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Journal Cover Pharmacological Research
  [SJR: 2.108]   [H-I: 99]   [1 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [3042 journals]
  • Role of the area postrema in the hypophagic effects of oleoylethanolamide
    • Authors: Adele Romano; Cristina Anna Gallelli; Justyna Barbara Koczwara; Fiona E. Braegger; Annabella Vitalone; Mario Falchi; Maria Vittoria Micioni Di Bonaventura; Carlo Cifani; Tommaso Cassano; Thomas A. Lutz; Silvana Gaetani
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Adele Romano, Cristina Anna Gallelli, Justyna Barbara Koczwara, Fiona E. Braegger, Annabella Vitalone, Mario Falchi, Maria Vittoria Micioni Di Bonaventura, Carlo Cifani, Tommaso Cassano, Thomas A. Lutz, Silvana Gaetani
      The satiety-promoting action of oleoylethanolamide (OEA) has been associated to the indirect activation of selected brain areas, such as the nucleus of the solitary tract (NST) in the brainstem and the tuberomammillary (TMN) and paraventricular (PVN) nuclei in the hypothalamus, where noradrenergic, histaminergic and oxytocinergic neurons play a necessary role. Visceral ascending fibers were hypothesized to mediate such effects. However, our previous findings demonstrated that the hypophagic action of peripherally administered OEA does not require intact vagal afferents and is associated to a strong activation of the area postrema (AP). Therefore, we hypothesized that OEA may exert its central effects through the direct activation of this circumventricular organ. To test this hypothesis, we subjected rats to the surgical ablation of the AP (APX rats) and evaluated the effects of OEA (10mgkg−1 i.p.) on food intake, Fos expression, hypothalamic oxytocin (OXY) immunoreactivity and on the expression of dopamine beta hydroxylase (DBH) in the brainstem and hypothalamus. We found that the AP lesion completely prevented OEA’s behavioral and neurochemical effects in the brainstem and the hypothalamus. Moreover OEA increased DBH expression in AP and NST neurons of SHAM rats while the effect in the NST was absent in APX rats, thus suggesting the possible involvement of noradrenergic AP neurons. These results support the hypothesis of a necessary role of the AP in mediating OEA’s central effects that sustain its pro-satiety action.
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      PubDate: 2017-05-28T06:38:35Z
      DOI: 10.1016/j.phrs.2017.05.017
      Issue No: Vol. 122 (2017)
       
  • Obesity and hypertension
    • Authors: Gino Seravalle; Guido Grassi
      Pages: 1 - 7
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Gino Seravalle, Guido Grassi
      Obesity and in particular the excessive visceral fat distribution is accompanied by several alterations at hormonal, inflammatory and endothelial level. These alterations induce a stimulation of several other mechanisms that contribute to the hypertensive state and on the other side to increase the cardiovascular morbidity. In these chapter we will examine the main mechanisms of obesity and obesity-related hypertension and in particular the role of sympathetic nervous system, the alterations of the renal function and at the microvascular level. We will also depict the role of insulin resistance as factor stimulating and potentiating the other mechanisms. The second part will be focalized on the major target organ damage linked with obesity and obesity-related hypertension. We will finally describe the management and treatment of obesity and the antihypertensive drug therapies more effective in hypertensive obeses.
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      PubDate: 2017-05-28T06:38:35Z
      DOI: 10.1016/j.phrs.2017.05.013
      Issue No: Vol. 122 (2017)
       
  • Is dual inhibition of metalloenzymes HDAC-8 and MMP-2 a potential
           pharmacological target to combat hematological malignancies?
    • Authors: Sk. Abdul Amin; Nilanjan Adhikari; Tarun Jha
      Pages: 8 - 19
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Sk. Abdul Amin, Nilanjan Adhikari, Tarun Jha
      For the last three decades, metalloenzymes such as histone deacetylases (HDACs) and matrix metalloproteinases (MMPs) have been identified in promoting solid as well as hematological carcinogenesis. Histone deacetylase 8 (HDAC-8), a class I HDAC enzyme, may serve as ‘epigenetic player' that affects in the regulation of transcription factors and alters the structure of chromosome associated with tumorigenesis. It is established that the influence of MMP-2 in invasion, metastasis and angiogenenic events of hematological malignancies may be suppressed by HDAC inhibitors through reversion-inducing-cysteine-rich protein with kazal motifs (RECK) protein. Therefore, the isoform-specific HDAC-8 and MMP-2 inhibitors may provide synergistic medicinal benefit in leukemia. However, a paucity of articles is available on dual acting HDAC-8/MMP-2 inhibitors. In this circumstance, a lot of works are still necessary to identify novel dual HDAC-8/MMP-2 inhibitors and this review will surely provide an initial idea regarding the utility of designing such type of dual inhibitors. Here, the importance of MMP-2 and HDAC-8 inhibition in hematological malignancies are focussed for the first time as per our knowledge along with the structure-activity relationships (SARs) of a handful of molecules, some of which were synthesised in-house, have been highlighted that will inspire more interactions between the medicinal chemistry and biology community to harness their expertise in design and discovery of the better acting dual inhibitors in future.
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      PubDate: 2017-05-28T06:38:35Z
      DOI: 10.1016/j.phrs.2017.05.002
      Issue No: Vol. 122 (2017)
       
  • Propranolol treatment lowers blood pressure, reduces vascular inflammatory
           markers and improves endothelial function in obese mice
    • Authors: Nathalia da Silva Franco; Camila Lubaczeuski; Daniele M. Guizoni; Jamaira A. Victorio; Junia C. Santos-Silva; Patricia C. Brum; Everardo M. Carneiro; Ana P. Davel
      Pages: 35 - 45
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Nathalia da Silva Franco, Camila Lubaczeuski, Daniele M. Guizoni, Jamaira A. Victorio, Junia C. Santos-Silva, Patricia C. Brum, Everardo M. Carneiro, Ana P. Davel
      Obesity-associated hypertension is accompanied by a number of cardiovascular risk factors including vascular insulin resistance (IR) and higher sympathetic nervous activity. Therefore, autonomic blockade was demonstrated to reverse hypertension, endothelial dysfunction and IR in obese individuals. We hypothesized that β-AR blockade with propranolol would restore endothelial function and vascular insulin signaling in obesity, associated with an anti-inflammatory effect. Body weight, systolic blood pressure (SBP), plasma biochemical parameters and aortic endothelial function were analyzed in mice fed standard diet (control group) or a high fat diet (HFD) that were treated with vehicle (water) or propranolol (10mg/kg/day) for 8weeks. Propranolol treatment did not modify obesogenic effect of HFD feeding. However, propranolol was effective in preventing the rise in SBP, the hyperinsulinemia and the impaired endothelium-dependent relaxation to acetylcholine and to insulin in obese mice. Protective effect of propranolol administration in endothelial function was associated with increased nitric oxide (NO) production and phosphorylation of Akt (Ser473) and eNOS (Ser1177), but with reduced phospho-IRS-1(Ser307) and phospho-ERK1/2 (Thr202/Tyr204). In addition, β-blocker propranolol prevented the NF-kB nuclear translocation and the increase in phospho-IκB-α (Ser32) and in interleukin(IL)-6 expression in aorta of obese mice, without significant changes in either aortic reactive oxygen species production or in circulating IL-6 and TNF-α levels. In β2-AR knockout mice, despite increasing body weight and visceral fat, HFD did not increase SBP and showed a partial improvement of endothelial function, revealing a role of β2-AR in cardiovascular effects of obesity. In conclusion, our results suggest that β-AR blockade with propranolol is effective to prevent the endothelial dysfunction, vascular IR and pro-inflammatory state displayed in HFD-induced obesity, independent of changes in body weight.
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      PubDate: 2017-06-07T07:13:28Z
      DOI: 10.1016/j.phrs.2017.05.018
      Issue No: Vol. 122 (2017)
       
  • Netrins as prophylactic targets in skeletal diseases: A double-edged
           sword?
    • Authors: Kenta Maruyama; Naoki Takemura; Mikaël M. Martino; Takeshi Kondo; Shizuo Akira
      Pages: 46 - 52
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Kenta Maruyama, Naoki Takemura, Mikaël M. Martino, Takeshi Kondo, Shizuo Akira
      The netrin family of proteins are involved in axon guidance during central nervous system development. In vertebrates, two membrane bound forms and five secreted forms of netrin have been reported. In addition to their critical role in neural morphogenesis, a growing number of reports suggest that netrin family proteins also play a role in inflammatory conditions, angiogenesis, and tumorigenesis. In these processes, Unc5 and DCC family proteins serve as receptors of netrin proteins. Recently, it was reported that some netrin family proteins may be involved in the pathogenesis of skeletal diseases including osteoporosis and arthritis. For example, administration of secreted netrin family proteins such as netrin 1 and netrin 4 has prophylactic potential in pathogenic bone degradation in mice. However, netrin 1 blocking antibody also protects mice from inflammatory bone destruction. Therefore, netrin family proteins are involved in the regulation of bone homeostasis, but their bona fide roles in the skeletal system remain controversial. In this review, we discuss the osteo-innate-immune functions of the netrin family of proteins, and summarize their therapeutic potential.
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      PubDate: 2017-06-07T07:13:28Z
      DOI: 10.1016/j.phrs.2017.05.011
      Issue No: Vol. 122 (2017)
       
