treatment with LD extract. On the other hand, IL-4 production was significantly decreased by treatment with LD extract. These results suggest that LD extract exerts anti-allergic actions by suppressing the serum IgE and Th2-type immune responses.

  2. A novel dopamine D3 receptor antagonist YQA14 inhibits methamphetamine self-administration and relapse to drug-seeking behaviour in rats.

    PubMed

    Chen, Ying; Song, Rui; Yang, Ri-Fang; Wu, Ning; Li, Jin

    2014-11-15

    Growing preclinical evidence suggests that dopamine D3 receptor antagonists are promising for the treatment of addiction. We have previously reported a novel dopamine D3 receptor antagonist YQA14 with better pharmacokinetic behaviours and pharmacotherapeutic efficacy than other tested compounds in attenuating the reward and relapse of cocaine. In the present study, we investigated whether YQA14 can similarly inhibit methamphetamine self-administration and cue- or methamphetamine-trigged reinstatement of drug-seeking behaviour. The research illustrated that systemic administration of YQA14 (6.25-25mg/kg, i.p. 20min prior to methamphetamine) failed to alter methamphetamine (0.05mg/kg) self-administration under fixed-ratio 2. However, YQA14 (6.25-25mg/kg, i.p. 20min prior to methamphetamine) significantly and dose-dependently reduced methamphetamine self-administration under fixed-ratio 2 by a low dose (0.006, 0.0125, 0.025mg/kg) of methamphetamine and shifted the dose curve right and down. Further, YQA14 also lowered the break point under progressive-ratio reinforcement conditions in rats. Finally, YQA14 also significantly inhibited cue- or methamphetamine-triggered reinstatement of extinguished drug-seeking behaviour. Overall, our findings suggest that blockade of the dopamine D3 receptor by YQA14 attenuated the rewarding and incentive motivational effects of methamphetamine in rats and may have pharmacotherapeutic potential in the treatment of methamphetamine addiction. Thus, YQA14 deserves further investigation as a promising medication for the treatment of addiction.

  3. Potent inhibition of alcohol self-administration in alcohol-preferring rats by a κ-opioid receptor antagonist.

    PubMed

    Cashman, John R; Azar, Marc R

    2014-07-01

    A substituted aryl amide derivative of 6-naltrexamine--17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan-hydrochloride--(compound 5), previously shown to be a potent κ-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other κ-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED50 values of 4-5 μg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED50 value of 8 μg/kg. The results suggest that compound 5 is a potent drug-like κ-opioid receptor antagonist of utility in alcohol cessation medications development.

  4. Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells

    PubMed Central

    Zemanova, Jana; Hylse, Ondrej; Collakova, Jana; Vesely, Pavel; Oltova, Alexandra; Borsky, Marek; Zaprazna, Kristina; Kasparkova, Marie; Janovska, Pavlina; Verner, Jan; Kohoutek, Jiri; Dzimkova, Marta; Bryja, Vitezslav; Jaskova, Zuzana; Brychtova, Yvona; Paruch, Kamil; Trbusek, Martin

    2016-01-01

    Treatment options for TP53-mutated lymphoid tumors are very limited. In experimental models, TP53-mutated lymphomas were sensitive to direct inhibition of checkpoint kinase 1 (Chk1), a pivotal regulator of replication. We initially tested the potential of the highly specific Chk1 inhibitor SCH900776 to synergize with nucleoside analogs (NAs) fludarabine, cytarabine and gemcitabine in cell lines derived from B-cell malignancies. In p53-proficient NALM-6 cells, SCH900776 added to NAs enhanced signaling towards Chk1 (pSer317/pSer345), effectively blocked Chk1 activation (Ser296 autophosphorylation), increased replication stress (p53 and γ-H2AX accumulation) and temporarily potentiated apoptosis. In p53-defective MEC-1 cell line representing adverse chronic lymphocytic leukemia (CLL), Chk1 inhibition together with NAs led to enhanced and sustained replication stress and significantly potentiated apoptosis. Altogether, among 17 tested cell lines SCH900776 sensitized four of them to all three NAs. Focusing further on MEC-1 and co-treatment of SCH900776 with fludarabine, we disclosed chromosome pulverization in cells undergoing aberrant mitoses. SCH900776 also increased the effect of fludarabine in a proportion of primary CLL samples treated with pro-proliferative stimuli, including those with TP53 disruption. Finally, we observed a fludarabine potentiation by SCH900776 in a T-cell leukemia 1 (TCL1)-driven mouse model of CLL. Collectively, we have substantiated the significant potential of Chk1 inhibition in B-lymphoid cells. PMID:27556692

  5. Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2

    PubMed Central

    Arlow, Tim; Scott, Kristan; Wagenseller, Aubrey; Gammie, Alison

    2013-01-01

    MSH2 is required for DNA mismatch repair recognition in eukaryotes. Deleterious mutations in human MSH2 account for approximately half of the alleles associated with a common hereditary cancer syndrome. Previously, we characterized clinically identified MSH2 missense mutations, using yeast as a model system, and found that the most common cause of defective DNA mismatch repair was low levels of the variant Msh2 proteins. Here, we show that increased protein turnover is responsible for the reduced cellular levels. Increasing gene dosage of more than half of the missense alleles fully restored function. A titration experiment revealed that raising the expression level of one variant to less than wild-type levels restored mismatch repair, suggesting that overexpression is not always required to regain function. We found that the ubiquitin-mediated proteasome degradation pathway is the major mechanism for increased turnover of the Msh2 variants and identified the primary ubiquitin ligase as San1. Deletion of San1 restored protein levels for all but one variant, but did not elevate wild-type Msh2 levels. The unstable variants interacted with San1, whereas wild-type Msh2 did not. Additionally, san1Δ suppressed the mismatch repair defect of unstable variants. Of medical significance, the clinically approved drug Bortezomib partially restored protein levels and mismatch repair function for low-level variants and reversed the resistance to cisplatin, a common chemotherapeutic. Our results provide the foundation for an innovative therapeutic regime for certain mismatch-repair-defective cancers that are refractory to conventional chemotherapies. PMID:23248292

  6. Inhibition of effector antigen-specific T cells by intradermal administration of heme oxygenase-1 inducers.

    PubMed

    Simon, Thomas; Pogu, Julien; Rémy, Séverine; Brau, Frédéric; Pogu, Sylvie; Maquigneau, Maud; Fonteneau, Jean-François; Poirier, Nicolas; Vanhove, Bernard; Blancho, Gilles; Piaggio, Eliane; Anegon, Ignacio; Blancou, Philippe

    2017-03-22

    Developing protocols aimed at inhibiting effector T cells would be key for the treatment of T cell-dependent autoimmune diseases including type 1 autoimmune diabetes (T1D) and multiple sclerosis (MS). While heme oxygenase-1 (HO-1) inducers are clinically approved drugs for non-immune-related diseases, they do have immunosuppressive properties when administered systemically in rodents. Here we show that HO-1 inducers inhibit antigen-specific effector T cells when injected intradermally together with the T cell cognate antigens in mice. This phenomenon was observed in both a CD8(+) T cell-mediated model of T1D and in a CD4(+) T cell-dependent MS model. Intradermal injection of HO-1 inducers induced the recruitment of HO-1(+) monocyte-derived dendritic cell (MoDCs) exclusively to the lymph nodes (LN) draining the site of intradermal injection. After encountering HO-1(+)MoDCs, effector T-cells exhibited a lower velocity and a reduced ability to migrate towards chemokine gradients resulting in impaired accumulation to the inflamed organ. Intradermal co-injection of a clinically approved HO-1 inducer and a specific antigen to non-human primates also induced HO-1(+) MoDCs to accumulate in dermal draining LN and to suppress delayed-type hypersensitivity. Therefore, in both mice and non-human primates, HO-1 inducers delivered locally inhibited effector T-cells in an antigen-specific manner, paving the way for repositioning these drugs for the treatment of immune-mediated diseases.

  7. Lateral/basolateral amygdala serotonin type-2 receptors modulate operant self-administration of a sweetened ethanol solution via inhibition of principal neuron activity

    PubMed Central

    McCool, Brian A.; Christian, Daniel T.; Fetzer, Jonathan A.; Chappell, Ann M.

    2014-01-01

    The lateral/basolateral amygdala (BLA) forms an integral part of the neural circuitry controlling innate anxiety and learned fear. More recently, BLA dependent modulation of self-administration behaviors suggests a much broader role in the regulation of reward evaluation. To test this, we employed a self-administration paradigm that procedurally segregates “seeking” (exemplified as lever-press behaviors) from consumption (drinking) directed at a sweetened ethanol solution. Microinjection of the nonselective serotonin type-2 receptor agonist, alpha-methyl-5-hydroxytryptamine (α-m5HT) into the BLA reduced lever pressing behaviors in a dose-dependent fashion. This was associated with a significant reduction in the number of response-bouts expressed during non-reinforced sessions without altering the size of a bout or the rate of responding. Conversely, intra-BLA α-m5HT only modestly effected consumption-related behaviors; the highest dose reduced the total time spent consuming a sweetened ethanol solution but did not inhibit the total number of licks, number of lick bouts, or amount of solution consumed during a session. In vitro neurophysiological characterization of BLA synaptic responses showed that α-m5HT significantly reduced extracellular field potentials. This was blocked by the 5-HT2A/C antagonist ketanserin suggesting that 5-HT2-like receptors mediate the behavioral effect of α-m5HT. During whole-cell patch current-clamp recordings, we subsequently found that α-m5HT increased action potential threshold and hyperpolarized the resting membrane potential of BLA pyramidal neurons. Together, our findings show that the activation of BLA 5-HT2A/C receptors inhibits behaviors related to reward-seeking by suppressing BLA principal neuron activity. These data are consistent with the hypothesis that the BLA modulates reward-related behaviors and provides specific insight into BLA contributions during operant self-administration of a sweetened ethanol solution

  8. Oral administration of heat-killed Lactobacillus brevis SBC8803 ameliorates the development of dermatitis and inhibits immunoglobulin E production in atopic dermatitis model NC/Nga mice.

    PubMed

    Segawa, Shuichi; Hayashi, Atsushi; Nakakita, Yasukazu; Kaneda, Hirotaka; Watari, Junji; Yasui, Hisako

    2008-05-01

    We have previously shown that the oral administration of heat-killed Lactobacillus brevis (L. brevis) SBC8803 strain inhibits IgE production in ovalbumin (OVA)-sensitized BALB/c mice through improvement of the type-1 helper T (Th1)/Th2 balance toward Th1 dominance. Atopic dermatitis is one of the most common skin diseases and is frequently associated with elevated immunoglobulin E (IgE) antibodies against many kinds of allergens. In this study, we investigated the inhibitory effect of oral administration of L. brevis SBC8803 on the development of dermatitis and IgE elevation using the NC/Nga atopic dermatitis model mice. Male 8-week-old NC/Nga mice were sensitized by the topical application of picryl chloride to foot pads and shaved abdomen. These mice were boosted with picryl chloride by topical application onto the ears once a week for 9 weeks. The mice (n=10 per group) were fed a diet containing 0%, 0.05% or 0.5% of heat-killed L. brevis SBC8803 from 2 weeks before the first sensitization to the end of the study. Total IgE concentration in serum, clinical score, and ear thickness were periodically examined throughout the study. Finally, cytokine (interleukin (IL)-4, IL-5, IL-6, IL-10, IL-12, IFN-gamma and transforming growth factor (TGF)-beta) productions from splenocytes and Peyer's patch (PP) cells of mice were measured. Oral administration of L. brevis SBC8803 significantly inhibited IgE production and ear swelling, and suppressed the development of dermatitis in a dose-dependent manner. Immunosuppressive cytokines such as IL-10 and TGF-beta production from PP cells significantly increased in the 0.5% group compared to the control group although Th1-type and Th2-type cytokines production was not affected.

  9. Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling

    PubMed Central

    Zheng, Hongming; Zheng, Liang; Liu, Wenqin; Wu, Jinjun; Ou, Rilan; Zhang, Guiyu; Li, Fangyuan; Hu, Ming; Liu, Zhongqiu; Lu, Linlin

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is the most prevalent malignancy worldwide given its high incidence, considerable mortality, and poor prognosis. The anti-malaria compounds artemisinin (ART), dihydroartemisinin (DHA), and artesunate (ARTS) reportedly have anti-cancer potential, although the underlying mechanisms remain unclear. In this work, we used flow cytometry to show that ART, DHA, and ARTS could inhibit the proliferation of A549 and H1299 cells by arresting cell cycle in G1 phase. Meanwhile, tumor malignancy including migration, invasion, cancer stem cells, and epithelial–mesenchymal transition were also significantly suppressed by these compounds. Furthermore, ART, DHA, and ARTS remarkably decreased tumor growth in vivo. By using IWP-2, the inhibitor of Wnt/β-catenin pathway, and Wnt5a siRNA, we found that ART, DHA, and ARTS could render tumor inhibition partially dependent on Wnt/β-catenin inactivation. These compounds could strikingly decrease the protein level of Wnt5-a/b and simultaneously increase those of NKD2 and Axin2, ultimately resulting in β-catenin downregulation. In summary, our findings revealed that ART, DHA, and ARTS could suppress lung-tumor progression by inhibiting Wnt/β-catenin pathway, thereby suggesting a novel target for ART, DHA, and ARTS in cancer treatment. PMID:27119499

  10. Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis.

    PubMed

    He, Chang; Yu, Cheng-Rong; Sun, Lin; Mahdi, Rashid M; Larkin, Joseph; Egwuagu, Charles E

    2015-08-01

    Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases and pathology derives from sustained production of pro-inflammatory cytokines in the optical axis. Although topical or systemic steroids are effective therapies, their adverse effects preclude prolonged usage and are impetus for seeking alternative immunosuppressive agents, particularly for patients with refractory uveitis. In this study, we synthesized a 16 amino acid membrane-penetrating lipophilic suppressor of cytokine signaling 1 peptide (SOCS1-KIR) that inhibits JAK/STAT signaling pathways and show that it suppresses and ameliorates experimental autoimmune uveitis (EAU), the mouse model of human uveitis. Fundus images, histological and optical coherence tomography analysis of eyes showed significant suppression of clinical disease, with average clinical score of 0.5 compared to 2.0 observed in control mice treated with scrambled peptide. We further show that SOCS1-KIR conferred protection from ocular pathology by inhibiting the expansion of pathogenic Th17 cells and inhibiting trafficking of inflammatory cells into the neuroretina during EAU. Dark-adapted scotopic and photopic electroretinograms further reveal that SOCS1-KIR prevented decrement of retinal function, underscoring potential neuroprotective effects of SOCS1-KIR in uveitis. Importantly, SOCS1-KIR is non-toxic, suggesting that topical administration of SOCS1-Mimetics can be exploited as a non-invasive treatment for uveitis and for limiting cytokine-mediated pathology in other ocular inflammatory diseases including scleritis.

  11. Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats.

    PubMed

    He, Wan-You; Zhang, Bin; Xiong, Qing-Ming; Yang, Cheng-Xiang; Zhao, Wei-Cheng; He, Jian; Zhou, Jun; Wang, Han-Bing

    2016-04-21

    The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation and protein synthesis, and it is specifically inhibited by rapamycin. In chronic pain conditions, mTOR-mediated local protein synthesis is crucial for neuronal hyperexcitability and synaptic plasticity. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 plays a major role in action potential initiation and propagation and cellular excitability in DRG (dorsal root ganglion) neurons. In this study, we investigated if mTOR modulates the phosphorylation of Nav1.8 that is associated with neuronal hyperexcitability and behavioral hypersensitivity in STZ-induced diabetic rats. Painful diabetic neuropathy (PDN) was induced in Sprague-Dawley rats by intraperitoneal injection with streptozotocin (STZ) at 60mg/kg. After the onset of PDN, the rats received daily intrathecal administrations of rapamycin (1μg, 3μg, or 10μg/day) for 7 days; other diabetic rats received the same volumes of dimethyl sulfoxide (DMSO). Herein, we demonstrate a marked increase in protein expression of total mTOR and phospho-mTOR (p-mTOR) together with the up-regulation of phosphor-Nav1.8 (p-Nav1.8) prior to the mechanical withdrawal threshold reaching a significant reduction in dorsal root ganglions (DRGs). Furthermore, the intrathecal administration of rapamycin, inhibiting the activity of mTOR, suppressed the phosphorylation of DRG Nav1.8, reduced the TTX-R current density, heightened the voltage threshold for activation and lowered the voltage threshold for inactivation and relieved mechanical hypersensitivity in diabetic rats. An intrathecal injection (i.t.) of rapamycin inhibited the phosphorylation and enhanced the functional availability of DRG Nav1.8 attenuated STZ-induced hyperalgesia. These results suggest that rapamycin is a potential therapeutic intervention for clinical PDN.

  12. Post-exposure administration of diazepam combined with soluble epoxide hydrolase inhibition stops seizures and modulates neuroinflammation in a murine model of acute TETS intoxication.

    PubMed

    Vito, Stephen T; Austin, Adam T; Banks, Christopher N; Inceoglu, Bora; Bruun, Donald A; Zolkowska, Dorota; Tancredi, Daniel J; Rogawski, Michael A; Hammock, Bruce D; Lein, Pamela J

    2014-12-01

    Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison for which there is currently no approved antidote. The convulsant action of TETS is thought to be mediated by inhibition of type A gamma-aminobutyric acid receptor (GABAAR) function. We, therefore, investigated the effects of post-exposure administration of diazepam, a GABAAR positive allosteric modulator, on seizure activity, death and neuroinflammation in adult male Swiss mice injected with a lethal dose of TETS (0.15mg/kg, ip). Administration of a high dose of diazepam (5mg/kg, ip) immediately following the second clonic seizure (approximately 20min post-TETS injection) effectively prevented progression to tonic seizures and death. However, this treatment did not prevent persistent reactive astrogliosis and microglial activation, as determined by GFAP and Iba-1 immunoreactivity and microglial cell morphology. Inhibition of soluble epoxide hydrolase (sEH) has been shown to exert potent anti-inflammatory effects and to increase survival in mice intoxicated with other GABAAR antagonists. The sEH inhibitor TUPS (1mg/kg, ip) administered immediately after the second clonic seizure did not protect TETS-intoxicated animals from tonic seizures or death. Combined administration of diazepam (5mg/kg, ip) and TUPS (1mg/kg, ip, starting 1h after diazepam and repeated every 24h) prevented TETS-induced lethality and influenced signs of neuroinflammation in some brain regions. Significantly decreased microglial activation and enhanced reactive astrogliosis were observed in the hippocampus, with no changes in the cortex. Combining an agent that targets specific anti-inflammatory mechanisms with a traditional antiseizure drug may enhance treatment outcome in TETS intoxication.

  13. The truth about the lower plasma concentration of the (-)-isomer after racemic doxazosin administration in rats: Stereoselective inhibition of the (-)-isomer by the (+)-isomer at CYP3A.

    PubMed

    Kong, Dezhi; Li, Qing; Zhang, Panpan; Zhang, Wei; Zhen, Yaqin; Ren, Leiming

    2015-09-18

    Doxazosin (DOX), a long-lasting α1-adrenoceptor antagonist, is used clinically as a racemate that consists of two optical isomers. In humans and rats, following oral administration of racemic DOX [(±)-DOX], the plasma concentration of the (-)-isomer is lower than that of the (+)-isomer, but the mechanism for this interaction is not known. In this study, a chiral HPLC with fluorescence detection was used to measure the drug concentrations for analysis of the stereoselective metabolism of DOX in in vivo and in vitro experiments. We found that the plasma levels of the (-)-isomer were significantly lower than those of the (+)-enantiomer following i.v. administration of (±)-DOX to the rats and that the depletion rate constant (kdep) of (-)-DOX (0.0107±0.0007L/min) was significantly larger than that of (+)-DOX (kdep 0.0088±0.0005L/min) (p<0.05) when (±)-DOX was incubated with rat liver microsomes (RLMs). However, (-)-DOX was not depleted faster than (+)-DOX following their separate incubation with RLMs. The metabolism of (-)- or (+)-isomer in RLMs was catalysed by CYP3A because the depletion of the compounds was inhibited by ketoconazole (a potent CYP3A-selective inhibitor) similarly. More importantly, the kdep of (+)-DOX in the 1.0/2.0 and 0.5/2.5 (+)-DOX/(-)-DOX mixtures was significantly lower than that of (-)-DOX in the 1.0/2.0 and 0.5/2.5 (-)-DOX/(+)-DOX mixtures (p<0.05). In conclusion, although (-)-DOX is not depleted faster than (+)-DOX when only a single isomer of DOX is incubated with rat liver microsomes, it is depleted much faster than (+)-DOX when a mixture of the two isomers was used, suggesting a prominent and stereoselective inhibition of the (-)-isomer over the (+)-isomer at the CYP3A enzyme.

  14. Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome.

    PubMed

    Cámara, Yolanda; González-Vioque, Emiliano; Scarpelli, Mauro; Torres-Torronteras, Javier; Caballero, Andrea; Hirano, Michio; Martí, Ramon

    2014-05-01

    Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and consequent mitochondrial dysfunction in affected tissues. A subgroup of MDS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism, which ultimately leads to limited availability of one or several deoxyribonucleoside triphosphates (dNTPs), and subsequent mtDNA depletion. Here, using in vitro experimental approaches (primary cell culture of deoxyguanosine kinase-deficient cells and thymidine-induced mtDNA depletion in culture as a model of mitochondrial neurogastrointestinal encephalomyopathy, MNGIE), we show that supplements of those deoxyribonucleosides (dNs) involved in each biochemical defect (deoxyguanosine or deoxycytidine, dCtd) prevents mtDNA copy number reduction. Similar effects can be obtained by specific inhibition of dN catabolism using tetrahydrouridine (THU; inhibitor of cytidine deaminase) or immucillin H (inhibitor of purine nucleoside phosphorylase). In addition, using an MNGIE animal model, we provide evidence that mitochondrial dNTP content can be modulated in vivo by systemic administration of dCtd or THU. In spite of the severity associated with diseases due to defects in mtDNA replication, there are currently no effective therapeutic options available. Only in the case of MNGIE, allogeneic hematopoietic stem cell transplantation has proven efficient as a long-term therapeutic strategy. We propose increasing cellular availability of the deficient dNTP precursor by direct administration of the dN or inhibition of its catabolism, as a potential treatment for mtDNA depletion syndrome caused by defects in dNTP metabolism.

  15. Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by Plasmodium

    PubMed Central

    Marques, Joana; Vilanova, Eduardo; Mourão, Paulo A. S.; Fernàndez-Busquets, Xavier

    2016-01-01

    The antimalarial activity of heparin, against which there are no resistances known, has not been therapeutically exploited due to its potent anticoagulating activity. Here, we have explored the antiplasmodial capacity of heparin-like sulfated polysaccharides from the sea cucumbers Ludwigothurea grisea and Isostichopus badionotus, from the red alga Botryocladia occidentalis, and from the marine sponge Desmapsamma anchorata. In vitro experiments demonstrated for most compounds significant inhibition of Plasmodium falciparum growth at low-anticoagulant concentrations. This activity was found to operate through inhibition of erythrocyte invasion by Plasmodium, likely mediated by a coating of the parasite similar to that observed for heparin. In vivo four-day suppressive tests showed that several of the sulfated polysaccharides improved the survival of Plasmodium yoelii-infected mice. In one animal treated with I. badionotus fucan parasitemia was reduced from 10.4% to undetectable levels, and Western blot analysis revealed the presence of antibodies against P. yoelii antigens in its plasma. The retarded invasion mediated by sulfated polysaccharides, and the ensuing prolonged exposure of Plasmodium to the immune system, can be explored for the design of new therapeutic approaches against malaria where heparin-related polysaccharides of low anticoagulating activity could play a dual role as drugs and as potentiators of immune responses. PMID:27071342

  16. All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro.

    PubMed Central

    Van heusden, J.; Wouters, W.; Ramaekers, F. C.; Krekels, M. D.; Dillen, L.; Borgers, M.; Smets, G.

    1998-01-01

    All-trans-retinoic acid (ATRA) is well known to inhibit the proliferation of human breast cancer cells. Much less is known about the antiproliferative activity of the naturally occurring metabolites and isomers of ATRA. In the present study, we investigated the antiproliferative activity of ATRA, its physiological catabolites 4-oxo-ATRA and 5,6-epoxy-ATRA and isomers 9-cis-RA and 13-cis-RA in MCF-7 human breast cancer cells by bromodeoxyuridine incorporation. MCF-7 cells were grown in steroid- and retinoid-free medium supplemented with growth factors. Under these culture conditions, ATRA and its naturally occurring catabolites and isomers showed significant antiproliferative activity in MCF-7 cells in a concentration-dependent manner (10[-11] M to 10[-6] M). The antiproliferative activity of ATRA catabolites and isomers was equal to that of the parent compound ATRA at concentrations of 10(-8) M and 10(-7) M. Only at 10(-6) M were the catabolites and the stereoisomer 13-cis-RA less potent. The stereoisomer 9-cis-RA was as potent as ATRA at all concentrations tested (10[-11] M to 10[-6] M). In addition, we show that the catabolites and isomers were formed from ATRA to only a limited extent. Together, our findings suggest that in spite of their high antiproliferative activity the catabolites and isomers of ATRA cannot be responsible for the observed growth inhibition induced by ATRA. PMID:9459142

  17. Chronic Dietary Administration of the Glycolytic Inhibitor 2-Deoxy-D-Glucose (2-DG) Inhibits the Growth of Implanted Ehrlich’s Ascites Tumor in Mice

    PubMed Central

    Singh, Saurabh; Pandey, Sanjay; Bhatt, Anant Narayan; Chaudhary, Richa; Bhuria, Vikas; Kalra, Namita; Soni, Ravi; Roy, Bal Gangadhar; Saluja, Daman; Dwarakanath, Bilikere S.

    2015-01-01

    Background Dietary energy restriction (DER) has been well established as a potent anticancer strategy. Non-adoption of restricted diet for an extended period has limited its practical implementation in humans with a compelling need to develop agents that mimic effects similar to DER, without reduction in actual dietary intake. Glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), has recently been shown to possess potential as an energy restriction mimetic agent (ERMA). In the present study we evaluated the effect of dietary 2-DG administration on a mouse tumor model, with a focus on several potential mechanisms that may account for the inhibition of tumorigenesis. Methodology/Principal Findings Swiss albino strain ‘A’ mice were administered with 0.2% and 0.4% w/v 2-DG in drinking water for 3 months prior to tumor implantation (Ehrlich’s ascites carcinoma; EAC) and continued till the termination of the study with no adverse effects on general physiology and animal growth. Dietary 2-DG significantly reduced the tumor incidence, delayed the onset, and compromised the tumor growth along with enhanced survival. We observed reduced blood glucose and serum insulin levels along with decreased proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine positive (BrdU+) tumor cells in 2-DG fed mice. Also, reduced levels of certain key players of metabolic pathways such as phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt and hypoxia inducible factor-1 alpha (HIF-1α) were also noted in tumors of 2-DG fed mice. Further, decrease in CD4+/CD8+ ratio and T-regulatory cells observed in 2-DG fed mice suggested enhanced antitumor immunity and T cell effector function. Conclusion/Significance These results strongly suggest that dietary 2-DG administration in mice, at doses easily achievable in humans, suitably modulates several pleotrophic factors mimicking DER and inhibits tumorigenesis, emphasizing the use of ERMAs as a promising cancer preventive strategy. PMID

  18. Coadministration of Pinellia ternata Can Significantly Reduce Aconitum carmichaelii to Inhibit CYP3A Activity in Rats

    PubMed Central

    Wu, Jinjun; Cheng, Zaixing; Zhu, Lijun; Lu, Linlin; Zhang, Guiyu; Wang, Ying; Xu, Ying; Lin, Na; Liu, Zhongqiu

    2014-01-01

    Chuanwu (CW), the mother root of Aconitum carmichaelii Debx., is a traditional Chinese medicine (TCM) for treating traumatic injuries, rheumatoid arthritis, and tumors. CW coadministered with banxia (BX), the root of Pinellia ternata, is also widely prescribed in clinical practice. However, the mechanism of this combination is yet deciphered. Current study aimed to investigate the effects of CW, including raw chuanwu (RCW) and processed chuanwu (PCW) alone, as well as CW coadministered with BX on CYP3A activity. Buspirone (BP) and testosterone (Tes) were used as specific probe substrates in vivo and ex vivo, respectively. CYP3A activity was determined by the metabolites formation ratios from the substrates. Compared with those in the control group, the metabolites formation ratios significantly decreased in the RCW and PCW alone groups, accompanied by a marked decrease in CYP3A protein and mRNA levels. However, there was a significant increase in those ratios in the RCW-BX and PCW-BX groups compared to the RCW and PCW alone groups. The results indicated that both RCW and PCW can inhibit CYP3A activity in rats because of downregulation of CYP3A protein and mRNA levels. Decreases in CYP3A activity can be reversed by coadministration with BX. PMID:25371696

  19. Prophylactic Administration of Fucoidan Represses Cancer Metastasis by Inhibiting Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinases (MMPs) in Lewis Tumor-Bearing Mice

    PubMed Central

    Huang, Tse-Hung; Chiu, Yi-Han; Chan, Yi-Lin; Chiu, Ya-Huang; Wang, Hang; Huang, Kuo-Chin; Li, Tsung-Lin; Hsu, Kuang-Hung; Wu, Chang-Jer

    2015-01-01

    Fucoidan, a heparin-like sulfated polysaccharide, is rich in brown algae. It has a wide assortment of protective activities against cancer, for example, induction of hepatocellular carcinoma senescence, induction of human breast and colon carcinoma apoptosis, and impediment of lung cancer cells migration and invasion. However, the anti-metastatic mechanism that fucoidan exploits remains elusive. In this report, we explored the effects of fucoidan on cachectic symptoms, tumor development, lung carcinoma cell spreading and proliferation, as well as expression of metastasis-associated proteins in the Lewis lung carcinoma (LLC) cells-inoculated mice model. We discovered that administration of fucoidan has prophylactic effects on mitigation of cachectic body weight loss and improvement of lung masses in tumor-inoculated mice. These desired effects are attributed to inhibition of LLC spreading and proliferation in lung tissues. Fucoidan also down-regulates expression of matrix metalloproteinases (MMPs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and vascular endothelial growth factor (VEGF). Moreover, the tumor-bearing mice supplemented with fucoidan indeed benefit from an ensemble of the chemo-phylacticity. The fact is that fucoidan significantly decreases viability, migration, invasion, and MMPs activities of LLC cells. In summary, fucoidan is suitable to act as a chemo-preventative agent for minimizing cachectic symptoms as well as inhibiting lung carcinoma metastasis through down-regulating metastatic factors VEGF and MMPs. PMID:25854641

  20. Prophylactic administration of fucoidan represses cancer metastasis by inhibiting vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in Lewis tumor-bearing mice.

    PubMed

    Huang, Tse-Hung; Chiu, Yi-Han; Chan, Yi-Lin; Chiu, Ya-Huang; Wang, Hang; Huang, Kuo-Chin; Li, Tsung-Lin; Hsu, Kuang-Hung; Wu, Chang-Jer

    2015-04-03

    Fucoidan, a heparin-like sulfated polysaccharide, is rich in brown algae. It has a wide assortment of protective activities against cancer, for example, induction of hepatocellular carcinoma senescence, induction of human breast and colon carcinoma apoptosis, and impediment of lung cancer cells migration and invasion. However, the anti-metastatic mechanism that fucoidan exploits remains elusive. In this report, we explored the effects of fucoidan on cachectic symptoms, tumor development, lung carcinoma cell spreading and proliferation, as well as expression of metastasis-associated proteins in the Lewis lung carcinoma (LLC) cells-inoculated mice model. We discovered that administration of fucoidan has prophylactic effects on mitigation of cachectic body weight loss and improvement of lung masses in tumor-inoculated mice. These desired effects are attributed to inhibition of LLC spreading and proliferation in lung tissues. Fucoidan also down-regulates expression of matrix metalloproteinases (MMPs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and vascular endothelial growth factor (VEGF). Moreover, the tumor-bearing mice supplemented with fucoidan indeed benefit from an ensemble of the chemo-phylacticity. The fact is that fucoidan significantly decreases viability, migration, invasion, and MMPs activities of LLC cells. In summary, fucoidan is suitable to act as a chemo-preventative agent for minimizing cachectic symptoms as well as inhibiting lung carcinoma metastasis through down-regulating metastatic factors VEGF and MMPs.

  1. Annual committee reports on significant legislative, judicial and administrative developments in 1983: Public Lands and Land-Use Committee

    SciTech Connect

    Not Available

    1984-01-01

    The Supreme Court made three major land-use decisions during 1983, two dealing with federalism and the third with federal jiduciary obligation. The US Forest Service Small Tracts Act added flexibility to the disposal of small tracts. Court cases relating to national forests dealt with title disputes, oil and gas leasing, Indian religious practices, dual permitting under the Wilderness Act, and licensing hydro projects on Indian lands. The committee reports uneven administrative progress by the Forests Service in managing the forests. Legislation relating to Department of Interior Management Lands focuses on Outer Continental Shelf and federal coal leases and wilderness areas. The Supreme Court made several decisions involving the classification of sand and gravel as minerals, trespass, nonimpairment standards, herbicides, and other issues. 132 references.

  2. Inhibition of lung carcinogenesis and effects on angiogenesis and apoptosis in A/J mice by oral administration of green tea.

    PubMed

    Liao, Jie; Yang, Guang-Yu; Park, Eon Sub; Meng, Xiaofeng; Sun, Yuhai; Jia, Dongxuan; Seril, Darren N; Yang, Chung S

    2004-01-01

    Oral administration of tea (Camellia sinensis) has been shown to inhibit the formation and growth of several tumor types in animal models. The present study investigated the effects of treatment with different concentrations of green tea on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice. Two days after a single dose of NNK (100 mg/kg body weight, i.p.), the mice were given 0.1, 0.2, 0.4, and 0.6% green tea solution (1, 2, 4, and 6 g of tea solids, respectively, dissolved in 1 l of water), 0.02% caffeine, or water as the sole source of drinking fluid until the termination of the experiment. Only the treatment with 0.6% tea preparation significantly reduced lung tumor multiplicity (mean +/- SE, 6.07 +/- 0.77 vs. 8.60 +/- 0.50 tumors per mouse, P = 0.018). Treatment with 0.6% tea also inhibited angiogenesis, as indicated by the lower microvessel density (number of blood vessels/mm2) based on immunostaining for the von Willebrand factor antigen (81.9 +/- 9.5 vs. 129.4 +/- 8.2, P = 0.0018) and anti-CD31 antibody staining (465.3 +/- 61.4 vs. 657.1 +/- 43.6, P = 0.0012). Significantly lower vascular endothelial growth factor immunostaining scores were also observed in the 0.6% tea-treated group (0.98 +/- 0.17 vs. 1.43 +/- 0.07, P = 0.006). The apoptosis index was significantly higher in lung adenomas from 0.6% tea-treated mice based on morphological analysis of cell apoptosis (2.51 +/- 0.18% vs. 1.57 +/- 0.11%, P = 0.00005), and the result was further confirmed using the TUNEL method. Inhibition of angiogenesis and the induction of apoptosis by green tea may be closely related to the inhibition of pulmonary carcinogenesis.

  3. Chronic ethanol self-administration in macaques shifts dopamine feedback inhibition to predominantly D2 receptors in nucleus accumbens core

    PubMed Central

    Siciliano, Cody A.; Calipari, Erin S.; Yorgason, Jordan T.; Mateo, Yolanda; Helms, Christa M.; Lovinger, David M.; Grant, Kathleen A.; Jones, Sara R.

    2015-01-01

    Background Given the high level of homology between nonhuman primates and humans in regard to anatomy, physiology and ethanol drinking patterns, nonhuman primates represent an unparalleled preclinical model for examining the neurobiological basis of ethanol abuse. Methods Here we examined the neurochemical consequences of chronic daily ethanol use using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core or dorsolateral caudate taken from male cynomolgus macaques following ethanol drinking. Results We found that in both regions the ability of ethanol to decrease dopamine release was unchanged, indicating that ethanol self-administration does not produce tolerance or sensitization to ethanol effects on dopamine release at the dopamine terminal at this time point. We also found that in the nucleus accumbens core, autoregulation of dopamine release was shifted from equal D2 and D3 receptor involvement in control animals to primarily D2 receptor-mediated in drinkers. Specifically, the effect quinpirole, a D2/D3 receptor agonist, on dopamine release was equal across groups; however, dopamine signals were reversed to a greater extent by the selective D3 receptor antagonist SB-277,011A in control animals, indicating a greater contribution of D2 receptors in quinpirole-induced inhibition following ethanol self-administration. In the dorsolateral caudate, the effects of quinpirole and reversal with SB-277,011A was not different between ethanol and control slices. Conclusions This work provides novel insight into the dopaminergic adaptations resulting from chronic ethanol use in nonhuman primates and indicates that alterations in D2/D3 dopamine autoreceptor signaling may be an important neurochemical adaptation to ethanol consumption during early use. PMID:26627912

  4. Long-term administration of pyridostigmine attenuates pressure overload-induced cardiac hypertrophy by inhibiting calcineurin signalling.

    PubMed

    Lu, Yi; Zhao, Ming; Liu, Jin-Jun; He, Xi; Yu, Xiao-Jiang; Liu, Long-Zhu; Sun, Lei; Chen, Li-Na; Zang, Wei-Jin

    2017-03-10

    Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload-induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and β-myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4

  5. Insights into significance of combined inhibition of MEK and m-TOR signalling output in KRAS mutant non-small-cell lung cancer

    PubMed Central

    Broutin, Sophie; Stewart, Adam; Thavasu, Parames; Paci, Angelo; Bidart, Jean-Michel; Banerji, Udai

    2016-01-01

    Background: We aimed to understand the dependence of MEK and m-TOR inhibition in EGFRWT/ALKnon-rearranged NSCLC cell lines. Methods: In a panel of KRASM and KRASWT NSCLC cell lines, we determined growth inhibition (GI) following maximal reduction in p-ERK and p-S6RP caused by trametinib (MEK inhibitor) and AZD2014 (m-TOR inhibitor), respectively. Results: GI caused by maximal m-TOR inhibition was significantly greater than GI caused by maximal MEK inhibition in the cell line panel (52% vs 18%, P<10−4). There was no significant difference in GI caused by maximal m-TOR compared with maximal m-TOR+MEK inhibition. However, GI caused by the combination was significantly greater in the KRASM cell lines (79% vs 61%, P=0.017). Conclusions: m-TOR inhibition was more critical to GI than MEK inhibition in EGFRWT/ALKnon-rearranged NSCLC cells. The combination of MEK and m-TOR inhibition was most effective in KRASM cells. PMID:27441499

  6. Post-exposure administration of diazepam combined with soluble epoxide hydrolase inhibition stops seizures and modulates neuroinflammation in a murine model of acute TETS intoxication

    SciTech Connect

    Vito, Stephen T.; Austin, Adam T.; Banks, Christopher N.; Inceoglu, Bora; Bruun, Donald A.; Zolkowska, Dorota; Tancredi, Daniel J.; Rogawski, Michael A.; Hammock, Bruce D.; Lein, Pamela J.

    2014-12-01

    Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison for which there is currently no approved antidote. The convulsant action of TETS is thought to be mediated by inhibition of type A gamma-aminobutyric acid receptor (GABA{sub A}R) function. We, therefore, investigated the effects of post-exposure administration of diazepam, a GABA{sub A}R positive allosteric modulator, on seizure activity, death and neuroinflammation in adult male Swiss mice injected with a lethal dose of TETS (0.15 mg/kg, ip). Administration of a high dose of diazepam (5 mg/kg, ip) immediately following the second clonic seizure (approximately 20 min post-TETS injection) effectively prevented progression to tonic seizures and death. However, this treatment did not prevent persistent reactive astrogliosis and microglial activation, as determined by GFAP and Iba-1 immunoreactivity and microglial cell morphology. Inhibition of soluble epoxide hydrolase (sEH) has been shown to exert potent anti-inflammatory effects and to increase survival in mice intoxicated with other GABA{sub A}R antagonists. The sEH inhibitor TUPS (1 mg/kg, ip) administered immediately after the second clonic seizure did not protect TETS-intoxicated animals from tonic seizures or death. Combined administration of diazepam (5 mg/kg, ip) and TUPS (1 mg/kg, ip, starting 1 h after diazepam and repeated every 24 h) prevented TETS-induced lethality and influenced signs of neuroinflammation in some brain regions. Significantly decreased microglial activation and enhanced reactive astrogliosis were observed in the hippocampus, with no changes in the cortex. Combining an agent that targets specific anti-inflammatory mechanisms with a traditional antiseizure drug may enhance treatment outcome in TETS intoxication. - Highlights: • Acute TETS intoxication causes delayed and persistent neuroinflammation. • Diazepam given post-TETS prevents lethal tonic seizures but not neuroinflammation. • A soluble epoxide hydrolase

  7. Administration of caffeine inhibited adenosine receptor agonist-induced decreases in motor performance, thermoregulation, and brain neurotransmitter release in exercising rats.

    PubMed

    Zheng, Xinyan; Hasegawa, Hiroshi

    2016-01-01

    We examined the effects of an adenosine receptor agonist on caffeine-induced changes in thermoregulation, neurotransmitter release in the preoptic area and anterior hypothalamus, and endurance exercise performance in rats. One hour before the start of exercise, rats were intraperitoneally injected with either saline alone (SAL), 10 mg kg(-1) caffeine and saline (CAF), a non-selective adenosine receptor agonist (5'-N-ethylcarboxamidoadenosine [NECA]: 0.5 mg kg(-1)) and saline (NECA), or the combination of caffeine and NECA (CAF+NECA). Rats ran until fatigue on the treadmill with a 5% grade at a speed of 18 m min(-1) at 23 °C. Compared to the SAL group, the run time to fatigue (RTTF) was significantly increased by 52% following caffeine administration and significantly decreased by 65% following NECA injection (SAL: 91 ± 14.1 min; CAF: 137 ± 25.8 min; NECA: 31 ± 13.7 min; CAF+NECA: 85 ± 11.8 min; p<0.05). NECA decreased the core body temperature (Tcore), oxygen consumption, which is an index of heat production, tail skin temperature, which is an index of heat loss, and extracellular dopamine (DA) release at rest and during exercise. Furthermore, caffeine injection inhibited the NECA-induced decreases in the RTTF, Tcore, heat production, heat loss, and extracellular DA release. Neither caffeine nor NECA affected extracellular noradrenaline or serotonin release. These results support the findings of previous studies showing improved endurance performance and overrides in body limitations after caffeine administration, and imply that the ergogenic effects of caffeine may be associated with the adenosine receptor blockade-induced increases in brain DA release.

  8. Inhibition of murine renal carcinoma pulmonary metastases by systemic administration of interferon gamma: mechanism of action and potential for combination with interleukin 4.

    PubMed

    Hillman, G G; Younes, E; Visscher, D; Hamzavi, F; Kim, S; Lam, J S; Montecillo, E J; Ali, E; Pontes, J E; Puri, R K; Haas, G P

    1997-10-01

    We have previously demonstrated that IFN-gamma causes cell growth inhibition and up-regulation of MHC antigens in human renal cell carcinoma cell lines. In this study, we have investigated the therapeutic potential of IFN-gamma for the treatment of 5-day established pulmonary metastases induced by i.v. injection of Renca cells, a murine renal adenocarcinoma. We found that systemic injections of IFN-gamma significantly reduced the number of lung metastases in a dose-dependent manner and increased mouse survival. Histological evaluation of IFN-gamma-treated lungs showed residual small tumor nodules containing extensive necrosis and mononuclear infiltrates. Immunohistochemistry studies on lung sections showed macrophage infiltration into tumor nodules, and in vivo depletion of macrophages partially inhibited IFN-gamma antitumor effect, suggesting a role for the macrophages in tumor destruction. Lymphocyte depletion of either natural killer (NK) cells or CD4+ or CD8+ T-cell subsets or both T-cell subsets did not affect the IFN-gamma effect, whereas depletion of both NK and T cells decreased the antitumor activity of IFN-gamma. These data indicate that neither T cells nor NK cells are essential for this activity but that either lymphocyte population can contribute to the IFN-gamma effect. An optimal dose of IFN-gamma inhibited by 60% the growth of Renca cells treated for 3 days in vitro, but this effect was transient and less pronounced in a long-term colony assay, suggesting that IFN-gamma direct growth inhibition may play a role but may not be sufficient to mediate its antitumor effect in vivo. In vitro, IFN-gamma caused up-regulation of class I MHC antigens and induction of class II antigen expression in Renca cells, an effect that may enhance Renca immunogenicity but may be relevant only when a T-cell response is elicited. A sequential administration of IFN-gamma followed by interleukin 4 was therapeutically better than IFN-gamma alone for the treatment of advanced

  9. Does cortisol influence core executive functions? A meta-analysis of acute cortisol administration effects on working memory, inhibition, and set-shifting.

    PubMed

    Shields, Grant S; Bonner, Joseph C; Moons, Wesley G

    2015-08-01

    The hormone cortisol is often believed to play a pivotal role in the effects of stress on human cognition. This meta-analysis is an attempt to determine the effects of acute cortisol administration on core executive functions. Drawing on both rodent and stress literatures, we hypothesized that acute cortisol administration would impair working memory and set-shifting but enhance inhibition. Additionally, because cortisol is thought to exert different nongenomic (rapid) and genomic (slow) effects, we further hypothesized that the effects of cortisol would differ as a function of the delay between cortisol administration and cognitive testing. Although the overall analyses were nonsignificant, after separating the rapid, nongenomic effects of cortisol from the slower, genomic effects of cortisol, the rapid effects of cortisol enhanced response inhibition, g+ = 0.113, p=.016, but impaired working memory, g+ = -0.315, p=.008, although these effects reversed over time. Contrary to our hypotheses, there was no effect of cortisol administration on set-shifting. Thus, although we did not find support for the idea that increases in cortisol influence set-shifting, we found that acute increases in cortisol exert differential effects on working memory and inhibition over time.

  10. [Inhibition of morphine intake by antibodies to serotonin-modulating anticonsolidation protein in model of self-administration in rats].

    PubMed

    Mekhtiev, A A; Rashidova, A M; Muslimov, I A

    2014-01-01

    The article concerns study of effects of polyclonal antibodies to serotonin-modulating anticonsolidation protein (SMAP) being in direct dependence on serotonin level and providing intracellular transduction of serotonergic signal, on positive reinforcement effect of morphine in rats. The task was formed in Wistar male rats in the model of morphine self-administration as a result of pressing of one of two levers attached to the wall, joined to the pump delivering each time 100 μg of morphine directly into the vena jugularis. In the 1st series of studies brain cingulate cortex and hypothalamus were taken from the rats achieved stable level of morphine intake and SMAP level was measured with indirect immune-enzyme assay. It was shown that in the morphine-self-injected rats SMAP level in the cingulate cortex is significantly upregulated (p = 0.01), while in the hypothalamus it was left unchanged. In the 2nd series of studies the rats with stable level of morphine intake were administered intraperitoneally with anti-SMAP rabbit polyclonal antibodies (experimental group) or non-immune γ-globulins (control group). Soon after antibodies administration the animals of the experimental group demonstrated manifold decrease of morphine intake lasted for 8 days (p < 0.008), whereas it did not change in the controls. SMAP upregulation in the brain cingulate cortex in the rats with stable morphine intake, obviously, indicates to its engagement in positive reinforcement effect of morphine. Blockade of SMAP activity with anti-SMAP antibodies in the nerve cells induced sharp decrease of morphine intake due to disturbances of transduction through intracellular serotonin's signal channels.

  11. ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer

    PubMed Central

    Cedó, Lídia; García-León, Annabel; Baila-Rueda, Lucía; Santos, David; Grijalva, Victor; Martínez-Cignoni, Melanie Raquel; Carbó, José M.; Metso, Jari; López-Vilaró, Laura; Zorzano, Antonio; Valledor, Annabel F.; Cenarro, Ana; Jauhiainen, Matti; Lerma, Enrique; Fogelman, Alan M.; Reddy, Srinivasa T.; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco

    2016-01-01

    Low levels of high-density lipoprotein cholesterol (HDLc) have been associated with breast cancer risk, but several epidemiologic studies have reported contradictory results with regard to the relationship between apolipoprotein (apo) A-I and breast cancer. We aimed to determine the effects of human apoA-I overexpression and administration of specific apoA-I mimetic peptide (D-4F) on tumour progression by using mammary tumour virus-polyoma middle T-antigen transgenic (PyMT) mice as a model of inherited breast cancer. Expression of human apoA-I in the mice did not affect tumour onset and growth in PyMT transgenic mice, despite an increase in the HDLc level. In contrast, D-4F treatment significantly increased tumour latency and inhibited the development of tumours. The effects of D-4F on tumour development were independent of 27-hydroxycholesterol. However, D-4F treatment reduced the plasma oxidized low-density lipoprotein (oxLDL) levels in mice and prevented oxLDL-mediated proliferative response in human breast adenocarcinoma MCF-7 cells. In conclusion, our study shows that D-4F, but not apoA-I-containing HDL, hinders tumour growth in mice with inherited breast cancer in association with a higher protection against LDL oxidative modification. PMID:27808249

  12. Chronic administration of a combination of six herbs inhibits the progression of hyperglycemia and decreases serum lipids and aspartate amino transferase activity in diabetic rats.

    PubMed

    Shafiee-Nick, Reza; Ghorbani, Ahmad; Vafaee Bagheri, Farzaneh; Rakhshandeh, Hassan

    2012-01-01

    The effects of a polyherbal compound, containing six plants (Allium sativum, Cinnamomum zeylanicum, Nigella sativa, Punica granatum, Salvia officinalis and Teucrium polium) were tested on biochemical parameters in streptozotocin-induced diabetic rats. Streptozotocin caused an approximately 3-fold increase in fasting blood sugar level after 2 days. The diabetic control rats showed further increase in blood glucose after 30 days (384 ± 25 mg/dl in day 30 versus 280 ± 12 mg/dl in day 2, P < 0.001). Administration of the compound blocked the increase of blood glucose (272 ± 7 and 269 ± 48 mg/dl at day 2 and day 30, respectively). Also, there was significant difference in the level of triglyceride (60 ± 9 versus 158 ± 37 mg/dl, P < 0.01), total cholesterol (55 ± 2 versus 97 ± 11 mg/dl, P < 0.01) and aspartate amino transferase activity (75 ± 12 versus 129 ± 18 U/L, P < 0.05) between treated rats and diabetic control group. In conclusion, the MSEC inhibited the progression of hyperglycemia and decreased serum lipids and hepatic enzyme activity in diabetic rats. Therefore, it has the potential to be used as a natural product for the management of diabetes.

  13. Chronic Administration of a Combination of Six Herbs Inhibits the Progression of Hyperglycemia and Decreases Serum Lipids and Aspartate Amino Transferase Activity in Diabetic Rats

    PubMed Central

    Shafiee-Nick, Reza; Vafaee Bagheri, Farzaneh; Rakhshandeh, Hassan

    2012-01-01

    The effects of a polyherbal compound, containing six plants (Allium sativum, Cinnamomum zeylanicum, Nigella sativa, Punica granatum, Salvia officinalis and Teucrium polium) were tested on biochemical parameters in streptozotocin-induced diabetic rats. Streptozotocin caused an approximately 3-fold increase in fasting blood sugar level after 2 days. The diabetic control rats showed further increase in blood glucose after 30 days (384 ± 25 mg/dl in day 30 versus 280 ± 12 mg/dl in day 2, P < 0.001). Administration of the compound blocked the increase of blood glucose (272 ± 7 and 269 ± 48 mg/dl at day 2 and day 30, respectively). Also, there was significant difference in the level of triglyceride (60 ± 9 versus 158 ± 37 mg/dl, P < 0.01), total cholesterol (55 ± 2 versus 97 ± 11 mg/dl, P < 0.01) and aspartate amino transferase activity (75 ± 12 versus 129 ± 18 U/L, P < 0.05) between treated rats and diabetic control group. In conclusion, the MSEC inhibited the progression of hyperglycemia and decreased serum lipids and hepatic enzyme activity in diabetic rats. Therefore, it has the potential to be used as a natural product for the management of diabetes. PMID:23304131

  14. The inhibition of cocaine-induced locomotor activity by CART 55-102 is lost after repeated cocaine administration.

    PubMed

    Job, Martin O; Shen, Li L; Kuhar, Michael J

    2013-08-29

    CART peptide is known for having an inhibitory effect on cocaine- and dopamine-mediated actions after acute administration of cocaine and dopamine. In this regard, it is postulated to be a homeostatic, regulatory factor on dopaminergic activity in the nucleus accumbens (NAc). However, there is no data on the effect of CART peptide after chronic administration of cocaine, and this study addresses this. It was found that CART peptide blunted cocaine-induced locomotion (LMA) after acute administration of cocaine, as expected, but it did not affect cocaine-mediated LMA after chronic administration of cocaine. The loss of CART peptide's inhibitory effect did not return for up to 9 weeks after stopping the repeated cocaine administration. It may not be surprising that homeostatic regulatory mechanisms in the NAc are lost after repeated cocaine administration, and that this may be a mechanism in the development of addiction.

  15. Impact of p-glycoprotein inhibition and lipopolysaccharide administration on blood-brain barrier transport of colistin in mice.

    PubMed

    Jin, Liang; Li, Jian; Nation, Roger L; Nicolazzo, Joseph A

    2011-02-01

    The aim of this study was to investigate the factors limiting the blood-brain barrier (BBB) transport of colistin in healthy mice and to assess the impact of systemic inflammation on the transport of this antibiotic across the BBB. Colistin sulfate (40 mg/kg) was administered subcutaneously to Swiss outbred mice as single and multiple doses to determine any relationship between brain uptake and plasma concentrations of colistin. To assess the effect of P-glycoprotein (P-gp) on BBB transport, colistin sulfate (5 mg/kg) was concomitantly administered intravenously with PSC833 or GF120918 (10 mg/kg). Systemic inflammation was induced by three intraperitoneal injections of lipopolysaccharide (LPS; 3 mg/kg), and BBB transport of colistin was subsequently measured following subcutaneous administration and by an in situ brain perfusion. The brain uptake of colistin was low following single and multiple subcutaneous doses, with brain-to-plasma concentration ratios ranging between 0.021 and 0.037, and this was not significantly enhanced by coadministration of GF120918 or PSC833 (P > 0.05). LPS significantly increased the brain uptake of subcutaneously administered colistin with area under the brain concentration time curve (AUC(brain)) values of 11.7 ± 2.7 μg·h/g and 4.0 ± 0.3 μg·h/g for LPS- and saline-treated mice, respectively (mean ± standard deviation). Similarly, in situ perfusion of colistin led to higher antibiotic brain concentrations in LPS-treated animals than in saline-treated animals, with colistin brain-to-perfusate concentration ratios of 0.019 ± 0.001 and 0.014 ± 0.001, respectively. This study demonstrates that the BBB transport of colistin is negligible in healthy mice; however, brain concentrations of colistin can be significantly enhanced during systemic inflammation, as might be observed in infected patients.

  16. Oral administration of the p38α MAPK inhibitor, UR13870, inhibits affective pain behavior after spinal cord injury.

    PubMed

    Galan-Arriero, Iriana; Avila-Martin, Gerardo; Ferrer-Donato, Agueda; Gomez-Soriano, Julio; Bravo-Esteban, Elisabeth; Taylor, Julian

    2014-10-01

    The p38α mitogenous activated protein kinase (MAPK) cell signaling pathway is a key mechanism of microglia activation and has been studied as a target for neuropathic pain. The effect of UR13870, a p38α MAPK inhibitor, on microglia expression in the anterior cingulate cortex (ACC) and spinal dorsal horn was addressed after T9 contusion spinal cord injury (SCI) in the rat, in addition to behavioral testing of pain-related aversion and anxiety. Administration of intravenous UR13870 (1mg/kg i.v.) and pregabalin (30 mg/kg i.v.) reduced place escape avoidance paradigm (PEAP) but did not affect open-field anxiety behavior 42 days after SCI. PEAP behavior was also reduced in animals administered daily with oral UR13870 (10mg/kg p.o.) and preserved spinal tissue 28 days after SCI. Although UR13870 (10mg/kg p.o.) failed to reduce OX-42 and glial fibrillar acid protein immunoreactivity within the spinal dorsal horn, a reduction toward the control level was observed close to the SCI site. In the anterior cingulate cortex (ACC), a significant increase in OX-42 immunoreactivity was identified after SCI. UR13870 (10mg/kg p.o.) treatment significantly reduced OX-42, metabotropic glutamate type 5 receptor (mGluR5), and NMDA (N-methyl-d-aspartate) 2B subunit receptor (NR2B) expression in the ACC after SCI. To conclude, oral treatment with a p38α MAPK inhibitor reduces the affective behavioral component of pain after SCI in association with a reduction of microglia and specific glutamate receptors within the ACC. Nevertheless the role of neuroinflammatory processes within the vicinity of the SCI site in the development of affective neuropathic pain cannot be excluded.

  17. Interactions outside the proteinase-binding loop contribute significantly to the inhibition of activated coagulation factor XII by its canonical inhibitor from corn.

    PubMed

    Korneeva, Vera A; Trubetskov, Mikhail M; Korshunova, Alena V; Lushchekina, Sofya V; Kolyadko, Vladimir N; Sergienko, Olga V; Lunin, Vladimir G; Panteleev, Mikhail A; Ataullakhanov, Fazoil I

    2014-05-16

    Activated factor XII (FXIIa) is selectively inhibited by corn Hageman factor inhibitor (CHFI) among other plasma proteases. CHFI is considered a canonical serine protease inhibitor that interacts with FXIIa through its protease-binding loop. Here we examined whether the protease-binding loop alone is sufficient for the selective inhibition of serine proteases or whether other regions of a canonical inhibitor are involved. Six CHFI mutants lacking different N- and C-terminal portions were generated. CHFI-234, which lacks the first and fifth disulfide bonds and 11 and 19 amino acid residues at the N and C termini, respectively, exhibited no significant changes in FXIIa inhibition (Ki = 3.2 ± 0.4 nm). CHFI-123, which lacks 34 amino acid residues at the C terminus and the fourth and fifth disulfide bridges, inhibited FXIIa with a Ki of 116 ± 16 nm. To exclude interactions outside the FXIIa active site, a synthetic cyclic peptide was tested. The peptide contained residues 20-45 (Protein Data Bank code 1BEA), and a C29D substitution was included to avoid unwanted disulfide bond formation between unpaired cysteines. Surprisingly, the isolated protease-binding loop failed to inhibit FXIIa but retained partial inhibition of trypsin (Ki = 11.7 ± 1.2 μm) and activated factor XI (Ki = 94 ± 11 μm). Full-length CHFI inhibited trypsin with a Ki of 1.3 ± 0.2 nm and activated factor XI with a Ki of 5.4 ± 0.2 μm. Our results suggest that the protease-binding loop is not sufficient for the interaction between FXIIa and CHFI; other regions of the inhibitor also contribute to specific inhibition.

  18. Significant increase of salivary testosterone levels after single therapeutic transdermal administration of testosterone: suitability as a potential screening parameter in doping control.

