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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  [3043 journals]
  • Taltirelin alleviates fatigue-like behavior in mouse models of
           cancer-related fatigue
    • Authors: John P. Dougherty; Brian S. Wolff; Mary J. Cullen; Leorey N. Saligan; Marvin C. Gershengorn
      Pages: 1 - 8
      Abstract: Publication date: October 2017
      Source:Pharmacological Research, Volume 124
      Author(s): John P. Dougherty, Brian S. Wolff, Mary J. Cullen, Leorey N. Saligan, Marvin C. Gershengorn
      Fatigue affects most cancer patients and has numerous potential causes, including cancer itself and cancer treatment. Cancer-related fatigue (CRF) is not relieved by rest, can decrease quality of life, and has no FDA-approved therapy. Thyrotropin-releasing hormone (TRH) has been proposed as a potential novel treatment for CRF, but its efficacy against CRF remains largely untested. Thus, we tested the TRH analog, taltirelin (TAL), in mouse models of CRF. To model fatigue, we used a mouse model of chemotherapy, a mouse model of radiation therapy, and mice bearing colon 26 carcinoma tumors. We used the treadmill fatigue test to assess fatigue-like behavior after treatment with TAL. Additionally, we used wild-type and TRH receptor knockout mice to determine which TRH receptor was necessary for the actions of TAL. Tumor-bearing mice displayed muscle wasting and all models caused fatigue-like behavior, with mice running a shorter distance in the treadmill fatigue test than controls. TAL reversed fatigue-like behavior in all three models and the mouse TRH1 receptor was necessary for the effects of TAL. These data suggest that TAL may be useful in alleviating fatigue in all cancer patients and provide further support for evaluating TAL as a potential therapy for CRF in humans.
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      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.012
      Issue No: Vol. 124 (2017)
       
  • Orlistat on plasma lipids and body weight reduction: A really effective
           drug'
    • Authors: Salman Khazaei; Shiva Mansouri Hanis; Kamyar Mansori
      First page: 26
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Salman Khazaei, Shiva Mansouri Hanis, Kamyar Mansori


      PubDate: 2017-07-11T19:26:04Z
      DOI: 10.1016/j.phrs.2017.06.010
      Issue No: Vol. 123 (2017)
       
  • G protein-coupled receptor 35 contributes to mucosal repair in mice via
           migration of colonic epithelial cells
    • Authors: Takuya Tsukahara; Nahla Hamouda; Daichi Utsumi; Kenjiro Matsumoto; Kikuko Amagase; Shinichi Kato
      Pages: 27 - 39
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Takuya Tsukahara, Nahla Hamouda, Daichi Utsumi, Kenjiro Matsumoto, Kikuko Amagase, Shinichi Kato
      G protein-coupled receptor 35 (GPR35), a receptor for lysophosphatidic acid, is highly expressed in the gastrointestinal tract. Recently, GPR35 has been implicated in the onset of inflammatory bowel disease (IBD), but its role in physiological and pathological processes in the colon remains undefined. In this study, we investigated the contribution of GPR35-mediated signalling to mucosal repair of colonic epithelium in IBD. GPR35 function was examined in a wound healing model, using young adult mouse colon epithelium (YAMC) cells, and in a dextran sulphate sodium (DSS)-induced mouse model of colitis. Cell proliferation, mRNA expression, extracellular signal-regulated kinase (ERK) activation, and protein localization were determined by MTT assay, quantitative RT-PCR, western blotting, and immunohistochemistry, respectively. GPR35 agonists (YE120, zaprinast, and pamoic acid) promoted wound repair in a concentration-dependent manner independently of cell proliferation, whereas a specific GPR35 antagonist CID2745687, forskolin, and pertussis toxin reversed the YE120-induced effect. YE120 increased the mRNA expression of fibronectin and its receptor integrin α5, and ERK1/2 phosphorylation, but these responses were attenuated by CID2745687 and forskolin. Furthermore, the severity of DSS-induced colitis was significantly reduced by daily injections of pamoic acid via upregulation of fibronectin and integrin α5 in the colonic epithelium. GPR35 signalling promotes mucosal repair by inducing fibronectin and integrin α5 expression, coupling to Gi protein, and activating ERK1/2 in colonic epithelial cells. These findings define GPR35 as a candidate therapeutic target in IBD.
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      PubDate: 2017-07-11T19:26:04Z
      DOI: 10.1016/j.phrs.2017.06.009
      Issue No: Vol. 123 (2017)
       
  • Current topics in angiotensin II type 1 receptor research: Focus on
           inverse agonism, receptor dimerization and biased agonism
    • Authors: Takanobu Takezako; Hamiyet Unal; Sadashiva S. Karnik; Koichi Node
      Pages: 40 - 50
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Takanobu Takezako, Hamiyet Unal, Sadashiva S. Karnik, Koichi Node
      Although the octapeptide hormone angiotensin II (Ang II) regulates cardiovascular and renal homeostasis through the Ang II type 1 receptor (AT1R), overstimulation of AT1R causes various human diseases, such as hypertension and cardiac hypertrophy. Therefore, AT1R blockers (ARBs) have been widely used as therapeutic drugs for these diseases. Recent basic research and clinical studies have resulted in the discovery of interesting phenomena associated with AT1R function. For example, ligand-independent activation of AT1R by mechanical stress and agonistic autoantibodies, as well as via receptor mutations, has been shown to decrease the inverse agonistic efficacy of ARBs, though the molecular mechanisms of such phenomena had remained elusive until recently. Furthermore, although AT1R is believed to exist as a monomer, recent studies have demonstrated that AT1R can homodimerize and heterodimerize with other G-protein coupled receptors (GPCR), altering the receptor signaling properties. Therefore, formation of both AT1R homodimers and AT1R-GPCR heterodimer may be involved in the pathogenesis of human disease states, such as atherosclerosis and preeclampsia. Finally, biased AT1R ligands that can preferentially activate the β-arrestin-mediated signaling pathway have been discovered. Such β-arrestin-biased AT1R ligands may be better therapeutic drugs for cardiovascular diseases. New findings on AT1R described herein could provide a conceptual framework for application of ARBs in the treatment of diseases, as well as for novel drug development. Since AT1R is an extensively studied member of the GPCR superfamily encoded in the human genome, this review is relevant for understanding the functions of other members of this superfamily.
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      PubDate: 2017-07-11T19:26:04Z
      DOI: 10.1016/j.phrs.2017.06.013
      Issue No: Vol. 123 (2017)
       
