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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  [3039 journals]
  • Protective effect of gedunin on TLR-mediated inflammation by modulation of
           inflammasome activation and cytokine production: Evidence of a multitarget
           compound
    • Authors: Perla Villani Borges; Katelim Hottz Moret; Nulgumnalli Manjunathaiah Raghavendra; Thadeu Estevam Maramaldo Costa; Ana Paula Monteiro; Alan Brito Carneiro; Patrícia Pacheco; Jairo Ramos Temerozo; Dumith Chequer Bou-Habib; Maria das Graças Henriques; Carmen Penido
      Pages: 65 - 77
      Abstract: Publication date: January 2017
      Source:Pharmacological Research, Volume 115
      Author(s): Perla Villani Borges, Katelim Hottz Moret, Nulgumnalli Manjunathaiah Raghavendra, Thadeu Estevam Maramaldo Costa, Ana Paula Monteiro, Alan Brito Carneiro, Patrícia Pacheco, Jairo Ramos Temerozo, Dumith Chequer Bou-Habib, Maria das Graças Henriques, Carmen Penido
      Activation of toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) triggers an innate immune response, via cytokine production and inflammasome activation. Herein, we have investigated the modulatory effect of the natural limonoid gedunin on TLR activation in vitro and in vivo. Intraperitoneal (i.p.) pre- and post-treatments of C57BL/6 mouse with gedunin impaired the influx of mononuclear cells, eosinophils and neutrophils, as well as the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nitric oxide (NO), triggered by lipopolysaccharide (LPS) in mouse pleura. Accordingly, in vitro post-treatment of immortalized murine macrophages with gedunin also impaired LPS-induced production of such mediators. Gedunin diminished LPS-induced expression of the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) on pleural leukocytes in vivo and in immortalized macrophages in vitro. In line with this, gedunin inhibited LPS-induced caspase-1 activation and the production of IL-1β in vivo and in vitro. In addition, gedunin treatment triggered the generation of the anti-inflammatory factors IL-10 and heme oxigenase-1 (HO-1) at resting conditions or upon stimulation. We also demonstrate that gedunin effect is not restricted to TLR4-mediated response, since this compound diminished TNF-α, IL-6, NO, NLRP3 and IL-1β, as well as enhanced IL-10 and HO-1, by macrophages stimulated with the TLR2 and TLR3 agonists, palmitoyl-3-Cys-Ser-(Lys)4 (PAM3) and polyriboinosinic:polyribocytidylic acid (POLY I:C), in vitro. In silico modeling studies revealed that gedunin efficiently docked into caspase-1, TLR2, TLR3 and to the myeloid differentiation protein-2 (MD-2) component of TLR4. Overall, our data demonstrate that gedunin modulates TLR4, TLR3 and TLR2-mediated responses and reveal new molecular targets for this compound.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.09.015
      Issue No: Vol. 115 (2016)
       
  • Niclosamide ethanolamine inhibits artery constriction
    • Authors: Shan-Liang Li; Jie Yan; Yan-Qiu Zhang; Chang-Lin Zhen; Ming-Yu Liu; Jing Jin; Jin-Lai Gao; Xiao-Lin Xiao; Xin Shen; Yu Tai; Nan Hu; Xin-Zi Zhang; Zhi-Jie Sun; De-Li Dong
      Pages: 78 - 86
      Abstract: Publication date: January 2017
      Source:Pharmacological Research, Volume 115
      Author(s): Shan-Liang Li, Jie Yan, Yan-Qiu Zhang, Chang-Lin Zhen, Ming-Yu Liu, Jing Jin, Jin-Lai Gao, Xiao-Lin Xiao, Xin Shen, Yu Tai, Nan Hu, Xin-Zi Zhang, Zhi-Jie Sun, De-Li Dong
      We previously demonstrated that the typical mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) inhibited artery constriction, but CCCP was used only as a pharmacological tool. Niclosamide is an anthelmintic drug approved by FDA. Niclosamide ethanolamine (NEN) is a salt form of niclosamide and has been demonstrated to uncouple mitochondrial oxidative phosphorylation. The aim of the present study was to elucidate the vasoactivity of NEN and the potential mechanisms. Isometric tension of rat mesenteric artery and thoracic aorta was recorded by using multi-wire myograph system. The protein levels were measured by using western blot techniques. Niclosamide ethanolamine (NEN) treatment relaxed phenylephrine (PE)- and high K+ (KPSS)-induced constriction, and pre-treatment with NEN inhibited PE- and KPSS-induced constriction of rat mesenteric arteries. In rat thoracic aorta, NEN also showed antagonism against PE- and KPSS-induced constriction. NEN induced increase of cellular ADP/ATP ratio in vascular smooth muscle cells (A10) and activated AMP-activated protein kinase (AMPK) in A10 cells and rat thoracic aorta. NEN-induced aorta relaxation was attenuated in AMPKα1 knockout (-/-) mice. SERCA inhibitors cyclopiazonic acid and thapsigargin, but not KATP channel blockers glibenclamide and 5-hydroxydecanoic acid, attenuated NEN-induced vasorelaxation in rat mesenteric arteries. NEN treatment increased cytosolic [Ca2+]i and depolarized mitochondrial membrane potential in vascular smooth muscle cells (A10). Niclosamide in non-salt form showed the similar vasoactivity as NEN in rat mesenteric arteries. Niclosamide ethanolamine inhibits artery constriction, indicating that it would be promising to be developed as an anti-hypertensive drug or it would induce vasodilation-related side effects when absorbed in vivo.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.008
      Issue No: Vol. 115 (2016)
       
  • Epigenetic regulation of active Chinese herbal components for cancer
           prevention and treatment: A follow-up review
    • Authors: Zhiying Huang; Qiuju Huang; Liyan Ji; Ying Wang; Xiaoxiao Qi; Liang Liu; Zhongqiu Liu; Linlin Lu
      Pages: 1 - 12
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Zhiying Huang, Qiuju Huang, Liyan Ji, Ying Wang, Xiaoxiao Qi, Liang Liu, Zhongqiu Liu, Linlin Lu
      Epigenetic modifications include DNA methylation, histone modification, and other patterns. These processes are associated with carcinogenesis and cancer progression. Thus, epigenetic modification-related enzymes, such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone demethylases (HDMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs), as well as some related proteins, including methyl-CpG binding proteins (MBPs) and DNMT1-associated protein (DMAP 1), are considered as potential targets for cancer prevention and therapy. Numerous natural compounds, mainly derived from Chinese herbs and chemically ranging from polyphenols and flavonoids to mineral salts, inhibit the growth and development of various cancers by targeting multiple genetic and epigenetic alterations. This review summarizes the epigenetic mechanisms by which active compounds from Chinese herbs exert their anti-cancer effect. A subset of these compounds, such as curcumin and resveratrol, affect multiple epigenetic processes, including DNMT inhibition, HDAC inactivation, MBP suppression, HAT activation, and microRNA modulation. Other compounds also regulate epigenetic modification processes, but the underlying mechanisms and clear targets remain unknown. Accordingly, further studies are required.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.09.023
      Issue No: Vol. 114 (2016)
       
  • Label-free versus conventional cellular assays: Functional investigations
           on the human histamine H1 receptor
    • Authors: S. Lieb; T. Littmann; N. Plank; J. Felixberger; M. Tanaka; T. Schäfer; S. Krief; S. Elz; K. Friedland; G. Bernhardt; J. Wegener; T. Ozawa; A. Buschauer
      Pages: 13 - 26
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): S. Lieb, T. Littmann, N. Plank, J. Felixberger, M. Tanaka, T. Schäfer, S. Krief, S. Elz, K. Friedland, G. Bernhardt, J. Wegener, T. Ozawa, A. Buschauer
      A set of histamine H1 receptor (H1R) agonists and antagonists was characterized in functional assays, using dynamic mass redistribution (DMR), electric cell-substrate impedance sensing (ECIS) and various signaling pathway specific readouts (Fura-2 and aequorin calcium assays, arrestin recruitment (luciferase fragment complementation) assay, luciferase gene reporter assay). Data were gained from genetically engineered HEK293T cells and compared with reference data from GTPase assays and radioligand binding. Histamine and the other H1R agonists gave different assay-related pEC50 values, however, the order of potency was maintained. In the luciferase fragment complementation assay, the H1R preferred β-arrestin2 over β-arrestin1. The calcium and the impedimetric assay depended on Gq coupling of the H1R, as demonstrated by complete inhibition of the histamine-induced signals in the presence of the Gq inhibitor FR900359 (UBO-QIC). Whereas partial inhibition by FR900359 was observed in DMR and the gene reporter assay, pertussis toxin substantially decreased the response in DMR, but increased the luciferase signal, reflecting the contribution of both, Gq and Gi, to signaling in these assays. For antagonists, the results from DMR were essentially compatible with those from conventional readouts, whereas the impedance-based data revealed a trend towards higher pKb values. ECIS and calcium assays apparently only reflect Gq signaling, whereas DMR and gene reporter assays appear to integrate both, Gq and Gi mediated signaling. The results confirm the value of the label-free methods, DMR and ECIS, for the characterization of H1R ligands. Both noninvasive techniques are complementary to each other, but cannot fully replace reductionist signaling pathway focused assays.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.010
      Issue No: Vol. 114 (2016)
       
  • Histamine type 1-receptor activation by low dose of histamine undermines
           human glomerular slit diaphragm integrity
    • Authors: Eleonora Veglia; Alessandro Pini; Aldo Moggio; Cristina Grange; Federica Premoselli; Gianluca Miglio; Katerina Tiligada; Roberto Fantozzi; Paul L. Chazot; Arianna Carolina Rosa
      Pages: 27 - 38
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Eleonora Veglia, Alessandro Pini, Aldo Moggio, Cristina Grange, Federica Premoselli, Gianluca Miglio, Katerina Tiligada, Roberto Fantozzi, Paul L. Chazot, Arianna Carolina Rosa
      Histamine has been reported to decrease the ultrafiltration coefficient, which inversely correlates with glomerular permselectivity, however the mechanism(s) underling this effect have never been investigated. This study aimed to assess whether histamine could exert a direct detrimental effect on podocyte permeability and the possible involvement of two key proteins for the glomerular slit diaphragm (SD) integrity, zonula occludens-1 (ZO-1) and P-cadherin. The effect of histamine (100 pM–1000nM) on coloured podocytes junctional integrity was evaluated functionally by a transwell assay of monolayer permeability and morphologically by electron microscopy. Histamine receptor (H1-4R) presence was evaluated at both mRNA (RT-PCR) and protein (immunofluorescence) levels. The Kd and Bmax values for [3H]mepyramine were determined by saturation binding analysis; IP1 and cAMP production evoked by histamine were measured by TR-FRET. ZO-1, P-cadherin and vimentin expression was assessed by qRT-PCR and quantitative immunoblotting. Histamine elicited a time- and sigmoidal dose-dependent (maximum effect at 8h, 10nM) increase in podocyte paracellular permeability widening the paracellular spaces. Only H1R was predominantly localised to the podocyte membrane. Consistently, histamine elicited a sigmoidal dose-dependent increase in IP1, but not in cAMP. Histamine exposure evoked a concentration-dependent reduction in both ZO-1 and P-cadherin and a parallel induction of vimentin mRNA expression with a maximum effect after 6h, and protein expression with a maximum effect after 8h. These effects were prevented by the selective H1R antagonist chlorpheniramine. In conclusion, our data demonstrate that histamine, via the H1R, modifies SD morphological and functional integrity, in part, by decreasing the expression of ZO-1 and P-cadherin.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.011
      Issue No: Vol. 114 (2016)
       