    PubMed

    Thieme, Detlef; Rautenberg, Claudia; Grosse, Joachim; Schoenfelder, Martin

    2013-01-01

    The legally defensible proof of the abuse of endogenous steroids in sports is currently based on carbon isotope ratio mass spectrometry (IRMS), i.e. a comparison between (13)C/(12)C ratios of diagnostic precursors and metabolites of testosterone. The application of this technique requires a chromatographic baseline separation of respective steroids prior to IRMS detection and hence laborious sample pre-processing of the urinary steroid extracts including clean up by solid-phase extraction and/or liquid chromatography. Consequently, an efficient pre-selection of suspicious control urine samples is essential for appropriate follow up confirmation by IRMS and effective doping control. Two single transdermal administration studies of testosterone (50 mg Testogel® and Testopatch® at 3.8 mg in 16 h, respectively) were conducted and resulting profiles of salivary testosterone and urinary steroid profiles and corresponding carbon isotope ratios were determined. Conventional doping control markers (testosterone/epitestosterone ratio, threshold concentrations of androsterone, etiocholanolone, or androstanediols) did not approach or exceed critical thresholds. In contrast to these moderate variations, the testosterone concentration in oral fluid increased from basal values (30-142 pg/mg) to peak concentrations above 1000 pg/mg. It is likely that this significant increase in oral fluid is due to a pulsatile elevation of free (protein unbound) circulating testosterone after transdermal administration and may be assumed to represent a more diagnostic marker for transdermal testosterone administration.

  19. Significant mucosal sIgA production after a single oral or parenteral administration using in vivo CD40 targeting in the chicken.

    PubMed

    Chou, Wen-Ko; Chen, Chang-Hsin; Vuong, Christine N; Abi-Ghanem, Daad; Waghela, Suryakant D; Mwangi, Waithaka; Bielke, Lisa R; Hargis, Billy M; Berghman, Luc R

    2016-10-01

    Many pathogens enter the host through mucosal surfaces and spread rapidly via the circulation. The most effective way to prevent disease is to establish mucosal and systemic immunity against the pathogen. However, current vaccination programs in poultry industry require repeated administrations of live-attenuated virus or large amounts (10 to 100μg) of antigen together with adjuvant to induce specific secretory IgA immune responses at the mucosal effector sites. In the present study, we show that a single administration of 0.4μg of oligopeptide complexed with an agonistic anti-chicken CD40 (chCD40) monoclonal antibody (Mab) effectively targets antigen-presenting cells of the bird's mucosa-associated lymphoid tissue in vivo, and induces peptide-specific secretory IgA (sIgA) in the trachea 7days post administration. Anti-chCD40 Mab-peptide complex was administered once to four-week old male Leghorns via various mucosal routes (orally, via cloacal drinking, or oculo-nasally) or via subcutaneous (s.c.) immunization. Immunization through any of the three mucosal induction routes induced significant peptide-specific mucosal sIgA responses 7 and 14days after immunization. Interestingly, s.c. injection of the complex also induced mucosal sIgA. Our data suggest in vivo targeting of CD40 as a potential adjuvant platform, particularly for the purpose of enhancing and speeding up mucosal vaccine responses in chickens, and potentially other food animals. This is the first study able to elicit specific sIgA immune responses in remote mucosal sites with a single administration of only 0.4μg of antigen.

  20. Electrographic seizures are significantly reduced by in vivo inhibition of neuronal uptake of extracellular glutamine in rat hippocampus

    PubMed Central

    Kanamori, Keiko; Ross, Brian D.

    2013-01-01

    Summary Rats were given unilateral kainate injection into hippocampal CA3 region, and the effect of chronic electrographic seizures on extracellular glutamine (GLNECF) was examined in those with low and steady levels of extracellular glutamate (GLUECF). GLNECF, collected by microdialysis in awake rats for 5 h, decreased to 62 ± 4.4% of the initial concentration (n = 6). This change correlated with the frequency and magnitude of seizure activity, and occurred in the ipsilateral but not in contralateral hippocampus, nor in kainate-injected rats that did not undergo seizure (n = 6). Hippocampal intracellular GLN did not differ between the Seizure and No-Seizure Groups. These results suggested an intriguing possibility that seizure-induced decrease of GLNECF reflects not decreased GLN efflux into the extracellular fluid, but increased uptake into neurons. To examine this possibility, neuronal uptake of GLNECF was inhibited in vivo by intrahippocampal perfusion of 2-(methylamino)isobutyrate, a competitive and reversible inhibitor of the sodium-coupled neutral amino acid transporter (SNAT) subtypes 1 and 2, as demonstrated by 1.8 ± 0.17 fold elevation of GLNECF (n = 7). The frequency of electrographic seizures during uptake inhibition was reduced to 35 ± 7% (n = 7) of the frequency in pre-perfusion period, and returned to 88 ± 9% in the post-perfusion period. These novel in vivo results strongly suggest that, in this well-established animal model of temporal-lobe epilepsy, the observed seizure-induced decrease of GLNECF reflects its increased uptake into neurons to sustain enhanced glutamatergic epileptiform activity, thereby demonstrating a possible new target for anti-seizure therapies. PMID:24070846

  1. Oral administration of L-mR18L, a single domain cationic amphipathic helical peptide, inhibits lesion formation in ApoE null mice.

    PubMed

    Handattu, Shaila P; Datta, Geeta; Epand, Richard M; Epand, Raquel F; Palgunachari, Mayakonda N; Mishra, Vinod K; Monroe, Candyce E; Keenum, Tamara D; Chaddha, Manjula; Anantharamaiah, G M; Garber, David W

    2010-12-01

    We have shown that Ac-hE18A-NH₂, a dual-domain cationic apolipoprotein-mimetic peptide, reduces plasma cholesterol levels in dyslipidemic mice. Two single-domain cationic peptides based on the lytic class L peptide 18L were developed to test the hypothesis that a single-domain cationic amphipathic peptide can reduce atherosclerosis in apolipoprotein (apo)E null mice when orally administered. To incorporate anti-inflammatory properties, aromatic residues were clustered in the nonpolar face similar to peptide 4F, resulting in modified 18L (m18L). To reduce lytic properties, the Lys residues of 18L were replaced with Arg with the resulting peptide called modified R18L (mR18L). Biophysical studies showed that mR18L had stronger interactions with lipids than did m18L. Peptide mR18L was also more effective than m18L in promoting LDL uptake by HepG2 cells. ApoE null mice received normal chow or chow containing m18L or mR18L for six weeks. A significant reduction in plasma cholesterol and aortic sinus lesion area was seen only in the mR18L group. Plasma from mice administered mR18L, unlike those from the control and m18L groups, did not enhance monocyte adhesion to endothelial cells. Thus oral administration of mR18L reduces plasma cholesterol and lesion formation and inhibits monocyte adhesion.

  2. Inhibition of L-dopa induced growth hormone release in normal and diabetic subjects by glucose administration.

    PubMed

    Vigas, M; Klimes, I; Jurcovicova, J; Kolesar, P; Repcekova-Jezova, D

    1977-12-01

    Administration of L-dopa 1 g induced an increase of plasma growth hormone (GH) levels in seven of ten healthy volunteers and in six of ten hyperglycemic insulin-dependent diabetic subjects; the maximal GH response was higher in normal subjects. Addition of 100 g glucose orally to the L-dopa completely abolished the GH response of both groups. The difference between the effect of endogenous hyperglycemia and the effect of a sudden increase of blood sugar after glucose administration on L-dopa induced GH release in diabetic subjects may be explain by the resetting of the hypothalamic control for pituitary GH release to higher levels of blood glucose.

  3. Efficacy of topical antibiotic administration on the inhibition of perioperative oral bacterial growth in oral cancer patients: a preliminary study.

    PubMed

    Funahara, M; Hayashida, S; Sakamoto, Y; Yanamoto, S; Kosai, K; Yanagihara, K; Umeda, M

    2015-10-01

    Parenteral antibiotic prophylaxis is the current standard of therapy in clean-contaminated oral cancer surgery. Nevertheless, the incidence of surgical site infection (SSI) in oral oncological surgery is relatively high, especially in major surgery with reconstruction and tracheotomy. The aims of this study were to investigate the perioperative condition related to microorganisms in the oral cavity and to examine the efficacy of the topical administration of tetracycline in reducing the number of bacteria in the oropharyngeal fluid during intubation. The number of oral bacteria was measured during intubation in patients undergoing major oral cancer surgery. The efficacy of the topical administration of tetracycline or povidone iodine gel in reducing the bacteria was then investigated. Bacteria in the oropharyngeal fluid grew from 10(6)CFU/ml to 10(8)CFU/ml during the 3h after intubation (CFU, colony-forming units). When tetracycline was applied to the dorsum of the tongue, oral bacteria decreased immediately to 10(5)CFU/ml, and the number of bacteria in the oropharyngeal fluid was maintained below 10(7)CFU/ml for 7h. The concentration of tetracycline in the oropharyngeal fluid was extremely high for several hours after topical administration. The topical administration of tetracycline could reduce oral bacteria in patients undergoing clean-contaminated oral cancer surgery. This method is expected to be effective in the prevention of SSI.

  4. Targeted downregulation of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S6ST) significantly mitigates chondroitin sulfate proteoglycan (CSPG) mediated inhibition

    PubMed Central

    Karumbaiah, Lohitash; Anand, Sanjay; Thazhath, Rupal; Zhong, Yinghui; McKeon, Robert J.; Bellamkonda, Ravi V.

    2011-01-01

    Chondroitin Sulfate-4,6 (CS-E) glycosaminoglycan (GAG) upregulation in astroglial scars is a major contributor to CS proteoglycan (CSPG) mediated inhibition (Gilbert et al. 2005). However, the role of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S6ST) catalyzed sulfation of CS-E, and its contribution to CSPG mediated inhibition of CNS regeneration remains to be fully elucidated. Here, we used in situ hybridization to show localized upregulation of GalNAc4S6ST mRNA after CNS injury. Using in vitro spot assays with immobilized CS-E, we demonstrate dose dependent inhibition of rat embryonic day 18 (E18) cortical neurons. To determine whether selective downregulation of CS-E affected the overall inhibitory character of extracellular matrix produced by reactive astrocytes, single [against (chondroitin 4) sulfotransferase 11 (C4ST1) or GalNAc4S6ST mRNA) or double (against C4ST1 and GalNAc4S6ST mRNA] siRNA treatments were conducted and assayed using quantitative real-time PCR (qRT-PCR) and high performance liquid chromatography (HPLC) to confirm the specific downregulation of CS-4S GAG (CS-A) and CS-E. Spot and Bonhoeffer stripe assays using astrocyte conditioned media (ACM) from siRNA treated rat astrocytes showed a significant decrease in inhibition of neuronal attachment and neurite extensions when compared to untreated and TGFα treated astrocytes. These findings reveal that selective attenuation of CS-E via siRNA targeting of GalNAc4S6ST significantly mitigates CSPG mediated inhibition of neurons, potentially offering a novel intervention strategy for CNS injury. PMID:21456043

  5. Long-term administration of Delta9-tetrahydrocannabinol desensitizes CB1-, adenosine A1-, and GABAB-mediated inhibition of adenylyl cyclase in mouse cerebellum.

    PubMed

    Selley, Dana E; Cassidy, Michael P; Martin, Billy R; Sim-Selley, Laura J

    2004-11-01

    Cannabinoid CB(1) receptors in the cerebellum mediate the inhibitory effects of Delta(9)-tetrahydrocannabinol (THC) on motor coordination. Intracellular effects of CB(1) receptors include inhibition of adenylyl cyclase via activation of G(i/o) proteins. There is evidence for the convergence of other neuronal receptors, such as adenosine A(1) and GABA(B), with the cannabinoid system on this signaling pathway to influence motor function. Previous studies have shown that brain CB(1) receptors are desensitized and down-regulated by long-term THC treatment, but few studies have examined the effects of long-term THC treatment on downstream effector activity in brain. Therefore, these studies examined the relationship between CB(1), adenosine A(1), and GABA(B) receptors in cerebella of mice undergoing prolonged treatment with vehicle or THC at the level of G protein activation and adenylyl cyclase inhibition. In control cerebella, CB(1) receptors produced less than additive inhibition of adenylyl cyclase with GABA(B) and A(1) receptors, indicating that these receptors are localized on overlapping populations of cells. Long-term THC treatment produced CB(1) receptor down-regulation and desensitization of both cannabinoid agonist-stimulated G protein activation and inhibition of forskolin-stimulated adenylyl cyclase. However, G protein activation by GABA(B) or A(1) receptors was unaffected. It is noteworthy that heterologous attenuation of GABA(B) and A(1) receptor-mediated inhibition of adenylyl cyclase was observed, even though absolute levels of basal and forskolin- or G(s)-stimulated activity were unchanged. These results indicate that long-term THC administration produces a disruption of inhibitory receptor control of cerebellar adenylyl cyclase and suggest a potential mechanism of cross-tolerance to the motor incoordinating effects of cannabinoid, GABA(B), and A(1) agonists.

  6. Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome.

    PubMed

    Wilding, Laura A; Bassis, Christine M; Walacavage, Kim; Hashway, Sara; Leroueil, Pascale R; Morishita, Masako; Maynard, Andrew D; Philbert, Martin A; Bergin, Ingrid L

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100-400 times the effective in vitro anti-microbial concentration, does not affect the indigenous murine gut microbiome.

  7. Levo-tetrahydropalmatine, a natural, mixed dopamine receptor antagonist, inhibits methamphetamine self-administration and methamphetamine-induced reinstatement.

    PubMed

    Gong, Xiaokang; Yue, Kai; Ma, Baomiao; Xing, Junqiao; Gan, Yongping; Wang, Daisong; Jin, Guozhang; Li, Chaoying

    2016-05-01

    Despite the high prevalence of methamphetamine (METH) use, no FDA-approved pharmacological treatment is currently available for individuals with a METH addiction. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance derived from corydalis and stephania that has been used in traditional Asian medicine for its analgesic, sedative and hypnotic properties. Previous pharmacological studies of l-THP indicated that it not only binds to D1 and D2 receptors but also has a low affinity for D3 receptors and may function as an antagonist. The unique pharmacological profile of l-THP suggests that it may have potential therapeutic effects on drug addiction; however, the effects of l-THP in individuals with METH addictions are largely unknown. In this study, we investigated the effects of l-THP on METH self-administration and METH-induced reinstatement. In our experiments, l-THP (1.25, 2.50 and 5.00 mg/kg, i.p.) decreased METH self-administration under the fixed-ratio 1 schedule. l-THP (2.50 and 5.00 mg/kg, i.p) also prevented the METH-induced reinstatement of METH-seeking behaviors. Interestingly, l-THP (1.25 and 2.50mg/kg, i.p) did not affect locomotor activity following METH injection (1mg/kg) suggesting that the observed effects of l-THP (2.50mg/kg) on METH-induced reinstatement were not due to motor impairments. Thus, l-THP (a natural, mixed dopamine (DA) receptor antagonist) attenuates METH self-administration and METH-induced reinstatement.

  8. N,N-Dimethylacetamide Significantly Attenuates LPS- and TNFα-Induced Proinflammatory Responses Via Inhibition of the Nuclear Factor Kappa B Pathway

    PubMed Central

    Pekson, Ryan; Poltoratsky, Vladimir; Gorasiya, Samir; Sundaram, Sruthi; Ashby, Charles R; Vancurova, Ivana; Reznik, Sandra E

    2016-01-01

    Previously, we have shown that N,N-dimethylacetamide (DMA) prevents inflammation-induced preterm birth in a murine model, inhibits lipopolysaccharide (LPS)-induced increases in placental proinflammatory cytokines and upregulates the antiinflammatory cytokine interleukin-10 (IL-10). However, DMA’s mechanism of action remains to be elucidated. In the current study, we investigate how DMA produces its antiinflammatory effect. Using in vitro and ex vivo models, we show that DMA suppresses secretion of proinflammatory cytokines in lipopolysaccharide (LPS)-induced RAW 264.7 cells, TNFα-challenged JEG-3 cells and LPS-stimulated human placental explants. DMA significantly attenuated secretion of TNFα, IL-6, IL-10 and granulocyte macrophage colony stimulating factor (GM-CSF) from LPS-stimulated RAW 264.7 cells; IL-6 secretion from TNFα-stimulated JEG-3 cells; and TNFα, IL-6, IL-10, GM-CSF and Interleukin-8 (IL-8) from LPS-stimulated human placental explants. We further investigated whether DMA’s effect on cytokine expression involves the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. DMA (10 mM) significantly inhibited degradation of nuclear factor of kappa light polypeptide gene enhancer in B cell inhibitor α (IκBα) in LPS-stimulated RAW 264.7 cells, but there was no significant change in the expression of phosphorylated or native forms of downstream proteins in the MAPK pathway. In addition, DMA significantly attenuated luciferase activity in cells co-transfected with NF-κB-Luc reporter plasmid, but not with AP-1-Luc or CEBP-Luc reporters. Overall, our findings suggest that the antiinflammatory activity of DMA is mediated by inhibition of the NF-κB pathway via decreased IκBα degradation. PMID:27782292

  9. Oral administration of paeoniflorin attenuates allergic contact dermatitis by inhibiting dendritic cell migration and Th1 and Th17 differentiation in a mouse model.

    PubMed

    Shi, Dongmei; Li, Xuefeng; Li, Dongmei; Zhao, Quanjing; Shen, Yongnian; Yan, Hongxia; Fu, Hongjun; Zheng, Hailin; Lu, Guixia; Qiu, Ying; Liu, Weida

    2015-04-01

    Allergic contact dermatitis (ACD) is a hapten-specific CD4(+) T-cells mediated inflammatory response of the skin. Its pathomechanism involves 2 phases, an induction phase and an elicitation phase. Langerhans cells (LCs) and dendritic cells (DCs) in the skin play key roles in presenting low molecular weight chemicals (haptens) to the lymph nodes. Therefore, inhibition of the migration of LCs or DCs and T-cell proliferation is each expected to control ACD disease. To explore the effectiveness of paeoniflorin (PF) on the migration of LCs and T-cell proliferation in vivo, we establish a murine model of ACD, promoted by repeated exposure to an allergen (specifically 1-Chloro-2,4-dinitrobenzene (DNCB)). Administration of PF inhibits DC migration in this DNCB-induced model in the induction phase. As a result, epidermal LC density in the elicitation phase increased in PF-treated mice when compared to PF-untreated mice. At the same time, PF reduced IFN-γ(+)CD4(+) and IL-17(+)CD4(+) T cells proliferation (but not IL-4(+)CD4(+) T cells proliferation), leading to an attenuated cutaneous inflammatory response. Consistent with this T-cell proliferation profile, secretions of IFN-γ and IL-17 were reduced and IL-10 secretion increased in PF-treated mice, but production of IL-4 and IL-5 remained unchanged in the skin and blood samples. These results suggest that oral administration of PF can treat and prevent ACD effectively through inhibition of DC migration, and thus decrease the capacity of DCs to stimulate Th1 and Th17 cell differentiation and cytokine production.

  10. Mass Administration of Ivermectin for the Elimination of Onchocerciasis Significantly Reduced and Maintained Low the Prevalence of Strongyloides stercoralis in Esmeraldas, Ecuador

    PubMed Central

    Anselmi, Mariella; Buonfrate, Dora; Guevara Espinoza, Angel; Prandi, Rosanna; Marquez, Monica; Gobbo, Maria; Montresor, Antonio; Albonico, Marco; Racines Orbe, Marcia; Bisoffi, Zeno

    2015-01-01

    Objectives To evaluate the effect of ivermectin mass drug administration on strongyloidiasis and other soil transmitted helminthiases. Methods We conducted a retrospective analysis of data collected in Esmeraldas (Ecuador) during surveys conducted in areas where ivermectin was annually administered to the entire population for the control of onchocerciasis. Data from 5 surveys, conducted between 1990 (before the start of the distribution of ivermectin) and 2013 (six years after the interruption of the intervention) were analyzed. The surveys also comprised areas where ivermectin was not distributed because onchocerciasis was not endemic. Different laboratory techniques were used in the different surveys (direct fecal smear, formol-ether concentration, IFAT and IVD ELISA for Strongyloides stercoralis). Results In the areas where ivermectin was distributed the strongyloidiasis prevalence fell from 6.8% in 1990 to zero in 1996 and 1999. In 2013 prevalence in children was zero with stool examination and 1.3% with serology, in adult 0.7% and 2.7%. In areas not covered by ivermectin distribution the prevalence was 23.5% and 16.1% in 1996 and 1999, respectively. In 2013 the prevalence was 0.6% with fecal exam and 9.3% with serology in children and 2.3% and 17.9% in adults. Regarding other soil transmitted helminthiases: in areas where ivermectin was distributed the prevalence of T. trichiura was significantly reduced, while A. lumbricoides and hookworms were seemingly unaffected. Conclusions Periodic mass distribution of ivermectin had a significant impact on the prevalence of strongyloidiasis, less on trichuriasis and apparently no effect on ascariasis and hookworm infections. PMID:26540412

  11. Functional Analysis of Variants of Unknown Significance in BRCA1 and BRCA2 Using Complementation of a Synthetic Lethal Interaction with PARP Inhibition

    DTIC Science & Technology

    2014-12-01

    Award Number: W81XWH-12-1-0569 TITLE: Functional Analysis of Variants of Unknown Significance in BRCA1 and BRCA2 Using Complementation of a...synergistic decrease in cell survival in cells with loss of function of either BRCA1 or BRCA2 and loss or inhibition of Parp1 activity15,17. SLI has...Develop a robust assay by which individual VUSs can be tested for their effect on BRCA1 /2 function by expressing a BRCA1 or BRCA2 gene (cDNA) carrying the

  12. Avastin® in combination with gemcitabine and cisplatin significantly inhibits tumor angiogenesis and increases the survival rate of human A549 tumor-bearing mice

    PubMed Central

    LIU, YING; XIA, XIZHENG; ZHOU, MINGKAI; LIU, XIAOJUN

    2015-01-01

    The aim of this study was to investigate the effect of Avastin® in combination with gemcitabine and cisplatin (GP) on the tumor growth of A549 tumor-bearing mice and the potential anti-tumor mechanism. A total of 30 human A549 tumor-bearing nude mice were randomly divided into the Avastin, chemotherapy and combined treatment groups for treatment with an intraperitoneal injection of Avastin (5 mg/kg) (Avastin group); an intraperitoneal injection of gemcitabine (4 mg/kg) and cisplatin (4 mg/kg) (chemotherapy group); or intraperitoneal injections of Avastin and GP (combined treatment group). The mice were observed for 30 days and the tumor growth, survival and body weight of the mice in the three groups were analyzed. The protein level of vascular endothelial growth factor (VEGF) in the tumor tissues was analyzed by ELISA. The vascular density and structural changes of the tumor were analyzed using immunohistochemistry. Compared with the Avastin and chemotherapy groups, the tumor growth of mice in the combined treatment group was significantly inhibited, and the survival rate of the mice was increased significantly. No difference in body weight was observed among the three groups of mice (P>0.05). The levels of VEGF in the combined treatment group tumor tissues were significantly reduced compared with those in the chemotherapy group tumor tissues (P<0.05). Furthermore, the vessel density of the tumor tissue in the combined treatment group was significantly reduced compared with that in the chemotherapy group (P<0.05), and the number of normal vessels in the combined treatment group tumors was significantly higher than that in the chemotherapy group tumors after 7 days of treatment (P<0.05). In conclusion, Avastin can significantly decrease the level of VEGF in tumor tissue, inhibit tumor angiogenesis and promote the normalization of tumor vascular structure, which may explain the enhanced efficacy of Avastin in combination with chemotherapy. PMID:26136956

  13. Oral administration of cobalt acetate alters milk fatty acid composition, consistent with an inhibition of stearoyl-coenzyme A desaturase in lactating ewes.

    PubMed

    Frutos, P; Toral, P G; Ramos-Morales, E; Shingfield, K J; Belenguer, A; Hervás, G

    2014-02-01

    Previous investigations have shown that cobalt (Co) modifies milk fat composition in cattle, consistent with an inhibition of stearoyl-coenzyme A desaturase (SCD) activity, but it remains unclear whether other ruminant species are also affected. The present study examined the effects of oral administration of Co acetate on intake, rumen function, and milk production and fatty acid (FA) composition in sheep. Twenty lactating Assaf ewes were allocated into 1 of 4 groups and used in a continuous randomized block design that involved a 15-d adaptation, a 6-d treatment, and a 10-d posttreatment period. During the treatment period, animals received an oral drench supplying 0 (control), 3 (Co3), 6 (Co6), and 9 (Co9) mg of Co/kg of BW per day, administered in 3 equal doses at 8-h intervals. Cobalt acetate had no influence on intake or milk fat and protein concentrations, whereas treatments Co6 and Co9 tended to lower milk yield. Results on rumen parameters showed no effects on rumen fermentation, FA composition, or bacterial community structure. Administration of Co acetate decreased milk concentrations of FA containing a cis-9 double bond and SCD product:substrate ratios, consistent with an inhibition of SCD activity in the ovine mammary gland. Temporal changes in milk fat composition indicated that the effects of treatments were evident within 3d of dosing, with further changes being apparent after 6d and reverting to pretreatment values by d 6 after administration. Effect on milk FA composition did not differ substantially in response to incremental doses of Co acetate. On average, Co decreased milk cis-9 10:1/10:0, cis-9 12:1/12:0, cis-9 14:1/14:0, cis-9 16:1/16:0, cis-9 17:1/17:0, cis-9 18:1/18:0, and cis-9,trans-11 18:2/trans-11 18:1 concentration ratios by 30, 32, 38, 33, 21, 24, and 25%, respectively. Changes in milk fat cis-9 10:1, cis-9 12:1, and cis-9 14:1 concentrations to Co treatment indicated that 51% of cis-9 18:1 and cis-9,trans-11 18:2 secreted in milk

  14. Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo.

    PubMed

    Beconi, Maria; Aziz, Omar; Matthews, Kim; Moumné, Lara; O'Connell, Catherine; Yates, Dawn; Clifton, Steven; Pett, Hannah; Vann, Julie; Crowley, Lynsey; Haughan, Alan F; Smith, Donna L; Woodman, Ben; Bates, Gillian P; Brookfield, Fred; Bürli, Roland W; McAllister, George; Dominguez, Celia; Munoz-Sanjuan, Ignacio; Beaumont, Vahri

    2012-01-01

    Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.

  15. Oral Administration of the Pimelic Diphenylamide HDAC Inhibitor HDACi 4b Is Unsuitable for Chronic Inhibition of HDAC Activity in the CNS In Vivo

    PubMed Central

    Beconi, Maria; Aziz, Omar; Matthews, Kim; Moumné, Lara; O’Connell, Catherine; Yates, Dawn; Clifton, Steven; Pett, Hannah; Vann, Julie; Crowley, Lynsey; Haughan, Alan F.; Smith, Donna L.; Woodman, Ben; Bates, Gillian P.; Brookfield, Fred; Bürli, Roland W.; McAllister, George; Dominguez, Celia; Munoz-Sanjuan, Ignacio; Beaumont, Vahri

    2012-01-01

    Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich’s ataxia and Huntington’s disease, based on efficacy in cell and mouse models. These studies’ authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington’s disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington’s disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general. PMID:22973455

  16. Regeneration of coenzyme Q9 redox state and inhibition of oxidative stress by Rooibos tea (Aspalathus linearis) administration in carbon tetrachloride liver damage.

    PubMed

    Kucharská, J; Ulicná, O; Gvozdjáková, A; Sumbalová, Z; Vancová, O; Bozek, P; Nakano, M; Greksák, M

    2004-01-01

    The effect of rooibos tea (Aspalathus linearis) on liver antioxidant status and oxidative stress was investigated in rat model of carbon tetrachloride-induced liver damage. Synthetic antioxidant N-acetyl-L-cysteine (NAC) was used for comparison. Administration of carbon tetrachloride (CCl4) for 10 weeks decreased liver concentrations of reduced and oxidized forms of coenzyme Q9 (CoQ9H2 and CoQ9), reduced -tocopherol content and simultaneously increased the formation of malondialdehyde (MDA) as indicator of lipid peroxidation. Rooibos tea and NAC administered to CCl4-damaged rats restored liver concentrations of CoQ9H2 and alpha-tocopherol and inhibited the formation of MDA, all to the values comparable with healthy animals. Rooibos tea did not counteract the decrease in CoQ9, whereas NAC was able to do it. Improved regeneration of coenzyme Q9 redox state and inhibition of oxidative stress in CCl4-damaged livers may explain the beneficial effect of antioxidant therapy. Therefore, the consumption of rooibos tea as a rich source of natural antioxidants could be recommended as a market available, safe and effective hepatoprotector in patients with liver diseases.

  17. Inhibition of 1,2-dimethylhydrazine induced colon genotoxicity in rats by the administration of probiotic curd.

    PubMed

    Kumar, Arvind; Singh, Nikhlesh Kumar; Sinha, Pushpalata Rabindra

    2010-03-01

    Epidemiologic and experimental studies suggest that the probiotic organisms are effective in preventing colon carcinogenesis, which is the major cause of mortality and morbidity in western countries. Keeping this in view, a curd (a common Indian fermented milk product) was prepared by the addition of probiotic cultures Lactobacillus acidophilus, Lactobacillus casei and curd culture Lactococcus lactis biovar. diacetylactis. In present study, we have evaluated the anti tumor effect of probiotic curd by monitoring the DNA damage through comet assay. The rats were allocated to four groups, first group was DMH control group, second group was probiotic curd group in which probiotic curd was given along with DMH (1,2-dimethylhydrazine) injection, third group was normal curd group in which normal curd was given along with DMH injection and fourth group was normal control group. Animals received subcutaneous injection of DMH dissolved in normal saline at a dose rate of 20 mg/kg body weight, once weekly for 15 weeks. The rats were dissected at 40th week of experiment and comet assay was done in colonic cells to assess the DNA damage. A significant reduction in DNA damage (54.7%) was observed in probiotic curd group as compared to DMH control group (88.1%). The probiotic curd was effective to significantly reduce the L:W ratio in comparison to DMH control group and normal curd. The results of present study show the protective effects of probiotic curd against DMH induced genotoxicity in colonic cells.

  18. In vitro exposure to the herbicide atrazine inhibits T cell activation, proliferation, and cytokine production and significantly increases the frequency of Foxp3+ regulatory T cells.

    PubMed

    Thueson, Lindsay E; Emmons, Tiffany R; Browning, Dianna L; Kreitinger, Joanna M; Shepherd, David M; Wetzel, Scott A

    2015-02-01

    The herbicide atrazine (2-chloro-4-[ethylamino]-6-[isopropylamino]-s-triazine) is the most common water contaminant in the United States. Atrazine is a phosphodiesterase inhibitor and is classified as an estrogen disrupting compound because it elevates estrogen levels via induction of the enzyme aromatase. Previous studies have shown that atrazine exposure alters the function of innate immune cells such as NK cells, DC, mast cells, and macrophages. In this study we have examined the impact of in vitro atrazine exposure on the activation, proliferation, and effector cytokine production by primary murine CD4(+) T lymphocytes. We found that atrazine exposure significantly inhibited CD4(+) T cell proliferation and accumulation as well as the expression of the activation markers CD25 and CD69 in a dose-dependent manner. Interestingly, the effects were more pronounced in cells from male animals. These effects were partially mimicked by pharmacological reagents that elevate intracellular cAMP levels and addition of exogenous rmIL-2 further inhibited proliferation and CD25 expression. Consistent with these findings, atrazine exposure during T cell activation resulted in a 2- to 5-fold increase in the frequency of Foxp3(+) CD4(+) T cells.

  19. Silvestrol exhibits significant in vivo and in vitro antileukemic activities and inhibits FLT3 and miR-155 expressions in acute myeloid leukemia

    PubMed Central

    2013-01-01

    Background Activating mutations [internal tandem duplication (ITD)] or overexpression of the FMS-like tyrosine kinase receptor-3 (FLT3) gene are associated with poor outcome in acute myeloid leukemia (AML) patients, underscoring the need for novel therapeutic approaches. The natural product silvestrol has potent antitumor activity in several malignancies, but its therapeutic impact on distinct molecular high-risk AML subsets remains to be fully investigated. We examined here the preclinical activity of silvestrol in FLT3-ITD and FLT3 wild-type (wt) AML. Methods Silvestrol in vitro anti-leukemic activity was examined by colorimetric cell viability assay, colony-forming and flow cytometry assays assessing growth inhibition and apoptosis, respectively. Pharmacological activity of silvestrol on FLT3 mRNA translation, mRNA and protein expression was determined by RNA-immunoprecipitation, qRT-PCR and immunoblot analyses, respectively. Silvestrol in vivo efficacy was investigated using MV4-11 leukemia-engrafted mice. Results Silvestrol shows antileukemia activity at nanomolar concentrations both in FLT3-wt overexpressing (THP-1) and FLT3-ITD (MV4-11) expressing AML cell lines (IC50 = 3.8 and 2.7 nM, respectively) and patients’ primary blasts [IC50 = ~12 nM (FLT3-wt) and ~5 nM (FLT3-ITD)]. Silvestrol increased apoptosis (~4fold, P = 0.0001), and inhibited colony-formation (100%, P < 0.0001) in primary blasts. Silvestrol efficiently inhibited FLT3 translation reducing FLT3 protein expression by 80–90% and decreased miR-155 levels (~60%), a frequently co-regulated onco-miR in FLT3-ITD-positive AML. The median survival of silvestrol-treated vs vehicle-treated mice was 63 vs 29 days post-engraftment, respectively (P < 0.0001). Conclusions Silvestrol exhibits significant in vivo and in vitro antileukemic activities in AML through a novel mechanism resulting in inhibition of FLT3 and miR-155 expression. These encouraging results warrant a rapid

  20. Intravenous Administration of Manuka Honey Inhibits Tumor Growth and Improves Host Survival When Used in Combination with Chemotherapy in a Melanoma Mouse Model

    PubMed Central

    Fernandez-Cabezudo, Maria J.; El-Kharrag, Rkia; Torab, Fawaz; Bashir, Ghada; George, Junu A.; El-Taji, Hakam; al-Ramadi, Basel K.

    2013-01-01

    Manuka honey has been recognized for its anti-bacterial and wound-healing activity but its potential antitumor effect is poorly studied despite the fact that it contains many antioxidant compounds. In this study, we investigated the antiproliferative activity of manuka honey on three different cancer cell lines, murine melanoma (B16.F1) and colorectal carcinoma (CT26) as well as human breast cancer (MCF-7) cells in vitro. The data demonstrate that manuka honey has potent anti-proliferative effect on all three cancer cell lines in a time- and dose-dependent manner, being effective at concentrations as low as 0.6% (w/v). This effect is mediated via the activation of a caspase 9-dependent apoptotic pathway, leading to the induction of caspase 3, reduced Bcl-2 expression, DNA fragmentation and cell death. Combination treatment of cancer cells with manuka and paclitaxel in vitro, however, revealed no evidence of a synergistic action on cancer cell proliferation. Furthermore, we utilized an in vivo syngeneic mouse melanoma model to assess the potential effect of intravenously-administered manuka honey, alone or in combination with paclitaxel, on the growth of established tumors. Our findings indicate that systemic administration of manuka honey was not associated with any alterations in haematological or clinical chemistry values in serum of treated mice, demonstrating its safety profile. Treatment with manuka honey alone resulted in about 33% inhibition of tumor growth, which correlated with histologically observable increase in tumor apoptosis. Although better control of tumor growth was observed in animals treated with paclitaxel alone or in combination with manuka honey (61% inhibition), a dramatic improvement in host survival was seen in the co-treatment group. This highlights a potentially novel role for manuka honey in alleviating chemotherapy-induced toxicity. PMID:23409104

  1. Significant decrease of ADP release rate underlies the potent activity of dimethylenastron to inhibit mitotic kinesin Eg5 and cancer cell proliferation

    SciTech Connect

    Sun, Linlin; Sun, Xiaodong; Xie, Songbo; Yu, Haiyang; Zhong, Diansheng

    2014-05-09

    Highlights: • DIMEN displays higher anti-proliferative activity than enastron. • DIMEN induced mitotic arrest and apoptosis more significantly than enastron. • DIMEN blocked the conformational change of ADP-binding pocket more effectively. • DIMEN hindered ADP release more potently than enastron. - Abstract: Eg5 is a mitotic kinesin that plays a crucial role in the formation of bipolar mitotic spindles, by hydrolyzing ATP to push apart anti-parallel microtubules. Dimethylenastron is potent specific small molecule inhibitor of Eg5. The mechanism by which dimethylenastron inhibits Eg5 function remains unclear. By comparing with enastron, here we report that dimethylenastron prevents the growth of pancreatic and lung cancer cells more effectively, by halting mitotic progression and triggering apoptosis. We analyze their interactions with ADP-bound Eg5 crystal structure, and find that dimethylenastron binds Eg5 motor domain with higher affinity. In addition, dimethylenastron allosterically blocks the conformational change of the “sandwich”-like ADP-binding pocket more effectively. We subsequently use biochemical approach to reveal that dimethylenastron slows ADP release more significantly than enastron. These data thus provide biological, structural and mechanistic insights into the potent inhibitory activity of dimethylenastron.

  2. Orally Administrated Lactobacillus pentosus var. plantarum C29 Ameliorates Age-Dependent Colitis by Inhibiting the Nuclear Factor-Kappa B Signaling Pathway via the Regulation of Lipopolysaccharide Production by Gut Microbiota

    PubMed Central

    Jeong, Jin-Ju; Kim, Kyung-Ah; Jang, Se-Eun; Woo, Jae-Yeon; Han, Myung Joo; Kim, Dong-Hyun

    2015-01-01

    To evaluate the anti-inflammaging effect of lactic acid bacteria (LAB) on age-dependent inflammation, we first screened and selected a tumor necrosis factor (TNF)-α and reactive oxygen species (ROS)-inhibitory LAB, Lactobacillus pentosus var. plantarum C29, among the LABs isolated from fermented vegetables using LPS-stimulated mouse peritoneal macrophages. Oral administration of C29 (2 × 109 CFU/rat) for 8 weeks in aged Fischer 344 rats (age, 16 months) inhibited the expression of the inflammatory markers myeloperoxidase, inducible nitric oxide (NO) synthase, cyclooxygenase-2, pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-6 and the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP1), and mitogen-activated protein kinases (MAPKs). Treatment with C29 induced the expression of tight junction proteins ZO-1, occludin, and claudin-1, and reduced intestinal microbial LPS and plasmatic LPS levels and ROS, as well as the Firmicutes to Bacteroidetes ratio, which is significantly higher in aged rats than in young rats. C29 treatment also reduced plasmatic reactive oxygen species, malondialdehyde, C-reactive protein, and TNF-α, and suppressed expression of senescence markers p16 and p53 in the colon of the aged rats, but increased SIRT 1 expression. Based on these findings, we concluded that C29 treatment may suppress aging-dependent colitis by inhibiting NF-κB, AP1, and MAPK activation via the inhibition of gut microbiota LPS production and the induction of tight junction protein expression. PMID:25689583

  3. Orally administrated Lactobacillus pentosus var. plantarum C29 ameliorates age-dependent colitis by inhibiting the nuclear factor-kappa B signaling pathway via the regulation of lipopolysaccharide production by gut microbiota.

    PubMed

    Jeong, Jin-Ju; Kim, Kyung-Ah; Jang, Se-Eun; Woo, Jae-Yeon; Han, Myung Joo; Kim, Dong-Hyun

    2015-01-01

    To evaluate the anti-inflammaging effect of lactic acid bacteria (LAB) on age-dependent inflammation, we first screened and selected a tumor necrosis factor (TNF)-α and reactive oxygen species (ROS)-inhibitory LAB, Lactobacillus pentosus var. plantarum C29, among the LABs isolated from fermented vegetables using LPS-stimulated mouse peritoneal macrophages. Oral administration of C29 (2 × 109 CFU/rat) for 8 weeks in aged Fischer 344 rats (age, 16 months) inhibited the expression of the inflammatory markers myeloperoxidase, inducible nitric oxide (NO) synthase, cyclooxygenase-2, pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-6 and the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP1), and mitogen-activated protein kinases (MAPKs). Treatment with C29 induced the expression of tight junction proteins ZO-1, occludin, and claudin-1, and reduced intestinal microbial LPS and plasmatic LPS levels and ROS, as well as the Firmicutes to Bacteroidetes ratio, which is significantly higher in aged rats than in young rats. C29 treatment also reduced plasmatic reactive oxygen species, malondialdehyde, C-reactive protein, and TNF-α, and suppressed expression of senescence markers p16 and p53 in the colon of the aged rats, but increased SIRT 1 expression. Based on these findings, we concluded that C29 treatment may suppress aging-dependent colitis by inhibiting NF-κB, AP1, and MAPK activation via the inhibition of gut microbiota LPS production and the induction of tight junction protein expression.

  4. Oral administration of Lactococcus chungangensis inhibits 2,4-dinitrochlorobenzene-induced atopic-like dermatitis in NC/Nga mice.

    PubMed

    Choi, Woo Jin; Konkit, Maytiya; Kim, Yena; Kim, Mi-Kyung; Kim, Wonyong

    2016-09-01

    Interest is increasing in the potentially beneficial role of probiotics in the prevention and treatment of atopic diseases. In this study, we investigated the protective effects of Lactococcus chungangensis CAU 28(T) against atopic dermatitis using murine macrophage RAW 264.7 cells, human keratinocyte HaCaT cells, human mast cell line HMC-1 cells, and a 2,4-dinitrochlorobenzene-induced atopic dermatitis model (NC/Nga mice). The results showed that L. chungangensis CAU 28(T) exhibited potent antiinflammatory activity by inhibiting the production of the proinflammatory mediators nitric oxide and prostaglandin E2 in lipopolysaccharide-stimulated RAW 264.7 cells. Treatment with L. chungangensis CAU 28(T) reduced the release of β-hexosaminidase and histamine in HMC-1 cells stimulated with mast cell activator compound 48/80. In addition, the back skin and ears of NC/Nga mice exhibited reduced histological manifestations of atopic skin lesions such as erosion, hyperplasia of the epidermis and dermis, and inflammatory cell infiltration. Oral administration of L. chungangensis CAU 28(T) suppressed the production of IL-4, IL-5, IL-12, IFN-γ, tumor necrosis factor-α, and thymus- and activation-regulated chemokine (TARC) in skin lesions, indicating that it strongly drives the local immune system with efficacy comparable to that of tacrolimus, a topical immunomodulatory drug used for the treatment of atopic dermatitis. The findings indicate that L. chungangensis CAU 28(T) could be a novel probiotic candidate for controlling the symptoms of atopic dermatitis.

  5. Artemether Combined with shRNA Interference of Vascular Cell Adhesion Molecule-1 Significantly Inhibited the Malignant Biological Behavior of Human Glioma Cells

    PubMed Central

    Wang, Ping; Xue, Yi-Xue; Yao, Yi-Long; Yu, Bo; Liu, Yun-Hui

    2013-01-01

    Artemether is the derivative extracted from Chinese traditional herb and originally used for malaria. Artemether also has potential therapeutic effects against tumors. Vascular cell adhesion molecule-1 (VCAM-1) is an important cell surface adhesion molecule associated with malignancy of gliomas. In this work, we investigated the role and mechanism of artemether combined with shRNA interference of VCAM-1 (shRNA-VCAM-1) on the migration, invasion and apoptosis of glioma cells. U87 human glioma cells were treated with artemether at various concentrations and shRNA interfering technology was employed to silence the expression of VCAM-1. Cell viability, migration, invasiveness and apoptosis were assessed with MTT, wound healing, Transwell and Annexin V-FITC/PI staining. The expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and phosphorylated Akt (p-Akt) was checked by Western blot assay. Results showed that artemether and shRNA-VCAM-1 not only significantly inhibited the migration, invasiveness and expression of MMP-2/9 and p-Akt, but also promoted the apoptosis of U87 cells. Combined treatment of both displayed the maximum inhibitory effects on the malignant biological behavior of glioma cells. Our work revealed the potential therapeutic effects of artemether and antiVCAM-1 in the treatments of gliomas. PMID:23593320

  6. Administration of Brevibacillus laterosporus spores as a poultry feed additive to inhibit house fly development in feces: a new eco-sustainable concept.

    PubMed

    Ruiu, L; Satta, A; Floris, I

    2014-03-01

    The success of a microbial pesticide application against house flies developing in manure should accomplish the uniform mixing of active ingredients with this breeding medium, thus enhancing residual effects. The oral administration of the entomopathogenic bacterium Brevibacillus laterosporus to caged poultry species allows the homogeneous incorporation of its active ingredients with fly breeding media. Feces from treated broilers or hens show toxicity against exposed fly adults and larvae. Insecticidal effects are concentration-dependent with a lethal median concentration (LC50) value of 1.34 × 10(8) and 0.61 × 10(8) spores/g of feces for adults and larvae, respectively. Manure toxicity against flies was maintained as long as chickens were fed a diet containing adequate concentrations of B. laterosporus spores. Toxicity significantly decreased after spore administration to birds was interrupted. When poultry diet contained 10(10) spores/g, mortality of flies reared on feces exceeded 80%. The use of B. lateroporus spores as a feed additive in poultry production systems fostering a more integrated approach to farming is discussed.

  7. Dermal Lipogenesis Inhibits Adiponectin Production in Human Dermal Fibroblasts while Exogenous Adiponectin Administration Prevents against UVA-Induced Dermal Matrix Degradation in Human Skin

    PubMed Central

    Fang, Chien-Liang; Huang, Ling-Hung; Tsai, Hung-Yueh; Chang, Hsin-I

    2016-01-01

    Adiponectin is one of the most abundant adipokines from the subcutaneous fat, and regulates multiple activities through endocrine, paracrine, or autocrine mechanisms. However, its expression in adipogenic induced fibroblasts, and the potential role in photoaging has not been determined. Here, human dermal fibroblasts, Hs68, were presented as a cell model of dermal lipogenesis through stimulation of adipogenic differentiation medium (ADM). Similar to other studies in murine pre-adipocyte models (i.e., 3T3-L1), Hs68 fibroblasts showed a tendency to lipogenesis based on lipid accumulation, triglyceride formation, and the expressions of PPAR-γ, lipoprotein lipase (LPL), and FABP4 mRNA. As expected, ADM-treated fibroblasts displayed a reduction on adiponectin expression. Next, we emphasized the photoprotective effects of adiponectin against UVA-induced damage in Hs68 fibroblasts. UVA radiation can downregulate cell adhesion strength and elastic modulus of Hs68 fibroblasts. Moreover, UVA radiation could induce the mRNA expressions of epidermal growth factor receptor (EGFR), adiponectin receptor 1 (AdipoR1), matrix metalloproteinase-1 (MMP-1), MMP-3, and cyclooxygenase-2 (COX-2), but downregulate the mRNA expressions of type I and type III collagen. On the other hand, post-treatment of adiponectin can partially overcome UVA-induced reduction in the cell adhesion strength of Hs68 fibroblasts through the activation of AdipoR1 and the suppression of EGF-R. In addition, post-treatment of adiponectin indicated the increase of type III collagen and elastin mRNA expression and the decrease of MMP-1 and MMP-3 mRNA expression, but a limited degree of recovery of elastic modulus on UVA-irradiated Hs68 fibroblasts. Overall, these results suggest that dermal lipogenesis may inhibit the expression of adiponectin while exogenous adiponectin administration prevents against UVA-induced dermal matrix degradation in Hs68 fibroblasts. PMID:27428951

  8. Dermal Lipogenesis Inhibits Adiponectin Production in Human Dermal Fibroblasts while Exogenous Adiponectin Administration Prevents against UVA-Induced Dermal Matrix Degradation in Human Skin.

    PubMed

    Fang, Chien-Liang; Huang, Ling-Hung; Tsai, Hung-Yueh; Chang, Hsin-I

    2016-07-14

    Adiponectin is one of the most abundant adipokines from the subcutaneous fat, and regulates multiple activities through endocrine, paracrine, or autocrine mechanisms. However, its expression in adipogenic induced fibroblasts, and the potential role in photoaging has not been determined. Here, human dermal fibroblasts, Hs68, were presented as a cell model of dermal lipogenesis through stimulation of adipogenic differentiation medium (ADM). Similar to other studies in murine pre-adipocyte models (i.e., 3T3-L1), Hs68 fibroblasts showed a tendency to lipogenesis based on lipid accumulation, triglyceride formation, and the expressions of PPAR-γ, lipoprotein lipase (LPL), and FABP4 mRNA. As expected, ADM-treated fibroblasts displayed a reduction on adiponectin expression. Next, we emphasized the photoprotective effects of adiponectin against UVA-induced damage in Hs68 fibroblasts. UVA radiation can downregulate cell adhesion strength and elastic modulus of Hs68 fibroblasts. Moreover, UVA radiation could induce the mRNA expressions of epidermal growth factor receptor (EGFR), adiponectin receptor 1 (AdipoR1), matrix metalloproteinase-1 (MMP-1), MMP-3, and cyclooxygenase-2 (COX-2), but downregulate the mRNA expressions of type I and type III collagen. On the other hand, post-treatment of adiponectin can partially overcome UVA-induced reduction in the cell adhesion strength of Hs68 fibroblasts through the activation of AdipoR1 and the suppression of EGF-R. In addition, post-treatment of adiponectin indicated the increase of type III collagen and elastin mRNA expression and the decrease of MMP-1 and MMP-3 mRNA expression, but a limited degree of recovery of elastic modulus on UVA-irradiated Hs68 fibroblasts. Overall, these results suggest that dermal lipogenesis may inhibit the expression of adiponectin while exogenous adiponectin administration prevents against UVA-induced dermal matrix degradation in Hs68 fibroblasts.

  9. Co-administration of the flavanol (−)-epicatechin with doxycycline synergistically reduces infarct size in a model of ischemia reperfusion injury by inhibition of mitochondrial swelling

    PubMed Central

    Ortiz-Vilchis, Pilar; Yamazaki, Katrina Go; Rubio-Gayosso, Ivan; Ramirez-Sanchez, Israel; Calzada, Claudia; Romero-Perez, Diego; Ortiz, Alicia; Meaney, Eduardo; Taub, Pam; Villarreal, Francisco; Ceballos, Guillermo

    2016-01-01

    (−)-Epicatechin (EPI) is cardioprotective in the setting of ischemia/reperfusion (IR) injury and doxycycline (DOX) is known to preserve cardiac structure/function after myocardial infarction (MI). The main objective of this study was to examine the effects of EPI and DOX co-administration on MI size after IR injury and to determine if cardioprotection may involve the mitigation of mitochondrial swelling. For this purpose, a rat model of IR was used. Animals were subjected to a temporary 45 min occlusion of the left anterior descending coronary artery. Treatment consisted of a single or double dose of EPI (10 mg/kg) combined with DOX (5 mg/kg). The first dose was given 15 min prior to reperfusion and the second 12 h post-MI. The effects of EPI +/− DOX on mitochondrial swelling (i.e. mPTP opening) were determined using isolated mitochondria exposed to calcium overload and data examined using isobolographic analysis. To ascertain for the specificity of EPI effects on mitochondrial swelling other flavonoids were also evaluated. Single dose treatment reduced MI size by ~46% at 48 h and 44% at three weeks. Double dosing evidenced a synergistic, 82% reduction at 3 weeks. EPI plus DOX also inhibited mitochondrial swelling in a synergic manner thus, possibly accounting for the cardioprotective effects whereas limited efficacy was observed with the other flavonoids. Given the apparent lack of toxicity in humans, the combination of EPI and DOX may have clinical potential for the treatment of myocardial IR injury. PMID:25281837

  10. Potential triple helix-mediated inhibition of IGF-I gene expression significantly reduces tumorigenicity of glioblastoma in an animal model.

    PubMed

    Shevelev, A; Burfeind, P; Schulze, E; Rininsland, F; Johnson, T R; Trojan, J; Chernicky, C L; Hélène, C; Ilan, J; Ilan, J

    1997-01-01

    Oligonucleotide-directed triple helix formation is a powerful approach to block transcription of specific genes. Although the oligonucleotide triplex approach is efficient for inhibiting gene expression in cultured cells, suppression is transient. We developed an approach which inhibits insulin-like growth factor-I (IGF-I) expression following stable transfection of C6 rat glioblastoma cells with a plasmid from which an RNA is transcribed that codes for the third strand of a potential triple helix. We tested the ability of this expression vector to inhibit IGF-I gene expression in vitro as well as tumorigenesis in an animal. A dramatic reduction of IGF-I RNA and protein levels in cultured cells occurred following transfection of rat C6 cells with a eukaryotic expression plasmid encoding the oligopurine variant of the triple helix but not the oligopyrimidine or a control sequence. The cells transfected with the oligopurine variant displayed morphological changes, upregulation of major histocompatibility complex I, and increased expression of protease nexin I. Dramatic inhibition of tumor growth occurred in nude mice following injection of transfected C6 cells. To our knowledge, this is the first example of tumor growth inhibition in an animal model employing a triple helix approach.

  11. The inhibition of mitochondrial cytochrome oxidase by the gases carbon monoxide, nitric oxide, hydrogen cyanide and hydrogen sulfide: chemical mechanism and physiological significance.

    PubMed

    Cooper, Chris E; Brown, Guy C

    2008-10-01

    The four gases, nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H(2)S) and hydrogen cyanide (HCN) all readily inhibit oxygen consumption by mitochondrial cytochrome oxidase. This inhibition is responsible for much of their toxicity when they are applied externally to the body. However, recently these gases have all been implicated, to greater or lesser extents, in normal cellular signalling events. In this review we analyse the chemistry of this inhibition, comparing and contrasting mechanism and discussing physiological consequences. The inhibition by NO and CO is dependent on oxygen concentration, but that of HCN and H(2)S is not. NO and H(2)S are readily metabolised by oxidative processes within cytochrome oxidase. In these cases the enzyme may act as a physiological detoxifier of these gases. CO oxidation is much slower and unlikely to be as physiologically important. The evidence for normal physiological levels of these gases interacting with cytochrome oxidase is equivocal, in part because there is little robust data about their steady state concentrations. A reasonable case can be made for NO, and perhaps CO and H(2)S, inhibiting cytochrome oxidase in vivo, but endogenous levels of HCN seem unlikely to be high enough.

  12. Repeated administration of Yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT)2A receptors in the prefrontal cortex.

    PubMed

    Egashira, Nobuaki; Iwasaki, Katsunori; Ishibashi, Ayumi; Hayakawa, Kazuhide; Okuno, Ryoko; Abe, Moe; Uchida, Naoki; Mishima, Kenichi; Takasaki, Kotaro; Nishimura, Ryoji; Oishi, Ryozo; Fujiwara, Michihiro

    2008-08-01

    Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.

  13. Targeting CXCR1/2 Significantly Reduces Breast Cancer Stem Cell Activity and Increases the Efficacy of Inhibiting HER2 via HER2-dependent and -independent Mechanisms

    PubMed Central

    Singh, Jagdeep K.; Farnie, Gillian; Bundred, Nigel J.; Simões, Bruno M; Shergill, Amrita; Landberg, Göran; Howell, Sacha; Clarke, Robert B.

    2012-01-01

    Purpose Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are predicted to be responsible for tumour initiation, maintenance and metastases. Interleukin-8 (IL-8) is upregulated in breast cancer and associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy. Experimental design CSC activity of metastatic and invasive human breast cancers (n=19) was assessed ex vivo using the mammosphere colony forming assay. Results Metastatic fluid IL-8 level correlated directly with mammosphere formation (r=0.652; P<0.05; n=10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n=17). IL-8 induced activation of EGFR/HER2 and downstream signalling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, PI3K or MEK. Furthermore, lapatinib inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers. Conclusions These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and demonstrate that IL-8/CXCR1/2 signalling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients. PMID:23149820

  14. The effects of p38 MAPK inhibition combined with G-CSF administration on the hematoimmune system in mice with irradiation injury.

    PubMed

    Li, Deguan; Wang, Yueying; Wu, Hongying; Lu, Lu; Wang, Xiaochun; Zhang, Junling; Zhang, Heng; Fan, Saijun; Fan, Feiyue; Zhou, Daohong; Meng, Aimin

    2013-01-01

    The acute and residual (or long-term) bone marrow (BM) injury induced by ionizing radiation (IR) is a major clinic concern for patients receiving conventional radiotherapy and victims accidentally exposed to a moderate-to-high dose of IR. In this study, we investigated the effects of the treatment with the p38 inhibitor SB203580 (SB) and/or granulocyte colony-stimulating factor (G-CSF) on the hematoimmune damage induced by IR in a mouse model. Specifically, C57BL/6 mice were exposed to a sublethal dose (6 Gy) of total body irradiation (TBI) and then treated with vehicle, G-CSF, SB, and G-CSF plus SB. G-CSF (1 µg/mouse) was administrated to mice by intraperitoneal (ip) injection twice a day for six successive days; SB (15 mg/kg) by ip injection every other day for 10 days. It was found that the treatment with SB and/or G-CSF significantly enhanced the recovery of various peripheral blood cell counts and the number of BM mononuclear cells 10 and 30 days after the mice were exposed to TBI compared with vehicle treatment. Moreover, SB and/or G-CSF treatment also increased the clonogenic function of BM hematopoietic progenitor cells (HPCs) and the frequency of BM lineage -Sca1+c-kit+ cells (LSK cells) and short-term and long term hematopoietic stem cells (HSCs) 30 days after TBI, in comparison with vehicle treated controls. However, the recovery of peripheral blood B cells and CD4+ and CD8+ T cells was not significantly affected by SB and/or G-CSF treatment. These results suggest that the treatment with SB and/or G-CSF can reduce IR-induced BM injury probably in part via promoting HSC and HPC regeneration.

  15. Differences between nicotine-abstinent smokers and non-smokers in terms of visuospatial attention and inhibition before and after single-blind nicotine administration.

    PubMed

    Logemann, H N A; Böcker, K B E; Deschamps, P K H; Kemner, C; Kenemans, J L

    2014-09-26

    The cholinergic system is implicated in visuospatial attention and inhibition, however the exact role is still unclear. Two key mechanisms in visuospatial attention are bias and disengagement. Bias refers to neuronal signals that enhance the sensitivity of the sensory cortex, disengagement is the decoupling of attention. Previous studies suggest that nicotine affects disengagement and (related) inhibition. However the exact relation is still unknown. Furthermore, nicotine-abstinence in 'healthy' smokers may resemble some anomalies of visuospatial attention and inhibition as seen in Attention Deficit/Hyperactivity Disorder (ADHD). Smokers and non-smokers (32 male students) performed in a visuospatial cueing (VSC) task, to assess bias and disengagement, and in a stop-signal task (SST) to assess inhibition. It was expected that nicotine abstinent smokers compared to non-smokers, would show poor disengagement (indicated by an enhanced validity effect) and poor inhibitory control (indicated by an enhanced stop-signal reaction time (SSRT)). It was expected that nicotine would positively affect disengagement and inhibition: hypothesis 1 stated that this effect would be larger in smokers as opposed to non-smokers, in terms of smoking-related deficient inhibitory control. Hypothesis 2 stated the exact opposite, in terms of drug-tolerance. Results indicated no baseline differences. Nicotine enhanced inhibition more in non-smokers relative to smokers. Integrating the results, nicotine-abstinent smokers do not seem to resemble ADHD patients, and do not seem to smoke in order to self-medicate a pre-existing deficit pertaining to mechanisms of visuospatial attention and inhibition. Nicotine may affect inhibition more in non-smokers relative to smokers, consistent with a drug-tolerance account.