  • Carbenoxolone prevents chemical eye ischemia-reperfusion-induced cell
           death via 11β-hydroxysteroid dehydrogenase type 1 inhibition
    • Authors: Kyoung-Jin Choi; Yoon-Ju Na; Sung Bum Park; Won Hoon Jung; Hye-Rim Sung; Ki Young Kim
      Pages: 62 - 72
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Kyoung-Jin Choi, Yoon-Ju Na, Sung Bum Park, Won Hoon Jung, Hye-Rim Sung, Ki Young Kim
      Glaucoma is one of the leading causes of preventable blindness diseases, affecting more than 2 million people in the United States. Recently, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors were found to exert preventive effects against glaucoma. Therefore, we investigated whether carbenoxolone (CBX), an 11β-HSD1 inhibitor, prevents chemical ischemia-reperfusion-induced cell death in human trabecular meshwork (HTM) cells. The present study demonstrated that CBX inhibited cell death caused by iodoacetic acid (IAA)-induced ischemia-reperfusion, and its effect was associated with the inhibition of 11β-HSD1 expression and activity. Furthermore, CBX reversed the IAA-induced structural damage on filamentous actin in HTM cells. In IAA-treated cells, the levels of 11β-HSD1 and the apoptosis-related factors Bax and FASL were increased throughout the reperfusion period, and CBX was able to attenuate the expression of 11β-HSD1 and the apoptosis-related factors. CBX also effectively suppressed IAA-induced intracellular ROS formation and cytochrome c release, which are involved in the mitochondrial apoptosis pathway. In addition, IAA-induced chemical ischemia-reperfusion stimulated TNF-α expression and NF-κB p65 phosphorylation, and these effects were attenuated by CBX. 11β-HSD1 RNAi also suppressed IAA-induced cell apoptosis via reduction of oxidative stress and inhibition of the pro-inflammatory pathway. Taken together, the present study demonstrated that the inhibition of 11β-HSD1 protected the TM against chemical ischemia-reperfusion injury, suggesting that the use of 11β-HSD1 inhibitors could be a useful strategy for glaucoma therapy.
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      PubDate: 2017-07-11T19:26:04Z
      DOI: 10.1016/j.phrs.2017.07.002
      Issue No: Vol. 123 (2017)
       
  • Activation of sirtuin 1 by catalpol-induced down-regulation of
           microRNA-132 attenuates endoplasmic reticulum stress in colitis
    • Authors: Yongjian Xiong; Liqiang Shi; Liang Wang; Zijuan Zhou; Chenou Wang; Yuan Lin; Dong Luo; Juanjuan Qiu; Dapeng Chen
      Pages: 73 - 82
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Yongjian Xiong, Liqiang Shi, Liang Wang, Zijuan Zhou, Chenou Wang, Yuan Lin, Dong Luo, Juanjuan Qiu, Dapeng Chen
      Defective expression of NAD-dependent protein deacetylase sirtuin 1 (SIRT1) triggers endoplasmic reticulum (ER) stress and epithelial cell apoptosis in inflammatory bowel disease. MicroRNA-132 (miR-132) has been shown to regulate inflammatory processes through down-regulating SIRT1. Catalpol is a potential antioxidant and anti-apoptotic agent in inflammatory disease. This study aimed to investigate the signaling mechanisms underlying catalpol-induced SIRT1 activation and inhibition of ER stress in a rat colitis model. Colitis was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid. miR-132 expression was measured by quantitative real-time polymerase chain reaction and in situ hybridization, and the regulation of SIRT1 by miR-132 was examined by dual luciferase reporter assay. Protein expression related to ER stress and apoptosis was measured by western blotting. The ER stress marker proteins ATF6, CHOP, and caspase12, and acetylation of heat-shock factor-1 were increased in colitis and these increases were significantly reversed by catalpol, while the colitis-induced reduction in GRP78 was also reversed by catalpol. The inhibition of ER stress by catalpol was significantly inhibited by small interfering RNA targeting SIRT1 or miR-132. Moreover, other colitis symptoms including infiltration of inflammatory cells, cytokine profiles, oxidative responses, and epithelial cell apoptosis were also significantly decreased by catalpol. Mechanistically, the defective expression of SIRT1 in colitis was significantly counteracted by catalpol, while miR-132, which is a negative targeting regulator of SIRT1, was confirmed as the potential target of catalpol. These results support a link between ER stress and the miR-132/SIRT1/heat-shock factor-1 signaling pathway, and the modulation of this pathway by catalpol in colitis.
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      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.05.030
      Issue No: Vol. 123 (2017)
       
  • Palmitoylethanolamide and Polydatin combination reduces inflammation and
           oxidative stress in vascular injury
    • Authors: Enrico Gugliandolo; Roberta Fusco; Flavia Biundo; Ramona D’Amico; Filippo Benedetto; Rosanna Di Paola; Salvatore Cuzzocrea
      Pages: 83 - 92
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Enrico Gugliandolo, Roberta Fusco, Flavia Biundo, Ramona D’Amico, Filippo Benedetto, Rosanna Di Paola, Salvatore Cuzzocrea
      Acute and chronic inflammation responses are important risk factors for vascular remodeling processes such as in atherosclerosis, arteriosclerosis and restenosis. Inflammation and oxidative stress in the intimal region after vascular damage are a key event in the development of neointimal hyperplasia. In this study, we used this model of vascular damage, which involves the complete ligature of the left carotid artery for 14days, to observe the role of N-palmitoylethanolamine in combination with Polydatin at the dose of 30mg/kg, on regulation of inflammatory process, and oxidative stress. Palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the N-acylethanolamine family, has anti-inflammatory and neuroprotective effects. However, PEA lacks direct capacity to prevent formation of free radicals. Polydatin (PLD) that is a natural precursor of resveratrol has antioxidant activity. Thus, the combination of PEA and PLD could have beneficial effects on inflammatory process and oxidative stress. This model shows that 14days after carotid artery ligation there is a significant structural change within the vessel, and that there is an important involvement of the inflammatory pathway in the progression of this disease. In this study we demonstrated that PEA/PLD combination treatment reduces vessel damage, adhesion molecules expression such as intercellular adhesion molecules-1(ICAM-1) and vascular cell adhesion molecules-1(V-CAM), proinflammatory cytokines production (Tumor Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL-1β), the inducible nitric oxide synthase (iNOS) and Poly (ADP-ribose) polymerase (PAR), formation, Nuclear factor kappa-B expression and apoptosis (BAX, Fas-Ligand) activation. Our results clearly demonstrated that treatment with PEA/PLD 30mg/Kg is able to reduce vascular damage and attenuates the inflammatory process.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.06.014
      Issue No: Vol. 123 (2017)
       
  • Isomalto-oligosaccharides, a prebiotic, functionally augment green tea
           effects against high fat diet-induced metabolic alterations via preventing
           gut dysbacteriosis in mice
    • Authors: Dhirendra Pratap Singh; Jagdeep Singh; Ravneet Kaur Boparai; JianHua Zhu; Shrikant Mantri; Pragyanshu Khare; Romesh Khardori; Kanthi Kiran Kondepudi; Kanwaljit Chopra; Mahendra Bishnoi
      Pages: 103 - 113
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Dhirendra Pratap Singh, Jagdeep Singh, Ravneet Kaur Boparai, JianHua Zhu, Shrikant Mantri, Pragyanshu Khare, Romesh Khardori, Kanthi Kiran Kondepudi, Kanwaljit Chopra, Mahendra Bishnoi
      High fat diet (HFD)-induced alterations in gut microbiota and resultant ‘leaky gut’ phenomenon promotes metabolic endotoxemia, ectopic fat deposition, and low-grade systemic inflammation. Here we evaluated the effects of a combination of green tea extract (GTE) with isomalto-oligosaccharide (IMOs) on HFD-induced alterations in mice. Male Swiss albino mice were fed with HFD (58% fat kcal) for 12 weeks. Systemic adiposity, gut derangement parameters and V3-V4 region based 16S rRNA metagenomic sequencing, ectopic fat deposition, liver metabolome analysis, systemic and tissue inflammation, and energy homeostasis markers along with gene expression analysis in multiple tissues were done in mice supplemented with GTE, IMOs or their combination. The combination of GTE and IMOs effectively prevented HFD-induced adiposity and lipid accumulation in liver and muscle while normalizing fasting blood glucose, insulin, glucagon, and leptin levels. Co-administration of GTE with IMOs effectively modulated liver metabolome associated with lipid metabolism. It also prevented leaky gut phenotype and HFD-induced increase in circulating lipopolysaccharides and pro-inflammatory cytokines (e.g. resistin, TNF-α, and IL-1β) and reduction in anti-inflammatory cytokines (e.g. adiponectin and IL-6). Gene expression analysis across multiple tissues further supported these functional outcomes. Most importantly, this combination improved beneficial gut microbiota (Lactobacillus sp., Bifidobacteria, Akkermansia muciniphila, Roseburia spp.) abundances, restored Firmicutes/Bacteriodetes and improved Prevotella/Bacteroides proportions. In particular, a combination of these two agents has shown improved beneficial effects on multiple parameters studied. Data presented herein suggests that strategically chosen food components might be highly effective in the prevention of HFD-induced alterations and may further be developed as functional foods.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.06.015
      Issue No: Vol. 123 (2017)
       
  • Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition
           and metastasis by down-regulating β-catenin
    • Authors: Liping Chen; Weiqian Mai; Minfeng Chen; Jianyang Hu; Zhenjian Zhuo; Xueping Lei; Lijuan Deng; Junshan Liu; Nan Yao; Maohua Huang; Yinghui Peng; Wencai Ye; Dongmei Zhang
      Pages: 130 - 142
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Liping Chen, Weiqian Mai, Minfeng Chen, Jianyang Hu, Zhenjian Zhuo, Xueping Lei, Lijuan Deng, Junshan Liu, Nan Yao, Maohua Huang, Yinghui Peng, Wencai Ye, Dongmei Zhang
      Epithelial-mesenchymal transition (EMT) plays an important role in prostate cancer (PCa) metastasis; thus, developing EMT inhibitors may be a feasible treatment for metastatic PCa. Here, we discovered that arenobufagin and four other bufadienolides suppressed PC3 cell EMT. These compounds modulated EMT marker expression with elevating E-cadherin and reducing ZEB1, vimentin and slug expression, and attenuated the migration and invasion of PC3 cells. Among these five compounds, arenobufagin exhibited the most potent activity. We found that the mRNA and protein expression of β-catenin and β-catenin/TCF4 target genes, which are related to tumor invasion and metastasis, were down-regulated after arenobufagin treatment. Overexpression of β-catenin in PC3 cells antagonized the EMT inhibition effect of arenobufagin, while silencing β-catenin with siRNA enhanced the inhibitory effect of arenobufagin on EMT. In addition, arenobufagin restrained xenograft tumor EMT, as demonstrated by decreased mesenchymal marker expression and increased epithelial marker expression, and reduced the tumor metastatic foci in lung. This study demonstrates a novel anticancer activity of arenobufagin, which inhibits PC3 cell EMT by down-regulating β-catenin, thereby reducing PCa metastasis. In addition, it also provides new evidence for the development of arenobufagin as a treatment for metastatic prostate cancer.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.009
      Issue No: Vol. 123 (2017)
       
  • Improved oral bioavailability and brain accumulation of afatinib due to
           dual inhibition of the efflux mechanisms of BCRP and Pgp transporters
           —What next'
    • Authors: Nuggehally R. Srinivas
      First page: 143
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Nuggehally R. Srinivas


      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.05.014
      Issue No: Vol. 123 (2017)
       
  • What next' Preferably development of drugs that are no longer
           transported by the ABCB1 and ABCG2 efflux transporters
    • Authors: Stéphanie van Hoppe; Alfred H. Schinkel
      First page: 144
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Stéphanie van Hoppe, Alfred H. Schinkel


      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.05.015
      Issue No: Vol. 123 (2017)
       
  • Treatment of type 2 diabetes mellitus patients with insulin: Possible
           lowering of protective effect of female gender on the cardiovascular
           outcomes'
    • Authors: Mykola Khalangot; Victor Kravchenko
      First page: 145
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Mykola Khalangot, Victor Kravchenko


      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.03.005
      Issue No: Vol. 123 (2017)
       
  • Low molecular weight heparins prevent the induction of autophagy of
           
    • Authors: Angelo A. Manfredi; Patrizia Rovere-Querini; Armando D’Angelo; Norma Maugeri
      Pages: 146 - 156
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Angelo A. Manfredi, Patrizia Rovere-Querini, Armando D’Angelo, Norma Maugeri
      The protection exerted by neutrophils against invading microbes is partially mediated via the generation of neutrophil extracellular traps (NETs). In sterile conditions NETs are damaging species, enriched in autoantigens and endowed with the ability to damage the vessel wall and bystander tissues, to promote thrombogenesis, and to impair wound healing. To identify and reposition agents that can be used to modulate the formation of NETs is a priority in the research agenda. Low molecular weight heparins (LMWH) are currently used, mostly on an empirical basis, in conditions in which NETs play a critical role, such as pregnancy complications associated to autoimmune disease. Here we report that LMWHs induce a profound change in the ability of human neutrophils to generate NETs and to mobilize the content of the primary granules in response to unrelated inflammatory stimuli, such as IL-8, PMA and HMGB1. Autophagy consistently accompanies NET generation in our system and autophagy inhibitors, 3-MA and wortmannin, prevent NET generation. Pretreatment with LMWH in vitro critically jeopardizes neutrophil ability to activate autophagy, a mechanism that might contribute to neutrophil unresponsiveness. Finally, we verified that treatment of healthy volunteers with a single prophylactic dose of parnaparin abrogated the ability of neutrophils to activate autophagy and to generate NETs. Together, these results support the contention that neutrophils, and NET generation in particular, might represent a preferential target of the anti-inflammatory action of LMWH.
      Graphical abstract image

      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2016.08.008
      Issue No: Vol. 123 (2017)
       
  • Low Molecular Weight Heparins—A new tool to disetangle from the NETs
    • Authors: Javier Sanchez
      First page: 157
      Abstract: Publication date: September 2017
      Source:Pharmacological Research, Volume 123
      Author(s): Javier Sanchez


      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.01.027
      Issue No: Vol. 123 (2017)
       
  • 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)
       
  • 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)
       
  • 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)
       
