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Sample records for addition pharmacological inhibition

  1. 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

  2. Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice.

    PubMed

    Bettaieb, Ahmed; Chahed, Samah; Bachaalany, Santana; Griffey, Stephen; Hammock, Bruce D; Haj, Fawaz G

    2015-08-01

    Acute pancreatitis (AP) is an inflammatory disease, and is one of the most common gastrointestinal disorders worldwide. Soluble epoxide hydrolase (sEH; encoded by Ephx2) deficiency and pharmacological inhibition have beneficial effects in inflammatory diseases. Ephx2 whole-body deficiency mitigates experimental AP in mice, but the suitability of sEH pharmacological inhibition for treating AP remains to be determined. We investigated the effects of sEH pharmacological inhibition on cerulein- and arginine-induced AP using the selective sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which was administered before and after induction of pancreatitis. Serum amylase and lipase levels were lower in TPPU-treated mice compared with controls. In addition, circulating levels and pancreatic mRNA of the inflammatory cytokines tumor necrosis factor-α, interleukin Il-1β, and Il-6 were reduced in TPPU-treated mice. Moreover, sEH pharmacological inhibition before and after induction of pancreatitis was associated with decreased cerulein- and arginine-induced nuclear factor-κB inflammatory response, endoplasmic reticulum stress, and cell death. sEH pharmacological inhibition before and after induction of pancreatitis mitigated cerulein- and arginine-induced AP. This work suggests that sEH pharmacological inhibition may be of therapeutic value in acute pancreatitis. PMID:25993999

  3. Bromodomains: Structure, function and pharmacology of inhibition.

    PubMed

    Ferri, Elena; Petosa, Carlo; McKenna, Charles E

    2016-04-15

    Bromodomains are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation. The human proteome comprises 46 bromodomain-containing proteins with a total of 61 bromodomains, which, despite highly conserved structural features, recognize a wide array of natural peptide ligands. Over the past five years, bromodomains have attracted great interest as promising new epigenetic targets for diverse human diseases, including inflammation, cancer, and cardiovascular disease. The demonstration in 2010 that two small molecule compounds, JQ1 and I-BET762, potently inhibit proteins of the bromodomain and extra-terminal (BET) family with translational potential for cancer and inflammatory disease sparked intense efforts in academia and pharmaceutical industry to develop novel bromodomain antagonists for therapeutic applications. Several BET inhibitors are already in clinical trials for hematological malignancies, solid tumors and cardiovascular disease. Currently, the field faces the challenge of single-target selectivity, especially within the BET family, and of overcoming problems related to the development of drug resistance. At the same time, new trends in bromodomain inhibitor research are emerging, including an increased interest in non-BET bromodomains and a focus on drug synergy with established antitumor agents to improve chemotherapeutic efficacy. This review presents an updated view of the structure and function of bromodomains, traces the development of bromodomain inhibitors and their potential therapeutic applications, and surveys the current challenges and future directions of this vibrant new field in drug discovery.

  4. Bromodomains: Structure, function and pharmacology of inhibition.

    PubMed

    Ferri, Elena; Petosa, Carlo; McKenna, Charles E

    2016-04-15

    Bromodomains are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation. The human proteome comprises 46 bromodomain-containing proteins with a total of 61 bromodomains, which, despite highly conserved structural features, recognize a wide array of natural peptide ligands. Over the past five years, bromodomains have attracted great interest as promising new epigenetic targets for diverse human diseases, including inflammation, cancer, and cardiovascular disease. The demonstration in 2010 that two small molecule compounds, JQ1 and I-BET762, potently inhibit proteins of the bromodomain and extra-terminal (BET) family with translational potential for cancer and inflammatory disease sparked intense efforts in academia and pharmaceutical industry to develop novel bromodomain antagonists for therapeutic applications. Several BET inhibitors are already in clinical trials for hematological malignancies, solid tumors and cardiovascular disease. Currently, the field faces the challenge of single-target selectivity, especially within the BET family, and of overcoming problems related to the development of drug resistance. At the same time, new trends in bromodomain inhibitor research are emerging, including an increased interest in non-BET bromodomains and a focus on drug synergy with established antitumor agents to improve chemotherapeutic efficacy. This review presents an updated view of the structure and function of bromodomains, traces the development of bromodomain inhibitors and their potential therapeutic applications, and surveys the current challenges and future directions of this vibrant new field in drug discovery. PMID:26707800

  5. Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.

    PubMed

    Kottmann, Robert Matthew; Trawick, Emma; Judge, Jennifer L; Wahl, Lindsay A; Epa, Amali P; Owens, Kristina M; Thatcher, Thomas H; Phipps, Richard P; Sime, Patricia J

    2015-12-01

    Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-β (TGF-β) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-β. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-β-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-β and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-β-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-β bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-β-induced myofibroblast differentiation. Gossypol inhibits TGF-β-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-β bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis.

  6. Rust inhibiting additive compositions for oils

    SciTech Connect

    Haugen, H.

    1980-09-23

    Compositions which include mixtures of a calcium hydroxide overbased oil-soluble calcium sulfonate, hexylene glycol and a surfactant consisting of an ethoxylated aliphatic amine, particularly, diethoxylated cocoamine or diethoxylated soyamine, are useful as rust inhibiting additives for oils and the like. By incorporating these compositions in petroleum based oils such as petroleum based oils of lubricating oil quality which come into contact with metal surfaces under conditions such that the metal surfaces tend to rust or otherwise be subject to deterioration it is possible to inhibit rust formation on such metal surfaces.

  7. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth.

    PubMed

    Harel, Sivan; Higgins, Claire A; Cerise, Jane E; Dai, Zhenpeng; Chen, James C; Clynes, Raphael; Christiano, Angela M

    2015-10-01

    Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells. PMID:26601320

  8. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth

    PubMed Central

    Harel, Sivan; Higgins, Claire A.; Cerise, Jane E.; Dai, Zhenpeng; Chen, James C.; Clynes, Raphael; Christiano, Angela M.

    2015-01-01

    Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells. PMID:26601320

  9. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth.

    PubMed

    Harel, Sivan; Higgins, Claire A; Cerise, Jane E; Dai, Zhenpeng; Chen, James C; Clynes, Raphael; Christiano, Angela M

    2015-10-01

    Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells.

  10. Pharmacological inhibition of caspase-8 limits lung tumour outgrowth

    PubMed Central

    Terlizzi, Michela; Di Crescenzo, Vincenzo Giuseppe; Perillo, Giuseppe; Galderisi, Antonio; Pinto, Aldo; Sorrentino, Rosalinda

    2015-01-01

    Background and Purpose Lung cancer is one of the leading causes of cancer death worldwide. Despite advances in therapy, conventional therapy is still the main treatment and has a high risk of chemotherapy resistance. Caspase-8 is involved in cell death and is a recognized marker for poor patient prognosis. Experimental Approach To elucidate the role of caspase-8 in lung carcinoma, we used human samples of non-small cell lung cancer (NSCLC) and a mouse model of carcinogen-induced lung cancer. Key Results Healthy and cancerous NSCLC samples had similar levels of the active form of caspase-8. Similarly, lung tumour-bearing mice had high levels of the active form of caspase-8. Pharmacological inhibition of caspase-8 by z-IETD-FMK robustly reduced tumour outgrowth and this was closely associated with a reduction in the release of pro-inflammatory cytokines, IL-6, TNF-α, IL-18, IL-1α, IL-33, but not IL-1β. Furthermore, inhibition of caspase-8 reduced the recruitment of innate suppressive cells, such as myeloid-derived suppressor cells, but not of regulatory T cells to lungs of tumour-bearing mice. However, despite the well-known role of caspase-8 in cell death, the apoptotic cascade (caspase-3, caspase-9 and Bcl-2 dependent) was not active in lungs of z-IETD-treated tumour-bearing mice, but instead higher levels of the short segment of c-FLIP (c-FLIPs) were detected. Similarly, human healthy lung samples had higher levels of c-FLIPs than cancerous samples. Conclusions and Implications Our data suggest that caspase-8 is an important orchestrator of cancer-associated inflammation and the presence of short segment of c-FLIP determines whether caspase-8 induces tumour proliferation or tumour arrest/regression in the lung. PMID:25917370

  11. Direct renin inhibition: from pharmacological innovation to novel therapeutic opportunities.

    PubMed

    Volpe, Massimo; Pontremoli, Roberto; Borghi, Claudio

    2011-09-01

    Nowadays, social and economic burden related to cardiovascular and renal diseases still remains extremely high, although there has been a dramatic improvement of diagnostic options and therapeutic strategies reported in the last 30 years. The progressively higher attention towards integrated pharmacological strategies, which are able to interfere with different pathophysiological mechanisms, has certainly led to better control of cardiovascular and renal diseases. In view of the large involvement of the renin-angiotensin system (RAS) in the vast majority of pathophysiological mechanisms leading to the development and progression of cardiovascular and renal diseases, it can be easily understood why it has been long viewed as the 'ideal' target for the pharmacological treatment of several clinical conditions. Recently, besides the well known therapeutic approaches for RAS blockade, based on the use of ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) and aldosterone antagonists, both the scientific and medical community have focused their attention on a novel therapeutic option. In 2007, aliskiren, the first compound of a new drug class, the direct renin inhibitors (DRIs), has become available for clinical use, being a novel and innovative therapeutic option. Aliskiren is able to interfere with the enzymatic activity of renin by blocking the catalytic site of the molecule and inducing an 'upstream' RAS blockade. This leads to a modulation of the biological properties of renin, thus resulting in the missed cleavage of angiotensinogen to angiotensin I. Aliskiren has demonstrated antihypertensive efficacy comparable or even superior to that of other classes of antihypertensive drugs, both in monotherapy and in combination therapies. Its safety and tolerability are comparable with those of other antihypertensive drug classes and almost similar to placebo. In addition, it has been demonstrated to reduce progression of

  12. Pharmacological inhibition of ATM by KU55933 stimulates ATM transcription.

    PubMed

    Khalil, Hilal S; Tummala, Hemanth; Hupp, Tedd R; Zhelev, Nikolai

    2012-06-01

    Ataxia-telangiectasia mutated (ATM) kinase is a component of a signalling mechanism that determines the process of decision-making in response to DNA damage and involves the participation of multiple proteins. ATM is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and orchestrates signalling cascades that initiate the DNA damage response. Cells lacking ATM are hypersensitive to insults, particularly genotoxic stress, induced through radiation or radiomimetic drugs. Here, we investigate the degree of ATM activation during time-dependent treatment with genotoxic agents and the effects of ATM on phospho-induction and localization of its downstream substrates. Additionally, we have demonstrated a new cell-cycle-independent mechanism of ATM gene regulation following ATM kinase inhibition with KU5593. Inhibition of ATM activity causes induction of ATM protein followed by oscillation and this mechanism is governed at the transcriptional level. Furthermore, this autoregulatory induction of ATM is also accompanied by a transient upregulation of p53, pATR and E2F1 levels. Since ATM inhibition is believed to sensitize cancer cells to genotoxic agents, this novel insight into the mechanism of ATM regulation might be useful for designing more precise strategies for modulation of ATM activity in cancer therapy.

  13. Selective Pharmacologic Inhibition of a PASTA Kinase Increases Listeria monocytogenes Susceptibility to β-Lactam Antibiotics

    PubMed Central

    Pensinger, Daniel A.; Aliota, Matthew T.; Schaenzer, Adam J.; Boldon, Kyle M.; Ansari, Israr-ul H.; Vincent, William J. B.; Knight, Benjamin; Reniere, Michelle L.; Striker, Rob

    2014-01-01

    While β-lactam antibiotics are a critical part of the antimicrobial arsenal, they are frequently compromised by various resistance mechanisms, including changes in penicillin binding proteins of the bacterial cell wall. Genetic deletion of the penicillin binding protein and serine/threonine kinase-associated protein (PASTA) kinase in methicillin-resistant Staphylococcus aureus (MRSA) has been shown to restore β-lactam susceptibility. However, the mechanism remains unclear, and whether pharmacologic inhibition would have the same effect is unknown. In this study, we found that deletion or pharmacologic inhibition of the PASTA kinase in Listeria monocytogenes by the nonselective kinase inhibitor staurosporine results in enhanced susceptibility to both aminopenicillin and cephalosporin antibiotics. Resistance to vancomycin, another class of cell wall synthesis inhibitors, or antibiotics that inhibit protein synthesis was unaffected by staurosporine treatment. Phosphorylation assays with purified kinases revealed that staurosporine selectively inhibited the PASTA kinase of L. monocytogenes (PrkA). Importantly, staurosporine did not inhibit a L. monocytogenes kinase without a PASTA domain (Lmo0618) or the PASTA kinase from MRSA (Stk1). Finally, inhibition of PrkA with a more selective kinase inhibitor, AZD5438, similarly led to sensitization of L. monocytogenes to β-lactam antibiotics. Overall, these results suggest that pharmacologic targeting of PASTA kinases can increase the efficacy of β-lactam antibiotics. PMID:24867981

  14. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

    PubMed Central

    Boulter, Luke; Guest, Rachel V.; Kendall, Timothy J.; Wilson, David H.; Wojtacha, Davina; Robson, Andrew J.; Ridgway, Rachel A.; Samuel, Kay; Van Rooijen, Nico; Barry, Simon T.; Wigmore, Stephen J.; Sansom, Owen J.; Forbes, Stuart J.

    2015-01-01

    Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC. PMID:25689248

  15. Endothelial transcriptome in response to pharmacological methyltransferase inhibition.

    PubMed

    Okabe, Jun; Fernandez, Ana Z; Ziemann, Mark; Keating, Samuel T; Balcerczyk, Aneta; El-Osta, Assam

    2014-08-01

    The enzymatic activities of protein methyltransferases serve to write covalent modifications on histone and non-histone proteins in the control of gene transcription. Here, we describe gene expression changes in human endothelial cells caused by treatment with methyltransferase inhibitors 7,7'-carbonylbis (azanediyl) bis(4-hydroxynaphthalene-2 -sulfonic acid (AMI-1) and disodium-2-(2,4,5,7- tetrabromo-3-oxido-6-oxoxanthen-9-yl) benzoate trihydrate (AMI-5). Deep sequencing of mRNA indicated robust change on transcription following AMI-5 treatment compared with AMI-1. Functional annotation analysis revealed that both compounds suppress the expression of genes associated with translational regulation, suggesting arginine methylation by protein arginine methyltransferases (PRMTs) could be associated with regulation of this pathway. Interestingly, AMI-5 but not AMI-1 was found to decrease methylation of H3 histones at lysine 4 and down-regulate gene expression associated with interleukin-6 (IL-6) and activator protein-1 (AP-1) signaling pathways. These results imply that inhibition of protein methylation by AMI-1 and AMI-5 can differentially regulate specific pathways with potential to interrupt pathological signaling in the vascular endothelium. PMID:24850797

  16. Endothelial transcriptome in response to pharmacological methyltransferase inhibition.

    PubMed

    Okabe, Jun; Fernandez, Ana Z; Ziemann, Mark; Keating, Samuel T; Balcerczyk, Aneta; El-Osta, Assam

    2014-08-01

    The enzymatic activities of protein methyltransferases serve to write covalent modifications on histone and non-histone proteins in the control of gene transcription. Here, we describe gene expression changes in human endothelial cells caused by treatment with methyltransferase inhibitors 7,7'-carbonylbis (azanediyl) bis(4-hydroxynaphthalene-2 -sulfonic acid (AMI-1) and disodium-2-(2,4,5,7- tetrabromo-3-oxido-6-oxoxanthen-9-yl) benzoate trihydrate (AMI-5). Deep sequencing of mRNA indicated robust change on transcription following AMI-5 treatment compared with AMI-1. Functional annotation analysis revealed that both compounds suppress the expression of genes associated with translational regulation, suggesting arginine methylation by protein arginine methyltransferases (PRMTs) could be associated with regulation of this pathway. Interestingly, AMI-5 but not AMI-1 was found to decrease methylation of H3 histones at lysine 4 and down-regulate gene expression associated with interleukin-6 (IL-6) and activator protein-1 (AP-1) signaling pathways. These results imply that inhibition of protein methylation by AMI-1 and AMI-5 can differentially regulate specific pathways with potential to interrupt pathological signaling in the vascular endothelium.

  17. Generalized Additive Mixed-Models for Pharmacology Using Integrated Discrete Multiple Organ Co-Culture

    PubMed Central

    Ingersoll, Thomas; Cole, Stephanie; Madren-Whalley, Janna; Booker, Lamont; Dorsey, Russell; Li, Albert; Salem, Harry

    2016-01-01

    Integrated Discrete Multiple Organ Co-culture (IDMOC) is emerging as an in-vitro alternative to in-vivo animal models for pharmacology studies. IDMOC allows dose-response relationships to be investigated at the tissue and organoid levels, yet, these relationships often exhibit responses that are far more complex than the binary responses often measured in whole animals. To accommodate departure from binary endpoints, IDMOC requires an expansion of analytic techniques beyond simple linear probit and logistic models familiar in toxicology. IDMOC dose-responses may be measured at continuous scales, exhibit significant non-linearity such as local maxima or minima, and may include non-independent measures. Generalized additive mixed-modeling (GAMM) provides an alternative description of dose-response that relaxes assumptions of independence and linearity. We compared GAMMs to traditional linear models for describing dose-response in IDMOC pharmacology studies. PMID:27110941

  18. Pharmacological inhibition of cathepsin K: A promising novel approach for postmenopausal osteoporosis therapy.

    PubMed

    Mukherjee, Kakoli; Chattopadhyay, Naibedya

    2016-10-01

    Osteoporosis is a metabolic bone disease that is characterized by heightened state of bone resorption accompanied by diminished bone formation, leading to a reduction of bone mineral density (BMD) and deterioration of bone quality, thus increasing the risk of developing fractures. Molecular insight into bone biology identified cathepsin K (CatK) as a novel therapeutic target. CatK is a lysosomal cysteine protease secreted by activated osteoclasts during bone resorption, whose primary substrate is type I collagen, the major component of organic bone matrix. Available anti-resorptive drugs affect osteoclast survival and influence both resorption and formation of bone. CatK inhibitors are distinct from the existing anti-resorptives as they only target the resorption process itself without impairing osteoclast differentiation and do not interfere with bone formation. An inhibitor of CatK, odanacatib, robustly increased both trabecular and cortical BMD in postmenopausal osteoporosis patients. The phase III fracture prevention trial with odanacatib ended early due to good efficacy and a favorable benefit/risk profile, thus, enhancing the opportunity for CatK as a pharmacological target for osteoporosis. So far, all the inhibitors that reached to the stage of clinical trial targeted active site of CatK to abrogate the entire proteolytic activity of the enzyme in addition to the desired blockage of excessive elastin and collagen degradation, and could thus pose safety concerns with long term use. Identification of selective exosite inhibitors that inhibit CatK's elastase and/or collagenase activity but do not affect the hydrolysis of other physiologically relevant substrates of CatK would be an improved strategy to inhibit this enzyme.

  19. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma.

    PubMed

    Hashizume, Rintaro; Andor, Noemi; Ihara, Yuichiro; Lerner, Robin; Gan, Haiyun; Chen, Xiaoyue; Fang, Dong; Huang, Xi; Tom, Maxwell W; Ngo, Vy; Solomon, David; Mueller, Sabine; Paris, Pamela L; Zhang, Zhiguo; Petritsch, Claudia; Gupta, Nalin; Waldman, Todd A; James, C David

    2014-12-01

    Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma. PMID:25401693

  20. Children's Additive Concepts: Promoting Understanding and the Role of Inhibition

    ERIC Educational Resources Information Center

    Robinson, Katherine M.; Dube, Adam K.

    2013-01-01

    This study investigated the promotion of children's understanding and acquisition of arithmetic concepts and the effects of inhibitory skills. Children in Grades 3, 4, and 5 solved two sets of three-term addition and subtraction problems (e.g., 3 + 24 - 24, 3 + 24 - 22) and completed an inhibition task. Half of the participants received a…

  1. Pharmacological inhibition of soluble epoxide hydrolase prevents renal interstitial fibrogenesis in obstructive nephropathy

    PubMed Central

    Kim, Jinu; Yoon, Sang Pil; Toews, Myron L.; Imig, John D.; Hwang, Sung Hee; Hammock, Bruce D.

    2014-01-01

    Treating chronic kidney disease (CKD) has been challenging because of its pathogenic complexity. Epoxyeicosatrienoic acids (EETs) are cytochrome P-450-dependent derivatives of arachidonic acid with antihypertensive, anti-inflammatory, and profibrinolytic functions. We recently reported that genetic ablation of soluble epoxide hydrolase (sEH), an enzyme that converts EETs to less active dihydroxyeicosatrienoic acids, prevents renal tubulointerstitial fibrosis and inflammation in experimental mouse models of CKD. Here, we tested the hypothesis that pharmacological inhibition of sEH after unilateral ureteral obstruction (UUO) would attenuate tubulointerstitial fibrosis and inflammation in mouse kidneys and may provide a novel approach to manage the progression of CKD. Inhibition of sEH enhanced levels of EET regioisomers and abolished tubulointerstitial fibrosis, as demonstrated by reduced collagen deposition and myofibroblast formation after UUO. The inflammatory response was also attenuated, as demonstrated by decreased influx of neutrophils and macrophages and decreased expression of inflammatory cytokines keratinocyte chemoattractant, macrophage inflammatory protein-2, monocyte chemotactic protein-1, TNF-α, and ICAM-1 in kidneys after UUO. UUO upregulated transforming growth factor-β1/Smad3 signaling and induced NF-κB activation, oxidative stress, tubular injury, and apoptosis; in contrast, it downregulated antifibrotic factors, including peroxisome proliferator-activated receptor (PPAR) isoforms, especially PPAR-γ. sEH inhibition mitigated the aforementioned malevolent effects in UUO kidneys. These data demonstrate that pharmacological inhibition of sEH promotes anti-inflammatory and fibroprotective effects in UUO kidneys by preventing tubular injury, downregulation of NF-κB, transforming growth factor-β1/Smad3, and inflammatory signaling pathways, and activation of PPAR isoforms. Our data suggest the potential use of sEH inhibitors in treating fibrogenesis

  2. Pharmacological inhibition of interleukin-1 activity on T cells by hydrocortisone, cyclosporine, prostaglandins, and cyclic nucleotides.

    PubMed

    Tracey, D E; Hardee, M M; Richard, K A; Paslay, J W

    1988-01-01

    The effects of a panel of hormones and pharmacological agents on the activation of T cells by a combination of interleukin-1 and phytohemagglutinin (IL-1/PHA) was studied. Pharmacological effects on various stages of IL-1/PHA-induced interleukin-2 (IL-2) production by the cloned murine thymoma cell line LBRM-33-1A5.7 were dissected using a multi-step assay procedure. A 4-h lag phase in the kinetics of IL-2 production allowed the operational definition of an early, IL-1-dependent programming stage, followed by an IL-2-production stage of the assay. A cell-washing procedure between these stages was introduced in order to distinguish IL-1 receptor antagonists from functional IL-1/PHA antagonists. Hydrocortisone and cyclosporine were potent inhibitors (active in the nM range) of both stages of IL-2 production, suggesting that neither is an IL-1 receptor antagonist. The cyclic adenosine monophosphate (cAMP)-elevating agents prostaglandin E2, dibutyryl cAMP, and theophylline inhibited IL-2 production during the early, IL-1-dependent programming stage. By contrast, prostaglandin F2 alpha and dibutyryl cyclic guanosine monophosphate did not appreciably inhibit IL-1/PHA activity. These results are discussed in relationship to the effects of these test agents in thymocyte IL-1 assays or mitogenesis assays and the implications toward understanding the mechanisms underlying IL-1/PHA activation of T cells.

  3. Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats

    PubMed Central

    Zhang, Ning; Liang, Hanyu; Farese, Robert V.; Li, Ji

    2015-01-01

    Aims To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats. Materials and Methods For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp. Results Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP. Conclusions Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo. PMID:26196892

  4. Factor IXa as a target for pharmacologic inhibition in acute coronary syndrome.

    PubMed

    Roser-Jones, Christopher; Chan, Mark; Howard, Emily L; Becker, Kristian C D; Rusconi, Christopher P; Becker, Richard C

    2011-08-01

    Anticoagulant therapy, combined with platelet-directed inhibitors, represents a standard-of-care in the management of patients with acute coronary syndrome, particularly those who require percutaneous coronary interventions. While a vast clinical experience, coupled with large clinical trials have collectively provided guidance, an optimal anticoagulant drug and applied strategy, defined as one that reduces thrombotic and hemorrhagic events consistently, with minimal off-target effects and active control of systemic anticoagulation according to patient and clinical-setting specific need, remains at large. An advancing knowledge of coagulation, hemostasis, and thrombosis suggests that factor IXa, a protease that governs thrombin generation in common thrombotic disorders may represent a prime target for pharmacologic inhibition.

  5. Pharmacologic inhibition of reactive gliosis blocks TNF-α-mediated neuronal apoptosis

    PubMed Central

    Livne-Bar, Izhar; Lam, Susy; Chan, Darren; Guo, Xiaoxin; Askar, Idil; Nahirnyj, Adrian; Flanagan, John G; Sivak, Jeremy M

    2016-01-01

    Reactive gliosis is an early pathological feature common to most neurodegenerative diseases, yet its regulation and impact remain poorly understood. Normally astrocytes maintain a critical homeostatic balance. After stress or injury they undergo rapid parainflammatory activation, characterized by hypertrophy, and increased polymerization of type III intermediate filaments (IFs), particularly glial fibrillary acidic protein and vimentin. However, the consequences of IF dynamics in the adult CNS remains unclear, and no pharmacologic tools have been available to target this mechanism in vivo. The mammalian retina is an accessible model to study the regulation of astrocyte stress responses, and their influence on retinal neuronal homeostasis. In particular, our work and others have implicated p38 mitogen-activated protein kinase (MAPK) signaling as a key regulator of glutamate recycling, antioxidant activity and cytokine secretion by astrocytes and related Müller glia, with potent influences on neighboring neurons. Here we report experiments with the small molecule inhibitor, withaferin A (WFA), to specifically block type III IF dynamics in vivo. WFA was administered in a model of metabolic retinal injury induced by kainic acid, and in combination with a recent model of debridement-induced astrocyte reactivity. We show that WFA specifically targets IFs and reduces astrocyte and Müller glial reactivity in vivo. Inhibition of glial IF polymerization blocked p38 MAPK-dependent secretion of TNF-α, resulting in markedly reduced neuronal apoptosis. To our knowledge this is the first study to demonstrate that pharmacologic inhibition of IF dynamics in reactive glia protects neurons in vivo. PMID:27685630

  6. Selective and reversible suppression of intestinal stem cell differentiation by pharmacological inhibition of BET bromodomains

    PubMed Central

    Nakagawa, Akifumi; Adams, Curtis E.; Huang, Yinshi; Hamarneh, Sulaiman R.; Liu, Wei; Von Alt, Kate N.; Mino-Kenudson, Mari; Hodin, Richard A.; Lillemoe, Keith D.; Fernández-del Castillo, Carlos; Warshaw, Andrew L.; Liss, Andrew S.

    2016-01-01

    Absorptive and secretory cells of the small intestine are derived from a single population of Lgr5-expressing stem cells. While key genetic pathways required for differentiation into specific lineages have been defined, epigenetic programs contributing to this process remain poorly characterized. Members of the BET family of chromatin adaptors contain tandem bromodomains that mediate binding to acetylated lysines on target proteins to regulate gene expression. In this study, we demonstrate that mice treated with a small molecule inhibitor of BET bromodomains, CPI203, exhibit greater than 90% decrease in tuft and enteroendocrine cells in both crypts and villi of the small intestine, with no changes observed in goblet or Paneth cells. BET bromodomain inhibition did not alter the abundance of Lgr5-expressing stem cells in crypts, but rather exerted its effects on intermediate progenitors, in part through regulation of Ngn3 expression. When BET bromodomain inhibition was combined with the chemotherapeutic gemcitabine, pervasive apoptosis was observed in intestinal crypts, revealing an important role for BET bromodomain activity in intestinal homeostasis. Pharmacological targeting of BET bromodomains defines a novel pathway required for tuft and enteroendocrine differentiation and provides an important tool to further dissect the progression from stem cell to terminally differentiated secretory cell. PMID:26856877

  7. Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis

    PubMed Central

    Kramann, Rafael; Fleig, Susanne V.; Schneider, Rebekka K.; Fabian, Steven L.; DiRocco, Derek P.; Maarouf, Omar; Wongboonsin, Janewit; Ikeda, Yoichiro; Heckl, Dirk; Chang, Steven L.; Rennke, Helmut G.; Waikar, Sushrut S.; Humphreys, Benjamin D.

    2015-01-01

    Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scar-secreting myofibroblasts, ultimately leading to end-stage renal disease. The hedgehog (Hh) pathway transcriptional effectors GLI1 and GLI2 are expressed in myofibroblast progenitors; however, the role of these effectors during fibrogenesis is poorly understood. Here, we demonstrated that GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell–like progenitors. In animals exposed to unilateral ureteral obstruction, Hh pathway suppression by expression of the GLI3 repressor in GLI1+ myofibroblast progenitors limited kidney fibrosis. Myofibroblast-specific deletion of Gli2, but not Gli1, also limited kidney fibrosis, and induction of myofibroblast-specific cell-cycle arrest mediated this inhibition. Pharmacologic targeting of this pathway with darinaparsin, an arsenical in clinical trials, reduced fibrosis through reduction of GLI2 protein levels and subsequent cell-cycle arrest in myofibroblasts. GLI2 overexpression rescued the cell-cycle effect of darinaparsin in vitro. While darinaparsin ameliorated fibrosis in WT and Gli1-KO mice, it was not effective in conditional Gli2-KO mice, supporting GLI2 as a direct darinaparsin target. The GLI inhibitor GANT61 also reduced fibrosis in mice. Finally, GLI1 and GLI2 were upregulated in the kidneys of patients with high-grade fibrosis. Together, these data indicate that GLI inhibition has potential as a therapeutic strategy to limit myofibroblast proliferation in kidney fibrosis. PMID:26193634

  8. Pharmacological doses of gamma-hydroxybutyrate (GHB) potentiate histone acetylation in the rat brain by histone deacetylase inhibition.

    PubMed

    Klein, Christian; Kemmel, Véronique; Taleb, Omar; Aunis, Dominique; Maitre, Michel

    2009-08-01

    Several small chain fatty acids, including butyrate, valproate, phenylbutyrate and its derivatives, inhibit several HDAC activities in the brain at a several hundred micromolar concentration. Gamma-hydroxy-butyrate (GHB), a natural compound found in the brain originating from the metabolism of GABA, is structurally related to these fatty acids. The average physiological tissue concentration of GHB in the brain is below 50 microM, but when GHB is administered or absorbed for therapeutic or recreative purposes, its concentration reaches several hundred micromolars. In the present scenario, we demonstrate that pharmacological concentrations of GHB significantly induce brain histone H3 acetylation with a heterogeneous distribution in the brain and reduce in vitro HDAC activity. The degree of HDAC inhibition was also different according to the region of the brain considered. Taking into account the multiple physiological and functional roles attributed to the modification of histone acetylation and its consequences at the level of gene expression, we propose that part of the therapeutic or toxic effects of high concentrations of GHB in the brain after therapeutic administration of the drug could be partly due to GHB-induced epigenetic factors. In addition, we hypothesize that GHB, being naturally synthesized in the cytosolic compartment of certain neurons, could penetrate into the nuclei and may reach sufficient levels that could significantly modulate histone acetylation and may participate in the epigenetic modification of gene expression.

  9. Pharmacological inhibition of Polo Like Kinase 2 (PLK2) does not cause chromosomal damage or result in the formation of micronuclei

    SciTech Connect

    Fitzgerald, Kent; Bergeron, Marcelle; Willits, Christopher; Bowers, Simeon; Aubele, Danielle L.; Goldbach, Erich; Tonn, George; Ness, Daniel; Olaharski, Andrew

    2013-05-15

    Polo Like Kinase 2 (PLK2) phosphorylates α-synuclein and is considered a putative therapeutic target for Parkinson's disease. Several lines of evidence indicate that PLK2 is involved with proper centriole duplication and cell cycle regulation, inhibition of which could impact chromosomal integrity during mitosis. The objectives of the series of experiments presented herein were to assess whether specific inhibition of PLK2 is genotoxic and determine if PLK2 could be considered a tractable pharmacological target for Parkinson's disease. Several selective PLK2 inhibitors, ELN 582175 and ELN 582646, and their inactive enantiomers, ELN 582176 and ELN 582647, did not significantly increase the number of micronuclei in the in vitro micronucleus assay. ELN 582646 was administered to male Sprague Dawley rats in an exploratory 14-day study where flow cytometric analysis of peripheral blood identified a dose-dependent increase in the number of micronucleated reticulocytes. A follow-up investigative study demonstrated that ELN 582646 administered to PLK2 deficient and wildtype mice significantly increased the number of peripheral micronucleated reticulocytes in both genotypes, suggesting that ELN 582646-induced genotoxicity is not through the inhibition of PLK2. Furthermore, significant reduction of retinal phosphorylated α-synuclein levels was observed at three non-genotoxic doses, additional data to suggest that pharmacological inhibition of PLK2 is not the cause of the observed genotoxicity. These data, in aggregate, indicate that PLK2 inhibition is a tractable CNS pharmacological target that does not cause genotoxicity at doses and exposures that engage the target in the sensory retina. - Highlights: • Active and inactive enantiomers test negative in the in vitro micronucleus test. • ELN 582646 significantly increased micronuclei at 100 and 300 mg/kg/day doses. • ELN 582646 significantly increased micronuclei in PLK2 knockout mice. • ELN 582646 decreased

  10. Chemoprevention of prostate cancer by d,l-sulforaphane is augmented by pharmacological inhibition of autophagy.

    PubMed

    Vyas, Avani R; Hahm, Eun-Ryeong; Arlotti, Julie A; Watkins, Simon; Stolz, Donna Beer; Desai, Dhimant; Amin, Shantu; Singh, Shivendra V

    2013-10-01

    There is a preclinical evidence that the oral administration of d,l-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer [prostatic intraepithelial neoplasia (PIN)] and well-differentiated cancer (WDC) but not late-stage poorly differentiated cancer (PDC). Because SFN treatment induces cytoprotective autophagy in cultured human prostate cancer cells, the present study tested the hypothesis that chemopreventive efficacy of SFN could be augmented by the pharmacologic inhibition of autophagy using chloroquine (CQ). Incidence of PDC characterized by prostate weight of more than 1 g was significantly lower in the SFN + CQ group than in control (P = 0.004), CQ group (P = 0.026), or SFN group (P = 0.002 by Fisher exact test). Average size of the metastatic lymph node was lower by about 42% in the SFN + CQ group than in control (P = 0.043 by Wilcoxon test). On the other hand, the SFN + CQ combination was not superior to SFN alone with respect to inhibition of incidence or burden of microscopic PIN or WDC. SFN treatment caused in vivo autophagy as evidenced by transmission electron microscopy. Mechanistic studies showed that prevention of prostate cancer and metastasis by the SFN + CQ combination was associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial-mesenchymal transition. Plasma proteomics identified protein expression signature that may serve as biomarker of SFN + CQ exposure/response. This study offers a novel combination regimen for future clinical investigations for prevention of prostate cancer in humans.

  11. Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood.

    PubMed

    Hall, J Perry; Kurdi, Yahya; Hsu, Sang; Cuozzo, John; Liu, Julie; Telliez, Jean-Baptiste; Seidl, Katherine J; Winkler, Aaron; Hu, Yonghan; Green, Neal; Askew, G Roger; Tam, Steve; Clark, James D; Lin, Lih-Ling

    2007-11-16

    Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine that controls the initiation and progression of inflammatory diseases such as rheumatoid arthritis. Tpl2 is a MAPKKK in the MAPK (i.e. ERK) pathway, and the Tpl2-MEK-ERK signaling pathway is activated by the pro-inflammatory mediators TNFalpha, interleukin (IL)-1beta, and bacterial endotoxin (lipopolysaccharide (LPS)). Moreover, Tpl2 is required for TNFalpha expression. Thus, pharmacologic inhibition of Tpl2 should be a valid approach to therapeutic intervention in the pathogenesis of rheumatoid arthritis and other inflammatory diseases in humans. We have developed a series of highly selective and potent Tpl2 inhibitors, and in the present study we have used these inhibitors to demonstrate that the catalytic activity of Tpl2 is required for the LPS-induced activation of MEK and ERK in primary human monocytes. These inhibitors selectively target Tpl2 in these cells, and they block LPS- and IL-1beta-induced TNFalpha production in both primary human monocytes and human blood. In rheumatoid arthritis fibroblast-like synoviocytes these inhibitors block ERK activation, cyclooxygenase-2 expression, and the production of IL-6, IL-8, and prostaglandin E(2), and the matrix metalloproteinases MMP-1 and MMP-3. Taken together, our results show that inhibition of Tpl2 in primary human cell types can decrease the production of TNFalpha and other pro-inflammatory mediators during inflammatory events, and they further support the notion that Tpl2 is an appropriate therapeutic target for rheumatoid arthritis and other human inflammatory diseases. PMID:17848581

  12. Pharmacological HIF2α inhibition improves VHL disease-associated phenotypes in zebrafish model.

    PubMed

    Metelo, Ana Martins; Noonan, Haley R; Li, Xiang; Jin, Youngnam; Baker, Rania; Kamentsky, Lee; Zhang, Yiyun; van Rooijen, Ellen; Shin, Jordan; Carpenter, Anne E; Yeh, Jing-Ruey; Peterson, Randall T; Iliopoulos, Othon

    2015-05-01

    Patients with a germline mutation in von Hippel-Lindau (VHL) develop renal cell cancers and hypervascular tumors of the brain, adrenal glands, and pancreas as well as erythrocytosis. These phenotypes are driven by aberrant expression of HIF2α, which induces expression of genes involved in cell proliferation, angiogenesis, and red blood cell production. Currently, there are no effective treatments available for VHL disease. Here, using an animal model of VHL, we report a marked improvement of VHL-associated phenotypes following treatment with HIF2α inhibitors. Inactivation of vhl in zebrafish led to constitutive activation of HIF2α orthologs and modeled several aspects of the human disease, including erythrocytosis, pathologic angiogenesis in the brain and retina, and aberrant kidney and liver proliferation. Treatment of vhl(-/-) mutant embryos with HIF2α-specific inhibitors downregulated Hif target gene expression in a dose-dependent manner, improved abnormal hematopoiesis, and substantially suppressed erythrocytosis and angiogenic sprouting. Moreover, pharmacologic inhibition of HIF2α reversed the compromised cardiac contractility of vhl(-/-) embryos and partially rescued early lethality. This study demonstrates that small-molecule targeting of HIF2α improves VHL-related phenotypes in a vertebrate animal model and supports further exploration of this strategy for treating VHL disease. PMID:25866969

  13. Pharmacological inhibition of soluble epoxide hydrolase ameliorates diet-induced metabolic syndrome in rats.

    PubMed

    Iyer, Abishek; Kauter, Kathleen; Alam, Md Ashraful; Hwang, Sung Hee; Morisseau, Christophe; Hammock, Bruce D; Brown, Lindsay

    2012-01-01

    The signs of metabolic syndrome following chronic excessive macronutrient intake include body weight gain, excess visceral adipose deposition, hyperglycaemia, glucose and insulin intolerances, hypertension, dyslipidaemia, endothelial damage, cardiovascular hypertrophy, inflammation, ventricular contractile dysfunction, fibrosis, and fatty liver disease. Recent studies show increased activity of soluble epoxide hydrolase (sEH) during obesity and metabolic dysfunction. We have tested whether sEH inhibition has therapeutic potential in a rat model of diet-induced metabolic syndrome. In these high-carbohydrate, high-fat-fed rats, chronic oral treatment with trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a potent sEH inhibitor, alleviated the signs of metabolic syndrome in vivo including glucose, insulin, and lipid abnormalities, changes in pancreatic structure, increased systolic blood pressure, cardiovascular structural and functional abnormalities, and structural and functional changes in the liver. The present study describes the pharmacological responses to this selective sEH inhibitor in rats with the signs of diet-induced metabolic syndrome.

  14. Pharmacological HIF2α inhibition improves VHL disease–associated phenotypes in zebrafish model

    PubMed Central

    Metelo, Ana Martins; Noonan, Haley R.; Li, Xiang; Jin, Youngnam; Baker, Rania; Kamentsky, Lee; Zhang, Yiyun; van Rooijen, Ellen; Shin, Jordan; Carpenter, Anne E.; Yeh, Jing-Ruey; Peterson, Randall T.; Iliopoulos, Othon

    2015-01-01

    Patients with a germline mutation in von Hippel-Lindau (VHL) develop renal cell cancers and hypervascular tumors of the brain, adrenal glands, and pancreas as well as erythrocytosis. These phenotypes are driven by aberrant expression of HIF2α, which induces expression of genes involved in cell proliferation, angiogenesis, and red blood cell production. Currently, there are no effective treatments available for VHL disease. Here, using an animal model of VHL, we report a marked improvement of VHL-associated phenotypes following treatment with HIF2α inhibitors. Inactivation of vhl in zebrafish led to constitutive activation of HIF2α orthologs and modeled several aspects of the human disease, including erythrocytosis, pathologic angiogenesis in the brain and retina, and aberrant kidney and liver proliferation. Treatment of vhl–/– mutant embryos with HIF2α-specific inhibitors downregulated Hif target gene expression in a dose-dependent manner, improved abnormal hematopoiesis, and substantially suppressed erythrocytosis and angiogenic sprouting. Moreover, pharmacologic inhibition of HIF2α reversed the compromised cardiac contractility of vhl–/– embryos and partially rescued early lethality. This study demonstrates that small-molecule targeting of HIF2α improves VHL-related phenotypes in a vertebrate animal model and supports further exploration of this strategy for treating VHL disease. PMID:25866969

  15. Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation

    PubMed Central

    Lobbestael, E.; Civiero, L.; De Wit, T.; Taymans, J.-M.; Greggio, E.; Baekelandt, V.

    2016-01-01

    Leucine-rich repeat kinase 2 (LRRK2) kinase activity is increased in several pathogenic mutations, including the most common mutation, G2019S, and is known to play a role in Parkinson’s disease (PD) pathobiology. This has stimulated the development of potent, selective LRRK2 kinase inhibitors as one of the most prevailing disease-modifying therapeutic PD strategies. Although several lines of evidence support beneficial effects of LRRK2 kinase inhibitors, many questions need to be answered before clinical applications can be envisaged. Using six different LRRK2 kinase inhibitors, we show that LRRK2 kinase inhibition induces LRRK2 dephosphorylation and can reduce LRRK2 protein levels of overexpressed wild type and G2019S, but not A2016T or K1906M, LRRK2 as well as endogenous LRRK2 in mouse brain, lung and kidney. The inhibitor-induced reduction in LRRK2 levels could be reversed by proteasomal inhibition, but not by lysosomal inhibition, while mRNA levels remained unaffected. In addition, using LRRK2 S910A and S935A phosphorylation mutants, we show that dephosphorylation of these sites is not required for LRRK2 degradation. Increasing our insight in the molecular and cellular consequences of LRRK2 kinase inhibition will be crucial in the further development of LRRK2-based PD therapies. PMID:27658356

  16. Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice

    PubMed Central

    Shimshek, Derya R.; Jacobson, Laura H.; Kolly, Carine; Zamurovic, Natasa; Balavenkatraman, Kamal Kumar; Morawiec, Laurent; Kreutzer, Robert; Schelle, Juliane; Jucker, Mathias; Bertschi, Barbara; Theil, Diethilde; Heier, Annabelle; Bigot, Karine; Beltz, Karen; Machauer, Rainer; Brzak, Irena; Perrot, Ludovic; Neumann, Ulf

    2016-01-01

    Melanocytes of the hair follicle produce melanin and are essential in determining the differences in hair color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role in melanogenesis. One of the critical steps is the amyloid-like functional oligomerization of PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) and γ-secretase have been shown to be key players in generating the proteolytic fragments of PMEL17. The β-secretase (BACE1) is responsible for the generation of amyloid-β (Aβ) fragments in the brain and is therefore proposed as a therapeutic target for Alzheimer’s disease (AD). Currently BACE1 inhibitors, most of which lack selectivity over BACE2, have demonstrated efficacious reduction of amyloid-β peptides in animals and the CSF of humans. BACE2 knock-out mice have a deficiency in PMEL17 proteolytic processing leading to impaired melanin storage and hair depigmentation. Here, we confirm BACE2-mediated inhibition of PMEL17 proteolytic processing in vitro in mouse and human melanocytes. Furthermore, we show that wildtype as well as bace2+/− and bace2−/− mice treated with a potent dual BACE1/BACE2 inhibitor NB-360 display dose-dependent appearance of irreversibly depigmented hair. Retinal pigmented epithelium showed no morphological changes. Our data demonstrates that BACE2 as well as additional BACE1 inhibition affects melanosome maturation and induces hair depigmentation in mice. PMID:26912421

  17. Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice.

    PubMed

    Shimshek, Derya R; Jacobson, Laura H; Kolly, Carine; Zamurovic, Natasa; Balavenkatraman, Kamal Kumar; Morawiec, Laurent; Kreutzer, Robert; Schelle, Juliane; Jucker, Mathias; Bertschi, Barbara; Theil, Diethilde; Heier, Annabelle; Bigot, Karine; Beltz, Karen; Machauer, Rainer; Brzak, Irena; Perrot, Ludovic; Neumann, Ulf

    2016-01-01

    Melanocytes of the hair follicle produce melanin and are essential in determining the differences in hair color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role in melanogenesis. One of the critical steps is the amyloid-like functional oligomerization of PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) and γ-secretase have been shown to be key players in generating the proteolytic fragments of PMEL17. The β-secretase (BACE1) is responsible for the generation of amyloid-β (Aβ) fragments in the brain and is therefore proposed as a therapeutic target for Alzheimer's disease (AD). Currently BACE1 inhibitors, most of which lack selectivity over BACE2, have demonstrated efficacious reduction of amyloid-β peptides in animals and the CSF of humans. BACE2 knock-out mice have a deficiency in PMEL17 proteolytic processing leading to impaired melanin storage and hair depigmentation. Here, we confirm BACE2-mediated inhibition of PMEL17 proteolytic processing in vitro in mouse and human melanocytes. Furthermore, we show that wildtype as well as bace2(+/-) and bace2(-/-) mice treated with a potent dual BACE1/BACE2 inhibitor NB-360 display dose-dependent appearance of irreversibly depigmented hair. Retinal pigmented epithelium showed no morphological changes. Our data demonstrates that BACE2 as well as additional BACE1 inhibition affects melanosome maturation and induces hair depigmentation in mice. PMID:26912421

  18. Pharmacological Inhibition of O-GlcNAcase Does Not Increase Sensitivity of Glucocorticoid Receptor-Mediated Transrepression

    PubMed Central

    Stivers, Peter J.; Harmonay, Lauren; Hicks, Alexandra; Mehmet, Huseyin; Morris, Melody; Robinson, Gain M.; Strack, Peter R.; Savage, Mary J.; Zaller, Dennis M.; Zwierzynski, Izabela; Brandish, Philip E.

    2015-01-01

    Glucocorticoid signaling regulates target genes by multiple mechanisms, including the repression of transcriptional activities of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) though direct protein-protein interactions and subsequent O-GlcNAcylation of RNA polymerase II (pol II). Recent studies have shown that overexpression of O-linked β-N-acetylglucosamine transferase (OGT), which adds an O-linked β-N-acetylglucosamine (O-GlcNAc) group to the C-terminal domain of RNA pol II, increases the transrepression effects of glucocorticoids (GC). As O-GlcNAcase (OGA) is an enzyme that removes O-GlcNAc from O-GlcNAcylated proteins, we hypothesized that the potentiation of GC effects following OGT overexpression could be similarly observed via the direct inhibition of OGA, inhibiting O-GlcNAc removal from pol II. Here we show that despite pharmacological evidence of target engagement by a selective small molecule inhibitor of OGA, there is no evidence for a sensitizing effect on glucocorticoid-mediated effects on TNF-α promoter activity, or gene expression generally, in human cells. Furthermore, inhibition of OGA did not potentiate glucocorticoid–induced apoptosis in several cancer cell lines. Thus, despite evidence for O-GlcNAc modification of RNA pol II in GR-mediated transrepression, our data indicate that pharmacological inhibition of OGA does not potentiate or enhance glucocorticoid-mediated transrepression. PMID:26670328

  19. A pharmacologic inhibitor of the protease Taspase1 effectively inhibits breast and brain tumor growth.

    PubMed

    Chen, David Y; Lee, Yishan; Van Tine, Brian A; Searleman, Adam C; Westergard, Todd D; Liu, Han; Tu, Ho-Chou; Takeda, Shugaku; Dong, Yiyu; Piwnica-Worms, David R; Oh, Kyoung J; Korsmeyer, Stanley J; Hermone, Ann; Gussio, Richard; Shoemaker, Robert H; Cheng, Emily H-Y; Hsieh, James J-D

    2012-02-01

    The threonine endopeptidase Taspase1 has a critical role in cancer cell proliferation and apoptosis. In this study, we developed and evaluated small molecule inhibitors of Taspase1 as a new candidate class of therapeutic modalities. Genetic deletion of Taspase1 in the mouse produced no overt deficiencies, suggesting the possibility of a wide therapeutic index for use of Taspase1 inhibitors in cancers. We defined the peptidyl motifs recognized by Taspase1 and conducted a cell-based dual-fluorescent proteolytic screen of the National Cancer Institute diversity library to identify Taspase1 inhibitors (TASPIN). On the basis of secondary and tertiary screens the 4-[(4-arsonophenyl)methyl]phenyl] arsonic acid NSC48300 was determined to be the most specific active compound. Structure-activity relationship studies indicated a crucial role for the arsenic acid moiety in mediating Taspase1 inhibition. Additional fluorescence resonance energy transfer-based kinetic analysis characterized NSC48300 as a reversible, noncompetitive inhibitor of Taspase1 (K(i) = 4.22 μmol/L). In the MMTV-neu mouse model of breast cancer and the U251 xenograft model of brain cancer, NSC48300 produced effective tumor growth inhibition. Our results offer an initial preclinical proof-of-concept to develop TASPINs for cancer therapy.

  20. Pharmacological Characterization of an Antisense Knockdown Zebrafish Model of Dravet Syndrome: Inhibition of Epileptic Seizures by the Serotonin Agonist Fenfluramine

    PubMed Central

    Copmans, Daniëlle; Langlois, Mélanie; Crawford, Alexander D.; Ceulemans, Berten; Lagae, Lieven; de Witte, Peter A. M.; Esguerra, Camila V.

    2015-01-01

    Dravet syndrome (DS) is one of the most pharmacoresistant and devastating forms of childhood epilepsy syndromes. Distinct de novo mutations in the SCN1A gene are responsible for over 80% of DS cases. While DS is largely resistant to treatment with existing anti-epileptic drugs, promising results have been obtained in clinical trials with human patients treated with the serotonin agonist fenfluramine as an add-on therapeutic. We developed a zebrafish model of DS using morpholino antisense oligomers (MOs) targeting scn1Lab, the zebrafish ortholog of SCN1A. Zebrafish larvae with an antisense knockdown of scn1Lab (scn1Lab morphants) were characterized by automated behavioral tracking and high-resolution video imaging, in addition to measuring brain activity through local field potential recordings. Our findings reveal that scn1Lab morphants display hyperactivity, convulsive seizure-like behavior, loss of posture, repetitive jerking and a myoclonic seizure-like pattern. The occurrence of spontaneous seizures was confirmed by local field potential recordings of the forebrain, measuring epileptiform discharges. Furthermore, we show that these larvae are remarkably sensitive to hyperthermia, similar to what has been described for mouse models of DS, as well as for human DS patients. Pharmacological evaluation revealed that sodium valproate and fenfluramine significantly reduce epileptiform discharges in scn1Lab morphants. Our findings for this zebrafish model of DS are in accordance with clinical data for human DS patients. To our knowledge, this is the first study demonstrating effective seizure inhibition of fenfluramine in an animal model of Dravet syndrome. Moreover, these results provide a basis for identifying novel analogs with improved activity and significantly milder or no side effects. PMID:25965391

  1. Genetic and Pharmacological Inhibition of PDK1 in Cancer Cells: Characterization of a Selective Allosteric Kinase Inhibitor

    SciTech Connect

    Nagashima, Kumiko; Shumway, Stuart D.; Sathyanarayanan, Sriram; Chen, Albert H.; Dolinski, Brian; Xu, Youyuan; Keilhack, Heike; Nguyen, Thi; Wiznerowicz, Maciej; Li, Lixia; Lutterbach, Bart A.; Chi, An; Paweletz, Cloud; Allison, Timothy; Yan, Youwei; Munshi, Sanjeev K.; Klippel, Anke; Kraus, Manfred; Bobkova, Ekaterina V.; Deshmukh, Sujal; Xu, Zangwei; Mueller, Uwe; Szewczak, Alexander A.; Pan, Bo-Sheng; Richon, Victoria; Pollock, Roy; Blume-Jensen, Peter; Northrup, Alan; Andersen, Jannik N.

    2013-11-20

    Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems.

  2. Heterogeneous kinetics and pharmacology of synaptic inhibition in the chick auditory brainstem

    PubMed Central

    Kuo, Sidney P.; Bradley, Laura A.; Trussell, Laurence O.

    2010-01-01

    Identification of shared features between avian and mammalian auditory brainstem circuits has provided much insight into the mechanisms underlying early auditory processing. However, previous studies have highlighted an apparent difference in inhibitory systems; synaptic inhibition is thought to be slow and GABAergic in birds, but to have fast kinetics and be predominantly glycinergic in mammals. Using patch-clamp recordings in chick brainstem slices, we found this distinction is not exclusively true. Consistent with previous work, inhibitory postsynaptic currents (IPSCs) in nucleus magnocellularis (NM) were slow and mediated by GABAA receptors. However, IPSCs in nucleus laminaris (NL) and a subset of neurons in nucleus angularis (NA) had rapid time courses two to three-fold faster than those in NM. Further, we found IPSCs in NA were mediated by both glycine and GABAA receptors, demonstrating for the first time a role for fast glycinergic transmission in the avian auditory brainstem. Although NM, NL and NA have unique roles in auditory processing, the majority of inhibitory input to each nucleus arises from the same source, ipsilateral superior olivary nucleus (SON). Our results demonstrate remarkable diversity of inhibitory transmission among the avian brainstem nuclei and suggest differential glycine and GABAA receptor activity tailors inhibition to the specific functional roles of NM, NL, and NA despite common SON input. We additionally observed that glycinergic/GABAergic activity in NA was usually depolarizing and could elicit spiking activity in NA neurons. Because NA projects to SON, these excitatory effects may influence the recruitment of inhibitory activity in the brainstem nuclei. PMID:19641125

  3. Pharmacological Inhibition of Myostatin Protects Against Atrophy and Weakness after ACL Tear

    PubMed Central

    Wolfe, Caroline Nicole; Gumucio, Jonathan P.; Grekin, Jeremy; Khouri, Roger Karl; Bedi, Asheesh; Mendias, Christopher

    2016-01-01

    decreases in the expression of these genes at 7D (Figure 1A). Additionally, IGF-1Ea and IGF-1Eb which are important growth factors that induce muscle protein synthesis, were elevated in the myostatin antibody groups at the 21D time point. For genes related to fibrosis (Figure 1B), although there was no significant difference in MMP-2, there was a significant decrease of MMP-8 expression in the 21D MSTN group when compared to the 21D sham. There were also increases in the expression of TIMP-1 and 2 in the 21D MSTN group. Conclusion: In a preclinical rat model, the targeted inhibition of myostatin protected leg muscles from muscle atrophy and improved force production after ACL tear. While the mechanism of action is not entirely clear, it is possible that the inhibition of myostatin preserves strength by limiting the expression of proteolytic enzymes in the post-acute atrophy phase and increasing protein synthesis in later phases.

  4. Synthesis and pharmacological screening for muscle relaxant, anticonvulsant, and sedative activities of certain organic compounds produced by Michael addition.

    PubMed

    Said, Makarem M; Ahmed, Amany A E; El-Alfy, Abir T

    2004-12-01

    Michael addition of certain nucleophiles on alpha, beta-unsaturated ketones 1 led to the formation of adducts 2-7 as well as the reaction of arylidene derivatives with secondary amines afforded the amino compounds 9 and 11. Also, dialkylmalonates were treated with alpha-cyano cinnamide to afford 13. On the other hand, double Michael cycloaddition of ethylcyanoacetate or tetrachlorophthalic anhydride to the suitable divinylketone were synthesized to produce 15-17. Selected compounds (13 and 6) were screened for muscle relaxant, anticonvulsant, and sedative activities using established pharmacological models. Their activities were compared with that of phenobarbital sodium taken as standard. Compound 6 was the most potent muscle relaxant while compounds 13a and 13c offered the highest anticonvulsant activity. Meanwhile compound 13c showed the highest potentiation of phenobarbital induced sleep in mice. PMID:15646790

  5. Inhibition of hot salt corrosion by metallic additives

    NASA Technical Reports Server (NTRS)

    Deadmore, D. L.; Lowell, C. E.

    1978-01-01

    The effectiveness of several potential fuel additives in reducing the effects of sodium sulfate-induced hot corrosion was evaluated in a cyclic Mach 0.3 burner rig. The potential inhibitors examined were salts of Al, Si, Cr, Fe, Zn, Mg, Ca, and Ba. The alloys tested were IN-100, U-700, IN-738, IN-792, Mar M-509, and 304 stainless steel. Each alloy was exposed for 100 cycles of 1 hour each at 900 C in combustion gases doped with the corrodant and inhibitor salts and the extent of attack was determined by measuring maximum metal thickness loss. The most effective and consistent inhibitor additive was Ba (NO3)2 which reduced the hot corrosion attack to nearly that of simple oxidation.

  6. Pharmacologic inhibition of cdk4/6 arrests the growth of glioblastoma multiforme intracranial xenografts

    PubMed Central

    Michaud, Karine; Solomon, David A.; Oermann, Eric; Kim, Jung-Sik; Zhong, Wei-Zhu; Prados, Michael D.; Ozawa, Tomoko; James, C. David; Waldman, Todd

    2010-01-01

    Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6 specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induction of senescence in each of 16 Rb-proficient cell lines regardless of other genetic lesions, whereas each of 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. shRNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 had significant disease progression or died while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly-diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy. PMID:20354191

  7. Structural Basis for Feedback and Pharmacological Inhibition of Saccharomyces cerevisiae Glutamate Cysteine Ligase

    SciTech Connect

    Biterova, Ekaterina I.; Barycki, Joseph J.

    2010-04-30

    Structural characterization of glutamate cysteine ligase (GCL), the enzyme that catalyzes the initial, rate-limiting step in glutathione biosynthesis, has revealed many of the molecular details of substrate recognition. To further delineate the mechanistic details of this critical enzyme, we have determined the structures of two inhibited forms of Saccharomyces cerevisiae GCL (ScGCL), which shares significant sequence identity with the human enzyme. In vivo, GCL activity is feedback regulated by glutathione. Examination of the structure of ScGCL-glutathione complex (2.5 A; R = 19.9%, R(free) = 25.1%) indicates that the inhibitor occupies both the glutamate- and the presumed cysteine-binding site and disrupts the previously observed Mg(2+) coordination in the ATP-binding site. l-Buthionine-S-sulfoximine (BSO) is a mechanism-based inhibitor of GCL and has been used extensively to deplete glutathione in cell culture and in vivo model systems. Inspection of the ScGCL-BSO structure (2.2 A; R = 18.1%, R(free) = 23.9%) confirms that BSO is phosphorylated on the sulfoximine nitrogen to generate the inhibitory species and reveals contacts that likely contribute to transition state stabilization. Overall, these structures advance our understanding of the molecular regulation of this critical enzyme and provide additional details of the catalytic mechanism of the enzyme.

  8. Neurohormonal activation and pharmacological inhibition in pulmonary arterial hypertension and related right ventricular failure.

    PubMed

    Ameri, Pietro; Bertero, Edoardo; Meliota, Giovanni; Cheli, Martino; Canepa, Marco; Brunelli, Claudio; Balbi, Manrico

    2016-09-01

    During the last decade, hyperactivity of the sympathetic nervous and renin-angiotensin-aldosterone systems (SNS and RAAS, respectively) has repeatedly been related to the pathophysiology of pulmonary arterial hypertension (PAH) and PAH-related right ventricular failure (PAH-RVF), raising the question of whether neurohormonal inhibition may be indicated for these conditions. Experimental data indicate that the RAAS may be involved in pulmonary vascular remodeling, which is in fact halted by RAAS antagonism. Favorable actions of β-blockers on the pulmonary vasculature have also been described, even if information about β-adrenergic receptors in PAH is lacking. Furthermore, the available evidence suggests that stimulation of the pressure-overloaded RV by the SNS and RAAS is initially compensatory, but becomes maladaptive over time. Consistently, RV reverse remodeling has been shown in PAH animal models treated with either β-blockers or RAAS inhibitors, although important differences with human PAH may limit the translational value of these findings. Only few observational studies of neurohormonal antagonism in PAH and PAH-RVF have been published. Nonetheless, β-blockers on top of specific therapy appear to be safe and possibly also effective. The combination of mineralocorticoid receptor and endothelin-A receptor antagonists may result in an additive effect because of a positive pharmacodynamic interaction. While neurohormonal inhibitors cannot be recommended at present for treatment of PAH and PAH-RVF, they are worth being further investigated. PMID:27206576

  9. Effects of Pharmacological Inhibition and Genetic Deficiency of Plasminogen Activator Inhibitor-1 in Radiation-Induced Intestinal Injury

    SciTech Connect

    Abderrahmani, Rym; Francois, Agnes; Buard, Valerie; Benderitter, Marc; Sabourin, Jean-Christophe; Crandall, David L.; Milliat, Fabien

    2009-07-01

    Purpose: To investigate effects of plasminogen activator inhibitor 1 (PAI-1) genetic deficiency and pharmacological PAI-1 inhibition with PAI-039 in a mouse model of radiation-induced enteropathy. Methods and Materials: Wild-type (Wt) and PAI-1{sup -/-} knockout mice received a single dose of 19 Gy to an exteriorized localized intestinal segment. Sham and irradiated Wt mice were treated orally with 1 mg/g of PAI-039. Histological modifications were quantified using a radiation injury score. Moreover, intestinal gene expression was monitored by real-time PCR. Results: At 3 days after irradiation, PAI-039 abolished the radiation-induced increase in the plasma active form of PAI-1 and limited the radiation-induced gene expression of transforming growth factor {beta}1 (TGF-{beta}1), CTGF, PAI-1, and COL1A2. Moreover, PAI-039 conferred temporary protection against early lethality. PAI-039 treatment limited the radiation-induced increase of CTGF and PAI-1 at 2 weeks after irradiation but had no effect at 6 weeks. Radiation injuries were less severe in PAI-1{sup -/-} mice than in Wt mice, and despite the beneficial effect, 3 days after irradiation, PAI-039 had no effects on microscopic radiation injuries compared to untreated Wt mice. Conclusions: A genetic deficiency of PAI-1 is associated with amelioration of late radiation enteropathy. Pharmacological inhibition of PAI-1 by PAI-039 positively impacts the early, acute phase increase in plasma PAI-1 and the associated radiation-induced gene expression of inflammatory/extracellular matrix proteins. Since PAI-039 has been shown to inhibit the active form of PAI-1, as opposed to the complete loss of PAI-1 in the knockout animals, these data suggest that a PAI-1 inhibitor could be beneficial in treating radiation-induced tissue injury in acute settings where PAI-1 is elevated.

  10. Pharmacological Inhibition of Microsomal Prostaglandin E Synthase-1 Suppresses Epidermal Growth Factor Receptor-Mediated Tumor Growth and Angiogenesis

    PubMed Central

    Bocci, Elena; Coletta, Isabella; Polenzani, Lorenzo; Mangano, Giorgina; Alisi, Maria Alessandra; Cazzolla, Nicola; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

    2012-01-01

    Background Blockade of Prostaglandin (PG) E2 production via deletion of microsomal Prostaglandin E synthase-1 (mPGES-1) gene reduces tumor cell proliferation in vitro and in vivo on xenograft tumors. So far the therapeutic potential of the pharmacological inhibition of mPGES-1 has not been elucidated. PGE2 promotes epithelial tumor progression via multiple signaling pathways including the epidermal growth factor receptor (EGFR) signaling pathway. Methodology/Principal Findings Here we evaluated the antitumor activity of AF3485, a compound of a novel family of human mPGES-1 inhibitors, in vitro and in vivo, in mice bearing human A431 xenografts overexpressing EGFR. Treatment of the human cell line A431 with interleukin-1beta (IL-1β) increased mPGES-1 expression, PGE2 production and induced EGFR phosphorylation, and vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expression. AF3485 reduced PGE2 production, both in quiescent and in cells stimulated by IL-1β. AF3485 abolished IL-1β-induced activation of the EGFR, decreasing VEGF and FGF-2 expression, and tumor-mediated endothelial tube formation. In vivo, in A431 xenograft, AF3485, administered sub-chronically, decreased tumor growth, an effect related to inhibition of EGFR signalling, and to tumor microvessel rarefaction. In fact, we observed a decrease of EGFR phosphorylation, and VEGF and FGF-2 expression in tumours explanted from treated mice. Conclusion Our work demonstrates that the pharmacological inhibition of mPGES-1 reduces squamous carcinoma growth by suppressing PGE2 mediated-EGFR signalling and by impairing tumor associated angiogenesis. These results underscore the potential of mPGES-1 inhibitors as agents capable of controlling tumor growth. PMID:22815767

  11. Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections

    PubMed Central

    Hentzer, Morten; Givskov, Michael

    2003-01-01

    Traditional treatment of infectious diseases is based on compounds that aim to kill or inhibit bacterial growth. A major concern with this approach is the frequently observed development of resistance to antimicrobial compounds. The discovery of bacterial-communication systems (quorum-sensing systems), which orchestrate important temporal events during the infection process, has afforded a novel opportunity to ameliorate bacterial infection by means other than growth inhibition. Compounds able to override bacterial signaling are present in nature. Herein we discuss the known signaling mechanisms and potential antipathogenic drugs that specifically target quorum-sensing systems in a manner unlikely to pose a selective pressure for the development of resistant mutants. PMID:14597754

  12. Clinical pharmacology of cyclooxygenase inhibition and pharmacodynamic interaction with aspirin by floctafenine in Thai healthy subjects.

    PubMed

    Maenthaisong, R; Tacconelli, S; Sritara, P; Del Boccio, P; Di Francesco, L; Sacchetta, P; Archararit, N; Aryurachai, K; Patrignani, P; Suthisisang, C

    2013-01-01

    Floctafenine, a hydroxyquinoline derivative with analgesic properties, is widely used in Thailand and many other countries. The objectives of this study were to evaluate in Thai healthy volunteers: i) the inhibition of whole blood cyclooxygenase(COX)-2 and COX-1 activity by floctafenine and its metabolite floctafenic acid in vitro and ex vivo after dosing with floctafenine; ii) the possible interference of floctafenine administration with aspirin antiplatelet effects. We performed an open-label, cross-over, 3-period study, on 11 healthy Thai volunteers, who received consecutively floctafenine(200mg/TID), low-dose aspirin(81mg/daily) or their combination for 4 days, separated by washout periods. Floctafenine and floctafenic acid resulted potent inhibitors of COX-1 and COX-2 in vitro (floctafenic acid was more potent than floctafenine) showing a slight preference for COX-1. After dosing with floctafenine alone, whole blood COX-1 and COX-2 activities were inhibited ex vivo in a time-dependent fashion which paralleled floctafenic acid plasma concentrations. Aspirin alone inhibited profoundly and persistently platelet COX-1 activity and AA-induced platelet aggregation throughout 24-h dosing interval which was affected by the co-administration of floctafenine. At 24 h after dosing with aspirin and floctafenine, the inhibition of platelet thromboxane(TX)B2 generation and aggregation were significantly(P less than 0.05) lower than that caused by aspirin alone. Therapeutic dosing with floctafenine profoundly inhibited prostanoid biosynthesis through the rapid conversion to floctafenic acid. Floctafenine interfered with the antiplatelet effect of aspirin. Our results suggest that floctafenine should be avoided in patients with cardiovascular disease under treatment with low-dose aspirin. PMID:23755755

  13. Ultrastructure, pharmacologic inhibition, and transport selectivity of aquaporin channel-forming integral protein in proteoliposomes.

    PubMed

    Zeidel, M L; Nielsen, S; Smith, B L; Ambudkar, S V; Maunsbach, A B; Agre, P

    1994-02-15

    Reconstitution of highly purified aquaporin CHIP (channel-forming integral protein) into proteoliposomes was previously shown to confer high osmotic water permeability (Pf) to the membranes [Zeidel et al. (1992) Biochemistry 31, 7436-7440]. Here we report detailed ultrastructural, pharmacologic, and transport studies of human red cell CHIP in proteoliposomes. Freeze-fracture and transmission electron microscopy revealed a uniform distribution of CHIP which was incorporated into the membranes in both native and inverse orientations. Morphometric analysis of membranes reconstituted at three different concentrations of CHIP revealed that the intramembrane particles correspond to tetramers or possible higher order oligomers, and the Pf increased in direct proportion to the CHIP density. Proteolytic removal of the 4-kDa C-terminal cytoplasmic domain of CHIP did not alter the Pf or oligomerization in red cell membranes. CHIP exhibited a similar conductance for water when reconstituted into membranes of varied lipid compositions. The sensitivities of CHIP-mediated Pf to specific sulfhydryl reagents were identical to known sensitivities of red cell Pf, including a delayed response to p-(chloromercuri)benzenesulfonate. CHIP did not increase the permeability of the proteoliposome membranes to H+/OH- or NH3. These studies demonstrate that CHIP proteoliposomes exhibit all known characteristics of water channels in native red cells and therefore provide a defined system for biophysical analysis of transmembrane water movements.

  14. Pharmacological inhibition of PHOSPHO1 suppresses vascular smooth muscle cell calcification.

    PubMed

    Kiffer-Moreira, Tina; Yadav, Manisha C; Zhu, Dongxing; Narisawa, Sonoko; Sheen, Campbell; Stec, Boguslaw; Cosford, Nicholas D; Dahl, Russell; Farquharson, Colin; Hoylaerts, Marc F; Macrae, Vicky E; Millán, José Luis

    2013-01-01

    Medial vascular calcification (MVC) is common in patients with chronic kidney disease, obesity, and aging. MVC is an actively regulated process that resembles skeletal mineralization, resulting from chondro-osteogenic transformation of vascular smooth muscle cells (VSMCs). Here, we used mineralizing murine VSMCs to study the expression of PHOSPHO1, a phosphatase that participates in the first step of matrix vesicles-mediated initiation of mineralization during endochondral ossification. Wild-type (WT) VSMCs cultured under calcifying conditions exhibited increased Phospho1 gene expression and Phospho1(-/-) VSMCs failed to mineralize in vitro. Using natural PHOSPHO1 substrates, potent and specific inhibitors of PHOSPHO1 were identified via high-throughput screening and mechanistic analysis and two of these inhibitors, designated MLS-0390838 and MLS-0263839, were selected for further analysis. Their effectiveness in preventing VSMC calcification by targeting PHOSPHO1 function was assessed, alone and in combination with a potent tissue-nonspecific alkaline phosphatase (TNAP) inhibitor MLS-0038949. PHOSPHO1 inhibition by MLS-0263839 in mineralizing WT cells (cultured with added inorganic phosphate) reduced calcification in culture to 41.8% ± 2.0% of control. Combined inhibition of PHOSPHO1 by MLS-0263839 and TNAP by MLS-0038949 significantly reduced calcification to 20.9% ± 0.74% of control. Furthermore, the dual inhibition strategy affected the expression of several mineralization-related enzymes while increasing expression of the smooth muscle cell marker Acta2. We conclude that PHOSPHO1 plays a critical role in VSMC mineralization and that "phosphatase inhibition" may be a useful therapeutic strategy to reduce MVC.

  15. p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases.

    PubMed

    Marxer, M; Ma, H T; Man, W Y; Poon, R Y C

    2014-07-01

    A number of small-molecule inhibitors of Aurora kinases have been developed and are undergoing clinical trials for anti-cancer therapies. Different Aurora kinases, however, behave as very different targets: while inhibition of Aurora A (AURKA) induces a delay in mitotic exit, inhibition of Aurora B (AURKB) triggers mitotic slippage. Furthermore, while it is evident that p53 is regulated by Aurora kinase-dependent phosphorylation, how p53 may in turn regulate Aurora kinases remains mysterious. To address these issues, isogenic p53-containing and -negative cells were exposed to classic inhibitors that target both AURKA and AURKB (Alisertib and ZM447439), as well as to new generation of inhibitors that target AURKA (MK-5108), AURKB (Barasertib) individually. The fate of individual cells was then tracked with time-lapse microscopy. Remarkably, loss of p53, either by gene disruption or small interfering RNA-mediated depletion, sensitized cells to inhibition of both AURKA and AURKB, promoting mitotic arrest and slippage respectively. As the p53-dependent post-mitotic checkpoint is also important for preventing genome reduplication after mitotic slippage, these studies indicate that the loss of p53 in cancer cells represents a major opportunity for anti-cancer drugs targeting the Aurora kinases.

  16. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models.

    PubMed

    Souchet, Benoit; Guedj, Fayçal; Penke-Verdier, Zsuza; Daubigney, Fabrice; Duchon, Arnaud; Herault, Yann; Bizot, Jean-Charles; Janel, Nathalie; Créau, Nicole; Delatour, Benoit; Delabar, Jean M

    2015-01-01

    Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models.

  17. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models.