  16. Brief Report: Secukinumab Provides Significant and Sustained Inhibition of Joint Structural Damage in a Phase III Study of Active Psoriatic Arthritis

    PubMed Central

    Landewé, Robert B.; Mease, Philip J.; McInnes, Iain B.; Conaghan, Philip G.; Pricop, Luminita; Ligozio, Greg; Richards, Hanno B.; Mpofu, Shephard

    2016-01-01

    Objective To assess whether secukinumab treatment in patients with active psoriatic arthritis (PsA) is associated with sustained inhibition of radiographic progression. Methods In this phase III, double‐blind, placebo‐controlled study, 606 patients with PsA were randomized to receive intravenous (IV) secukinumab at a dose of 10 mg/kg (weeks 0, 2, 4) followed by subcutaneous secukinumab at a dose of 150 mg or 75 mg (the IV→150 mg and IV→75 mg groups, respectively) or placebo. Patients were stratified according to prior anti–tumor necrosis factor (anti‐TNF) exposure (71% were anti‐TNF naive). At week 16, placebo‐treated patients who had at least a 20% reduction in the tender and swollen joint counts (responders) continued to receive placebo until week 24; nonresponders were re‐randomized to receive secukinumab at a dose of 150 mg or 75 mg. The modified total Sharp/van der Heijde score (SHS) was determined at baseline, week 16 or 24, and week 52. Results In the overall population, radiographic progression was inhibited through 52 weeks; efficacy was demonstrated for both erosion and joint space narrowing scores and in patients who switched from placebo to secukinumab at week 24. Subgroup analyses showed that secukinumab reduced radiographic progression at week 24, regardless of previous anti‐TNF treatment. Among anti‐TNF–naive patients, the mean changes from baseline to week 24 in the modified total SHS were 0.05 in the pooled secukinumab group and 0.57 in the placebo group; among patients with an inadequate response or intolerance to anti‐TNF treatment, the mean changes were 0.16 and 0.58, respectively. Anti‐TNF–naive patients showed negligible progression through week 52. Inhibition of structural damage was observed through week 52 irrespective of concomitant methotrexate use. A high proportion of patients receiving secukinumab showed no progression (change in SHS of ≤ 0.5) from baseline to week 24 (82.3% of the IV→150 mg group

  17. Administrators: Nursing Home Administrator

    ERIC Educational Resources Information Center

    Kahl, Anne

    1976-01-01

    Responsibilities, skills needed, training needed, earnings, employment outlook, and sources of additional information are outlined for the administrator who holds the top management job in a nursing home. (JT)

  18. Inhibition of titanium-particle-induced inflammatory osteolysis after local administration of dopamine and suppression of osteoclastogenesis via D2-like receptor signaling pathway.

    PubMed

    Yang, Huilin; Xu, Yaozeng; Zhu, Mo; Gu, Ye; Zhang, Wen; Shao, Hongguo; Wang, Yijun; Ping, Zichuan; Hu, Xuanyang; Wang, Liangliang; Geng, Dechun

    2016-02-01

    Chronic inflammation and extensive osteoclast formation play critical roles in wear-debris-induced peri-implant osteolysis. We investigated the potential impact of dopamine on titanium-particle-induced inflammatory osteolysis in vivo and in vitro. Twenty-eight C57BL/6J mice were randomly assigned to four groups: sham control (PBS treatment), titanium (titanium/PBS treatment), low- (titanium/2 μg kg(-1) day(-1) dopamine) and high-dopamine (titanium/10 μg kg(-1) day(-1) dopamine). After 2 weeks, mouse calvariae were collected for micro-computed tomography (micro-CT) and histomorphometry analysis. Bone-marrow-derived macrophages (BMMs) were isolated to assess osteoclast differentiation. Dopamine significantly reduced titanium-particle-induced osteolysis compared with the titanium group as confirmed by micro-CT and histomorphometric data. Osteoclast numbers were 34.9% and 59.7% (both p < 0.01) lower in the low- and high-dopamine-treatment groups, respectively, than in the titanium group. Additionally, low RANKL, tumor necrosis factor-α, interleukin-1β and interleukin-6 immunochemistry staining were noted in dopamine-treatment groups. Dopamine markedly inhibited osteoclast formation, osteoclastogenesis-related gene expression and pro-inflammatory cytokine expression in BMMs in a dose-dependent manner. Moreover, the resorption area was decreased with 10(-9) M and 10(-8) M dopamine to 40.0% and 14.5% (both p < 0.01), respectively. Furthermore, the inhibitory effect of dopamine was reversed by the D2-like-receptor antagonist haloperidol but not by the D1-like-receptor antagonist SCH23390. These results suggest that dopamine therapy could be developed into an effective and safe method for osteolysis-related disease caused by chronic inflammation and excessive osteoclast formation.

  19. Significance of the methyl group on the oxazine ring of ofloxacin derivatives in the inhibition of bacterial and mammalian type II topoisomerases.

    PubMed Central

    Hoshino, K; Sato, K; Akahane, K; Yoshida, A; Hayakawa, I; Sato, M; Une, T; Osada, Y

    1991-01-01

    A study was made of the correlation between the in vitro inhibitory effects of several quinolones, including four ofloxacin derivatives, on bacterial DNA gyrase from Escherichia coli KL-16 and on topoisomerase II from fetal calf thymus. No correlation was observed between the inhibitions of DNA gyrase activity and topoisomerase II activity. On the other hand, the inhibitory effects of these quinolones against topoisomerase II were closely correlated with their inhibition of cell growth. Furthermore, among the oxazine derivatives tested, the derivative with a methyl group at position 3 in an S configuration showed the highest activity against DNA gyrase and derivatives without a methyl group on the oxazine ring were more potent against topoisomerase II than those with a methyl group. Among these derivatives, DR-3355, the S isomer of ofloxacin, showed the highest activity against DNA gyrase and low activity against topoisomerase II. These results indicate that the methyl group on the oxazine ring plays an important role in the inhibitory activities of ofloxacin derivatives for these enzymes. PMID:1850968

  20. A bis-malonic acid fullerene derivative significantly suppressed IL-33-induced IL-6 expression by inhibiting NF-κB activation.

    PubMed

    Funakoshi-Tago, Megumi; Miyagawa, Yurika; Ueda, Fumihito; Mashino, Tadahiko; Moriwaki, Yasuhiro; Tago, Kenji; Kasahara, Tadashi; Tamura, Hiroomi

    2016-11-01

    IL-33 functions as a ligand for ST2L, which is mainly expressed in immune cells, including mast cells. IL-33 is a potent inducer of pro-inflammatory cytokines, such as IL-6, and has been implicated in the pathogenesis of allergic inflammatory diseases. Therefore, IL-33 has recently been attracting attention as a new target for the treatment of inflammatory diseases. In the present study, we demonstrated that a water-soluble bis-malonic acid fullerene derivative (C60-dicyclopropane-1,1,1',1'-tetracarboxylic acid) markedly diminished the IL-33-induced expression of IL-6 in bone marrow-derived mast cells (BMMC). The bis-malonic acid fullerene derivative suppressed the canonical signaling steps required for NF-κB activation such as the degradation of IκBα and nuclear translocation of NF-κB by directly inhibiting the IL-33-induced IKK activation. Although p38 and JNK also contributed to IL-33-induced expression of IL-6, the bis-malonic acid fullerene derivative did not affect their activation. Furthermore, the bis-malonic acid fullerene derivative had no effect on the NF-κB activation pathway induced by TNFα and IL-1. These results suggest that the bis-malonic fullerene derivative has potential as a specific drug for the treatment of IL-33-induced inflammatory diseases by specifically inhibiting the NF-κB activation pathway.

  1. E-configuration structures of EPA and DHA derived from Euphausia superba and their significant inhibitive effects on growth of human cancer cell lines in vitro.

    PubMed

    Zheng, Weilong; Wang, Xudong; Cao, Wenjing; Yang, Bowen; Mu, Ying; Dong, Yuesheng; Xiu, Zhilong

    2017-02-01

    Many bioactive components such as poly-unsaturated fatty acids (e.g. EPA and DHA), phospholipids and astaxanthin are known in Antarctic krill (Euphausia superba) oil. The krill DHA and EPA are generally considered to be similar to natural ones. However, two chemical compounds which were separated from Antarctic krill oil and identified as EPA and DHA by HRESIMS and NMR acted much more effective inhibitive activities on growth of several cell lines (U937, K562, SMMC-7721, PC-3, MDA-MB-231, HL60 and MCF-7) than those from sturgeon liver and commercial fish oil. Taking MCF-7 as an example, the IC50 values of Antarctic krill EPA and DHA were 14.01 and 19.94μM,while the IC50 values of sturgeon liver and commercial fish EPA and DHA were 81.45, 73.13, 82.11 and 75.31μM, respectively. Raman spectra revealed that the Antarctic krill EPA and DHA have E-configuration structures, which were different from those in commercial fish oil. Additionally, the Antarctic krill EPA and DHA had no effects on human normal liver cell line HL7702. These results indicated that the Antarctic krill E-EPA and E-DHA had a great prospect in cancer therapy.

  2. No significant differences in the breadth of the foot-and-mouth disease serotype A vaccine induced antibody responses in cattle, using different adjuvants, mixed antigens and different routes of administration.

    PubMed

    Tekleghiorghis, Tesfaalem; Weerdmeester, Klaas; van Hemert-Kluitenberg, Froukje; Moormann, Rob J M; Dekker, Aldo

    2014-09-15

    Inactivated whole virus foot-and-mouth disease (FMD) vaccines are used worldwide for protection against FMD, but not all vaccines induce protection against all genetic variants of the same FMD virus serotype. The aim of this study is to investigate whether the "breadth" of the antibody response against different strains of the same FMD virus serotype in cattle could be improved by using a different adjuvant, a mix of antigens and/or different routes of administration. To this end, six groups of five cattle were vaccinated with different FMD virus serotype A strain vaccines formulated with Montanide ISA 206 VG adjuvant. Antibody responses for homologous and heterologous cross-reactivity against a panel of 10 different FMD virus serotype A strains were tested by a liquid-phase blocking ELISA. Results of cattle vaccinated with ISA 206 VG adjuvanted vaccine were compared with results obtained in a previous study using aluminium hydroxide-saponin adjuvant. No significant effect of adjuvant on the breadth of the antibody response was observed, neither for mixing of antigens nor for the route of administration (subcutaneous vs. intradermal). Comparison of antigen payload, however, increased both homologous and heterologous titres; a 10-fold higher antigen dose resulted in approximately four times higher titres against all tested strains. Our study shows that breadth of the antibody response depends mainly on the vaccine strain; we therefore propose that, for vaccine preparation, only FMD virus strains are selected that, among other important characteristics, will induce a wide antibody response to different field strains.

  3. Prolonged Oral Administration of a Pan-Retinoic Acid Receptor Antagonist Inhibits Spermatogenesis in Mice With a Rapid Recovery and Changes in the Expression of Influx and Efflux Transporters.

    PubMed

    Chung, Sanny S W; Wang, Xiangyuan; Wolgemuth, Debra J

    2016-04-01

    We have previously shown that oral administration of a pan-retinoic acid receptor antagonist in mice daily at 2.5 mg/kg for 4 weeks reversibly inhibited spermatogenesis, with no detectable side effects. To elucidate the lowest dose and the longest dosing regimen that inhibits spermatogenesis but results in complete restoration of fertility upon cessation of administration of the drug, we examined the effects of daily doses as low as 1.0 mg/kg with dosing periods of 4, 8, and 16 weeks. We observed 100% sterility in all regimens, with restoration of fertility upon cessation of the drug treatment even for as long as 16 weeks. There was no change in testosterone levels in these males and the progeny examined from 2 of the recovered males were healthy and fertile, with normal testicular weight and testicular histology. Strikingly, a more rapid recovery, as assessed by mating studies, was observed at the lower dose and longer dosing periods. Insight into possible mechanisms underlying this rapid recovery was obtained at 2 levels. First, histological examination revealed that spermatogenesis was not as severely disrupted at the lower dose and with the longer treatment regimens. Second, gene expression analysis revealed that the more rapid recovery may involve the interplay of ATP-binding cassette efflux and solute carrier influx transporters in the testes.

  4. Inhibition of Carrageenan-Induced Acute Inflammation in Mice by Oral Administration of Anthocyanin Mixture from Wild Mulberry and Cyanidin-3-Glucoside

    PubMed Central

    Hassimotto, Neuza Mariko Aymoto; Moreira, Vanessa; do Nascimento, Neide Galvão; Souto, Pollyana Cristina Maggio de Castro; Teixeira, Catarina; Lajolo, Franco Maria

    2013-01-01

    Anthocyanins are flavonoids which demonstrated biological activities in in vivo and in vitro models. Here in the anti-inflammatory properties of an anthocyanin-enriched fraction (AF) extracted from wild mulberry and the cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, were studied in two acute inflammation experimental models, in the peritonitis and in the paw oedema assays, both of which were induced by carrageenan (cg) in mice. In each trial, AF and C3G (4 mg/100 g/animal) were orally administered in two distinct protocols: 30 min before and 1 h after cg stimulus. The administration of both AF and C3G suppresses the paw oedema in both administration times (P < 0.05). In the peritonitis, AF and C3G reduced the polymorphonuclear leukocytes (PMN) influx in the peritoneal exudates when administered 1 h after cg injection. AF was more efficient reducing the PMN when administered 30 min before cg. Both AF and C3G were found to suppress mRNA as well as protein levels of COX-2 upregulated by cg in both protocols, but the inhibitory effect on PGE2 production in the peritoneal exudates was observed when administered 30 min before cg (P < 0.05). Our findings suggest that AF and C3G minimize acute inflammation and they present positive contributions as dietary supplements. PMID:23484081

  5. Acute administration of alprazolam, a benzodiazepine activating GABA receptors, inhibits cortisol secretion in patients with subclinical but not overt Cushing's syndrome.

    PubMed

    Giordano, Roberta; Berardelli, Rita; Karamouzis, Ioannis; D'Angelo, Valentina; Picu, Andreea; Zichi, Clizia; Fussotto, Beatrice; Manzo, Maria; Mengozzi, Giulio; Ghigo, Ezio; Arvat, Emanuela

    2013-09-01

    The purpose of this study is to verify whether acute pre-treatment with alprazolam (ALP), a benzodiazepine that inhibits HPA secretion in normal subjects, could better characterize patients with subclinical Cushing's syndrome (SCS) than the 1-mg dexamethasone test (DST). In 22 patients with SCS, 10 with overt Cushing's syndrome (CS), 11 with non-functioning adrenal incidentalomas (NF) and 14 normal subjects (NS) we studied the effect of ALP (1 mg, p.o. at 2300 hours) on cortisol levels after 1-mg DST. Cortisol levels (mean ± SEM) after DST were lower (P = 0.012) in SCS (3.9 ± 0.3 μg/dl) than in overt CS (10.4 ± 1.9 μg/dl), while they were higher (P = 0.0005) than in NF (1.1 ± 0.1 μg/dl) and NS (1.5 ± 0.1 μg/dl). After ALP pre-treatment, cortisol levels further decreased (P = 0.004) in SCS (3.0 ± 0.3 μg/dl), but neither in CS (9.3 ± 1.3 μg/dl) nor in NF (1.3 ± 0.1 μg/dl) and in NS (1.3 ± 0.1 μg/dl). In SCS, cortisol levels after ALP + 1-mg DST persisted lower (P = 0.0005) than those in CS, but higher (P = 0.0005) than those in NF and NS. Considering individual cases, ALP pre-treatment reduced cortisol levels < 3 and < 1.8 μg/dl in 50 and 23 % of SCS patients, respectively. ALP amplifies the cortisol inhibition exerted by 1-mg DST in patients with SCS but not in those with CS. The clinical usefulness of ALP to increase the sensitivity of 1-mg DST to identify true autonomous cortisol release in patients with adrenal incidentalomas as well as to predict different clinical outcomes remains to be clarified.

  6. Bacterial Ammonia Causes Significant Plant Growth Inhibition

    PubMed Central

    Weise, Teresa; Kai, Marco; Piechulla, Birgit

    2013-01-01

    Many and complex plant-bacteria inter-relationships are found in the rhizosphere, since plants release a variety of photosynthetic exudates from their roots and rhizobacteria produce multifaceted specialized compounds including rich mixtures of volatiles, e.g., the bouquet of Serratia odorifera 4Rx13 is composed of up to 100 volatile organic and inorganic compounds. Here we show that when growing on peptone-rich nutrient medium S. odorifera 4Rx13 and six other rhizobacteria emit high levels of ammonia, which during co-cultivation in compartmented Petri dishes caused alkalization of the neighboring plant medium and subsequently reduced the growth of A. thaliana. It is argued that in nature high-protein resource degradations (carcasses, whey, manure and compost) are also accompanied by bacterial ammonia emission which alters the pH of the rhizosphere and thereby influences organismal diversity and plant-microbe interactions. Consequently, bacterial ammonia emission may be more relevant for plant colonization and growth development than previously thought. PMID:23691060

  7. Oxidative activation of acylguanidine prodrugs: intestinal presystemic activation in rats limits absorption and can be inhibited by co-administration of ketoconazole.

    PubMed

    Humphreys, W G; Obermeier, M T; Chong, S; Kimball, S D; Das, J; Chen, P; Moquin, R; Han, W-C; Gedamke, R; White, R E; Morrison, R A

    2003-01-01

    1. The disposition of acyl prodrugs was studied to improve the delivery of a guanidine-containing parent compound with poor membrane permeability and poor absorption. 2. The prodrugs were evaluated in vitro and in vivo for conversion to drug. Prodrugs were evaluated for hydrolytic or oxidative bioactivation in intestinal homogenate and rat liver S9 or microsomes. The disposition of the prodrugs in vivo was monitored in bile duct-cannulated rats. 3. Compounds with n-alkylacyl groups were efficiently bioactivated, but were hydrolysed before absorption. 4. Hydrolytic bioactivation could be blocked in vitro by branching in the alkyl chain. These compounds showed modest improvements in absorption, despite favourable permeability. Experiments with liver microsomes demonstrated efficient NADPH-dependent oxidative bioactivation, which was proposed to occur through a CYP-mediated side chain oxidation followed by cyclization and release of parent compound. Ketoconazole co-administration yielded approximately a twofold increase in absorption. 5. The hydrolytically stable prodrugs were successful in increasing absorption of parent drug and were efficiently bioactivated, but they did not yield increased systemic levels of drug.

  8. Pharmacological administration of granulocyte/macrophage-colony-stimulating factor is of significant importance for the induction of a strong humoral and cellular response in patients immunized with recombinant carcinoembryonic antigen.

    PubMed

    Samanci, A; Yi, Q; Fagerberg, J; Strigård, K; Smith, G; Rudén, U; Wahren, B; Mellstedt, H

    1998-11-01

    Eighteen colorectal carcinoma patients without macroscopic disease after surgery were immunized using recombinant (r) human (h) carcinoembryonic antigen (CEA) with (n=9) or without (n=9) the addition of soluble granulocyte/macrophage-colony-stimulating factor (GM-CSF). The dose of rhCEA per immunization was 100 microg (n=6), 316 microg (n=6) or 1000 microg (n=6). rhCEA was given s.c. on day 1 and 80 microg/day of GM-CSF s.c. on days 1-4. The schedule was repeated six times during a period of 9 months. All patients in the GM-CSF group developed a strong rhCEA-dose-dependent IgG antibody response while only one-third of the non-GM-CSF patients mounted a weak antibody response. All patients (9/9) in the GM-CSF group developed a strong rhCEA-specific proliferative T cell response as well as type I T cells (interferon gamma secretion). In 45% of the patients also a weak type II T cell response (interleukin-4 secretion) was evoked. Both MHC-class-I- and -II restricted rhCEA-specific T cells were noted. A specific cellular response (proliferation and/or cytokine secretion) against native hCEA could be found in 8/9 patients in the GM-CSF group, although at a significantly lower level than against rhCEA. In the non-GM-CSF group a weak rhCEA-specific T cell response was induced. Three patients had a proliferative response, 4 patients type I T cells and 6 patients type II T cells. No signs of autoimmune reactions were noted. Local pharmacological administration of GM-CSF seemed to be a prerequisite for the induction of a strong immunity against baculovirus-produced hCEA protein. However, the cellular response against native CEA was of a significantly lower magnitude.

  9. Administrative Synergy

    ERIC Educational Resources Information Center

    Hewitt, Kimberly Kappler; Weckstein, Daniel K.

    2012-01-01

    One of the biggest obstacles to overcome in creating and sustaining an administrative professional learning community (PLC) is time. Administrators are constantly deluged by the tyranny of the urgent. It is a Herculean task to carve out time for PLCs, but it is imperative to do so. In this article, the authors describe how an administrative PLC…

  10. Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study

    PubMed Central

    Duijkers, Ingrid J.M.; Klipping, Christine; Zimmerman, Yvette; Appels, Nicole; Jost, Maud; Maillard, Catherine; Mawet, Marie; Foidart, Jean-Michel; Coelingh Bennink, Herjan J. T.

    2015-01-01

    Abstract Objectives The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary–ovarian axis and ovulation in healthy premenopausal women. Methods This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 μg levonorgestrel; or 20 μg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary–ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication. Results A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe. Conclusions Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day. Chinese Abstract 摘要 目的 这项研究的目的是评估不同剂量的雌四醇联合两种孕激素中的其中一种对垂体-卵巢轴以及健康的绝经前妇女的排卵方面的抑制疗效。 方法 这是一个在18到35岁的健康女性中进行的开放的、平行的,关于II期药物剂量探索的初步研究,这些女

  11. Oral administration of fermented wild ginseng ameliorates DSS-induced acute colitis by inhibiting NF-κB signaling and protects intestinal epithelial barrier

    PubMed Central

    Seong, Myeong A; Woo, Jong Kyu; Kang, Ju-Hee; Jang, Yeong Su; Choi, Seungho; Jang, Young Saeng; Lee, Taek Hwan; Jung, Kyung Hoon; Kang, Dong Kyu; Hurh, Byung Seok; Kim, Dae Eung; Kim, Sun Yeou; Oh, Seung Hyun

    2015-01-01

    Ginseng has been widely used for therapeutic and preventive purposes for thousands of years. However, orally administered ginseng has very low bioavailability and absorption in the intestine. Therefore, fermented ginseng was developed to enhance the beneficial effects of ginseng in the intestine. In this study, we investigated the molecular mechanisms underlying the anti-inflammatory activity of fermented wild ginseng (FWG). We found that FWG significantly alleviated the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis mouse model, and decreased expression level of pro-inflammatory cytokines in colonic tissue. Moreover, we observed that FWG suppressed the infiltration of macrophages in DSS-induced colitis. FWG also attenuated the transcriptional activity of nuclear factor-κB (NF-κB) by reducing the translocation of NF-κB into the nucleus. Our data indicate that FWG contains anti-inflammatory activity via NF-κB inactivation and could be useful for treating colitis. [BMB Reports 2015; 48(7): 419-425] PMID:25936779

  12. Melatonin administration to wild-type mice and non-treated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis.

    PubMed

    Rahim, Ibtissem; Djerdjouri, Bahia; Sayed, Ramy K; Fernández-Ortiz, Marisol; Fernández-Gil, Beatriz; Hidalgo-Gutiérrez, Agustín; López, Luis C; Escames, Germaine; Reiter, Russel J; Acuna-Castroviejo, Dario

    2017-03-31

    The NLRP3 inflammasome is involved in the innate immune response during inflammation. Moreover, melatonin blunts the NF-κB/NLRP3 connection during sepsis. Thus, we compared the roles of the NLRP3 inflammasome and/or melatonin treatment in the septic response of wild-type and NLRP3(-/-) mice. Mouse myocardial tissue was used for this purpose. The nuclear turnover of NF-κB was enhanced during sepsis, with an increase in TNFα, iNOS, and pro-IL-1β. The lack of inflammasome in NLRP3(-/-) mice significantly reduced that response and blunted IL-1β maturation due to the lack of caspase-1. Clock and Bmal1 did not change in both mouse strains, enhancing Chrono expression in mutants. RORα, which positively regulates Bmal1 was enhanced at a similar extend in both mouse strains, whereas the expression of the Bmal1 repressor, Rev-NDASH-Erbα increased in WT but was depressed in NLRP3(-/-) mice. Nampt, transcriptionally controlled by Bmal1, increased in WT mice together with Sirt1, whereas they remained unchanged in NLRP3(-/-) mice. Melatonin treatment reduced the septic response in a comparable manner as did the lack of NLRP3, but unlike the latter, it normalized the clock genes turnover through the induction of RORα and repression of Rev-NDASH-Erbα and Per2, leading to enhanced Nampt and Sirt1. The lack of NLRP3 inflammasome converts sepsis to a moderate inflammatory disease, and identifies NLRP3 as a main target for the treatment of sepsis. The efficacy of melatonin in counteracting the NLRP3 inflammasome activation further confirms the indoleamine as a useful therapeutic drug against this serious condition. This article is protected by copyright. All rights reserved.

  13. IGF-I administration advances the decrease in hypersensitivity to oestradiol negative feedback inhibition of serum LH in adolescent female rhesus monkeys.

    PubMed

    Wilson, M E

    1995-04-01

    feedback were evaluated. Treatment with IGF-I had no effect on the initial increases in serum LH occurring in the absence of oestradiol. In contrast, the decrease in hypersensitivity to the negative feedback effects of the low oestradiol dose was significantly accelerated in IGF-I-treated females, as the interval from the initiation of treatment to the point at which serum LH was no longer suppressed was shorter in IGF-I-treated (4.4 +/- 0.7 months; mean +/- S.E.M.) compared with control group females (8.4 +/- 1.9 months).(ABSTRACT TRUNCATED AT 400 WORDS)

  14. Administrators Say Funding Inhibits Use of Databases.

    ERIC Educational Resources Information Center

    Gerhard, Michael E.

    1990-01-01

    Surveys journalism and mass communication department heads to address questions related to the use of online databases in journalism higher education, database policy, resources used in providing online services, and satisfaction with database service. Reports that electronic information retrieval is just beginning to penetrate journalism at the…

  15. Administrative Ecology

    ERIC Educational Resources Information Center

    McGarity, Augustus C., III; Maulding, Wanda

    2007-01-01

    This article discusses how all four facets of administrative ecology help dispel the claims about the "impossibility" of the superintendency. These are personal ecology, professional ecology, organizational ecology, and community ecology. Using today's superintendency as an administrative platform, current literature describes a preponderance of…

  16. Engineering Administration.

    ERIC Educational Resources Information Center

    Naval Personnel Program Support Activity, Washington, DC.

    This book is intended to acquaint naval engineering officers with their duties in the engineering department. Standard shipboard organizations are analyzed in connection with personnel assignments, division operations, and watch systems. Detailed descriptions are included for the administration of directives, ship's bills, damage control, training…

  17. Administrative IT

    ERIC Educational Resources Information Center

    Grayson, Katherine, Ed.

    2006-01-01

    When it comes to Administrative IT solutions and processes, best practices range across the spectrum. Enterprise resource planning (ERP), student information systems (SIS), and tech support are prominent and continuing areas of focus. But widespread change can also be accomplished via the implementation of campuswide document imaging and sharing,…

  18. Database Administrator

    ERIC Educational Resources Information Center

    Moore, Pam

    2010-01-01

    The Internet and electronic commerce (e-commerce) generate lots of data. Data must be stored, organized, and managed. Database administrators, or DBAs, work with database software to find ways to do this. They identify user needs, set up computer databases, and test systems. They ensure that systems perform as they should and add people to the…

  19. The Kinetics of Intramolecular Distribution of 15N in Uric Acid after Administration of [15N]Glycine A REAPPRAISAL OF THE SIGNIFICANCE OF PREFERENTIAL LABELING OF N-(3 + 9) OF URIC ACID IN PRIMARY GOUT

    PubMed Central

    Sperling, Oded; Wyngaarden, James B.; Starmer, C. Frank

    1973-01-01

    The concept of an abnormality of glutamine metabolism in primary gout was first proposed on the basis of isotope data: when [15N]glycine was administered to gouty subjects, there was disproportionately great enrichment of N-(3 + 9) of uric acid, which derive from the amide-N of glutamine. An unduly high concentration of 15N in glutamine was postulated, and attributed to a hypothetical defect in catabolism of glutamine. Excess glutamine was proposed as the driving force of uric acid overproduction. We have reexamined this proposition in four gouty subjects: one mild overproducer of uric acid with “idiopathic gout,” one marked overproducer with high-grade but “partial” hypoxanthine-guanine phosphoribosyl-transferase deficiency, and two extraordinary overproducers with superactive phosphoribosylpyrophosphate synthetases. In the last three, the driving force of excessive purine biosynthesis is a known surplus of α-5-phosphoribosyl-1-pyrophosphate. Disproportionately high labeling of N-(3 + 9) was present in all four gouty subjects, most marked in the most flamboyant overproducers. The precursor glucine pool was sampled by periodic administration of benzoic acid and isolation of urinary hippuric acid. Similarly, the precursor glutamine pool was sampled by periodic administration of phenylacetic acid and isolation of the amide-N of urinary phenylacetylglutamine. The time course of 15N enrichment of hippurate differed from that of the amide-N of glutamine. Whereas initial enrichment values of hippurate were very high, those of glutamine-amide-N were low, increasing to a maximum at about 3 h, and then declining less rapidly than those of hippurate. However, enrichment values of hippurate and of phenacetyl glutamine were normal in all of the gouty subjects studied. Thus, preferential enrichment of N-(3 + 9) in gouty overproducers given [15N]glycine does not necessarily reflect a specific abnormality of glutamine metabolism, but rather appears to be a kinetic

  20. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: L-glutamine inhibits the generation of L-arginine by cultured endothelial cells

    SciTech Connect

    Sessa, W.C.; Hecker, M.; Mitchell, J.A. Vane, J.R. )

    1990-11-01

    The mechanism by which L-glutamine (L-Gln) inhibits the release of endothelium-derived factor from bovine aortic cultured endothelial cells was investigated. The intracellular concentration of L-arginine (L-Arg) in Arg-depleted endothelial cells was inversely related to the level of L-Gln. Removal of L-Gln from the culture medium (usually containing L-Gln at 2 mM) abolished the inhibitory effect of the culture medium on L-Arg generation. L-Gln (0.2 and 2 mM) but not D-Gln inhibited the generation of L-Arg by both Arg-depleted and nondepleted endothelial cells. L-Gln did not interfere with the uptake of L-Arg or the metabolism of L-Arg-L-Phe to L-Arg but inhibited the formation of L-Arg from L-citrulline (L-Cit), L-Cit-L-Phe, and N{sup G}-monomethyl-L-arginine. L-Gln also inhibited the conversion of L-({sup 14}C)Cit to L-({sup 14}C)Arg by Arg-depleted endothelial cells. However, L-Gln did not inhibit the conversion of L-argininosuccinic acid to L-Arg by endothelial cell homogenates. Thus, L-Gln interferes with the conversion of L-Cit to L-Arg probably by acting on argininosuccinate synthetase rather than argininosuccinate lyase. L-Gln also inhibited the generation of L-Arg by the monocyte-macrophage cell line J774 but had no effect on the conversion of L-Cit to L-Arg by these cells. As the release of endothelium-derived relaxing factor from cultured and non-cultured endothelial cells is limited by the availability of L-Arg, endogenous L-Gln may play a regulatory role in the biosynthesis of endothelium-derived relaxing factor.

  1. A Change of Administration: A Significant Organizational Life Event.

    ERIC Educational Resources Information Center

    Stine, Deborah E.

    The case study presented in this paper illustrates how the succession process for principals is similar to that described by Gabarro in his study of corporate succession. Leader succession involves five major stages: (1) taking hold; (2) immersion; (3) reshaping; (4) consolidation; and (5) refinement. Success most frequently occurs in conjunction…

  2. The number and distances of positive charges of polyamine side chains in a series of perylene diimides significantly influence their ability to induce G-quadruplex structures and inhibit human telomerase.

    PubMed

    Franceschin, Marco; Lombardo, Caterina Maria; Pascucci, Emanuela; D'Ambrosio, Danilo; Micheli, Emanuela; Bianco, Armandodoriano; Ortaggi, Giancarlo; Savino, Maria

    2008-03-01

    We have synthesized eight polyamine perylene diimides to conjugate the efficiency of perylene derivatives in stabilizing G-quadruplex structures and the polyamines' biological activity, due to specific interactions with different DNA domains. Our study was carried out by investigating the ability of these derivatives to induce inter- and intramolecular G-quadruplex structures by polyacrylamide gel electrophoresis (PAGE) and to inhibit telomerase in a modified TRAP assay. The two properties appear to be satisfactorily correlated and they show that the number and distances of positive charges in the side chains dramatically influence both these features. Although our previous studies on perylene derivatives with mono-positively charged side chains indicated that self assembly in aqueous solution leads to a major efficiency, the result observed with the spermine derivative suggests that a too strong aggregation is unfavourable, because it determines a lower solubility of the compounds.

  3. Effects of taurine administration on exercise.

    PubMed

    Yatabe, Yoshihisa; Miyakawa, Shumpei; Ohmori, Hajime; Mishima, Hajime; Adachi, Takako

    2009-01-01

    Taurine concentration in rat skeletal muscles after endurance running, with and without taurine administration was studied. Taurine concentrations in skeletal muscles was significantly decreased in exercised groups without taurine administration. However, taurine administration reduced the decrease of taurine concentration in skeletal muscles in exercise. Oral administration of taurine has effect for maintaining taurine concentration in skeletal muscles in exercise. The duration of running time to exhaustion of rats, with and without taurine administration were studied. The duration of running time to exhaustion was significantly increased by taurine administration. Oral administration of taurine increases the ability of physical endurance. Rat urinary excretions of creatinine, creatine, 3-methylhistidine (3-MH) after treadmill running, with and without taurine administration were studied. Rat urinary excretions of creatinine, creatine, 3-MH after treadmill running was significantly decreased with taurine administration. Taurine administration was considered to reduce the exercise-induced muscle fatigue.

  4. Inhibition by alcohols of the localization of radioactive nitrosonornicotine in sites of tumor formation

    SciTech Connect

    Waddell, W.J.; Marlowe, C.

    1983-06-01

    Oral administration of ethanol, n-butanol, or t-butanol to mice 20 minutes before injection of carbon-14-labeled nitrosonornicotine inhibited the localization of radioactivity in bronchial and salivary duct epithelium and in the liver. Localization of radioactivity in the nasal epithelium and esophagus was not significantly reduced. These alcohols therefore may selectively inhibit tumor formation in three of the five sites where this carcinogen typically acts.

  5. [THE SPIRIT CHOLESTEROL, BIOLOGICA L ROLE AT STAGES OF PHYLOGENESIS, MECHANISMS OF INHIBITION OF SYNTHESIS OF STEROL BY STATINS, FACTORS OF PHARMACOGENOMICS AND DIAGNOSTIC SIGNIFICANCE OF CHOLESTEROL OF LIPOPROTEINS OF LOW DENSITY].

    PubMed

    Titov, V N; Kotlovskii, M Yu; Pokrovskii, A A; Kotlovskaia, O S; Osedko, A V; Titova, N M; Kotlovskii, Yu V; Digaii, A M

    2015-04-01

    The hypolipidemic effect of statins is realized by inhibition of synthesis of local pool of cholesterol spirit in endoplasmic net of hepatocytes. The cholesterol spirit covers all hydrophobic medium of triglycerides with polar mono layer of phosphatidylcholines and cholesterol spirit prior to secretion of lipoproteins of very low density into hydrophilic medium. The lesser mono layer between lipase enzyme and triglycerides substrate contains of cholesterol spirit the higher are the parameters of hydrolysis of palmitic and oleic lipoproteins of very low density. The sequence of effect of statins is as follows: blocking of synthesis in hepatocytes and decreasing of content of unesterified cholesterol spirit in blood plasma; activation of hydrolysis of triglycerides in palmitic and oleic lipoproteins of very low density; formation of ligand lipoproteins of very low density and their absorption by cells by force of apoB-100 endocytosis; decreasing in blood of content of polyenoic fatty acids, equimolar esterified by cholesterol spirit, polyethers of cholesterol spirit and decreasing of level of cholesterol spirit-lipoproteins of very low density. There is no way to eliminate aphysiological effect of disordered biological function of trophology (nutrition) on metabolism of fatty acids in population by means of pharmaceuticals intake. It is necessary to eliminate aphysiological effect of environment. To decrease rate of diseases of cardiovascular system one has to decrease in food content of saturated fatty acids and in the first instance palmitic saturated fatty acid, trans-form fatty acid, palmitoleic fatty acids up to physiological values and increase to the same degree the content of polyenoic fatty acids. The saturated fatty acids block absorption of polyenoic fatty acids by cells. The atherosclerosis is a deficiency of polyenoic fatty acids under surplus of palmitic saturated fatty acid.

  6. Dimethyl sulfoxide inhibits bioactivation of sulindac.

    PubMed

    Swanson, B N; Boppana, V K; Vlasses, P H; Rotmensch, H H; Ferguson, R K

    1983-07-01

    Sulindac, a nonsteroidal anti-inflammatory agent, is converted to a bioactive sulfide metabolite via reversible reduction of its sulfoxide moiety. To test whether DMSO can inhibit conversion of sulindac to its active form, eight healthy men received, in a randomized, crossover manner, 400 mg of sulindac, orally, either alone or 60 min after an oral dose of DMSO (30 ml, 70% solution). After the drug combination, mean plasma concentrations of the sulfide metabolite were significantly lower than in controls at 1.5, 2, 3, 4, and 8 hr after sulindac administration. The mean area under the plasma sulfide concentration-time curve for 0 to 12 hr was 30% (range 7% to 56%) lower after DMSO treatment. This study suggests that DMSO can inhibit metabolism of other sulfoxides in man and may antagonize the therapeutic efficacy of sulindac.

  7. Senior Administrators Should Have Administrative Contracts.

    ERIC Educational Resources Information Center

    Posner, Gary J.

    1987-01-01

    Recognizing that termination is viewed by the employee as the equivalent to capital punishment of a career, an administrative contract can reduce the emotional and financial entanglements that often result. Administrative contracts are described. (MLW)

  8. Xanthatin, a novel potent inhibitor of VEGFR2 signaling, inhibits angiogenesis and tumor growth in breast cancer cells.

    PubMed

    Yu, Yao; Yu, Jing; Pei, Chong Gang; Li, Yun Yan; Tu, Ping; Gao, Gui Ping; Shao, Yi

    2015-01-01

    Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer treatment. In this study, we described a novel VEGFR2 inhibitor, xanthatin, which inhibits tumor angiogenesis and growth. The biochemical profiles of xanthatin were investigated using kinase assay, migration assay, tube formation, Matrigel plug assay, western blot, immunofluorescence and human tumor xenograft model. Xanthatin significantly inhibited growth, migration and tube formation of human umbilical vascular endothelial cell as well as inhibited vascular endothelial growth factor (VEGF)-stimulated angiogenesis. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator. Moreover, xanthatin directly inhibit proliferation of breast cancer cells MDA-MB-231. Oral administration of xanthatin could markedly inhibit human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that xanthatin inhibits angiogenesis and may be a promising anticancer drug candidate.

  9. The effect of antivitamin B6 administration on gamma-aminobutyric acid metabolism in retina and electroretinogram.

    PubMed

    Mizuno, A; Kamada, Y; Kunita, M; Matsuda, M

    1980-01-01

    The effect of several antivitamin B6 on gamma-aminobutyric acid (GABA) metabolism was studied in the rat retina. The rat electroretinogram (ERG) was also recorded after administration of these drugs. Aminooxyacetic acid (AOAA) and hydrazine administration increased the GABA content and inhibited the GABA degrading enzyme, GABA transaminase in retina. In addition, there drugs elongated the peak latency of the oscillatory potential in the rat ERG. In contrast, 4-deoxypyridoxine (DOP) or isonicotinic acid hydrazide (INAH) administration decreased the GABA content and inhibited the GABA synthesizing enzyme, glutamic acid decarboxylase in retina, and administration of these drugs together with AOAA lessened the degrees of elevation of GABA content and of the elongation of the peak latency produced as compared with AOAA alone, though neither of the former drugs had a significant effect on ERG. The retinal GABA seems to play an important role in relation to the oscillatory potential of ERG.

  10. Veterans Health Administration

    MedlinePlus

    ... code here VA » Veterans Health Administration Veterans Health Administration Marine Continues to Serve by Serving Veterans David ... Read more » VA Medical Centers The Veterans Health Administration is home to the United States’ largest integrated ...

  11. Attenuation of methylphenidate-induced sensitization by co-administration of buspirone.

    PubMed

    Alam, Nausheen; Najam, Rahila; Naeem, Sadaf

    2016-03-01

    Methylphenidate, which inhibit dopamine transporter is effective in the treatment of ADHD (attention deficit hyperactivity disorder), but long term use of this drug is often associated with addiction and dependence. Locomotor sensitization development to psychostimulants like methylphenidate is an important contributor to drug abuse induced by psychostimulants. Different studies have shown that long term administration of drugs of abuse increases the effectiveness of 5-hydroxytryptamine (5-HT)-1A somatodendritic receptors. Repeated buspirone administration reduces the effectiveness of 5-HT1A somatodendritic receptors. This study was designed to determine that buspirone co-administration may reduce methylphenidate-induced sensitization. The motor activity was compared by using familiar and novel environments after long-term administration of methylphenidate, buspirone and their co-administration. Long term oral administration of methylphenidate at a dose of 2.0 mg/kg/day enhanced motor activity in home cage i.e. activity of familiar environment monitored at alternate day. Locomotor enhancing effects of methylphenidate were augmented on 13th day of drug administration suggesting sensitization induced by the drug. The sensitization effects were significant in home cage monitored on alternate day and also in an open field monitored weekly. Buspirone co-administration at a dose of 10 mg/kg/day prevented methylphenidate-induced sensitization. It is suggested that the sensitization development to methylphenidate may oppose by buspirone co-administration due to the reduction in the sensitivity of 5-HT1A somatodendritic receptors. These findings may help extend future therapeutics in ADHD.

  12. A study on the effects of inhibition of prostaglandin biosynthesis with flunixin meglumine and later administration of prostaglandin F2 alpha on the intraluminal pressure variations in the isthmus of the oviduct in unrestrained gilts.

    PubMed

    Pettersson, A; Einarsson, S; Kindahl, H

    1993-01-01

    Three gilts were each equipped with 2 ultra-miniature pressure sensors, placed at 2 different points along the same isthmus of the oviduct. Following base recordings of isthmic intraluminal pressure, the gilts were treated with 2.2 mg flunixin meglumine (FM) per kg body weight. After FM treatment, the peripheral plasma levels of 15-ketodihydro-PGF2 alpha, the major metabolite of prostaglandin F2 alpha (PGF2 alpha), decreased within 30 min. The frequency of the phasic pressure fluctuations in the isthmus of the oviduct decreased after FM treatment. Exogenous administration of PGF2 alpha increased the peripheral plasma levels of 15-ketodihydro-PGF2 alpha. When administered at a dose of 0.1 mg, PGF2 alpha produced an increase in the frequency of the phasic pressure fluctuations in the oviductal isthmus. When the PGF2 alpha dose was increased to 0.5 mg, a marked increase in the base and total pressures was seen in addition to the increase in the frequency of the phasic pressure fluctuations.

  13. Factors significantly increasing or inhibiting early stages of malignant melanoma (M.M.) and non-invasive evaluation of new treatment by ingestion and external application of optimal doses of the most effective anti-M.M. substances: haritaki, cilantro, vitamin D3, nori, EPA with DHA, & application of special (+) solar energy stored paper, which reduced the M.M. active area & asbestos rapidly.

    PubMed

    Omura, Yoshiaki; Jones, Marilyn; Duvvi, Harsha; Paluch, Kamila; Shimotsuura, Yasuhiro; Ohki, Motomu

    2013-01-01

    Sterilizing the pre-cancer skin of malignant melanoma (M.M.) with 70% Isopropyl alcohol intensified malignancy & the malignant response extended to surrounding normal looking skin, while sterilizing with 80% (vodka) or 12% (plum wine) ethyl alcohol completely inhibited M.M. in the area (both effects lasted for about 90 minutes initially). Burnt food (bread, vegetables, meat, and fish), a variety of smoked & non-smoked fish-skin, many animal's skin, pepper, Vitamin C over 75 mg, mango, pineapple, coconut, almond, sugars, Saccharine & Aspartame, garlic, onion, etc & Electromagnetic field from cellular phones worsened M.M. & induced abnormal M.M. response of surrounding skin. We found the following factors inhibit early stage of M.M. significantly: 1) Increasing normal cell telomere, by taking 500 mg Haritaki, often reached between 400-1150 ng& gradually diminished, but the M.M. response was completely inhibited until normal cell telomeres are reduced to 150 ng, which takes 6-8 hours. More than 70 mg Vitamin C, Orange Juice, & other high Vitamin C containing substances shouldn't be taken because they completely inhibit the effects of Haritaki. 2) We found Chrysotile asbestos & Tremolite asbestos (% of the Chrysotile amount) coexist. A special Cilantro tablet was used to remove asbestos & some toxic metals. 3) Vitamin D3 400 I.U. has a maximum inhibiting effect on M.M. but 800 I.U. or higher promotes malignancy. 4) Noricontaining Iodine, etc., was used. 5) EPA 180 mm with DHA 120 mg was most effectively used after metastasis to the surrounding skin was eliminated. When we combined 1 Cilantro tablet & Vitamin D3 400 I.U. withsmall Nori pieces & EPA with DHA, the effect of complete inhibition of M.M. lasted 9-11 hours. When these anti-M.M.substances (Haritaki, Vitamin D3, Cilantro, Nori, EPA. with DHA) were taken together, the effect lasted 12-14 hoursand M.M. involvement in surrounding normal-looking skin disappeared rapidly & original dark brown or black are as

  14. Paine Appointed Administrator

    NASA Technical Reports Server (NTRS)

    1969-01-01

    President Richard M. Nixon announcing the appointment of Dr. Thomas O. Paine as Administrator for the National Aeronautics and Space Administration. The ceremony was held at the White House. Paine had been serving as acting administrator. From left to right: President Richard M. Nixon NASA Administrator Dr. Thomas O. Paine Vice President Spiro T. Agnew

  15. Inhibition of sulindac metabolism by dimethyl sulfoxide in the rat.

    PubMed

    Swanson, B N; Mojaverian, P; Boppana, V K

    1983-01-01

    Dimethyl sulfoxide (DMSO) suppresses conversion of the prodrug sulindac to its bioactive sulfide metabolite (SD) by competitively inhibiting sulfoxide reductase. During continuous iv infusions of sulindac (1 mg/kg X h), plasma concentrations of SD at steady-state equilibrium were 80% lower when DMSO was infused concomitantly at 0.34 ml/kg X h, whereas sulindac plasma concentrations were not significantly affected by DMSO. Dermal application and intragastric administration of DMSO also inhibited SD accumulation in plasma. DMSO was only a weak inhibitor of SD oxidation in vitro and did not affect the rate of SD elimination in vivo. In contrast, dimethyl sulfide, a metabolite of DMSO, was a potent inhibitor of SD oxidase in vitro. These data suggest that DMSO can inhibit bioactivation and, hence, the antiinflammatory effects of sulindac.

  16. Involvement of spinal glutamate in nociceptive behavior induced by intrathecal administration of hemokinin-1 in mice.

    PubMed

    Watanabe, Chizuko; Mizoguchi, Hirokazu; Bagetta, Giacinto; Sakurada, Shinobu

    2016-03-23

    The most recently identified tachykinin, hemokinin-1, was cloned from mouse bone marrow. While several studies indicated that hemokinin-1 is involved in pain and inflammation, the physiological functions of hemokinin-1 are not fully understood. Our previous research demonstrated that the intrathecal (i.t.) administration of hemokinin-1 (0.00625-1.6 nmol) dose-dependently induced nociceptive behaviors, consisting of scratching, biting and licking in mice, which are very similar with the nociceptive behaviors induced by the i.t. administration of substance P. Low-dose (0.0125 nmol) hemokinin-1-induced nociceptive behavior was inhibited by a specific NK1 receptor antagonist; however, high-dose (0.1 nmol) hemokinin-1-induced nociceptive behavior was not affected. In the present study, we found that the nociceptive behaviors induced by hemokinin-1 (0.1 nmol) were inhibited by the i.t. co-administration of MK-801 or D-APV, which are NMDA receptor antagonists. Moreover, we measured glutamate in the extracellular fluid of the mouse spinal cord using microdialysis. The i.t. administration of hemokinin-1 produced a significant increase in glutamate in the spinal cord, which was significantly reduced by co-administration with NMDA receptor antagonists. These results suggest that hemokinin-1-induced nociceptive behaviors may be mediated by the NMDA receptor in the spinal cord.

  17. Transportation Security Administration

    MedlinePlus

    ... content Official website of the Department of Homeland Security Transportation Security Administration A - Z Index What Can I Bring? ... form Search the Site Main menu Administrator Travel Security Screening Special Procedures TSA Pre✓® Passenger Support Travel ...

  18. Administration on Aging

    MedlinePlus

    ... Federal Initiatives Career Opportunities Contact Us Administration on Aging (AoA) The Administration on Aging (AOA) is the ... themselves. Back to top Older Americans Act and Aging Network To meet the diverse needs of the ...

  19. Rehabilitation Services Administration

    MedlinePlus

    ... Contacts OSEP Reports & Resources RSA Welcome to RSA Rehabilitation Services Administration RSA Spotlight News Commissioner's Quarterly Newsletter ... The Office of Special Education and Rehabilitative Services’ Rehabilitation Services Administration is proud to announce the publication ...

  20. Administration on Aging

    MedlinePlus

    ... Administration on Aging Administration on Disabilities Center for Integrated Programs Center for Performance and Evaluation National Institute ... Project Aging Statistics Profile of Older Americans AGing Integrated Database (AGID) Census Data & Population Estimates Projected Future ...

  1. Negative allosteric modulation of nicotinic acetylcholine receptors blocks nicotine self-administration in rats.

    PubMed

    Yoshimura, Ryan F; Hogenkamp, Derk J; Li, Wen Y; Tran, Minhtam B; Belluzzi, James D; Whittemore, Edward R; Leslie, Frances M; Gee, Kelvin W

    2007-12-01

    Drugs that antagonize nicotinic acetylcholine receptors (nAChRs) can be used to inhibit nicotine-induced behavior in both humans and animals. The aim of our experiments is to establish a proof-of-principle that antagonism of nAChRs by negative allosteric modulation can alter behavior in a relevant animal model of addiction, nicotine self-administration. We have identified a novel, negative allosteric modulator of nAChRs, UCI-30002 [N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline], with selectivity for the major neuronal nAChR subtypes over muscle-type nAChRs. After systemic administration, UCI-30002 significantly reduces nicotine self-administration in rats on both fixed ratio and progressive ratio schedules of reinforcement. The minimum effective dose that significantly alters nicotine self-administration corresponds to brain concentrations of UCI-30002 that produce at least 30% inhibition of the major neuronal nAChR subtypes measured in vitro. UCI-30002 has no effect on responding for food reinforcement in rats on either type of schedule, indicating that there is no effect on general responding or natural reward. UCI-30002 represents validation of the concept that negative allosteric modulators may have significant benefits as a strategy for treating nicotine addiction and encourages the development of subtype-selective modulators.

  2. Legal and Administrative Language

    ERIC Educational Resources Information Center

    Schwarz, Hans

    1977-01-01

    A discussion of legal and administrative language, and the necessity for accurate translation of this language in the field of international relations. Topics treated are: characteristic features of legal and administrative terminology; the interpretation of it; and the technique of translating legal and administrative texts. (AMH)

  3. Women in Administration 1978.

    ERIC Educational Resources Information Center

    National Association of State Universities and Land Grant Colleges, Washington, DC. Office of Communications Services.

    In a survey by the National Association of State Universities and Land-Grant Colleges (NASULGC), women are shown to hold 2,905 of the 13,638 administrative positions reported by 106 major U.S. public universities--slightly more than 21 percent of the administrators at state and land-grant universities. The median number of women administrators at…

  4. School Business Administration.

    ERIC Educational Resources Information Center

    Jordan, K. Forbis; And Others

    This textbook reviews the principal concerns within each of 13 major responsibility areas in school business administration. The first chapter assesses the political, social, and economic context in which schools function and school administrators work. The role and function of the school business administrator within this context is addressed in…

  5. Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries.

    PubMed

    Kresty, L A; Morse, M A; Morgan, C; Carlton, P S; Lu, J; Gupta, A; Blackwood, M; Stoner, G D

    2001-08-15

    Fruit and vegetable consumption has consistently been associated with decreased risk of a number of aerodigestive tract cancers, including esophageal cancer. We have taken a "food-based" chemopreventive approach to evaluate the inhibitory potential of lyophilized black raspberries (LBRs) against N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in the F344 rat, during initiation and postinitiation phases of carcinogenesis. Anti-initiation studies included a 30-week tumorigenicity bioassay, quantification of DNA adducts, and NMBA metabolism study. Feeding 5 and 10% LBRs, for 2 weeks prior to NMBA treatment (0.25 mg/kg, weekly for 15 weeks) and throughout a 30-week bioassay, significantly reduced tumor multiplicity (39 and 49%, respectively). In a short-term bioassay, 5 and 10% LBRs inhibited formation of the promutagenic adduct O(6)-methylguanine (O(6)-meGua) by 73 and 80%, respectively, after a single dose of NMBA at 0.25 mg/kg. Feeding 5% LBRs also significantly inhibited adduct formation (64%) after NMBA administration at 0.50 mg/kg. The postinitiation inhibitory potential of berries was evaluated in a second bioassay with sacrifices at 15, 25, and 35 weeks. Administration of LBRs began after NMBA treatment (0.25 mg/kg, three times per week for 5 weeks). LBRs inhibited tumor progression as evidenced by significant reductions in the formation of preneoplastic esophageal lesions, decreased tumor incidence and multiplicity, and reduced cellular proliferation. At 25 weeks, both 5 and 10% LBRs significantly reduced tumor incidence (54 and 46%, respectively), tumor multiplicity (62 and 43%, respectively), proliferation rates, and preneoplastic lesion development. Yet, at 35 weeks, only 5% LBRs significantly reduced tumor incidence and multiplicity, proliferation indices and preneoplastic lesion formation. In conclusion, dietary administration of LBRs inhibited events associated with both the initiation and promotion/progression stages of carcinogenesis

  6. Matricaria chamomilla extract inhibits both development of morphine dependence and expression of abstinence syndrome in rats.

    PubMed

    Gomaa, Adel; Hashem, Tahia; Mohamed, Mahmoud; Ashry, Esraa

    2003-05-01

    The effect of Matricaria chamomilla (M. chamomilla) on the development of morphine dependence and expression of abstinence was investigated in rats. The frequencies of withdrawal behavioral signs (paw tremor, rearing, teeth chattering, body shakes, ptosis, diarrhea, and urination) and weight loss induced by naloxone challenge were demonstrated in morphine-dependent rats receiving M. chamomilla extract or saline. The withdrawal behavioral manifestations and weight loss were inhibited significantly by chronic co-administration of M. chamomilla extract with morphine. Administration of a single dose of M. chamomilla before the naloxone challenge in morphine-dependent animals abolished the withdrawal behavioral manifestations. The dramatic increase of plasma cAMP induced by naloxone-precipitated abstinence was prevented by chronic co-administration of M. chamomilla extract with morphine. These results suggest that M. chamomilla extract inhibits the development of morphine dependence and expression of abstinence syndrome.

  7. Effects of renin inhibition in systemic hypertension.

    PubMed

    Anderson, P W; Do, Y S; Schambelan, M; Horton, R; Boger, R S; Luther, R R; Hsueh, W A

    1990-12-01

    The effect of the direct renin inhibitor enalkiren (Abbott Laboratories) was examined in 8 healthy patients with essential hypertension. With an unrestricted sodium diet, plasma renin concentration was inhibited within 10 minutes by intravenous enalkiren and remained essentially undetectable for greater than or equal to 6 hours (11.9 +/- 4 to 1.0 +/- 0.6 ng angiotensin I/ml/hour, p less than 0.05). Mean arterial blood pressure declined gradually (108 +/- 5 to 84 +/- 4 mm Hg, p = 0.02), as did plasma aldosterone concentration (14.4 +/- 3.8 to 4.4 +/- 0.8 ng/dl, p = 0.03), whereas plasma immunoreactive active renin concentration increased progressively (35 +/- 14 to 160 +/- 60 pg/ml, p greater than 0.05). Urinary excretion of the stable metabolite of prostacyclin (6-keto-prostaglandin F1 alpha) decreased slightly, but not significantly (42 +/- 10 to 33 +/- 11 ng/g creatinine, p = 0.13). The addition of a diuretic decreased baseline blood pressure and increased baseline plasma renin and aldosterone values. Blood pressure responses to enalkiren were slightly (though not significantly) greater than those observed before diuretic administration. We conclude that enalkiren is effective in decreasing blood pressure and in inhibiting the renin system, without significantly altering urinary prostacyclin excretion, in patients with essential hypertension. These results suggest that the renin system contributes to the maintenance of elevated blood pressure in some patients with essential hypertension.

  8. Corticosterone inhibits normal and FSH-induced testicular recrudescence in the lizard, Mabuya carinata.

    PubMed

    Yajurvedi, H N; Nijagal, B S

    2000-12-01

    Administration (ip) of 1, 10, or 20 microg corticosterone (alternate days for 30 days) to adult male Mabuya carinata did not affect the seasonal recrudescence of spermatogenesis whereas administration of 40 microg corticosterone did result in inhibition of spermatogenesis. Further, administration of FSH (10 IU/lizard/alternate day for 30 days) during the quiescent phase of the testicular cycle stimulated spermatogenetic and steroidogenic activity of the testis as shown by significant increases in the mean number of spermatogonia, spermatocytes, and spermatids and serum levels of testosterone. In addition there were abundant spermatozoa in the lumen of the tubules in FSH-treated lizards. Administration of 10 IU FSH + 40 microg corticosterone (per lizard on alternate days for 30 days) increased the mean number of primary and secondary spermatocytes whereas the mean number of spermatids did not show significant variation compared with that of controls. Further, the mean numbers of spermatocytes and spermatids and serum levels of testosterone were significantly less when compared to those of FSH alone treated lizards. In addition, FSH-induced development of epididymis was also inhibited by corticosterone treatment. The results indicate that corticosterone inhibits FSH-induced testicular recrudescence, possibly by suppressing testosterone secretion in M. carinata.

  9. Protective effect of selenium on certain hepatotoxic and pancreotoxic manifestations of subacute cadmium administration.

    PubMed

    Merali, Z; Singhal, R L

    1975-10-01

    Administration of cadmium chloride (1.0 mg/kg s.c.) to rats, twice a day for 7 days, significantly stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-diphosphatase and glucose 6-phosphatase, markedly increased the concentration of hepatic cyclic adenosine monophosphate and circulating blood glucose and significantly reduced serum insulin levels. Furthermore, subacute exposure to cadmium induced glucose intolerance that was associated with a decreased pancreatic secretory activity as evidenced by lowered insulinogenic indices and marked inhibition of phentolamine-stimulated insulin release. In contrast to cadmium, administration of selenium dioxide (2 X 1.0 mg/kg/day s.c., 7 days) failed to alter significantly the activities of gluconeogenic enzymes, hepatic cyclic adenosine monophosphate, blood glucose or serum insulin levels, glucose tolerance or the pancreatic secretory activity. However, administration of selenium concurrently with cadmium completely prevented the cadmium-induced increases of hepatic gluconeogenic enzymes. Treatment with selenium ameliorated the cadmium-induced hyperglycemia, hypoinsulinemia, glucose intolerance and the suppression of pancreatic secretory activity, whereas it failed to alter significantly the cadmium-induced elevation of hepatic cyclic AMP levels. Data provide evidence suggesting that subacute exposure to cadmium alters several parameters of carbohydrate metabolism and suppresses pancreatic secretory activity and that administration of selenium alone is without any appreciable effect on the above parameters. However, administration of selenium concurrently with cadmium prevents, to varying degrees, several of the cadmium-induced metabolic and functional changes.