  • The effect of statins on cardiovascular outcomes by smoking status: A
           systematic review and meta-analysis of randomized controlled trials
    • Authors: Sorin Ursoniu; Dimitri P. Mikhailidis; Maria-Corina Serban; Peter Penson; Peter P. Toth; Paul M. Ridker; Kausik K. Ray; G. Kees Hovingh; John J. Kastelein; Adrian V. Hernandez; JoAnn E. Manson; Jacek Rysz; Maciej Banach
      Pages: 105 - 117
      Abstract: Publication date: August 2017
      Source:Pharmacological Research, Volume 122
      Author(s): Sorin Ursoniu, Dimitri P. Mikhailidis, Maria-Corina Serban, Peter Penson, Peter P. Toth, Paul M. Ridker, Kausik K. Ray, G. Kees Hovingh, John J. Kastelein, Adrian V. Hernandez, JoAnn E. Manson, Jacek Rysz, Maciej Banach
      Smoking is an important risk factor for cardiovascular disease (CVD) morbidity and mortality. The impact of statin therapy on CVD risk by smoking status has not been fully investigated. Therefore we assessed the impact of statin therapy on CVD outcomes by smoking status through a systematic review of the literature and meta-analysis of available randomized controlled trials (RCTs). The literature search included EMBASE, ProQuest, CINAHL and PUBMED databases to 30 January 2016 to identify RCTs that investigated the effect of statin therapy on cumulative incidence of major CVD endpoints (e.g. non-fatal myocardial infarction, revascularization, unstable angina, and stroke). Relative risks (RR) ratios were calculated from the number of events in different treatment groups for both smokers and non-smokers. Finally 11 trials with 89,604 individuals were included. The number of smokers and non-smokers in the statin groups of the analyzed studies was 8826 and 36,090, respectively. The RR for major CV events was 0.73 (95% confidence interval [CI]: 0.67–0.81; p< 0.001) in nonsmokers and 0.72 (95%CI: 0.64–0.81; p< 0.001) in smokers. Moderate to high heterogeneity was observed both in non-smokers (I2 =77.1%, p<0.001) and in smokers (I2 =51.6%, p=0.024) groups. Smokers seemed to benefit slightly more from statins than non-smokers according to the number needed to treat (NNT) analysis (23.5 vs 26.8) based on RRs applied to the control event rates. The number of avoided events per 1000 individuals was 42.5 (95%CI: 28.9–54.6) in smokers and 37.3 (95%CI: 27.2–46.4) in non-smokers. In conclusion, this meta-analysis suggests that the effect of statins on CVD is similar for smokers and non-smokers, but in terms of NNTs and number of avoided events, smokers seem to benefit more although non-significantly.

      PubDate: 2017-07-02T03:58:24Z
      DOI: 10.1016/j.phrs.2017.06.002
      Issue No: Vol. 122 (2017)
       
  • Probiotics And Antibiotic-associated Diarrhea In Children: A Review And
           New Evidence On Lactobacillus Rhamnosus GG During And After Antibiotic
           Treatment
    • Authors: Cecilia Mantegazza; Paola Molinari; Enza D’Auria; Micol Sonnino; Lorenzo Morelli
      Abstract: Publication date: Available online 19 August 2017
      Source:Pharmacological Research
      Author(s): Cecilia Mantegazza, Paola Molinari, Enza D’Auria, Micol Sonnino, Lorenzo Morelli
      Antibiotic associated diarrhea (AAD) is a common complication in childhood in the outpatient and inpatient settings. This review provides up to date information on the use of probiotics in the prevention and treatment of AAD, including that from Clostridium Difficile, in children. The most recently systematic reviews and subsequently published randomized controlleds trials are considered. Different single and multistrain probiotics are described; a specific recommendation for the use of Lactobacillus Rhamnosus GG (LGG) and Saccharomyces boulardii (Sb) emerges. New information on LGG survival under amoxicillin/clavulanate therapy in children is also provided. This information is relevant in view of the frequent use of this molecule in children, its association with AAD, and LGG’s sensitivity to penicillin that might make this probiotic ineffective. In spite of a demonstrated positive effect of specific strains of probiotics on AAD, safety issues still remain among which the risk of associated severe infections and of antibiotic resistant gene exchange

      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.08.001
       
  • Dendritic Spine Anomalies and PTEN Alterations in a Mouse Model of
           VPA-induced Autism Spectrum Disorder
    • Authors: Usman Mahmood; Sangzin Ahn; Eun-Jeong Yang; Moonseok Choi; Hyunju Kim; Philip Regan; Kwangwook Cho; Hye-Sun Kim
      Abstract: Publication date: Available online 18 August 2017
      Source:Pharmacological Research
      Author(s): Usman Mahmood, Sangzin Ahn, Eun-Jeong Yang, Moonseok Choi, Hyunju Kim, Philip Regan, Kwangwook Cho, Hye-Sun Kim
      Mounting evidence suggests that the etiology of autism spectrum disorders (ASDs) is profoundly influenced by exposure to environmental factors, although the precise molecular and cellular links remain ill-defined. In this study, we examined how exposure to valproic acid (VPA) during pregnancy is associated with an increased incidence of ASD. A mouse model was established by injecting VPA at embryonic day 13, and its behavioral phenotypes including impaired social interaction, increased repetitive behaviors and decreased nociception were observed at postnatal days 21-42. VPA-treated mice showed dysregulation of synaptic structure in cortical neurons, including a reduced proportion of filopodium-type and stubby spines and increased proportions of thin and mushroom-type spines, along with a decreased spine head size. We also found that VPA-treatment led to decreased expression of phosphate and tensin homolog (PTEN) and increased levels of p-AKT protein in the hippocampus and cortex. Our data suggest that there is a correlation between VPA exposure and dysregulation of PTEN with ASD-like behavioral and neuroanatomical changes, and this may be a potential mechanism of VPA-induced ASD.
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      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.08.006
       
  • Epigenetics in osteoarthritis: Potential of HDAC inhibitors as
           therapeutics
    • Authors: Nazir M. Khan; Tariq M. Haqqi
      Abstract: Publication date: Available online 18 August 2017
      Source:Pharmacological Research
      Author(s): Nazir M. Khan, Tariq M. Haqqi
      Osteoarthritis (OA) is the most common joint disease and the leading cause of chronic disability in middle-aged and older populations worldwide. The development of disease modifying therapy for OA is in its infancy largely because the regulatory mechanisms for the molecular effectors of OA pathogenesis are poorly understood. Recent studies identified epigenetic events as a critical regulator of molecular players involved in the induction and development of OA. Epigenetic mechanisms include DNA methylation, non-coding RNA and histone modifications. The aim of this review is to briefly highlight the recent advances in the epigenetics of cartilage and potential of HDACs (Histone deacetylases) inhibitors in the therapeutic management of OA. We summarize the recent studies utilizing HDAC inhibitors as potential therapeutics for inhibiting disease progression and preventing the cartilage destruction in OA. HDACs control normal cartilage development and homeostasis and understanding the impact of HDACs inhibitors on the disease pathogenesis is of interest because of its importance in affecting overall cartilage health and homeostasis. These findings also shed new light on cartilage disease pathophysiology and provide substantial evidence that HDACs may be potential novel therapeutic targets in OA.
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      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.08.007
       
  • Single-nucleotide polymorphisms in the genes of CES2, CDA and enzymatic
           activity of CDA for prediction of the efficacy of capecitabine-containing
           chemotherapy in patients with metastatic breast cancer
    • Authors: Siu W. Lam; Vincent van der Noort; Tahar van der Straaten; Aafke H. Honkoop; Godefridus J. Peters; Henk-Jan Guchelaarc; Epie Boven
      Abstract: Publication date: Available online 18 August 2017
      Source:Pharmacological Research
      Author(s): Siu W. Lam, Vincent van der Noort, Tahar van der Straaten, Aafke H. Honkoop, Godefridus J. Peters, Henk-Jan Guchelaarc, Epie Boven
      We examined whether genetic polymorphisms (SNPs) in the capecitabine activation pathway and CDA enzymatic activity were associated with prognosis, benefit from capecitabine-containing treatment or capecitabine-related toxicities. The study population comprised 188 metastatic breast cancer patients of the ATX trial (EudraCT 2006-006058-83) randomized for first-line paclitaxel and bevacizumab with (ATX) or without capecitabine (AT). Cumulative capecitabine dose until grade ≥2 hand-foot syndrome or until first dose reduction were toxicity endpoints. We genotyped CDA c.-451C > T (rs532545), CDA c.-33delC (rs3215400) and CES2 c.-806C > G (rs11075646). CDA activity in baseline serum was measured with a spectrophotometric assay and values were analyzed using a median cut-off or as continuous variable. CDA c.-33delC was prognostic for OS independent of hormone receptor status. For the predictive analysis, PFS benefit from ATX over AT was observed in patients with a CDA c.-33del/del or del/insC genotype, a CDA c.-451CC or CT genotype, and a CES2 c.-806CC genotype compared with their counterparts. There was a higher response rate for ATX over AT in patients with a CDA c.-451CT or TT genotype. Patients with high CDA enzymatic activity had more benefit from capecitabine, while this was marginally observed in the CDA low group. Toxicity endpoints were not associated with any candidate markers. In conclusion, CDA c.-33delC was associated with OS. Since particular SNPs in CDA and CES2 were associated with benefit from the addition of capecitabine to AT, their predictive value should be explored in a higher number of patients.
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      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.08.005
       
