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European Journal of Pharmacology
Journal Prestige (SJR): 1.057
Citation Impact (citeScore): 3
Number of Followers: 11  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0014-2999
Published by Elsevier Homepage  [3177 journals]
  • Dopamine attenuates lipopolysaccharide-induced expression of
           proinflammatory cytokines by inhibiting the nuclear translocation of
           NF-κB p65 through the formation of dopamine quinone in microglia.
    • Abstract: Publication date: 5 January 2020Source: European Journal of Pharmacology, Volume 866Author(s): Yasuhiro Yoshioka, Yuta Sugino, Fumiya Shibagaki, Akiko Yamamuro, Yuki Ishimaru, Sadaaki MaedaAbstractMany reports have indicated that dopamine has immunomodulatory effects on peripheral immune cells. The purpose of this study was to reveal the immunomodulatory effect of dopamine on the expression of proinflammatory cytokines in microglial cells, which are the immune cells of the central nervous system. In murine microglial cell line BV-2 cells, pretreatment with dopamine for 24 h attenuated the lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines such as tumor-necrosis factor-α, interleukin-1β, and interleukin-6. Neither (5R)-8-chloro-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol; hydrochloride (SCH-23390) nor sulpiride, which are dopamine D1-like and D2-like receptor antagonists, respectively, affected the attenuation of LPS-induced expression of cytokines by dopamine. In addition, pretreatment with neither (−)-(6aR,12bR)-4,6,6a,7,8,12b-Hexahydro-7-methylindolo[4,3-a]phenanthridin (CY208-243) nor bromocriptine, dopamine D1-like and D2-like receptor agonists, respectively, was effective in doing so. However, N-acetylcysteine (NAC), which inhibits dopamine oxidation to dopamine quinone, did inhibit this attenuated expression. Dopamine increased the level of quinoproteins, and this increase was inhibited by NAC. Western blot and immunocytochemical analyses revealed that dopamine inhibited LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB) p65. Dopamine also attenuated the expression of cytokines and the nuclear translocation of NF-κB p65 induced by LPS in mouse microglial cells in primary culture. These results suggest that dopamine attenuated LPS-induced expression of cytokines by inhibiting the nuclear translocation of NF-κB p65 through the formation of dopamine quinone in microglial cells.
  • The effects of dopamine D4 receptor ligands on operant alcohol
           self-administration and cue- and stress-induced reinstatement in rats
    • Abstract: Publication date: Available online 30 November 2019Source: European Journal of PharmacologyAuthor(s): Aaron Kim, Patricia Di Ciano, Abhiram Pushparaj, Jacques Leca, Bernard Le FollAbstractDopamine, a neurotransmitter with 5 receptor subtypes, is critical to the dependence-forming properties of drugs of abuse. The role of the dopamine D4 receptor subtype in substance use disorders has remained somewhat elusive but the recent development of selective ligands holds promise for future investigations of this receptor subtype in substance use disorders, including alcohol use disorder. The purpose of the present study was to further elucidate the effects of a selective antagonist (L-745,870) and agonist (PD 168,077) on alcohol self-administration and reinstatement induced either by cues or stress. It was found that the D4 antagonist, but not agonist, reduced alcohol intake at the highest doses. Further, the D4 antagonist reduced stress-induced reinstatement, with no effects on cue-induced reinstatement; the agonist was without effect on either form of reinstatement. The dopamine D4 receptor antagonist was without effect on food reinforcement. This work deepens existing lines of evidence that the dopamine D4 receptor is involved in substance use disorders and suggests that dopamine D4 receptor blockade diminishes motivation for alcohol-taking without influencing natural food rewards. Furthermore, there appears to be a plausible effect of dopamine D4 receptor blockade interfering with stress- but not cue-induced alcohol-seeking.
  • Therapeutic efficacy of arginine-rich exenatide on diabetic neuropathy in
    • Abstract: Publication date: Available online 30 November 2019Source: European Journal of PharmacologyAuthor(s): Elena V. Shekunova, Vladimir A. Kashkin, Arman А. Muzhikyan, Marina N. Makarova, Valery G. Makarov, Vadim Y. BalabanyanAbstractDiabetes mellitus is characterized by metabolic dysregulation associated with a number of health complications. More than 50% of patients with diabetes mellitus suffer from diabetic polyneuropathy, which involves the presence of peripheral nerve dysfunction symptoms. The aim of this study was to evaluate the potential of a new synthetic arginine-rich exendin-4 (Peptide D) in the treatment of complications caused by diabetes, including peripheral neuropathy, in rats. Diabetes was induced by administering streptozotocin (STZ). Three groups of diabetic rats were treated with Peptide D (0.1, 1, and 10 μg/kg). One group of diabetic rats was treated with Byetta® (1 μg/kg) for 80 days. Neuropathic pain development was assessed by tactile allodynia. STZ-treated rats showed an increased level of tactile allodynia unlike naïve animals. A histological study revealed that the diameter of the sciatic nerve fibers in STZ-treated rats was smaller than that of the naïve animals. An IGH study demonstrated decreased expression of myelin basic protein (MBP) in the sciatic nerve of diabetic rats compared to that in the naïve animals. Peptide D reduced the severity of tactile allodynia. This effect was more pronounced in the Peptide D treated groups than in the group treated with Byetta®. Peptide D and Byetta® treatment resulted in increased MBP expression in the sciatic nerve and increased diameter of myelinated nerve fibers. These findings suggest that poly-arginine peptides are promising agents for the treatment of peripheral polyneuropathies.
  • KCa and KV channels modulate the venoarteriolar reflex in non-glabrous
           human skin with no roles of KATP channels, NOS, and COX
    • Abstract: Publication date: Available online 30 November 2019Source: European Journal of PharmacologyAuthor(s): Naoto Fujii, Gregory W. McGarr, Brendan D. McNeely, Masashi Ichinose, Takeshi Nishiyasu, Glen P. KennyAbstractThe venoarteriolar reflex is a local mechanism that induces vasoconstriction during venous congestion in various tissues, including skin. This response is thought to play a critical role in minimizing capillary damage or edema resulting from overperfusion, though factors that modulate this response remain largely unknown. Here, we hypothesized that nitric oxide synthase (NOS), cyclooxygenase (COX), and Ca2+-activated, ATP-sensitive, and voltage-gated K+ channels (KCa, KATP, and KV channels, respectively) modulate the venoarteriolar reflex in human skin. Cutaneous blood flow (laser-Doppler flowmetry) was monitored during a 3-min pre-occlusion baseline and following a 3-min venous occlusion of 45 mmHg, the latter maneuver was used to induce the venoarteriolar reflex. The venoarteriolar reflex was assessed at the following forearm skin sites: Experiment 1 (n = 11): 1) lactated Ringer solution (Control), 2) 10 mM Nω-nitro-L-arginine (NOS inhibitor), 3) 10 mM ketorolac (COX inhibitor), and 4) combined NOS + COX inhibition; Experiment 2 (n = 15): 1) lactated Ringer solution (Control), 2) 50 mM tetraethylammonium (KCa channel blocker), 3) 5 mM glybenclamide (KATP channel blocker), and 4) 10 mM 4-aminopyridine (KV channel blocker). Separate and combined NOS and COX inhibition as well as KATP channel blocker had no effect on venoarteriolar reflex. Conversely, venoarteriolar reflex was attenuated by KCa channel blockade (36–38%) and augmented by KV channel blockade (38–55%). We showed that KCa and KV channels modulate the venoarteriolar reflex with minimum roles of NOS, COX, and KATP channels in human non-glabrous forearm skin in vivo. Thus, cutaneous venoarteriolar reflex changes could reflect altered K+ channel function.
  • Pharmacological rewriting of fear memories: A beacon for post-traumatic
           stress disorder
    • Abstract: Publication date: Available online 25 November 2019Source: European Journal of PharmacologyAuthor(s): Ankit Uniyal, Raghunath Singh, Ansab Akhtar, Jatinder Dhaliwal, Anurag Kuhad, Sangeeta Pilkhwal SahAbstractPost-traumatic stress disorder (PTSD) is a psychopathological response that develops after exposure to an extreme life-threatening traumatic event. Its prevalence ranges from 0.5% to 14.5% worldwide. Due to the complex pathophysiology of PTSD, currently available treatment approaches are associated with high chances of failure, thus further research to identify better pharmacotherapeutic approaches is needed. The traumatic event associated with fear memories plays an important role in the development of PTSD and could be considered as the main culprit. PTSD patient feels frightened in a safe environment as the memories of the traumatic event are revisited. Neurocircuit involving normal processing of fear memories get disturbed in PTSD hence making a fear memory to remain to dominate even after years of trauma. Persistence of fear memories could be explained by acquisition, re-(consolidation) and extinction triad as all of these processes have been widely explored in preclinical as well as clinical studies and set a therapeutic platform for fear memory associated disorders. This review focuses on neurocircuit and pathophysiology of PTSD in context to fear memories and pharmacological targeting of fear memory for the management of PTSD.
  • Ferrocenes as new anticancer drug candidates: Determination of the
           mechanism of action
    • Abstract: Publication date: Available online 23 November 2019Source: European Journal of PharmacologyAuthor(s): Hana Skoupilova, Martin Bartosik, Lucia Sommerova, Jiri Pinkas, Tomas Vaculovic, Viktor Kanicky, Jindrich Karban, Roman HrstkaChemotherapy plays an essential role in the management of cancer worldwide. However, it is a non-specific treatment limited by major drawbacks, thus identification and testing of new promising molecular structures representing potential drug candidates are urgently needed. In this work, ferrocene complexes as potential antitumor drugs that display cytotoxicity in low micromolar concentrations against ovarian cancer cells A2780 and SK-OV-3 were investigated to identify their mode of action. Their mechanism of cellular accumulation was studied using differential pulse voltammetry and inductively coupled plasma - mass spectrometry. Their mode of cell death induction was determined by changes in the mitochondrial membrane potential, production of reactive oxygen species and by Annexin V staining.Transferrin receptors were identified as key mediators of intracellular accumulation of ferrocenes and the extent of cellular uptake reflected the anticancer activity of individual compounds. Functional analysis revealed activation of intrinsic apoptosis as a dominant mechanism leading to regulated cell death induced in ovarian cancer cells by ferrocenes.Ferrocenes represent a group of promising sandwich organometallic complexes exerting cytotoxic activity. We suggest their application not only as standalone chemotherapeutics but also as modifying substituents of known drugs to improve their antitumor effects.Graphical abstractImage 1
  • Leukotriene B4 induces proliferation of rat pulmonary arterial smooth
           muscle cells via modulating GSK-3β/β-catenin pathway
    • Abstract: Publication date: Available online 23 November 2019Source: European Journal of PharmacologyAuthor(s): Shaojun Li, Cui Zhai, Wenhua Shi, Wei Feng, Xinming Xie, Yilin Pan, Jian Wang, Xin Yan, Limin Chai, Qingting Wang, Qianqian Zhang, Pengtao Liu, Manxiang LiAbstractLeukotriene B4 (LTB4) has been found to contribute to pulmonary arterial smooth muscle cells (PASMCs) proliferation and pulmonary arterial remodeling therefore the development of pulmonary arterial hypertension (PAH). Yet, the underlying molecular mechanisms remain poorly understood. The present study aims to address this issue. Our results demonstrate that LTB4 dose- and time-dependently induced proliferation of primary cultured rat PASMCs, this was accompanied with the activation of phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways, and consequent inactivation of glycogen synthase kinase-3β (GSK-3β), up-regulation of β-catenin and induction of cyclin D1 expression. The presence of PI3K inhibitor (LY294002) or MEK inhibitor (U0126) or prior silencing of β-catenin with siRNA suppressed LTB4-induced cyclin D1 up-regulation and PASMCs proliferation. In addition, inactivation or lack of GSK-3β up-regulated β-catenin and cyclin D1 in PASMCs. Taken together, our study indicates that activation of PI3K/Akt and ERK1/2 pathways mediate LTB4-induced PASMCs proliferation by modulating GSK-3β/β-catenin/cyclin D1 axis and suggests that targeting this pathway might have potential value in alleviating vascular remodeling and benefit PAH.