  • Effect of orlistat on plasma lipids and body weight: A systematic review
           and meta-analysis of 33 randomized controlled trials
    • Authors: Amirhossein Sahebkar; Luis E. Simental-Mendía; Željko Reiner; Petri T. Kovanen; Mario Simental-Mendía; Vanessa Bianconi; Matteo Pirro
      Pages: 53 - 65
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Amirhossein Sahebkar, Luis E. Simental-Mendía, Željko Reiner, Petri T. Kovanen, Mario Simental-Mendía, Vanessa Bianconi, Matteo Pirro
      Orlistat, an inhibitor of intestinal lipase, promotes body weight reduction. The lipid-lowering efficacy of orlistat is controversial and the effect of orlistat-induced body weight reduction on lipid changes has not been explored in meta-regression analyses. A systematic literature search was conducted to identify randomized controlled trials investigating the efficacy of orlistat on plasma total, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides and lipoprotein(a) levels. Thirty-three studies were included in the meta-analysis (5522 and 4210 participants in the orlistat therapy and control groups, respectively). Orlistat reduced body weight (weighted mean difference: −2.12, p <0.001), total-cholesterol (weighted mean difference: −0.30mmol/L, p <0.001), low-density lipoprotein cholesterol (weighted mean difference: −0.27mmol/L, p <0.001), high-density lipoprotein cholesterol (weighted mean difference: −0.034mmol/L, p <0.001) and triglyceride (weighted mean difference: −0.09mmol/L, p <0.001) concentrations, while no effect on lipoprotein(a) was observed. Total- and low-density lipoprotein cholesterol-lowering were associated negatively with duration of orlistat treatment and positively with body weight changes. In conclusion, Orlistat treatment slightly reduces cholesterol and triglyceride levels, but not lipoprotein(a) levels. Total- and low-density lipoprotein cholesterol levels reductions are more consistent in patients with greater body weight reduction and shorter duration of orlistat treatment.
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      PubDate: 2017-06-07T07:13:28Z
      DOI: 10.1016/j.phrs.2017.05.022
      Issue No: Vol. 122 (2017)
       
  • LPE-1, an orally active pyrimidine derivative, inhibits growth and
           mobility of human esophageal cancers by targeting LSD1
    • Authors: Bo Wang; Bing Zhao; Lu-Ping Pang; Yuan-Di Zhao; Qian Guo; Jun-Wei Wang; Yi-Chao Zheng; Xin-Hui Zhang; Ying Liu; Guang-Yao Liu; Wen-Ge Guo; Chao Wang; Zhong-Hua Li; Xue-Jing Mao; Bin Yu; Li-Ying Ma; Hong-Min Liu
      Pages: 66 - 77
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Bo Wang, Bing Zhao, Lu-Ping Pang, Yuan-Di Zhao, Qian Guo, Jun-Wei Wang, Yi-Chao Zheng, Xin-Hui Zhang, Ying Liu, Guang-Yao Liu, Wen-Ge Guo, Chao Wang, Zhong-Hua Li, Xue-Jing Mao, Bin Yu, Li-Ying Ma, Hong-Min Liu
      Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC50 =0.336±0.003μM) significantly suppressed proliferation, induced apoptosis, arrested cell cycle of EC109 cells at G2/M phase, and caused changes of the associated protein markers correspondingly. We also found that compound LPE-1 potently inhibited the migration and invasion of EC-109 cells. Docking studies showed that the cyano group formed hydrogen bonds with Val811 and Thr810. Additionally, the thiophene moiety formed arene-H interaction with Trp761 residue. In vivo studies showed that compound LPE-1 inhibited tumor growth of xenograft models bearing EC-109 without obvious toxicity. Collectively, our findings indicate that LSD1 may be a potential therapeutic target in ESCC, and compound LPE-1 could serve as a lead compound for further development for anti-ESCC drug discovery.
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      PubDate: 2017-06-07T07:13:28Z
      DOI: 10.1016/j.phrs.2017.05.025
      Issue No: Vol. 122 (2017)
       
  • Cinnamaldehyde in diabetes: A review of pharmacology, pharmacokinetics and
           safety
    • Authors: Ruyuan Zhu; Haixia Liu; Chenyue Liu; Lili Wang; Rufeng Ma; Beibei Chen; Lin Li; Jianzhao Niu; Min Fu; Dongwei Zhang; Sihua Gao
      Pages: 78 - 89
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Ruyuan Zhu, Haixia Liu, Chenyue Liu, Lili Wang, Rufeng Ma, Beibei Chen, Lin Li, Jianzhao Niu, Min Fu, Dongwei Zhang, Sihua Gao
      Cinnamaldehyde, one of the active components derived from Cinnamon, has been used as a natural flavorant and fragrance agent in kitchen and industry. Emerging studies have been performed over the past decades to evaluate its beneficial role in management of diabetes and its complications. This review highlights recent advances of cinnamaldehyde in its glucolipid lowering effects, its pharmacokinetics, and its safety by consulting the Pubmed, China Knowledge Resource Integrated, China Science and Technology Journal, National Science and Technology Library, Wanfang Data, and the Web of Science Databases. For the inquiries, keywords such as Cinnamon, cinnamaldehyde, property, synthesis, diabetes, obesity, pharmacokinetics, and safety were used in various combinations. Accumulating evidence supports the notion that cinnamaldehyde exhibits glucolipid lowering effects in diabetic animals by increasing glucose uptake and improving insulin sensitivity in adipose and skeletal muscle tissues, improving glycogen synthesis in liver, restoring pancreatic islets dysfunction, slowing gastric emptying rates, and improving diabetic renal and brain disorders. Cinnamaldehyde exerts these effects through its action on multiple signaling pathways, including PPARs, AMPK, PI3K/IRS-1, RBP4-GLUT4, and ERK/JNK/p38MAPK, TRPA1-ghrelin and Nrf2 pathways. In addition, cinnamaldehyde seems to regulate the activities of PTP1B and α-amylase. Furthermore, cinnamaldehyde has the potential of metalizing into cinnamyl alcohol and methyl cinnamate and cinnamic acid in the body. Finally, there is a potential toxicity concern about this compound. In summary, cinnamaldehyde supplementation is shown to improve glucose and lipid homeostasis in diabetic animals, which may provide a new option for diabetic intervention. To this end, further scientific evidences are required from clinical trials on its glucose regulating effects and safety.
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      PubDate: 2017-06-07T07:13:28Z
      DOI: 10.1016/j.phrs.2017.05.019
      Issue No: Vol. 122 (2017)
       
  • Gut microbiota and acute graft-versus-host disease
    • Authors: Kosuke Yoshioka; Kazuhiko Kakihana; Noriko Doki; Kazuteru Ohashi
      Pages: 90 - 95
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Kosuke Yoshioka, Kazuhiko Kakihana, Noriko Doki, Kazuteru Ohashi
      Although allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for various hematological diseases, acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality, and its management is clinically important. Advances in biological techniques have led to great progress in understanding the complex interactions between the host and the gut microbiota. The gut microbiota clearly modulates the immune response and is associated with the pathogenesis of various disorders. Also in allo-SCT, both preclinical and clinical results indicate that the gut microbiota is closely associated with the development of acute GVHD and transplant outcomes. These results led to the idea that improvement in quantitative and/or qualitative abnormalities of microbiota (dysbiosis) may be a new treatment strategy for acute GVHD. Evaluations of therapies targeting the gut microbiota such as probiotics or fecal microbiota transplantation have just begun. Furthermore, intervention in the gut microbiota with a nutritional approach including prebiotics, postbiotics, and antibiotics selection may also be another promising treatment option for acute GVHD.
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      PubDate: 2017-06-12T07:41:06Z
      DOI: 10.1016/j.phrs.2017.05.028
      Issue No: Vol. 122 (2017)
       
  • Geranylgeraniol prevents the simvastatin-induced PCSK9 expression: Role of
           the small G protein Rac1
    • Authors: Nicola Ferri; Silvia Marchianò; Maria Giovanna Lupo; Annalisa Trenti; Giuseppe Biondo; Paola Castaldello; Alberto Corsini
      Pages: 96 - 104
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Nicola Ferri, Silvia Marchianò, Maria Giovanna Lupo, Annalisa Trenti, Giuseppe Biondo, Paola Castaldello, Alberto Corsini
      Statins are known to increase the plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) through the activation of the sterol responsive element binding protein (SREBP) pathway due to the inhibition of cholesterol biosynthesis. In the present study, we explore a possible role of the prenylated proteins on the statin-mediated PCSK9 induction in Caco-2 cells. Simvastatin (40μM) induced both PCSK9 mRNA (10.7±3.2 fold) and protein (2.2±0.3 fold), after 24h incubation. The induction of PCSK9 mRNA was partially, but significantly, prevented by the co-incubation with mevalonate (MVA), farnesol (FOH) and geranylgeraniol (GGOH), while a complete prevention was observed on secreted PCSK9, evaluated by ELISA assay. Under the same experimental conditions, MVA, GGOH, but not FOH, prevented the activation of the PCSK9 promoter by simvastatin in a SRE-dependent manner. Simvastatin reduced by −35.7±15.2% the Rac1-GTP levels, while no changes were observed on RhoA- and Cdc42-GTP. This effect was prevented by MVA and GGOH. A Rac inhibitor, and N17Rac1 dominant negative mutant, significantly induced PCSK9 levels, and a suppression of Rac1 expression by siRNA, counteract the effect of simvastatin on the induction of PCSK9 mRNA. Finally, simvastatin, and Rac inhibitor inhibited the nuclear translocation of STAT3 and its knock-down by siRNA increased significantly the susceptibility of Caco-2 to simvastatin on PCSK9 expression. Taken together, the present study reveal a direct role of Rac1 on simvastatin-mediated PCSK9 expression via the reduction of STAT3 nuclear translocation.
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      PubDate: 2017-06-12T07:41:06Z
      DOI: 10.1016/j.phrs.2017.05.021
      Issue No: Vol. 122 (2017)
       