  • Curcumin in Alzheimer’s disease: Can we think to new strategies and
           perspectives for this molecule'
    • Authors: Serafini Melania Maria; Catanzaro Michele; Rosini Michela; Racchi Marco; Lanni Cristina
      Abstract: Publication date: Available online 12 August 2017
      Source:Pharmacological Research
      Author(s): Serafini Melania Maria, Catanzaro Michele, Rosini Michela, Racchi Marco, Lanni Cristina
      Population aging is an irreversible global trend with economic and socio-political consequences. One of the most invalidating outcomes of aging in the elderly is cognitive decline, leading to dementia and often related to neurodegenerative disorders. Among these latter, Alzheimer’s disease (AD) is the major cause of dementia, affecting more than 30 million of individuals worldwide. To date, the treatment of AD remains a challenge because of an incomplete understanding of the events that lead to the selective neurodegeneration typical of Alzheimer’s brains. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of nutraceuticals as integrative, complementary and preventive therapy. Curcumin is one example of natural product with anti-AD properties, with promising potential for prevention, treatment and diagnostic. The limitations in the use of curcumin as therapeutic are represented by its pharmacokinetics profile and the low bioavailability after oral administration. However, curcumin has been the focus of intense research for new drug development. Here we analyzed some new approaches that have been applied in the attempt to improve its use, particularly new formulations, changes in the way of administration, nanotechnology-based delivery systems and the hybridization strategy.
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      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.08.004
       
  • Anti-inflammatory activity of natural stilbenoids: A review
    • Authors: Marcela Dvorakova; Premysl Landa
      Abstract: Publication date: Available online 9 August 2017
      Source:Pharmacological Research
      Author(s): Marcela Dvorakova, Premysl Landa
      Resveratrol and other natural stilbenoids, including piceatannol, pterostilbene, and gnetol, are well-known anti-inflammatory compounds with indisputable activity in vitro as well as in vivo. Their molecular targets include inducible nitric oxide synthase, cyclooxygenases, leukotrienes, nuclear factor kappa B, tumor necrosis factor α, interleukins and many more. This anti-inflammatory activity together with their antioxidant activity is believed to stand behind their other positive health effects against cancer, cardiovascular and neurodegenerative diseases or diabetes. Thus, they are nowadays commercially marketed as nutraceuticals. Naturally, they are present in wine, grapes or berries. However, there is a rigorous debate about the real effect of these compounds on human health. It is argued that the concentration of stilbenoids in food and beverages is too low to have any therapeutic potential and this concentration is further reduced by their low bioavailability and extensive metabolism. Therefore, this review focuses on in vitro, in vivo, preclinical as well as clinical data available for various natural stilbenoids and summarizes the anti-inflammatory targets on molecular level, compares the relevance of the experimental studies, discusses the metabolism of stilbenoids and the potential activity of their metabolites and relates this knowledge to human health. Moreover, the ways to augment stilbenoidś efficacy are suggested with special focus on multitargeted therapy and nanocarriers.
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      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.08.002
       
  • Antihypertensive drugs
    • Authors: Laurent
      Abstract: Publication date: Available online 2 August 2017
      Source:Pharmacological Research
      Author(s): Stéphane Laurent
      Successful treatment of hypertension is possible with limited side effects given the availability of multiple antihypertensive drug classes. This review describes the various pharmacological classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side effects. The mechanism of action is analysed through a pharmacological approach, i.e. the molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites of action, in order to better understand in which type of hypertension a given pharmacological class of antihypertensive drug is most indicated. In addition, side effects are described and explained through their pharmacological mechanisms, in order to better understand their mechanism of occurrence and in which patients drugs are contra-indicated. This review does not address the effectiveness of monotherapies in large randomized clinical trials and combination therapies, since these are the matters of other articles of the present issue. Five major pharmacological classes of antihypertensive drugs are detailed here: beta-blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers. Four additional pharmacological classes are described in a shorter manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct acting vasodilators.
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      PubDate: 2017-08-08T13:24:39Z
       
  • β3 adrenergic receptor activation relaxes human corpus cavernosum and
           penile artery through a hydrogen sulfide/cGMP-dependent mechanism
    • Authors: Emma Mitidieri; Teresa Tramontano; Danila Gurgone; Ciro Imbimbo; Vincenzo Mirone; Ferdinando Fusco; Giuseppe Cirino; Roberta d’Emmanuele di Villa Bianca; Raffaella Sorrentino
      Abstract: Publication date: Available online 29 July 2017
      Source:Pharmacological Research
      Author(s): Emma Mitidieri, Teresa Tramontano, Danila Gurgone, Ciro Imbimbo, Vincenzo Mirone, Ferdinando Fusco, Giuseppe Cirino, Roberta d’Emmanuele di Villa Bianca, Raffaella Sorrentino
      Erectile function is a widely accepted indicator of systemic endothelial activity since from a clinical standpoint erectile dysfunction (ED) often precedes cardiovascular events. Recently it has been described a potential role for β3 adrenoceptor in cardiovascular diseases emphasizing a possible development of new drugs. β3 adrenoceptor stimulation relaxes human corpus cavernosum (HCC) strips in cyclic guanosine monophosphate (cGMP)-dependent and endothelium/nitric oxide (NO)-independent manner. Hydrogen sulfide (H2S), along with NO, is another gaseous molecule involved in cardiovascular system and as a consequence also in penile erection. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), the enzymes mainly responsible for H2S biosynthesis, are constitutively expressed in HCC. CSE rather than CBS is more abundant in human penile tissue. Herein we investigated the involvement of H2S pathway in β3 adrenoceptor-induced relaxation in HCC and penile artery. Penile artery expresses both CSE and β3 adrenoceptor. BRL37344, a β3 selective agonist, relaxed HCC strips and penile artery rings and this effect was significantly reduced by CSE inhibition. Incubation of HCC and penile artery homogenate with BRL37344 significantly increased H2S production. This effect was significantly reduced by the inhibition of either CSE or β3 adrenoceptor. Finally, the BRL37344-induced increase in cGMP was reduced by CSE inhibition in both tissues. Thus, BRL37344-induced relaxation in HCC and penile artery occurs in a H2S/cGMP-dependent manner. In conclusion, β3/H2S/cGMP pathway can act as an alternative to NO. Since about 15% of patients do not respond to phosphodiesterase-5 inhibitors, β3 agonists could represent a therapeutic alternative or a useful adjuvant therapy to treat these patients.
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      PubDate: 2017-07-29T12:55:44Z
      DOI: 10.1016/j.phrs.2017.07.025
       