  • C-Myc inhibition sensitizes pre-B ALL cells to the anti-tumor effect of
           vincristine by altering apoptosis and autophagy: Proposing a probable
           mechanism of action for 10058-F4
    • Abstract: Publication date: Available online 23 November 2019Source: European Journal of PharmacologyAuthor(s): Negar Sheikh‐Zeineddini, Ava Safaroghli-azar, Sina Salari, Davood BashashAbstractUnlike the broad spectrum efficacies in wiping the malignant cells out, application of vincristine (VCR) in acute lymphoblastic leukemia (ALL) therapeutic protocol is partially restricted due to its high frequent resistant rate. Although several mechanisms have been enumerated for VCR resistance, to the best of our knowledge, there is no report reflecting the suppressive effect of oncogenic pathways on VCR cytotoxicity in ALL. The results of the present study indicated that both pre-B ALL-derived REH and Nalm-6 cells were partly resistant to VCR, with this note that Nalm-6 cells displayed more resistant phenotype. More interestingly, we showed for the first time that among inhibitors of different signaling pathways including those targeting PI3K, ERK, and NF-κB, the enhancive effect of small molecule inhibitor of c-Myc 10058-F4 was more significant on VCR cytotoxicity. Inhibition of c-Myc in VCR-treated Nalm-6 cells promoted a caspase-3-dependent apoptosis not only through altering the balance between death promoters to death suppressors, but also via modulating the expression of autophagy-related genes. Noteworthy, favorable impact of 10058-F4 on VCR anti-leukemic effect was not restricted to the induction of cell death and this agent also reinforced VCR anti-proliferative effect through disturbing cell cycle progression and hampering the expression of Pin1 and hTERT. In conclusion, it seems that targeting c-Myc could produce a synergistic anti-cancer effect with VCR and provide a fundamental infrastructure for a promising approach in ALL.
  • Downregulation of osteopontin inhibits browning of white adipose tissues
           through PI3K-AKT pathway in C57BL / 6 mice
    • Abstract: Publication date: Available online 22 November 2019Source: European Journal of PharmacologyAuthor(s): Yi Lu, Yuhong Xu, Wanwan Yuan, Mengxi Wang, Yumeng Zhou, Kai Chen, Qiren HuangAbstractBrown adipose tissue (BAT) plays important roles in regulating energy homeostasis and combating obesity. Accordingly, increasing the abundance and/or activating BAT would be effective and promising approaches to combat obesity and obesity-relative diseases. Our previous data in vitro have shown that osteopontin (OPN) induces the brown adipogenesis in 3T3-L1 cells via a phosphatidylinositol 3 kinase (PI3K)-AKT pathway. However, it is currently unknown whether OPN exerts such an effect on animals in vivo. Therefore, in the study we sought to investigate the pro-browning effects of OPN and to explore its underlying mechanisms by transfecting with Ad-GFP-aP2-OPN-shRNA to specifically down-regulate the OPN of white adipose tissue (WAT) in mice. Our present results show that downregulation of OPN in WAT exacerbates obesity and inhibits WAT-browning. Moreover, immunohistochemical results also exhibit that the downregulation of OPN significantly diminishes the expression and sub-cellular localization of UCP-1, PRDM16 and PGC-1α. Besides, the western blotting results reveal that the expression levels of PI3K, AKT-pS473 and PPARγ markedly reduce. Consequently, we conclude that the downregulation of OPN inhibits the browning of WAT through inhibiting the expression of PPARγ mediated by the PI3K-AKT pathway. The findings suggest that OPN is involved in regulation of WAT-browning and regulating its expression would become a potential strategy to combat obesity and obesity-relative metabolic diseases.
  • Osthole ameliorates cartilage degradation by downregulation of NF-κB and
           HIF-2α pathways in an osteoarthritis murine model
    • Abstract: Publication date: Available online 22 November 2019Source: European Journal of PharmacologyAuthor(s): Chang-Ming Chern, Han Zhou, Yea-Hwey Wang, Chia-Lin Chang, Wen-Fei Chiou, Wen-Te Chang, Chun-Hsu Yao, Kuo-Tong Liou, Yuh-Chiang ShenAbstractOsteoarthritis (OA) is a common and disabling joint disease mainly characterized by cartilage degradation, with the knees most commonly affected. No effective treatment for the cartilage degradation of OA exists. Preliminary studies have revealed the protective and osteogenic effects of osthole, a natural coumarin first isolated from Cnidium monnieri (Fructus Cnidii); however, no evidence of osthole in an OA-related model has been published to date. This study further explored the effects of osthole in a monoiodoacetate (MIA)-induced OA-related animal model and focused on the molecular mechanism(s) behind the anti-inflammatory and cartilage protective effects of osthole. Our study revealed that the cartilage protective effect of osthole in a MIA-induced osteoarthritis (OA) murine model could be explained by downregulation of COX-2 and RUNX2 by inhibition of NF-κB and HIF-2α up-regulated by OA induction, resulting in downregulation of MMP-13, Syndecan IV and ADAMTS-5. In addition, osthole might have anti-inflammatory and analgesic effects due to COX-2 inhibition. We conclude that osthole can be considered as a potential component of the treatment of OA, for it possesses a cartilage protective effect, as well as inflammation, analgesic, and movement improving effects. Further preclinical and human clinical studies are needed to examine the efficacy and safety profile of long-term therapy.
  • Effect of ischemic preconditioning and a Kv7 channel blocker on cardiac
           ischemia-reperfusion injury in rats
    • Abstract: Publication date: Available online 21 November 2019Source: European Journal of PharmacologyAuthor(s): Krestine Kjeldsen Corydon, Vladimir Matchkov, Rafael Fais, Denis Abramochkin, Elise Røge Hedegaard, Simon Comerma-Steffensen, Ulf SimonsenAbstractRecently, we found cardioprotective effects of ischemic preconditioning (IPC), and from a blocker of KCNQ voltage-gated K+ channels (KV7), XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone), in isolated rat hearts. The purpose of the present study was to investigate the cardiovascular effects of IPC and XE991 and whether they are cardioprotective in intact rats. In conscious rats, we measured the effect of the KV7 channel blocker XE991 on heart rate and blood pressure by use of telemetry. In anaesthetized rats, cardiac ischemia was induced by occluding the left coronary artery, and the animals received IPC (2 × 5 min of occlusion), XE991, or a combination. After a 2 h reperfusion period, the hearts were excised, and the area at risk and infarct size were determined. In both anaesthetized and conscious rats, XE991 increased blood pressure, and the highest dose (7.5 mg/kg) of XE991 also increased heart rate, and 44% of conscious rats died. XE991 induced marked changes in the electrocardiogram (e.g., increased PR interval and prolonged QTC interval) without changing cardiac action potentials. The infarct size to area at risk ratio was reduced from 53 ± 2% (n = 8) in the vehicle compared to 36 ± 3% in the IPC group (P 
  • Differential sympathetic vasomotor control by spinal AT1 and V1a receptors
           in the acute phase of hemorrhagic shock
    • Abstract: Publication date: Available online 20 November 2019Source: European Journal of PharmacologyAuthor(s): Maycon I.O. Milanez, Gustavo R. Martins, Erika E. Nishi, Cássia T. Bergamaschi, Ruy R. CamposAbstractThe role of the renin-angiotensin-aldosterone system and arginine vasopressin (AVP) as humoral components in maintaining blood pressure (BP) during hemorrhagic shock (HS) is well established. However, little is known about the role of angiotensin II (Ang II) and AVP in the control of preganglionic sympathetic neuron activity. We studied the effects evoked by spinal Ang II type I (AT1) and V1a receptors antagonism on cardiovascular and sympathetic responses during HS. A catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anesthetized rats. The effects of HS on BP, heart rate (HR), and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were analyzed in the presence or absence (HS rats) of intrathecally injected losartan (HS-Los rats) or V1a antagonist (HS–V1a rats). The right femoral artery was catheterized for bleeding. Using a 5 ml syringe, hemorrhage was maintained continuously until a BP reduction of ∼50 mmHg was achieved. We found that bleeding caused a reflex increase in HR, rSNA and sSNA in the HS rats. However, such responses were attenuated in the HS-Los rats. HS-V1a rats showed a reflex increase in HR, rSNA and sSNA in terms of frequency (spikes/s) but not in amplitude. Nevertheless, the BP recovery of the groups was similar. Our data showed that spinal AT1 receptors are essential for sympathoexcitation during the acute phase of HS. Moreover, spinal AVP seems to be a neuromodulator that controls the recruitment of spinal sympathetic vasomotor neurons during the acute phase of HS.