    PubMed

    Souchet, Benoit; Guedj, Fayçal; Penke-Verdier, Zsuza; Daubigney, Fabrice; Duchon, Arnaud; Herault, Yann; Bizot, Jean-Charles; Janel, Nathalie; Créau, Nicole; Delatour, Benoit; Delabar, Jean M

    2015-01-01

    Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models. PMID:26539088

  18. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models

    PubMed Central

    Souchet, Benoit; Guedj, Fayçal; Penke-Verdier, Zsuza; Daubigney, Fabrice; Duchon, Arnaud; Herault, Yann; Bizot, Jean-Charles; Janel, Nathalie; Créau, Nicole; Delatour, Benoit; Delabar, Jean M.

    2015-01-01

    Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models. PMID:26539088

  19. Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors

    PubMed Central

    Cohen, Noah A.; Zeng, Shan; Seifert, Adrian M.; Kim, Teresa S.; Sorenson, Eric C.; Greer, Jonathan B.; Beckman, Michael J.; Santamaria-Barria, Juan A.; Crawley, Megan H.; Green, Benjamin L.; Rossi, Ferdinand; Besmer, Peter; Antonescu, Cristina R.; DeMatteo, Ronald P.

    2015-01-01

    Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. While GIST are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Lastly, cabozantinib, a dual MET and KIT small molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment. PMID:25836719

  20. Pharmacological Activation/Inhibition of the Cannabinoid System Affects Alcohol Withdrawal-Induced Neuronal Hypersensitivity to Excitotoxic Insults

    PubMed Central

    Rubio, Marina; Villain, Hélène; Docagne, Fabian; Roussel, Benoit D.; Ramos, José Antonio; Vivien, Denis; Fernandez-Ruiz, Javier; Ali, Carine

    2011-01-01

    Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA)-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716) during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal. PMID:21886913

  1. Pharmacologic Inhibition of ROCK2 Suppresses Amyloid-β Production in an Alzheimer's Disease Mouse Model

    PubMed Central

    Herskowitz, Jeremy H.; Feng, Yangbo; Mattheyses, Alexa L.; Hales, Chadwick M.; Higginbotham, Lenora A.; Duong, Duc M.; Montine, Thomas J.; Troncoso, Juan C.; Thambisetty, Madhav; Seyfried, Nicholas T.; Levey, Allan I.

    2013-01-01

    Alzheimer's disease (AD) is the leading cause of dementia and has no cure. Genetic, cell biological, and biochemical studies suggest that reducing amyloid-β (Aβ) production may serve as a rational therapeutic avenue to delay or prevent AD progression. Inhibition of RhoA, a Rho GTPase family member, is proposed to curb Aβ production. However, a barrier to this hypothesis has been the limited understanding of how the principal downstream effectors of RhoA, Rho-associated, coiled-coil containing protein kinase (ROCK) 1 and ROCK2, modulate Aβ generation. Here, we report that ROCK1 knockdown increased endogenous human Aβ production, whereas ROCK2 knockdown decreased Aβ levels. Inhibition of ROCK2 kinase activity, using an isoform-selective small molecule (SR3677), suppressed β-site APP cleaving enzyme 1 (BACE1) enzymatic action and diminished production of Aβ in AD mouse brain. Immunofluorescence and confocal microscopy analyses revealed that SR3677 alters BACE1 endocytic distribution and promotes amyloid precursor protein (APP) traffic to lysosomes. Moreover, SR3677 blocked ROCK2 phosphorylation of APP at threonine 654 (T654); in neurons, T654 was critical for APP processing to Aβ. These observations suggest that ROCK2 inhibition reduces Aβ levels through independent mechanisms. Finally, ROCK2 protein levels were increased in asymptomatic AD, mild cognitive impairment, and AD brains, demonstrating that ROCK2 levels change in the earliest stages of AD and remain elevated throughout disease progression. Collectively, these findings highlight ROCK2 as a mechanism-based therapeutic target to combat Aβ production in AD. PMID:24305806

  2. Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis.

    PubMed

    So, Po-Lin; Fujimoto, Michele A; Epstein, Ervin H

    2008-05-01

    Basal cell carcinoma (BCC) is the most common human cancer. Patients with basal cell nevus syndrome (Gorlin syndrome) are highly susceptible to developing many BCCs as a result of a constitutive inactivating mutation in one allele of PATCHED 1, which encodes a tumor suppressor that is a major inhibitor of Hedgehog signaling. Dysregulated Hedgehog signaling is a common feature of both hereditary and sporadic BCCs. Recently, we showed remarkable anti-BCC chemopreventive efficacy of tazarotene, a retinoid with retinoic acid receptor (RAR) beta/gamma specificity, in Ptch1+/- mice when treatment was commenced before carcinogenic insults. In this study, we assessed whether the effect of tazarotene against BCC carcinogenesis is sustained after its withdrawal and whether tazarotene is effective against preexisting microscopic BCC lesions. We found that BCCs did not reappear for at least 5 months after topical drug treatment was stopped and that already developed, microscopic BCCs were susceptible to tazarotene inhibition. In vitro, tazarotene inhibited a murine BCC keratinocyte cell line, ASZ001, suggesting that its effect in vivo is by direct action on the actual tumor cells. Down-regulation of Gli1, a target gene of Hedgehog signaling and up-regulation of CRABPII, a target gene of retinoid signaling, were observed with tazarotene treatment. Finally, we investigated the effects of topical applications of other retinoid-related compounds on BCC tumorigenesis in vivo. Tazarotene was the most effective of the preparations studied, and its effect most likely was mediated by RARgamma activation. Furthermore, inhibition of basal RAR signaling in the skin promoted BCC carcinogenesis, suggesting that endogenous RAR signaling restrains BCC growth.

  3. Enantioselective inhibition of the biotransformation and pharmacological actions of isoidide dinitrate by diphenyleneiodonium sulphate

    PubMed Central

    Ratz, Jodan D; McGuire, John J; Bennett, Brian M

    1999-01-01

    We have shown previously that the D- and L- enantiomers of isoidide dinitrate (D-IIDN and L-IIDN) exhibit a potency difference for relaxation and cyclic GMP accumulation in isolated rat aorta and that this is related to preferential biotransformation of the more potent enantiomer (D-IIDN). The objective of the current study was to examine the effect of the flavoprotein inhibitor, diphenyleneiodonium sulphate (DPI), on the enantioselectivity of IIDN action.In isolated rat aortic strip preparations, exposure to 0.3 μM DPI resulted in a 3.6 fold increase in the EC50 value for D-IIDN-induced relaxation, but had no effect on L-IIDN-induced relaxation.Incubation of aortic strips with 2 μM D- or L-IIDN for 5 min resulted in significantly more D-isoidide mononitrate formed (5.0±1.5 pmol mg  protein−1) than L-isoidide mononitrate (2.1±0.7 pmol mg protein−1) and this difference was abolished by pretreatment of tissues with 0.3 μM DPI. DPI had no effect on glutathione S-transferase (GST) activity or GSH-dependent biotransformation of D- or L-IIDN in the 105,000×g supernatant fraction of rat aorta.Consistent with both the relaxation and biotransformation data, treatment of tissues with 0.3 μM DPI significantly inhibited D-IIDN-induced cyclic GMP accumulation, but had no effect on L-IIDN-induced cyclic GMP accumulation.In the intact animal, 2 mg kg−1 DPI significantly inhibited the pharmacokinetic and haemodynamic properties of D-IIDN, but had no effect L-IIDN.These data suggest that the basis for the potency difference for relaxation by the two enantiomers is preferential biotransformation of D-IIDN to NO, by an enzyme that is inhibited by DPI. Given that DPI binds to and inhibits NADPH-cytochrome P450 reductase, the data are consistent with a role for the cytochromes P450-NADPH-cytochrome P450 reductase system in this enantioselective biotransformation process. PMID:10051121

  4. Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma.

    PubMed

    Zhang, Issan; Cui, Yiming; Amiri, Abdolali; Ding, Yidan; Campbell, Robert E; Maysinger, Dusica

    2016-03-01

    Increased lipid droplet number and fatty acid synthesis allow glioblastoma multiforme, the most common and aggressive type of brain cancer, to withstand accelerated metabolic rates and resist therapeutic treatments. Lipid droplets are postulated to sequester hydrophobic therapeutic agents, thereby reducing drug effectiveness. We hypothesized that the inhibition of lipid droplet accumulation in glioblastoma cells using pyrrolidine-2, a cytoplasmic phospholipase A2 alpha inhibitor, can sensitize cancer cells to the killing effect of curcumin, a promising anticancer agent isolated from the turmeric spice. We observed that curcumin localized in the lipid droplets of human U251N glioblastoma cells. Reduction of lipid droplet number using pyrrolidine-2 drastically enhanced the therapeutic effect of curcumin in both 2D and 3D glioblastoma cell models. The mode of cell death involved was found to be mediated by caspase-3. Comparatively, the current clinical chemotherapeutic standard, temozolomide, was significantly less effective in inducing glioblastoma cell death. Together, our results suggest that the inhibition of lipid droplet accumulation is an effective way to enhance the chemotherapeutic effect of curcumin against glioblastoma multiforme.

  5. Identification, synthesis and pharmacological evaluation of novel anti-EV71 agents via cyclophilin A inhibition.

    PubMed

    Yan, Wenzhong; Qing, Jie; Mei, Hanbing; Nong, Junxiu; Huang, Jin; Zhu, Jin; Jiang, Hualiang; Liu, Lei; Zhang, Linqi; Li, Jian

    2015-12-15

    In this work, the relationship between cyclophilin A (CypA) and EV71 prompted us to screen a series of small molecular CypA inhibitors which were previously reported by our group. Among them, compounds 1 and 2 were discovered as non-immunosuppressive anti-EV71 agents with an EC50 values of 1.07±0.17μM and 3.36±0.45μM in virus assay, respectively, which were desirably for the further study. The subsequent chemical modifications derived a novel class of molecules, among which compound 11 demonstrated the most potent anti-EV71 activity in virus assay (EC50=0.37±0.17μM), and low cytotoxicity (CC50>25μM). The following CypA enzyme inhibition studies indicated that there was not only the enzyme inhibition activity, undoubtedly important, functioning in the antiviral process, but also some unknown mechanisms worked in combination, and the further study is underway in our laboratory. Nevertheless, to the best of our knowledge, compound 11 was probably the most potent small molecular anti-EV71 agent via CypA inhibitory mechanism to date. Consequently, our study provided a new potential small molecule for curing EV71 infection.

  6. Pharmacologic efficacy of PU.1 inhibition by heterocyclic dications: a mechanistic analysis

    PubMed Central

    Stephens, Dominique C.; Kim, Hye Mi; Kumar, Arvind; Farahat, Abdelbasset A.; Boykin, David W.; K. Poon, Gregory M.

    2016-01-01

    Heterocyclic dications are receiving increasing attention as targeted inhibitors of transcription factors. While many dications act as purely competitive inhibitors, some fail to displace protein efficiently at drug concentrations expected to saturate their DNA target. To achieve a mechanistic understanding of these non-competitive effects, we used a combination of dications, which are intrinsically fluorescent and spectrally-separated fluorescently labeled DNA to dissect complex interactions in multi-component drug/DNA/protein systems. Specifically, we interrogated site-specific binding by the transcription factor PU.1 and its perturbation by DB270, a furan-bisbenzimidazole-diamidine that strongly targets PU.1 binding sites yet poorly inhibits PU.1/DNA complexes. By titrating DB270 and/or cyanine-labeled DNA with protein or unlabeled DNA, and following the changes in their fluorescence polarization, we found direct evidence that DB270 bound protein independently of their mutual affinities for sequence-specific DNA. Each of the three species competed for the other two, and this interplay of mutually dependent equilibria abrogated DB270's inhibitory activity, which was substantively restored under conditions that attenuated DB270/PU.1 binding. PU.1 binding was consistent with DB270's poor inhibitory efficacy of PU.1 in vivo, while its isosteric selenophene analog (DB1976), which did not bind PU.1 and strongly inhibited the PU.1/DNA complex in vitro, fully antagonized PU.1-dependent transactivation in vivo. PMID:27079976

  7. Pharmacologic efficacy of PU.1 inhibition by heterocyclic dications: a mechanistic analysis.

    PubMed

    Stephens, Dominique C; Kim, Hye Mi; Kumar, Arvind; Farahat, Abdelbasset A; Boykin, David W; K Poon, Gregory M

    2016-05-19

    Heterocyclic dications are receiving increasing attention as targeted inhibitors of transcription factors. While many dications act as purely competitive inhibitors, some fail to displace protein efficiently at drug concentrations expected to saturate their DNA target. To achieve a mechanistic understanding of these non-competitive effects, we used a combination of dications, which are intrinsically fluorescent and spectrally-separated fluorescently labeled DNA to dissect complex interactions in multi-component drug/DNA/protein systems. Specifically, we interrogated site-specific binding by the transcription factor PU.1 and its perturbation by DB270, a furan-bisbenzimidazole-diamidine that strongly targets PU.1 binding sites yet poorly inhibits PU.1/DNA complexes. By titrating DB270 and/or cyanine-labeled DNA with protein or unlabeled DNA, and following the changes in their fluorescence polarization, we found direct evidence that DB270 bound protein independently of their mutual affinities for sequence-specific DNA. Each of the three species competed for the other two, and this interplay of mutually dependent equilibria abrogated DB270's inhibitory activity, which was substantively restored under conditions that attenuated DB270/PU.1 binding. PU.1 binding was consistent with DB270's poor inhibitory efficacy of PU.1 in vivo, while its isosteric selenophene analog (DB1976), which did not bind PU.1 and strongly inhibited the PU.1/DNA complex in vitro, fully antagonized PU.1-dependent transactivation in vivo.

  8. Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis.

    PubMed

    Garcia, Maria L; Priest, Birgit T; Alonso-Galicia, Magdalena; Zhou, Xiaoyan; Felix, John P; Brochu, Richard M; Bailey, Timothy; Thomas-Fowlkes, Brande; Liu, Jessica; Swensen, Andrew; Pai, Lee-Yuh; Xiao, Jianying; Hernandez, Melba; Hoagland, Kimberly; Owens, Karen; Tang, Haifeng; de Jesus, Reynalda K; Roy, Sophie; Kaczorowski, Gregory J; Pasternak, Alexander

    2014-01-01

    The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.

  9. A novel pharmacological strategy by PTEN inhibition for improving metabolic resuscitation and survival after mouse cardiac arrest.

    PubMed

    Li, Jing; Wang, Huashan; Zhong, Qiang; Zhu, Xiangdong; Chen, Sy-Jou; Qian, Yuanyu; Costakis, Jim; Bunney, Gabrielle; Beiser, David G; Leff, Alan R; Lewandowski, E Douglas; ÓDonnell, J Michael; Vanden Hoek, Terry L

    2015-06-01

    Sudden cardiac arrest (SCA) is a leading cause of death in the United States. Despite return of spontaneous circulation, patients die due to post-SCA syndrome that includes myocardial dysfunction, brain injury, impaired metabolism, and inflammation. No medications improve SCA survival. Our prior work suggests that optimal Akt activation is critical for cooling protection and SCA recovery. Here, we investigate a small inhibitor of PTEN, an Akt-related phosphatase present in heart and brain, as a potential therapy in improving cardiac and neurological recovery after SCA. Anesthetized adult female wild-type C57BL/6 mice were randomized to pretreatment of VO-OHpic (VO) 30 min before SCA or vehicle control. Mice underwent 8 min of KCl-induced asystolic arrest followed by CPR. Resuscitated animals were hemodynamically monitored for 2 h and observed for 72 h. Outcomes included heart pressure-volume loops, energetics (phosphocreatine and ATP from (31)P NMR), protein phosphorylation of Akt, GSK3β, pyruvate dehydrogenase (PDH) and phospholamban, circulating inflammatory cytokines, plasma lactate, and glucose as measures of systemic metabolic recovery. VO reduced deterioration of left ventricular maximum pressure, maximum rate of change in the left ventricular pressure, and Petco2 and improved 72 h neurological intact survival (50% vs. 10%; P < 0.05). It reduced plasma lactate, glucose, IL-1β, and Pre-B cell colony enhancing factor, while increasing IL-10. VO increased phosphorylation of Akt and GSK3β in both heart and brain, and cardiac phospholamban phosphorylation while reducing p-PDH. Moreover, VO improved cardiac bioenergetic recovery. We concluded that pharmacologic PTEN inhibition enhances Akt activation, improving metabolic, cardiovascular, and neurologic recovery with increased survival after SCA. PTEN inhibitors may be a novel pharmacologic strategy for treating SCA. PMID:25795713

  10. Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis.

    PubMed

    Garcia, Maria L; Priest, Birgit T; Alonso-Galicia, Magdalena; Zhou, Xiaoyan; Felix, John P; Brochu, Richard M; Bailey, Timothy; Thomas-Fowlkes, Brande; Liu, Jessica; Swensen, Andrew; Pai, Lee-Yuh; Xiao, Jianying; Hernandez, Melba; Hoagland, Kimberly; Owens, Karen; Tang, Haifeng; de Jesus, Reynalda K; Roy, Sophie; Kaczorowski, Gregory J; Pasternak, Alexander

    2014-01-01

    The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics. PMID:24142912

  11. A novel pharmacological strategy by PTEN inhibition for improving metabolic resuscitation and survival after mouse cardiac arrest

    PubMed Central

    Li, Jing; Wang, Huashan; Zhong, Qiang; Zhu, Xiangdong; Chen, Sy-Jou; Qian, Yuanyu; Costakis, Jim; Bunney, Gabrielle; Beiser, David G.; Leff, Alan R.; Lewandowski, E. Douglas; ÓDonnell, J. Michael

    2015-01-01

    Sudden cardiac arrest (SCA) is a leading cause of death in the United States. Despite return of spontaneous circulation, patients die due to post-SCA syndrome that includes myocardial dysfunction, brain injury, impaired metabolism, and inflammation. No medications improve SCA survival. Our prior work suggests that optimal Akt activation is critical for cooling protection and SCA recovery. Here, we investigate a small inhibitor of PTEN, an Akt-related phosphatase present in heart and brain, as a potential therapy in improving cardiac and neurological recovery after SCA. Anesthetized adult female wild-type C57BL/6 mice were randomized to pretreatment of VO-OHpic (VO) 30 min before SCA or vehicle control. Mice underwent 8 min of KCl-induced asystolic arrest followed by CPR. Resuscitated animals were hemodynamically monitored for 2 h and observed for 72 h. Outcomes included heart pressure-volume loops, energetics (phosphocreatine and ATP from 31P NMR), protein phosphorylation of Akt, GSK3β, pyruvate dehydrogenase (PDH) and phospholamban, circulating inflammatory cytokines, plasma lactate, and glucose as measures of systemic metabolic recovery. VO reduced deterioration of left ventricular maximum pressure, maximum rate of change in the left ventricular pressure, and Petco2 and improved 72 h neurological intact survival (50% vs. 10%; P < 0.05). It reduced plasma lactate, glucose, IL-1β, and Pre-B cell colony enhancing factor, while increasing IL-10. VO increased phosphorylation of Akt and GSK3β in both heart and brain, and cardiac phospholamban phosphorylation while reducing p-PDH. Moreover, VO improved cardiac bioenergetic recovery. We concluded that pharmacologic PTEN inhibition enhances Akt activation, improving metabolic, cardiovascular, and neurologic recovery with increased survival after SCA. PTEN inhibitors may be a novel pharmacologic strategy for treating SCA. PMID:25795713

  12. Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration*

    PubMed Central

    Daher, João P. L.; Abdelmotilib, Hisham A.; Hu, Xianzhen; Volpicelli-Daley, Laura A.; Moehle, Mark S.; Fraser, Kyle B.; Needle, Elie; Chen, Yi; Steyn, Stefanus J.; Galatsis, Paul; Hirst, Warren D.; West, Andrew B.

    2015-01-01

    Therapeutic approaches to slow or block the progression of Parkinson disease (PD) do not exist. Genetic and biochemical studies implicate α-synuclein and leucine-rich repeat kinase 2 (LRRK2) in late-onset PD. LRRK2 kinase activity has been linked to neurodegenerative pathways. However, the therapeutic potential of LRRK2 kinase inhibitors is not clear because significant toxicities have been associated with one class of LRRK2 kinase inhibitors. Furthermore, LRRK2 kinase inhibitors have not been tested previously for efficacy in models of α-synuclein-induced neurodegeneration. To better understand the therapeutic potential of LRRK2 kinase inhibition in PD, we evaluated the tolerability and efficacy of a LRRK2 kinase inhibitor, PF-06447475, in preventing α-synuclein-induced neurodegeneration in rats. Both wild-type rats as well as transgenic G2019S-LRRK2 rats were injected intracranially with adeno-associated viral vectors expressing human α-synuclein in the substantia nigra. Rats were treated with PF-06447475 or a control compound for 4 weeks post-viral transduction. We found that rats expressing G2019S-LRRK2 have exacerbated dopaminergic neurodegeneration and inflammation in response to the overexpression of α-synuclein. Both neurodegeneration and neuroinflammation associated with G2019S-LRRK2 expression were mitigated by LRRK2 kinase inhibition. Furthermore, PF-06447475 provided neuroprotection in wild-type rats. We could not detect adverse pathological indications in the lung, kidney, or liver of rats treated with PF-06447475. These results demonstrate that pharmacological inhibition of LRRK2 is well tolerated for a 4-week period of time in rats and can counteract dopaminergic neurodegeneration caused by acute α-synuclein overexpression. PMID:26078453

  13. Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis.

    PubMed

    Atochina-Vasserman, Elena N; Abramova, Elena; James, Melane L; Rue, Ryan; Liu, Amy Y; Ersumo, Nathan Tessema; Guo, Chang-Jiang; Gow, Andrew J; Krymskaya, Vera P

    2015-12-15

    Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.

  14. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology

    PubMed Central

    Olmos-Alonso, Adrian; Schetters, Sjoerd T. T.; Sri, Sarmi; Askew, Katharine; Mancuso, Renzo; Vargas-Caballero, Mariana; Holscher, Christian; Perry, V. Hugh

    2016-01-01

    The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer’s disease. However, the study of microglial proliferation in Alzheimer’s disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer’s disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer’s-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer’s disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer’s disease. PMID:26747862

  15. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology.

    PubMed

    Olmos-Alonso, Adrian; Schetters, Sjoerd T T; Sri, Sarmi; Askew, Katharine; Mancuso, Renzo; Vargas-Caballero, Mariana; Holscher, Christian; Perry, V Hugh; Gomez-Nicola, Diego

    2016-03-01

    The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer's-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer's disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer's disease.

  16. Mealtime versus nighttime acid inhibition. A clinical pharmacological study with ranitidine.

    PubMed

    Savarino, V; Mela, G S; Zentilin, P; Vigneri, S; Cutela, P; Mele, R; Di Mario, F

    1992-09-01

    This study was carried out in order to compare the effects of mealtime and bedtime regimens of ranitidine on gastric acidity. Fifteen duodenal ulcer patients in clinical remission were randomized to receive in single-blind fashion either placebo, ranitidine 300 mg at night (2200 hr) or ranitidine 150 mg three times a day given before each of the three daily meals (1800, 0800 and 1200 hr). Over 24 hr, the two active treatments produced a significantly greater acid inhibition than placebo, while the single daily regimen was superior to the three times a day regimen of ranitidine in terms of both rise in pH values (P less than 0.001) and duration of action expressed as time spent above 3.0 pH units (P less than 0.05). The analysis of these two parameters during fractioned periods of the circadian cycle showed that the three divided doses of ranitidine were more effective during the daytime (P less than 0.01) and the evening (P less than 0.001), whereas the bedtime dose of ranitidine was superior during the night (P less than 0.0001). Thus a short-lasting antisecretory action, which is, however, capable of fully controlling the high acidity of postprandial periods, might be the key to understanding the results of several recent clinical trials in which the suppression of daytime gastric acidity has been shown to promote similar or even faster duodenal ulcer healing rates than the suppression of nocturnal acidity.

  17. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC

    PubMed Central

    Amato, Katherine R.; Wang, Shan; Hastings, Andrew K.; Youngblood, Victoria M.; Santapuram, Pranav R.; Chen, Haiying; Cates, Justin M.; Colvin, Daniel C.; Ye, Fei; Brantley-Sieders, Dana M.; Cook, Rebecca S.; Tan, Li; Gray, Nathanael S.; Chen, Jin

    2014-01-01

    Genome-wide analyses determined previously that the receptor tyrosine kinase (RTK) EPHA2 is commonly overexpressed in non–small cell lung cancers (NSCLCs). EPHA2 overexpression is associated with poor clinical outcomes; therefore, EPHA2 may represent a promising therapeutic target for patients with NSCLC. In support of this hypothesis, here we have shown that targeted disruption of EphA2 in a murine model of aggressive Kras-mutant NSCLC impairs tumor growth. Knockdown of EPHA2 in human NSCLC cell lines reduced cell growth and viability, confirming the epithelial cell autonomous requirements for EPHA2 in NSCLCs. Targeting EPHA2 in NSCLCs decreased S6K1-mediated phosphorylation of cell death agonist BAD and induced apoptosis. Induction of EPHA2 knockdown within established NSCLC tumors in a subcutaneous murine model reduced tumor volume and induced tumor cell death. Furthermore, an ATP-competitive EPHA2 RTK inhibitor, ALW-II-41-27, reduced the number of viable NSCLC cells in a time-dependent and dose-dependent manner in vitro and induced tumor regression in human NSCLC xenografts in vivo. Collectively, these data demonstrate a role for EPHA2 in the maintenance and progression of NSCLCs and provide evidence that ALW-II-41-27 effectively inhibits EPHA2-mediated tumor growth in preclinical models of NSCLC. PMID:24713656

  18. The FLT3 and PDGFR inhibitor crenolanib is a substrate of the multidrug resistance protein ABCB1 but does not inhibit transport function at pharmacologically relevant concentrations.

    PubMed

    Mathias, Trevor J; Natarajan, Karthika; Shukla, Suneet; Doshi, Kshama A; Singh, Zeba N; Ambudkar, Suresh V; Baer, Maria R

    2015-04-01

    Background Crenolanib (crenolanib besylate, 4-piperidinamine, 1-[2-[5-[(3-methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-, monobenzenesulfonate) is a potent and specific type I inhibitor of fms-like tyrosine kinase 3 (FLT3) that targets the active kinase conformation and is effective against FLT3 with internal tandem duplication (ITD) with point mutations induced by, and conferring resistance to, type II FLT3 inhibitors in acute myeloid leukemia (AML) cells. Crenolanib is also an inhibitor of platelet-derived growth factor receptor alpha and beta and is in clinical trials in both gastrointestinal stromal tumors and gliomas. Methods We tested crenolanib interactions with the multidrug resistance-associated ATP-binding cassette proteins ABCB1 (P-glycoprotein), ABCG2 (breast cancer resistance protein) and ABCC1 (multidrug resistance-associated protein 1), which are expressed on AML cells and other cancer cells and are important components of the blood-brain barrier. Results We found that crenolanib is a substrate of ABCB1, as evidenced by approximate five-fold resistance of ABCB1-overexpressing cells to crenolanib, reversal of this resistance by the ABCB1-specific inhibitor PSC-833 and stimulation of ABCB1 ATPase activity by crenolanib. In contrast, crenolanib was not a substrate of ABCG2 or ABCC1. Additionally, it did not inhibit substrate transport by ABCB1, ABCG2 or ABCC1, at pharmacologically relevant concentrations. Finally, incubation of the FLT3-ITD AML cell lines MV4-11 and MOLM-14 with crenolanib at a pharmacologically relevant concentration of 500 nM did not induce upregulation of ABCB1 cell surface expression. Conclusions Thus ABCB1 expression confers resistance to crenolanib and likely limits crenolanib penetration of the central nervous system, but crenolanib at therapeutic concentrations should not alter cellular exposure to ABC protein substrate chemotherapy drugs.

  19. Validation of the AQT Color-Form Additive Model for Screening and Monitoring Pharmacological Treatment of ADHD

    ERIC Educational Resources Information Center

    Nielsen, Niels Peter; Wiig, Elisabeth Hemmersam

    2013-01-01

    Objective:This retrospective study used A Quick Test of Cognitive Speed (AQT) processing-speed and efficiency measures for evaluating sensitivity and monitoring effects during pharmacological treatment of adults with ADHD. Method: Color (C), form (F), and color-form (CF) combination naming were administered to 69 adults during outpatient…

  20. Pharmacologic Inhibition of Nedd8 Activation Enzyme Exposes CD4-Induced Epitopes within Env on Cells Expressing HIV-1

    PubMed Central

    Tokarev, Andrey; Stoneham, Charlotte; Lewinski, Mary K.; Mukim, Amey; Deshmukh, Savitha; Vollbrecht, Thomas; Spina, Celsa A.

    2015-01-01

    ABSTRACT HIV-1 Vpu decreases the exposure of epitopes within the viral envelope glycoprotein (Env) on the surface of infected cells by downregulating both BST2 and CD4. To test the hypothesis that inhibiting Vpu activity would increase the exposure of these epitopes and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC), we treated cells with the Nedd8 activation enzyme (NAE) inhibitor MLN4924, which inhibits the cullin1-based ubiquitin ligase complex coopted by Vpu to degrade cellular targets. Treatment of HeLa cells with MLN4924 or expression of a dominant negative mutant of cullin1 inhibited the Vpu-mediated downregulation of CD4 but not the downregulation of BST2. NAE inhibition also increased the surface exposure of CD4-induced epitopes within Env on HEK293 cells containing an inducible HIV genome, on infected CEM T cells, and on infected primary T cells. In contrast, the Vpu-mediated downregulation of BST2 was substantially inhibited by MLN4924 only when T cells were treated with alpha interferon (IFN-α) to induce high levels of BST2 expression. As reported previously, the absence of vpu or nef and even more so the combined absence of these two genes sensitized infected cells to ADCC. However, NAE inhibition affected ADCC minimally. Paradoxically, even in infected, IFN-treated cells in which NAE inhibition substantially rescued the surface level of BST2, the surface level of Env detected with an antibody recognizing a CD4-independent epitope (2G12) was minimally increased. Mutation of the C-terminal Vpu residue W76, which supports the ability of Vpu to stimulate virion release by displacing BST2 from assembly sites on the plasma membrane by a cullin1-independent mechanism, increased the exposure of Env detected by 2G12 on infected T cells. Thus, inhibiting the displacement function of Vpu together with its ability to degrade CD4 and BST2 may be required to sensitize infected cells to ADCC. IMPORTANCE Pathogenic viruses encode gene

  1. Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin.

    PubMed

    Ganesh, Shanthi; Koser, Martin L; Cyr, Wendy A; Chopda, Girish R; Tao, Junyan; Shui, Xue; Ying, Bo; Chen, Dongyu; Pandya, Purva; Chipumuro, Edmond; Siddiquee, Zakir; Craig, Kevin; Lai, Chengjung; Dudek, Henryk; Monga, Satdarshan P; Wang, Weimin; Brown, Bob D; Abrams, Marc T

    2016-09-01

    The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level and therefore can be applied to previously undruggable targets. Lipid nanoparticles (LNP) represent an elegant solution for the delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens, and identify efficacious combinations with standard-of-care therapeutics. Mol Cancer Ther; 15(9); 2143-54. ©2016 AACR. PMID:27390343

  2. Pharmacologic inhibition of the NLRP3 inflammasome preserves cardiac function after ischemic and non-ischemic injury in the mouse

    PubMed Central

    Marchetti, Carlo; Toldo, Stefano; Chojnacki, Jeremy; Mezzaroma, Eleonora; Liu, Kai; Salloum, Fadi N.; Nordio, Andrea; Carbone, Salvatore; Mauro, Adolfo Gabriele; Das, Anindita; Zalavadia, Ankit A.; Halquist, Matthew S.; Federici, Massimo; Van Tassell, Benjamin W.; Zhang, Shijun; Abbate, Antonio

    2015-01-01

    Background Sterile inflammation resulting from myocardial injury activates the NLRP3 inflammasome and amplifies the inflammatory response mediating further damage. Methods We used two experimental models of ischemic injury (acute myocardial infarction [AMI] with and without reperfusion) and a model of non-ischemic injury due to doxorubicin 10 mg/Kg, to determine whether the NLRP3 inflammasome preserved cardiac function after injury. Results Treatment with the NLRP3 inflammasome inhibitor in the reperfused AMI model caused a significant reduction in infarct size measured at pathology or as serum cardiac troponin I level (−56% and −82% respectively, both p<0.001), and preserved LV fractional shortening (LVFS, 31±2 vs vehicle 26±1%, p=0.003). In the non-reperfused AMI model treatment with the NLRP3 inhibitor significantly limited LV systolic dysfunction at 7 days (LVFS of 20±2 vs 14±1%, p=0.002), without a significant effect on infarct size. In the DOX model, a significant increase in myocardial interstitial fibrosis and a decline in systolic function were seen in vehicle-treated mice, whereas treatment with the NLRP3 inhibitor significantly reduced fibrosis (−80%, p=0.001) and preserved systolic function (LVFS 35±2 vs vehicle 27±2%, p=0.017). Conclusion Pharmacological inhibition of the NLRP3 inflammasome limits cell death and LV systolic dysfunction following ischemic and non-ischemic injury in the mouse. PMID:25915511

  3. Pharmacological activity in growth inhibition and apoptosis of cultured human leiomyomal cells of tropical plant Scutellaria barbata D. Don (Lamiaceae).

    PubMed

    Lee, Tae-Kyun; Lee, Yun-Jeong; Kim, Dong-Il; Kim, Hyung-Min; Chang, Young-Chae; Kim, Cheorl-Ho

    2006-01-01

    Scutellaria barbata D. Don (Lamiaceae) (SB), which is known in traditional Korean medicine, has been used as an anti-inflammatory and antitumor agent. Since uterine leiomyoma is the most common benign smooth muscle cell tumor of the myometrium, we aimed to determine the growth inhibition and the induction of apoptotic cell death brought about by the herb SB in two different leiomyomal cells, named LM-1 and LM-2, and to clarify the mechanism of this apoptosis. Water-soluble ingredients of SB, and the leiomyomal cell lines of LM-1 and LM-2, were used in vitro. Growth inhibition, induction of cell death, morphological features, the presence of DNA ladders, increases in Caspase 3-like activity, the effects of a Caspase 3 inhibitor on apoptotic cell death, and the release of Cytochrome C by SB were analyzed. SB inhibited the growth and decreased the viability of the leiomyomal cells. The viability of normal myomatrial smooth muscle cells (SMC) in the presence of low concentrations of SB was higher than those of leiomyomal cells. Apoptotic bodies and DNA ladders were observed to be induced in leiomyomal cells of LM-1 and LM-2 by SB. The synthetic tetrapeptide Caspase 3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), inhibited the apoptotic cell death of leiomyomal cells induced by SB. The Caspase 3-like activity in leiomyomal cells LM-1 and LM-2 increased after the addition of SB. Cytochrome C was released from mitochondria into the cytosol 8h after the addition of SB, and reached a peak at 16h. The peak of Cytochrome C release was earlier than that of Caspase 3-like activity. We concluded that SB inhibited the growth of the leiomyomal cells and induced apoptosis. The apoptosis of leiomyomal cells induced by SB was associated with the release of Cytochrome C from the mitochondria, followed by an increase in Caspase 3-like activity.

  4. Large scale integration of drug-target information reveals poly-pharmacological drug action mechanisms in tumor cell line growth inhibition assays

    PubMed Central

    Knight, Richard A.; Gostev, Mikhail; Ilisavskii, Sergei; Willis, Anne E.; Melino, Gerry; Antonov, Alexey V.

    2014-01-01

    Understanding therapeutic mechanisms of drug anticancer cytotoxicity represents a key challenge in preclinical testing. Here we have performed a meta-analysis of publicly available tumor cell line growth inhibition assays (~ 70 assays from 6 independent experimental groups covering ~ 500 000 molecules) with the primary goal of understanding molecular therapeutic mechanisms of cancer cytotoxicity. To implement this we have collected currently available information on protein targets for molecules that were tested in the assays. We used a statistical methodology to identify protein targets overrepresented among molecules exhibiting cancer cytotoxicity with the particular focus of identifying overrepresented patterns consisting of several proteins (i.e. proteins “A” and “B” and “C”). Our analysis demonstrates that targeting individual proteins can result in a significant increase (up to 50-fold) of the observed odds for a molecule to be an efficient inhibitor of tumour cell line growth. However, further insight into potential molecular mechanisms reveals a multi-target mode of action: targeting a pattern of several proteins drastically increases the observed odds (up to 500-fold) for a molecule to be tumour cytotoxic. In contrast, molecules targeting only one protein but not targeting an additional set of proteins tend to be nontoxic. Our findings support a poly-pharmacology drug discovery paradigm, demonstrating that anticancer cytotoxicity is a product, in most cases, of multi-target mode of drug action PMID:24553133

  5. Genetic and pharmacologic evidence that mTOR targeting outweighs mTORC1 inhibition as an antimyeloma strategy.

    PubMed

    Chen, Xi; Díaz-Rodríguez, Elena; Ocio, Enrique M; Paiva, Bruno; Mortensen, Deborah S; Lopez-Girona, Antonia; Chopra, Rajesh; Miguel, Jesús San; Pandiella, Atanasio

    2014-02-01

    The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, proliferation, metabolism, and cell survival, and plays those roles by forming two functionally distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Deregulation of the mTOR pathway has been found in different cancers, including multiple myeloma. Agents acting on mTORC1, such as rapamycin and derivatives, are being explored as antitumoral strategies. However, whether targeting mTOR would be a more effective antimyeloma strategy than exclusively acting on the mTORC1 branch remains to be established. In this report, we explored the activation status of mTOR routes in malignant plasma cells, and analyzed the contribution of mTOR and its two signaling branches to the proliferation of myeloma cells. Gene expression profiling demonstrated deregulation of mTOR pathway-related genes in myeloma plasma cells from patients. Activation of the mTOR pathway in myelomatous plasma cells was corroborated by flow cytometric analyses. RNA interference (RNAi) experiments indicated that mTORC1 predominated over mTORC2 in the control of myeloma cell proliferation. However, mTOR knockdown had a superior antiproliferative effect than acting only on mTORC1 or mTORC2. Pharmacologic studies corroborated that the neutralization of mTOR has a stronger antimyeloma effect than the individual inhibition of mTORC1 or mTORC2. Together, our data support the clinical development of agents that widely target mTOR, instead of agents, such as rapamycin or its derivatives, that solely act on mTORC1. PMID:24431075

  6. Pharmacological inhibition of IK1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness.

    PubMed

    Skarsfeldt, Mark A; Carstensen, Helena; Skibsbye, Lasse; Tang, Chuyi; Buhl, Rikke; Bentzen, Bo H; Jespersen, Thomas

    2016-04-01

    The inwardly rectifying potassium current (IK 1) conducted through Kir2.X channels contribute to repolarization of the cardiac action potential and to stabilization of the resting membrane potential in cardiomyocytes. Our aim was to investigate the effect of the recently discovered IK 1 inhibitor PA-6 on action potential repolarization and refractoriness in isolated rat hearts. Transiently transfected HEK-293 cells expressing IK 1 were voltage-clamped with ramp protocols. Langendorff-perfused heart experiments were performed on male Sprague-Dawley rats, effective refractory period, Wenckebach cycle length, and ventricular effective refractory period were determined following 200 nmol/L PA-6 perfusion. 200 nmol/L PA-6 resulted in a significant time-latency in drug effect on the IK 1 current expressed in HEK-293 cells, giving rise to a maximal effect at 20 min. In the Langendorff-perfused heart experiments, PA-6 prolonged the ventricular action potential duration at 90% repolarization (from 41.8 ± 6.5 msec to 72.6 ± 21.1 msec, 74% compared to baseline, P < 0.01, n = 6). In parallel, PA-6 significantly prolonged the ventricular effective refractory period compared to baseline (from 34.8 ± 4.6 msec to 58.1 ± 14.7 msec, 67%, P < 0.01, n = 6). PA-6 increased the short-term beat-to-beat variability and ventricular fibrillation was observed in two of six hearts. Neither atrial ERP nor duration of atrial fibrillation was altered following PA-6 application. The results show that pharmacological inhibition of cardiac IK 1 affects ventricular action potential repolarization and refractoriness and increases the risk of ventricular arrhythmia in isolated rat hearts. PMID:27117805

  7. Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity.

    PubMed

    Kuhajda, Francis P; Aja, Susan; Tu, Yajun; Han, Wan Fang; Medghalchi, Susan M; El Meskini, Rajaa; Landree, Leslie E; Peterson, Jonathan M; Daniels, Khadija; Wong, Kody; Wydysh, Edward A; Townsend, Craig A; Ronnett, Gabriele V

    2011-07-01

    Storage of excess calories as triglycerides is central to obesity and its associated disorders. Glycerol-3-phosphate acyltransferases (GPATs) catalyze the initial step in acylglyceride syntheses, including triglyceride synthesis. We utilized a novel small-molecule GPAT inhibitor, FSG67, to investigate metabolic consequences of systemic pharmacological GPAT inhibition in lean and diet-induced obese (DIO) mice. FSG67 administered intraperitoneally decreased body weight and energy intake, without producing conditioned taste aversion. Daily FSG67 (5 mg/kg, 15.3 μmol/kg) produced gradual 12% weight loss in DIO mice beyond that due to transient 9- to 10-day hypophagia (6% weight loss in pair-fed controls). Continued FSG67 maintained the weight loss despite return to baseline energy intake. Weight was lost specifically from fat mass. Indirect calorimetry showed partial protection by FSG67 against decreased rates of oxygen consumption seen with hypophagia. Despite low respiratory exchange ratio due to a high-fat diet, FSG67-treated mice showed further decreased respiratory exchange ratio, beyond pair-fed controls, indicating enhanced fat oxidation. Chronic FSG67 increased glucose tolerance and insulin sensitivity in DIO mice. Chronic FSG67 decreased gene expression for lipogenic enzymes in white adipose tissue and liver and decreased lipid accumulation in white adipose, brown adipose, and liver tissues without signs of damage. RT-PCR showed decreased gene expression for orexigenic hypothalamic neuropeptides AgRP or NPY after acute and chronic systemic FSG67. FSG67 given intracerebroventricularly (100 and 320 nmol icv) produced 24-h weight loss and feeding suppression, indicating contributions from direct central nervous system sites of action. Together, these data point to GPAT as a new potential therapeutic target for the management of obesity and its comorbidities. PMID:21490364

  8. Pharmacological inhibition of IK1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness.

    PubMed

    Skarsfeldt, Mark A; Carstensen, Helena; Skibsbye, Lasse; Tang, Chuyi; Buhl, Rikke; Bentzen, Bo H; Jespersen, Thomas

    2016-04-01

    The inwardly rectifying potassium current (IK 1) conducted through Kir2.X channels contribute to repolarization of the cardiac action potential and to stabilization of the resting membrane potential in cardiomyocytes. Our aim was to investigate the effect of the recently discovered IK 1 inhibitor PA-6 on action potential repolarization and refractoriness in isolated rat hearts. Transiently transfected HEK-293 cells expressing IK 1 were voltage-clamped with ramp protocols. Langendorff-perfused heart experiments were performed on male Sprague-Dawley rats, effective refractory period, Wenckebach cycle length, and ventricular effective refractory period were determined following 200 nmol/L PA-6 perfusion. 200 nmol/L PA-6 resulted in a significant time-latency in drug effect on the IK 1 current expressed in HEK-293 cells, giving rise to a maximal effect at 20 min. In the Langendorff-perfused heart experiments, PA-6 prolonged the ventricular action potential duration at 90% repolarization (from 41.8 ± 6.5 msec to 72.6 ± 21.1 msec, 74% compared to baseline, P < 0.01, n = 6). In parallel, PA-6 significantly prolonged the ventricular effective refractory period compared to baseline (from 34.8 ± 4.6 msec to 58.1 ± 14.7 msec, 67%, P < 0.01, n = 6). PA-6 increased the short-term beat-to-beat variability and ventricular fibrillation was observed in two of six hearts. Neither atrial ERP nor duration of atrial fibrillation was altered following PA-6 application. The results show that pharmacological inhibition of cardiac IK 1 affects ventricular action potential repolarization and refractoriness and increases the risk of ventricular arrhythmia in isolated rat hearts.

  9. Genetic inactivation and prolonged pharmacologic inhibition of monoacylglycerol lipase have opposite effects on anesthetic sensitivity to propofol.

    PubMed

    Petrenko, Andrey B; Yamazaki, Maya; Sakimura, Kenji; Kano, Masanobu; Baba, Hiroshi

    2015-10-15

    Monoacylglycerol lipase (MGL) is a major enzyme involved in degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective inhibitors of MGL are regarded as promising analgesics and anticancer agents. To gain insight into the possible consequences of their prolonged administration for anesthetic action, the effects of several inhalational and intravenous anesthetics were tested in knockout mice lacking the MGL gene in the loss of righting reflex (LORR) assay. Sensitivity to inhalational and most intravenous anesthetics was not altered in knockout mice. However, compared with wild-type littermates, they showed increased sensitivity to the intravenous anesthetic propofol. Permanently elevated levels of 2-AG after MGL knockout are known to cause desensitization of cannabinoid (CB1) receptors, which have been advocated as possible mediators of propofol anesthesia. Therefore, increased sensitivity to propofol in knockout mice at first suggested that 2-AG may potentiate CB1 receptors despite their hypofunction in these animals. Pharmacologic inhibition of MGL also causes desensitization of CB1 receptors, so sensitivity to propofol was tested further in C57BL/6N mice pretreated chronically with the selective MGL inhibitor JZL 184. Contrary to the results in knockout mice, these animals showed drastically reduced sensitivity to propofol. The reason for increased sensitivity to propofol after MGL knockout remains unclear, but may result from changes occurring in these animals during development. However, our results in C57BL/6N mice pretreated with JZL 184 confirmed the role of CB1 receptors in propofol anesthesia advocated previously, and also suggest that prolonged use of MGL inhibitors may be associated with the development of resistance to propofol.

  10. Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling

    PubMed Central

    Baer, Alexandra S.; Syed, Yasir A.; Kang, Sung Ung; Mitteregger, Dieter; Vig, Raluca; ffrench-Constant, Charles; Franklin, Robin J. M.; Altmann, Friedrich; Lubec, Gert

    2009-01-01

    Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by demyelination inhibits remyelination by inhibiting OPC differentiation and that the inhibitory effects are associated with myelin proteins. In the present study, we narrow down the spectrum of potential protein candidates by proteomic analysis of inhibitory protein fractions prepared by CM and HighQ column chromatography followed by BN/SDS/SDS–PAGE gel separation using Nano-HPLC-ESI-Q-TOF mass spectrometry. We show that the inhibitory effects on OPC differentiation mediated by myelin are regulated by Fyn-RhoA-ROCK signalling as well as by modulation of protein kinase C (PKC) signalling. We demonstrate that pharmacological or siRNA-mediated inhibition of RhoA-ROCK-II and/or PKC signalling can induce OPC differentiation in the presence of myelin. Our results, which provide a mechanistic link between myelin, a mediator of OPC differentiation inhibition associated with demyelinating pathologies and specific signalling pathways amenable to pharmacological manipulation, are therefore of significant potential value for future strategies aimed at enhancing CNS remyelination. PMID:19208690

  11. Inhibition by antimicrobial food additives of ochratoxin A production by Aspergillus sulphureus and Penicillium viridicatum.

    PubMed Central

    Tong, C H; Draughon, F A

    1985-01-01

    The effects of antimicrobial food additives on growth and ochratoxin A production by Aspergillus sulphureus NRRL 4077 and Penicillium viridicatum NRRL 3711 were investigated. At pH 4.5, growth and toxin production by both A. sulphureus and P. viridicatum were completely inhibited by 0.02% potassium sorbate, 0.067% methyl paraben, 0.0667% methyl paraben, and 0.2% sodium propionate. At pH 5.5, 0.134% potassium sorbate and 0.067% methyl paraben completely inhibited growth and ochratoxin A production by both fungi. Sodium bisulfite at 0.1%, the maximum level tested, was found to inhibit growth of A. sulphureus and P. viridicatum by 45 and 89%, respectively. Toxin production was inhibited by 97 and 99%, respectively. Sodium propionate (0.64%) at pH 5.5 inhibited growth of A. sulphureus and P. viridicatum by 76 and 90%, respectively. Toxin production was inhibited by greater than 99% for each fungus. Antimicrobial agents were ranked as to effectiveness by comparing the level required for complete inhibition of ochratoxin A production to the highest antimicrobial agent level normally used in food. At pH 4.5, the most effective inhibitor of growth and toxin production was potassium sorbate, followed by sodium propionate, methyl paraben, and sodium bisulfite, respectively, for both fungi. However, at pH 5.5, the most effective antimicrobial agents for inhibiting ochratoxin production were methyl paraben and potassium sorbate, followed by sodium propionate. Sodium bisulfite was not highly inhibitory to these toxigenic fungi at the higher pH value tested. PMID:4015085

  12. Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization

    PubMed Central

    Romero, L; Zamanillo, D; Nadal, X; Sánchez-Arroyos, R; Rivera-Arconada, I; Dordal, A; Montero, A; Muro, A; Bura, A; Segalés, C; Laloya, M; Hernández, E; Portillo-Salido, E; Escriche, M; Codony, X; Encina, G; Burgueño, J; Merlos, M; Baeyens, JM; Giraldo, J; López-García, JA; Maldonado, R; Plata-Salamán, CR; Vela, JM

    2012-01-01

    BACKGROUND AND PURPOSE The sigma-1 (σ1) receptor is a ligand-regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of σ1 receptor ligands used as pharmacological tools are unclear and the demonstration that σ1 receptor antagonists have efficacy in reversing central sensitization-related pain sensitivity is still missing. EXPERIMENTAL APPROACH The pharmacological properties of a novel σ1 receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of σ1 receptors on in vivo nociception in sensitizing conditions and on in vitro spinal cord sensitization in mice. Drug levels and autoradiographic, ex vivo binding for σ1 receptor occupancy were measured to substantiate behavioural data. KEY RESULTS Formalin-induced nociception (both phases), capsaicin-induced mechanical hypersensitivity and sciatic nerve injury-induced mechanical and thermal hypersensitivity were dose-dependently inhibited by systemic administration of S1RA. Occupancy of σ1 receptors in the CNS was significantly correlated with the antinociceptive effects. No pharmacodynamic tolerance to the antiallodynic and antihyperalgesic effect developed following repeated administration of S1RA to nerve-injured mice. As a mechanistic correlate, electrophysiological recordings demonstrated that pharmacological antagonism of σ1 receptors attenuated the wind-up responses in spinal cords sensitized by repetitive nociceptive stimulation. CONCLUSIONS AND IMPLICATIONS These findings contribute to evidence identifying the σ1 receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ1 receptor antagonists as potential novel treatments for neuropathic pain. PMID:22404321

  13. Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance.

    PubMed

    Nawrocki, Andrea R; Rodriguez, Carlos G; Toolan, Dawn M; Price, Olga; Henry, Melanie; Forrest, Gail; Szeto, Daphne; Keohane, Carol Ann; Pan, Yie; Smith, Karen M; Raheem, Izzat T; Cox, Christopher D; Hwa, Joyce; Renger, John J; Smith, Sean M

    2014-01-01

    Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes. PMID:24101672

  14. Pharmacological inhibitions of glutamate transporters EAAT1 and EAAT2 compromise glutamate transport in photoreceptor to ON- bipolar cell synapses

    PubMed Central

    Tse, Dennis Y.; Chung, Inyoung; Wu, Samuel M.

    2015-01-01

    To maintain reliable signal transmission across a synapse, free synaptic neurotransmitters must be removed from the cleft in a timely manner. In the first visual synapse, this critical task is mainly undertaken by glutamate transporters (EAATs). Here we study the differential roles of the EAAT1, EAAT2 and EAAT5 subtypes in glutamate (GLU) uptake at the photoreceptor-to-depolarizing bipolar cell synapse in intact dark-adapted retina. Various doses of EAAT blockers and/or GLU were injected into the eye before the electroretinogram (ERG) was measured. Their effectiveness and potency in inhibiting the ERG b-wave were studied to determine their relative contributions to the GLU clearing activity at the synapse. The results showed that EAAT1 and EAAT2 plays different roles. Selectively blocking glial EAAT1 alone using UCPH101 inhibited the b-wave 2–24 hours following injection, suggesting a dominating role of EAAT1 in the overall GLU clearing capacity in the synaptic cleft. Selectively blocking EAAT2 on photoreceptor terminals had no significant effect on the b-wave, but increased the potency of exogenous GLU in inhibiting the b-wave. These suggest that EAAT2 play a secondary yet significant role in the GLU reuptake activity at the rod and the cone output synapses. Additionally, we have verified our electrophysiological findings with double-label immunohistochemistry, and extend the literature on the spatial distribution of EAAT2 splice variants in the mouse retina. PMID:25152321

  15. Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance.

    PubMed

    Nawrocki, Andrea R; Rodriguez, Carlos G; Toolan, Dawn M; Price, Olga; Henry, Melanie; Forrest, Gail; Szeto, Daphne; Keohane, Carol Ann; Pan, Yie; Smith, Karen M; Raheem, Izzat T; Cox, Christopher D; Hwa, Joyce; Renger, John J; Smith, Sean M

    2014-01-01

    Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.

  16. Addition of lysophospholipids with large head groups to cells inhibits Shiga toxin binding.

    PubMed

    Ailte, Ieva; Lingelem, Anne Berit Dyve; Kavaliauskiene, Simona; Bergan, Jonas; Kvalvaag, Audun Sverre; Myrann, Anne-Grethe; Skotland, Tore; Sandvig, Kirsten

    2016-01-01

    Shiga toxin (Stx), an AB5 toxin, binds specifically to the neutral glycosphingolipid Gb3 at the cell surface before being transported into cells. We here demonstrate that addition of conical lysophospholipids (LPLs) with large head groups inhibit Stx binding to cells whereas LPLs with small head groups do not. Lysophosphatidylinositol (LPI 18:0), the most efficient LPL with the largest head group, was selected for in-depth investigations to study how the binding of Stx is regulated. We show that the inhibition of Stx binding by LPI is reversible and possibly regulated by cholesterol since addition of methyl-β-cyclodextrin (mβCD) reversed the ability of LPI to inhibit binding. LPI-induced inhibition of Stx binding is independent of signalling and membrane turnover as it occurs in fixed cells as well as after depletion of cellular ATP. Furthermore, data obtained with fluorescent membrane dyes suggest that LPI treatment has a direct effect on plasma membrane lipid packing with shift towards a liquid disordered phase in the outer leaflet, while lysophosphoethanolamine (LPE), which has a small head group, does not. In conclusion, our data show that cellular treatment with conical LPLs with large head groups changes intrinsic properties of the plasma membrane and modulates Stx binding to Gb3. PMID:27458147

  17. Addition of lysophospholipids with large head groups to cells inhibits Shiga toxin binding

    PubMed Central

    Ailte, Ieva; Lingelem, Anne Berit Dyve; Kavaliauskiene, Simona; Bergan, Jonas; Kvalvaag, Audun Sverre; Myrann, Anne-Grethe; Skotland, Tore; Sandvig, Kirsten

    2016-01-01

    Shiga toxin (Stx), an AB5 toxin, binds specifically to the neutral glycosphingolipid Gb3 at the cell surface before being transported into cells. We here demonstrate that addition of conical lysophospholipids (LPLs) with large head groups inhibit Stx binding to cells whereas LPLs with small head groups do not. Lysophosphatidylinositol (LPI 18:0), the most efficient LPL with the largest head group, was selected for in-depth investigations to study how the binding of Stx is regulated. We show that the inhibition of Stx binding by LPI is reversible and possibly regulated by cholesterol since addition of methyl-β-cyclodextrin (mβCD) reversed the ability of LPI to inhibit binding. LPI-induced inhibition of Stx binding is independent of signalling and membrane turnover as it occurs in fixed cells as well as after depletion of cellular ATP. Furthermore, data obtained with fluorescent membrane dyes suggest that LPI treatment has a direct effect on plasma membrane lipid packing with shift towards a liquid disordered phase in the outer leaflet, while lysophosphoethanolamine (LPE), which has a small head group, does not. In conclusion, our data show that cellular treatment with conical LPLs with large head groups changes intrinsic properties of the plasma membrane and modulates Stx binding to Gb3. PMID:27458147

  18. Pharmacologic inhibition of the renin-angiotensin system did not attenuate hepatic toxicity induced by carbon tetrachloride in rats.

    PubMed

    Ekor, Martins; Odewabi, Adesina O; Kale, Oluwafemi E; Oritogun, Kolawole S; Adesanoye, Omolola A; Bamidele, Titilayo O

    2011-11-01

    The renin-angiotensin system (RAS) subserves vital physiological functions and also implicated in certain pathological states. Modulation of this system has been proposed in recent studies to be a promising strategy in treating liver fibrosis. We investigated the effect of the pharmacologic inhibition of RAS with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in CCl(4)-induced liver injury with a view to ascertaining the chemopreventive benefit. Fifty-six Wistar albino rats were divided into eight experimental groups of seven rats/group. Groups 1-4 received normal saline (10 ml/kg), enalapril (0.6 mg/kg), losartan (1.4 mg/kg) and CCl(4) (80 mg/kg), respectively. Groups 5-8 were pretreated with enalapril (0.3 mg/kg), enalapril (0.6 mg/kg), losartan (0.7 mg/kg) and losartan (1.4 mg/kg) 1 hour before CCl(4) administration. Experiment lasted 11 days and dosing was via oral route. Rats were killed 24 hours after the last treatment. Serum activities of alkaline phosphatase, aspartate and alanine aminotransferases increased significantly (p < 0.05) by 46.0%, 90.6% and 122.3%, respectively, with severe hepatic centrilobular necrosis, fatty infiltration and increase in liver weight (p < 0.05) in the CCl(4)-treated rats. Enalapril (0.6 mg/kg) and losartan (1.4 mg/kg) significantly (p < 0.05) increased aspartate aminotransferase activity by 37.0% and 94.7% and produced mild centrilobular and periportal hepatic necrosis, respectively, with enalapril significantly (p < 0.05) increasing liver weight. Serum total cholesterol, triglyceride, albumin and total protein did not change significantly in these rats. Also, glutathione, malondialdehyde and uric acid levels were not significantly altered. Enalapril and losartan failed to attenuate liver injury associated with CCl(4) treatment. Although both drugs did not significantly alter serum biochemistry in the CCl(4)-treated rats, they however produced slight elevations in biomarkers of liver function and

  19. Capillary electrophoretic behaviors of pharmacologically active xanthones from Securidaca inappendiculata with beta-cyclodextrin as a buffer additive.

    PubMed

    Bo, Tao; Huang, Yongfa; Yang, Xuedong; Li, Ke An; Liu, Huwei; Xu, Lizhen

    2003-04-01

    The capillary electrophoretic (CE) behaviors of ten xanthones in the presence of beta-cyclodextrin (CD) are investigated, and apparent analyte-selector binding constants between beta-CD and the xanthones in the CE running buffer are calculated to elucidate the migration order. Also, the separation selectivity with beta-CD additive is compared with that of sulfated beta-CD additive. It is indicated that beta-CD can greatly change the separation selectivity of xanthones, and the electrophoretic behaviors of xanthones are rather different when using beta-CD from that when using sulfated beta-CD as an additive. PMID:12803804

  20. NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta.

    PubMed

    Greten, Florian R; Arkan, Melek C; Bollrath, Julia; Hsu, Li-Chung; Goode, Jason; Miething, Cornelius; Göktuna, Serkan I; Neuenhahn, Michael; Fierer, Joshua; Paxian, Stephan; Van Rooijen, Nico; Xu, Yajun; O'Cain, Timothy; Jaffee, Bruce B; Busch, Dirk H; Duyster, Justus; Schmid, Roland M; Eckmann, Lars; Karin, Michael

    2007-09-01

    IKKbeta-dependent NF-kappaB activation plays a key role in innate immunity and inflammation, and inhibition of IKKbeta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKbeta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1beta as a result of increased pro-IL-1beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1beta processing depends on caspase-1, whose activation is inhibited by NF-kappaB-dependent gene products. In neutrophils, however, IL-1beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappaB gene products. Prolonged pharmacologic inhibition of IKKbeta also augments IL-1beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKbeta-dependent NF-kappaB signaling in the negative control of IL-1beta production and highlight potential complications of long-term IKKbeta inhibition.

  1. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  2. Sodium orthovanadate associated with pharmacological doses of ascorbate causes an increased generation of ROS in tumor cells that inhibits proliferation and triggers apoptosis.

    PubMed

    Günther, Tânia Mara Fischer; Kviecinski, Maicon Roberto; Baron, Carla Cristine; Felipe, Karina Bettega; Farias, Mirelle Sifroni; da Silva, Fabiana Ourique; Bücker, Nádia Cristina Falcão; Pich, Claus Tröger; Ferreira, Eduardo Antonio; Wilhelm Filho, Danilo; Verrax, Julien; Calderon, Pedro Buc; Pedrosa, Rozangela Curi

    2013-01-18

    Pharmacological doses of ascorbate were evaluated for its ability to potentiate the toxicity of sodium orthovanadate (Na(3)VO(4)) in tumor cells. Cytotoxicity, inhibition of cell proliferation, generation of ROS and DNA fragmentation were assessed in T24 cells. Na(3)VO(4) was cytotoxic against T24 cells (EC(50)=5.8 μM at 24 h), but in the presence of ascorbate (100 μM) the EC(50) fell to 3.3 μM. Na(3)VO(4) plus ascorbate caused a strong inhibition of cell proliferation (up to 20%) and increased the generation of ROS (4-fold). Na(3)VO(4) did not directly cleave plasmid DNA, at this aspect no synergism was found occurring between Na(3)VO(4) and ascorbate once the resulting action of the combination was no greater than that of both substances administered separately. Cells from Ehrlich ascites carcinoma-bearing mice were used to determine the activity of antioxidant enzymes, the extent of the oxidative damage and the type of cell death. Na(3)VO(4) alone, or combined with ascorbate, increased catalase activity, but only Na(3)VO(4) plus ascorbate increased superoxide dismutase activity (up to 4-fold). Oxidative damage on proteins and lipids was higher due to the treatment done with Na(3)VO(4) plus ascorbate (2-3-fold). Ascorbate potentiated apoptosis in tumor cells from mice treated with Na(3)VO(4). The results indicate that pharmacological doses of ascorbate enhance the generation of ROS induced by Na(3)VO(4) in tumor cells causing inhibition of proliferation and apoptosis. Apoptosis induced by orthovanadate and ascorbate is closer related to inhibition on Bcl-xL and activation of Bax. Our data apparently rule out a mechanism of cell demise p53-dependent or related to Cdk2 impairment. PMID:23261463

  3. Pharmacological Inhibition of Gal-3 in Mesenchymal Stem Cells Enhances Their Capacity to Promote Alternative Activation of Macrophages in Dextran Sulphate Sodium-Induced Colitis

    PubMed Central

    Simovic Markovic, Bojana; Nikolic, Aleksandar; Gazdic, Marina; Nurkovic, Jasmin; Djordjevic, Irena; Arsenijevic, Nebojsa; Stojkovic, Miodrag; Lukic, Miodrag L.; Volarevic, Vladislav

    2016-01-01

    Transplantation of mesenchymal stem cells (MSCs) reduces the severity of dextran sulphate sodium- (DSS-) induced colitis. MSCs are able to secrete Galectin-3 (Gal-3), a protein known to affect proliferation, adhesion, and migration of immune cells. We investigate whether newly synthetized inhibitor of Gal-3 (Davanat) will affect production of Gal-3 in MSCs and enhance their potential to attenuate DSS-induced colitis. Pharmacological inhibition of Gal-3 in MSCs enhances their capacity to promote alternative activation of peritoneal macrophages in vitro and in vivo. Injection of MSCs cultured in the presence of Davanat increased concentration of IL-10 in sera of DSS-treated animals and markedly enhanced presence of alternatively activated and IL-10 producing macrophages in the colons of DSS-treated mice. Pharmacological inhibition of Gal-3 in MSCs significantly attenuates concentration of Gal-3 in sera of DSS-treated animals, indicating that MSCs produce Gal-3 in this disease. In conclusion, our findings indicate that Davanat could be used for improvement of MSC-mediated polarization towards immunosuppressive M2 phenotype of macrophages. PMID:27057168

  4. Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics

    SciTech Connect

    Meeuwen, J.A. van Son, O. van; Piersma, A.H.; Jong, P.C. de; Berg, M. van den

    2008-08-01

    There is concern widely on the increase in human exposure to exogenous (anti)estrogenic compounds. Typical are certain ingredients in cosmetic consumer products such as musks, phthalates and parabens. Monitoring a variety of human samples revealed that these ingredients, including the ones that generally are considered to undergo rapid metabolism, are present at low levels. In this in vitro research individual compounds and combinations of parabens and endogenous estradiol (E{sub 2}) were investigated in the MCF-7 cell proliferation assay. The experimental design applied a concentration addition model (CA). Data were analyzed with the estrogen equivalency (EEQ) and method of isoboles approach. In addition, the catalytic inhibitory properties of parabens on an enzyme involved in a rate limiting step in steroid genesis (aromatase) were studied in human placental microsomes. Our results point to an additive estrogenic effect in a CA model for parabens. In addition, it was found that parabens inhibit aromatase. Noticeably, the effective levels in both our in vitro systems were far higher than the levels detected in human samples. However, estrogenic compounds may contribute in a cumulative way to the circulating estrogen burden. Our calculation for the extra estrogen burden due to exposure to parabens, phthalates and polycyclic musks indicates an insignificant estrogenic load relative to the endogenous or therapeutic estrogen burden.

  5. Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics.

    PubMed

    van Meeuwen, J A; van Son, O; Piersma, A H; de Jong, P C; van den Berg, M

    2008-08-01

    There is concern widely on the increase in human exposure to exogenous (anti)estrogenic compounds. Typical are certain ingredients in cosmetic consumer products such as musks, phthalates and parabens. Monitoring a variety of human samples revealed that these ingredients, including the ones that generally are considered to undergo rapid metabolism, are present at low levels. In this in vitro research individual compounds and combinations of parabens and endogenous estradiol (E(2)) were investigated in the MCF-7 cell proliferation assay. The experimental design applied a concentration addition model (CA). Data were analyzed with the estrogen equivalency (EEQ) and method of isoboles approach. In addition, the catalytic inhibitory properties of parabens on an enzyme involved in a rate limiting step in steroid genesis (aromatase) were studied in human placental microsomes. Our results point to an additive estrogenic effect in a CA model for parabens. In addition, it was found that parabens inhibit aromatase. Noticeably, the effective levels in both our in vitro systems were far higher than the levels detected in human samples. However, estrogenic compounds may contribute in a cumulative way to the circulating estrogen burden. Our calculation for the extra estrogen burden due to exposure to parabens, phthalates and polycyclic musks indicates an insignificant estrogenic load relative to the endogenous or therapeutic estrogen burden.

  6. Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

    PubMed Central

    Kiyatkin, Michael E.; Feng, Bin; Schwartz, Erica S.

    2013-01-01

    The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity. PMID:23989007

  7. Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization.

    PubMed

    Kiyatkin, Michael E; Feng, Bin; Schwartz, Erica S; Gebhart, G F

    2013-11-01

    The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity.

  8. Switch of SpnR function from activating to inhibiting quorum sensing by its exogenous addition.

    PubMed

    Takayama, Yuriko; Kato, Norihiro

    2016-09-01

    The opportunistic human pathogen Serratia marcescens AS-1 produces the N-hexanoylhomoserine lactone (C6HSL) receptor SpnR, a homologue of LuxR from Vibrio fischeri, which activates pig clusters to produce the antibacterial prodigiosin. In this study, we attempted to artificially regulate quorum sensing (QS) by changing the role of SpnR in N-acylhomoserine lactone (AHL)-mediated QS. SpnR was obtained as a fusion protein tagged with maltose-binding protein (MBP) from overexpression in Escherichia coli, and its specific affinity to C6HSL was demonstrated by quartz crystal microbalance analysis and AHL-bioassay with Chromobacterium violaceum CV026. Prodigiosin production was effectively inhibited by externally added MBP-SpnR in both wild-type AS-1 and the AHL synthase-defective mutant AS-1(ΔspnI). For the mutant, the induced amount of prodigiosin was drastically reduced to approximately 4% with the addition of 18 μM MBP-SpnR to the liquid medium, indicating 81% trapping of C6HSL. A system for inhibiting QS can be constructed by adding exogenous AHL receptor to the culture broth to keep the concentration of free AHL low, whereas intracellular SpnR naturally functions as the activator in response to QS. PMID:27387237

  9. Switch of SpnR function from activating to inhibiting quorum sensing by its exogenous addition.

    PubMed

    Takayama, Yuriko; Kato, Norihiro

    2016-09-01

    The opportunistic human pathogen Serratia marcescens AS-1 produces the N-hexanoylhomoserine lactone (C6HSL) receptor SpnR, a homologue of LuxR from Vibrio fischeri, which activates pig clusters to produce the antibacterial prodigiosin. In this study, we attempted to artificially regulate quorum sensing (QS) by changing the role of SpnR in N-acylhomoserine lactone (AHL)-mediated QS. SpnR was obtained as a fusion protein tagged with maltose-binding protein (MBP) from overexpression in Escherichia coli, and its specific affinity to C6HSL was demonstrated by quartz crystal microbalance analysis and AHL-bioassay with Chromobacterium violaceum CV026. Prodigiosin production was effectively inhibited by externally added MBP-SpnR in both wild-type AS-1 and the AHL synthase-defective mutant AS-1(ΔspnI). For the mutant, the induced amount of prodigiosin was drastically reduced to approximately 4% with the addition of 18 μM MBP-SpnR to the liquid medium, indicating 81% trapping of C6HSL. A system for inhibiting QS can be constructed by adding exogenous AHL receptor to the culture broth to keep the concentration of free AHL low, whereas intracellular SpnR naturally functions as the activator in response to QS.

  10. (S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology.

    PubMed

    Moutal, Aubin; Chew, Lindsey A; Yang, Xiaofang; Wang, Yue; Yeon, Seul Ki; Telemi, Edwin; Meroueh, Seeneen; Park, Ki Duk; Shrinivasan, Raghuraman; Gilbraith, Kerry B; Qu, Chaoling; Xie, Jennifer Y; Patwardhan, Amol; Vanderah, Todd W; Khanna, May; Porreca, Frank; Khanna, Rajesh

    2016-07-01

    Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2-CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration-approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations. PMID:26967696

  11. (S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology.

    PubMed

    Moutal, Aubin; Chew, Lindsey A; Yang, Xiaofang; Wang, Yue; Yeon, Seul Ki; Telemi, Edwin; Meroueh, Seeneen; Park, Ki Duk; Shrinivasan, Raghuraman; Gilbraith, Kerry B; Qu, Chaoling; Xie, Jennifer Y; Patwardhan, Amol; Vanderah, Todd W; Khanna, May; Porreca, Frank; Khanna, Rajesh

    2016-07-01

    Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2-CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration-approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.

  12. Effects of lipids on thermophilic anaerobic digestion and reduction of lipid inhibition upon addition of bentonite.

    PubMed

    Angelidaki, I; Petersen, S P; Ahring, B K

    1990-07-01

    The effect of bentonite-bound oil on thermophilic anaerobic digestion of cattle manure was investigated. In digestor experiments, addition of oil was found to be inhibitory during start-up and the inhibitory effect was less pronounced when the oil was added in the form of bentonite-bound oil compared to when the oil was added alone. After adaptation of the digestors, very rapid degradation of oil was observed and more than 80% of the oil was degraded within a few hours after daily feeding. In batch experiments, glyceride trioleate was found to be inhibitory to thermophilic anaerobic digestion when the concentrations were higher than 2.0 g/l. However, addition of bentonite (a clay mineral) at concentrations of 0.15% and 0.45% was found to partly overcome this inhibition. Addition of calcium chloride in concentration of 3 mM (0.033% w/v) showed a similar positive effect on the utilization of oil, but the effect was lower than with bentonite. PMID:1366749

  13. The genetic ablation or pharmacological inhibition of TRPV1 signalling is beneficial for the restoration of quiescent osteoclast activity in ovariectomized mice

    PubMed Central

    Rossi, F; Bellini, G; Torella, M; Tortora, C; Manzo, I; Giordano, C; Guida, F; Luongo, L; Papale, F; Rosso, F; Nobili, B; Maione, S

    2014-01-01

    Background and Purpose Osteoporosis is a condition characterized by a decrease in bone density, which decreases its strength and results in fragile bones. The endocannabinoid/endovanilloid system has been shown to be involved in the regulation of skeletal remodelling. The aim of this study was to investigate the possible modulation of bone mass mediated by the transient receptor potential vanilloid type 1 channel (TRPV1) in vivo and in vitro. Experimental Approach A multidisciplinary approach, including biomolecular, biochemical and morphological analysis, was used to investigate the involvement of TRPV1 in changes in bone density in vivo and osteoclast activity in vitro, in wild-type and Trpv1−/− mice, that had undergone ovariectomy or had a sham operation. Key Results Genetic deletion of Trpv1 as well as pharmacological inhibition/desensitization of TRPV1 signalling dramatically reduced the osteoclast activity in vitro and prevented the ovariectomy-induced bone loss in vivo, whereas the expression of cannabinoid type 2 (CB2) receptors was increased. Conclusions and Implications These findings highlight the pivotal role TRPV1 channels play in bone resorption and suggest a possible cross-talk between TRPV1 and CB2 receptors. Based on these results, hybrid compounds acting on both TRPV1 and CB2 receptors in an opposite manner could provide a future pharmacological tool for the treatment of diseases associated with disturbances in the bone remodelling process. Linked Articles This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10 PMID:24308803

  14. Inhibition of peroxynitrite-mediated DNA strand cleavage and hydroxyl radical formation by aspirin at pharmacologically relevant concentrations: Implications for cancer intervention

    SciTech Connect

    Chen, Wei; Zhu, Hong; Jia, Zhenquan; Li, Jianrong; Misra, Hara P.; Zhou, Kequan; Li, Yunbo

    2009-12-04

    Epidemiological studies have suggested that the long-term use of aspirin is associated with a decreased incidence of human malignancies, especially colorectal cancer. Since accumulating evidence indicates that peroxynitrite is critically involved in multistage carcinogenesis, this study was undertaken to investigate the ability of aspirin to inhibit peroxynitrite-mediated DNA damage. Peroxynitrite and its generator 3-morpholinosydnonimine (SIN-1) were used to cause DNA strand breaks in {phi}X-174 plasmid DNA. We demonstrated that the presence of aspirin at concentrations (0.25-2 mM) compatible with amounts in plasma during chronic anti-inflammatory therapy resulted in a significant inhibition of DNA cleavage induced by both peroxynitrite and SIN-1. Moreover, the consumption of oxygen caused by 250 {mu}M SIN-1 was found to be decreased in the presence of aspirin, indicating that aspirin might affect the auto-oxidation of SIN-1. Furthermore, EPR spectroscopy using 5,5-dimethylpyrroline-N-oxide (DMPO) as a spin trap demonstrated the formation of DMPO-hydroxyl radical adduct (DMPO-OH) from authentic peroxynitrite, and that aspirin at 0.25-2 mM potently diminished the radical adduct formation in a concentration-dependent manner. Taken together, these results demonstrate for the first time that aspirin at pharmacologically relevant concentrations can inhibit peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation. These results may have implications for cancer intervention by aspirin.