  10. 1-o-acetylbritannilactone (ABL) inhibits angiogenesis and lung cancer cell growth through regulating VEGF-Src-FAK signaling

    SciTech Connect

    Zhengfu, He; Hu, Zhang; Huiwen, Miao; Zhijun, Li; Jiaojie, Zhou; Xiaoyi, Yan; Xiujun, Cai

    2015-08-21

    The search for safe, effective and affordable therapeutics against non-small cell lung cancer (NSCLC) and other lung cancers is important. Here we explored the potential effect of 1-o-acetylbritannilactone (ABL), a novel extract from Inula britannica-F, on angiogenesis and lung cancer cell growth. We demonstrated that ABL dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, and capillary structure formation of cultured human umbilical vascular endothelial cells (HUVECs). In vivo, ABL administration suppressed VEGF-induced new vasculature formation in Matrigel plugs. For the mechanism investigations, we found that ABL largely inhibited VEGF-mediated activation of Src kinase and focal adhesion kinase (FAK) in HUVECs. Furthermore, treatment of A549 NSCLC cells with ABL resulted in cell growth inhibition and Src-FAK in-activation. Significantly, administration of a single dose of ABL (12 mg/kg/day) remarkably suppressed growth of A549 xenografts in nude mice. In vivo microvessels formation and Src activation were also significantly inhibited in ABL-treated xenograft tumors. Taken together, our findings suggest that ABL suppresses angiogenesis and lung cancer cell growth possibly via regulating the VEGFR-Src-FAK signaling. - Highlights: • 1-o-acetylbritannilactone (ABL) inhibits VEGF-induced angiogenesis in vivo. • ABL inhibits VEGF-induced HUVEC migration, proliferation, capillary tube formation. • ABL inhibits VEGF-mediated activation of Src and FAK in HUVECs. • ABL inhibits growth and Src-FAK activation in A549 cells. • ABL administration inhibits A549 tumor angiogenesis and growth in nude mice.

  11. The effects of co-administration of butter on the absorption, metabolism and excretion of catechins in rats after oral administration of tea polyphenols.

    PubMed

    Zhang, Liang; Han, Yuhui; Xu, Liwei; Liang, Yuhong; Chen, Xin; Li, Junsong; Wan, Xiaochun

    2015-07-01

    In Southwest China, tea polyphenols are usually utilized by way of butter tea. Tea polyphenols inhibit the absorption and biosynthesis of fatty acids in vivo, but the effects of butter on the pharmacokinetics of tea polyphenols have drawn less concern. A rapid UHPLC-MS/MS method was used to quantitatively determine the catechins in the plasma, feces and bile of rats after the oral administration of tea polyphenol or its combination with butter. In comparison with the single tea polyphenol treatment, the maximum plasma concentrations (Cmax) of the free EGCG, EGC, EC, GCG, GC and ECG significantly decreased after the co-administration of butter. The mean residence times (MRT) of the free EGCG, EGC, EC, GC and ECG were also significantly prolonged. When the plasma samples were treated with β-glucuronidase and arylsulfatase, the pharmacokinetic parameters of the total catechins (free and conjugated forms) were not affected by the co-administration of butter. These results indicated that the total absorption of catechins was not affected by butter, but the metabolism of catechins had been changed. Furthermore, the fecal catechins were significantly increased by butter. The total fecal amount and excretion ratio of all catechins were increased highly. The biliary excretion of EGCG, EGC, EC, GCG and GC was significantly increased by the co-administration of butter. To sum up, the butter changed the metabolism of catechins in vivo by decreasing the plasma concentration of the free catechins but increasing the conjugated catechins.

  12. Repeated administration of adenosine increases its cardiovascular effects in rats.

    PubMed

    Vidrio, H; García-Márquez, F; Magos, G A

    1987-01-20

    Hypotensive and negative chronotropic responses to adenosine in anesthetized rats increased after previous administration of the nucleoside. Bradycardia after adenosine in the isolated perfused rat heart was also potentiated after repeated administration at short intervals. This self-potentiation could be due to extracellular accumulation of adenosine and persistent stimulation of receptors caused by saturation or inhibition of cellular uptake of adenosine.

  13. Obestatin acts in brain to inhibit thirst.

    PubMed

    Samson, Willis K; White, Meghan M; Price, Christopher; Ferguson, Alastair V

    2007-01-01

    Derived from the same prohormone, obestatin has been reported to exert effects on food intake that oppose those of ghrelin. The obestatin receptor GPR39 is present in brain and pituitary gland. Since the gene encoding those two peptides is expressed also in those tissues, we examined further the possible actions of obestatin in vivo and in vitro. Intracerebroventricular administration of obestatin inhibited water drinking in ad libitum-fed and -watered rats, and in food-and water-deprived animals. The effects on water drinking preceded and were more pronounced than any effect on food intake, and did not appear to be the result of altered locomotor/behavioral activity. In addition, obestatin inhibited ANG II-induced water drinking in animals provided free access to water and food. Current-clamp recordings from cultured, subfornical organ neurons revealed significant effects of the peptide on membrane potential, suggesting this as a potential site of action. In pituitary cell cultures, log molar concentrations of obestatin ranging from 1.0 pM to 100 nM failed to alter basal growth hormone (GH) secretion. In addition, 100 nM obestatin failed to interfere with the stimulation of GH secretion by GH-releasing hormone or ghrelin and did not alter the inhibition by somatostatin in vitro. We conclude that obestatin does not act in pituitary gland to regulate GH secretion but may act in brain to alter thirst mechanisms. Importantly, in rats the effects of obestatin on food intake may be secondary to an action of the peptide to inhibit water drinking.

  14. Inhibition of leukocyte-type 12-lipoxygenase by guava tea leaves prevents development of atherosclerosis.

    PubMed

    Takahashi, Yoshitaka; Otsuki, Akemi; Mori, Yoshiko; Kawakami, Yuki; Ito, Hideyuki

    2015-11-01

    Oxidation of low-density lipoprotein (LDL) is one of the crucial steps for atherosclerosis development, and an essential role of leukocyte-type 12-lipoxygenase expressed in macrophages in this process has been demonstrated. The biochemical mechanism of the oxidation of circulating LDL by leukocyte-type 12-lipoxygenase in macrophages has been proposed. The major ingredients in guava tea leaves which inhibited the catalytic activity of leukocyte-type 12-lipoxygenase were quercetin and ethyl gallate. Administration of extracts from guava tea leaves to apoE-deficient mice significantly attenuated atherogenic lesions in the aorta and aortic sinus. We recently showed that Qing Shan Lu Shui inhibited the catalytic activity of leukocyte-type 12-lipoxygenase. The major components inhibiting the enzyme contained in Qing Shan Lu Shui were identified to be novel monoterpene glycosides. The anti-atherogenic effect of the tea leaves might be attributed to the inhibition of leukocyte-type 12-lipoxygenase by these components.

  15. Veterans Administration Databases

    Cancer.gov

    The Veterans Administration Information Resource Center provides database and informatics experts, customer service, expert advice, information products, and web technology to VA researchers and others.

  16. Oral administration of Lactobacillus plantarum HY7714 protects hairless mouse against ultraviolet B-induced photoaging.

    PubMed

    Kim, Hyun Mee; Lee, Dong Eun; Park, Soo Dong; Kim, Yong-Tae; Kim, Yu Jin; Jeong, Ji Woong; Jang, Sung Sik; Ahn, Young-Tae; Sim, Jae-Hun; Huh, Chul-Sung; Chung, Dae Kyun; Lee, Jung-Hee

    2014-11-28

    Ultraviolet (UV) irradiation alters multiple molecular pathways in the skin, thereby inducing skin damage, including photoaging. In recent years, probiotics have gained interest due to their beneficial effects on skin health, such as inhibiting atopic dermatitis and improving skin immunity or inflammation. However, little is known about the effects of probiotics on UVBinduced photoaging. In this study, we evaluated the effect of Lactobacillus plantarum HY7714 against UVB-induced photoaging in human dermal fibroblasts and hairless mice. The results showed that L. plantarum HY7714 treatment effectively rescued UVB-reduced procollagen expression through the inhibition of UVB-induced matrix metalloproteinase (MMP)-1 expression in human dermal fibroblasts. Data from a western blot showed that L. plantarum HY7714 inhibited the phosphorylation of Jun N-terminal kinase, thereby suppressing the UVB-induced phosphorylation and expression of c-Jun. Oral administration of L. plantarum HY7714 clearly inhibited the number, depth, and area of wrinkles in hairless mouse skin. Histological data showed that L. plantarum HY7714 significantly inhibited UVB-induced epidermal thickness in mice. Western blot and zymography data also revealed that L. plantarum HY7714 effectively inhibited MMP-13 expression as well as MMP-2 and -9 activities in dermal tissue. Collectively, these results provide further insight regarding the skin biological actions of L. plantarum HY7714, a potential skin anti-photoaging agent.

  17. Migrant Education Administrative Guide.

    ERIC Educational Resources Information Center

    North Carolina State Dept. of Public Instruction, Raleigh. Div. of Compensatory Education.

    Relating specifically to the North Carolina migrant education program's administrative responsibilities, this guide is designed to aid administrators in program management, monitoring project activities, project evaluation, self-assessment, determining needs for training and staff development, site-visit preparation, policy development, and…

  18. Champions of Children. Administrators . . .

    ERIC Educational Resources Information Center

    Chaffee, John; Olds, H. Robert

    Today, in an era of taxpayer revolts, lack of clarity in values, and changing family structure, children need advocates in the political arena as well as in the schools. This pamphlet suggests that administrators are in an excellent position to defend the rights of children on all fronts. It focuses on what administrators have done and specific…

  19. The Administrative Power Grab

    ERIC Educational Resources Information Center

    Sorenson, Richard D.

    2007-01-01

    Administrative power for some school teachers can be an aphrodisiac that can be applied negatively, especially when a leader has devastating instinct for the weaknesses of others. A leader's intellect and heart closes shop and ceases to function when drunk on power. In this article, the author describes how the use of administrative power can be…

  20. Traditionalism and Educational Administration.

    ERIC Educational Resources Information Center

    Holmes, Mark

    Administration is defined as the enactment of moral choices influencing subordinates within an organizational setting. It is distinguished from management, which is considered to involve a lower level of discretion. Educational administration is therefore in the moral domain; it involves discretionary, moral choices in a field that is itself moral…

  1. Test Administration Models

    ERIC Educational Resources Information Center

    Becker, Kirk A.; Bergstrom, Betty A.

    2013-01-01

    The need for increased exam security, improved test formats, more flexible scheduling, better measurement, and more efficient administrative processes has caused testing agencies to consider converting the administration of their exams from paper-and-pencil to computer-based testing (CBT). Many decisions must be made in order to provide an optimal…

  2. The Administrative Team.

    ERIC Educational Resources Information Center

    Ohio Association of Elementary School Principals, Westerville.

    Although needs of school districts vary with size, degree of teacher negotiation procedures, and type of community involvement, the administrative team model is presented as an effective, appropriate administrative organization. Based on an assumption that each level of authority in a school district possesses and exercises expertise and unique…

  3. Administrative Theory in Transition.

    ERIC Educational Resources Information Center

    Griffiths, Daniel E.

    This monograph analyzes transition in educational administrative theory. A brief introductory section describes the theoretical movement, the substance and repercussions of Thomas Greenfield's critique of educational administrative theory in 1974, and emerging qualitative approaches. Seven readings, all written by the volume's author, view…

  4. Improving Educational Administrative Decisions.

    ERIC Educational Resources Information Center

    Wolfe, A. E.

    This paper discusses the financial crisis facing public education in the United States today and argues that the most effective response to this crisis is to improve the decision-making skills of educational administrators. Based on a review of the literature on administrative decision-making and organizational change, the author examines several…

  5. Rural Administrative Leadership Handbook.

    ERIC Educational Resources Information Center

    Tift, Carolyn

    This resource book on rural administrative leadership is the result of 1988 interviews with school administrators involved in successful rural educational programs. The material is divided into eight chapters, each self-contained for separate use. Chapter 1, "Getting to Know the Community," addresses qualities of living and working in…

  6. Handbook for the ESL/ABE Administrator.

    ERIC Educational Resources Information Center

    Escobar, Joanna Sculley; Daugherty, John

    This 1975 handbook consists of three books to be used, together or independently, by administrators in developing, implementing, and evaluating an adult English-as-a-Second-Language (ESL) program. The first book, an administrator's checklist, is designed as an inventory that specifies succinctly the critical and significant program elements. The…

  7. Preparing College Administrators: Fact and Fancy.

    ERIC Educational Resources Information Center

    Stalcup, Robert J.; Wilson, Jerry L.

    The universality of administrative functions and tasks is sufficiently established to make special preparation programs for any one group of higher education administrators unjustifiable. This thesis is based on research undertaken to determine if significant differences existed in the functions or tasks performed by presidents, vice-presidents of…

  8. Inhibition of CaMKK2 Stimulates Osteoblast Formation and Inhibits Osteoclast Differentiation

    PubMed Central

    Cary, Rachel L.; Waddell, Seid; Racioppi, Luigi; Long, Fanxin; Novack, Deborah V.; Voor, Michael J.; Sankar, Uma

    2013-01-01

    Bone remodeling, a physiological process characterized by bone formation by osteoblasts (OB) and resorption of pre-existing bone matrix by osteoclasts (OC), is vital for the maintenance of healthy bone tissue in adult humans. Imbalances in this vital process result in pathological conditions including osteoporosis. Owing to its initial asymptomatic nature, osteoporosis is often detected only after the patient has sustained significant bone loss or a fracture. Hence, anabolic therapeutics that stimulates bone accrual is in high clinical demand. Here we identify Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) as a potential target for such therapeutics, as its inhibition enhances OB differentiation and bone growth and suppresses OC differentiation. Mice null for CaMKK2 possess higher trabecular bone mass in their long bones, along with significantly more OBs and fewer multinuclear OCs. Whereas Camkk2−/− MSCs yield significantly higher numbers of OBs, bone marrow cells from Camkk2−/− mice produce fewer multinuclear OCs, in vitro. Acute inhibition of CaMKK2 by its selective, cell-permeable pharmacological inhibitor STO-609 also results in increased OB and diminished OC formation. Further, we find phospho-protein kinase A (PKA) and Ser133 phosphorylated form of cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB) to be markedly elevated in OB progenitors deficient in CaMKK2. On the other hand, genetic ablation of CaMKK2 or its pharmacological inhibition in OC progenitors results in reduced pCREB as well as significantly reduced levels of its transcriptional target, nuclear factor of activated T cells c1 (NFATc1). Moreover, in vivo administration of STO-609 results in increased OBs and diminished OCs, conferring significant protection from ovariectomy (OVX)-induced osteoporosis in adult mice. Overall, our findings reveal a novel function for CaMKK2 in bone remodeling and highlight the potential for its therapeutic

  9. Changes in plasma glucose in Otsuka Long-Evans Tokushima Fatty rats after oral administration of maple syrup.

    PubMed

    Nagai, Noriaki; Yamamoto, Tetsushi; Tanabe, Wataru; Ito, Yoshimasa; Kurabuchi, Satoshi; Mitamura, Kuniko; Taga, Atsushi

    2015-01-01

    We investigate whether maple syrup is a suitable sweetener in the management of type 2 diabetes using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The enhancement in plasma glucose (PG) and glucose absorption in the small intestine were lower after the oral administration of maple syrup than after sucrose administration in OLETF rats, and no significant differences were observed in insulin levels. These data suggested that maple syrup might inhibit the absorption of glucose from the small intestine and preventing the enhancement of PG in OLETF rats. Therefore, maple syrup might help in the prevention of type 2 diabetes.

  10. Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition.

    PubMed

    Li, Shun; Zhang, Jing; Yang, Hong; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

    2015-07-15

    Copper, a strictly regulated trace element, is essential for many physiological processes including angiogenesis. Dysregulated angiogenesis has been associated with increased copper in tumors, and thus copper chelators have been used to inhibit tumor angiogenesis. However, it remains unclear whether copper has any effect on epithelial-mesenchymal transition (EMT). Using CoCl2-induced EMT of human breast carcinoma MCF-7 cells, we found that TEPA, a copper chelator, inhibited EMT-like cell morphology and cytoskeleton arrangement triggered by CoCl2; decreased the expression of vimentin and fibronectin, markers typical of EMT; inhibited HIF-1 activation and HIF1-α accumulation in nuclear; and down-regulated the expression of hypoxia-associated transcription factors, Snail and Twist1. Moreover, knockdown copper transport protein, Ctr1, also inhibited CoCl2-induced EMT and reversed the mesenchymal phenotype. In EMT6 xenograft mouse models, TEPA administration inhibited the tumor growth and increased mice survival. Immunohistochemical analysis of the xenograft further demonstrated that TEPA administration significantly inhibited tumor angiogenesis, down-regulated hypoxia-induced transcription factors, Snail and Twist1, leading to decreased transactivation of EMT-associated marker genes, vimentin and fibronectin. These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-α-Snail/Twist signaling pathway, and copper depletion may be exploited as a therapeutic for breast cancer.

  11. Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition

    PubMed Central

    Li, Shun; Zhang, Jing; Yang, Hong; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

    2015-01-01

    Copper, a strictly regulated trace element, is essential for many physiological processes including angiogenesis. Dysregulated angiogenesis has been associated with increased copper in tumors, and thus copper chelators have been used to inhibit tumor angiogenesis. However, it remains unclear whether copper has any effect on epithelial-mesenchymal transition (EMT). Using CoCl2-induced EMT of human breast carcinoma MCF-7 cells, we found that TEPA, a copper chelator, inhibited EMT-like cell morphology and cytoskeleton arrangement triggered by CoCl2; decreased the expression of vimentin and fibronectin, markers typical of EMT; inhibited HIF-1 activation and HIF1-α accumulation in nuclear; and down-regulated the expression of hypoxia-associated transcription factors, Snail and Twist1. Moreover, knockdown copper transport protein, Ctr1, also inhibited CoCl2-induced EMT and reversed the mesenchymal phenotype. In EMT6 xenograft mouse models, TEPA administration inhibited the tumor growth and increased mice survival. Immunohistochemical analysis of the xenograft further demonstrated that TEPA administration significantly inhibited tumor angiogenesis, down-regulated hypoxia-induced transcription factors, Snail and Twist1, leading to decreased transactivation of EMT-associated marker genes, vimentin and fibronectin. These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-α-Snail/Twist signaling pathway, and copper depletion may be exploited as a therapeutic for breast cancer. PMID:26174737

  12. Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs.

    PubMed

    Kuroha, Masanori; Kayaba, Hideki; Kishimoto, Shizuka; Khalil, Waleed F; Shimoda, Minoru; Kokue, Eiichi

    2002-03-01

    The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans.

  13. Safe administration of blood components.

    PubMed

    Hurrell, Katy

    The transfusion process has many stages, each involving different members of staff in different locations. This gives rise to a significant potential for errors. Nurses are involved in many of these stages and therefore require knowledge, skills and competence in the process to ensure the safety of patients. This third article in our five-part series on blood transfusion discusses the safe administration of blood components and the key principles to which nurses must adhere.

  14. Pathological Significance of Mitochondrial Glycation

    PubMed Central

    Pun, Pamela Boon Li; Murphy, Michael P.

    2012-01-01

    Glycation, the nonenzymatic glycosylation of biomolecules, is commonly observed in diabetes and ageing. Reactive dicarbonyl species such as methylglyoxal and glyoxal are thought to be major physiological precursors of glycation. Because these dicarbonyls tend to be formed intracellularly, the levels of advanced glycation end products on cellular proteins are higher than on extracellular ones. The formation of glycation adducts within cells can have severe functional consequences such as inhibition of protein activity and promotion of DNA mutations. Although several lines of evidence suggest that there are specific mitochondrial targets of glycation, and mitochondrial dysfunction itself has been implicated in disease and ageing, it is unclear if glycation of biomolecules specifically within mitochondria induces dysfunction and contributes to disease pathology. We discuss here the possibility that mitochondrial glycation contributes to disease, focussing on diabetes, ageing, cancer, and neurodegeneration, and highlight the current limitations in our understanding of the pathological significance of mitochondrial glycation. PMID:22778743

  15. PARP-1 inhibition alleviates diabetic cardiac complications in experimental animals.

    PubMed

    Zakaria, Esraa M; El-Bassossy, Hany M; El-Maraghy, Nabila N; Ahmed, Ahmed F; Ali, Abdelmoneim A

    2016-11-15

    Cardiovascular complications are the major causes of mortality among diabetic population. Poly(ADP-ribose) polymerase-1 enzyme (PARP-1) is activated by oxidative stress leading to cellular damage. We investigated the implication of PARP-1 in diabetic cardiac complications. Type 2 diabetes was induced in rats by high fructose-high fat diet and low streptozotocin dose. PARP inhibitor 4-aminobenzamide (4-AB) was administered daily for ten weeks after diabetes induction. At the end of study, surface ECG, blood pressure and vascular reactivity were studied. PARP-1 activity, reduced glutathione (GSH) and nitrite contents were assessed in heart muscle. Fasting glucose, fructosamine, insulin, and tumor necrosis factor alpha (TNF-α) levels were measured in serum. Finally, histological examination and collagen deposition detection in rat ventricular and aortic sections were carried out. Hearts isolated from diabetic animals showed increased PARP-1 enzyme activity compared to control animals while significantly reduced by 4-AB administration. PARP-1 inhibition by 4-AB alleviated cardiac ischemia in diabetic animals as indicated by ECG changes. PARP-1 inhibition also reduced cardiac inflammation in diabetic animals as evidenced by histopathological changes. In addition, 4-AB administration improved the elevated blood pressure and the associated exaggerated vascular contractility, endothelial destruction and vascular inflammation seen in diabetic animals. Moreover, PARP-1 inhibition decreased serum levels of TNF-α and cardiac nitrite but increased cardiac GSH contents in diabetic animals. However, PARP-1 inhibition did not significantly affect the developed hyperglycemia. Our findings prove that PARP-1 enzyme plays an important role in diabetic cardiac complications through combining inflammation, oxidative stress, and fibrosis mechanisms.

  16. Galectin-3 Inhibition Is Associated with Neuropathic Pain Attenuation after Peripheral Nerve Injury.

    PubMed

    Ma, Zhicong; Han, Qi; Wang, Xiaolei; Ai, Zisheng; Zheng, Yongjun

    2016-01-01

    Neuropathic pain remains a prevalent and persistent clinical problem because it is often poorly responsive to the currently used analgesics. It is very urgent to develop novel drugs to alleviate neuropathic pain. Galectin-3 (gal3) is a multifunctional protein belonging to the carbohydrate-ligand lectin family, which is expressed by different cells. Emerging studies showed that gal3 elicits a pro-inflammatory response by recruiting and activating lymphocytes, macrophages and microglia. In the study we investigated whether gal3 inhibition could suppress neuroinflammation and alleviate neuropathic pain following peripheral nerve injury. We found that L5 spinal nerve ligation (SNL) increases the expression of gal3 in dorsal root ganglions at the mRNA and protein level. Intrathecal administration of modified citrus pectin (MCP), a gal3 inhibitor, reduces gal3 expression in dorsal root ganglions. MCP treatment also inhibits SNL-induced gal3 expression in primary rat microglia. SNL results in an increased activation of autophagy that contributes to microglial activation and subsequent inflammatory response. Intrathecal administration of MCP significantly suppresses SNL-induced autophagy activation. MCP also inhibits lipopolysaccharide (LPS)-induced autophagy in cultured microglia in vitro. MCP further decreases LPS-induced expression of proinflammatory mediators including IL-1β, TNF-α and IL-6 by regulating autophagy. Intrathecal administration of MCP results in adecreased mechanical and cold hypersensitivity following SNL. These results demonstrated that gal3 inhibition is associated with the suppression of SNL-induced inflammatory process andneurophathic pain attenuation.

  17. Galectin-3 Inhibition Is Associated with Neuropathic Pain Attenuation after Peripheral Nerve Injury

    PubMed Central

    Ai, Zisheng; Zheng, Yongjun

    2016-01-01

    Neuropathic pain remains a prevalent and persistent clinical problem because it is often poorly responsive to the currently used analgesics. It is very urgent to develop novel drugs to alleviate neuropathic pain. Galectin-3 (gal3) is a multifunctional protein belonging to the carbohydrate-ligand lectin family, which is expressed by different cells. Emerging studies showed that gal3 elicits a pro-inflammatory response by recruiting and activating lymphocytes, macrophages and microglia. In the study we investigated whether gal3 inhibition could suppress neuroinflammation and alleviate neuropathic pain following peripheral nerve injury. We found that L5 spinal nerve ligation (SNL) increases the expression of gal3 in dorsal root ganglions at the mRNA and protein level. Intrathecal administration of modified citrus pectin (MCP), a gal3 inhibitor, reduces gal3 expression in dorsal root ganglions. MCP treatment also inhibits SNL-induced gal3 expression in primary rat microglia. SNL results in an increased activation of autophagy that contributes to microglial activation and subsequent inflammatory response. Intrathecal administration of MCP significantly suppresses SNL-induced autophagy activation. MCP also inhibits lipopolysaccharide (LPS)-induced autophagy in cultured microglia in vitro. MCP further decreases LPS-induced expression of proinflammatory mediators including IL-1β, TNF-α and IL-6 by regulating autophagy. Intrathecal administration of MCP results in adecreased mechanical and cold hypersensitivity following SNL. These results demonstrated that gal3 inhibition is associated with the suppression of SNL-induced inflammatory process andneurophathic pain attenuation. PMID:26872020

  18. Drug Education for Administrators

    ERIC Educational Resources Information Center

    Hackett, Peter; McKeon, Thomas L.

    1976-01-01

    The formulation of a drug policy and the implementation of that policy in a firm but fair manner are the responsibility of the school administrator. Authors give serious consideration to this responsibility. (Editor/RK)

  19. Food and Drug Administration

    MedlinePlus

    ... blog post. April 11, 2017 ‘Organs-on-Chips’ Technology: FDA Testing Groundbreaking Science More FDA Voice Blog ... FEAR Act Site Map Nondiscrimination Website Policies U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver ...

  20. Administrative Law Judges

    EPA Pesticide Factsheets

    The Administrative Law Judges conduct hearings and render decisions in proceedings between the EPA and persons, businesses, government entities, and other organizations which are or are alleged to be regulated under environmental laws.

  1. Needed: Nursing Administration Leaders

    ERIC Educational Resources Information Center

    Blair, Eunice M.

    1976-01-01

    A master's program that synthesizes clinical nursing knowledge with management theory and skills is one way to prepare nursing service administrators capable of exerting an influence on today's complex health care system. (Editor)

  2. The Administrator Selection Process

    ERIC Educational Resources Information Center

    Griffin, Michael F.

    1974-01-01

    Proposes that education establish for administrators systematic, rigorous, albeit subjective, selection procedures that recognize the principle of organizational democracy and the public nature of the educational enterprise. (Author/DN)

  3. Confrontation and Administrative Response

    ERIC Educational Resources Information Center

    Auerbach, Arnold J.

    1969-01-01

    Describes some of the sociological and psychological effects of organizational conflict and offers 10 operational principles to guide public administrators of schools and social agencies in meeting the confrontation tactics of activist groups. (JH)

  4. One for the Administrators

    ERIC Educational Resources Information Center

    American School and University, 1978

    1978-01-01

    Earth berms, a heavily insulated roof, and a narrow band of thermal pane windows, save energy at the administrative headquarters of the Anoka Hennepin school district in Coon Rapids, a suburb of Minneapolis, Minnesota. (Author/MLF)

  5. Goldstone (GDSCC) administrative computing

    NASA Technical Reports Server (NTRS)

    Martin, H.

    1981-01-01

    The GDSCC Data Processing Unit provides various administrative computing services for Goldstone. Those activities, including finance, manpower and station utilization, deep-space station scheduling and engineering change order (ECO) control are discussed.

  6. Company Administration Study.

    DTIC Science & Technology

    1974-01-01

    iTRATION CENTER AND FORT BENJAMIN HARRISON FORT BENJAMIN HARRISON. INDIANA 46216 ATZI -XO 16 October 1973 SUBJECT: Letter of Instruction - Company...Mail, files, records management* publications, voting, etc.). ... AnnexA II ATZI -XO 18 October 1973 SUBJECT: Letter of Instruction - Company...administration as follows: A. 2 I * * " " " ’+ " " ’ ’ ’ ’’ ’ , ’" I ATZI -XO 18 October 1973 SUBJECT: Letter of Instruction - Company Administration Study tea

  7. Clinically significant drug interactions with newer antidepressants.

    PubMed

    Spina, Edoardo; Trifirò, Gianluca; Caraci, Filippo

    2012-01-01

    After the introduction of selective serotonin reuptake inhibitors (SSRIs), other newer antidepressants with different mechanisms of action have been introduced in clinical practice. Because antidepressants are commonly prescribed in combination with other medications used to treat co-morbid psychiatric or somatic disorders, they are likely to be involved in clinically significant drug interactions. This review examines the drug interaction profiles of the following newer antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone. In general, by virtue of a more selective mechanism of action and receptor profile, newer antidepressants carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants, i.e. monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). On the other hand, they are susceptible to pharmacokinetic drug interactions. All new antidepressants are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes, and therefore may be the target of metabolically based drug interactions. Concomitant administration of inhibitors or inducers of the CYP isoenzymes involved in the biotransformation of specific antidepressants may cause changes in their plasma concentrations. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications are usually not clinically relevant. Conversely, some newer antidepressants may cause pharmacokinetic interactions through their ability to inhibit specific CYPs. With regard to this, duloxetine and bupropion are moderate inhibitors of CYP2D6. Therefore, potentially harmful drug interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. The other new antidepressants are only weak inhibitors or are not inhibitors of CYP isoforms at

  8. Significance of periodogram peaks

    NASA Astrophysics Data System (ADS)

    Süveges, Maria; Guy, Leanne; Zucker, Shay

    2016-10-01

    Three versions of significance measures or False Alarm Probabilities (FAPs) for periodogram peaks are presented and compared for sinusoidal and box-like signals, with specific application on large-scale surveys in mind.

  9. Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: Role of the TNF signaling axis

    SciTech Connect

    Wahl, Elizabeth C.; Aronson, James; Liu, Lichu; Liu, Zhendong; Perrien, Daniel S.; Skinner, Robert A.; Badger, Thomas M.; Ronis, Martin J.J.; Lumpkin, Charles K. . E-mail: lumpkincharlesk@uams.edu

    2007-05-01

    Tumor necrosis factor-alpha (TNF-{alpha}) is an inflammatory cytokine that modulates osteoblastogenesis. In addition, the demonstrated inhibitory effects of chronic ethanol exposure on direct bone formation in rats are hypothetically mediated by TNF-{alpha} signaling. The effects in mice are unreported. Therefore, we hypothesized that in mice (1) administration of a soluble TNF receptor 1 derivative (sTNF-R1) would protect direct bone formation during chronic ethanol exposure, and (2) administration of recombinant mouse TNF-{alpha} (rmTNF-{alpha}) to ethanol naive mice would inhibit direct bone formation. We utilized a unique model of limb lengthening (distraction osteogenesis, DO) combined with liquid diets to measure chronic ethanol's effects on direct bone formation. Chronic ethanol exposure resulted in increased marrow TNF, IL-1, and CYP 2E1 RNA levels in ethanol-treated vs. control mice, while no significant weight differences were noted. Systemic administration of sTNF-R1 during DO (8.0 mg/kg/2 days) to chronic ethanol-exposed mice resulted in enhanced direct bone formation as measured radiologically and histologically. Systemic rmTNF-{alpha} (10 {mu}g/kg/day) administration decreased direct bone formation measures, while no significant weight differences were noted. We conclude that chronic ethanol-associated inhibition of direct bone formation is mediated to a significant extent by the TNF signaling axis in a mouse model.

  10. Peripheral oxytocin administration reduces ethanol consumption in rats

    PubMed Central

    MacFadyen, Kaley; Loveless, Rebecca; DeLucca, Brandon; Wardley, Krystal; Deogan, Sumeet; Thomas, Cameron; Peris, Joanna

    2016-01-01

    The neuropeptide oxytocin interacts with mesolimbic dopamine neurons to mediate reward associated with filial behaviors, but also other rewarding behaviors such as eating or taking drugs of abuse. Based on its efficacy to decrease intake of other abused substances, oxytocin administration is implicated as a possible treatment for excessive alcohol consumption. We tested this hypothesis by measuring ethanol intake in male Sprague–Dawley rats injected with oxytocin or saline using two different ethanol self-administration paradigms. First, a dose–response curve was constructed for oxytocin inhibition of fluid intake using a modified drinking-in-the-dark model with three bottles containing .05% saccharine, 10% ethanol in saccharine, and 15% ethanol in saccharine. Doses of oxytocin tested were 0.05, 0.1, 0.3, and 0.5 mg/kg (I.P.). Next, rats received 0.3 mg/kg oxytocin preceding operant sessions in which they were trained to lever-press for either plain gelatin or ethanol gelatin in order to compare oxytocin inhibition of ethanol intake versus caloric intake. For the three-bottle choice study, rats consumed significantly less ethanol when treated with the three higher doses of oxytocin on the injection day. In the operant study, 0.3 mg/kg oxytocin significantly decreased ethanol gel consumption to a greater extent than plain gel consumption, both in terms of the amount of gel eaten and calories consumed. These data affirm oxytocin's efficacy for decreasing ethanol intake in rats, and confirm clinical studies suggesting oxytocin as a potential treatment for alcoholism. PMID:26519603

  11. Peripheral oxytocin administration reduces ethanol consumption in rats.

    PubMed

    MacFadyen, Kaley; Loveless, Rebecca; DeLucca, Brandon; Wardley, Krystal; Deogan, Sumeet; Thomas, Cameron; Peris, Joanna

    2016-01-01

    The neuropeptide oxytocin interacts with mesolimbic dopamine neurons to mediate reward associated with filial behaviors, but also other rewarding behaviors such as eating or taking drugs of abuse. Based on its efficacy to decrease intake of other abused substances, oxytocin administration is implicated as a possible treatment for excessive alcohol consumption. We tested this hypothesis by measuring ethanol intake in male Sprague-Dawley rats injected with oxytocin or saline using two different ethanol self-administration paradigms. First, a dose-response curve was constructed for oxytocin inhibition of fluid intake using a modified drinking-in-the-dark model with three bottles containing .05% saccharine, 10% ethanol in saccharine, and 15% ethanol in saccharine. Doses of oxytocin tested were 0.05, 0.1, 0.3, and 0.5mg/kg (I.P.). Next, rats received 0.3mg/kg oxytocin preceding operant sessions in which they were trained to lever-press for either plain gelatin or ethanol gelatin in order to compare oxytocin inhibition of ethanol intake versus caloric intake. For the three-bottle choice study, rats consumed significantly less ethanol when treated with the three higher doses of oxytocin on the injection day. In the operant study, 0.3mg/kg oxytocin significantly decreased ethanol gel consumption to a greater extent than plain gel consumption, both in terms of the amount of gel eaten and calories consumed. These data affirm oxytocin's efficacy for decreasing ethanol intake in rats, and confirm clinical studies suggesting oxytocin as a potential treatment for alcoholism.

  12. Selective inhibition of the cytochrome P450 isoform by hyperoside and its potent inhibition of CYP2D6.

    PubMed

    Song, Min; Hong, Miri; Lee, Min Young; Jee, Jun-Goo; Lee, You Mie; Bae, Jong-Sup; Jeong, Tae Cheon; Lee, Sangkyu

    2013-09-01

    Hyperoside, quercetin-3-O-galactoside, is a flavonoid isolated from Oenanthe javanica. In the present study, we investigated potential herb-drug inhibitory effects of hyperoside on nine cytochrome P450 (CYP) isoforms in pooled human liver microsomes (HLMs) and human recombinant cDNA expressed CYP using a cocktail probe assay. Hyperoside strongly inhibited CYP2D6-catalyzed dextromethorphan O-demethylation, with IC₅₀ values of 1.2 and 0.81 μM after 0 and 15 min of preincubation, and a Ki value of 2.01 μM in HLMs, respectively. Hyperoside strongly decreased CYP2D6 activity dose-, but not time-, dependently in HLMs. In addition, the Lineweaver-Burk and Secondary plots for the inhibition of CYP2D6 in HLMs fitted a competitive inhibition mode. Furthermore, hyperoside decreased CYP2D6-catalyzed dextromethorphan O-demethylation activity of human recombinant cDNA-expressed CYP2D6, with an IC₅₀ value of 3.87 μM. However, other CYPs were not inhibited significantly by hyperoside. In conclusion, our data demonstrate that hyperoside is a potent selective CYP2D6 inhibitor in HLMs, and suggest that hyperoside might cause herb-drug interactions when co-administrated with CYP2D substrates.

  13. Effects of single cortisol administrations on human affect reviewed: Coping with stress through adaptive regulation of automatic cognitive processing.

    PubMed

    Putman, Peter; Roelofs, Karin

    2011-05-01

    The human stress hormone cortisol may facilitate effective coping after psychological stress. In apparent agreement, administration of cortisol has been demonstrated to reduce fear in response to stressors. For anxious patients with phobias or posttraumatic stress disorder this has been ascribed to hypothetical inhibition of retrieval of traumatic memories. However, such stress-protective effects may also work via adaptive regulation of early cognitive processing of threatening information from the environment. This paper selectively reviews the available literature on effects of single cortisol administrations on affect and early cognitive processing of affectively significant information. The concluded working hypothesis is that immediate effects of high concentration of cortisol may facilitate stress-coping via inhibition of automatic processing of goal-irrelevant threatening information and through increased automatic approach-avoidance responses in early emotional processing. Limitations in the existing literature and suggestions for future directions are briefly discussed.

  14. Statistical Significance Testing.

    ERIC Educational Resources Information Center

    McLean, James E., Ed.; Kaufman, Alan S., Ed.

    1998-01-01

    The controversy about the use or misuse of statistical significance testing has become the major methodological issue in educational research. This special issue contains three articles that explore the controversy, three commentaries on these articles, an overall response, and three rejoinders by the first three authors. They are: (1)…

  15. Significance of brown dwarfs

    NASA Technical Reports Server (NTRS)

    Black, D. C.

    1986-01-01

    The significance of brown dwarfs for resolving some major problems in astronomy is discussed. The importance of brown dwarfs for models of star formation by fragmentation of molecular clouds and for obtaining independent measurements of the ages of stars in binary systems is addressed. The relationship of brown dwarfs to planets is considered.

  16. Influence of the route of administration on immunomodulatory properties of bovine beta-lactoglobulin-producing Lactobacillus casei.

    PubMed

    Hazebrouck, S; Przybylski-Nicaise, L; Ah-Leung, S; Adel-Patient, K; Corthier, G; Langella, P; Wal, J-M

    2009-09-25

    Because of their intrinsic immunomodulatory properties, some lactic acid bacteria were reported to modulate allergic immune responses in mice and humans. We recently developed recombinant strains of Lactobacillus casei that produce beta-lactoglobulin (BLG), a major cow's milk allergen. Here, we investigated immunomodulatory potency of intranasal and oral administrations of recombinant lactobacilli on a subsequent sensitization of mice to BLG. Intranasal administration of the BLG-producing Lb. casei stimulated serum BLG-specific IgG2a and IgG1 responses, and fecal IgA response as well, but did not inhibit BLG-specific IgE production. In contrast, oral administration led to a significant inhibition of BLG-specific IgE production while IgG1 and IgG2a responses were not stimulated. After both oral and intranasal administrations, production of IL-17 cytokine by BLG-reactivated splenocytes was similarly enhanced, thus confirming the adjuvant effect of the Lb. casei strain. However, a mixed Th1/Th2 cell response was evidenced in BLG-reactivated splenocytes from mice intranasally pretreated, with enhanced secretions of Th1 cytokines (IFN-gamma and IL-12) and Th2 cytokines (IL-4 and IL-5) whereas only production of Th1 cytokines, but not Th2 cytokines, was enhanced in BLG-reactivated splenocytes from mice orally pretreated. Our results show that the mode of administration of live bacteria may be critical for their immunomodulatory effects.

  17. Centralized administrative services management.

    PubMed

    Freed, D H

    1994-06-01

    Virtually every hospital has imposed guidelines or controls on one or more administrative service expenses. However, the actual deployment of such strategies is often voluntary, decentralized, disjointed and episodic. An alternative approach is to cluster administrative elements across hospital departments and make them the responsibility of a dedicated manager. This approach treats administrative services as an organizing principle with uniform, predictable standards of service and cost. Customer requirements for products and services are met without the need for them to physically manage that process. Materiel managers can demonstrate a leadership role by applying their professionalism and know-how to a set of products and services traditionally ignored or dealt with in an uncoordinated manner. While some initial resistance can be expected as traditional barriers are disassembled, the results should be very rewarding for the hospital and materiel manager alike.

  18. Methamphetamine Self-Administration in Mice Decreases GIRK Channel-Mediated Currents in Midbrain Dopamine Neurons

    PubMed Central

    Sharpe, Amanda L.; Varela, Erika; Bettinger, Lynne

    2015-01-01

    Background: Methamphetamine is a psychomotor stimulant with abuse liability and a substrate for catecholamine uptake transporters. Acute methamphetamine elevates extracellular dopamine, which in the midbrain can activate D2 autoreceptors to increase a G-protein gated inwardly rectifying potassium (GIRK) conductance that inhibits dopamine neuron firing. These studies examined the neurophysiological consequences of methamphetamine self-administration on GIRK channel-mediated currents in dopaminergic neurons in the substantia nigra and ventral tegmental area. Methods: Male DBA/2J mice were trained to self-administer intravenous methamphetamine. A dose response was conducted as well as extinction and cue-induced reinstatement. In a second study, after at least 2 weeks of stable self-administration of methamphetamine, electrophysiological brain slice recordings were conducted on dopamine neurons from self-administering and control mice. Results: In the first experiment, ad libitum-fed, nonfood-trained mice exhibited a significant increase in intake and locomotion following self-administration as the concentration of methamphetamine per infusion was increased (0.0015–0.15mg/kg/infusion). Mice exhibited extinction in responding and cue-induced reinstatement. In the second experiment, dopamine cells in both the substantia nigra and ventral tegmental area from adult mice with a history of methamphetamine self-administration exhibited significantly smaller D2 and GABAB receptor-mediated currents compared with control mice, regardless of whether their daily self-administration sessions had been 1 or 4 hours. Interestingly, the effects of methamphetamine self-administration were not present when intracellular calcium was chelated by including BAPTA in the recording pipette. Conclusions: Our results suggest that methamphetamine self-administration decreases GIRK channel-mediated currents in dopaminergic neurons and that this effect may be calcium dependent. PMID:25522412

  19. Computer hardware fault administration

    DOEpatents

    Archer, Charles J.; Megerian, Mark G.; Ratterman, Joseph D.; Smith, Brian E.

    2010-09-14

    Computer hardware fault administration carried out in a parallel computer, where the parallel computer includes a plurality of compute nodes. The compute nodes are coupled for data communications by at least two independent data communications networks, where each data communications network includes data communications links connected to the compute nodes. Typical embodiments carry out hardware fault administration by identifying a location of a defective link in the first data communications network of the parallel computer and routing communications data around the defective link through the second data communications network of the parallel computer.

  20. Shared services centers can drive significant savings.

    PubMed

    McDowell, Jim

    2011-06-01

    A study of more than 30 U.S. integrated delivery systems (IDSs) found that implementing effective shared services centers can drive significant cost savings in human resources, accounts payable, and procurement. Many IDSs have not adopted effective shared services strategies. Implementing administrative shared services involves low risk and a relatively low start-up investment.

  1. Composite Defect Significance.

    DTIC Science & Technology

    1982-07-13

    A12i 299 COMPOSITE DEFECT SIGNIFICANCE(U) MATERIALS SCIENCES 1/1 \\ CORP SPRING HOUSE PA S N CHATTERJEE ET AL. 13 JUL 82 MSC/TFR/1288/il87 NADC-80848...Directorate 30 Sensors & Avionics Technology Directorate 40 Communication & Navigation Technology Directorate 50 Software Computer Directorate 60 Aircraft ...instructions concerning commercial products herein do not constitute an endorsement by the Government nor do they convey or imply the license or right to use

  2. Significant Tsunami Events

    NASA Astrophysics Data System (ADS)

    Dunbar, P. K.; Furtney, M.; McLean, S. J.; Sweeney, A. D.

    2014-12-01

    Tsunamis have inflicted death and destruction on the coastlines of the world throughout history. The occurrence of tsunamis and the resulting effects have been collected and studied as far back as the second millennium B.C. The knowledge gained from cataloging and examining these events has led to significant changes in our understanding of tsunamis, tsunami sources, and methods to mitigate the effects of tsunamis. The most significant, not surprisingly, are often the most devastating, such as the 2011 Tohoku, Japan earthquake and tsunami. The goal of this poster is to give a brief overview of the occurrence of tsunamis and then focus specifically on several significant tsunamis. There are various criteria to determine the most significant tsunamis: the number of deaths, amount of damage, maximum runup height, had a major impact on tsunami science or policy, etc. As a result, descriptions will include some of the most costly (2011 Tohoku, Japan), the most deadly (2004 Sumatra, 1883 Krakatau), and the highest runup ever observed (1958 Lituya Bay, Alaska). The discovery of the Cascadia subduction zone as the source of the 1700 Japanese "Orphan" tsunami and a future tsunami threat to the U.S. northwest coast, contributed to the decision to form the U.S. National Tsunami Hazard Mitigation Program. The great Lisbon earthquake of 1755 marked the beginning of the modern era of seismology. Knowledge gained from the 1964 Alaska earthquake and tsunami helped confirm the theory of plate tectonics. The 1946 Alaska, 1952 Kuril Islands, 1960 Chile, 1964 Alaska, and the 2004 Banda Aceh, tsunamis all resulted in warning centers or systems being established.The data descriptions on this poster were extracted from NOAA's National Geophysical Data Center (NGDC) global historical tsunami database. Additional information about these tsunamis, as well as water level data can be found by accessing the NGDC website www.ngdc.noaa.gov/hazard/

  3. Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo.

    PubMed

    Urakawa, Hiroshi; Nishida, Yoshihiro; Wasa, Junji; Arai, Eisuke; Zhuo, Lisheng; Kimata, Koji; Kozawa, Eiji; Futamura, Naohisa; Ishiguro, Naoki

    2012-01-15

    Hyaluronan (HA) has been shown to play crucial roles in the tumorigenicity of malignant tumors. Previous studies demonstrated that inhibition of HA suppressed the tumorigenicity of various malignant tumors including breast cancer. 4-methylumbelliferone (MU) has been reported to inhibit HA synthesis in several cell types. However, few studies have focused on the effects of HA inhibition in breast cancer cells by MU, nor the effects on bone metastasis. We hypothesized that MU would suppress the progression of bone metastasis via inhibition of HA synthesis. Here, we investigated the effects of MU on HA expression in MDA-MB-231 breast cancer cell line in addition to their tumorigenicity in vitro and in vivo. HAS2 mRNA expression was downregulated after 6 and 24 hr treatment with MU. Quantitative analysis of HA revealed that MU significantly inhibited the intracellular and cell surface HA. MU significantly inhibited cell growth and induced apoptosis as determined by cell proliferation and TUNEL assays, respectively. Phosphorylation of Akt was suppressed after 12 and 24 hr treatment with MU. MU treatment also inhibited cell motility as well as cell invasiveness. MU also inhibited cell growth and motility in murine fibroblast cell line NIH3T3. In vivo, administration of MU inhibited the expansion of osteolytic lesions on soft X-rays in mouse breast cancer xenograft models. HA accumulation in bone metastatic lesions was perturbed peripherally. These data suggest that MU might be a therapeutic candidate for bone metastasis of breast cancer via suppression of HA synthesis and accumulation.

  4. Administrative Utility Analysis: Appendices.

    ERIC Educational Resources Information Center

    Peat, Marwick, Mitchell and Co., San Juan, Puerto Rico.

    Appendixes to a study on administrative utility analysis and vocational education programs for the Area of Vocational and Technical Education (AVTE) in the Puerto Rico Department of Education contain the planning and budgeting system elements, position descriptions, and information on the growth of vocational education in Puerto Rico. The elements…

  5. Administrative Sides of Librarying.

    ERIC Educational Resources Information Center

    Lott, Carolyn

    2003-01-01

    Discusses how the author used administrative skills learned as a school library media specialist to meet the demands of a university department chair. Topics include the influence of decisions that are made; budgeting; evaluation concerns and responsibilities; determining guidelines and goals; political concerns; and the flow of information. (LRW)

  6. The Administration of Admissions

    ERIC Educational Resources Information Center

    Campbell, Clifford C.

    1978-01-01

    Among all the tasks of the admissions officer in developing a successful marketing program, the hardest may be that of convincing other college administrators of the importance of admissions to the institution's survival. Discussed are long-range planning, budgeting, staff selection and training, and implementing a plan. (Author/LBH)

  7. Administrators Confront Student "Sexting"

    ERIC Educational Resources Information Center

    Manzo, Kathleen Kennedy

    2009-01-01

    Cellphone-savvy students have created instructional and disciplinary challenges for educators for years. But the recent emergence of "sexting" by adolescents over their mobile phones caught many school administrators off guard, and the practice is prompting efforts around the country to craft policy responses. Students' sharing of nude or…

  8. IVA: Improving Vocational Administration.

    ERIC Educational Resources Information Center

    EPD Consortium D, Richardson, TX.

    These six instructional units are intended to provide instructors of vocational education administration with a systematic package of materials for their programs of preservice and/or inservice instruction and to provide materials which could be reproduced for learner use. These units cover the following subject matter: (1) federal legislation…

  9. Migrant Education Administrative Handbook.

    ERIC Educational Resources Information Center

    Louisiana State Dept. of Education, Baton Rouge. Bureau of Migrant Education.

    Intended to provide information pertaining to the administration of migrant education projects in Louisiana, the handbook is divided into two sections: basic guidelines for program operations and support services--nursing. Section I covers the Federal and State migrant program, local migrant projects, project personnel and staff development, and…

  10. Educational Administration's Weber.

    ERIC Educational Resources Information Center

    Gronn, Peter

    1994-01-01

    Discusses Max Weber's importance in Greenfield's work, particularly in Greenfield and Ribbins'"Greenfield on Educational Administration" (1993). In concentrating on human actors' subjective understanding, Greenfield was a faithful Weberian. However, he deviated from Weber by disavowing structural explanations of social and organizational…

  11. The Administrative Internship.

    ERIC Educational Resources Information Center

    Adkison, Judith A., Ed.; Warren, Andrea, Ed.

    This monograph was developed as part of the project known as Internships, Certification, Equity-Leadership, and Support (ICES). The Kansas project successfully field-tested a model for mobilizing statewide resources to prepare women for administrative careers and to place them in appropriate positions. The crucial component of the training program…

  12. Standards and Administration.

    ERIC Educational Resources Information Center

    Gross, S. P.

    1978-01-01

    Presents a literature review of water quality standards and administration, covering publications of 1976-77. Consideration is given to municipal facilities, National Pollutant Discharge Elimination Systems, regional and international water quality management, and effluent standards. A list of 99 references is also presented. (HM)

  13. Championing the Latino Administrator

    ERIC Educational Resources Information Center

    Garcia, Carlos A.

    2011-01-01

    When the author worked as a vice principal at a K-8 school in Watsonville, California, a school predominantly filled with migrant workers' children, he felt a lack of support as a Latino as he began moving up into school administration. He also continued to see what he had seen as a teacher--which was how underserved minority students were. These…

  14. Redis database administration tool

    SciTech Connect

    Martinez, J. J.

    2013-02-13

    MyRedis is a product of the Lorenz subproject under the ASC Scirntific Data Management effort. MyRedis is a web based utility designed to allow easy administration of instances of Redis databases. It can be usedd to view and manipulate data as well as run commands directly against a variety of different Redis hosts.

  15. Administrative Uses of Microcomputers.

    ERIC Educational Resources Information Center

    Crawford, Chase

    1987-01-01

    This paper examines the administrative uses of the microcomputer, stating that high performance educational managers are likely to have microcomputers in their organizations. Four situations that would justify the use of a computer are: (1) when massive amounts of data are processed through well-defined operations; (2) when data processing is…

  16. Educator Effectiveness Administrative Manual

    ERIC Educational Resources Information Center

    Pennsylvania Department of Education, 2014

    2014-01-01

    The goal of this manual is to provide guidance in the evaluation of educators, highlight critical components of effectiveness training, and offer opportunities for professional growth. The term "educator" includes teachers, all professional and temporary professional employees, education specialists, and school administrators/principals.…

  17. Discretionary Grants Administration Manual.

    ERIC Educational Resources Information Center

    Office of Human Development Services (DHHS), Washington, DC.

    This manual sets forth applicable administrative policies and procedures to recipients of discretionary project grants or cooperative agreements awarded by program offices in the Office of Human Development Services (HDS). It is intended to serve as a basic reference for project directors and business officers of recipient organizations who are…

  18. [Rural School Administrator's Resources.

    ERIC Educational Resources Information Center

    AEL, Inc., Charleston, WV.

    This packet contains resources on five topics relevant to rural school administrators. "Assessing Parent Involvement: A Checklist for Rural Schools": discusses educator beliefs that support successful parent engagement programs, challenges and advantages of rural schools attempting to involve parents and community, and aspects of…

  19. Standards for Administrators.

    ERIC Educational Resources Information Center

    Lashway, Larry

    1998-01-01

    This newsletter reviews five reports that address the implications of standards for administrators. These texts include "Designing and Implementing Standards-Based Accountability System" (Education Commission of the States), which describes some of the policy implications of standards-driven accountability; "Why Principals Fail: Are National…

  20. Inhibition of colonization of the chicken alimentary tract with Salmonella typhimurium gram-negative facultatively anaerobic bacteria.

    PubMed Central

    Barrow, P. A.; Tucker, J. F.; Simpson, J. M.

    1987-01-01

    Oral administration of strains of food poisoning salmonellas to day-old chickens produced a profound inhibition in the subsequent colonization of the caeca by a strain of Salmonella typhimurium given one day later. Closely related genera were unable to produce a similar inhibition. The inhibition was not the result of bacteriophages produced by the first strain. Neither was it the result of an immunological response by the host induced by the first strain. In additional experiments in day-old chickens, inhibition of an Escherichia coli Nalr strain and of a Citrobacter sp. Nalr strain was produced by the antibiotic-sensitive forms of the homologous strains while strains from other genera did not produce any inhibition. When an avirulent mutant of S. typhimurium was used for pre-treatment a statistically significant reduction in the excretion of the super-infecting S. typhimurium Nalr strain over several weeks was produced. A genus specific inhibition was reproduced in vitro by mixed culture experiments. Live cultures were necessary for in vitro inhibition. Killed cells or a culture supernatant produced no inhibition. PMID:2954839

  1. Advanced Contract Administration. First Week

    DTIC Science & Technology

    1988-04-14

    administration. Keywords: Contracting/administrative contracting officer relations Financial management; Production management , Quality assurance; Subcontracting; Claims; Government property; Ethics data sources and modifications.

  2. Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis.

    PubMed

    Donà, Massimo; Dell'Aica, Isabella; Calabrese, Fiorella; Benelli, Roberto; Morini, Monica; Albini, Adriana; Garbisa, Spiridione

    2003-04-15

    Neutrophils play an essential role in host defense and inflammation, but the latter may trigger and sustain the pathogenesis of a range of acute and chronic diseases. Green tea has been claimed to exert anti-inflammatory properties through unknown molecular mechanisms. We have previously shown that the most abundant catechin of green tea, (-)epigallocatechin-3-gallate (EGCG), strongly inhibits neutrophil elastase. Here we show that 1) micromolar EGCG represses reactive oxygen species activity and inhibits apoptosis of activated neutrophils, and 2) dramatically inhibits chemokine-induced neutrophil chemotaxis in vitro; 3) both oral EGCG and green tea extract block neutrophil-mediated angiogenesis in vivo in an inflammatory angiogenesis model, and 4) oral administration of green tea extract enhances resolution in a pulmonary inflammation model, significantly reducing consequent fibrosis. These results provide molecular and cellular insights into the claimed beneficial properties of green tea and indicate that EGCG is a potent anti-inflammatory compound with therapeutic potential.

  3. Naoxintong/PPARγ Signaling Inhibits Cardiac Hypertrophy via Activation of Autophagy

    PubMed Central

    Yuan, Shuping; Jin, Jianhua; Chen, Lu

    2017-01-01

    As a traditional Chinese medicine, Naoxintong capsule (NXT) has been approved by China Food and Drug Administration (CFDA), which is used for cardiocerebrovascular disease treatment. Here we found that NXT extract significantly promoted H9c2 cardiomyocyte cell autophagy involved in increased autophagy-associated gene expression leading to inhibition of mTOR signaling. Moreover, NXT extract increased PPARγ protein expression and transcription activity of H9c2 cell. Consistent with this, in PPARγ gene silenced H9c2 cells, NXT had no effect on autophagy and mTOR signaling. Furthermore, NXT/PPARγ-mediated H9c2 autophagy led to inhibition of cardiomyocyte cell hypertrophy. These findings suggest that the extract of NXT inhibited H9c2 cardiomyocyte cell hypertrophy via PPARγ-mediated cell autophagy. PMID:28293264

  4. Dopaminergic inhibition involved in the alpha-naphthoxyacetic acid-induced jumping behavior in mice.

    PubMed

    Yamada, K; Furukawa, T

    1980-05-16

    alpha-Naphthoxyacetic acid (alpha-NOAA), one of the retching-inducers, elicited a dose-dependent jumping behavior shortly after i.p. administration in doses ranging from 250 to 700 mg/kg in ddY mice, the incidence of jumping being 97% at a dose of 700 mg/kg. alpha-NOAA also induced hypothermia, retching, head shaking, salivation and lacrimation. Phentolamine, reserpine, disulfiram, tranylcypromine, haloperidol, scopolamine, bicuculline, diazepam and lithium among the drugs tested inhibited to a certain degree but not markedly the alpha-NOAA-induced jumping behavior. However, the behavior was markedly inhibited by a dopaminergic agonist, apomorphine (1 mg/kg, i.p.), and this inhibitory effect was significantly antagonized by a dopaminergic antagonist, haloperidol (2 mg/kg, i.p.). These findings suggest that the jumping behavior elicited by alpha-NOAA may be due to the inhibition of dopaminergic neuron activity.