  • Cytostatic pharmaceuticals as water contaminants
    • Abstract: Publication date: Available online 20 November 2019Source: European Journal of PharmacologyAuthor(s): Marcelina Jureczko, Joanna KalkaDue to the growing problem of cancer diseases, cytostatic drugs have become a great environmental threat. Their main sources are hospital effluents, household discharge and drug manufacturers. As these compounds are not removed during wastewater treatment with sufficient efficiency, they are found in the surface, ground and drinking water in quantities up to 2.12 × 10−4 mg/l. The current knowledge about their harmful influence on humans does not indicate a significant risk to the health of water consumers, although it points to certain groups of risk (children and lactating women) in particular. In aquatic organisms, anticancer drugs in detected concentrations can cause chronic toxicity and have a detrimental impact on their genetic material. The acute toxicity effect is less likely. The HC5 value calculated by us (the concentration at which 5% of the species is potentially affected) equalling 2.1 × 10−4 mg/l shows that anticancer drugs are real hazardous contaminants for the environment. It indicates that effective elimination of cytostatics from water still requires intensive research.Graphical abstractImage 1
  • Triptolide inhibits PDGF-induced proliferation of ASMCs through G0/G1 cell
    • Abstract: Publication date: Available online 19 November 2019Source: European Journal of PharmacologyAuthor(s): Siyun He, Ming Chen, Xiaoling Lin, Zhiqiang Lv, Ruiyun Liang, Linjie HuangAbnormal proliferation of airway smooth muscle cells (ASMCs) is a hallmark of airway remodeling. Platelet-derived growth factor (PDGF) is known to be a major stimulus inducing the proliferation of ASMCs. It has been reported that triptolide demonstrates protective effects against airway remodeling. In this study, we investigated the antiproliferative effects of triptolide on PDGF-induced ASMCs and its underlying mechanisms. Cell proliferation was determined using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was used to study the influence of triptolide on cell cycle and apoptosis. Quantitative real-time PCR and Western blot analysis were employed to detect the expression of proliferating cell nuclear antigen (PCNA), cyclinD1 and cyclin dependent kinase 4 (CDK4). Proteins involved in the protein kinase B (AKT) and nuclear factor kappa B (NF-κB) signaling pathways were evaluated using Western blot analysis. Triptolide could significantly inhibit cell proliferation, induce cell cycle arrest in the G0/G1 phase, and reduce the expression of PCNA, cyclinD1, and CDK4 in PDGF-treated ASMCs. Levels of phosphorylated AKT, p65 and NF-κB inhibitor α (IκBα) stimulated by the presence of PDGF were markedly suppressed after triptolide treatment. Moreover, triptolide cotreatment with the phosphatidylinositol 3 kinase (PI3k) inhibitor, 2-(4-morpholinyl)-8-phenylchromone (LY294002), could further suppress the proliferation, NF-κB activation and cyclinD1 expression. Similar results were observed after triptolide cotreatment with the NF-κB inhibitor, ammonium pyrrolidinedithiocarbamate (PDTC). Our results suggest that triptolide could inhibit the PDGF-induced proliferation of ASMCs through G0/G1 cell cycle arrest and suppression of the AKT/NF-κB/cyclinD1 signaling pathway.Graphical abstractImage 1
  • Inhibitory effect of α 1D/1A antagonist
           2-(1H-indol-3-yl)-N-[3-(4-(2-methoxyphenyl) piperazinyl) propyl] acetamide
           on estrogen/androgen-induced rat benign prostatic hyperplasia model in
    • Abstract: Publication date: Available online 19 November 2019Source: European Journal of PharmacologyAuthor(s): Qi-meng Liu, Qing Xiao, Xiang Zhu, Kai-feng Chen, Xia-wen Liu, Ru-chao Jiang, Dan Wu, Jun-min Shi, Li-jun Dai, Jun–jun HuangAbstractBenign prostatic hyperplasia (BPH) is a common disorder of the urinary system in aging men. 2-(1H-indol-3-yl)-N-[3-(4-(2-methoxyphenyl) piperazinyl) propyl] acetamide (HJZ-3), which is derived from naftopidil, exhibited 97.7- and 64.6-fold greater inhibitory effects for a1D adrenoceptor than for a1B- and a1A-adrenoceptors in vitro, respectively. To investigate the therapeutic potential for treating BPH, we evaluated the pharmacological activity of HJZ-3. Specifically, we evaluated through estrogen/androgen-induced rat benign prostatic hyperplasia model in vivo. HJZ-3 effectively prevented the progression of rat prostatic hyperplasia by suppressing the increase in prostate index and reducing the quantitative analysis of the relative acinus volume, relative stroma, epithelial volume and epithelial thickness and expression of proliferating cell nuclear antigen and α-smooth muscle actin. HJZ-3 decreased α1A- and α1D-adrenoceptor protein expressions in prostate tissue. HJZ-3 is a good alternative for α1A- and α1D-adrenoceptor blocker. It may relax smooth muscle tone and relieve symptoms of BPH.
  • Possible osteoprotective effects of myricetin in STZ induced diabetic
           osteoporosis in rats
    • Abstract: Publication date: Available online 19 November 2019Source: European Journal of PharmacologyAuthor(s): Xiaozhou Ying, Xiaowei Chen, Te Wang, Wenhao Zheng, Long Chen, Youjia XuMyricetin is a flavonoid which has many pharmacological effects. However, to date there is no evidence study on the effect of myricetin in diabetic condition. This study was aimed to investigate whether myricetin could protect against diabetic osteoporosis in streptozotocin induced rats.Female Wistar rats were randomly allocated to four equal groups: diabetic group (DG), diabetic group with myricetin (50 mg per kilogram per day), (D) diabetic group with myricetin (100 mg/kg/day) and normal control group (CG). Body weight was recorded once a week. After treatment with myricetin for 12 weeks, serum biochemical analyses, the microarchitecture of femora, and histological changes were evaluated.We found that the bone mineral density (BMD) of myricetin (100 mg per kilogram per day)treatment group significantly increased than in the diabetic group (P 
  • Unilateral lesion of the nigroestriatal pathway with 6-OHDA induced
           allodynia and hyperalgesia reverted by pramipexol in rats
    • Abstract: Publication date: Available online 18 November 2019Source: European Journal of PharmacologyAuthor(s): Héctor Alonso Romero-Sánchez, Liliana Mendieta, Amaya Montserat Austrich-Olivares, Gabriela Garza-Mouriño, Marcela Benitez-Diaz Mirón, Arrigo Coen, Beatriz Godínez-ChaparroAbstractPain is the non-motor symptom with the highest prevalence in patients with Parkinson's Disease (PD) affecting 40–85%. This study aimed to investigate the development of tactile allodynia and mechanical hyperalgesia after the nigrostriatal dopaminergic lesion induced by the unilateral 6-hydroxydopamine (6-OHDA) injection at different doses in the substantia nigra pars compacta (SNpc). Moreover, we studied the possible antiallodynic and antihyperalgesic effect with the acute and the subacute treatment of the pramipexole (PPX) in rats. First, dopaminergic lesion was realized by the unilateral injection of 6-OHDA (6, 10 and 16 μg/μl) into the SNpc. To know the establishment of motor deficits, we measure several turns and forelimb-use asymmetry by rotational behavior and cylinder, respectively. On the other hand, to investigate allodynia and hyperalgesia induced by 6-OHDA, we used the von Frey filaments. Moreover, antiallodynic and antihyperalgesic effect induced by PPX (0.03, 0.3 and 3 mg/kg, s.c.) was examined on acute and subacute conditions. We found that major dopaminergic lesion with 16 μg/μl of 6-OHDA caused the highest allodynia and hyperalgesia effects in both paws, as well as the major motor deficits. In addition, the treatment with PPX at 0.3 mg/kg reverts the allodynia and the hyperalgesia induced by 6-OHDA. In conclusion, the dopaminergic lesion into SNpc induce allodynia and hyperalgesia in both paws; interestingly the treatment with PPX can be suggested as an analgesic drug for patients with PD.
  • Subchronic MK-801 treatment during adolescence induces long-term, not
           permanent, excitatory-inhibitory imbalance in the rat hippocampus
    • Abstract: Publication date: Available online 18 November 2019Source: European Journal of PharmacologyAuthor(s): Yu-Nu Ma, Ya-Xin Sun, Ting Wang, Han Wang, Yue Zhang, Yun-Ai Su, Ji-Tao Li, Tian-Mei SiAbstractAdolescence is a critical neurodevelopmental period for both excitatory and inhibitory (E/I) neurotransmission and often witnesses the typical onsets of schizophrenia. One possibility is that disruptions in adolescent neurodevelopmental processes may produce schizophrenia-like behavioral and neurobiological abnormalities. We previously reported that subchronic treatment of adolescent animals with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 induced cognitive deficits and reduced interneuron densities in rat medial prefrontal cortex, and these changes persisted one week after MK-801 exposure. However, it remains unclear how this treatment may affect E/I balance in hippocampus, which has long been associated with the pathophysiology of schizophrenia. Here, we examined hippocampal E/I biomarkers in adolescent rats treated with MK-801 (0.2 mg/kg, i.p., 14 days) and found increases in the ratio of the expression levels of vesicular glutamate transporter-1 (VGluT1) and vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) 24 h and 7 days after MK-801 exposure. Interestingly, the increased VGluT1/VGAT ratio at the two time points was driven by upregulated VGluT1 expression and downregulated VGAT expression, respectively. The decrease in VGAT expression persisted 14 days after MK-801 exposure and recovered two weeks later. No alterations in hippocampal interneuron densities were observed. Behaviorally, the treatment decreased prepulse inhibition at 24 h but not 14 days, after MK-801 exposure. Taken together, these results demonstrate that subchronic NMDA receptor blockade during adolescence induces long-term, but not permanent, E/I imbalance in the rat hippocampus, which could be attributed to the dysregulation of glutamatergic transmission in the short term and of GABAergic transmission in the long term.
  • Antimicrobial pharmaceuticals in the aquatic environment - occurrence and
           environmental implications
    • Abstract: Publication date: Available online 18 November 2019Source: European Journal of PharmacologyAuthor(s): Ewa Felis, Joanna Kalka, Adam Sochacki, Katarzyna Kowalska, Sylwia Bajkacz, Monika Harnisz, Ewa KorzeniewskaAbstractThe environmental occurrence of antimicrobial pharmaceuticals and antibiotic resistant bacteria and antibiotic resistant genes has become a global phenomenon and a multifaceted threat. Integrated actions of many parties are needed to prevent further aggravation of the problem. Well-directed actions require clear understanding of the problem, which can be ensured by frequent revaluation of the existing knowledge and disseminating it among relevant audiences. The goal of this review paper is to discuss the occurrence and abundance of antimicrobial pharmaceuticals in the aquatic environment in context of adverse effects caused directly by these substances and the threat associated with the antibiotics resistance phenomenon. Several classes of antimicrobial pharmaceuticals (aminoglycosides, β-lactams, glycopeptides, macrolides, fluoroquinolones, sulfonamides and trimethoprim, tetracyclines) have been selected to illustrate their sources, environmental abundance, degradation routes (transformation products) and environmental implications including their ecotoxic effect and the spread of antibiotic resistance within the compartments of the aquatic environment and wastewater treatment plants. Wastewater treatment plants are indeed the main source responsible for the prevalence of these factors in the aquatic environment, since predominantly the plants have not been designed to retain antimicrobial pharmaceuticals. In order to limit the prevalence of these impurities into the environment, better source control is recommended as well as the establishment of stricter environmental quality standards. Counteracting all the above-mentioned threats requires to undertake integrated activities based on cooperation of professionals and scientists from various fields of science or industry, such as environmental sciences, medicine, veterinary, pharmacology, chemical engineering and others.