  • BPI-3016, a novel long-acting hGLP-1 analogue for the treatment of Type 2
           diabetes mellitus
    • Authors: Lieming Ding; Sisi Lu; Yanping Wang; Haibo Chen; Wei Long; Cunbo Ma; Erlong He; Dan Yan; Fenlai Tan
      Pages: 130 - 139
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Lieming Ding, Sisi Lu, Yanping Wang, Haibo Chen, Wei Long, Cunbo Ma, Erlong He, Dan Yan, Fenlai Tan
      Glucagon-like peptide-1 (GLP-1) analogues have been commonly used as add-on medications for patients with Type 2 diabetes mellitus (T2DM). Currently, the development of long-acting GLP-1 analogues which allow the freedom and flexibility of once-weekly injections while maintaining their potency for a relatively long period has become the mainstream. Here, we successfully developed a long-acting human GLP-1(7–37) analogue (BPI-3016) with significantly extended half-life and increased resistance to dipeptidyl peptidase IV (DPP-IV) cleavage by structural modifications of human GLP-1. In vitro activity of BPI-3016 including GLP-1 receptor affinity and stimulation of cyclic adenosine monophosphate (cAMP) production was measured. In vivo activity of BPI-3016 such as its effects on glycemic control, β-cell mass and body weight was evaluated in ob/ob mice, db/db mice, and spontaneous diabetic cynomolgus monkeys. The results indicated that BPI-3016 preserved receptor affinity to GLP receptors, and was capable of stimulating cAMP production. In in vivo pharmacokinetic study, the half-life of BPI-3016 was more than 95h after single dosing in diabetic cynomolgus monkeys. Also, BPI-3016 reduced fasting and post-prandial plasma glucose levels for up to a week after a single dose; It reduced body mass index (BMI), body fat, improved glucose tolerance and showed insulinotropic effects after once-weekly injection for 7 weeks. In conclusion, BPI-3016 retains the effects of GLP-1 with significantly prolonged half-life, making it a promising therapy for type 2 diabetes with once-weekly treatment in the clinic.
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      PubDate: 2017-06-17T08:01:54Z
      DOI: 10.1016/j.phrs.2017.05.007
      Issue No: Vol. 122 (2017)
       
  • Short- and long-term effects of risperidone on catalepsy sensitisation and
           acquisition of conditioned avoidance response: Adolescent vs adult rats
    • Authors: Aung Aung Kywe Moe; Gregory A. Medely; Timothy Reeks; Thomas H.J. Burne; Darryl W. Eyles
      Pages: 1 - 13
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Aung Aung Kywe Moe, Gregory A. Medely, Timothy Reeks, Thomas H.J. Burne, Darryl W. Eyles
      The effects of antipsychotic drugs (APDs) on the adolescent brain are poorly understood despite a dramatic increase in prescription of these drugs in adolescents over the past twenty years. Neuronal systems continue to be remodeled during adolescence. Therefore, when given in adolescence, antipsychotic drugs (APDs) have the potential to affect this remodeling. In this study we investigated the effects of chronic 22-day risperidone treatment (1.3mg/kg/day) in both adolescent and adult rats. We examined short- and long-term changes in behaviour (catalepsy, locomotion and conditioned avoidance response (CAR)), and dopaminergic and serotonergic neurochemistry in the striatum and the nucleus accumbens. Here, we report that, both during chronic treatment and after a lengthy drug-free interval, risperidone induced a sensitised cataleptic response regardless of the age of exposure. Selectively in adolescents, risperidone-induced catalepsy was inversely correlated with striatal dopamine turnover immediately after chronic treatment. After a drug-free interval, a significant proportion of rats with prior adolescent risperidone treatment also failed to acquire CAR to a defined criterion. Our data provide evidence that the same chronic risperidone treatment regimen can induce contrasting short- and long-term neural outcomes in the adolescent and adult brains.
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      PubDate: 2017-04-26T11:43:45Z
      DOI: 10.1016/j.phrs.2017.04.013
      Issue No: Vol. 121 (2017)
       
  • Toll-like receptor activation, vascular endothelial function, and
           hypertensive disorders of pregnancy
    • Authors: Dakshnapriya Balasubbramanian; Catalina A. Lopez Gelston; Brett M. Mitchell; Piyali Chatterjee
      Pages: 14 - 21
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Dakshnapriya Balasubbramanian, Catalina A. Lopez Gelston, Brett M. Mitchell, Piyali Chatterjee
      Aberrant innate immune system activation in the mother contributes greatly to the development of hypertension during pregnancy. Numerous groups have elicited vascular inflammation, endothelial dysfunction, and hypertension in animals during gestation by directly activating Toll-like receptors. Additionally, several experimental therapies that reduce pro-inflammatory immune cells and cytokines restore vascular endothelial function and normalize blood pressure. This review will summarize the research demonstrating that an excessive maternal innate immune response is sufficient to cause vascular inflammation and endothelial dysfunction, which contributes to the development of hypertension during pregnancy. Dampening the vascular inflammation caused by immune responses may reduce the incidence and severity of hypertensive disorders of pregnancy.
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      PubDate: 2017-04-26T11:43:45Z
      DOI: 10.1016/j.phrs.2017.04.018
      Issue No: Vol. 121 (2017)
       
  • Cycloastragenol improves hepatic steatosis by activating farnesoid X
           receptor signalling
    • Authors: Ming Gu; Shiying Zhang; Yuanyuan Zhao; Jinwen Huang; Yahui Wang; Yin Li; Shengjie Fan; Li Yang; Guang Ji; Qingchun Tong; Cheng Huang
      Pages: 22 - 32
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Ming Gu, Shiying Zhang, Yuanyuan Zhao, Jinwen Huang, Yahui Wang, Yin Li, Shengjie Fan, Li Yang, Guang Ji, Qingchun Tong, Cheng Huang
      Non-alcoholic fatty liver disease (NAFLD) has become a global health problem. However, there is no approved therapy for NAFLD. Farnesoid X receptor (FXR) is a potential drug target for treatment of NAFLD. In an attempt to screen FXR agonists, we found that cycloastragenol (CAG), a natural occurring compound in Astragali Radix, stimulated FXR transcription activity. In animal studies, we demonstrated that CAG treatment resulted in obvious reduction of high-fat diet induced lipid accumulation in liver accompanied by lowered blood glucose, serum triglyceride levels and hepatic bile acid pool size. The stimulation of FXR signalling by CAG treatment in DIO mice was confirmed via gene expression and western blot analysis. Molecular docking data further supported the interaction of CAG and FXR. In addition, CAG alleviated hepatic steatosis in methionine and choline deficient L-amino acid diet (MCD) induced non-alcoholic steatohepatitis (NASH) mice. Our data suggest that CAG ameliorates NAFLD via the enhancement of FXR signalling.
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      PubDate: 2017-04-26T11:43:45Z
      DOI: 10.1016/j.phrs.2017.04.021
      Issue No: Vol. 121 (2017)
       
  • p300 and C/EBPβ-regulated IKKβ expression are involved in
           thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells
    • Authors: Zheng-Wei Huang; Gi-Shih Lien; Chien-Huang Lin; Chun-Ping Jiang; Bing-Chang Chen
      Pages: 33 - 41
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Zheng-Wei Huang, Gi-Shih Lien, Chien-Huang Lin, Chun-Ping Jiang, Bing-Chang Chen
      Asthma and chronic obstructive pulmonary disease (COPD) are common chronic lung inflammatory diseases. Thrombin and interleukin (IL)-8/C-X-C chemokine ligand 8 (CXCL8) play critical roles in lung inflammation. Our previous study showed that c-Src-dependent IκB kinase (IKK)/IκBα/nuclear factor (NF)-κB and mitogen-activated protein kinase kinase kinase 1 (MEKK1)/extracellular signal-regulated kinase (ERK)/ribosomal S6 protein kinase (RSK)-dependent CAAT/enhancer-binding protein β (C/EBPβ) activation are involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells. In this study, we aimed to investigate the roles of p300 and C/EBPβ-reliant IKKβ expression in thrombin-induced IL-8/CXCL8 expression. Thrombin-induced increases in IL-8/CXCL8-luciferase activity and IL-8/CXCL8 release were inhibited by p300 small interfering (siRNA). Thrombin-caused histone H3 acetylation was attenuated by p300 siRNA. Stimulation of cells with thrombin for 12h resulted in increases in IKKβ expression and phosphorylation in human lung epithelial cells. However, thrombin did not affect p65 expression. Moreover, 12h of thrombin stimulation produced increases in IKKβ expression and phosphorylation, and IκBα phosphorylation, which were inhibited by C/EBPβ siRNA. Finally, treatment of cells with thrombin caused increases in p300 and C/EBPβ complex formation, p65 and C/EBPβ complex formation, and recruitment of p300, p65, and C/EBPβ to the IL-8/CXCL8 promoter. These results imply that p300-dependent histone H3 acetylation and C/EBPβ-regulated IKKβ expression contribute to thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells. Results of this study will help clarify C/EBPβ signaling pathways involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells.
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      PubDate: 2017-04-26T11:43:45Z
      DOI: 10.1016/j.phrs.2017.04.020
      Issue No: Vol. 121 (2017)
       
  • Glucocorticoids activate a synapse weakening pathway culminating in tau
           phosphorylation in the hippocampus
    • Authors: Jee Hyun Yi; Christopher Brown; Garry Whitehead; Thomas Piers; Young Seok Lee; Celia Martinez Perez; Philip Regan; Daniel J. Whitcomb; Kwangwook Cho
      Pages: 42 - 51
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Jee Hyun Yi, Christopher Brown, Garry Whitehead, Thomas Piers, Young Seok Lee, Celia Martinez Perez, Philip Regan, Daniel J. Whitcomb, Kwangwook Cho
      Evidence suggests that the stress hormones glucocorticoids (GCs) can cause cognitive deficits and neurodegeneration. Previous studies have found GCs facilitate physiological synapse weakening, termed long-term depression (LTD), though the precise mechanisms underlying this are poorly understood. Here we show that GCs activate glycogen synthase kinase-3 (GSK-3), a kinase crucial to synapse weakening signals. Critically, this ultimately leads to phosphorylation of the microtubule associated protein tau, specifically at the serine 396 residue, and this is a causal factor in the GC-mediated impairment of synaptic function. These findings reveal the link between GCs and synapse weakening signals, and the potential for stress-induced priming of neurodegeneration. This could have important implications for our understanding of how stress can lead to neurodegenerative disease.
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      PubDate: 2017-05-03T12:03:35Z
      DOI: 10.1016/j.phrs.2017.04.015
      Issue No: Vol. 121 (2017)
       