  • Eyes on systems pharmacology
    • Authors: Yu Chen; Timothy S. Kern; Philip D. Kiser; Krzysztof Palczewski
      Pages: 39 - 41
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Yu Chen, Timothy S. Kern, Philip D. Kiser, Krzysztof Palczewski


      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.09.026
      Issue No: Vol. 114 (2016)
       
  • D-003 (Saccharum officinarum): The forgotten lipid-lowering agent
    • Authors: Kamal Awad; Peter Penson; Maciej Banach
      Pages: 42 - 46
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Kamal Awad, Peter Penson, Maciej Banach
      Reduction of elevated cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-C), is essential in primary and secondary prevention of cardiovascular disease (CVD). Therefore there is still a large need for new effective drugs, which would be able to essentially reduce LDL-C and in the consequence CV residual risk. D-003 is a mixture of high aliphatic primary acids purified from sugarcane (Saccharum officinarum) wax. It showed promising hypocholesterolemic effects in both animal and human studies; it significantly lowers both serum total cholesterol (TC) and LDL-C, and increases high-density lipoprotein cholesterol (HDL-C). In addition, it showed a favorable safety profile. In this review, we evaluated the profile of D-003 as a lipid-lowering agent based on data from available preclinical and clinical studies.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.008
      Issue No: Vol. 114 (2016)
       
  • Upregulation of MKP-7 in response to rosiglitazone treatment ameliorates
           lipopolysaccharide-induced destabilization of SIRT1 by inactivating JNK
    • Authors: Jung Seok Hwang; Sun Ah Ham; Taesik Yoo; Won Jin Lee; Kyung Shin Paek; Jae-Hwan Kim; Chi-Ho Lee; Han Geuk Seo
      Pages: 47 - 55
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Jung Seok Hwang, Sun Ah Ham, Taesik Yoo, Won Jin Lee, Kyung Shin Paek, Jae-Hwan Kim, Chi-Ho Lee, Han Geuk Seo
      Silent mating type information regulation 2 homolog 1 (SIRT1), a NAD-dependent deacetylase, mediates cellular processes involved in gene silencing and aging. The regulation of lifespan by SIRT1 has been extensively investigated, but less is known about the mechanisms associated with its cellular turnover during inflammatory responses. In this study, we found that peroxisome proliferator-activated receptor (PPAR) γ is associated with SIRT1 stability in murine macrophage RAW 264.7 cells exposed to lipopolysaccharide (LPS). Activation of PPARγ by rosiglitazone, a specific ligand of PPARγ, rescues LPS-induced destabilization of SIRT1, with a concomitant decrease in phosphorylation of residue Ser-46, which is targeted by JNK-1 to promote proteasome-mediated degradation of SIRT1. The rosiglitazone-mediated increase in SIRT1 stability is accompanied by upregulation of mitogen-activated protein kinase phosphatase (MKP)-7, a JNK-specific phosphatase. These effects are significantly influenced by ablation or ectopic expression of PPARγ, indicating that PPARγ is directly involved in the regulation of SIRT1 stability. Furthermore, gain of MKP-7 function mimicked the effect of rosiglitazone on LPS-induced destabilization and ubiquitination of SIRT1. These results indicate that PPARγ-dependent upregulation of MKP-7 improves the stability of SIRT1 by inactivating JNK during inflammatory responses of LPS-activated macrophages.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.014
      Issue No: Vol. 114 (2016)
       
  • Nanoparticles for cancer gene therapy: Recent advances, challenges, and
           strategies
    • Authors: Kui Wang; Forrest M. Kievit; Miqin Zhang
      Pages: 56 - 66
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Kui Wang, Forrest M. Kievit, Miqin Zhang
      Compared to conventional treatments, gene therapy offers a variety of advantages for cancer treatment including high potency and specificity, low off-target toxicity, and delivery of multiple genes that concurrently target cancer tumorigenesis, recurrence, and drug resistance. In the past decades, gene therapy has undergone remarkable progress, and is now poised to become a first line therapy for cancer. Among various gene delivery systems, nanoparticles have attracted much attention because of their desirable characteristics including low toxicity profiles, well-controlled and high gene delivery efficiency, and multi-functionalities. This review provides an overview on gene therapeutics and gene delivery technologies, and highlight recent advances, challenges and insights into the design and the utility of nanoparticles in gene therapy for cancer treatment.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.016
      Issue No: Vol. 114 (2016)
       
  • ATB-346, a novel hydrogen sulfide-releasing anti-inflammatory drug,
           induces apoptosis of human melanoma cells and inhibits melanoma
           development in vivo
    • Authors: Paola De Cicco; Elisabetta Panza; Giuseppe Ercolano; Chiara Armogida; Giuseppe Sessa; Giuseppe Pirozzi; Giuseppe Cirino; John L. Wallace; Angela Ianaro
      Pages: 67 - 73
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Paola De Cicco, Elisabetta Panza, Giuseppe Ercolano, Chiara Armogida, Giuseppe Sessa, Giuseppe Pirozzi, Giuseppe Cirino, John L. Wallace, Angela Ianaro
      Inflammation plays a key role in tumor promotion and development. Indeed, cyclooxygenase-2 (COX-2) expression is strongly associated with different types of cancer. An emerging class of compounds with significant anti-inflammatory properties is the hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (H2S-NSAIDs). They consist of a traditional NSAID to which an H2S-releasing moiety is covalently attached. We have recently demonstrated that H2S donors inhibit melanoma cell proliferation. In the current study, we evaluated the potential beneficial effects of a new H2S-releasing derivative of naproxen, ATB-346 [2-(6-methoxynapthalen-2-yl)-propionic acid 4-thiocarbamoyl phenyl ester] which inhibits COX activity but also releases H2S. We used cell culture and a mouse melanoma model to evaluate the effect of ATB-346 on: i) in vitro growth of human melanoma cells; ii) in vivo melanoma development in mice. Cell culture studies demonstrated that ATB-346 reduced the in vitro proliferation of human melanoma cells and this effect was associated to induction of apoptosis and inhibition of NF-κB activation. Moreover, ATB-346 had novel Akt signaling inhibitory properties. Daily oral dosing of ATB-346 (43μmol/kg) significantly reduced melanoma development in vivo. This study shows that ATB-346, a novel H2S-NSAID, inhibits human melanoma cell proliferation by inhibiting pro-survival pathways associated with NF-κB and Akt activation. Furthermore, oral treatment with ATB-346 inhibits melanoma growth in mice. In conclusion, the combination of inhibition of cyclooxygenase and delivery of H2S by ATB-346 may offer a promising alternative to existing therapies for melanoma.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.019
      Issue No: Vol. 114 (2016)
       
  • Editorial to the special issue on the challenge of histamine and histamine
           receptor pharmacology and therapeutics in the 21st century
    • Authors: Ekaterini Tiligada
      First page: 74
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Ekaterini Tiligada


      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.009
      Issue No: Vol. 114 (2016)
       
  • Prophylactic treatment with the tricyclic antidepressant desipramine
           prevents development of paclitaxel-induced neuropathic pain through
           activation of endogenous analgesic systems
    • Authors: Liting Deng; Wan-Hung Lee; Zhili Xu; Alexandros Makriyannis; Andrea G. Hohmann
      Pages: 75 - 89
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Liting Deng, Wan-Hung Lee, Zhili Xu, Alexandros Makriyannis, Andrea G. Hohmann
      Neuropathic pain impacts approximately 3–4.5% of the global population and remains an unresolved health problem. The management of neuropathic pain has two distinct goals—prevention of development and control of established neuropathic pain. We examined the impact of both prophylactic and therapeutic treatments with the tricyclic antidepressant desipramine on the development and maintenance of toxic neuropathic pain induced by the chemotherapeutic agent paclitaxel. We also investigated the involvement of endogenous analgesic (i.e., endogenous opioid and endocannabinoid) systems in the antinociceptive actions of desipramine in these two distinct phases of neuropathic pain. Chronic subcutaneous infusion of desipramine via osmotic pumps suppressed both the development and maintenance of paclitaxel-induced neuropathic pain. However, only prophylactic desipramine treatment blocked the development of neuropathic pain throughout the three month observation interval; neuropathic pain did not return. The opioid receptor antagonist naloxone blocked the antinociceptive effects of both prophylactic and therapeutic desipramine treatments throughout the entire timecourse of desipramine-induced antinociception. By contrast, cannabinoid CB1 and CB2 receptor antagonists partially attenuated the antinociceptive actions of desipramine in a manner that was restricted to the development phase of paclitaxel-induced neuropathic pain only. Paclitaxel decreased cell viability in TMD231 tumor cells in an MTT assay in vitro. Notably, desipramine (1nM–1μM) alone did not alter tumor cell viability and did not prevent the cytotoxic effects of paclitaxel under identical conditions. The highest concentration of desipramine (10μM) reduced tumor cell viability alone and enhanced the cytotoxic effects of paclitaxel. Our study identifies a previously unrecognized preemptive analgesic strategy that prevents development of paclitaxel-induced neuropathic pain, and also dissects receptor mechanisms underlying desipramine-induced antinociceptive effects. This information may be applied to improve current therapeutic strategies with the goal of preventing and managing neuropathic pain induced by chemotherapeutic treatment.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.007
      Issue No: Vol. 114 (2016)
       
  • Structural and functional analogies and differences between histidine
           decarboxylase and aromatic l-amino acid decarboxylase molecular networks:
           Biomedical implications
    • Authors: Francisca Sanchez-Jiménez; Almudena Pino-Ángeles; Rocio Rodríguez-López; María Morales; José Luis Urdiales
      Pages: 90 - 102
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Francisca Sanchez-Jiménez, Almudena Pino-Ángeles, Rocio Rodríguez-López, María Morales, José Luis Urdiales
      Human histidine decarboxylase (HDC) and dopa decarboxilase (DDC) are highly homologous enzymes responsible for the synthesis of biogenic amines (BA) like histamine, and serotonin and dopamine, respectively. The enzymes share many structural and functional analogies, while their product metabolisms also follow similar patterns that are confluent in some metabolic steps. They are involved in common physiological functions, such as neurotransmission, gastrointestinal track function, immunity, cell growth and cell differentiation. As a consequence, metabolic elements of both BA subfamilies are also co-participants in a long list of human diseases. This review summarizes the analogies and differences in their origin (HDC and DDC) as well as their common pathophysiological scenarios. The major gaps of information are also underlined, as they delay the possibility of holistic approaches that would help personalized medicine and pharmacological initiatives for prevalent and rare diseases.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.08.032
      Issue No: Vol. 114 (2016)
       
  • Gender-related differences in pulmonary arterial hypertension targeted
           drugs administration
    • Authors: Alberto M. Marra; Nicola Benjamin; Christina Eichstaedt; Andrea Salzano; Michele Arcopinto; Luna Gargani; Michele D́Alto; Paola Argiento; Lorenzo Falsetti; Paolo Di Giosia; Andrea M. Isidori; Francesco Ferrara; Eduardo Bossone; Antonio Cittadini; Ekkehard Grünig
      Pages: 103 - 109
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Alberto M. Marra, Nicola Benjamin, Christina Eichstaedt, Andrea Salzano, Michele Arcopinto, Luna Gargani, Michele D́Alto, Paola Argiento, Lorenzo Falsetti, Paolo Di Giosia, Andrea M. Isidori, Francesco Ferrara, Eduardo Bossone, Antonio Cittadini, Ekkehard Grünig
      During the last 15 years, a real “paradigm-shift” occurred, due to the development of PAH-targeted drugs, leading to crucial improvements in symptoms, exercise capacity, hemodynamics and outcome of PAH patients. In order to describe differences regarding epidemiology and therapy in PAH according to gender, we performed a review of the available literature in “PubMed” and “Web of Science” databases. In order to find relevant articles, we combined each of the following the keywords “pulmonary arterial hypertension”, “gender”, “sex”, “men”, “woman”, “male”, “female”, “phosphodiesterase inhibitors”, “endothelin receptor antagonists”, “prostanoids”. While there is a substantial agreement among epidemiological studies in reporting an increased prevalence of pulmonary arterial hypertension (PAH) among women, male PAH patients are affected by a higher impairment of the right ventricular function and consequently experience poorer outcomes. With regards to PAH-targeted drug administration, endothelin receptor antagonists (ERAs) and prostacyclin analogues (PC) show better treatment results in female PAH patients, while phosphodiesterase-5 inhibitors (PD5-I) seem to exert a more beneficial effect on male patients. However, to date no clear consensus could be formed by the available literature, which is constituted mainly by retrospective studies. Females with PAH are more prone to develop PAH, while males experience poorer outcomes. Females PAH might benefit more from ERAs and PC, while males seem to have more beneficial effects from PD5-I administration. However, more research is warranted in order to assess the most effective treatment for PAH patients according to gender.
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      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.018
      Issue No: Vol. 114 (2016)
       