  • Mechanisms mediating the vasodilatory effects of juglone in porcine
           isolated coronary artery
    • Abstract: Publication date: Available online 17 November 2019Source: European Journal of PharmacologyAuthor(s): Taseer Ahmad, Abdul Jabbar Shah, Richard RobertsAbstractJuglone (5-hydroxy-1, 4-naphthoquinone), is a natural phenolic compound that has been shown to relax smooth muscle. Therefore the aim of this study was to determine the effect of juglone on vascular tone using porcine coronary artery (PCA). Segments of PCA, with or without endothelium, were mounted for isometric tension recording in isolated tissue baths and precontracted with the thromboxane A2 analog U46619 or KCl. After pre-contraction, cumulative concentrations of juglone were added to the tissues, in the presence or absence of a variety of inhibitors on intracellular signaling pathways. Juglone (10-9 to 10-5 M) produced a concentration-dependent relaxation of the PCA which was reduced in endothelium-denuded vessels, as well as in vessels pre-treated with the nitric oxide synthase inhibitor L-NAME, indicating that at least part of the effect of juglone is mediated through an endothelium, NO-dependent mechanism. Juglone also inhibited contractions in response to influx of extracellular calcium and release of intracellular calcium, indicating that juglone may inhibit a common signaling pathway downstream of calcium. Contractions to the protein kinase C activator Phorbol 12-myristate 13-acetate were also reduced by juglone, suggesting that juglone might be acting through inhibition of protein kinase C. In summary, juglone produces a relaxation of the porcine coronary artery through activation of the nitric oxide pathway and inhibition of calcium-induced contractions.
  • Salidroside ameliorates endothelial inflammation and oxidative stress by
    • Abstract: Publication date: Available online 17 November 2019Source: European Journal of PharmacologyAuthor(s): Rong Hu, Ming-qing Wang, Shi-hao Ni, Ming Wang, Ling-yu Liu, Hai-yan You, Xiao-hui Wu, Yan-jing Wang, Lu Lu, Lian-bo WeiEndothelial dysfunction plays important roles in vascular dysfunction under diabetic conditions. The generation of advanced glycation end products (AGEs), which can induce inflammation and oxidative stress, is pivotal in endothelial dysfunction. Salidroside, a major active compound in Rhodiola rosea, exerts protective effects against vascular diseases. To study the effects and mechanism of salidroside in diabetes-induced vascular endothelial dysfunction, an in vitro model was established with AGEs-induced human umbilical vein endothelial cells (HUVECs). Then, cell viability, cell apoptosis, pro-inflammatory cytokines and oxidative biomarkers were tested to determine the effects of salidroside at 10, 50 and 100 μM doses on AGEs induced HUVECs. Additionally, RNA-Seq and bioinformatics analyses were used to search for the underlying mechanism of salidroside. The results showed that salidroside promoted cell viability and significantly alleviated cell apoptosis in AGEs-induced HUVECs. Furthermore, salidroside remarkably decreased the levels of the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 and impeded the expression of VCAM-1 and ICAM-1 induced by AGEs. Additionally, salidroside promoted superoxide dismutase (SOD) activity and increased catalase (CAT) and glutathione peroxidase (GSH-Px) levels while inhibiting the intracellular generation of reactive oxygen species (ROS) and malondialdehyde (MDA) in AGEs-induced HUVECs. Importantly, salidroside alleviated endothelial inflammation and oxidative stress by activating AMPK phosphorylation and inhibiting NF-ĸB p65 and NLRP3 inflammasome activation. Therefore, we used compound C, an accepted AMPK inhibitor, to further demonstrate the mechanism. Interestingly, the phenomenon produced by salidroside was abolished. Our findings suggest that salidroside ameliorates AGEs-induced endothelial inflammation and oxidative stress, partially via the AMPK/NF-κB/NLRP3 signaling pathway.Graphical abstractImage 1
  • Geroprotection in the future. In memoriam of Joseph Knoll: The selegiline
           story continues
    • Abstract: Publication date: Available online 16 November 2019Source: European Journal of PharmacologyAuthor(s): Peter Ferdinandy, Fumio Yoneda, Shizuko Muraoka, Susanna Fürst, Klara Gyires, Ildiko MiklyaAbstractIn memoriam of Joseph Knoll: the selegiline story continues.
  • Ginsenoside Rg1 protects mice against streptozotocin-induced type 1
           diabetic by modulating the NLRP3 and Keap1/Nrf2/HO-1 pathways
    • Abstract: Publication date: Available online 16 November 2019Source: European Journal of PharmacologyAuthor(s): Yan Gao, Juntong Li, Shifeng Chu, Zhao Zhang, Naihong Chen, Lin Li, Lan ZhangAbstractGinseng has been traditionally used to treat diabetes mellitus (DM) in China. Ginsenoside Rg1 is a major active ingredient in processed ginseng, which elicits proven biological and pharmacological effects. Although a correlation between nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and predisposition to type 1 diabetes mellitus (T1DM) has been identified, the mechanism underlying the potential function and activation of NLRP3 inflammasome in DM have not been elucidated to date. The present study aimed to elucidate the effects and underlying mechanism of Rg1 on streptozotocin (STZ)-induced T1DM in mice through short or long-term observation. Concurrently, we intended to explore the relationships between inflammasome, pyroptosis and oxidative stress and the role of NLRP3 and Keap1/Nrf2/HO-1 pathways in the development and progression of DM. Using ELISA and Western blot analysis, we found that Rg1 attenuated abnormally elevated blood glucose, reduced inflammatory factors IL-1β and IL-18 in the blood, decreased ALT and AST levels, promoted insulin secretion, and weakened the function of NLRP3 in mouse liver and pancreas. In addition, Rg1 protected against STZ-induced reactive oxygen species-mediated inflammation by upregulating Nrf2/ARE pathway, which further activated antioxidant enzymes. Interestingly, Rg1 also regulated H3K9 methylation in liver and pancreas, as detected by immunohistochemistry. In summary, these data provide new understanding about the mechanism of Rg1 action, suggesting that it is a potential drug applied for preventing the occurrence and development of T1DM.
  • Mechanisms of orexin 2 receptor-mediated depolarization in the rat
           paraventricular nucleus of the hypothalamus
    • Abstract: Publication date: Available online 16 November 2019Source: European Journal of PharmacologyAuthor(s): Yu-Wen E. Dai, Yen-Hsien Lee, Tzu-Ling Li, Ling-Ling HwangAbstractThe paraventricular nucleus of the hypothalamus (PVN) contains dense orexin 2 (OX2) receptor. We examined the mechanisms of OX2 receptor-mediated excitation on electrophysiologically identified type I (putative magnocellular), low-threshold spikes (LTS)-expressing type II (putative preautonomic), and non-LTS type II (putative parvocellular neuroendocrine) neurons. In the presence of tetrodotoxin, an OX2 receptor agonist, ALOXB (30–1000 nM) depolarized 56% of type I, and 73–75% of type II neurons. In type I neurons, ALOXB-induced inward current displayed increased-conductance current-voltage (I–V) relationship and reversed polarity at -27.5 ± 4.8 mV. A Na+-Ca2+ exchanger (NCX) inhibitor, KBR-7943, attenuated ALOXB responses in the majority of type I neurons, while no attenuation was observed in nearly all type II neurons. Type II neurons exhibited three types of I–V relationships in response to ALOXB, characterized by decreased, increased, and unchanged conductance, respectively. The reversal potential of the decreased-conductance responses was near the equilibrium potential of K+ (Ek+) and became more positive in a high-K+ solution, suggesting that K+ conductance blockade is involved. In a low-Na+ solution, non-reversed I–V curves of increased-conductance responses became decreased-conductance responses and reversed polarity near Ek+, suggesting the involvement of both K+ conductance and non-selective cation conductance (NSCC). Approximately 35% of LTS-expressing type II neurons were vasopressin-immunoreactive and 71% of them responded to ALOXB. In conclusion, orexins may activate OX2 receptor on PVN neurons and cause depolarization by promoting NCX and/or NSCC in magnocellular neurons, and by decreasing K+ conductance and/or increasing NSCC in parvocellular neurons. Furthermore, the majority of vasopressinergic preautonomic neurons are under OX2 receptor regulation.
  • Pharmacological characterization of
           (NFP) as a dual selective MOR/KOR ligand with potential applications in
           treating opioid use disorder
    • Abstract: Publication date: Available online 16 November 2019Source: European Journal of PharmacologyAuthor(s): Yi Zheng, Samuel Obeng, Bethany A. Reinecke, Chongguang Chen, Palak S. Phansalkar, David M. Walentiny, Phillip M. Gerk, Lee-Yuan Liu-Chen, Dana E. Selley, Patrick M. Beardsley, Yan ZhangFor thousands of years opioids have been the first-line treatment option for pain management. However, the tolerance and addiction potential of opioids limit their applications in clinic. NFP, a MOR/KOR dual-selective opioid antagonist, was identified as a ligand that significantly antagonized the antinociceptive effects of morphine with lesser withdrawal effects than naloxone at similar doses. To validate the potential application of NFP in opioid addiction treatment, a series of in vitro and in vivo assays were conducted to further characterize its pharmacological profile. In calcium mobilization assays and MOR internalization studies, NFP showed the apparent capacity to antagonize DAMGO-induced calcium flux and etorphine-induced MOR internalization. In contrast to the opioid agonists DAMGO and morphine, cells pretreated with NFP did not show apparent desensitization and down regulation of the MOR. Though in vitro bidirectional transport studies showed that NFP might be a P-gp substrate, in warm-water tail-withdrawal assays it was able to antagonize the antinociceptive effects of morphine indicating its potential central nervous system activity. Overall these results suggest that NFP is a promising dual selective opioid antagonist that may have the potential to be used therapeutically in opioid use disorder treatment.Graphical abstractNFP was able to antagonize the effect of morphine indicative of tolerance developed by Day 7.Image 1
  • Peripheral antinociception induced by ketamine is mediated by the
           endogenous opioid system
    • Abstract: Publication date: Available online 15 November 2019Source: European Journal of PharmacologyAuthor(s): Julia Alvarenga Petrocchi, Douglas Lamounier de Almeida, Patrícia Paiva-Lima, Celso Queiroz-Junior, Marcelo Vidigal Caliari, Igor Dimitri Gama Duarte, Thiago Roberto Lima RomeroAbstractKetamine is a drug largely used in clinical practice as an anesthetic and it can also be used as an analgesic to manage chronic pain symptoms. Despite its interactions with several other signaling systems such as cholinergic, serotoninergic and adrenergic, it is accepted that NMDA receptor antagonism is the main mechanism of action of this drug. In this study we investigated the actions of endogenous opioids in the mechanism of peripheral analgesia induced by ketamine. The nociceptive threshold for mechanical stimuli was measured in Swiss mice using the Randall and Selitto test. The drugs used in this study were administered via intraplantar injection. Our results demonstrated that non selective opioid receptor antagonism (naloxone), selective μ- and δ-opioid receptors antagonism (clocinamox and naltrindole, respectively) but not κ-opioid receptor antagonism (nor-binaltorphimine NORBNI) antagonized ketamine-induced peripheral antinociception in a dose-dependent manner. In addition, administration of aminopeptidase inhibitor bestatin significantly potentiated ketamine-induced peripheral antinociception. Ketamine injection in the right hind paw induced β-endorphine synthesis in the epithelial tissue of the hindpaw. Together these results indicate a role for μ- and δ-opioid receptors and for the endogenous opioid β-endorphine increased synthesis in ketamine-induced peripheral analgesia mechanism of action.