  • Epigenetics: The third pillar of nitric oxide signaling
    • Authors: Samantha Socco; Rhea C. Bovee; Marianne B. Palczewski; Jason R. Hickok; Douglas D. Thomas
      Pages: 52 - 58
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Samantha Socco, Rhea C. Bovee, Marianne B. Palczewski, Jason R. Hickok, Douglas D. Thomas
      Nitric oxide (NO), the endogenously produced free radical signaling molecule, is generally thought to function via its interactions with heme-containing proteins, such as soluble guanylyl cyclase (sGC), or by the formation of protein adducts containing nitrogen oxide functional groups (such as S-nitrosothiols, 3-nitrotyrosine, and dinitrosyliron complexes). These two types of interactions result in a multitude of down-stream effects that regulate numerous functions in physiology and disease. Of the numerous purported NO signaling mechanisms, epigenetic regulation has gained considerable interest in recent years. There is now abundant experimental evidence to establish NO as an endogenous epigenetic regulator of gene expression and cell phenotype. Nitric oxide has been shown to influence key aspects of epigenetic regulation that include histone posttranslational modifications, DNA methylation, and microRNA levels. Studies across disease states have observed NO-mediated regulation of epigenetic protein expression and enzymatic activity resulting in remodeling of the epigenetic landscape to ultimately influence gene expression. In addition to the well-established pathways of NO signaling, epigenetic mechanisms may provide much-needed explanations for poorly understood context-specific effects of NO. These findings provide more insight into the molecular mechanisms of NO signaling and increase our ability to dissect its functional role(s) in specific micro-environments in health and disease. This review will summarize the current state of NO signaling via epigenetic mechanisms (the “third pillar” of NO signaling).
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      PubDate: 2017-05-03T12:03:35Z
      DOI: 10.1016/j.phrs.2017.04.011
      Issue No: Vol. 121 (2017)
       
  • Upregulation of neurotrophins by S 47445, a novel positive allosteric
           modulator of AMPA receptors in aged rats
    • Authors: Francesca Calabrese; Elisa Savino; Elisabeth Mocaer; Sylvie Bretin; Giorgio Racagni; Marco A. Riva
      Pages: 59 - 69
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Francesca Calabrese, Elisa Savino, Elisabeth Mocaer, Sylvie Bretin, Giorgio Racagni, Marco A. Riva
      At molecular levels, it has been shown that aging is associated with alterations in neuroplastic mechanisms. In this study, it was examined if the altered expression of neurotrophins observed in aged rats could be corrected by a chronic treatment with S 47445 (1–3–10mg/kg, p.o.), a novel selective positive allosteric modulator of the AMPA receptors. Both the mRNA and the protein levels of the neurotrophins Bdnf, NT-3 and Ngf were specifically measured in the prefrontal cortex and hippocampus (ventral and dorsal) of aged rats. It was found that 2-week-treatment with S 47445 corrected the age-related deficits of these neurotrophins and/or positively modulated their expression in comparison to vehicle aged rats in the range of procognitive and antidepressant active doses in rodents. Collectively, the ability of S 47445 to modulate various neurotrophins demonstrated its neurotrophic properties in two major brain structures involved in cognition and mood regulation suggesting its therapeutic potential for improving several diseases such as Alzheimer’s disease and/or Major Depressive Disorders.
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      PubDate: 2017-05-03T12:03:35Z
      DOI: 10.1016/j.phrs.2017.04.019
      Issue No: Vol. 121 (2017)
       
  • Patchouli alcohol ameliorates dextran sodium sulfate-induced experimental
           colitis and suppresses tryptophan catabolism
    • Authors: Chang Qu; Zhong-Wen Yuan; Xiu-Ting Yu; Yan-Feng Huang; Guang-Hua Yang; Jian-Nan Chen; Xiao-Ping Lai; Zi-Ren Su; Hui-Fang Zeng; Ying Xie; Xiao-Jun Zhang
      Pages: 70 - 82
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Chang Qu, Zhong-Wen Yuan, Xiu-Ting Yu, Yan-Feng Huang, Guang-Hua Yang, Jian-Nan Chen, Xiao-Ping Lai, Zi-Ren Su, Hui-Fang Zeng, Ying Xie, Xiao-Jun Zhang
      Despite the increased morbidity of ulcerative colitis (UC) in recent years, available treatments remain unsatisfactory. Pogostemon cablin has been widely applied to treat a variety of gastrointestinal disorders in clinic for centuries, in which patchouli alcohol (PA, C15H26O) has been identified as the major active component. This study attempted to determine the bioactivity of PA on dextran sulfate sodium (DSS)-induced mice colitis and clarify the mechanism of action. Acute colitis was induced in mice by 3% DSS for 7 days. The mice were then given PA (10, 20 and 40mg/kg) or sulfasalazine (SASP, 200mg/kg) as positive control via oral administration for 7 days. At the end of study, animals were sacrificed and samples were collected for pathological and other analysis. In addition, a metabolite profiling and a targeted metabolite analysis, based on the Ultra-Performance Liquid Chromatography coupled with mass spectrometry (UPLC–MS) approach, were performed to characterize the metabolic changes in plasma. The results revealed that PA significantly reduced the disease activity index (DAI) and ameliorated the colonic injury of DSS mice. The levels of colonic MPO and cytokines involving TNF-α, IFN-γ, IL-1β, IL-6, IL-4 and IL-10 also declined. Furthermore, PA improved the intestinal epithelial barrier by enhancing the level of colonic expression of the tight junction (TJ) proteins, for instance ZO-1, ZO-2, claudin-1 and occludin, and by elevating the levels of mucin-1 and mucin-2 mRNA. The study also demonstrated that PA inhibited the DSS-induced cell death signaling by modulating the apoptosis related Bax and Bcl-2 proteins and down-regulating the necroptosis related RIP3 and MLKL proteins. By comparison, up-regulation of IDO-1 and TPH-1 protein expression in DSS group was suppressed by PA, which was in line with the declined levels of kynurenine (Kyn) and 5-hydroxytryptophan (5-HTP) in plasma. The therapeutic effect of PA was evidently reduced when Kyn was given to mice. In summary, the study successfully demonstrated that PA ameliorated DSS-induced mice acute colitis by suppressing inflammation, maintaining the integrity of intestinal epithelial barrier, inhibiting cell death signaling, and suppressing tryptophan catabolism. The results provided valuable information and guidance for using PA in treatment of UC.
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      PubDate: 2017-05-08T12:07:03Z
      DOI: 10.1016/j.phrs.2017.04.017
      Issue No: Vol. 121 (2017)
       
  • Age and sex in drug development and testing for adults
    • Authors: Cara Tannenbaum; Danielle Day
      Pages: 83 - 93
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Cara Tannenbaum, Danielle Day
      Individualization of drug therapy requires that the right drug be administered at the correct dose to patients who are likely to achieve the highest benefit and lowest risk. Female sex and age comprise two important risk factors for altered drug exposure and response. This review summarizes the current state of science for considering age and sex-related factors along the drug development pipeline, from cell culture and animal research through all phases of clinical trials in humans. A set of recommendations is provided to improve standards for integrating age and sex into the study design, analysis, and reporting of pre-clinical and clinical assessment of new molecular entities and biologics in adults.
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      PubDate: 2017-05-08T12:07:03Z
      DOI: 10.1016/j.phrs.2017.04.027
      Issue No: Vol. 121 (2017)
       
  • Deciphering the mechanism of Huang-Lian-Jie-Du-Decoction on the treatment
           of sepsis by formula decomposition and metabolomics: Enhancement of
           cholinergic pathways and inhibition of HMGB-1/TLR4/NF-κB signaling
    • Authors: Dingqiao Xu; Yan Lv; Junsong Wang; Minghua Yang; Lingyi Kong
      Pages: 94 - 113
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Dingqiao Xu, Yan Lv, Junsong Wang, Minghua Yang, Lingyi Kong
      Sepsis is the major cause of morbidity and mortality in surgical patients. Huang-Lian-Jie-Du-Decoction (HLJDD), a well-known Chinese herb formula, has long been used for the treatment of sepsis. In this investigation, by leaving one herb out each time, the four component herbs of HLJDD were reformulated to four HLJDD variants Form1-4, corresponding to the removal of Phellodendri Chinensis Cortex, Scutellariae Radix, Gardeniae Fructu and Coptidis Rhizoma, respectively. Metabolomics approach combined with histological inspection, biochemical measurement and molecular biology was used to investigate the treatment effects of HLJDD and its four variants on cecal ligation and puncture (CLP) model of sepsis, which were compared to decipher the formulating principles of HLJDD. Our results showed that HLJDD exhibit the strongest therapeutic effects in the CLP models as compared with the four variants, which could be ascribed to its most significant enhancement of cholinergic anti-inflammatory pathway and inhibition of HMGB-1/TLR4/NF-κB signaling pathway. Most of all, metabolites changed specifically between groups of HLJDD and its four variants were related with the exceptional treatment effects of HLJDD.
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      PubDate: 2017-05-08T12:07:03Z
      DOI: 10.1016/j.phrs.2017.04.016
      Issue No: Vol. 121 (2017)
       