  • Effects of Tibolone on Fibrinogen and Anti-Thrombin III: A Systematic
           Review and Meta-Analysis of Controlled Trials
    • Authors: Małgorzata Bała; Amirhossein Sahebkar; Sorin Ursoniu; Maria-Corina Serban; Anetta Undas; Dimitri P. Mikhailidis; Gregory Y.H. Lip; Jacek Rysz; Maciej Banach
      Abstract: Publication date: Available online 29 July 2017
      Source:Pharmacological Research
      Author(s): Małgorzata Bała, Amirhossein Sahebkar, Sorin Ursoniu, Maria-Corina Serban, Anetta Undas, Dimitri P. Mikhailidis, Gregory Y.H. Lip, Jacek Rysz, Maciej Banach
      Tibolone is a synthetic steroid with estrogenic, androgenic and progestogenic activity, but the evidence regarding its effects on fibrinogen and anti-thrombin III (ATIII) has not been conclusive. We assessed the impact of tibolone on fibrinogen and ATIII through a systematic review and meta-analysis of available randomized controlled trials (RCTs). The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2016) to identify controlled clinical studies investigating the effects of oral tibolone treatment on fibrinogen and ATIII. Overall, the impact of tibolone on plasma fibrinogen concentrations was reported in 10 trials comprising 11 treatment arms. Meta-analysis did not suggest a significant reduction of fibrinogen levels following treatment with tibolone (WMD: −5.38%, 95% CI: −11.92, +1.16, p =0.107). This result was robust in the sensitivity analysis and not influenced after omitting each of the included studies from meta-analysis. When the studies were categorized according to the duration of treatment, there was no effect in the subsets of trials lasting either <12months (WMD: −7.64%, 95% CI: −16.58, +1.29, p =0.094) or ≥12months (WMD: −0.62%, 95% CI: −8.40, +7.17, p =0.876). With regard to ATIII, there was no change following treatment with tibolone (WMD: +0.74%, 95% CI: −1.44, +2.93, p =0.505) and this effect was robust in sensitivity analysis. There was no differential effect of tibolone on plasma ATIII concentrations in trials with either <12months (WMD: +2.26%, 95% CI: −3.14, +7.66, p =0.411) or ≥12months (WMD: +0.06%, 95% CI: −1.16, +1.28, p =0.926) duration. Consistent with the results of subgroup analysis, meta-regression did not suggest any significant association between the changes in plasma concentrations of fibrinogen (slope: +0.40; 95% CI: −0.39, +1.19; p =0.317) and ATIII (slope: −0.17; 95% CI: −0.54, +0.20; p =0.374) with duration of treatment. In conclusion, meta-analysis did not suggest a significant reduction of fibrinogen and ATIII levels following treatment with tibolone.
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      PubDate: 2017-07-29T12:55:44Z
      DOI: 10.1016/j.phrs.2017.07.024
       
  • Terfenadine combined with epirubicin impedes the chemo-resistant human
           non-small cell lung cancer both in vitro and in vivo through EMT and Notch
           reversal
    • Authors: Li An; Dan-Dan Li; Hai-Xiao Chu; Qiao Zhang; Chang-Li Wang; Yan-Hua Fan; Qi Song; Hong-Da Ma; Fan Feng; Qing-Chun Zhao
      Abstract: Publication date: Available online 25 July 2017
      Source:Pharmacological Research
      Author(s): Li An, Dan-Dan Li, Hai-Xiao Chu, Qiao Zhang, Chang-Li Wang, Yan-Hua Fan, Qi Song, Hong-Da Ma, Fan Feng, Qing-Chun Zhao
      The acquired resistance of non-small cell lung cancer (NSCLC) to taxanes eventually leads to the recurrence and metastasis of tumours. Thus, the development of therapeutic strategies based on the mechanisms by which cells acquire resistance to prolong their survival rate in chemotherapy drug treatment failure patients are warranted. In this study, we found that the resistant cells acquired increased migratory and invasive capabilities, and this transformation was correlated with epithelial-mesenchymal transition (EMT) and Notch pathway deregulation in the resistant cells. Finally, we reported for the first time that terfenadine augmented the effect of epirubicin (EPI) better than Taxol and cisplatin (DDP) by inhibiting migration, invasion, and the EMT phenotype, and the combination therapy also reversed Notch signalling pathway and enhanced the accumulation of fluorescent P-gp substrate rhodamine 123 (Rh123). Similar activities of terfenadine on EPI were observed in xenografts. All of our results confirmed that terfenadine combined with EPI synergistically inhibits the growth and metastatic processes of resistant cells both in vitro and in vivo. Therefore, terfenadine or its derivatives are a promising approach for the clinical challenge of resistance in patients with advanced NSCLC.
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      PubDate: 2017-07-29T12:55:44Z
      DOI: 10.1016/j.phrs.2017.07.021
       
  • Labdane diterpenoids as potential anti-inflammatory agents
    • Authors: Quy T.N. Tran; W.S. Fred Wong; Christina L.L. Chai
      Abstract: Publication date: Available online 25 July 2017
      Source:Pharmacological Research
      Author(s): Quy T.N. Tran, W.S. Fred Wong, Christina L.L. Chai
      The search for new anti-inflammatory agents is challenging due to the complexity of the inflammatory process and its role in host defense. Over the past few decades, a significant body of evidence has emerged, supporting the prominent role of labdane diterpenoids in therapeutic interventions of various inflammatory diseases. The anti-inflammatory activity of labdane diterpenoids has been attributed mainly to the inhibition of nuclear factor-κB (NF-κB) activity, the modulation of arachidonic acid (AA) metabolism and the reduction of nitric oxide (NO) production. This article provides extensive coverage of naturally occurring labdane diterpenes, discovered between 1981 and 2016, which have been verified as NF-κB, NO, or AA modulators. Herein, we also discuss the role of Michael acceptor, a common structural feature present in most of the active labdane diterpenes, and its association with NF-κB signaling inhibition. In the cases where a sufficient amount of data exists, structure-activity relationship (SAR) studies and clinical studies performed on the anti-inflammatory labdane diterpenoids are also discussed.
      Graphical abstract image