  • Evaluation of pharmacochaperone-mediated rescue of mutant V2 receptor
    • Abstract: Publication date: Available online 15 November 2019Source: European Journal of PharmacologyAuthor(s): Beril Erdem Tuncdemir, Hatice Mergen, Emel Saglar OzerAbstractNephrogenic Diabetes Insipidus is a rare disorder which is characterized by severe water imbalance in the body. The disease can be acquired or inherited. AVPR2 (arginine vasopressin type 2 receptor) mutations are responsible for genetical type of the disorder. Mutations in the AVPR2 gene may cause loss-of-function due to conformational defects. According to the mutation type, the three-dimensional structure of AVPR2 may be affected even if it is functional and therefore it may not reach the plasma membrane where it is functional. Consequently, it is generally trapped in the Endoplasmic reticulum or Golgi apparatus, which are the quality control systems of the cell. Pharmacological chaperones have been used to retrieve these mutant AVPR2s from these quality control systems of the cell and take them to the plasma membrane for therapeutic purposes. In this study, in order to analyze the effects of two pharmacological chaperones, SR121463B and SR49059, we performed total ELISA and surface ELISA studies and cAMP accumulation assays on mutant receptors (G12E, R68W, V88M, ΔR67_G69/G107W, R106C, V162A and T273M). We observed that pharmacological chaperones may act differently on mutated AVPR2s. Cell surface expression of the mutant receptors and cAMP accumulation response, after stimulation with AVP, were mostly improved by these pharmacological chaperones. We believe that, this study presents important results with respect to the process of the variable type of mutated proteins in the cell and may help in developing a process of new types of chaperones.
  • Synthesis and in vitro cytotoxicity evaluation of star-shaped
           polymethacrylic conjugates with methotrexate or acitretin as potential
           antipsoriatic prodrugs
    • Abstract: Publication date: Available online 15 November 2019Source: European Journal of PharmacologyAuthor(s): Anna Mielanczyk, Katarzyna Mrowiec, Maria Kupczak, Łukasz Mielanczyk, Dorota Scieglinska, Agnieszka Gogler-Piglowska, Marek Michalski, Andrzej Gabriel, Dorota Neugebauer, Magdalena SkoniecznaAbstractWater-soluble polymer-drug conjugates were obtained and analyzed towards their potential use as prodrugs for two hydrophobic antipsoriatic agents, including methotrexate (MTX) and acitretin (AC). The conjugation efficacy of MTX decreased with a decreasing molar ratio of N,N-dimethylaminoethyl methacrylate (DMAEMA) repeating units in the polymethacrylic chains. Cytotoxicity of positively charged (from +5 to +10 mV) nano- and microparticles (3–1500 nm in DMEM at 37 °C) were estimated by in vitro MTT and Annexin-V apoptosis assays on Me45, NHDF, HaCaT and BEAS-2B cell lines. Further, cell cycle analysis revealed arrest in G0/G1 phase in melanoma cells, while neither apoptosis induction nor cell cycle arrest occurred in normal epidermal and epithelial cells. Tested conjugates displayed a novel cytostatic effect in Me45 cells and a pro-apoptotic effect in HaCaT cells. Epithelial BEAS-2B cells were the most sensitive to the tested conjugates and responded via induction of necrosis. Cell line models allowed for characterization of the biologically relevant potential action of pro-drugs. Additionally, a skin in vitro evaluation assay provided the first known evidence of side-effect reduction with pro-drug use. Histological examinations confirmed the lack of negative effects of conjugates on the skin and showed no irritating properties.
  • Empagliflozin restores lowered exercise endurance capacity via the
           activation of skeletal muscle fatty acid oxidation in a murine model of
           heart failure
    • Abstract: Publication date: Available online 15 November 2019Source: European Journal of PharmacologyAuthor(s): Hideo Nambu, Shingo Takada, Arata Fukushima, Junichi Matsumoto, Naoya Kakutani, Satoshi Maekawa, Ryosuke Shirakawa, Ippei Nakano, Takaaki Furihata, Takashi Katayama, Katsuma Yamanashi, Yoshikuni Obata, Akimichi Saito, Takashi Yokota, Shintaro KinugawaAbstractDecreased exercise capacity, which is an independent predictor of the poor prognosis of patients with heart failure (HF), is attributed to markedly impaired skeletal muscle mitochondrial function and fatty acid oxidation. Previous studies reported that the administration of an inhibitor of sodium-glucose cotransporter 2 (SGLT2) increases ketone body production and fat utilization in type 2 diabetic mice. In this study, we investigated the effects of SGLT2 inhibitor administration on exercise endurance and skeletal muscle mitochondrial function with fatty acid oxidation in a murine model of HF after the induction of myocardial infarction (MI). Two weeks post-MI, HF mice were divided into 2 groups, i.e., with or without treatment with the SGLT2 inhibitor empagliflozin (Empa, 300 mg/kg of food). Consistent with previous studies, urinary glucose and blood beta-hydroxybutyrate levels were increased in the HF+Empa mice compared with the sham and HF mice 4 weeks after the start of Empa administration. Exercise endurance capacity was limited in the HF mice but was ameliorated in the HF+Empa mice, without any effects on cardiac function, food intake, spontaneous physical activity, skeletal muscle strength, and skeletal muscle weight. Mitochondrial oxidative phosphorylation capacity with fatty acid substrates was reduced in the skeletal muscle of HF mice, and this decrease was ameliorated in the HF+Empa mice. Our results demonstrate that SGLT2 inhibitors may be novel therapeutics against reduced exercise endurance capacity in HF, by improving mitochondrial fatty acid oxidation in skeletal muscle.
  • PP2Cm overexpression alleviates MI/R injury mediated by a BCAA catabolism
           defect and oxidative stress in diabetic mice
    • Abstract: Publication date: Available online 15 November 2019Source: European Journal of PharmacologyAuthor(s): Kun Lian, Xiong Guo, Qin Wang, Yi Liu, Ru-Tao Wang, Chao Gao, Cong-Ye Li, Cheng-Xiang Li, Ling TaoAbstractDiabetic patients are sensitive to myocardial ischemia-reperfusion (MI/R) injury. During diabetes, branched-chain amino acid (BCAA) catabolism is defective and mitochondrial phosphatase 2C (PP2Cm) expression is reduced. This study aims to elucidate the relationship between PP2Cm downregulation and BCAA catabolism defect in diabetic mice against MI/R injury. PP2Cm was significantly downregulated in hearts of diabetic mice. The cardiac function was improved and the myocardial infarct size and apoptosis were decreased in diabetic mice overexpressing PP2Cm after MI/R. In diabetic mice, the cardiac BCAA and its metabolites branched-chain keto-acids (BCKA) levels, and p-BCKDE1α (E1 subunit of BCKA dehydrogenase)/BCKDE1α ratio were increased while the BCKD activity was decreased. Treatment of diabetic mice subjected to MI/R injury with BT2, a BCKD kinase (BDK) inhibitor, alleviated the BCAA catabolism defect, and improved the cardiac function alongside reduced apoptosis. PP2Cm overexpression alleviated the BCAA catabolism defect and MI/R injury. Similarly, MnTBAP ameliorated the oxidative stress and MI/R injury. BCKA treatment of H9C2 cells under simulated ischemia/reperfusion (SI/R) injury significantly decreased cell viability and increased LDH release and apoptosis. These effects were alleviated by BT2 and MnTBAP treatments. These results suggested that PP2Cm directly mediates the BCAA catabolism defect and oxidative stress observed after MI/R in diabetes. Overexpression of PP2Cm alleviates MI/R injury by reducing the catabolism of BCAA and oxidative stress.
  • Δ9-THC and related cannabinoids suppress substance P- induced neurokinin
    • Abstract: Publication date: Available online 15 November 2019Source: European Journal of PharmacologyAuthor(s): Nissar A. Darmani, Louiza Belkacemi, Weixia ZhongAbstractΔ9-THC suppresses cisplatin-induced vomiting through activation of cannabinoid CB1 receptors. Cisplatin-evoked emesis is predominantly due to release of serotonin and substance P (SP) in the gut and the brainstem which subsequently stimulate their corresponding 5-HT3-and neurokinin NK1-receptors to induce vomiting. Δ9-THC can inhibit vomiting caused either by the serotonin precursor 5-HTP, or the 5-HT3 receptor selective agonist, 2-methyserotonin. In the current study, we explored whether Δ9-THC and related CB1/CB2 receptor agonists (WIN55,212–2 and CP55,940) inhibit vomiting evoked by SP (50 mg/kg, i.p.) or the NK1 receptor selective agonist GR73632 (5 mg/kg, i.p.). Behavioral methods were employed to determine the antiemetic efficacy of cannabinoids in least shrews. Our results showed that administration of varying doses of Δ9-THC (i.p. or s.c.), WIN55,212–2 (i.p.), or CP55,940 (i.p.) caused significant suppression of SP-evoked vomiting in a dose-dependent manner. When tested against GR73632, Δ9-THC also dose-dependently reduced the evoked emesis. The antiemetic effect of Δ9-THC against SP-induced vomiting was prevented by low non-emetic doses of the CB1 receptor inverse-agonist/antagonist SR141716A (
  • A novel GABAB receptor positive allosteric modulator, ASP8062, exerts
           analgesic effects in a rat model of fibromyalgia
    • Abstract: Publication date: Available online 21 October 2019Source: European Journal of PharmacologyAuthor(s): Nobuhito Murai, Yuji Kondo, Shinobu Akuzawa, Takuma Mihara, Nobuyuki Shiraishi, Shuichiro Kakimoto, Mitsuyuki MatsumotoAbstractThe gamma-aminobutyric acid type B (GABAB) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABAB receptor agonists is limited by their undesirable side-effects. To clarify whether GABAB receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABAB receptor agonist in FM, we investigated the potential of a novel GABAB receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABAB receptor PAM and an agonist on pain in a rat model of FM, and the sleep/wake cycle, EEG during sleep stages and motor coordination in rats. ASP8062 showed PAM activity on human and rat GABAB receptors. Oral administration of ASP8062 significantly reversed the decrease in muscle pressure threshold in reserpine-induced myalgia rats. The analgesic effects of ASP8062 were significantly blocked by a GABAB receptor antagonist. ASP8062 had a significant effect on motor coordination at a 1000-fold higher dose than the analgesic dose in rats. ASP8062 significantly decreased total REM sleep time and frequency of sleep interruptions, and increased the power in delta waves frequency during non-REM sleep in rats. ASP8062, a novel GABAB receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABAB receptor agonists in patients with FM.