  15. Pharmacological Inhibition of Monoacylglycerol O-Acyltransferase 2 Improves Hyperlipidemia, Obesity, and Diabetes by Change in Intestinal Fat Utilization.

    PubMed

    Take, Kazumi; Mochida, Taisuke; Maki, Toshiyuki; Satomi, Yoshinori; Hirayama, Megumi; Nakakariya, Masanori; Amano, Nobuyuki; Adachi, Ryutaro; Sato, Kenjiro; Kitazaki, Tomoyuki; Takekawa, Shiro

    2016-01-01

    Monoacylglycerol O-acyltransferase 2 (MGAT2) catalyzes the synthesis of diacylglycerol (DG), a triacylglycerol precursor and potential peripheral target for novel anti-obesity therapeutics. High-throughput screening identified lead compounds with MGAT2 inhibitory activity. Through structural modification, a potent, selective, and orally bioavailable MGAT2 inhibitor, compound A (compA), was discovered. CompA dose-dependently inhibited postprandial increases in plasma triglyceride (TG) levels. Metabolic flux analysis revealed that compA inhibited triglyceride/diacylglycerol resynthesis in the small intestine and increased free fatty acid and acyl-carnitine with shorter acyl chains than originally labelled fatty acid. CompA decreased high-fat diet (HFD) intake in C57BL/6J mice. MGAT2-null mice showed a similar phenotype as compA-treated mice and compA did not suppress a food intake in MGAT2 KO mice, indicating that the anorectic effects were dependent on MGAT2 inhibition. Chronic administration of compA significantly prevented body weight gain and fat accumulation in mice fed HFD. MGAT2 inhibition by CompA under severe diabetes ameliorated hyperglycemia and fatty liver in HFD-streptozotocin (STZ)-treated mice. Homeostatic model assessments (HOMA-IR) revealed that compA treatment significantly improved insulin sensitivity. The proximal half of the small intestine displayed weight gain following compA treatment. A similar phenomenon has been observed in Roux-en-Y gastric bypass-treated animals and some studies have reported that this intestinal remodeling is essential to the anti-diabetic effects of bariatric surgery. These results clearly demonstrated that MGAT2 inhibition improved dyslipidemia, obesity, and diabetes, suggesting that compA is an effective therapeutic for obesity-related metabolic disorders. PMID:26938273

  16. Pharmacological Inhibition of Monoacylglycerol O-Acyltransferase 2 Improves Hyperlipidemia, Obesity, and Diabetes by Change in Intestinal Fat Utilization

    PubMed Central

    Take, Kazumi; Mochida, Taisuke; Maki, Toshiyuki; Satomi, Yoshinori; Hirayama, Megumi; Nakakariya, Masanori; Amano, Nobuyuki; Adachi, Ryutaro; Sato, Kenjiro; Kitazaki, Tomoyuki; Takekawa, Shiro

    2016-01-01

    Monoacylglycerol O-acyltransferase 2 (MGAT2) catalyzes the synthesis of diacylglycerol (DG), a triacylglycerol precursor and potential peripheral target for novel anti-obesity therapeutics. High-throughput screening identified lead compounds with MGAT2 inhibitory activity. Through structural modification, a potent, selective, and orally bioavailable MGAT2 inhibitor, compound A (compA), was discovered. CompA dose-dependently inhibited postprandial increases in plasma triglyceride (TG) levels. Metabolic flux analysis revealed that compA inhibited triglyceride/diacylglycerol resynthesis in the small intestine and increased free fatty acid and acyl-carnitine with shorter acyl chains than originally labelled fatty acid. CompA decreased high-fat diet (HFD) intake in C57BL/6J mice. MGAT2-null mice showed a similar phenotype as compA-treated mice and compA did not suppress a food intake in MGAT2 KO mice, indicating that the anorectic effects were dependent on MGAT2 inhibition. Chronic administration of compA significantly prevented body weight gain and fat accumulation in mice fed HFD. MGAT2 inhibition by CompA under severe diabetes ameliorated hyperglycemia and fatty liver in HFD-streptozotocin (STZ)-treated mice. Homeostatic model assessments (HOMA-IR) revealed that compA treatment significantly improved insulin sensitivity. The proximal half of the small intestine displayed weight gain following compA treatment. A similar phenomenon has been observed in Roux-en-Y gastric bypass-treated animals and some studies have reported that this intestinal remodeling is essential to the anti-diabetic effects of bariatric surgery. These results clearly demonstrated that MGAT2 inhibition improved dyslipidemia, obesity, and diabetes, suggesting that compA is an effective therapeutic for obesity-related metabolic disorders. PMID:26938273

  17. Sodium orthovanadate associated with pharmacological doses of ascorbate causes an increased generation of ROS in tumor cells that inhibits proliferation and triggers apoptosis

    SciTech Connect

    Günther, T-hat nia Mara Fischer; Kviecinski, Maicon Roberto; Baron, Carla Cristine; Felipe, Karina Bettega; Farias, Mirelle Sifroni; Ourique da Silva, Fabiana; Bücker, Nádia Cristina Falcão; Pich, Claus Tröger; Ferreira, Eduardo Antonio; Filho, Danilo Wilhelm; Verrax, Julien; Calderon, Pedro Buc; Pedrosa, Rozangela Curi

    2013-01-18

    Graphical abstract: -- Abstract: Pharmacological doses of ascorbate were evaluated for its ability to potentiate the toxicity of sodium orthovanadate (Na{sub 3}VO{sub 4}) in tumor cells. Cytotoxicity, inhibition of cell proliferation, generation of ROS and DNA fragmentation were assessed in T24 cells. Na{sub 3}VO{sub 4} was cytotoxic against T24 cells (EC{sub 50} = 5.8 μM at 24 h), but in the presence of ascorbate (100 μM) the EC{sub 50} fell to 3.3 μM. Na{sub 3}VO{sub 4} plus ascorbate caused a strong inhibition of cell proliferation (up to 20%) and increased the generation of ROS (4-fold). Na{sub 3}VO{sub 4} did not directly cleave plasmid DNA, at this aspect no synergism was found occurring between Na{sub 3}VO{sub 4} and ascorbate once the resulting action of the combination was no greater than that of both substances administered separately. Cells from Ehrlich ascites carcinoma-bearing mice were used to determine the activity of antioxidant enzymes, the extent of the oxidative damage and the type of cell death. Na{sub 3}VO{sub 4} alone, or combined with ascorbate, increased catalase activity, but only Na{sub 3}VO{sub 4} plus ascorbate increased superoxide dismutase activity (up to 4-fold). Oxidative damage on proteins and lipids was higher due to the treatment done with Na{sub 3}VO{sub 4} plus ascorbate (2–3-fold). Ascorbate potentiated apoptosis in tumor cells from mice treated with Na{sub 3}VO{sub 4}. The results indicate that pharmacological doses of ascorbate enhance the generation of ROS induced by Na{sub 3}VO{sub 4} in tumor cells causing inhibition of proliferation and apoptosis. Apoptosis induced by orthovanadate and ascorbate is closer related to inhibition on Bcl-xL and activation of Bax. Our data apparently rule out a mechanism of cell demise p53-dependent or related to Cdk2 impairment.

  18. Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

    PubMed Central

    Čolović, Mirjana B; Krstić, Danijela Z; Lazarević-Pašti, Tamara D; Bondžić, Aleksandra M; Vasić, Vesna M

    2013-01-01

    Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases. PMID:24179466

  19. Pharmacological inhibition of lysosomes activates the MTORC1 signaling pathway in chondrocytes in an autophagy-independent manner

    PubMed Central

    Newton, Phillip T; Vuppalapati, Karuna K; Bouderlique, Thibault; Chagin, Andrei S

    2015-01-01

    Mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) is a protein-signaling complex at the fulcrum of anabolic and catabolic processes, which acts depending on wide-ranging environmental cues. It is generally accepted that lysosomes facilitate MTORC1 activation by generating an internal pool of amino acids. Amino acids activate MTORC1 by stimulating its translocation to the lysosomal membrane where it forms a super-complex involving the lysosomal-membrane-bound vacuolar-type H+-ATPase (v-ATPase) proton pump. This translocation and MTORC1 activation require functional lysosomes. Here we found that, in contrast to this well-accepted concept, in epiphyseal chondrocytes inhibition of lysosomal activity by v-ATPase inhibitors bafilomycin A1 or concanamycin A potently activated MTORC1 signaling. The activity of MTORC1 was visualized by phosphorylated forms of RPS6 (ribosomal protein S6) and EIF4EBP1, 2 well-known downstream targets of MTORC1. Maximal RPS6 phosphorylation was observed at 48-h treatment and reached as high as a 12-fold increase (p < 0.018). This activation of MTORC1 was further confirmed in bone organ culture and promoted potent stimulation of longitudinal growth (p < 0.001). Importantly, the same effect was observed in ATG5 (autophagy-related 5)-deficient bones suggesting a macroautophagy-independent mechanism of MTORC1 inhibition by lysosomes. Thus, our data show that in epiphyseal chondrocytes lysosomes inhibit MTORC1 in a macroautophagy-independent manner and this inhibition likely depends on v-ATPase activity. PMID:26259639

  20. The pharmacological NF-κB inhibitor BAY11-7082 induces cell apoptosis and inhibits the migration of human uveal melanoma cells.

    PubMed

    Hu, Shuiqing; Luo, Qingqiong; Cun, Biyun; Hu, Dan; Ge, Shengfang; Fan, Xianqun; Chen, Fuxiang

    2012-01-01

    Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy. The identification of important survival pathways in uveal melanomas provides novel therapeutic targets for effective treatment. In the present study, we found that the NF-κB signaling pathway was constitutively and highly activated in uveal melanoma cells. Treatment with the pharmacological NF-κB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-κB. In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle. The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment. Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti-apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax. Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo. Collectively, the present study identified NF-κB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-κB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma.

  1. The Pharmacological NF-κB Inhibitor BAY11-7082 Induces Cell Apoptosis and Inhibits the Migration of Human Uveal Melanoma Cells

    PubMed Central

    Hu, Shuiqing; Luo, Qingqiong; Cun, Biyun; Hu, Dan; Ge, Shengfang; Fan, Xianqun; Chen, Fuxiang

    2012-01-01

    Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy. The identification of important survival pathways in uveal melanomas provides novel therapeutic targets for effective treatment. In the present study, we found that the NF-κB signaling pathway was constitutively and highly activated in uveal melanoma cells. Treatment with the pharmacological NF-κB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-κB. In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle. The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment. Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti-apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax. Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo. Collectively, the present study identified NF-κB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-κB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma. PMID:23443086

  2. The pharmacological NF-κB inhibitor BAY11-7082 induces cell apoptosis and inhibits the migration of human uveal melanoma cells.

    PubMed

    Hu, Shuiqing; Luo, Qingqiong; Cun, Biyun; Hu, Dan; Ge, Shengfang; Fan, Xianqun; Chen, Fuxiang

    2012-01-01

    Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy. The identification of important survival pathways in uveal melanomas provides novel therapeutic targets for effective treatment. In the present study, we found that the NF-κB signaling pathway was constitutively and highly activated in uveal melanoma cells. Treatment with the pharmacological NF-κB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-κB. In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle. The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment. Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti-apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax. Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo. Collectively, the present study identified NF-κB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-κB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma. PMID:23443086

  3. Effects of Pharmacologic Dopamine β-Hydroxylase Inhibition on Cocaine-Induced Reinstatement and Dopamine Neurochemistry in Squirrel Monkeys

    PubMed Central

    Cooper, Debra A.; Kimmel, Heather L.; Manvich, Daniel F.; Schmidt, Karl T.; Weinshenker, David

    2014-01-01

    Disulfiram has shown promise as a pharmacotherapy for cocaine dependence in clinical settings, although it has many targets, and the behavioral and molecular mechanisms underlying its efficacy are unclear. One of many biochemical actions of disulfiram is inhibition of dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. Thus, disulfiram simultaneously reduces NE and elevates DA tissue levels in the brain. In rats, both disulfiram and the selective DBH inhibitor nepicastat block cocaine-primed reinstatement, a paradigm which is thought to model some aspects of drug relapse. This is consistent with some clinical results and supports the use of DBH inhibitors for the treatment of cocaine dependence. The present study was conducted to confirm and extend these results in nonhuman primates. Squirrel monkeys trained to self-administer cocaine were pretreated with disulfiram or nepicastat prior to cocaine-induced reinstatement sessions. Neither DBH inhibitor altered cocaine-induced reinstatement. Unexpectedly, nepicastat administered alone induced a modest reinstatement effect in squirrel monkeys, but not in rats. To investigate the neurochemical mechanisms underlying the behavioral results, the effects of DBH inhibition on extracellular DA were analyzed in the nucleus accumbens (NAc) using in vivo microdialysis in squirrel monkeys. Both DBH inhibitors attenuated cocaine-induced DA overflow in the NAc. Hence, the attenuation of cocaine-induced changes in accumbal DA neurochemistry was not associated with altered cocaine-seeking behavior. Overall, the reported behavioral effects of DBH inhibition in rodent models of relapse did not extend to nonhuman primates under the conditions used in the current studies. PMID:24817036

  4. Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis.

    PubMed

    Perera, Yasser; Pedroso, Seidy; Borras-Hidalgo, Orlando; Vázquez, Dania M; Miranda, Jamilet; Villareal, Adelaida; Falcón, Viviana; Cruz, Luis D; Farinas, Hernán G; Perea, Silvio E

    2015-06-01

    B23/NPM is a multifunctional nucleolar protein frequently overexpressed, mutated, or rearranged in neoplastic tissues. B23/NPM is involved in diverse biological processes and is mainly regulated by heteroligomer association and posttranslational modification, phosphorylation being a major posttranslational event. While the role of B23/NPM in supporting and/or driving malignant transformation is widely recognized, the particular relevance of its CK2-mediated phosphorylation remains unsolved. Interestingly, the pharmacologic inhibition of such phosphorylation event by CIGB-300, a clinical-grade peptide drug, was previously associated to apoptosis induction in tumor cell lines. In this work, we sought to identify the biological processes modulated by CIGB-300 in a lung cancer cell line using subtractive suppression hybridization and subsequent functional annotation clustering. Our results indicate that CIGB-300 modulates a subset of genes involved in protein synthesis (ES = 8.4, p < 0.001), mitochondrial ATP metabolism (ES = 2.5, p < 0.001), and ribosomal biogenesis (ES = 1.5, p < 0.05). The impairment of these cellular processes by CIGB-300 was corroborated at the molecular and cellular levels by Western blot (P-S6/P-4EBP1, translation), confocal microscopy (JC-1, mitochondrial potential), qPCR (45SrRNA/p21, ribosome biogenesis), and electron microscopy (nucleolar structure, ribosome biogenesis). Altogether, our findings provide new insights on the potential relevance of the CK2-mediated phosphorylation of B23/NPM in cancer cells, revealing at the same time the potentialities of its pharmacological manipulation for cancer therapy. Finally, this work also suggests several candidate gene biomarkers to be evaluated during the clinical development of the anti-CK2 peptide CIGB-300.

  5. Additivity of water sorption, alpha-relaxations and crystallization inhibition in lactose-maltodextrin systems.

    PubMed

    Potes, Naritchaya; Kerry, Joseph P; Roos, Yrjö H

    2012-08-01

    Water sorption of lactose-maltodextrin (MD) systems, structural relaxations and lactose crystallization were studied. Accurate water sorption data for non-crystalline lactose previously not available over a wide range of water activity, aw (<0.76aw) were derived from lactose-MD systems data. Structural relaxations and crystallization of lactose in lactose-maltodextrin (MD) systems were strongly affected by water and MD. At high MD contents, inhibition of crystallization was significant. Inhibition with a high dextrose equivalent (DE) MD was more pronounced possibly because of molecular number and size effects. At 0.55-0.76aw, inhibition increased with increasing MD content. At aw>0.66, the rate of lactose crystallization decreased at increasing MD contents. Different MDs with similar Tg in lactose-MD systems showed different crystallization inhibition effects. The results of the present study showed that the DE in selection of MD for applications has important effects on component crystallization characteristics.

  6. Cohesion Fatigue Explains Why Pharmacological Inhibition of the APC/C Induces a Spindle Checkpoint-Dependent Mitotic Arrest

    PubMed Central

    Lara-Gonzalez, Pablo; Taylor, Stephen S.

    2012-01-01

    The Spindle Assembly Checkpoint (SAC) delays the onset of anaphase in response to unattached kinetochores by inhibiting the activity of the Anaphase-Promoting Complex/Cyclosome (APC/C), an E3 ubiquitin ligase. Once all the chromosomes have bioriented, SAC signalling is somehow silenced, which allows progression through mitosis. Recent studies suggest that the APC/C itself participates in SAC silencing by targeting an unknown factor for proteolytic degradation. Key evidence in favour of this model comes from the use of proTAME, a small molecule inhibitor of the APC/C. In cells, proTAME causes a mitotic arrest that is SAC-dependent. Even though this observation comes at odds with the current view that the APC/C acts downstream of the SAC, it was nonetheless argued that these results revealed a role for APC/C activity in SAC silencing. However, we show here that the mitotic arrest induced by proTAME is due to the induction of cohesion fatigue, a phenotype that is caused by the loss of sister chromatid cohesion following a prolonged metaphase. Under these conditions, the SAC is re-activated and APC/C inhibition is maintained independently of proTAME. Therefore, these results provide a simpler explanation for why the proTAME-induced mitotic arrest is also dependent on the SAC. While these observations question the notion that the APC/C is required for SAC silencing, we nevertheless show that APC/C activity does partially contribute to its own release from inhibitory complexes, and importantly, this does not depend on proteasome-mediated degradation. PMID:23145059

  7. Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of BrafV600E::Pten−/− melanoma

    PubMed Central

    Scortegagna, Marzia; Ruller, Chelsea; Feng, Yongmei; Lazova, Rossitza; Kluger, Harriet; Li, Jian-Liang; De, Surya K; Rickert, Robert; Pellecchia, Maurizio; Bosenberg, Marcus; Ronai, Ze’ev A.

    2014-01-01

    Phosphoinositide-dependent kinase-1 (PDK-1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and PKC, and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significantly higher in primary melanoma, compared with nevi, and was further increased in metastatic melanoma. PDK1 expression suffices for its activity, due to auto-activation, or elevated phosphorylation by phosphoinositide 3'-OH-kinase (PI 3-K). Selective inactivation of Pdk1 in the melanocytes of BrafV600E::Pten−/− or BrafV600E::Cdkn2a−/−::Pten−/− mice delayed the development of pigmented lesions and melanoma induced by systemic or local administration of 4-HT. Melanoma invasion and metastasis were significantly reduced or completely prevented by Pdk1 deletion. Administration of the PDK1 inhibitor GSK2334470 (PDKi) effectively delayed melanomagenesis and metastasis in BrafV600E::Pten−/− mice. Pdk1−/− melanomas exhibit a marked decrease in the activity of AKT, P70S6K and PKC. Notably, PDKi was as effective in inhibiting AGC kinases and colony forming efficiency of melanoma with Pten WT genotypes. Gene expression analyses identified Pdk1-dependent changes in FOXO3a-regulated genes and inhibition of FOXO3a restored proliferation and colony formation of Pdk1−/− melanoma cells. Our studies provide direct genetic evidence for the importance of PDK1, in part through FOXO3a-dependent pathway, in melanoma development and progression. PMID:24037523

  8. Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes

    PubMed Central

    Costa, Diego L.; Namasivayam, Sivaranjani; Amaral, Eduardo P.; Arora, Kriti; Chao, Alex; Mittereder, Lara R.; Maiga, Mamoudou; Boshoff, Helena I.; Barry, Clifton E.; Goulding, Celia W.; Andrade, Bruno B.

    2016-01-01

    ABSTRACT Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function. PMID:27795400

  9. Short-term selective breeding for high and low prepulse inhibition of the acoustic startle response; pharmacological characterization and QTL mapping in the selected lines.

    PubMed

    Hitzemann, Robert; Malmanger, Barry; Belknap, John; Darakjian, Priscila; McWeeney, Shannon

    2008-10-01

    Selective breeding offers several important advantages over using inbred strain panels in detecting genetically correlated traits to the selection phenotype. The purpose of the current study was to selectively breed for prepulse inhibition (PPI) of the acoustic startle response (ASR), to pharmacologically and behaviorally characterize the selected lines and to use the lines for quantitative trait loci (QTL) mapping. Starting with heterogeneous stock mice formed by crossing the C57BL/6J, DBA/2J, BALB/cJ and LP/J inbred strains and using a short-term selective breeding strategy, animals were selected for High and Low PPI. The selection phenotype was the 80 dB prepulse tone (15 dB above the background noise). After five generations of selection, the High and Low lines differed significantly (78.1 +/- 3.1 vs. 45.2 +/- 3.9 [percent inhibition], p < 0.00001). The effects of haloperidol and MK-801 on PPI were not different between the High and Low lines. However, at the highest dose tested (10 mg/kg), the High line was more sensitive than the Low line to the disruptive PPI effects of methamphetamine. The lines did not differ in terms of basal activity or methamphetamine-induced changes in locomotor activity. The High and Low lines were genotyped using a panel of 768 SNPs. Significant QTLs (LOD > 10) were detected on chromosomes 11 and 16 that appeared similar to those detected previously [Hitzemann, R., Bell, J., Rasmussen, E., McCaughran, J. Mapping the genes for the acoustic startle response (ASR) and prepulse inhibition of the ASR in the BXD recombinant inbred series: effect of high-frequency hearing loss and cochlear pathology. In: Willott JF, editor. Handbook of mouse auditory research: From behavior to molecular biology. New York: CRC Press; 2001, p. 441-455.; Petryshen, T. L, Kirby, A., Hammer, R.P. Jr, Purcell, S., O'Leary, S.B., Singer, J.B., et al. Two quantitative trait loci for prepulse inhibition of startle identified on mouse chromosome 16 using chromosome

  10. Pharmacological inhibition of eicosanoids and platelet-activating factor signaling impairs zymosan-induced release of IL-23 by dendritic cells.

    PubMed

    Rodríguez, Mario; Márquez, Saioa; Montero, Olimpio; Alonso, Sara; Frade, Javier García; Crespo, Mariano Sánchez; Fernández, Nieves

    2016-02-15

    The engagement of the receptors for fungal patterns induces the expression of cytokines, the release of arachidonic acid, and the production of PGE2 in human dendritic cells (DC), but few data are available about other lipid mediators that may modulate DC function. The combined antagonism of leukotriene (LT) B4, cysteinyl-LT, and platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) inhibited IL23A mRNA expression in response to the fungal surrogate zymosan and to a lower extent TNFA (tumor necrosis factor-α) and CSF2 (granulocyte macrophage colony-stimulating factor) mRNA. The combination of lipid mediators and the lipid extract of zymosan-conditioned medium increased the induction of IL23A by LPS (bacterial lipopolysaccharide), thus suggesting that unlike LPS, zymosan elicits the production of mediators at a concentration enough for optimal response. Zymosan induced the release of LTB4, LTE4, 12-hydroxyeicosatetraenoic acid (12-HETE), and PAF C16:0. DC showed a high expression and detectable Ser663 phosphorylation of 5-lipoxygenase in response to zymosan, and a high expression and activity of LPCAT1/2 (lysophosphatidylcholine acyltransferase 1 and 2), the enzymes that incorporate acetate from acetyl-CoA into choline-containing lysophospholipids to produce PAF. Pharmacological modulation of the arachidonic acid cascade and the PAF receptor inhibited the binding of P-71Thr-ATF2 (activating transcription factor 2) to the IL23A promoter, thus mirroring their effects on the expression of IL23A mRNA and IL-23 protein. These results indicate that LTB4, cysteinyl-LT, and PAF, acting through their cognate G protein-coupled receptors, contribute to the phosphorylation of ATF2 and play a central role in IL23A promoter trans-activation and the cytokine signature induced by fungal patterns. PMID:26673542

  11. NO-donating nonsteroidal antiinflammatory drugs (NSAIDs) inhibit colon cancer cell growth more potently than traditional NSAIDs: a general pharmacological property?

    PubMed

    Yeh, Raymond K; Chen, Jie; Williams, Jennie L; Baluch, Mehdi; Hundley, Thomas R; Rosenbaum, Raphael E; Kalala, Srinivas; Traganos, Frank; Benardini, Francesca; del Soldato, Piero; Kashfi, Khosrow; Rigas, Basil

    2004-06-15

    The novel nitric oxide-donating nonsteroidal antiinflammatory drugs (NO-NSAIDs), consisting of a traditional NSAID to which a NO releasing moiety is covalently attached, may have an important role in colon cancer prevention and/or treatment. Preclinical studies have shown that NO-aspirin (NO-ASA) is more potent than traditional ASA in preventing colon cancer. Preclinical and clinical studies have also documented its superior safety, compared to traditional ASA. To evaluate the role of this structural modification on the cancer cell growth inhibitory effect of NSAIDs, we studied seven pairs of traditional NSAIDs (ASA, salicylic acid, indomethacin, sulindac, ibuprofen, flurbiprofen, piroxicam) and their corresponding NO-NSAIDs. All NO-NSAIDs (except NO-piroxicam which is a salt and not a true NO-NSAID) have greater potency in inhibiting HT-29 and HCT-15 colon cancer cell growth compared to their NSAID counterparts: the IC(50)s of the NO-NSAIDs were enhanced between 7- and 689-fold in HT-29 cells and 1.7- to 1083-fold in HCT-15 cells over those of the corresponding NSAIDs. Their growth inhibitory effect is due to a profound cell kinetic effect consisting of reduced cell proliferation and enhanced cell death. Since HT-29 cells express cyclooxygenases but HCT-15 do not, this effect appears independent of cyclooxygenase in the colon cancer cells. Thus the structural modification of these traditional NSAIDs leading to NO-NSAIDs enhances their potency in inhibiting colon cancer cell growth. Our findings suggest that the enhanced potency imparted on NSAIDs by this structural modification represents a pharmacological property that may be a general one for this class of compounds.

  12. Pharmacological inhibition of eicosanoids and platelet-activating factor signaling impairs zymosan-induced release of IL-23 by dendritic cells.

    PubMed

    Rodríguez, Mario; Márquez, Saioa; Montero, Olimpio; Alonso, Sara; Frade, Javier García; Crespo, Mariano Sánchez; Fernández, Nieves

    2016-02-15

    The engagement of the receptors for fungal patterns induces the expression of cytokines, the release of arachidonic acid, and the production of PGE2 in human dendritic cells (DC), but few data are available about other lipid mediators that may modulate DC function. The combined antagonism of leukotriene (LT) B4, cysteinyl-LT, and platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) inhibited IL23A mRNA expression in response to the fungal surrogate zymosan and to a lower extent TNFA (tumor necrosis factor-α) and CSF2 (granulocyte macrophage colony-stimulating factor) mRNA. The combination of lipid mediators and the lipid extract of zymosan-conditioned medium increased the induction of IL23A by LPS (bacterial lipopolysaccharide), thus suggesting that unlike LPS, zymosan elicits the production of mediators at a concentration enough for optimal response. Zymosan induced the release of LTB4, LTE4, 12-hydroxyeicosatetraenoic acid (12-HETE), and PAF C16:0. DC showed a high expression and detectable Ser663 phosphorylation of 5-lipoxygenase in response to zymosan, and a high expression and activity of LPCAT1/2 (lysophosphatidylcholine acyltransferase 1 and 2), the enzymes that incorporate acetate from acetyl-CoA into choline-containing lysophospholipids to produce PAF. Pharmacological modulation of the arachidonic acid cascade and the PAF receptor inhibited the binding of P-71Thr-ATF2 (activating transcription factor 2) to the IL23A promoter, thus mirroring their effects on the expression of IL23A mRNA and IL-23 protein. These results indicate that LTB4, cysteinyl-LT, and PAF, acting through their cognate G protein-coupled receptors, contribute to the phosphorylation of ATF2 and play a central role in IL23A promoter trans-activation and the cytokine signature induced by fungal patterns.

  13. Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis

    PubMed Central

    Husson, Hervé; Moreno, Sarah; Smith, Laurie A.; Smith, Mandy M.; Russo, Ryan J.; Pitstick, Rose; Sergeev, Mikhail; Ledbetter, Steven R.; Bukanov, Nikolay O.; Lane, Monica; Zhang, Kate; Billot, Katy; Carlson, George; Shah, Jagesh; Meijer, Laurent; Beier, David R.; Ibraghimov-Beskrovnaya, Oxana

    2016-01-01

    Polycystic kidney diseases (PKDs) comprise a subgroup of ciliopathies characterized by the formation of fluid-filled kidney cysts and progression to end-stage renal disease. A mechanistic understanding of cystogenesis is crucial for the development of viable therapeutic options. Here, we identify CDK5, a kinase active in post mitotic cells, as a new and important mediator of PKD progression. We show that long-lasting attenuation of PKD in the juvenile cystic kidneys (jck) mouse model of nephronophthisis by pharmacological inhibition of CDK5 using either R-roscovitine or S-CR8 is accompanied by sustained shortening of cilia and a more normal epithelial phenotype, suggesting this treatment results in a reprogramming of cellular differentiation. Also, a knock down of Cdk5 in jck cells using small interfering RNA results in significant shortening of ciliary length, similar to what we observed with R-roscovitine. Finally, conditional inactivation of Cdk5 in the jck mice significantly attenuates cystic disease progression and is associated with shortening of ciliary length as well as restoration of cellular differentiation. Our results suggest that CDK5 may regulate ciliary length by affecting tubulin dynamics via its substrate collapsin response mediator protein 2. Taken together, our data support therapeutic approaches aimed at restoration of ciliogenesis and cellular differentiation as a promising strategy for the treatment of renal cystic diseases. PMID:27053712

  14. [Pharmacology of bone resorption inhibitor].

    PubMed

    Menuki, Kunitaka; Sakai, Akinori

    2015-10-01

    Currently, bone resorption inhibitor is mainly used for osteoporosis. A number of these agents have been developed. These pharmacological action are various. Bisphosphonate inhibit functions of the osteoclasts by inducing apoptosis. On the one hand, RANK-ligand inhibitor and selective estrogen receptor modulator inhibit formation of osteoclasts. It is important to understand these pharmacological action for the selection of the appropriate medicine. PMID:26529923

  15. Inhibition of psychrotrophic bacterial growth in refrigerated milk by addition of carbon dioxide

    SciTech Connect

    Roberts, R.F.; Torrey, G.S.

    1988-01-01

    Treatment of refrigerated milk with 20 to 30 mM CO/sub 2/ was evaluated as a method for extending storage-life by inhibiting growth of psychrotrophic bacteria. Generation times for each of five psychrotrophic pseudomonads were significantly longer when grown at 7/sup 0/C in sterile milk treated with CO/sub 2/ than when the same bacteria were grown in ungassed sterile milk. When raw milks were stored at 7/sup 0/C and treated with CO/sub 2/, the time required for aerobic plate counts to increase 10-fold was at least 24 h longer than in the same milks left untreated. Numbers of coliforms, psychrotrophs, and anaerobes (facultative and obligate) were significantly lower in raw milks treated with CO/sub 2/ than in untreated milks incubated at 7/sup 0/C for 6 d.

  16. Healthspan Pharmacology.

    PubMed

    Jafari, Mahtab

    2015-12-01

    The main goal of this paper is to present the case for shifting the focus of research on aging and anti-aging from lifespan pharmacology to what I like to call healthspan pharmacology, in which the desired outcome is the extension of healthy years of life rather than lifespan alone. Lifespan could be influenced by both genetic and epigenetic factors, but a long lifespan may not be a good indicator of an optimal healthspan. Without improving healthspan, prolonging longevity would have enormous negative socioeconomic outcomes for humans. Therefore, the goal of aging and anti-aging research should be to add healthy years to life and not merely to increase the chronological age. This article summarizes and compares two categories of pharmacologically induced lifespan extension studies in animal model systems from the last two decades-those reporting the effects of pharmacological interventions on lifespan extension alone versus others that include their effects on both lifespan and healthspan in the analysis. The conclusion is that the extrapolation of pharmacological results from animal studies to humans is likely to be more relevant when both lifespan and healthspan extension properties of pharmacological intervention are taken into account.

  17. Molecular and pharmacological blockade of the EP4 receptor selectively inhibits both proliferation and invasion of human inflammatory breast cancer cells.

    PubMed

    Robertson, Fredika M; Simeone, Ann-Marie; Mazumdar, Abhijit; Shah, Ashish H; McMurray, John S; Ghosh, Sukhen; Cristofanilli, Massimo

    2008-01-01

    Inflammatory breast cancer (IBC) is the most aggressive form of locally advanced breast cancer (LABC) characterized by rapid growth and aggressive invasion with no selective therapies developed to treat IBC. Cyclooxygenase-2 (Cox-2), which produces prostaglandin E2 (PGE2) is known to be upregulated in primary IBC tumors and metastatic lesions, however the use of selective Cox-2 inhibitors has diminished due to cardiovascular side effects. One alternative approach to targeting Cox-2 enzyme activity is to block binding of the PGE2 ligand to its prostanoid (EP) receptors, which are designated as EP1, EP2, EP3, and EP4 and are members of a subfamily of G protein coupled receptors (GPCRs). While SUM149 IBC tumor cells and MCF-7 non-IBC breast tumor cells produce both EP2 and EP4 receptors, the invasive MDA-MB-231 non-IBC breast tumor cells produced low but detectable levels of these receptors. PGE2 and the EP4 agonist, PGE2 alcohol, stimulated significantly increased (p < 0.05) levels of proliferation and invasion by SUM149 IBC tumor cells, with no effect on proliferation of either of the two non-IBC breast tumor cell lines. In contrast, the EP2 agonist butaprost had no effect on proliferation or invasion of any cell line examined. The selective EP4 antagonist, GW627368X, induced inhibition of proliferation and invasion of human SUM149 IBC tumor cells beginning at 0.1 microM, with inhibition of proliferation and invasion by MDA-MB-231 non-IBC cells at higher concentrations of GW627368X. Molecular knockdown of the EP4 receptor was accomplished by stable transfection of an EP4 short hairpin RNA (shRNA) construct, with a clonally derived cell line designated as SUM149/Clone 1 exhibiting significantly slowed proliferation and diminished invasion compared to SUM149/Vector 5 which contained a scrambled shRNA control vector. This is the first report using both a selective pharmacologic inhibitor and a molecular shRNA knockdown approach to demonstrate that EP4 is directly

  18. Mixture additives inhibit the dermal permeation of the fatty acid, ricinoleic acid.

    PubMed

    Baynes, R E; Riviere, J E

    2004-02-28

    Ricinoleic acid (RA) like many of the ingredients in machine cutting fluids and other industrial formulations are potential dermal irritants, yet very little is known about its permeability in skin. 3H-ricinoleic acid mixtures were formulated with three commonly used cutting fluid additives; namely, triazine (TRI), linear alkylbenzene sulfonate (LAS), and triethanolamine (TEA) and topically applied to inert silastic membranes and porcine skin in vitro as aqueous mineral oil (MO) or polyethylene glycol (PEG) mixtures. These additives significantly decreased ricinoleic acid partitioning from the formulation into the stratum corneum (SC) in PEG-based mixtures. Except for LAS, all other additives produced a more basic formulation (pH = 9.3-10.3). In silastic membranes and porcine skin, individual additives or combination of additives significantly reduced ricinoleic permeability. This trend in ricinoleic acid disposition in both membranes suggests that the mixture interaction is more physicochemical in nature and probably not related to the chemical-induced changes in the biological membrane as may be assumed with topical exposures to potentially irritant formulations.

  19. Effect of jenny milk addition on the inhibition of late blowing in semihard cheese.

    PubMed

    Cosentino, C; Paolino, R; Valentini, V; Musto, M; Ricciardi, A; Adduci, F; D'Adamo, C; Pecora, G; Freschi, P

    2015-08-01

    The occurrence of late blowing defects in cheese produces negative effects on the quality and commercial value of the product. In this work, we verified whether the addition of raw jenny milk to bulk cow milk reduced the late blowing defects in semihard cheeses. During cheesemaking, different aliquots of jenny milk were poured into 2 groups of 4 vats, each containing a fixed amount of cow milk. A group of cheeses was created by deliberately contaminating the 4 vats with approximately 3 log10 cfu/mL milk of Clostridium tyrobutyricum CLST01. The other 4 vats, which were not contaminated, were used for a second group of cheeses. After 120 d of ripening, some physical, chemical, and microbiological parameters were evaluated on the obtained semihard cheeses. Differences in sensory properties among cheeses belonging to the uncontaminated group were evaluated by 80 regular consumers of cheese. Our results showed that the increasing addition of jenny milk to cow milk led to a reduction of pH and total bacterial count in both cheese groups, as well as C. tyrobutyricum spores that either grew naturally or artificially inoculated. We observed a progressive reduction of the occurrence of late blowing defects in cheese as consequence of the increasing addition of jenny milk during cheese making. Moreover, the addition of jenny milk did not affect the acceptability of the product, as consumers found no difference among cheeses concerning sensorial aspects. In conclusion, the important antimicrobial activity of lysozyme contained in jenny milk has been confirmed in the current research. It is recommend for use as a possible and viable alternative to egg lysozyme for controlling late blowing defects in cheese.

  20. Electrical inhibition of lens epithelial cell proliferation: an additional factor in secondary cataract?

    PubMed Central

    Wang, Entong; Reid, Brian; Lois, Noemi; Forrester, John V.; McCaig, Colin D.; Zhao, Min

    2005-01-01

    Cataract is the most common cause of blindness but is at least curable by surgery. Unfortunately, many patients gradually develop the complication of posterior capsule opacification (PCO) or secondary cataract. This arises from stimulated cell growth within the lens capsule and can greatly impair vision. It is not fully understood why residual lens epithelial cell growth occurs after surgery. We propose and show that cataract surgery might remove an important inhibitory factor for lens cell growth, namely electric fields. The lens generates a unique pattern of electric currents constantly flowing out from the equator and entering the anterior and posterior poles. We show here that cutting and removing part of the anterior capsule as in cataract surgery significantly decreases the equatorial outward electric currents. Application of electric fields in culture inhibits proliferation of human lens epithelial cells. This inhibitory effect is likely to be mediated through a cell cycle control mechanism that decreases entry of cells into S phase from G1 phase by decreasing the G1-specific cell cycle protein cyclin E and increasing the cyclin-Cdk complex inhibitor p27kip1. Capsulorrhexis in vivo, which reduced endogenous lens electric fields, significantly increased LEC growth. This, together with our previous findings that electric fields have significant effects on the direction of lens cell migration, points to a controlling mechanism for the aberrant cell growth in posterior capsule opacification. A novel approach to control growth of lens epithelial cells using electric fields combined with other controlling mechanisms may be more effective in the prevention and treatment of this common complication of cataract surgery. PMID:15764648

  1. Conditional pharmacology/toxicology V: ambivalent effects of thiocyanate upon the development and the inhibition of experimental arthritis in rats by aurothiomalate (Myocrysin®) and metallic silver.

    PubMed

    Whitehouse, Michael; Butters, Desley; Vernon-Roberts, Barrie

    2013-08-01

    This article discusses the bizarre and contrary effects of thiocyanate, the major detoxication product of hydrogen cyanide inhaled from tobacco smoke or liberated from cyanogenic foods, e.g. cassava. Thiocyanate both (1) promotes inflammatory disease in rats and (2) facilitates the anti-inflammatory action of historic metal therapies based on gold (Au) or silver (Ag) in three models of chronic polyarthritis in rats. Low doses of nanoparticulate metallic silver (NMS) preparations, i.e. zerovalent silver (Ag°) administered orally, suppressed the mycobacterial ('adjuvant')-induced arthritis (MIA) in rats. Similar doses of cationic silver, Ag(I), administered orally as silver oxide or soluble silver salts were inactive. By contrast, NMS only inhibited the development of the collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) in rats when thiocyanate was also co-administered in drinking water. These (a) arthritis-selective and (b) thiocyanate-inducible effects of Ag° were also observed in some previous, and now extended, studies with the classic anti-arthritic drug, sodium aurothiomalate (ATM, Myocrisin(®)) and its silver analogue (STM), administered subcutaneously to rats developing the same three forms of polyarthritis. In the absence of either Ag° or ATM, thiocyanate considerably increased the severity of the MIA, CIA and PIA, i.e. acting as a pro-pathogen. Hitherto, thiocyanate was considered relatively harmless. This may not be true in rats/people with immuno-inflammatory stress and concomitant leukocyte activation. Collectively, these findings show how the drug action of a xenobiotic might be determined by the nature (and severity) of the experimental inflammation, as an example of conditional pharmacology. They also suggest that an incipient toxicity, even of normobiotics such as thiocyanate, might likewise be modulated beneficially by well-chosen xenobiotics (drugs, nutritional supplements, etc.), i.e. conditional toxicology (Powanda 1995

  2. CBR antimicrobials inhibit RNA polymerase via at least two bridge-helix cap-mediated effects on nucleotide addition

    SciTech Connect

    Bae, Brian; Nayak, Dhananjaya; Ray, Ananya; Mustaev, Arkady; Landick, Robert; Darst, Seth A.

    2015-07-20

    RNA polymerase inhibitors like the CBR class that target the enzyme’s complex catalytic center are attractive leads for new antimicrobials. The catalysis by RNA polymerase involves multiple rearrangements of bridge helix, trigger loop, and active-center side chains that isomerize the triphosphate of bound NTP and two Mg2+ ions from a preinsertion state to a reactive configuration. CBR inhibitors target a crevice between the N-terminal portion of the bridge helix and a surrounding cap region within which the bridge helix is thought to rearrange during the nucleotide addition cycle. Here, we report crystal structures of CBR inhibitor/Escherichia coli RNA polymerase complexes as well as biochemical tests that establish two distinct effects of the inhibitors on the RNA polymerase catalytic site. One effect involves inhibition of trigger-loop folding via the F loop in the cap, which affects both nucleotide addition and hydrolysis of 3'-terminal dinucleotides in certain backtracked complexes. The second effect is trigger-loop independent, affects only nucleotide addition and pyrophosphorolysis, and may involve inhibition of bridge-helix movements that facilitate reactive triphosphate alignment.

  3. Sofosbuvir Inhibits Hepatitis E Virus Replication In Vitro and Results in an Additive Effect When Combined With Ribavirin.

    PubMed

    Dao Thi, Viet Loan; Debing, Yannick; Wu, Xianfang; Rice, Charles M; Neyts, Johan; Moradpour, Darius; Gouttenoire, Jérôme

    2016-01-01

    Infection with hepatitis E virus genotype 3 may result in chronic hepatitis in immunocompromised patients. Reduction of immunosuppression or treatment with ribavirin or pegylated interferon-α can result in viral clearance. However, safer and more effective treatment options are needed. Here, we show that sofosbuvir inhibits the replication of hepatitis E virus genotype 3 both in subgenomic replicon systems as well as a full-length infectious clone. Moreover, the combination of sofosbuvir and ribavirin results in an additive antiviral effect. Sofosbuvir may be considered as an add-on therapy to ribavirin for the treatment of chronic hepatitis E in immunocompromised patients.

  4. Inhibition of non-templated nucleotide addition by DNA polymerases in primer extension using twisted intercalating nucleic acid modified templates.

    PubMed

    Güixens-Gallardo, Pedro; Hocek, Michal; Perlíková, Pavla

    2016-01-15

    A simple and elegant method for inhibition of non-templated nucleotide addition by DNA polymerases and for following DNA 3'-heterogeneity in enzymatic DNA synthesis by primer extension (PEX) is described. When template bearing ortho-twisted intercalating nucleic acid (ortho-TINA) at the 5'-end is used, non-templated nucleotide addition is reduced in both the A- and B-family DNA polymerases (KOD XL, KOD (exo-), Bst 2.0, Therminator, Deep Vent (exo-) and Taq). Formation of a single oligonucleotide product was observed with ortho-TINA modified template and KOD XL, KOD (exo-), Bst 2.0, Deep Vent (exo-) and Taq DNA polymerases. This approach can be applied to the synthesis of both unmodified and base-modified oligonucleotides. PMID:26707394

  5. The role of FOXO and PPAR transcription factors in diet-mediated inhibition of PDC activation and carbohydrate oxidation during exercise in humans and the role of pharmacological activation of PDC in overriding these changes.

    PubMed

    Constantin-Teodosiu, Dumitru; Constantin, Despina; Stephens, Francis; Laithwaite, David; Greenhaff, Paul L

    2012-05-01

    High-fat feeding inhibits pyruvate dehydrogenase complex (PDC)-controlled carbohydrate (CHO) oxidation, which contributes to muscle insulin resistance. We aimed to reveal molecular changes underpinning this process in resting and exercising humans. We also tested whether pharmacological activation of PDC overrides these diet-induced changes. Healthy males consumed a control diet (CD) and on two further occasions an isocaloric high-fat diet (HFD). After each diet, subjects cycled for 60 min after intravenous infusion with saline (CD and HFD) or dichloroacetate (HFD+DCA). Quadriceps muscle biopsies obtained before and after 10 and 60 min of exercise were used to estimate CHO use, PDC activation, and mRNAs associated with insulin, fat, and CHO signaling. Compared with CD, HFD increased resting pyruvate dehydrogenase kinase 2 (PDK2), PDK4, forkhead box class O transcription factor 1 (FOXO1), and peroxisome proliferator-activated receptor transcription factor α (PPARα) mRNA and reduced PDC activation. Exercise increased PDC activation and whole-body CHO use in HFD, but to a lower extent than in CD. Meanwhile PDK4 and FOXO1, but not PPARα or PDK2, mRNA remained elevated. HFD+DCA activated PDC throughout and restored whole-body CHO use during exercise. FOXO1 appears to play a role in HFD-mediated muscle PDK4 upregulation and inhibition of PDC and CHO oxidation in humans. Also, pharmacological activation of PDC restores HFD-mediated inhibition of CHO oxidation during exercise. PMID:22315317

  6. Pharmacologic vitreolysis.

    PubMed

    Rhéaume, Marc-André; Vavvas, Demetrios

    2010-01-01

    It is now well recognized that vitreous plays an important role in the pathogenesis of various retinal disorders. In many instances it can be addressed with pars plana vitrectomy, although this approach, like any surgery, has its limitations. The search for alternatives or adjunct to surgery has led to the development of pharmacologic vitreolysis. The use of intravitreal agents to alter the vitreous in order to reduce or eliminate its role in disease seems promising. The purpose of this article is to summarize the present knowledge on pharmacologic vitreolysis. A review of the different agents used and of ongoing trials will be presented. Also, current understanding of vitreous structure and its interaction with the retina will be discussed.

  7. High Affinity Pharmacological Profiling of Dual Inhibitors Targeting RET and VEGFR2 in Inhibition of Kinase and Angiogeneis Events in Medullary Thyroid Carcinoma.

    PubMed

    Dunna, Nageswara Rao; Kandula, Venkatesh; Girdhar, Amandeep; Pudutha, Amareshwari; Hussain, Tajamul; Bandaru, Srinivas; Nayarisseri, Anuraj

    2015-01-01

    Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGN- PC-0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.

  8. High Affinity Pharmacological Profiling of Dual Inhibitors Targeting RET and VEGFR2 in Inhibition of Kinase and Angiogeneis Events in Medullary Thyroid Carcinoma.

    PubMed

    Dunna, Nageswara Rao; Kandula, Venkatesh; Girdhar, Amandeep; Pudutha, Amareshwari; Hussain, Tajamul; Bandaru, Srinivas; Nayarisseri, Anuraj

    2015-01-01

    Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGN- PC-0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC. PMID:26514495

  9. Michael addition of dehydroalanine-containing MAPK peptides to catalytic lysine inhibits the activity of phosphothreonine lyase.

    PubMed

    Zhang, Yuan; Yang, Ru; Huang, Juan; Liang, Qiujin; Guo, Yanmin; Bian, Weixiang; Luo, Lingfei; Li, Hongtao

    2015-11-30

    The phosphothreonine lyases OspF and SpvC irreversibly inactivate host dual-phosphorylated mitogen-activated protein kinases (MAPKs) [pThr-X-pTyr motif] through β-elimination. We found that dual-phosphorylated (pSer-X-pTyr) MAPK substrate peptides and their resulting catalytic products cross-link to OspF and SpvC. Mass spectrometry results revealed that these linkages form between lysine, which acts as a general base, and dehydroalanine (Dha) on catalytic products. The nucleophilic addition efficiency is dependent on the K136 residue being in a deprotonated state. Peptide cross-linking inhibits the activity of SpvC and blocks the inactivation of MAPK signaling by SpvC. Small compounds mimicking these sequences may act as phosphothreonine lyase inhibitors. PMID:26519561

  10. Additive cardioprotection by pharmacological postconditioning with hydrogen sulfide and nitric oxide donors in mouse heart: S-sulfhydration vs. S-nitrosylation.

    PubMed

    Sun, Junhui; Aponte, Angel M; Menazza, Sara; Gucek, Marjan; Steenbergen, Charles; Murphy, Elizabeth

    2016-05-01

    Hydrogen sulfide (H2S), as a gaseous signalling molecule, has been found to play important roles in postconditioning (PostC)-induced cardioprotection. Similar to nitric oxide (NO)-mediated protein S-nitrosylation (SNO), recent studies suggest that H2S could regulate protein function through another redox-based post-translational modification on protein cysteine residue(s), i.e. S-sulfhydration (SSH). In this study, we examined whether there are changes in protein SSH associated with cardioprotection induced by treatment with H2S on reperfusion. In addition, we also examined whether there is cross talk between H2S and NO. Compared with control, treatment on reperfusion with NaHS (H2S donor, 100 µmol/L) significantly reduced post-ischaemic contractile dysfunction and infarct size. A comparable cardioprotective effect could be also achieved by reperfusion treatment with SNAP (NO donor, 10 µmol/L). Interestingly, simultaneous reperfusion with both donors had an additive protective effect. In addition, C-PTIO (NO scavenger, 20 µmol/L) eliminated the protection induced by NaHS and also the additive protection by SNAP + NaHS together. Using a modified biotin switch method, we observed a small increase in SSH following NaHS treatment on reperfusion. We also found that NaHS treatment on reperfusion increases SNO to a level comparable to that with SNAP treatment. In addition, there was an additive increase in SNO but not SSH when SNAP and NaHS were added together at reperfusion. Thus, part of the benefit of NaHS is an increase in SNO, and the magnitude of the protective effect is related to the magnitude of the increase in SNO.

  11. Combined Use of Etomidate and Dexmedetomidine Produces an Additive Effect in Inhibiting the Secretion of Human Adrenocortical Hormones

    PubMed Central

    Gu, Hongbin; Zhang, Mazhong; Cai, Meihua; Liu, Jinfen

    2015-01-01

    Background The direct effects of etomidate were investigated on the secretion of cortisol and its precursors by dispersed cells from the adrenal cortex of human of animals. Dexmedetomidine (DEX) is an anesthetic agent that may interfere with cortisol secretion via an unknown mechanism, such as involving inhibition of 11β-hydroxylase and the cholesterol side-chain cleavage enzyme system. The aim of this study was to determine whether dexmedetomidine (DEX) has a similar inhibitory effect on adrenocortical function, and whether combined use of etomidate (ETO) and DEX could produce a synergistic action in inhibiting the secretion of human adrenocortical hormones. Material/Methods Human adrenocortical cells were exposed to different concentrations of ETO and DEX. The dose-effect model between the ETO concentration and the mean secretion of cortisone (CORT) and aldosterone (ALDO) per hour was estimated. Results Hill’s equation well-described the dose-effect correlation between the ETO concentration and the amount of ALDO and CORT secretion. When the DEX concentration was introduced into the model by using E0 (basal secretion) as the covariate, the goodness of fit of the ETO-CORT dose-effect model was improved significantly and the objective function value was reduced by 4.55 points (P<0.05). The parameters of the final ETO-ALDO pharmacodynamics model were EC50=9.74, Emax=1.20, E0=1.33, and γ=18.5; the parameters of the final ETO-CORT pharmacodynamics model were EC50=9.49, Emax=8.16, E0=8.57, and γ=37.0. In the presence of DEX, E0 was 8.57–0.0247×(CDEX–4.6), and the other parameters remained unchanged. All parameters but γ were natural logarithm conversion values. Conclusions Combined use of DEX and ETO reduced ETO’s inhibitory E0 (basal secretion) of CORT from human adrenocortical cells in a dose-dependent manner, suggesting that combined use of ETO and DEX produced an additive effect in inhibiting the secretion of human adrenocortical hormones. PMID

  12. Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity.

    PubMed

    Menendez, Javier A; Vellon, Luciano; Colomer, Ramon; Lupu, Ruth

    2005-05-20

    The relationship between breast cancer-associated fatty acid synthase (FAS; oncogenic antigen-519) and chemotherapy-induced cell damage has not been studied. We examined the ability of C75, a synthetic slow-binding inhibitor of FAS activity, to modulate the cytotoxic activity of the microtubule-interfering agent Taxol (paclitaxel) in SK-Br3, MDA-MB-231, MCF-7 and multidrug-resistant MDR-1 (P-Glycoprotein)-overexpressing MCF-7/AdrR breast cancer cells. When the combination of C75 with Taxol in either concurrent (C75 + Taxol 24 hr) or sequential (C75 24 hr --> Taxol 24 hr) schedules were tested for synergism, addition or antagonism using the isobologram and the median-effect plot analyses, co-exposure of C75 and Taxol mostly demonstrated synergistic effects, whereas sequential exposure to C75 followed by Taxol mainly showed additive or antagonistic interactions. Because the nature of the cytotoxic interactions was definitely schedule-dependent in MCF-7 cells, we next evaluated the effects of C75 on Taxol-induced apoptosis as well as Taxol-activated cell death and cell survival-signaling pathways in this breast cancer cell model. An ELISA for histone-associated DNA fragments demonstrated that C75 and Taxol co-exposure caused a synergistic enhancement of apoptotic cell death, whereas C75 pre-treatment did not enhance the apoptosis-inducing activity of Taxol. Co-exposure to C75 and Taxol induced a remarkable nuclear accumulation of activated p38 mitogen-activated protein kinase (p38 MAPK), which was accompanied by a synergistic nuclear accumulation of the p53 tumor-suppressor protein that was phosphorylated at Ser46, a p38 MAPK-regulated pro-apoptotic modification of p53. As single agents, FAS blocker C75 and Taxol induced a significant stimulation of the proliferation and cell survival mitogen-activated protein kinase extracellular signal-regulated kinase (ERK1/ERK2 MAPK) activity, whereas, in combination, they interfered with ERK1/ERK2 activation. Moreover, the

  13. Pro-cognitive and antipsychotic efficacy of the alpha7 nicotinic partial agonist SSR180711 in pharmacological and neurodevelopmental latent inhibition models of schizophrenia.

    PubMed

    Barak, Segev; Arad, Michal; De Levie, Amaya; Black, Mark D; Griebel, Guy; Weiner, Ina

    2009-06-01

    Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of alpha7 nicotinic receptor (nAChR) agonists for cognitive deficits in schizophrenia but their activity against positive symptoms is thought to be minimal. The present study examined potential pro-cognitive and antipsychotic activity of the novel selective alpha7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, compared with a novel stimulus. Here, no-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak but not strong conditioning (2 vs 5 tone-shock pairings). MK801 (0.05 mg/kg, i.p.) -treated rats as well as rats neonatally treated with nitric oxide synthase inhibitor L-NoArg (10 mg/kg, s.c.) on postnatal days 4-5, persisted in displaying LI with strong conditioning, whereas amphetamine (1 mg/kg) -treated rats failed to show LI with weak conditioning. SSR180711 (0.3, 1, 3 mg/kg, i.p.) was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal L-NoArg; these models are believed to model cognitive aspects of schizophrenia and activity here was consistent with previous findings with alpha7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in no-drug controls and reversed amphetamine-induced LI disruption, two effects considered predictive of activity against positive symptoms of schizophrenia. These findings suggest that SSR180711 may be beneficial not only for the treatment of cognitive symptoms in schizophrenia, as reported multiple times previously, but also positive symptoms.

  14. Pro-cognitive and antipsychotic efficacy of the alpha7 nicotinic partial agonist SSR180711 in pharmacological and neurodevelopmental latent inhibition models of schizophrenia.

    PubMed

    Barak, Segev; Arad, Michal; De Levie, Amaya; Black, Mark D; Griebel, Guy; Weiner, Ina

    2009-06-01

    Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of alpha7 nicotinic receptor (nAChR) agonists for cognitive deficits in schizophrenia but their activity against positive symptoms is thought to be minimal. The present study examined potential pro-cognitive and antipsychotic activity of the novel selective alpha7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, compared with a novel stimulus. Here, no-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak but not strong conditioning (2 vs 5 tone-shock pairings). MK801 (0.05 mg/kg, i.p.) -treated rats as well as rats neonatally treated with nitric oxide synthase inhibitor L-NoArg (10 mg/kg, s.c.) on postnatal days 4-5, persisted in displaying LI with strong conditioning, whereas amphetamine (1 mg/kg) -treated rats failed to show LI with weak conditioning. SSR180711 (0.3, 1, 3 mg/kg, i.p.) was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal L-NoArg; these models are believed to model cognitive aspects of schizophrenia and activity here was consistent with previous findings with alpha7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in no-drug controls and reversed amphetamine-induced LI disruption, two effects considered predictive of activity against positive symptoms of schizophrenia. These findings suggest that SSR180711 may be beneficial not only for the treatment of cognitive symptoms in schizophrenia, as reported multiple times previously, but also positive symptoms. PMID:19158670

  15. High Glucose-Induced Mitochondrial Respiration and Reactive Oxygen Species in Mouse Cerebral Pericytes is Reversed by Pharmacological Inhibition of Mitochondrial Carbonic Anhydrases: Implications for Cerebral Microvascular Disease in Diabetes

    PubMed Central

    Shah, Gul N.; Morofuji, Yoichi; Banks, William A.; Price, Tulin O.

    2013-01-01

    Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration. PMID:24076121

  16. High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes.

    PubMed

    Shah, Gul N; Morofuji, Yoichi; Banks, William A; Price, Tulin O

    2013-10-18

    Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration.

  17. Inhibition of key aroma compound generated during ultrahigh-temperature processing of bovine milk via epicatechin addition.

    PubMed

    Colahan-Sederstrom, Paula M; Peterson, Devin G

    2005-01-26

    The ability of epicatechin (EC) to inhibit the thermal development of aroma compounds (i.e., Maillard reaction products) formed during ultrahigh-temperature (UHT) processing of bovine milk was evaluated. Volatile extracts were prepared for two UHT-processed milk samples made from (1) raw milk and (2) raw milk containing 0.1% EC by solvent-assisted flavor evaporation (SAFE) and subsequently analyzed by aroma extract dilution analysis (AEDA). Sensory evaluation was also conducted by a trained panel on the intensity of cooked flavor and bitterness in four UHT-processed milk samples (0.00, 0.01, 0.10, and 0.20% EC added prior to processing), as well as a commercial pasteurized milk sample for comparison. AEDA indicated that addition of EC to raw fluid milk prior to UHT processing reduced the overall thermal formation of key aroma-active compounds in comparison to the traditional UHT milk sample. The largest changes in FD values were reported for methional, furfural, 2-isopropyl-3-methoxypyrazine, 2-acetyl-1-pyrroline, and 2-acetyl-2-thiazoline (Maillard-type aroma compounds) with 32-, 8-, 8-, 4-, and 4-fold reductions in formation, respectively. Sensory evaluation also revealed that all EC-containing UHT milk samples had statistically (P < 0.05) lower cooked flavor intensity in comparison to the control, whereas the 0.2% EC sample was statistically similar to a pasteurized milk sample. Furthermore, addition of EC at or below 0.1% in UHT fluid milk did not significantly increase the bitterness intensity.

  18. NASA 2010 Pharmacology Evidence Review

    NASA Technical Reports Server (NTRS)

    Steinberg, Susan

    2011-01-01

    In 2008, the Institute of Medicine reviewed NASA's Human Research Program Evidence in assessing the Pharmacology risk identified in NASA's Human Research Program Requirements Document (PRD). Since this review there was a major reorganization of the Pharmacology discipline within the HRP, as well as a re-evaluation of the Pharmacology evidence. This panel is being asked to review the latest version of the Pharmacology Evidence Report. Specifically, this panel will: (1) Appraise the descriptions of the human health-related risk in the HRP PRD. (2) Assess the relevance and comprehensiveness of the evidence in identifying potential threats to long-term space missions. (3) Assess the associated gaps in knowledge and identify additional areas for research as necessary.

  19. Neonatal clinical pharmacology

    PubMed Central

    Allegaert, Karel; van de Velde, Marc; van den Anker, John

    2013-01-01

    Effective and safe drug administration in neonates should be based on integrated knowledge on the evolving physiological characteristics of the infant who will receive the drug, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. Consequently, clinical pharmacology in neonates is as dynamic and diverse as the neonates we admit to our units while covariates explaining the variability are at least as relevant as median estimates. The unique setting of neonatal clinical pharmacology will be highlighted based on the hazards of simple extrapolation of maturational drug clearance when only based on ‘adult’ metabolism (propofol, paracetamol). Secondly, maturational trends are not at the same pace for all maturational processes. This will be illustrated based on the differences between hepatic and renal maturation (tramadol, morphine, midazolam). Finally, pharmacogenetics should be tailored to neonates, not just mirror adult concepts. Because of this diversity, clinical research in the field of neonatal clinical pharmacology is urgently needed, and facilitated through PK/PD modeling. In addition, irrespective of already available data to guide pharmacotherapy, pharmacovigilance is needed to recognize specific side effects. Consequently, paediatric anesthesiologists should consider to contribute to improved pharmacotherapy through clinical trial design and collaboration, as well as reporting on adverse effects of specific drugs. PMID:23617305

  20. Pharmacologic inhibition of MLK3 kinase activity blocks the in vitro migratory capacity of breast cancer cells but has no effect on breast cancer brain metastasis in a mouse xenograft model.

    PubMed

    Rhoo, Kun Hyoe; Granger, Megan; Sur, Joynita; Feng, Changyong; Gelbard, Harris A; Dewhurst, Stephen; Polesskaya, Oksana

    2014-01-01

    Brain metastasis of breast cancer is an important clinical problem, with few therapeutic options and a poor prognosis. Recent data have implicated mixed lineage kinase 3 (MLK3) in controlling the in vitro migratory capacity of breast cancer cells, as well as the metastasis of MDA-MB-231 breast cancer cells from the mammary fat pad to distant lymph nodes in a mouse xenograft model. We therefore set out to test whether MLK3 plays a role in brain metastasis of breast cancer cells. To address this question, we used a novel, brain penetrant, MLK3 inhibitor, URMC099. URMC099 efficiently inhibited the migration of breast cancer cells in an in vitro cell monolayer wounding assay, and an in vitro transwell migration assay, but had no effect on in vitro cell growth. We also tested the effect of URMC099 on tumor formation in a mouse xenograft model of breast cancer brain metastasis. This analysis showed that URMC099 had no effect on the either the frequency or size of breast cancer brain metastases. We conclude that pharmacologic inhibition of MLK3 by URMC099 can reduce the in vitro migratory capacity of breast cancer cells, but that it has no effect on either the frequency or size of breast cancer brain metastases, in a mouse xenograft model.

  1. Pharmacological evidence that potentiation of plasmalemmal Ca(2+)-extrusion is functionally coupled to inhibition of SR Ca(2+)-ATPases in vascular smooth muscle cells.

    PubMed

    Zhang, Wen-Bo; Kwan, Chiu-Yin

    2016-04-01

    Cyclopiazonic acid (CPA), a specific inhibitor of sarcoplasmic reticulum (SR) Ca(2+)-ATPases, causes slowly developing and subsequently diminishing characteristic contractions in vascular smooth muscle, and the second application of CPA has incompletely repeatable effects, depending on the vessel type. The objective of the present study was to examine the mechanisms underlying the significant decrease of CPA-induced contractions upon the second application. A pharmacological intervention of Ca(2+) extrusion process as a strategy was performed to modulate vasoconstrictor effects of CPA in rat aortic ring preparations. CPA-induced contractions, expressed as percentages of the contractions induced by KCl (80 mM), were significantly decreased from 44.1 ± 5.7 to 7.6 ± 1.8 % (P < 0.001) upon the second application. The contractions, however, were completely repeatable in the presence of vanadate, an inhibitor of ATPases, but not of ouabain, an inhibitor of Na(+)-pumps. Strikingly, CPA-induced contractions were sustained and completely repeatable in Na(+)-free and low Na(+) medium. Furthermore, we found that the contractions were completely repeatable in the presence of 2',4'-dichlorobenzamil, an inhibitor of the forward mode of Na(+)/Ca(2+) exchangers, but not of KBR7943, an inhibitor of the reverse mode of Na(+)/Ca(2+) exchangers. Our findings indicate that CPA by inducing a transient rise in cytosolic Ca(2+) level causes a long-lasting upregulation of plasma membrane (PM) Ca(2+) extruders and thus leads to a diminished contraction upon its second application in blood vessels. This suggests that there is a functional coupling between PM Ca(2+) extruders and SR Ca(2+)-ATPases in rat aortic smooth muscle cells. PMID:26842648

  2. Pharmacological blockade of the DP2 receptor inhibits cigarette smoke-induced inflammation, mucus cell metaplasia, and epithelial hyperplasia in the mouse lung.

    PubMed

    Stebbins, Karin J; Broadhead, Alex R; Baccei, Christopher S; Scott, Jill M; Truong, Yen P; Coate, Heather; Stock, Nicholas S; Santini, Angelina M; Fagan, Patrick; Prodanovich, Patricia; Bain, Gretchen; Stearns, Brian A; King, Christopher D; Hutchinson, John H; Prasit, Peppi; Evans, Jilly F; Lorrain, Daniel S

    2010-03-01

    Prostaglandin D(2) (PGD(2)) is one of a family of biologically active lipids derived from arachidonic acid via the action of COX-1 and COX-2. PGD(2) is released from mast cells and binds primarily to two G protein-coupled receptors, namely DP1 and DP2, the latter also known as chemoattractant receptor-homologous molecule expressed on Th2 cells. DP2 is predominantly expressed on eosinophils, Th2 cells, and basophils, but it is also expressed to a lesser extent on monocytes, mast cells, and epithelial cells. Interaction of PGD(2) and its active metabolites with DP2 results in cellular chemotaxis, degranulation, up-regulation of adhesion molecules, and cytokine production. Chronic obstructive pulmonary disease (COPD) is a chronic progressive inflammatory disease characterized by elevated lung neutrophils, macrophages, and CD8+ T lymphocytes and mucus hypersecretion. Cigarette smoke contributes to the etiology of COPD and was used here as a provoking agent in a murine model of COPD. In an acute model, {2'-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4'-trifluoro-methyl-biphenyl-3-yl}-acetic acid, sodium salt (AM156) and (5-{2-[(benzoyloxycarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid, sodium salt) (AM206), potent DP2 receptor antagonists, dose-dependently inhibited influx of neutrophils and lymphocytes to smoke-exposed airways. In a subchronic model, AM156 and AM206 inhibited neutrophil and lymphocyte trafficking to the airways. Furthermore, AM156 and AM206 treatment inhibited mucus cell metaplasia and prevented the thickening of the airway epithelial layer induced by cigarette smoke. These data suggest that DP2 receptor antagonism may represent a novel therapy for COPD or other conditions characterized by neutrophil influx, mucus hypersecretion, and airway remodeling.

  3. Recombinant albumins containing additional peptide sequences smaller than barbourin retain the ability of barbourin-albumin to inhibit platelet aggregation.

    PubMed

    Sheffield, William P; Wilson, Brianna; Eltringham-Smith, Louise J; Gataiance, Sharon; Bhakta, Varsha

    2005-05-01

    The previously described fusion protein BLAH(6) (Marques JA et al.,Thromb Haemost 2001; 86: 902-8) is a recombinant protein that combines the small disintegrin barbourin with hexahistidine-tagged rabbit serumalbumin (RSA) produced in Pichia pastoris yeast. We sought to determine: (1) if BLAH(6) was immunogenic; and (2) if its barbourin domain could be productively replaced with smaller peptides. Purified BLAH(6) was injected into rabbits, and anti-barbourin antibodies were universally detected in plasma 28 days later; BLAH(6) was, however, equally effective in reducing platelet aggregation in both naive and pre-treated rabbits. Thrombocytopenia was not observed, and complexing BLAH(6) to alpha(IIb)beta(3) had no effect on antibody detection. The barbourin moiety of BLAH(6) was replaced with each of four sequences: Pep I (VCKGDWPC); PepII (VCRGDWPC); PepIII (bar-bourin 41-54); and PepIV (LPSPGDWR). The corresponding fusion proteins were tested for their ability to inhibit ADP-induced platelet aggregation. PepIII-LAH(6) inhibited neither rabbit nor human platelets. PepI-LAH(6) and PepIV-LAH(6) inhibited rabbit platelet aggregation as effectively as BLAH(6), but PepIV-LAH(6) did not inhibit human platelet aggregation. PepI-LAH(6) and PepIILAH(6) inhibited human platelet aggregation with IC(50)s 10- and 20-fold higher than BLAH(6). Cross-immunoprecipitation assays with human platelet lysates confirmed that all proteins and peptides interacted with the platelet integrin alpha(IIb)beta(3), but with greatly varying affinities. Our results suggest that the antiplatelet activity of BLAH(6) can be retained in albumin fusion proteins in which smaller peptides replace the barbourin domain; these proteins may be less immunogenic than BLAH(6).

  4. Neuroimmune pharmacological approaches

    PubMed Central

    Holzer, Peter; Hassan, Ahmed; Jain, Piyush; Reichmann, Florian; Farzi, Aitak

    2016-01-01

    Intestinal inflammation is a major health problem which impairs the quality of life, impacts mental health and is exacerbated by stress and psychiatric disturbances which, in turn, can affect disease prognosis and response to treatment. Accumulating evidence indicates that the immune system is an important interface between intestinal inflammation and the enteric, sensory, central and autonomic nervous systems. In addition, the neuroimmune interactions originating from the gastrointestinal tract are orchestrated by the gut microbiota. This article reviews some major insights into this complex homeostatic network that have been achieved during the past two years and attempts to put these advances into perspective with novel opportunities of pharmacological intervention. PMID:26426677

  5. Pharmacologic IKK/NF-κB inhibition causes antigen presenting cells to undergo TNFα dependent ROS-mediated programmed cell death

    NASA Astrophysics Data System (ADS)

    Tilstra, Jeremy S.; Gaddy, Daniel F.; Zhao, Jing; Davé, Shaival H.; Niedernhofer, Laura J.; Plevy, Scott E.; Robbins, Paul D.

    2014-01-01

    Monocyte-derived antigen presenting cells (APC) are central mediators of the innate and adaptive immune response in inflammatory diseases. As such, APC are appropriate targets for therapeutic intervention to ameliorate certain diseases. APC differentiation, activation and functions are regulated by the NF-κB family of transcription factors. Herein, we examined the effect of NF-κB inhibition, via suppression of the IκB Kinase (IKK) complex, on APC function. Murine bone marrow-derived macrophages and dendritic cells (DC), as well as macrophage and DC lines, underwent rapid programmed cell death (PCD) after treatment with several IKK/NF-κB inhibitors through a TNFα-dependent mechanism. PCD was induced proximally by reactive oxygen species (ROS) formation, which causes a loss of mitochondrial membrane potential and activation of a caspase signaling cascade. NF-κB-inhibition-induced PCD of APC may be a key mechanism through which therapeutic targeting of NF-κB reduces inflammatory pathologies.