  • NADPH oxidases and vascular remodeling in cardiovascular diseases
    • Authors: Ana B. García-Redondo; Andrea Aguado; Ana M. Briones; Mercedes Salaices
      Pages: 110 - 120
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Ana B. García-Redondo, Andrea Aguado, Ana M. Briones, Mercedes Salaices
      Reactive oxygen species (ROS) are key signaling molecules that regulate vascular function and structure in physiological conditions. A misbalance between the production and detoxification of ROS increases oxidative stress that is involved in the vascular remodeling associated with cardiovascular diseases such as hypertension by affecting inflammation, hypertrophy, migration, growth/apoptosis and extracellular matrix protein turnover. The major and more specific source of ROS in the cardiovascular system is the NADPH oxidase (NOX) family of enzymes composed of seven members (NOX1-5, DUOX 1/2). Vascular cells express several NOXs being NOX-1 and NOX-4 the most abundant NOXs present in vascular smooth muscle cells. This review focuses on specific aspects of NOX-1 and NOX-4 isoforms including information on regulation, function and their role in vascular remodeling. In order to obtain a more integrated view about the role of the different NOX isoforms in different types of vascular remodeling, we discuss the available literature not only on hypertension but also in atherosclerosis, restenosis and aortic dilation.

      PubDate: 2016-10-28T22:25:48Z
      DOI: 10.1016/j.phrs.2016.10.015
      Issue No: Vol. 114 (2016)
       
  • Genetic variations within the promotor region of the human histamine H4
           receptor gene in psoriasis patients
    • Authors: Susanne Mommert; Lisanne Ratz; Kira Herwig; Maren Rost; Ralf Gutzmer; Thomas Werfel
      Pages: 121 - 127
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Susanne Mommert, Lisanne Ratz, Kira Herwig, Maren Rost, Ralf Gutzmer, Thomas Werfel
      Environmental triggers and genetic factors are supposed to lead to complex gene expression changes in psoriasis and interact in the manifestation of the disease. The histamine H4 receptor (HRH4) is functionally expressed on Th17 cells and plasmacytoid dendritic cells (pDCs) which play a prominent role in the pathogenesis of psoriasis. On pDCs a higher basal expression level of the HRH4 in psoriasis patients compared to healthy controls has been detected. The functional relationship between predisposing genetic variations in the HRH4 gene and psoriasis is yet not known. The aim of the study was to evaluate a possible association between single nucleotide polymorphisms (SNPs) in the HRH4 gene primarily in the promotor region and incidence, severity as well as special clinical features (nail involvement, arthritis, palmoplantar location) of psoriasis. For this approach genomic DNA from 206 patients with psoriasis and 213 healthy controls of Caucasian origin was extracted and three SNPs in the promotor region and one SNP located in an intron of the HRH4 gene were analysed by PCR and pyrophosphate DNA-sequencing. The genotype distributions and allele frequencies between the different groups were compared by chi-square test. The analysis of association between HRH4 polymorphisms and psoriasis was assessed by odds ratio with 95% confidence interval. The genotype distributions and allele frequencies of the four SNPs in the HRH4 gene did not show obvious differences between the whole group of psoriasis patients and healthy controls. However, there were differences by trend in subgroup analysis: The mutant genotypes (A/G) of rs17203314 and (G/A) of rs615283 were more frequent in patients with severe psoriasis PASI≥30 (34.8% and 34.8%) when compared to the control groups (23.5% and 27.2%), respectively. The mutant G/A genotype of rs615283 was significantly more frequent in patients with moderate-to-severe psoriasis PASI≥10 when compared to mild psoriasis PASI<10 (33.3% vs 21.7%, p=0.022). For rs524149 and rs17797945 the wildtype CC genotype was more frequent by trend in moderately-to-severely affected patients with PASI≥10 (85.2% and 63.0%) when compared to the group with mild psoriasis PASI<10 (77.0% and 49.4%), respectively. Furthermore, a significant association of rs615283 with psoriasis palmoplantaris was detected. In conclusion our study suggests that genetic variations within the HRH4 gene might be associated with special clinical features of psoriasis. Further studies are needed in larger study populations to confirm the reported associations and investigate the functional relevance of the identified SNPs.
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      PubDate: 2016-11-02T23:50:45Z
      DOI: 10.1016/j.phrs.2016.10.003
      Issue No: Vol. 114 (2016)
       
  • Phytomedicine—Modulating oxidative stress and the tumor
           microenvironment for cancer therapy
    • Authors: Yu-Ting Cheng; Chun-Chih Yang; Lie-Fen Shyur
      Pages: 128 - 143
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Yu-Ting Cheng, Chun-Chih Yang, Lie-Fen Shyur
      In spite of the current advances and achievements in systems biology and translational medicinal research, the current strategies for cancer therapy, such as radiotherapy, targeted therapy, immunotherapy and chemotherapy remain palliative or unsatisfactory due to tumor metastasis or recurrence after surgery/therapy, drug resistance, adverse side effects, and so on. Oxidative stress (OS) plays a critical role in chronic/acute inflammation, carcinogenesis, tumor progression, and tumor invasion/metastasis which is also attributed to the dynamic and complex properties and activities in the tumor microenvironment (TME). Re-educating or reprogramming tumor-associated stromal or immune cells in the TME provides an approach for restoring immune surveillance impaired by disease in cancer patients to increase overall survival and reduce drug resistance. Herbal medicines or plant-derived natural products have historically been a major source of anti-cancer drugs. Delving into the lore of herbal medicine may uncover new leads for anti-cancer drugs. Phytomedicines have been widely documented to directly or indirectly target multiple signaling pathways and networks in cancer cells. A combination of anti-cancer drugs and polypharmacological plant-derived extracts or compounds may offer a significant advantage in sensitizing the efficacy of monotherapy and overcoming drug-induced resistance in cancer patients. This review introduces several phytochemicals and phytoextracts derived from medicinal plants or dietary vegetables that have been studied for their efficacy in preclinical cancer models. We address the underlying modes of action of induction of OS and deregulation of TME-associated stromal cells, mediators and signaling pathways, and reference the related clinical investigations that look at the single or combination use of phytochemicals and phytoextracts to sensitize anti-cancer drug effects and/or overcome drug resistance.
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      PubDate: 2016-11-02T23:50:45Z
      DOI: 10.1016/j.phrs.2016.10.022
      Issue No: Vol. 114 (2016)
       
  • Focused ultrasound induced hyperthermia accelerates and increases the
           uptake of anti-HER-2 antibodies in a xenograft model
    • Authors: Miguel N. Centelles; Michael Wright; Wladyslaw Gedroyc; Maya Thanou
      Pages: 144 - 151
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Miguel N. Centelles, Michael Wright, Wladyslaw Gedroyc, Maya Thanou
      Image guided drug delivery has gained significant attention during the last few years. Labelling nanoparticles or macromolecules and monitoring their fate in the body provides information that can be used to modulate their biodistribution and improve their pharmacokinetics. In this study we label antibodies and monitor their distribution in the tumours post intravenous injection. Using Focused Ultrasound (FUS, a non-invasive method of hyperthermia) we increase the tumour temperature to 42°C for a short period of time (3–5min) and we observe an increased accumulation of labelled antibody. Repetition of focused ultrasound induced hyperthermic treatment increased still further the accumulation of the antibodies in the tumour. This treatment also augmented the accumulation of other macromolecules non-specific to the tumour, such as IgG and albumin. These effects may be used to enhance the therapeutic efficiency of antibodies and/or targeted nanoparticles.
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      PubDate: 2016-11-02T23:50:45Z
      DOI: 10.1016/j.phrs.2016.10.017
      Issue No: Vol. 114 (2016)
       
  • Androgen receptor variation affects prostate cancer progression and drug
           resistance
    • Authors: Edel McCrea; Tristan M. Sissung; Douglas K. Price; Cindy H. Chau; William D. Figg
      Pages: 152 - 162
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Edel McCrea, Tristan M. Sissung, Douglas K. Price, Cindy H. Chau, William D. Figg
      Significant therapeutic progress has been made in treating prostate cancer in recent years. Drugs such as enzalutamide, abiraterone, and cabazitaxel have expanded the treatment armamentarium, although it is not completely clear which of these drugs are the most-effective option for individual patients. Moreover, such advances have been tempered by the development of therapeutic resistance. The purpose of this review is to summarize the current literature pertaining to the biochemical effects of AR variants and their consequences on prostate cancer therapies at both the molecular level and in clinical treatment. We address how these AR splice variants and mutations affect tumor progression and therapeutic resistance and discuss potential novel therapeutic strategies under development. It is hoped that these therapies can be administered with increasing precision as tumor genotyping methods become more sophisticated, thereby lending clinicians a better understanding of the underlying biology of prostate tumors in individual patients.
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      PubDate: 2016-11-02T23:50:45Z
      DOI: 10.1016/j.phrs.2016.10.001
      Issue No: Vol. 114 (2016)
       
  • Incorporating imaging into personalized medicine for the detection of
           prostate cancer
    • Authors: Francesca Mertan; Baris Turkbey
      Pages: 163 - 165
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Francesca Mertan, Baris Turkbey
      Imaging has played an important role in the administration of personalized medicine. From diagnosing diseases to guiding therapies, imaging has become an all-encompassing modality. With respect to prostate cancer, personalized management of the disease has been transformed by imaging. Specifically, multiparametric magnetic resonance imaging has emerged as a vital player in the detection, characterization, and localization of the disease thus making the incorporation of imaging in personalized prostate cancer management integral. In this review, the current role of imaging in personalized medicine for the management of prostate cancer is discussed.
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      PubDate: 2016-11-03T23:58:44Z
      DOI: 10.1016/j.phrs.2016.10.020
      Issue No: Vol. 114 (2016)
       
  • ACE inhibitors, left ventricular mass and renal cyst growth in ADPKD
    • Authors: Robert W. Schrier
      Pages: 166 - 168
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Robert W. Schrier
      The review focuses on the common kidney disorder of Autosomal Dominant Polycystic Kidney Disease (ADPKD). The potential pathogenetic role of the renin-angiotensin-aldosterone system (RAAS) in the renal cyst growth, the accompanying hypertension, and the frequency of increased left ventricular mass is considered. The therapeutic benefit of angiotensin converting enzyme inhibition (ACEI) in diminishing the renal cyst growth, treatment of the hypertension, and reversing the increased left ventricular mass in ADPKD is supportive of this possibility. The effects of ACEI related and unrelated to control of blood pressure are discussed.