  5. A synthetic manassantin a derivative inhibits hypoxia-inducible factor 1 and tumor growth.

    PubMed

    Lang, Liwei; Liu, Xiaoyu; Li, Yan; Zhou, Qing; Xie, Ping; Yan, Chunhong; Chen, Xiaoguang

    2014-01-01

    The dineolignan manassantin A from Saururaceae was recently identified as a hypoxia-inducible factor 1 (HIF-1) inhibitor, but its in-vivo anti-tumor effect has not been explored. We synthesized a series of manassantin A derivatives, and found that replacing the central tetrahydrofuran moiety with a cyclopentane ring yielded a compound (LXY6006) with increased HIF-1-inhibitory activity yet decreased stereochemically complexity amenable to a simplified synthesis scheme. LXY6006 inhibited HIF-1α nuclear accumulation induced by hypoxia, and inhibited cancer cell growth as a consequence of G2/M arrest. Oral administration of LXY6006 significantly inhibited growth of breast, lung, and pancreatic tumors implanted in nude mice. These results indicate that LXY6006 represents a novel class of agents targeting a broad range of human cancers.

  6. A Synthetic Manassantin A Derivative Inhibits Hypoxia-Inducible Factor 1 and Tumor Growth

    PubMed Central

    Li, Yan; Zhou, Qing; Xie, Ping; Yan, Chunhong; Chen, Xiaoguang

    2014-01-01

    The dineolignan manassantin A from Saururaceae was recently identified as a hypoxia-inducible factor 1 (HIF-1) inhibitor, but its in-vivo anti-tumor effect has not been explored. We synthesized a series of manassantin A derivatives, and found that replacing the central tetrahydrofuran moiety with a cyclopentane ring yielded a compound (LXY6006) with increased HIF-1-inhibitory activity yet decreased stereochemically complexity amenable to a simplified synthesis scheme. LXY6006 inhibited HIF-1α nuclear accumulation induced by hypoxia, and inhibited cancer cell growth as a consequence of G2/M arrest. Oral administration of LXY6006 significantly inhibited growth of breast, lung, and pancreatic tumors implanted in nude mice. These results indicate that LXY6006 represents a novel class of agents targeting a broad range of human cancers. PMID:24925080

  7. Pharmacological inhibition of FTO.

    PubMed

    McMurray, Fiona; Demetriades, Marina; Aik, WeiShen; Merkestein, Myrte; Kramer, Holger; Andrew, Daniel S; Scudamore, Cheryl L; Hough, Tertius A; Wells, Sara; Ashcroft, Frances M; McDonough, Michael A; Schofield, Christopher J; Cox, Roger D

    2015-01-01

    In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO's demethylase activity could be therapeutically useful for the treatment of obesity.

  8. Pharmacological Inhibition of FTO

    PubMed Central

    McMurray, Fiona; Demetriades, Marina; Aik, WeiShen; Merkestein, Myrte; Kramer, Holger; Andrew, Daniel S.; Scudamore, Cheryl L.; Hough, Tertius A.; Wells, Sara; Ashcroft, Frances M.; McDonough, Michael A.; Schofield, Christopher J.; Cox, Roger D.

    2015-01-01

    In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO’s demethylase activity could be therapeutically useful for the treatment of obesity. PMID:25830347

  9. Intratracheal Administration of Prostacyclin Analogue–incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension

    PubMed Central

    Matsubara, Hiromi; Kondo, Megumi; Miura, Daiji; Matoba, Tetsuya; Egashira, Kensuke; Ito, Hiroshi

    2016-01-01

    Abstract: Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs. PMID:26745002

  10. Intratracheal Administration of Prostacyclin Analogue-incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension.

    PubMed

    Akagi, Satoshi; Nakamura, Kazufumi; Matsubara, Hiromi; Kondo, Megumi; Miura, Daiji; Matoba, Tetsuya; Egashira, Kensuke; Ito, Hiroshi

    2016-04-01

    Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.

  11. Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis

    PubMed Central

    Moran, Corey S.; Seto, Sai-Wang; Krishna, Smriti M.; Sharma, Surabhi; Jose, Roby J.; Biros, Erik; Wang, Yutang; Morton, Susan K.; Golledge, Jonathan

    2017-01-01

    Intraluminal thrombus is a consistent feature of human abdominal aortic aneurysm (AAA). Coagulation factor Xa (FXa) catalyses FII to thrombin (FIIa). We examined the effect of FXa/FIIa inhibition on experimental aortic aneurysm in apolipoprotein E-deficient (ApoE−/−) mice infused with angiotensin II (AngII). The concentration of FXa within the supra-renal aorta (SRA) correlated positively with SRA diameter. Parenteral administration of enoxaparin (FXa/IIa inhibitor) and fondaparinux (FXa inhibitor) over 14 days reduced to severity of aortic aneurysm and atherosclerosis in AngII-infused ApoE−/− mice. Enteral administration of the FIIa inhibitor dabigatran had no significant effect. Aortic protease-activated receptor (PAR)-2 expression increased in response to AngII infusion. Fondaparinux reduced SRA levels of FXa, FIIa, PAR-2, matrix metalloproteinase (MMP)2, Smad2/3 phosphorylation, and MOMA-2 positive cells in the mouse model. FXa stimulated Smad2/3 phosphorylation and MMP2 expression in aortic vascular smooth muscle cells (VSMC) in vitro. Expression of MMP2 in FXa-stimulated VSMC was downregulated in the presence of a PAR-2 but not a PAR-1 inhibitor. These findings suggest that FXa/FIIa inhibition limits aortic aneurysm and atherosclerosis severity due to down-regulation of vascular PAR-2-mediated Smad2/3 signalling and MMP2 expression. Inhibition of FXa/FIIa may be a potential therapy for limiting aortic aneurysm. PMID:28220880

  12. Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis.

    PubMed

    Moran, Corey S; Seto, Sai-Wang; Krishna, Smriti M; Sharma, Surabhi; Jose, Roby J; Biros, Erik; Wang, Yutang; Morton, Susan K; Golledge, Jonathan

    2017-02-21

    Intraluminal thrombus is a consistent feature of human abdominal aortic aneurysm (AAA). Coagulation factor Xa (FXa) catalyses FII to thrombin (FIIa). We examined the effect of FXa/FIIa inhibition on experimental aortic aneurysm in apolipoprotein E-deficient (ApoE(-/-)) mice infused with angiotensin II (AngII). The concentration of FXa within the supra-renal aorta (SRA) correlated positively with SRA diameter. Parenteral administration of enoxaparin (FXa/IIa inhibitor) and fondaparinux (FXa inhibitor) over 14 days reduced to severity of aortic aneurysm and atherosclerosis in AngII-infused ApoE(-/-) mice. Enteral administration of the FIIa inhibitor dabigatran had no significant effect. Aortic protease-activated receptor (PAR)-2 expression increased in response to AngII infusion. Fondaparinux reduced SRA levels of FXa, FIIa, PAR-2, matrix metalloproteinase (MMP)2, Smad2/3 phosphorylation, and MOMA-2 positive cells in the mouse model. FXa stimulated Smad2/3 phosphorylation and MMP2 expression in aortic vascular smooth muscle cells (VSMC) in vitro. Expression of MMP2 in FXa-stimulated VSMC was downregulated in the presence of a PAR-2 but not a PAR-1 inhibitor. These findings suggest that FXa/FIIa inhibition limits aortic aneurysm and atherosclerosis severity due to down-regulation of vascular PAR-2-mediated Smad2/3 signalling and MMP2 expression. Inhibition of FXa/FIIa may be a potential therapy for limiting aortic aneurysm.

  13. Inhibition of Streptococcus pneumoniae adherence to human epithelial cells in vitro by the probiotic Lactobacillus rhamnosus GG

    PubMed Central

    2013-01-01

    Background Colonization of the nasopharynx by Streptococcus pneumoniae is considered a prerequisite for pneumococcal infections such as pneumonia and otitis media. Probiotic bacteria can influence disease outcomes through various mechanisms, including inhibition of pathogen colonization. Here, we examine the effect of the probiotic Lactobacillus rhamnosus GG (LGG) on S. pneumoniae colonization of human epithelial cells using an in vitro model. We investigated the effects of LGG administered before, at the same time as, or after the addition of S. pneumoniae on the adherence of four pneumococcal isolates. Results LGG significantly inhibited the adherence of all the pneumococcal isolates tested. The magnitude of inhibition varied with LGG dose, time of administration, and the pneumococcal isolate used. Inhibition was most effective when a higher dose of LGG was administered prior to establishment of pneumococcal colonization. Mechanistic studies showed that LGG binds to epithelial cells but does not affect pneumococcal growth or viability. Administration of LGG did not lead to any significant changes in host cytokine responses. Conclusions These findings demonstrate that LGG can inhibit pneumococcal colonization of human epithelial cells in vitro and suggest that probiotics could be used clinically to prevent the establishment of pneumococcal carriage. PMID:23561014

  14. Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization.

    PubMed

    Rossi, Antonietta; Caiazzo, Elisabetta; Bilancia, Rossella; Riemma, Maria A; Pagano, Ester; Cicala, Carla; Ialenti, Armando; Zjawiony, Jordan K; Izzo, Angelo A; Capasso, Raffaele; Roviezzo, Fiorentina

    2016-01-01

    Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma.

  15. Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

    PubMed Central

    Rossi, Antonietta; Caiazzo, Elisabetta; Bilancia, Rossella; Riemma, Maria A.; Pagano, Ester; Cicala, Carla; Ialenti, Armando; Zjawiony, Jordan K.; Izzo, Angelo A.; Capasso, Raffaele; Roviezzo, Fiorentina

    2017-01-01

    Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma. PMID

  16. Quantifying nursing workflow in medication administration.

    PubMed

    Keohane, Carol A; Bane, Anne D; Featherstone, Erica; Hayes, Judy; Woolf, Seth; Hurley, Ann; Bates, David W; Gandhi, Tejal K; Poon, Eric G

    2008-01-01

    New medication administration systems are showing promise in improving patient safety at the point of care, but adoption of these systems requires significant changes in nursing workflow. To prepare for these changes, the authors report on a time-motion study that measured the proportion of time that nurses spend on various patient care activities, focusing on medication administration-related activities. Implications of their findings are discussed.

  17. Neurokinin B administration induces hot flushes in women.

    PubMed

    Jayasena, Channa N; Comninos, Alexander N; Stefanopoulou, Evgenia; Buckley, Adam; Narayanaswamy, Shakunthala; Izzi-Engbeaya, Chioma; Abbara, Ali; Ratnasabapathy, Risheka; Mogford, Julianne; Ng, Noel; Sarang, Zubair; Ghatei, Mohammad A; Bloom, Stephen R; Hunter, Myra S; Dhillo, Waljit S

    2015-02-16

    Neurokinin B (NKB) is a hypothalamic neuropeptide binding preferentially to the neurokinin 3 receptor. Expression of the gene encoding NKB is elevated in postmenopausal women. Furthermore, rodent studies suggest that NKB signalling may mediate menopausal hot flushes. However, the effects of NKB administration on hot flushes have not been investigated in humans. To address this, we performed a randomised, double-blinded, placebo-controlled, 2-way cross-over study. Ten healthy women were admitted to a temperature and humidity-controlled research unit. Participants received 30 minute intravenous infusions of NKB and vehicle in random order. Symptoms, heart rate, blood pressure, sweating and skin temperature were compared between NKB and vehicle in a double-blinded manner. Eight of ten participants experienced flushing during NKB infusion with none experiencing flushing during vehicle infusion (P = 0.0007). Significant elevations in heart rate (P = 0.0106 vs. pre-symptoms), and skin temperature measured using skin probe (P = 0.0258 vs. pre-symptoms) and thermal imaging (P = 0.0491 vs. pre-symptoms) characteristic of menopausal flushing were observed during hot flush episodes. Our findings provide evidence that NKB administration can cause hot flushes in women. Further studies are required to determine if pharmacological blockade of NKB signalling could inhibit hot flushes during the menopause and during treatment for sex-steroid dependent cancers.

  18. Intravenous Administration of Lycopene, a Tomato Extract, Protects against Myocardial Ischemia-Reperfusion Injury

    PubMed Central

    Tong, Chao; Peng, Chuan; Wang, Lianlian; Zhang, Li; Yang, Xiaotao; Xu, Ping; Li, Jinjin; Delplancke, Thibaut; Zhang, Hua; Qi, Hongbo

    2016-01-01

    Background: Oral uptake of lycopene has been shown to be beneficial for preventing myocardial ischemia-reperfusion (I/R) injury. However, the strong first-pass metabolism of lycopene influences its bioavailability and impedes its clinic application. In this study, we determined an intravenous (IV) administration dose of lycopene protects against myocardial infarction (MI) in a mouse model, and investigated the effects of acute lycopene administration on reactive oxygen species (ROS) production and related signaling pathways during myocardial I/R. Methods: In this study, we established both in vitro hypoxia/reoxygenation (H/R) cell model and in vivo regional myocardial I/R mouse model by ligating left anterior artery descending. TTC dual staining was used to assess I/R induced MI in the absence and presence of acute lycopene administration via tail vein injection. Results: Lycopene treatment (1 μM) before reoxygenation significantly reduced cardiomyocyte death induced by H/R. Intravenous administration of lycopene to achieve 1 μM concentration in circulating blood significantly suppressed MI, ROS production, and JNK phosphorylation in the cardiac tissue of mice during in vivo regional I/R. Conclusion: Elevating circulating lycopene to 1 μM via IV injection protects against myocardial I/R injury through inhibition of ROS accumulation and consequent inflammation in mice. PMID:26950150

  19. Administration of Murine Stromal Vascular Fraction Ameliorates Chronic Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Semon, Julie A.; Zhang, Xiujuan; Pandey, Amitabh C.; Alandete, Sandra M.; Maness, Catherine; Zhang, Shijia; Scruggs, Brittni A.; Strong, Amy L.; Sharkey, Steven A.; Beuttler, Marc M.; Gimble, Jeffrey M.

    2013-01-01

    Administration of adipose-derived stromal/stem cells (ASCs) represents a promising therapeutic approach for autoimmune diseases since they have been shown to have immunomodulatory properties. The uncultured, nonexpanded counterpart of ASCs, the stromal vascular fraction (SVF), is composed of a heterogeneous mixture of cells. Although administration of ex vivo culture-expanded ASCs has been used to study immunomodulatory mechanisms in multiple models of autoimmune diseases, less is known about SVF-based therapy. The ability of murine SVF cells to treat myelin oligodendrocyte glycoprotein35–55-induced experimental autoimmune encephalitis (EAE) was compared with that of culture-expanded ASCs in C57Bl/6J mice. A total of 1 × 106 SVF cells or ASCs were administered intraperitoneally concomitantly with the induction of disease. The data indicate that intraperitoneal administration of ASCs significantly ameliorated the severity of disease course. They also demonstrate, for the first time, that the SVF effectively inhibited disease severity and was statistically more effective than ASCs. Both cell therapies also demonstrated a reduction in tissue damage, a decrease in inflammatory infiltrates, and a reduction in sera levels of interferon-γ and interleukin-12. Based on these data, SVF cells effectively inhibited EAE disease progression more than culture-expanded ASCs. PMID:23981726

  20. Effects of nicotine on response inhibition and interference control.

    PubMed

    Ettinger, Ulrich; Faiola, Eliana; Kasparbauer, Anna-Maria; Petrovsky, Nadine; Chan, Raymond C K; Liepelt, Roman; Kumari, Veena

    2017-04-01

    Nicotine is a cholinergic agonist with known pro-cognitive effects in the domains of alerting and orienting attention. However, its effects on attentional top-down functions such as response inhibition and interference control are less well characterised. Here, we investigated the effects of 7 mg transdermal nicotine on performance on a battery of response inhibition and interference control tasks. A sample of N = 44 healthy adult non-smokers performed antisaccade, stop signal, Stroop, go/no-go, flanker, shape matching and Simon tasks, as well as the attentional network test (ANT) and a continuous performance task (CPT). Nicotine was administered in a within-subjects, double-blind, placebo-controlled design, with order of drug administration counterbalanced. Relative to placebo, nicotine led to significantly shorter reaction times on a prosaccade task and on CPT hits but did not significantly improve inhibitory or interference control performance on any task. Instead, nicotine had a negative influence in increasing the interference effect on the Simon task. Nicotine did not alter inter-individual associations between reaction times on congruent trials and error rates on incongruent trials on any task. Finally, there were effects involving order of drug administration, suggesting practice effects but also beneficial nicotine effects when the compound was administered first. Overall, our findings support previous studies showing positive effects of nicotine on basic attentional functions but do not provide direct evidence for an improvement of top-down cognitive control through acute administration of nicotine at this dose in healthy non-smokers.

  1. Inhibition of MMPs by alcohols

    PubMed Central

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

    2011-01-01

    Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

  2. Olive leaf extract inhibits lead poisoning-induced brain injury

    PubMed Central

    Wang, Yu; Wang, Shengqing; Cui, Wenhui; He, Jiujun; Wang, Zhenfu; Yang, Xiaolu

    2013-01-01

    Olive leaves have an antioxidant capacity, and olive leaf extract can protect the blood, spleen and hippocampus in lead-poisoned mice. However, little is known about the effects of olive leaf extract on lead-induced brain injury. This study was designed to determine whether olive leaf extract can inhibit lead-induced brain injury, and whether this effect is associated with antioxidant capacity. First, we established a mouse model of lead poisoning by continuous intragastric administration of lead acetate for 30 days. Two hours after successful model establishment, lead-poisoned mice were given olive leaf extract at doses of 250, 500 or 1 000 mg/kg daily by intragastric administration for 50 days. Under the transmission electron microscope, olive leaf extract attenuated neuronal and capillary injury and reduced damage to organelles and the matrix around the capillaries in the frontal lobe of the cerebral cortex in the lead-poisoned mice. Olive leaf extract at a dose of 1 000 mg/kg had the greatest protective effect. Spectrophotometry showed that olive leaf extract significantly increased the activities of superoxide dismutase, catalase, alkaline phosphatase and acid phosphatase, while it reduced malondialdehyde content, in a dose-dependent manner. Furthermore, immunohistochemical staining revealed that olive leaf extract dose-dependently decreased Bax protein expression in the cerebral cortex of lead-poisoned mice. Our findings indicate that olive leaf extract can inhibit lead-induced brain injury by increasing antioxidant capacity and reducing apoptosis. PMID:25206510

  3. Therapeutic inhibition of the alternative complement pathway attenuates chronic EAE.

    PubMed

    Hu, Xianzhen; Holers, V Michael; Thurman, Joshua M; Schoeb, Trent R; Ramos, Theresa N; Barnum, Scott R

    2013-07-01

    Previous studies from our laboratory using complement-mutant mice demonstrated that the alternative pathway is the dominant activation pathway responsible for complement-mediated pathology in demyelinating disease. Using a well-characterized inhibitory monoclonal antibody (mAb 1379) directed against mouse factor B, we assessed the therapeutic value of inhibiting the alternative complement pathway in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Administration of anti-factor B antibody to mice prior to the onset of clinical signs of active EAE had no affect on the onset or acute phase of disease, but significantly attenuated the chronic phase of disease resulting in reduced cellular infiltration, inflammation and demyelination in antibody-treated mice. Attenuation of the chronic phase of disease was long lasting even though antibody administration was terminated shortly after disease onset. Chronic disease was also attenuated in transferred EAE when anti-factor B antibody was administered before or after disease onset. Similar levels of disease attenuation were observed in transferred EAE using MOG-specific encephalitogenic T cells. These studies demonstrate the therapeutic potential for inhibition of factor B in the chronic phase of demyelinating disease, where treatment options are limited.

  4. Therapeutic Inhibition of the Alternative Complement Pathway Attenuates Chronic EAE

    PubMed Central

    Hu, Xianzhen; Holers, V. Michael; Thurman, Joshua M.; Schoeb, Trent R.; Ramos, Theresa N; Barnum, Scott R.

    2013-01-01

    Previous studies from our laboratory using complement-mutant mice demonstrated that the alternative pathway is the dominant activation pathway responsible for complement-mediated pathology in demyelinating disease. Using a well-characterized inhibitory monoclonal antibody (mAb 1379) directed against mouse factor B, we assessed the therapeutic value of inhibiting the alternative complement pathway in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Administration of anti-factor B antibody to mice prior to the onset of clinical signs of active EAE had no affect on the onset or acute phase of disease, but significantly attenuated the chronic phase of disease resulting in reduced cellular infiltration, inflammation and demyelination in antibody-treated mice. Attenuation of the chronic phase of disease was long lasting even though antibody administration was terminated shortly after disease onset. Chronic disease was also attenuated in transferred EAE when anti-factor B antibody was administered before or after disease onset. Similar levels of disease attenuation were observed in transferred EAE using MOG-specific encephalitogenic T cells. These studies demonstrate the therapeutic potential for inhibition of factor B in the chronic phase of demyelinating disease, where treatment options are limited. PMID:23337717

  5. Mentoring and Tutoring within Administrative Internship Programs in American Universities

    ERIC Educational Resources Information Center

    Wilmore, Elaine L.; Bratlien, Maynard J.

    2005-01-01

    The article presents a significant national research project conducted by the authors and sponsored by the National Council of Professors of Educational Administration. It analyzes the varying aspects of administrative internships in American universities today. Professors of Educational Administration from around the nation were surveyed on-line…

  6. Fungi producing significant mycotoxins.

    PubMed

    2012-01-01

    Mycotoxins are secondary metabolites of microfungi that are known to cause sickness or death in humans or animals. Although many such toxic metabolites are known, it is generally agreed that only a few are significant in causing disease: aflatoxins, fumonisins, ochratoxin A, deoxynivalenol, zearalenone, and ergot alkaloids. These toxins are produced by just a few species from the common genera Aspergillus, Penicillium, Fusarium, and Claviceps. All Aspergillus and Penicillium species either are commensals, growing in crops without obvious signs of pathogenicity, or invade crops after harvest and produce toxins during drying and storage. In contrast, the important Fusarium and Claviceps species infect crops before harvest. The most important Aspergillus species, occurring in warmer climates, are A. flavus and A. parasiticus, which produce aflatoxins in maize, groundnuts, tree nuts, and, less frequently, other commodities. The main ochratoxin A producers, A. ochraceus and A. carbonarius, commonly occur in grapes, dried vine fruits, wine, and coffee. Penicillium verrucosum also produces ochratoxin A but occurs only in cool temperate climates, where it infects small grains. F. verticillioides is ubiquitous in maize, with an endophytic nature, and produces fumonisins, which are generally more prevalent when crops are under drought stress or suffer excessive insect damage. It has recently been shown that Aspergillus niger also produces fumonisins, and several commodities may be affected. F. graminearum, which is the major producer of deoxynivalenol and zearalenone, is pathogenic on maize, wheat, and barley and produces these toxins whenever it infects these grains before harvest. Also included is a short section on Claviceps purpurea, which produces sclerotia among the seeds in grasses, including wheat, barley, and triticale. The main thrust of the chapter contains information on the identification of these fungi and their morphological characteristics, as well as factors

  7. Treatment with pyrophosphate inhibits uremic vascular calcification.

    PubMed

    O'Neill, W Charles; Lomashvili, Koba A; Malluche, Hartmut H; Faugere, Marie-Claude; Riser, Bruce L

    2011-03-01

    Pyrophosphate, which may be deficient in advanced renal failure, is a potent inhibitor of vascular calcification. To explore its use as a potential therapeutic, we injected exogenous pyrophosphate subcutaneously or intraperitoneally in normal rats and found that their plasma pyrophosphate concentrations peaked within 15 min. There was a single exponential decay with a half-life of 33 min. The kinetics were indistinguishable between the two routes of administration or in anephric rats. The effect of daily intraperitoneal pyrophosphate injections on uremic vascular calcification was then tested in rats fed a high-phosphate diet containing adenine for 28 days to induce uremia. Although the incidence of aortic calcification varied and was not altered by pyrophosphate, the calcium content of calcified aortas was significantly reduced by 70%. Studies were repeated in uremic rats given calcitriol to produce more consistent aortic calcification and treated with sodium pyrophosphate delivered intraperitoneally in a larger volume of glucose-containing solution to prolong plasma pyrophosphate levels. This maneuver significantly reduced both the incidence and amount of calcification. Quantitative histomorphometry of bone samples after double-labeling with calcein indicated that there was no effect of pyrophosphate on the rates of bone formation or mineralization. Thus, exogenous pyrophosphate can inhibit uremic vascular calcification without producing adverse effects on bone.

  8. Amitifadine, a triple monoamine re-uptake inhibitor, reduces nicotine self-administration in female rats

    PubMed Central

    Levin, Edward D; Wells, Corinne; Johnson, Joshua E; Rezvani, Amir H.; Bymaster, Frank P.; Rose, Jed E.

    2016-01-01

    A wider diversity of drug treatments to aid smoking cessation is needed to help tailor the most efficacious treatment for different types of smokers. This study was conducted to determine whether amitifadine, which inhibits re-uptake of dopamine, norepinephrine and serotonin, would decrease nicotine self-administration at doses that do not cause adverse side effects. Adult female Sprague-Dawley rats were trained to self-administer nicotine intravenous (IV) and were given acute doses of amitifadine in a repeated measures counterbalanced design. Effects of amitifadine on locomotor activity and food motivated responding were also evaluated. Chronic amitifadine effects were also examined. The 30 mg/kg amitifadine dose significantly reduced nicotine self-administration. The 5 and 10 mg/kg doses reduced nicotine self-administration during the first 15 min. of the session when the greatest amount of nicotine was self-administered. The 30 mg/kg amitifadine dose, but not the lower doses caused a significant reduction in locomotor activity averaged over the 1-hour session and reduced food motivated responding. The 10 mg/kg dose caused hypoactivity at the beginning of the session, but 5 mg/kg did not cause any hypoactivity. The effects of chronic amitifadine treatment (10 mg/kg) over the course of 15 sessions was also determined. Amitifadine caused a significant reduction in nicotine self-administration, which was not seen to diminish over two consecutive weeks of treatment and a week after enforced abstinence. Amitifadine significantly reduced nicotine self-administration. This prompts further research to determine if amitifadine might be an effective treatment for smoking cessation. PMID:26101069

  9. Amitifadine, a triple monoamine re-uptake inhibitor, reduces nicotine self-administration in female rats.

    PubMed

    Levin, Edward D; Wells, Corinne; Johnson, Joshua E; Rezvani, Amir H; Bymaster, Frank P; Rose, Jed E

    2015-10-05

    A wider diversity of drug treatments to aid smoking cessation is needed to help tailor the most efficacious treatment for different types of smokers. This study was conducted to determine whether amitifadine, which inhibits re-uptake of dopamine, norepinephrine and serotonin, would decrease nicotine self-administration at doses that do not cause adverse side effects. Adult female Sprague-Dawley rats were trained to self-administer nicotine intravenous (IV) and were given acute doses of amitifadine in a repeated measures counterbalanced design. Effects of amitifadine on locomotor activity and food motivated responding were also evaluated. Chronic amitifadine effects were also examined. The 30 mg/kg amitifadine dose significantly reduced nicotine self-administration. The 5 and 10 mg/kg doses reduced nicotine self-administration during the first 15 min of the session when the greatest amount of nicotine was self-administered. The 30 mg/kg amitifadine dose, but not the lower doses caused a significant reduction in locomotor activity averaged over the one-hour session and reduced food motivated responding. The 10 mg/kg dose caused hypoactivity at the beginning of the session, but 5 mg/kg did not cause any hypoactivity. The effects of chronic amitifadine treatment (10 mg/kg) over the course of 15 sessions was also determined. Amitifadine caused a significant reduction in nicotine self-administration, which was not seen to diminish over two consecutive weeks of treatment and a week after enforced abstinence. Amitifadine significantly reduced nicotine self-administration. This prompts further research to determine if amitifadine might be an effective treatment for smoking cessation.

  10. Diospyros kaki Extract Inhibits Alkali Burn-Induced Corneal Neovascularization.

    PubMed

    Yang, Sung Jae; Jo, Hyoung; Kim, Kyung-A; Ahn, Hong Ryul; Kang, Suk Woo; Jung, Sang Hoon

    2016-01-01

    The purpose of this study was to evaluate the effect of ethanol extract of Diospyros kaki (EEDK) leaves on corneal neovascularization (CoNV) in rats. One week after the alkali burns in the corneas, the CoNV area coverage in the CoNV-positive control group, 100 mg/kg EEDK group, and 200 mg/kg EEDK group was 43.3% ± 5.5%, 337.7% ± 2.5%, and 27.2% ± 4.3%, respectively. The areas of CoNV in the EEDK-treated groups were significantly different from those of the CoNV group. EEDK significantly attenuated the upregulation of vascular endothelial growth factor, fibroblast growth factor, interleukin-6, and matrix metalloproteinase-2 (MMP-2) protein levels. Orally administrated D. kaki inhibited CoNV development in rats.

  11. Lateral Inhibition during Nociceptive Processing.

    PubMed

    Quevedo, Alexandre S; Mørch, Carsten Dahl; Andersen, Ole K; Coghill, Robert C

    2017-02-11

    Spatial summation of pain is the increase of perceived intensity that occurs as the stimulated area increases. Spatial summation of pain is sub-additive in that increasing the stimulus area produces a disproportionately small increase in the perceived intensity of pain. A possible explanation for sub-additive summation may be that convergent excitatory information is modulated by lateral inhibition. To test the hypothesis that lateral inhibition may limit spatial summation of pain, we delivered different patterns of noxious thermal stimuli to the abdomens of 15 subjects using a computer-controlled CO2-laser. Lines (5mm wide) of variable lengths (4cm, 8cm) were compared to two-point stimuli delivered at the same position/separation as the length of lines. When compared to one-point control stimuli, two-point stimulus patterns produced statistically significant spatial summation of pain, while no such summation was detected during line stimulus patterns. Direct comparison of pain intensity evoked by two-point pattern stimuli with line pattern stimuli revealed that two-point patterns were perceived as significantly more painful, despite the fact that the two-point pattern stimulated far smaller areas of skin. Thus, the stimulation of the skin region between the endpoints of the lines appears to produce inhibition. These findings indicate that lateral inhibition limits spatial summation of pain and is an intrinsic component of nociceptive information processing. Disruption of such lateral inhibition may contribute substantially to the radiation of some types of chronic pain.

  12. Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

    PubMed Central

    Mojadadi, Shafi; Jamali, Abbas; Khansarinejad, Behzad; Soleimanjahi, Hoorieh; Bamdad, Taravat

    2009-01-01

    Acute morphine administration is known to alter the course of herpes simplex virus infection. In this study, the effect of acute morphine administration on the reactivation of latent herpes was investigated in a mouse model. Because of the important role of cytolytic T lymphocyte (CTL) activity in the inhibition of herpes simplex virus type 1 (HSV-1) reactivation, the effect of acute morphine administration on CTL responses was also evaluated. Furthermore, lymphocyte proliferation and IFN-γ production were evaluated for their roles in the induction of the CTL response. The findings showed that acute morphine administration significantly reduced CTL responses, lymphocyte proliferation, and IFN-γ production. Furthermore, acute morphine administration has been shown to reactivate latent HSV-1. Previous studies have shown that cellular immune responses have important roles in the inhibition of HSV reactivation. These findings suggest that suppression of a portion of the cellular immune response after acute morphine administration may constitute one part of the mechanism that induces HSV reactivation. PMID:19403060

  13. Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by Tideglusib*

    PubMed Central

    Domínguez, Juan Manuel; Fuertes, Ana; Orozco, Leyre; del Monte-Millán, María; Delgado, Elena; Medina, Miguel

    2012-01-01

    Tideglusib is a GSK-3 inhibitor currently in phase II clinical trials for the treatment of Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of the compound to a variety of animal models decreases Tau hyperphosphorylation, lowers brain amyloid plaque load, improves learning and memory, and prevents neuronal loss. We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug has been removed from the reaction medium and the fact that its dissociation rate constant is non-significantly different from zero. Such irreversibility may explain the non-competitive inhibition pattern with respect to ATP shown by tideglusib and perhaps other structurally related compounds. The replacement of Cys-199 by an Ala residue in the enzyme seems to increase the dissociation rate, although the drug retains its inhibitory activity with decreased potency and long residence time. In addition, tideglusib failed to inhibit a series of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3β obeys to a specific mechanism and is not a consequence of nonspecific reactivity. Results obtained with [35S]tideglusib do not support unequivocally the existence of a covalent bond between the drug and GSK-3β. The irreversibility of the inhibition and the very low protein turnover rate observed for the enzyme are particularly relevant from a pharmacological perspective and could have significant implications on its therapeutic potential. PMID:22102280

  14. The effects of iohexol administration on technetium thyroid scintigraphy in normal cats.

    PubMed

    Lee, William R; Pease, Anthony P; Berry, Clifford R

    2010-01-01

    Administration of iodinated contrast medium interferes with iodide uptake in the human thyroid gland and compromises diagnostic thyroid scintigraphy and radioiodine treatment for 4-6 weeks. However, the degree and duration of inhibition of thyroid uptake of pertechnetate (99mTcO4-) by iodinated contrast medium has not been established in any species. The main objective of this study was to better understand the temporal characteristics and magnitude of inhibition of feline thyroid uptake of 99mTcO4- due to iohexol administration. Routine thyroid scintigraphy was performed in eight cats by intravenous (IV) injection of 185 MBq (5 mCi) of 99mTcO4- both 4 days before and 0, 1, 3, 7, 14, and 28 days after IV administration of 880 mg I/kg iohexol (240 mg I/ml). Thyroid scintigraphy data were used to calculate thyroid:salivary gland ratios (T:S) and the percentage of total injected 99mTcO4- dose uptake within the thyroid (%TU) at 20 min postinjection. After iohexol administration, mean T:S was significantly decreased below baseline only on day 1. At no point during the study did any cat have a T:S that fell below the published normal reference range of 0.71 +/- 0.14. There was a significant decrease in %TU on day 1, 3, and 14; however, at no point during the study, did any cat have a %TU that fell below the published normal reference ranges of 0.64 +/- 0.57, 0.68 +/- 0.9, or 0.75 +/- 1.38.

  15. Betulin inhibited cigarette smoke-induced COPD in mice.

    PubMed

    Chunhua, Ma; Long, Hongyan; Zhu, Weina; Liu, Zheng; Jie, Ruan; Zhang, Yajie; Wang, Yarui

    2017-01-01

    The purpose of the present study was to evaluate the protective effect of betulin (BE) on CS (cigarette smoke)-induced COPD in mice and explore its underlying mechanisms. 60 male ICR mice were randomly assigned to five groups: control group, model group, dexamethasone (2mg/kg) group, BE (20mg/kg) group and BE (40mg/kg) group. The COPD mice were induced by cigarette smoke exposure for 8 weeks. The result of H&E staining demonstrated that BE inhibited CS-induced pathological injury in lung tissue. Besides, BE could restore the activities of superoxide dismutase (SOD) in serum and in lung, catalase (CAT) in serum and reduce the content of malondialdehyde (MDA) in serum and in lung. BE also inhibited the overproductions of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). Furthermore, the administration of BE significantly inhibited the protein expression of ROCK/NF-κB pathway in CS-induced mice. Our findings suggested that BE might effectively ameliorate the progression of COPD via ROCK/NF-κB pathway in mice.

  16. Specific bile acids inhibit hepatic fatty acid uptake

    PubMed Central

    Nie, Biao; Park, Hyo Min; Kazantzis, Melissa; Lin, Min; Henkin, Amy; Ng, Stephanie; Song, Sujin; Chen, Yuli; Tran, Heather; Lai, Robin; Her, Chris; Maher, Jacquelyn J.; Forman, Barry M.; Stahl, Andreas

    2012-01-01

    Bile acids are known to play important roles as detergents in the absorption of hydrophobic nutrients and as signaling molecules in the regulation of metabolism. Here we tested the novel hypothesis that naturally occurring bile acids interfere with protein-mediated hepatic long chain free fatty acid (LCFA) uptake. To this end stable cell lines expressing fatty acid transporters as well as primary hepatocytes from mouse and human livers were incubated with primary and secondary bile acids to determine their effects on LCFA uptake rates. We identified ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) as the two most potent inhibitors of the liver-specific fatty acid transport protein 5 (FATP5). Both UDCA and DCA were able to inhibit LCFA uptake by primary hepatocytes in a FATP5-dependent manner. Subsequently, mice were treated with these secondary bile acids in vivo to assess their ability to inhibit diet-induced hepatic triglyceride accumulation. Administration of DCA in vivo via injection or as part of a high-fat diet significantly inhibited hepatic fatty acid uptake and reduced liver triglycerides by more than 50%. In summary, the data demonstrate a novel role for specific bile acids, and the secondary bile acid DCA in particular, in the regulation of hepatic LCFA uptake. The results illuminate a previously unappreciated means by which specific bile acids, such as UDCA and DCA, can impact hepatic triglyceride metabolism and may lead to novel approaches to combat obesity-associated fatty liver disease. PMID:22531947

  17. Cloricromene inhibits the induction of nitric oxide synthase.

    PubMed

    Zingarelli, B; Carnuccio, R; Di Rosa, M

    1993-10-19

    The effect of cloricromene, a coumarin derivative, was investigated on the lipopolysaccharide-stimulated nitric oxide (NO) synthase induction in intact aortas from endotoxin shocked rats and in the murine macrophage cell line J774. Rings of thoracic aortas from lipopolysaccharide (4 mg/kg, i.v.)-shocked rats, contracted with phenylephrine, showed a progressive decrease in tone, that was of a greater magnitude than that of aortas from naive rats. Moreover, a decreased response to the constrictor effect of phenylephrine was observed in aortas from shocked rats. In vivo treatment with cloricromene (2 mg/kg, i.v.) 30 min before lipopolysaccharide administration partially prevented the loss in tone of aortic rings and improved their reactivity to phenylephrine. Murine J774 macrophages activated with lipopolysaccharide (100 ng/ml) produced significant amounts of nitrites (NO2-; 28.2 +/- 3.5 nmol/10(6) cells per 24 h). Cloricromene (2, 20 or 200 microM) added to the cells concomitantly with lipopolysaccharide inhibited NO2- production in a concentration-dependent manner. Maximum inhibition (84.0 +/- 8.0%) was observed when cloricromene (200 microM) was added to the cells 6 h before lipopolysaccharide, whereas it was ineffective when given 6 h after endotoxin. These results demonstrate that cloricromene inhibits the expression but not the activity of the inducible NO synthase.

  18. The significance of the washout period in Preconditioning.

    PubMed

    Salie, Ruduwaan; Lochner, Amanda; Loubser, Dirk J

    2017-01-24

    Exposure of the heart to 5 min global ischaemia (I) followed by 5 min reperfusion (R) (ischaemic preconditioning, IPC) or transient Beta 2-adrenergic receptor (B2-AR) stimulation with formoterol (B2PC), followed by 5 min washout before index ischaemia, elicits cardioprotection against subsequent sustained ischaemia. Since the washout period during preconditioning is essential for subsequent cardioprotection, the aim of this study was to investigate the involvement of protein kinase A (PKA), reactive oxygen species (ROS), extracellular signal-regulated kinase (ERK), PKB/Akt, p38 MAPK and c-jun N-terminal kinase (JNK) during this period. Isolated perfused rat hearts were exposed to IPC (1x5min I / 5min R) or B2PC (1x5min Formoterol / 5min R) followed by 35 min regional ischaemia and reperfusion. Inhibitors for PKA (Rp-8CPT-cAMP)(16μM), ROS (NAC)(300μM), PKB (A-6730)(2.5μM), ERKp44/p42 (PD98,059)(10μM), p38MAPK (SB239063)(1μM) or JNK (SP600125)(10μM) were administered for 5 minutes before 5 minutes global ischaemia / 5 min reperfusion (IPC) or for 5 minutes before and during administration of formoterol ( B2PC) prior to regional ischaemia, reperfusion and infarct size (IS) determination. Hearts exposed to B2PC or IPC were freeze-clamped during the washout period for Western blots analysis of PKB, ERKp44/p42, p38MAPK and JNK. The PKA blocker abolished both B2PC and IPC, while NAC significantly increased IS of IPC but not of B2PC. Western blot analysis showed that ERKp44/p42 and PKB activation during washout after B2PC compared to IPC was significantly increased. IPC compared to B2PC showed significant p38MAPK and JNKp54/p46 activation. PKB and ERK inhibition or p38MAPK and JNK inhibition during the washout period of B2PC and IPC respectively, significantly increased IS. PKA activation before regional ischaemia is a prerequisite for cardioprotection in both B2PC and IPC. However, ROS was crucial only in IPC. Kinase activation during the washout phase of IPC and B2

  19. [Behavioral correlations of gradual forced administration of psychoactive drugs].

    PubMed

    Shabanov, P D; Lebedev, A A

    2011-01-01

    The study was aimed at evaluating the behavioral correlations of the forced administration of psychoactive drugs. Wistar rats received the following drugs in elevated doses (over 4 days, i. p.): (i) physiological saline (control; 0.1-0.2-0.4-0.8 ml/rat), (ii) psychostimulant amphetamine (0.5-1.0--2.0-4.0 mg/kg); (iii) opioid analgetic fentanyl (0.00625-0.0125--0.025-0.05 mg/kg), (iv) ethanol 40% solution (0.5-1.0--2.0-4.0 g/kg), (v) barbiturate sodium ethaminal (2.5-5--10-20 mg/kg); and(vi) synthetic glucocorticoid dexamethasone (0.5-1.0--2.0-4.0 mg/kg). The forced regime of drug administration led to gradual load of the organism and prevented drug tolerance. The dynamics of self-stimulation reaction of the lateral hypothalamus was registered every day over drug administration period and revealed the following regularities: (I) dose-dependent effect of psychostimulant amphetamine and opioid analgetic fentanyl; (II) dexamethasone modulated self-stimulation, increasing (2 day, 1 mg/kg) or decreasing it (3 day, 2 mg/kg); (III) ethanol (1-2 g/kg) activated self-stimulation slightly; (IV) sodium ethaminal slightly inhibited self-stimulation and increased the thresholds of self-stimulation. In 24 h and 72 h after the last administration of drugs, the rat behavior was assessed in open field, elevated plus maze, resident-intruder paradigm, and Porsolt's test. In the open field, significant signs of post-intoxication exposure of psychoactive drugs were revealed, which were registered for 24-72 h after drug withdrawal. The withdrawal of drugs was accompanied with reduction (in 24 h) and subsequent recovery (in 72 h) of the vertical motor activity, exploration behavior, and emotionality. The anxiety indexes were increased up to the 3rd day after withdrawal. The antidepressant effect was also increased. The system of aggression-defense was restored only in rats treated with ethanol. The indexes of individual behavior and communicability in the post-intoxication period were

  20. MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

    PubMed Central

    Bobustuc, George C; Smith, Joshua S; Maddipatla, Sreeram; Jeudy, Sheila; Limaye, Arati; Isley, Beth; Caparas, Maria-Lourdes M; Constantino, Susan M; Shah, Nikita; Baker, Cheryl H; Srivenugopal, Kalkunte S; Baidas, Said; Konduri, Santhi D

    2012-01-01

    Antiestrogen therapy resistance remains a huge stumbling block in the treatment of breast cancer. We have found significant elevation of O6 methylguanine DNA methyl transferase (MGMT) expression in a small sample of consecutive patients who have failed tamoxifen treatment. Here, we show that tamoxifen resistance is accompanied by upregulation of MGMT. Further we show that administration of the MGMT inhibitor, O6-benzylguanine (BG), at nontoxic doses, leads to restoration of a favorable estrogen receptor alpha (ERα) phosphorylation phenotype (high p-ERα Ser167/low p-ERα Ser118), which has been reported to correlate with sensitivity to endocrine therapy and improved survival. We also show BG to be a dual inhibitor of MGMT and ERα. In tamoxifen-resistant breast cancer cells, BG alone or in combination with antiestrogen (tamoxifen [TAM]/ICI 182,780 [fulvestrant, Faslodex]) therapy enhances p53 upregulated modulator of apoptosis (PUMA) expression, cytochrome C release and poly (ADP-ribose) polymerase (PARP) cleavage, all indicative of apoptosis. In addition, BG increases the expression of p21cip1/waf1. We also show that BG, alone or in combination therapy, curtails the growth of tamoxifen-resistant breast cancer in vitro and in vivo. In tamoxifen-resistant MCF7 breast cancer xenografts, BG alone or in combination treatment causes significant delay in tumor growth. Immunohistochemistry confirms that BG increases p21cip1/waf1 and p-ERα Ser167 expression and inhibits MGMT, ERα, p-ERα Ser118 and ki-67 expression. Collectively, our results suggest that MGMT inhibition leads to growth inhibition of tamoxifen-resistant breast cancer in vitro and in vivo and resensitizes tamoxifen-resistant breast cancer cells to antiestrogen therapy. These findings suggest that MGMT inhibition may provide a novel therapeutic strategy for overcoming antiestrogen resistance. PMID:22549111

  1. Mechanism of an unusual, but clinically significant, digoxin-bupropion drug interaction.

    PubMed

    He, Jiake; Yu, Yang; Prasad, Bhagwat; Chen, Xijing; Unadkat, Jashvant D

    2014-07-01

    An unusual, but clinically significant, digoxin (DIG)-bupropion (BUP) drug interaction (DDI), in which BUP increased DIG renal clearance by 80% is reported. To investigate the mechanism(s) of this unusual DDI, first the effect of BUP, its circulating metabolites or their combination on [(3) H]-DIG transport by cells expressing human P-gp or human OATP4C1 was determined. Second, the study asked whether this DDI could be replicated in the rat so that it could be used to conduct mechanistic studies. Then, the effect of BUP and its rat metabolites on [(3) H]-DIG transport were tested by cells expressing rat Oatp4c1. Bupropion and its metabolites had no effect on human P-gp mediated transepithelial transport of [(3) H]-DIG. Bupropion and hydroxybupropion (HBUP) significantly stimulated H-OATP4C1 mediated transport of [(3) H]-DIG. In addition, BUP cocktail (BUP plus its metabolites) significantly increased the H-OATP4C1 mediated transport of [(3) H]-DIG, and partially reversed the inhibition by 100 µm DIG. However, erythro-hydrobupropion (EBUP) and threo-hydrobupropion (TBUP) did not affect the [(3) H]-DIG uptake by H-OATP4C1 cells. Bupropion administration significantly increased digoxin renal clearance in rats. Surprisingly, bupropion significantly inhibited r-Oatp4c1 mediated transport of [(3) H]-DIG at clinically relevant unbound plasma concentrations of BUP or those observed in the rat study, while HBUP or TBUP did not. These data support our hypothesis that at clinically relevant plasma concentrations, bupropion and its metabolites activate H-OATP4C1 mediated DIG tubular secretion, and could possibly explain the increase in digoxin renal clearance produced by bupropion. While bupropion increased digoxin renal clearance in the rat, it appeared to do so by inhibiting r-Oatp4c1-mediated digoxin renal reabsorption.

  2. Amiodarone Inhibits Apamin-Sensitive Potassium Currents

    PubMed Central

    Turker, Isik; Yu, Chih-Chieh; Chang, Po-Cheng; Chen, Zhenhui; Sohma, Yoshiro; Lin, Shien-Fong; Chen, Peng-Sheng; Ai, Tomohiko

    2013-01-01

    Background Apamin sensitive potassium current (IKAS), carried by the type 2 small conductance Ca2+-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. Objective To test the hypothesis that amiodarone inhibits IKAS in human embryonic kidney 293 (HEK-293) cells. Methods We used the patch-clamp technique to study IKAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration. Results Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67±0.25 µM with 1 µM intrapipette Ca2+). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6±3.1% of IKAS induced with 1 µM intrapipette Ca2+ (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca2+-dependent: 30 µM amiodarone inhibited 81.5±1.9% of IKAS induced with 1 µM Ca2+ (n = 4), and 16.4±4.9% with 250 nM Ca2+ (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca2+ dependent inhibition of IKAS. Conclusion Both amiodarone and desethylamiodarone inhibit IKAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca2+ concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles. PMID:23922993

  3. Bevacizumab radiosensitizes non-small cell lung cancer xenografts by inhibiting DNA double-strand break repair in endothelial cells.

    PubMed

    Gao, Hui; Xue, Jianxin; Zhou, Lin; Lan, Jie; He, Jiazhuo; Na, Feifei; Yang, Lifei; Deng, Lei; Lu, You

    2015-08-28

    The aims of this study were to evaluate the effects of biweekly bevacizumab administration on a tumor microenvironment and to investigate the mechanisms of radiosensitization that were induced by it. Briefly, bevacizumab was administered intravenously to Balb/c nude mice bearing non-small cell lung cancer (NSCLC) H1975 xenografts; in addition, bevacizumab was added to NSCLC or endothelial cells (ECs) in vitro, followed by irradiation (IR). The anti-tumor efficacy, anti-angiogenic efficacy and repair of DNA double-strand breaks (DSBs) were evaluated. The activation of signaling pathways was determined using immunoprecipitation (IP) and WB analyses. Finally, biweekly bevacizumab administration inhibited the growth of H1975 xenografts and induced vascular normalization periodically. Bevacizumab more significantly increased cellular DSB and EC apoptosis when administered 1 h prior to 12 Gy/1f IR than when administered 5 days prior to IR, thereby inhibiting tumor angiogenesis and growth. In vitro, bevacizumab more effectively increased DSBs and apoptosis prior to IR and inhibited the clonogenic survival of ECs but not NSCLC cells. Using IP and WB analyses, we confirmed that bevacizumab can directly inhibit the phosphorylation of components of the VEGR2/PI3K/Akt/DNA-PKcs signaling pathway that are induced by IR in ECs. In conclusion, bevacizumab radiosensitizes NSCLC xenografts mainly by inhibiting DSB repair in ECs rather than by inducing vascular normalization.

  4. Brain-derived mast cells could mediate histamine-induced inhibition of food intake in neonatal chicks.

    PubMed

    Kawakami, S; Bungo, T; Ohgushi, A; Ando, R; Shimojo, M; Masuda, Y; Denbow, D M; Furuse, M

    2000-02-28

    In the present study, the effect of intracerebroventricular (i.c.v.) administration of histamine on food intake of neonatal chicks was examined over 2 h. Histamine (100, 200 or 400 nmol, respectively) was injected in the lateral ventricle of 2-day-old chicks, and cumulative food intakes were measured. i.c.v. injection of histamine significantly inhibited food intake in a dose-dependent manner. In addition, compound 48/80, which causes degranulation of mast cells and release of histamine, or thioperamide, which is an antagonist of the histamine H3 autoreceptor and increases histamine release from histaminergic nerve terminals, was injected i.c.v. to clarify whether mast cell- or neuron-derived histamine in the central nervous system of chicks is essential to the feeding inhibition. Central administration of compound 48/80 inhibited food intake with a dose-dependent manner, but thioperamide had no effect on feeding. An inhibitor of mast cell degranulation, sodium cromoglycate, somewhat attenuated food intake inhibited by compound 48/80. These results suggest that brain-derived mast cells could be a major source of histamine in the inhibition of food intake of neonatal chicks.

  5. Inhibition of Ca²⁺/calmodulin-dependent protein kinase kinase 2 stimulates osteoblast formation and inhibits osteoclast differentiation.

    PubMed

    Cary, Rachel L; Waddell, Seid; Racioppi, Luigi; Long, Fanxin; Novack, Deborah V; Voor, Michael J; Sankar, Uma

    2013-07-01

    Bone remodeling, a physiological process characterized by bone formation by osteoblasts (OBs) and resorption of preexisting bone matrix by osteoclasts (OCs), is vital for the maintenance of healthy bone tissue in adult humans. Imbalances in this vital process result in pathological conditions including osteoporosis. Owing to its initial asymptomatic nature, osteoporosis is often detected only after the patient has sustained significant bone loss or a fracture. Hence, anabolic therapeutics that stimulate bone accrual is in high clinical demand. Here we identify Ca²⁺/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) as a potential target for such therapeutics because its inhibition enhances OB differentiation and bone growth and suppresses OC differentiation. Mice null for CaMKK2 possess higher trabecular bone mass in their long bones, along with significantly more OBs and fewer multinuclear OCs. In vitro, although Camkk2⁻/⁻ mesenchymal stem cells (MSCs) yield significantly higher numbers of OBs, bone marrow cells from Camkk2⁻/⁻ mice produce fewer multinuclear OCs. Acute inhibition of CaMKK2 by its selective, cell-permeable pharmacological inhibitor STO-609 also results in increased OB and diminished OC formation. Further, we find phospho-protein kinase A (PKA) and Ser¹³³ phosphorylated form of cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB) to be markedly elevated in OB progenitors deficient in CaMKK2. On the other hand, genetic ablation of CaMKK2 or its pharmacological inhibition in OC progenitors results in reduced pCREB as well as significantly reduced levels of its transcriptional target, nuclear factor of activated T cells, cytoplasmic (NFATc1). Moreover, in vivo administration of STO-609 results in increased OBs and diminished OCs, conferring significant protection from ovariectomy (OVX)-induced osteoporosis in adult mice. Overall, our findings reveal a novel function for CaMKK2 in bone remodeling and

  6. Lansoprazole induces apoptosis of breast cancer cells through inhibition of intracellular proton extrusion.

    PubMed

    Zhang, Shangrong; Wang, Yifan; Li, Shu Jie

    2014-06-13

    The increased glycolysis and proton secretion in tumors is proposed to contribute to the proliferation and invasion of cancer cells during the process of tumorigenesis and metastasis. Here, treatment of human breast cancer cells with proton pump inhibitor (PPI) lansoprazole (LPZ) induces cell apoptosis in a dose-dependent manner. In the implantation of the MDA-MB-231 xenografts in nude mice, administration of LPZ significantly inhibits tumorigenesis and induces large-scale apopotosis of tumor cells. LPZ markedly inhibits intracellular proton extrusion, induces an increase in intracellular ATP level, lysosomal alkalinization and accumulation of reactive oxygen species (ROS) in breast cancer cells. The ROS scavenger N-acetyl-l-cysteine (NAC) and diphenyleneiodonium (DPI), a specific pharmacological inhibitor of NADPH oxidases (NOX), significantly abolish LPZ-induced ROS accumulation in breast cancer cells. Our results suggested that LPZ may be used as a new therapeutic drug for breast tumor.

  7. Milnacipran inhibits oxaliplatin-induced mechanical allodynia through spinal action in mice.

    PubMed

    Andoh, Tsugunobu; Kitamura, Ryo; Kuraishi, Yasushi

    2015-01-01

    We investigated whether milnacipran, a serotonin-noradrenaline reuptake inhibitor, would have therapeutic effect on oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin (3 mg/kg) induced mechanical allodynia, which peaked on day 10 after injection and almost completely subsided by day 20. Ten days post-oxaliplatin injection, the intraperitoneal administration of milnacipran (3-30 mg/kg) significantly and dose-dependently inhibited the established mechanical allodynia. Intrathecal injections of milnacipran (2.1-21 µg/site) also significantly and dose-dependently inhibited mechanical allodynia, but intracisternal and intracereboventricular injections at the same doses did not. The present results suggest that milnacipran is effective against oxaliplatin-induced mechanical allodynia and that the antiallodynic effect is mainly mediated by actions on the spinal cord.

  8. Administrator Protections in Negotiated Contracts.

    ERIC Educational Resources Information Center

    Pisapia, John Ralph; Sells, Jack D.

    1978-01-01

    Presents specific examples of provisions currently found in administrator-board collective bargaining agreements that protect administrators from the adverse effects of both bilateral decisions made by boards with teachers, and unilateral decisions made by boards concerning principals. (Author)

  9. Administrative Aspects of Human Experimentation.

    ERIC Educational Resources Information Center

    Irvine, George W.

    1992-01-01

    The following administrative aspects of scientific experimentation with human subjects are discussed: the definition of human experimentation; the distinction between experimentation and treatment; investigator responsibility; documentation; the elements and principles of informed consent; and the administrator's role in establishing and…

  10. Administration for Children and Families

    MedlinePlus

    ... Speeches Videos What is the Administration for Children & Families? The Administration for Children and Families (ACF) is ... Visit the Office of Community Services Website The Family Room Blog RSS Feed Building Community, Building Hope: ...

  11. The Role of GABAB Receptors in Morphine Self-Administration

    PubMed Central

    Ramshini, Effat; Alaei, Hojjatallah; Reisi, Parham; Alaei, Samaneh; Shahidani, Somaye

    2013-01-01

    Background: There is only little information about the effects of GABA receptors agonist and antagonist on morphine self-administration. Present study was designed to assess role of GABAB receptors in the regulation of morphine-reinforced self-administration. Methods: This study was performed in four groups of rats: (1) Saline group, which received saline in the self-administration session. (2) Morphine group, which received morphine in saline solution in the self-administration session. (3) Baclofen + Morphine group, which received both baclofen 20 min before self- administration test and morphine in the self-administration session. (4) Phaclofen + Morphine group, which received both phaclofen 20 min before self- administration test and morphine in the self-administration session. The number of lever pressing and self-infusion were recorded. Results: Morphine significantly increased the number of active lever pressing dose dependently in self-administration session in comparative with saline group. Administration of baclofen, 20 min before morphine self-administration produced significant decrease in the initiation of morphine self-administration during all session. Conversely, pre-treatment of phaclofen increased the number of active lever pressing and self-infusion in this test. Conclusion: Our results indicated a short-term treatment by baclofen, reduced morphine-maintenance response in a dose-dependent manner, suggesting that GABAB receptor agonists could be useful for reversing the neuroadaptations related to opiates. PMID:23542877

  12. Administrative Uses of the Microcomputer.

    ERIC Educational Resources Information Center

    Spuck, Dennis W.; Atkinson, Gene

    1983-01-01

    An outline of microcomputer applications for administrative computing in education is followed by discussions of aspects of office automation, database management systems, management information systems, administrative computer systems, and software. Several potential problems relating to administrative computing in education are identified.…

  13. Administrators' Decisions about Resource Allocation

    ERIC Educational Resources Information Center

    Knight, William E.; Folkins, John W.; Hakel, Milton D.; Kennell, Richard P.

    2011-01-01

    Do academic administrators make decisions about resource allocation differently depending on the discipline receiving the funding? Does an administrator's academic identity influence these decisions? This study explored those questions with a sample of 1,690 academic administrators at doctoral-research universities. Participants used fictional…

  14. Three Generations of Educational Administration.

    ERIC Educational Resources Information Center

    Sharpe, F. G.

    This paper compares two Australian educational administration texts published in 1963 to reflect critically on the radical changes that have occurred in educational administration in Australia since then. The books are "Headmasters for Better Schools," by Bassett, Crane, and Walker; and "Training the Administrator," by…

  15. Certification of Financial Aid Administrators

    ERIC Educational Resources Information Center

    Peterson, Stacey A.

    2011-01-01

    The certification of financial aid administrators has been debated for over 37 years. A job satisfaction survey conducted by the National Association of Student Financial Aid Administrators (NASFAA, 2008a) revealed that college and university administrators' perceptions of the efficiency, effectiveness, and quality of the services provided by the…

  16. The Cultural Context of Administration.

    ERIC Educational Resources Information Center

    Ortiz, Flora Ida

    To explicate the relevance of cultural context to educational administration practices, this paper contrasts United States cultural attitudes and administrative practices with those of Latin America. Drawing on Leslie A. White's definition of culture, the author presents the Weberian model of administration as exemplary for the United States,…

  17. Comparing Administrators' Perceptions of SBM.

    ERIC Educational Resources Information Center

    Jacobson, Stephen L.; Woodworth, Beth

    The purpose of this study was to examine the perceptions of administrators of small rural districts hold about school-based management (SBM) and to compare them with the perceptions of administrators in larger, nonrural districts. Administrators' perceptions of what should occur in SBM were compared with what they perceived does occur. Responses…

  18. Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity

    PubMed Central

    Dudhgaonkar, Shailesh; Ranade, Sourabh; Nagar, Jignesh; Subramani, Siva; Prasad, Durga Shiv; Karunanithi, Preethi; Srivastava, Ratika; Venkatesh, Kamala; Selvam, Sabariya; Krishnamurthy, Prasad; Mariappan, T. Thanga; Saxena, Ajay; Fan, Li; Stetsko, Dawn K.; Holloway, Deborah A.; Li, Xin; Zhu, Jun; Yang, Wen-Pin; Ruepp, Stefan; Nair, Satheesh; Santella, Joseph; Duncia, John; Hynes, John; McIntyre, Kim W.