  6. Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity123

    PubMed Central

    Ferrari-Amorotti, Giovanna; Chiodoni, Claudia; Shen, Fei; Cattelani, Sara; Soliera, Angela Rachele; Manzotti, Gloria; Grisendi, Giulia; Dominici, Massimo; Rivasi, Francesco; Colombo, Mario Paolo; Fatatis, Alessandro; Calabretta, Bruno

    2014-01-01

    Most triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1); thus, we investigated whether tranylcypromine [also known as trans-2-phenylcyclopropylamine hydrochloride (PCPA) or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic spread of TNBC cell lines. We show here that PCPA treatment induces the expression of E-cadherin and other epithelial markers and markedly suppresses migration and invasion of TNBC cell lines MDA-MB-231 and BT-549. These effects were phenocopied by Slug or LSD1 silencing. In two models of orthotopic breast cancer, PCPA treatment reduced local tumor growth and the number of lung metastases. In mice injected directly in the blood circulation with MDA-MB-231 cells, PCPA treatment or Slug silencing markedly inhibited bone metastases but had no effect on lung infiltration. Thus, blocking Slug activity may suppress the metastatic spread of TNBC and, perhaps, specifically inhibit homing/colonization to the bone. PMID:25499218

  7. Selective inhibition of the Kir2 family of inward rectifier potassium channels by a small molecule probe: the discovery, SAR and pharmacological characterization of ML133

    PubMed Central

    Wang, Hao-Ran; Wu, Meng; Yu, Haibo; Long, Shunyou; Stevens, Amy; Engers, Darren W.; Sackin, Henry; Daniels, J. Scott; Dawson, Eric S.; Hopkins, Corey R.; Lindsley, Craig W.; Li, Min; McManus, Owen B

    2011-01-01

    The Kir inward rectifying potassium channels have a broad tissue distribution and are implicated in a variety of functional roles. At least seven classes (Kir1 – Kir7) of structurally related inward rectifier potassium channels are known, and there are no selective small molecule tools to study their function. In an effort to develop selective Kir2.1 inhibitors, we performed a high-throughput screen (HTS) of more than 300,000 small molecules within the MLPCN for modulators of Kir2.1 function. Here we report one potent Kir2.1 inhibitor, ML133, which inhibits Kir2.1 with IC50 of 1.8 μM at pH 7.4 and 290 nM at pH 8.5, but exhibits little selectivity against other members of Kir2.x family channels. However, ML133 has no effect on Kir1.1 (IC50 > 300 μM), and displays weak activity for Kir4.1 (76 μM) and Kir7.1 (33 μM), making ML133 the most selective small molecule inhibitor of the Kir family reported to date. Due to the high homology within the Kir family, the channels share a common design of a pore region flanked by two transmembrane domains, identification of site(s) critical for isoform specificity would be an important basis for future development of more specific and potent Kir inhibitors. Using chimeric channels between Kir2.1 and Kir1.1 and site-directed mutagenesis, we have identified D172 and I176 within M2 segment of Kir2.1 as molecular determinants critical for the potency of ML133 mediated inhibition. Double mutation of the corresponding residues of Kir1.1 to those of Kir2.1 (N171D and C175I) transplants ML133 inhibition to Kir1.1. Together, the combination of a potent, Kir2 family selective inhibitor and identification of molecular determinants for the specificity provides both a tool and a model system to enable further mechanistic studies of modulation of Kir2 inward rectifier potassium channels. PMID:21615117

  8. Pharmacological Inactivation of Src Family Kinases Inhibits LPS-Induced TNF-α Production in PBMC of Patients with Behçet's Disease

    PubMed Central

    Pektanc, Gulsum; Akkurt, Zeynep M.; Bozkurt, Mehtap; Turkcu, Fatih M.; Kalkanli-Tas, Sevgi

    2016-01-01

    Behçet's disease (BD) is a multisystemic chronic inflammatory disease characterized by relapsing oral and genital ulcers, uveitis, and skin lesions. The pathogenesis of BD is still unknown. Aberrant production of some cytokines/chemokines plays an important role in the pathogenesis of various inflammatory diseases. Revealing a key signaling regulatory mechanism involved in proinflammatory cytokines/chemokines production is critical for understanding of the pathogenesis of BD. The aim of this study was to determine the role of Src family kinases (SFKs) in production of some LPS-induced proinflammatory cytokines/chemokines in peripheral blood mononuclear cells (PBMC) of active BD patients. Chemical inhibition of SFKs activity impaired LPS-induced TNF-α production in PBMC of active BD patients, suggesting that modulating SFKs activity may be a potential target for BD treatment. PMID:27445436

  9. Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats

    PubMed Central

    Ahnaou, Abdallah; Biermans, Ria; Drinkenburg, Wilhelmus H.

    2016-01-01

    Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A) and activation of metabotropic glutamate receptor (mGluR2) signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1) model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP); 2) confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3) evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not. PMID:26808689

  10. Blocking the chaperone kinome pathway: Mechanistic insights into a novel dual inhibition approach for supra-additive suppression of malignant tumors

    SciTech Connect

    Grover, Abhinav; Shandilya, Ashutosh; Agrawal, Vibhuti; Pratik, Piyush; Bhasme, Divya; Bisaria, Virendra S.; Sundar, Durai

    2011-01-07

    Research highlights: {yields} Withaferin A and 17-DMAG synergistically inhibit the Hsp90-Cdc37 chaperone pair. {yields} Binding of WA to Cdc37 cleft suppresses its kinase binding activity. {yields} 17-DMAG binding to the association complex results in H-bonds with 60% clustering. {yields} The ligands' bound complex was found structurally and thermodynamically stable. -- Abstract: The chaperone Hsp90 is involved in regulating the stability and activation state of more than 200 'client' proteins and takes part in the cancer diseased states. The major clientele-protein kinases depend on Hsp90 for their proper folding and functioning. Cdc37, a kinase targeting co-chaperone of Hsp90, mediates the interactions between Hsp90 and protein kinases. Targeting of Cdc37 has the prospect of delivering predominantly kinase-selective molecular responses as compared to the current pharmacologic Hsp90 inhibitors. The present work reports a bio-computational study carried out with the aim of exploring the dual inhibition of Hsp90/Cdc37 chaperone/co-chaperone association complex by the naturally occurring drug candidates withaferin A and 17-DMAG along with their possible modes of action. Our molecular docking studies reveal that withaferin A in combination with 17-DMAG can act as potent chaperone system inhibitors. The structural and thermodynamic stability of the ligands' bound complex was also observed from molecular dynamics simulations in water. Our results suggest a novel tumor suppressive action mechanism of herbal ligands which can be looked forward for further clinical investigations for possible anticancer drug formulations.

  11. Postnatal ethanol exposure alters levels of 2-arachidonylglycerol-metabolizing enzymes and pharmacological inhibition of monoacylglycerol lipase does not cause neurodegeneration in neonatal mice.

    PubMed

    Subbanna, Shivakumar; Psychoyos, Delphine; Xie, Shan; Basavarajappa, Balapal S

    2015-07-01

    The consumption of ethanol by pregnant women may cause neurological abnormalities, affecting learning and memory processes in children, and are collectively described as fetal alcohol spectrum disorders. However, the molecular mechanisms underlying these changes are still poorly understood. In our previous studies, we found that ethanol treatment of postnatal day 7 (P7) mice significantly enhances the anandamide levels but not the 2-arachidonylglycerol (2-AG) levels and induces widespread neurodegeneration, but the reason for the lack of significant effects of ethanol on the 2-AG level is unknown. In this study, we examined developmental changes in diacylglycerol lipase-α, β (DAGL-α and β) and monoacylglycerol lipase (MAGL). We found that the levels of these proteins were significantly higher in adult brains compared to those detected early in brain development. Next, we examined the influence of P7 ethanol treatment on these enzymes, finding that it differentially altered the DAGL-α protein and mRNA levels but consistently enhanced those of the DAGL-β. Interestingly, the ethanol treatment enhanced MAGL protein and mRNA levels. Inhibition of MAGL with KML29 failed to induce neurodegeneration in P7 mice. Collectively, these findings suggest that ethanol significantly activates DAGL-β and MAGL in the neonatal brain, resulting in no net change in 2-AG levels.

  12. Synergistic Induction of Apoptosis in High-Risk DLBCL by BCL2 Inhibition with ABT-199 Combined With Pharmacologic Loss of MCL1

    PubMed Central

    Li, Lingxiao; Pongtornpipat, Praechompoo; Tiutan, Timothy; Kendrick, Samantha L.; Park, Soyoung; Persky, Daniel O.; Rimsza, Lisa M.; Puvvada, Soham D.; Schatz, Jonathan H.

    2015-01-01

    Better treatments are needed for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of failing standard therapy. Avoiding apoptosis is a hallmark of cancer, and in DLBCL the redundantly functioning anti-apoptotic proteins BCL2 and MCL1 are frequently expressed. Here, we explore drugs that cause loss of MCL1, particularly the potent new cyclin-dependent kinase inhibitor dinaciclib, which knocks down MCL1 by inhibiting CDK9. Dinaciclib induces apoptosis in DLBCL cells but is completely overcome by increased activity of BCL2. We find clinical samples have frequent co-expression of MCL1 and BCL2, suggesting therapeutic strategies targeting only one will lead to treatment failures due to activity of the other. The BH3 mimetic ABT-199 potently and specifically targets BCL2. Single-agent ABT-199 had modest anti-tumor activity against most DLBCL lines and resulted in compensatory up-regulation of MCL1 expression. ABT-199 synergized strongly, however, when combined with dinaciclib and with other drugs affecting MCL1, including standard DLBCL chemotherapy drugs. We show potent anti-tumor activities of these combinations in xenografts and in a genetically accurate murine model of MYC-BCL2 double-hit lymphoma. In sum, we reveal a rational treatment paradigm to strip DLBCL of its protection from apoptosis and improve outcomes for high-risk patients. PMID:25882699

  13. Protonophore properties of hyperforin are essential for its pharmacological activity

    PubMed Central

    Sell, Thomas S.; Belkacemi, Thabet; Flockerzi, Veit; Beck, Andreas

    2014-01-01

    Hyperforin is a pharmacologically active component of the medicinal plant Hypericum perforatum (St. John's wort), recommended as a treatment for a range of ailments including mild to moderate depression. Part of its action has been attributed to TRPC6 channel activation. We found that hyperforin induces TRPC6-independent H+ currents in HEK-293 cells, cortical microglia, chromaffin cells and lipid bilayers. The latter demonstrates that hyperforin itself acts as a protonophore. The protonophore activity of hyperforin causes cytosolic acidification, which strongly depends on the holding potential, and which fuels the plasma membrane sodium-proton exchanger. Thereby the free intracellular sodium concentration increases and the neurotransmitter uptake by Na+ cotransport is inhibited. Additionally, hyperforin depletes and reduces loading of large dense core vesicles in chromaffin cells, which requires a pH gradient in order to accumulate monoamines. In summary the pharmacological actions of the “herbal Prozac” hyperforin are essentially determined by its protonophore properties shown here. PMID:25511254

  14. Protonophore properties of hyperforin are essential for its pharmacological activity.

    PubMed

    Sell, Thomas S; Belkacemi, Thabet; Flockerzi, Veit; Beck, Andreas

    2014-01-01

    Hyperforin is a pharmacologically active component of the medicinal plant Hypericum perforatum (St. John's wort), recommended as a treatment for a range of ailments including mild to moderate depression. Part of its action has been attributed to TRPC6 channel activation. We found that hyperforin induces TRPC6-independent H(+) currents in HEK-293 cells, cortical microglia, chromaffin cells and lipid bilayers. The latter demonstrates that hyperforin itself acts as a protonophore. The protonophore activity of hyperforin causes cytosolic acidification, which strongly depends on the holding potential, and which fuels the plasma membrane sodium-proton exchanger. Thereby the free intracellular sodium concentration increases and the neurotransmitter uptake by Na(+) cotransport is inhibited. Additionally, hyperforin depletes and reduces loading of large dense core vesicles in chromaffin cells, which requires a pH gradient in order to accumulate monoamines. In summary the pharmacological actions of the "herbal Prozac" hyperforin are essentially determined by its protonophore properties shown here. PMID:25511254

  15. Systems pharmacology of adiposity reveals inhibition of EP300 as a common therapeutic mechanism of caloric restriction and resveratrol for obesity

    PubMed Central

    Nishimura, Yuhei; Sasagawa, Shota; Ariyoshi, Michiko; Ichikawa, Sayuri; Shimada, Yasuhito; Kawaguchi, Koki; Kawase, Reiko; Yamamoto, Reiko; Uehara, Takuma; Yanai, Takaaki; Takata, Ryoji; Tanaka, Toshio

    2015-01-01

    Both caloric restriction (CR) and resveratrol (RSV) have beneficial effects on obesity. However, the biochemical pathways that mediate these beneficial effects might be complex and interconnected and have not been fully elucidated. To reveal the common therapeutic mechanism of CR and RSV, we performed a comparative transcriptome analysis of adipose tissues from diet-induced obese (DIO) zebrafish and obese humans. We identified nine genes in DIO zebrafish and seven genes in obese humans whose expressions were regulated by CR and RSV. Although the gene lists did not overlap except for one gene, the gene ontologies enriched in the gene lists were highly overlapped, and included genes involved in adipocyte differentiation, lipid storage and lipid metabolism. Bioinformatic analysis of cis-regulatory sequences of these genes revealed that their transcriptional regulators also overlapped, including EP300, HDAC2, CEBPB, CEBPD, FOXA1, and FOXA2. We also identified 15 and 46 genes that were dysregulated in the adipose tissue of DIO zebrafish and obese humans, respectively. Bioinformatics analysis identified EP300, HDAC2, and CEBPB as common transcriptional regulators for these genes. EP300 is a histone and lysyl acetyltransferase that modulates the function of histone and various proteins including CEBPB, CEBPD, FOXA1, and FOXA2. We demonstrated that adiposity in larval zebrafish was significantly reduced by C646, an inhibitor of EP300 that antagonizes acetyl-CoA. The reduction of adiposity by C646 was not significantly different from that induced by RSV or co-treatment of C646 and RSV. These results indicate that the inhibition of EP300 might be a common therapeutic mechanism between CR and RSV in adipose tissues of obese individuals. PMID:26441656

  16. Anti-Candida-biofilm activity of micafungin is attenuated by voriconazole but restored by pharmacological inhibition of Hsp90-related stress responses.

    PubMed

    Kaneko, Yukihiro; Ohno, Hideaki; Fukazawa, Hidesuke; Murakami, Yuko; Imamura, Yoshifumi; Kohno, Shigeru; Miyazaki, Yoshitsugu

    2010-06-01

    We have conducted an in vitro evaluation of the efficacy of a voriconazole-micafungin combination against Candida albicans. When used alone, both micafungin and voriconazole decreased the metabolic activity of planktonic cells, but only micafungin displayed potent anti-biofilm activity. Their combination appeared to have an additive effect against planktonic cells. However, voriconazole significantly antagonized the fungicidal effect of micafungin against Candida biofilms. Time-lag experiments showed that pre-treatment with voriconazole induced resistance to micafungin in Candida biofilms. The micafungin-antagonizing effect of voriconazole persisted even when the biofilm was no longer exposed to voriconazole. In contrast, voriconazole addition after 24 h of micafungin treatment did not alter micafungin sensitivity. To investigate the mechanism of antagonism, we used inhibitors of Hsp90 and its effectors because Hsp90 seems to be implicated in the resistance to micafungin. These molecules reversed the voriconazole-induced resistance to micafungin which suggests that Hsp90-related stress responses are involved in the antagonism. Our results may provide clues as to the mechanism of increased drug resistance in Candida biofilms and raises concerns about the use of the voriconazole-micafungin combination in clinical settings. PMID:19958255

  17. The Emergence of Nitroxyl (HNO) as a Pharmacological Agent

    PubMed Central

    Switzer, Christopher H.; Flores-Santana, Wilmarie; Mancardi, Danellie; Donzelli, Sonia; Basudhar, Debashree; Ridnour, Lisa A.; Miranda, Katrina M.; Fukuto, Jon M.; Paolocci, Nazerano; Wink, David A.

    2009-01-01

    Once a virtually unknown nitrogen oxide, nitroxyl (HNO) has emerged as a potential pharmacological agent. Recent advances in the understanding of the chemistry of HNO has led to the an understanding of HNO biochemistry which is vastly different from the known chemistry and biochemistry of nitric oxide (NO), the one electron-oxidation product of HNO. The cardiovascular roles of NO have been extensively studied, as NO is a key modulator of vascular tone and is involved in a number of vascular related pathologies. HNO displays unique cardiovascular properties and has been shown to have positive lusitropic and ionotropic effects in failing hearts without a chronotropic effect. Additionally, HNO causes a release of CGRP and modulates calcium channels such as ryanodine receptors. HNO has shown beneficial effects in ischemia reperfusion injury, as HNO treatment during reperfusion reduces infarct size. In addition to the cardiovascular effects observed, HNO has shown initial promise in the realm of cancer therapy. HNO has been demonstrated to inhibit GAPDH, a key glycolytic enzyme. Due to the Warburg effect, inhibiting glycolysis is an attractive target for inhibiting tumor proliferation. Indeed, HNO has recently been shown to inhibit tumor proliferation in mouse xenografts. Additionally, HNO inhibits tumor angiogenesis and induces cancer cell apoptosis. The effects seen with HNO donors are quite different from NO donors and in some cases are opposite. The chemical nature of HNO explains how HNO and NO, although closely chemically related, act so differently in biochemical systems. This also gives insight into the potential molecular motifs that may be reactive towards HNO and opens up a novel field of pharmacological development. PMID:19426703

  18. Changes in the rheological and colloidal properties of paper coating liquids with paper-yellowing inhibition additives.

    PubMed

    El-Sadi, Haifa; Carreau, Pierre; Esmail, Nabil

    2004-03-15

    This is an investigation of the effect of paper-yellowing inhibitors on the rheological, colloidal, and interfacial properties of paper-coating liquids and the associated changes in the liquid surface microstructure. In addition to rheological measurements, we measured the zeta potential and imaged the surface microstructure of coating liquids by transmission electron microscopy (TEM) using an advanced Pt/C replica technique. The zeta potential is related to the concentration of added inhibitors. The images reveal interparticle structuring with increasing concentration of inhibitors. The structuring is related to the interaction between the coating liquids and the inhibitors. It was also found that the viscosity and the elastic modulus increased with inhibitor concentration. The significant changes in mixture properties due to the additives show the importance of the rheological and surface characterization of liquids and the ensuing effect on the corresponding engineering process.

  19. Telechelic Poly(2-oxazoline)s with a biocidal and a polymerizable terminal as collagenase inhibiting additive for long-term active antimicrobial dental materials

    PubMed Central

    Fik, Christoph P.; Konieczny, Stefan; Pashley, David H.; Waschinski, Christian J.; Ladisch, Reinhild S.; Salz, Ulrich; Bock, Thorsten; Tiller, Joerg C.

    2015-01-01

    Although modern dental repair materials show excellent mechanical and adhesion properties, they still face two major problems: First, any microbes that remain alive below the composite fillings actively decompose dentin and thus, subsequently cause secondary caries. Second, even if those microbes are killed, the extracellular proteases such as MMP, remain active and can still degrade collagenousdental tissue. In order to address both problems, a poly(2-methyloxazoline) with a biocidal quaternary ammonium and a polymerizable methacrylate terminal was explored as additive for a commercial dental adhesive. It could be demonstrated that the adhesive rendered the adhesive contact-active antimicrobial against S. mutans at a concentration of only 2.5 wt% and even constant washing with water for 101 days did not diminish this effect. Increasing the amount of the additive to 5 wt% allowed killing S. mutans cells in the tubuli of bovinedentin upon application of the adhesive. Further, the additive fully inhibited bacterial collagenase at a concentration of 0.5 wt% and reduced human recombinant collagenase MMP-9 to 13% of its original activity at that concentration. Human MMPs naturally bound to dentin were inhibited by more than 96% in a medium containing 5 wt% of the additive. Moreover, no adverse effect on the enamel/dentine shear bond strength was detected in combination with a dental composite. PMID:25130877

  20. Accelerated solvent extraction of animal feedingstuffs for microbial growth inhibition screening for the presence of antimicrobial feed additives.

    PubMed

    Higgins, H C; McEvoy, J D G

    2002-09-01

    Three plate systems (combinations of indicator organism and growth medium) were evaluated for the detection of analytical standards of the banned feed additives avoparcin, bacitracin zinc, spiramycin, tylosin and virginiamycin. When authorized in the EU, the previously recommended minimum inclusion rate (MIR) for each compound was 5 mg kg(-1). One of the plate systems (Micrococcus luteus ATCC 10240, nutrient agar) detected all five additives. This plate was used in a further study that evaluated the suitability of accelerated solvent extraction (ASE) as a first step in the development of a rapid single-plate screening assay. A drug-free (negative control) feedingstuff was fortified with the compounds (0-50 mg kg(-1)), extracted by ASE and the extracts applied to the plate at each of three pH ranges - unadjusted extract (pH 5.7-5.9), pH 6.5 and 8.0. At pH 6.5, sub-MIR concentrations of virginiamycin and tylosin were detectable. Avoparcin was detectable at 6.3 mg kg(-1). The detection of zinc bacitracin was#10; pH-independent (10 mg kg(-1)). At pH 8.0, spiramycin was detectable at 5.4 mg kg(-1). Mean +/- SD analytical recoveries from fortified feedingstuffs (n = 10) ranged from 57 +/- 1.5% for avoparcin to 96 +/- 4% for virginiamycin. The five additives were also detectable following ASE extraction from a range of different feedingstuffs fortified with each of the drugs. A further 24 compounds permitted for use in animal feeds were tested. Of these, nine were detectable at their recommended MIR. It is concluded that ASE is a versatile technique suitable for the automated extraction of a range of antimicrobials from animal feedingstuffs. Employing ASE with this single-plate detection system permits the rapid antimicrobial screening of animal feedingstuffs and allows the detection of the banned additives. Whilst the method is applicable as a screening test, more specific postscreening methods would be necessary for subsequent identification (and quantification) of

  1. The pharmacology of neurosteroidogenesis.

    PubMed

    Costa, E; Auta, J; Guidotti, A; Korneyev, A; Romeo, E

    1994-06-01

    In adrenal cortex and other steroidogenic tissues including glial cells, the conversion of cholesterol into pregnenolone is catalyzed by the cytochrome P450scc located in the inner mitochondrial membrane. A complex mechanism operative in regulating cholesterol access to P450scc limits the rate of pregnenolone biosynthesis. Participating in this mechanism are DBI (diazepam binding inhibitor), an endogenous peptide that is highly expressed in steroidogenic cells and some of the DBI processing products including DBI 17-50 (TTN). DBI and TTN activate steroidogenesis by binding to a specific receptor located in the outer mitochondrial membrane, termed mitochondrial DBI receptor complex (MDRC). MDRC is a hetero-oligomeric protein: only the subunit that includes the DBI and benzodiazepine (BZD) recognition sites has been cloned. Several 2-aryl-3-indoleacetamide derivatives (FGIN-1-X) with highly selective affinity (nM) for MDRC were synthesized which can stimulate steroidogenesis in mitochondrial preparations. These compounds stimulate adrenal cortex steroidogenesis in hypophysectomized rats but not in intact animals. Moreover, this steroidogenesis is inhibited by the isoquinoline carboxamide derivative PK 11195, a specific high affinity ligand for MDRC with a low intrinsic steroidogenic activity. Some of the FGIN-1-X derivatives stimulate brain pregnenolone accumulation in adrenalectomized-castrated rats. The FGIN-1-X derivatives that increase brain pregnenolone content, elicit antineophobic activity and antagonize punished behavior in the Vogel conflict test in rats. These actions of FGIN-1-X are resistant to inhibition by flumazenil, a specific inhibitor of BZD action in GABAA receptors but are antagonized by PK 11195, a specific blocker of the steroidogenesis activation via MDRC stimulation. It is postulated that the pharmacological action of FGIN-1-X depends on a positive modulation of the GABA action on GABAA receptors mediated by the stimulation of brain

  2. [Pharmacological effects of hordenine].

    PubMed

    Hapke, H J; Strathmann, W

    1995-06-01

    Hordenine is an ingredient of some plants which are used as feed for animals, i.e. in sprouting barley. After ingestion of such feed hordenine may be detected in blood or urine of horses which in case of racing horses may be the facts of using prohibited compounds. Results of some experiments in pharmacological models show that hordenine is an indirectly acting adrenergic drug. It liberates norepinephrine from stores. In isolated organs and those structures with reduced epinephrine contents the hordenine-effect is only very poor. Experiments in intact animals (rats, dogs) show that hordenine has a positive inotropic effect upon the heart, increases systolic and diastolic blood pressure, peripheral blood flow volume, inhibits gut movements but has no effect upon the psychomotorical behaviour of mice. All effects are short and only possible after high doses which are not to be expected after ingestion of hordenine containing feed for horses. A measurable increase of the performance of racing horses is quite improbable.

  3. The effect of membrane fluidization on protein kinase C: Inhibition by ethanol and higher alcohols and stimulation by increased lipid unsaturation or addition non-esterified fatty acids

    SciTech Connect

    Cox, K.J.A.; Rubin, E.; Stubbs, C.D. )

    1992-01-01

    Protein kinase C (PKC) is a membrane bound enzyme that is dependent on calcium, anionic phospholipids, and sn-1,2-diacylglycerol (DAG) to be fully active. The relationship between membrane fluidity and PKC activity was investigated using model vesicle systems composed of phosphatidylserine alone or in combination with phosphatidylcholine. Effects on membrane fluidity were assessed using the fluorescence anisotropy of diphenylhexatriene. When membrane fluidity was increased by the addition of short chain n-alkanols, PKC activity was inhibited. There was a linear relationship for a given level of inhibition and the membrane-buffer partition coefficient. By contrast, when the degree of unsaturation in the phosphatidylcholine was increased, although the bilayer was again fluidized, PKC activity was enhanced. The addition of non-esterified fatty acid also activated PKC, either when directly added to the vesicles or when generated by the addition of exogenous phospholipase A[sub 2], and again the bilayer was fluidized. It is proposed that a more fluid membrane lipid bilayer, induced by increased unsaturation or non-esterified fatty acids, facilitated optimal interaction at the DAG site since the effect could be demonstrated in a lipid free system using protamine sulfate.

  4. Characteristics of concentration-inhibition curves of individual chemicals and applicability of the concentration addition model for mixture toxicity prediction.

    PubMed

    Wang, Na; Wang, Xiaochang C; Ma, Xiaoyan

    2015-03-01

    The concentration addition (CA) model has been widely applied to predict mixture toxicity. However, its applicability is difficult to evaluate due to the complexity of interactions among substances. Considering that the concentration-response curve (CRC) of each component of the mixture is closely related to the prediction of mixture toxicity, mathematical treatments were used to derive a characteristic index kECx (k was the slope of the tangent line of a CRC at concentration ECx). The implication is that the CA model would be applicable for predicting the mixture toxicity only when chemical components have similar kECx in the whole or part of the concentration range. For five selected chemicals whose toxicity was detected using luminescent bacteria, sodium dodecyl benzene sulfonate (SDBS) showed much higher kECx values than the others and its existence in the binary mixtures brought about overestimation of the mixture toxicity with the CA model. The higher the mass ratio of SDBS in a multi-mixture was, the more the toxicity prediction deviated from measurements. By applying the method proposed in this study to analyze some published data, it is confirmed that some components having significantly different kECx values from the other components could explain the large deviation of the mixture toxicity predicted by the CA model. PMID:25499050

  5. Advances in the pharmacological activities and mechanisms of diosgenin.

    PubMed

    Chen, Yan; Tang, You-Mei; Yu, Su-Lan; Han, Yu-Wei; Kou, Jun-Ping; Liu, Bao-Lin; Yu, Bo-Yang

    2015-08-01

    Diosgenin, a well-known steroid sapogenin derived from plants, has been used as a starting material for production of steroidal hormones. The present review will summarize published literature concerning pharmacological potential of diosgenin, and the underlying mechanisms of actions. Diosgenin has shown a vast range of pharmacological activities in preclinical studies. It exhibits anticancer, cardiovascular protective, anti-diabetes, neuroprotective, immunomodulatory, estrogenic, and skin protective effects, mainly by inducing apoptosis, suppressing malignant transformation, decreasing oxidative stress, preventing inflammatory events, promoting cellular differentiation/proliferation, and regulating T-cell immune response, etc. It interferes with cell death pathways and their regulators to induce apoptosis. Diosgenin antagonizes tumor metastasis by modulating epithelial-mesenchymal transition and actin cytoskeleton to change cellular motility, suppressing degradation of matrix barrier, and inhibiting angiogenesis. Additionally, diosgenin improves antioxidant status and inhibits lipid peroxidation. Its anti-inflammatory activity is through inhibiting production of pro-inflammatory cytokines, enzymes and adhesion molecules. Furthermore, diosgenin drives cellular growth/differentiation through the estrogen receptor (ER) cascade and transcriptional factor PPARγ. In summary, these mechanistic studies provide a basis for further development of this compound for pharmacotherapy of various diseases. PMID:26253490

  6. Super pharmacological levels of calcitriol (1,25-(OH)2D3) inhibits mineral deposition and decreases cell proliferation in a strain dependent manner in chicken mesenchymal stem cells undergoing osteogenic differentiation in vitro

    PubMed Central

    Pande, Vivek V.; Chousalkar, Kapil C.; Bhanugopan, Marie S.; Quinn, Jane C.

    2015-01-01

    The biologically active form of vitamin D3, calcitriol (1,25-(OH)2D3), plays a key role in mineral homeostasis and bone formation and dietary vitamin D3 deficiency is a major cause of bone disorders in poultry. Supplementary dietary cholecalciferol (25-hydroxyvitamin D, 25-OH), the precursor of calcitriol, is commonly employed to combat this problem; however, dosage must be carefully determined as excess dietary vitamin D can cause toxicity resulting in a decrease in bone calcification, hypercalcinemia and renal failure. Despite much research on the therapeutic administration of dietary vitamin D in humans, the relative sensitivity of avian species to exogenous vitamin D has not been well defined. In order to determine the effects of exogenous 1,25-(OH)2D3 during avian osteogenesis, chicken bone marrow-derived mesenchymal stem cells (BM-MSCs) were exposed to varying doses of 1,25-(OH)2D3 during in vitro osteogenic differentiation and examined for markers of early proliferation and osteogenic induction. Similar to humans and other mammals, poultry BM-MSCs were found to be highly sensitive to exogenous 1,25-(OH)2D3 with super pharmacological levels exerting significant inhibition of mineralization and loss of cell proliferation in vitro. Strain related differences were apparent, with BM-MCSs derived from layers strains showing a higher level of sensitivity to 1,25-(OH)2D3 than those from broilers. These data suggest that understanding species and strain specific sensitivities to 1,25-(OH)2D3 is important for optimizing bone health in the poultry industry and that use of avian BM-MSCs are a useful tool for examining underlying effects of genetic variation in poultry. PMID:26500277

  7. Studies in neuroendocrine pharmacology

    NASA Technical Reports Server (NTRS)

    Maickel, R. P.

    1976-01-01

    The expertise and facilities available within the Medical Sciences Program section on Pharmacology were used along with informational input from various NASA sources to study areas relevant to the manned space effort. Topics discussed include effects of drugs on deprivation-induced fluid consumption, brain biogenic amines, biochemical responses to stressful stimuli, biochemical and behavioral pharmacology of amphetamines, biochemical and pharmacological studies of analogues to biologically active indole compounds, chemical pharmacology: drug metabolism and disposition, toxicology, and chemical methodology. Appendices include a bibliography, and papers submitted for publication or already published.

  8. Inhibition of protein kinase C catalytic activity by additional regions within the human protein kinase Calpha-regulatory domain lying outside of the pseudosubstrate sequence.

    PubMed Central

    Kirwan, Angie F; Bibby, Ashley C; Mvilongo, Thierry; Riedel, Heimo; Burke, Thomas; Millis, Sherri Z; Parissenti, Amadeo M

    2003-01-01

    The N-terminal pseudosubstrate site within the protein kinase Calpha (PKCalpha)-regulatory domain has long been regarded as the major determinant for autoinhibition of catalytic domain activity. Previously, we observed that the PKC-inhibitory capacity of the human PKCalpha-regulatory domain was only reduced partially on removal of the pseudosubstrate sequence [Parissenti, Kirwan, Kim, Colantonio and Schimmer (1998) J. Biol. Chem. 273, 8940-8945]. This finding suggested that one or more additional region(s) contributes to the inhibition of catalytic domain activity. To assess this hypothesis, we first examined the PKC-inhibitory capacity of a smaller fragment of the PKCalpha-regulatory domain consisting of the C1a, C1b and V2 regions [GST-Ralpha(39-177): this protein contained the full regulatory domain of human PKCalpha fused to glutathione S-transferase (GST), but lacked amino acids 1-38 (including the pseudosubstrate sequence) and amino acids 178-270 (including the C2 region)]. GST-Ralpha(39-177) significantly inhibited PKC in a phorbol-independent manner and could not bind the peptide substrate used in our assays. These results suggested that a region within C1/V2 directly inhibits catalytic domain activity. Providing further in vivo support for this hypothesis, we found that expression of N-terminally truncated pseudosubstrate-less bovine PKCalpha holoenzymes in yeast was capable of inhibiting cell growth in a phorbol-dependent manner. This suggested that additional autoinhibitory force(s) remained within the truncated holoenzymes that could be relieved by phorbol ester. Using tandem PCR-mediated mutagenesis, we observed that mutation of amino acids 33-86 within GST-Ralpha(39-177) dramatically reduced its PKC-inhibitory capacity when protamine was used as substrate. Mutagenesis of a broad range of sequences within C2 (amino acids 159-242) also significantly reduced PKC-inhibitory capacity. Taken together, these observations support strongly the existence of

  9. MAP Kinase Phosphatase 1 (MKP-1/DUSP1) is Neuroprotective in Huntington’s Disease Via Additive Effects of JNK and p38 Inhibition

    PubMed Central

    Taylor, David M.; Moser, Roger; Régulier, Etienne; Breuillaud, Lionel; Dixon, Meredith; Beesen, Ayshe Ana; Elliston, Linda; Silva Santos, Mariana de Fatima; Kim, Jinho; Jones, Lesley; Goldstein, Darlene R.; Ferrante, Robert J.; Luthi-Carter, Ruth

    2013-01-01

    We previously demonstrated that sodium butyrate is neuroprotective in Huntington’s disease (HD) mice and that this therapeutic effect is associated with increased expression of mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1/DUSP1). Here we show that enhancing MKP-1 expression is sufficient to achieve neuroprotection in lentiviral models of HD. Wild-type MKP-1 overexpression inhibited apoptosis in primary striatal neurons exposed to an N-terminal fragment of polyglutamine-expanded huntingtin (Htt171-82Q), blocking caspase-3 activation and significantly reducing neuronal cell death. This neuroprotective effect of MKP-1 was demonstrated to be dependent on its enzymatic activity, being ablated by mutation of its phosphatase domain and being attributed to inhibition of specific MAP kinases (MAPKs). Overexpression of MKP-1 prevented the polyglutamine-expanded huntingtin-induced activation of c-Jun N-terminal kinases (JNKs) and p38 MAPKs, whereas extracellular signal-regulated kinase 1/2 (ERK1/2) activation was not altered by either polyglutamine-expanded Htt or MKP-1. Moreover, mutants of MKP-1 that selectively prevented p38 or JNK binding confirmed the important dual contributions of p38 and JNK regulation to MKP-1-mediated neuroprotection. These results demonstrate additive effects of p38 and JNK MAPK inhibition by MKP-1 without consequence to ERK activation in this striatal neuron-based paradigm. MKP-1 also provided neuroprotection in vivo in a lentiviral model of HD neuropathology in rat striatum. Taken together, these data extend previous evidence that JNK- and p38-mediated pathways contribute to HD pathogenesis and, importantly, show that therapies simultaneously inhibiting both JNK and p38 signalling pathways may lead to improved neuroprotective outcomes. PMID:23392662

  10. Additive inhibition of porcine reproductive and respiratory syndrome virus infection with the soluble sialoadhesin and CD163 receptors.

    PubMed

    Chen, Yang; Guo, Rui; He, Shan; Zhang, Xinyu; Xia, Xiaoli; Sun, Huaichang

    2014-01-22

    -delivered soluble receptors Sn4D-Fc and SRCR59-Fc had dose-dependent and temporal antiviral effect against three different PRRSV strains. Since the data presented indicate an additive anti-PRRSV activity between the soluble receptors Sn4D-Fc and SRCR59-Fc, we conclude that the two rAd vectors generated will be useful for development a novel reagent for PRRS control.

  11. Total synthesis and evaluation of cytostatin, its C10-C11 diastereomers, and additional key analogues: impact on PP2A inhibition.

    PubMed

    Lawhorn, Brian G; Boga, Sobhana B; Wolkenberg, Scott E; Colby, David A; Gauss, Carla-Maria; Swingle, Mark R; Amable, Lauren; Honkanen, Richard E; Boger, Dale L

    2006-12-27

    The total synthesis of cytostatin, an antitumor agent belonging to the fostriecin family of natural products, is described in full detail. The convergent approach relied on a key epoxide-opening reaction to join the two stereotriad units and a single-step late-stage stereoselective installation of the sensitive (Z,Z,E)-triene through a beta-chelation-controlled nucleophilic addition. The synthetic route provided rapid access to the C4-C6 stereoisomers of the cytostatin lactone, which were prepared and used to define the C4-C6 relative stereochemistry of the natural product. In addition to the natural product, each of the C10-C11 diastereomers of cytostatin was divergently prepared (11 steps from key convergence step) by this route and used to unequivocally confirm the relative and absolute stereochemistry of cytostatin. Each of the cytostatin diastereomers exhibited a reduced activity toward inhibition of PP2A (>100-fold), demonstrating the importance of the presence and stereochemistry of the C10-methyl and C11-hydroxy groups for potent PP2A inhibition. Extensions of the studies provided dephosphocytostatin, sulfocytostatin (a key analogue related to the natural product sultriecin), 11-deshydroxycytostatin, and an analogue lacking the entire C12-C18 (Z,Z,E)-triene segment, which were used to define the magnitude of the C9-phosphate (>4000-fold), C11-alcohol (250-fold), and triene (220-fold) contribution to PP2A inhibition. A model of cytostatin bound to the active site of PP2A is presented, compared to that of fostriecin, which is also presented in detail for the first time, and used to provide insights into the role of the key substituents. Notably, the alpha,beta unsaturated lactone of cytostatin, like that of fostriecin, is projected to serve as a key electrophile, providing a covalent adduct with Cys269 unique to PP2A, contributing to its potency (> or =200-fold for fostriecin) and accounting for its selectivity.

  12. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    SciTech Connect

    Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  13. [Pharmacologic treatment of Asperger syndrome].

    PubMed

    Yamada, Satoru

    2007-03-01

    Asperger syndrome is associated with various dysfunctional and problematic behaviors, in addition to the core features of communication and social skills dysfunction that define these conditions. Although there is currently no pharmacologic cure for the core features of Asperger syndrome. This article discusses the various medications for the behavioral symptoms of Asperger syndrome, which include hyperactivity, aggression, tantrums, self-injury, depression, obsession and so on. Methylphenidate, SSRIs, atypical antipsychotics and mood stabilizer were introduced.

  14. Pharmacology for the Psychotherapist.

    ERIC Educational Resources Information Center

    Goldenberg, Myron Michael

    This book covers those areas of pharmacology that are of importance and interest to the psychotherapist. The 1st chapter introduces the various types of drugs. The 2nd chapter presents an overview of pharmacology and its principles. The 3rd chapter reviews aspects of the human body of importance to understanding the workings of psychotropic drugs.…

  15. Nurse Practitioner Pharmacology Education.

    ERIC Educational Resources Information Center

    Waigandt, Alex; Chang, Jane

    A study compared the pharmacology training of nurse practitioner programs with medical and dental programs. Seventy-three schools in 14 states (40 nurse practitioner programs, 19 schools of medicine, and 14 schools of dentistry) were surveyed by mailed questionnaire about the number of hours devoted to the study of pharmacology. The major findings…

  16. Pharmacology Information System Ready

    ERIC Educational Resources Information Center

    Chemical and Engineering News, 1973

    1973-01-01

    Discusses the development and future of Prophet,'' a specialized information handling system for pharmacology research. It is designed to facilitate the acquisition and dissemination of knowledge about mechanisms of drug action, and it is hoped that it will aid in converting pharmacology research from an empirical to a predictive science. (JR)

  17. Curriculum Guidelines for Pharmacology.

    ERIC Educational Resources Information Center

    Shaw, David H.; And Others

    1990-01-01

    Pharmacology embraces the physical and chemical properties of drugs; the preparation of pharmaceutical agents; the absorption, fate, and excretion of drugs; and the effects of drugs on living systems. These guidelines represent a consensus on what would constitute a minimally acceptable pharmacology course for predoctoral dental students. (MLW)

  18. Addition of vasopressin synthetic analogue [V(4)Q(5)]dDAVP to standard chemotherapy enhances tumour growth inhibition and impairs metastatic spread in aggressive breast tumour models.

    PubMed

    Garona, Juan; Pifano, Marina; Pastrian, Maria B; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

    2016-08-01

    [V(4)Q(5)]dDAVP is a novel 2nd generation vasopressin analogue with robust antitumour activity against metastatic breast cancer. We recently reported that, by acting on vasopressin V2r membrane receptor present in tumour cells and microvascular endothelium, [V(4)Q(5)]dDAVP inhibits angiogenesis and metastatic progression of the disease without overt toxicity. Despite chemotherapy remaining as a primary therapeutic option for aggressive breast cancer, its use is limited by low selectivity and associated adverse effects. In this regard, we evaluated potential combinational benefits by adding [V(4)Q(5)]dDAVP to standard-of-care chemotherapy. In vitro, combination of [V(4)Q(5)]dDAVP with sub-IC50 concentrations of paclitaxel or carmustine resulted in a cooperative inhibition of breast cancer cell growth in comparison to single-agent therapy. In vivo antitumour efficacy of [V(4)Q(5)]dDAVP addition to chemotherapy was first evaluated using the triple-negative MDA-MB-231 breast cancer xenograft model. Tumour-bearing mice were treated with i.v. injections of [V(4)Q(5)]dDAVP (0.3 μg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.). After 6 weeks of treatment, combination regimen resulted in greater tumour growth inhibition compared to monotherapy. [V(4)Q(5)]dDAVP addition was also associated with reduction of local aggressiveness, and impairment of tumour invasion and infiltration of the skin. Benefits of combined therapy were confirmed in the hormone-independent and metastatic F3II breast cancer model by combining [V(4)Q(5)]dDAVP with carmustine (25 mg/kg i.p.). Interestingly, [V(4)Q(5)]dDAVP plus cytotoxic agents severely impaired colony forming ability of tumour cells and inhibited breast cancer metastasis to lung. The present study shows that [V(4)Q(5)]dDAVP may complement conventional chemotherapy by modulating metastatic progression and early stages of microtumour establishment, and thus supports further preclinical testing of

  19. Addition of vasopressin synthetic analogue [V(4)Q(5)]dDAVP to standard chemotherapy enhances tumour growth inhibition and impairs metastatic spread in aggressive breast tumour models.

    PubMed

    Garona, Juan; Pifano, Marina; Pastrian, Maria B; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

    2016-08-01

    [V(4)Q(5)]dDAVP is a novel 2nd generation vasopressin analogue with robust antitumour activity against metastatic breast cancer. We recently reported that, by acting on vasopressin V2r membrane receptor present in tumour cells and microvascular endothelium, [V(4)Q(5)]dDAVP inhibits angiogenesis and metastatic progression of the disease without overt toxicity. Despite chemotherapy remaining as a primary therapeutic option for aggressive breast cancer, its use is limited by low selectivity and associated adverse effects. In this regard, we evaluated potential combinational benefits by adding [V(4)Q(5)]dDAVP to standard-of-care chemotherapy. In vitro, combination of [V(4)Q(5)]dDAVP with sub-IC50 concentrations of paclitaxel or carmustine resulted in a cooperative inhibition of breast cancer cell growth in comparison to single-agent therapy. In vivo antitumour efficacy of [V(4)Q(5)]dDAVP addition to chemotherapy was first evaluated using the triple-negative MDA-MB-231 breast cancer xenograft model. Tumour-bearing mice were treated with i.v. injections of [V(4)Q(5)]dDAVP (0.3 μg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.). After 6 weeks of treatment, combination regimen resulted in greater tumour growth inhibition compared to monotherapy. [V(4)Q(5)]dDAVP addition was also associated with reduction of local aggressiveness, and impairment of tumour invasion and infiltration of the skin. Benefits of combined therapy were confirmed in the hormone-independent and metastatic F3II breast cancer model by combining [V(4)Q(5)]dDAVP with carmustine (25 mg/kg i.p.). Interestingly, [V(4)Q(5)]dDAVP plus cytotoxic agents severely impaired colony forming ability of tumour cells and inhibited breast cancer metastasis to lung. The present study shows that [V(4)Q(5)]dDAVP may complement conventional chemotherapy by modulating metastatic progression and early stages of microtumour establishment, and thus supports further preclinical testing of

  20. Selection of autochthonous lactic acid bacteria from goat dairies and their addition to evaluate the inhibition of Salmonella typhi in artisanal cheese.

    PubMed

    Ferrari, Iris da Silva; de Souza, Jane Viana; Ramos, Cintia Lacerda; da Costa, Mateus Matiuzzi; Schwan, Rosane Freitas; Dias, Francesca Silva

    2016-12-01

    This study aimed to select autochthonous lactic acid bacteria (LAB) with probiotic and functional properties from goat dairies and test their addition to artisanal cheese for the inhibition of Salmonella typhi. In vitro tests, including survival in the gastrointestinal tract (GIT), auto- and co-aggregation, the hemolytic test, DNase activity, antimicrobial susceptibility, antibacterial activity, tolerance to NaCl and exopolysaccharide (EPS), gas and diacetyl production were conducted for sixty isolates. Based on these tests, four LAB isolates (UNIVASF CAP 16, 45, 84 and 279) were selected and identified. Additional tests, such as production of lactic and citric acids by UNIVASF CAP isolates were performed in addition to assays of bile salt hydrolase (BSH), β-galactosidase and decarboxylase activity. The four selected LAB produced high lactic acid (>17 g/L) and low citric acid (0.2 g/L) concentrations. All selected strains showed BSH and β-galactosidase activity and none showed decarboxylase activity. Three goat cheeses (1, 2 and control) were produced and evaluated for the inhibitory action of selected LAB against Salmonella typhi. The cheese inoculated with LAB (cheese 2) decreased 0.38 log10 CFU/g of S. Typhy population while in the cheese without LAB inoculation (cheese 1) the pathogen population increased by 0.29 log units. Further, the pH value increased linearly over time, by 0.004 units per day in cheese 1. In the cheese 2, the pH value decreased linearly over time, by 0.066 units per day. The cocktail containing selected Lactobacillus strains with potential probiotic and technological properties showed antibacterial activity against S. typhi in vitro and in artisanal goat cheese. Thus, goat milk is important source of potential probiotic LAB which may be used to inhibit the growth of Salmonella population in cheese goat, contributing to safety and functional value of the product. PMID:27554143

  1. Pharmacological profile of droxicam.

    PubMed

    Esteve, J; Farré, A J; Roser, R

    1988-01-01

    In Studies of anti-inflammatory activity, droxicam has shown itself to be as active as piroxicam and much more active than phenylbutazone, isoxicam and suprofen, both in acute studies such as carrageenin oedema, nystatin oedema and ultraviolet erythema, and in longer-term tests such as that of the cotton pellet. In the studies of anti-arthritic activity, which require long-term treatment, droxicam was as effective as piroxicam, both on primary and on secondary lesions. The study of analgaesic activity, conducted by means of the tests of protective activity against writhing induced by phenylbenzoquinone and acetylcholine bromide in the mouse and by acetic acid in the rat, droxicam activity was superior to that of acetylsalicylic acid, dipyrone, isoxicam and phenylbutazone. Droxicam also showed antipyretic activity in the rat, greater than that of acetylsalicylic acid, dipyrone and 4-aminoantipyrine, in the brewer's yeast and Salmonella typhi tests. Droxicam also acts as an ex vivo platelet aggregation inhibitor in the dog. In the study of inhibition of peritoneal capillary permeability in the mouse, droxicam was considerably more potent than isoxicam or phenylbutazone. Studies of general pharmacology have demonstrated that droxicam, at high doses, has no cardiovascular or respiratory effects, and that neither does it modify behaviour in rats and mice, determined by the Irwin test. Gastrointestinal tolerance of droxicam has been compared with that of piroxicam, and it has been found that droxicam is far better tolerated. The study of induction of gastrointestinal lesions in the rat demonstrated that the gastrolesive potential of droxicam is 10 times inferior to that of piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3278945

  2. Pharmacology of bevantolol hydrochloride.

    PubMed

    Kaplan, H R

    1986-11-26

    Bevantolol is a cardioselective, beta-adrenoreceptor antagonist, devoid of intrinsic beta sympathomimetic activity and with weak membrane-stabilizing and local anesthetic properties. The 3,4-dimethoxyphenylethylamino moiety, substituted on the side chain amine function, confers cardioselectivity, which has been confirmed by a number of experiments. In vitro, bevantolol demonstrated greater antagonism of atrial than tracheal responses to isoproterenol. In vivo, bevantolol preferentially inhibited isoproterenol-induced tachycardias in conscious and anesthetized dogs, compared with the nonselective agent propranolol. Conversely, its effect on blood pressure after isoproterenol was minimal compared with propranolol, reflecting its muted effect on beta 2 peripheral receptors. A functional difference between bevantolol and propranolol was demonstrated in histamine-challenged guinea pigs. Bevantolol had little effect on the antiasthmatic effect of isoproterenol, whereas propranolol blocked it totally. Bevantolol's lack of intrinsic sympathomimetic activity was demonstrated in normal and reserpinized dogs, where it was devoid of intrinsic sympathomimetic activity at doses up to 10 mg/kg. Similarly, intravenous doses of 10 mg/kg had to be administered before direct myocardial depression occurred in the reserpinized animals. Metabolite 3, which is excreted in trace amounts in human urine, demonstrates intrinsic sympathomimetic activity when administered in pharmacologic doses to dogs; however, any clinical relevance remains to be established. Several laboratories have demonstrated that bevantolol interacts at alpha-adrenergic sites. These data require further investigation. The dose-related antihypertensive effect of bevantolol has been demonstrated in spontaneously hypertensive and 2 kidney, 1 clip renal hypertensive rats. Animal experiments also suggest that bevantolol may be useful in angina: It caused a favorable redistribution of blood flow in dogs in which the left

  3. Treatment of Pancreatic Cancer with Pharmacological Ascorbate

    PubMed Central

    Cieslak, John A.; Cullen, Joseph J.

    2016-01-01

    The prognosis for patients diagnosed with pancreatic cancer remains dismal, with less than 3% survival at 5 years. Recent studies have demonstrated that high-dose, intravenous pharmacological ascorbate (ascorbic acid, vitamin C) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells vs. normal cells, suggesting a promising new role of ascorbate as a therapeutic agent. At physiologic concentrations, ascorbate functions as a reducing agent and antioxidant. However, when pharmacological ascorbate is given intravenously, it is possible to achieve millimolar plasma concentration. At these pharmacological levels, and in the presence of catalytic metal ions, ascorbate can induce oxidative stress through the generation of hydrogen peroxide (H2O2). Recent in vitro and in vivo studies have demonstrated ascorbate oxidation occurs extracellularly, generating H2O2 flux into cells resulting in oxidative stress. Pharmacologic ascorbate also inhibits the growth of pancreatic tumor xenografts and displays synergistic cytotoxic effects when combined with gemcitabine in pancreatic cancer. Phase I trials of pharmacological ascorbate in pancreatic cancer patients have demonstrated safety and potential efficacy. In this chapter, we will review the mechanism of ascorbate-induced cytotoxicity, examine the use of pharmacological ascorbate in treatment and assess the current data supporting its potential as an adjuvant in pancreatic cancer. PMID:26201606

  4. Biosensor studies of collagen and laminin binding with immobilized Escherichia coli O157:H7 and inhibition with naturally occurring food additives

    NASA Astrophysics Data System (ADS)

    Medina, Marjorie B.

    1999-01-01

    Escherichia coli O157:H7 outbreaks were mostly due to consumption of undercooked contaminated beef which resulted in severe illness and several fatalities. Recalls of contaminated meat are costly for the meat industry. Our research attempts to understand the mechanisms of bacterial adhesion on animal carcass in order to eliminate or reduce pathogens in foods. We have reported the interactions of immobilized E. coli O157:H7 cells with extracellular matrix (ECM) components using a surface plasmon resonance biosensor (BIAcore). These studies showed that immobilized bacterial cells allowed the study of real-time binding interactions of bacterial surface with the ECM compounds, collagen I, laminin and fibronectin. Collagen I and laminin bound to the E. coli sensor surface with dissociation and association rates ranging from 106 to 109. Binding of collagen I and laminin mixture resulted in synergistic binding signals. An inhibition model was derived using collagen-laminin as the ligand which binds with E. coli sensor. A select group of naturally occurring food additives was evaluated by determining their effectivity in inhibiting the collagen-laminin binding to the bacterial sensor. Bound collagen-laminin was detached from the E. coli sensor surface with the aid of an organic acid. The biosensor results were verified with cell aggregation assays which were observed with optical and electron microscopes. These biosensor studies provided understanding of bacterial adhesion to connective tissue macromolecules. It also provided a model system for the rapid assessment of potential inhibitors that can be used in carcass treatment to inhibit or reduce bacterial contamination.

  5. The expanding roles of 1-methyl-tryptophan (1-MT): in addition to inhibiting kynurenine production, 1-MT activates the synthesis of melatonin in skin cells.

    PubMed

    Moreno, Ana C R; Clara, Renan O; Coimbra, Janine B; Júlio, Ariane R; Albuquerque, Renata C; Oliveira, Edson M; Maria-Engler, Silvya S; Campa, Ana

    2013-10-01

    Indoleamine 2,3-dioxygenase 1 (IDO1), the rate-limiting enzyme of tryptophan catabolism, has been strongly associated with the progression of malignancy and poor survival in melanoma patients. As a result, IDO1 is a leading target for interventions aimed at restoring melanoma immune surveillance. Here, in a scenario involving the tryptophan catabolism, we report that melatonin biosynthesis is driven by 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO1, in human fibroblasts, melanocytes and melanoma cells. In addition to melatonin biosynthesis, 1-MT induced the expression of tryptophan hydroxylase, arylalkylamine-N-acetyltransferase and hydroxyindole O-methyltransferase mRNA in fibroblasts and melanocytes. We observed a great variability in the levels of IDO1 mRNA expression and kynurenine release between skin cells and melanoma cell lines in response to interferon-γ, a classical IDO1 inducer. In this setting, melatonin was shown to downregulate kynurenine production. Furthermore, in a condition of low basal activity of IDO1, it was observed that 1-MT, as well melatonin, inhibited the proliferation of human melanoma cells. Taken together, our results suggest that 1-MT may serve as more than just a tool to disrupt tumor immune escape (via the inhibition of IDO1) because it was shown to act directly on the proliferation of human melanoma cells and induce melatonin biosynthesis in the tumor milieu. Moreover, 1-MT-mediated inhibition of IDO occurs in normal skin and melanoma cells, which addresses the possibility that all cells in the skin microenvironment can be targeted by 1-MT. Our findings provide innovative approaches into understanding tumor therapy related to the control of tryptophan metabolism by 1-MT.

  6. [Addition of pomegranate juice to statin inhibits cholesterol accumulation in macrophages: protective role for the phytosterol beta-sitosterol and for the polyphenolic antioxidant punicalagin].

    PubMed

    Rosenblat, Mira; Volkova, Nina; Aviram, Michael

    2013-09-01

    Macrophage cholesterol and oxidized lipids accumulation and foam cell formation occur in the early stages of atherosclerosis development. In the current study we used the J774A.1 murine macrophage cell line in order to analyze two atherogenic functions: a. the ability of the cells to produce reactive oxygen species (ROS), and to increase cellular oxidative stress, and b. the ability of the cells to synthesize cholesterol, leading to cholesterol accumulation in the cells. The addition of punicalagin, or beta-sitosterol, or pomegranate juice (which contains both of the above) to simvastatin, significantly improved the statin's ability to inhibit macrophage cholesterol biosynthesis. Furthermore, the addition of pomegranate juice (or punicalagin, but not beta sitosterol) to simvastatin significantly increased the statin ability to protect the cells from oxidative stress. Taken together, the current research provides evidence for the additional cardio protection of statins, that is provided by pomegranate juice antioxidant and hypocholesterolemic effects. The use of statins in combination with pomegranate juice in hypercholesterolemic patients, may allow for the use of lower dosages of statin in order to prevent statin deleterious side effects.

  7. Clinical pharmacology of bimatoprost.

    PubMed

    Cantor, Louis B

    2005-06-01

    Bimatoprost (Lumigan), Allergan) is a highly efficacious ocular hypotensive agent that provides good diurnal control of intraocular pressure in glaucoma and ocular hypertensive patients. Bimatoprost is a synthetic molecule that is structurally and pharmacologically similar to prostamide F(2), and appears to mimic the activity of the prostamides. Consistent with prostamide-mimetic activity, bimatoprost has potent inherent pharmacological activity in prostamide-sensitive preparations and essentially remains intact in the living primate eye. This is sufficient to explain its potent and efficacious ocular hypotensive activity, and suggests that bimatoprost is a pharmacologically unique compound. PMID:16922657

  8. Pharmacology of Iron Transport

    PubMed Central

    Byrne, Shaina L.; Krishnamurthy, Divya; Wessling-Resnick, Marianne

    2013-01-01

    Elucidating the molecular basis for the regulation of iron uptake, storage, and distribution is necessary to understand iron homeostasis. Pharmacological tools are emerging to identify and distinguish among different iron transport pathways. Stimulatory or inhibitory small molecules with effects on iron uptake can help characterize the mechanistic elements of iron transport and the roles of the transporters involved in these processes. In particular, iron chelators can serve as potential pharmacological tools to alleviate diseases of iron overload. This review focuses on the pharmacology of iron transport, introducing iron transport membrane proteins and known inhibitors. PMID:23020294

  9. The pharmacology of topical analgesics.

    PubMed

    Barkin, Robert L

    2013-07-01

    Pain management of patients continues to pose challenges to clinicians. Given the multiple dimensions of pain--whether acute or chronic, mild, moderate, or severe, nociceptive or neuropathic--a multimodal approach may be needed. Fortunately, clinicians have an array of nonpharmacologic and pharmacologic treatment choices; however, each modality must be chosen carefully, because some often used oral agents are associated with safety and tolerability issues that restrict their use in certain patients. In particular, orally administered nonsteroidal antiinflammatory drugs, opioids, antidepressants, and anticonvulsants are known to cause systemic adverse effects in some patients. To address this problem, a number of topical therapies in various therapeutic classes have been developed to reduce systemic exposure and minimize the risks of patients developing adverse events. For example, topical nonsteroidal anti-inflammatory drug formulations produce a site-specific effect (ie, cyclo-oxygenase inhibition) while decreasing the systemic exposure that may lead to undesired effects in patients. Similarly, derivatives of acetylsalicylic acid (ie, salicylates) are used in topical analgesic formulations that do not significantly enter the patient's systemic circulation. Salicylates, along with capsaicin, menthol, and camphor, compose the counterirritant class of topical analgesics, which produce analgesia by activating and then desensitizing epidermal nociceptors. Additionally, patches and creams that contain the local anesthetic lidocaine, alone or co-formulated with other local anesthetics, are also used to manage patients with select acute and chronic pain states. Perhaps the most common topical analgesic modality is the cautious application of cutaneous cold and heat. Such treatments may decrease pain not by reaching the target tissue through systemic distribution, but by acting more directly on the affected tissue. Despite the tolerability benefits associated with avoiding

  10. The pharmacology of psilocybin.

    PubMed

    Passie, Torsten; Seifert, Juergen; Schneider, Udo; Emrich, Hinderk M

    2002-10-01

    Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.

  11. Pharmacological profile of sulodexide.

    PubMed

    Hoppensteadt, D A; Fareed, J

    2014-06-01

    Since its introduction, sulodexide has been used on and off for several indications. More recently this agent has become revitalized and tested in newer indications. Sulodexide is composed of glycosaminoglycan that includes a mixture of fast-moving heparin and dermatan sulfate. It exerts its anticoagulant and antithrombotic action through interactions with both AT and HCII. Sulodexide has been proven to have effects on the fibrinolytic system, platelets, endothelial cells, inflammation and more recently metalloproteases. The administration of sulodexide results in the release of lipoprotein lipase and has been shown to reduce the circulating level of lipids. It has also shown to decrease the viscosity of both whole blood and plasma. Sulodexide differs from heparin in its oral bioavailability and longer half-life. There is also less bleeding associated with sulodexide. In addition, oral administration of sulodexide does not interfere with the pharmacologic actions of commonly used agents. Similar to heparin, sulodexide releases TFPI which contributes to its antithrombotic effect and anti-inflammatory properties. Sulodexide has been proven to be effective in peripheral arterial thrombosis and venous thrombosis. It is also clinically active in the treatment of venous leg ulcers and intermittent claudication. More recent data suggest that sulodexide can be used in tinnitus and in vascular vertigo. Additional studies in these indications are required. Sulodexide was generally safe and well tolerated in the clinical trials, without any severe bleeding complications. Therefore sulodexide appears to be a good treatment for all arterial and venous diseases and for the prevention of progression of disease. PMID:24936531

  12. Clinical pharmacology of axitinib.

    PubMed

    Chen, Ying; Tortorici, Michael A; Garrett, May; Hee, Brian; Klamerus, Karen J; Pithavala, Yazdi K

    2013-09-01

    Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 that is approved in the US and several other countries for treatment of patients with advanced renal cell carcinoma after failure of one prior systemic therapy. The recommended clinical starting dose of axitinib is 5 mg twice daily, taken with or without food. Dose increase (up to a maximum of 10 mg twice daily) or reduction is permitted based on individual tolerability. Axitinib pharmacokinetics are dose-proportional within 1-20 mg twice daily, which includes the clinical dose range. Axitinib has a short effective plasma half-life (range 2.5-6.1 h), and the plasma accumulation of axitinib is in agreement with what is expected based on the plasma half-life of the drug. Axitinib is absorbed relatively rapidly, reaching maximum observed plasma concentrations (C max) within 4 h of oral administration. The mean absolute bioavailability of axitinib is 58 %. Axitinib is highly (>99 %) bound to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with advanced renal cell carcinoma, at the 5-mg twice-daily dose in the fed state, the geometric mean (% coefficient of variation) C max and area under the plasma concentration-time curve (AUC) from time 0-24 h (AUC24) were 27.8 ng/mL (79 %) and 265 ng·h/mL (77 %), respectively. Axitinib is metabolized primarily in the liver by cytochrome P450 (CYP) 3A4/5 and, to a lesser extent (<10 % each), by CYP1A2, CYP2C19, and uridine diphosphate glucuronosyltransferase (UGT) 1A1. The two major human plasma metabolites, M12 (sulfoxide product) and M7 (glucuronide product), are considered pharmacologically inactive. Axitinib is eliminated via hepatobiliary excretion with negligible urinary excretion. Although mild hepatic impairment does not affect axitinib plasma exposures compared with subjects with normal hepatic function, there was a 2

  13. Multitask Imidazolium Salt Additives for Innovative Poly(l-lactide) Biomaterials: Morphology Control, Candida spp. Biofilm Inhibition, Human Mesenchymal Stem Cell Biocompatibility, and Skin Tolerance.

    PubMed

    Schrekker, Clarissa M L; Sokolovicz, Yuri C A; Raucci, Maria G; Selukar, Balaji S; Klitzke, Joice S; Lopes, William; Leal, Claudio A M; de Souza, Igor O P; Galland, Griselda B; Dos Santos, João Henrique Z; Mauler, Raquel S; Kol, Moshe; Dagorne, Samuel; Ambrosio, Luigi; Teixeira, Mário L; Morais, Jonder; Landers, Richard; Fuentefria, Alexandre M; Schrekker, Henri S

    2016-08-24

    Candida species have great ability to colonize and form biofilms on medical devices, causing infections in human hosts. In this study, poly(l-lactide) films with different imidazolium salt (1-n-hexadecyl-3-methylimidazolium chloride (C16MImCl) and 1-n-hexadecyl-3-methylimidazolium methanesulfonate (C16MImMeS)) contents were prepared, using the solvent casting process. Poly(l-lactide)-imidazolium salt films were obtained with different surface morphologies (spherical and directional), and the presence of the imidazolium salt in the surface was confirmed. These films with different concentrations of the imidazolium salts C16MImCl and C16MImMeS presented antibiofilm activity against isolates of Candida tropicalis, Candida parapsilosis, and Candida albicans. The minor antibiofilm concentration assay enabled one to determine that an increasing imidazolium salt content promoted, in general, an increase in the inhibition percentage of biofilm formation. Scanning electron microscopy micrographs confirmed the effective prevention of biofilm formation on the imidazolium salt containing biomaterials. Lower concentrations of the imidazolium salts showed no cytotoxicity, and the poly(l-lactide)-imidazolium salt films presented good cell adhesion and proliferation percentages with human mesenchymal stem cells. Furthermore, no acute microscopic lesions were identified in the histopathological evaluation after contact between the films and pig ear skin. In combination with the good morphological, physicochemical, and mechanical properties, these poly(l-lactide)-based materials with imidazolium salt additives can be considered as promising biomaterials for use in the manufacturing of medical devices.

  14. Methodological innovations expand the safety pharmacology horizon.

    PubMed

    Pugsley, M K; Curtis, M J

    2012-09-01

    Almost uniquely in pharmacology, drug safety assessment is driven by the need for elaboration and validation of methods for detecting drug actions. This is the 9th consecutive year that the Journal of Pharmacological and Toxicological Methods (JPTM) has published themed issues arising from the annual meeting of the Safety Pharmacology Society (SPS). The SPS is now past its 10th year as a distinct (from pharmacology to toxicology) discipline that integrates safety pharmacologists from industry with those in academia and the various global regulatory authorities. The themes of the 2011 meeting were (i) the bridging of safety assessment of a new chemical entity (NCE) between all the parties involved, (ii) applied technologies and (iii) translation. This issue of JPTM reflects these themes. The content is informed by the regulatory guidance documents (S7A and S7B) that apply prior to first in human (FIH) studies, which emphasize the importance of seeking model validation. The manuscripts encompass a broad spectrum of safety pharmacology topics including application of state-of-the-art techniques for study conduct and data processing and evaluation. This includes some exciting novel integrated core battery study designs, refinements in hemodynamic assessment, arrhythmia analysis algorithms, and additionally an overview of safety immunopharmacology, and a brief survey discussing similarities and differences in business models that pharmaceutical companies employ in safety pharmacology, together with SPS recommendations on 'best practice' for the conduct of a non-clinical cardiovascular assessment of a NCE.

  15. Mitochondrial biogenesis: pharmacological approaches.

    PubMed

    Valero, Teresa

    2014-01-01

    ), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or -lipoic acid. As aforementioned, other

  16. Mitochondrial biogenesis: pharmacological approaches.

    PubMed

    Valero, Teresa

    2014-01-01

    ), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or -lipoic acid. As aforementioned, other

  17. Pharmacology. Teacher Edition.

    ERIC Educational Resources Information Center

    Oklahoma State Dept. of Vocational and Technical Education, Stillwater. Curriculum and Instructional Materials Center.

    This instructor's guide contains the materials required to teach a competency-based course in pharmacology for practical nursing. The following are covered in the five instructional units: calculating medication dosages, documenting medications, identifying classification and effects of medications, administering medications, and assisting with…

  18. [Indications and future perspectives in the pharmacological treatment of hypercortisolism].

    PubMed

    Stigliano, Antonio; Toscano, Vincenzo

    2016-03-01

    The hypercortisolism is a rare endocrine disease characterized by an autonomous steroid secretion or excessive adrenal stimulation by ACTH. the Surgical removal of the lesion directly responsible hypercortisolism represents the treatment of choice. When neurosurgery for pituitary adenoma is contraindicated, radiotherapy is candidate as the second line of therapy. Currently, the recent advances in medical therapy provide a viable alternative to surgery and radiotherapy, when these are not feasible or followed by relapses (present in more than one third of cases) of the underlying disease. Recently, also in Italy, are available pharmacological agents with central activity (pasireotide) specifically indicated for treating Cushing's disease together with peripherally acting drugs (metyrapone and ketoconazole) that are used in a broader spectrum of hypercortisolemic clinical pictures. In addition, drugs active in the inhibition of steroidogenesis provide a valid support to the patient's surgical preparation allowing the reduction or normalization of plasma cortisol levels. PMID:27030224

  19. [Indications and future perspectives in the pharmacological treatment of hypercortisolism].

    PubMed

    Stigliano, Antonio; Toscano, Vincenzo

    2016-03-01

    The hypercortisolism is a rare endocrine disease characterized by an autonomous steroid secretion or excessive adrenal stimulation by ACTH. the Surgical removal of the lesion directly responsible hypercortisolism represents the treatment of choice. When neurosurgery for pituitary adenoma is contraindicated, radiotherapy is candidate as the second line of therapy. Currently, the recent advances in medical therapy provide a viable alternative to surgery and radiotherapy, when these are not feasible or followed by relapses (present in more than one third of cases) of the underlying disease. Recently, also in Italy, are available pharmacological agents with central activity (pasireotide) specifically indicated for treating Cushing's disease together with peripherally acting drugs (metyrapone and ketoconazole) that are used in a broader spectrum of hypercortisolemic clinical pictures. In addition, drugs active in the inhibition of steroidogenesis provide a valid support to the patient's surgical preparation allowing the reduction or normalization of plasma cortisol levels.

  20. Some arguments in favor of a Myriophyllum aquaticum growth inhibition test in a water-sediment system as an additional test in risk assessment of herbicides.

    PubMed

    Tunić, Tanja; Knežević, Varja; Kerkez, Đurđa; Tubić, Aleksandra; Šunjka, Dragana; Lazić, Sanja; Brkić, Dragica; Teodorović, Ivana

    2015-09-01

    The present study compares the practicability, reproducibility, power, and sensitivity of a Myriophyllum aquaticum growth inhibition test in a water-sediment system with the recently accepted Myriophyllum spicatum test in an equivalent testing system and the standard Lemna sp. test. Special consideration was given to endpoints based on M. aquaticum control plant growth and variability of relative growth rate and yield: shoot length, fresh weight, dry weight, and root weight. Sensitivity analysis was based on tests performed with 3,5-dichlorophenol, atrazine, isoproturon, trifluralin, 2,4-dichlorophenoloxyacetic acid, and dicamba. Growth rates for average M. aquaticum control plants were 0.119 d(-1) and 0.112 d(-1), with average estimated doubling time 6.33 d and 6.74 d for relative growth rate fresh weight and shoot length, respectively. Intrinsic variability of M. aquaticum endpoints was low: 12.9%, 12.5%, and 17.8% for relative growth rate shoot length, relative growth rate fresh weight and yield fresh weight, respectively. The power of the test was fairly high. When the most sensitive endpoints were used for comparison, the 2 Myriophyllum species were similarly sensitive, more sensitive (in the case of auxin simulators), or at least equally sensitive as Lemna minor to other tested herbicides. The M. aquaticum 10-d test with a 7-d exposure period in a water-sediment system has acceptable sensitivity and can provide repeatable, reliable, and reproducible results; therefore, it should not be disregarded as a good and representative additional test in environmental risk assessment. PMID:25943248

  1. Axl Inhibition Primes Chronic Lymphocytic Leukemia B-Cells to Apoptosis and Show Synergistic/Additive Effects in Combination with BTK inhibitors

    PubMed Central

    Sinha, Sutapa; Boysen, Justin; Nelson, Michael; Secreto, Charla; Warner, Steven L.; Bearss, David J.; Lesnick, Connie; Shanafelt, Tait D.; Kay, Neil E.; Ghosh, Asish K.

    2015-01-01

    Purpose B-cell chronic lymphocytic leukemia (CLL) is an incurable disease despite aggressive therapeutic approaches. We previously found that Axl receptor tyrosine kinase (RTK) plays a critical role in CLL B-cell survival. Here, we explored the possibility of using a high-affinity Axl inhibitor as a single agent or in combination with Bruton’s tyrosine kinase (BTK) inhibitors for future clinical trial to treat CLL patients. Experimental Design Expression/activation status of other members of the TAM (Tyro3, Axl, MER) family of RTKs in CLL B-cells was evaluated. Cells were treated with a high-affinity orally bioavailable Axl inhibitor TP-0903 with or without presence of CLL bone marrow stromal cells (BMSCs). Inhibitory effects of TP-0903 on Axl signaling pathway was also evaluated in CLL B-cells. Finally, cells were exposed to TP-0903 in combination with BTK inhibitors to determine any synergistic/additive effects of the combination. Results CLL B-cells overexpress Tyro3, but not MER. Of interest, Tyro3 remains as constitutively phosphorylated and form a complex with Axl in CLL B-cells. TP-0903 induces massive apoptosis in CLL B-cells with LD50 values of nanomolar ranges. Importantly, CLL BMSCs could not protect the leukemic B-cells from TP-0903 induced apoptosis. A marked reduction of the anti-apoptotic proteins Mcl-1, Bcl-2, XIAP and upregulation of the pro-apoptotic protein BIM in CLL B-cells were detected as a result of Axl inhibition. Finally, combination of TP-0903 with BTK inhibitors augments CLL B-cell apoptosis. Conclusion Administration of TP-0903 either as a single agent or in combination with BTK inhibitors may be effective in treating CLL patients. PMID:25673699

  2. Multitask Imidazolium Salt Additives for Innovative Poly(l-lactide) Biomaterials: Morphology Control, Candida spp. Biofilm Inhibition, Human Mesenchymal Stem Cell Biocompatibility, and Skin Tolerance.