      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.10.002
      Issue No: Vol. 114 (2016)
       
  • Over-expression of V1A receptors in PVN modulates autonomic cardiovascular
           control
    • Authors: Maja Lozić; Tatjana Tasić; Andrew Martin; Michael Greenwood; Olivera Šarenac; Charles Hindmarch; Julian F. Paton; David Murphy; Nina Japundžić-Žigon
      Pages: 185 - 195
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Maja Lozić, Tatjana Tasić, Andrew Martin, Michael Greenwood, Olivera Šarenac, Charles Hindmarch, Julian F. Paton, David Murphy, Nina Japundžić-Žigon
      The hypothalamic paraventricular nucleus (PVN) is a key integrative site for the neuroendocrine control of the circulation and of the stress response. It is also a major source of the neuropeptide hormone vasopressin (VP), and co-expresses V1a receptors (V1aR). We thus sought to investigate the role of V1aR in PVN in cardiovascular control in response to stress. Experiments were performed in male Wistar rats equipped with radiotelemetric device. The right PVN was transfected with adenoviral vectors (Ads) engineered to over-express V1aR along with an enhanced green fluorescent protein (eGFP) tag. Control groups were PVN transfected with Ads expressing eGFP alone, or wild-type rats (Wt). Rats were recorded with and without selective blockade of V1aR (V1aRX) in PVN under both baseline and stressed conditions. Blood pressure (BP), heart rate (HR), their short-term variabilities, and baroreflex sensitivity (BRS) were evaluated using spectral analysis and the sequence method, respectively. Under baseline physiological conditions,V1aR rats exhibited reduced BRS and a marked increase of BP and HR variability during exposure to stress. These effects were all prevented by V1aRX pretreatment. In Wt rats, V1aRX did not modify cardiovascular parameters under baseline conditions, and prevented BP variability increase by stress. However, V1aRX pretreatment did not modify baroreflex desensitization by stress in either rat strain. It follows that increased expression of V1aR in PVN influences autonomic cardiovascular regulation and demarcates vulnerability to stress. We thus suggest a possible role of hypothalamic V1aR in cardiovascular pathology.
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      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.10.024
      Issue No: Vol. 114 (2016)
       
  • Opioid gene expression changes and post-translational histone
           modifications at promoter regions in the rat nucleus accumbens after acute
           and repeated 3,4-methylenedioxy-methamphetamine (MDMA) exposure
    • Authors: Francesca Felicia Caputi; Martina Palmisano; Lucia Carboni; Sanzio Candeletti; Patrizia Romualdi
      Pages: 209 - 218
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Francesca Felicia Caputi, Martina Palmisano, Lucia Carboni, Sanzio Candeletti, Patrizia Romualdi
      The recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has been shown to produce neurotoxic damage and long-lasting changes in several brain areas. In addition to the involvement of serotoninergic and dopaminergic systems, little information exists about the contribution of nociceptin/orphaninFQ (N/OFQ)-NOP and dynorphin (DYN)-KOP systems in neuronal adaptations evoked by MDMA. Here we investigated the behavioral and molecular effects induced by acute (8mg/kg) or repeated (8mg/kg twice daily for seven days) MDMA exposure. MDMA exposure affected body weight gain and induced hyperlocomotion; this latter effect progressively decreased after repeated administration. Gene expression analysis indicated a down-regulation of the N/OFQ system and an up-regulation of the DYN system in the nucleus accumbens (NAc), highlighting an opposite systems regulation in response to MDMA exposure. Since histone modifications have been strongly associated to the addiction-related maladaptive changes, we examined two permissive (acH3K9 and me3H3K4) and two repressive transcription marks (me3H3K27 and me2H3K9) at the pertinent opioid gene promoter regions. Chromatin immunoprecipitation assays revealed that acute MDMA increased me3H3K4 at the pN/OFQ, pDYN and NOP promoters. Following acute and repeated treatment a significant decrease of acH3K9 at the pN/OFQ promoter was observed, which correlated with gene expression results. Acute treatment caused an acH3K9 increase and a me2H3K9 decrease at the pDYN promoter which matched its mRNA up-regulation. Our data indicate that the activation of the DYNergic stress system together with the inactivation of the N/OFQergic anti-stress system contribute to the neuroadaptive actions of MDMA and offer novel epigenetic information associated with MDMA abuse.
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      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.10.023
      Issue No: Vol. 114 (2016)
       
  • Interaction between endogenous carbon monoxide and hydrogen sulfide in the
           mechanism of gastroprotection against acute aspirin-induced gastric damage
           
    • Authors: Marcin Magierowski; Katarzyna Magierowska; Magdalena Hubalewska-Mazgaj; Juliusz Adamski; Dominik Bakalarz; Zbigniew Sliwowski; Robert Pajdo; Slawomir Kwiecien; Tomasz Brzozowski
      Pages: 235 - 250
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Marcin Magierowski, Katarzyna Magierowska, Magdalena Hubalewska-Mazgaj, Juliusz Adamski, Dominik Bakalarz, Zbigniew Sliwowski, Robert Pajdo, Slawomir Kwiecien, Tomasz Brzozowski
      Acetylsalicylic acid (ASA) is mainly recognized as painkiller or anti-inflammatory drug. However, ASA causes serious side effects towards gastrointestinal (GI) tract which limits its usefulness. Carbon monoxide (CO) and hydrogen sulfide (H2S) have been described to act as important endogenous messengers and mediators of gastroprotection but whether they can interact in gastroprotection against acute ASA-induced gastric damage remains unknown. In this study male Wistar rats were pretreated with 1) vehicle (saline, i.g.), 2) tricarbonyldichlororuthenium (II) dimer (CORM-2, 5mg/kg i.g.), 3) sodium hydrosulfide (NaHS, 5mg/kg i.g.), 4) zinc protoporphyrin (ZnPP, 10mg/kg i.p.), 5) D,L-propargylglycine (PAG, 30mg/kg i.g.), 6) ZnPP combined with NaHS, 7) PAG combined with CORM-2 or 8) 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10mg/kg i.p.) combined with CORM-2 or NaHS and 30min later ASA was administered i.g. in a single dose of 125mg/kg. After 1h, gastric blood flow (GBF) was determined by H2 gas clearance technique and gastric lesions were assessed by planimetry and histology. CO content in gastric mucosa and COHb concentration in blood were determined by gas chromatography and H2S production was assessed in gastric mucosa using methylene blue method. Protein and/or mRNA expression for cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), heme oxygenase (HO)-1, HO-2, hypoxia inducible factor-alpha (HIF)-1α, nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX)-1 and COX-2, inducible nitric oxide synthase (iNOS) and interleukin (IL)-1β were determined by Western blot or real-time PCR, respectively. ASA caused hemorrhagic gastric mucosal damage and significantly decreased GBF, H2S production, CO content, mRNA or protein expression for CSE, 3-MST, HO-2 and increased mRNA and/or protein expression for CBS, HO-1, Nrf-2, HIF-1α, iNOS, IL-1β, COX-2 in gastric mucosa and COHb concentration in blood. Pretreatment with CORM-2 or NaHS but not with PAG decreased ASA-damage and increased GBF. ZnPP reversed protective and hyperemic effect of NaHS but PAG failed to affect CORM-2-induced gastroprotection. CORM-2 elevated CO content, mRNA or protein expression for HO-1, Nrf-2, and decreased expression of CBS, HIF-1α, COX-2, IL-1β, iNOS, the H2S production in gastric mucosa and COHb concentration in blood. NaHS raised mRNA or protein expression for CSE, COX-1 and decreased mRNA expression for IL-1β and COHb level in blood. We conclude that CO is involved in gastroprotection induced by H2S while beneficial protective action of CO released from CORM-2 in gastric mucosa seems to be H2S-independent. In contrast to H2S, CO ameliorates hypoxia, regulates Nrf-2 expression but similarly to H2S acts on sGC-dependent manner to restore gastric microcirculation and exhibit anti-inflammatory activity in gastric mucosa compromised by ASA.
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      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.11.001
      Issue No: Vol. 114 (2016)
       
  • Roles of the NLRP3 inflammasome in the pathogenesis of diabetic
           nephropathy
    • Authors: Yuan-ye Qiu; Li-qin Tang
      Pages: 251 - 264
      Abstract: Publication date: December 2016
      Source:Pharmacological Research, Volume 114
      Author(s): Yuan-ye Qiu, Li-qin Tang
      Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and persistent inflammation in circulatory and renal tissues is an important pathophysiological basis for DN. The essence of the microinflammatory state is the innate immune response, which is central to the occurrence and development of DN. Members of the inflammasome family, including both “receptors” and “regulators”, are key to the inflammatory immune response. Nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) and other inflammasome components are able to detect endogenous danger signals, resulting in activation of caspase-1 as well as interleukin (IL)-1β, IL-18 and other cytokines; these events stimulate the inflammatory cascade reaction, which is crucial for DN. Hyperglycaemia, hyperlipidaemia and hyperuricaemia can activate the NLRP3 inflammasome, which then mediates the occurrence and development of DN through the K+ channel model, the lysosomal damage model and the active oxygen cluster model. In this review, we survey the involvement of the NLRP3 inflammasome in various signalling pathways and highlight different aspects of their influence on DN. We also explore the important effects of the NLRP3 inflammasome on kidney function and structural changes that occur during DN development and progression. It is becoming more evident that NLRP3 inflammasome targeting has therapeutic potential for the treatment of DN.
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      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.11.004
      Issue No: Vol. 114 (2016)
       
  • Therapeutic Implications of Toll-like Receptors in Peripheral Neuropathic
           Pain
    • Authors: Krishan K. Thakur; Jyoti Saini; Kanika Mahajan; Dhyanendra Singh; Dinkar P. Jaiswal; Srishti Mishra; Anupam Bishyaee; Gautam Sethi; Ajaikumar B. Kunnumakkara
      Abstract: Publication date: Available online 25 November 2016
      Source:Pharmacological Research
      Author(s): Krishan K. Thakur, Jyoti Saini, Kanika Mahajan, Dhyanendra Singh, Dinkar P. Jaiswal, Srishti Mishra, Anupam Bishyaee, Gautam Sethi, Ajaikumar B. Kunnumakkara
      Neuropathic pain is a state of chronic pain arising after peripheral or central nerve injury. These injuries can be mediated through the activation of various cells (astrocytes, microglia and Schwann cells), as well as the dissolution of distal axons. Recent studies have suggested that after nerve injury, Toll-like receptors (TLRs) are involved in Wallerian degeneration and generation of neuropathic pain. Furthermore, these TLRs are responsible for the stimulation of astrocytes and microglia that can cause induction of the proinflammatory mediators and cytokines in the spinal cord, thereby leading to the generation and maintenance of neuropathic pain. Indeed considering the prevalence of neuropathic pain and the suffering of the affected patients, insights into the diverse mechanism(s) of activation of TLR signaling cascades may open novel avenues for the management of this chronic condition. Moreover, existing therapies like antidepressants, anticonvulsants, opiates and other analgesic are not sufficiently effective in reducing the pain. In this review, we present substantial evidences highlighting the diverse roles of TLRs and their signaling pathways involved in the progression of neuropathic pain. Furthermore, an elaborate discussion on various existing treatment regimens and future targets involving TLRs has also been included.
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      PubDate: 2016-12-01T09:16:25Z
      DOI: 10.1016/j.phrs.2016.11.019
       