    2017-01-01

    The serine/threonine kinase IL-1R–associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus. PMID:28003376

  19. Targeting autophagy potentiates chemotherapy-induced apoptosis and proliferation inhibition in hepatocarcinoma cells.

    PubMed

    Guo, Xian-Ling; Li, Ding; Hu, Fei; Song, Jian-Rui; Zhang, Shan-Shan; Deng, Wei-Jie; Sun, Kai; Zhao, Qiu-Dong; Xie, Xu-Qin; Song, Yu-Jiao; Wu, Meng-Chao; Wei, Li-Xin

    2012-07-28

    Induction of cell death and inhibition of cell growth are the main targets of cancer therapy. Here we evaluated the role of autophagy on chemoresistance of human hepatocarcinoma (HCC) cell lines, focusing on its crosstalk with cell apoptosis and proliferation. In this study, a chemotherapeutic agent (cisplatin or 5FU) induced the formation of autophagosomes in three human HCC cell lines and upregulated the expression of autophagy protein LC3-II. Inhibition of autophagy by 3-methyladenine or si-beclin 1 increased chemotherapy-induced apoptosis in HCC cells. Meanwhile, increased damage of the mitochondrial membrane potential was also observed in HCC cells when autophagy was inhibited. Furthermore, inhibition of autophagy reduced clone formation and impaired cell growth of HCC cells when treated with chemotherapy. Co-administration of an autophagy inhibitor (chloroquine) and chemotherapy significantly inhibited tumor growth in a mouse xenograft tumor model, with greater extent of apoptosis and impaired proliferation of tumor cells. This study suggests that autophagy is a potential novel target to improve therapy efficiency of conventional chemotherapeutics towards HCC.

  20. Inhibition of prolyl hydroxylase domain-containing protein downregulates vascular angiotensin II type 1 receptor.

    PubMed

    Matsuura, Hirohide; Ichiki, Toshihiro; Ikeda, Jiro; Takeda, Kotaro; Miyazaki, Ryohei; Hashimoto, Toru; Narabayashi, Eriko; Kitamoto, Shiro; Tokunou, Tomotake; Sunagawa, Kenji

    2011-09-01

    Inhibition of prolyl hydroxylase domain-containing protein (PHD) by hypoxia stabilizes hypoxia-inducible factor 1 and increases the expression of target genes, such as vascular endothelial growth factor. Although the systemic renin-angiotensin system is activated by hypoxia, the role of PHD in the regulation of the renin-angiotensin system remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin II type 1 receptor (AT(1)R). Hypoxia, cobalt chloride, and dimethyloxalylglycine, all known to inhibit PHD, reduced AT(1)R expression in vascular smooth muscle cells. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT(1)R expression. Cobalt chloride diminished angiotensin II-induced extracellular signal-regulated kinase phosphorylation. Cobalt chloride decreased AT(1)R mRNA through transcriptional and posttranscriptional mechanisms. Oral administration of cobalt chloride (14 mg/kg per day) to C57BL/6J mice receiving angiotensin II infusion (490 ng/kg per minute) for 4 weeks significantly attenuated perivascular fibrosis of the coronary arteries without affecting blood pressure level. These data suggest that PHD inhibition may be beneficial for the treatment of cardiovascular diseases by inhibiting renin-angiotensin system via AT(1)R downregulation.

  1. Operations Research and Higher Education Administration.

    ERIC Educational Resources Information Center

    Cheng, T. C . E.

    1993-01-01

    Illustrates the uses of operations research (OR) in higher education administration by reviewing the higher education system's most significant operational problems: resource allocation, financial planning, budgeting, formation of student project groups, scheduling and classroom allocation, student registration, tuition and fee structure…

  2. The Wage Gap and Administrative Salaries Today.

    ERIC Educational Resources Information Center

    Beyer, Kirk D.

    1992-01-01

    Analysis of national data on college administrator salaries by gender, minority/nonminority status, years of service, and institution type found that wage gaps related to gender and minority status persisted in 1991-92 but that interaction of length of service with other study variables explained a significant amount of this gap. (MSE)

  3. Mode of inhibitory actions of acute and chronic chloroquine administration on the electrically stimulated mouse diaphragm in vitro.

    PubMed Central

    Okwuasaba, F. K.; Otubu, J. A.; Udoh, F. V.

    1990-01-01

    1. The effects of bath applied chloroquine (Chlo) and of acute and chronic Chlo administration on skeletal muscle reactivity to electrical stimulation and to drugs have been studied on mouse hemidiaphragm preparations in vitro. 2. Chlo (0.15-150 micrograms) produced a concentration-dependent inhibition twitch and tetanic contractions due to direct muscle stimulation (MS). Acute and chronic administration of Chlo (45 mg kg-1, i.p. daily, for 3-28 days) progressively shifted the concentration-response curve to bath-applied Chlo to the right, with maximum effect occurring from day 14 of Chlo pretreatment. 3. Acute and chronic administration of Chlo decreased the twitch and tetanus tension, raised the minimal fusion frequency (MFR) for tetanic contraction to occur and did not alter the twitch/tetanus tension ratio. Tetanus tension unlike twitch tension was not significantly decreased on day 3. 4. Caffeine (5-500 microM)--and isoprenaline (0.001-0.8 microM)-induced potentiations of twitch contraction were attenuated in a concentration-dependent manner by bath-applied Chlo and by acute and chronic administration of Chlo. Higher concentrations of caffeine (0.1-5 microM) and KCl (10 mM-130 mM) produced contracture of the muscle which was sensitive to inhibition by Chlo (50-150 microM). Moreover, the spike contractions superimposed on caffeine contracture were more sensitive to the inhibitory effect of Chlo than the contracture. 5. The inhibitory effects of dantrolene sodium and (+)-tubocurarine on MS and on indirectly stimulated hemidiaphragm respectively were not significantly altered by acute and chronic administration of Chlo. In contrast, the inhibitory concentration-response curve to procaine was shifted to the right.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2282456

  4. Key Obama officials leave administration

    NASA Astrophysics Data System (ADS)

    Showstack, Randy

    2013-01-01

    Secretary of the Interior Ken Salazar is one of the latest members of the Obama administration to announce that he is leaving his position near the start of President Obama's second term in office. Salazar, who has served as interior secretary since January 2009, intends to leave the department by the end of March, the department noted on 16 January. Salazar joins a number of other key officials who are planning to leave the administration. They include Environmental Protection Agency administrator Lisa Jackson, National Oceanic and Atmospheric Administration administrator Jane Lubchenco, and U.S. Geological Survey director Marcia McNutt.

  5. Olopatadine hydrochloride inhibits capsaicin-induced flare response in humans.

    PubMed

    Shindo, Masahisa; Yoshida, Yuichi; Yamamoto, Osamu

    2011-01-01

    Capsaicin, a vanilloid, has the potential for releasing substance P (SP) from sensory nerves. Topical application of capsaicin induces a flare response in the skin. However, it has not been clarified whether the release of SP is involved in the process of flare response or not. A potent antihistamine drug, olopatadine hydrochloride, is known to have inhibitory action against the release of SP. We examined the effects of olopatadine (at a dose of 5 mg) on skin reaction induced by topical application of capsaicin in 10 healthy subjects. The scores of capsaicin-induced flare responses after olopatadine administration were significantly lower at 30 min than at baseline. Our findings suggest that olopatadine hydrochloride could inhibit capsaicin-induced flare responses.

  6. Coptis chinensis Polysaccharides Inhibit Advanced Glycation End Product Formation.

    PubMed

    Yang, Ye; Li, Yun; Yin, Dengke; Chen, Song; Gao, Xiangdong

    2016-06-01

    Coptis chinensis Franch (Huanglian) is commonly used to treat diabetes in China. In this study, the effects of the C. chinensis Franch polysaccharides (CCP) on advanced glycation end product (AGE) formation in vitro and in streptozotocin-induced diabetic mice were investigated. CCP significantly inhibited all the three periods of nonenzymatic protein glycation in vitro, including Amadori product, dicarbonyl compound, and AGE formation (P < .01). In diabetic mice, the administration of CCP not only improved both bodyweight and serum insulin and decreased fasting blood glucose and glycated serum protein concentrations but also decreased the AGE accumulations and morphological abnormalities in pancreas and liver. The inhibitory effects of CCP on AGE formation afford a potential therapeutic use in the prevention and treatment of diabetes.

  7. Development of tolerance after repeated administration of a selective muscarinic M1 antagonist biperiden in healthy human volunteers.

    PubMed

    Salin-Pascual, R J; Granados-Fuentes, D; Galicia-Polo, L; Nieves, E; Gillin, J C

    1993-02-01

    The muscarinic antagonist biperiden produces a dose-dependent inhibition of (REM) sleep on acute administration. The present study addressed the possibility of pharmacological tolerance after repeated biperiden administration. Six healthy volunteers were studied under sleep laboratory conditions in the following situations: one acclimatization, night, two baseline (that were averaged), 4 nights of biperiden administration, and 4 nights of placebo recovery administration. Six milligrams of biperiden and placebo were administered in identical capsules. Volunteers and technicians were blind to the order of the administration of the capsules. REM sleep time was reduced during the first and the second night, but was not significantly different in comparison with baseline by the third night. During placebo recovery nights, REM sleep time was not different from baseline. REM sleep latency was increased during the first and second nights of biperiden administration, but tolerance to this effect was observed by the third night. On placebo nights a dramatic shortening of REM latency was observed. The present findings support the hypothesis that anticholinergic drugs, even a selective M1 antagonist such as biperiden, induce tolerance soon after administration. A similar effect has been reported with scopolamine, a nonselective muscarinic antagonist, but the main difference is that biperiden withdrawal was not followed by an REM sleep rebound. The observed effect on REM sleep latency during placebo administration may be related to a supersensitivity to muscarinic M-1 receptors that trigger the first REM sleep period. Because short REM latency has been the main finding in the sleep of depressed patients, some implications of the present findings are discussed.

  8. Effects of intracerebroventricular administration of N-acetylhistamine on body temperature in mice.

    PubMed

    Onodera, K; Shinoda, H; Imaizumi, M; Hiraki-Sakurai, E; Yamatodani, A

    1994-10-01

    The purpose of this study was to examine the effects of intracerebroventricular (i.c.v.) administration of N-acetylhistamine on rectal temperature, histamine level, histidine decarboxylase (HDC) activity, and the turnover rate of monoamines in mice. More than 60 micrograms of N-acetylhistamine induced hypothermia. The maximum effect of hypothermia was observed 20 min after administration of N-acetylhistamine (60-120 micrograms/mouse). A significant drop in rectal temperature of 3 degrees C was induced by 120 micrograms of N-acetylhistamine. Concurrent with the appearance of hypothermia, the histamine levels were increased. However, both histamine H1 and H2 antagonists did not prevent hypothermia. The i.c.v. administration of N-acetylhistamine inhibited HDC activity, but had no effect on the turnover rates of monoamines. These data confirmed that endogenous N-acetylhistamine may be a metabolite which lacks significant physiological roles, and demonstrated that exogenous N-acetylhistamine is not a good pharmacological tool for the study of the functions of the brain histaminergic system in mammals.

  9. Acute intravenous administration of dietary constituent theanine suppresses noxious neuronal transmission of trigeminal spinal nucleus caudalis in rats.

    PubMed

    Takehana, Shiori; Kubota, Yoshiko; Uotsu, Nobuo; Yui, Kei; Shimazu, Yoshihito; Takeda, Mamoru

    2017-03-15

    Theanine is a non-dietary amino acid linked to the modulation of synaptic transmission in the central nervous system, although the acute effects of theanine in vivo, particularly on nociceptive transmission in the trigeminal system, remain to be determined. The present study investigated whether acute intravenous theanine administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from 15 SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats, and responses to non-noxious and noxious mechanical stimuli were analyzed. The mean firing frequency of SpVc WDR neurons in response to all mechanical stimuli was dose-dependently inhibited by theanine (10, 50, and 100mM, i.v.) with the maximum inhibition of discharge frequency reached within 5min. These inhibitory effects were reversed after approximately 10min. The relative magnitude of theanine's inhibition of SpVc WDR neuronal discharge frequency was significantly greater for noxious than non-noxious stimulation. Iontophoretic application of l-glutamate induced the mean firing frequency of SpVc WDR neuron responding to noxious mechanical stimulation was also inhibited by intravenous administration of 100mM theanine. These results suggest that acute intravenous theanine administration suppresses glutaminergic noxious synaptic transmission in the SpVc, implicating theanine as a potential complementary and alternative therapeutic agent for the treatment of trigeminal nociceptive pain.

  10. Inhibition of hepatic S-3-hydroxy-3-methylglutaryl-CoA reductase and in vivo rates of lipogenesis by a mixture of pure cyclic monoterpenes.

    PubMed

    Middleton, B; Hui, K P

    1982-09-15

    A proprietary mixture of pure cyclic monoterpenes (Rowachol) inhibited hepatic HMGCoA reductase by 50-60% when measured 17 hr after the oral administration of a single dose to rats. The extent of this inhibition was independent of the normal activity range of HMGCoA reductase within its diurnal cycle and the same inhibition (65%) was found in 24 hr starved animals where the control reductase activity was less than 20% that of normal fed rats. De novo sterol and fatty acid synthesis in intact, fed rats was measured by incorporation of 3H from injected H2O. In rats treated with Rowachol the rate of sterol synthesis in vivo was inhibited 52% in liver and 44% in testis with no significant effects in other tissues. The synthesis of non sterol (isoprenoid) compounds in testis was unaffected and the inhibition of sterol synthesis in this tissue probably reflects decreased acquisition of newly synthesized material from liver rather than any effect on the endogenous process. In the same animals the rate of fatty acid synthesis was inhibited 55% in liver. These effects were associated with a significant depletion of liver glycogen which may account for the reduction in rate of fatty acid synthesis. We conclude that the reported cholelitholytic action of monoterpenes is associated with the physiological inhibition of hepatic sterol synthesis mediated by decrease HMGCoA reductase activity.

  11. P2Y12 receptor inhibition and effect of morphine in patients undergoing primary PCI for ST-segment elevation myocardial infarction. The PRIVATE-ATLANTIC study.

    PubMed

    Silvain, Johanne; Storey, Robert F; Cayla, Guillaume; Esteve, Jean-Baptiste; Dillinger, Jean-Guillaume; Rousseau, Hélène; Tsatsaris, Anne; Baradat, Caroline; Salhi, Néjoua; Hamm, Christian W; Lapostolle, Frédéric; Lassen, Jens Flensted; Collet, Jean-Philippe; Ten Berg, Jurriën M; Van't Hof, Arnoud W; Montalescot, Gilles

    2016-08-01

    PRIVATE-ATLANTIC (P2Y12 Receptor Inhibition with VASP Testing using Elisa kit during the ATLANTIC study) is a pre-specified substudy of the randomised, double-blind ATLANTIC trial in patients with ST-segment elevation myocardial infarction, designed to help interpret the main trial results. The primary objective of ATLANTIC was to assess coronary reperfusion prior to percutaneous coronary intervention (PCI) with pre- vs in-hospital ticagrelor 180 mg loading dose (LD). PRIVATE-ATLANTIC assessed platelet inhibition in 37 patients by measurement of vasodilator-associated stimulated phosphoprotein (VASP) platelet reactivity index (PRI) and VerifyNow platelet reactivity units (PRU) before angiogram (T1), immediately after PCI (T2), 1 (T3), and 6 (T4) hours (h) after PCI, and before next study drug administration (T5). The median time difference between the two ticagrelor LD was 41 minutes. Platelet reactivity was unaffected at T1 when measured by VASP-PRI (89.8 vs 93.9 % for pre- and in-hospital ticagrelor, respectively; p = 0.18) or PRU (239 vs 241; p = 0.82). Numerical differences were apparent at T2 and maximal at T3. Morphine administration significantly delayed onset of platelet inhibition at T3 (VASP-PRI 78.2 vs 23.4 % without morphine; p = 0.0116) and T4 (33.1 vs 11.0 %; p = 0.0057). In conclusion, platelet inhibition in ATLANTIC was unaffected by pre-hospital ticagrelor administration at the time of initial angiogram due to the short transfer delay. The maximum difference in platelet inhibition was detected 1 h after PCI (T3). Morphine administration was associated with delayed onset of action of ticagrelor and appeared more important than timing of ticagrelor administration.

  12. Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts

    PubMed Central

    Cheng, Michelle; Ho, Samantha; Yoo, Jun Hwan; Tran, Deanna Hoang-Yen; Bakirtzi, Kyriaki; Su, Bowei; Tran, Diana Hoang-Ngoc; Kubota, Yuzu; Ichikawa, Ryan; Koon, Hon Wai

    2015-01-01

    Background Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. Methods We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial–mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Results Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-β1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation. Conclusion Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast

  13. Pharmacokinetic interaction between ϵ-acetamidocaproic acid (AACA) and cimetidine in indomethacin-induced acute gastric ulcer and control rats: inhibition of active renal secretion of AACA by cimetidine.

    PubMed

    Choi, Y H; Lee, U; Suh, J H; Kim, Y G; Lee, M; Oh, E; Lee, M G

    2011-05-01

    After both the intravenous and oral administration of zinc acexamate [ZAC; ion-pairing between zinc and ϵ-acetamidocaproic acid (AACA)] and cimetidine together, the areas under the curve (AUCs) of AACA were significantly greater [by 28.2 and 98.9% after the intravenous and oral administration, respectively, for control rats and 13.5 and 16.9% for indomethacin-induced acute gastric ulcer (IAGU) rats, respectively] than those of ZAC alone due to the significantly slower renal clearance (CL(R)). The significantly greater AUCs of AACA after both the intravenous and oral administration of ZAC and cimetidine together in control and IAGU rats could have been due to the inhibition of active renal tubular secretion of AACA by cimetidine. After the intravenous and oral administration of both drugs together, the AUCs of cimetidine in control and IAGU rats were not different compared with those with cimetidine alone.

  14. Women: A Significant National Resource.

    ERIC Educational Resources Information Center

    National Council of Administrative Women in Education, Washington, DC.

    Believing that society, including children, suffers from the underutilization of more than half the talents available to educational administration, an annual meeting was devoted to a workshop designed to present and provide study of the pertinent facts. Keynote addresses by Congresswoman Edith Green, Wayne O. Reed, Earl C. Funderburk, Dorothy…

  15. Sonic hedgehog inhibitors prevent colitis-associated cancer via orchestrated mechanisms of IL-6/gp130 inhibition, 15-PGDH induction, Bcl-2 abrogation, and tumorsphere inhibition.

    PubMed

    Kangwan, Napapan; Kim, Yoon-Jae; Han, Young Min; Jeong, Migyeong; Park, Jong-Min; Go, Eun-Jin; Hahm, Ki-Baik

    2016-02-16

    Sonic hedgehog (SHH) signaling is essential in normal development of the gastrointestinal (GI) tract, whereas aberrantly activated SHH is implicated in GI cancers because it facilitates carcinogenesis by redirecting stem cells. Since colitis-associated cancer (CAC) is associated with inflammatory bowel diseases, in which SHH and IL-6 signaling, inflammation propagation, and cancer stem cell (CSC) activation have been implicated, we hypothesized that SHH inhibitors may prevent CAC by blocking the above SHH-related carcinogenic pathways. In the intestinal epithelial cells IEC-6 and colon cancer cells HCT-116, IL-6 expression and its signaling were assessed with SHH inhibitors and levels of other inflammatory mediators, proliferation, apoptosis, tumorsphere formation, and tumorigenesis were also measured. CAC was induced in C57BL/6 mice by administration of azoxymethane followed by dextran sodium sulfate administration. SHH inhibitors were administered by oral gavage and the mice were sacrificed at 16 weeks. TNF-α-stimulated IEC-6 cells exhibited increased levels of proinflammatory cytokines and enzymes, whereas SHH inhibitors suppressed TNF-α-induced inflammatory signaling, especially IL-6/IL-6R/gp130 signaling. SHH inhibitors significantly induced apoptosis, inhibited cell proliferation, suppressed tumorsphere formation, and reduced stemness factors. In the mouse model, SHH inhibitors significantly reduced tumor incidence and multiplicity, decreased the expression of IL-6, TNF-α, COX-2, STAT3, and NF-κB, and significantly induced apoptosis. In colosphere xenografts, SHH inhibitor significantly suppressed tumorigenesis by inhibiting tumorsphere formation. Taken together, our data suggest that administration of SHH inhibitors could be an effective strategy to prevent colitis-induced colorectal carcinogenesis, mainly by targeting IL-6 signaling, ablating CSCs, and suppressing oncogenic inflammation, achieving chemoquiescence ultimately.

  16. Inhibition of osteoporosis by the αvβ3 integrin antagonist of rhodostomin variants.

    PubMed

    Lin, Tzu-Hung; Yang, Rong-Sen; Tu, Huang-Ju; Liou, Houng-Chi; Lin, Yen-Ming; Chuang, Woie-Jer; Fu, Wen-Mei

    2017-03-14

    Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-matrix interaction. The vitronectin and osteopontin receptor αvβ3 integrin has increased expression levels and is implicated in the adhesion, activation, and migration of osteoclasts on the bone surface as well as osteoclast polarization. αvβ3 integrin plays an important role in osteoclast differentiation and resorption. In addition, Arg-Gly-Asp (RGD)-containing peptides, small molecular inhibitors, and antibodies to αvβ3 integrin have been shown to inhibit bone resorption in vitro and in vivo. Here we examined the effects of a disintegrin HSA-ARLDDL a genetically modified mutant of rhodostomin conjugated with human serum albumin, which is highly selective of αvβ3, on RANKL-induced osteoclastogenesis and ovariectomy (OVX)-induced osteoporosis. In RANKL-induced osteoclastogenesis, HSA-ARLDDL significantly inhibited osteoclast formation, and IC50 was at nM range. Post-treatment HSA-ARLDDL also inhibits osteoclast formation. Furthermore, weekly administration of HSA-ARLDDL significantly inhibits the increase in serum bone resorption marker levels and decrease in cancellous bone loss in tibia and femur induced by OVX. On the other hand, HSA-ARLDDL did not affect the differentiation and calcium deposition of osteoblasts. These results indicate that the highly selective and long-acting αvβ3 integrin antagonists could be developed as effective drugs for postmenopausal osteoporosis.

  17. DCT015, a new sorafenib derivate, inhibits tumor growth and angiogenesis in gastric cancer models.

    PubMed

    Wang, Wenyan; Wang, Hui; Ni, Yingying; Yao, Zhenming; Ye, Liang; Tian, Jingwei

    2016-07-01

    The objective of this study is to investigate antiproliferative activities against gastric cancer and anti-angiogenesis of DCT015, a novel sorafenib derivate, and potential mechanisms. The effects of DCT015 on proliferation and apoptosis in gastric cancer cells were evaluated by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blotting assays. The in vivo antitumor effects were carried out in nude mice bearing gastric cancer. On the other hand, the anti-angiogenesis effects of DCT015 were measured by human umbilical vein endothelial cell (HUVEC) proliferation, migration, tube formation, and Western blotting analysis. The results showed that DCT015 inhibited the proliferation, induced the morphological changes of apoptosis, and increased the apoptosis percentage, as well as increased the "sub-G1" population in gastric cancer cells. DCT015 also significantly decreased the tumor volumes and tumor weights in vivo by oral administration. Immunohistochemistry assay demonstrated that DCT015 inhibited tumor growth and neovascularization. In vitro studies found that DCT015 inhibited both MEK/ERK and PI3K/Akt signaling pathways by Western blotting assays. Moreover, DCT015 significantly inhibited VEGF-induced migration and tube formation in HUVECs. Western blotting analysis showed that DCT015 downregulated VEGF-induced VEGFR2 phosphorylation with the decreased phosphorylation of the downstream key proteins. Taken together, our findings highlight that DCT015 is a promising orally anticancer drug for treating gastric cancer.

  18. Inhibition of cholesterol synthesis ex vivo and in vivo by fluvastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.

    PubMed

    Yamamoto, A; Itoh, S; Hoshi, K; Ichihara, K

    1995-03-15

    The inhibitory effect of fluvastatin sodium (fluvastatin), a new type of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A inhibitor, on de novo cholesterol synthesis was investigated and compared with that of pravastatin. Fluvastatin at a concentration of 12.5 mg/kg inhibited sterol synthesis ex vivo from [14C]acetate in rat liver and ileum by 97-99% with respect to the control, while the inhibition in kidney was 55%. The inhibition by fluvastatin in the liver and ileum persisted for approximately 9 h after administration. Significant differences between fluvastatin also had an inhibitory effect on cholesterol synthesis in vivo in various tissues of rats given [14C]acetate intraperitoneally. Sterol synthesis in the liver, ileum and kidney was inhibited by over 95% 3 h after administration of 6.25 mg/kg of fluvastatin. Significant differences between fluvastatin and pravastatin were found in the liver and ileum. Fluvastatin was more potent than pravastatin in inhibiting both ex vivo and in vivo sterol synthesis in the ileum (but not in kidney) and liver.

  19. Prevention of photocarcinogenesis by topical administration of pure epigallocatechin gallate isolated from green tea.

    PubMed

    Gensler, H L; Timmermann, B N; Valcic, S; Wächter, G A; Dorr, R; Dvorakova, K; Alberts, D S

    1996-01-01

    Topical application of purified (-)-epigallocatechin-3-gallate (EGCG), a polyphenolic antioxidant isolated from green tea, inhibited photocarcinogenesis in BALB/cAnNHsd mice with no visible toxicity. Mice were treated with 0, 10, or 50 mg of EGCG in 200 microliters of acetone three times weekly for three weeks before ultraviolet (UV) treatments began and throughout the experiment. UV radiation consisted of five 30-minute exposures per week to banks of six FS40 Westinghouse sunlamps for 25 weeks. In the photocarcinogenesis study, mice received a total dose of approximately 2.1 x 10(6) J/m2. Skin cancer incidence in UV-irradiated mice was 96% at 28 weeks after the first UV treatment; EGCG at 10 or 50 mg reduced this incidence to 62% and 29%, respectively. UV-induced immunosuppression, assessed by the inability of UVB-irradiated mice to reject a syngeneic antigenic tumor, was not influenced by topical EGCG. Oral administration of 0, 100, or 500 mg of pure EGCG per liter of drinking water (approximately 0, 0.56, or 2.8 mg/day, respectively) did not decrease UV-induced skin tumor incidence, rate of primary tumor growth, or inability to reject antigenic tumors. Thus induction of skin tumors by UV radiation was significantly reduced by topical, but not by oral, administration of purified EGCG through a mechanism distinct from inhibition of photoimmunosuppression.

  20. The potentiation of taurocholate-induced rat gastric erosions following parenteral administration of cyclo-oxygenase inhibitors.

    PubMed Central

    Whittle, B. J.

    1983-01-01

    Subcutaneous administration of anti-inflammatory doses of aspirin, indomethacin, naproxen and flurbiprofen inhibited prostacyclin formation ex vivo in the luminally-perfused gastric mucosa of anaesthetized rats. These doses of anti-inflammatory compounds potentiated the formation of gastric mucosal erosions following 3 h luminal perfusion of the topical irritant, acidified sodium taurocholate (2 mM in 100 mM HCl). The increase in luminal acid-loss during gastric perfusion of acidified taurocholate was not significantly enhanced by these anti-inflammatory agents. A correlation was found between the increase in gastric erosion formation and the inhibition of mucosal prostacyclin formation ex vivo by intravenous injection of aspirin or ketoprofen during acid-taurocholate perfusion. BW755C, which failed to inhibit mucosal prostacyclin formation ex vivo, did not significantly augment acid-taurocholate induced gastric damage. The present findings support the potentiating interactions between topical irritation and inhibition of gastric cyclo-oxygenase in the genesis of the gastric lesions. PMID:6416343

  1. Altered prefrontal connectivity after acute heroin administration during cognitive control.

    PubMed

    Schmidt, André; Borgwardt, Stefan; Gerber, Hana; Schmid, Otto; Wiesbeck, Gerhard A; Riecher-Rössler, Anita; Bendfeldt, Kerstin; Smieskova, Renata; Lang, Undine E; Rubia, Katya; Walter, Marc

    2014-09-01

    Neuroimaging studies have reported reduced activity in a broad network of brain regions during response inhibition in heroin-dependent patients. However, how heroin in an acute dose modulates the neural correlates of response inhibition and the underlying brain connectivity has not yet been investigated. In this double-blind placebo-controlled study, we used functional magnetic resonance imaging to examine whether acute heroin administration changed whole brain activity during response inhibition in 26 heroin-dependent patients. We then applied dynamic causal modelling to investigate the effect of an acute dose of heroin on the functional interactions between the dorsal anterior cingulate cortex (dACC) and the bilateral inferior frontal gyri (IFG). Heroin acutely reduced dACC activity, as well as the inhibition-induced modulation of connectivity from the dACC to the right IFG compared with placebo. Furthermore, dACC activity was positively related to false alarm rates after placebo but not heroin administration. These results suggest that acute heroin administration impairs cognitive control in dependent patients by reducing the activity in the dACC activity and the functional connectivity from the dACC to the right IFG.

  2. Low Level Chlorpyrifos Exposure Increases Anandamide Accumulation in Juvenile Rat Brain in the Absence of Brain Cholinesterase Inhibition

    PubMed Central

    Carr, Russell L.; Graves, Casey A.; Mangum, Lee C.; Nail, Carole A.; Ross, Matthew K.

    2014-01-01

    The prevailing dogma is that chlorpyrifos (CPF) mediates its toxicity through inhibition of cholinesterase (ChE). However, in recent years, the toxicological effects of developmental CPF exposure have been attributed to an unknown non-cholinergic mechanism of action. We hypothesize that the endocannabinoid system may be an important target because of its vital role in nervous system development. We have previously reported that repeated exposure to CPF results in greater inhibition of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide (AEA), than inhibition of either forebrain ChE or monoacylglycerol lipase (MAGL), the enzyme that metabolizes the endocannabinoid 2-arachidonylglycerol (2-AG). This exposure resulted in the accumulation of 2-AG and AEA in the forebrain of juvenile rats; however, even at the lowest dosage level used (1.0 mg/kg), forebrain ChE inhibition was still present. Thus, it is not clear if FAAH activity would be inhibited at dosage levels that do not inhibit ChE. To determine this, 10 day old rat pups were exposed daily for 7 days to either corn oil or 0.5 mg/kg CPF by oral gavage. At 4 and 12 h post-exposure on the last day of administration, the activities of serum ChE and carboxylesterase (CES) and forebrain ChE, MAGL, and FAAH were determined as well as the forebrain AEA and 2-AG levels. Significant inhibition of serum ChE and CES was present at both 4 and 12 h. There was no significant inhibition of the activities of forebrain ChE or MAGL and no significant change in the amount of 2-AG at either time point. On the other hand, while no statistically significant effects were observed at 4 h, FAAH activity was significantly inhibited at 12 h resulting in a significant accumulation of AEA. Although it is not clear if this level of accumulation impacts brain maturation, this study demonstrates that developmental CPF exposure at a level that does not inhibit brain ChE can alter components of

  3. Prostacyclin analogs inhibit fibroblast migration.

    PubMed

    Kohyama, Tadashi; Liu, Xiangde; Kim, Hui Jung; Kobayashi, Tetsu; Ertl, Ronald F; Wen, Fu-Qiang; Takizawa, Hajime; Rennard, Stephen I

    2002-08-01

    The controlled accumulation of fibroblasts to sites of inflammation is crucial to effective tissue repair after injury. Either inadequate or excessive accumulation of fibroblasts could result in abnormal tissue function. Prostacyclin (PGI(2)) is a potent mediator in the coagulation and inflammatory processes. The aim of this study was to investigate the effect of PGI(2) on chemotaxis of human fetal lung fibroblasts (HFL-1). Using the blind well chamber technique, we found that the PGI(2) analog carbaprostacyclin (10(-6) M) inhibited HFL-1 chemotaxis to human plasma fibronectin (20 microg/ml) 58.0 +/- 13.2% (P < 0.05) and to platelet-derived growth factor (PDGF)-BB (10 ng/ml) 48.7 +/- 4.6% (P < 0.05). Checkerboard analysis demonstrated that carbaprostacyclin inhibits both directed and undirected migration. The inhibitory effect of the carbaprostacyclin was concentration dependent and blocked by the cAMP-dependent protein kinase (PKA) inhibitor KT-5720, suggesting that a cAMP-PKA pathway may be involved in the process. Two other PGI(2) analogs, ciprostene and dehydro-15-cyclohexyl carbaprostacyclin (both 10(-6) M), significantly inhibited fibroblast migration to fibronectin. In summary, PGI(2) appears to inhibit fibroblast chemotaxis to fibronectin and PDGF-BB. Such an effect may contribute to the regulation of fibroblasts in wound healing and could contribute to the pathogenesis of diseases characterized by abnormal tissue repair remodeling.

  4. Participation of tri-iodothyronine and metabolic clearance rate in the inhibition of growth hormone secretion in thyroxine-treated domestic fowl.

    PubMed

    Harvey, S; Klandorf, H; Scanes, C G

    1990-02-01

    Surgical thyroidectomy increases basal and TRH-induced GH concentrations in the peripheral plasma of immature domestic fowl. Replacement therapy with thyroxine (T4; 100 micrograms/kg per day for 7 days, i.m.) suppressed the GH responses to thyroidectomy. Bolus administration of T4 (10 micrograms/kg, i.m.) to thyroidectomized birds promptly lowered the circulating GH concentrations, which remained suppressed for at least 4 h. Chronic (daily injections for 7 days) or acute (one injection) pretreatment of thyroidectomized birds with iopanoic acid (IOP; 40 mg/bird, i.m.) before the bolus administration of T4 attenuated, but did not prevent, inhibition of circulating GH levels by T4. Administration of IOP (40 mg/bird i.m.) 24 h and immediately before the administration of tri-iodothyronine (T3; 3 micrograms/kg, i.m.) or T4 (10 micrograms/kg, i.m.) also failed to suppress thyroidal inhibition of circulating GH concentrations in thyroidectomized birds. Administration of IOP alone had no effect on GH concentrations. Circulating T3 concentrations were not enhanced following the administration of T4 to IOP-treated birds, indicating its inhibition of hepatic monodeiodinase activity. The metabolic clearance rate (MCR) of 125I-labelled chicken GH in the plasma of thyroidectomized fowl was less than that in sham-thyroidectomized birds. Following pretreatment with T4 (100 micrograms/kg per day for 7 days) sham-thyroidectomized and thyroidectomized birds did not differ significantly in their MCR. The GH secretion rate in thyroidectomized birds was similar to that in sham-thyroidectomized birds and in both groups was markedly reduced following pretreatment with T4. These results demonstrate thyroidal inhibition of circulating GH concentrations in fowl.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Occurrence of neutral endopeptidase activity in the cat carotid body and its significance in chemoreception.

    PubMed

    Kumar, G K; Runold, M; Ghai, R D; Cherniack, N S; Prabhakar, N R

    1990-05-28

    The carotid body contains both tachykinins and enkephalins. Neutral endopeptidase (NEP, E.C. 3.4.24.11), has been suggested to involve in the metabolism of these neuropeptides in several organs. In the present study we determined neutral endopeptidase activity of the cat carotid body and assessed its significance in chemoreception. The cytosolic and membrane fractions of the carotid body contained NEP-like activity whereas it occurred only in the membrane fractions of the superior cervical and the nodose ganglia. Phosphoramidon, thiorphan and metal ion chelators inhibited NEP-like activity of all the 3 tissues studied; other protease inhibitors, however, were ineffective. Close carotid body administration of phosphoramidon significantly potentiated the carotid body response to low PO2 but not to hypercapnia. The enhanced response to hypoxia following phosphoramidon was further augmented by naloxone, an enkephalin antagonist. These results demonstrate that the glomus tissue contains detectable amounts of NEP-like activity and its inhibition selectively affects the hypoxic response of the carotid body.

  6. Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice

    PubMed Central

    Ghosh, Sudeshna; Kinsey, Steven G.; Liu, Qing-song; Hruba, Lenka; McMahon, Lance R.; Grim, Travis W.; Merritt, Christina R.; Wise, Laura E.; Abdullah, Rehab A.; Selley, Dana E.; Sim-Selley, Laura J.; Cravatt, Benjamin F.

    2015-01-01

    Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (N-​3-​pyridinyl-​4-​[[3-​[[5-​(trifluoromethyl)-​2-​pyridinyl]oxy]phenyl]methyl]-​1-​piperidinecarboxamide; 10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold) but only 2- to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for Δ9-tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition combined

  7. Saccadic Inhibition in Reading

    ERIC Educational Resources Information Center

    Reingold, Eyal M.; Stampe, Dave M.

    2004-01-01

    In 5 experiments, participants read text that was briefly replaced by a transient image for 33 ms at random intervals. A decrease in saccadic frequency, referred to as saccadic inhibition, occurred as early as 60-70 ms following the onset of abrupt changes in visual input. It was demonstrated that the saccadic inhibition was influenced by the…

  8. Administrators' Views on Factors Influencing Full-Time Faculty Members' Participation in Online Education

    ERIC Educational Resources Information Center

    Lesht, Faye; Windes, Deborah L.

    2011-01-01

    This pilot study was conducted in order to explore factors that facilitate and inhibit the teaching of online courses from an administrative perspective. A random sample of community college and public and private universities was selected, and administrators working closely in online education were invited to participate. A qualitative…

  9. [Administrative support for Asperger's syndrome].

    PubMed

    Yamaoka, Shu

    2007-03-01

    In recent years, administrative support for developmental disabilities, such as Asperger's syndrome, has come to be conspicuous with "Law for Supporting Persons with Developmental Disabilities", which went into effect in 2005, and promotion of "Special Support Education". However, these supports are still insufficient, because administrative support for the Asperger's syndrome in Japan, having just started very recently. Developmental disabilities, such as Asperger's syndrome, are by no means mild as disabilities, it is required to fill up administrative support for them from now on.

  10. Development management for nursing administration.

    PubMed

    Heyden, R; Luyas, G; Henry, B

    1990-04-01

    What are the needs of a nurse administrator in a developing country? For that matter, what are the requirements for a nurse administrator in areas of lesser developed delivery in this country (e.g., care of the homeless, care of indigent populations)? Heyden, Luyas, and Henry look at the educational needs of these nurse managers and compare the needs to the typical education received in nursing administration programs.

  11. Differential response of neurotensin to methamphetamine self-administration.

    PubMed

    Frankel, Paul S; Hoonakker, Amanda J; Hanson, Glen R

    2008-10-01

    Neurotensin (NT) is a tridecapeptide associated with extrapyramidal and limbic pathways and is thought to inhibit dopamine (DA) functions in nigrostriatal, mesocortical, and mesolimbic systems. Because of these effects, NT has been referred to as an endogenous neuroleptic. We previously reported that low, high, and multiple doses of psychostimulants such as methamphetamine (METH) have profound effects on tissue levels, expression of associated mRNA, and release of NT in DA-linked brain structures via activation of DA D-1 and D-2 receptors. In order to investigate the potential clinical significance of responses by NT systems to these stimulants, we have examined METH in a self-administration paradigm and evaluated changes in tissue levels of NT in limbic and extrapyramidal regions. After food training, adult Sprague-Dawley rats were allowed to self-administer (i.v.) METH (0.03 or 0.06 mg/0.01 mL) by lever-pressing (FR = 5) during 4-hr sessions until a cumulative total of approximately 3-4 mg was infused. Animals were sacrificed 6 hr after the last infusion of drug, and NT tissue levels were determined by established RIA techniques. For comparisons, the treatment sessions also included yoked animals that received identical quantities and/or patterns of either METH or saline solution. The results demonstrated four distinct patterns of NT response including (1) regions of no NT changes in either self-administering or yoked METH groups; (2) regions of comparably increased NT levels in both METH-treated groups; (3) regions where self-administration of METH potentiated the increased NT levels relative to yoked METH groups; and (4) a region of increased NT levels only in self-administering, and not yoked, METH-treated groups.

  12. Training for Effective School Administrators.

    ERIC Educational Resources Information Center

    Cawelti, Gordon

    1982-01-01

    Describes a human resources development program for school administrators, including training in management functions, leader behavior skills, instructional leadership skills, and more traditional topics. (Author/JM)

  13. Ethical Dilemmas in Administrative Practice.

    ERIC Educational Resources Information Center

    Price, David W.

    1997-01-01

    Discusses the dimensions of ethics in administrative practice, identifies some of the characteristic circumstances that frequently precipitate ethical dilemmas, and suggests strategies for addressing ethical dilemmas. (Author)

  14. The Educational Administrator's Survival Guide to Administrative Uses of Microcomputers.

    ERIC Educational Resources Information Center

    Florida State Dept. of Education, Tallahassee. Div. of Public Schools.

    Guidelines are presented for use by educational administrators in selecting a microcomputer for administrative purposes. The selection process described is based on the determination of functions to be automated, and the identification of the software that best automates these functions. Topics addressed include general software applications that…

  15. Inhibition of Lung Inflammation by Acanthopanax divaricatus var. Albeofructus and Its Constituents

    PubMed Central

    Lee, Ju Hee; Sun, Ya Nan; Kim, Young Ho; Lee, Sang Kook; Kim, Hyun Pyo

    2016-01-01

    In order to find potential therapeutic agents on lung inflammatory conditions, the extracts of Acanthopanax divaricatus var. albeofructus were prepared and its constituents were isolated. They include lignans such as (+)-syringaresinol (1), acanthoside B (2), salvadoraside (3) and acanthoside D (4), lariciresinol-9-O-β-D-glucopyranoside (5) and phenylpropanoids such as 4-[(1E)-3-methoxy-1-propenyl]phenol (6), coniferin (7), and methyl caffeate (8). The extracts and several constituents such as compound 1, 6 and 8 inhibited the production of inflammatory markers, IL-6 and nitric oxide, from IL-1β-treated lung epithelial cells and lipopolysaccharide (LPS)-treated alveolar macrophages. Furthermore, the extracts and compound 4 significantly inhibited lung inflammation in lipolysaccharide-treated acute lung injury in mice by oral administration. Thus it is suggested that A. divaricatus var. albeofructus and its several constituents may be effective against lung inflammation. PMID:26759704

  16. Ruthenium-containing P450 inhibitors for dual enzyme inhibition and DNA damage.

    PubMed

    Zamora, Ana; Denning, Catherine A; Heidary, David K; Wachter, Erin; Nease, Leona A; Ruiz, José; Glazer, Edith C

    2017-02-14

    Cytochrome P450s are key players in drug metabolism, and overexpression in tumors is associated with significant resistance to many medicinal agents. Consequently, inhibition of P450s could serve as a strategy to restore drug efficacy. However, the widespread expression of P450s throughout the human body and the critical roles they play in various biosynthetic pathways motivates the development of P450 inhibitors capable of controlled local administration. Ruthenium complexes containing P450 inhibitors as ligands were synthesized in order to develop pro-drugs that can be triggered to release the inhibitors in a spatially and temporally controlled fashion. Upon light activation the compounds release ligands that directly bind and inhibit P450 enzymes, while the ruthenium center is able to directly damage DNA.

  17. Lysophosphatidic Acid Inhibits Apoptosis Induced by Cisplatin in Cervical Cancer Cells

    PubMed Central

    Sui, Yanxia; Yang, Ya; Wang, Ji; Li, Yi; Ma, Hongbing; Cai, Hui; Liu, Xiaoping; Zhang, Yong; Wang, Shufeng; Li, Zongfang; Zhang, Xiaozhi; Wang, Jiansheng; Liu, Rui; Yan, Yanli; Xue, Chaofan; Shi, Xiaowei; Tan, Li; Ren, Juan

    2015-01-01

    Cervical cancer is the second most common cause of cancer death in women worldwide. Lysophosphatidic acid (LPA) level has been found significantly increased in the serum of patients with ovarian, cervical, and colon cancers. LPA level in cervical cancer patients is significantly higher than in healthy controls. LPA receptors were found highly expressed in cervical cancer cells, suggesting LPA may play a role in the development of cervical cancer. The aim of this study is to investigate the effect of LPA on the apoptosis induced by cisplatin (DDP) in cervical cancer cell line and the underlying changes in signaling pathways. Our study found that cisplatin induced apoptosis of Hela cell through inhibiting expression of Bcl-2, upregulating the expression of Bax, Fas-L, and the enzyme activity of caspase-3 (p < 0.05); LPA significantly provided protection against the apoptosis induced by cisplatin by inhibiting the above alterations in apoptotic factor caused by cisplatin (p < 0.05). Moreover, PI3K/AKT pathway was found to be important for the LPA antiapoptosis effect, and administration of PI3K/AKT partially reversed the LPA-mediated protection against cisplatin-induced apoptosis (p < 0.05). These findings have shed new lights on the LPA bioactivity in cervical cancer cells and pointed to a possible sensitization scheme through combined administration of PI3K inhibitor and cisplatin for better treatment of cervical cancer patients, especially those with elevated LPA levels. PMID:26366416

  18. Combination Therapy of Transcatheter Arterial Chemoembolization and Arterial Administration of Antiangiogenesis on VX2 Liver Tumor

    SciTech Connect

    Deng Gang; Zhao DenglLing; Li Guangchao; Yu Hui; Teng Gaojun

    2011-08-15

    Purpose: This study was designed to evaluate the antitumorigenic efficiency of Endostar (an antiangiogenic agent) arterially administrated combined with transcatheter arterial chemoembolization (TACE) on liver tumor, and validation of perfusion CT for quantitative measurements of the results.Experimental DesignThirty rabbits bearing VX2 liver tumors were randomly and equally distributed into three groups. One of the following treatment protocols was performed in each group: 1) group 1 was treated with TACE and simultaneously arterially administrated Endostar; 2) group 2 with TACE alone, and 3) a control group that had saline injected through hepatic artery. Routine CT scan was performed before treatment, and perfusion CT imaging was performed 2 weeks after treatment. Immunohistochemical biomarkers of microvascular density (MVD) and the expression of vascular endothelial growth factor (VEGF) were measured for assessments of angiogenesis. Results: We observed a statistically significant reduction from the control in the volume, growth rate, and size of the tumor 2 weeks after treatment with both TACE plus Endostar and with TACE alone (P < 0.01). Although there was no statistically significant difference in tumor size between the group with TACE plus Endostar and the group with TACE alone (P > 0.05), MVD and VEGF were significantly less expressed in the TACE plus Endostar group than both groups with TACE alone and the control group (P < 0.01). Blood flow (BF), blood volume (BV), and permeability-surface area products (PS) in the group with TACE plus Endostar on perfusion CT were significantly higher than other two groups (P < 0.05), which were positively correlated with the MVD and VEGF values (P < 0.05). Conclusions: TACE with arterial administration of Endostar simultaneously significantly inhibited the angiogenesis biomarkers associated with TACE in a rabbit model bearing VX2 liver tumor, which indicates that the combined treatment protocol may have potential

  19. Oral administration of Bruton's tyrosine kinase inhibitors impairs GPVI-mediated platelet function

    PubMed Central

    Aslan, Joseph E.; Healy, Laura D.; Wallisch, Michael; Thierheimer, Marisa L. D.; Loren, Cassandra P.; Pang, Jiaqing; Hinds, Monica T.; Gruber, András; McCarty, Owen J. T.

    2015-01-01

    The Tec family kinase Bruton's tyrosine kinase (Btk) plays an important signaling role downstream of immunoreceptor tyrosine-based activation motifs in hematopoietic cells. Mutations in Btk are involved in impaired B-cell maturation in X-linked agammaglobulinemia, and Btk has been investigated for its role in platelet activation via activation of the effector protein phospholipase Cγ2 downstream of the platelet membrane glycoprotein VI (GPVI). Because of its role in hematopoietic cell signaling, Btk has become a target in the treatment of chronic lymphocytic leukemia and mantle cell lymphoma; the covalent Btk inhibitor ibrutinib was recently approved by the US Food and Drug Administration for treatment of these conditions. Antihemostatic events have been reported in some patients taking ibrutinib, although the mechanism of these events remains unknown. We sought to determine the effects of Btk inhibition on platelet function in a series of in vitro studies of platelet activation, spreading, and aggregation. Our results show that irreversible inhibition of Btk with two ibrutinib analogs in vitro decreased human platelet activation, phosphorylation of Btk, P-selectin exposure, spreading on fibrinogen, and aggregation under shear flow conditions. Short-term studies of ibrutinib analogs administered in vivo also showed abrogation of platelet aggregation in vitro, but without measurable effects on plasma clotting times or on bleeding in vivo. Taken together, our results suggest that inhibition of Btk significantly decreased GPVI-mediated platelet activation, spreading, and aggregation in vitro; however, prolonged bleeding was not observed in a model of bleeding. PMID:26659727

  20. Acute administration of diosgenin or dioscorea improves hyperglycemia with increases muscular steroidogenesis in STZ-induced type 1 diabetic rats.

    PubMed

    Sato, K; Fujita, S; Iemitsu, M

    2014-09-01

    Acute dehydroepiandrosterone (DHEA) administration improves hyperglycemia in rats with streptozotocin (STZ)-induced type 1 diabetes mellitus. Diosgenin, a steroid structurally similar to DHEA (dehydroepiandrosterone), is contained highly levels in dioscorea; however, it is still unclear whether this natural product improves hyperglycemia in the type 1 diabetes model rats through an increase muscular GLUT4 signaling. After 1 week of STZ injection, fasting glucose level was measured in blood taken from the tail vein every 30 min for 150 min after injection of diosgenin or dioscorea (3mg/kg). On another day, muscle was resected 150 min after diosgenin or dioscorea injections. Serum DHEA level increased significantly 120 min after diosgenin or dioscorea injections; concomitantly, blood glucose level decreased significantly. Moreover, GLUT4 translocation, as well as phosphorylation of Akt and PKC ζ/λ, increased significantly by diosgenin or dioscorea administration. However, these effects of diosgenin and dioscorea were blocked by a 5α-reductase inhibitor that inhibits synthesizing dehydrotestosterone (DHT) from testosterone. Additionally, significant correlations were observed between blood glucose level, GLUT4 translocation level, and muscular sex steroid hormone level 150 min after the administrations. These results suggest that the diosgenin-induced increase in the DHEA level may contribute to the improvement of hyperglycemia by activating the muscular GLUT4 signaling pathway in type 1 diabetes model rats.

  1. Apomorphine can increase cutaneous inhibition of motor activity in Parkinson's disease.

    PubMed

    Clouston, P D; Lim, C L; Sue, C; Morris, J G; Yiannikas, C

    1996-02-01

    We studied the effect of non-nociceptive ipsilateral digital stimulation on EMG recorded from a small hand muscle before and after the administration of subcutaneous apomorphine in 6 patients with Parkinson's disease. All were receiving the drug to control ¿on-off¿ fluctuations in motor performance. Averaged rectified EMG was recorded from tonically contracted abductor pollicis brevis (APB) following index finger stimulation using a brief stimulus train. In 5 patients motor evoked potentials (MEPs) were also recorded from APB during tonic contraction. A conditioning stimulus train was applied to the index finger at intervals between 15 and 65 msec prior to the transcranial magnetic stimulus. After apomorphine administration the patient group showed a significant increase in both EMG and MEP inhibition induced by digital stimulation. In patients with Parkinson's disease who have marked motor fluctuations, the inhibitory response of upper limb motor neurones to low level digital cutaneous stimulation can be altered by dopamine agonists.

  2. Nicotine administration enhances negative occasion setting in adolescent rats.

    PubMed

    Meyer, Heidi C; Chodakewitz, Molly I; Bucci, David J

    2016-04-01

    Substantial research has established that exposure to nicotine during adolescence can lead to long-term changes in neural circuitry and behavior. However, relatively few studies have considered the effects of nicotine use on cognition during this critical stage of brain development. This is significant because the influence of nicotine on cognitive performance during adolescence may contribute to the development of regular nicotine use. For example, improvements in cognitive functioning may increase the perceived value of smoking and facilitate impulses to smoke. To address this, the present research tested the effects of nicotine on a form of inhibitory learning during adolescence. Specifically, adolescent rats were exposed to nicotine as they were trained in a negative occasion setting paradigm, in which successful performance depends on learning the conditions under which it is, or is not, appropriate to respond to a target stimulus. Here, we found that nicotine administration enhances negative occasion setting in adolescents. In addition, nicotine increased the amount of orienting behavior directed toward the inhibitory stimulus, suggesting that improvements in this form of behavioral inhibition may be attributed to nicotine-induced increases in attentional processing. These results may help elucidate the factors that contribute to the onset as well as continued use of products containing nicotine during adolescence and provide insight to increase the effectiveness of interventions targeted at reducing the prevalence of adolescent smoking.

  3. Vocational Schools in Turkey: An Administrative and Organizational Analysis

    NASA Astrophysics Data System (ADS)

    Simsek, Hasan; Yildirim, Ali

    2000-07-01

    The data used in this paper were derived from a larger project which had the aim of critically evaluating the Turkish vocational education system on a number of different levels. This article examines the administrative and organisational practices in a selected group of secondary vocational schools in Turkey from the point of view of school administrators, teachers and industrial managers. The results indicate that the Turkish vocational education system is characterised by a centralised, top-down bureaucracy, which inhibits innovative capacity. The authors argue that a degree of decentralisation is necessary at various levels of the system.

  4. Autoinduction of nuclear hormone receptors during metamorphosis and its significance.

    PubMed

    Tata, J R

    2000-01-01

    Metamorphosis is a most dramatic example of hormonally regulated genetic reprogramming during postembryonic development. The initiation and sustenance of the process are under the control of ecdysteroids in invertebrates and thyroid hormone, 3,3', 5-triiodothyronine, in oviparous vertebrates. Their actions are inhibited or potentiated by other endogenous or exogenous hormones - juvenile hormone in invertebrates and prolactin and glucocorticoids in vertebrates. The nuclear receptors for ecdysteroids and thyroid hormone are the most closely related members of the steroid/retinoid/thyroid hormone receptor supergene family. In many pre-metamorphic amphibia and insects, the onset of natural metamorphosis and the administration of the exogenous hormones to the early larvae are characterized by a substantial and rapid autoinduction of the respective nuclear receptors. This review will largely deal with the phenomenon of receptor autoinduction during amphibian metamorphosis, although many of its features resemble those in insect metamorphosis. In the frog Xenopus, thyroid hormone receptor autoinduction has been shown to be brought about by the direct interaction between the receptor protein and the thyroid-responsive elements in the promoter of its own gene. Three lines of evidence point towards the involvement of receptor autoinduction in the process of initiation of amphibian metamorphosis: (1) a close association between the extent of inhibition or potentiation by prolactin and glucocorticoid, respectively, and metamorphic response in whole tadpoles and in organ and cell cultures; (2) thyroid hormone fails to upregulate the expression of its own receptor in obligatorily neotenic amphibia but does so in facultatively neotenic amphibia; and (3) dominant-negative receptors known to block hormonal response prevent the autoinduction of wild-type Xenopus receptors in vivo and in cell lines. Autoinduction is not restricted to insect and amphibian metamorphic hormones but is

  5. Principals' Values in School Administration

    ERIC Educational Resources Information Center

    Aslanargun, Engin

    2012-01-01

    School administration is value driven area depending on the emotions, cultures, and human values as well as technique and structure. Over the long years, educational administration throughout the world have experienced the influence of logical positivism that is based on rational techniques more than philosophical consideration, ignored values and…

  6. Training for Effective School Administrators.

    ERIC Educational Resources Information Center

    Cawelti, Gordon

    Forces of societal change have placed new demands on school administrators for skills to manage schools. The result has been an increasing realization of the need for improved university preparation programs and for more effective Human Resource Development (HRD) for practicing administrators. A growing body of research shows a very positive…

  7. Attitudes, Administrative Styles, and Outcomes.

    ERIC Educational Resources Information Center

    Laughlin, J. Stanley

    1984-01-01

    The literature on administrative style is reviewed. Attention is directed to four basic concepts of administrative style: (1) the structured, classical, traditional model; (2) the participatory or employee-involved operation; (3) a more behavioral scientific style; and (4) the situational or environmental style. These ideas are more fully…

  8. Network Systems Administration Needs Assessment.

    ERIC Educational Resources Information Center

    Lexington Community Coll., KY. Office of Institutional Research.

    In spring 1996, Lexington Community College (LCC) in Kentucky, conducted a survey to gather information on employment trends and educational needs in the field of network systems administration (NSA). NSA duties involve the installation and administration of network operating systems, applications software, and networking infrastructure;…

  9. Selecting Child Care Administrative Software.

    ERIC Educational Resources Information Center

    Kalinowski, Michael

    1998-01-01

    Offers advice on the selection of child care administrative software. Directors should consider needs, computer experience, budget, time, and temperament, and should also ask lots of questions and test demo versions. Choices range from custom programs and existing business products to child care administrative software packages. Includes directory…

  10. Development Management for Nursing Administration.

    ERIC Educational Resources Information Center

    Heyden, Richard; And Others

    1990-01-01

    Discusses the educational needs of nurse administrators in developing counties and in areas of lesser development in the United States and compares them to the typical education received in nursing administration programs. Concludes that a focus on development management is needed. (JOW)

  11. Public Finance Administration. Second Edition.

    ERIC Educational Resources Information Center

    Reed, B. J.; Swain, John W.

    This book is intended for the nonexpert in finance who has a public administration background. It opens with a broad introduction to public finance administration and how this job is related to public budgeting, the practice of public-sector accounting, and the economic concepts of money and value. Issues surrounding public revenue, its sources,…

  12. Faculty Perspectives on Administrator Effectiveness.

    ERIC Educational Resources Information Center

    Bess, James L.

    The sources of faculty perspectives on the personal effectiveness of administrators are analyzed. It is proposed that faculty will be predisposed to see administrators in different lights, depending on structural elements in decision making and the orientation of the faculty members. Attention is directed to Talcott Parson's theory for classifying…

  13. The Magic of Library Administration.

    ERIC Educational Resources Information Center

    Holley, Edward G.

    We are better prepared today to deal with the problems in library administration, because we not only have the basic work of management theorists, but also staffs who are better educated and more interested in participation. During the last 25 years, there have been two strands in library administration. The older, human relations approach allowed…

  14. Outsourcing real estate lease administration.

    PubMed

    Kardel, S

    1996-09-01

    Real estate lease administration is becoming increasingly important to healthcare organizations; however, not all organizations possess the in-house expertise to carry out this specialized function. For such organizations, outsourcing lease administration may be a more efficient way to manage their real estate portfolios and possibly improve their bottom lines.

  15. Cardinal Virtues of Academic Administration

    ERIC Educational Resources Information Center

    Curren, Randall

    2008-01-01

    The aim of this article is to articulate the basic elements of a comprehensive ethic of academic administration, organized around a set of three cardinal virtues: "commitment" to the good of the institution; good administrative "judgment"; and "conscientiousness" in discharging the duties of the office. In addition to explaining this framework and…

  16. College Administration: Concepts and Techniques.

    ERIC Educational Resources Information Center

    Feltner, Bill D., Ed.