    PubMed

    Schrekker, Clarissa M L; Sokolovicz, Yuri C A; Raucci, Maria G; Selukar, Balaji S; Klitzke, Joice S; Lopes, William; Leal, Claudio A M; de Souza, Igor O P; Galland, Griselda B; Dos Santos, João Henrique Z; Mauler, Raquel S; Kol, Moshe; Dagorne, Samuel; Ambrosio, Luigi; Teixeira, Mário L; Morais, Jonder; Landers, Richard; Fuentefria, Alexandre M; Schrekker, Henri S

    2016-08-24

    Candida species have great ability to colonize and form biofilms on medical devices, causing infections in human hosts. In this study, poly(l-lactide) films with different imidazolium salt (1-n-hexadecyl-3-methylimidazolium chloride (C16MImCl) and 1-n-hexadecyl-3-methylimidazolium methanesulfonate (C16MImMeS)) contents were prepared, using the solvent casting process. Poly(l-lactide)-imidazolium salt films were obtained with different surface morphologies (spherical and directional), and the presence of the imidazolium salt in the surface was confirmed. These films with different concentrations of the imidazolium salts C16MImCl and C16MImMeS presented antibiofilm activity against isolates of Candida tropicalis, Candida parapsilosis, and Candida albicans. The minor antibiofilm concentration assay enabled one to determine that an increasing imidazolium salt content promoted, in general, an increase in the inhibition percentage of biofilm formation. Scanning electron microscopy micrographs confirmed the effective prevention of biofilm formation on the imidazolium salt containing biomaterials. Lower concentrations of the imidazolium salts showed no cytotoxicity, and the poly(l-lactide)-imidazolium salt films presented good cell adhesion and proliferation percentages with human mesenchymal stem cells. Furthermore, no acute microscopic lesions were identified in the histopathological evaluation after contact between the films and pig ear skin. In combination with the good morphological, physicochemical, and mechanical properties, these poly(l-lactide)-based materials with imidazolium salt additives can be considered as promising biomaterials for use in the manufacturing of medical devices. PMID:27486827

  3. Some arguments in favor of a Myriophyllum aquaticum growth inhibition test in a water-sediment system as an additional test in risk assessment of herbicides.

    PubMed

    Tunić, Tanja; Knežević, Varja; Kerkez, Đurđa; Tubić, Aleksandra; Šunjka, Dragana; Lazić, Sanja; Brkić, Dragica; Teodorović, Ivana

    2015-09-01

    The present study compares the practicability, reproducibility, power, and sensitivity of a Myriophyllum aquaticum growth inhibition test in a water-sediment system with the recently accepted Myriophyllum spicatum test in an equivalent testing system and the standard Lemna sp. test. Special consideration was given to endpoints based on M. aquaticum control plant growth and variability of relative growth rate and yield: shoot length, fresh weight, dry weight, and root weight. Sensitivity analysis was based on tests performed with 3,5-dichlorophenol, atrazine, isoproturon, trifluralin, 2,4-dichlorophenoloxyacetic acid, and dicamba. Growth rates for average M. aquaticum control plants were 0.119 d(-1) and 0.112 d(-1), with average estimated doubling time 6.33 d and 6.74 d for relative growth rate fresh weight and shoot length, respectively. Intrinsic variability of M. aquaticum endpoints was low: 12.9%, 12.5%, and 17.8% for relative growth rate shoot length, relative growth rate fresh weight and yield fresh weight, respectively. The power of the test was fairly high. When the most sensitive endpoints were used for comparison, the 2 Myriophyllum species were similarly sensitive, more sensitive (in the case of auxin simulators), or at least equally sensitive as Lemna minor to other tested herbicides. The M. aquaticum 10-d test with a 7-d exposure period in a water-sediment system has acceptable sensitivity and can provide repeatable, reliable, and reproducible results; therefore, it should not be disregarded as a good and representative additional test in environmental risk assessment.

  4. [Pharmacological therapy of obesity].

    PubMed

    Pagotto, Uberto; Vanuzzo, Diego; Vicennati, Valentina; Pasquali, Renato

    2008-04-01

    Obesity is reaching epidemic proportions worldwide and it is correlated with various comorbidities, among which the most relevant are diabetes mellitus, arterial hypertension, and cardiovascular diseases. Obesity management is a modern challenge because of the rapid evolution of unfavorable lifestyles and unfortunately there are no effective treatments applicable to the large majority of obese/overweight people. The current medical attitude is to treat the complications of obesity (e.g. dyslipidemia, hypertension, diabetes, and cardiovascular diseases). However, the potential of treating obesity is enormous, bearing in mind that a volitional weight loss of 10 kg is associated with important risk factor improvement: blood pressure -10 mmHg, total cholesterol -10%, LDL cholesterol -15%, triglycerides -30%, fasting glucose -50%, HDL cholesterol +8%. Drug treatment for obesity is an evolving branch of pharmacology, burdened by severe side effects and consequences of the early drugs, withdrawn from the market, and challenged by the lack of long-term data on the effect of medications on obesity-related morbidity and mortality, first of all cardiovascular diseases. In Europe three antiobesity drugs are currently licensed: sibutramine, orlistat, and rimonabant; important trials with clinical endpoints are ongoing for sibutramine and rimonabant. While waiting for their results, it is convenient to evaluate these drugs for their effects on body weight and cardiometabolic risk factors. Sibutramine is a centrally acting serotonin/noradrenaline reuptake inhibitor that mainly increases satiety. At the level of brown adipose tissue, sibutramine can also facilitate energy expenditure by increasing thermogenesis. The long-term studies (five) documented a mean differential weight reduction of 4.45 kg for sibutramine vs placebo. Considering the principal studies, attrition rate was 43%. This drug not only reduces body weight and waist circumference, but it decreases triglycerides and

  5. Pharmacology of systemic analgesics.

    PubMed

    Camu, Frederic; Vanlersberghe, Caroline

    2002-12-01

    Systemic administration of analgesic drugs is still the most widely used method for providing pain relief in acute painful situations. Opioids may be selected on the basis of their physicochemical characteristics and their diffusion index to the brain. But in clinical practice, their very steep concentration-analgesic effect relationship remains a critical aspect of opioid therapy. Thus, small fluctuations in plasma concentrations of opioids may lead to profound fluctuations in analgesic effect when their plasma and effect-site concentrations are near the minimum effective analgesic concentration (MEAC). Combining drugs acting on different mechanisms of nociceptive modulation offers benefits from additive/synergistic effects and will decrease the incidence of their adverse effects. Evidence-based reviews showed that effective pain relief using non-opioid analgesics relied on paracetamol supplemented with non-steroidal anti-inflammatory drugs (NSAIDs). The role of COX-2 selective inhibitors (CSIs) in acute pain relief still requires further evaluation. NSAIDs, CSIs and paracetamol share the property of morphine sparing in situations of severe (post-operative) pain. CSIs may be beneficial in patients in whom post-operative bleeding is a major surgical risk as the effects of NSAIDs on coagulation may last for days. Finally, low-dose ketamine infusions remain a worthwhile addition to opioid therapy. Analgesic concentrations of ketamine are 1/5th to 1/10th the anaesthetic concentration and exert significant inhibition on N-methyl-d-aspartate (NMDA) receptor activation. PMID:12516886

  6. Cardiovascular Safety Pharmacology of Sibutramine

    PubMed Central

    Yun, Jaesuk; Chung, Eunyong; Choi, Ki Hwan; Cho, Dae Hyun; Song, Yun Jeong; Han, Kyoung Moon; Cha, Hey Jin; Shin, Ji Soon; Seong, Won-Keun; Kim, Young-Hoon; Kim, Hyung Soo

    2015-01-01

    Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an IC50 of 3.92 μM in patch clamp assay and increased the heart rate and blood pressure (76 Δbpm in heart rate and 51 ΔmmHg in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at 10 μM and 30 μM, resulted in 15% and 29% decreases in APD50, and 9% and 17% decreases in APD90, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation. PMID:26157557

  7. Cardiovascular Safety Pharmacology of Sibutramine.

    PubMed

    Yun, Jaesuk; Chung, Eunyong; Choi, Ki Hwan; Cho, Dae Hyun; Song, Yun Jeong; Han, Kyoung Moon; Cha, Hey Jin; Shin, Ji Soon; Seong, Won-Keun; Kim, Young-Hoon; Kim, Hyung Soo

    2015-07-01

    Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an IC50 of 3.92 μM in patch clamp assay and increased the heart rate and blood pressure (76 Δbpm in heart rate and 51 ΔmmHg in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at 10 μM and 30 μM, resulted in 15% and 29% decreases in APD50, and 9% and 17% decreases in APD90, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation. PMID:26157557

  8. A Survey of Predoctoral Dental Basic Pharmacology Education.

    ERIC Educational Resources Information Center

    Robertson, Lee T.

    1996-01-01

    A survey of 51 of the 53 dental schools in the continental United States investigated pharmacology curriculum content and time allocation. Found that most schools offered a traditional didactic course in basic pharmacology, with half of the medical school-based and three-fourths of the dental school-based programs providing additional pharmacology…

  9. Pharmacological chaperones for human α-N-acetylgalactosaminidase

    PubMed Central

    Clark, Nathaniel E.; Metcalf, Matthew C.; Best, Daniel; Fleet, George W. J.; Garman, Scott C.

    2012-01-01

    Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal α-N-acetylgalactosaminidase (α-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human α-NAGAL both in vitro and in vivo. We demonstrate that a related iminosugar DGJ (currently in phase III clinical trials for another metabolic disorder, Fabry disease) can also chaperone human α-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-Å crystal structures of human α-NAGAL complexes reveal the different binding modes of iminosugars compared with glycosides. We show how differences in two functional groups result in >9 kcal/mol of additional binding energy and explain the molecular interactions responsible for the unexpectedly high affinity of the pharmacological chaperones. These results open two avenues for treatment of Schindler/Kanzaki disease and elucidate the atomic basis for pharmacological chaperoning in the entire family of lysosomal storage diseases. PMID:23045655

  10. New approaches to pharmacological treatment of osteoporosis.

    PubMed Central

    Akesson, Kristina

    2003-01-01

    Osteoporosis has been recognized as a major public health problem for less than two decades. The increasing incidence of fragility fractures, such as vertebral, hip, and wrist fractures, first became apparent from epidemiological studies in the early and mid-1980s, when effective treatment was virtually unavailable. Pharmacological therapies that effectively reduce the number of fractures by improving bone mass are now available widely in countries around the world. Most current agents inhibit bone loss by reducing bone resorption, but emerging therapies may increase bone mass by directly promoting bone formation--as is the case with parathyroid hormone. Current treatment alternatives include bisphosphonates, calcitonin, and selective estrogen receptor modulators, but sufficient calcium and vitamin D are a prerequisite. The availability of evidence-based data that show reductions in the incidence of fractures of 30-50% during treatment has been a major step forward in the pharmacological prevention of fractures. With all agents, fracture reduction is most pronounced for vertebral fracture in high-risk individuals; alendronate and risedronate also may protect against hip fracture in the elderly. New approaches to pharmacological treatment will include further development of existing drugs, especially with regard to tolerance and frequency of dosing. New avenues for targeting the condition will emerge as our knowledge of the regulatory mechanisms of bone remodelling increases, although issues of tissue specificity may be difficult to solve. In the long term, information gained through knowledge of bone genetics may be used to adapt pharmacological treatments more precisely to each individual. PMID:14710507

  11. Ginsenoside Re: pharmacological effects on cardiovascular system.

    PubMed

    Peng, Lu; Sun, Shi; Xie, Lai-Hua; Wicks, Sheila M; Xie, Jing-Tian

    2012-08-01

    Ginsenosides are the bioactive constituents of ginseng, a key herb in traditional Chinese medicine. As a single component of ginseng, ginsenoside Re (G-Re) belongs to the panaxatriol group. Many reports demonstrated that G-Re possesses the multifaceted beneficial pharmacological effects on cardiovascular system. G-Re has negative effect on cardiac contractility and autorhythmicity. It causes alternations in cardiac electrophysiological properties, which may account for its antiarrhythmic effect. In addition, G-Re also exerts antiischemic effect and induces angiogenic regeneration. In this review, we first outline the chemistry and the pharmacological effects of G-Re on the cardiovascular system.

  12. Pharmacologic issues in management of chronic disease.

    PubMed

    DeSevo, Gina; Klootwyk, Jacqueline

    2012-06-01

    A significant portion of the adult population uses one or more medications on a regular basis to manage chronic conditions. As the number of medications that patients are prescribed increases, an increase in pharmacologic-related issues and complications may occur, such as polypharmacy, inappropriate prescribing, medication nonadherence and nonpersistence, and adverse drug reactions and events. Risk factors and consequences of these issues have been identified and are discussed in this article. In addition, a review is presented of the numerous methods that have been evaluated to help prevent and minimize these pharmacologic issues in the management of chronic disease.

  13. Pharmacological strategies for detoxification.

    PubMed

    Diaper, Alison M; Law, Fergus D; Melichar, Jan K

    2014-02-01

    Detoxification refers to the safe discontinuation from a substance of dependence and is distinct from relapse prevention. Detoxification usually takes between a few days and a few weeks to complete, depending on the substance being misused, the severity of dependence and the support available to the user. Psychosocial therapies alongside pharmacological treatments are essential to improve outcome. The dependencies considered in this overview are detoxification from opioids (with methadone, buprenorphine, α2-adrenoceptor agonists and adjunct medications), alcohol (with benzodiazepines, anti-glutamatergics and γ-aminobutyric acid (GABA)-ergic drugs), stimulants and cannabis (with no clear recommended pharmacological treatments), benzodiazepines (with dose tapering) and nicotine (with nicotine replacement therapy, antidepressants and partial agonists). Evidence is limited by a lack of controlled trials robust enough for review bodies, and more research is required into optimal treatment doses and regimes, alone and in combination.

  14. Pharmacological strategies for detoxification.

    PubMed

    Diaper, Alison M; Law, Fergus D; Melichar, Jan K

    2014-02-01

    Detoxification refers to the safe discontinuation from a substance of dependence and is distinct from relapse prevention. Detoxification usually takes between a few days and a few weeks to complete, depending on the substance being misused, the severity of dependence and the support available to the user. Psychosocial therapies alongside pharmacological treatments are essential to improve outcome. The dependencies considered in this overview are detoxification from opioids (with methadone, buprenorphine, α2-adrenoceptor agonists and adjunct medications), alcohol (with benzodiazepines, anti-glutamatergics and γ-aminobutyric acid (GABA)-ergic drugs), stimulants and cannabis (with no clear recommended pharmacological treatments), benzodiazepines (with dose tapering) and nicotine (with nicotine replacement therapy, antidepressants and partial agonists). Evidence is limited by a lack of controlled trials robust enough for review bodies, and more research is required into optimal treatment doses and regimes, alone and in combination. PMID:24118014

  15. Pharmacological strategies for detoxification

    PubMed Central

    Diaper, Alison M; Law, Fergus D; Melichar, Jan K

    2014-01-01

    Detoxification refers to the safe discontinuation from a substance of dependence and is distinct from relapse prevention. Detoxification usually takes between a few days and a few weeks to complete, depending on the substance being misused, the severity of dependence and the support available to the user. Psychosocial therapies alongside pharmacological treatments are essential to improve outcome. The dependencies considered in this overview are detoxification from opioids (with methadone, buprenorphine, α2-adrenoceptor agonists and adjunct medications), alcohol (with benzodiazepines, anti-glutamatergics and γ-aminobutyric acid (GABA)-ergic drugs), stimulants and cannabis (with no clear recommended pharmacological treatments), benzodiazepines (with dose tapering) and nicotine (with nicotine replacement therapy, antidepressants and partial agonists). Evidence is limited by a lack of controlled trials robust enough for review bodies, and more research is required into optimal treatment doses and regimes, alone and in combination. PMID:24118014

  16. [Pharmacological biomodulation in cancer].

    PubMed

    Arvelo, F; Merentes, E

    2001-01-01

    The discovery of the P-glycoprotein as a mediator of multidrug resistance (MDR) represents one of the most important research accomplishments in antineoplastic pharmacology during the last decade. Demonstration of Pgp in epithelial tissues, untreated and chemotherapeutically pretreated human malignancies, and identification of various agents capable of reversing in vitro resistance has generated enthusiasm for clinical studies throughout the world. This review discusses recent developments of experimental and clinical investigations of MDR reversing agents in cancer.

  17. Pharmacological enhancement of fear reduction: preclinical models

    PubMed Central

    Graham, Bronwyn M; Langton, Julia M; Richardson, Rick

    2011-01-01

    Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit fear. Animal models of exposure therapy, particularly fear extinction, have proved to be a very useful way of examining the neural and molecular correlates of fear inhibition, which has in turn led to the identification of numerous drugs that enhance these processes in rats. Several of these drugs have subsequently been tested as novel pharmacological adjuncts to exposure therapy in humans with a range of anxiety disorders. The purpose of this review is to outline the key animal models of exposure therapy and to describe how these have been used to develop potential pharmacological adjuncts for anxiety disorders. Drugs that are currently in clinical use, as well as those currently in the preclinical stages of investigation, are described. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21175588

  18. Pharmacological effects of biotin.

    PubMed

    Fernandez-Mejia, Cristina

    2005-07-01

    In the last few decades, more vitamin-mediated effects have been discovered at the level of gene expression. Increasing knowledge on the molecular mechanisms of these vitamins has opened new perspectives that form a connection between nutritional signals and the development of new therapeutic agents. Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism: Biotin has stimulatory effects on genes whose action favors hypoglycemia (insulin, insulin receptor, pancreatic and hepatic glucokinase); on the contrary, biotin decreases the expression of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme that stimulates glucose production by the liver. The findings that biotin regulates the expression of genes that are critical in the regulation of intermediary metabolism are in agreement with several observations that indicate that biotin supply is involved in glucose and lipid homeostasis. Biotin deficiency has been linked to impaired glucose tolerance and decreased utilization of glucose. On the other hand, the diabetic state appears to be ameliorated by pharmacological doses of biotin. Likewise, pharmacological doses of biotin appear to decrease plasma lipid concentrations and modify lipid metabolism. The effects of biotin on carbohydrate metabolism and the lack of toxic effects of the vitamin at pharmacological doses suggest that biotin could be used in the development of new therapeutics in the treatment of hyperglycemia and hyperlipidemia, an area that we are actively investigating. PMID:15992683

  19. Pharmacological interactions of vasoconstrictors.

    PubMed

    Gómez-Moreno, Gerardo; Guardia, Javier; Cutando, Antonio; Calvo-Guirado, José Luis

    2009-01-01

    This article is the first of a series on pharmacological interactions involving medicaments commonly prescribed and/or used in odontology: vasoconstrictors in local anaesthetics and anti-inflammatory and anti-microbial analgesics. The necessity for the odontologist to be aware of adverse reactions as a result of the pharmacological interactions is due to the increase in medicament consumption by the general population. There is a demographic change with greater life expectancy and patients have increased chronic health problems and therefore have increased medicament intake. The presence of adrenaline (epinephrine) and other vasoconstrictors in local odontological anaesthetics is beneficial in relation to the duration and depth of anaesthesia and reduces bleeding and systemic toxicity of the local anaesthetic. However, it might produce pharmacological interactions between the injected vasoconstrictors and the local anaesthetic and adrenergic medicament administered exogenically which the odontologist should be aware of, especially because of the risk of consequent adverse reactions. Therefore the importance of conducting a detailed clinical history of the general state of health and include all medicaments, legal as well as illegal, taken by the patient. PMID:19114951

  20. Social Pharmacology: Expanding horizons

    PubMed Central

    Maiti, Rituparna; Alloza, José Luis

    2014-01-01

    In the current modern and global society, social changes are in constant evolution due to scientific progress (technology, culture, customs, and hygiene) and produce the freedom in individuals to take decisions by themselves or with their doctors toward drug consumption. In the arena of marketed drug products which includes society, individual, administration, and pharmaceutical industry, the young discipline emerged is social pharmacology or sociopharmacology. This science arises from clinical pharmacology, and deals with different parameters, which are important in creating knowledge on marketed drugs. However, the scope of “social pharmacology” is not covered by the so-called “Phase IV” alone, but it is the science that handles the postmarketing knowledge of drugs. The social pharmacology studies the “life cycle” of any marketed pharmaceutical product in the social terrain, and evaluates the effects of the real environment under circumstances totally different in the drug development process. Therefore, there are far-reaching horizons, plural, and shared predictions among health professionals and other, for beneficial use of a drug, toward maximizing the benefits of therapy, while minimizing negative social consequences. PMID:24987168

  1. Overview of safety pharmacology.

    PubMed

    Goineau, Sonia; Lemaire, Martine; Froget, Guillaume

    2013-01-01

    Safety pharmacology entails the assessment of the potential risks of novel pharmaceuticals for human use. As detailed in the ICH S7A guidelines, safety pharmacology for drug discovery involves a core battery of studies on three vital systems: central nervous (CNS), cardiovascular (CV), and respiratory. Primary CNS studies are aimed at defining compound effects on general behavior, locomotion, neuromuscular coordination, seizure threshold, and vigilance. The primary CV test battery includes an evaluation of proarrhythmic risk using in vitro tests (hERG channel and Purkinje fiber assays) and in vivo measurements in conscious animals via telemetry. Comprehensive cardiac risk assessment also includes full hemodynamic evaluation in a large, anesthetized animal. Basic respiratory function can be examined in conscious animals using whole-body plethysmography. This allows for an assessment of whether the sensitivity to respiratory-depressant effects can be enhanced by exposure to increased CO2 . Other safety pharmacology topics detailed in this unit are the timing of such studies, ethical and animal welfare issues, and statistical evaluation. PMID:24510755

  2. Pharmacology and function of melatonin receptors

    SciTech Connect

    Dubocovich, M.L.

    1988-09-01

    The hormone melatonin is secreted primarily from the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone, through an action in the brain, appears to be involved in the regulation of various neural and endocrine processes that are cued by the daily change in photoperiod. This article reviews the pharmacological characteristics and function of melatonin receptors in the central nervous system, and the role of melatonin in mediating physiological functions in mammals. Melatonin and melatonin agonists, at picomolar concentrations, inhibit the release of dopamine from retina through activation of a site that is pharmacologically different from a serotonin receptor. These inhibitory effects are antagonized by the novel melatonin receptor antagonist luzindole (N-0774), which suggests that melatonin activates a presynaptic melatonin receptor. In chicken and rabbit retina, the pharmacological characteristics of the presynaptic melatonin receptor and the site labeled by 2-(125I)iodomelatonin are identical. It is proposed that 2-(125I)iodomelatonin binding sites (e.g., chicken brain) that possess the pharmacological characteristics of the retinal melatonin receptor site (order of affinities: 2-iodomelatonin greater than 6-chloromelatonin greater than or equal to melatonin greater than or equal to 6,7-di-chloro-2-methylmelatonin greater than 6-hydroxymelatonin greater than or equal to 6-methoxymelatonin greater than N-acetyltryptamine greater than or equal to luzindole greater than N-acetyl-5-hydroxytryptamine greater than 5-methoxytryptamine much greater than 5-hydroxytryptamine) be classified as ML-1 (melatonin 1). The 2-(125I)iodomelatonin binding site of hamster brain membranes possesses different binding and pharmacological characteristics from the retinal melatonin receptor site and should be classified as ML-2. 64 references.

  3. Pharmacological profile of novel psychoactive benzofurans

    PubMed Central

    Rickli, Anna; Kopf, Simone; Hoener, Marius C; Liechti, Matthias E

    2015-01-01

    Background and Purpose Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro. Experimental Approach We assessed the effects of the benzofurans 5-APB, 5-APDB, 6-APB, 6-APDB, 4-APB, 7-APB, 5-EAPB and 5-MAPDB and benzodifuran 2C-B-FLY on the human noradrenaline (NA), dopamine and 5-HT uptake transporters using HEK 293 cells that express the respective transporters. We also investigated the release of NA, dopamine and 5-HT from monoamine-preloaded cells, monoamine receptor-binding affinity and 5-HT2A and 5-HT2B receptor activation. Key Results All of the benzofurans inhibited NA and 5-HT uptake more than dopamine uptake, similar to methylenedioxymethamphetamine (MDMA) and unlike methamphetamine. All of the benzofurans also released monoamines and interacted with trace amine-associated receptor 1 (TA1 receptor), similar to classic amphetamines. Most benzofurans were partial 5-HT2A receptor agonists similar to MDMA, but also 5-HT2B receptor agonists, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY very potently interacted with 5-HT2 receptors and also bound to TA1 receptors. Conclusions and Implications Despite very similar structures, differences were found in the pharmacological profiles of different benzofurans and compared with their amphetamine analogues. Benzofurans acted as indirect monoamine agonists that interact with transporters similarly to MDMA. The benzofurans also interacted with 5-HT receptors. This pharmacological profile probably results in MDMA-like entactogenic psychoactive properties. However, benzofurans induce 5-HT2B receptor activation associated with heart valve fibrosis. The pharmacology of 2C-B-FLY indicates predominant hallucinogenic properties and a risk for vasoconstriction. PMID:25765500

  4. Pharmacology in space: pharmacotherapy.

    PubMed

    Pavy-Le Traon, A; Saivin, S; Soulez-LaRivière, C; Pujos, M; Güell, A; Houin, G

    1997-01-01

    This chapter summarized the information available on the pharmacological kits onboard spacecraft and on the use of drugs in space, while the next chapter is dedicated to the impacts of weightlessness on drug pharmacokinetics. The need of a selected group of drugs for the use of astronauts during short-term and long-term spaceflights has been discussed. Recommendations are made for a Space Pharmacopoeia as well as for the areas of research needed to adapt medication to the weightlessness of the space environment. Although the usefulness of these drugs has been clearly demonstrated, their use also raises several problems. Physiological changes due to weightlessness may induce changes in pharmacokinetic behavior of drugs and influence their dosage regimen. Inflight data obtained by salivary drug monitoring have shown changes in the distribution of scopolamine and a significant change in the disposition of the common pain-relief agent acetaminophen taken inflight, in both drug concentration and time course. The authors of this study emphasize, however, that their data are preliminary and as yet incomplete. Further simulation studies and, if possible, inflight experiments are required. In vitro studies of the antibacterial activity of antibiotics under space conditions have shown an increased resistance of Escherichia Coli to colistin and kanamycin, and a lowered resistance of Staphylococcus Aureus to oxacillin, chloramphenicol, and erythromycin. The possible consequences of these findings for the treatment of infections contracted by astronauts are yet to be elucidated. There is still a lack of pharmacological countermeasures, particularly for preventing the progressive bone demineralization occurring in weightlessness. The treatment of space motion sickness with drugs carries with it the problem of undesirable side-effects on psychomotor performance. In order to arrive at the most appropriate medical kit for a particular mission, the best trade-off of risk versus

  5. Pharmacologic treatment of paraphilias.

    PubMed

    Assumpção, Alessandra Almeida; Garcia, Frederico Duarte; Garcia, Heloise Delavenne; Bradford, John M W; Thibaut, Florence

    2014-06-01

    The treatment of paraphilias remains a challenge in the mental health field. Combined pharmacologic and psychotherapeutic treatment is associated with better efficacy. The gold standard treatment of severe paraphilias in adult males is antiandrogen treatment with cognitive behavioral therapy. Selective serotonin reuptake inhibitors have been used in mild types of paraphilia and in cases of sexual compulsions and juvenile paraphilias. Antiandrogen treatments seem to be effective in severe paraphilic subjects committing sexual offenses. In particular, gonadotropin-releasing hormone analogs have shown high efficacy working in a similar way to physical castration but being reversible at any time. Treatment recommendations, side effects, and contraindications are discussed.

  6. Pharmacological treatment of schizophrenia.

    PubMed

    Leucht, S; Heres, S; Kissling, W; Davis, J M

    2013-05-01

    We present the pharmacological treatment of schizophrenia based on a simple algorithm that starts with the most important decisions starting from the choice of an antipsychotic drug for an acutely ill patient and ends with maintenance treatment. It represents experts opinions, a formal guideline development process was not followed. Concerning acute treatment we present recommendations for the choice of drug in acutely patients, the treatment of agitated patients, persistent depression, negative symptoms and treatment resistance. Concerning maintenance treatment with antipsychotics we discuss indication, choice of drug, continuous versus intermittent treatment, duration of relapse prevention and dose.

  7. The pharmacology of anxiety.

    PubMed

    Durant, C; Christmas, D; Nutt, D

    2010-01-01

    Understanding the neurochemistry of anxiety is of fundamental importance in the development and use of novel anxiolytics. Through measuring peripheral markers of brain biochemistry, direct pharmacological challenges and brain neuroimaging techniques our understanding of this field has increased substantially in the past few decades. We review the four most studied neurotransmitter systems with respect to in anxiety disorders: gamma amino-butyric acid, serotonin, noradrenaline and dopamine. We have focussed upon clinical studies to highlight the current techniques used to determine brain neurochemistry in vivo. Future research in this field will greatly benefit from recent advances in neuroimaging techniques and the discovery of novel ligands targeting specific receptors.

  8. The role of 5-alpha reductase inhibitors in prostate pathophysiology: Is there an additional advantage to inhibition of type 1 isoenzyme?

    PubMed

    Goldenberg, Larry; So, Alan; Fleshner, Neil; Rendon, Ricardo; Drachenberg, Darrel; Elhilali, Mostafa

    2009-06-01

    Normal growth and function of the prostate are contingent on the reduction of testosterone to dihydrotestosterone (DHT) by 5-alpha reductase (5-AR) enzymes types 1 and 2. It has been theorized that an overabundance of DHT may be implicated in the pathogenesis of both benign prostatic hyperplasia (BPH) and prostate cancer. Inhibitors of 5-AR such as dutasteride and finasteride may therefore have an important role in the prevention and treatment of BPH and prostate cancer. Dutasteride provides greater suppression of DHT than finasteride, thereby underlying the hypothesis that inhibition of both type 1 and type 2 would provide correspondingly greater protection than inhibition of type 2 alone. We review the potential significance of the 5-AR inhibitors in reducing the risk of prostate cancer according to the basic biology of prostate disease. PMID:19543428

  9. Pharmacologic Agents for Chronic Diarrhea.

    PubMed

    Lee, Kwang Jae

    2015-10-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly. PMID:26576135

  10. Pharmacologic Agents for Chronic Diarrhea

    PubMed Central

    2015-01-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly. PMID:26576135

  11. Pharmacologic Agents for Chronic Diarrhea.

    PubMed

    Lee, Kwang Jae

    2015-10-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly.

  12. Combinations of siRNAs against La Autoantigen with NS5B or hVAP-A Have Additive Effect on Inhibition of HCV Replication

    PubMed Central

    Mandal, Anirban; Ganta, Krishna Kumar

    2016-01-01

    Hepatitis C virus is major cause of chronic liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Presently available direct-acting antiviral drugs have improved success rate; however, high cost limits their utilization, especially in developing countries like India. In the present study, we evaluated anti-HCV potential of several siRNAs targeted against the HCV RNA-dependent RNA polymerase NS5B and cellular factors, La autoantigen, PSMA7, and human VAMP-associated protein to intercept different steps of viral life cycle. The target genes were downregulated individually as well as in combinations and their impact on viral replication was evaluated. Individual downregulation of La autoantigen, PSMA7, hVAP-A, and NS5B resulted in inhibition of HCV replication by about 67.2%, 50.7%, 39%, and 52%, respectively. However, antiviral effect was more pronounced when multiple genes were downregulated simultaneously. Combinations of siRNAs against La autoantigen with NS5B or hVAP-A resulted in greater inhibition in HCV replication. Our findings indicate that siRNA is a potential therapeutic tool for inhibiting HCV replication and simultaneously targeting multiple viral steps with the combination of siRNAs is more effective than silencing a single target. PMID:27446609

  13. Combinations of siRNAs against La Autoantigen with NS5B or hVAP-A Have Additive Effect on Inhibition of HCV Replication.

    PubMed

    Mandal, Anirban; Ganta, Krishna Kumar; Chaubey, Binay

    2016-01-01

    Hepatitis C virus is major cause of chronic liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Presently available direct-acting antiviral drugs have improved success rate; however, high cost limits their utilization, especially in developing countries like India. In the present study, we evaluated anti-HCV potential of several siRNAs targeted against the HCV RNA-dependent RNA polymerase NS5B and cellular factors, La autoantigen, PSMA7, and human VAMP-associated protein to intercept different steps of viral life cycle. The target genes were downregulated individually as well as in combinations and their impact on viral replication was evaluated. Individual downregulation of La autoantigen, PSMA7, hVAP-A, and NS5B resulted in inhibition of HCV replication by about 67.2%, 50.7%, 39%, and 52%, respectively. However, antiviral effect was more pronounced when multiple genes were downregulated simultaneously. Combinations of siRNAs against La autoantigen with NS5B or hVAP-A resulted in greater inhibition in HCV replication. Our findings indicate that siRNA is a potential therapeutic tool for inhibiting HCV replication and simultaneously targeting multiple viral steps with the combination of siRNAs is more effective than silencing a single target. PMID:27446609

  14. The solution of pharmacological problems with computers. Part 9: Kinetics of the inhibition of the enzyme morphine-N-demethylase by N-allylnormorphine. Mathematical analysis by a FORTRAN-program.

    PubMed

    Krüger-Thiemer, E; Feinberg, M

    1975-03-01

    In this paper, we present a method for statistical analysis of enzyme-kinetic data. This analysis allows determination of the character of the inhibition of an enzyme reaction, and computes the 95% confidence limits of the dissociation constants and of Vmax. This method involves the solution of the Michaelis-Menten equation, (see article for formula), using the Guass-Newton iteration.

  15. [Pharmacological treatment of hyperinflation].

    PubMed

    Devillier, P; Roche, N

    2009-06-01

    Introduction Lung hyperinflation leads to breathlessness, limitation in exercise capacity and tolerance, and impaired quality of life. Thus, it is important to target this key and characteristic feature of COPD. Current knowledge Available pharmacological approaches rely mainly on bronchodilators, in particular beta2 agonists and anticholinergic agents. These treatments act through the reduction of expiratory airflow limitation. However, changes in classical indices of airflow obstruction do not accurately predict effects on hyperinflation and symptoms. The decrease in operating lung volumes (as reflected by inspiratory capacity or functional residual capacity) at rest and during exercise is one of the mechanisms by which these treatments improve quality of life and maybe also decrease the impact of exacerbations. The effect of beta2 agonists on hyperinflation might be amplified by concurrent treatment with inhaled corticosteroids. Perspectives The effect of new treatments targeting airways inflammation on hyperinflation remains to be explored. Conclusions Measuring the reduction in the degree of lung hyperinflation allows a better understanding of the symptomatic effect of COPD pharmacological treatments.

  16. The pharmacology of extinction.

    PubMed

    Huxtable, R J

    1992-08-01

    It is impossible to predict what compounds of pharmacological interest may be present in an unexamined species. The extinction of such species may result, therefore, in the loss of therapeutically significant compounds. The fact that science will never know what has been lost does not lessen the significance of the loss. A number of species are discussed to exemplify the potential loss. Ginkgo biloba is an ancient plant, apparently saved from a natural extinction by human intervention. From this tree, the ginkgolides have been isolated. These are potent inhibitors of platelet activating factor and hold promise in the treatment of cerebral ischemia and brain edema. Two species, the tree Taxus brevifolia and the leech Hirudo medicinalis, are threatened as a result of human activity. Both have recently yielded complex compounds of therapeutic importance. The antitumor agent, taxol, is obtained from T. brevifolia and the thrombin inhibitor, hirudin, is found in H. medicinalis. Catharanthus roseus, source of the anticancer agents vincristine and vinblastine, although not threatened, derives from a largely unexamined but severely stressed ecosystem of some 5000 plant species. In other examples, ethnobotanical knowledge of certain plants may be lost while the species survive, as exemplified by the suppression of the Aztec ethnobotany of Mesoamerica by the invading Spanish. Finally, the fallacy of the 'snail darter syndrome', where species may be viewed as too insignificant to worry about, is exposed by consideration of the pharmacological activities of a sea hare (a shell-less marine mollusc) and various leeches.

  17. Epigenetics and pharmacology.

    PubMed

    Stefanska, Barbara; MacEwan, David J

    2015-06-01

    Recent advances in the understanding of gene regulation have shown there to be much more regulation of the genome than first thought, through epigenetic mechanisms. These epigenetic mechanisms are systems that have evolved to either switch off gene activity altogether, or fine-tune any existing genetic activation. Such systems are present in all genes and include chromatin modifications and remodelling, DNA methylation (such as CpG island methylation rates) and histone covalent modifications (e.g. acetylation, methylation), RNA interference by short interfering RNAs (siRNAs) and long non-coding RNAs (ncRNAs). These systems regulate genomic activity 'beyond' simple transcriptional factor inducer or repressor function of genes to generate mRNA. Epigenetic regulation of gene activity has been shown to be important in maintaining normal phenotypic activity of cells, as well as having a role in development and diseases such as cancer and neurodegenerative disorders such as Alzheimer's. Newer classes of drugs regulate epigenetic mechanisms to counteract disease states in humans. The reports in this issue describe some advances in epigenetic understanding that relate to human disease, and our ability to control these mechanisms by pharmacological means. Increasingly the importance of epigenetics is being uncovered - it is pharmacology that will have to keep pace.

  18. Epigenetics and pharmacology

    PubMed Central

    Stefanska, Barbara; MacEwan, David J

    2015-01-01

    Recent advances in the understanding of gene regulation have shown there to be much more regulation of the genome than first thought, through epigenetic mechanisms. These epigenetic mechanisms are systems that have evolved to either switch off gene activity altogether, or fine-tune any existing genetic activation. Such systems are present in all genes and include chromatin modifications and remodelling, DNA methylation (such as CpG island methylation rates) and histone covalent modifications (e.g. acetylation, methylation), RNA interference by short interfering RNAs (siRNAs) and long non-coding RNAs (ncRNAs). These systems regulate genomic activity ‘beyond’ simple transcriptional factor inducer or repressor function of genes to generate mRNA. Epigenetic regulation of gene activity has been shown to be important in maintaining normal phenotypic activity of cells, as well as having a role in development and diseases such as cancer and neurodegenerative disorders such as Alzheimer's. Newer classes of drugs regulate epigenetic mechanisms to counteract disease states in humans. The reports in this issue describe some advances in epigenetic understanding that relate to human disease, and our ability to control these mechanisms by pharmacological means. Increasingly the importance of epigenetics is being uncovered – it is pharmacology that will have to keep pace. PMID:25966315

  19. Citicoline: pharmacological and clinical review, 2006 update.

    PubMed

    Secades, Julio J; Lorenzo, José Luis

    2006-09-01

    Cytidine 5'-diphosphocholine, CDP-choline, or citicoline is an essential intermediate in the biosynthetic pathway of structural phospholipids in cell membranes, particularly phosphatidylcholine. Following administration by both the oral and parenteral routes, citicoline releases its two main components, cytidine and choline. Absorption by the oral route is virtually complete, and bioavailability by the oral route is therefore approximately the same as by the intravenous route. Once absorbed, citicoline is widely distributed throughout the body, crosses the blood-brain barrier and reaches the central nervous system (CNS), where it is incorporated into the membrane and microsomal phospholipid fraction. Citicoline activates biosynthesis of structural phospholipids of neuronal membranes, increases brain metabolism, and acts upon the levels of different neurotransmitters. Thus, citicoline has been experimentally shown to increase norepinephrine and dopamine levels in the CNS. Owing to these pharmacological mechanisms, citicoline has a neuroprotective effect in hypoxic and ischemic conditions, decreasing the volume of ischemic lesion, and also improves learning and memory performance in animal models of brain aging. In addition, citicoline has been shown to restore the activity of mitochondrial ATPase and membrane Na+/K+ATPase, to inhibit activation of certain phospholipases, and to accelerate reabsorption of cerebral edema in various experimental models. Citicoline has also been shown to be able to inhibit mechanisms of apoptosis associated to cerebral ischemia and in certain neurodegeneration models, and to potentiate neuroplasticity mechanisms. Citicoline is a safe drug, as shown by the toxicological tests conducted, that has no significant systemic cholinergic effects and is a well tolerated product. These pharmacological characteristics and the action mechanisms of citicoline suggest that this product may be indicated for treatment of cerebral vascular disease, head

  20. Citicoline: pharmacological and clinical review, 2006 update.

    PubMed

    Secades, Julio J; Lorenzo, José Luis

    2006-09-01

    Cytidine 5'-diphosphocholine, CDP-choline, or citicoline is an essential intermediate in the biosynthetic pathway of structural phospholipids in cell membranes, particularly phosphatidylcholine. Following administration by both the oral and parenteral routes, citicoline releases its two main components, cytidine and choline. Absorption by the oral route is virtually complete, and bioavailability by the oral route is therefore approximately the same as by the intravenous route. Once absorbed, citicoline is widely distributed throughout the body, crosses the blood-brain barrier and reaches the central nervous system (CNS), where it is incorporated into the membrane and microsomal phospholipid fraction. Citicoline activates biosynthesis of structural phospholipids of neuronal membranes, increases brain metabolism, and acts upon the levels of different neurotransmitters. Thus, citicoline has been experimentally shown to increase norepinephrine and dopamine levels in the CNS. Owing to these pharmacological mechanisms, citicoline has a neuroprotective effect in hypoxic and ischemic conditions, decreasing the volume of ischemic lesion, and also improves learning and memory performance in animal models of brain aging. In addition, citicoline has been shown to restore the activity of mitochondrial ATPase and membrane Na+/K+ATPase, to inhibit activation of certain phospholipases, and to accelerate reabsorption of cerebral edema in various experimental models. Citicoline has also been shown to be able to inhibit mechanisms of apoptosis associated to cerebral ischemia and in certain neurodegeneration models, and to potentiate neuroplasticity mechanisms. Citicoline is a safe drug, as shown by the toxicological tests conducted, that has no significant systemic cholinergic effects and is a well tolerated product. These pharmacological characteristics and the action mechanisms of citicoline suggest that this product may be indicated for treatment of cerebral vascular disease, head

  1. Bioactive Compounds of Aristotelia chilensis Stuntz and their Pharmacological Effects.

    PubMed

    Romanucci, Valeria; D'Alonzo, Daniele; Guaragna, Annalisa; Di Marino, Cinzia; Davinelli, Sergio; Scapagnini, Giovanni; Di Fabio, Giovanni; Zarrelli, Armando

    2016-01-01

    Aristotelia chilensis ([Molina], Stuntz) a member of the family Eleocarpaceae, is a plant native to Chile that is distributed in tropical and temperate Asia, Australia, the Pacific Area, and South America. The juice of its berries has important medicinal properties, as an astringent, tonic, and antidiarrhoeal. Its many qualities make the maqui berry the undisputed sovereign of the family of so-called "superfruits", as well as a valuable tool to combat cellular inflammation of bones and joints. Recently, it is discovered that the leaves of the maqui berry have important antibacterial and antitumour activities. This review provides a comprehensive overview of the traditional use, phytochemistry, and biological activity of A. chilensis using information collected from scientific journals, books, and electronic searches. Anthocyanins, other flavonoids, alkaloids, cinnamic acid derivatives, benzoic acid derivatives, other bioactive molecules, and mineral elements are summarized. A broad range of activities of plant extracts and fractions are presented, including antioxidant activity, inhibition of visible light-induced damage of photoreceptor cells, inhibition of α-glucosidase, inhibition of pancreatic lipase, anti-diabetic effects, anti-inflammatory effects, analgesic effects, anti-diabetes, effective prevention of atherosclerosis, promotion of hair growth, anti-photo ageing of the skin, and inhibition of lipid peroxidation. Although some ethnobotanical uses have been supported in in vitro experiments, further studies of the individual compounds or chemical classes of compounds responsible for the pharmacological effects and the mechanisms of action are necessary. In addition, the toxicity and the side effects from the use of A. chilensis, as well as clinical trials, require attention. PMID:26778456

  2. Pharmacological and biological antiviral therapeutics for cardiac coxsackievirus infections.

    PubMed

    Fechner, Henry; Pinkert, Sandra; Geisler, Anja; Poller, Wolfgang; Kurreck, Jens

    2011-10-11

    Subtype B coxsackieviruses (CVB) represent the most commonly identified infectious agents associated with acute and chronic myocarditis, with CVB3 being the most common variant. Damage to the heart is induced both directly by virally mediated cell destruction and indirectly due to the immune and autoimmune processes reacting to virus infection. This review addresses antiviral therapeutics for cardiac coxsackievirus infections discovered over the last 25 years. One group represents pharmacologically active low molecular weight substances that inhibit virus uptake by binding to the virus capsid (e.g., pleconaril) or inactivate viral proteins (e.g., NO-metoprolol and ribavirin) or inhibit cellular proteins which are essential for viral replication (e.g., ubiquitination inhibitors). A second important group of substances are interferons. They have antiviral but also immunomodulating activities. The third and most recently discovered group includes biological and cellular therapeutics. Soluble receptor analogues (e.g., sCAR-Fc) bind to the virus capsid and block virus uptake. Small interfering RNAs, short hairpin RNAs and antisense oligonucleotides bind to and led to degradation of the viral RNA genome or cellular RNAs, thereby preventing their translation and viral replication. Most recently mesenchymal stem cell transplantation has been shown to possess antiviral activity in CVB3 infections. Taken together, a number of antiviral therapeutics has been developed for the treatment of myocardial CVB infection in recent years. In addition to low molecular weight inhibitors, biological therapeutics have become promising anti-viral agents.

  3. Recent advances in the pharmacological management of hypercholesterolaemia.

    PubMed

    Ajufo, Ezim; Rader, Daniel J

    2016-05-01

    The recent developments in pharmacological interventions that reduce LDL cholesterol have been remarkable, coming more than a decade after the approval of the last LDL-cholesterol-lowering drug, the cholesterol absorption inhibitor ezetimibe. Within just a few years, four new LDL-cholesterol-lowering agents have received regulatory approval. Lomitapide and mipomersen inhibit the production of LDL, but also increase hepatic fat and are licensed specifically for homozygous familial hypercholesterolaemia. Alirocumab and evolocumab are monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowering LDL by about 50-60%. These drugs are approved for use in patients with cardiovascular disease or familial hypercholesterolaemia whose LDL cholesterol levels are insufficiently controlled on standard agents. Although definitive clinical efficacy and long-term safety data are still needed, antibody-based PCSK9 inhibitors promise to meet much of the unmet medical need in the treatment of raised LDL cholesterol. However, several additional approaches to inhibiting PCSK9, as well as other classes of LDL-lowering therapies, are in clinical development. Here we summarise the science behind the development of the newly approved LDL-cholesterol-lowering drugs and critically review their efficacy and safety data, highlighting unanswered research questions. Finally, we discuss emerging LDL-lowering therapies in clinical development. PMID:27012540

  4. Pharmacological and biological antiviral therapeutics for cardiac coxsackievirus infections.

    PubMed

    Fechner, Henry; Pinkert, Sandra; Geisler, Anja; Poller, Wolfgang; Kurreck, Jens

    2011-01-01

    Subtype B coxsackieviruses (CVB) represent the most commonly identified infectious agents associated with acute and chronic myocarditis, with CVB3 being the most common variant. Damage to the heart is induced both directly by virally mediated cell destruction and indirectly due to the immune and autoimmune processes reacting to virus infection. This review addresses antiviral therapeutics for cardiac coxsackievirus infections discovered over the last 25 years. One group represents pharmacologically active low molecular weight substances that inhibit virus uptake by binding to the virus capsid (e.g., pleconaril) or inactivate viral proteins (e.g., NO-metoprolol and ribavirin) or inhibit cellular proteins which are essential for viral replication (e.g., ubiquitination inhibitors). A second important group of substances are interferons. They have antiviral but also immunomodulating activities. The third and most recently discovered group includes biological and cellular therapeutics. Soluble receptor analogues (e.g., sCAR-Fc) bind to the virus capsid and block virus uptake. Small interfering RNAs, short hairpin RNAs and antisense oligonucleotides bind to and led to degradation of the viral RNA genome or cellular RNAs, thereby preventing their translation and viral replication. Most recently mesenchymal stem cell transplantation has been shown to possess antiviral activity in CVB3 infections. Taken together, a number of antiviral therapeutics has been developed for the treatment of myocardial CVB infection in recent years. In addition to low molecular weight inhibitors, biological therapeutics have become promising anti-viral agents. PMID:21989310

  5. Inflammation and Pharmacological Treatment in Diabetic Retinopathy

    PubMed Central

    Kaštelan, Snježana; Tomić, Martina; Gverović Antunica, Antonela; Salopek Rabatić, Jasminka; Ljubić, Spomenka

    2013-01-01

    Diabetic retinopathy (DR), the most common microvascular complication of diabetes mellitus, is estimated to be the leading cause of new blindness in the working population of developed countries. Primary interventions such as intensive glycemic control, strict blood pressure regulation, and lipid-modifying therapy as well as local ocular treatment (laser photocoagulation and pars plana vitrectomy) can significantly reduce the risk of retinopathy occurrence and progression. Considering the limitations of current DR treatments development of new therapeutic strategies, it becomes necessary to focus on pharmacological treatment. Currently, there is increasing evidence that inflammatory processes have a considerable role in the pathogenesis of DR with multiple studies showing an association of various systemic as well as local (vitreous and aqueous fluid) inflammatory factors and the progression of DR. Since inflammation is identified as a relevant mechanism, significant effort has been directed to the development of new concepts for the prevention and treatment of DR acting on the inflammatory processes and the use of pharmacological agents with anti-inflammatory effect. Inhibiting the inflammatory pathway could be an appealing treatment option for DR in future practices, and as further prospective randomized clinical trials accumulate data, the role and guidelines of anti-inflammatory pharmacologic treatments will become clearer. PMID:24288441

  6. Basic obstetric pharmacology.

    PubMed

    Zhao, Yang; Hebert, Mary F; Venkataramanan, Raman

    2014-12-01

    Pregnancy is associated with a variety of physiological changes that can alter the pharmacokinetics and pharmacodynamics of several drugs. However, limited data exists on the pharmacokinetics and pharmacodynamics of the majority of the medications used in pregnancy. In this article, we first describe basic concepts (drug absorption, bioavailability, distribution, metabolism, elimination, and transport) in pharmacokinetics. Then, we discuss several physiological changes that occur during pregnancy that theoretically affect absorption, distribution, metabolism, and elimination. Further, we provide a brief review of the literature on the clinical pharmacokinetic studies performed in pregnant women in recent years. In general, pregnancy increases the clearance of several drugs and correspondingly decreases drug exposure during pregnancy. Based on current drug exposure measurements during pregnancy, alterations in the dose or dosing regimen of certain drugs are essential during pregnancy. More pharmacological studies in pregnant women are needed to optimize drug therapy in pregnancy.

  7. [Pharmacological treatment of schizophrenia].

    PubMed

    Thomas, Pierre

    2013-03-01

    Decades of practice in psychiatriy and hundreds of clinical trials have demonstrated the efficacy of antipsychotics on symptoms of schizophrenia. Recently, the knowledge acquired from non-interventional studies have supplemented the information needed in daily practice by raising the issue of efficiency by incorporating not only the effectiveness and safety of treatment but also its acceptability by the patient. Adherence to antipsychotic treatment has become the key issue of the prognosis. The pharmacological management of patients with an acute episode of schizophrenia requires rapid therapeutic decisions to treat a patient who is likely to be sometimes unhelpful and agitated. The choice of treatment will have a significant impact on the prevention of psychotic relapses, on the overall prognosis and on the quality of life of the patient. In many countries of the recommendations and treatment algorithms for the management of acute psychosis were distributed, considering factors specific to the patient and his environment, his mental characteristics and local care setting.

  8. The mass action equation in pharmacology.

    PubMed

    Kenakin, Terry

    2016-01-01

    The mass action equation is the building block from which all models of drug-receptor interaction are built. In the simplest case, the equation predicts a sigmoidal relationship between the amount of drug-receptor complex and the logarithm of the concentration of drug. The form of this function is also the same as most dose-response relationships in pharmacology (such as enzyme inhibition and the protein binding of drugs) but the potency term in dose-response relationships very often differs in meaning from the similar term in the simple mass action relationship. This is because (i) most pharmacological systems are collections of mass action reactions in series and/or in parallel and (ii) the important assumptions in the mass action reaction are violated in complex pharmacological systems. In some systems, the affinity of the receptor R for some ligand A is modified by interaction of the receptor with the allosteric ligand B and concomitantly the affinity of the receptor for ligand B is modified to the same degree. When this occurs, the observed affinity of the ligand A for the receptor will depend on both the concentration of the co-binding allosteric ligand and its nature. The relationships between drug potency in pharmacological models and the equilibrium dissociation constants defined in single mass action reactions are discussed. More detailed knowledge of efficacy has led to new models of drug action that depend on the relative probabilities of different states, and these have taken knowledge of drug-receptor interactions beyond Guldberg and Waage.

  9. The neurochemistry and pharmacology of extinction behavior.

    PubMed

    Mason, S T

    1983-01-01

    The role of various neurotransmitter systems in the brain in extinction behavior is examined. An attempt is made to suggest psychological mechanisms (such as attention, secondary reinforcement or internal inhibition) by which the neurotransmitter systems or drugs act to produce the observed alteration in extinction behavior. The putative neurotransmitters acetylcholine, noradrenaline, dopamine, serotonin, endorphins and the peptides are reviewed, as are pharmacological agents such as the benzodiazepines, the barbiturates, the psychodelics, the neuroleptics, the psychomotor stimulants and cannabinoids. Other treatments and factors are considered such as peripheral hormones and the adrenal-pituitary axis. It is suggested that the noradrenergic system may be involved in the expression of extinction behavior by a role in selective attention, the dopamine system via an involvement with secondary reinforcement, the cholinergic system by a mechanism of response inhibition and the barbiturates and benzodiazepines by a block of nonreward.

  10. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison.

    PubMed

    Sansone, Randy A; Sansone, Lori A

    2014-03-01

    The serotonin norepinephrine reuptake inhibitors are a family of antidepressants that inhibit the reuptake of both serotonin and norepinephrine. While these drugs are traditionally considered a group of inter-related antidepressants based upon reuptake inhibition, they generally display different chemical structures as well as different pharmacological properties. In this article, we discuss these and other differences among the serotonin norepinephrine reuptake inhibitors, including the year of approval by the United States Food and Drug Administration, generic availability, approved clinical indications, half-lives, metabolism and excretion, presence or not of active metabolites, dosing schedules, proportionate effects on serotonin and norepinephrine, and the timing of serotonin and norepinephrine reuptake (i.e., sequential or simultaneous). Again, while serotonin norepinephrine reuptake inhibitors are grouped as a family of antidepressants, they exhibit a surprising number of differences- differences that may ultimately relate to clinical nuances in patient care. PMID:24800132

  11. Basic advances in serotonin pharmacology.

    PubMed

    Fuller, R W

    1992-10-01

    Several advances in serotonin pharmacology have implications for psychiatry. The introduction of selective inhibitors of serotonin uptake into clinical use has established more firmly the relevance of brain serotonin neurons to depressive illness and is permitting an exploration of other therapeutic consequences of amplifying serotonergic function. A recent major advance in basic pharmacology has been the definition and characterization of multiple serotonin receptor subtypes in brain. Highly selective agonists and antagonists at these receptor subtypes are being developed as candidate drugs for therapy and as pharmacologic probes for assessing functionality of brain serotonin neurons in disease. Improved pharmacologic specificity will provide better tools for eliciting measurable responses mediated by brain serotonin receptors and for imaging key presynaptic and postsynaptic constituents of serotonin neuronal systems. Advances in serotonin pharmacology should therefore expand our understanding of serotonin's roles as a brain neurotransmitter in health and disease and lead to improved therapeutic agents.

  12. Eugenol: a natural compound with versatile pharmacological actions.

    PubMed

    Pramod, Kannissery; Ansari, Shahid H; Ali, Javed

    2010-12-01

    Eugenol, the major constituent of clove oil, has been widely used for its anesthetic and analgesic action in dentistry. Eugenol exhibits pharmacological effects on almost all systems and our aim is to review the research work that has identified these pharmacological actions. Eugenol possesses significant antioxidant, anti-inflammatory and cardiovascular properties, in addition to analgesic and local anesthetic activity. The metabolism and pharmacokinetics of the compound in humans have been studied. Eugenol has also been used as a penetration enhancer. The compound is a very promising candidate for versatile applications, and the design of new drugs based on the pharmacological effects of eugenol could be beneficial. PMID:21299140

  13. [Novelties in the pharmacological treatment of chronic heart failure].

    PubMed

    Nyolczas, Noémi

    2016-09-01

    Recently, results of several novel clinical trials on the pharmacological treatment of chronic heart failure have been published. In addition, the new European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure and a focused update by the ACC/AHA/HFSA on new pharmacological therapy for heart failure has been reported in 2016. This paper intends to provide an overview of the current state of the pharmacological treatment of chronic heart failure in the light of the new guidelines which incorporate the results of the new clinical trials. Orv. Hetil., 2016, 157(38), 1517-1521. PMID:27640618

  14. Food additives such as sodium sulphite, sodium benzoate and curcumin inhibit leptin release in lipopolysaccharide-treated murine adipocytes in vitro.

    PubMed

    Ciardi, Christian; Jenny, Marcel; Tschoner, Alexander; Ueberall, Florian; Patsch, Josef; Pedrini, Michael; Ebenbichler, Christoph; Fuchs, Dietmar

    2012-03-01

    Obesity leads to the activation of pro-inflammatory pathways, resulting in a state of low-grade inflammation. Recently, several studies have shown that the exposure to lipopolysaccharide (LPS) could initiate and maintain a chronic state of low-grade inflammation in obese people. As the daily intake of food additives has increased substantially, the aim of the present study was to investigate a potential influence of food additives on the release of leptin, IL-6 and nitrite in the presence of LPS in murine adipocytes. Leptin, IL-6 and nitrite concentrations were analysed in the supernatants of murine 3T3-L1 adipocytes after co-incubation with LPS and the food preservatives, sodium sulphite (SS), sodium benzoate (SB) and the spice and colourant, curcumin, for 24 h. In addition, the kinetics of leptin secretion was analysed. A significant and dose-dependent decrease in leptin was observed after incubating the cells with SB and curcumin for 12 and 24 h, whereas SS decreased leptin concentrations after 24 h of treatment. Moreover, SS increased, while curcumin decreased LPS-stimulated secretion of IL-6, whereas SB had no such effect. None of the compounds that were investigated influenced nitrite production. The food additives SS, SB and curcumin affect the leptin release after co-incubation with LPS from cultured adipocytes in a dose- and time-dependent manner. Decreased leptin release during the consumption of nutrition-derived food additives could decrease the amount of circulating leptin to which the central nervous system is exposed and may therefore contribute to an obesogenic environment.

  15. Biochemical pharmacology of biflavonoids: implications for anti-inflammatory action.

    PubMed

    Kim, Hyun Pyo; Park, Haeil; Son, Kun Ho; Chang, Hyeun Wook; Kang, Sam Sik

    2008-03-01

    Biflavonoids belong to a subclass of the plant flavonoid family. Distribution of biflavonoids in the plant kingdom is limited to several species. Previously, some pharmacological activities of biflavonoids were described such as inhibition of histamine release from mast cells and inhibition of lymphocyte proliferation, suggesting the anti-inflammatory/antiallergic potential of the biflavonoids. Furthermore, several natural biflavonoids including ochnaflavone and ginkgetin inhibit phospholipase A2. Most importantly, certain biflavonoids exhibit anti-inflammatory activity through the regulation of proinflammatory gene expression in vitro and in vivo. Recently, several synthetic approaches yielded new biflavonoid molecules with anti-inflammatory potential. These molecules also exhibit phospholipase A2 and cyclooxygenase-2 inhibitory activity. Although the bioavailability needs be improved, certain biflavonoids may have potential as new anti-inflammatory agents. This is the first review of biflavonoid pharmacology to date.

  16. Pharmacologic treatment of alcoholism.

    PubMed

    Anton, Raymond F; Schacht, Joseph P; Book, Sarah W

    2014-01-01

    Progress in understanding the neuroscience of addiction has significantly advanced the development of more efficacious medications for the treatment of alcohol use disorders (AUD). While several medications have been approved by regulatory bodies around the world for the treatment of AUD, they are not universally efficacious. Recent research has yielded improved understanding of the genetics and brain circuits that underlie alcohol reward and its habitual use. This research has contributed to pharmacogenetic studies of medication response, and will ultimately lead to a more "personalized medicine" approach to AUD pharmacotherapy. This chapter summarizes work on clinically available medications (both approved by regulatory bodies and investigational) for the treatment of alcohol dependence, as well as the psychiatric disorders that are commonly comorbid with AUD. Studies that have evaluated genetic influences on medication response and those that have employed neuroimaging to probe mechanisms of medication action or response are highlighted. Finally, new targets discovered in animal models for possible pharmacologic intervention in humans are overviewed and future directions in medications development provided.

  17. Designer psychostimulants: pharmacology and differences.

    PubMed

    Iversen, Leslie; White, Michael; Treble, Ric

    2014-12-01

    More than 200 novel psychoactive drugs have been reported in Europe, with 73 added in 2012 and additional compounds encountered every week in 2013. Many of these are "designer psychostimulants" which aim to mimic the subjective effects of amphetamines, cocaine or 3,4-methylenedioxymethylamphetamine (MDMA; "Ecstasy"). Several drugs are based on the beta-ketoamphetamine cathinone chemical structure, others include aminoindanes, aminotetralins, piperazines, amphetamine analogues and pipradrol derivatives. Although a detailed analysis of the pharmacology of these novel drugs is largely lacking, a number of scientific studies have been reported in 2011-2013 and these are reviewed. All of the novel psychostimulants activate monoamine systems in the brain - with differing dopamine (DA) v serotonin (5-HT) preferences. Those activating principally DA systems are amphetamine-like stimulants, such as naphyrone, desoxypipradrol, 3,4-methylenedioxypyrovalerone (MDPV), and benzylpiperazine while those preferentially activating 5-HT mechanisms are MDMA-like or cocaine-like stimulants, such as mephedrone, methylone and other substituted cathinones, aminoindanes, aminotetralins and piperazines. The ability of mephedrone and other novel psychostimulants to substitute for methylamphetamine or cocaine in drug discrimination tests in rats, and the ability of mephedrone to induce conditioned place preference and to sustain self-administration behaviour suggests that this and other cocaine/methylamphetamine-like drugs have dependence liability. This article is part of the Special Issue entitled 'CNS Stimulants'. PMID:24456744

  18. Inhibition of ammonia poisoning by addition of platinum to Ru/α-Al2 O3 for preferential CO oxidation in fuel cells.

    PubMed

    Sato, Katsutoshi; Yagi, Sho; Zaitsu, Shuhei; Kitayama, Godai; Kayada, Yuto; Teramura, Kentaro; Takita, Yusaku; Nagaoka, Katsutoshi

    2014-12-01

    In polymer electrolyte fuel cell (PEFC) systems, small amounts of ammonia (NH3 ) present in the reformate gas deactivate the supported ruthenium catalysts used for preferential oxidation (PROX) of carbon monoxide (CO). In this study, we investigated how the addition of a small amount of platinum to a Ru/α-Al2 O3 catalyst (Pt/Ru=1:9 w/w) affected the catalyst's PROX activity in both the absence and the presence of NH3 (130 ppm) under conditions mimicking the reformate conditions during steam reforming of natural gas. The activity of undoped Ru/α-Al2 O3 decreased sharply upon addition of NH3 , whereas Pt/Ru/α-Al2 O3 exhibited excellent PROX activity even in the presence of NH3 . Ruthenium K-edge X-ray absorption near-edge structure (XANES) spectra indicated that in the presence of NH3 , some of the ruthenium in the undoped catalyst was oxidized in the presence of NH3 , whereas ruthenium oxidation was not observed with Pt/Ru/α-Al2 O3 . These results suggest that ruthenium oxidation is retarded by the platinum, so that the catalyst shows high activity even in the presence of NH3 .

  19. Clofilium inhibits Slick and Slack potassium channels

    PubMed Central

    de los Angeles Tejada, Maria; Stolpe, Kathleen; Meinild, Anne-Kristine; Klaerke, Dan A

    2012-01-01

    Slick and Slack high-conductance potassium channels have been recently discovered, and are found in the central nervous system and in the heart. Both channels are activated by Na+ and Cl−, and Slick channels are also inhibited by adenosine triphospate (ATP). An important role of setting the resting membrane potential and controlling the basal excitability of neurons has been suggested for these channels. In addition, no specific blockers for these channels are known up to the present. With the purpose of studying the pharmacological characteristics of Slick and Slack channels, the effects of exposure to the antiarrhythmic compound clofilium were evaluated. Clofilium was able to modulate the activity of Slick and Slack channels effectively, with a stronger effect on Slack than Slick channels. In order to evaluate the pharmacological behavior of Slick and Slack channels further, 38 commonly used potassium channel blockers were tested. Screening of these compounds did not reveal any modulators of Slick and Slack channels, except for clofilium. The present study provides a first approach towards elucidating the pharmacological characteristics of Slick and Slack channels and could be the basis for future studies aimed at developing potent and specific blockers and activators for these channels. PMID:23271893

  20. Teaching Pharmacology by Case Study.

    ERIC Educational Resources Information Center

    Jordan, Sue

    1997-01-01

    Using pharmacology case studies with nursing students encourages theory-practice links and infuses real-life content. Cases provide rich qualitative data for evaluating curriculum. However, they are not a substitute for evidence-based practice. (SK)

  1. Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid-lowering effect

    PubMed Central

    Gómez-Garre, D; Muñoz-Pacheco, P; González-Rubio, ML; Aragoncillo, P; Granados, R; Fernández-Cruz, A

    2009-01-01

    Background and purpose: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, might also suppress inflammatory components of atherogenesis. We have studied the effects of ezetimibe on two characteristics of atherosclerotic plaques (infiltrate and fibrosis) and on expression of inflammatory genes in a rabbit model of accelerated atherosclerosis. Experimental approach: Femoral atherosclerosis was induced by a combination of endothelial desiccation and atherogenic diet. Animals were randomized to ezetimibe (0.6 mg·kg−1·day−1), simvastatin (5 mg·kg−1·day−1), ezetimibe plus simvastatin or no treatment, still on atherogenic diet. A control group of rabbits received normolipidemic diet. Key results: Rabbits fed the normolipidemic diet showed normal plasma lipid levels. Either the normolipidemic diet or drug treatment reduced the intima/media ratio (normolipidemic diet: 22%, ezetimibe: 13%, simvastatin: 27%, ezetimibe + simvastatin: 28%), compared with rabbits with atherosclerosis. Ezetimibe also decreased macrophage content and monocyte chemoattractant protein-1 expression in atherosclerotic lesions. Furthermore, ezetimibe reduced the increased activity of nuclear factor κB in peripheral blood leucocytes and plasma C-reactive protein levels in rabbits with atherosclerosis. In THP-1 cells, ezetimibe decreased monocyte chemoattractant protein-1-induced monocyte migration. Importantly, the combination of ezetimibe with simvastatin was associated with a more significant reduction in plaque monocyte/macrophage content and some proinflammatory markers than observed with each drug alone. Conclusions and implications: Ezetimibe had beneficial effects both on atherosclerosis progression and plaque stabilization and showed additional anti-atherogenic benefits when combined with simvastatin. Its effect on monocyte migration provides a potentially beneficial action, in addition to its effects on lipids. PMID:19222481

  2. microRNA miR-142-3p Inhibits Breast Cancer Cell Invasiveness by Synchronous Targeting of WASL, Integrin Alpha V, and Additional Cytoskeletal Elements

    PubMed Central

    Schwickert, Alexander; Weghake, Esther; Brüggemann, Kathrin; Engbers, Annika; Brinkmann, Benjamin F.; Kemper, Björn; Seggewiß, Jochen; Stock, Christian; Ebnet, Klaus; Kiesel, Ludwig; Riethmüller, Christoph; Götte, Martin

    2015-01-01

    MicroRNAs (miRNAs, micro ribonucleic acids) are pivotal post-transcriptional regulators of gene expression. These endogenous small non-coding RNAs play significant roles in tumorigenesis and tumor progression. miR-142-3p expression is dysregulated in several breast cancer subtypes. We aimed at investigating the role of miR-142-3p in breast cancer cell invasiveness. Supported by transcriptomic Affymetrix array analysis and confirmatory investigations at the mRNA and protein level, we demonstrate that overexpression of miR-142-3p in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells leads to downregulation of WASL (Wiskott-Aldrich syndrome-like, protein: N-WASP), Integrin-αV, RAC1, and CFL2, molecules implicated in cytoskeletal regulation and cell motility. ROCK2, IL6ST, KLF4, PGRMC2 and ADCY9 were identified as additional targets in a subset of cell lines. Decreased Matrigel invasiveness was associated with the miR-142-3p-induced expression changes. Confocal immunofluorescence microscopy, nanoscale atomic force microscopy and digital holographic microscopy revealed a change in cell morphology as well as a reduced cell volume and size. A more cortical actin distribution and a loss of membrane protrusions were observed in cells overexpressing miR-142-3p. Luciferase activation assays confirmed direct miR-142-3p-dependent regulation of the 3’-untranslated region of ITGAV and WASL. siRNA-mediated depletion of ITGAV and WASL resulted in a significant reduction of cellular invasiveness, highlighting the contribution of these factors to the miRNA-dependent invasion phenotype. While knockdown of WASL significantly reduced the number of membrane protrusions compared to controls, knockdown of ITGAV resulted in a decreased cell volume, indicating differential contributions of these factors to the miR-142-3p-induced phenotype. Our data identify WASL, ITGAV and several additional cytoskeleton-associated molecules as novel invasion-promoting targets of miR-142-3p in breast

  3. [Social pharmacology: a new topic in clinical pharmacology].

    PubMed

    Montastruc, J L

    2002-01-01

    Social Pharmacology, a new field in Clinical Pharmacology, describes the relationships between Society and Drugs. Topics of Social Pharmacology are first, the social consequences of populations' exposure to drugs and, secondly, the social factors explaining drug use behind clinical or rational explanations. Social Pharmacology also investigates the reasons for prescription, delivery, consumption and self-medication of drugs (behind clinical or rational factors). The paper discusses the role of the different players of Social Pharmacology in the field of drug development, evaluation, prescription and consumption. For example, the pharmaceutical industry should play an important role in the discovery of new medically and socially "desirable" drugs. Drug companies are also involved in this field for drug information to doctors but also patients. Regulatory agencies are concerned by social factors involved in drug approval, regulation of the maximal level of drug use, application and transferability of clinical trials to daily clinical practice. Social Pharmacologists also investigate the factors (others than clinical or rational) regulating drug use. Drug consumption varies according to social characteristics of physicians (sub-speciality, medical education, cultural origin, etc) or patients (gender, age, education, country, kind of work, social status etc). Relationships between drugs and religion make up a large chapter of Social Pharmacology. Other topics in Social Pharmacology involving other health professionals (pharmacists), lawyers and the media are also discussed. Finally, drugs should be considered as important social markers of population behaviour. The role of the Social Pharmacologist is to identify these social and irrational factors governing drug use in order to adapt and rationalize drug utilization in daily clinical practice.

  4. 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.

  5. 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. PMID:24604843

  6. Nitrate addition to groundwater impacted by ethanol-blended fuel accelerates ethanol removal and mitigates the associated metabolic flux dilution and inhibition of BTEX biodegradation.

    PubMed

    Corseuil, Henry Xavier; Gomez, Diego E; Schambeck, Cássio Moraes; Ramos, Débora Toledo; Alvarez, Pedro J J

    2015-03-01

    A comparison of two controlled ethanol-blended fuel releases under monitored natural attenuation (MNA) versus nitrate biostimulation (NB) illustrates the potential benefits of augmenting the electron acceptor pool with nitrate to accelerate ethanol removal and thus mitigate its inhibitory effects on BTEX biodegradation. Groundwater concentrations of ethanol and BTEX were measured 2 m downgradient of the source zones. In both field experiments, initial source-zone BTEX concentrations represented less than 5% of the dissolved total organic carbon (TOC) associated with the release, and measurable BTEX degradation occurred only after the ethanol fraction in the multicomponent substrate mixture decreased sharply. However, ethanol removal was faster in the nitrate amended plot (1.4 years) than under natural attenuation conditions (3.0 years), which led to faster BTEX degradation. This reflects, in part, that an abundant substrate (ethanol) can dilute the metabolic flux of target pollutants (BTEX) whose biodegradation rate eventually increases with its relative abundance after ethanol is preferentially consumed. The fate and transport of ethanol and benzene were accurately simulated in both releases using RT3D with our general substrate interaction module (GSIM) that considers metabolic flux dilution. Since source zone benzene concentrations are relatively low compared to those of ethanol (or its degradation byproduct, acetate), our simulations imply that the initial focus of cleanup efforts (after free-product recovery) should be to stimulate the degradation of ethanol (e.g., by nitrate addition) to decrease its fraction in the mixture and speed up BTEX biodegradation.

  7. Nitrate addition to groundwater impacted by ethanol-blended fuel accelerates ethanol removal and mitigates the associated metabolic flux dilution and inhibition of BTEX biodegradation

    NASA Astrophysics Data System (ADS)

    Corseuil, Henry Xavier; Gomez, Diego E.; Schambeck, Cássio Moraes; Ramos, Débora Toledo; Alvarez, Pedro J. J.

    2015-03-01

    A comparison of two controlled ethanol-blended fuel releases under monitored natural attenuation (MNA) versus nitrate biostimulation (NB) illustrates the potential benefits of augmenting the electron acceptor pool with nitrate to accelerate ethanol removal and thus mitigate its inhibitory effects on BTEX biodegradation. Groundwater concentrations of ethanol and BTEX were measured 2 m downgradient of the source zones. In both field experiments, initial source-zone BTEX concentrations represented less than 5% of the dissolved total organic carbon (TOC) associated with the release, and measurable BTEX degradation occurred only after the ethanol fraction in the multicomponent substrate mixture decreased sharply. However, ethanol removal was faster in the nitrate amended plot (1.4 years) than under natural attenuation conditions (3.0 years), which led to faster BTEX degradation. This reflects, in part, that an abundant substrate (ethanol) can dilute the metabolic flux of target pollutants (BTEX) whose biodegradation rate eventually increases with its relative abundance after ethanol is preferentially consumed. The fate and transport of ethanol and benzene were accurately simulated in both releases using RT3D with our general substrate interaction module (GSIM) that considers metabolic flux dilution. Since source zone benzene concentrations are relatively low compared to those of ethanol (or its degradation byproduct, acetate), our simulations imply that the initial focus of cleanup efforts (after free-product recovery) should be to stimulate the degradation of ethanol (e.g., by nitrate addition) to decrease its fraction in the mixture and speed up BTEX biodegradation.