  • Valproic acid promotes the epithelial-to-mesenchymal transition of breast
           cancer cells through stabilization of Snail and transcriptional
           upregulation of Zeb1
    • Abstract: Publication date: Available online 19 October 2019Source: European Journal of PharmacologyAuthor(s): Siyuan Zhang, Zhaohui Tang, Bohua Qing, Ruoting Tang, Qunhuan Duan, Sijuan Ding, Dan DengAbstractHistone deacetylases (HDACs) can regulate cancer progression and its inhibitors (HDACIs) have been widely used for cancer therapy. Valproic acid (VPA, 2-propylpentanoic acid) can inhibit the class I HDAC and suppress the malignancy of solid cancers. Our present study revealed that 1 mM VPA, which has no effect on cell proliferation, can significantly increase the migration and induce epithelial to mesenchymal transition (EMT) like properties of breast cancer cells. Further, VPA increased the expression of EMT-transcription factors (EMT-TFs) Snail and Zeb1. Knockdown of Snail and Zeb1 can attenuate VPA induced cell migration and EMT. Mechanistically, VPA increased the protein stability of Snail via suppression its phosphorylation at Ser 11. As to Zeb1, VPA can increase its promoter activity and transcription via a HDAC2 dependent manner. Over expression of HDAC2 can block VPA induced expression of Zeb1. Collectively, our data revealed that VPA can trigger the EMT of breast cancer cells via upregulation of Snail and Zeb1. It indicated that more attention should be paid to the effects of VPA on the clinical therapy of breast cancer.
  • Identification of nicotinic acetylcholine receptor subunits in different
           lung cancer cell lines and the inhibitory effect of alpha-conotoxin TxID
           on lung cancer cell growth
    • Abstract: Publication date: Available online 18 October 2019Source: European Journal of PharmacologyAuthor(s): Jiang Qian, Yi-qiao Liu, Zhi-hua Sun, Dong-ting Zhangsun, Su-lan LuoLung cancer is an aggressive tumor with high incidence and mortality rate. There was growing evidence supporting that nicotinic acetylcholine receptors (nAChRs) play vital role inlung cancer development. In this study, the expression of α3, α4, α5, α6, α7, α9, α10, β2, β3, β4 nAChR subunits on protein and mRNA level were studied in A549, NCI–H1299, NCI–H1688, DMS114 and normal human embryonic lung fibroblast (HEL) cell lines by real-time quantitative PCR (qPCR) and Western blot assay respectively. The results indicated that most of these nAChR subunits were expressed in these five cell lines. Compared with normal cells, the expression of α3 and β4 nAChR subunits were upregulated in A549 and NCI–H1299. Thus, we treated A549 and NCI–H1299 with an antagonist α-conotoxin TxID which potently and selectively blocks α3β4 nAChRs. TxID treatment could inhibit A549 and NCI–H1299 cell growth and enhance the inhibitory effect of adriamycin when treated simultaneously. To sum up, our study identified the expression of nAChR subunits in different lung cells and the anti-tumor effect of α-conotoxin TxID, which may provide novel strategies for lung cancer therapy.Graphical abstractImage 1
  • Selected nucleos(t)ide-based prescribed drugs and their multi-target
    • Abstract: Publication date: Available online 18 October 2019Source: European Journal of PharmacologyAuthor(s): Gabriela Pastuch-Gawołek, Danuta Gillner, Ewelina Król, Krzysztof Walczak, Ilona WandzikAbstractNucleos(t)ide analogues play pivotal roles as antiviral, cytotoxic or immunosuppressive agents. Here, we review recent reports of nucleoside analogues that exhibit broad-spectrum activity towards multiple life-threatening RNA and DNA viruses. We also present a discussion about nucleoside antimetabolites—approved antineoplastic agents—that have recently been shown to have antiviral and/or antibacterial activity. The approved drugs and drug combinations, as well as recently identified candidates for investigation and/or experimentation, are discussed. Several examples of repurposed drugs that have already been approved for use are presented. This strategy can be crucial for the first-line treatment of acute infections or coinfections and for the management of drug-resistant strains.
  • Matrine pre-treatment suppresses AGEs- induced HCSMCs fibrotic responses
           by regulating Poldip2/mTOR pathway
    • Abstract: Publication date: Available online 18 October 2019Source: European Journal of PharmacologyAuthor(s): Wangxia Ma, Jing Xu, Yong Zhang, Hong Zhang, Zhu Zhang, Liqin Zhou, Xincheng Wang, Hongbo Liu, Yani Chen, Peng Du, Ningbin Min, Zhongwei Liu, Yanrong YinAbstractThe fibrotic response of vascular smooth muscle cells (VSMCs) takes responsibilities in atherosclerosis. Advanced glycation end products (AGEs) induce and promote the fibrotic responses of VSMCs. Matrine shows potent anti-fibrotic and cardio-protective effects. This study was aimed to investigate the underlying mechanisms of matrine's inhibitory effects on AGEs-induced VSMCs fibrotic responses. Cultured human coronary smooth muscle cells (HCSMCs) were pre-treated with matrine and exposed to AGEs. Specific siRNA was used to silence polymerase delta interacting protein 2 (Poldip2) expression. Sircol collagen assay was used to assess collagen content. Protein expression and phosphorylation levels were determined by Western blotting. Matrine pre-treatment significantly reduced collagen content, increased smooth muscle myosin heavy chain 11 (MYH11) and Poldip2 expression, decreased expressions of collagen I, β1-integrin, phsphoinositide-3-kinase (PI3K) and nuclear phosphorylated p70S6k, and reduced phosphorylation levels of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR) in HCSMCs exposed to AGEs in a concentration dependent manner. Specific siRNA effectively silenced Poldip2 expression and impaired matrine's effect on collagen content, expressions of MYH11, collagen I, β1-integrin, PI3K, nuclear p-p70S6k and phosphorylation levels of Akt and mTOR in HCSMCs exposed to AGEs. Matrine suppresses AGEs- induced fibrotic responses in HCSMCs via regulating Poldip2/mTOR signaling pathway.
  • Inhibition of long noncoding RNA BLACAT1 protects anesthesia-induced
           neural cytotoxicity in human induced pluripotent stem cells derived
    • Abstract: Publication date: Available online 14 October 2019Source: European Journal of PharmacologyAuthor(s): Dongge Niu, Lei Wang, Jing Cui, Baolong Zhou, Lan YaoAbstractStrong evidence has shown that long non-coding RNAs (lncRNAs) play important roles in genetic modulations in human CNS. In this study, we utilized an in vitro model of human induced pluripotent stem cells (hiPSCs)-derived neurons, and hypothesized that lncRNA of bladder cancer associated transcript 1 (BLACAT1) had a functional role in anesthesia-induced cytotoxicity in human lineage neural cells. To test that, HiPSCs were induced toward neural cells and then treated with ketamine in vitro. We demonstrated that, ketamine induced neuronal apoptosis, neurite degeneration, and upregulated BLACAT1 gene expression. Inversely, lentiviral-induced BLACAT1 downregulation rescued ketamine-induced neural cytotoxicity in hiPSCs-derived neurons. In addition, BLACAT1 downregulation was demonstrated to prevent ketamine-induced mitochondrial dysregulations by suppressing ROS and caspase 3/7 activities in hiPSCs-derived neurons. Thus, we discovered a new mechanism that inhibition of LncRNA BLACAT1 could rescue anesthesia-induced neural cytotoxicity in human induced pluripotent stem cells derived neurons.
  • Off-label uses of drugs for depression
    • Abstract: Publication date: Available online 14 October 2019Source: European Journal of PharmacologyAuthor(s): Sigrid S. Skånland, Artur Cieslar-PobudaAbstractThe prescription of drugs for depression is rising rapidly. One of the reasons for this trend is their many off-label uses. Up to one third of all prescriptions are for non-indicated use, which in addition to drug repurposing includes different dosing or duration than those recommended. In this review, we elaborate on what antidepressants can treat besides depression. The five classes of drugs for depression are introduced, and their mechanisms of action and serious side effects are described. The most common off-label uses of antidepressants are discussed, with a special focus on treating eating disorders, sleep problems, smoking cessation and managing chronic pain. Depression is often a comorbidity when antidepressants are chosen as therapy, but good therapeutic effects have been observed for other conditions also when depression is not involved. Finally, a new type of antidepressant developed from the hallucinogenic “party drug” ketamine is briefly introduced. This recent development suggest that antidepressants will keep playing a central role in medicine for years to come.