  • Sex and gender differences in the treatment of Alzheimer’s disease: a
           systematic review of randomized controlled trials
    • Authors: Marco Canevelli; Federica Quarata; Francesca Remiddi; Flaminia Lucchini; Eleonora Lacorte; Nicola Vanacore; Giuseppe Bruno; Matteo Cesari
      Abstract: Publication date: Available online 30 November 2016
      Source:Pharmacological Research
      Author(s): Marco Canevelli, Federica Quarata, Francesca Remiddi, Flaminia Lucchini, Eleonora Lacorte, Nicola Vanacore, Giuseppe Bruno, Matteo Cesari
      In recent years, epidemiological, clinical, and biological evidence has drawn the attention on the influence of sex and gender on Alzheimer’s disease (AD). Nevertheless, not enough attention has been paid to their impact on treatment outcomes. The present study is aimed at systematically retrieve, review and discuss data coming from available randomized placebo-controlled trials (RCTs) on currently marketed treatments for AD (i.e., cholinesterase inhibitors [ChEIs] and memantine) in order to describe possible sex and gender differences in their efficacy, safety and tolerability. A systematic review of literature was performed. None of the retrieved studies reported data on the efficacy, safety and tolerability of considered medications separately in male and female patients with AD. We thus analyzed 48 excluded studies of potential interest, that is, almost all of the currently available trials on the four considered drugs. Nearly all the considered RCTs recruited a larger number of female participants to mirror the sexually unbalanced prevalence of AD. Only two studies took into account the potential influence of sex and gender on treatment efficacy, reporting no significant differences between men and women. None of the studies investigated potential sex and gender differences in the safety and tolerability of the four considered treatments. The existence of sex and gender differences in the efficacy and tolerability of ChEIs and memantine in AD has, to date, drawn limited to no attention. However, a considerable amount of data, with an adequate representativeness in terms of sex/gender distribution, seem to be already available for dedicated analyses on this topic. A greater effort should be made to collect and report data on those factors interacting with sex and gender that may significantly influence clinical manifestations, outcomes, and trajectories over time of AD patients.
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      PubDate: 2016-12-01T09:16:25Z
      DOI: 10.1016/j.phrs.2016.11.035
       
  • New preclinical model are required to discover neuroprotective compound in
           Parkinson’s disease
    • Authors: Juan Segura-Aguilar
      Abstract: Publication date: Available online 25 November 2016
      Source:Pharmacological Research
      Author(s): Juan Segura-Aguilar


      PubDate: 2016-12-01T09:16:25Z
      DOI: 10.1016/j.phrs.2016.11.034
       
  • The anabolic steroid nandrolone alters cannabinoid self-administration and
           brain CB1 receptor density and function
    • Authors: Dicky Struik; Paola Fadda; Tamara Zara; Erica Zamberletti; Tiziana Rubino; Daniela Parolaro; Walter Fratta; Liana Fattore
      Abstract: Publication date: Available online 24 November 2016
      Source:Pharmacological Research
      Author(s): Dicky Struik, Paola Fadda, Tamara Zara, Erica Zamberletti, Tiziana Rubino, Daniela Parolaro, Walter Fratta, Liana Fattore
      Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN) in rats. Lister Hooded male rats were treated intramuscularly with nandrolone (15mg/kg) or vehicle for 14 consecutive days, and then allowed to self-administer WIN (12.5μg/kg/infusion) intravenously. After reaching stable drug intake, self-administration behavior was extinguished to examine drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Other behavioral parameters presumed to influence drug-taking and drug-seeking behaviors were examined to gain more insight into the behavioral specificity of nandrolone treatment. Finally, animals were sacrificed for analysis of CB1 receptor density and function in selected brain areas. We found that nandrolone-treated rats self-administered up to 2 times more cannabinoid than vehicle-treated rats, but behaved similarly to control rats when tested for drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Enhanced cannabinoid intake by nandrolone-treated rats was not accompanied by changes in locomotor activity, sensorimotor gating, or memory function. However, our molecular data show that after chronic WIN self-administration nandrolone-treated rats display altered CB1 receptor density and function in selected brain areas. We hypothesize that increased cannabinoid self-administration in nandrolone-treated rats results from a nandrolone-induced decrease in reward function, which rats seem to compensate by voluntarily increasing their cannabinoid intake. Altogether, our findings corroborate the hypothesis that chronic exposure to anabolic-androgenic steroids induces dysfunction of the reward pathway in rats and might represent a potential risk factor for abuse of cannabis and other drugs in humans.
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      PubDate: 2016-12-01T09:16:25Z
      DOI: 10.1016/j.phrs.2016.11.031
       
  • Effects of Zacopride, a Moderate IK1 channel agonist, on Triggered
           Arrhythmia and Contractility in Human Ventricular Myocardium
    • Authors: Mohammad T. Elnakish; Benjamin D. Canan; Ahmet Kilic; Peter J. Mohler; Paul M.L. Janssen
      Abstract: Publication date: Available online 30 November 2016
      Source:Pharmacological Research
      Author(s): Mohammad T. Elnakish, Benjamin D. Canan, Ahmet Kilic, Peter J. Mohler, Paul M.L. Janssen
      Ventricular tachycardia is the leading cause of sudden arrhythmic death in the U.S. Recently, the moderate IK1 channel activator, zacopride, was shown to suppress triggered ventricular tachycardia in rats. Nonetheless, concerns were raised about the possibility of pro-arrhythmic activity after IK1 channel stimulation based on the promising anti-arrhythmic strategy of IK1 blockade in other animal models. Therefore, the goal of the current study was to investigate the ex-vivo effects of zacopride on triggered arrhythmia and contractility in ventricular human myocardium in order to validate data that was solely obtained from animal models. Application of 100nmol/L isoproterenol and 0.5mmol/L caffeine led to triggered arrhythmia in isolated cardiac muscles from non-failing and end-stage failing hearts. However, the occurrence of arrhythmia in muscles of non-failing hearts was markedly higher than those of end-stage failing hearts. Interestingly, zacopride eliminated the ex-vivo triggered arrhythmia in these muscles of non-failing and failing hearts in a concentration-dependent manner, with an effective IC50 in the range of 28 to 40μmol/L. Conversely, in the absence of isoproterenol/caffeine, zacopride led to a negative inotropic effect in a concentration-dependent manner. Reduced cardiac contraction was clearly observed at high zacopride concentration of 200μmol/L, along with the occurrence of contractile alternans in muscles of non-failing and failing hearts. Zacopride shows promising antiarrhythmic effects against triggered arrhythmia in ventricular human myocardium. However, in the absence of Ca2+ overload/arrhythmia, zacopride, albeit at high concentrations, decreases the force of contraction and increases the likelihood of occurrence of contractile alternans, which may predispose the heart to contractile dysfunction and/or arrhythmia. Overall, our results represent a key step in translating this drug from the benchtop to the bedside in the research area.
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      PubDate: 2016-12-01T09:16:25Z
      DOI: 10.1016/j.phrs.2016.11.033
       
  • Significant HLA class I type associations with aromatic antiepileptic drug
           (AED)-induced SJS/TEN are different from those found for the same
           AED-induced DRESS in the Spanish population
    • Authors: Elena Ramírez; Teresa Bellón; Hoi Y. Tong; Alberto M. Borobia; Francisco J. de Abajo; Victoria Lerma; Miguel A. Moreno Hidalgo; José L. Castañer; Rosario Cabañas; Ana Fiandor; Jessica González-Ramos; Pedro Herranz; Lucía Cachafeiro; Carlos González-Herrada; Olga González; José A. Aramburu; Olga Laosa; Rafael Hernández; Antonio J. Carcas; Jesús Frías
      Abstract: Publication date: Available online 22 November 2016
      Source:Pharmacological Research
      Author(s): Elena Ramírez, Teresa Bellón, Hoi Y. Tong, Alberto M. Borobia, Francisco J. de Abajo, Victoria Lerma, Miguel A. Moreno Hidalgo, José L. Castañer, Rosario Cabañas, Ana Fiandor, Jessica González-Ramos, Pedro Herranz, Lucía Cachafeiro, Carlos González-Herrada, Olga González, José A. Aramburu, Olga Laosa, Rafael Hernández, Antonio J. Carcas, Jesús Frías
      Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class-I and AED-induced SCARs in the Spanish population. HLA class-I genotypes were determined in AED (phenytoin[PHT],lamotrigine[LTG],carbamazepine[CBZ],phenobarbital[PB])-induced SJS/TEN(n=15) or DRESS(n=12) cases included in the Spanish SCAR registry,PIELenRed. There were 3 control groups:(A)tolerant to a single AED, (B)tolerant to any AED, and (C)Spanish population controls. For SJS/TEN, concomitant HLA-A*02:01/Cw15:02 alleles were significantly associated with PHT-cases compared to control groups B and C [(B)odds ratio(OR):14.75,p=.009;(C)OR:27.50, p<.001], and were close to significance with respect to control group A (p=.060). The genotype frequency of the HLA-B*38:01 was significantly associated with PHT-LTG-cases compared with the 3 groups of controls [(A)OR:12.86, p=.012;(B)OR:13.81; p=.002;(C)OR:14.35,p<.001], and with LTG-cases [(A)OR:147.00, p=.001;(B)OR:115.00, p<.001;(C)OR:124.70,p<.001]. We found the HLA-B*15:02 allele in a Spanish Romani patient with a CBZ-case. The HLA-A*11:01 was significantly associated with CBZ-cases [(A)OR:63.89, p=.002;(B)OR:36.33,p=.005;(C)OR:28.29,p=.007]. For DRESS, the HLA-A*24:02 genotype frequency was statistically significant in the PHT-LTG-cases [(A)OR:22.56, p=.003;(B)OR:23.50.p=.001;(C)OR:33.25,p<.001], and in the LTG-cases [(A),OR:49.00, p=.015;(B)OR:27.77,p=.005;(C)OR:34.53,p=.002]. HLA-A*31:01 was significantly associated with the CBZ-cases [(A)OR:22.00,p=.047;(B)OR:29.50,p=.033;(C)OR:35.14, p=.006]. In conclusion, we identified several significant genetic risk factors for the first time in the Spanish Caucasian population: HLA-A*02:01/Cw*15:02 combination as a risk factor for PHT-induced SJS/TEN, HLA-B*38:01 for LTG- and PHT- induced SJS/TEN, HLA-A*11:01 for CBZ-induced SJS/TEN, and HLA-A*24:02 for LTG- and PHT- induced DRESS. The strong association between HLA*31:01 and CBZ-DRESS in Europeans was confirmed in this study.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.027
       
  • CURCUMIN USE IN PULMONARY DISEASES: STATE OF THE ART AND FUTURE
           PERSPECTIVES
    • Authors: Diana Lelli; Amirhossein Sahebkar; Thomas P. Johnston; Claudio Pedone
      Abstract: Publication date: Available online 22 November 2016
      Source:Pharmacological Research
      Author(s): Diana Lelli, Amirhossein Sahebkar, Thomas P. Johnston, Claudio Pedone
      Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa). It has been used for centuries in Ayurveda (Indian traditional medicine) for the treatment of several diseases. Over the last several decades, the therapeutic properties of curcumin have slowly been elucidated. It has been shown that curcumin has pleiotropic effects, regulating transcription factors (e.g., NF-kB), cytokines (e.g., IL6, TNF-alpha), adhesion molecules (e.g., ICAM-1), and enzymes (e.g., MMPs) that play a major role in inflammation and cancerogenesis. These effects may be relevant for several pulmonary diseases that are characterized by abnormal inflammatory responses, such as asthma or chronic obstructive pulmonary disease, acute respiratory distress syndrome, pulmonary fibrosis, and acute lung injury. Furthermore, some preliminary evidence suggests that curcumin may have a role in the treatment of lung cancer. The evidence for the use of curcumin in pulmonary disease is still sparse and has mostly been obtained using either in vitro or animal models. The most important issue with the use of curcumin in humans is its poor bioavailability, which makes it necessary to use adjuvants or curcumin nanoparticles or liposomes. The aim of this review is to summarize the available evidence on curcumin’s effectiveness in pulmonary diseases, including lung cancer, and to provide our perspective on future research with curcumin so as to improve its pharmacological effects, as well as provide additional evidence of curcumin’s efficacy in the treatment of pulmonary diseases.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.017
       