  8. β-Lactam antibiotics and vancomycin inhibit the growth of planktonic and biofilm Candida spp.: an additional benefit of antibiotic-lock therapy?

    PubMed

    Sidrim, José J C; Teixeira, Carlos E C; Cordeiro, Rossana A; Brilhante, Raimunda S N; Castelo-Branco, Débora S C M; Bandeira, Silviane P; Alencar, Lucas P; Oliveira, Jonathas S; Monteiro, André J; Moreira, José L B; Bandeira, Tereza J P G; Rocha, Marcos F G

    2015-04-01

    The aim of this study was to evaluate the effects of cefepime, meropenem, piperacillin/tazobactam (TZP) and vancomycin on strains of Candida albicans and Candida tropicalis in planktonic and biofilm forms. Twenty azole-derivative-resistant strains of C. albicans (n=10) and C. tropicalis (n=10) were tested. The susceptibility of planktonic Candida spp. to the antibacterial agents was investigated by broth microdilution. The XTT reduction assay was performed to evaluate the viability of growing and mature biofilms following exposure to these drugs. Minimum inhibitory concentrations (MICs) ranged from 0.5 mg/mL to 2 mg/mL for cefepime, TZP and vancomycin and from 0.5 mg/mL to 1 mg/mL for meropenem and the drugs also caused statistically significant reductions in biofilm cellular activity both in growing and mature biofilm. Since all of the tested drugs are commonly used in patients with hospital-acquired infections and in those with catheter-related infections under antibiotic-lock therapy, it may be possible to obtain an additional benefit from antibiotic-lock therapy with these drugs, namely the control of Candida biofilm formation.

  9. Modeling and Validating Chronic Pharmacological Manipulation of Circadian Rhythms

    PubMed Central

    Kim, J K; Forger, D B; Marconi, M; Wood, D; Doran, A; Wager, T; Chang, C; Walton, K M

    2013-01-01

    Circadian rhythms can be entrained by a light-dark (LD) cycle and can also be reset pharmacologically, for example, by the CK1δ/ε inhibitor PF-670462. Here, we determine how these two independent signals affect circadian timekeeping from the molecular to the behavioral level. By developing a systems pharmacology model, we predict and experimentally validate that chronic CK1δ/ε inhibition during the earlier hours of a LD cycle can produce a constant stable delay of rhythm. However, chronic dosing later during the day, or in the presence of longer light intervals, is not predicted to yield an entrained rhythm. We also propose a simple method based on phase response curves (PRCs) that predicts the effects of a LD cycle and chronic dosing of a circadian drug. This work indicates that dosing timing and environmental signals must be carefully considered for accurate pharmacological manipulation of circadian phase. PMID:23863866

  10. Design of a Drug-in-Adhesive Transdermal Patch for Risperidone: Effect of Drug-Additive Interactions on the Crystallization Inhibition and In Vitro/In Vivo Correlation Study.

    PubMed

    Weng, Wei; Quan, Peng; Liu, Chao; Zhao, Hanqing; Fang, Liang

    2016-10-01

    The purpose of this work was to develop and design an appropriate drug-in-adhesive patch for transdermal delivery of risperidone (RISP). Various formulation factors were investigated by in vitro permeation study using excised rabbit skin. Increasing the drug concentration in the pressure sensitive adhesive (PSA) was used to enhance the drug permeation. To overcome the high crystallization tendency of the patch, several crystallization inhibitors such as PVP, PEG, and surfactants and fatty acids were evaluated by microscopy study. The mechanism of crystallization inhibition was investigated by differential scanning calorimetry, nuclear magnetic resonance spectrometer, and FT-IR studies. RISP and its active metabolite were determined after topical application of the optimized transdermal patch, and the in vivo pharmacokinetic parameters were compared with the intravenous administration group. The microscopy study indicated that fatty acid greatly inhibited the crystallization of RISP in PSA. The inhibition was attributed to the drug-additive interaction between amino group of RISP and the carboxyl group of fatty acid which was further confirmed by (1)H-NMR and FT-IR studies. The optimal permeation profile was obtained with the patches containing 5% RISP and 5% oleic acid in Duro-Tak(®) 87-2287. The in vivo pharmacokinetic study exhibited a sustained absorption and metabolism profile and well correlated with the in vitro permeation data. PMID:27522527

  11. Pharmacological management of osteogenesis.

    PubMed

    Nardone, Valeria; D'Asta, Federica; Brandi, Maria Luisa

    2014-06-01

    Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases. PMID:24964310

  12. Pharmacological management of osteogenesis

    PubMed Central

    Nardone, Valeria; D'Asta, Federica; Brandi, Maria Luisa

    2014-01-01

    Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases. PMID:24964310

  13. Effects of pharmacological treatment and photoinactivation on the directional responses of an insect neuron.

    PubMed

    Molina, Jorge; Stumpner, Andreas

    2005-12-01

    Soma-ipsilateral branches of the large segmental omega neuron of the phaneropterid bush cricket Ancistrura nigrovittata have smooth endings, which extend through most of the auditory neuropile. Correspondingly, it shows a broad frequency tuning. Large excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) are observed when recording from soma-ipsilateral branches. Stimulation from the soma-ipsilateral side leads to a strong excitation. Soma-contralateral branches have a strong, beaded appearance. IPSPs, which seem to be of soma-contralateral origin, can be recorded from these branches. Stimulation from the soma-contralateral side leads to a strong inhibition of the omega neuron. Soma-contralateral stimulation must be 30-40 dB more intense than soma-ipsilateral stimulation to evoke similar spike numbers in the omega neuron. The side-to-side difference is reduced to 10-15 dB after cutting the input from the soma-contralateral leg (tympanic nerve). The thresholds for eliciting IPSPs by soma-contralateral stimulation correspond roughly to excitatory thresholds of the mirror-image omega with the same stimuli. Pharmacological treatment with picrotoxin (PTX) or photoinactivation of the Lucifer Yellow filled mirror-image omega neuron reduces contralateral inhibition considerably and eliminates all visible IPSPs. Nevertheless, an additional contralateral inhibition survives both procedures and is only eliminated after cutting the soma-contralateral tympanic nerve. These results demonstrate that the mirror-image partners of the omega neuron mutually inhibit each other in bush crickets--as in crickets. This mutual inhibition is PTX-sensitive. At least one additional element exerts contralateral PTX-insensitive inhibition on the omega neuron.

  14. Acetylsalicylic acid (ASA) - How much, how often, and when? A clinical-pharmacological perspective.

    PubMed

    Loew, Dieter; Belz, Gustav G

    2016-08-01

    The dose of acetylsalicylic acid (ASA) commonly used in the prevention and treatment of arteriosclerotic angiopathies is equal to or less than 100 mg daily. This choice of dose is predominantly based on molecular-pharmacological findings showing an inhibition in synthesis of the prothrombotic thromboxane (TXB2) and an irreversible inhibition in blood platelet aggregation. However, an analysis of ASA dose-effect relationships for doses of 50 - 500 mg (PO and IV) shows that doses of ASA up to 100 mg daily produce only a small or moderate inhibition in collagen/epinephrine-induced platelet aggregation and have no significant effect on the important platelet factors, PF3 and PF4. Doses of ASA 300 - 500 mg, on the other hand, inhibit platelet aggregation almost completely and, in addition, produce a 50 - 70% inhibition in PF3 and PF4 lasting at least 24 hours. There is also evidence that doses of ASA above 100 mg daily markedly inhibit thromboxane synthesis for up to 24 hours and that doses of 500 mg daily produce a clinically relevant inhibition in platelet adhesion to vessel walls for up 72 hours and prevent procoagulatory shape changes for up to 12 hours. These findings suggest that a dose of ≥ 300 mg at intervals of 2 - 3 days would be more appropriate for primary and secondary prophylaxis of arteriosclerotic angiopathies and that the benefit-risk ratio would be greater because of the increased availability of mucoprotective prostaglandins, PGI2 (prostacyclin) and the gastroprotective, PGE2. Our viewpoint, predominantly based on findings with biomarkers, could serve as a basis for further randomized controlled studies.

  15. Molecular Docking and Pharmacological Investigations of Rivastigmine-Fluoxetine and Coumarin–Tacrine hybrids against Acetyl Choline Esterase

    PubMed Central

    Babitha, Pallikkara Pulikkal; Sahila, Mohammed Marunnan; Bandaru, Srinivas; Nayarisseri, Anuraj; Sureshkumar, Sivanpillai

    2015-01-01

    The present AChE inhibitors have been successful in the treatment of Alzheimer׳s Diseases however suffers serious side effects. Therefore in this view, the present study was sought to identify compounds with appreciable pharmacological profile targeting AChE. Analogue of Rivastigmine and Fluoxetine hybrid synthesized by Toda et al, 2003 (dataset1), and Coumarin−Tacrine hybrids synthesized by Qi Sun et al (dataset2) formed the test compounds for the present pharmacological evaluation. p-cholorophenyl substituted Rivastigmine and Fluoxetine hybrid compound (26d) from dataset 1 and −OCH3 substitute Coumarin−Tacrine hybrids (1h) from dataset 2 demonstrated superior pharmacological profile. 26 d showed superior pharmacological profile comparison to the entire compounds in either dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify still better compound with pharmacological profile than 26 d and 1h, virtual screening was performed. The best docked compound (PubCId: PubCid: 68874404) showed better affinity than its parent 26 d, however showed poor ADME profile and AMES toxicity. CHEMBL2391475 (PubCid: 71699632) similar to 1h had reduced affinity in comparison to its parent compound 1h. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report p-cholorophenyl substituted rivastigmine and fluoxetine hybrid (26d) to be a potential candidate for AcHE inhibition which in addition can overcome narrow therapeutic window of present AChE inhibitors in clinical treatment of Alzheimer׳s disease. Abbreviations AD - Alzheimer׳s Disease, AChE - Acetyl Choline Estarase, OPLS - Optimized Potentials for Liquid Simulations, PDB - Protein Data Bank. PMID:26420918

  16. Pharmacology of the lower urinary tract

    PubMed Central

    Hennenberg, Martin; Stief, Christian G.; Gratzke, Christian

    2014-01-01

    Pharmacology of the lower urinary tract provides the basis for medical treatment of lower urinary tract symptoms (LUTS). Therapy of LUTS addresses obstructive symptoms (frequently explained by increased prostate smooth muscle tone and prostate enlargement) in patients with benign prostate hyperplasia (BPH) and storage symptoms in patients with overactive bladder (OAB). Targets for medical treatment include G protein-coupled receptors (α1-adrenoceptors, muscarinic acetylcholine receptors, β3-adrenoceptors) or intracellular enzymes (5α-reductase; phosphodiesterase-5, PDE5). Established therapies of obstructive symptoms aim to induce prostate smooth muscle relaxation by α1-blockers or PDE5 inhibitors, or to reduce prostate growth and volume with 5α-reductase inhibitors. Available options for treatment of OAB comprise anitmuscarinics, β3-adrenoceptor agonists, and botulinum toxin A, which improve storage symptoms by inhibition of bladder smooth muscle contraction. With the recent approval of β3-antagonists, PDE inhibitors, and silodosin for therapy of LUTS, progress from basic research of lower urinary tract pharmacology was translated into new clinical applications. Further targets are in preclinical stages of examination, including modulators of the endocannabinoid system and transient receptor potential (TRP) channels. PMID:24744518

  17. Clinical and Molecular Pharmacology of Etomidate

    PubMed Central

    Forman, Stuart A.

    2011-01-01

    This review focuses on the unique clinical and molecular pharmacology of etomidate. Among general anesthesia induction drugs, etomidate is the only imidazole, and it has the most favorable therapeutic index for single bolus administration. It also produces a unique toxicity among anesthetic drugs-- inhibition of adrenal steroid synthesis that far outlasts its hypnotic action and that may reduce survival of critically ill patients. The major molecular targets mediating anesthetic effects of etomidate in the central nervous system are specific γ-aminobutyric acid type A receptor subtypes. Amino acids forming etomidate binding sites have been identified in transmembrane domains of these proteins. Etomidate binding site structure models for the main enzyme mediating etomidate adrenotoxicity have also been developed. Based on this deepening understanding of molecular targets and actions, new etomidate derivatives are being investigated as potentially improved sedative-hypnotics or for use as highly selective inhibitors of adrenal steroid synthesis. PMID:21263301

  18. Network analyses in systems pharmacology

    PubMed Central

    Berger, Seth I.; Iyengar, Ravi

    2009-01-01

    Systems pharmacology is an emerging area of pharmacology which utilizes network analysis of drug action as one of its approaches. By considering drug actions and side effects in the context of the regulatory networks within which the drug targets and disease gene products function, network analysis promises to greatly increase our knowledge of the mechanisms underlying the multiple actions of drugs. Systems pharmacology can provide new approaches for drug discovery for complex diseases. The integrated approach used in systems pharmacology can allow for drug action to be considered in the context of the whole genome. Network-based studies are becoming an increasingly important tool in understanding the relationships between drug action and disease susceptibility genes. This review discusses how analysis of biological networks has contributed to the genesis of systems pharmacology and how these studies have improved global understanding of drug targets, suggested new targets and approaches for therapeutics, and provided a deeper understanding of the effects of drugs. Taken together, these types of analyses can lead to new therapeutic options while improving the safety and efficacy of existing medications. Contact: ravi.iyengar@mssm.edu PMID:19648136

  19. Venomic and pharmacological activity of Acanthoscurria paulensis (Theraphosidae) spider venom.

    PubMed

    Mourão, Caroline Barbosa F; Oliveira, Fagner Neves; e Carvalho, Andréa C; Arenas, Claudia J; Duque, Harry Morales; Gonçalves, Jacqueline C; Macêdo, Jéssica K A; Galante, Priscilla; Schwartz, Carlos A; Mortari, Márcia R; Almeida Santos, Maria de Fátima M; Schwartz, Elisabeth F

    2013-01-01

    In the present study we conducted proteomic and pharmacological characterizations of the venom extracted from the Brazilian tarantula Acanthoscurria paulensis, and evaluated the cardiotoxicity of its two main fractions. The molecular masses of the venom components were identified by mass spectrometry (MALDI-TOF-MS) after chromatographic separation (HPLC). The lethal dose (LD(50)) was determined in mice. Nociceptive behavior was evaluated by intradermal injection in mice and the edematogenic activity by the rat hind-paw assay. Cardiotoxic activity was evaluated on in situ frog heart and on isolated frog ventricle strip. From 60 chromatographic fractions, 97 distinct components were identified, with molecular masses between 601.4 and 21,932.3 Da. A trimodal molecular mass distribution was observed: 30% of the components within 500-1999 Da, 38% within 3500-5999 Da and 21% within 6500-7999 Da. The LD(50) in mice was 25.4 ± 2.4 μg/g and the effects observed were hypoactivity, anuria, constipation, dyspnea and prostration until death, which occurred at higher doses. Despite presenting a dose-dependent edematogenic activity in the rat hind-paw assay, the venom had no nociceptive activity in mice. Additionally, the venom induced a rapid blockage of electrical activity and subsequent diastolic arrest on in situ frog heart preparation, which was inhibited by pretreatment with atropine. In the electrically driven frog ventricle strip, the whole venom and its low molecular mass fraction, but not the proteic one, induced a negative inotropic effect that was also inhibited by atropine. These results suggest that despite low toxicity, A. paulensis venom can induce severe physiological disturbances in mice.

  20. Pharmacological actions of nobiletin in the modulation of platelet function

    PubMed Central

    Vaiyapuri, Sakthivel; Roweth, Harvey; Ali, Marfoua S; Unsworth, Amanda J; Stainer, Alexander R; Flora, Gagan D; Crescente, Marilena; Jones, Chris I; Moraes, Leonardo A; Gibbins, Jonathan M

    2015-01-01

    Background and Purpose The discovery that flavonoids are capable of inhibiting platelet function has led to their investigation as potential antithrombotic agents. However, despite the range of studies on the antiplatelet properties of flavonoids, little is known about the mechanisms by which flavonoids inhibit platelet function. In this study, we aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin, in the modulation of platelet function. Experimental Approach The ability of nobiletin to modulate platelet function was explored by using a range of in vitro and in vivo experimental approaches. Aggregation, dense granule secretion and spreading assays were performed using washed platelets. Fibrinogen binding, α-granule secretion and calcium mobilization assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice. Key Results Nobiletin was shown to suppress a range of well-established activatory mechanisms, including platelet aggregation, granule secretion, integrin modulation, calcium mobilization and thrombus formation. Nobiletin extended bleeding time in mice and reduced the phosphorylation of PKB (Akt) and PLCγ2 within the collagen receptor (glycoprotein VI)-stimulated pathway, in addition to increasing the levels of cGMP and phosphorylation of vasodilator-stimulated phosphoprotein, a protein whose activity is associated with inhibitory cyclic nucleotide signalling. Conclusions and Implications This study provides insight into the underlying molecular mechanisms through which nobiletin modulates haemostasis and thrombus formation. Therefore, nobiletin may represent a potential antithrombotic agent of dietary origins. PMID:25988959

  1. Venomic and pharmacological activity of Acanthoscurria paulensis (Theraphosidae) spider venom.

    PubMed

    Mourão, Caroline Barbosa F; Oliveira, Fagner Neves; e Carvalho, Andréa C; Arenas, Claudia J; Duque, Harry Morales; Gonçalves, Jacqueline C; Macêdo, Jéssica K A; Galante, Priscilla; Schwartz, Carlos A; Mortari, Márcia R; Almeida Santos, Maria de Fátima M; Schwartz, Elisabeth F

    2013-01-01

    In the present study we conducted proteomic and pharmacological characterizations of the venom extracted from the Brazilian tarantula Acanthoscurria paulensis, and evaluated the cardiotoxicity of its two main fractions. The molecular masses of the venom components were identified by mass spectrometry (MALDI-TOF-MS) after chromatographic separation (HPLC). The lethal dose (LD(50)) was determined in mice. Nociceptive behavior was evaluated by intradermal injection in mice and the edematogenic activity by the rat hind-paw assay. Cardiotoxic activity was evaluated on in situ frog heart and on isolated frog ventricle strip. From 60 chromatographic fractions, 97 distinct components were identified, with molecular masses between 601.4 and 21,932.3 Da. A trimodal molecular mass distribution was observed: 30% of the components within 500-1999 Da, 38% within 3500-5999 Da and 21% within 6500-7999 Da. The LD(50) in mice was 25.4 ± 2.4 μg/g and the effects observed were hypoactivity, anuria, constipation, dyspnea and prostration until death, which occurred at higher doses. Despite presenting a dose-dependent edematogenic activity in the rat hind-paw assay, the venom had no nociceptive activity in mice. Additionally, the venom induced a rapid blockage of electrical activity and subsequent diastolic arrest on in situ frog heart preparation, which was inhibited by pretreatment with atropine. In the electrically driven frog ventricle strip, the whole venom and its low molecular mass fraction, but not the proteic one, induced a negative inotropic effect that was also inhibited by atropine. These results suggest that despite low toxicity, A. paulensis venom can induce severe physiological disturbances in mice. PMID:23178240

  2. The Pharmacology of Regenerative Medicine

    PubMed Central

    Saul, Justin M.; Furth, Mark E.; Andersson, Karl-Erik

    2013-01-01

    Regenerative medicine is a rapidly evolving multidisciplinary, translational research enterprise whose explicit purpose is to advance technologies for the repair and replacement of damaged cells, tissues, and organs. Scientific progress in the field has been steady and expectations for its robust clinical application continue to rise. The major thesis of this review is that the pharmacological sciences will contribute critically to the accelerated translational progress and clinical utility of regenerative medicine technologies. In 2007, we coined the phrase “regenerative pharmacology” to describe the enormous possibilities that could occur at the interface between pharmacology, regenerative medicine, and tissue engineering. The operational definition of regenerative pharmacology is “the application of pharmacological sciences to accelerate, optimize, and characterize (either in vitro or in vivo) the development, maturation, and function of bioengineered and regenerating tissues.” As such, regenerative pharmacology seeks to cure disease through restoration of tissue/organ function. This strategy is distinct from standard pharmacotherapy, which is often limited to the amelioration of symptoms. Our goal here is to get pharmacologists more involved in this field of research by exposing them to the tools, opportunities, challenges, and interdisciplinary expertise that will be required to ensure awareness and galvanize involvement. To this end, we illustrate ways in which the pharmacological sciences can drive future innovations in regenerative medicine and tissue engineering and thus help to revolutionize the discovery of curative therapeutics. Hopefully, the broad foundational knowledge provided herein will spark sustained conversations among experts in diverse fields of scientific research to the benefit of all. PMID:23818131

  3. Pharmacological Effects of Rosa Damascena

    PubMed Central

    Boskabady, Mohammad Hossein; Shafei, Mohammad Naser; Saberi, Zahra; Amini, Somayeh

    2011-01-01

    Rosa damascena mill L., known as Gole Mohammadi in is one of the most important species of Rosaceae family flowers. R. damascena is an ornamental plant and beside perfuming effect, several pharmacological properties including anti-HIV, antibacterial, antioxidant, antitussive, hypnotic, antidiabetic, and relaxant effect on tracheal chains have been reported for this plant. This article is a comprehensive review on pharmacological effects of R. damascena. Online literature searches were performed using Medline, medex, Scopus, and Google Scholar websites backed to 1972 to identify researches about R. damascena. Searches also were done by going through the author's files and the bibliographies of all located papers. PMID:23493250

  4. Pharmacology of intracellular signalling pathways

    PubMed Central

    Nahorski, Stefan R

    2006-01-01

    This article provides a brief and somewhat personalized review of the dramatic developments that have occurred over the last 45 years in our understanding of intracellular signalling pathways associated with G-protein-coupled receptor activation. Signalling via cyclic AMP, the phosphoinositides and Ca2+ is emphasized and these systems have already been revealed as new pharmacological targets. The therapeutic benefits of most of such targets are, however, yet to be realized, but it is certain that the discipline of pharmacology needs to widen its boundaries to meet these challenges in the future. PMID:16402119

  5. PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

    PubMed

    Choi, Catherine H; Schoenfeld, Brian P; Weisz, Eliana D; Bell, Aaron J; Chambers, Daniel B; Hinchey, Joseph; Choi, Richard J; Hinchey, Paul; Kollaros, Maria; Gertner, Michael J; Ferrick, Neal J; Terlizzi, Allison M; Yohn, Nicole; Koenigsberg, Eric; Liebelt, David A; Zukin, R Suzanne; Woo, Newton H; Tranfaglia, Michael R; Louneva, Natalia; Arnold, Steven E; Siegel, Steven J; Bolduc, Francois V; McDonald, Thomas V; Jongens, Thomas A; McBride, Sean M J

    2015-01-01

    Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

  6. Parallel inhibition of active force and relaxed fiber stiffness by caldesmon fragments at physiological ionic strength and temperature conditions: additional evidence that weak cross-bridge binding to actin is an essential intermediate for force generation.

    PubMed Central

    Kraft, T; Chalovich, J M; Yu, L C; Brenner, B

    1995-01-01

    Previously we showed that stiffness of relaxed fibers and active force generated in single skinned fibers of rabbit psoas muscle are inhibited in parallel by actin-binding fragments of caldesmon, an actin-associated protein of smooth muscle, under conditions in which a large fraction of cross-bridges is weakly attached to actin (ionic strength of 50 mM and temperature of 5 degrees C). These results suggested that weak cross-bridge attachment to actin is essential for force generation. The present study provides evidence that this is also true for physiological ionic strength (170 mM) at temperatures up to 30 degrees C, suggesting that weak cross-bridge binding to actin is generally required for force generation. In addition, we show that the inhibition of active force is not a result of changes in cross-bridge cycling kinetics but apparently results from selective inhibition of weak cross-bridge binding to actin. Together with our previous biochemical, mechanical, and structural studies, these findings support the proposal that weak cross-bridge attachment to actin is an essential intermediate on the path to force generation and are consistent with the concept that isometric force mainly results from an increase in strain of the attached cross-bridge as a result of a structural change associated with the transition from a weakly bound to a strongly bound actomyosin complex. This mechanism is different from the processes responsible for quick tension recovery that were proposed by Huxley and Simmons (Proposed mechanism of force generation in striated muscle. Nature. 233:533-538.) to represent the elementary mechanism of force generation. Images FIGURE 1 PMID:7647245

  7. Pharmacology Experiments on the Computer.

    ERIC Educational Resources Information Center

    Keller, Daniel

    1990-01-01

    A computer program that replaces a set of pharmacology and physiology laboratory experiments on live animals or isolated organs is described and illustrated. Five experiments are simulated: dose-effect relationships on smooth muscle, blood pressure and catecholamines, neuromuscular signal transmission, acetylcholine and the circulation, and…

  8. Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer

    PubMed Central

    Du, Juan; Cieslak, John A.; Welsh, Jessemae L.; Sibenaller, Zita A.; Allen, Bryan G.; Wagner, Brett A.; Kalen, Amanda L.; Doskey, Claire M.; Strother, Robert K.; Button, Anna M.; Mott, Sarah L.; Smith, Brian; Tsai, Susan; Mezhir, James; Goswami, Prabhat C.; Spitz, Douglas R.; Buettner, Garry R.; Cullen, Joseph J.

    2015-01-01

    The toxicity of pharmacological ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Since pancreatic cancer cells are sensitive to H2O2 generated by ascorbate they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacological ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in non-tumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacological ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacological ascorbate as a radiosensitizer in the treatment of pancreatic cancer. PMID:26081808

  9. Pharmacology of Marihuana (Cannabis sativa)

    ERIC Educational Resources Information Center

    Maickel, Roger P.

    1973-01-01

    A detailed discussion of marihuana (Cannabis sativa) providing the modes of use, history, chemistry, and physiologic properties of the drug. Cites research results relating to the pharmacologic effects of marihuana. These effects are categorized into five areas: behavioral, cardiovascular-respiratory, central nervous system, toxicity-toxicology,…

  10. The Pharmacological Potential of Mushrooms

    PubMed Central

    2005-01-01

    This review describes pharmacologically active compounds from mushrooms. Compounds and complex substances with antimicrobial, antiviral, antitumor, antiallergic, immunomodulating, anti-inflammatory, antiatherogenic, hypoglycemic, hepatoprotective and central activities are covered, focusing on the review of recent literature. The production of mushrooms or mushroom compounds is discussed briefly. PMID:16136207

  11. Pharmacological Inhibition of Glucosylceramide Synthase Enhances Insulin Sensitivity

    PubMed Central

    Aerts, Johannes M.; Ottenhoff, Roelof; Powlson, Andrew S.; Grefhorst, Aldo; van Eijk, Marco; Dubbelhuis, Peter F.; Aten, Jan; Kuipers, Folkert; Serlie, Mireille J.; Wennekes, Tom; Sethi, Jaswinder K.; O’Rahilly, Stephen; Overkleeft, Hermen S.

    2015-01-01

    A growing body of evidence implicates ceramide and/or its glycosphingolipid metabolites in the pathogenesis of insulin resistance. We have developed a highly specific small molecule inhibitor of glucosylceramide synthase, an enzyme that catalyzes a necessary step in the conversion of ceramide to glycosphingolipids. In cultured 3T3-L1 adipocytes, the iminosugar derivative N-(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM) counteracted tumor necrosis factor-α-induced abnormalities in glycosphingo-lipid concentrations and concomitantly reversed abnormalities in insulin signal transduction. When administered to mice and rats, AMP-DNM significantly reduced glycosphin-golipid but not ceramide concentrations in various tissues. Treatment of ob/ob mice with AMP-DNM normalized their elevated tissue glucosylceramide levels, markedly lowered circulating glucose levels, improved oral glucose tolerance, reduced A1C, and improved insulin sensitivity in muscle and liver. Similarly beneficial metabolic effects were seen in high fat-fed mice and ZDF rats. These findings provide further evidence that glycosphingolipid metabolites of ceramide may be involved in mediating the link between obesity and insulin resistance and that interference with glycosphingolipid biosynthesis might present a novel approach to the therapy of states of impaired insulin action such as type 2 diabetes. PMID:17287460

  12. Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma

    PubMed Central

    Andersen, Nicholas J.; Nickoloff, Brian J.; Dykema, Karl J.; Boguslawski, Elissa A.; Krivochenitser, Roman I.; Froman, Roe E.; Dawes, Michelle J.; Baker, Laurence H.; Thomas, Dafydd G.; Kamstock, Debra A.; Kitchell, Barbara E.; Furge, Kyle A.; Duesbery, Nicholas S.

    2013-01-01

    Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human AS, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive ERK activation. The MEK inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multi-receptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human AS, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was up-regulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human AS. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human AS, and it highlights the utility of spontaneous canine cancers as a model of human disease. PMID:23804705

  13. Pharmacological Analysis of Vorinostat Analogues as Potential Anti-tumor Agents Targeting Human Histone Deacetylases: an Epigenetic Treatment Stratagem for Cancers.

    PubMed

    Praseetha, Sugathan; Bandaru, Srinivas; Nayarisseri, Anuraj; Sureshkumar, Sivanpillai

    2016-01-01

    Alteration of the acetylation status of chromatin and other non-histone proteins by HDAC inhibitors has evolved as an excellent epigenetic strategy in treatment of cancers. The present study was sought to identify compounds with positive pharmacological profiles targeting HDAC1. Analogues of Vorinostat synthesized by Cai et al, 2015 formed the test compounds for the present pharmacological evaluation. Hydroxamte analogue 6H showed superior pharmacological profile in comparison to all the compounds in the analogue dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify compounds with even better high affinity and pharmacological profile than 6H and Vorinostat, virtual screening was performed. A total of 83 compounds similar to Vorinostat and 154 compounds akin to analogue 6H were retrieved. SCHEMBL15675695 (PubCid: 15739209) and AKOS019005527 (PubCid: 80442147) similar to Vorinostat and 6H, were the best docked compounds among the virtually screened compounds. However, in spite of having good affinity, none of the virtually screened compounds had better affinity than that of 6H. In addition SCHEMBL15675695 was predicted to be a carcinogen while AKOS019005527 is Ames toxic. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report Vorinostat hydroxamate analogue 6H to be a potential candidate for HDAC inhibition in treatment of cancers through an epigenetic strategy. PMID:27039807

  14. Pharmacology for sleep disturbance in PTSD.

    PubMed

    Lipinska, Gosia; Baldwin, David S; Thomas, Kevin G F

    2016-03-01

    Symptoms of sleep disturbance, particularly nightmares and insomnia, are a central feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that specific treatment of PTSD-related sleep disturbance improves other symptoms of the disorder, which in turn suggests that such disturbance may be fundamental to development and maintenance of the disorder. This mini-review focuses on pharmacological treatment of sleep disturbance in adult PTSD (specifically, studies testing the efficacy of antidepressants, adrenergic inhibiting agents, antipsychotics and benzodiazepine and non-benzodiazepine hypnotics). We conclude that only prazosin, an adrenergic inhibiting agent, has had its efficacy established by multiple randomised controlled trials. There is also high-level evidence supporting use of eszopiclone, as well as risperidone and olanzapine as adjunct therapy. Antidepressants such as sertraline, venlafaxine and mirtazapine, benzodiazepines such as alprazolam and clonazepam and non-benzodiazepine hypnotics such as zolpidem appear ineffective in treating PTSD-related sleep disturbance. Most studies that report reduced frequency of nightmares and insomnia also report decreases in overall symptom severity. Such findings suggest that (i) sleep disruption is central to PTSD; (ii) treating sleep disruption may be an effective way to address other symptoms of the disorder and (iii) PTSD symptoms tend to cluster together in predictable ways. PMID:26856810

  15. Chemical constituents and pharmacological properties of Poria cocos.

    PubMed

    Ríos, José-Luis

    2011-05-01

    Poria cocos (Polyporaceae) is a saprophytic fungus that grows in diverse species of Pinus. Its sclerotium, called fu-ling or hoelen, is used in traditional Chinese and Japanese medicine for its diuretic, sedative, and tonic effects. Various studies of this fungus have demonstrated its marked anti-inflammatory activity in different experimental models of acute and chronic inflammation. It is widely used as a constituent of many preparations in Asian medicine, but the number of research papers on its clinical properties is insufficient for establishing its efficacy and safety from a scientific point of view. In this review, we have compiled all the published data concerning the chemistry, pharmacology, and clinical uses of this drug in order to evaluate its clinical interest for future use against various pathologies in which inflammation and immunodepression are implicated. We selected the papers for review on the basis of their ethnopharmacological relevance, using the most relevant databases for the biomedical sciences. Studies on various fungus extracts as well as on the major phytochemical compounds (polysaccharides and triterpenoids) present in Poria cocos comprised the principal objectives of this review. In several of the studies reviewed, the inhibitory effects of triterpenes on phospholipase A (2) (PLA (2)) have been clearly demonstrated. In addition, the inhibitory effects of Poria cocoson the secretion of different cytokines from human peripheral blood monocytes have also been described. Triterpenoids are known to have a pivotal influence on certain diseases such as rheumatoid arthritis, psoriasis, autoimmune uveitis, septic shock, and possibly bronchial asthma, while polysaccharides can potentiate the immune response. Reviewing the literature, we found that polysaccharides from Poria cocos enhanced the secretion of immune stimulators and suppressed the secretion of immune suppressors, thus potentiating the immune response. In addition, they showed

  16. Review on Polygonum minus. Huds, a commonly used food additive in Southeast Asia

    PubMed Central

    Christapher, Parayil Varghese; Parasuraman, Subramani; Christina, Josephine Maria Arokiaswamy; Asmawi, Mohd. Zaini; Vikneswaran, Murugaiyah

    2015-01-01

    Polygonum minus (Polygonaceae), generally known as ‘kesum’ in Malaysia is among the most commonly used food additive, flavoring agent and traditionally used to treat stomach and body aches. Raw or cooked leaves of P. minus are used in digestive disorders in the form of a decoction and the oil is used for dandruff. The pharmacological studies on P. minus have demonstrated antioxidant, in vitro LDL oxidation inhibition, antiulcer activity, analgesic activity, anti-inflammatory activity, in vitro antiplatelet aggregation activity, antimicrobial activity, digestive enhancing property and cytotoxic activity. The spectroscopic studies of essential oil of P. minus showed the presence of about 69 compounds, which are responsible for the aroma. The phytochemical studies showed presence of flavonoids and essential oils. This review is an effort to update the botanical, phytochemical, pharmacological and toxicological data of the plant P. minus. PMID:25598627

  17. Review on Polygonum minus. Huds, a commonly used food additive in Southeast Asia.

    PubMed

    Christapher, Parayil Varghese; Parasuraman, Subramani; Christina, Josephine Maria Arokiaswamy; Asmawi, Mohd Zaini; Vikneswaran, Murugaiyah

    2015-01-01

    Polygonum minus (Polygonaceae), generally known as 'kesum' in Malaysia is among the most commonly used food additive, flavoring agent and traditionally used to treat stomach and body aches. Raw or cooked leaves of P. minus are used in digestive disorders in the form of a decoction and the oil is used for dandruff. The pharmacological studies on P. minus have demonstrated antioxidant, in vitro LDL oxidation inhibition, antiulcer activity, analgesic activity, anti-inflammatory activity, in vitro antiplatelet aggregation activity, antimicrobial activity, digestive enhancing property and cytotoxic activity. The spectroscopic studies of essential oil of P. minus showed the presence of about 69 compounds, which are responsible for the aroma. The phytochemical studies showed presence of flavonoids and essential oils. This review is an effort to update the botanical, phytochemical, pharmacological and toxicological data of the plant P. minus. PMID:25598627

  18. Current status and future directions of pharmacological therapy for acromegaly.

    PubMed

    Mercado, Moisés; Espinosa, Etual; Ramírez, Claudia

    2016-09-01

    Acromegaly is a chronic systemic disorder caused in the vast majority of cases by a GH-secreting pituitary adenoma and resulting in significant morbidity and mortality if left untreated. The treatment of choice is the trans-sphenoidal resection of the adenoma, and although 80% of patients with microadenomas or confined macroadenomas achieve biochemical remission, the surgical success rate for patients harboring tumors with extrasellar extension is below 50%. Thus, a considerable proportion of patients will require some form of adjuvant treatment. Acromegaly can be approached pharmacologically by inhibiting GH secretion by the tumor (somatostatin analogues, dopamine agonists) or by antagonizing GH actions at its target tissues (GH receptor antagonists). The primary pharmacological treatment of acromegaly is increasingly gaining acceptance by both physicians and patients. The decision to use primary pharmacological treatment has to take into account the clinical characteristics of the patient (presence of comorbidities that significantly increase the surgical risk) and the biological nature of the adenoma (tumor size and location), as well as other aspects such as the availability of a pituitary surgeon and the cost of medications. This review provides a critical summary and update of the pharmacological treatment of acromegaly focusing both, on well-established agents and strategies as well as on novel compounds that are currently being developed.

  19. Phytochemistry, pharmacology, and clinical trials of Morus alba.

    PubMed

    Chan, Eric Wei-Chiang; Lye, Phui-Yan; Wong, Siu-Kuin

    2016-01-01

    The present review is aimed at providing a comprehensive summary on the botany, utility, phytochemistry, pharmacology, and clinical trials of Morus alba (mulberry or sang shu). The mulberry foliage has remained the primary food for silkworms for centuries. Its leaves have also been used as animal feed for livestock and its fruits have been made into a variety of food products. With flavonoids as major constituents, mulberry leaves possess various biological activities, including antioxidant, antimicrobial, skin-whitening, cytotoxic, anti-diabetic, glucosidase inhibition, anti-hyperlipidemic, anti-atherosclerotic, anti-obesity, cardioprotective, and cognitive enhancement activities. Rich in anthocyanins and alkaloids, mulberry fruits have pharmacological properties, such as antioxidant, anti-diabetic, anti-atherosclerotic, anti-obesity, and hepatoprotective activities. The root bark of mulberry, containing flavonoids, alkaloids and stilbenoids, has antimicrobial, skin-whitening, cytotoxic, anti-inflammatory, and anti-hyperlipidemic properties. Other pharmacological properties of M. alba include anti-platelet, anxiolytic, anti-asthmatic, anthelmintic, antidepressant, cardioprotective, and immunomodulatory activities. Clinical trials on the efficiency of M. alba extracts in reducing blood glucose and cholesterol levels and enhancing cognitive ability have been conducted. The phytochemistry and pharmacology of the different parts of the mulberry tree confer its traditional and current uses as fodder, food, cosmetics, and medicine. Overall, M. alba is a multi-functional plant with promising medicinal properties. PMID:26850343

  20. Phytochemistry, pharmacology, and clinical trials of Morus alba.

    PubMed

    Chan, Eric Wei-Chiang; Lye, Phui-Yan; Wong, Siu-Kuin

    2016-01-01

    The present review is aimed at providing a comprehensive summary on the botany, utility, phytochemistry, pharmacology, and clinical trials of Morus alba (mulberry or sang shu). The mulberry foliage has remained the primary food for silkworms for centuries. Its leaves have also been used as animal feed for livestock and its fruits have been made into a variety of food products. With flavonoids as major constituents, mulberry leaves possess various biological activities, including antioxidant, antimicrobial, skin-whitening, cytotoxic, anti-diabetic, glucosidase inhibition, anti-hyperlipidemic, anti-atherosclerotic, anti-obesity, cardioprotective, and cognitive enhancement activities. Rich in anthocyanins and alkaloids, mulberry fruits have pharmacological properties, such as antioxidant, anti-diabetic, anti-atherosclerotic, anti-obesity, and hepatoprotective activities. The root bark of mulberry, containing flavonoids, alkaloids and stilbenoids, has antimicrobial, skin-whitening, cytotoxic, anti-inflammatory, and anti-hyperlipidemic properties. Other pharmacological properties of M. alba include anti-platelet, anxiolytic, anti-asthmatic, anthelmintic, antidepressant, cardioprotective, and immunomodulatory activities. Clinical trials on the efficiency of M. alba extracts in reducing blood glucose and cholesterol levels and enhancing cognitive ability have been conducted. The phytochemistry and pharmacology of the different parts of the mulberry tree confer its traditional and current uses as fodder, food, cosmetics, and medicine. Overall, M. alba is a multi-functional plant with promising medicinal properties.

  1. The Chemical Constituents and Pharmacological Actions of Cordyceps sinensis

    PubMed Central

    Liu, Yi; Wang, Jihui; Wang, Wei; Zhang, Hanyue; Zhang, Xuelan; Han, Chunchao

    2015-01-01

    Cordyceps sinensis, also called DongChongXiaCao (winter worm, summer grass) in Chinese, is becoming increasingly popular and important in the public and scientific communities. This study summarizes the chemical constituents and their corresponding pharmacological actions of Cordyceps sinensis. Many bioactive components of Cordyceps sinensis have been extracted including nucleoside, polysaccharide, sterol, protein, amino acid, and polypeptide. In addition, these constituents' corresponding pharmacological actions were also shown in the study such as anti-inflammatory, antioxidant, antitumour, antiapoptosis, and immunomodulatory actions. Therefore can use different effects of C. sinensis against different diseases and provide reference for the study of Cordyceps sinensis in the future. PMID:25960753

  2. Perioperative pharmacology: blood coagulation modifiers.

    PubMed

    Hicks, Rodney W; Wanzer, Linda J; Goeckner, Bradlee

    2011-06-01

    Blood coagulation is the process that results in the formation of a blood clot to stop bleeding from a damaged blood vessel. Various pharmacologic agents can affect the coagulation process. The American College of Chest Physicians' evidence-based practice guidelines for perioperative management of antithrombotic therapy provide guidance for anticoagulant or antiplatelet therapy and bridge therapy. Perioperative nurses must understand the pharmacologic principles of the most common blood coagulation modifiers related to perioperative use. The perioperative nurse's responsibilities regarding administration of blood coagulation modifiers include reviewing the patient's pertinent laboratory results (eg, prothrombin time, partial thromboplastin time, international normalized ratio), recognizing the underlying conditions that require blood coagulation therapy, and documenting all pertinent information. Perioperative nurses also should participate in development of detailed storage and retrieval policies related to heparin.

  3. Clinical Pharmacology in Sleep Medicine

    PubMed Central

    Proctor, Ashley; Bianchi, Matt T.

    2012-01-01

    The basic treatment goals of pharmacological therapies in sleep medicine are to improve waking function by either improving sleep or by increasing energy during wakefulness. Stimulants to improve waking function include amphetamine derivatives, modafinil, and caffeine. Sleep aids encompass several classes, from benzodiazepine hypnotics to over-the-counter antihistamines. Other medications used in sleep medicine include those initially used in other disorders, such as epilepsy, Parkinson's disease, and psychiatric disorders. As these medications are prescribed or encountered by providers in diverse fields of medicine, it is important to recognize the distribution of adverse effects, drug interaction profiles, metabolism, and cytochrome substrate activity. In this paper, we review the pharmacological armamentarium in the field of sleep medicine to provide a framework for risk-benefit considerations in clinical practice. PMID:23213564

  4. Pharmacological potential of cerium oxidenanoparticles

    NASA Astrophysics Data System (ADS)

    Celardo, Ivana; Pedersen, Jens Z.; Traversa, Enrico; Ghibelli, Lina

    2011-04-01

    Nanotechnology promises a revolution in pharmacology to improve or create ex novo therapies. Cerium oxidenanoparticles (nanoceria), well-known as catalysts, possess an astonishing pharmacological potential due to their antioxidant properties, deriving from a fraction of Ce3+ ions present in CeO2. These defects, compensated by oxygen vacancies, are enriched at the surface and therefore in nanosized particles. Reactions involving redox cycles between the Ce3+ and Ce4+oxidation states allow nanoceria to react catalytically with superoxide and hydrogen peroxide, mimicking the behavior of two key antioxidant enzymes, superoxide dismutase and catalase, potentially abating all noxious intracellularreactive oxygen species (ROS) via a self-regenerating mechanism. Hence nanoceria, apparently well tolerated by the organism, might fight chronic inflammation and the pathologies associated with oxidative stress, which include cancer and neurodegeneration. Here we review the biological effects of nanoceria as they emerge from in vitro and in vivo studies, considering biocompatibility and the peculiar antioxidant mechanisms.

  5. The Pharmacological Activities of Licorice.

    PubMed

    Yang, Rui; Wang, Li-qiang; Yuan, Bo-chuan; Liu, Ying

    2015-12-01

    Licorice is one of the oldest and most frequently used herbs in traditional Chinese medicine. It contains more than 20 triterpenoids and 300 flavonoids. In recent years, a lot of studies have reported that the active compounds isolated from licorice possess antitumor, antimicrobial, antiviral, anti-inflammatory, immunoregulatory, and several other activities that contribute to the recovery and protection of the nervous, alimentary, respiratory, endocrine, and cardiovascular systems. In this paper, nine different pharmacological activities of licorice are summarized. The active compounds responsible for these pharmacological activities, the molecular mechanisms, and in vivo and in vitro studies are listed in detail. Furthermore, the clinical therapeutics and toxicity studies of licorice are also discussed. We hope this work can provide a basis for further studies concerning with the safe and effective use of licorice.

  6. Current pharmacological interventions in panic disorder.

    PubMed

    Freire, Rafael C; Machado, Sergio; Arias-Carrión, Oscar; Nardi, Antonio E

    2014-01-01

    The aim of this review was to summarize the recent evidences regarding the pharmacological treatment of panic disorder (PD). The authors performed a review of the literature regarding the pharmacological treatment of PD since the year 2000. The research done in the last decade brought strong evidences of effectiveness for paroxetine, venlafaxine, sertraline, fluvoxamine, citalopram, fluoxetine, clonazepam, and the relatively novel agent escitalopram. There are evidences indicating that the other new compounds inositol, duloxetine, mirtazapine, milnacipran, and nefazodone have antipanic properties and may be effective compounds in the treatment of PD. The effectiveness of reboxetine and anticonvulsants is a subject of controversy. In addition to selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, benzodiazepines and atypical antipsychotics may be valid alternatives in the treatment of PD. Recent data indicate that augmentation strategies with aripiprazole, olanzapine, pindolol or clonazepam may be effective. D-cycloserine is a promising agent in the augmentation of cognitive behavioral therapy. PMID:24923349

  7. Pharmacoprophylaxis of alcohol dependence: Review and update Part I: Pharmacology

    PubMed Central

    Grover, Sandeep; Bhateja, Gaurav; Basu, Debasish

    2007-01-01

    Alcohol dependence is a major problem in India. The pharmacological armamentarium for relapse prevention of alcohol has widened with the addition of new drugs. In this article, we review the pharmacology and efficacy of the four most important such drugs: disulfiram, naltrexone, acamprosate and topiramate. The first part of this two-part review series concerns the comparative pharmacology and the second part concerns the efficacy studies. Overall, all four of these drugs have modest but clinically significant usefulness as pharmacoprophylactic agents for relapse prevention or minimization of alcohol dependence. Combinations might be helpful, especially for naltrexone and acamprosate. The issue of supervision and compliance remains important, especially for such drugs as disulfiram and naltrexone. Topiramate is a promising new agent and requires further study. Disulfiram, while very effective in compliant patients, presents challenges in terms of patient selection and side effects. For patients with hepatic impairment, acamprosate is a good choice. PMID:20640061

  8. Classifying neuronal subclasses of the cerebellum through constellation pharmacology.

    PubMed

    Curtice, Kigen J; Leavitt, Lee S; Chase, Kevin; Raghuraman, Shrinivasan; Horvath, Martin P; Olivera, Baldomero M; Teichert, Russell W

    2016-02-01

    A pressing need in neurobiology is the comprehensive identification and characterization of neuronal subclasses within the mammalian nervous system. To this end, we used constellation pharmacology as a method to interrogate the neuronal and glial subclasses of the mouse cerebellum individually and simultaneously. We then evaluated the data obtained from constellation-pharmacology experiments by cluster analysis to classify cells into neuronal and glial subclasses, based on their functional expression of glutamate, acetylcholine, and GABA receptors, among other ion channels. Conantokin peptides were used to identify N-methyl-d-aspartate (NMDA) receptor subtypes, which revealed that neurons of the young mouse cerebellum expressed NR2A and NR2B NMDA receptor subunits. Additional pharmacological tools disclosed differential expression of α-amino-3-hydroxy-5-methyl-4-isoxazloepropionic, nicotinic acetylcholine, and muscarinic acetylcholine receptors in different neuronal and glial subclasses. Certain cell subclasses correlated with known attributes of granule cells, and we combined constellation pharmacology with genetically labeled neurons to identify and characterize Purkinje cells. This study illustrates the utility of applying constellation pharmacology to classify neuronal and glial subclasses in specific anatomical regions of the brain.

  9. The pharmacology of bimatoprost (Lumigan).

    PubMed

    Woodward, D F; Krauss, A H; Chen, J; Lai, R K; Spada, C S; Burk, R M; Andrews, S W; Shi, L; Liang, Y; Kedzie, K M; Chen, R; Gil, D W; Kharlamb, A; Archeampong, A; Ling, J; Madhu, C; Ni, J; Rix, P; Usansky, J; Usansky, H; Weber, A; Welty, D; Yang, W; Tang-Liu, D D; Garst, M E; Brar, B; Wheeler, L A; Kaplan, L J

    2001-05-01

    Bimatoprost (Lumigan) is a pharmacologically unique and highly efficacious ocular hypotensive agent. It appears to mimic the activity of a newly discovered family of fatty acid amides, termed prostamides. One biosynthetic route to the prostamides involves anandamide as the precursor. Bimatoprost pharmacology has been extensively characterized by binding and functional studies at more than 100 drug targets, which comprise a diverse variety of receptors, ion channels, and transporters. Bimatoprost exhibited no meaningful activity at receptors known to include antiglaucoma drug targets as follows: adenosine (A(1-3)), adrenergic (alpha(1), alpha(2), beta(1), beta(2)), cannabinoid (CB(1), CB(2)), dopamine (D(1-5)), muscarinic (M(1-5)), prostanoid (DP, EP(1-4), FP, IP, TP), and serotonin (5HT(1-7)). Bimatoprost does, however, exhibit potent inherent pharmacological activity in the feline iris sphincter preparation, which is prostamide-sensitive. Bimatoprost also resembles the prostamides in that it is a potent and highly efficacious ocular hypotensive agent. A single dose of bimatoprost markedly reduces intraocular pressure in dogs and laser-induced ocular hypertensive monkeys. Decreases in intraocular pressure are well maintained for at least 24 hr post-dose. Human studies have demonstrated that systemic exposure to bimatoprost is low and that accumulation does not occur. The sclera is the preferred route of accession to the eye. The high scleral permeability coefficient Papp is a likely contributing factor to the rapid onset and long-acting ocular hypotensive profile of bimatoprost. PMID:11434936

  10. [The future of pharmacological models].

    PubMed

    Bourin, M

    1995-01-01

    Do pharmacological models have a future? This was the question that had to be answered during seminar n.3 of the annual clinical pharmacology meeting in GIENS. The concept of 'model' is very extensive: it comprises both simple physiological testing and the replication in animals of human diseases. The main problems of pharmacological models are their predictive value and their validity in relation to the pragmatic target of finding new active molecules. Among numerous models proposed by the participants, three types have been selected as examples in this paper: a human model (cholecystokinin inducing panic attacks), the goal of which is to discover new molecules active in panic disorders. an animal model close to clinical features (coronary restenosis) which was to date unable to help in identifying molecules acting in human pathology transgenic animals as tools in drug development. The guidelines are very clear: models, however far they are from human pathology, are useful in predicting new molecular developments. Models are necessary steps to go from receptors to ill patients.

  11. Pharmacological disruption of maladaptive memory.

    PubMed

    Taylor, Jane R; Torregrossa, Mary M

    2015-01-01

    Many psychiatric disorders are characterized by intrusive, distracting, and disturbing memories that either perpetuate the illness or hinder successful treatment. For example, posttraumatic stress disorder (PTSD) involves such strong reemergence of memories associated with a traumatic event that the individual feels like the event is happening again. Furthermore, drug addiction is characterized by compulsive use and repeated relapse that is often driven by internal memories of drug use and/or by exposure to external stimuli that were associated with drug use. Therefore, identifying pharmacological methods to weaken the strength of maladaptive memories is a major goal of research efforts aimed at finding new treatments for these disorders. The primary mechanism by which memories could be pharmacologically disrupted or altered is through manipulation of memory reconsolidation. Reconsolidation occurs when an established memory is remembered or reactivated, reentering a labile state before again being consolidated into long-term memory storage. Memories are subject to disruption during this labile state. In this chapter we will discuss the preclinical and clinical studies identifying potential pharmacological methods for disrupting the integrity of maladaptive memory to treat mental illness.

  12. [Pharmacologic therapy in the elderly].

    PubMed

    Pettenati, C

    2001-05-01

    The pharmacological treatment in the older people should be carefully considered: older patients are at the same time the greatest consumers of drugs and the population with the greatest risk of adverse drug reactions (ADR). The ADR are in the old patient more frequent and serious for the greater number of concurrent drugs. The incorrect drug's use consists in prescribing too much or too little, for an excessive period, without a defined diagnosis and an appropriate selection of the better compound. Moreover, beneficial drugs may be frequent underused, some chronic conditions do not receive adequate pharmacologic treatment, and an ADR may be misinterpreted as a new pathological condition that requires a new prescription. The unusual presentation of many diseases in elderly play a role to complicate the clinical process necessary to optimising the drug treatment. About the risks and the benefits of pharmacological treatment, adequate data in older patients are in general lacking for the poor inclusion in clinical trials of the elderly subjects, especially frail persons. PMID:11413893

  13. Food additives

    PubMed Central

    Spencer, Michael

    1974-01-01

    Food additives are discussed from the food technology point of view. The reasons for their use are summarized: (1) to protect food from chemical and microbiological attack; (2) to even out seasonal supplies; (3) to improve their eating quality; (4) to improve their nutritional value. The various types of food additives are considered, e.g. colours, flavours, emulsifiers, bread and flour additives, preservatives, and nutritional additives. The paper concludes with consideration of those circumstances in which the use of additives is (a) justified and (b) unjustified. PMID:4467857

  14. Pharmacological separation between peripheral and central functions of cyclooxygenase-2 with CIAA, a novel cyclooxygenase-2 inhibitor.

    PubMed

    Okumura, Takako; Murata, Yoko; Hizue, Masanori; Matsuura, Tomomi; Naganeo, Rie; Kanai, Yoshihito; Murase, Akio; Sakakibara, Ayano; Fujita, Isami; Nakao, Kazunari

    2006-06-01

    There are many reports concerning the physiological and pathological involvement of cyclooxygenase (COX)-2 in the central nervous system and peripheral tissue cells. Selective COX-2 inhibitors that mainly distribute peripherally have not been reported thus far. Therefore central and peripheral roles of COX-2 remain classified pharmacologically. In this study, in vivo pharmacological profiles of CIAA ([6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid), a novel selective COX-2 inhibitor which distributes at higher concentrations in plasma than in brain, were compared with those of well-known selective COX-2 inhibitors, celecoxib and rofecoxib. Additionally, the possibility of pharmacological separation between peripheral and central actions of COX-2 with the inhibitors was investigated. CIAA selectively inhibited COX-2 activity compared with COX-1 in in vitro assays with rat whole blood. The compound exhibited lower brain penetration and higher plasma concentration (the brain/plasma concentration ratio was approximately 0.02) than celecoxib and rofecoxib after oral administration. Therefore, CIAA is mainly expected to act peripherally. Edema and prostaglandin E2 (PGE2) production in Carrageenan-injected rat paws, and pyrexia and PGE2 production in the brain in lipopolysaccharide (LPS)-injected rats were measured in in vivo experiments. CIAA exhibited lower ratios of anti-pyretic/anti-edematous activities and of inhibitory activities of PGE2 production in brain/paw than those of celecoxib and rofecoxib, and these ratios well-reflected brain/plasma concentration ratios. In conclusion, we discovered a novel selective COX-2 inhibitor, CIAA, which distributes at higher concentrations in plasma than in brain, which would make possible the pharmacological separation of the peripheral and central functions of COX-2. PMID:16690052

  15. Information technology in veterinary pharmacology instruction.

    PubMed

    Kochevar, Deborah T

    2003-01-01

    Veterinary clinical pharmacology encompasses all interactions between drugs and animals and applies basic and clinical knowledge to improve rational drug use and patient outcomes. Veterinary pharmacology instructors set educational goals and objectives that, when mastered by students, lead to improved animal health. The special needs of pharmacology instruction include establishing a functional interface between basic and clinical knowledge, managing a large quantity of information, and mastering quantitative skills essential to successful drug administration and analysis of drug action. In the present study, a survey was conducted to determine the extent to which veterinary pharmacology instructors utilize information technology (IT) in their teaching. Several IT categories were investigated, including Web-based instructional aids, stand-alone pharmacology software, interactive videoconferencing, databases, personal digital assistants (PDAs), and e-book applications. Currently IT plays a largely ancillary role in pharmacology instruction. IT use is being expanded primarily through the efforts of two veterinary professional pharmacology groups, the American College of Veterinary Clinical Pharmacology (ACVCP) and the American Academy of Veterinary Pharmacology and Therapeutics (AAVPT). The long-term outcome of improved IT use in pharmacology instruction should be to support the larger educational mission of active learning and problem solving. Creation of high-quality IT resources that promote this goal has the potential to improve veterinary pharmacology instruction within and across institutions. PMID:14976618

  16. Resolution Pharmacology: Opportunities for Therapeutic Innovation in Inflammation.

    PubMed

    Perretti, Mauro; Leroy, Xavier; Bland, Elliot J; Montero-Melendez, Trinidad

    2015-11-01

    Current medicines for the clinical management of inflammatory diseases act by inhibiting specific enzymes or antagonising specific receptors or blocking their ligands. In the past decade, a new paradigm in our understanding of the inflammatory process has emerged with the appreciation of genetic, molecular, and cellular mechanisms that are engaged to actively resolve inflammation. The 'resolution of acute inflammation' is enabled by counter-regulatory checkpoints to terminate the inflammatory reaction, promoting healing and repair. It may be possible to harness this knowledge for innovative approaches to the treatment of inflammatory pathologies. Here we discuss current translational attempts to develop agonists at proresolving targets as a strategy to rectify chronic inflammatory status. We reason this new approach will lead to the identification of better drugs that will establish a new branch of pharmacology, 'resolution pharmacology'.

  17. Sodium selenite and cancer related lymphedema: Biological and pharmacological effects.

    PubMed

    Pfister, Christina; Dawzcynski, Horst; Schingale, Franz-Josef

    2016-09-01

    A significant percentage of cancer patients develop secondary lymphedema after surgery or radiotherapy. The preferred treatment of secondary lymphedema is complex physical therapy. Pharmacotherapy, for example with diuretics, has received little attention, because they were not effective and only offered short-term solutions. Sodium selenite showed promise as a cost-effective, nontoxic anti-inflammatory agent. Treatment with sodium selenite lowers reactive oxygen species (ROS) production, causes a spontaneous reduction in lymphedema volume, increases the efficacy of physical therapy for lymphedema, and reduces the incidence of erysipelas infections in patients with chronic lymphedema. Besides biological effects in reducing excessive production of ROS, sodium selenite also displays various pharmacological effects. So far the exact mechanisms of these pharmacological effects are mostly unknown, but probably include inhibition of adhesion protein expression.

  18. Sodium selenite and cancer related lymphedema: Biological and pharmacological effects.

    PubMed

    Pfister, Christina; Dawzcynski, Horst; Schingale, Franz-Josef

    2016-09-01

    A significant percentage of cancer patients develop secondary lymphedema after surgery or radiotherapy. The preferred treatment of secondary lymphedema is complex physical therapy. Pharmacotherapy, for example with diuretics, has received little attention, because they were not effective and only offered short-term solutions. Sodium selenite showed promise as a cost-effective, nontoxic anti-inflammatory agent. Treatment with sodium selenite lowers reactive oxygen species (ROS) production, causes a spontaneous reduction in lymphedema volume, increases the efficacy of physical therapy for lymphedema, and reduces the incidence of erysipelas infections in patients with chronic lymphedema. Besides biological effects in reducing excessive production of ROS, sodium selenite also displays various pharmacological effects. So far the exact mechanisms of these pharmacological effects are mostly unknown, but probably include inhibition of adhesion protein expression. PMID:27267968

  19. Pharmacological characterization of an opioid receptor in the ciliate Tetrahymena.

    PubMed

    Chiesa, R; Silva, W I; Renaud, F L

    1993-01-01

    A pharmacological characterization has been performed of the opioid receptor involved in modulation of phagocytosis in the protozoan ciliate Tetrahymena. Studies on inhibition of phagocytosis by mammalian prototypic opioid agonists revealed that morphine and beta-endorphin have the highest intrinsic activity, whereas all the other opioids tested can only be considered partial agonists. However, morphine (a mu-receptor agonist) is twice as potent as beta-endorphin (a delta-receptor agonist). Furthermore, the sensitivity for the opioid antagonist naloxone, determined in the presence of morphine and beta-endorphin, is very similar to the sensitivity exhibited by mammalian tissues rich in mu-opioid receptors. We suggest that the opioid receptor coupled to phagocytosis in Tetrahymena is mu-like in some of its pharmacological characteristics and may serve as a model system for studies on opioid receptor function and evolution.

  20. INHIBITION OF INDOLEAMINE 2,3-DIOXYGENASE DOES NOT IMPEDE ORAL TOLERANCE

    EPA Science Inventory

    Rationale: Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, regulates immune tolerance through inhibition of T-cell proliferation. Pharmacologic inhibition of IDO, which causes fetal rejection and increased tumor resistance in mice, may prove useful in cancer...

  1. Pharmacological treatment of obsessive-compulsive disorder

    PubMed Central

    Bloch, Michael H.

    2014-01-01

    Synopsis Obsessive-compulsive disorder (OCD) affects up to 2.5% of the population of the course of a lifetime and produces substantial morbidity. Approximately 70% of patients can experience significant symptomatic relief with appropriate pharmacotherapy. The selective serotonin reuptake inhibitors (SSRIs) are the main stay of pharmacological treatment. These are typically used at higher doses and for longer periods than in depression. Remission is, unfortunately, uncommon. Proven second-line treatments include the tricyclic clomipramine and the addition of low-dose neuroleptic medications. Other augmentation strategies have been explored for patients refractory to proven interventions, but they are not as of yet robustly supported by controlled studies. The combination of medication with psychotherapy is often used, though careful studies have not documented synergistic benefit in adult patients. OCD refractory to available treatments remains a profound clinical challenge. PMID:25150568

  2. Cefuroxime: antimicrobial activity, Pharmacology, and clinical efficacy.

    PubMed

    Smith, B R; LeFrock, J L

    1983-06-01

    The antimicrobial activity, pharmacology, toxicity, and clinical efficacy of cefuroxime are reviewed. Cefuroxime has a second-generation cephalosporin spectrum of activity similar to cefamandole. Addition of a methoxyimino side chain has enhanced its beta-lactamase stability. Cefuroxime is active against certain cephalothin-, cefamandole-, and gentamicin-resistant bacteria. Cefuroxime has an extended half-life which allows dosing every 8 h. If penetrates into bodily tissues and fluids, including the cerebrospinal fluid, in therapeutic concentrations. Cefuroxime has been used successfully in the treatment of meningitis; sepsis; urinary tract, bone and joint, pulmonary, skin, and soft tissue infections; and gonorrhea. Competitive pricing of cefuroxime should provide a cost-effective substitute for cefamandole and, in certain situations, third-generation cephalosporins.

  3. Perchlorate Clinical Pharmacology and Human Health: A Review

    PubMed Central

    Soldin, Offie Porat; Braverman, Lewis E.; Lamm, Steven H.

    2013-01-01

    Summary Potassium perchlorate has been used at various times during the last 50 years to treat hyperthyroidism. Since World War II ammonium perchlorate has been used as a propellant for rockets. In 1997, the assay sensitivity for perchlorate in water was improved from 0.4 mg/L (ppm) to 4 µg/L (ppb). As a result, public water supplies in Southern California were found to contain perchlorate ions in the range of 5 to 8 ppb, and those in Southern Nevada were found to contain 5 to 24 ppb. Research programs have been developed to assess the safety or risk from these exposures and to assist state and regulatory agencies in setting a reasonable safe level for perchlorate in drinking water. This report reviews the evidence on the human health effects of perchlorate exposure. Perchlorate is a competitive inhibitor of iodine uptake. All of its pharmacologic effects at current therapeutic levels or lower are associated with inhibition of the sodium-iodide symporter (NIS) on the thyroid follicular cell membrane. A review of the medical and occupational studies has been undertaken to identify perchlorate exposure levels at which thyroid hormone levels may be reduced or thyrotropin levels increased. This exposure level may begin in the 35 to 100 mg/d range. Volunteer studies have been designed to determine the exposure levels at which perchlorate begins to affect iodine uptake in humans. Such effects may begin at levels of approximately 1 mg/d. Environmental studies have assessed the thyroidal health of newborns and adults at current environmental exposures to perchlorate and have concluded that the present levels appear to be safe. Whereas additional studies are underway both in laboratory animals and in the field, it appears that a safe level can be established for perchlorate in water and that regulatory agencies and others are now trying to determine that level. PMID:11477312

  4. Modulation of the pharmacological effects of enzymatically-active PLA2 by BTL-2, an isolectin isolated from the Bryothamnion triquetrum red alga

    PubMed Central

    Oliveira, Simone CB; Fonseca, Fabiana V; Antunes, Edson; Camargo, Enilton A; Morganti, Rafael P; Aparício, Ricardo; Toyama, Daniela O; Beriam, Luís OS; Nunes, Eudismar V; Cavada, Benildo S; Nagano, Celso S; Sampaio, Alexandre H; Nascimento, Kyria S; Toyama, Marcos H

    2008-01-01

    Background An interaction between lectins from marine algae and PLA2 from rattlesnake was suggested some years ago. We, herein, studied the effects elicited by a small isolectin (BTL-2), isolated from Bryothamnion triquetrum, on the pharmacological and biological activities of a PLA2 isolated from rattlesnake venom (Crotalus durissus cascavella), to better understand the enzymatic and pharmacological mechanisms of the PLA2 and its complex. Results This PLA2 consisted of 122 amino acids (approximate molecular mass of 14 kDa), its pI was estimated to be 8.3, and its amino acid sequence shared a high degree of similarity with that of other neurotoxic and enzymatically-active PLA2s. BTL-2 had a molecular mass estimated in approximately 9 kDa and was characterized as a basic protein. In addition, BTL-2 did not exhibit any enzymatic activity. The PLA2 and BTL-2 formed a stable heterodimer with a molecular mass of approximately 24–26 kDa, estimated by molecular exclusion HPLC. In the presence of BTL-2, we observed a significant increase in PLA2 activity, 23% higher than that of PLA2 alone. BTL-2 demonstrated an inhibition of 98% in the growth of the Gram-positive bacterial strain, Clavibacter michiganensis michiganensis (Cmm), but only 9.8% inhibition of the Gram-negative bacterial strain, Xanthomonas axonopodis pv passiflorae (Xap). PLA2 decreased bacterial growth by 27.3% and 98.5% for Xap and Cmm, respectively, while incubating these two proteins with PLA2-BTL-2 inhibited their growths by 36.2% for Xap and 98.5% for Cmm. PLA2 significantly induced platelet aggregation in washed platelets, whereas BTL-2 did not induce significant platelet aggregation in any assay. However, BTL-2 significantly inhibited platelet aggregation induced by PLA2. In addition, PLA2 exhibited strong oedematogenic activity, which was decreased in the presence of BTL-2. BTL-2 alone did not induce oedema and did not decrease or abolish the oedema induced by the 48/80 compound. Conclusion The

  5. Local anesthetics: pharmacology and toxicity.

    PubMed

    Moore, Paul A; Hersh, Elliot V

    2010-10-01

    The development of safe and effective local anesthetic agents has possibly been the most important advancement in dental science to occur in the last century. The agents currently available in dentistry are extremely safe and fulfill most of the characteristics of an ideal local anesthetic. These local anesthetic agents can be administered with minimal tissue irritation and with little likelihood of inducing allergic reactions. A variety of agents are available that provide rapid onset and adequate duration of surgical anesthesia. This introductory article provides a brief update of the clinical pharmacology of local anesthetic agents and formulations used in dentistry at present.

  6. Pharmacologic considerations for Shuttle astronauts

    NASA Technical Reports Server (NTRS)

    Santy, Patricia A.; Bungo, Michael W.

    1991-01-01

    Medication usage by crewmembers in the preflight and inflight mission periods is common in the Shuttle Program. The most common medical reports for which medication is used are: space motion sickness (SMS), sleeplessness, headache, and backache. A number of medications are available in the Shuttle Medical Kit to treat these problems. Currently, astronauts test all frequently used medications before mission assignment to identify potential side-effects, problems related to performance, personal likes/dislikes, and individual therapeutic effect. However, microgravity-induced changes in drug pharmacokinetics, in combination with multiple operational factors, may significantly alter crewmember responses inflight. This article discusses those factors that may impact pharmacologic efficacy during Shuttle missions.

  7. Low back pain: pharmacologic management.

    PubMed

    Miller, Susan M

    2012-09-01

    Adequate treatment of low back pain is essential, but has been challenging for many primary care physicians. Most patients with low back pain can be treated in the primary care environment, provided the physician has enough knowledge of the medications used to treat low back pain. The main treatment goal for acute low back pain is to control the pain and maintain function. For patients with chronic back pain, the goal is continual pain management and prevention of future exacerbations. This article reviews current pharmacological options for the treatment of low back pain, and possible future innovations. PMID:22958559

  8. Pharmacologic management of overactive bladder.

    PubMed

    Lam, Sum; Hilas, Olga

    2007-01-01

    Overactive bladder (OAB) is a prevalent and costly condition that can affect any age group. Typical symptoms include urinary urgency, frequency, incontinence and nocturia. OAB occurs as a result of abnormal contractions of the bladder detrusor muscle caused by the stimulation of certain muscarinic receptors. Therefore, antimuscarinic agents have long been considered the mainstay of pharmacologic treatment for OAB. Currently, there are five such agents approved for the management of OAB in the United States: oxybutynin, tolterodine, trospium, solifenacin and darifenacin. This article summarizes the efficacy, contraindications, precautions, dosing and common side effects of these agents. All available clinical trials on trospium, solifenacin and darifenacin were reviewed to determine its place in therapy.

  9. Pharmacologic therapeutics for cardiac reperfusion injury.

    PubMed

    Gross, Eric R; Gross, Garrett J

    2007-09-01

    Cardiovascular disease is the leading cause of morbidity and mortality in industrial societies, with myocardial infarction as the primary assassin. Pharmacologic agents, including the myocardial cell membrane receptor agonists adenosine, bradykinin/angiotensin-converting enzyme inhibitors, opioids and erythropoietin or the mixed cell membrane and intracellular agonists, glucose insulin potassium, and volatile anesthetics, either clinically or experimentally reduce the extent of myocardial injury when administered just prior to reperfusion. Agents that specifically target proteins, transcription factors or ion channels, including PKC agonists/antagonists, PPAR, Phosphodiesterase-5 inhibitors, 3-Hydroxy-3-methyl glutaryl coenzyme A reductase and the ATP-dependent potassium channel are also promising. However, no agent has been specifically approved to reduce reperfusion injury clinically. In this review, we will discuss the advantages and limitations of agents to combat reperfusion injury, their market development status and findings reported in both clinical and preclinical studies. The molecular pathways activated by these agents that preserve myocardium from reperfusion injury, which appear to commonly involve glycogen synthase kinase 3beta and mitochondrial permeability transition pore inhibition, are also described. PMID:17874967

  10. Beyond traditional pharmacology: new tools and approaches.

    PubMed

    Gurevich, E V; Gurevich, V V

    2015-07-01

    Traditional pharmacology is defined as the science that deals with drugs and their actions. While small molecule drugs have clear advantages, there are many cases where they have proved to be ineffective, prone to unacceptable side effects, or where due to a particular disease aetiology they cannot possibly be effective. A dominant feature of the small molecule drugs is their single mindedness: they provide either continuous inhibition or continuous activation of the target. Because of that, these drugs tend to engage compensatory mechanisms leading to drug tolerance, drug resistance or, in some cases, sensitization and consequent loss of therapeutic efficacy over time and/or unwanted side effects. Here we discuss new and emerging therapeutic tools and approaches that have potential for treating the majority of disorders for which small molecules are either failing or cannot be developed. These new tools include biologics, such as recombinant hormones and antibodies, as well as approaches involving gene transfer (gene therapy and genome editing) and the introduction of specially designed self-replicating cells. It is clear that no single method is going to be a 'silver bullet', but collectively, these novel approaches hold promise for curing practically every disorder.

  11. [Pharmacologic treatment of fibromyalgia: Towards chemical neuromodulation].

    PubMed

    Collado, Antonio; Conesa, Arantxa

    2009-08-01

    Fibromyalgia is a chronic pathology and its main symptom is pain which usually does not respond to traditional analgesia. Its clinical characteristics and the diverse neurophysiologic findings in these patients point to a central sensitization process of the nociceptive system as the central physiopathologic axis in this disease. The knowledge of the nociceptive system functioning and its behavior in this disease has led, in the past few years, to new possibilities for the therapeutic approach. In that way, drugs with a differential mechanism of action, allowing a modulation of the nociceptive system capable of producing analgesia where other medications have failed are being developed. Different drugs with the capacity increasing the activity of biologically active amines implicated in the nociceptive inhibition process and others which are destined to reduce the excitability of the system through ion channels, are being tested with some benefit in Fibromyalgia patients and may constitute a more rational neuromodulating drug profile for this disease. This article reviews the different pharmacological strategies supported by scientific evidence and points to some future research lines that fortifies the therapeutic change taking place in the treatment approach of these patients.