  • NSAID-activated gene 1 and its implications for mucosal integrity and
           intervention beyond NSAIDs
    • Authors: Yuseok Moon
      Pages: 122 - 128
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Yuseok Moon
      In spite of the beneficial actions of non-steroid anti-inflammatory drugs (NSAIDs) in epithelial inflammation and cancers, their use is limited because of their cyclooxygenase-dependent or independent gastrointestinal toxicity. As an eicosanoid-independent mediator, NSAID-activated gene 1 (NAG-1) has been assessed for its involvement in cellular integrity and pathogenesis in mucosal inflammation and carcinogenesis. At the cellular levels, NAG-1 is involved in the cell growth regulation (cell death, cell cycle arrest, or proliferation) in epithelial and mesenchymal tissues. Moreover, NAG-1 can modulate inflammatory responses in either direct or indirect manner, which ultimately affects fibrogenic and tumorigenic processes in various disease states. Finally, NAG-1 has been assessed for its contribution to cellular behavior, such as the mobility of epithelial and malignant cells in response to the external insults or oncogenic stimulation in the mucosa. This review on the “Yin-Yang” nature of NAG-1-mediated responses provides comprehensive insights into therapeutic and diagnostic interventions for mucosal health and integrity in the human body.
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      PubDate: 2017-05-08T12:07:03Z
      DOI: 10.1016/j.phrs.2017.04.023
      Issue No: Vol. 121 (2017)
       
  • Neurotrophin receptors in the pathogenesis, diagnosis and therapy of
           neurodegenerative diseases
    • Authors: Jacopo Meldolesi
      Pages: 129 - 137
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Jacopo Meldolesi
      In the last few years, exciting properties have emerged regarding the activation, signaling, mechanisms of action, and therapeutic targeting of the two types of neurotrophin receptors: the p75NTR with its intracellular and extracellular peptides, the Trks, their precursors and their complexes. This review summarizes these new developments, with particular focus on neurodegenerative diseases. Based on the evolving knowledge, innovative concepts have been formulated regarding the pathogenesis of these diseases, especially the Alzheimer’s and two other, the Parkinson’s and Huntington’s diseases. The medical progresses include original procedures of diagnosis, started from studies in mice and now investigated for human application, based on innovative classes of receptor agonists and blockers. In parallel, comprehensive studies have been and are being carried out for the development of drugs. The relevance of these studies is based on the limitations of the therapies employed until recently, especially for the treatment of Alzheimer’s patients. Starting from well known drugs, previously employed for non-neurodegenerative diseases, the ongoing progress has lead to the development of small molecules that cross rapidly the blood-brain barrier. Among these molecules the most promising are specific blockers of the p75NTR receptor. Additional drugs, that activate Trk receptors, were shown effective against synaptic loss and memory deficits. In the near future such approaches, coordinated with treatments with monoclonal antibodies and with developments in the microRNA field, are expected to improve the therapy of neurodegenerative diseases, and may be relevant also for other human disease conditions.
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      PubDate: 2017-05-13T12:10:08Z
      DOI: 10.1016/j.phrs.2017.04.024
      Issue No: Vol. 121 (2017)
       
  • Towards therapeutic drug monitoring of everolimus in cancer? Results of an
           exploratory study of exposure-effect relationship
    • Authors: Marine Deppenweiler; Sabrina Falkowski; Franck Saint-Marcoux; Caroline Monchaud; Nicolas Picard; Marie-Laure Laroche; Nicole Tubiana-Mathieu; Laurence Venat-Bouvet; Pierre Marquet; Jean-Baptiste Woillard
      Pages: 138 - 144
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Marine Deppenweiler, Sabrina Falkowski, Franck Saint-Marcoux, Caroline Monchaud, Nicolas Picard, Marie-Laure Laroche, Nicole Tubiana-Mathieu, Laurence Venat-Bouvet, Pierre Marquet, Jean-Baptiste Woillard
      Introduction Therapeutic drug monitoring (TDM) of everolimus is not performed in oncology and no trough level (C0) target has been yet defined. The aim of this study was to determine everolimus C0 target for toxicity and efficacy. Materials and methods Clinical, biological and radiologic data from 54 patients were collected. Toxicity event was defined by termination, temporary interruption and/or dose reduction of everolimus while efficacy was defined as progression-free survival. C0 values were dichotomized by ROC curve analysis and the association between exposure and outcome was determined using Cox models for repeated events (toxicity) or Cox model censured at the first event (progression free survival). Results Among the 42 patients (77.8%) with breast cancer, 10 (18.5%) kidney cancer and 2 (3.7%) neuroendocrine cancer, adverse events were reported in 75.9% of the patients (everolimus termination in 25.9% patients). C0 everolimus higher than 26.3ng/mL (Sen=0.38,Spe=0.88) were associated with a 4-fold increased risk of toxicity (HR=4.12, IC95%=[1.48–11.5], p=0.0067) whereas C0 lower than 11.9ng/mL were associated with a 3-fold increased risk of progression (HR=3.2, IC95%=[1.33–7.81],p=0.001). Discussion Further studies are required to evaluate the everolimus C0 threshold proposed for toxicity (26.3ng/mL) and for progression (11.9ng/mL) especially with a large number of patients and more homogeneous types of cancer. However, these results are in favour of TDM for everolimus in oncology.
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      PubDate: 2017-05-13T12:10:08Z
      DOI: 10.1016/j.phrs.2017.04.029
      Issue No: Vol. 121 (2017)
       
  • Metabotropic glutamate receptor 5 mediates the suppressive effect of
           6-OHDA-induced model of Parkinson’s disease on liver cancer
    • Authors: Shao-Song Xi; Xiao-Xu Bai; Li Gu; Li-Hui Bao; Hui-Min Yang; Wei An; Xiao-Min Wang; Hong Zhang
      Pages: 145 - 157
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Shao-Song Xi, Xiao-Xu Bai, Li Gu, Li-Hui Bao, Hui-Min Yang, Wei An, Xiao-Min Wang, Hong Zhang
      Numerous epidemiological studies suggested that there is a variable cancer risk in patients with Parkinson’s disease (PD). However, the underlying mechanisms remain unclear. In the present study, the role of metabotropic glutamate receptor 5 (mGluR5) has been investigated in 6-hydroxydopamine (6-OHDA)-induced PD combined with liver cancer both in vitro and in vivo. We found that PD cellular model from 6-OHDA-lesioned MN9D cells suppressed the growth, migration, and invasion of Hepa1-6 cells via down-regulation of mGluR5-mediated ERK and Akt pathway. The application of 2-methyl-6-(phenylethyl)-pyridine and knockdown of mGluR5 further decreased the effect on Hepa-1-6 cells when co-cultured with conditioned media. The effect was increased by (S)-3,5-dihydroxyphenylglycine and overexpression of mGluR5. Moreover, more release of glutamate from 6-OHDA-lesioned MN9D cells suppressed mGluR5-mediated effect of Hepa1-6 cells. Application of riluzole eliminated the increased glutamate release induced by 6-OHDA in MN9D cells and aggravated the suppressive effect on Hepa-1-6 cells. In addition, the growth of implanted liver cancer was inhibited in 6-OHDA induced PD-like rats, and was associated with increased glutamate release in the serum and down-regulation of mGluR5 in tumor tissue. Collectively, these results indicate that selective antagonism of glutamate and mGluR5 has a potentially beneficial effect in both liver cancer and PD, and thus may provide more understanding for the clinical investigation and further an additional therapeutic target for these two diseases.
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      PubDate: 2017-05-13T12:10:08Z
      DOI: 10.1016/j.phrs.2017.04.026
      Issue No: Vol. 121 (2017)
       
  • The acitretin and methotrexate combination therapy for psoriasis vulgaris
           achieves higher effectiveness and less liver fibrosis
    • Authors: Jingang An; Dingwei Zhang; Jiawen Wu; Jiong Li; Xiu Teng; Xiaomin Gao; Ruilian Li; Xiuying Wang; Linlin Xia; Yumin Xia
      Pages: 158 - 168
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Jingang An, Dingwei Zhang, Jiawen Wu, Jiong Li, Xiu Teng, Xiaomin Gao, Ruilian Li, Xiuying Wang, Linlin Xia, Yumin Xia
      Both acitretin and methotrexate are effective in ameliorating psoriatic lesion. However, their combination has been seldom reported in the treatment of psoriasis because of the warning regarding the potential hepatotoxicity of the drug interactions. This study was designed to investigate the effectiveness of such combination therapy for psoriasis vulgaris, and the potential benefit as well as side effect during the treatment. Thirty-nine patients with psoriasis vulgaris were treated with acitretin, methotrexate or their combination or as control. Similarly, K14-VEGF transgenic psoriasis-like mice were treated with these drugs. Human primary keratinocytes and hepatic stellate cells were used for analyzing their effect in vitro. The results showed that the combination therapy exhibited higher effectiveness in remitting skin lesion, but did not significantly affect the liver function of both patients and mice. Moreover, the combination groups showed less elevation of profibrotic factors in sera when compared with methotrexate alone groups accordingly. Furthermore, primary keratinocytes expressed more involucrin as well as loricrin and proliferated more slowly on the combined stimulation. Interestingly, such combination treatment induced lower expression of profibrotic factors in hepatic stellate cells. In conclusion, the acitretin-methotrexate combination therapy for psoriasis vulgaris can achieve higher effectiveness and result in less liver fibrosis.
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      PubDate: 2017-05-18T05:10:58Z
      DOI: 10.1016/j.phrs.2017.04.014
      Issue No: Vol. 121 (2017)
       
  • Suppression of ABCG2 mediated MDR in vitro and in vivo by a novel
           inhibitor of ABCG2 drug transport
    • Authors: Atish Patel; Tian-Wen Li; Nagaraju Anreddy; De-Shen Wang; Kamlesh Sodani; Sanket Gadhia; Rishil Kathawala; Dong-Hua Yang; Changmei Cheng; Zhe-Sheng Chen
      Pages: 184 - 193
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Atish Patel, Tian-Wen Li, Nagaraju Anreddy, De-Shen Wang, Kamlesh Sodani, Sanket Gadhia, Rishil Kathawala, Dong-Hua Yang, Changmei Cheng, Zhe-Sheng Chen
      Cancer is a disease whose treatment is often limited due to the development of a phenomenon known as multidrug resistance (MDR). There is an immense demand for development of novel agents that can overcome the MDR in cancer. A group of transmembrane proteins called ATP-binding cassette transporters, present ubiquitously in the human body possesses a modular architecture, contributing immensely towards the development of MDR. An analysis of structural congeners among a group of compounds led to the discovery of CCTA-1523 that could selectively reverse ABCG2-mediated MDR in cancer cells in vitro and in vivo. CCTA-1523 (5μM) sensitized the ABCG2 overexpressing cancer cells and ABCG2 transfected cells to the substrate chemotherapeutic drugs. The reversal ability of CCTA-1523 was primarily due to the inhibition of the efflux function of ABCG2; also there was no change in the protein expression or the localization of the ABCG2 in the presence of CCTA-1523. The reversal effect of CCTA-1523 was reversible. Importantly, co-administration of CCTA-1523 restored the in vivo antitumor activity of doxorubicin in ABCG2 overexpressing tumor xenografts. Taken together, our findings indicate that CCTA-1523 is a potent, selective and reversible modulator of ABCG2 that may offer therapeutic promise for multidrug- resistant malignancies.
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      PubDate: 2017-05-13T12:10:08Z
      DOI: 10.1016/j.phrs.2017.04.025
      Issue No: Vol. 121 (2017)
       