      PubDate: 2017-07-29T12:55:44Z
      DOI: 10.1016/j.phrs.2017.07.019
       
  • Application of pharmacometrics and quantitative systems pharmacology to
           cancer therapy: The example of luminal a breast cancer
    • Authors: Brett Fleisher; Kayla Andrews; Ashley A. Brown; Sihem Ait-Oudhia
      Abstract: Publication date: Available online 19 July 2017
      Source:Pharmacological Research
      Author(s): Brett Fleisher, Kayla Andrews, Ashley A. Brown, Sihem Ait-Oudhia
      Breast cancer (BC) is the most common cancer in women, and the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct morphologies and clinical implications. Quantitative systems pharmacology (QSP) is an emerging discipline bridging systems biology with pharmacokinetics (PK) and pharmacodynamics (PD) leveraging the systematic understanding of drugs’ efficacy and toxicity. Despite numerous challenges in applying computational methodologies for QSP and mechanism-based PK/PD models to biological, physiological, and pharmacological data, bridging these disciplines has the potential to enhance our understanding of complex disease systems such as BC. In QSP/PK/PD models, various sources of data are combined including large, multi-scale experimental data such as −omics (i.e. genomics, transcriptomics, proteomics, and metabolomics), biomarkers (circulating and bound), PK, and PD endpoints. This offers a means for a translational application from pre-clinical mathematical models to patients, bridging the bench to bedside paradigm. Not only can these models be applied to inform and advance BC drug development, but they also could aid in optimizing combination therapies and rational dosing regimens for BC patients. Here, we review the current literature pertaining to the application of QSP and pharmacometrics-based pharmacotherapy in BC including bottom-up and top-down modeling approaches. Bottom-up modeling approaches employ mechanistic signal transduction pathways to predict the behavior of a biological system. The ones that are addressed in this review include signal transduction and homeostatic feedback modeling approaches. Alternatively, top-down modeling techniques are bioinformatics reconstruction techniques that infer static connections between molecules that make up a biological network and include (1) Bayesian networks, (2) co-expression networks, and (3) module-based approaches. This review also addresses novel techniques which utilize the principles of systems biology, synthetic lethality and tumor priming, both of which are discussed in relationship to novel drug targets and existing BC therapies. By utilizing QSP approaches, clinicians may develop a platform for improved dose individualization for subpopulation of BC patients, strengthen rationale in treatment designs, and explore mechanism elucidation for improving future treatments in BC medicine.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.015
       
  • Potential anti-cancer activity of 7-O-pentyl quercetin: efficient,
           membrane-targeted kinase inhibition and pro-oxidant effect
    • Authors: Nicola Sassi; Andrea Mattarei; Virginia Espina; Lance Liotta; Mario Zoratti; Cristina Paradisi; Lucia Biasutto
      Abstract: Publication date: Available online 17 July 2017
      Source:Pharmacological Research
      Author(s): Nicola Sassi, Andrea Mattarei, Virginia Espina, Lance Liotta, Mario Zoratti, Cristina Paradisi, Lucia Biasutto
      Quercetin is a redox-active plant-derived flavonoid with potential anticancer effects, stemming largely from its interaction with a number of proteins, and in particular from inhibition of pro-life kinases. To improve efficacy, we reasoned that a local increase in concentration of the compound at the level of cell membranes would result in a more efficient interaction with membrane-associated signaling kinases. We report here the synthesis of all five isomeric quercetin derivatives in which an n-pentyl group was linked via an ether bond to each hydroxyl of the flavonoid kernel. This strategy proved effective in directing quercetin to cellular membranes, and revealed a remarkable dependence of the derivatives’ bioactivity on the specific site of functionalization. The isomer bearing the pentyl group in position 7, Q-7P, turned out to be the most effective and promising derivative, selectively inducing apoptosis in tumoral and fast-growing cells, while sparing slow-growing, non-tumoral ones. Cytotoxicity for tumoral cells was strongly enhanced compared to quercetin itself. Q-7P induced massive ROS production, which however accounted only partially for cell death. Alterations in the levels of various signaling phospho-proteins were observed in a proteomics screen. An important contribution seems to come from inhibition of the PI3K/Akt pathway. This work opens new perspectives in developing membrane-associating, polyphenol-based anticancer agents.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.016
       
  • Transient receptor potential TRPM3 channels: pharmacology, signaling, and
           biological functions
    • Authors: Gerald Thiel; Sandra Rubil; Andrea Lesch; Lisbeth A. Guethlein; Oliver G. Rössler
      Abstract: Publication date: Available online 16 July 2017
      Source:Pharmacological Research
      Author(s): Gerald Thiel, Sandra Rubil, Andrea Lesch, Lisbeth A. Guethlein, Oliver G. Rössler
      The transient receptor potential melastatin-3 (TRPM3) channel belongs to the family of transient receptor potential (TRP) cation channels that are expressed in a variety of tissues and cell types, including dorsal root ganglia, cardiomyocytes and pancreatic beta-cells. Although its natural ligands are currently unknown, TRPM3 channels can be activated by the neurosteroid pregnenolone sulfate, the synthetic ligand CIM0216, and by noxious heat. TRPM3 channels are regulated by phosphoinositides, and perhaps by calmodulin. Stimulation of TRPM3 induces an intracellular signaling cascade involving a rise in intracellular Ca2+, activation of the protein kinases Raf, ERK and JNK, and the activation of the stimulus-responsive transcription factors AP-1, CREB, Egr-1, and Elk-1. Functionally, stimulation of TRPM3 channels is connected with heat sensation by somatosensory neurons, insulin secretion by pancreatic beta-cells, regulation of neurotransmitter release, iris constriction, and tumor promotion. With the development of highly specific activators and inhibitors of TRPM3 channels, we expect that additional tissue-specific functions of TRPM3 channels will be discovered, establishing TRPM3 channels as a new therapeutic target.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.014
       
  • Drug repurposing in cancer
    • Authors: Linda Sleire; Hilde Elisabeth Førde; Inger Anne Netland; Lina Leiss; Per Øyvind Enger
      Abstract: Publication date: Available online 13 July 2017
      Source:Pharmacological Research
      Author(s): Linda Sleire, Hilde Elisabeth Førde, Inger Anne Netland, Lina Leiss, Per Øyvind Enger
      Cancer is a major health issue worldwide, and the global burden of cancer is expected to increase in the coming years. Whereas the limited success with current therapies has driven huge investments into drug development, the average number of FDA approvals per year has declined since the 1990s. This unmet need for more effective anti-cancer drugs has sparked a growing interest for drug repurposing, i.e. using drugs already approved for other indications to treat cancer. As such, data both from pre-clinical experiments, clinical trials and observational studies have demonstrated anti-tumor efficacy for compounds within a wide range of drug classes other than cancer. Whereas some of them induce cancer cell death or suppress various aspects of cancer cell behavior in established tumors, others may prevent cancer development. Here, we provide an overview of promising candidates for drug repurposing in cancer, as well as studies describing the biological mechanisms underlying their anti-neoplastic effects.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.013
       
  • Coronary Microvascular Disease as an Early Culprit in the Pathophysiology
           of Diabetes and Metabolic Syndrome
    • Authors: Hicham Labazi; Aaron J. Trask
      Abstract: Publication date: Available online 9 July 2017
      Source:Pharmacological Research
      Author(s): Hicham Labazi, Aaron J. Trask
      Metabolic syndrome (MetS) is a group of cardio-metabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia; these are also a combination of independent coronary artery disease (CAD) risk factors. Alarmingly, the prevalence of MetS risk factors are increasing and a leading cause for mortality. In the vasculature, complications from MetS and type 2 diabetes (T2D) can be divided into microvascular (retinopathy and nephropathy) and macrovascular (cardiovascular diseases and erectile dysfunction). In addition to vascular and endothelial dysfunction, vascular remodeling and stiffness are also hallmarks of cardiovascular disease (CVD), and well-characterized vascular changes that are observed in the early stages of hypertension, T2D, and obesity [1–3]. In the heart, the link between obstructive atherosclerosis of coronary macrovessels and myocardial ischemia (MI) is well established. However, recent studies show that abnormalities in the coronary microcirculation are associated with functional and structural changes in coronary microvessels (classically defined as being ≤150–200μm internal diameter), which may cause or contribute to MI even in the absence of obstractive CAD. This suggests a prognostic value of an abnormal coronary microcirculation as an early sub-clinical culprit in the pathogenesis and progression of heart disease in T2D and MetS. The aim of this review is to summarize recent studies investigating the coronary microvascular remodeling in an early pre-atherosclerotic phase of MetS and T2D, and to explore potential mechanisms associated with the timing of coronary microvascular remodeling relative to that of the macrovasculature.
      Graphical abstract image