  • Mitochondrial outer membrane voltage-dependent anion channel is involved
           in renal dysfunction in a spontaneously hypertensive rat carrying transfer
           RNA mutations
    • Abstract: Publication date: Available online 13 October 2019Source: European Journal of PharmacologyAuthor(s): Chao Zhu, Liuyang Tian, Huanwan Yang, Pu Chen, Yang Li, Yuqi LiuMitochondrial DNA mutations promote hypertensive renal dysfunction, but the molecular mechanism remains unclear. This study compared renal damage between spontaneously hypertensive rats (SHR) and SHR with mitochondrial transfer (t)RNA mutations. To investigate the role of mitochondrial outer membrane voltage-dependent anion channel 1 (VDAC1) in the process of tRNA-promoting mitochondrial dysfunction, we treated HK-2 cells with H2O2, cyclosporine (CsA), or atractylodin (Atr) to observe the association between VDAC1 and mitochondrial function. Intriguingly, the mitochondrial structure of SHR carrying tRNA mutations was obviously disordered, and reactive oxygen species production and VDAC1 and Bax expression and binding were increased, which was associated with marked renal dysfunction. The expression of VDAC1 and Bax was also up-regulated in HK-2 cells by H2O2 treatment. However, CsA and Atr had no significant effect on the expression of VDAC1 and Bax. H2O2 caused mitochondrial membrane potential collapse, while CsA could increase the mitochondrial membrane potential and Atr had the opposite effect. Treatment with H2O2 significantly decreased ATP synthesis, which was improved by intervention with Atr. H2O2 also decreased the maximum oxygen consumption rate, while CsA and Atr had no significant effect. We found that H2O2 promoted the colocalization of VDAC1 and Bax, which was partially inhibited by intervention with CsA or Atr. In conclusion, we found that tRNA mutations promoted hypertensive renal insufficiency. Increased reactive oxygen species was an important associated mechanism, which inhibited mitochondrial function by affecting VDAC1 expression and function.Graphical abstractImage 1
  • Naringenin attenuates the progression of liver fibrosis via inactivation
           of hepatic stellate cells and profibrogenic pathways
    • Abstract: Publication date: Available online 13 October 2019Source: European Journal of PharmacologyAuthor(s): Erika Hernández-Aquino, Marco A. Quezada-Ramírez, Angélica Silva-Olivares, Sael Casas-Grajales, Erika Ramos-Tovar, Rosa E. Flores-Beltrán, José Segovia, Mineko Shibayama, Pablo MurielAbstractThere is no effective treatment for hepatic fibrosis. Previously, we demonstrated that naringenin possesses the ability to prevent experimental chronic liver damage. Therefore, the objective of this work was to investigate whether naringenin could reverse carbon tetrachloride (CCl4)-induced fibrosis in rats and, if so, to search for the mechanisms involved. CCl4 was given to male Wistar rats (400 mg/kg, three times per week, i. p.) for 12 weeks; naringenin (100 mg/kg twice per day, p. o.) was administered from weeks 9–12 of the CCl4 treatment. Liver damage and oxidative stress markers were measured. Masson's trichrome, hematoxylin-eosin staining and immunohistochemistry were performed. Zymography assays for MMP-9 and MMP-2 were carried out. TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1β, IL-10, Smad7, pSmad3 and pJNK protein levels were determined by western blotting. In addition, α-SMA and Smad3 protein and mRNA levels were studied. Naringenin reversed liver damage, biochemical and oxidative stress marker elevation, and fibrosis and restored normal MMP-9 and MMP-2 activity. The flavonoid also preserved NF-κB, IL-1β, IL-10, TGF-β, CTGF, Col-I, MMP-13 and Smad7 protein levels. Moreover, naringenin decreased JNK activation and Smad3 phosphorylation in the linker region. Finally, α-SMA and Smad3 protein and mRNA levels were reduced by naringenin administration. The results of this study demonstrate that naringenin blocks oxidative stress, inflammation and the TGF-β-Smad3 and JNK-Smad3 pathways, thereby carrying out its antifibrotic effects and making it a good candidate to treat human fibrosis, as previously demonstrated in toxicological and clinical studies.
  • Antidiabetic effects and sustained metabolic benefits of sub-chronic
           co-administration of exendin-4/gastrin and xenin-8-Gln in high fat fed
    • Abstract: Publication date: Available online 12 October 2019Source: European Journal of PharmacologyAuthor(s): A. Hasib, D. Khan, S.L. Craig, V.A. Gault, P.R. Flatt, N. IrwinAbstractThe present study has examined the antidiabetic effects of 21 days co-administration of xenin-8-Gln with the dual-acting fusion peptide, exendin-4/gastrin, as well as persistence of beneficial metabolic benefits, in high fat fed (HFF) mice. Xenin-8-Gln, exendin-4 and gastrin represent compounds that activate receptors of the gut-derived hormones, xenin, glucagon-like peptide-1 (GLP-1) and gastrin, respectively. Twice-daily administration of exendin-4/gastrin, xenin-8-Gln or a combination of both peptides significantly reduced circulating glucose, HbA1c and cumulative energy intake. Combination therapy with xenin-8-Gln and exendin-4/gastrin increased circulating insulin. All HFF mice treated with exendin-4/gastrin presented with body weight similar to lean control mice on day 21. Each treatment improved glucose tolerance and the glucose-lowering actions of glucose dependent insulinotropic polypeptide (GIP), as well as augmenting glucose- and GIP-induced insulin secretion, with benefits being most prominent in the combination group. Administration of exendin-4/gastrin alone, and in combination with xenin-8-Gln, increased pancreatic insulin content and improved the insulin sensitivity index. Pancreatic beta-cell area was significantly increased, and alpha cell area decreased, by all treatments, with the combination group also displaying enhanced overall islet area. Notably, metabolic benefits were generally retained in all groups of HFF mice, and especially in the combination group, following discontinuation of the treatment regimens for 21 days. This was associated with maintenance of increased islet and beta-cell areas. Together, these data confirm the antidiabetic effects of co-activation of GLP-1, gastrin and xenin cell signalling pathways, and highlight the sustainable benefits this type of treatment paradigm can offer in T2DM.
  • High expression of NAMPT in adult T-cell leukemia/lymphoma and anti-tumor
           activity of a NAMPT inhibitor
    • Abstract: Publication date: Available online 12 October 2019Source: European Journal of PharmacologyAuthor(s): Tomohiro Kozako, Akiyoshi Aikawa, Takeo Ohsugi, Yu-ichiro Uchida, Naho Kato, Keisuke Sato, Kenji Ishitsuka, Makoto Yoshimitsu, Shin-ichiro HondaAdult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes induced by human T-cell leukemia virus-1 and has a poor outcome. New molecular targets for the prevention and treatment of ATL are needed urgently. We previously reported high expression of Sirtuin 1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylase, in primary acute-type ATL cells. NAD+ biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) modulates Sirtuin 1 activity. Here, we examined the expression and effects of inhibiting NAMPT, a rate-limiting enzyme in NAD+ biosynthesis, in ATL cells. We found that peripheral blood mononuclear cells from patients with acute-type ATL expressed significantly higher levels of NAMPT protein than cells from healthy subjects. FK866, a NAMPT inhibitor, induced apoptosis of freshly isolated ATL cells ex vivo and HTLV-1-infected T-cell lines in vitro, which was accompanied by activation of caspases, DNA fragmentation, and disruption of mitochondrial transmembrane potential. However, a pan-caspase inhibitor failed to prevent this FK866-induced cell death, while FK866 increased the caspase-independent cell death mediator endonuclease G. Intriguingly, FK866 also activated autophagy, as demonstrated by increases in protein levels of autophagosome marker LC3-II. Thus, FK866 simultaneously activated apoptosis and autophagy. Finally, FK866 treatment markedly decreased the growth of human ATL tumor xenografts in immunodeficient mice. We showed that NAMPT is highly expressed in primary ATL cells ex vivo, and that FK866 induces autophagy and caspase-dependent and -independent cell death pathways in vitro and has an anti-tumor activity in vivo. These results suggest a novel therapeutic strategy for patients with this fatal disease.Graphical abstractImage 1
  • Morin hydrate inhibits platelet activation and clot retraction by
           regulating integrin αIIbβ3, TXA2, and cAMP levels
    • Abstract: Publication date: Available online 12 October 2019Source: European Journal of PharmacologyAuthor(s): Gi Suk Nam, Kyu-Shik Lee, Kyung-Soo NamAbstractMorin hydrate is an active constituent of Morus alba L, Prunus dulcis, and Cudrania tricuspidata and has been reported to inhibit platelet activation in vivo and in vitro, but no reports have been issued on its regulation of αIIbβ3, a platelet-specific integrin and thromboxane A2 (TXA2), positive feedback molecule.In this study, we investigated the anti-platelet activity of morin hydrate in collagen- and thrombin-induced human platelets and attempted to identify the mechanism responsible for integrin αIIbβ3 activation and TXA2 generation. Our results demonstrated that morin hydrate (25–100 μM) inhibited collagen- and thrombin-induced platelet aggregation, granule secretion (P-selectin expression, ATP, and serotonin release), calcium mobilization, TXA2 production, integrin αIIbβ3 activation, and clot retraction. Additionally, morin hydrate attenuated the phosphorylations of phospholipase Cγ2 (PLCγ2), cytosolic phospholipase A2 (cPLA2), phosphoinositide 3-kinase (PI3K), Akt, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), and enhanced the phosphorylations of inositol trisphosphate receptor (IP3 receptor) and cyclic adenosine monophosphate (cAMP) generation. However, it had no effect on the coagulation pathway. Taken together, these observations indicate morin hydrate inhibits platelet-mediated thrombosis by down-regulating TXA2 production and integrin αIIbβ3 activation, and by upregulating cAMP generation, and thus, inhibits clot retraction. These results suggest morin hydrate may have therapeutic potential as a treatment for platelet-activation-related diseases.
  • Trans-10-hydroxy-2-decenoic acid alleviates LPS-induced blood-brain
           barrier dysfunction by activating the AMPK/PI3K/AKT pathway
    • Abstract: Publication date: Available online 12 October 2019Source: European Journal of PharmacologyAuthor(s): Mengmeng You, Zhuoning Miao, Yongming Pan, Fuliang HuAbstractWe previously reported that trans-10-hydroxy-2-decenoic acid (10-HDA), the exclusive lipid component of royal jelly (RJ), alleviates Lipopolysaccharide (LPS)-induced neuroinflammation both in vivo and in vitro. However, whether 10-HDA can protect against LPS-induced blood-brain barrier (BBB) damage is largely unexplored. In this study, we first observed that 10-HDA decreased BBB permeability in LPS-stimulated C57BL/6 mice by Evan's blue (EB) dye. Immunostaining and Western blot results showed that 10-HDA alleviated BBB dysfunction by inhibiting the degradation of tight junction proteins (occludin, claudin-5 and ZO-1). In LPS-stimulated human brain microvascular endothelial cells (HBMECs), 10-HDA decreased the expression of chemokines (CCL-2 and CCL-3), adhesion molecules (ICAM-1 and VCAM-1), reactive oxygen species, matrix metalloproteinases (MMP-2 and MMP-9) and increased the expression of tight junction proteins. Interestingly, LC-MS/MS analysis showed that 10-HDA pretreatment upregulated the expression of mitochondria-associated proteins, which may reflect the mechanism underlying the regulatory effect of 10-HDA on reactive oxygen species. We further illustrated that 10-HDA promoted the activation of the AMPK pathway and the downstream PI3K/AKT pathway. Compound C (an AMPK inhibitor) and LY294002 (a PI3K inhibitor) markedly reversed the alleviating effect of 10-HDA on the expression of tight junction proteins, indicating that 10-HDA inhibited LPS-induced BBB dysfunction by triggering the activation of the AMPK/PI3K/AKT pathway. Collectively, these data reveal that 10-HDA may be an interesting candidate for clinical evaluation in the treatment of diseases related to BBB damage.