  • Effects of Pomegranate Juice on Blood Pressure: A Systematic Review and
           Meta-analysis of Randomized Controlled Trials
    • Authors: Amirhossein Sahebkar; Claudio Ferri; Paolo Giorgini; Simona Bo; Petr Nachtigal; Davide Grassi
      Abstract: Publication date: Available online 23 November 2016
      Source:Pharmacological Research
      Author(s): Amirhossein Sahebkar, Claudio Ferri, Paolo Giorgini, Simona Bo, Petr Nachtigal, Davide Grassi
      Punica granatum L. (Pomegranate) has been claimed to provide several health benefits. Pomegranate juice is a polyphenol-rich fruit juice with high antioxidant capacity. Several studies suggested that pomegranate juice can exert antiatherogenic, antioxidant, antihypertensive, and anti-inflammatory effects. Nevertheless, the potential cardioprotective benefits of pomegranate juice deserve further clinical investigation. To systematically review and meta-analyze available evidence from randomized placebo-controlled trials (RCTs) investigating the effects of pomegranate juice consumption and blood pressure (BP). A comprehensive literature search in Medline and Scopus was carried out to identify eligible RCTs. A meta-analysis of eligible studies was performed using a random-effects model. Quality assessment, sensitivity analysisand publication bias evaluations were conducted using standard methods. Quantitative data synthesis from 8 RCTs showed significant reductions in both systolic [weighed mean difference (WMD): −4.96mmHg, 95% CI: −7.67 to −2.25, p<0.001) and diastolic BP (WMD: −2.01mmHg, 95% CI: −3.71 to −0.31, p=0.021) after pomegranate juice consumption. Effects on SBP remained stable to sensitivity analyses. Pomegranate juice reduced SBP regardless of the duration (>12 wks: WMD=−4.36mmHg, 95% CI: −7.89 to −0.82, p=0.016) and <12 wks: WMD=−5.83 mmHg, 95% CI: −10.05 to −1.61, p=0.007) and dose consumed (>240cc: WMD=−3.62mmHg, 95% CI: −6.62 to −0.63, p=0.018) and <240cc: WMD=−11.01mmHg, 95% CI: −17.38 to −4.65, p=0.001, pomegranate juice per day) whereas doses >240cc provided a borderline significant effect in reducing DBP. The present meta-analysis suggests consistent benefits of pomegranate juice consumption on BP. This evidence suggests it may be prudent to include this fruit juice in a heart-healthy diet.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.018
       
  • Modulation of VEGF Receptor 2 signaling by Protein Phosphatases
    • Authors: Federico Corti; Michael Simons
      Abstract: Publication date: Available online 23 November 2016
      Source:Pharmacological Research
      Author(s): Federico Corti, Michael Simons
      Phosphorylation of serines, threonines, and tyrosines is a central event in signal transduction cascades in eukaryotic cells. The phosphorylation state of any particular protein reflects a balance of activity between kinases and phosphatases. Kinase biology has been exhaustively studied and is reasonably well understood, however, much less is known about phosphatases. A large body of evidence now shows that protein phosphatases do not behave as indiscriminate signal terminators, but can function both as negative or positive regulators of specific signaling pathways. Genetic models have also shown that different protein phosphatases play precise biological roles in health and disease. Finally, genome sequencing has unveiled the existence of many protein phosphatases and associated regulatory subunits comparable in number to kinases. A wide variety of roles for protein phosphatase roles have been recently described in the context of cancer, diabetes, hereditary disorders and other diseases. In particular, there have been several recent advances in our understanding of phosphatases involved in regulation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling. The receptor is the principal signaling molecule mediating a wide spectrum of VEGF signal and, thus, is of paramount significance in a wide variety of diseases ranging from cancer to cardiovascular to ophthalmic. This review focuses on the current knowledge about protein phosphatases’ regulation of VEGFR2 signaling and how these enzymes can modulate affect its biological effects.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.022
       
  • Metabolomic profile of children with recurrent respiratory infections
    • Authors: Sara Bozzetto; Paola Pirillo; Silvia Carraro; Mariangela Berardi; Laura Cesca; Matteo Stocchero; Giuseppe Giordano; Stefania Zanconato; Eugenio Baraldi
      Abstract: Publication date: Available online 22 November 2016
      Source:Pharmacological Research
      Author(s): Sara Bozzetto, Paola Pirillo, Silvia Carraro, Mariangela Berardi, Laura Cesca, Matteo Stocchero, Giuseppe Giordano, Stefania Zanconato, Eugenio Baraldi
      Recurrent respiratory infections (RRI) represent a widespread condition which has a severe social and economic impact. Immunostimulants are used for their prevention. It is crucial to better characterize children with RRI to refine their diagnosis and identify effective personalized prevention strategies. Metabolomics is a high-dimensional biological method that can be used for hypothesis-free biomarker profiling, examining a large number of metabolites in a given sample using spectroscopic techniques. Multivariate statistical data analysis then enables us to infer which metabolic information is relevant to the biological characterization of a given physiological or pathological condition. This can lead to the emergence of new, sometimes unexpected metabolites, and hitherto unknown metabolic pathways, enabling the formulation of new pathogenetic hypotheses, and the identification of new therapeutic targets. The aim of our pilot study was to apply mass-spectrometry-based metabolomics to the analysis of urine samples from children with RRI, comparing these children’s biochemical metabolic profiles with those of healthy peers. We also compared the RRI children’s and healthy controls’ metabolomic urinary profiles after the former had received pidotimod treatment for 3 months to see whether this immunostimulant was associated with biochemical changes in the RRI children’s metabolic profile. 13 children (age range 3–6 yeas) with RRI and 15 matched per age healthy peers with no history of respiratory diseases or allergies were enrolled. Their metabolomic urine samples were compared before and after the RRI children had been treated with pidotimod for a period of 3 months. Metabolomic analyses on the urine samples were done using mass spectrometry combined with ultra-performance liquid chromatography (UPLC-MS). The resulting spectroscopic data then underwent multivariate statistical analysis and the most relevant variables characterizing the two groups were identified. Data modeling with post-transformation of PLS2-Discriminant Analysis (ptPLS2-DA) generated a robust model capable of discriminating the urine samples from children with RRI from those of healthy controls (R2 = 0.92,Q2 CV7-fold = 0.75, p-value < 0.001). The dataset included 1502 time per mass variables, and 138 of them characterized the difference between the two groups. Thirty-five of these distinctive 138 variables persisted in the profiles of the children with RRI after pidotimod treatment. Metabolomics can discriminate children with RRI from healthy controls, suggesting that the former have a dysregulated metabolic profile. Among the variables characterizing children with RRI there are metabolites that may reflect the presence of a different microbiome. After pidotimod treatment, the metabolic profile of the children with RRI was no longer very different from that of the healthy controls, except for the persistence of some microbiome-related variables. We surmise that pidotimod partially “restores” the altered metabolic profile of children with RRI, without modifying the metabolites related to the composition of the gut microbiota. In the light of these results, we hypothesize a potential synergic effect of the combined use of immunostimulants and probiotics for the purpose of prevention in children with RRI.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.007
       
  • Transmembrane TNF-alpha reverse signaling leading to TGF-beta production
           is selectively activated by TNF targeting molecules: therapeutic
           implications
    • Authors: Zsuzsa Szondy; Anna Pallai
      Abstract: Publication date: Available online 22 November 2016
      Source:Pharmacological Research
      Author(s): Zsuzsa Szondy, Anna Pallai
      Tumor necrosis factor (TNF)-α is a potent pro-inflammatory cytokine exerting pleiotropic effects on various cell types. It is synthesized in a precursor form called transmembrane TNF-α (mTNF-α) which, after being processed by metalloproteinases, is released in a soluble form to mediate its biological activities through Type 1 and 2 TNF receptors in TNF receptor expressing cells. In addition to acting in soluble form, TNF-α also acts in the transmembrane form both as a ligand by activating TNF receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into mTNF-α bearing cells. Since the discovery that TNF-α plays a determining role in the pathogenesis of several chronic inflammatory diseases, anti-TNF agents are increasingly being used in the treatment of a rapidly expanding number of rheumatic and systemic autoimmune diseases, such as rheumatoid arthritis, Crohn’s disease, psoriasis, psoriatic arthritis, ankyloting spondylitis, Wegener granulomatosis and sarcoidosis. There are 5 TNF antagonists currently available: etanercept, a soluble TNF receptor construct; infliximab, a chimeric monoclonal antibody; adalimumab and golimumab, fully human antibodies; and certolizumab pegol, an Fab’ fragment of a humanized anti-TNF-α antibody. Though each compound can efficiently neutralize TNF-α, increasing evidence suggests that they show different efficacy in the treatment of these diseases. These observations indicate that in addition to neutralizing TNF-α, other biological effects induced by TNF-α targeting molecules dictate the success of the therapy. Recently, we found that mTNF-α reverse signaling leads to transforming growth factor (TGF)-β production in macrophages and anti-TNF agents selectively trigger this pathway. In this review we will focus on the potential contribution of the activation of the mTNF-α signaling pathway to the success of the anti-TNF therapy.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.025
       
  • Disruption of mitochondrial quality control in peripheral artery disease:
           new therapeutic opportunities
    • Authors: Cintia B. Ueta; Katia S. Gomes; Márcio A. Ribeiro; Daria Mochly-Rosen; Julio C.B. Ferreira
      Abstract: Publication date: Available online 19 November 2016
      Source:Pharmacological Research
      Author(s): Cintia B. Ueta, Katia S. Gomes, Márcio A. Ribeiro, Daria Mochly-Rosen, Julio C.B. Ferreira
      Peripheral artery disease (PAD) is a multifactorial disease initially triggered by reduced blood supply to the lower extremities due to atherosclerotic obstructions. It is considered a major public health problem worldwide, affecting over 200 million people. Management of PAD includes smoking cessation, exercise, statin therapy, antiplatelet therapy, antihypertensive therapy and surgical intervention. Although these pharmacological and non-pharmacological interventions usually increases blood flow to the ischemic limb, morbidity and mortality associated with PAD continue to increase. This scenario raises new fundamental questions regarding the contribution of intrinsic metabolic changes in the distal affected skeletal muscle to the progression of PAD. Recent evidence suggests that disruption of skeletal muscle mitochondrial quality control triggered by intermittent ischemia-reperfusion injury is associated with increased morbidity in individuals with PAD. The mitochondrial quality control machinery relies on surveillance systems that help maintaining mitochondrial homeostasis upon stress. In this review, we describe some of the most critical mechanisms responsible for the impaired skeletal muscle mitochondrial quality control in PAD. We also discuss recent findings on the central role of mitochondrial bioenergetics and quality control mechanisms including mitochondrial fusion-fission balance, turnover, oxidative stress and aldehyde metabolism in the pathophysiology of PAD, and highlight their potential as therapeutic targets.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.016
       
  • Metabotropic Glutamate Receptors and Neurodegenerative Diseases
    • Authors: Fabiola M. Ribeiro; Luciene B. Vieira; Rita G.W. Pires; Roenick P. Olmo; Stephen S.G. Ferguson
      Abstract: Publication date: Available online 19 November 2016
      Source:Pharmacological Research
      Author(s): Fabiola M. Ribeiro, Luciene B. Vieira, Rita G.W. Pires, Roenick P. Olmo, Stephen S.G. Ferguson
      Glutamate is the most important excitatory neurotransmitter of the mammalian central nervous system (CNS), playing an important role in memory, synaptic plasticity and neuronal development. However, glutamate overstimulation is also implicated in neuronal cell death. There are two major types of glutamate receptors: ionotropic and metabotropic. Thus far, eight metabotropic glutamate receptors (mGluRs) subtypes have been characterized and are divided into three subgroups based on sequence homology and cell signaling activation. mGluRs activate a wide variety of cell signaling pathways by G protein-coupled pathways or via G protein-independent cell signaling activation. Moreover, these receptors exhibit widespread distribution in the CNS and are implicated in several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). This review aims to discuss the latest updates concerning mGluRs and their role in neurodegenerative diseases. mGluRs agonists and antagonists as well as positive and negative allosteric modulators have been tested in several animal models of neurodegenerative diseases. Furthermore, mGluR knockout mouse models have been crossed to mouse models of AD and HD, providing important data about mGluRs role in neurodegenerative disease progression. Thus, mGluRs constitute potential therapeutic targets for the development of therapies to treat neurodegenerative diseases.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.013
       