    Ten colleges participated in a project to: (1) help organize and strengthen administrative teams in developing two-year and four-year colleges throughout the Southeast; (2) to assist administrative teams in identifying specific roles for each team member and in developing an understanding of team responsibilities; and (3) to assist administrative…

  17. Expanding Role of the Administrator.

    ERIC Educational Resources Information Center

    Gibb, Jack R.

    The role of the secondary school administrator can be viewed in two ways: From a defensive point of view with the administrator marshaling the forces of organization, stimulating effort, capturing the imagination, inspiring teachers, coordinating efforts, and serving as a model of sustained effort; or from an alternative point of view with the…

  18. Idaho Driver Education Administrative Guide.

    ERIC Educational Resources Information Center

    Idaho State Dept. of Education, Boise.

    This guide provides information for school administrators and directors of commercial driver training schools about conducting driver education courses in Idaho. The first part of the guide, which applies to both public schools and commercial schools, covers the following areas: administration, sample letters and forms, instructional time…

  19. Educational Administration: The Developing Decades.

    ERIC Educational Resources Information Center

    Cunningham, Luvern L., Ed.; And Others

    This book consists of 18 papers originally prepared for a 1975 conference that attempted to assess past developments in the knowledge and practice of educational administration and to identify future directions for research, leadership, and preparation. Individual papers include "Educational Administration, 1954-1974,""Roald F. Campbell: Teacher,…

  20. The Dissimilarity of Educational Administration

    ERIC Educational Resources Information Center

    Walton, John

    1970-01-01

    The responsibilities of educational administrators do not extend to the products of the educational institutions. Rather, they end at the point where they maintain satisfactory conditions for leisure activities. In this respect, educational administration may serve as a model for the governance of an increasing number of organizations, both public…

  1. The Enigma of Administrative Behaviour.

    ERIC Educational Resources Information Center

    Batchler, Merv

    1981-01-01

    Writers attempting to describe administration have approached the subject from a number of perspectives. Researchers such as Gulick (1937) identified planning, organizing, staffing, directing, coordinating, reporting, and budgeting as functional elements of administration. Hemphill, Griffiths, and Fredericksen (1962), using simulated job settings,…

  2. Postmodernism in Higher Educational Administration

    ERIC Educational Resources Information Center

    Demaris, Michalyn C.; Kritsonis, William Allan

    2007-01-01

    Postmodernism has many inferences that can be applied to the theory and practice of higher educational administration. Today, in higher education administrators are continuously focused on strategies that will ensure the future of minority educational institutions. As a result postmodernism is an important factor in the future of higher…

  3. Inhibition of selectin binding

    DOEpatents

    Nagy, Jon O.; Spevak, Wayne R.; Dasgupta, Falguni; Bertozzi, Carolyn

    1999-10-05

    This invention provides a system for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, this system can be used to palliate certain inflammatory and immunological conditions.

  4. Inhibition of selectin binding

    DOEpatents

    Nagy, Jon O.; Spevak, Wayne R.; Dasgupta, Falguni; Bertozzi, Caroline

    2001-10-09

    This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

  5. Inhibition of selectin binding

    DOEpatents

    Nagy, Jon O.; Spevak, Wayne R.; Dasgupta, Falguni; Bertozzi, Caroline

    1999-01-01

    This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

  6. CA-1H, a novel oxazole bearing analogue of combretastatin A-4, disrupts the tumor vasculatures and inhibits the tumor growth via inhibiting tubulin polymerization.

    PubMed

    Han, Fuguo; Wang, Peng; Zhang, Wei; Li, Jing; Zhang, Qun; Qi, Xin; Liu, Ming

    2016-05-01

    Vascular disrupting agents destroy established tumor vasculatures selectively, and have achieved encouraging antitumor activity in both pre-clinical and clinical trials. In the present study, we reported the vascular disruption and antitumor effects of CA-1H and its prodrug CA-1HP, oxazole bearing analogues of combretastatin A-4 (CA4). CA-1H was a tighter binder of tubulin than CA4 with the same binding site to chochcine and CA4, and inhibited tubulin polymerization both in cell free system and in human umbilical vein endothelial cells (HUVECs). Furthermore, CA-1H significantly disrupted the microtubulin skeleton in proliferating HUVECs rather than the quiescent ones, damaged the HUVECs-preformed tubes markedly, and lead to necrosis in tumor tissues in NCI-H1975 xenograft mice. Continuous administration for 19 days, CA-1HP could inhibit the NCI-H1975 xenograft tumor growth significantly without obvious weight loss and normal tissue damage, in addition, CA-1HP also inhibited the tumor growth in H22 hepatocellular carcinoma bearing mice; and combination CA-1HP with cisplatin showed more potent antitumor activity than used alone. Taken together, our present investigation suggested that CA-1H was a potential vascular disrupting agent for further development of antitumor drugs.

  7. Systemic administration of resveratrol suppress the nociceptive neuronal activity of spinal trigeminal nucleus caudalis in rats.

    PubMed

    Takehana, Shiori; Sekiguchi, Kenta; Inoue, Maki; Kubota, Yoshiko; Ito, Yukihiko; Yui, Kei; Shimazu, Yoshihito; Takeda, Mamoru

    2016-01-01

    Although a modulatory role has been reported for the red wine polyphenol resveratrol on several types of ion channels and excitatory synaptic transmission in the nervous system, the acute effects of resveratrol in vivo, particularly on nociceptive transmission of the trigeminal system, remain to be determined. The aim of the present study was to investigate whether acute intravenous resveratrol administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from 18 SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was inhibited by resveratrol (0.5-2 mg/kg, i.v.) and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. These inhibitory effects were reversed after approximately 20 min. The relative magnitude of inhibition by resveratrol of SpVc WDR neuronal discharge frequency was significantly greater for noxious than non-noxious stimulation. These results suggest that, in the absence of inflammatory or neuropathic pain, acute intravenous resveratrol administration suppresses trigeminal sensory transmission, including nociception, and so resveratrol may be used as a complementary and alternative medicine therapeutic agent for the treatment of trigeminal nociceptive pain, including hyperalgesia.

  8. Tenofovir Disoproxil Fumarate: Toxicity, Toxicokinetics, and Toxicogenomics Analysis After 13 Weeks of Oral Administration in Mice

    PubMed Central

    Ng, Hanna H.; Stock, Howard; Rausch, Linda; Bunin, Deborah; Wang, Abraham; Brill, Shirley; Gow, Jason; Mirsalis, Jon C.

    2014-01-01

    Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against human immunodeficiency virus (HIV) and hepatitis B. The goals of this study were to evaluate the molecular mechanism of TDF-induced toxicity in mice after 13 weeks of daily oral administration (50–1000 mg/kg) by correlating transcriptional changes with plasma drug levels and traditional toxicology endpoints. Plasma levels and systemic exposure of tenofovir increased less than dose-proportionally, and were similar on Days 1 and 91. No overt toxicity was observed following the completion of TDF administration. The kidneys of TDF-treated mice were histopathologically normal. This result is consistent with the genomic microarray results, which showed no significant differences in kidney transcriptional levels between TDF-treated animals and controls. In liver, cytomegaly was observed in mice treated with 1000 mg/kg of TDF after 4 and 13 weeks of TDF-treatment, but mice recovered from this effect following cessation of administration. Analysis of liver transcripts on Day 91 reported elevated levels of Cdkn1a in TDF-treated animals compared with controls, which may have contributed to the inhibition of liver cell cycle progression. PMID:25568137

  9. 5 CFR 551.206 - Administrative exemption criteria.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... judgment with respect to matters of significance merely because improper performance of the employee's... Administrative exemption criteria. An administrative employee is an employee whose primary duty is the performance of office or non-manual work directly related to the management or general business operations,...

  10. 5 CFR 551.206 - Administrative exemption criteria.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... judgment with respect to matters of significance merely because improper performance of the employee's... Administrative exemption criteria. An administrative employee is an employee whose primary duty is the performance of office or non-manual work directly related to the management or general business operations,...

  11. 5 CFR 551.206 - Administrative exemption criteria.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... judgment with respect to matters of significance merely because improper performance of the employee's... Administrative exemption criteria. An administrative employee is an employee whose primary duty is the performance of office or non-manual work directly related to the management or general business operations,...

  12. 5 CFR 551.206 - Administrative exemption criteria.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... judgment with respect to matters of significance merely because improper performance of the employee's... Administrative exemption criteria. An administrative employee is an employee whose primary duty is the performance of office or non-manual work directly related to the management or general business operations,...

  13. 5 CFR 551.206 - Administrative exemption criteria.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... judgment with respect to matters of significance merely because improper performance of the employee's... Administrative exemption criteria. An administrative employee is an employee whose primary duty is the performance of office or non-manual work directly related to the management or general business operations,...

  14. School Business Administration: A Planning Approach. Third Edition.

    ERIC Educational Resources Information Center

    Candoli, I. Carl; And Others

    The school business administration function in the operation of American schools has undergone dramatic changes during the past several years. Changing demographics, high technology, the movement to professionalize school administration, and changes by the legislative and judicial systems have all had significant impact on the character of school…

  15. Race and Gender Bias in the Administration of Corporal Punishment.

    ERIC Educational Resources Information Center

    Shaw, Steven R.; Braden, Jeffery B.

    1990-01-01

    Examined disciplinary actions taken by school building administrators after receiving discipline referral to identify evidence of race and gender bias in administration of corporal punishment (CP). Analysis of discipline files (n=6,244) demonstrated statistically significant relationships between race and CP and between gender and CP. Results…

  16. Influence of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist (WIN 55,212-2) and inverse agonist (AM 251) on the regulation of food intake and hypothalamic serotonin levels.

    PubMed

    Merroun, Ikram; Errami, Mohammed; Hoddah, Hanaa; Urbano, Gloria; Porres, Jesús M; Aranda, Pilar; Llopis, Juan; López-Jurado, María

    2009-05-01

    The effect of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist WIN 55,212-2 or inverse agonist AM 251 on food intake and extracellular levels of serotonin and acetic acid 5-hydroxy-indol from presatiated rats was studied. Compared to the vehicle-injected control, the intracerebroventricular administration of WIN 55,212-2 was associated with a significant increase in food intake, whereas the administration of AM 251 caused a significant reduction in this respect. These results were accompanied by considerable reductions or increases in serotonin and acetic acid 5-hydroxy-indol levels compared to the vehicle-injected control and the baseline values for the different experimental groups studied. Intraperitoneal administration of WIN 55,212-2 at doses of 1 and 2 mg/kg promoted hyperphagia up to 6 h after injection, whereas administration of a higher dose (5 mg/kg) significantly inhibited food intake and motor behaviour in partially satiated rats. Administration of any of the AM 251 doses studied (0.5, 1, 2, 5 mg/kg) led to a significant decrease in the amount of food ingested from 2 h after the injection, compared to the vehicle-injected control group, with the most striking effect being observed when the 5 mg/kg dose was injected.

  17. Effects of TrkB agonist 7,8-dihydroxyflavone on sensory gating deficits in mice after administration of methamphetamine.

    PubMed

    Ren, Qian; Zhang, Ji-Chun; Fujita, Yuko; Ma, Min; Wu, Jin; Hashimoto, Kenji

    2013-05-01

    Several lines of evidence suggest that the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway plays a role in behavioral abnormalities observed after administration of psychostimulants, such as methamphetamine (METH). This study was undertaken to examine whether the potent TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) could improve prepulse inhibition (PPI) deficits in mice seen after a single dose of METH. Treatment with 7,8-DHF (3.0, 10 or 30 mg/kg) improved PPI deficits in mice associated with exposure to METH (3.0 mg/kg), in a dose dependent manner. Furthermore, co-administration of ANA-12 (0.5 mg/kg), a TrkB antagonist, significantly blocked the effects of 7,8-DHF (30 mg/kg) on METH-induced PPI deficits. In contrast, administration of 5,7-dihydroxyflavone (5,7-DHF: 30 mg/kg), an inactive TrkB ligand, did not affect METH-induced PPI deficits in mice. An in vivo microdialysis study in conscious mice showed that 7,8-DHF (30 mg/kg) significantly attenuated increased dopamine release in the striatum, after METH administration (3 mg/kg). This study suggests that 7,8-DHF can improve PPI deficits in these mice, through the inhibition of METH-induced dopamine release. Therefore, it is likely that TrkB agonists, such as 7,8-DHF, may constitute a novel class of therapeutic drugs for neuropsychiatric diseases such as METH-use disorder and schizophrenia.

  18. Targeted Inhibition of Complement Using Complement Receptor 2-Conjugated Inhibitors Attenuates EAE

    PubMed Central

    Hu, Xianzhen; Tomlinson, Stephen; Barnum, Scott R.

    2012-01-01

    Multiple sclerosis (MS) is the most common autoimmune demyelinating disease, affecting millions of individuals worldwide. In the last two decades, many therapeutic options for the treatment of MS have become available, however they are limited in terms of effectiveness and some remain plagued by safety issues. The currently available treatment options target relapsing remitting forms of MS and are not effective against the more progressive forms of the disease. These limitations highlight a significant unmet treatment need for MS. In experimental autoimmune encephalomyelitis (EAE) studies from our laboratory, we have previously shown, using a number of complement mutant and transgenic mice, that inhibition of the alternative complement pathway and the C3 convertase confers significant protection from disease. We report here that targeted inhibition of complement activation using complement receptor 2 (CR2)-conjugated inhibitors significantly attenuates EAE. Administration of CR2-Crry (blocks all complement pathways at C3 activation) and CR2-fH (specifically blocks the alternative pathway) just prior to and during the onset of EAE blocks progression of both acute and chronic disease. These data indicate that inhibition of complement may offer an effective therapeutic approach to treating both acute and chronic forms of demyelinating disease through blocking the alternative pathway or complement convertases. PMID:23079547

  19. Targeted inhibition of complement using complement receptor 2-conjugated inhibitors attenuates EAE.

    PubMed

    Hu, Xianzhen; Tomlinson, Stephen; Barnum, Scott R

    2012-11-30

    Multiple sclerosis (MS) is the most common autoimmune demyelinating disease, affecting millions of individuals worldwide. In the last two decades, many therapeutic options for the treatment of MS have become available, however they are limited in terms of effectiveness and some remain plagued by safety issues. The currently available treatment options target relapsing remitting forms of MS and are not effective against the more progressive forms of the disease. These limitations highlight a significant unmet treatment need for MS. In experimental autoimmune encephalomyelitis (EAE) studies from our laboratory, we have previously shown, using a number of complement mutant and transgenic mice, that inhibition of the alternative complement pathway and the C3 convertase confers significant protection from disease. We report here that targeted inhibition of complement activation using complement receptor 2 (CR2)-conjugated inhibitors significantly attenuates EAE. Administration of CR2-Crry (blocks all complement pathways at C3 activation) and CR2-fH (specifically blocks the alternative pathway) just prior to and during the onset of EAE blocks progression of both acute and chronic disease. These data indicate that inhibition of complement may offer an effective therapeutic approach to treating both acute and chronic forms of demyelinating disease through blocking the alternative pathway or complement convertases.

  20. Mass drug administration for malaria

    PubMed Central

    Poirot, Eugenie; Skarbinski, Jacek; Sinclair, David; Kachur, S Patrick; Slutsker, Laurence; Hwang, Jimee

    2013-01-01

    Background Mass drug administration (MDA), defined as the empiric administration of a therapeutic antimalarial regimen to an entire population at the same time, has been a historic component of many malaria control and elimination programmes, but is not currently recommended. With renewed interest in MDA and its role in malaria elimination, this review aims to summarize the findings from existing research studies and program experiences of MDA strategies for reducing malaria burden and transmission. Objectives To assess the impact of antimalarial MDA on population asexual parasitaemia prevalence, parasitaemia incidence, gametocytaemia prevalence, anaemia prevalence, mortality and MDA-associated adverse events. Search methods We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE+, EMBASE, to February 2013. We also searched CABS Abstracts, LILACS, reference lists, and recent conference proceedings. Selection criteria Cluster-randomized trials and non-randomized controlled studies comparing therapeutic MDA versus placebo or no MDA, and uncontrolled before-and-after studies comparing post-MDA to baseline data were selected. Studies administering intermittent preventive treatment (IPT) to sub-populations (for example, pregnant women, children or infants) were excluded. Data collection and analysis Two authors independently reviewed studies for inclusion, extracted data and assessed risk of bias. Studies were stratified by study design and then subgrouped by endemicity, by co-administration of 8-aminoquinoline plus schizonticide drugs and by plasmodium species. The quality of evidence was assessed using the GRADE approach. Main results Two cluster-randomized trials, eight non-randomized controlled studies and 22 uncontrolled before-and-after studies are included in this review. Twenty-two studies (29 comparisons) compared MDA to placebo or no intervention of which two comparisons were

  1. Arginase inhibition in airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin

    SciTech Connect

    Bratt, Jennifer M.; Franzi, Lisa M.; Linderholm, Angela L.; O'Roark, Erin M.; Kenyon, Nicholas J.; Last, Jerold A.

    2010-01-01

    Arginase1 and nitric oxide synthase2 (NOS2) utilize L-arginine as a substrate, with both enzymes expressed at high levels in the asthmatic lung. Inhibition of arginase in ovalbumin-exposed C57BL/6 mice with the transition state inhibitor N{sup o}mega-hydroxy-nor-L-arginine (nor-NOHA) significantly increased total L-arginine content in the airway compartment. We hypothesized that such an increase in L-arginine content would increase the amount of nitric oxide (NO) being produced in the airways and thereby decrease airway hyperreactivity and eosinophilic influx. We further hypothesized that despite arginase inhibition, NOS2 knockout (NOS2-/-) mice would be unable to up-regulate NO production in response to allergen exposure and would demonstrate higher amounts of airway hyperreactivity and eosinophilia under conditions of arginase inhibition than C57BL/6 animals. We found that administration of nor-NOHA significantly decreased airway hyperreactivity and eosinophilic airway inflammation in ovalbumin-exposed C57BL/6 mice, but these parameters were unchanged in ovalbumin-exposed NOS2-/- mice. Arginase1 protein content was increased in mice exposed to ovalbumin, an effect that was reversed upon nor-NOHA treatment in C57BL/6 mice. Arginase1 protein content in the airway compartment directly correlated with the degree of airway hyperreactivity in all treatment groups. NOS2-/- mice had significantly greater arginase1 and arginase2 concentrations compared to their respective C57BL/6 groups, indicating that inhibition of arginase may be dependent upon NOS2 expression. Arginase1 and 2 content were not affected by nor-NOHA administration in the NOS2-/- mice. We conclude that L-arginine metabolism plays an important role in the development of airway hyperreactivity and eosinophilic airway inflammation. Inhibition of arginase early in the allergic inflammatory response decreases the severity of the chronic inflammatory phenotype. These effects appear to be attributable to NOS2

  2. Sanitary Surveys & Significant Deficiencies Presentation

    EPA Pesticide Factsheets

    The Sanitary Surveys & Significant Deficiencies Presentation highlights some of the things EPA looks for during drinking water system site visits, how to avoid significant deficiencies and what to do if you receive one.

  3. A Woman Administrator Speaks: Openness and Secrecy in Educational Administration

    ERIC Educational Resources Information Center

    Peterson, Martha

    1975-01-01

    In a speech presented to NAWDAC, NASPA and ACPA in Chicago, April 15, 1974, the author addresses problems encountered by administrators regarding the need to maintain credibility while recognizing theneed to maintain some amount of confidentiality. (HMV)

  4. Antiallergic and antiasthmatic effects of a novel enhydrazinone ester (CEE-1): inhibition of activation of both mast cells and eosinophils.

    PubMed

    Ezeamuzie, Charles I; El-Hashim, Ahmed Z; Renno, Waleed M; Edafiogho, Ivan O

    2014-08-01

    Activation of mast cells and eosinophils is a fundamental process in the pathophysiology of allergic diseases. We have previously reported that the novel enhydrazinone ester CEE-1 (ethyl 4-phenylhydrazinocyclohex-3-en-2-oxo-6-phenyl-1-oate) possesses potent anti-inflammatory activity. We have now tested whether the compound also possesses antiallergic and antiasthmatic effects in vitro and in vivo. The compound significantly inhibited degranulation and leukotriene C4 (LTC4) release from activated human eosinophils, as well as IgE-dependent degranulation and LTC4 release from passively sensitized rat basophilic leukemia cells and bone marrow-derived mouse mast cells. In human eosinophils, the drug was more potent in inhibiting degranulation than LTC4 release {IC50 = 0.4 μM [confidence interval (CI): 0.1-0.9] versus 3.8 μM (CI: 0.9-8.3)}, whereas in mast cells the reverse was essentially the case. The drug did not affect stimulus-induced calcium transients in eosinophils but significantly inhibited early phosphorylation of extracellular signal-regulated kinases 1/2 and p38-mitogen-activated protein kinases (MAPK). In vivo, topical application of 4.5-15 mg/kg of the compound significantly inhibited allergen-induced passive cutaneous anaphylaxis in mice. Similarly, in the mouse asthma model, the intranasal administration of 6.5-12.5 mg/kg of the compound significantly inhibited bronchial inflammation and eosinophil accumulation in bronchial lavage fluid, as well as abolishing airway hyper-responsiveness to methacholine. These results show that CEE-1 inhibits the activation of both mast cells and eosinophils in vitro, probably by blocking MAPK-activation pathways, and that these effects are translated into antiallergic and antiasthmatic effects in vivo. The compound, therefore, has potential application in the treatment of asthma and other allergic diseases.

  5. Interleukin-1 Inhibits Putative Cholinergic Neurons in Vitro and REM Sleep when Microinjected into the Rat Laterodorsal Tegmental Nucleus

    PubMed Central

    Brambilla, Dario; Barajon, Isabella; Bianchi, Susanna; Opp, Mark R.; Imeri, Luca

    2010-01-01

    Study Objectives: REM sleep is suppressed during infection, an effect mimicked by the administration of cytokines such as interleukin-1 (IL-1). In spite of this observation, brain sites and neurochemical systems mediating IL-1-induced suppression of REM sleep have not been identified. Cholinergic neurons in the brainstem laterodorsal tegmental nucleus (LDT) are part of the neuronal circuitry responsible for REM sleep generation. Since IL-1 inhibits acetylcholine synthesis and release, the aim of this study was to test the two different, but related hypotheses. We hypothesized that IL-1 inhibits LDT cholinergic neurons, and that, as a result of this inhibition, IL-1 suppresses REM sleep. Design, Measurement, and Results: To test these hypotheses, the electrophysiological activity of putative cholinergic LDT neurons was recorded in a rat brainstem slice preparation. Interleukin-1 significantly inhibited the firing rate of 76% of recorded putative cholinergic LDT neurons and reduced the amplitude of glutamatergic evoked potentials in 60% of recorded neurons. When IL-1 (1 ng) was microinjected into the LDT of freely behaving rats, REM sleep was reduced by about 50% (from 12.7% ± 1.5% of recording time [after vehicle] to 6.1% ± 1.4% following IL-1 administration) during post-injection hours 3-4. Conclusions: Results of this study support the hypothesis that IL-1 can suppress REM sleep by acting at the level of the LDT nucleus. Furthermore this effect may result from the inhibition of evoked glutamatergic responses and of spontaneous firing of putative cholinergic LDT neurons. Citation: Brambilla D; Barajon I; Bianchi S; Opp MR; Imeri L. Interleukin-1 inhibits putative cholinergic neurons in vitro and REM sleep when microinjected into the rat laterodorsal tegmental nucleus. SLEEP 2010;33(7):919-929. PMID:20614852

  6. Involvement of lipids in dimethoate-induced inhibition of testosterone biosynthesis in rat interstitial cells.

    PubMed

    Astiz, Mariana; Hurtado de Catalfo, Graciela E; de Alaniz, María J T; Marra, Carlos Alberto

    2009-08-01

    The mechanism involved in the inhibition of testosterone (Te) biosynthesis after a sub-chronic exposure to low doses of dimethoate (D) was studied in rat interstitial cells (IC). Expression of COX-2 in IC isolated from D-treated rats increased by 44% over C data, while transcription of StAR decreased by approx. 50% and the expression of this protein was diminished by approximately 40%. PGE(2) and PGF(2alpha) were increased by 61 and 78%, respectively. Te concentration decreased by 49% in IC homogenates. Concomitantly, plasma concentration of LH and FSH both increased. Araquidonate (ARA) and C(22) fatty acyl chains in phospholipids from IC mitochondrial fraction decreased by approx. 30% after D treatment. Protein carbonyls, lipoperoxides and nitrite content increased while alpha-tocopherol and the antioxidant capacity of the soluble cellular fraction decreased significantly. Stimulation with h-CG 10 nM overnight failed to overcome the inhibition caused by D on both Te biosynthesis and 3beta- and 17beta-hydroxysteroid dehydrogenases. Decreased Te biosynthesis may be attributed to (1) inhibition of StAR protein activity due to the stimulation of COX-2 and the overproduction of PGF(2alpha), (2) decreased stimulatory effect of ARA on StAR with a subsequent reduction in the availability of CHO for the androgenic pathway, and/or (3) indirect inhibition of steroidogenic enzymes by a lower transcriptional rate caused by elevated PGF(2alpha). Rofecoxib administration prevents the deleterious effect(s) exerted by D.

  7. Luteolin Attenuates Airway Mucus Overproduction via Inhibition of the GABAergic System

    PubMed Central

    Shen, Mei-Lin; Wang, Chen-Hung; Lin, Ching-Huei; Zhou, Ning; Kao, Shung-Te; Wu, Dong Chuan

    2016-01-01

    Airway mucus overproduction is one of the most common symptoms of asthma that causes severe clinical outcomes in patients. Despite the effectiveness of general asthma therapies, specific treatments that prevent mucus overproduction in asthma patients remain lacking. Recent studies have found that activation of GABAA receptors (GABAAR) is important for promoting mucus oversecretion in lung airway epithelia. Here, we report that luteolin, a natural flavonoid compound, suppresses mucus overproduction by functionally inhibiting the GABAergic system. This hypothesis was investigated by testing the effects of luteolin on goblet cell hyperplasia, excessive mucus secretion, and GABAergic transmission using histological and electrophysiological approaches. Our results showed that 10 mg/kg luteolin significantly decreased the number of goblet cells in the lung tissue and inhibited mucus overproduction in an in vivo asthma model induced by ovalbumin (OVA) in mice. Patch-clamp recordings showed that luteolin inhibited GABAAR-mediated currents in A549 cells. Furthermore, the inhibitory effects of luteolin on OVA-induced goblet cell hyperplasia and mucus overproduction were occluded by the GABAAR antagonist picrotoxin. In conclusion, our observations indicate that luteolin effectively attenuates mucus overproduction at least partially by inhibiting GABAARs, suggesting the potential for therapeutic administration of luteolin in the treatment of mucus overproduction in asthma patients. PMID:27595800

  8. Inhibition of fatty acid synthase by amentoflavone reduces coxsackievirus B3 replication.

    PubMed

    Wilsky, Steffi; Sobotta, Katharina; Wiesener, Nadine; Pilas, Johanna; Althof, Nadine; Munder, Thomas; Wutzler, Peter; Henke, Andreas

    2012-02-01

    Coxsackievirus B3 (CVB3) is a human pathogen that causes acute and chronic infections, but an antiviral drug to treat these diseases has not yet been developed for clinical use. Several intracellular pathways are altered to assist viral transcription, RNA replication, and progeny release. Among these, fatty acid synthase (FAS) expression is increased. In order to test the potential of FAS inhibition as an anti-CVB3 strategy, several experiments were performed, including studies on the correlation of CVB3 replication and FAS expression in human Raji cells and an analysis of the time and dose dependence of the antiviral effect of FAS inhibition due to treatment with amentoflavone. The results demonstrate that CVB3 infection induces an up-regulation of FAS expression already at 1 h postinfection (p.i.). Incubation with increasing concentrations of amentoflavone inhibited CVB3 replication significantly up to 8 h p.i. In addition, suppression of p38 MAP kinase activity by treatment with SB239063 decreased FAS expression as well as viral replication. These data provide evidence that FAS inhibition via amentoflavone administration might present a target for anti-CVB3 therapy.

  9. Luteolin Attenuates Airway Mucus Overproduction via Inhibition of the GABAergic System.

    PubMed

    Shen, Mei-Lin; Wang, Chen-Hung; Lin, Ching-Huei; Zhou, Ning; Kao, Shung-Te; Wu, Dong Chuan

    2016-09-06

    Airway mucus overproduction is one of the most common symptoms of asthma that causes severe clinical outcomes in patients. Despite the effectiveness of general asthma therapies, specific treatments that prevent mucus overproduction in asthma patients remain lacking. Recent studies have found that activation of GABAA receptors (GABAAR) is important for promoting mucus oversecretion in lung airway epithelia. Here, we report that luteolin, a natural flavonoid compound, suppresses mucus overproduction by functionally inhibiting the GABAergic system. This hypothesis was investigated by testing the effects of luteolin on goblet cell hyperplasia, excessive mucus secretion, and GABAergic transmission using histological and electrophysiological approaches. Our results showed that 10 mg/kg luteolin significantly decreased the number of goblet cells in the lung tissue and inhibited mucus overproduction in an in vivo asthma model induced by ovalbumin (OVA) in mice. Patch-clamp recordings showed that luteolin inhibited GABAAR-mediated currents in A549 cells. Furthermore, the inhibitory effects of luteolin on OVA-induced goblet cell hyperplasia and mucus overproduction were occluded by the GABAAR antagonist picrotoxin. In conclusion, our observations indicate that luteolin effectively attenuates mucus overproduction at least partially by inhibiting GABAARs, suggesting the potential for therapeutic administration of luteolin in the treatment of mucus overproduction in asthma patients.

  10. Via beta-adrenoceptors, stimulation of extrasplenic sympathetic nerve fibers inhibits lipopolysaccharide-induced TNF secretion in perfused rat spleen.

    PubMed

    Kees, Martin G; Pongratz, Georg; Kees, Frieder; Schölmerich, Jürgen; Straub, Rainer H

    2003-12-01

    Using a spleen slice microsuperfusion technique in mice, we have previously characterized the role of norepinephrine (NE) and other neurotransmitters for sympathetic modulation of IL-6 and TNF secretion of splenic macrophages. Since experiments in spleen slices do not reflect the situation of an entire perfused organ, we investigated sympathetic modulation of lipopolysaccharide (LPS)-induced secretion of IL-6 and TNF in perfusion experiments of rat spleen. In an organ bath, perfusion was performed in explanted whole spleens, and catecholamines and cytokines were measured by HPLC and ELISA, respectively. Release of NE depended on stimulation frequency (maximum at 10 Hz). Apart from NE, perfusates also contained significant amounts of dopamine and epinephrine. Furthermore, perfusate epinephrine levels correlated positively with perfusate NE levels (RRank=0.750, p<0.001) but not with plasma epinephrine concentrations. This indicates that epinephrine is a conversion product of sympathetically released NE. Early electrical stimulation of extrasplenic splenic nerves, 20 min after administration of LPS, significantly inhibited TNF secretion. This electrically induced effect was abrogated by simultaneous administration of propranolol (10(-6) M) but it was not influenced by administration of either an alpha1- or alpha2-adrenergic antagonist. Late electrical stimulation of splenic nerves, 2.5 h after administration of LPS, did not change TNF secretion. Interestingly, no influence of early or late sympathetic nerve fiber stimulation on IL-6 secretion was observed. In conclusion, this is the first perfusion study of the entire spleen that demonstrates that early electrical stimulation of sympathetic splenic nerve fibers directly inhibits LPS-induced TNF secretion. This study corroborates the idea that splenic sympathetic nerves are able to inhibit important activators of the innate immune system when stimulation happens very early or even prior to their induction by LPS.

  11. 21 CFR 201.18 - Drugs; significance of control numbers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drugs; significance of control numbers. 201.18 Section 201.18 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING General Labeling Provisions § 201.18 Drugs; significance of...

  12. San Huang Decoction downregulates Aurora kinase A to inhibit breast cancer cell growth and enhance chemosenstivity to anti-tumor drugs.

    PubMed

    Xu, Yanlei; Chen, Xu; Chen, Xiyan; Bian, Weihe; Yao, Chang; Zhang, Xiaoqing; Zhu, Xiaoshu; Chen, Jiajing; Ye, Xiaozhou

    2016-08-01

    Our study aimed to explore whether San Huang Decoction (SHD) inhibited the development of breast cancer by regulating Aurora A. Human breast cancer cell lines MCF-7 and MDA-MB-231 were cultured and SHD extract was prepared. Cell growth assay and apoptosis analysis were respectively performed to detect the effects of SHD on breast cancer cells. In addition, the effects of SHD on the expression of Aurora A and p53 were determined by RT-PCR and western blot. Besides, we used Aurora A siRNA to knock down Aurora A. We then co-administrated SHD and tamoxifen or epirubicin to detect the effect of SHD on chemosensitivity to tamoxifen or epirubicin. SHD treatment significantly inhibited cell growth in a dose-dependent manner. Moreover, SHD treatment resulted in a marked decrease in Aurora A expression and obvious increase in p53 expression. In addition, knockdown of Aurora A induced cell growth inhibition, which was similar to the effect of SHD treatment. Besides, SHD exerted an additive effect on cell growth inhibition and apoptosis induction when breast cancer cells were co-administration of SHD with tamoxifen or epirubicin. Our study indicates that SHD treatment may inhibit cell growth and enhance chemosenstivity to other anti-tumor drugs in breast cancer via down-regulation of Aurora A.

  13. Investigation of drug-drug interaction via mechanism-based inhibition of cytochrome P450 3A by macrolides in dexamethasone-treated female rats.

    PubMed

    Kanazu, Takushi; Sato, Norihito; Kadono, Kyoko; Touchi, Akira; Takeda, Yuri; Yamaguchi, Yoshitaka; Baba, Takahiko

    2012-05-01

    The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism-based inhibition (MBI) by macrolides was investigated using dexamethasone-treated female rats (DEX-female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar inhibition responses were observed between human and DEX-female rat liver microsomes, however, there were fewer effects in intact male rats. The ex vivo study showed that midazolam (MDZ) metabolism in liver microsomes of DEX-female rats was reduced by ERM administration and the inhibitory effect was increased with increasing ERM doses, indicating that metabolite intermediate complex formation caused irreversible inhibition of CYP3A activity in DEX-female rats as well as in humans. In the in vivo studies, ERM and CAM significantly increased the area under the plasma concentration-time curve of MDZ and decreased the total clearance in DEX-female rats. It was concluded that the DDIs via MBI of CYP3A following macrolide administration in humans could be reproduced in female rats, suggesting that DEX-female rats can serve as an in vivo model for assessing this DDI in humans.

  14. Co-administration of water containing magnesium ion prevents loxoprofen-induced lesions in gastric mucosa of adjuvant-induced arthritis rat.

    PubMed

    Nagai, Noriaki; Takeda, Atsushi; Itanami, Yuri; Ito, Yoshimasa

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) comprise one of the most frequently used classes of medicines in the world; however, NSAIDs have significant side effects, such as gastroenteropathy, and rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAID-induced gastric lesions as compared to patients with other diseases. In Asian countries, loxoprofen has been used clinically for many years as a standard NSAID. We demonstrate the preventive effect of the co-administration of water containing magnesium ion (magnesium water, 1-200 µg/kg) on the ulcerogenic response to loxoprofen in adjuvant-induced arthritis (AA) rats. Oral administration of loxoprofen (100 mg/kg) caused hemorrhagic lesions in the gastric mucosa of AA rats 14 d after adjuvant injection, and, following loxoprofen administration, the lesion score of AA rats was significantly higher than that of normal rats. The expression of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in the gastric mucosa of AA rats were also increased by the administration of loxoprofen, and the increase in lesions and NO were prevented by the administration of aminoguanidine, an iNOS inhibitor. The co-administration of magnesium water decreased the ulcerogenic response to loxoprofen in AA rats. In addition, the co-administration of magnesium water attenuated the increase in iNOS mRNA expression and NO production in AA rats receiving loxoprofen. These results suggest that the oral co-administration of magnesium water to AA rats has a potent preventive effect on the ulcerogenic response to loxoprofen, probably by inhibiting the rise in iNOS and NO levels in the gastric mucosa.

  15. Transcultural perspectives in nursing administration.

    PubMed

    Andrews, M M

    1998-11-01

    Population demographics are reshaping the healthcare work force with respect to race, ethnicity, gender, national origin, sexual orientation, age, handicap, disability, and related factors as national sensitivity to various forms of diversity grows. Given the demographic trends, it is inevitable that nurse administrators will need skill in transcultural administration as they manage diversity and identify the cultural origins of conflict in the multicultural workplace. Culture influences the manner in which administrators, staff and patients perceive, identify, define and solve problems. In this article, the complex and interrelated factors that influence workplace diversity are examined.

  16. Thiamine deficiency induces anorexia by inhibiting hypothalamic AMPK.

    PubMed

    Liu, M; Alimov, A P; Wang, H; Frank, J A; Katz, W; Xu, M; Ke, Z-J; Luo, J

    2014-05-16

    Obesity and eating disorders are prevailing health concerns worldwide. It is important to understand the regulation of food intake and energy metabolism. Thiamine (vitamin B1) is an essential nutrient. Thiamine deficiency (TD) can cause a number of disorders in humans, such as Beriberi and Wernicke-Korsakoff syndrome. We demonstrated here that TD caused anorexia in C57BL/6 mice. After feeding a TD diet for 16days, the mice displayed a significant decrease in food intake and an increase in resting energy expenditure (REE), which resulted in a severe weight loss. At the 22nd day, the food intake was reduced by 69% and 74% for male and female mice, respectively in TD group. The REE increased by ninefolds in TD group. The loss of body weight (17-24%) was similar between male and female animals and mainly resulted from the reduction of fat mass (49% decrease). Re-supplementation of thiamine (benfotiamine) restored animal's appetite, leading to a total recovery of body weight. The hypothalamic adenosine monophosphate-activated protein kinase (AMPK) is a critical regulator of food intake. TD inhibited the phosphorylation of AMPK in the arcuate nucleus (ARN) and paraventricular nucleus (PVN) of the hypothalamus without affecting its expression. TD-induced inhibition of AMPK phosphorylation was reversed once thiamine was re-supplemented. In contrast, TD increased AMPK phosphorylation in the skeletal muscle and upregulated the uncoupling protein (UCP)-1 in brown adipose tissues which was consistent with increased basal energy expenditure. Re-administration of thiamine stabilized AMPK phosphorylation in the skeletal muscle as well as energy expenditure. Taken together, TD may induce anorexia by inhibiting hypothalamic AMPK activity. With a simultaneous increase in energy expenditure, TD caused an overall body weight loss. The results suggest that the status of thiamine levels in the body may affect food intake and body weight.

  17. Inhibition of DMBA-induced mammary tumorigenesis by rosemary extract

    SciTech Connect

    Singletary, K. )

    1991-03-15

    Extracts of the spice, rosemary, have exhibited potent antioxidant properties. In order to evaluate the ability of rosemary extract to inhibit mammary tumorigenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA), two groups of 32 day old female SD rats weighing 99.4 {plus minus} 2.6 g were fed semipurified diets containing either 0 or 1.0% rosemary extract during both the initiation and promotion stages of tumor development. All rats were administered DMBA at 53 days of age. Terminal tumor incidence was 75% and 40% for rats fed the 0 and 1.0% diets, respectively. Tumors/tumor-bearing rat were 2.3 {plus minus} 0.5 and 1.8 {plus minus} 0.3, respectively. In a second study 3 groups of female rats were fed diets containing 0, 0.5 or 1.0% rosemary extract for {minus}3 to +2 weeks following DMBA administration at 53 days of age. By 13 weeks post-DMBA tumor incidence for rats fed the 1.0% rosemary diet was significantly less than for rats fed the control diet. However, by 20, weeks, incidence for rats fed 0, 0.5, and 1.0% rosemary was 72.2, 69.6 and 58.3%, respectively. Tumors/tumor bearing rat were 2.2 {plus minus} 0.3, 2.0 {plus minus} 0.4 and 2.4 {plus minus} 0.5 for rats fed the 0, 0.5 and 1.0% diets, respectively. Therefore, rosemary extract can inhibit DMBA-induced mammary tumorigenesis when fed prior to and after DMBA dosing. Its antitumorigenic effect is not due to inhibition of the initiation stage alone.

  18. Oxidative Tea Polyphenols Greatly Inhibit the Absorption of Atenolol

    PubMed Central

    Shan, Yun; Zhang, Mengmeng; Wang, Tengfei; Huang, Qin; Yin, Dan; Xiang, Zemin; Wang, Xuanjun; Sheng, Jun

    2016-01-01

    Oxidative tea polyphenols (OTPs) is the oxidative polymerization product of epigallocatechin-3-O-gallate (EGCG) forms during the process of Pu-er tea fermentation, and possesses absorption property, which may absorbs on drugs thus impact the drug bioavailability when taking medicines with Pu-er tea. Here we demonstrated that OTP inhibited the absorption of atenolol in the intestine, which was determined by testing atenolol levels of plasma via high performance liquid chromatography (HPLC). After administration of atenolol (50 mg/kg), atenolol was absorbed (Tmax: 1.867 h) with the half-life (t1/2) of 6.663 h in control group; Compared with atenolol group, AUC0-t (h*ng/ml), AUC0-∞(h∗ng/ml), and Cmax of OTP+atenolol group (OTP 500 mg/kg + atenolol 50 mg/kg) reduced 38.7, 27, and 51%, respectively, the atenolol concentration of plasma was reduced by OTP approximately 43, 49, and 55.5% at 30 min, 1 and 2 h, respectively, (P < 0.01). Furthermore, the level of atenolol in feces was higher in the OTP+atenolol group, indicating that the absorption of atenolol in rats was inhibited by OTP. Isothermal titration calorimetry assay identified that EGCG can bind to atenolol and the in vitro results showed that OTP absorbed on atenolol and formed precipitate in acid condition, demonstrating a significant positive relationship between atenolol levels and OTP dosage. Taken together, these results suggested that consuming Pu-er tea with atenolol might inhibit atenolol absorption and possible other drugs. PMID:27445825

  19. Cetirizine in horses: pharmacokinetics and pharmacodynamics following repeated oral administration.

    PubMed

    Olsén, Lena; Bondesson, Ulf; Broström, Hans; Tjälve, Hans; Ingvast-Larsson, Carina

    2008-08-01

    The pharmacokinetics of the histamine H(1)-antagonist cetirizine and its effect on histamine-induced cutaneous wheal formation were studied in six healthy horses following repeated oral administration. After three consecutive administrations of cetirizine (0.2 mg/kg body weight, bw) every 12h, the trough plasma concentration of cetirizine was 16+/-4 ng/mL (mean+/-SD) and the wheal formation was inhibited by 45+/-23%. After four additional administrations of cetirizine (0.4 mg/kg bw) every 12 h, the trough plasma concentration was 48+/-15 ng/mL and the wheal formation was inhibited by 68+/-11%. The terminal half-life was about 5.8 h. A pharmacokinetic/pharmacodynamic link model showed that the maximal inhibition of wheal formation was about 95% and the EC(50) about 18 ng/mL. It is concluded that cetirizine in doses of 0.2-0.4 mg/kg bw administered at 12 h intervals exhibits favourable pharmacokinetic and pharmacodynamic properties without causing visible side effects, and the drug may therefore be a useful antihistamine in equine medicine.

  20. Novel triple neurokinin receptor antagonist CS-003 inhibits respiratory disease models in guinea pigs.

    PubMed

    Tsuchida, Hiroshi; Takahashi, Sakiko; Nosaka, Emi; Kuraya, Takako; Yamashita, Makoto; Morimoto, Kiyoshi

    2008-10-31

    Neurokinins are known to induce neurogenic inflammation related to respiratory diseases. The effects of CS-003 ([1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo[c]thiophene-1(3H),4'-piperidine]-(2S)-oxide hydrochloride]), a novel triple neurokinin receptor antagonist, on several respiratory disease models were evaluated in guinea pigs. As we have already shown that CS-003 is intravenously effective, we first determined if CS-003 was orally effective. CS-003 dose-dependently inhibited substance P-induced tracheal vascular hyperpermeability, neurokinin A- and neurokinin B-induced bronchoconstriction with ID(50) values of 3.6, 1.3 and 0.89 mg/kg (p.o.), respectively. CS-003 (10 mg/kg, p.o.) inhibited the number of coughs induced by capsaicin aerosol (P<0.01) and the antitussive effect was comparable to that of codeine. CS-003 (10 mg/kg, p.o.) also inhibited airway hyperresponsiveness to methacholine chloride in ovalbumin-induced asthma models (P<0.01), a milder one and a severer one. On the other hand, montelukast (10 mg/kg, p.o.), a leukotriene receptor antagonist, significantly inhibited the hyperresponsiveness only in the milder model (P<0.05). In an ovalbumin-induced rhinitis model, oral administration of CS-003 inhibited nasal blockade in a dose-dependent manner and the inhibitory effect was comparable to that of dexamethasone (10 mg/kg, p.o.). CS-003 (i.v.) also dose-dependently inhibited cigarette smoke-induced bronchoconstriction, tracheal vascular hyperpermeability and mucus secretion. These data show that CS-003, a potent orally active triple neurokinin receptor antagonist, may be useful for the treatment of respiratory diseases associated with neurokinins, such as allergic asthma, allergic rhinitis, chronic obstructive pulmonary disease and cough.

  1. Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors

    PubMed Central

    François, Rony A.; Maeng, Kyungah; Nawab, Akbar; Kaye, Frederic J.; Hochwald, Steven N.; Zajac-Kaye, Maria

    2015-01-01

    Background: Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling. Methods: We characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested the FAK inhibitor PF-04554878 in human PanNET cells in vitro and in vivo (at least three mice per group). In addition, we evaluated the effect of combined FAK and mTOR inhibition on PanNET viability and apoptosis. All statistical tests were two-sided. Results: We found that FAK is overexpressed and hyperphosphorylated in human PanNETs and that PF-04554878 strongly inhibited FAK (Tyr397) autophosphorylation in a dose-dependent manner. We found that PF-04554878 inhibited cell proliferation and clonogenicity and induced apoptosis in PanNET cells. Moreover, oral administration of PF-04554878 statistically significantly reduced tumor growth in a patient-derived xenograft model of PanNET (P = .02) and in a human PanNET xenograft model of peritoneal carcinomatosis (P = .03). Importantly, PF-04554878 synergized with the mTOR inhibitor everolimus by preventing feedback AKT activation. Conclusions: We demonstrate for the first time that FAK is overexpressed in PanNETs and that inhibition of FAK activity induces apoptosis and inhibits PanNET proliferation. We found that the novel FAK inhibitor PF-04554878 synergizes with everolimus, a US Food and Drug Administration–approved agent for PanNETs. Our findings warrant the clinical investigation of combined FAK and mTOR inhibition in PanNETs. PMID:25971297

  2. Glaucocalyxin A Inhibits Platelet Activation and Thrombus Formation Preferentially via GPVI Signaling Pathway

    PubMed Central

    Li, Qiang; Ren, Lijie; Liu, Xiaohui; Chu, Chunjun; Ozaki, Yukio; Zhang, Jian; Zhu, Li

    2013-01-01

    Platelets play a pivotal role in atherothrombosis and the antiplatelet agents have been proved to be useful in preventing onset of acute clinical events including myocardial infarction and stroke. Increasing number of natural compounds has been identified to be potential antiplatelet agents. Here we report the antiplatelet effect of glaucocalyxin A (GLA), an ent-diterpenoid that we isolated and purified from the aerial parts of Rabdosia japonica (Burm. f.) var. glaucocalyx (Maxim.) Hara, and investigate the molecular mechanisms by which GLA inhibits platelet activation and thrombus formation. The effect of GLA on platelet activation was measured using platelets freshly isolated from peripheral blood of healthy donors. Results showed that pretreatment of human platelets with lower concentrations of GLA (0.01μg/ml, 0.1μg/ml) significantly inhibited platelet aggregation induced by collagen (P<0.001) and CRP (P<0.01), a synthetic GPVI ligand, but not by ADP and U46619. Accordingly, GLA inhibited collagen-stimulated tyrosine phosphorylation of Syk, LAT, and phospholipase Cγ2, the signaling events in collagen receptor GPⅥ pathway. GLA also inhibited platelet p-selectin secretion and integrin activation by convulxin, a GPVI selective ligand. Additionally, GLA was found to inhibit low-dose thrombin-induced platelet activation. Using a flow chamber device, GLA was found to attenuate platelet adhesion on collagen surfaces in high shear condition. In vivo studies showed that GLA administration increased the time for complete occlusion upon vascular injury in mice, but did not extend tail-bleeding time when mice were administered with relatively lower doses of GLA. Therefore, the present results provide the molecular basis for the inhibition effect of GLA on platelet activation and its in vivo effect on thrombus formation, suggesting that GLA could potentially be developed as an antiplatelet and antithrombotic agent. PMID:24386454

  3. Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells.

    PubMed

    Peng, Yuan-Fei; Shi, Ying-Hong; Ding, Zhen-Bin; Ke, Ai-Wu; Gu, Cheng-Yu; Hui, Bo; Zhou, Jian; Qiu, Shuang-Jian; Dai, Zhi; Fan, Jia

    2013-12-01

    Metastasis is one of the main causes of poor prognosis for hepatocellular carcinoma (HCC), which has been linked to cell-death resistance. Autophagy is an important survival mechanism under conditions of cell stress. We hypothesized that autophagy may play a role in HCC metastasis due to its prosurvival effect. Highly metastatic HCC cell lines with stable autophagy inhibition were established via lentivirus-mediated silencing of BECN1 and ATG5 genes. Mouse models of pulmonary metastasis were then developed using the cells with or without autophagy inhibition. The analysis of lung metastasis by histopathological examination and small animal imaging showed that autophagy inhibition significantly decreased the incidence of pulmonary metastases in vivo. Further invasion, migration, detachment, lung colonization, and epithelial-mesenchymal transition (EMT) assays indicated that autophagy inhibition did not affect cell invasiveness, migration or EMT but attenuated the anoikis-resistance and lung colonization of HCC cells. Investigation of the molecular mechanisms underlying showed that the autophagy-inhibition-mediated anoikis-resistance attenuation was associated with the regulation of apoptotic signaling. As autophagy inhibition was shown to be able to suppress HCC metastasis, an autophagy-based HCC tissue-specific target therapy system (AFP-Cre/LoxP-shRNA) was constructed. In vitro and in vivo analyses showed that the system was able to efficiently inhibit autophagy of HCC cells and tissue in a tissue-specific manner. Further in vivo metastasis assay showed that intratumoral administration of the system could significantly suppress lung metastasis. Together, our findings suggest that autophagy may be involved in HCC metastasis through facilitating anoikis resistance and lung colonization of HCC cells. Autophagy-based HCC tissue-specific target therapy may be a new strategy for the management of HCC metastasis.

  4. Serotonin, Inhibition, and Negative Mood

    PubMed Central

    Dayan, Peter; Huys, Quentin J. M

    2008-01-01

    Pavlovian predictions of future aversive outcomes lead to behavioral inhibition, suppression, and withdrawal. There is considerable evidence for the involvement of serotonin in both the learning of these predictions and the inhibitory consequences that ensue, although less for a causal relationship between the two. In the context of a highly simplified model of chains of affectively charged thoughts, we interpret the combined effects of serotonin in terms of pruning a tree of possible decisions, (i.e., eliminating those choices that have low or negative expected outcomes). We show how a drop in behavioral inhibition, putatively resulting from an experimentally or psychiatrically influenced drop in serotonin, could result in unexpectedly large negative prediction errors and a significant aversive shift in reinforcement statistics. We suggest an interpretation of this finding that helps dissolve the apparent contradiction between the fact that inhibition of serotonin reuptake is the first-line treatment of depression, although serotonin itself is most strongly linked with aversive rather than appetitive outcomes and predictions. PMID:18248087

  5. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

    PubMed

    Hubers, Scott A; Brown, Nancy J

    2016-03-15

    Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.

  6. Mangosteen pericarp extract inhibits the formation of pentosidine and ameliorates skin elasticity

    PubMed Central

    Ohno, Rei-ichi; Moroishi, Narumi; Sugawa, Hikari; Maejima, Kazuhiro; Saigusa, Musashi; Yamanaka, Mikihiro; Nagai, Mime; Yoshimura, Morio; Amakura, Yoshiaki; Nagai, Ryoji

    2015-01-01

    The inhibition of advanced glycation end-products (AGEs) by daily meals is believed to become an effective prevention for lifestyle-related diseases. In the present study, the inhibitory effect of hot water extracts of mangosteen (Garcinia mangostana L.) pericarp (WEM) on the formation of pentosidine, one of AGEs, in vitro and in vivo and the remedial effect on skin conditions were measured. WEM significantly inhibited pentosidine formation during gelatin incubation with ribose. Several compounds purified from WEM, such as garcimangosone D and rhodanthenone B, were identified as inhibitors of pentosidine formation. Oral administration of WEM at 100 mg/day to volunteer subjects for 3 months reduced the serum pentosidine contents. Because obtaining skin biopsies from healthy volunteers is ethically difficult, AGE accumulation in the skin was estimated by a fluorescence detector. The oral administration of WEM significantly reduced the skin autofluorescence intensity, demonstrating that WEM also reduced AGE accumulation in the skin. Furthermore, the elasticity and moisture content of the skin was also improved by WEM. These results demonstrate that intakes of WEM reduces the glycation stress and results in the improvement of skin conditions. PMID:26236097

  7. The coagulopathy in sepsis: significance and implications for treatment

    PubMed Central

    Saracco, Paola; Vitale, Pasquale; Scolfaro, Carlo; Pollio, Berardino; Pagliarino, Mauro; Timeus, Fabio

    2011-01-01

    Sepsis related coagulopathy ranges from mild laboratory alterations up to severe disseminated intravascular coagulation (DIC). There is evidence that DIC is involved in the pathogenesis of microvascular dysfunction contributing to organ failure. Additionally, the systemic activation of coagulation, by consuming platelets and coagulation factors, may cause bleeding. Thrombin generation via the tissue factor/factor VIIa route, contemporary depression of antithrombin and protein C anticoagulant systems, as well as impaired fibrin degradation, due to high circulating levels of PAI-1, contribute to enhanced intravascular fibrin deposition. This deranged coagulopathy is an independent predictor of clinical outcome in patients with severe sepsis. Innovative supportive strategies aiming at the inhibition of coagulation activation should comprise inhibition of tissue factor-mediated activation or restoration of physiological anticoagulant pathways, as the administration of recombinant human activated protein C or concentrate. In spite of some promising initial studies, additional trials are needed to define their clinical effectiveness in adults and children with severe sepsis. PMID:22355515

  8. Reagan Administration Prepares Budget Cuts.

    ERIC Educational Resources Information Center

    Norman, Colin

    1981-01-01

    Describes tentative federal budget cuts affecting science education in the National Science Foundation, National Aeronautics and Space Administration, Department of Energy, National Institutes of Health, and the specific areas these budget cuts will affect. (DS)

  9. Administrative Computing: Ideas That Work.

    ERIC Educational Resources Information Center

    White, Lawrence S.

    1984-01-01

    Describes administrative computer use in the Concord (NH) School District. Applications discussed include procurement, cash flow and investment, accounting and control, and teacher contracts, all performed with in-house programs. (MCG)

  10. Rehabilitation and the Veterans' Administration

    NASA Technical Reports Server (NTRS)

    Meister, F.

    1974-01-01

    The Veteran's Administration health care system provides prosthetic and sensory aids for the rehabilitation of neurologically handicapped veterans. Research and development centers include prosthetic clinic teams, orthopedic shops, restoration clinics, bioengineering services, orthotics, etc.

  11. Novel CC chemokine receptor 4 antagonist RS-1154 inhibits ovalbumin-induced ear swelling in mice.

    PubMed

    Nakagami, Yasuhiro; Kawashima, Kayo; Yonekubo, Kazuki; Etori, Maki; Jojima, Takaaki; Miyazaki, Shojiro; Sawamura, Ryoko; Hirahara, Kazuki; Nara, Futoshi; Yamashita, Makoto

    2009-12-10

    CC chemokine ligand 17 (CCL17/thymus and activation-regulated chemokine: TARC) and CCL22 (macrophage-derived chemokine: MDC) selectively bind to CC chemokine receptor 4 (CCR4). The CCR4 system is considered to be responsible for the pathology of allergic diseases such as atopic dermatitis. To find and develop potential medicines against allergic diseases, we screened an in-house library to search for compounds having a profile as a CCR4 antagonist. From among the screening hits, we focused on 3-{2-[(2R)-2-phenyl-4-(4-pyridin-4-ylbenzyl)morpholin-2-yl]ethyl}quinazoline-2,4(1H,3H)-dione (named RS-1154), which had been newly synthesized in our laboratory. This compound inhibited the binding of [(125)I]CCL17 to human CCR4-expressing CHO cells with an IC(50) value of 27.7 nM and moreover inhibited CCL17-induced migration of DO11.10 mice-derived T helper 2 cells with an IC(50) value of 1.5 nM in vitro. We then examined the effect of RS-1154 in an ovalbumin-induced ear swelling assay. The ear thickness was decreased by intravenous administration of anti-CCL17 or anti-CCL22 antibodies, suggesting that the CCR4 system is involved in the ear swelling. Though partially, the oral administration of RS-1154 also significantly ameliorated the ear swelling at the doses of 30 and 100 mg/kg. Furthermore, the serum level of interleukin-4 decreased after the administration of RS-1154. In this study, we succeeded in obtaining a newly-synthesized compound, RS-1154, which has a potential to inhibit the chemotaxis of T helper 2 cells in vitro and to ameliorate ovalbumin-induced ear swelling in vivo. These results raise the possibility that RS-1154 or one of derivatives might become a therapeutic agent for atopic dermatitis patients.

  12. 17β-Estradiol inhibits apoptotic cell death of oligodendrocytes by inhibiting RhoA-JNK3 activation after spinal cord injury.

    PubMed

    Lee, Jee Y; Choi, Soo Y; Oh, Tae H; Yune, Tae Y

    2012-08-01

    A delayed oligodendrocyte cell death after spinal cord injury (SCI) contributes to chronic demyelination of spared axons, leading to a permanent neurological deficit. Therefore, therapeutic approaches to prevent oligodendrocyte cell death after SCI should be considered. Estrogens are well known to have a broad neuroprotective effect, but the protective effect of estrogens on oligodendrocytes after injury is largely unknown. Here, we demonstrated that 17β-estradiol attenuates apoptosis of oligodendrocytes by inhibiting RhoA and c-Jun-N-terminal kinase activation after SCI. Estrogen receptor (ER)-α and -β were expressed in oligodendrocytes of the spinal cord, and 17β-estradiol treatment significantly inhibited oligodendrocyte cell death at 7 d after injury as compared with vehicle (cyclodextrin) control. 17β-Estradiol also attenuated caspase-3 and -9 activation at 7 d and reduced the loss of axons from progressive degeneration. In addition, 17β-estradiol inhibited RhoA and JNK3 activation, which were activated and peaked at 3 and/or 5 d after injury. Furthermore, administration of Rho inhibitor, PEP-1-C3 exoenzyme, inhibited RhoA and JNK3 activation, and decreased phosphorylated c-Jun level at 5 d after injury. Additionally, the attenuation of RhoA and JNK3 activation as well as oligodendrocyte cell death by 17β-estradiol was reversed by ER antagonist, ICI182780. Our results thus indicate that 17β-estradiol treatment improves functional recovery after SCI in part by reducing oligodendrocyte cell death via inhibition of RhoA and JNK3 activation, which were ER dependent. Furthermore, improvement of hindlimb motor function by posttreatment of 17β-estradiol suggests its potential as a therapeutic agent for SCI patients.