  • Neurotensin receptors regulate transactivation of the EGFR and HER2 in a
           reactive oxygen species-dependent manner
    • Abstract: Publication date: Available online 12 October 2019Source: European Journal of PharmacologyAuthor(s): Terry W. Moody, Lingaku Lee, Irene Ramos-Alvarez, Robert T. JensenAbstractNeurotensin is a 13 amino acid peptide which is present in many lung cancer cell lines. Neurotensin binds with high affinity to the neurotensin receptor 1, and functions as an autocrine growth factor in lung cancer cells. Neurotensin increases tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) and the neurotensin receptor 1 antagonist SR48692 blocks the transactivation of the EGFR. Here the effects of reactive oxygen species on the transactivation of the EGFR and HER2 were investigated. Using non-small cell lung cancer (NSCLC) cell lines, neurotensin receptor 1 mRNA and protein were present. Using NCI–H838 cells, neurotensin or neurotensin8−13 but not neurotensin1−8 increased EGFR, ERK and HER2 tyrosine phosphorylation which was blocked by SR48692. Neurotensin addition to NCI–H838 cells increased significantly reactive oxygen species which was inhibited by SR48692, Tiron (superoxide scavenger) and diphenylene iodonium (DPI inhibits the ability of NADPH oxidase and dual oxidase enzymes to produce reactive oxygen species). Tiron or DPI impaired the ability of neurotensin to increase EGFR, ERK and HER2 tyrosine phosphorylation. Neurotensin stimulated NSCLC cellular proliferation whereas the growth was inhibited by SR48692, DPI or lapatinib (lapatinib is tyrosine kinase inhibitor of the EGFR and HER2). Lapatinib inhibited the ability of the neurotensin receptor 1 to transactivate the EGFR and HER2. The results indicate that neurotensin receptor 1 regulates the transactivation of the EGFR and HER2 in a reactive oxygen species-dependent manner.
  • Sofalcone, a gastroprotective drug, covalently binds to KEAP1 to activate
           Nrf2 resulting in anti-colitic activity
    • Abstract: Publication date: Available online 12 October 2019Source: European Journal of PharmacologyAuthor(s): Wooseong Kim, Hanju Lee, Soojin Kim, Sanghyun Joo, Seongkeun Jeong, Jin-Wook Yoo, Yunjin JungSofalcone is a synthetic chalcone being used as a gastric mucosa protective agent in Japan. Sofalcone contains a 1,3-diaryl-2-propen-1-one moiety, which is a common chemical scaffold in naturally occurring chalcones. The α,β-unsaturated carbonyl group (Michael reaction acceptor) has electrophilic properties. We investigated the biochemical mechanisms by which sofalcone activated the cytoprotective and anti-inflammatory nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2)–heme oxygenase (HO)-1 pathway. Furthermore, we investigated whether the activation of this pathway was involved in sofalcone -mediated protective effects in an experimental colitis model. Sofalcone induced HO-1 protein expression, which was dependent on increased nuclear accumulation of Nrf2 in human colon carcinoma cells. In addition, Sofalcone reacted with nucleophilic thiol compounds to form Michael adducts. A reduced form of sofalcone (SFCR) in which the Michael reaction acceptor was deactivated, did not exert biological or chemical activity. Biotin-tagged sofalcone bound to Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor of Nrf2. This binding was prevented by pretreatment with sofalcone and a thiol compound but not with SFCR. Furthermore, sofalcone treatment induced dissociation of the Nrf2-KEAP1 complex. Rectal administration of sofalcone alleviated colon damage and inflammation and increased colon nuclear accumulation of Nrf2 and HO-1 levels in a dinitrobenzene sulfonic acid-induced rat colitis model. The protective effects of sofalcone against colon damage and inflammation were significantly inhibited by co-administration of an HO-1 inhibitor. In conclusion, sofalcone activated the Nrf2-HO-1 pathway by covalently binding to KEAP1 via Michael addition, and may confer anti-colitic effects by inducing Nrf2 activation.Graphical abstractImage 1
  • Flavonoids reduces lipopolysaccharide-induced release of inflammatory
           mediators in human bronchial epithelial cells: Structure-activity
    • Abstract: Publication date: Available online 11 October 2019Source: European Journal of PharmacologyAuthor(s): Peng Zhang, Judith CW. Mak, Ricky YK. Man, Susan WS. LeungAbstractFlavonoids are polyphenolic compounds that are widely present in food and Chinese medicine. The aim of the present study was to identify the flavonoids with anti-inflammatory effects in the airway; and to determine the role of anti-oxidant and cyclic adenosine monophosphate (cAMP) in the anti-inflammatory effect. Human bronchial epithelial BEAS-2B cells were exposed to bacterial endotoxin lipopolysaccharide (LPS) in the absence or presence of different flavonoids, which are categorized according to their chemical structures in seven subclasses [anthocyanidins, chalcones, flavanes, flavanones, flavones, flavonols, isoflavones]. Among the 17 flavonoids tested, only apigenin (flavones), luteolin (flavones), daidzein (isoflavones) and genistein (isoflavones) reduced LPS-induced release of inflammatory cytokines/chemokines interleukin (IL)-6, IL-8 and monocyte chemoattractant protein-1 in BEAS-2B cells. Quercetin caused further increase in LPS-induced IL-6 and IL-8 levels. It alone significantly increased nuclear factor-kappa B (NF-κB) p65 activity and the cellular oxidative stress marker malondiadehyde (MDA) level in BEAS-2B cells. By contrast, apigenin and genistein reduced LPS-induced increases in nuclear NF-κB activity and MDA level. Apigenin and genistein, but not quercetin, increased the cAMP level in BEAS-2B cells, and the cell-permeable cAMP analogue, 8-Br-cAMP, inhibited LPS-induced increase of IL-8 level. These findings suggest that the presence of C5–OH, C7–OH, C2=C3 and C4=O functional groups in the flavonoids is associated with greater anti-inflammatory effect, while that of C3–OH or glycosylation group at the A-ring greatly decreased the anti-inflammatory effect. The anti-inflammatory effect of these flavonoids may be related to their anti-oxidant properties, and partly to their ability in increasing cAMP level.
  • The angiotensin converting enzyme inhibitor captopril attenuates
           testosterone-induced benign prostatic hyperplasia in rats; a mechanistic
    • Abstract: Publication date: Available online 9 October 2019Source: European Journal of PharmacologyAuthor(s): Fatma Mostafa, Eman M. Mantawy, Samar S. Azab, Ebtehal El-DemerdashBenign prostatic hyperplasia (BPH) is the most widespread urological disorder among elderly men. It is influenced by several factors, among which is the prostatic renin angiotensin system (RAS). Prostatic RAS activates several signaling pathways as proliferation, inflammation and angiogenesis that contribute to BPH development and progression. Captopril is a potent inhibitor of the angiotensin converting enzyme. Therefore, this study was performed to explore the potential protective effect of captopril against testosterone-induced BPH in rats. Male Sprague-Dawley rats were treated with either testosterone (3 mg/kg, s. c.) and/or captopril (100 mg/kg, orally) for four weeks. After treatments, prostatic serum markers and histopathology were assessed. Mechanistically, apoptotic, inflammatory and angiogenic pathways were examined. Testosterone significantly increased prostate weight, prostatic index, prostatic acid phosphatase and prostate specific antigen. These effects were almost prevented by captopril (100 mg/kg). Moreover, testosterone significantly elevated proliferating cell nuclear antigen and reduced Bax/Bcl-2 ratio, p53 and caspase-3 activity. Furthermore, it significantly elevated nuclear factor kappa-B, cyclooxygenase-II, tumor necrosis factor-α and interleukin-8. Besides, it caused a significant rise in vascular endothelial growth factor, basic fibroblast growth factor and matrix metalloproteinase-9. On the contrary, captopril effectively neutralised the proliferative, inflammatory and angiogenic effects of testosterone. Finally, the angiotensin-1 receptor expression in the BPH group was markedly decreased while captopril restored the receptor expression. Collectively, these findings indicate that captopril possesses a potent protective effect against testosterone-induced BPH via inducing apoptotic and suppressing inflammatory and angiogenic signaling pathways.Graphical abstractImage 1
  • Factors affecting the transition of acute kidney injury to chronic kidney
           disease: Potential mechanisms and future perspectives
    • Abstract: Publication date: Available online 4 October 2019Source: European Journal of PharmacologyAuthor(s): Jeremiah Ogbadu, Gaaminepreet Singh, Devesh AggarwalAbstractAcute kidney injury (AKI) is defined as a rapid loss of kidney function characterised by inflammation and cell death, ultimately leading to further functional and structural renal alterations. Based on experimental and epidemiological pieces of evidence, AKI may progress to chronic kidney disease (CKD) even after a recovery period due to maladaptive repair and other underlying mechanisms such as heightened Wnt signalling, overstimulation of the renin-angiotensin-aldosterone-system (RAAS) pathway, epigenetic alterations and inhibition of hypoxia-inducible factor (HIF) dependent defences. It has been reported that RAAS activation subsequent to renal insult mediates inflammatory and fibrotic mechanisms, which are a hallmark of CKD. Moreover, interesting evidence regarding the exposure-dependent dual role of Wnt signalling in both injury and repair, epigenetic changes underlying kidney disease suggest a potential therapeutic role of these pathways in AKI to CKD continuum. In addition, the hypoxia-independent renal benefits of erythropoietin such as anti-apoptosis and tubular regeneration also present an auspicious target which could be useful in clinical settings. In this review, the specific roles of these pathways in kidney disease, their pathological mechanisms and therapeutic strategies are discussed. Moreover, notable reports concerning stem cell therapy which hold promise in halting AKI-CKD continuum will be elaborated.
  • Sirtuins as novel targets in the pathogenesis of airway inflammation in
           bronchial asthma
    • Abstract: Publication date: Available online 19 September 2019Source: European Journal of PharmacologyAuthor(s): Ke Ma, Na Lu, Fei Zou, Fan-Zheng MengAbstractSirtuins are NAD-dependent class III histone deacetylase, which modulate the epigenetic changes to influence the functions in normal and diseased conditions. Preclinical studies have described an increase in the levels of sirtuin 2 and decrease in the levels of sirtuin 6 in the lungs. Sirtuin 2 exerts proinflammatory actions and hence, its blockers reduce the airway inflammation and symptoms of asthma. On the other hand, sirtuin 6 is anti-inflammatory and its activators produce beneficial actions in asthma. The beneficial effects of sirtuin 6 have been attributed to decrease in acetylation of transcriptional factor GATA3 in the T cells, which is associated with decrease in the TH2 immune response. However, there seems to be dual role of sirtuin 1 in airway inflammation as its proinflammatory as well as anti-inflammatory actions have been described in asthma. The anti-inflammatory actions of sirtuin 1 have been attributed to decrease in acetylation of GATA3 and inhibition of Akt/NF-kappaB signaling. On the other hand, proinflammatory actions of sirtuin 1 have been attributed to increase in the expression of HIF-1α and VEGF along with repression of PPAR-γ activity. The present review discusses the role of different sirtuins in the pathogenesis of bronchial asthma. Moreover, it also discusses sirtuin-triggered signaling pathways that may contribute in modulating the disease state of bronchial asthma.
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