  • Outer membrane vesicles extracted from Neisseria meningitidis serogroup X
           for prevention of meningococcal disease in Africa
    • Authors: Reinaldo Acevedo; Caridad Zayas; Gunnstein Norheim; Sonsire Fernández; Barbara Cedré; Yisabel Aranguren; Maribel Cuello; Yaimara Rodriguez; Humberto González; Aleida Mandiarote; Marylin Pérez; Maritza Hernández; Mabel Hernández-Cedeño; Domingo González; Sverre-Henning Brorson; Einar Rosenqvist; Lisbeth Naess; Gro Tunheim; Daniel Cardoso; Luis García
      Pages: 194 - 201
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Reinaldo Acevedo, Caridad Zayas, Gunnstein Norheim, Sonsire Fernández, Barbara Cedré, Yisabel Aranguren, Maribel Cuello, Yaimara Rodriguez, Humberto González, Aleida Mandiarote, Marylin Pérez, Maritza Hernández, Mabel Hernández-Cedeño, Domingo González, Sverre-Henning Brorson, Einar Rosenqvist, Lisbeth Naess, Gro Tunheim, Daniel Cardoso, Luis García
      Meningococcal disease is caused mainly by serogroups A, B, C, Y, W of N. meningitidis. However, numerous cases of meningitis caused by serogroup X N. meningitidis (MenX) have recently been reported in several African countries. Currently, there are no licensed vaccines against this pathogen and most of the MenX cases have been caused by meningococci from clonal complex (c.c) 181. Detergent extracted meningococcal outer membrane vesicle (dOMV) vaccines have previously shown to be safe and effective against epidemics of serogroup B meningococcal disease in all age groups. The aim of this work is therefore to obtain, characterize and evaluate the vaccine potential of dOMVs derived from a MenX strain (OMVx). Three experimental lots of OMVx were prepared by deoxycholate extraction from the MenX strain BF 2/97. Size and morphology of the vesicles was determined by Dynamic Light Scattering and electron microscopy, whereas the antigenic composition was characterized by gel electrophoresis and immunoblotting. OMVx were thereafter adsorbed to aluminium hydroxide (OMVx/AL) and two doses of OMVx were administered s.c. to groups of Balb/c mice three weeks apart. The immunogenicity and functional antibody activities in sera were evaluated by ELISA (anti-OMVx specific IgG responses) and serum bactericidal activity (SBA) assay. The size range of OMVx was shown to be between 90 and 120nm, whereas some of the antigens detected were the outer membrane proteins PorA, OpcA and RmpM. The OMVx/AL elicited high anti-OMVx antibody responses with bactericidal activity and no bactericidal activity was observed in the control group of no immunised mice. The results demonstrate that OMVx are immunogenic and could form part of a future vaccine to prevent the majority of meningococcal disease in the African meningitis belt.
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      PubDate: 2017-05-18T05:10:58Z
      DOI: 10.1016/j.phrs.2017.04.030
      Issue No: Vol. 121 (2017)
       
  • Genomics of hypertension
    • Authors: Sandosh Padmanabhan; Alisha Aman; Anna F. Dominiczak
      Pages: 219 - 229
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Sandosh Padmanabhan, Alisha Aman, Anna F. Dominiczak
      A complex network of interacting pathways involving renal, neural, endocrine, vascular and other mechanisms controls the main determinants of blood pressure – cardiac output and total peripheral resistance. Multiple genes within each of these systems contribute to the specialized functions regulating blood pressure. The monogenic forms of blood pressure dysregulation have provided valuable insights into blood pressure regulation and expanded our understanding of both the mechanisms and the treatment of hypertension. Genome wide association studies have identified over 100 single nucleotide polymorphisms associated with blood pressure phenotypes and have identified plausible novel pathways of BP regulation and putative drug targets.

      PubDate: 2017-05-18T05:10:58Z
      DOI: 10.1016/j.phrs.2017.04.031
      Issue No: Vol. 121 (2017)
       
  • Sulfuretin has therapeutic activity against acquired lymphedema by
           reducing adipogenesis
    • Authors: Kangsan Roh; Suji Kim; Hee Kang; Jin-Mo Ku; Kye Won Park; Sukchan Lee
      Pages: 230 - 239
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Kangsan Roh, Suji Kim, Hee Kang, Jin-Mo Ku, Kye Won Park, Sukchan Lee
      Acquired lymphedema is a pathological condition associated with lymphatic dysfunction caused by surgical treatments for cancer. Although global estimates of the prevalence of acquired lymphedema have been rising, there are currently no effective therapeutics available. Since adipose tissue accumulation is a clinical hallmark of lymphedema, we hypothesized that regulation of adipogenesis in lymphedematous tissue could be used as a therapeutic intervention against lymphedema. Toward this, we investigated the possibility of anti-adipogenic 30% ethanol Rhus verniciflua Stokes (RVS) extract as a potential lymphedema treatment. Oral administration of RVS extract ameliorated volumetric symptoms of lymphedema in a mouse model. RVS administration also reduced adipose tissue accumulation in lymphedematous tissue and downregulated expression of adipocyte markers, including Pparγ and Fabp4. Sulfuretin was identified as a major bioactive compound in the 30% ethanol RVS extract in liquid chromatography-mass spectrometry analysis. Similar to the activities of RVS, sulfuretin inhibited adipocyte differentiation in 3T3-L1 preadipocytes. Moreover, treatment with sulfuretin on lymphedema-induced mice reduced lymphedema volume, decreased the expression of adipogenic markers, but induced the expression of markers associated with lymphangiogenesis. Taken together, our data raise the possibility that sulfuretin might be used in therapeutic interventions against acquired lymphedema.
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      PubDate: 2017-05-23T05:18:51Z
      DOI: 10.1016/j.phrs.2017.05.003
      Issue No: Vol. 121 (2017)
       
  • From head to toe: Sex and gender differences in the treatment of ischemic
           cerebral disease
    • Authors: Lorenzo Falsetti; Giovanna Viticchi; Laura Buratti; Clotilde Balucani; Alberto M. Marra; Mauro Silvestrini
      Pages: 240 - 250
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Lorenzo Falsetti, Giovanna Viticchi, Laura Buratti, Clotilde Balucani, Alberto M. Marra, Mauro Silvestrini
      Stroke is a major cause of mortality and morbidity, particularly in the older ages. Women have a longer life expectancy and are more likely to experience stroke than men. Interestingly, the increased risk of ischemic stroke in women seems to be independent from age or classical cardiovascular risk factors. Notwithstanding the fact that stroke outcomes and survival are usually poorer in women, current evidence suggests that thrombolysis, antiplatelet and anticoagulant therapies are more beneficial in women than in men. A possible explanation of this paradox might be that females are often undertreated and they have fewer chances to be submitted to an effective and timely treatment for stroke than the male counterpart. The first step in the attempt to solve this obvious discrimination is surely to emphasize any reasons for differences in the therapeutic approach in relation to gender and then to denounce the lack of a sustainable motivation for them. In this article, we aimed to review the existing literature about gender-related differences on efficacy, administration and side effects of the most common drugs used for the treatment of ischemic stroke. The most striking result was the evidence that the therapeutic approach for stroke is often different according to patients’ gender with a clear detrimental prognostic effect for women. A major effort is necessary to overcome this problem in order to ensure equal right to treatment without any sexual discrimination.
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      PubDate: 2017-05-23T05:18:51Z
      DOI: 10.1016/j.phrs.2017.05.006
      Issue No: Vol. 121 (2017)
       
  • P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to
           norbuprenorphine—Significance of zeitgeber time on pharmacokinetics
    • Authors: Ranjeet Prasad Dash; Rana Rais
      Pages: 251 - 252
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Ranjeet Prasad Dash, Rana Rais


      PubDate: 2017-06-12T07:41:06Z
      DOI: 10.1016/j.phrs.2017.04.004
      Issue No: Vol. 121 (2017)
       
  • P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to
           norbuprenorphine—Response to ‘Letter to the Editor’
    • Authors: Michael Z. Liao; Danny D. Shen; Qingcheng Mao
      First page: 253
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Michael Z. Liao, Danny D. Shen, Qingcheng Mao


      PubDate: 2017-06-12T07:41:06Z
      DOI: 10.1016/j.phrs.2017.04.007
      Issue No: Vol. 121 (2017)
       
  • Retraction notice to “Clinical significance of ITPA rs67002563
           polymorphism in patients with acute lymphoblastic leukemia treated with
           6-mercaptopurine” [Pharmacol. Res. (2015) 61–62]
    • Authors: Fatemeh Azimi; Abdolreza Esmaeilzadeh; Ali Ramazani
      First page: 254
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Fatemeh Azimi, Abdolreza Esmaeilzadeh, Ali Ramazani


      PubDate: 2017-06-12T07:41:06Z
      DOI: 10.1016/j.phrs.2017.05.026
      Issue No: Vol. 121 (2017)
       