  • The therapeutic potential of iron-targeting gallium compounds in human
           disease: From basic research to clinical application
    • Authors: Christopher R. Chitambar
      Abstract: Publication date: Available online 14 November 2016
      Source:Pharmacological Research
      Author(s): Christopher R. Chitambar
      Gallium, group IIIa metal, shares certain chemical characteristics with iron which enable it to function as an iron mimetic that can disrupt iron-dependent tumor cell growth. Gallium may also display antimicrobial activity by disrupting iron homeostasis in certain bacteria and fungi. Gallium’s action on iron homeostasis leads to inhibition of ribonucleotide reductase, mitochondrial function, and changes in proteins of iron transport and storage. In addition, gallium induces an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1. Early clinical trials evaluated the efficacy of the simple gallium salts, gallium nitrate and gallium chloride. However, newer gallium-ligands such as Tris(8-quinolinolato)gallium(III) (KP46) and gallium maltolate have been developed and are undergoing clinical evaluation. Additional gallium-ligands that demonstrate antitumor activity in preclinical studies have emerged. Their mechanisms of action and their spectrum of antitumor activity may extend beyond the earlier generations of gallium compounds and warrant further investigation. This review will focus on the evolution and potential of gallium-based therapeutics.
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      PubDate: 2016-11-18T01:09:35Z
      DOI: 10.1016/j.phrs.2016.11.009
       
  • Shikonin inhibits gefitinib-resistant non-small cell lung cancer by
           inhibiting TrxR and activating the EGFR proteasomal degradation pathway
    • Authors: Xia Li; Xing-Xing Fan; Ze-Bo Jiang; Wings TY Loo; Xiao-Jun Yao; Elaine Lai-Han Leung; Louis WC Chow; Liang Liu
      Abstract: Publication date: Available online 15 November 2016
      Source:Pharmacological Research
      Author(s): Xia Li, Xing-Xing Fan, Ze-Bo Jiang, Wings TY Loo, Xiao-Jun Yao, Elaine Lai-Han Leung, Louis WC Chow, Liang Liu
      Background Non-small cell lung cancer (NSCLC) is the dominant type of lung cancer. Molecular targeting has highly improved the treatment efficacy of lung cancer, but new challenges have emerged, such as gefitinib-resistance and cancer recurrence. Therefore, new chemotherapeutic agents and treatment strategies are urgently needed. Shikonin is the main active component of a Chinese medicinal plant ‘Zi Cao’, which has been shown to exhibit powerful anti-cancer activity in certain types of cancer; however, its activity in gefitinib-resistant lung cancer has never been addressed. In this study, we used a high-throughput screening assay for epidermal growth factor receptor (EGFR) inhibitors and discovered that Shikonin is a potent inhibitor of EGFR. Purpose The purpose of this study is to determine the cytotoxicity of Shikonin and its anti-cancer mechanism in NSCLC and its potential to be developed as a new molecularly targeted drug. Study design/methods The cytotoxicity of Shikonin was measured by the 3-(4, 5-dimetrylthiazol)-2, 5-diphenyltetrazolium bromide (MTT) assay in NSCLC cells. Flow cytometry was used to measure the intensity of intracellular reactive oxygen species (ROS) and apoptotic levels in NSCLC cells. Western blotting was applied to detect the expression level of related apoptotic proteins. Reduced glutathione (GSH) and oxidized glutathione (GSSG) assay kits were used to determine the intensity of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) activity. Results Shikonin exhibited selective cytotoxicity among two NSCLC cell lines (H1975 and H1650) and one normal lung fibroblast cell line (CCD-19LU). Shikonin significantly increased the activity of caspases and poly (ADP-ribosyl) polymerase (PARP), which are indicators of apoptosis, and the intensity of ROS by greater than 10-fold. NAC, an inhibitor of ROS, completely blocked apoptosis, caspase and PARP activation induced by Shikonin. Shikonin remarkably suppressed the phosphorylation of EGFR and led to EGFR degradation. Conclusion The enhancement of ROS generation in H1650 and H1975 gefitinib-resistant NSCLC cells leads to impairment of growth and induction of apoptosis, whereas modulation of EGFR degradation and its downstream signalling pathways by Shikonin contributes to its anti-tumour properties in H1975 gefitinib-resistant NSCLC cells (with T790M and L858R activating mutations). Shikonin-induced cell apoptosis is closely associated with ROS elevation in the cells. These findings indicate that Shikonin can be an effective small molecule treating gefitinib-resistant NSCLC.
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      PubDate: 2016-11-18T01:09:35Z
      DOI: 10.1016/j.phrs.2016.11.011
       
  • Tumor-targeted nanomedicines for cancer theranostics
    • Authors: Alexandra G. Arranja; Vertika Pathak; Twan Lammers; Yang Shi
      Abstract: Publication date: Available online 16 November 2016
      Source:Pharmacological Research
      Author(s): Alexandra G. Arranja, Vertika Pathak, Twan Lammers, Yang Shi
      Chemotherapeutic drugs have multiple drawbacks, including severe side effects and suboptimal therapeutic efficacy. Nanomedicines assist in improving the biodistribution and the target accumulation of chemotherapeutic drugs, and are therefore able to enhance the balance between efficacy and toxicity. Multiple different types of nanomedicines have been evaluated over the years, including liposomes, polymer-drug conjugates and polymeric micelles, which rely on strategies such as passive targeting, active targeting and triggered release for improved tumor-directed drug delivery. Based on the notion that tumors and metastases are highly heterogeneous, it is important to integrate imaging properties in nanomedicine formulations in order to enable non-invasive and quantitative assessment of targeting efficiency. By allowing for patient pre-selection, such next generation nanotheranostics are useful for facilitating clinical translation and personalizing nanomedicine treatments.
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      PubDate: 2016-11-18T01:09:35Z
      DOI: 10.1016/j.phrs.2016.11.014
       
  • Hypoxia-inducible factor prolyl 4-hydroxylase inhibition in
           cardiometabolic diseases
    • Authors: Peppi Koivunen; Raisa Serpi; Elitsa Y. Dimova
      Abstract: Publication date: Available online 8 November 2016
      Source:Pharmacological Research
      Author(s): Peppi Koivunen, Raisa Serpi, Elitsa Y. Dimova
      Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also called PHDs and EglNs) are enzymes that act as cellular oxygen sensors. They are the main downregulators of the hypoxia-inducible factor (HIF). HIF-P4Hs can be targeted with small molecule inhibitors, which stabilize HIF under normoxia and initiate the hypoxia response. Such inhibitors are in phase 2 and 3 clinical trials for the treatment of anemia due to their ability to induce erythropoietin and iron metabolism genes. Recent data suggest that HIF-P4H inhibition has a therapeutic role beyond anemia in cardiac ischemia, obesity and metabolic dysfunction, and atherosclerosis. The molecular level mechanisms involved are HIF stabilization driven changes in gene expression that improve perfusion and endothelial function, reprogram metabolism to promote glucose intake and glycolysis over oxidative metabolism, reduce inflammation and beneficially modify innate immune system. This review discusses the recent findings in detail.

      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.11.003
       
  • Transcriptome Profiling of NIH3T3 Cell Lines Expressing Opsin and the P23H
           Opsin Mutant Identifies Candidate Drugs for the Treatment of Retinitis
           Pigmentosa
    • Authors: Yuanyuan Chen; Matthew J. Brooks; Linn Gieser; Anand Swaroop; Krzysztof Palczewski
      Abstract: Publication date: Available online 9 November 2016
      Source:Pharmacological Research
      Author(s): Yuanyuan Chen, Matthew J. Brooks, Linn Gieser, Anand Swaroop, Krzysztof Palczewski
      Mammalian cells are commonly employed in screening assays to identify active compounds that could potentially affect the progression of different human diseases including retinitis pigmentosa (RP), a class of inherited diseases causing retinal degeneration with compromised vision. Using transcriptome analysis, we compared NIH3T3 cells expressing wildtype (WT) rod opsin with a retinal disease-causing single P23H mutation. Surprisingly, heterologous expression of WT opsin in NIH3T3 cells caused more than a 2-fold change in 783 out of 16,888 protein coding transcripts. The perturbed genes encoded extracellular matrix proteins, growth factors, cytoskeleton proteins, glycoproteins and metalloproteases involved in cell adhesion, morphology and migration. A different set of 347 transcripts was either up- or down-regulated when the P23H mutant opsin was expressed suggesting an altered molecular perturbation compared to WT opsin. Transcriptome perturbations elicited by drug candidates aimed at mitigating the effects of the mutant protein revealed that different drugs targeted distinct molecular pathways that resulted in a similar phenotype selected by a cell-based high-throughput screen. Thus, transcriptome profiling can provide essential information about the therapeutic potential of a candidate drug to restore normal gene expression in pathological conditions.
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      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.10.031
       
  • Hederagenin and α-hederin promote degradation of proteins in
           neurodegenerative diseases and improve motor deficits in MPTP-mice
    • Authors: An-Guo Wu; Wu Zeng; Vincent Kam-Wai Wong; Yi-Zhun Zhu; Amy C.Y. Lo; Liang Liu; Betty Yuen-Kwan Law
      Abstract: Publication date: Available online 9 November 2016
      Source:Pharmacological Research
      Author(s): An-Guo Wu, Wu Zeng, Vincent Kam-Wai Wong, Yi-Zhun Zhu, Amy C.Y. Lo, Liang Liu, Betty Yuen-Kwan Law
      Pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD) are closely related to the formation of protein aggregates and inclusion body. For instance, active autophagic components from Chinese herbal medicines (CHMs) are highlighted to modulate neurodegeneration via degradation of disease proteins. In this study, the neuroprotective effect of the purified Hedera helix (HH) fraction containing both hederagenin and α-hederin, is confirmed by the improvement of motor deficits in PD mice model. Furthermore, hederagenin and α-hederin derived from HH are confirmed as novel autophagic enhancers. Both compounds reduce the protein level of mutant huntingtin with 74 CAG repeats and A53T α-synuclein, and inhibit the oligomerization of α-synuclein and inclusion formation of huntingtin, via AMPK-mTOR dependent autophagy induction. Both hederagenin and α-hederin induce autophagy and promote the degradation of neurodegenerative mutant disease proteins in vitro, suggesting the therapeutic roles of HH in neurodegenerative disorders.
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      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.11.002
       
  • NON-INSULIN ANTI-DIABETIC DRUGS: AN UPDATE ON PHARMACOLOGICAL INTERACTIONS
    • Authors: M. Ruscica; L. Baldessin; D. Boccia; G. Racagni; N. Mitro
      Abstract: Publication date: Available online 9 November 2016
      Source:Pharmacological Research
      Author(s): M. Ruscica, L. Baldessin, D. Boccia, G. Racagni, N. Mitro
      Nowadays, the goal in the management of type 2 diabetes mellitus (T2DM) remains personalized control of glucose. Since less than 50% of patients with T2DM achieve glycemic treatment goal and most of them take medications for comorbidities associated to T2DM, drug interactions, namely pharmacokinetic and pharmacodynamic interactions, may enhance or reduce the effect of compounds involved in hyperglycemia. Hence, clinicians should be aware of the severe complications in T2DM patients in case of a concomitant use of these medications. It is within this context that this review aims to evaluate the effect of a second drug on the pharmacokinetic of these compounds which may lead, along with several pharmacodynamic interactions, to severe clinical complications, i.e., hypoglycemia. Available drugs already approved in Europe, USA and Japan have been included.
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      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.11.005
       