      PubDate: 2017-07-11T19:26:04Z
      DOI: 10.1016/j.phrs.2017.07.004
       
  • Can causality assessment fulfill the new European definition of adverse
           drug reaction' A review of methods used in spontaneous reporting.
    • Authors: Annamaria Mascolo; Cristina Scavone; Maurizio Sessa; Gabriella di Mauro; Daniela Cimmaruta; Valentina Orlando; Francesco Rossi; Liberata Sportiello; Annalisa Capuano
      Abstract: Publication date: Available online 8 July 2017
      Source:Pharmacological Research
      Author(s): Annamaria Mascolo, Cristina Scavone, Maurizio Sessa, Gabriella di Mauro, Daniela Cimmaruta, Valentina Orlando, Francesco Rossi, Liberata Sportiello, Annalisa Capuano
      Causality assessment is a fundamental biomedical technique for the signal detection performed by Pharmacovigilance centres in a Spontaneous reporting system. Moreover, it is a crucial and important practice for detecting preventable adverse drug reactions. Among different methods for causality assessment, algorithms (such as the Naranjo, or Begaud Methods) seem for their operational procedure and easier applicability one of the most commonly used methods With the upcoming of the new European Pharmacovigilance legislation including in the definition of the adverse event also effects resulting from abuse, misuse and medication error, all well-known preventable causes of ADRs, there was an emerging need to evaluate whether algorithms could fulfill this new definition. In this review, twenty-two algorithmic methods were identified and none of them seemed to fulfill perfectly the new criteria of adverse event although some of them come close. In fact, several issues were arisen in applying causality assessment algorithms to these new definitions as for example the impossibility to answer the rechallenge question in case of medication error or AEFI (Adverse Event Following Immunization). Moreover, the exact conditions at which events occurred, as for example dosage or mode of administration should be considered to better assess causality in conditions of abuse/overdose, or misuse as well as in conditions of lack of expected efficacy reports for biotechnological drugs and adverse event occurring after mixing of vaccines. Therefore, this review highlights the need of updating algorithmic methods: to allow a perfect applicability in all possible clinical scenarios accordingly or not with the terms of marketing authorization.
      Graphical abstract image

      PubDate: 2017-07-11T19:26:04Z
      DOI: 10.1016/j.phrs.2017.07.005
       
  • Assessing drug causality: it is time to become European!
    • Authors: Bernard
      Abstract: Publication date: Available online 8 July 2017
      Source:Pharmacological Research
      Author(s): Bernard Bégaud


      PubDate: 2017-07-11T19:26:04Z
       
  • Sex and gender landscape in pharmacology
    • Authors: Flavia Franconi; Valeria Raparelli; Vera Regitz-Zagrosek
      Abstract: Publication date: Available online 8 July 2017
      Source:Pharmacological Research
      Author(s): Flavia Franconi, Valeria Raparelli, Vera Regitz-Zagrosek


      PubDate: 2017-07-11T19:26:04Z
      DOI: 10.1016/j.phrs.2017.07.001
       
  • Tumor Microenvironment Changes Leading to Resistance of Immune Checkpoint
           Inhibitors in Metastatic Melanoma and Strategies to Overcome Resistance.
    • Authors: Bhargavi Pulluri; Abhijeet Kumar; Montaser Shaheen; Joanne Jeter; Srinath Sundararajan
      Abstract: Publication date: Available online 6 July 2017
      Source:Pharmacological Research
      Author(s): Bhargavi Pulluri, Abhijeet Kumar, Montaser Shaheen, Joanne Jeter, Srinath Sundararajan
      Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy. Here, we review the resistance mechanisms adopted by cancer cells to checkpoint inhibitor therapy and targeted therapy. In addition, we focus on the available and emerging evidence on tumor microenvironment modulation by BRAF/MEK inhibitor therapy and its role in improving responses to checkpoint inhibitor therapy.
      Graphical abstract image

      PubDate: 2017-07-11T19:26:04Z
      DOI: 10.1016/j.phrs.2017.07.006
       
  • Pregnenolone does not interfere with the effects of cannabinoids on
           synaptic transmission in the cerebellum and the nucleus accumbens
    • Authors: Anna Krohmer; Martin Brehm Volker Bela Szabo
      Abstract: Publication date: Available online 24 June 2017
      Source:Pharmacological Research
      Author(s): Anna Krohmer, Martin Brehm, Volker Auwärter, Bela Szabo
      The steroid hormone pregnenolone attenuates several in vivo behavioural and somatic effects of the phytocannabinoid Δ9-tetrahydrocannabinol, and it was suggested that pregnenolone can protect the brain from cannabis intoxication. The primary neuronal cannabinoid action behind most of the behavioural and somatic effects of cannabinoids is presynaptic inhibition of synaptic transmission. Therefore, the hypothesis of the present study was that pregnenolone attenuates the inhibition of synaptic transmission elicited by cannabinoids. Brain slices containing the cerebellum or the nucleus accumbens were prepared from brains of mice and rats. Spontaneous and electrically evoked GABAergic inhibitory postsynaptic currents (sIPSCs and eIPSCs) and evoked glutamatergic excitatory postsynaptic currents (eEPSCs) were recorded in superfused brain slices with patch-clamp electrophysiological techniques. Pregnenolone (10−7 M) did not affect the spontaneous GABAergic synaptic input (sIPSCs) to Purkinje cells in mouse cerebellar slices. The synthetic mixed CB1/CB2 receptor agonists JWH-210 (5×10−6 M) and JWH-018 (5×10−6 M) inhibited the spontaneous GABAergic synaptic input (sIPSCs) to Purkinje cells. This inhibition was not affected by pregnenolone (10−7 M). Tetrahydrodeoxycorticosterone (THDOC; 10−7 M), an in vivo metabolite of pregnenolone, also did not affect the inhibition of the GABAergic synaptic transmission by JWH-018. The depolarization of the Purkinje cells induced suppression of the GABAergic input to Purkinje cells; pregnenolone (10−7 M) did not affect this endocannabinoid-mediated form of synaptic suppression. In rat nucleus accumbens slices, glutamatergic and GABAergic synaptic input to medium spiny neurons was activated by electrical stimulation of axons. Δ9-Tetrahydrocannabinol (2×10−5 M), which is a partial agonist of both CB1 and CB2 receptors, suppressed the glutamatergic and GABAergic synaptic transmission in the rat nucleus accumbens. These suppressive effects of Δ9-tetrahydrocannabinol were not changed by pregnenolone (10−7 M). The suppression of the GABAergic synaptic transmission by Δ9-tetrahydrocannabinol in the rat nucleus accumbens was also not affected by THDOC (10−7 M). The results indicate that pregnenolone, a neurosteroid, does not affect GABAergic synaptic transmission. The inhibition of GABAergic and glutamatergic synaptic transmission elicited by synthetic, endogenous and phyto-cannabinoids is also not changed by pregnenolone. Therefore, it is unlikely that interference with cannabinoid-induced inhibition of synaptic transmission is the mechanism by which pregnenolone attenuates behavioural and somatic effects of Δ9-tetrahydrocannabinol in vivo.
      Graphical abstract image

      PubDate: 2017-07-02T03:58:24Z
       
  • 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
       
  • 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
       
  • 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
       
 
 
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