  13. A Novel Sulindac Derivative That Does Not Inhibit Cyclooxygenases but Potently Inhibits Colon Tumor Cell Growth and Induces Apoptosis with Antitumor Activity

    PubMed Central

    Piazza, Gary A.; Keeton, Adam B.; Tinsley, Heather N.; Gary, Bernard D.; Whitt, Jason D.; Mathew, Bini; Thaiparambil, Jose; Coward, Lori; Gorman, Gregory; Li, Yonghe; Sani, Brahma; Hobrath, Judith V.; Maxuitenko, Yulia Y.; Reynolds, Robert C.

    2011-01-01

    Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC50 values of 2 to 5 µmol/L compared with 73 to 85 µmol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC50 for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy. PMID:19470791

  14. A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity.

    PubMed

    Piazza, Gary A; Keeton, Adam B; Tinsley, Heather N; Gary, Bernard D; Whitt, Jason D; Mathew, Bini; Thaiparambil, Jose; Coward, Lori; Gorman, Gregory; Li, Yonghe; Sani, Brahma; Hobrath, Judith V; Maxuitenko, Yulia Y; Reynolds, Robert C

    2009-06-01

    Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC(50) values of 2 to 5 micromol/L compared with 73 to 85 micromol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC(50) for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy.

  15. Novel peptide VIP-TAT with higher affinity for PAC1 inhibited scopolamine induced amnesia.

    PubMed

    Yu, Rongjie; Yang, Yanxu; Cui, Zekai; Zheng, Lijun; Zeng, Zhixing; Zhang, Huahua

    2014-10-01

    A novel peptide VIP-TAT with a cell penetrating peptide TAT at the C-terminus of VIP was constructed and prepared using intein mediated purification with an affinity chitin-binding tag (IMPACT) system to enhance the brain uptake efficiency for the medical application in central nervous system. It was found by labeling VIP-TAT and VIP with fluorescein isothiocyanate (FITC) that the extension with TAT increased the brain uptake efficiency of VIP-TAT significantly. Then short-term and long-term treatment with scopolamine (Scop) was used to evaluate the effect of VIP-TAT or VIP on Scop induced amnesia. Both short-term and long-term administration of VIP-TAT inhibited the latent time reduction in step-through test induced by Scop significantly, but long-term administration of VIP aggravated the Scop induced amnesia. Long-term i.p. injection of VIP-TAT was shown to have positive effect by inhibiting the oxidative damage, apoptosis and the cholinergic system activity reduction that induced by Scop, while VIP exerted negative effect in brain opposite to that in periphery system. The in vitro data showed that VIP-TAT had not only protective but also proliferative effect on Neuro2a cells which was inhibited by PAC1 antagonist PACAP(6-38). Competition binding assay and cAMP assay confirmed that VIP-TAT had higher affinity and activation for PAC1 than VIP. So it was concluded that the significantly stronger protective effect of VIP-TAT against Scop induced amnesia than VIP was due to (1) the enhanced brain uptake efficiency of VIP-TAT and (2) the increased affinity and activation of VIP-TAT for receptor PAC1.

  16. Development of tolerance to the inhibitory effects of ethanol in the rat isolated vas deferens: effect of acute and chronic ethanol administration in vivo.

    PubMed Central

    DeTurck, K. H.; Pohorecky, L. A.

    1986-01-01

    Contractions of the rat vas deferens elicited by the addition of noradrenaline (NA), K+-depolarizing solutions or by electrical stimulation were recorded before and after incubation with ethanol 181 mM. In tissues from untreated rats, the contractions were inhibited 40-50% by such exposure. Injection of ethanol (2 g kg-1) significantly attenuated ethanol's reduction of peak tension generated by the lowest concentration of NA (10(-4) mM). Chronic administration of ethanol, 18-14 g kg-1 daily for two weeks, resulted in significant tolerance to ethanol. Tissues of treated animals demonstrated ethanol-induced decreases of roughly one-half those of the maltose dextrin (isocaloric) and water (fluid control) groups. This tolerance persisted for at least 48 h after ethanol treatment had been terminated. Overall, the data suggest that ethanol acts both pre- and postsynaptically to produce acute inhibition of smooth muscle contractions or tolerance to these actions upon chronic exposure. PMID:3730699

  17. Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma.

    PubMed

    Shimizu, Satoshi; Takehara, Tetsuo; Hikita, Hayato; Kodama, Takahiro; Tsunematsu, Hinako; Miyagi, Takuya; Hosui, Atsushi; Ishida, Hisashi; Tatsumi, Tomohide; Kanto, Tatsuya; Hiramatsu, Naoki; Fujita, Naonobu; Yoshimori, Tamotsu; Hayashi, Norio

    2012-08-01

    Multikinase inhibitor sorafenib inhibits proliferation and angiogenesis of tumors by suppressing the Raf/MEK/ERK signaling pathway and VEGF receptor tyrosine kinase. It significantly prolongs median survival of patients with advanced hepatocellular carcinoma (HCC) but the response is disease-stabilizing and cytostatic rather than one of tumor regression. To examine the mechanisms underlying the relative resistance in HCC, we investigated the role of autophagy, an evolutionarily conserved self-digestion pathway, in hepatoma cells in vitro and in vivo. Sorafenib treatment led to accumulation of autophagosomes as evidenced by conversion from LC3-I to LC3-II observed by immunoblot in Huh7, HLF and PLC/PRF/5 cells. This induction was due to activation of autophagic flux, as there was further increase in LC3-II expression upon treatment with lysosomal inhibitors, clear decline of the autophagy substrate p62, and an mRFP-GFP-LC3 fluorescence change in sorafenib-treated hepatoma cells. Sorafenib inhibited the mammalian target of rapamycin complex 1 and its inhibition led to accumulation of LC3-II. Pharmacological inhibition of autophagic flux by chloroquine increased apoptosis and decreased cell viability in hepatoma cells. siRNA-mediated knockdown of the ATG7 gene also sensitized hepatoma cells to sorafenib. Finally, sorafenib induced autophagy in Huh7 xenograft tumors in nude mice and coadministration with chloroquine significantly suppressed tumor growth compared with sorafenib alone. In conclusion, sorafenib administration induced autophagosome formation and enhanced autophagic activity, which conferred a survival advantage to hepatoma cells. Concomitant inhibition of autophagy may be an attractive strategy for unlocking the antitumor potential of sorafenib in HCC.

  18. 77 FR 76050 - Draft Environmental Assessment and Preliminary Finding of No Significant Impact Concerning a...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-26

    ... HUMAN SERVICES Food and Drug Administration Draft Environmental Assessment and Preliminary Finding of No Significant Impact Concerning a Genetically Engineered Atlantic Salmon; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA, the Agency) is...

  19. The Rac Inhibitor EHop-016 Inhibits Mammary Tumor Growth and Metastasis in a Nude Mouse Model

    PubMed Central

    Castillo-Pichardo, Linette; Humphries-Bickley, Tessa; De La Parra, Columba; Forestier-Roman, Ingrid; Martinez-Ferrer, Magaly; Hernandez, Eliud; Vlaar, Cornelis; Ferrer-Acosta, Yancy; Washington, Anthony V.; Cubano, Luis A.; Rodriguez-Orengo, Jose; Dharmawardhane, Suranganie

    2014-01-01

    Metastatic disease still lacks effective treatments, and remains the primary cause of cancer mortality. Therefore, there is a critical need to develop better strategies to inhibit metastatic cancer. The Rho family GTPase Rac is an ideal target for anti-metastatic cancer therapy, because Rac is a key molecular switch that is activated by a myriad of cell surface receptors to promote cancer cell migration/invasion and survival. Previously, we reported the design and development of EHop-016, a small molecule compound, which inhibits Rac activity of metastatic cancer cells with an IC50 of 1 μM. EHop-016 also inhibits the activity of the Rac downstream effector p21-activated kinase (PAK), lamellipodia extension, and cell migration in metastatic cancer cells. Herein, we tested the efficacy of EHop-016 in a nude mouse model of experimental metastasis, where EHop-016 administration at 25 mg/kg body weight (BW) significantly reduced mammary fat pad tumor growth, metastasis, and angiogenesis. As quantified by UPLC MS/MS, EHop-016 was detectable in the plasma of nude mice at 17 to 23 ng/ml levels at 12 h following intraperitoneal (i.p.) administration of 10 to 25 mg/kg BW EHop-016. The EHop-016 mediated inhibition of angiogenesis In Vivo was confirmed by immunohistochemistry of excised tumors and by In Vitro tube formation assays of endothelial cells. Moreover, EHop-016 affected cell viability by down-regulating Akt and Jun kinase activities and c-Myc and Cyclin D expression, as well as increasing caspase 3/7 activities in metastatic cancer cells. In conclusion, EHop-016 has potential as an anticancer compound to block cancer progression via multiple Rac-directed mechanisms. PMID:25389450

  20. BZ-26, a novel GW9662 derivate, attenuated inflammation by inhibiting the differentiation and activation of inflammatory macrophages.

    PubMed

    Bei, Yuncheng; Chen, Jiajia; Zhou, Feifei; Huang, Yahong; Jiang, Nan; Tan, Renxiang; Shen, Pingping

    2016-12-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is considered to be an important transcriptional factor in regulation of macrophages differentiation and activation. We have synthesized a series of novel structural molecules based on GW9662's structure (named BZ-24, BZ-25 and BZ-26), and interaction activity was calculated by computational docking. BZ-26 had shown stronger interaction with PPARγ and had higher transcriptional inhibitory activity of PPARγ with lower dosage compared with GW9662. BZ-26 was proved to inhibit inflammatory macrophage differentiation. LPS-induced acute inflammation mouse model was applied to demonstrate its anti-inflammatory activity. And the results showed that BZ-26 administration attenuated plasma tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) secretion, which are vital cytokines in acute inflammation. The anti-inflammatory activity was examined in THP-1 cell line, and TNF-α, IL-6 and MCP-1, were significantly inhibited. The results of Western blot and luciferase reporter assay indicated that BZ-26 not only inhibited NF-κB transcriptional activity, but also abolished LPS-induce nuclear translocation of P65. We also test BZ-26 action in tumor-bearing chronic inflammation mouse model, and BZ-26 was able to alter macrophages phenotype, resulting in antitumor effect. All our data revealed that BZ-26 modulated LPS-induced acute inflammation via inhibiting inflammatory macrophages differentiation and activation, potentially via inhibition of NF-κB signal pathway.

  1. Changes in CYP1A2 activity in humans after 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) administration using caffeine as a probe drug.

    PubMed

    Yubero-Lahoz, Samanta; Pardo, Ricardo; Farre, Magí; Mathuna, Brian Ó; Torrens, Marta; Mustata, Cristina; Perez-Mañá, Clara; Langohr, Klaus; Carbó, Marcel Lí; de la Torre, Rafael

    2012-01-01

    3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is a ring-substituted amphetamine widely used for recreational purposes. MDMA is predominantly O-demethylenated in humans by cytochrome P450 (CYP) 2D6, and is also a potent mechanism-based inhibitor of the enzyme. After assessing the inhibition and recovery of CYP2D6 in a previous study, the aim of this work was to study in humans the activity of CYP1A2 in vivo after CYP2D6 had been inhibited by MDMA, using caffeine as a probe drug. Twelve male and nine female recreational MDMA users were included. In session 1, 100 mg of caffeine was given at 0 h. In session 2, a 1.5 mg/kg MDMA dose (range 75-100 mg) was given at 0 h followed by a 100 mg dose of caffeine 4 h later. Aliquots of plasma were assayed for caffeine (137X) and paraxanthine (17X) and statistically significant differences were assessed with a one-way ANOVA. There were significant gender differences at basal condition, which persisted after MDMA administration. CYP1A2 activity was higher in both genders after drug administration, with an increase in 40% in females and 20% in males. Results show an increase in CYP1A2 activity when CYP2D6 is inhibited by MDMA in both genders, being more pronounced in females.

  2. 76 FR 19523 - Finding of No Significant Impact (FONSI) for the Beaumont Layberth Facility

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-07

    ... Significant Impact (FONSI) for the Beaumont Layberth Facility. An environmental assessment (EA) and FONSI have... Maritime Administration Finding of No Significant Impact (FONSI) for the Beaumont Layberth Facility AGENCY... Finding of No Significant Impact. SUMMARY: Notice is hereby given that the Maritime Administration, of...

  3. Increase in E-selectin expression in umbilical vein endothelial cells by anticancer drugs and inhibition by cimetidine.

    PubMed

    Kawase, Jin; Ozawa, Soji; Kobayashi, Kenichi; Imaeda, Yoshihiro; Umemoto, Shunji; Matsumoto, Sumio; Ueda, Masakazu

    2009-12-01

    E-selectin is expressed on the surfaces of stimulated vascular endothelial cells and is sometimes involved in cancer cell metastasis. The H2-receptor antagonist cimetidine inhibits the increase in E-selectin expression on vascular endothelial cells that is induced by interleukin-1beta (IL-1beta) and cimetidine. It also inhibits the adhesion of sialyl-Lewis-antigen-positive cancer cells to vascular endothelial cells, ultimately inhibiting hematogenous metastasis. Anticancer drugs are essential to cancer therapy, but whether they can alter the expression of E-selectin in vascular endothelial cells remains unclear. Whether cimetidine inhibits the expression of E-selectin in the same manner in the presence or absence of anticancer drugs also remains unknown. Human umbilical vein endothelial cells were cultured with 5-fluorouracil (5-FU), doxorubicin (DXR), cisplatin (CDDP), or IL-1beta and with or without cimetidine. The expression of E-selectin at the mRNA and protein levels was then determined using quantitative reverse transcription-polymerase chain reaction and immunohistochemical staining, respectively. The E-selectin mRNA level increased in cells exposed to 5-FU, DXR, or CDDP, but the addition of cimetidine had no effect on the E-selectin mRNA level. The expression of E-selectin protein was also significantly higher after the addition of 5-FU, DXR, or CDDP, compared with that of a negative control. However, when cimetidine was added prior to the addition of 5-FU, DXR, or CDDP, the expression of E-selectin was significantly suppressed. Thus, cimetidine significantly inhibited the expression of E-selectin at the protein level without affecting its expression at the mRNA level in cells treated with anticancer drugs. In conclusion, anticancer drugs increased the expression of E-selectin and this increase was inhibited by cimetidine. These findings suggest that the administration of cimetidine during treatment with anticancer drugs might be useful for preventing

  4. Dehydrocostuslactone inhibits LPS-induced inflammation by p38MAPK-dependent induction of hemeoxygenase-1 in vitro and improves survival of mice in CLP-induced sepsis in vivo.

    PubMed

    Park, Eun Jung; Park, Sang Won; Kim, Hye Jung; Kwak, Jong-Hwan; Lee, Dong-Ung; Chang, Ki Churl

    2014-10-01

    We investigated the hypothesis that the administration of dehydrocostuslactone (DL), a sesquiterpene lactone found in Saussurea lappa Clarke (Compositae), might reduce organ failure and increase survival in a cecal ligation and puncture (CLP)-induced mouse model of sepsis due to HO-1 induction. Treatment of RAW264.7 cells with DL increased HO-1 expression in a time- and concentration-dependent manner, and this up-regulation of HO-1 by DL was significantly inhibited by silencing either Nrf2 and p38 or treating cells with SB203580 (a p38MAPK inhibitor), but it was not inhibited in the presence of SP600125 (an ERK inhibitor), PD98059 (a JNK inhibitor), or LY294002 (PI3K inhibitor). As expected, DL concentration dependently inhibited the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), and the productions of NO and PGE2 in LPS-activated cells, and these inhibitions were reversed by silencing HO-1. Most importantly, administration of DL significantly reduced mortality and reduced serum IL-1β and TNF-α and the infiltration of macrophages into liver tissues of CLP-mice. Inducible NOS expression in lung and liver tissues of CLP-mice was reduced by DL, which was reversed by the co-administration of zinc-protoporphyrin IX (ZnPPIX; a competitive inhibitor of HO-1). Our findings indicate that DL might be useful for the treatment of sepsis.

  5. Potentiation of latent inhibition.

    PubMed

    Rodriguez, Gabriel; Hall, Geoffrey

    2008-07-01

    Rats were given exposure either to an odor (almond) or a compound of odor plus taste (almond plus saline), prior to training in which the odor served as the conditioned stimulus. It was found, for both appetitive and aversive procedures, that conditioning was retarded by preexposure (a latent inhibition effect), and the extent of the retardation was greater in rats preexposed to the compound (i.e., latent inhibition to the odor was potentiated by the presence of the taste). In contrast, the presence of the taste during conditioning itself overshadowed learning about the odor. We argue that the presence of the salient taste in compound with the odor enhances the rate of associative learning, producing a rapid loss in the associability of the odor. This loss of associability will generate both overshadowing and the potentiation of latent inhibition that is observed after preexposure to the compound.

  6. Chitin deacetylase product inhibition.

    PubMed

    Jaworska, Malgorzata M

    2011-02-01

    Chitin deacetylase is the only known enzyme catalyzing the hydrolysis of the acetamino linkage in the N-acetylglucosamine units of chitin and chitosan. This reaction can play an important role in enzymatic production of chitosan from chitin, or in enzymatic modification of chitosan, which has applications in medicine, pharmacy or plant protection. It was previously shown that acetic acid, a product of the deacetylation process, may act as an inhibitor of chitin deacetylase. Here we show the mechanism of inhibition of chitin deacetylase isolated from Absidia orchidis vel coerulea by acetic acid released during the deacetylation process. The process follows competitive inhibition with respect to acetic acid with an inhibition constant of K(i) = 0.286 mmol/L. These results will help to find the optimal system to carry out the enzymatic deacetylation process for industrial applications.

  7. Chronic administration of troxerutin protects mouse brain against D-galactose-induced impairment of cholinergic system.

    PubMed

    Lu, Jun; Wu, Dong-Mei; Hu, Bin; Cheng, Wei; Zheng, Yuan-Lin; Zhang, Zi-Feng; Ye, Qin; Fan, Shao-Hua; Shan, Qun; Wang, Yong-Jian

    2010-02-01

    Previous evidence showed that administration of d-galactose (d-gal) increased ROS production and resulted in impairment of cholinergic system. Troxerutin, a natural bioflavonoid, has been reported to have many benefits and medicinal properties. In this study, we evaluated the protective effect of troxerutin against d-gal-induced impairment of cholinergic system, and explored the potential mechanism of its action. Our results displayed that troxerutin administration significantly improved behavioral performance of d-gal-treated mice in step-through test and morris water maze task. One of the potential mechanisms of this action was decreased AGEs, ROS and protein carbonyl levels in the basal forebrain, hippocampus and front cortex of d-gal-treated mice. Furthermore, our results also showed that troxerutin significantly inhibited cholinesterase (AchE) activity, increased the expression of nicotinic acetylcholine receptor alpha 7 (nAchRalpha7) and enhanced interactions between nAchRalpha7 and either postsynaptic density protein 95 (PSD95) or N-methyl-d-aspartate receptors subunit 1 (NMDAR1) in the basal forebrain, hippocampus and front cortex of d-gal-treated mice, which could help restore impairment of brain function.

  8. Potentially significant versus clinically significant drug interactions: pomegranate juice as a case in point.

    PubMed

    Andrade, Chittaranjan

    2014-04-01

    In vitro and in vivo laboratory data show that pomegranate juice consistently inhibits intestinal CYP2C9 and CYP3A4 enzymes. Pomegranate juice may therefore increase the bioavailability of drugs that are metabolized by these enzymes. However, studies in humans find that pomegranate juice does not increase exposure to either CYP2C9 or CYP3A4 substrates. These contradictory findings suggest that potential drug interactions identified in the laboratory may not necessarily translate into clinically significant drug interactions in humans, and hence that laboratory data are insufficient grounds upon which clinical decisions may be based.

  9. Hepatic arterial administration of sorafenib and iodized oil effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX2 hepatocellular carcinoma model

    PubMed Central

    Zhang, Lin; Liu, Feng-Yong; Fu, Jin-Xin; Duan, Feng; Fan, Qing-Sheng; Wang, Mao-Qiang

    2014-01-01

    Aim: To investigate the therapeutic effect of the hepatic arterial administration of sorafenib in rabbit VX-2 hepatocellular carcinoma (HCC) model. Methods: Rabbit VX-2 HCC models were established via implanting VX-2 tumors into the livers, and randomly divided into four groups, respectively treated with (1) The hepatic arterial administration of iodized oil alone (TACE-i), (2) The hepatic arterial administration of iodized oil and pharmorubicin (TACE-ip), (3) The hepatic arterial administration of iodized and cis-DDP (TACE-ic), (4) The hepatic arterial administration of iodized and sorafenib (TACE-is). The growth rate and intrahepatic metastasis of implanted VX-2 tumor in each rabbit were measured. Microvessel density (MVD) in the adjacent tissues of implanted VX-2 tumor were estimated by detecting the expression of CD34 and VEGF level in tumor adjacent tissues were also examined by Immunohistochemistry. Results: Compared with other groups, TACE-is treatment group presented a better effect on inhibiting tumor growth rate and intrahepatic metastasis in rabbit VX-2 HCC model. The angiogenesis (assessed by MVD) in the adjacent tissues were suppressed more dramatically in TACE-is treated group. Moreover, TACE-is treatment did not significantly increase the levels of alanine transaminase and creatinine compared to the group with TACE-i treatment. Conclusion: The hepatic arterial administration of sorafenib and iodized oil (TACE-is) effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX-2 HCC model without obvious hepatic and renal toxicity. One of the related mechanisms may be due to the inhibition of angiogenesis in the adjacent tissues. Our data indicated that TACE-is may be a secure and effective treatment for HCC. PMID:25550815

  10. Ibuprofen administration attenuates serum TNF-{alpha} levels, hepatic glutathione depletion, hepatic apoptosis and mouse mortality after Fas stimulation

    SciTech Connect

    Cazanave, Sophie; Vadrot, Nathalie; Tinel, Marina; Berson, Alain; Letteron, Philippe; Larosche, Isabelle; Descatoire, Veronique; Feldmann, Gerard; Robin, Marie-Anne |; Pessayre, Dominique |

    2008-09-15

    Fas stimulation recruits neutrophils and activates macrophages that secrete tumor necrosis factor-{alpha} (TNF-{alpha}), which aggravates Fas-mediated liver injury. To determine whether nonsteroidal anti-inflammatory drugs modify these processes, we challenged 24-hour-fasted mice with the agonistic Jo2 anti-Fas antibody (4 {mu}g/mouse), and treated the animals 1 h later with saline or ibuprofen (250 mg/kg), a dual cyclooxygenase (COX)-1 and COX-2 inhibitor. Ibuprofen attenuated the Jo2-mediated recruitment/activation of myeloperoxidase-secreting neutrophils/macrophages in the liver, and attenuated the surge in serum TNF-{alpha}. Ibuprofen also minimized hepatic glutathione depletion, Bid truncation, caspase activation, outer mitochondrial membrane rupture, hepatocyte apoptosis and the increase in serum alanine aminotransferase (ALT) activity 5 h after Jo2 administration, to finally decrease mouse mortality at later times. The concomitant administration of pentoxifylline (decreasing TNF-{alpha} secretion) and infliximab (trapping TNF-{alpha}) likewise attenuated the Jo2-mediated increase in TNF-{alpha}, the decrease in hepatic glutathione, and the increase in serum ALT activity 5 h after Jo2 administration. The concomitant administration of the COX-1 inhibitor, SC-560 (10 mg/kg) and the COX-2 inhibitor, celecoxib (40 mg/kg) 1 h after Jo2 administration, also decreased liver injury 5 h after Jo2 administration. In contrast, SC-560 (10 mg/kg) or celecoxib (40 or 160 mg/kg) given alone had no significant protective effects. In conclusion, secondary TNF-{alpha} secretion plays an important role in Jo2-mediated glutathione depletion and liver injury. The combined inhibition of COX-1 and COX-2 by ibuprofen attenuates TNF-{alpha} secretion, glutathione depletion, mitochondrial alterations, hepatic apoptosis and mortality in Jo2-treated fasted mice.

  11. Lansoprazole induces apoptosis of breast cancer cells through inhibition of intracellular proton extrusion

    SciTech Connect

    Zhang, Shangrong; Wang, Yifan; Li, Shu Jie

    2014-06-13

    Highlights: • Lansoprazole (LPZ) induces cell apoptosis in breast cancer cells. • LPZ markedly inhibits intracellular proton extrusion. • LPZ induces an increase in intracellular ATP level, lysosomal alkalinization and ROS accumulation. - Abstract: The increased glycolysis and proton secretion in tumors is proposed to contribute to the proliferation and invasion of cancer cells during the process of tumorigenesis and metastasis. Here, treatment of human breast cancer cells with proton pump inhibitor (PPI) lansoprazole (LPZ) induces cell apoptosis in a dose-dependent manner. In the implantation of the MDA-MB-231 xenografts in nude mice, administration of LPZ significantly inhibits tumorigenesis and induces large-scale apopotosis of tumor cells. LPZ markedly inhibits intracellular proton extrusion, induces an increase in intracellular ATP level, lysosomal alkalinization and accumulation of reactive oxygen species (ROS) in breast cancer cells. The ROS scavenger N-acetyl-L-cysteine (NAC) and diphenyleneiodonium (DPI), a specific pharmacological inhibitor of NADPH oxidases (NOX), significantly abolish LPZ-induced ROS accumulation in breast cancer cells. Our results suggested that LPZ may be used as a new therapeutic drug for breast tumor.

  12. NOAA administrator reviews agency progress and challenges

    NASA Astrophysics Data System (ADS)

    Showstack, Randy

    2011-12-01

    The approach of the new year is a traditional time to tally up successes, failures, and the path ahead. Jane Lubchenco, administrator of the U.S. National Oceanic and Atmospheric Administration (NOAA), examined some agency advances and significant challenges during the 7 December Union Agency Lecture at the AGU Fall Meeting, during a press briefing, and in an interview with Eos. Lubchenco focused on several key areas including the concern about monitoring, mitigating, and managing extreme events; budgetary pressures the agency faces in current fiscal year (FY) 2012 and in FY 2013, with President Barack Obama on 18 November having signed into law a bill, HR 2112, following congressional agreement on a budget legislation conference report; and NOAA's newly released scientific integrity policy (see "NOAA issues scientific integrity policy," Eos Trans. AGU, 92(50), 467, doi:10.1029/2011EO500004, 2011).

  13. Predominant D1 Receptors Involvement in the Over-expression of CART Peptides after Repeated Cocaine Administration

    PubMed Central

    Hu, Zhenzhen; Oh, Eun-Hye; Chung, Yeon Bok; Hong, Jin Tae

    2015-01-01

    The aim of this study was to investigate the involvement of dopaminergic receptors (DR) in behavioral sensitization, as measured by locomotor activity, and the over-expression of cocaine- and amphetamine-regulated transcript (CART) peptides after repeated administration of cocaine in mice. Repeated administrations of cocaine induced behavioral sensitization and CART over-expression in mice. The levels of striatal CART mRNA were significantly increased on the 3rd day. CART peptides were over-expressed on the 5th day in the striata of behaviorally sensitized mice. A higher proportion of CART+ cells in the cocaine-treated mice were present in the nucleus accumbens (NAc) shell than in the dorsolateral (DL) part of caudate putamen (CP). The concomitant administration of both D1R and D2R antagonists, SCH 23390 (D1R selective) and raclopride (D2R selective), blocked cocaine induced-behavioral sensitization, CART over-expression, and cyclic adenosine 5'-monophosphate (cAMP)/protein kinase A (PKA)/phospho-cAMP response element-binding protein (pCREB) signal pathways. SCH 23390 more predominantly inhibited the locomotor activity, CART over-expression, pCREB and PKA activity than raclopride. Cocaine induced-behavioral sensitization was also attenuated in the both D1R and D2R knockout (KO) mice, respectively. CART over-expression and activated cAMP/PKA/pCREB signal pathways were inhibited in the D1R-KO mice, but not in the D2R-KO mice. It is suggested that behavioral sensitization, CART over-expression and activated cAMP/PKA/pCREB signal pathways induced by repeated administration of cocaine could be more predominantly mediated by D1R. PMID:25729269

  14. Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity

    PubMed Central

    Zhong, Ze-yu; Sun, Bin-bin; Shu, Nan; Xie, Qiu-shi; Tang, Xian-ge; Ling, Zhao-li; Wang, Fan; Zhao, Kai-jing; Xu, Ping; Zhang, Mian; Li, Ying; Chen, Yang; Liu, Li; Xia, Lun-zhu; Liu, Xiao-dong

    2016-01-01

    Aim: Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), which may cause serious intestinal adverse reactions (enteropathy). In this study we investigated whether co-administration of ciprofloxacin affected the pharmacokinetics of diclofenac and diclofenac-induced enteropathy in rats. Methods: The pharmacokinetics of diclofenac was assessed in rats after receiving diclofenac (10 mg/kg, ig, or 5 mg/kg, iv), with or without ciprofloxacin (20 mg/kg, ig) co-administered. After receiving 6 oral doses or 15 intravenous doses of diclofenac, the rats were sacrificed, and small intestine was removed to examine diclofenac-induced enteropathy. β-Glucuronidase activity in intestinal content, bovine liver and E coli was evaluated. Results: Following oral or intravenous administration, the pharmacokinetic profile of diclofenac displayed typical enterohepatic circulation, and co-administration of ciprofloxacin abolished the enterohepatic circulation, resulted in significant reduction in the plasma content of diclofenac. In control rats, β-glucuronidase activity in small intestinal content was region-dependent: proximal intestineAdministration of ciprofloxac caused significant reduction of β-glucuronidase activity in distal small intestine, and particularly in ileal valve. Furthermore, ciprofloxacin (10–2000 μmol/L) dose-dependently inhibited β-glucuronidase activity in distal small intestine content or E coli incubated in vitro, but did not affect that in proximal small intestine content or bovine liver incubated in vitro. After receiving 6 oral doses or 15 intravenous doses of diclofenac, typical enteropathy was developed with severe enteropathy occurred in distal small intestine. Co-administration of ciprofloxacin significantly alleviated diclofenac-induced enteropathy. Conclusion: Co-administration of ciprofloxacin attenuated enterohepatic circulation of diclofenac and alleviated diclofenac-induced enteropathy in rats, partly via

  15. Inhibition of Drp1 by Mdivi-1 attenuates cerebral ischemic injury via inhibition of the mitochondria-dependent apoptotic pathway after cardiac arrest.

    PubMed

    Li, Y; Wang, P; Wei, J; Fan, R; Zuo, Y; Shi, M; Wu, H; Zhou, M; Lin, J; Wu, M; Fang, X; Huang, Z

    2015-12-17

    Mitochondrial fission is predominantly controlled by the activity of dynamin-related protein1 (Drp1), which has been reported to be involved in mitochondria apoptosis pathways. However, the role of Drp1 in a rat model of cardiac arrest remains unknown. In this study, we found that activation of Drp1 in the mitochondria was increased after cardiac arrest and inhibition of Drp1 by 1.2 mg/kg of mitochondrial division inhibitor-1 (Mdivi-1) administration after the restoration of spontaneous circulation (ROSC) significantly protected against cerebral ischemic injury, shown by the increased 72-h survival rate and improved neurological function. Moreover, the increase of the vital neuron and the reduction of cytochrome c (CytC) release, apoptosis-inducing factor (AIF) translocation and caspase-3 activation in the brain indicate that this protection might result from the suppression of neuron apoptosis. Altogether, these results indicated that Drp1 is activated after cardiac arrest and the inhibition of Drp1 is protective against cerebral ischemic injury in a rat of cardiac arrest model via inhibition of the mitochondrial apoptosis pathway.

  16. Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol

    SciTech Connect

    Maeda, Masayo; Murakami, Manabu; Takegami, Tsutomu; Ota, Takahide

    2008-06-01

    Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonly used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent.

  17. Significant Decisions in Labor Cases.

    ERIC Educational Resources Information Center

    Monthly Labor Review, 1979

    1979-01-01

    Several significant court decisions involving labor cases are discussed including a series of decisions concerning constitutional protections afforded aliens; the First Amendment and national labor relations laws; and the bifurcated backpay rule. (BM)

  18. Significant Scales in Community Structure

    PubMed Central

    Traag, V. A.; Krings, G.; Van Dooren, P.

    2013-01-01

    Many complex networks show signs of modular structure, uncovered by community detection. Although many methods succeed in revealing various partitions, it remains difficult to detect at what scale some partition is significant. This problem shows foremost in multi-resolution methods. We here introduce an efficient method for scanning for resolutions in one such method. Additionally, we introduce the notion of “significance” of a partition, based on subgraph probabilities. Significance is independent of the exact method used, so could also be applied in other methods, and can be interpreted as the gain in encoding a graph by making use of a partition. Using significance, we can determine “good” resolution parameters, which we demonstrate on benchmark networks. Moreover, optimizing significance itself also shows excellent performance. We demonstrate our method on voting data from the European Parliament. Our analysis suggests the European Parliament has become increasingly ideologically divided and that nationality plays no role. PMID:24121597

  19. Astronomical Significance of Ancient Monuments

    NASA Astrophysics Data System (ADS)

    Simonia, I.

    2011-06-01

    Astronomical significance of Gokhnari megalithic monument (eastern Georgia) is considered. Possible connection of Amirani ancient legend with Gokhnari monument is discussed. Concepts of starry practicality and solar stations are proposed.

  20. Chrysin Inhibits Lymphangiogenesis in Vitro.

    PubMed

    Prangsaengtong, Orawin; Athikomkulchai, Sirivan; Xu, Jiuxiang; Koizumi, Keiichi; Inujima, Akiko; Shibahara, Naotoshi; Shimada, Yutaka; Tadtong, Sarin; Awale, Suresh

    2016-01-01

    The induction of lymphangiogenesis is an important process to promote cancer growth and cancer metastasis via the lymphatic system. Identifying the compounds that can prevent lymphangiogenesis for cancer therapy is urgently required. Chrysin, 5,7-dihydroxyflavone, a natural flavone extracted from Thai propolis, was used to investigate the effect on the lymphangiogenesis process of TR-LE, rat lymphatic endothelial cells. In this study, maximal nontoxic doses of chrysin on TR-LE cells were selected by performing a proliferation assay. The process of lymphangiogenesis in vitro was determined by cord formation assay, adhesion assay and migration assay. Chrysin at a nontoxic dose (25 μM) significantly inhibited cord formation, cell adhesion and migration of TR-LE cells when compared with the control group. We also found that chrysin significantly induced vascular endothelial growth factor C (VEGF-C) mRNA expression and nitric oxide (NO) production in TR-LE cells which was involved in decreasing the cord formation of TR-LE cells. In conclusion, we report for the first time that chrysin inhibited the process of lymphangiogenesis in an in vitro model. This finding may prove to be a natural compound for anti-lymphangiogenesis that could be developed for use in cancer therapy.

  1. Concomitant immunity against tumor development is enhanced by the oral administration of a kampo medicine, Hochu-ekki-to (TJ-41: Bu-Zhong-Yi-Qi-Tang).

    PubMed

    Harada, M; Seta, K; Ito, O; Tamada, K; Li, T; Terao, H; Takenoyama, M; Kimura, G; Nomoto, K

    1995-11-01

    The oral administration of a kampo herbal medicine, Hochu-ekki-to (TJ-41: Bu-Zhong-Yi-Qi-Tang) using a water-supplying bottle resulted in a slight but significant inhibition of Meth A growth. The oral administration of TJ-41 with gastric gavage significantly enhanced the specific antitumor activity against Meth A at rechallenge on day 9. In a tumor-neutralizing assay, the tumor draining LN cells of the TJ-41 administered mice showed an antitumor activity against Meth A. In a cytolytic assay, the anti-Meth A specific cytolytic T lymphocyte activity was not detected in the spleen cells of the Meth A bearing and TJ-41 administered mice. The oral administration of TJ-41 enhanced the natural killer (NK) activity of the spleen cells in naive mice but could not improve the decreased NK activity of spleen cells from the tumor bearing mice. In a cytostatic assay, the peritoneal exudate cells from the Meth A bearing and TJ-41 administered mice showed a significantly higher amount of cytostatic activity against Meth A than that from either Meth A bearing or TJ-41 administered mice. These results indicate that the oral administration of TJ-41 into the tumor bearing mice may thus be able to enhance concomitant antitumor immunity through the augmentation of the cytostatic activity.

  2. Statistical Significance vs. Practical Significance: An Exploration through Health Education

    ERIC Educational Resources Information Center

    Rosen, Brittany L.; DeMaria, Andrea L.

    2012-01-01

    The purpose of this paper is to examine the differences between statistical and practical significance, including strengths and criticisms of both methods, as well as provide information surrounding the application of various effect sizes and confidence intervals within health education research. Provided are recommendations, explanations and…

  3. Inhibition of immediate hypersensitivity reactions in laboratory animals by a phenanthroline salt (ICI 74,917).

    PubMed Central

    Evans, D P; Thomson, D S

    1975-01-01

    1. The activity of a new anti-allergic compound, I.C.I. 74,917, has been studied in the rat, mouse and guinea-pig. 2. Following intravenous administration, I.C.I. 74,917 inhibits in a dose-dependent manner passive cutaneous anaphylaxis induced in rats and mice by heat-labile homocytotropic antibody. In rats, its potency is approximately 300 times that of disodium cromoglycate. 3. To achieve maximal inhibition, it is necessary to administer I.C.I. 74,917 at the same time as antigenic challenge; dosing before or after challenge has much less effect. 4. Liberation of histamine, provoked by the antigenic challenge of mast cells passively sensitized in vitro by IgE-like antibody, is reduced in the presence of I.C.I. 74,917. 5. Intravenous administration of the compound has no significant effect upon local blueing reactions provoked in the rat by intradermal injection of histamine, 5-hydroxytryptamine or Compound 48/80. It has only a slight effect at high doses upon passive cutaneous anaphylaxis induced in the rat by heat-stable homocytotropic or heterologous (guinea-pig) antibodies. 6. Although not a bronchodilator in the guinea-pig, I.C.I. 74,917 partially inhibits systemic anaphylaxis. A consistent reduction in the severity of antigen-induced bronchospasm was demonstrated in the Konzett-Rossler preparation at doses comparable to those inhibiting passive cutaneous anaphylaxis in the rat. However, there was only slight inhibition of passive cutaneous anaphylaxis in the guinea-pig. 7. I.C.I. 74,917 itself induces bronchospasm when administered to anaesthetized guinea-pigs or to a guinea-pig isolated lung preparation. This effect is reversed by salbutamol, but is not prevented by the prior administration of mepyramine, atropine or methysergide. 8. These results indicate that in the rat, mouse and guinea-pig, I.C.I. 74,917 is a potent inhibitor of certain types of immediate hypersensitivity reactions. PMID:48393

  4. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants

    PubMed Central

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-01

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity. PMID:26744061

  5. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

    PubMed

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-08

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

  6. 45 CFR 1336.71 - Administrative costs.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false Administrative costs. 1336.71 Section 1336.71... Administrative costs. Reasonable administrative costs of the RLF may be paid out of the loan fund. The grant award agreement between the Loan Administrator and ANA will set forth the allowable administrative...

  7. 7 CFR 1000.25 - Market administrator.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 9 2011-01-01 2011-01-01 false Market administrator. 1000.25 Section 1000.25... Rules of Practice and Procedure Governing Market Administrators § 1000.25 Market administrator. (a) Designation. The agency for the administration of the order shall be a market administrator selected by...

  8. 7 CFR 1000.25 - Market administrator.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Market administrator. 1000.25 Section 1000.25... Rules of Practice and Procedure Governing Market Administrators § 1000.25 Market administrator. (a) Designation. The agency for the administration of the order shall be a market administrator selected by...

  9. 5 CFR 831.101 - Administration.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Administration. 831.101 Section 831.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Administration and General Provisions § 831.101 Administration. (a) OPM has charge of...

  10. 7 CFR 56.3 - Administration.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 3 2011-01-01 2011-01-01 false Administration. 56.3 Section 56.3 Agriculture... EGGS Grading of Shell Eggs General § 56.3 Administration. The Administrator shall perform, for and... administration of the provisions of the Act and the regulations in this part. The Administrator is authorized...

  11. 7 CFR 56.3 - Administration.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Administration. 56.3 Section 56.3 Agriculture... EGGS Grading of Shell Eggs General § 56.3 Administration. The Administrator shall perform, for and... administration of the provisions of the Act and the regulations in this part. The Administrator is authorized...

  12. 5 CFR 179.307 - Administrative offset.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Administrative offset. 179.307 Section 179.307 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS CLAIMS COLLECTION STANDARDS Administrative Offset § 179.307 Administrative offset. (a) If the debtor does...

  13. 7 CFR 1000.25 - Market administrator.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 9 2014-01-01 2013-01-01 true Market administrator. 1000.25 Section 1000.25... Rules of Practice and Procedure Governing Market Administrators § 1000.25 Market administrator. (a) Designation. The agency for the administration of the order shall be a market administrator selected by...

  14. 7 CFR 1000.25 - Market administrator.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 9 2013-01-01 2013-01-01 false Market administrator. 1000.25 Section 1000.25... Rules of Practice and Procedure Governing Market Administrators § 1000.25 Market administrator. (a) Designation. The agency for the administration of the order shall be a market administrator selected by...

  15. 7 CFR 1000.25 - Market administrator.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 9 2012-01-01 2012-01-01 false Market administrator. 1000.25 Section 1000.25... Rules of Practice and Procedure Governing Market Administrators § 1000.25 Market administrator. (a) Designation. The agency for the administration of the order shall be a market administrator selected by...

  16. Glycoprotein glycans that inhibit adhesion of Escherichia coli mediated by K99 fimbriae: treatment of experimental colibacillosis.

    PubMed Central

    Mouricout, M; Petit, J M; Carias, J R; Julien, R

    1990-01-01

    Calf diarrhea due to infection by enterotoxigenic Escherichia coli was treated by administration of glycoprotein glycans derived from bovine plasma. The glycan moieties of the nonimmunoglobulin fraction of plasma mimicked the oligosaccharide moiety of intestinal receptors recognized by K99 pili. These glycoprotein glycans inhibited adhesion of E. coli K99+ ST+ to erythrocyte glycoconjugates in vitro, and they protected colostrum-deprived newborn calves against lethal doses of enterotoxigenic E. coli (10(10) bacteria). Adhesion of bacteria to the intestines (duodenum, jejunum, and ileum) was significantly reduced (by 2 orders of magnitude) in treated calves. PMID:2403535

  17. Peptide bioregulators inhibit apoptosis.

    PubMed

    Khavinson, V K; Kvetnoii, I M

    2000-12-01

    The effects of peptide bioregulators epithalon and vilon on the dynamics of irradiation-induced apoptotic death of spleen lymphocytes in rats indicate that these agents inhibit physiologically programmed cell death. The antiapoptotic effect of vilon was more pronounced, which corroborates the concept on tissue-specific effect of peptide bioregulators.

  18. Serine proteases inhibiting cyanopeptides.

    PubMed

    Radau, G

    2000-08-01

    There are many compounds inhibiting serine proteases which play an important role in the human organism. This article reviews publications on the low-molecular weight, serine protease inhibitory cyanopeptides and reports on new developments in establishing structure-activity relationships.

  19. Reinforcement of inhibition

    PubMed Central

    Anger, Douglas

    1983-01-01

    A differential-reinforcement-of-other-behavior (DRO) schedule with trials and delayed reinforcement was investigated. Periodically a wheel was briefly available to rats, followed six seconds later by brief availability of a bar. Variable-ratio food reinforcement of wheel turns was adjusted to give 95% turns. After variable-ratio-five reinforcement of bar presses produced 100% pressing, then separate ratio schedules were used for presses following turns (turn presses) and presses following nonturns (nonturn presses). Increasing nonturn-press reinforcements decreased turns, even though total reinforcements increased. Reversal by decreasing nonturn-press reinforcements raised turns, though with hysteresis. Thus food reinforcement increased nonturns even though delayed six to ten seconds after nonturns, a delay that greatly reduces response reinforcement. Those and other results indicate that the turn decrease was not due to reinforcement of competing responses. Evidence against other alternatives, and the reduction of responding by increased reinforcement, indicate that the term inhibition is appropriate for the phenomenon reinforced. Response-specific inhibition appears appropriate for this particular kind, since its effects are more specific to particular responses than Pavlovian conditioned-inhibition. Response-specific inhibition seems best considered a behavioral output comparable to responses (e.g., both reinforcible) but with important properties different from responses (e.g., different reinforcement-delay gradients). PMID:16812315

  20. 47 CFR 54.715 - Administrative expenses of the Administrator.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    .... 54.715 Section 54.715 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER... employees of the federal government. (c) The Administrator shall submit to the Commission projected quarterly budgets at least sixty (60) days prior to the start of every quarter. The Commission must...

  1. TWRS information locator database system administrator`s manual

    SciTech Connect

    Knutson, B.J., Westinghouse Hanford

    1996-09-13

    This document is a guide for use by the Tank Waste Remediation System (TWRS) Information Locator Database (ILD) System Administrator. The TWRS ILD System is an inventory of information used in the TWRS Systems Engineering process to represent the TWRS Technical Baseline. The inventory is maintained in the form of a relational database developed in Paradox 4.5.

  2. An Analysis of Administrator Attitudes toward Tasks in School Administration

    ERIC Educational Resources Information Center

    Rayfield, Robin; Diamantes, Thomas

    2004-01-01

    This study reports attitudes of current school administrators toward routine tasks in an attempt to offer insight into why the job may or may not be considered a wise career choice or even a desirable job. The research question for this study is: What makes the principal's position desirable and what makes this important leadership position less…

  3. Significance Analysis of Prognostic Signatures

    PubMed Central

    Beck, Andrew H.; Knoblauch, Nicholas W.; Hefti, Marco M.; Kaplan, Jennifer; Schnitt, Stuart J.; Culhane, Aedin C.; Schroeder, Markus S.; Risch, Thomas; Quackenbush, John; Haibe-Kains, Benjamin

    2013-01-01

    A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that “random” gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS) which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date) of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically annotated

  4. Xanthohumol inhibits STAT3 activation pathway leading to growth suppression and apoptosis induction in human cholangiocarcinoma cells.

    PubMed

    Dokduang, Hasaya; Yongvanit, Puangrat; Namwat, Nisana; Pairojkul, Chawalit; Sangkhamanon, Sakkarn; Yageta, Mika Sakurai; Murakami, Yoshinori; Loilome, Watcharin

    2016-04-01

    STAT3 plays a significant role in the development of cholangiocarcinoma (CCA) associated with the liver fluke (Opisthorchis viverrini; Ov). Xanthohumol (XN), a prenylated flavonoid extracted from hops, has known anticancer activity and could potentially target STAT3. The present study determined the effect of XN on STAT3, as well as ascertained its usefulness against CCA. The CCA cell proliferation at 20 µM and 50 µM of XN was shown to inhibited, while 20 µM partially inhibited IL-6-induced STAT3 activation. At 50 µM, the inhibition was complete. The reduction in STAT3 activity at 20 and 50 µM was associated with a significant reduction of CCA cell growth and apoptosis. We also found that the administration of 50 µM XN orally in drinking water to nude mice inoculated with CCA led to a reduction in tumor growth in comparison with controls. In addition, apoptosis of cancer cells increased although there was no visible toxicity. The present study shows that XN can inhibit STAT3 activation both in vivo and in vitro due to suppression of the Akt-NFκB signaling pathway. XN should be considered as a possible therapeutic agent against CCA.

  5. d-Psicose Inhibits Intestinal alpha-Glucosidase and Suppresses the Glycemic Response after Ingestion of Carbohydrates in Rats.

    PubMed

    Matsuo, Tatsuhiro; Izumori, Ken

    2009-09-01

    d-psicose is one of the rare sugars present in small quantities in commercial carbohydrates and agricultural products. In this study, we investigated the effects of d-psicose on the activities of alpha-amylases and alpha-glucosidases in vitro, and evaluated the effects of d-psicose on the in vivo postprandial glycemic response using rats. In the in vitro study, d-psicose potently inhibited the intestinal sucrase and maltase, however, slightly inhibited the intestinal and salivary alpha-amylase activities. Male Wistar rats (6 months old) were administrated 2 g/kg of sucrose, maltose or soluble starch together with 0.2 g/kg of d-psicose or d-fructose. The d-psicose significantly inhibited the increment of plasma glucose concentration induced by sucrose or maltose. The starch-induced glycemic response tended to be suppressed by d-psicose, however the suppression was not significant. These results suggest that d-psicose inhibits intestinal sucrase and maltase activities and suppresses the plasma glucose increase the normally occurs after sucrose and maltose ingestion. Thus, d-psicose may be useful in preventing postprandial hyperglycemia in diabetic patients when foods containing sucrose and maltose are ingested.

  6. Impact of experimental trauma and niflumic acid administration on antimicrobials' concentration in serum and mandible of rats.

    PubMed

    Kotsiou, A; Anagnostou, M; Mourouzis, C; Rallis, G; Chantzi, Ch; Tesseromatis, C

    2006-01-01

    Administration of antibiotics and analgesics in surgery or trauma is of great importance for an effective treatment. Trauma, as stress stimulus, causes alterations in various functions of the organism as well as in drug pharmacokinetics. The aim of this study was to determine the effect of trauma upon the serum and bone levels of the antimicrobial ampicillin and cefapirin, with and without co-administration of a non-steroidal anti-inflammatory analgesic (NSAIDs). Fifty-six male Wistar rats were divided into two groups A (control) and B (experimental). Each group consisted of 4 subgroups (n=7) receiving ampicillin, ampicillin with niflunic acid, cefapirin, and cefapirin with niflunic acid. In group B traumatic injury was performed by incision (7 mm length) in the right cheek. The levels of the antibiotics were estimated by the inhibition zone of B. subtilis. An increase in antibiotic levels was observed in group B, being statistically significant only for cefapirin level in the mandible. Upon niflumic acid co-administration a statistically significant rise in serum ampicillin and mandible cefapirin levels was observed in both control and experimental groups (student t-test). It can be concluded that the combination of antibiotics and non-steroid antiinflammatory drugs (NSAIDs) may enhance the antibacterial drug concentration.

  7. Intraarterial administration of norcantharidin attenuates ischemic stroke damage in rodents when given at the time of reperfusion: novel uses of endovascular capabilities

    PubMed Central

    Khan, Imad S.; Odom, Mitchell; Ehtesham, Moneeb; Colvin, Daniel; Quarles, C. Chad; McLaughlin, BethAnn; Singer, Robert J.

    2016-01-01

    OBJECTIVE Matrix metalloprotease-9 (MMP-9) plays a critical role in infarct progression, blood-brain barrier (BBB) disruption, and vasogenic edema. While systemic administration of MMP-9 inhibitors has shown neuroprotective promise in ischemic stroke, there has been little effort to incorporate these drugs into endovascular modalities. By modifying the rodent middle cerebral artery occlusion (MCAO) model to allow local intraarterial delivery of drugs, one has the ability to mimic endovascular delivery of therapeutics. Using this model, the authors sought to maximize the protective potential of MMP-9 inhibition by intraarterial administration of an MMP-9 inhibitor, norcantharidin (NCTD). METHODS Spontaneously hypertensive rats were subjected to 90-minute MCAO followed immediately by local intraarterial administration of NCTD. The rats’ neurobehavioral performances were scored according to the ladder rung walking test results and the Garcia neurological test for as long as 7 days after stroke. MRI was also conducted 24 hours after the stroke to assess infarct volume and BBB disruption. At the end of the experimental protocol, rat brains were used for active MMP-9 immunohistochemical analysis to assess the degree of MMP-9 inhibition. RESULTS NCTD-treated rats showed significantly better neurobehavioral scores for all days tested. MR images also depicted significantly decreased infarct volumes and BBB disruption 24 hours after stroke. Inhibition of MMP-9 expression in the ischemic region was depicted on immunohistochemical analysis, wherein treated rats showed decreased active MMP-9 staining compared with controls. CONCLUSIONS Intraarterial NCTD significantly improved outcome when administered at the time of reperfusion in a spontaneously hypertensive rat stroke model. This study suggests that supplementing endovascular revascularization with local neuroprotective drug therapy may be a viable therapeutic strategy. PMID:26544777

  8. Nurse administrators: leading environmental change.

    PubMed

    Tullai-McGuinness, Susan; Ballard, Karen A; Gallagher, Rita Munley; Carpenter, Holly

    2010-01-01

    Evidence is building about the impact of environmental contaminants on patients and health care providers. The nurse administrator has a professional responsibility to provide leadership in assuring that the health care organization does not have a negative impact on health. This article presents critical environmental health concerns and an overview of the nursing profession efforts to improve the environment, which includes development of the American Nurses Association's Principles of Environmental Health for Nursing Practice with Implementation Strategies. An example is provided as to how the nurse administrator can use Appreciative Inquiry to harness the nurses collaborative energy for an environmentally healthy organization.

  9. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.

    PubMed

    Cooper, Zachary A; Juneja, Vikram R; Sage, Peter T; Frederick, Dennie T; Piris, Adriano; Mitra, Devarati; Lo, Jennifer A; Hodi, F Stephen; Freeman, Gordon J; Bosenberg, Marcus W; McMahon, Martin; Flaherty, Keith T; Fisher, David E; Sharpe, Arlene H; Wargo, Jennifer A

    2014-07-01

    BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8(+) T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten(-/-) syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8(+) T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8(+) T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy.

  10. A MIV-150/Zinc Acetate Gel Inhibits SHIV-RT Infection in Macaque Vaginal Explants

    PubMed Central

    Barnable, Patrick; Calenda, Giulia; Ouattara, Louise; Gettie, Agegnehu; Blanchard, James; Jean-Pierre, Ninochka; Kizima, Larisa; Rodríguez, Aixa; Abraham, Ciby; Menon, Radhika; Seidor, Samantha; Cooney, Michael L.; Roberts, Kevin D.; Sperling, Rhoda; Piatak, Michael; Lifson, Jeffrey D.; Fernandez-Romero, Jose A.; Zydowsky, Thomas M.; Robbiani, Melissa; Teleshova, Natalia

    2014-01-01

    To extend our observations that single or repeated application of a gel containing the NNRTI MIV-150 (M) and zinc acetate dihydrate (ZA) in carrageenan (CG) (MZC) inhibits vaginal transmission of simian/human immunodeficiency virus (SHIV)-RT in macaques, we evaluated safety and anti-SHIV-RT activity of MZC and related gel formulations ex vivo in macaque mucosal explants. In addition, safety was further evaluated in human ectocervical explants. The gels did not induce mucosal toxicity. A single ex vivo exposure to diluted MZC (1∶30, 1∶100) and MC (1∶30, the only dilution tested), but not to ZC gel, up to 4 days prior to viral challenge, significantly inhibited SHIV-RT infection in macaque vaginal mucosa. MZC's activity was not affected by seminal plasma. The antiviral activity of unformulated MIV-150 was not enhanced in the presence of ZA, suggesting that the antiviral activity of MZC was mediated predominantly by MIV-150. In vivo administration of MZC and CG significantly inhibited ex vivo SHIV-RT infection (51–62% inhibition relative to baselines) of vaginal (but not cervical) mucosa collected 24 h post last gel exposure, indicating barrier effect of CG. Although the inhibitory effect of MZC (65–74%) did not significantly differ from CG (32–45%), it was within the range of protection (∼75%) against vaginal SHIV-RT challenge 24 h after gel dosing. Overall, the data suggest that evaluation of candidate microbicides in macaque explants can inform macaque efficacy and clinical studies design. The data support advancing MZC gel for clinical evaluation. PMID:25259616

  11. Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

    PubMed Central

    Eberson, Lance S.; Sanchez, Pablo A.; Majeed, Beenish A.; Tawinwung, Supannikar; Secomb, Timothy W.; Larson, Douglas F.

    2015-01-01

    It is well accepted that angiotensin II (Ang II) induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX) through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, β -aminopropionitrile (BAPN), for 14 days. Pulse wave velocity (PWV) from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young’s modulus. The increase in effective Young’s modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05). Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002), with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN. PMID:25875748

  12. Turbo methanol extract inhibits bone resorption through regulation of T cell function.

    PubMed

    Balakrishnan, Babita; Indap, Madhavi M; Singh, Surya P; Krishna, C Murali; Chiplunkar, Shubhada V

    2014-01-01

    lymphocytes was observed upon TME administration. TME could significantly inhibit the in vitro osteoclastogenesis and the bone resorption observed using artificial calcium coated slides. Collectively, these results indicate that TME has the potential to inhibit bone resorption and may prove to be a potential candidate for the development of an anti-osteoporosis drug.

  13. 75 FR 18014 - Federal Highway Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-08

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF TRANSPORTATION Federal Highway Administration AGENCY: Federal Highway Administration (FHWA), DOT. ACTION: Notice of...: Federal Highway Administration, Kentucky Division: Mr. Greg Rawlings, Transportation Specialist, 330...

  14. 78 FR 9771 - Federal Highway Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-11

    ... Federal Highway Administration Notice of Final Federal Agency Action on Proposed Transportation Project in Illinois and Indiana AGENCY: Federal Highway Administration (FHWA), DOT. ACTION: Notice of limitation on..., Federal Highway Administration, 3250 Executive Park Drive, Springfield, Illinois 62703, Phone: (217)...

  15. 75 FR 6433 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-09

    ... Federal Aviation Administration Notice of Availability of a Draft Environmental Assessment and Public...: Federal Aviation Administration (FAA), DOT. ACTION: Notice of Availability of a Draft Environmental... Chicago, Illinois. SUMMARY: The Federal Aviation Administration (FAA) proposes to fund, construct,...

  16. 76 FR 78966 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-20

    ... Federal Aviation Administration Approval of Noise Compatibility Program for Kona International Airport at Keahole, Keahole, North Kona, HI AGENCY: Federal Aviation Administration, DOT. ACTION: Notice. SUMMARY: The Federal Aviation Administration (FAA) announces its findings on the noise compatibility...

  17. 78 FR 13395 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-27

    ... Federal Aviation Administration Notice of Availability of Draft Alaska National Interest Lands Conservation Act (ANILCA) Section 810 Subsistence Evaluation. AGENCY: Federal Aviation Administration (FAA... Aviation Administration, Airports Division, 222 West 7th Avenue, Box 14, Anchorage, AK 99513. 5....

  18. 7 CFR 201.3 - Administrator.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Administration § 201.3 Administrator. The Administrator of the Agricultural Marketing Service...

  19. 76 FR 5212 - Employment and Training Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-28

    ... Employment and Training Administration Comment Request for Information Collection for Internal Fraud and...: Employment and Training Administration (ETA), Department of Labor. ACTION: Notice. SUMMARY: The Department of.... Currently, the Employment and Training Administration is soliciting comments concerning the Office...

  20. 78 FR 32470 - Employment and Training Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-30

    ... Employment and Training Administration Investigations Regarding Eligibility To Apply for Worker Adjustment..., the Director of the Office of Trade Adjustment Assistance, Employment and Training Administration, has... Trade Adjustment Assistance, Employment and Training Administration, U.S. Department of Labor, Room...