  12. Beyond traditional pharmacology: new tools and approaches

    PubMed Central

    Gurevich, E V; Gurevich, V V

    2015-01-01

    Traditional pharmacology is defined as the science that deals with drugs and their actions. While small molecule drugs have clear advantages, there are many cases where they have proved to be ineffective, prone to unacceptable side effects, or where due to a particular disease aetiology they cannot possibly be effective. A dominant feature of the small molecule drugs is their single mindedness: they provide either continuous inhibition or continuous activation of the target. Because of that, these drugs tend to engage compensatory mechanisms leading to drug tolerance, drug resistance or, in some cases, sensitization and consequent loss of therapeutic efficacy over time and/or unwanted side effects. Here we discuss new and emerging therapeutic tools and approaches that have potential for treating the majority of disorders for which small molecules are either failing or cannot be developed. These new tools include biologics, such as recombinant hormones and antibodies, as well as approaches involving gene transfer (gene therapy and genome editing) and the introduction of specially designed self-replicating cells. It is clear that no single method is going to be a ‘silver bullet’, but collectively, these novel approaches hold promise for curing practically every disorder. PMID:25572005

  13. Pharmacological activation of lysophosphatidic acid receptors regulates erythropoiesis

    PubMed Central

    Lin, Kuan-Hung; Ho, Ya-Hsuan; Chiang, Jui-Chung; Li, Meng-Wei; Lin, Shi-Hung; Chen, Wei-Min; Chiang, Chi-Ling; Lin, Yu-Nung; Yang, Ya-Jan; Chen, Chiung-Nien; Lu, Jenher; Huang, Chang-Jen; Tigyi, Gabor; Yao, Chao-Ling; Lee, Hsinyu

    2016-01-01

    Lysophosphatidic acid (LPA), a growth factor-like phospholipid, regulates numerous physiological functions, including cell proliferation and differentiation. In a previous study, we have demonstrated that LPA activates erythropoiesis by activating the LPA 3 receptor subtype (LPA3) under erythropoietin (EPO) induction. In the present study, we applied a pharmacological approach to further elucidate the functions of LPA receptors during red blood cell (RBC) differentiation. In K562 human erythroleukemia cells, knockdown of LPA2 enhanced erythropoiesis, whereas knockdown of LPA3 inhibited RBC differentiation. In CD34+ human hematopoietic stem cells (hHSC) and K526 cells, the LPA3 agonist 1-oleoyl-2-methyl-sn-glycero-3-phosphothionate (2S-OMPT) promoted erythropoiesis, whereas the LPA2 agonist dodecyl monophosphate (DMP) and the nonlipid specific agonist GRI977143 (GRI) suppressed this process. In zebrafish embryos, hemoglobin expression was significantly increased by 2S-OMPT treatment but was inhibited by GRI. Furthermore, GRI treatment decreased, whereas 2S-OMPT treatment increased RBC counts and amount of hemoglobin level in adult BALB/c mice. These results indicate that LPA2 and LPA3 play opposing roles during RBC differentiation. The pharmacological activation of LPA receptor subtypes represent a novel strategies for augmenting or inhibiting erythropoiesis. PMID:27244685

  14. Pharmacologic therapy for acute pancreatitis

    PubMed Central

    Kambhampati, Swetha; Park, Walter; Habtezion, Aida

    2014-01-01

    While conservative management such as fluid, bowel rest, and antibiotics is the mainstay of current acute pancreatitis management, there is a lot of promise in pharmacologic therapies that target various aspects of the pathogenesis of pancreatitis. Extensive review of preclinical studies, which include assessment of therapies such as anti-secretory agents, protease inhibitors, anti-inflammatory agents, and anti-oxidants are discussed. Many of these studies have shown therapeutic benefit and improved survival in experimental models. Based on available preclinical studies, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of acute pancreatitis. To date a variety of clinical studies have assessed the translational potential of animal model effective experimental therapies and have shown either failure or mixed results in human studies. Despite these discouraging clinical studies, there is a great clinical need and there exist several preclinical effective therapies that await investigation in patients. Better understanding of acute pancreatitis pathophysiology and lessons learned from past clinical studies are likely to offer a great foundation upon which to expand future therapies in acute pancreatitis. PMID:25493000

  15. Pharmacologic interventions in aging hair

    PubMed Central

    Trüeb, Ralph M

    2006-01-01

    The appearance of hair plays an important role in people’s overall physical appearance and self-perception. With today’s increasing life-expectations, the desire to look youthful plays a bigger role than ever. The hair care industry has become aware of this and is delivering active products directed towards meeting this consumer demand. The discovery of pharmacological targets and the development of safe and effective drugs also indicate strategies of the drug industry for maintenance of healthy and beautiful hair. Hair aging comprises weathering of the hair shaft, decrease of melanocyte function, and decrease in hair production. The scalp is subject to intrinsic and extrinsic aging. Intrinsic factors are related to individual genetic and epigenetic mechanisms with interindividual variation: prototypes are familial premature graying, and androgenetic alopecia. Currently available pharmacologic treatment modalities with proven efficacy for treatment of androgenetic alopecia are topical minoxidil and oral finasteride. Extrinsic factors include ultraviolet radiation and air pollution. Experimental evidence supports the hypothesis that oxidative stress also plays a role in hair aging. Topical anti-aging compounds include photoprotectors and antioxidants. In the absence of another way to reverse hair graying, hair colorants remain the mainstay of recovering lost hair color. Topical liposome targeting for melanins, genes, and proteins selectively to hair follicles are currently under investigation. PMID:18044109

  16. Integrating pharmacology and clinical pharmacology in pharmaceutical companies.

    PubMed

    Hunter, Jackie A

    2012-06-01

    Integration of clinical and preclinical pharmacology in pharmaceutical companies could be improved by several key recommendations: Companies should ensure that there is an adequate pool of trained clinical pharmacologists and preclinical pharmacologists. Training should include topics that allow clinical pharmacologists to be cognizant of the methods, issues and challenges faced by the preclinical pharmacologists and vice versa. Companies should incentivize such integration internally by aligning objectives and metrics/incentives. In academic medicine and the NHS there should be support for involvement of clinical pharmacologists in basic academic research and industrial R & D and new ways of facilitating and incentivizing preclinical pharmacologists and clinical pharmacologists to move between these various environments should be sought.

  17. The pharmacological profile of ovalbumin-induced paw oedema in rats.

    PubMed

    Feitosa, R F G; Melcíades, G B; Assreuy, A M S; Rocha, M F G; Ribeiro, R A; Lima, A A M

    2002-06-01

    Rats are commonly used in anaphylaxis models, mainly in intestinal anaphylaxis. Hypersensitivity mechanisms are complex and they are not clearly defined. Ovalbumin (OVA) is commonly used for studies on the hypersensitivity mechanism. However, the potential pro-inflammatory mediators induced by this antigen in the model of paw oedema in immunized rats are still not completely understood. This work examines the pharmacological modulation of several mediators involved in rat hind paw immune oedema induced by OVA. Wistar rats were previously immunized (14-18 days) with OVA (30 microg, intraperitoneally) or sham-sensitized with aluminum hydroxide (control). The paw volumes were measured before the antigenic stimuli and 1, 2, 3 and 4 h after the intraplantar injection of OVA (10 microg/paw). Subcutaneous injection of dexamethasone, diphenhydramine, cyproheptadine, chlorpromazine or methysergide significantly inhibited (p < 0.05) the allergic paw oedema. The dual inhibitor of cyclooxygenase and lipoxygenase (NDGA), the cyclooxygenase inhibitor (indomethacin), the lipoxygenase inhibitor (MK-886), the PAF antagonist (WEB 2086), the mast cell stabilizer (ketotifen), and the anti-histamine (meclizine) did not inhibit the immune oedema. In addition, thalidomide and pentoxifylline (anti-tumour necrosis factor drugs) were ineffective against OVA-induced oedema. The fact that indomethacin, MK-886, NDGA and WEB 2086 are unable to inhibit this allergic oedema indicates that the dexamethasone action seems not to be via phospholipase A2, but possibly due to the synthesis and/or the inhibitory activity of cytokines. The paw oedema inhibition by diphenhydramine, but not by meclizine, may suggest a different mechanism, which is independent of the effect of histamine. These data indicate that allergic oedema is more sensitive to anti-serotonin drugs, mainly anti-5-HT2, suggesting that the principal mediator of this inflammatory response is serotonin. PMID:12137244

  18. The First 50 Years of Molecular Pharmacology.

    PubMed

    Brown, Joan Heller; Catterall, William A; Conn, P Jeffrey; Cull-Candy, Stuart G; Dingledine, Ray; Harden, T Kendall; Insel, Paul A; Milligan, Graeme; Traynelis, Stephen F

    2015-07-01

    In this Perspective, former and current editors of Molecular Pharmacology, together with the guest editors for this 50th Anniversary Issue, provide a historical overview of the journal since its founding in 1965. The substantial impact that Molecular Pharmacology has had on the field of pharmacology as well as on biomedical science is discussed, as is the broad scope of the journal. The authors conclude that, true to the original goals for the journal, Molecular Pharmacology today remains an outstanding venue for work that provides a mechanistic understanding of drugs, molecular probes, and their biologic targets.

  19. AtRH57, a DEAD-box RNA helicase, is involved in feedback inhibition of glucose-mediated abscisic acid accumulation during seedling development and additively affects pre-ribosomal RNA processing with high glucose

    PubMed Central

    Hsu, Yi-Feng; Chen, Yun-Chu; Hsiao, Yu-Chun; Wang, Bing-Jyun; Lin, Shih-Yun; Cheng, Wan-Hsing; Jauh, Guang-Yuh; Harada, John J; Wang, Co-Shine

    2014-01-01

    The Arabidopsis thalianaT-DNA insertion mutant rh57-1 exhibited hypersensitivity to glucose (Glc) and abscisic acid (ABA). The other two rh57 mutants also showed Glc hypersensitivity similar to rh57-1, strongly suggesting that the Glc-hypersensitive feature of these mutants results from mutation of AtRH57. rh57-1 and rh57-3 displayed severely impaired seedling growth when grown in Glc concentrations higher than 3%. The gene, AtRH57 (At3g09720), was expressed in all Arabidopsis organs and its transcript was significantly induced by ABA, high Glc and salt. The new AtRH57 belongs to class II DEAD-box RNA helicase gene family. Transient expression of AtRH57-EGFP (enhanced green fluorescent protein) in onion cells indicated that AtRH57 was localized in the nucleus and nucleolus. Purified AtRH57-His protein was shown to unwind double-stranded RNA independent of ATP in vitro. The ABA biosynthesis inhibitor fluridone profoundly redeemed seedling growth arrest mediated by sugar. rh57-1 showed increased ABA levels when exposed to high Glc. Quantitative real time polymerase chain reaction analysis showed that AtRH57 acts in a signaling network downstream of HXK1. A feedback inhibition of ABA accumulation mediated by AtRH57 exists within the sugar-mediated ABA signaling. AtRH57 mutation and high Glc conditions additively caused a severe defect in small ribosomal subunit formation. The accumulation of abnormal pre-rRNA and resistance to protein synthesis-related antibiotics were observed in rh57 mutants and in the wild-type Col-0 under high Glc conditions. These results suggested that AtRH57 plays an important role in rRNA biogenesis in Arabidopsis and participates in response to sugar involving Glc- and ABA signaling during germination and seedling growth. PMID:24176057

  20. AtRH57, a DEAD-box RNA helicase, is involved in feedback inhibition of glucose-mediated abscisic acid accumulation during seedling development and additively affects pre-ribosomal RNA processing with high glucose.

    PubMed

    Hsu, Yi-Feng; Chen, Yun-Chu; Hsiao, Yu-Chun; Wang, Bing-Jyun; Lin, Shih-Yun; Cheng, Wan-Hsing; Jauh, Guang-Yuh; Harada, John J; Wang, Co-Shine

    2014-01-01

    The Arabidopsis thaliana T-DNA insertion mutant rh57-1 exhibited hypersensitivity to glucose (Glc) and abscisic acid (ABA). The other two rh57 mutants also showed Glc hypersensitivity similar to rh57-1, strongly suggesting that the Glc-hypersensitive feature of these mutants results from mutation of AtRH57. rh57-1 and rh57-3 displayed severely impaired seedling growth when grown in Glc concentrations higher than 3%. The gene, AtRH57 (At3g09720), was expressed in all Arabidopsis organs and its transcript was significantly induced by ABA, high Glc and salt. The new AtRH57 belongs to class II DEAD-box RNA helicase gene family. Transient expression of AtRH57-EGFP (enhanced green fluorescent protein) in onion cells indicated that AtRH57 was localized in the nucleus and nucleolus. Purified AtRH57-His protein was shown to unwind double-stranded RNA independent of ATP in vitro. The ABA biosynthesis inhibitor fluridone profoundly redeemed seedling growth arrest mediated by sugar. rh57-1 showed increased ABA levels when exposed to high Glc. Quantitative real time polymerase chain reaction analysis showed that AtRH57 acts in a signaling network downstream of HXK1. A feedback inhibition of ABA accumulation mediated by AtRH57 exists within the sugar-mediated ABA signaling. AtRH57 mutation and high Glc conditions additively caused a severe defect in small ribosomal subunit formation. The accumulation of abnormal pre-rRNA and resistance to protein synthesis-related antibiotics were observed in rh57 mutants and in the wild-type Col-0 under high Glc conditions. These results suggested that AtRH57 plays an important role in rRNA biogenesis in Arabidopsis and participates in response to sugar involving Glc- and ABA signaling during germination and seedling growth.

  1. AtRH57, a DEAD-box RNA helicase, is involved in feedback inhibition of glucose-mediated abscisic acid accumulation during seedling development and additively affects pre-ribosomal RNA processing with high glucose.

    PubMed

    Hsu, Yi-Feng; Chen, Yun-Chu; Hsiao, Yu-Chun; Wang, Bing-Jyun; Lin, Shih-Yun; Cheng, Wan-Hsing; Jauh, Guang-Yuh; Harada, John J; Wang, Co-Shine

    2014-01-01

    The Arabidopsis thaliana T-DNA insertion mutant rh57-1 exhibited hypersensitivity to glucose (Glc) and abscisic acid (ABA). The other two rh57 mutants also showed Glc hypersensitivity similar to rh57-1, strongly suggesting that the Glc-hypersensitive feature of these mutants results from mutation of AtRH57. rh57-1 and rh57-3 displayed severely impaired seedling growth when grown in Glc concentrations higher than 3%. The gene, AtRH57 (At3g09720), was expressed in all Arabidopsis organs and its transcript was significantly induced by ABA, high Glc and salt. The new AtRH57 belongs to class II DEAD-box RNA helicase gene family. Transient expression of AtRH57-EGFP (enhanced green fluorescent protein) in onion cells indicated that AtRH57 was localized in the nucleus and nucleolus. Purified AtRH57-His protein was shown to unwind double-stranded RNA independent of ATP in vitro. The ABA biosynthesis inhibitor fluridone profoundly redeemed seedling growth arrest mediated by sugar. rh57-1 showed increased ABA levels when exposed to high Glc. Quantitative real time polymerase chain reaction analysis showed that AtRH57 acts in a signaling network downstream of HXK1. A feedback inhibition of ABA accumulation mediated by AtRH57 exists within the sugar-mediated ABA signaling. AtRH57 mutation and high Glc conditions additively caused a severe defect in small ribosomal subunit formation. The accumulation of abnormal pre-rRNA and resistance to protein synthesis-related antibiotics were observed in rh57 mutants and in the wild-type Col-0 under high Glc conditions. These results suggested that AtRH57 plays an important role in rRNA biogenesis in Arabidopsis and participates in response to sugar involving Glc- and ABA signaling during germination and seedling growth. PMID:24176057

  2. Discovery and Pharmacology of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors.

    PubMed

    Imbriglio, Jason E; Shen, Dong-Ming; Liang, Rui; Marby, Ken; You, Ming; Youm, Hye Won; Feng, Zhe; London, Clare; Xiong, Yusheng; Tata, Jim; Verras, Andreas; Garcia-Calvo, Margarita; Song, Xuelei; Addona, George H; McLaren, Dave G; He, Timothy; Murphy, Beth; Metzger, Dan E; Salituro, Gino; Deckman, Diana; Chen, Qing; Jin, Xiaoling; Stout, Steven J; Wang, Sheng-Ping; Wilsie, Larissa; Palyha, Oksana; Han, Seongah; Hubbard, Brian K; Previs, Stephen F; Pinto, Shirly; Taggart, Andrew

    2015-12-10

    DGAT2 plays a critical role in hepatic triglyceride production, and data suggests that inhibition of DGAT2 could prove to be beneficial in treating a number of disease states. This article documents the discovery and optimization of a selective small molecule inhibitor of DGAT2 as well as pharmacological proof of biology in a mouse model of triglyceride production.

  3. Advances in the nutritional and pharmacological management of phenylketonuria

    PubMed Central

    Ney, Denise M.; Blank, Robert D.; Hansen, Karen E.

    2014-01-01

    Structural Abstract Purpose of review The purpose is to discuss advances in the nutritional and pharmacological management of phenylketonuria (PKU). Recent findings Glycomacropeptide (GMP), a whey protein produced during cheese production, is a low-phe intact protein that represents a new dietary alternative to synthetic amino acids (AAs) for people with PKU. Skeletal fragility is a long-term complication of PKU that based on murine research, appears to result from both genetic and nutritional factors. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an AA diet, allowing greater radial bone growth. Pharmacologic therapy with tetrahydrobiopterin (BH4), acting as a molecular chaperone for phenylalanine hydroxylase, increases tolerance to dietary phe in some individuals. Large neutral AAs (LNAA) inhibit phe transport across the intestinal mucosa and blood brain barrier; LNAA are most effective for individuals unable to comply with the low-phe diet. Summary Although a low-phe synthetic AA diet remains the mainstay of PKU management, new nutritional and pharmacological treatment options offer alternative approaches to maintain lifelong low phe concentrations. GMP medical foods provide an alternative to AA formula that may improve bone health, and BH4 permits some individuals with PKU to increase tolerance to dietary phe. Further research is needed to characterize the long-term efficacy of these new approaches for PKU management. PMID:24136088

  4. Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model.

    PubMed

    Serrano, Oscar K; Parrow, Nermi L; Violet, Pierre-Christian; Yang, Jacqueline; Zornjak, Jennifer; Basseville, Agnes; Levine, Mark

    2015-10-01

    Because 5-year survival rates for patients with metastatic melanoma remain below 25%, there is continued need for new therapeutic approaches. For some tumors, pharmacologic ascorbate treatment may have a beneficial antitumor effect and may work synergistically with standard chemotherapeutics. To investigate this possibility in melanoma, we examined the effect of pharmacologic ascorbate on B16-F10 cells. Murine models were employed to compare tumor size following treatment with ascorbate, and the chemotherapeutic agents dacarbazine or valproic acid, alone or in combination with ascorbate. Results indicated that nearly all melanoma cell lines were susceptible to ascorbate-mediated cytotoxicity. Compared to saline controls, pharmacologic ascorbate decreased tumor size in both C57BL/6 (P < 0.0001) and NOD-scid tumor bearing mice (P < 0.0001). Pharmacologic ascorbate was superior or equivalent to dacarbazine as an antitumor agent. Synergy was not apparent when ascorbate was combined with either dacarbazine or valproic acid; the latter combination may have additional toxicities. Pharmacologic ascorbate induced DNA damage in melanoma cells, as evidenced by increased phosphorylation of the histone variant, H2A.X. Differences were not evident in tumor samples from C57BL/6 mice treated with pharmacologic ascorbate compared to tumors from saline-treated controls. Together, these results suggest that pharmacologic ascorbate has a cytotoxic effect against melanoma that is largely independent of lymphocytic immune functions and that continued investigation of pharmacologic ascorbate in cancer treatment is warranted. PMID:26119785

  5. Trends in utilization of the pharmacological potential of chalcones.

    PubMed

    Batovska, Daniela Ilieva; Todorova, Iva Todorova

    2010-02-01

    Chalcones (1,3-diaryl-2-propen-1-ones) are open chain flavonoids that are widely biosynthesized in plants. They are important for the pigmentation of flowers and, hence, act as attractants to the pollinators. As flavonoids, chalcones also play an important role in defense against pathogens and insects. A longstanding scientific research has shown that chalcones also display other interesting biological properties such as antioxidant, cytotoxic, anticancer, antimicrobial, antiprotozoal, antiulcer, antihistaminic and anti-inflammatory activities. Some lead compounds with various pharmacological properties have been developed based on the chalcone skeleton. Clinical trials have shown that these compounds reached reasonable plasma concentrations and did not cause toxicity. For these reasons, chalcones became an object of continued interest in both academia and industry. Nowadays, several chalcones are used for treatment of viral disorders, cardiovascular diseases, parasitic infections, pain, gastritis, and stomach cancer, as well as like food additives and cosmetic formulation ingredients. However, much of the pharmacological potential of chalcones is still not utilized. The purpose of this review is to describe the recent efforts of scientists in pharmacological screening of natural and synthetic chalcones, studying the mechanisms of chalcone action and relevant structure-activity relationships. Put together, these activities aimed at synthesis of pharmacologically active chalcones and their analogs. PMID:19891604

  6. Pharmacological Treatment of Uterine Fibroids

    PubMed Central

    Moroni, RM; Vieira, CS; Ferriani, RA; Candido-dos-Reis, FJ; Brito, LGO

    2014-01-01

    Uterine fibroids (UF) are common, benign gynecologic tumors, affecting one in three to four women, with estimates of up to 80%, depending on the population studied. Their etiology is not well established, but it is under the influence of several risk factors, such as early menarche, nulliparity and family history. More than 50% of affected women are asymptomatic, but the lesions may be related to bothersome symptoms, such as abnormal uterine bleeding, pelvic pain and bloating or urinary symptoms. The treatment of UF is classically surgical; however, various medical options are available, providing symptom control while minimizing risks and complications. A large number of clinical trials have evaluated commonly used medical treatments and potentially effective new ones. Through a comprehensive literature search using PubMed, EMBASE, CENTRAL, Scopus and Google Scholar databases, through which we included 41 studies out of 7658 results, we thoroughly explored the different pharmacological options available for management of UF, their indications, advantages and disadvantages. PMID:25364587

  7. Pharmacologic management of neuropsychiatric lupus.

    PubMed

    Kivity, Shaye; Baker, Britain; Arango, Maria-Teresa; Chapman, Joab; Shoenfeld, Yehuda

    2016-01-01

    Neuropsychiatric lupus affects above 50% of patients with systemic lupus erythematosus and may span from mild symptoms to acute devastating life-threatening ones. Owing to the clinical variability, most pharmacological data rely on small, uncontrolled trials and case reports. The mainstay of therapy relies on immune-suppression by glucocorticoids, in adjunction with cyclophosphamide or anti-B-cell therapy, in moderate to severe cases. In selected scenarios (e.g., chorea) intravenous immunoglobulin or plasmapheresis may be effective. Anticoagulation is warranted if anti-phospholipid antibodies are present. In parallel there may be a need for symptomatic treatment such as anti-epileptic or anti-depressive treatments, etc. In the future, more studies addressed to assess pathogenesis and preferred treatments of specific manifestations are needed in order to personalize treatments.

  8. Psychostimulants: Basic and Clinical Pharmacology.

    PubMed

    McCreary, Andrew C; Müller, Christian P; Filip, Małgorzata

    2015-01-01

    Substance use disorder, and particularly psychostimulant use disorder, has considerable socioeconomic burden globally. The psychostimulants include several chemical classes, being derivatives of benzoylecgonine, phenethylamine, phenylpropanolamine, or aminoaryloxazoline. Psychostimulant drugs activate the brain reward pathways of the mesoaccumbal system, and continued use leads to persistent neuroplastic and dysfunctional changes of a variety of structures involved in learning and memory, habit-forming learning, salience attribution, and inhibitory control. There are a variety of neurochemical and neurobehavioral changes in psychostimulant addiction, for example, dopaminergic, glutamatergic, serotonergic (5-HT-ergic), and γ-amino butyric acid (GABA) changes have all noted. In this chapter, we will review pharmacological changes associated with psychostimulant use and abuse in humans and animals, and on the basis of the best characterized and most widely abused psychostimulants (amphetamines, cocaine) discuss why use transitions into abuse and review basic science and clinical strategies that might assist in treating psychostimulant abuse.

  9. The Chemical Basis of Pharmacology

    PubMed Central

    2010-01-01

    Molecular biology now dominates pharmacology so thoroughly that it is difficult to recall that only a generation ago the field was very different. To understand drug action today, we characterize the targets through which they act and new drug leads are discovered on the basis of target structure and function. Until the mid-1980s the information often flowed in reverse: investigators began with organic molecules and sought targets, relating receptors not by sequence or structure but by their ligands. Recently, investigators have returned to this chemical view of biology, bringing to it systematic and quantitative methods of relating targets by their ligands. This has allowed the discovery of new targets for established drugs, suggested the bases for their side effects, and predicted the molecular targets underlying phenotypic screens. The bases for these new methods, some of their successes and liabilities, and new opportunities for their use are described. PMID:21058655

  10. Toxicological evidence in forensic pharmacology.

    PubMed

    Ferner, R E

    2012-01-01

    Laboratory evidence of the presence and concentration of a drug in a person who has come to harm is often helpful in forensic pharmacology, and may be crucial. However, its value depends on two critical interpretations by the expert. First, the expert must make a careful analysis of the relationship between the results as measured in the sample and the drug in the patient at the time that harm occurred. That is especially difficult with post-mortem samples. Secondly, the expert must syntheses the laboratory information with the available clinical history and clinical or pathological findings. Even in the most favourable circumstances, when the sample is correctly obtained, identified, and analyzed, it can be hard to say that beyond reasonable doubt a given concentration had a given effect.

  11. Phosphazene additives

    DOEpatents

    Harrup, Mason K; Rollins, Harry W

    2013-11-26

    An additive comprising a phosphazene compound that has at least two reactive functional groups and at least one capping functional group bonded to phosphorus atoms of the phosphazene compound. One of the at least two reactive functional groups is configured to react with cellulose and the other of the at least two reactive functional groups is configured to react with a resin, such as an amine resin of a polycarboxylic acid resin. The at least one capping functional group is selected from the group consisting of a short chain ether group, an alkoxy group, or an aryloxy group. Also disclosed are an additive-resin admixture, a method of treating a wood product, and a wood product.

  12. Potlining Additives

    SciTech Connect

    Rudolf Keller

    2004-08-10

    In this project, a concept to improve the performance of aluminum production cells by introducing potlining additives was examined and tested. Boron oxide was added to cathode blocks, and titanium was dissolved in the metal pool; this resulted in the formation of titanium diboride and caused the molten aluminum to wet the carbonaceous cathode surface. Such wetting reportedly leads to operational improvements and extended cell life. In addition, boron oxide suppresses cyanide formation. This final report presents and discusses the results of this project. Substantial economic benefits for the practical implementation of the technology are projected, especially for modern cells with graphitized blocks. For example, with an energy savings of about 5% and an increase in pot life from 1500 to 2500 days, a cost savings of $ 0.023 per pound of aluminum produced is projected for a 200 kA pot.

  13. Pharmacologic management of chronic pain.

    PubMed

    Park, Hue Jung; Moon, Dong Eon

    2010-06-01

    Chronic pain is a multifactorial condition with both physical and psychological symptoms, and it affects around 20% of the population in the developed world. In spite of outstanding advances in pain management over the past decades, chronic pain remains a significant problem. This article provides a mechanism- and evidence-based approach to improve the outcome for pharmacologic management of chronic pain. The usual approach to treat mild to moderate pain is to start with a nonopioid analgesic. If this is inadequate, and if there is an element of sleep deprivation, then it is reasonable to add an antidepressant with analgesic qualities. If there is a component of neuropathic pain or fibromyalgia, then a trial with one of the gabapentinoids is appropriate. If these steps are inadequate, then an opioid analgesic may be added. For moderate to severe pain, one would initiate an earlier trial of a long term opioid. Skeletal muscle relaxants and topicals may also be appropriate as single agents or in combination. Meanwhile, the steps of pharmacologic treatments for neuropathic pain include (1) certain antidepressants (tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors), calcium channel alpha(2)-delta ligands (gabapentin and pregabalin) and topical lidocaine, (2) opioid analgesics and tramadol (for first-line use in selected clinical circumstances) and (3) certain other antidepressant and antiepileptic medications (topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists). It is essential to have a thorough understanding about the different pain mechanisms of chronic pain and evidence-based multi-mechanistic treatment. It is also essential to increase the individualization of treatment. PMID:20556211

  14. Pharmacological actions of statins: potential utility in COPD.

    PubMed

    Young, R P; Hopkins, R; Eaton, T E

    2009-12-01

    Chronic obstructive pulmonary disease (COPD) is characterised by minimally reversible airflow limitation and features of systemic inflammation. Current therapies for COPD have been shown to reduce symptoms and infective exacerbations and to improve quality of life. However, these drugs have little effect on the natural history of the disease (progressive decline in lung function and exercise tolerance) and do not improve mortality. The anti-inflammatory effects of statins on both pulmonary and systemic inflammation through inhibition of guanosine triphosphatase and nuclear factor-κB mediated activation of inflammatory and matrix remodelling pathways could have substantial benefits in patients with COPD due to the following. 1) Inhibition of cytokine production (tumour necrosis factor-α, interleukin (IL)-6 and IL-8) and neutrophil infiltration into the lung; 2) inhibition of the fibrotic activity in the lung leading to small airways fibrosis and irreversible airflow limitation; 3) antioxidant and anti-inflammatory (IL-6 mediated) effects on skeletal muscle; 4) reduced inflammatory response to pulmonary infection; and 5) inhibition of the development (or reversal) of epithelial-mesenchymal transition, a precursor event to lung cancer. This review examines the pleiotropic pharmacological action of statins which inhibit key inflammatory and remodelling pathways in COPD and concludes that statins have considerable potential as adjunct therapy in COPD. PMID:20956147

  15. First Employment of British Pharmacology Graduates

    ERIC Educational Resources Information Center

    Hollingsworth, Michael; Markham, Anthony

    2006-01-01

    A survey was conducted in UK Universities to identify the employment of pharmacology graduates (BSc, MSc and PhD) 6 months after graduation in 2003. The aim was to provide data for the British Pharmacological Society (BPS) so they could offer advice to interested bodies and to University staff for careers information. 85% of 52 Universities…

  16. Rate dependency, behavioral mechanisms, and behavioral pharmacology.

    PubMed

    Branch, M N

    1984-11-01

    Behavioral pharmacology has become increasingly independent of the experimental analysis of behavior. At its beginning, behavioral pharmacology was closely related to the experimental analysis of behavior, with developments in each field aiding the other. Early attempts to systematize data in behavioral pharmacology culminated with the development of the rate-dependency concept, but as this principle was found to have more limited generality than originally was hoped, a theoretical void developed. This circumstance was followed by increased reliance on pharmacological theory as a basis for experimentation and interpretation, with an attendant decrease in emphasis on environmental variables and behavioral interpretations. Lack of interplay between behavioral pharmacology and the experimental analysis of behavior is detrimental to both disciplines because each could contribute significantly to the other. The current trend might be reversed if more research were directed at elucidating behavioral mechanisms of drug action.

  17. Systems pharmacology-based dissection of mechanisms of Chinese medicinal formula Bufei Yishen as an effective treatment for chronic obstructive pulmonary disease

    PubMed Central

    Li, Jiansheng; Zhao, Peng; Li, Ya; Tian, Yange; Wang, Yonghua

    2015-01-01

    The present work adopted a systems pharmacology-based approach to provide new insights into the active compounds and therapeutic targets of Bufei Yishen formula (BYF) for the treatment of chronic obstructive pulmonary disease (COPD). In addition, we established a rat model of cigarette smoke- and bacterial infection-induced COPD to validate the mechanisms of BYF action that were predicted in systems pharmacology study. The systems pharmacology model derived 216 active compounds from BYF and 195 potential targets related to various diseases. The compound-target network showed that each herbal drug in the BYF formula acted on similar targets, suggesting potential synergistic effects among these herbal drugs. The ClueGo assay, a Cytoscape plugin, revealed that most targets were related to activation of MAP kinase and matrix metalloproteinases. By using target-diseases network analysis, we found that BYF had great potential to treatment of multiple diseases, such as respiratory tract diseases, immune system, and cardiovascular diseases. Furthermore, we found that BYF had the ability to prevent COPD and its comorbidities, such as ventricular hypertrophy, in vivo. Moreover, BYF inhibited the inflammatory cytokine, and hypertrophic factors expression, protease-antiprotease imbalance and the collagen deposition, which may be the underlying mechanisms of action of BYF. PMID:26469778

  18. Combining systems pharmacology, transcriptomics, proteomics, and metabolomics to dissect the therapeutic mechanism of Chinese herbal Bufei Jianpi formula for application to COPD

    PubMed Central

    Zhao, Peng; Yang, Liping; Li, Jiansheng; Li, Ya; Tian, Yange; Li, Suyun

    2016-01-01

    Bufei Jianpi formula (BJF) has long been used as a therapeutic agent in the treatment of COPD. Systems pharmacology identified 145 active compounds and 175 potential targets of BJF in a previous study. Additionally, BJF was previously shown to effectively prevent COPD and its comorbidities, such as ventricular hypertrophy, by inhibition of inflammatory cytokine production, matrix metalloproteinases expression, and other cytokine production, in vivo. However, the system-level mechanism of BJF for the treatment of COPD is still unclear. The aim of this study was to gain insight into its system-level mechanisms by integrating transcriptomics, proteomics, and metabolomics together with systems pharmacology datasets. Using molecular function, pathway, and network analyses, the genes and proteins regulated in COPD rats and BJF-treated rats could be mainly attributed to oxidoreductase activity, antioxidant activity, focal adhesion, tight junction, or adherens junction. Furthermore, a comprehensive analysis of systems pharmacology, transcript, protein, and metabolite datasets is performed. The results showed that a number of genes, proteins, metabolites regulated in BJF-treated rats and potential target proteins of BJF were involved in lipid metabolism, cell junction, oxidative stress, and inflammatory response, which might be the system-level therapeutic mechanism of BJF treatment. PMID:27042044

  19. Inhibition of poly(adenosine diphosphate-ribose) polymerase using quinazolinone nucleus.

    PubMed

    Hemalatha, K; Madhumitha, G

    2016-09-01

    Poly(adenosine diphosphate-ribose) polymerase (PARP) is a group of enzymes with several subtypes and it manages various ailment such as cancer, inflammatory disorders, diabetes mellitus, neuronal injury, HIV infection, Parkinsonism, aging, and ischemia-reperfusion injury. Various PARP inhibitors share a common property of bicyclic lactam in its main structural frame. The core moiety containing bicyclic lactam rings are isoquinolinones, dihydroisoquinolinones, quinazolinediones, phthalazinones, quinazolinones, and phenanthridones. The quinazolinone with diverse substituents displayed low nanomolar inhibition. Quinazolinone is an important and vital molecule in the field of medicinal chemistry possessing multitude pharmacological actions. Though the chemistry of quinazolinones has been discussed through centuries, its concise role on PARP inhibition needed a special consideration. The aim of this review is to discover the effect of quinazolinone substitutents and its role in PARP inhibition. This precise review will discuss the effect of quinazolinones on PARP subtypes such as PARP-1, PARP-2, PARP-5a, and PARP-5b. In addition to its pharmacological actions, PARP inhibitors can also act as a chemosensitizing agent, and it is used in combination with the other anticancer agents. This summarization will definitely be a supportive report for the scientist working toward the novelty in the quinazolinone nucleus and its role in PARP inhibition. PMID:27470142

  20. Pharmacology of alpha-adrenoceptors in male sexual function.

    PubMed

    Rampin, O

    1999-01-01

    Data issued from morphological and physiological experiments suggests that the noradrenergic system, through ascending pathways to the brain and descending pathways to the spinal cord, may regulate male sexual functions. Adrenoceptors have been shown to be present in the brain and spinal cord of animals and humans. The activity of spinal preganglionic neurons is modulated by noradrenaline. Pharmacological approaches aiming at selectively targeting alpha1- or alpha2-adrenoceptors have been conducted in patients with erectile dysfunction or in monkeys and rats in a variety of tests. Briefly, conclusions arising from these studies are: activation of alpha1-adrenoceptors facilitates copulation, where activation of alpha2-adrenoceptors inhibits copulation. alpha2-adrenoceptors antagonists like yohimbine facilitate sexual behavior, reducing ejaculation latency in male rats and increasing their sexual motivation. Furthermore, yohimbine induces copulation in rats either castrated or sexually naive. In contrast, activation of alpha1-adrenoceptors depresses sexual responses in another context, i.e. reflexive erections. Activation of alpha2-adrenoceptors activates reflexive erections in rats, and alpha2-adrenoceptors antagonists (yohimbine) inhibit them. Today's challenge is to separate the effects of any drug acting at the level of the alpha-adrenoceptors on the central vs. peripheral control of sexual functions, on the brain vs. spinal cord control of the same functions, and the search for any specialization of alpha-adrenoceptors subtypes in a given sexual function. Treatment of sexual dysfunctions in man (e.g. ejaculation) focusing on the spinal cord as a pharmacological target should also be expanded. Finally, considering the similarities between neural networks controlling male and female sexual functions, the treatment of female sexual dysfunction with comparable pharmacological approaches should be evaluated. PMID:10393482

  1. Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease.

    PubMed

    González-Naranjo, Pedro; Pérez-Macias, Natalia; Campillo, Nuria E; Pérez, Concepción; Arán, Vicente J; Girón, Rocio; Sánchez-Robles, Eva; Martín, María Isabel; Gómez-Cañas, María; García-Arencibia, Moisés; Fernández-Ruiz, Javier; Páez, Juan A

    2014-02-12

    Designing drugs with a specific multi-target profile is a promising approach against multifactorial illnesses as Alzheimer's disease. In this work, new indazole ethers that possess dual activity as both cannabinoid agonists CB2 and inhibitors of BuChE have been designed by computational methods. On the basis of this knowledge, the synthesis, pharmacological evaluation and docking studies of a new class of indazoles has been performed. Pharmacological evaluation includes radioligand binding assays with [(3)H]-CP55940 for CB1R and CB2R and functional activity for cannabinoid receptors on isolated tissue. Additionally, in vitro inhibitory assays of AChE/BuChE and the corresponding competition studies have been carried out. The results of pharmacological tests have revealed that three of these derivatives behave as CB2 cannabinoid agonists and simultaneously show BuChE inhibition. In particular, compounds 3 and 24 have emerged as promising candidates as novel cannabinoids that inhibit BuChE by a non-competitive or mixed mechanism, respectively. On the other hand, both molecules show antioxidant properties. PMID:24378710

  2. Pharmacological applications of antioxidants: lights and shadows.

    PubMed

    Saso, Luciano; Firuzi, Omidreza

    2014-01-01

    Oxidative stress is linked with many pathologies ranging from cancer to neurodegenerative disorders and antioxidants have presumably therapeutic value in such diseases. In this review, we categorize different direct and indirect mechanisms by which antioxidants exert their action. These include scavenging and metal chelating effects, mimicking the antioxidant enzymes or upregulation of their expression, activation of nuclear factor erythroid 2-related factor 2 (Nrf2), increasing the activity of sirtuins and inhibition of pro-oxidant enzymes among others. Recent findings on the most frequently investigated antioxidants including polyphenolics, thiolics, spin trapping agents, SOD mimetics, inducers of heme oxygenase-1 and nitric oxide synthase, activators of Nrf2, NADPH oxidase inhibitors and herbal supplements are summarized. Furthermore, the antioxidant effects of drugs that are clinically used for other pharmacological purposes including ACE inhibitors and statins are discussed. Cost-effectiveness and adverse effects of antioxidants are also evaluated. Since antioxidant therapy has failed in many instances, we have classified the reasons that may explain these shortcomings in different categories. Novel approaches to antioxidant therapy, that include mitochondria-targeting drugs, antioxidant gene therapy and approaches for improvement of cell uptake and alteration of subcellular compartment localization are also described. In the end, "shadows" that are shortcomings of antioxidant therapy as well as "lights" that include positive outcomes are addressed. It is concluded that if we learn from failures, invest on agents with higher potential and take advantage of novel emerging approaches, antioxidants could be an asset for the management of certain carefully chosen oxidative stress-related diseases.

  3. Characterization and pharmacology of the GHB receptor.

    PubMed

    Ticku, Maharaj K; Mehta, Ashok K

    2008-10-01

    Radioligand binding using [(3)H]NCS-382, an antagonist of the GHB receptor, revealed specific binding sites in the rat cerebrocortical and hippocampal membranes. Scatchard analysis of saturation isotherms revealed two different populations of binding sites. NCS-382 was about 10 times more potent than GHB in inhibiting [(3)H]NCS-382 binding. A variety of ligands for other receptors did not affect [(3)H]NCS-382 binding. Quantitative autoradiographic analysis of [(3)H]NCS-382 binding revealed similar characteristics. Thus [(3)H]NCS-382, being more potent and selective, offers advantage over [(3)H]GHB as a radioligand. Unlike GHB, several analogues of GHB such as UMB68 (a tertiary alcohol analogue of GHB), UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), UMB66 (3-chloropropanoic acid), gamma-hydroxyvaleric acid (that is, GHV, a 4-methyl-substituted analogue of GHB), 3-HPA (3-hydroxyphenylacetic acid), and ethers of 3-hydroxyphenylacetic acid (UMB108, UMB109, and UMB119) displaced [(3)H]NCS-382 without affecting [(3)H]GABA binding to GABA(B) receptor. Thus these compounds offer an advantage over GHB as an experimental tool. Our study, aimed at exploring the potential involvement of the GHB receptor in the pharmacology of ethanol, indicated that ethanol does not affect [(3)H]NCS-382 binding in the rat brain, thereby suggesting that ethanol does not interact directly with the GHB receptor. Our study, aimed at exploring the involvement of the GHB receptor in the pathology of succinate semialdehyde dehydrogenase deficiency, which is known to cause elevation of GHB levels, revealed no change in the affinity, receptor density or displacement potency as determined by using [(3)H]NCS-382 as a radioligand in Aldh5a1(-/-) vs. Aldh5a1(+/+) mouse brain.

  4. Pharmacological and autoradiographic characterization of sigma receptors

    SciTech Connect

    Largent, B.L.

    1986-01-01

    The existence of three types of opioid receptors - ..mu.., kappa, and sigma - was postulated to explain the effects of different opioids in the chronic spinal dog. Sigma receptors, named for the prototypic agonist SKF 10,047 (N-allylnormetazocine), were suggested to mediate the psychotomimetic-like effects of SKF 10,047 in the dog. 3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist. However, the drug specificity of (+)(/sup 3/H)3-PPP binding in brain is identical to that of sigma receptor binding sites which may mediate psychotomimetic effects of some opioids. Pharmacological and autoradiographic analyses reveal that (+)(/sup 3/H)SKF 10,047, the prototypic sigma agonist, labels two sites in brain. The drug specificity of the high affinity site for (+)(/sup 3/H)SKF 10,047 resembles that of putative sigma receptors labeled with (+)(/sup 3/H)3-PPP, being potently inhibited by (+)3-PPP, haloperidol, and (+/-)pentazocine, and demonstrating stereoselectivity for the (+) isomer of SKF 10,047. Autoradiographic localizations of high affinity (+)(/sup 3/H)SKF 10,047 binding sites closely resemble those of (+)(/sup 3/H)3-PPP labeled sites with high levels of binding in the hippocampal pyramidal cell layer, hypothalamus, and pontine and cranial nerve nuclei. Thus, putative sigma receptors and PCP receptors represent distinct receptor populations in brain. This proposal is supported by the presence of sigma binding sites - and absence of PCP receptors - on NCB-20 cell membranes, a hybrid neurotumor cell line that provides a model system for the physiological and biochemical study of sigma receptors.

  5. Biological and pharmacological roles of HCA receptors.

    PubMed

    Blad, Clara C; Ahmed, Kashan; IJzerman, Ad P; Offermanns, Stefan

    2011-01-01

    The hydroxy-carboxylic acid (HCA) receptors HCA(1), HCA(2), and HCA(3) were previously known as GPR81, GPR109A, and GPR109B, respectively, or as the nicotinic acid receptor family. They form a cluster of G protein-coupled receptors with high sequence homology. Recently, intermediates of energy metabolism, all HCAs, have been reported as endogenous ligands for each of these receptors. The HCA receptors are predominantly expressed on adipocytes and mediate the inhibition of lipolysis by coupling to G(i)-type proteins. HCA(1) is activated by lactate, HCA(2) by the ketone body 3-hydroxy-butyrate, and HCA(3) by hydroxylated β-oxidation intermediates, especially 3-hydroxy-octanoic acid. Both HCA(2) and HCA(3) are part of a negative feedback loop which keeps the release of fat stores in check under starvation conditions, whereas HCA(1) plays a role in the antilipolytic (fat-conserving) effect of insulin. HCA(2) was first discovered as the molecular target of the antidyslipidemic drug nicotinic acid (or niacin). Many synthetic agonists have since been designed for HCA(2) and HCA(3), but the development of a new, improved HCA-targeted drug has not been successful so far, despite a number of clinical studies. Recently, it has been shown that the major side effect of nicotinic acid, skin flushing, is mediated by HCA(2) receptors on keratinocytes, as well as on Langerhans cells in the skin. In this chapter, we summarize the latest developments in the field of HCA receptor research, with emphasis on (patho)physiology, receptor pharmacology, major ligand classes, and the therapeutic potential of HCA ligands.

  6. Artemisinins: pharmacological actions beyond anti-malarial.

    PubMed

    Ho, Wanxing Eugene; Peh, Hong Yong; Chan, Tze Khee; Wong, W S Fred

    2014-04-01

    Artemisinins are a family of sesquiterpene trioxane lactone anti-malarial agents originally derived from Artemisia annua L. The anti-malarial action of artemisinins involves the formation of free radicals via cleavage of the endoperoxide bond in its structure, which mediate eradication of the Plasmodium species. With its established safety record in millions of malarial patients, artemisinins are also being investigated in diseases like infections, cancers and inflammation. Artemisinins have been reported to possess robust inhibitory effects against viruses (e.g. Human cytomegalovirus), protozoa (e.g. Toxoplasma gondii), helminths (e.g. Schistosoma species and Fasciola hepatica) and fungi (e.g. Cryptococcus neoformans). Artemisinins have demonstrated cytotoxic effects against a variety of cancer cells by inducing cell cycle arrest, promoting apoptosis, preventing angiogenesis, and abrogating cancer invasion and metastasis. Artemisinins have been evaluated in animal models of autoimmune diseases, allergic disorders and septic inflammation. The anti-inflammatory effects of artemisinins have been attributed to the inhibition of Toll-like receptors, Syk tyrosine kinase, phospholipase Cγ, PI3K/Akt, MAPK, STAT-1/3/5, NF-κB, Sp1 and Nrf2/ARE signaling pathways. This review provides a comprehensive update on non-malarial use of artemisinins, modes of action of artemisinins in different disease conditions, and drug development of artemisinins beyond anti-malarial. With the concerted efforts in the novel synthesis of artemisinin analogs and clinical pharmacology of artemisinins, it is likely that artemisinin drugs will become a major armamentarium combating a variety of human diseases beyond malaria. PMID:24316259

  7. Glucocorticoid physiology, pharmacology and stress.

    PubMed

    Munck, A; Guyre, P M

    1986-01-01

    Basal levels of glucocorticoids maintained by negative feedback regulation are known to modulate a wide range of physiological processes, through a variety of effects such as those on carbohydrate metabolism and "permissive" actions on effects of other hormones. Glucocorticoid levels increase sharply in response to the stress of any kind of threat to homeostasis. The increased levels have traditionally been ascribed the function of enhancing the organism's resistance to stress. How known physiological and pharmacological effects of high levels of glucocorticoids might accomplish this function, however, has been a mystery. A generalization that is beginning to emerge is that many of these effects may be secondary to modulation by glucocorticoids of the actions of numerous intercellular mediators, including established hormones, prostanoids, neutral proteinases, and cytokines such as interferon. These mediators participate in physiological mechanisms--endocrine, renal, immune, neural, etc.--that mount a first line of defense against such challenges to homeostasis as hemorrhage, metabolic disturbances, infection, anxiety, and others. Contrary to the traditional view that the role of glucocorticoids in stress is to enhance these defense mechanisms, it has become increasingly clear that glucocorticoids at moderate to high levels generally suppress them. This paradox first emerged when glucocorticoids were discovered to be antiinflammatory agents, and had remained a major obstacle to a unified picture of glucocorticoid function. We have suggested that stress-induced increases in glucocorticoid levels protect not against the source of stress itself but rather against the body's normal reactions to stress, preventing those reactions from overshooting and themselves threatening homeostasis. This hypothesis, the seeds of which are to be found in many earlier discussions of glucocorticoid effects, immediately accounts for the paradox noted above, and provides glucocorticoid

  8. Pharmacology of sexually compulsive behavior.

    PubMed

    Codispoti, Victoria L

    2008-12-01

    In a meta-analysis on controlled outcomes evaluations of 22,000 sex offenders, Losel and Schmucker found 80 comparisons between treatment and control groups. The recidivism rate averaged 19% in treated groups, and 27% in controls. Most other reviews reported a lower rate of sexual recidivism in treated sexual offenders. Of 2039 citations in this study (including literature in five languages), 60 studies held independent comparisons. Problematic issues included the control groups; various hormonal, surgical, cognitive behavioral, and psychotherapeutic treatments; and sample sizes. In the 80 studies compared after the year 2000, 32% were reported after 2000, 45% originated in the United States, 45% were reported in journals, and 36% were unpublished. Treatment characteristics showed a significant lack of pharmacologic treatment (7.5%), whereas use cognitive and classical behavioral therapy was 64%. In 68% of the studies, no information was available on the integrity of the treatment implementation; 36% of the treatment settings were outpatient only, 31% were prison settings, and 12% were mixed settings (prison, hospital, and outpatient). Integrating research interpretations is complicated by the heterogeneity of sex offenders, with only 56% being adult men and 17.5% adolescents. Offense types reported included 74% child molestation, 48% incest, and 30% exhibitionism. Pedophilia was not singled out. Follow-up periods varied from 12 months to greater than 84 months. The definition of recidivism ran the gamut from arrest (24%), conviction (30%), charges (19%), and no indication (16%). Results were difficult to interpret because of the methodological problems with this type of study. Overall, a positive outcome was noted with sex offender treatment. Cognitive-behavioral and hormonal treatment were the most promising. Voluntary treatment led to a slightly better outcome than mandatory participation. When accounting for a low base rate of sexual recidivism, the reduction

  9. Characterization and Pharmacological Properties of a Novel Multifunctional Kunitz Inhibitor from Erythrina velutina Seeds

    PubMed Central

    Machado, Richele J. A.; Monteiro, Norberto K. V.; Migliolo, Ludovico; Silva, Osmar N.; Pinto, Michele F. S.; Oliveira, Adeliana S.; Franco, Octávio L.; Kiyota, Sumika; Bemquerer, Marcelo P.; Uchoa, Adriana F.; Morais, Ana H. A.; Santos, Elizeu A.

    2013-01-01

    Inhibitors of peptidases isolated from leguminous seeds have been studied for their pharmacological properties. The present study focused on purification, biochemical characterization and anti-inflammatory and anticoagulant evaluation of a novel Kunitz trypsin inhibitor from Erythrina velutina seeds (EvTI). Trypsin inhibitors were purified by ammonium sulfate (30–60%), fractionation followed by Trypsin-Sepharose affinity chromatography and reversed-phase high performance liquid chromatography. The purified inhibitor showed molecular mass of 19,210.48 Da. Furthermore, a second isoform with 19,228.16 Da was also observed. The inhibitor that showed highest trypsin specificity and enhanced recovery yield was named EvTI (P2) and was selected for further analysis. The EvTI peptide fragments, generated by trypsin and pepsin digestion, were further analyzed by MALDI-ToF-ToF mass spectrometry, allowing a partial primary structure elucidation. EvTI exhibited inhibitory activity against trypsin with IC50 of 2.2×10−8 mol.L−1 and constant inhibition (Ki) of 1.0×10−8 mol.L−1, by a non-competitive mechanism. In addition to inhibit the activity of trypsin, EvTI also inhibited factor Xa and neutrophil elastase, but do not inhibit thrombin, chymotrypsin or peptidase 3. EvTI was investigated for its anti-inflammatory and anti-coagulant properties. Firstly, EvTI showed no cytotoxic effect on human peripheral blood cells. Nevertheless, the inhibitor was able to prolong the clotting time in a dose-dependent manner by using in vitro and in vivo models. Due to anti-inflammatory and anticoagulant EvTI properties, two sepsis models were here challenged. EvTI inhibited leukocyte migration and specifically acted by inhibiting TNF-α release and stimulating IFN-α and IL-12 synthesis. The data presented clearly contribute to a better understanding of the use of Kunitz inhibitors in sepsis as a bioactive agent capable of interfering in blood coagulation and inflammation. PMID

  10. Pharmacological characterization of the dopamine-sensitive adenylate cyclase in cockroach brain: evidence for a distinct dopamine receptor

    SciTech Connect

    Orr, G.L.; Gole, J.W.D.; Notman, H.J.; Downer, R.G.H.

    1987-12-21

    Dopamine increases cyclic AMP production in crude membrane preparations of cockroach brain with plateaus in cyclic AMP production occurring between 1-10 ..mu..M and 10 mM. Maximal production of cyclic AMP is 2.25 fold greater than that of control values. Octopamine also increases cyclic AMP production with a Ka of 1.4 ..mu..M and maximal production 3.5 fold greater than that of control. 5-Hydroxytryptamine does not increase cyclic AMP production. The effects of octopamine and dopamine are fully additive. The vertebrate dopamine agonists ADTN and epinine stimulate the dopamine-sensitive adenylate cyclase (AC) with Ka values of 4.5 and 0.6 ..mu..M respectively and with maximal effectiveness 1.7 fold greater than that of control. The selective D/sub 2/-dopamine agonist LY-171555 stimulates cyclic AMP production to a similar extent with a Ka of 50 ..mu..M. Other dopamine agonists have no stimulatory effects. With the exception of mianserin, /sup 3/H-piflutixol is displaced from brain membranes by dopamine antagonists with an order of potency similar to that observed for the inhibition of dopamine-sensitive AC. The results indicate that the octopamine- and dopamine-sensitive AC in cockroach brain can be distinguished pharmacologically and the dopamine receptors coupled to AC have pharmacological characteristics distinct from vertebrate D/sup 1/- and D/sup 2/-dopamine receptors. 33 references, 3 figures, 2 tables.

  11. Histamine receptors and cancer pharmacology

    PubMed Central

    Medina, Vanina A; Rivera, Elena S

    2010-01-01

    Considerable evidence has been collected indicating that histamine can modulate proliferation of different normal and malignant cells. High histamine biosynthesis and content together with histamine receptors have been reported in different human neoplasias including melanoma, colon and breast cancer, as well as in experimental tumours in which histamine has been postulated to behave as an important paracrine and autocrine regulator of proliferation. The discovery of the human histamine H4 receptor in different tissues has contributed to our understanding of histamine role in numerous physiological and pathological conditions revealing novel functions for histamine and opening new perspectives in histamine pharmacology research. In the present review we aimed to briefly summarize current knowledge on histamine and histamine receptor involvement in cancer before focusing on some recent evidence supporting the novel role of histamine H4 receptor in cancer progression representing a promising molecular target and avenue for cancer drug development. LINKED ARTICLES BJP has previously published a Histamine themed issue (2009). To view this issue visit http://dx.doi.org/10.1111/bph.2009.157.issue-1 PMID:20636392

  12. Safety Pharmacology Evaluation of Biopharmaceuticals.

    PubMed

    Amouzadeh, Hamid R; Engwall, Michael J; Vargas, Hugo M

    2015-01-01

    Biotechnology-derived pharmaceuticals or biopharmaceuticals (BPs) are molecules such as monoclonal antibodies, soluble/decoy receptors, hormones, enzymes, cytokines, and growth factors that are produced in various biological expression systems and are used to diagnose, treat, or prevent various diseases. Safety pharmacology (SP) assessment of BPs has evolved since the approval of the first BP (recombinant human insulin) in 1982. This evolution is ongoing and is informed by various international harmonization guidelines. Based on these guidelines, the potential undesirable effect of every drug candidate (small molecule or BP) on the cardiovascular, central nervous, and respiratory systems, referred to as the "core battery," should be assessed prior to first-in-human administration. However, SP assessment of BPs poses unique challenges such as choice of test species and integration of SP parameters into repeat-dose toxicity studies. This chapter reviews the evolution of SP assessment of BPs using the approval packages of marketed BPs and discusses the past, current, and new and upcoming approach and methods that can be used to generate high-quality data for the assessment of SP of BPs.

  13. Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs

    PubMed Central

    Hudson, Brian D.; Christiansen, Elisabeth; Tikhonova, Irina G.; Grundmann, Manuel; Kostenis, Evi; Adams, David R.; Ulven, Trond; Milligan, Graeme

    2012-01-01

    When it is difficult to develop selective ligands within a family of related G-protein-coupled receptors (GPCRs), chemically engineered receptors activated solely by synthetic ligands (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether a RASSL of the free fatty acid receptor 2 (FFA2) could be developed on the basis of pharmacological variation between species orthologs. For this, bovine FFA2 was characterized, revealing distinct ligand selectivity compared with human FFA2. Homology modeling and mutational analysis demonstrated a single mutation in human FFA2 of C4.57G resulted in a human FFA2 receptor with ligand selectivity similar to the bovine receptor. This was exploited to generate human FFA2-RASSL by the addition of a second mutation at a known orthosteric ligand interaction site, H6.55Q. The resulting FFA2-RASSL displayed a >100-fold loss of activity to endogenous ligands, while responding to the distinct ligand sorbic acid with pEC50 values for inhibition of cAMP, 5.83 ± 0.11; Ca2+ mobilization, 4.63 ± 0.05; ERK phosphorylation, 5.61 ± 0.06; and dynamic mass redistribution, 5.35 ± 0.06. This FFA2-RASSL will be useful in future studies on this receptor and demonstrates that exploitation of pharmacological variation between species orthologs is a powerful method to generate novel chemically engineered GPCRs.—Hudson, B. D., Christiansen, E., Tikhonova, I. G., Grundmann, M., Kostenis, E., Adams, D. R., Ulven, T., Milligan, G. Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs. PMID:22919070

  14. Chemical engineering and structural and pharmacological characterization of the α-scorpion toxin OD1.

    PubMed

    Durek, Thomas; Vetter, Irina; Wang, Ching-I Anderson; Motin, Leonid; Knapp, Oliver; Adams, David J; Lewis, Richard J; Alewood, Paul F

    2013-01-01

    Scorpion α-toxins are invaluable pharmacological tools for studying voltage-gated sodium channels, but few structure-function studies have been undertaken due to their challenging synthesis. To address this deficiency, we report a chemical engineering strategy based upon native chemical ligation. The chemical synthesis of α-toxin OD1 was achieved by chemical ligation of three unprotected peptide segments. A high resolution X-ray structure (1.8 Å) of synthetic OD1 showed the typical βαββ α-toxin fold and revealed important conformational differences in the pharmacophore region when compared with other α-toxin structures. Pharmacological analysis of synthetic OD1 revealed potent α-toxin activity (inhibition of fast inactivation) at Nav1.7, as well as Nav1.4 and Nav1.6. In addition, OD1 also produced potent β-toxin activity at Nav1.4 and Nav1.6 (shift of channel activation in the hyperpolarizing direction), indicating that OD1 might interact at more than one site with Nav1.4 and Nav1.6. Investigation of nine OD1 mutants revealed that three residues in the reverse turn contributed significantly to selectivity, with the triple OD1 mutant (D9K, D10P, K11H) being 40-fold more selective for Nav1.7 over Nav1.6, while OD1 K11V was 5-fold more selective for Nav1.6 than Nav1.7. This switch in selectivity highlights the importance of the reverse turn for engineering α-toxins with altered selectivity at Nav subtypes.

  15. Pharmacological blockage and P2X7 deletion hinder aversive memories: reversion in an enriched environment.

    PubMed

    Campos, R C; Parfitt, G M; Polese, C E; Coutinho-Silva, R; Morrone, F B; Barros, D M

    2014-11-01

    Adenosine triphosphate (ATP) plays a role in cell signaling. It was soon proposed that ATP activates ionotropic P2X receptors, exerting an influence on neurons as well as on glial cells. In addition to the fact that the activation of P2X and P2Y receptors can stimulate or inhibit the release of glutamate from rat hippocampal neurons, the release of ATP has been implicated in hippocampal long-term potentiation (LTP). Through different behavioral paradigms, this study aimed to investigate the participation of P2X7R in genetically modified (knockout (KO)) mice with the suppressed expression of this receptor and in the pharmacological blockage of this receptor in rats, as well as to evaluate the effect of environmental enrichment on potential mnemonic deficits. The results suggest that P2X7R participates in aversive memory processes: pharmacological blockage with the selective P2X7R antagonist, A-740003, in different time frames elicited dose-dependent impairments in memory acquisition, consolidation and retrieval in rats that were submitted to the contextual fear-conditioning (FC) task, and the deletion of P2X7R hampered the aversive memory processes of mice that were subjected to the FC paradigm. Experiments using mice that were subjected to environmental enrichment suggest that this form of stimulation reverses mnemonic impairments that are ascribed to the absence of the P2X7R, suggesting that these receptors do not participate on such a reversal. Finally, no alterations were observed in the habituation memory of P2X7KO mice.

  16. Pharmacological blockage and P2X7 deletion hinder aversive memories: reversion in an enriched environment.

    PubMed

    Campos, R C; Parfitt, G M; Polese, C E; Coutinho-Silva, R; Morrone, F B; Barros, D M

    2014-11-01

    Adenosine triphosphate (ATP) plays a role in cell signaling. It was soon proposed that ATP activates ionotropic P2X receptors, exerting an influence on neurons as well as on glial cells. In addition to the fact that the activation of P2X and P2Y receptors can stimulate or inhibit the release of glutamate from rat hippocampal neurons, the release of ATP has been implicated in hippocampal long-term potentiation (LTP). Through different behavioral paradigms, this study aimed to investigate the participation of P2X7R in genetically modified (knockout (KO)) mice with the suppressed expression of this receptor and in the pharmacological blockage of this receptor in rats, as well as to evaluate the effect of environmental enrichment on potential mnemonic deficits. The results suggest that P2X7R participates in aversive memory processes: pharmacological blockage with the selective P2X7R antagonist, A-740003, in different time frames elicited dose-dependent impairments in memory acquisition, consolidation and retrieval in rats that were submitted to the contextual fear-conditioning (FC) task, and the deletion of P2X7R hampered the aversive memory processes of mice that were subjected to the FC paradigm. Experiments using mice that were subjected to environmental enrichment suggest that this form of stimulation reverses mnemonic impairments that are ascribed to the absence of the P2X7R, suggesting that these receptors do not participate on such a reversal. Finally, no alterations were observed in the habituation memory of P2X7KO mice. PMID:25239372

  17. Mechanisms of Caffeine-Induced Inhibition of UVB Carcinogenesis.

    PubMed

    Conney, Allan H; Lu, Yao-Ping; Lou, You-Rong; Kawasumi, Masaoki; Nghiem, Paul

    2013-01-01

    Sunlight-induced non-melanoma skin cancer is the most prevalent cancer in the United States with more than two million cases per year. Several studies have shown an inhibitory effect of caffeine administration on UVB-induced skin cancer in mice, and these studies are paralleled by epidemiology studies that indicate an inhibitory effect of coffee drinking on non-melanoma skin cancer in humans. Strikingly, decaffeinated coffee consumption had no such inhibitory effect. Mechanism studies indicate that caffeine has a sunscreen effect that inhibits UVB-induced formation of thymine dimers and sunburn lesions in the epidermis of mice. In addition, caffeine administration has a biological effect that enhances UVB-induced apoptosis thereby enhancing the elimination of damaged precancerous cells, and caffeine administration also enhances apoptosis in tumors. Caffeine administration enhances UVB-induced apoptosis by p53-dependent and p53-independent mechanisms. Exploration of the p53-independent effect indicated that caffeine administration enhanced UVB-induced apoptosis by inhibiting the UVB-induced increase in ATR-mediated formation of phospho-Chk1 (Ser345) and abolishing the UVB-induced decrease in cyclin B1 which resulted in caffeine-induced premature and lethal mitosis in mouse skin. In studies with cultured primary human keratinocytes, inhibition of ATR with siRNA against ATR inhibited Chk1 phosphorylation and enhanced UVB-induced apoptosis. Transgenic mice with decreased epidermal ATR function that were irradiated chronically with UVB had 69% fewer tumors at the end of the study compared with irradiated littermate controls with normal ATR function. These results, which indicate that genetic inhibition of ATR (like pharmacologic inhibition of ATR via caffeine) inhibits UVB-induced carcinogenesis support the concept that ATR-mediated phosphorylation of Chk1 is an important target for caffeine's inhibitory effect on UVB-induced carcinogenesis. PMID:23785666

  18. Dissociation of the Pharmacological Effects of THC by mTOR Blockade

    PubMed Central

    Puighermanal, Emma; Busquets-Garcia, Arnau; Gomis-González, Maria; Marsicano, Giovanni; Maldonado, Rafael; Ozaita, Andrés

    2013-01-01

    The potential therapeutic benefits of cannabinoid compounds have raised interest in understanding the molecular mechanisms that underlie cannabinoid-mediated effects. We previously showed that the acute amnesic-like effects of delta9-tetrahydrocannabinol (THC) were prevented by the subchronic inhibition of the mammalian target of rapamycin (mTOR) pathway. In the present study, we assess the relevance of the mTOR pathway in other acute and chronic pharmacological effects of THC. The rapamycin derivative temsirolimus, an inhibitor of the mTOR pathway approved by the Food and Drug Administration, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC. In contrast, THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception are not sensitive to the mTOR inhibition. In addition, a clear tolerance to THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception was observed after chronic treatment, but not to its anxiogenic- and amnesic-like effects. Temsirolimus pre-treatment prevented the amnesic-like effects of chronic THC without affecting the downregulation of CB1 receptors (CB1R) induced by this chronic treatment. Instead, temsirolimus blockade after chronic THC cessation did not prevent the residual cognitive deficit produced by chronic THC. Using conditional knockout mice lacking CB1R in GABAergic or glutamatergic neurons, we found that GABAergic CB1Rs are mainly downregulated under chronic THC treatment conditions, and CB1–GABA–KO mice did not develop cognitive deficits after chronic THC exposure. Therefore, mTOR inhibition by temsirolimus allows the segregation of the potentially beneficial effects of cannabinoid agonists, such as the anxiolytic and antinociceptive effects, from the negative effects, such as anxiogenic- and amnesic-like responses. Altogether, these results provide new insights for targeting the endocannabinoid system in order to prevent possible side effects. PMID:23358238

  19. Dissociation of the pharmacological effects of THC by mTOR blockade.

    PubMed

    Puighermanal, Emma; Busquets-Garcia, Arnau; Gomis-González, Maria; Marsicano, Giovanni; Maldonado, Rafael; Ozaita, Andrés

    2013-06-01

    The potential therapeutic benefits of cannabinoid compounds have raised interest in understanding the molecular mechanisms that underlie cannabinoid-mediated effects. We previously showed that the acute amnesic-like effects of delta9-tetrahydrocannabinol (THC) were prevented by the subchronic inhibition of the mammalian target of rapamycin (mTOR) pathway. In the present study, we assess the relevance of the mTOR pathway in other acute and chronic pharmacological effects of THC. The rapamycin derivative temsirolimus, an inhibitor of the mTOR pathway approved by the Food and Drug Administration, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC. In contrast, THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception are not sensitive to the mTOR inhibition. In addition, a clear tolerance to THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception was observed after chronic treatment, but not to its anxiogenic- and amnesic-like effects. Temsirolimus pre-treatment prevented the amnesic-like effects of chronic THC without affecting the downregulation of CB1 receptors (CB1R) induced by this chronic treatment. Instead, temsirolimus blockade after chronic THC cessation did not prevent the residual cognitive deficit produced by chronic THC. Using conditional knockout mice lacking CB1R in GABAergic or glutamatergic neurons, we found that GABAergic CB1Rs are mainly downregulated under chronic THC treatment conditions, and CB1-GABA-KO mice did not develop cognitive deficits after chronic THC exposure. Therefore, mTOR inhibition by temsirolimus allows the segregation of the potentially beneficial effects of cannabinoid agonists, such as the anxiolytic and antinociceptive effects, from the negative effects, such as anxiogenic- and amnesic-like responses. Altogether, these results provide new insights for targeting the endocannabinoid system in order to prevent possible side effects.

  20. Pharmacological properties of the homomeric alpha 7 receptor.

    PubMed

    Bertrand, D; Bertrand, S; Ballivet, M

    1992-10-26

    The pharmacological properties of the alpha-bungarotoxin sensitive alpha 7 neuronal nicotinic acetylcholine receptor (nAChR) were studied upon reconstitution in Xenopus oocytes. Channels formed by alpha 7 are about 10-fold more sensitive to nicotine and cytisine than to ACh but are little, if at all, activated by the ganglionic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). Tubocurarine (TC) was found to act as a non-competitive inhibitor, whereas dihydro-beta-erythroidine (DH beta E) behaves as a pure competitive inhibitor whose blockade is fast and fully reversible. In addition, the alpha 7 receptor displays a poor sensitivity to methonium salts. The pharmacological properties of the alpha 7 channels are readily distinguishable from those of other identified neuronal nicotinic receptors.

  1. Pharmacologic overview of Withania somnifera, the Indian Ginseng.

    PubMed

    Dar, Nawab John; Hamid, Abid; Ahmad, Muzamil

    2015-12-01

    Withania somnifera, also called 'Indian ginseng', is an important medicinal plant of the Indian subcontinent. It is widely used, singly or in combination, with other herbs against many ailments in Indian Systems of Medicine since time immemorial. Withania somnifera contains a spectrum of diverse phytochemicals enabling it to have a broad range of biological implications. In preclinical studies, it has shown anti-microbial, anti-inflammatory, anti-tumor, anti-stress, neuroprotective, cardioprotective, and anti-diabetic properties. Additionally, it has demonstrated the ability to reduce reactive oxygen species, modulate mitochondrial function, regulate apoptosis, and reduce inflammation and enhance endothelial function. In view of these pharmacologic properties, W. somnifera is a potential drug candidate to treat various clinical conditions, particularly related to the nervous system. In this review, we summarize the pharmacologic characteristics and discuss the mechanisms of action and potential therapeutic applications of the plant and its active constituents.

  2. Emerging preclinical pharmacological targets for Parkinson's disease.

    PubMed

    More, Sandeep Vasant; Choi, Dong-Kug

    2016-05-17

    Parkinson's disease (PD) is a progressive neurological condition caused by the degeneration of dopaminergic neurons in the basal ganglia. It is the most prevalent form of Parkinsonism, categorized by cardinal features such as bradykinesia, rigidity, tremors, and postural instability. Due to the multicentric pathology of PD involving inflammation, oxidative stress, excitotoxicity, apoptosis, and protein aggregation, it has become difficult to pin-point a single therapeutic target and evaluate its potential application. Currently available drugs for treating PD provide only symptomatic relief and do not decrease or avert disease progression resulting in poor patient satisfaction and compliance. Significant amount of understanding concerning the pathophysiology of PD has offered a range of potential targets for PD. Several emerging targets including AAV-hAADC gene therapy, phosphodiesterase-4, potassium channels, myeloperoxidase, acetylcholinesterase, MAO-B, dopamine, A2A, mGlu5, and 5-HT-1A/1B receptors are in different stages of clinical development. Additionally, alternative interventions such as deep brain stimulation, thalamotomy, transcranial magnetic stimulation, and gamma knife surgery, are also being developed for patients with advanced PD. As much as these therapeutic targets hold potential to delay the onset and reverse the disease, more targets and alternative interventions need to be examined in different stages of PD. In this review, we discuss various emerging preclinical pharmacological targets that may serve as a new promising neuroprotective strategy that could actually help alleviate PD and its symptoms. PMID:26988916

  3. Aldosterone blockade in CKD: emphasis on pharmacology.

    PubMed

    Schwenk, Michael H; Hirsch, Jamie S; Bomback, Andrew S

    2015-03-01

    Besides its epithelial effect on sodium retention and potassium excretion in the distal tubule, aldosterone promotes inflammation and fibrosis in the heart, kidneys, and blood vessels. As glomerular filtration rate falls, aldosterone is inappropriately elevated relative to extracellular fluid expansion. In addition, studies in CKD patients on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and/or direct renin inhibitors have shown that aldosterone levels paradoxically rise in approximately 30% to 40% of patients on these renin-angiotensin system-blocking drugs. Hence, there is interest in using mineralocorticoid receptor blockers that directly target the inflammatory and fibrotic effects of aldosterone in CKD patients. This interest, however, is tempered by a number of unresolved issues, including the safety of using such drugs in advanced CKD and ESRD populations, and the potential for differences in drug efficacy according to race and ethnicity of patient populations. A better understanding of mineralocorticoid receptor blocker pharmacology should help inform future research directions and clinical practice decisions as to how best to use these agents in CKD.

  4. Emerging preclinical pharmacological targets for Parkinson's disease

    PubMed Central

    More, Sandeep Vasant; Choi, Dong-Kug

    2016-01-01

    Parkinson's disease (PD) is a progressive neurological condition caused by the degeneration of dopaminergic neurons in the basal ganglia. It is the most prevalent form of Parkinsonism, categorized by cardinal features such as bradykinesia, rigidity, tremors, and postural instability. Due to the multicentric pathology of PD involving inflammation, oxidative stress, excitotoxicity, apoptosis, and protein aggregation, it has become difficult to pin-point a single therapeutic target and evaluate its potential application. Currently available drugs for treating PD provide only symptomatic relief and do not decrease or avert disease progression resulting in poor patient satisfaction and compliance. Significant amount of understanding concerning the pathophysiology of PD has offered a range of potential targets for PD. Several emerging targets including AAV-hAADC gene therapy, phosphodiesterase-4, potassium channels, myeloperoxidase, acetylcholinesterase, MAO-B, dopamine, A2A, mGlu5, and 5-HT-1A/1B receptors are in different stages of clinical development. Additionally, alternative interventions such as deep brain stimulation, thalamotomy, transcranial magnetic stimulation, and gamma knife surgery, are also being developed for patients with advanced PD. As much as these therapeutic targets hold potential to delay the onset and reverse the disease, more targets and alternative interventions need to be examined in different stages of PD. In this review, we discuss various emerging preclinical pharmacological targets that may serve as a new promising neuroprotective strategy that could actually help alleviate PD and its symptoms. PMID:26988916

  5. [Pharmacologic therapy of depression during pregnancy].