  • Retraction notice to “Evaluation of the positive effects on
           insulin-resistance and β-cell measurements of vildagliptin in addition to
           metformin in type 2 diabetic patients” [Pharmacol. Res. 73 (2013)
           20–26]
    • Authors: Giuseppe Derosa; Pietro D. Ragonesi; Anna Carbone; Elena Fogari; Angela D’Angelo; Arrigo F.G. Cicero; Pamela Maffioli
      First page: 255
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Giuseppe Derosa, Pietro D. Ragonesi, Anna Carbone, Elena Fogari, Angela D’Angelo, Arrigo F.G. Cicero, Pamela Maffioli


      PubDate: 2017-06-12T07:41:06Z
      DOI: 10.1016/j.phrs.2017.05.027
      Issue No: Vol. 121 (2017)
       
  • Drug Delivery to Melanoma Brain Metastases: Can Current Challenges Lead to
           New Opportunities'
    • Authors: Gautham Gampa; Shruthi Vaidhyanathan; Jann N. Sarkaria; William F. Elmquist
      Abstract: Publication date: Available online 17 June 2017
      Source:Pharmacological Research
      Author(s): Gautham Gampa, Shruthi Vaidhyanathan, Jann N. Sarkaria, William F. Elmquist
      Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease. While these studies are encouraging, there remains significant room for improvement in the treatment of MBM, given the lack of durable response and the development of resistance to current therapies. Critical questions remain regarding mechanisms that lead to this lack of durable response and development of resistance, and how those mechanisms may differ in systemic sites versus brain metastases. One issue that may not be fully appreciated is that the delivery of several small molecule molecularly-targeted therapies to the brain is often restricted due to active efflux at the blood-brain barrier (BBB) interface. Inadequate local drug concentrations may be partially responsible for the development of unique patterns of resistance at metastatic sites in the brain. It is clear that there can be local, heterogeneous BBB breakdown in MBM, as exemplified by contrast-enhancement on T1-weighted MR imaging. However, it is possible that the successful treatment of MBM with small molecule targeted therapies will depend, in part, on the ability of these therapies to penetrate an intact BBB and reach the protected micro-metastases (so called “sub-clinical” disease) that escape early detection by contrast-enhanced MRI, as well as regions of tumor within MRI-detectable metastases that may have a less compromised BBB. The emergence of resistance in MBM may be related to several diverse, yet interrelated, factors including the distinct microenvironment of the brain and inadequate brain penetration of targeted therapies to specific regions of tumor. The tumor microenvironment has been ascribed to play a key role in steering the course of disease progression, by dictating changes in expression of tumor drivers and resistance-related signaling mechanisms. Therefore, a key issue to consider is how changes in drug delivery, and hence local drug concentrations within a metastatic microenvironment, will influence the development of resistance. Herein we discuss our perspective on several critical questions that focus on many aspects relevant to the treatment of melanoma brain metastases; the answers to which may lead to important advances in the treatment of this devastating disease.
      Graphical abstract image

      PubDate: 2017-06-22T08:20:45Z
      DOI: 10.1016/j.phrs.2017.06.008
       
  • Interactions between microRNAs and long non-coding RNAs in cardiac
           development and repair
    • Authors: Alessio Rotini; Ester Martínez-Sarrà; Enrico Pozzo; Maurilio Sampaolesi
      Abstract: Publication date: Available online 17 June 2017
      Source:Pharmacological Research
      Author(s): Alessio Rotini, Ester Martínez-Sarrà, Enrico Pozzo, Maurilio Sampaolesi
      Non-coding RNAs (ncRNAs) are emerging players in muscle regulation. Based on their length and differences in molecular structure, ncRNAs are subdivided into several categories including small interfering RNAs, stable non-coding RNAs, microRNAs (miRs), long non-coding RNAs (lncRNAs), and circular RNAs. miRs and lncRNAs are able to post-transcriptionally regulate many genes and bring into play several traits simultaneously due to a myriad of different targets. Recent studies have emphasized their importance in cardiac regeneration and repair. As their altered expression affects cardiac function, miRs and lncRNAs could be potential targets for therapeutic intervention. In this context, miR- and lncRNA-based gene therapies are an interesting field for harnessing the complexity of ncRNA-based therapeutic approaches in cardiac diseases. In this review we will focus on lncRNA- and miR-driven regulations of cardiac development and repair. Finally, we will summarize miRs and lncRNAs as promising candidates for the treatment of heart diseases.
      Graphical abstract image

      PubDate: 2017-06-22T08:20:45Z
      DOI: 10.1016/j.phrs.2017.05.029
       
  • Distinct characteristics of neonatal platelet reactivity
    • Authors: Belay Tesfamariam
      Abstract: Publication date: Available online 15 June 2017
      Source:Pharmacological Research
      Author(s): Belay Tesfamariam
      Platelets undergo a process of developmental maturation, and hence its regulation of vascular integrity and control of hemostasis at various stages of neonatal ages deserves better characterization. Functional assays for platelets require a larger volume of blood than what is feasible to collect in neonates, creating a technical hurdle that has been a challenge to investigate neonatal platelets. For this reason, the current knowledge of neonatal platelet function has been based on studies from cord blood-derived platelets as a surrogate for neonatal peripheral blood. Studies indicate that neonatal platelets are hypofunctional to various agonists, although neonates tend to maintain normal hemostasis. This apparently paradoxical finding may be due to several factors, such as elevated functionally potent von Willebrand factor multimers or hematocrit levels, in the neonatal blood that enhance the platelet and vessel wall interaction, and counteract platelet hyporeactivity. This review describes the functional characteristics of neonatal platelets, differences in platelet reactivity between neonates and adults, and potential biomarkers of platelet activation.
      Graphical abstract image

      PubDate: 2017-06-17T08:01:54Z
      DOI: 10.1016/j.phrs.2017.06.003
       
  • Chasing c-Kit through the heart: taking a broader view
    • Authors: Natalie A. Gude; Mark A. Sussman
      Abstract: Publication date: Available online 13 June 2017
      Source:Pharmacological Research
      Author(s): Natalie A. Gude, Mark A. Sussman
      Graphical abstract image

      PubDate: 2017-06-17T08:01:54Z
      DOI: 10.1016/j.phrs.2017.06.007
       
  • The vasoprotective axes of the renin-angiotensin system: physiological
           relevance and therapeutic implications in cardiovascular, hypertensive and
           kidney diseases
    • Authors: Xiao C. Li; Jianfeng Zhang; Jia L. Zhuo
      Abstract: Publication date: Available online 12 June 2017
      Source:Pharmacological Research
      Author(s): Xiao C. Li, Jianfeng Zhang, Jia L. Zhuo
      The renin-angiotensin system (RAS) is undisputedly one of the most prominent endocrine (tissue-to-tissue), paracrine (cell-to-cell) and intracrine (intracellular/nuclear) vasoactive systems in the physiological regulation of neural, cardiovascular, blood pressure, and kidney function. The importance of the RAS in the development and pathogenesis of cardiovascular, hypertensive and kidney diseases has now been firmly established in clinical trials and practice using renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, type 1 (AT1) angiotensin II (ANG II) receptor blockers (ARBs), or aldosterone receptor antagonists as major therapeutic drugs. The major mechanisms of actions for these RAS inhibitors or receptor blockers are mediated primarily by blocking the detrimental effects of the classic angiotensinogen/renin/ACE/ANG II/AT1/aldosterone axis. However, the RAS has expanded from this classic axis to include several other complex biochemical and physiological axes, which are derived from the metabolism of this classic axis. Currently, at least five axes of the RAS have been described, with each having its key substrate, enzyme, effector peptide, receptor, and/or downstream signaling pathways. These include the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor, the ANG II/APA/ANG III/AT2/NO/cGMP, the ANG I/ANG II/ACE2/ANG (1-7)/Mas receptor, the prorenin/renin/prorenin receptor (PRR or Atp6ap2)/MAP kinases ERK1/2/V-ATPase, and the ANG III/APN/ANG IV/IRAP/AT4 receptor axes. Since the roles and therapeutic implications of the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor axis have been extensively reviewed, this article will focus primarily on reviewing the roles and therapeutic implications of the vasoprotective axes of the RAS in cardiovascular, hypertensive and kidney diseases.
      Graphical abstract image

      PubDate: 2017-06-17T08:01:54Z
      DOI: 10.1016/j.phrs.2017.06.005
       
  • Effectiveness of heart rate control on hemodynamics in critically ill
           patients with atrial tachyarrhythmias managed by amiodarone
    • Authors: Joe-Elie Salem; Pauline Dureau; Christian Funck-Brentano; Jean-Sébastien Hulot; Maria El-Aissaoui; Nadia Aissaoui; Saik Urien; Christophe Faisy
      Abstract: Publication date: Available online 10 June 2017
      Source:Pharmacological Research
      Author(s): Joe-Elie Salem, Pauline Dureau, Christian Funck-Brentano, Jean-Sébastien Hulot, Maria El-Aissaoui, Nadia Aissaoui, Saik Urien, Christophe Faisy
      Atrial tachyarrhythmias (AT) are common in intensive care unit (ICU) patients and might contribute to hemodynamic instability if heart rate (HR) is persistently too rapid. We aimed to assess if HR control below 115 or 130 bpm with amiodarone improves hemodynamics in ICU patients with AT. This observational study included 73 ICU patients with disabling AT receiving amiodarone for HR control. A total of 525 changes (mainly within 4–8h) in mean arterial pressure (MAP) and 167 changes in plasma lactate in response to HR variations above 115 or 130 bpm were analyzed. Epinephrine, sedative drugs, fluid loading, use of diuretics, continuous renal replacement therapy and amiodarone dosing were among covariables assessed. Univariable analysis showed that HR variations above 115 bpm were poorly correlated to change in MAP (r=0.11, p<0.01). Multivariable analysis showed that changes in MAP were still positively associated to HR variation (p<0.05) and to initiation or termination of epinephrine (p<0.05) or sedatives infusions (p<0.05). Changes in plasma lactate did not correlate to HR variations above 115 bpm. When considering 130 bpm as a threshold, HR variations were not associated to changes in MAP or to changes in plasma lactate. Amiodarone dose was associated to HR decrease but not to MAP or plasma lactate increase. In ICU patients with AT, strict HR control below 115bpm or 130bpm with amiodarone does not improve hemodynamics. A prospective randomized trial assessing strict versus lenient HR control in this setting is needed.
      Graphical abstract image