  • The genetics of exceptional longevity identifies new druggable targets for
           vascular protection and repair
    • Authors: Annibale A. Puca; Gaia Spinetti; Rosa Vono; Carmine Vecchione; Paolo Madeddu
      Abstract: Publication date: Available online 3 November 2016
      Source:Pharmacological Research
      Author(s): Annibale A. Puca, Gaia Spinetti, Rosa Vono, Carmine Vecchione, Paolo Madeddu
      Therapeutic angiogenesis is a relatively new medical strategy in the field of cardiovascular diseases. The underpinning concept is that angiogenic growth factors or proangiogenic cells could be exploited therapeutically in cardiovascular patients to enhance native revascularization responses to an ischemic insult, thereby accelerating tissue healing. The initial enthusiasm generated by preclinical studies has been tempered by the modest success of clinical trials assessing therapeutic angiogenesis. Similarly, proangiogenic cell therapy has so far not maintained the original promises. Intriguingly, the current trend is to consider regeneration as a prerogative of the youngest organism. Consequentially, the embryonic and foetal models are attracting much attention for clinical translation into corrective modalities in the adulthood. Scientists seem to undervalue the lesson from Mother Nature, e.g. all humans are born young but very few achieve the goal of an exceptional healthy longevity. Either natural experimentation is driven by a supreme intelligence or stochastic phenomena, one has to accept the evidence that healthy longevity is the fruit of an evolutionary process lasting million years. It is therefore extremely likely that results of this natural experimentation are more reliable and translatable than the intensive, but very short human investigation on mechanisms governing repair and regeneration. With this preamble in mind, here we propose to shift the focus from the very beginning to the very end of human life and thus capture the secret of prolonged health span to improve well-being in the adulthood.
      Graphical abstract image

      PubDate: 2016-11-03T23:58:44Z
      DOI: 10.1016/j.phrs.2016.10.028
       
  • Epigenetic Reactivation of RASSF1A by Phenethyl Isothiocyanate (PEITC) and
           promotion of apoptosis in LNCaP cells
    • Authors: Sarandeep S.S. Boyanapalli; Wenji Li; Francisco Fuentes; Yue Guo; Christina N. Ramirez; Ximena-Parades Gonzalez; Douglas Pung; Ah-Ng Tony Kong
      Abstract: Publication date: Available online 3 November 2016
      Source:Pharmacological Research
      Author(s): Sarandeep S.S. Boyanapalli, Wenji Li, Francisco Fuentes, Yue Guo, Christina N. Ramirez, Ximena-Parades Gonzalez, Douglas Pung, Ah-Ng Tony Kong
      Epigenetic silencing of tumor suppressor genes is a phenomenon frequently observed in multiple cancers. Ras-association domain family 1 isoform A (RASSF1A) is a well-characterized tumor suppressor that belongs to the Ras-association domain family. Several studies have demonstrated that hypermethylation of the RASSF1A promoter is frequently observed in lung, prostate, and breast cancers. Phenethyl isothiocyanate (PEITC), a phytochemical abundant in cruciferous vegetables, possesses chemopreventive activities; however, its potential involvement in epigenetic mechanisms remains elusive. The present study aimed to examine the role of PEITC in the epigenetic reactivation of RASSF1A and the induction of apoptosis in LNCaP cells. LNCaP cells were treated for 5days with 0.01% DMSO, 2.5 or 5μM PETIC or 2.5μM azadeoxycytidine (5-Aza) with 0.5 μM trichostatin A (TSA). We evaluated the effects of these treatments on CpG demethylation using methylation-specific polymerase chain reaction (MSP) and bisulfite genomic sequencing (BGS). CpG demethylation was significantly enhanced in cells treated with 5μM PEITC and 5-Aza+TSA; therefore, the latter treatment was used as a positive control in subsequent experiments. The decrease in RASSF1A promoter methylation correlated with an increase in expression of the RASSF1A gene in a dose-dependent manner. To confirm that promoter demethylation was mediated by DNA methyltransferases (DNMTs), we analyzed the expression levels of DNMTs and histone deacetylases (HDACs) at the gene and protein levels. PEITC reduced DNMT1, 3A and 3B protein levels in a dose-dependent manner, and 5μM PEITC significantly reduced DNMT3A and 3B protein levels. HDAC1, 2, 4 and 6 protein expression was also inhibited by 5μM PEITC. The combination of 5-Aza and TSA, a DNMT inhibitor and a HDAC inhibitor, respectively, was used as a positive control as this treatment significantly inhibited both HDACs and DNMTs. The function of RASSF1A reactivation in promoting apoptosis and inducing G2/M cell cycle arrest was analyzed using flow-cytometry analysis with Annexin V and propidium iodide (PI). Growth inhibition effect on LNCaP cells were investigated by colony formation assay. In addition, we analyzed p21, caspase-3 and 7, Bax, and Cyclin B1 protein levels. Flow-cytometry analysis of cells stained with PI alone demonstrated that 5μM PEITC promotes early apoptosis and G2/M cell cycle arrest. Flow cytometry analysis of cells stained with Annexin V and PI also demonstrated an increased proportion of cells in early apoptosis in cells treated with 5μM PEITC or 5-Aza with TSA. PEITC and efficiently inhibit colony numbers and total area. In addition, 5μM PEITC significantly enhanced p21, caspase-3, 7 and Bax levels and reduced Cyclin B1 expression compared with the control group. Collectively, the results of our study suggest that PEITC induces apoptosis in LNCaP cells potentially by reactivating RASSF1A via epigenetic mechanisms.
      Graphical abstract image

      PubDate: 2016-11-03T23:58:44Z
      DOI: 10.1016/j.phrs.2016.10.021
       
  • Systems-biology dissection of mechanisms and chemical basis of herbal
           formula in treating chronic myocardial ischemia
    • Authors: Shuzhen Guo; Peng Li; Bangze Fu; Wenjing Chuo; Kuo Gao; Wuxia Zhang; Junyao Wang; Jianxin Chen; Wei Wang
      Abstract: Publication date: Available online 3 November 2016
      Source:Pharmacological Research
      Author(s): Shuzhen Guo, Peng Li, Bangze Fu, Wenjing Chuo, Kuo Gao, Wuxia Zhang, Junyao Wang, Jianxin Chen, Wei Wang
      Herbal medicine is a mixture of multiple compounds, and is intended to exhibit therapeutic effects by attacking multiple disease-causing modules simultaneously. However, it is still a challenge for scientists to untangle the complex biological mechanisms and underlying material basis of herbal medicine. Here, this study was designed to build a systems-biology platform for exploring the molecular mechanisms and corresponding active compounds, with a typical example applied to an herbal formula Qishenkel (QSKL) in the treatment of chronic myocardial ischemia. We have applied an approach integrating transcriptome sequencing, bioactivity profiling inference, computational ligand-receptor evaluation and experimental validation to study the effects on pig myocardial ischemia treated with QSKL. Numerous biological modules were revealed and indicated the coordinated regulation of molecular networks from various aspects of cardiac function. In addition, gene expression profiles were utilized to identify a number of key therapeutic targets of herbal formula, such as angiotensin-converting enzyme and calcium channels. Then, these therapeutic targets were used to fish the potential active ingredients based on a combination of target structure-based and chemical ligand-based methods. Some active compounds, including luteolin, cryptotanshinone, licochalcone A, glycyrrhetinic acid, salsolinol, isoacid chlorogenic C, salvianolic acid A and salvianolic acid B, have been validated by direct biochemical methods. This strategy integrating different types of technologies is expected to provide not only a detailed understanding about the combined therapeutic effects of herbal mixture but also a new opportunity for discovering novel natural molecules with pharmacological activities.

      PubDate: 2016-11-03T23:58:44Z
      DOI: 10.1016/j.phrs.2016.10.026
       
  • The genus Rosa and arthritis: Overview on pharmacological perspectives
    • Authors: Brian Chi Yan Cheng; Xiu-Qiong Fu; Hui Guo; Ting Li; Zheng-Zhi Wu; Kelvin Chan; Zhi-Ling Yu
      Abstract: Publication date: Available online 2 November 2016
      Source:Pharmacological Research
      Author(s): Brian Chi Yan Cheng, Xiu-Qiong Fu, Hui Guo, Ting Li, Zheng-Zhi Wu, Kelvin Chan, Zhi-Ling Yu
      The genus Rosa (roses) has long been used in traditional or folk medicine worldwide for the treatment of various types of arthritis including rheumatoid arthritis and osteoarthritis. The active constituents of Rosa spp., such as flavonoids, triterpenoids, and phytosterols, could act on different targets in the NF-κB signalling pathway, inhibit pro-inflammatory enzymes (e.g. MMPs and COX-2), lower the production of inflammatory cytokines and chemokines (e.g. TNF-α, IL-1β, IL-6, CCL5), and reduce oxidative stress, which in turn suppress inflammatory processes. Preclinical and clinical studies have demonstrated that these species possess analgesic, anti-arthritic, anti-inflammatory, anti-oxidative and bone-preserving activities. This review presents comprehensive overview of the mode and mechanism of action of various extracts, preparations, and active constituents from this genus. The dynamic beneficial effects of the products prepared from this genus in arthritis management are summarized. The Rosa genus is a treasure waiting for further exploration by researchers interested in the development of safe and effective anti-arthritic agents.
      Graphical abstract image

      PubDate: 2016-11-02T23:50:45Z
      DOI: 10.1016/j.phrs.2016.10.029
       
  • NAD+ salvage pathway in cancer metabolism and therapy
    • Authors: Barry E. Kennedy; Tanveer Sharif; Emma Martell; Cathleen Dai; Youra Kim; Patrick W.K. Lee; Shashi A. Gujar
      Abstract: Publication date: Available online 2 November 2016
      Source:Pharmacological Research
      Author(s): Barry E. Kennedy, Tanveer Sharif, Emma Martell, Cathleen Dai, Youra Kim, Patrick W.K. Lee, Shashi A. Gujar
      Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme for various physiological processes including energy metabolism, DNA repair, cell growth, and cell death. Many of these pathways are typically dysregulated in cancer cells, making NAD+ an intriguing target for cancer therapeutics. NAD+ is mainly synthesized by the NAD+ salvage pathway in cancer cells, and not surprisingly, the pharmacological targeting of the NAD+ salvage pathway causes cancer cell cytotoxicity in vitro and in vivo. Several studies have described the precise consequences of NAD+ depletion on cancer biology, and have demonstrated that NAD+ depletion results in depletion of energy levels through lowered rates of glycolysis, reduced citric acid cycle activity, and decreased oxidative phosphorylation. Additionally, depletion of NAD+ causes sensitization of cancer cells to oxidative damage by disruption of the anti-oxidant defense system, decreased cell proliferation, and initiation of cell death through manipulation of cell signaling pathways (e.g., SIRT1 and p53). Recently, studies have explored the effect of well-known cancer therapeutics in combination with pharmacological depletion of NAD+ levels, and found in many cases a synergistic effect on cancer cell cytotoxicity. In this context, we will discuss the effects of NAD+ salvage pathway inhibition on cancer cell biology and provide insight on this pathway as a novel anti-cancer therapeutic target.
      Graphical abstract image

      PubDate: 2016-11-02T23:50:45Z
      DOI: 10.1016/j.phrs.2016.10.027
       
 
 
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