    PubMed

    Bellantuono, Cesario; Migliarese, Giovanni; Imperadore, Giuseppe

    2006-02-01

    The pregnancy is considered to be relatively high risk period for depressive episodes in women, particularly for those with pre-existing affective disorders. Epidemiological studies indicate that between 10% to 16% of pregnant women fulfil the diagnostic criteria for major depression and on average 20% is affected by an anxiety disorder. Pharmacological treatment of depression during pregnancy, however, brings with it certainties and dilemmas. It has been reported that untreated depression is associated with impaired feto-placental function, premature delivery, miscarriage, low fetal growth and perinatal unwanted effects. On the other hand, the use of antidepressant drugs in pregnancy might be at risk of major malformations (teratogenesis), neonatal toxicity, especially withdrawal symptoms and neuropsychological-behavioural impairment. In addition, the abrupt discontinuation of antidepressants, because of fear for adverse fetal effects, exposes women to serious clinical problems, in particular the disease relapse. A number of reviews indicates that among antidepressant drugs, the older SSRIs (in particular fluoxetine, sertraline, citalopram) seem to be avoided of teratogenic risks; for these reasons such drugs are nowadays considered of choice for the treatment of depression during pregnancy. Less information is available for other drugs, including triciclycs, venlafaxine, mirtazapine, bupropion, escitalopram and duloxetine. Withdrawal symptoms have been reported for all antidepressants; these symptoms, however, were self-limiting in majority of cases and had a favourable outcome. Inconclusive findings emerge, so far, from the few longitudinal studies focusing on the long-term neurodevelopment outcome in children.

  6. Pharmacological studies of cardamom oil in animals.

    PubMed

    al-Zuhair, H; el-Sayeh, B; Ameen, H A; al-Shoora, H

    1996-01-01

    Cardamom seeds are widely used for flavouring purposes in food and as carminative. Little information has been reported on their pharmacological and toxicological properties or, for their volatile oil which constitutes about 5% of the seed's total weight. A comparative study of the anti-inflammatory activity of the oil extracted from commercial Elettaria cardamomum seeds, in doses of 175 and 280 microliters/kg and indomethacin in a dose of 30 mg/kg against acute carrageenan-induced planter oedema in male albino rats was performed, which proved to be marked. Moreover, investigation of the analgesic activity using p-benzoquinone as a chemical stimulus proved that a dose of 233 microliters/kg of the oil produced 50% protection against the writhing (stretching syndrome) induced by intraperitoneal administration of a 0.02% solution of p-benzoquinone in mice. In addition the antispasmodic activity was determined on a rabbit intestine preparation using acetylcholine as agonist, the results proving that cardamom oil exerts its antispasmodic action through muscarinic receptor blockage.

  7. Pharmacological pain management in chronic pancreatitis

    PubMed Central

    Olesen, Søren S; Juel, Jacob; Graversen, Carina; Kolesnikov, Yuri; Wilder-Smith, Oliver HG; Drewes, Asbjørn M

    2013-01-01

    Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical challenge. Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders. An important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established, the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive drive. Consequently, the management of pain by traditional methods based on nociceptive deafferentation (e.g., surgery and visceral nerve blockade) becomes difficult and often ineffective. This novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic pancreatitis. Modern mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source, which should be reserved for special and carefully selected cases. In this review, we offer an overview of the current available pharmacological options for pain management in chronic pancreatitis. In addition, future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity. PMID:24259960

  8. Tetrahydrobiopterin biosynthesis, utilization and pharmacological effects.

    PubMed

    Werner-Felmayer, G; Golderer, G; Werner, E R

    2002-04-01

    Tetrahydrobiopterin (H4-biopterin) is an essential cofactor of a set of enzymes that are of central metabolic importance, i.e. the hydroxylases of the three aromatic amino acids phenylalanine, tyrosine, and tryptophan, of ether lipid oxidase, and of the three nitric oxide synthase (NOS) isoenzymes. As a consequence, H4-biopterin plays a key role in a vast number of biological processes and pathological states associated with neurotransmitter formation, vasorelaxation, and immune response. In mammals, its biosynthesis is controlled by hormones, cytokines and certain immune stimuli. This review aims to summarize recent developments concerning regulation of H4-biopterin biosynthetic and regulatory enzymes and pharmacological effects of H4-biopterin in various conditions, e.g. endothelial dysfunction or apoptosis of neuronal cells. Also, approaches towards gene therapy of diseases like the different forms of phenylketonuria or of Parkinson's disease are reviewed. Additional emphasis is given to H4-biopterin biosynthesis and function in non-mammalian species such as fruit fly, zebra fish, fungi, slime molds, the bacterium Nocardia as well as to the parasitic protozoan genus of Leishmania that is not capable of pteridine biosynthesis but has evolved a sophisticated salvage network for scavenging various pteridine compounds, notably folate and biopterin. PMID:12003348

  9. 21 CFR 170.18 - Tolerances for related food additives.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES General Provisions § 170.18 Tolerances for related food additives. (a) Food additives that cause similar or related pharmacological effects will be... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Tolerances for related food additives....

  10. Molecular pharmacology and antitumor activity of PHT-427 a novel AKT/PDPK1 pleckstrin homology domain inhibitor

    PubMed Central

    Meuillet, Emmanuelle J.; Zuohe, Song; Lemos, Robert; Ihle, Nathan; Kingston, John; Watkins, Ryan; Moses, Sylvestor A.; Zhang, Shuxing; Cuny, Lei Du; Herbst, Roy; Jacoby, Jörg J.; Zhou, Li Li; Ahad, Ali M.; Mash, Eugene A; Kirkpatrick, D Lynn; Powis, Garth

    2010-01-01

    Phosphatidylinositol 3-kinase (PIK3)/ PtdIns dependent protein kinase-1(PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology and antitumor activity of PHT-427 a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1. A series of PHT-427 analogs with variable C-4 to C-16 alkyl chain length were synthesized and tested. PHT-427 itself (C-12 chain) bound with the highest affinity to the PH domains of both PDPK1 and Akt. PHT-427 inhibited Akt and PDKP1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. When given orally PHT-427 inhibited the growth of human tumor xenografts in immunodeficient mice with up to 80% inhibition in the most sensitive tumors and showed greater activity than analogs with C4, C6 or C8 alkyl chains. Inhibition of PDKP1 was more closely correlated to antitumor activity than Akt inhibition. Tumors with PIK3CA mutation were the most sensitive and K-Ras mutant tumors the least sensitive. Combination studies showed that PHT-427 has greater than additive antitumor activity with paclitaxel in breast cancer, and with erlotinib in NSC lung cancer. When given over 5 days PHT-427 caused no weight loss or change in blood chemistry. Thus, we report a novel PH domain binding inhibitor of PDPK1/Akt signaling with significant in vivo antitumor activity and minimal toxicity. PMID:20197390

  11. Selectivity of pharmacological tools: implications for use in cell physiology. A review in the theme: Cell signaling: proteins, pathways and mechanisms.

    PubMed

    Michel, Martin C; Seifert, Roland

    2015-04-01

    Pharmacological inhibitors are frequently used to identify the receptors, receptor subtypes, and associated signaling pathways involved in physiological cell responses. Based on the effects of such inhibitors conclusions are drawn about the involvement of their assumed target or lack thereof. While such inhibitors can be useful tools for a better physiological understanding, their uncritical use can lead to incorrect conclusions. This article reviews the concept of inhibitor selectivity and its implication for cell physiology. Specifically, we discuss the implications of using inhibitor vs. activator approaches, issues of direct vs. indirect pathway modulation, implications of inverse agonism and biased signaling, and those of orthosteric vs. allosteric, competitive vs. noncompetitive, and reversible vs. irreversible inhibition. Additional problems can result from inconsistent estimates of inhibitor potency and differences in potency between cell-free systems and intact cells. These concepts are illustrated by several examples of inhibitors displaying affinity for related but distinct targets or even unrelated targets. Of note, many of the issues being addressed are also applicable to genetic inhibition strategies. The main practical conclusion following from these concepts is that investigators should be critical in the choice of inhibitor, its concentrations, and its mode of application. When this advice is adhered to, small-molecule pharmacological inhibitors can be important experimental tools in the hand of physiologists. PMID:25631871

  12. Selectivity of pharmacological tools: implications for use in cell physiology. A review in the theme: Cell signaling: proteins, pathways and mechanisms.

    PubMed

    Michel, Martin C; Seifert, Roland

    2015-04-01

    Pharmacological inhibitors are frequently used to identify the receptors, receptor subtypes, and associated signaling pathways involved in physiological cell responses. Based on the effects of such inhibitors conclusions are drawn about the involvement of their assumed target or lack thereof. While such inhibitors can be useful tools for a better physiological understanding, their uncritical use can lead to incorrect conclusions. This article reviews the concept of inhibitor selectivity and its implication for cell physiology. Specifically, we discuss the implications of using inhibitor vs. activator approaches, issues of direct vs. indirect pathway modulation, implications of inverse agonism and biased signaling, and those of orthosteric vs. allosteric, competitive vs. noncompetitive, and reversible vs. irreversible inhibition. Additional problems can result from inconsistent estimates of inhibitor potency and differences in potency between cell-free systems and intact cells. These concepts are illustrated by several examples of inhibitors displaying affinity for related but distinct targets or even unrelated targets. Of note, many of the issues being addressed are also applicable to genetic inhibition strategies. The main practical conclusion following from these concepts is that investigators should be critical in the choice of inhibitor, its concentrations, and its mode of application. When this advice is adhered to, small-molecule pharmacological inhibitors can be important experimental tools in the hand of physiologists.

  13. International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands.

    PubMed

    Christopoulos, Arthur; Changeux, Jean-Pierre; Catterall, William A; Fabbro, Doriano; Burris, Thomas P; Cidlowski, John A; Olsen, Richard W; Peters, John A; Neubig, Richard R; Pin, Jean-Philippe; Sexton, Patrick M; Kenakin, Terry P; Ehlert, Frederick J; Spedding, Michael; Langmead, Christopher J

    2014-10-01

    Allosteric interactions play vital roles in metabolic processes and signal transduction and, more recently, have become the focus of numerous pharmacological studies because of the potential for discovering more target-selective chemical probes and therapeutic agents. In addition to classic early studies on enzymes, there are now examples of small molecule allosteric modulators for all superfamilies of receptors encoded by the genome, including ligand- and voltage-gated ion channels, G protein-coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases. As a consequence, a vast array of pharmacologic behaviors has been ascribed to allosteric ligands that can vary in a target-, ligand-, and cell-/tissue-dependent manner. The current article presents an overview of allostery as applied to receptor families and approaches for detecting and validating allosteric interactions and gives recommendations for the nomenclature of allosteric ligands and their properties.

  14. A new role for GABA: inhibition of tumor cell migration.

    PubMed

    Ortega, Arturo

    2003-04-01

    GABA, the main inhibitory neurotransmitter in the vertebrate brain, participates outside the CNS in diverse functions such as platelet aggregation and the acrosomal reaction in spermatozoa. A recent study now demonstrates that GABA inhibits the migration of colon carcinoma cells, paving the way to the development of specific pharmacological agents that delay or inhibit invasion and metastasis of various cancer types.

  15. Anti-aging pharmacology: Promises and pitfalls.

    PubMed

    Vaiserman, Alexander M; Lushchak, Oleh V; Koliada, Alexander K

    2016-11-01

    Life expectancy has grown dramatically in modern times. This increase, however, is not accompanied by the same increase in healthspan. Efforts to extend healthspan through pharmacological agents targeting aging-related pathological changes are now in the spotlight of geroscience, the main idea of which is that delaying of aging is far more effective than preventing the particular chronic disorders. Currently, anti-aging pharmacology is a rapidly developing discipline. It is a preventive field of health care, as opposed to conventional medicine which focuses on treating symptoms rather than root causes of illness. A number of pharmacological agents targeting basic aging pathways (i.e., calorie restriction mimetics, autophagy inducers, senolytics etc.) are now under investigation. This review summarizes the literature related to advances, perspectives and challenges in the field of anti-aging pharmacology. PMID:27524412

  16. Integrating Behavioral and Pharmacological Therapeutic Modalities

    PubMed Central

    Dworkin, Samuel F.

    1986-01-01

    Fear of dental procedures and associated anxiety are widely accepted as important deterents to optimal oral health. Such health care-related fears and anxieties are also common in many areas of medicine. For both medical and dental care a large body of psychologically derived therapeutic modalities have evolved. These methods have been shown to interact positively with pharmacological therapies also designed to help patients better tolerate medical and dental treatment. Despite these findings, behavioral interventions have not found widespread acceptance in medical and dental practice. A multidimensional model which emphasizes the simultaneous consideration of pharmacologic, psychologic, and clinical dental factors is suggested in order to arrive at therapeutic decisions. Further research could address more powerful behavioral modalities, safer pharmacologic methods, and behavioral and pharmacologic combinations which interact optimally for particular clinical conditions. PMID:3458386

  17. INTERSPECIES DOSIMETRY MODELS FOR PULMONARY PHARMACOLOGY

    EPA Science Inventory

    Interspecies Dosimetry Models for Pulmonary Pharmacology

    Ted B. Martonen, Jeffry D. Schroeter, and John S. Fleming

    Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangl...

  18. Pharmacological prophylaxis of venous thrombo-embolism.

    PubMed

    Flute, P T

    1976-02-01

    The pathogenesis of venous thrombosis is briefly discussed as a basis for the understanding of preventive measures used in this condition. Prophylaxis in venous thrombosis is then reviewed with emphasis on pharmacological treatment, and more particularly on heparin.

  19. Anti-aging pharmacology: Promises and pitfalls.

    PubMed

    Vaiserman, Alexander M; Lushchak, Oleh V; Koliada, Alexander K

    2016-11-01

    Life expectancy has grown dramatically in modern times. This increase, however, is not accompanied by the same increase in healthspan. Efforts to extend healthspan through pharmacological agents targeting aging-related pathological changes are now in the spotlight of geroscience, the main idea of which is that delaying of aging is far more effective than preventing the particular chronic disorders. Currently, anti-aging pharmacology is a rapidly developing discipline. It is a preventive field of health care, as opposed to conventional medicine which focuses on treating symptoms rather than root causes of illness. A number of pharmacological agents targeting basic aging pathways (i.e., calorie restriction mimetics, autophagy inducers, senolytics etc.) are now under investigation. This review summarizes the literature related to advances, perspectives and challenges in the field of anti-aging pharmacology.

  20. Pharmacology of myocardial calcium-handling.

    PubMed

    Vogler, Julia; Eckardt, Lars

    2012-07-01

    Disturbed myocardial calcium (Ca(+)) handling is one of the pathophysiologic hallmarks of cardiovascular diseases such as congestive heart failure, cardiac hypertrophy, and certain types of tachyarrhythmias. Pharmacologic treatment of these diseases thus focuses on restoring myocardial Ca(2+) homeostasis by interacting with Ca(2+)-dependent signaling pathways. In this article, we review the currently used pharmacologic agents that are able to restore or maintain myocardial Ca(2+) homeostasis and their mechanism of action as well as emerging new substances.

  1. [Non-pharmacological methods of stroke prevention].

    PubMed

    Planjar-Prvan, Miljenka

    2010-03-01

    Stroke is a major health problem and the leading cause of functional disability, so that effective primary prevention remains the best, easiest and most cost-effective approach to reduce serious consequences of stroke. It is well known that prevention includes pharmacological and non-pharmacological methods. However, it seems that non-pharmacological methods of stroke prevention are generally neglected and placed in an inferior position in relation to pharmacological prevention. Therefore, the objective of this review is to present the most relevant literature data on non-pharmacological methods of stroke prevention and highlight their effectiveness with the use of quantitative parameters of evidence-based medicine. The main sources of data were the American, European and Croatian guidelines for stroke prevention, along with recent research results. Literature data have shown the relative risk of stroke to be greater than 2.0 in the group with unhealthy lifestyle; in fact, healthy lifestyle predicts more than twofold difference in the incidence of stroke. It is important to emphasize the public health value of non-pharmacological stroke prevention and to underline that it should be constant, irrespective of taking pharmacotherapy for stroke prevention or not. Healthy lifestyle is fundamental for non-pharmacological stroke prevention and includes healthy diet, regular physical activity, low-normal body mass index, smoking abstinence, and moderate drinking of alcohol. It is essential to inform patients on the importance, value and benefits of non-pharmacological stroke prevention, in particular when it remains the only therapeutic option in case of adverse side effects of pharmacotherapy prevention. Numerous studies demonstrated that even small lifestyle modifications could significantly reduce the risk of stroke. Therefore, it is necessary that physicians promote moderate and healthy lifestyle and habits in primary and secondary stroke prevention because there is

  2. Pharmacology of human sulphonylurea receptor SUR1 and inward rectifier K+ channel Kir6.2 combination expressed in HEK-293 cells

    PubMed Central

    Gopalakrishnan, Murali; Molinari, Eduardo J; Shieh, Char-Chang; Monteggia, Lisa M; Roch, Jean-Marc; Whiteaker, Kristi L; Scott, Victoria E S; Sullivan, James P; Brioni, Jorge D

    2000-01-01

    The pharmacological properties of KATP channels generated by stable co-expression of the sulphonylurea receptor SUR1 and the inwardly rectifying K+ channel Kir6.2 were characterized in HEK-293 cells.[3H]-Glyburide (glibenclamide) bound to transfected cells with a Bmax value of 18.5 pmol mg−1 protein and with a KD value of 0.7 nM. Specific binding was displaced by a series of sulphonylurea analogues with rank order potencies consistent with those observed in pancreatic RINm5F insulinoma and in the brain.Functional activity of KATP channels was assessed by whole cell patch clamp, cation efflux and membrane potential measurements. Whole cell currents were detected in transfected cells upon depletion of internal ATP or by exposure to 500 μM diazoxide. The currents showed weak inward rectification and were sensitive to inhibition by glyburide (IC50=0.92 nM).Metabolic inhibition by 2-deoxyglucose and oligomycin treatment triggered 86Rb+ efflux from transfected cells that was sensitive to inhibition by glyburide (IC50=3.6 nM).Diazoxide, but not levcromakalim, evoked concentration-dependent decreases in DiBAC4(3) fluorescence responses with an EC50 value of 14.1 μM which were attenuated by the addition of glyburide. Diazoxide-evoked responses were inhibited by various sulphonylurea analogues with rank order potencies that correlated well with their binding affinities.In summary, results from ligand binding and functional assays demonstrate that the pharmacological properties of SUR1 and Kir6.2 channels co-expressed in HEK-293 cells resemble those typical of native KATP channels described in pancreatic and neuronal tissues. PMID:10742287

  3. Pharmacological Properties of Protocatechuic Acid and Its Potential Roles as Complementary Medicine

    PubMed Central

    Semaming, Yoswaris; Pannengpetch, Patchareewan; Chattipakorn, Siriporn C.

    2015-01-01

    This paper reviews the reported pharmacological properties of protocatechuic acid (PCA, 3,4-dihydroxy benzoic acid), a type of phenolic acid found in many food plants such as olives and white grapes. PCA is a major metabolite of anthocyanin. The pharmacological actions of PCA have been shown to include strong in vitro and in vivo antioxidant activity. In in vivo experiments using rats and mice, PCA has been shown to exert anti-inflammatory as well as antihyperglycemic and antiapoptotic activities. Furthermore, PCA has been shown to inhibit chemical carcinogenesis and exert proapoptotic and antiproliferative effects in different cancerous tissues. Moreover, in vitro studies have shown PCA to have antimicrobial activities and also to exert synergistic interaction with some antibiotics against resistant pathogens. This review aims to comprehensively summarize the pharmacological properties of PCA reported to date with an emphasis on its biological properties and mechanisms of action which could be therapeutically useful in a clinical setting. PMID:25737736

  4. Osthole: A Review on Its Bioactivities, Pharmacological Properties, and Potential as Alternative Medicine

    PubMed Central

    Zhang, Zhong-Rong; Leung, Wing Nang; Cheung, Ho Yee; Chan, Chun Wai

    2015-01-01

    This paper reviews the latest understanding of biological and pharmacological properties of osthole (7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one), a natural product found in several medicinal plants such as Cnidium monnieri and Angelica pubescens. In vitro and in vivo experimental results have revealed that osthole demonstrates multiple pharmacological actions including neuroprotective, osteogenic, immunomodulatory, anticancer, hepatoprotective, cardiovascular protective, and antimicrobial activities. In addition, pharmacokinetic studies showed osthole uptake and utilization are fast and efficient in body. Moreover, the mechanisms of multiple pharmacological activities of osthole are very likely related to the modulatory effect on cyclic adenosine monophosphate (cAMP) and cyclic adenosine monophosphate (cGMP) level, though some mechanisms remain unclear. This review aims to summarize the pharmacological properties of osthole and give an overview of the underlying mechanisms, which showcase its potential as a multitarget alternative medicine. PMID:26246843

  5. Systematic review of pharmacological treatments in fragile X syndrome

    PubMed Central

    Rueda, Jose-Ramon; Ballesteros, Javier; Tejada, Maria-Isabel

    2009-01-01

    Background Fragile X syndrome (FXS) is considered the most common cause of inherited mental retardation. Affected people have mental impairment that can include Attention Deficit and/or Hyperactivity Disorder (ADHD), autism disorder, and speech and behavioural disorders. Several pharmacological interventions have been proposed to treat those impairments. Methods Systematic review of the literature and summary of the evidence from clinical controlled trials that compared at least one pharmacological treatment with placebo or other treatment in individuals with diagnosis of FXS syndrome and assessed the efficacy and/or safety of the treatments. Studies were identified by a search of PubMed, EMBASE and the Cochrane Databases using the terms fragile X and treatment. Risk of bias of the studies was assessed by using the Cochrane Collaboration criteria. Results The search identified 276 potential articles and 14 studies satisfied inclusion criteria. Of these, 10 studies on folic acid (9 with crossover design, only 1 of them with good methodological quality and low risk of bias) did not find in general significant improvements. A small sample size trial assessed dextroamphetamine and methylphenidate in patients with an additional diagnosis of ADHD and found some improvements in those taking methylphenidate, but the length of follow-up was too short. Two studies on L-acetylcarnitine, showed positive effects and no side effects in patients with an additional diagnosis of ADHD. Finally, one study on patients with an additional diagnosis of autism assessed ampakine compound CX516 and found no significant differences between treatment and placebo. Regarding safety, none of the studies that assessed that area found relevant side effects, but the number of patients included was too small to detect side effects with low incidence. Conclusion Currently there is no robust evidence to support recommendations on pharmacological treatments in patients with FXS in general or in those

  6. Integrating electrodermal biofeedback into pharmacologic treatment of grand mal seizures

    PubMed Central

    Scrimali, Tullio; Tomasello, Damiana; Sciuto, Massimo

    2015-01-01

    Electrodermal activity (EDA) and electrodermal biofeedback, when integrated with pharmacologic treatments, indicate promising methods for the treatment of grand mal seizures. They can be used to monitor patient arousal and help patients learn new strategies to better cope with stress and anxiety. Our proposed method can possibly reduce the number of crises for patients who are dependent on pharmacologic therapy and can improve their quality of life. This article describes the scientific background of electrodermal monitoring and electrodermal biofeedback for patients affected by grand mal seizures. In this study, we have reported a clinical case study. The patient was treated for 2 years with electrodermal biofeedback to augment pharmacologic treatments. The trial has been designed in accordance with “n = 1 case study research”. Our results have shown that our methods could achieve a significant reduction in grand mal seizures and sympathetic arousal when applied. The patient under consideration was also relaxed and exhibited greater competency to cope with stress. Additionally, the patient’s sense of mastery and self-efficacy was enhanced. PMID:26029078

  7. Integrating electrodermal biofeedback into pharmacologic treatment of grand mal seizures.

    PubMed

    Scrimali, Tullio; Tomasello, Damiana; Sciuto, Massimo

    2015-01-01

    Electrodermal activity (EDA) and electrodermal biofeedback, when integrated with pharmacologic treatments, indicate promising methods for the treatment of grand mal seizures. They can be used to monitor patient arousal and help patients learn new strategies to better cope with stress and anxiety. Our proposed method can possibly reduce the number of crises for patients who are dependent on pharmacologic therapy and can improve their quality of life. This article describes the scientific background of electrodermal monitoring and electrodermal biofeedback for patients affected by grand mal seizures. In this study, we have reported a clinical case study. The patient was treated for 2 years with electrodermal biofeedback to augment pharmacologic treatments. The trial has been designed in accordance with "n = 1 case study research". Our results have shown that our methods could achieve a significant reduction in grand mal seizures and sympathetic arousal when applied. The patient under consideration was also relaxed and exhibited greater competency to cope with stress. Additionally, the patient's sense of mastery and self-efficacy was enhanced. PMID:26029078

  8. PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons.

    PubMed

    Christie, Kimberly J; Webber, Christine A; Martinez, Jose A; Singh, Bhagat; Zochodne, Douglas W

    2010-07-01

    In vivo regeneration of peripheral neurons is constrained and rarely complete, and unfortunately patients with major nerve trunk transections experience only limited recovery. Intracellular inhibition of neuronal growth signals may be among these constraints. In this work, we investigated the role of PTEN (phosphatase and tensin homolog deleted on chromosome 10) during regeneration of peripheral neurons in adult Sprague Dawley rats. PTEN inhibits phosphoinositide 3-kinase (PI3-K)/Akt signaling, a common and central outgrowth and survival pathway downstream of neuronal growth factors. While PI3-K and Akt outgrowth signals were expressed and activated within adult peripheral neurons during regeneration, PTEN was similarly expressed and poised to inhibit their support. PTEN was expressed in neuron perikaryal cytoplasm, nuclei, regenerating axons, and Schwann cells. Adult sensory neurons in vitro responded to both graded pharmacological inhibition of PTEN and its mRNA knockdown using siRNA. Both approaches were associated with robust rises in the plasticity of neurite outgrowth that were independent of the mTOR (mammalian target of rapamycin) pathway. Importantly, this accelerated outgrowth was in addition to the increased outgrowth generated in neurons that had undergone a preconditioning lesion. Moreover, following severe nerve transection injuries, local pharmacological inhibition of PTEN or siRNA knockdown of PTEN at the injury site accelerated axon outgrowth in vivo. The findings indicated a remarkable impact on peripheral neuron plasticity through PTEN inhibition, even within a complex regenerative milieu. Overall, these findings identify a novel route to propagate intrinsic regeneration pathways within axons to benefit nerve repair.

  9. Swiss University Students’ Attitudes toward Pharmacological Cognitive Enhancement

    PubMed Central

    Maier, Larissa J.; Liakoni, Evangelia; Schildmann, Jan; Schaub, Michael P.; Liechti, Matthias E.

    2015-01-01

    Pharmacological cognitive enhancement (PCE) refers to the nonmedical use of prescription or recreational drugs to enhance cognitive performance. Several concerns about PCE have been raised in the public. The aim of the present study was to investigate students’ attitudes toward PCE. Students at three Swiss universities were invited by e-mail to participate in a web-based survey. Of the 29,282 students who were contacted, 3,056 participated. Of these students, 22% indicated that they had used prescription drugs (12%) or recreational substances including alcohol (14%) at least once for PCE. The use of prescription drugs or recreational substances including alcohol prior to the last exam was reported by 16%. Users of pharmacological cognitive enhancers were more likely to consider PCE fair (24%) compared with nonusers (11%). Only a minority of the participants agreed with the nonmedical use of prescription drugs by fellow students when assuming weak (7%) or hypothetically strong efficacy and availability to everyone (14%). Two-thirds (68%) considered performance that is obtained with PCE less worthy of recognition. Additionally, 80% disagreed that PCE is acceptable in a competitive environment. More than half (64%) agreed that PCE in academia is similar to doping in sports. Nearly half (48%) claimed that unregulated access to pharmacological cognitive enhancers increases the pressure to engage in PCE and educational inequality (55%). In conclusion, Swiss students’ main concerns regarding PCE were related to coercion and fairness. As expected, these concerns were more prevalent among nonusers than among users of pharmacological cognitive enhancers. More balanced information on PCE should be shared with students, and future monitoring of PCE is recommended. PMID:26657300

  10. Swiss University Students' Attitudes toward Pharmacological Cognitive Enhancement.

    PubMed

    Maier, Larissa J; Liakoni, Evangelia; Schildmann, Jan; Schaub, Michael P; Liechti, Matthias E

    2015-01-01

    Pharmacological cognitive enhancement (PCE) refers to the nonmedical use of prescription or recreational drugs to enhance cognitive performance. Several concerns about PCE have been raised in the public. The aim of the present study was to investigate students' attitudes toward PCE. Students at three Swiss universities were invited by e-mail to participate in a web-based survey. Of the 29,282 students who were contacted, 3,056 participated. Of these students, 22% indicated that they had used prescription drugs (12%) or recreational substances including alcohol (14%) at least once for PCE. The use of prescription drugs or recreational substances including alcohol prior to the last exam was reported by 16%. Users of pharmacological cognitive enhancers were more likely to consider PCE fair (24%) compared with nonusers (11%). Only a minority of the participants agreed with the nonmedical use of prescription drugs by fellow students when assuming weak (7%) or hypothetically strong efficacy and availability to everyone (14%). Two-thirds (68%) considered performance that is obtained with PCE less worthy of recognition. Additionally, 80% disagreed that PCE is acceptable in a competitive environment. More than half (64%) agreed that PCE in academia is similar to doping in sports. Nearly half (48%) claimed that unregulated access to pharmacological cognitive enhancers increases the pressure to engage in PCE and educational inequality (55%). In conclusion, Swiss students' main concerns regarding PCE were related to coercion and fairness. As expected, these concerns were more prevalent among nonusers than among users of pharmacological cognitive enhancers. More balanced information on PCE should be shared with students, and future monitoring of PCE is recommended. PMID:26657300

  11. Pharmacological characterization of TMEM16A currents.

    PubMed

    Bradley, Eamonn; Fedigan, Stephen; Webb, Timothy; Hollywood, Mark A; Thornbury, Keith D; McHale, Noel G; Sergeant, Gerard P

    2014-01-01

    Recent studies have shown that transmembrane protein 16 A (TMEM16A) is a subunit of calcium-activated chloride channels (CACCs). Pharmacological agents have been used to probe the functional role of CACCs, however their effect on TMEM16A currents has not been systematically investigated. In the present study, we characterized the voltage and concentration-dependent effects of 2 traditional CACC inhibitors (niflumic acid and anthracene-9-carboxcylic acid) and 2 novel CACC / TMEM16A inhibitors (CACC(inh)A01 and T16A(inh)A01) on TMEM16A currents. The whole cell patch clamp technique was used to record TMEM16A currents from HE K 293 cells that stably expressed human TMEM16A. Niflumic acid, A-9-C, CACC(inh)A01 and T16A(inh)A01 inhibited TMEM16A currents with IC50 values of 12, 58, 1.7 and 1.5 μM, respectively, however, A-9-C and niflumic acid were less efficacious at negative membrane potentials. A-9-C and niflumic acid reduced the rate of TMEM16A tail current deactivation at negative membrane potentials and A-9-C (1 mM) enhanced peak TMEM16A tail current amplitude. In contrast, the inhibitory effects of CACC(inh)A01 and T16A(inh)A01 were independent of voltage and they did not prolong the rate of TMEM16A tail current deactivation. The effects of niflumic acid and A-9-C on TMEM16A currents were similar to previous observations on CACCs in vascular smooth muscle, strengthening the hypothesis that they are encoded by TMEM16A. However, CACC(inh)A01 and T16A(inh)A01 were more potent inhibitors of TMEM16A channels and their effects were not diminished at negative membrane potentials making them attractive candidates to interrogate the functional role of TMEM16A channels in future studies.

  12. Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis

    PubMed Central

    Misra, Ashish; Sheikh, Abdul Q.; Kumar, Abhishek; Luo, Jiesi; Zhang, Jiasheng; Hinton, Robert B.; Smoot, Leslie; Kaplan, Paige; Urban, Zsolt; Qyang, Yibing; Tellides, George

    2016-01-01

    The aorta is the largest artery in the body, yet processes underlying aortic pathology are poorly understood. The arterial media consists of circumferential layers of elastic lamellae and smooth muscle cells (SMCs), and many arterial diseases are characterized by defective lamellae and excess SMCs; however, a mechanism linking these pathological features is lacking. In this study, we use lineage and genetic analysis, pharmacological inhibition, explant cultures, and induced pluripotent stem cells (iPSCs) to investigate supravalvular aortic stenosis (SVAS) patients and/or elastin mutant mice that model SVAS. These experiments demonstrate that multiple preexisting SMCs give rise to excess aortic SMCs in elastin mutants, and these SMCs are hyperproliferative and dedifferentiated. In addition, SVAS iPSC-derived SMCs and the aortic media of elastin mutant mice and SVAS patients have enhanced integrin β3 levels, activation, and downstream signaling, resulting in SMC misalignment and hyperproliferation. Reduced β3 gene dosage in elastin-null mice mitigates pathological aortic muscularization, SMC misorientation, and lumen loss and extends survival, which is unprecedented. Finally, pharmacological β3 inhibition in elastin mutant mice and explants attenuates aortic hypermuscularization and stenosis. Thus, integrin β3–mediated signaling in SMCs links elastin deficiency and pathological stenosis, and inhibiting this pathway is an attractive therapeutic strategy for SVAS. PMID:26858344

  13. Finding a VOICE for UK clinical pharmacology.

    PubMed

    Aronson, Jeffrey K

    2012-06-01

    At a James Black Conference held in Oxford on 20-22 June 2011, a group of senior clinical pharmacologists and their junior colleagues, other medical specialists, and pharmacists discussed an agenda for UK clinical pharmacology for the next 5 years, addressing the following broad questions. How should UK clinical pharmacology be further developed and delivered as a discipline in universities, the NHS, pharmaceutical companies, and regulatory authorities? How should teaching and training in UK clinical pharmacology and therapeutics be delivered and assessed? What topics should be priorities for research in UK academic clinical pharmacology? How should clinical pharmacology contribute to UK drugs policy? How should pharmacology and clinical pharmacology be further integrated, to the benefit of both? Numerous recommendations emerged, under the collective acronym VOICE, standing for Visibility, Outreach, Integration, Coverage and Emissaries. VISIBILITY: The visibility of the discipline needs to be increased. This could be done, for example, by increased activities in acute general medicine/toxicology, through activities of Medicines and Therapeutics Committees, participation in grand rounds, teaching and training, and monitoring therapeutic interventions, and by offering bolt-on training for other specialists (for example, short courses, MSc courses, and training programmes). OUTREACH: Methods of increasing outreach include roadshows in schools/medical schools, national special study modules, public education, press coverage, and social marketing. INTEGRATION: Closer collaborations with pharmacologists, clinical pharmacists, other prescribers, and pharmaceutical companies (e.g. through joint training programmes) are desirable. COVERAGE: Attention to neglected areas, such as general practice, paediatrics, obstetrics, geriatrics, anaesthetics, cancer, and immunology. EMISSARIES: Trainees to spread the word. PMID:22360150

  14. Finding a VOICE for UK clinical pharmacology.

    PubMed

    Aronson, Jeffrey K

    2012-06-01

    At a James Black Conference held in Oxford on 20-22 June 2011, a group of senior clinical pharmacologists and their junior colleagues, other medical specialists, and pharmacists discussed an agenda for UK clinical pharmacology for the next 5 years, addressing the following broad questions. How should UK clinical pharmacology be further developed and delivered as a discipline in universities, the NHS, pharmaceutical companies, and regulatory authorities? How should teaching and training in UK clinical pharmacology and therapeutics be delivered and assessed? What topics should be priorities for research in UK academic clinical pharmacology? How should clinical pharmacology contribute to UK drugs policy? How should pharmacology and clinical pharmacology be further integrated, to the benefit of both? Numerous recommendations emerged, under the collective acronym VOICE, standing for Visibility, Outreach, Integration, Coverage and Emissaries. VISIBILITY: The visibility of the discipline needs to be increased. This could be done, for example, by increased activities in acute general medicine/toxicology, through activities of Medicines and Therapeutics Committees, participation in grand rounds, teaching and training, and monitoring therapeutic interventions, and by offering bolt-on training for other specialists (for example, short courses, MSc courses, and training programmes). OUTREACH: Methods of increasing outreach include roadshows in schools/medical schools, national special study modules, public education, press coverage, and social marketing. INTEGRATION: Closer collaborations with pharmacologists, clinical pharmacists, other prescribers, and pharmaceutical companies (e.g. through joint training programmes) are desirable. COVERAGE: Attention to neglected areas, such as general practice, paediatrics, obstetrics, geriatrics, anaesthetics, cancer, and immunology. EMISSARIES: Trainees to spread the word.

  15. Carbon-11-cocaine binding compared at subpharmacological and pharmacological doses: A PET study

    SciTech Connect

    Volkow, N.D.; Fowler, J.S.; Logan, J. |

    1995-07-01

    The authors have characterized cocaine binding in the brain to a high-affinity site on the dopamine transporter using PET and tracer doses of [{sup 11}C]cocaine in the baboon in vivo. The binding pattern, however, of cocaine at tracer (subpharmacological) doses may differ from that observed when the drug is taken in behaviorally active doses, particularly since in vitro studies have shown that cocaine also binds to low affinity binding sites. PET was used to compare and characterize [{sup 11}C]cocaine binding in the baboon brain at low subpharmacological (18 {mu}g average dose) and at pharmacological (8000 {mu}g) doses. Serial studies on the same day in the same baboon were used to assess the reproducibility of repeated measures and to assess the effects of drugs which inhibit the dopamine, norepinephrine and serotonin transporters. Time-activity curves from brain and the arterial plasma input function were used to calculate the steady-state distribution volume (DV). At subpharmacological doses, [{sup 11}C]cocaine had a more homogeneous distribution. Bmax/Kd for sub-pharmacological [{sup 11}C]cocaine corresponded to 0.5-0.6 and for pharmacological [{sup 11}C]cocaine it corresponded to 0.1-0.2. Two-point Scatchard analysis gave Bmax = 2300 pmole/g and Kd = 3600 nM. Bmax/Kd for sub-pharmacological doses of [{sup 11}C]cocaine was decreased by cocaine and drugs that inhibit the dopamine transporter, to 0.1-0.2, but not by drugs that inhibit the serotonin or the norepinephrine transporter. None of these drugs changed Bmax/Kd for a pharmacological dose of [{sup 11}C]cocaine. At subpharmacological doses, [{sup 11}C]cocaine binds predominantly to a high-affinity site on the dopamine transporter. 36 refs., 4 figs., 5 tabs.

  16. Azasugar inhibitors as pharmacological chaperones for Krabbe disease

    DOE PAGES

    Hill, Chris H.; Viuff, Agnete H.; Spratley, Samantha J.; Salamone, Stéphane; Christensen, Stig H.; Read, Randy J.; Moriarty, Nigel W.; Jensen, Henrik H.; Deane, Janet E.

    2015-03-23

    Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe amore » new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.« less

  17. Pharmacology of heart failure: From basic science to novel therapies.

    PubMed

    Lother, Achim; Hein, Lutz

    2016-10-01

    Chronic heart failure is one of the leading causes for hospitalization in the United States and Europe, and is accompanied by high mortality. Current pharmacological therapy of chronic heart failure with reduced ejection fraction is largely based on compounds that inhibit the detrimental action of the adrenergic and the renin-angiotensin-aldosterone systems on the heart. More than one decade after spironolactone, two novel therapeutic principles have been added to the very recently released guidelines on heart failure therapy: the HCN-channel inhibitor ivabradine and the combined angiotensin and neprilysin inhibitor valsartan/sacubitril. New compounds that are in phase II or III clinical evaluation include novel non-steroidal mineralocorticoid receptor antagonists, guanylate cyclase activators or myosine activators. A variety of novel candidate targets have been identified and the availability of gene transfer has just begun to accelerate translation from basic science to clinical application. This review provides an overview of current pharmacology and pharmacotherapy in chronic heart failure at three stages: the updated clinical guidelines of the American Heart Association and the European Society of Cardiology, new drugs which are in clinical development, and finally innovative drug targets and their mechanisms in heart failure which are emerging from preclinical studies will be discussed.

  18. Pharmacology and Clinical Drug Candidates in Redox Medicine

    PubMed Central

    Casas, Ana I.; Maghzal, Ghassan J.; Seredenina, Tamara; Kaludercic, Nina; Robledinos-Anton, Natalia; Di Lisa, Fabio; Stocker, Roland; Ghezzi, Pietro; Jaquet, Vincent; Cuadrado, Antonio

    2015-01-01

    Abstract Significance: Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. Recent Advances: An alternative emerging approach is to target the enzymatic sources of disease-relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. Critical Issues: For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. Future Directions: The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine. Antioxid. Redox Signal. 23, 1113–1129. PMID:26415051

  19. Species-specific pharmacology of antiestrogens: role of metabolism

    SciTech Connect

    Jordan, V.C.; Robinson, S.P.

    1987-04-01

    The nonsteroidal antiestrogen tamoxifen exhibits a paradoxial space species pharmacology. The drug is a full estrogen in the mouse, a partial estrogen/antiestrogen in humans and the rat, and an antiestrogen in the chick oviduct. Inasmuch as tamoxifen has antiestrogenic effects in vitro, differential metabolism of tamoxifen to estrogens might occur in the species in which it has antiestrogen pharmacology. Tamoxifen or its metabolite 4-hydroxytamoxifen could lose the alkylaminoethane side chain to form the estrogenic compound metabolite E of bisphenol. Sensitive metabolic studies with (/sup 3/H)tamoxifen in chicks, rats, and mice identified 4-hydroxytamoxifen as the major metabolite. Athymic mice with transplanted human breast tumors can be used to study the ability of tamoxifen to stimulate tissue or tumor growth. Estradiol caused the growth of transplanted breast cancer cells into solid tumors and a uterotrophic response. However, tamoxifen does not support tumor growth when administered alone, although it stimulates uterines growth. Since a similar profile of metabolites is sequestered in human mouse tissues, these studies strongly support the concept that the drug can selectively stimulate or inhibit events in the target tissues of different species without hometabolic intervention.

  20. Azasugar inhibitors as pharmacological chaperones for Krabbe disease

    SciTech Connect

    Hill, Chris H.; Viuff, Agnete H.; Spratley, Samantha J.; Salamone, Stéphane; Christensen, Stig H.; Read, Randy J.; Moriarty, Nigel W.; Jensen, Henrik H.; Deane, Janet E.

    2015-03-23

    Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.

  1. Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization.

    PubMed

    Saito, Max Seidy; Lourenço, André Luiz; Dias, Luiza Rosaria Sousa; Freitas, Antônio Carlos Carreira; Vitorino, Maíra Ingrid; Albuquerque, Magaly Girão; Rodrigues, Carlos Rangel; Cabral, Lúcio Mendes; Dias, Eliane Pedra; Castro, Helena Carla; Satlher, Plínio Cunha

    2016-12-01

    Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N'-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3 h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE2 and TXB2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.

  2. Pharmacological Neuroprotection after Perinatal Hypoxic-Ischemic Brain Injury

    PubMed Central

    Fan, Xiyong; Kavelaars, Annemieke; Heijnen, Cobi J; Groenendaal, Floris; van Bel, Frank

    2010-01-01

    Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentrated on prevention of the production of reactive oxygen species or free radicals (xanthine-oxidase-, nitric oxide synthase-, and prostaglandin inhibition), anti-inflammatory effects (erythropoietin, melatonin, Xenon) and anti-apoptotic interventions (nuclear factor kappa B- and c-jun N-terminal kinase inhibition); in a later stage stimulation of neurotrophic properties in the neonatal brain (erythropoietin, growth factors) can be targeted to promote neuronal and oligodendrocyte regeneration. Combination of pharmacological means of treatment with moderate hypothermia, which is accepted now as a meaningful therapy, is probably the next step in clinical treatment to fight post-asphyxial brain damage. Further studies should be directed at a more rational use of therapies by determining the optimal time and dose to inhibit the different potentially destructive molecular pathways or to enhance endogenous repair while at the same time avoiding adverse effects of the drugs used. PMID:21629441

  3. From non-pharmacological treatments for post-traumatic stress disorder to novel therapeutic targets.

    PubMed

    Hendriksen, Hendrikus; Olivier, Berend; Oosting, Ronald S

    2014-06-01

    The development of new pharmacological therapies starts with target discovery. Finding new therapeutic targets for anxiety disorders is a difficult process. Most of the currently described drugs for post-traumatic stress disorder (PTSD) are based on the inhibition of serotonin reuptake. The mechanism of action of selective serotonin reuptake inhibitors was already described in 1977 (Benkert et al., 1977). Now, almost 40 years later, we still rely on the same mechanism of action and more effective pharmacological therapies, based on other working mechanisms, are not on the market yet. Finding new molecular switches that upon modulation cure or alleviate the disorder is hampered by a lack of valid animal models. Many of the characteristics of psychiatric disorders are typically human and hence animal models feature only part of the underlying pathology. In this review we define a set of criteria for animal models of PTSD. First, we describe the symptomatology and pathology of PTSD and the current pharmacological and non-pharmacological treatment options. Next, we compare three often-used animal models and analyze how these models comply with the set of criteria. Finally, we discuss how resolving the underlying mechanisms of effective non-pharmacological treatments (environmental enrichment, re-exposure) may aid therapeutic target discovery.

  4. Pharmacological treatment of negative symptoms in schizophrenia.

    PubMed

    Möller, Hans-Jürgen; Czobor, Pal

    2015-10-01

    Effective treatment of negative symptoms is one of the most important unmet needs in schizophrenic disorders. Because the evidence on current psychopharmacological treatments is unclear, the authors reviewed the findings published to date by searching PubMed with the keywords negative symptoms, antipsychotics, antidepressants, glutamatergic compounds, monotherapy and add-on therapy and identifying additional articles in the reference lists of the resulting publications. The findings presented here predominantly focus on results of meta-analyses. Evidence for efficacy of current psychopharmacological medications is difficult to assess because of methodological problems and inconsistent results. In general, the second-generation antipsychotics (SGAs) do not appear to have good efficacy in negative symptoms, although some show better efficacy than first-generation antipsychotics, some of which also demonstrated efficacy in negative symptoms. Specific trials on predominant persistent negative symptoms are rare and have been performed with only a few SGAs. More often, trials on somewhat persistent negative symptoms evaluate add-on strategies to ongoing antipsychotic treatment. Such trials, mostly on modern antidepressants, have demonstrated some efficacy. Several trials with small samples have evaluated add-on treatment with glutamatergic compounds, such as the naturally occurring amino acids glycine and D-serine and new pharmacological compounds. The results are highly inconsistent, although overall efficacy results appear to be positive. The unsatisfactory and inconsistent results can be partially explained by methodological problems. These problems need to be solved in the future, and the authors propose some possible solutions. Further research is required to identify effective treatment for the negative symptoms of schizophrenia. PMID:25895634

  5. Pharmacological potential of bioactive engineered nanomaterials.

    PubMed

    Caputo, Fanny; De Nicola, Milena; Ghibelli, Lina

    2014-11-01

    In this study we present an overview of the recent results of a novel approach to antioxidant and anticancer therapies, consisting in the administration of intrinsically active nano-structured particles. Their particulate (as opposed to molecular) nature allows designing multifunctional platforms via the binding of molecular determinants, including targeting molecules and chemotherapy drugs, thereby facilitating their localization at the desired site. The intrinsic activity of nanomaterials with pharmacological potential include peculiar trans-excitation reactions that render them able to transform radiofrequency, UV, visible or infrared radiations into cytocidal reactive oxygen species or heat, thereby inducing local cytotoxity in selected areas. The use of such devices has been shown to improve the efficacy of antitumor chemo- and radio-therapies, increasing the selectivity of the cytocidal effects, and reducing systemic side effects. In addition, catalytic nanomaterials such as cerium oxide nanoparticles can perform energy-free antioxidant cycles that scavenge the most noxious reactive oxygen species via SOD- and catalase-mimetic activities. A vast body of in vivo and in vitro studies has demonstrated that they reduce the damage induced by environmental stress and ameliorate an impressive series of clinically relevant oxidation-related pathologies. Similar effects are reported for carbon-based materials such as fullerenes. Overall, great improvements are expected by this novel approach. However, caution must be posed due to the poor knowledge of possible adverse body reactions against these novel devices, thoroughly analyzing the biocompatibility of these nanomaterials, especially concerning the biokinetics and the problems potentially caused by long term retention of non-biodegradable inorganic nanomaterials. PMID:25175739

  6. Pharmacological treatment of negative symptoms in schizophrenia.

    PubMed

    Möller, Hans-Jürgen; Czobor, Pal

    2015-10-01

    Effective treatment of negative symptoms is one of the most important unmet needs in schizophrenic disorders. Because the evidence on current psychopharmacological treatments is unclear, the authors reviewed the findings published to date by searching PubMed with the keywords negative symptoms, antipsychotics, antidepressants, glutamatergic compounds, monotherapy and add-on therapy and identifying additional articles in the reference lists of the resulting publications. The findings presented here predominantly focus on results of meta-analyses. Evidence for efficacy of current psychopharmacological medications is difficult to assess because of methodological problems and inconsistent results. In general, the second-generation antipsychotics (SGAs) do not appear to have good efficacy in negative symptoms, although some show better efficacy than first-generation antipsychotics, some of which also demonstrated efficacy in negative symptoms. Specific trials on predominant persistent negative symptoms are rare and have been performed with only a few SGAs. More often, trials on somewhat persistent negative symptoms evaluate add-on strategies to ongoing antipsychotic treatment. Such trials, mostly on modern antidepressants, have demonstrated some efficacy. Several trials with small samples have evaluated add-on treatment with glutamatergic compounds, such as the naturally occurring amino acids glycine and D-serine and new pharmacological compounds. The results are highly inconsistent, although overall efficacy results appear to be positive. The unsatisfactory and inconsistent results can be partially explained by methodological problems. These problems need to be solved in the future, and the authors propose some possible solutions. Further research is required to identify effective treatment for the negative symptoms of schizophrenia.

  7. The pharmacological profile of auranofin, an orally active gold compound.

    PubMed

    Walz, D T; DiMartino, M J; Griswold, D E

    1983-01-01

    Auranofin (AF; ' Ridaura '), an oral chrysotherapeutic agent, parenteral gold sodium thiomalate (GST) and gold thioglucose (GTG) were evaluated in order to compare their preclinical profiles. AF was found to be more effective than GST and GTG in suppressing inflammation and stimulating cell-mediated immunity. In contrast to GST, AF inhibited cellular release of lysosomal enzymes, antibody-dependent cellular cytotoxicity, production of antibodies in adjuvant arthritic rats, and antibodies involved in cytotoxicity reactions. In pharmacokinetic studies, plasma gold in rats following AF administration, exhibited greater cell association than after GST administration. In conclusion, the pharmacological profile of AF is markedly different from those of GST and GTG and this suggests potential for improvements in chrysotherapy. PMID:6426049

  8. International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

    PubMed Central

    Chazot, Paul L.; Cowart, Marlon; Gutzmer, Ralf; Leurs, Rob; Liu, Wai L. S.; Stark, Holger; Thurmond, Robin L.; Haas, Helmut L.

    2015-01-01

    Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein–coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated. PMID:26084539

  9. Isolation and pharmacological activity of phenylpropanoid esters from Marrubium vulgare.

    PubMed

    Sahpaz, Sevser; Garbacki, Nancy; Tits, Monique; Bailleul, Francois

    2002-03-01

    The isolation and identification of major phenylpropanoid esters from Marrubium vulgare: (+) (E)-caffeoyl-L-malic acid 1, acteoside 2, forsythoside B 3, arenarioside 4, ballotetroside 5, as well as their anti-inflammatory activity are reported for the first time. We evaluated the inhibitory effects of these five compounds on cyclooxygenase (Cox) catalysed prostaglandin biosynthesis activity. Only the glycosidic phenylpropanoid esters showed an inhibitory activity towards the Cox-2 enzyme and three of them: acteoside 2, forsythoside B 3, arenarioside 4, exhibited higher inhibitory potencies on Cox-2 than on Cox-1. These results are of interest, as Cox-2 is mainly associated with inflammation and the Cox-1 inhibition with adverse side effects often observed with non-steroidal anti-inflammatory drugs. The occurrence of these phenylpropanoid esters could also explain some other pharmacological properties of M. vulgare.

  10. The consequences of genetic and pharmacologic reduction in sphingolipid synthesis.

    PubMed

    Schiffmann, Raphael

    2015-01-01

    A new therapy based on substrate synthesis reduction in sphingolipidoses is showing promise. The consequences of decreasing sphingolipid synthesis depend on the level at which synthetic blockage occurs and on the extent of the blockage. Complete synthetic blockage may be lethal if it includes all sphingolipids, such as in a global knockout of serine palmitoyltransferase. Partial inhibition of sphingolipid synthetic pathways is usually benign and may have beneficial effects in a number of lysosomal diseases and in more common pathologies, as seen in animal models for atherosclerosis, polycystic kidney disease, diabetes, and asthma. Studies of various forms of sphingolipid synthesis reduction serve to highlight not only the cellular role of these lipids but also the potential risks and therapeutic benefits of pharmacological agents to be used in therapy for human diseases.

  11. [Comparative pharmacological effectiveness of dexamethasone esters in pigs (author's transl)].

    PubMed

    Mormède, P; Moré, J

    1980-01-01

    Leucocytosis with neutrophilia, lymphopenia and eosinopenia, and decreases in plasma endogenous glucocorticoid levels were used to study the pharmacological kinetics of dexamethasone in pigs. The return to baseline of endogenous plasma glucocorticoid levels was the most sensitive index of dexamethasone action. Intravenous administration of 38 microgram/kg of the soluble phosphate ester produced a maximal response. Higher dosages (76 and 152 microgram/kg) did not increase the intensity of the response, but did increase its duration, which was less than 24 hours. The same response was obtained when dexamethasone phosphate (75 microgram/kg) was given by the intramuscular route. Insoluble esters had a weaker but longer action which lasted for 28 hours with terethoxy-acetate, and approximatively 48 hours with acetate and isonicotinate, on the basis of the pituitary-adrenal axis inhibition. After intramuscular administration, dexamethasone esters induced a weak hyperglycemia but no changes in plasma sodium, chloride or calcium levels were observed.

  12. International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors.

    PubMed

    Panula, Pertti; Chazot, Paul L; Cowart, Marlon; Gutzmer, Ralf; Leurs, Rob; Liu, Wai L S; Stark, Holger; Thurmond, Robin L; Haas, Helmut L

    2015-07-01

    Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.

  13. Cocaine inhibits store-operated Ca2+ entry in brain microvascular endothelial cells: critical role for sigma-1 receptors.

    PubMed

    Brailoiu, G Cristina; Deliu, Elena; Console-Bram, Linda M; Soboloff, Jonathan; Abood, Mary E; Unterwald, Ellen M; Brailoiu, Eugen

    2016-01-01

    Sigma-1 receptor (Sig-1R) is an intracellular chaperone protein with many ligands, located at the endoplasmic reticulum (ER). Binding of cocaine to Sig-1R has previously been found to modulate endothelial functions. In the present study, we show that cocaine dramatically inhibits store-operated Ca(2+) entry (SOCE), a Ca(2+) influx mechanism promoted by depletion of intracellular Ca(2+) stores, in rat brain microvascular endothelial cells (RBMVEC). Using either Sig-1R shRNA or pharmacological inhibition with the unrelated Sig-1R antagonists BD-1063 and NE-100, we show that cocaine-induced SOCE inhibition is dependent on Sig-1R. In addition to revealing new insight into fundamental mechanisms of cocaine-induced changes in endothelial function, these studies indicate an unprecedented role for Sig-1R as a SOCE inhibitor. PMID:26467159

  14. MicroRNAs as targets for dietary and pharmacological inhibitors of mutagenesis and carcinogenesis

    PubMed Central

    Izzotti, Alberto; Cartiglia, Cristina; Steele, Vernon E.; De Flora, Silvio

    2012-01-01

    MicroRNAs (miRNAs) have been implicated in many biological processes, cancer, and other diseases. In addition, miRNAs are dysregulated following exposure to toxic and genotoxic agents. Here we review studies evaluating modulation of miRNAs by dietary and pharmacological agents, which could potentially be exploited for inhibition of mutagenesis and carcinogenesis. This review covers natural agents, including vitamins, oligoelements, polyphenols, isoflavones, indoles, isothiocyanates, phospholipids, saponins, anthraquinones and polyunsaturated fatty acids, and synthetic agents, including thiols, nuclear receptor agonists, histone deacetylase inhibitors, antiinflammatory drugs, and selective estrogen receptor modulators. As many as 145 miRNAs, involved in the control of a variety of carcinogenesis mechanisms, were modulated by these agents, either individually or in combination. Most studies used cancer cells in vitro with the goal of modifying their phenotype by changing miRNA expression profiles. In vivo studies evaluated regulation of miRNAs by chemopreventive agents in organs of mice and rats, either untreated or exposed to carcinogens, with the objective of evaluating their safety and efficacy. The tissue specificity of miRNAs could be exploited for the chemoprevention of site-specific cancers, and the study of polymorphic miRNAs is expected to predict the individual response to chemopreventive agents as a tool for developing new prevention strategies. PMID:22683846

  15. Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency

    PubMed Central

    Yan, Meng; Zhang, Kaiping; Shi, Yanhui; Feng, Lifang; Lv, Lin; Li, Baoxin

    2015-01-01

    Berberine (BBR), an isoquinoline alkaloid mainly isolated from plants of Berberidaceae family, is extensively used to treat gastrointestinal infections in clinics. It has been reported that BBR can block human ether-a-go-go-related gene (hERG) potassium channel and inhibit its membrane expression. The hERG channel plays crucial role in cardiac repolarization and is the target of diverse proarrhythmic drugs. Dysfunction of hERG channel can cause long QT syndrome. However, the regulatory mechanisms of BBR effects on hERG at cell membrane level remain unknown. This study was designed to investigate in detail how BBR decreased hERG expression on cell surface and further explore its pharmacological rescue strategies. In this study, BBR decreases caveolin-1 expression in a concentration-dependent manner in human embryonic kidney 293 (HEK293) cells stably expressing hERG channel. Knocking down the basal expression of caveolin-1 alleviates BBR-induced hERG reduction. In addition, we found that aromatic tyrosine (Tyr652) and phenylalanine (Phe656) in S6 domain mediate the long-term effect of BBR on hERG by using mutation techniques. Considering both our previous and present work, we propose that BBR reduces hERG membrane stability with multiple mechanisms. Furthermore, we found that fexofenadine and resveratrol shorten action potential duration prolongated by BBR, thus having the potential effects of alleviating the cardiotoxicity of BBR. PMID:26543354

  16. Immunomodulatory effects of fluoxetine: A new potential pharmacological action for a classic antidepressant drug?

    PubMed

    Di Rosso, María Emilia; Palumbo, María Laura; Genaro, Ana María

    2016-07-01

    Selective serotonin reuptake inhibitors are frequently used antidepressants. In particular, fluoxetine is usually chosen for the treatment of the symptoms of depression, obsessive-compulsive, panic attack and bulimia nervosa. Antidepressant therapy has been associated with immune dysfunction. However, there is contradictory evidence about the effect of fluoxetine on the immune system. Experimental findings indicate that lymphocytes express the serotonin transporter. Moreover it has been shown that fluoxetine is able to modulate the immune function through a serotonin-dependent pathway and through a novel independent mechanism. In addition, several studies have shown that fluoxetine can alter tumor cell viability. Thus, it was recently demonstrated in vivo that chronic fluoxetine treatment inhibits tumor growth by increasing antitumor T-cell activity. Here we briefly review some of the literature referring to how fluoxetine is able to modify, for better or worse, the functionality of the immune system. These results of our analysis point to the relevance of the novel pharmacological action of this drug as an immunomodulator helping to treat several pathologies in which immune deficiency and/or deregulation is present.

  17. Amphetamine sensitization and amygdala kindling: pharmacological evaluation of catecholaminergic and cholinergic mechanisms.

    PubMed

    Kirkby, R D; Kokkinidis, L

    1991-03-01

    Chronic pharmacological experiments were conducted to evaluate the relationship between sensitization induced by repeated administration of amphetamine (AMPH) and electrical stimulation of the amygdala. While AMPH withdrawal did not influence the kindling process, AMPH administered during the kindling procedure increased the rate at which seizures evolved, and under these conditions withdrawal from chronic AMPH further facilitated the propensity to kindle. Haloperidol (HAL) treatment failed to block the stimulant-induced increase in kindling acquisition indicating that changes in dopamine (DA) are not necessary for the AMPH/kindling synergism to develop. Scopolamine dose-dependently retarded kindling evolution irrespective of prior AMPH pretreatment also ruling out a cholinergic mechanism in the kindling sensitization. Subsequent experiments assessed the interactive effects of AMPH and desipramine (DMI) on the kindling process. Animals chronically exposed to AMPH and switched to DMI treatment during the kindling procedure kindled faster than control subjects. In addition, withdrawal from DMI preexposure advanced the AMPH-induced increase in kindling rate. These results were discussed in terms of the role of norepinephrine-mediated inhibition of the kindling process, and were related to drug-elicited alterations in beta-adrenergic receptor functioning. Taken together, these findings implicate the amygdala as an important structure in the development of non-DA forms of AMPH sensitization.

  18. Pharmacological mechanisms underlying gastroprotective activities of the fractions obtained from Polygonum minus in Sprague Dawley rats.

    PubMed

    Qader, Suhailah Wasman; Abdulla, Mahmood Ameen; Chua, Lee Suan; Sirat, Hasnah Mohd; Hamdan, Salehhuddin

    2012-01-01

    The leaves of Polygonum minus were fractionated using an eluting solvent to evaluate the pharmacological mechanisms underlying the anti-ulcerogenic activity of P. minus. Different P. minus fractions were obtained and evaluated for their ulcer preventing capabilities using the ethanol induction method. In this study, Sprague Dawley rats weighing 150-200 g were used. Different parameters were estimated to identify the active fraction underlying the mechanism of the gastroprotective action of P. minus: the gastric mucus barrier, as well as superoxide dismutase, total hexosamine, and prostaglandin synthesis. Amongst the five fractions from the ethanolic extract of P. minus, the ethyl acetate:methanol 1:1 v/v fraction (F2) significantly (p < 0.005) exhibited better inhibition of ulcer lesions in a dose-dependent manner. In addition, rats pre-treated with F2 showed a significant elevation in superoxide dismutase (SOD), hexosamine and PGE2 levels in the stomach wall mucosa in a dose-dependent matter. Based on these results, the ethyl acetate:methanol 1:1 v/v fraction was considered to be the best fraction for mucous protection in the ethanol induction model. The mechanisms underlying this protection were attributed to the synthesis of antioxidants and PGE2. PMID:22408403

  19. Immunomodulatory effects of fluoxetine: A new potential pharmacological action for a classic antidepressant drug?

    PubMed

    Di Rosso, María Emilia; Palumbo, María Laura; Genaro, Ana María

    2016-07-01

    Selective serotonin reuptake inhibitors are frequently used antidepressants. In particular, fluoxetine is usually chosen for the treatment of the symptoms of depression, obsessive-compulsive, panic attack and bulimia nervosa. Antidepressant therapy has been associated with immune dysfunction. However, there is contradictory evidence about the effect of fluoxetine on the immune system. Experimental findings indicate that lymphocytes express the serotonin transporter. Moreover it has been shown that fluoxetine is able to modulate the immune function through a serotonin-dependent pathway and through a novel independent mechanism. In addition, several studies have shown that fluoxetine can alter tumor cell viability. Thus, it was recently demonstrated in vivo that chronic fluoxetine treatment inhibits tumor growth by increasing antitumor T-cell activity. Here we briefly review some of the literature referring to how fluoxetine is able to modify, for better or worse, the functionality of the immune system. These results of our analysis point to the relevance of the novel pharmacological action of this drug as an immunomodulator helping to treat several pathologies in which immune deficiency and/or deregulation is present. PMID:26644208

  20. ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes.

    PubMed

    Davis, Robert E; Correll, Christoph U

    2016-06-01

    ITI-007 is an investigational drug being developed for schizophrenia and other neuropsychiatric/neurodegenerative diseases. ITI-007 has a unique pharmacological profile, combining potent 5-HT2a receptor antagonism with cell-type-specific dopamine and glutamate receptor modulation, plus serotonin reuptake inhibition. At dopamine-D2 receptors, ITI-007 acts as a post-synaptic antagonist and pre-synaptic partial agonist. Additionally, ITI-007 stimulates phosphorylation of glutamatergic NMDA-NR2B receptors, downstream of dopamine-D1 receptor intracellular signaling. Based on a large, placebo and risperidone controlled, Phase-II trial, ITI-007 60 mg was shown to be effective in reducing symptoms in patients with acutely exacerbated schizophrenia. The antipsychotic efficacy of ITI-007 60 mg in this patient population was confirmed in a recently completed Phase III study. ITI-007 was associated with minimal safety risk compared to risperidone (Phase II study) or placebo (both studies) for neuromotor disturbances, prolactin changes, weight gain and metabolic abnormalities. A second 6-week, placebo and risperidone-controlled Phase-III trial in acutely exacerbated schizophrenia is ongoing. PMID:27042868

  1. Identification of Three Antiviral Inhibitors against Japanese Encephalitis Virus from Library of Pharmacologically Active Compounds 1280

    PubMed Central

    Peng, Guiqing; Xu, Jia; Zhou, Rui; Cao, Shengbo; Chen, Huanchun; Song, Yunfeng

    2013-01-01

    Japanese encephalitis virus (JEV) can cause severe central nervous disease with a high mortality rate. There is no antiviral drug available for JEV-specific treatment. In this study, a cytopathic-effect-based, high-throughput screening assay was developed and applied to screen JEV inhibitors from Library of Pharmacologically Active Compounds 1280. The antiviral effects of three hit compounds including FGIN-1-27, cilnidipine, and niclosamide were evaluated in cells by western blotting, indirect immunofluorescence assay, and plaque reduction assay. A time-of-addition assay proved that all three compounds inhibited JEV at the stage of replication. The EC50s of FGIN-1-27, cilnidipine, and niclosamide were 3.21, 6.52, and 5.80 µM, respectively, while the selectivity indexes were 38.79, 30.67, and 7.49. FGIN-1-27 and cilnidipine have high efficiency and selectivity against JEV. This study provided two JEV antiviral inhibitors as candidates for treatment of JEV infection. PMID:24348901

  2. Non Pharmacological Cognitive Enhancers - Current Perspectives.

    PubMed

    Sachdeva, Ankur; Kumar, Kuldip; Anand, Kuljeet Singh

    2015-07-01

    Cognition refers to the mental processes involved in thinking, knowing, remembering, judging, and problem solving. Cognitive dysfunctions are an integral part of neuropsychiatric disorders as well as in healthy ageing. Cognitive Enhancers are molecules that help improve aspects of cognition like memory, intelligence, motivation, attention and concentration. Recently, Non Pharmacological Cognitive Enhancers have gained popularity as effective and safe alternative to various established drugs. Many of these Non Pharmacological Cognitive Enhancers seem to be more efficacious compared to currently available Pharmacological Cognitive Enhancers. This review describes and summarizes evidence on various Non Pharmacological Cognitive Enhancers such as physical exercise, sleep, meditation and yoga, spirituality, nutrients, computer training, brain stimulation, and music. We also discuss their role in ageing and different neuro-psychiatric disorders, and current status of Cochrane database recommendations. We searched the Pubmed database for the articles and reviews having the terms 'non pharmacological and cognitive' in the title, published from 2000 till 2014. A total of 11 results displayed, out of which 10 were relevant to the review. These were selected and reviewed. Appropriate cross-references within the articles along with Cochrane reviews were also considered and studied. PMID:26393186

  3. Non Pharmacological Cognitive Enhancers – Current Perspectives

    PubMed Central

    Kumar, Kuldip; Anand, Kuljeet Singh

    2015-01-01

    Cognition refers to the mental processes involved in thinking, knowing, remembering, judging, and problem solving. Cognitive dysfunctions are an integral part of neuropsychiatric disorders as well as in healthy ageing. Cognitive Enhancers are molecules that help improve aspects of cognition like memory, intelligence, motivation, attention and concentration. Recently, Non Pharmacological Cognitive Enhancers have gained popularity as effective and safe alternative to various established drugs. Many of these Non Pharmacological Cognitive Enhancers seem to be more efficacious compared to currently available Pharmacological Cognitive Enhancers. This review describes and summarizes evidence on various Non Pharmacological Cognitive Enhancers such as physical exercise, sleep, meditation and yoga, spirituality, nutrients, computer training, brain stimulation, and music. We also discuss their role in ageing and different neuro-psychiatric disorders, and current status of Cochrane database recommendations. We searched the Pubmed database for the articles and reviews having the terms ‘non pharmacological and cognitive’ in the title, published from 2000 till 2014. A total of 11 results displayed, out of which 10 were relevant to the review. These were selected and reviewed. Appropriate cross-references within the articles along with Cochrane reviews were also considered and studied. PMID:26393186

  4. Physiological and pharmacologic aspects of peripheral nerve blocks

    PubMed Central

    Vadhanan, Prasanna; Tripaty, Debendra Kumar; Adinarayanan, S.

    2015-01-01

    A successful peripheral nerve block not only involves a proper technique, but also a thorough knowledge and understanding of the physiology of nerve conduction and pharmacology of local anesthetics (LAs). This article focuses on what happens after the block. Pharmacodynamics of LAs, underlying mechanisms of clinically observable phenomena such as differential blockade, tachyphylaxis, C fiber resistance, tonic and phasic blockade and effect of volume and concentration of LAs. Judicious use of additives along with LAs in peripheral nerve blocks can prolong analgesia. An entirely new group of drugs-neurotoxins has shown potential as local anesthetics. Various methods are available now to prolong the duration of peripheral nerve blocks. PMID:26330722

  5. New developments in the pharmacologic treatment of obesity.

    PubMed

    Fantasia, Heidi Collins

    2013-01-01

    Obesity, defined as a body mass index (BMI, kg/m(2) ) >30, is a significant public health problem. It's estimated that 50 percent of the U.S. population will be classified as obese by the year 2030. Due to associated health complications and rising health care costs related to obesity, new treatment options are being explored. For people who need additional treatment beyond lifestyle modification, new pharmacologic options have been developed that may assist in reducing BMI. Health care providers and patients should consider each person's individual health history and consider both the potential risks and benefits of these therapies. PMID:23399013

  6. Biochemical pharmacology of paradoxical sleep

    PubMed Central

    Gaillard, J. -M.

    1983-01-01

    1 The role of noradrenergic cells in the regulation of paradoxical sleep is still controversial, and experimental data have given rise to contradictory interpretations. 2 Early investigations focused primarily on chemical neurotransmissions. However, the process of information transmission between cells involves many other factors, and the cell surface is an important site for transduction of messages into modifications of the activity of postsynaptic cells. 3 α-adrenoceptors are believed to play an important role in the control of wakefulness and paradoxical sleep. Experimental evidence suggests that physiological modulation of receptor sensitivity, possibly by specific neuro-modulators, may be a key mechanism in synaptic transmission. 4 In the investigation of the mechanisms involved in paradoxical sleep regulation, lesions of the locus coeruleus have given equivocal results. Collateral inhibition, probably mediated by α2-adrenoceptors, appears to be a powerful mechanism. The exact temporal relationship between noradrenergic cell activation and paradoxical sleep production is not established, but 5-HT appears to be involved. Differences between paradoxical sleep and waking may be related to a physiological modulation of α2-adrenoceptor sensitivity. PMID:6140943

  7. Episodic Inhibition

    ERIC Educational Resources Information Center

    Racsmany, Mihaly; Conway, Martin A.

    2006-01-01

    Six experiments examined the proposal that an item of long-term knowledge can be simultaneously inhibited and activated. In 2 directed forgetting experiments items to-be-forgotten were found to be inhibited in list-cued recall but activated in lexical decision tasks. In 3 retrieval practice experiments, unpracticed items from practiced categories…

  8. Investigational pharmacology for low back pain

    PubMed Central

    Bhandary, Avinash K; Chimes, Gary P; Malanga, Gerard A

    2010-01-01

    Study design: Review and reinterpretation of existing literature. Objective: This review article summarizes the anatomy and pathogenesis of disease processes that contribute to low back pain, and discusses key issues in existing therapies for chronic low back pain. The article also explains the scientific rationale for investigational pharmacology and highlights emerging compounds in late development. Results/conclusion: While the diverse and complex nature of chronic low back pain continues to challenge clinicians, a growing understanding of chronic low back pain on a cellular level has refined our approach to managing chronic low back pain with pharmacology. Many emerging therapies with improved safety profiles are currently in the research pipeline and will contribute to a multimodal therapeutic algorithm in the near future. With the heterogeneity of the patient population suffering from chronic low back pain, the clinical challenge will be accurately stratifying the optimal pharmacologic approach for each patient. PMID:21197321

  9. [Recent advances in pharmacological intervention for prediabetes].

    PubMed

    Lan, Jia-qi; Zhu, Chuan-jiang

    2015-12-01

    Prediabetes is an abnormal condition between normal glucose metabolism and diabetes mellitus. Impaired glucose tolerance (IGT) is an indicator of high-risk state of prediabetes. Positive interve