      PubDate: 2017-06-12T07:41:06Z
      DOI: 10.1016/j.phrs.2017.06.004
       
  • Sulfate, Nitrate and Blood Pressure − An EPIC Interaction between
           Sulfur and Nitrogen
    • Authors: Gunter G. Kuhnle; Robert Luben; Kay-Tee Khaw; Martin Feelisch
      Abstract: Publication date: Available online 10 June 2017
      Source:Pharmacological Research
      Author(s): Gunter G. Kuhnle, Robert Luben, Kay-Tee Khaw, Martin Feelisch
      Nitrate (NO3 −)-rich foods such as green leafy vegetables are not only part of a healthy diet, but increasingly marketed for primary prevention of cardiovascular disease (CVD) and used as ergogenic aids by competitive athletes. While there is abundant evidence for mild hypotensive effects of nitrate on acute application there is limited data on chronic intake in humans, and results from animal studies suggest no long-term benefit. This is important as nitrate can also promote the formation of nitrosamines. It is therefore classified as ‘probably carcinogenic to humans', although a beneficial effect on CVD risk might compensate for an increased cancer risk. Dietary nitrate requires reduction to nitrite (NO2 −) by oral commensal bacteria to contribute to the formation of nitric oxide (NO). The extensive crosstalk between NO and hydrogen sulfide (H2S) related metabolites may further affect nitrate’s bioactivity. Using nitrate and nitrite concentrations of drinking water − the only dietary source continuously monitored for which detailed data exist − in conjunction with data of >14,000 participants of the EPIC-Norfolk study, we found no inverse associations with blood pressure or CVD risk. Instead, we found a strong interaction with sulfate (SO4 2−). At low sulfate concentrations, nitrate was inversely associated with BP (–4mmHg in top quintile) whereas this was reversed at higher concentrations (+3mmHg in top quintile). Our findings have a potentially significant impact for pharmacology, physiology and public health, redirecting our attention from the oral microbiome and mouthwash use to interaction with sulfur-containing dietary constituents. These results also indicate that nitrate bioactivation is more complex than hitherto assumed. The modulation of nitrate bioactivity by sulfate may render dietary lifestyle interventions aimed at increasing nitrate intake ineffective and even reverse potential antihypertensive effects, warranting further investigation.
      Graphical abstract image

      PubDate: 2017-06-12T07:41:06Z
      DOI: 10.1016/j.phrs.2017.06.006
       
  • Granulocyte colony-stimulating factor for the treatment of cardiovascular
           diseases: an update with a critical appraisal
    • Authors: Domenico D’Amario; Antonio Maria Leone; Josip Andjelo Borovac; Francesco Cannata; Andrea Siracusano; Giampaolo Niccoli; Filippo Crea
      Abstract: Publication date: Available online 7 June 2017
      Source:Pharmacological Research
      Author(s): Domenico D’Amario, Antonio Maria Leone, Josip Andjelo Borovac, Francesco Cannata, Andrea Siracusano, Giampaolo Niccoli, Filippo Crea
      Heart failure and acute myocardial infarction are conditions that are associated with high morbidity and mortality. Significant dysfunction of the heart muscle can occur as the consequence of end-stage chronic cardiovascular diseases or acute ischemic events that are marked by large infarction area and significant tissue necrosis. Despite the remarkable improvement of conventional treatments, a substantial proportion of patients still develops severe heart failure that can only be resolved by heart transplantation or mechanical device implantation. Therefore, novel approaches based on stem-cell therapy can directly modify the disease process and alter its prognosis. The ability of the stem-cells to modify and repair the injured myocardium is a challenging but intriguing concept that can potentially replace expensive and invasive methods of treatment that are associated with increased risks and significant financial costs. In that sense, granulocyte colony-stimulating factor (G-CSF) seems as an attractive treatment approach. Based on the series of pre-clinical experiments and a limited amount of clinical data, it was demonstrated that G-CSF agents possess the ability to mobilize stem-cells from bone marrow and induce their differentiation into cardiomyocytes or endothelial cells when brought into contact with injured regions of the myocardium. However, clinical benefits of G-CSF use in damaged myocardium remain unclear and are the topic of expert discussion. The main goal of this review is to present relevant and up-to-date evidence on G-CSF therapy use in pre-clinical models and in humans and to provide a rationale for its potential clinical applications in the future.
      Graphical abstract image

      PubDate: 2017-06-12T07:41:06Z
      DOI: 10.1016/j.phrs.2017.06.001
       
  • Cannabidiol in Medical Marijuana: Research Vistas and Potential
           Opportunities
    • Authors: Carola Rong; Yena Lee; Nicole E. Carmona; Danielle S. Cha; Renee-Marie Ragguett; Joshua D. Rosenblat; Rodrigo B. Mansur; Roger C. Ho; Roger S. McIntyre
      Abstract: Publication date: Available online 10 May 2017
      Source:Pharmacological Research
      Author(s): Carola Rong, Yena Lee, Nicole E. Carmona, Danielle S. Cha, Renee-Marie Ragguett, Joshua D. Rosenblat, Rodrigo B. Mansur, Roger C. Ho, Roger S. McIntyre
      The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects. The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC. Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties. It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD. Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.
      Graphical abstract image

      PubDate: 2017-05-13T12:10:08Z
      DOI: 10.1016/j.phrs.2017.05.005
       
  • UDP-glucuronosyltransferases (UGTs) and their related metabolic cross-talk
           with internal homeostasis: a systematic review of UGT isoforms for
           precision medicine
    • Authors: Na Yang; Runbin Sun; Xiaoying Liao; Jiye Aa; Guangji Wang
      Abstract: Publication date: Available online 4 May 2017
      Source:Pharmacological Research
      Author(s): Na Yang, Runbin Sun, Xiaoying Liao, Jiye Aa, Guangji Wang
      UDP-glucuronosyltransferases (UGTs) are the primary phase II enzymes catalyzing the conjugation of glucuronic acid to the xenobiotics with polar groups for facilitating their clearance. The UGTs belong to a superfamily that consists of diverse isoforms possessing distinct but overlapping metabolic activity. The abnormality or deficiency of UGTs in vivo is highly associated with some diseases, efficacy and toxicity of drugs, and precisely therapeutic personality. Despite the great effects and fruitful results achieved, to date, the expression and functions of individual UGTs have not been well clarified, the inconsistency of UGTs is often observed in human and experimental animals, and the complex regulation factors affecting UGTs have not been systematically summarized. This article gives an overview of updated reports on UGTs involving the various regulatory factors in terms of the genetic, environmental, pathological, and physiological effects on the functioning of individual UGTs, in turn, the dysfunction of UGTs induced disease risk and endo- or xenobiotic metabolism-related toxicity. The complex cross-talk effect of UGTs with internal homeostasis is systematically summarized and discussed in detail, which would be of great importance for personalized precision medicine.
      Graphical abstract image

      PubDate: 2017-05-08T12:07:03Z
      DOI: 10.1016/j.phrs.2017.05.001
       
  • Antidepressants induce autophagy dependent-NLRP3-inflammasome inhibition
           in Major depressive disorder
    • Authors: Elísabet Alcocer-Gómez; Nieves Casas-Barquero; Matthew R. Williams; Samuel L. Romero-Guillena; Diego Cañadas-Lozano; Pedro Bullón; José Antonio Sánchez-Alcazar; José M. Navarro-Pando; Mario D. Cordero
      Abstract: Publication date: Available online 2 May 2017
      Source:Pharmacological Research
      Author(s): Elísabet Alcocer-Gómez, Nieves Casas-Barquero, Matthew R. Williams, Samuel L. Romero-Guillena, Diego Cañadas-Lozano, Pedro Bullón, José Antonio Sánchez-Alcazar, José M. Navarro-Pando, Mario D. Cordero
      Major Depressive Disorder (MDD, ICD-10: F-33) is a prevalent illness in which the pathogenic mechanism remains elusive. Recently an important role has been attributed to neuro-inflammation, and specifically the NLRP3-inflammasome complex, in the pathogenesis of MDD. This suggests a key role for immunomodulation as a key pathway in the treatment of this disorder. This study evaluates the involvement of nine common antidepressants in the NLRP3-inflammasome complex (fluoxetine, paroxetine, mianserin, mirtazapine, venlafaxine, desvenlafaxine, amitriptyline, imipramine and agomelatine), both in in vitro THP-1 cells stimulated by ATP, and in a stress-induced depressive animal or MDD patients. Antidepressant treatment induced inflammasome inhibition was observed by decreased serum levels of IL-1β and IL-18 and decrease of NLRP3 and IL-1β (p17) protein expression. This was also observed under stress-induced depressive behaviour and inflammasome activation in C57Bl/6 mice in vivo. Deletion of key autophagy mediator Atg5 in embryonic fibroblasts (MEF cells) showed an autophagy dependent-NLRP3-inflammasome inhibition by antidepressant treatment. These results suggest the NLRP3-inflammasome could be a biomarker for antidepressant treatment response in MDD patients, and therefore the monitoring of NLRP3 expression levels and/or IL-1β/IL-18 release may have clinical value in drug selection. Existing evidence suggests an anti-inflammatory effect of some antidepressants shown by IL-1β, IL-6 and TNF-α. Our data have shown that antidepressant-mediated autophagy may have a role in restoration of certain metabolic and immunological pathways in MDD patients.
      Graphical abstract image

      PubDate: 2017-05-03T12:03:35Z
      DOI: 10.1016/j.phrs.2017.04.028
       
 
 
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