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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  [3123 journals]
  • Carotid intima-media thickness and anti-hypertensive treatment: Focus on
           angiotensin II receptor blockers
    • Authors: Cesare Cuspidi; Carla Sala; Marijana Tadic; Guido Grassi; Giuseppe Mancia
      Pages: 20 - 26
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Cesare Cuspidi, Carla Sala, Marijana Tadic, Guido Grassi, Giuseppe Mancia
      Carotid intima-media thickness (CIMT), as assessed by ultrasonography, has been shown to be directly related to cardiovascular (CV) morbidity and mortality independently of conventional risk factors. Thus, CIMT has been proposed as a marker of CV risk and a surrogate end-point for therapeutic interventions. In the present article we will review available literature about CIMT clinical/prognostic significance in order to offer an updated comprehensive information on this topic. In particular, the anti-atherosclerotic effect of angiotensin II receptor blockers (ARBs) in the hypertensive setting will be addressed, based on findings provided by double blind, randomized, prospective studies comparing CIMT longitudinal changes. Our review, including 8 studies totaling 1154 hypertensive participants, shows that ARBs are as effective as the other classes of antihypertensive drugs in preventing/regressing subclinical carotid damage and that findings supporting their superiority in this field are limited and not univocal. Future studies aimed to clarify the therapeutic impact of ARBs on CIMT changes and their prognostic implications are warranted.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2018.01.007
      Issue No: Vol. 129 (2018)
       
  • Impact of adenosine A2a receptor polymorphism rs5751876 on platelet
           reactivity in ticagrelor treated patients
    • Authors: Matteo Nardin; Monica Verdoia; Patrizia Pergolini; Roberta Rolla; Lucia Barbieri; Paolo Marino; Giorgio Bellomo; Elvin Kedhi; Harry Suryapranata; Alessandro Carriero; Giuseppe De Luca
      Pages: 27 - 33
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Matteo Nardin, Monica Verdoia, Patrizia Pergolini, Roberta Rolla, Lucia Barbieri, Paolo Marino, Giorgio Bellomo, Elvin Kedhi, Harry Suryapranata, Alessandro Carriero, Giuseppe De Luca
      Dual antiplatelet therapy constitutes a key point in the management of patients with acute coronary syndromes. In particular, ticagrelor, an ADP-antagonist, can provide a more potent and predictable platelet inhibition as compared to clopidogrel, and adenosine-mediated pathways have been involved in its beneficial effects on mortality and myocardial perfusion. However, a quote of patients still displays a suboptimal platelet inhibition on ticagrelor, and, while the role of genetics in conditioning clopidogrel resistance is well established, few data have been reported for ticagrelor. We investigated the impact of rs5751876 C > T polymorphism of adenosine A2a receptor (ADORA2a) on platelet reactivity in patients during chronic treatment with ticagrelor. We included patients treated with ASA and ticagrelor for a recent ACS or elective coronary revascularization. Platelet reactivity was assessed at 30–90 days post-discharge by multiple-electrode aggregometry. HRPR for ticagrelor was defined as ADP-test results >417 AU*min. Genetic analysis was performed to assess the presence of rs5751876 C > T polymorphism of ADORA2a receptor. We included 244 patients in our study, 174 (71.3%) patients carried the polymorphism (T allele), 51 (20.9%) of them in homozygosis (T/T). C-allele carriers (homozygotes C/C and heterozygotes C/T) showed no difference in baseline characteristics but for lower HDL-cholesterol (p = 0.01). An absolute lower rate of HRPR on ticagrelor was observed in homozygotes T/T (p = 0.03). At multivariate analysis, C allele carriage was independently associated with the rate of HRPR on ticagrelor (adjusted OR[95%CI] = 4.63[1.02–21.01], p = 0.048). Our study results showed a significant independent association between rs5751876 allele C carriage and a higher rate of high residual platelet reactivity in patients on ticagrelor after a recent ACS or PCI.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.12.035
      Issue No: Vol. 129 (2018)
       
  • A glance at the therapeutic potential of irisin against diseases involving
           inflammation, oxidative stress, and apoptosis: An introductory review
    • Authors: Hassan Askari; Sulail Fatima Rajani; Mansour Poorebrahim; Hamed Haghi-Aminjan; Ehsan Raeis-Abdollahi; Mohammad Abdollahi
      Pages: 44 - 55
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Hassan Askari, Sulail Fatima Rajani, Mansour Poorebrahim, Hamed Haghi-Aminjan, Ehsan Raeis-Abdollahi, Mohammad Abdollahi
      Irisin is a hormone-like molecule mainly released by skeletal muscles in response to exercise. Irisin induces browning of the white adipose tissue and has been shown to regulate glucose and lipid homeostasis. Keeping its energy expenditure and metabolic properties in view, numerous studies have focused on its therapeutic potential for the treatment of metabolic disorders like obesity and type 2 diabetes. Recently, the anti-inflammatory, anti-apoptotic and anti-oxidative properties of irisin have received a great deal of attention of the scientific society. These pathogenic processes are often associated with initiation, progression, and prognosis of numerous diseases like myocardial infarction, kidney diseases, cancer, lung injury, inflammatory bowel diseases, atherosclerosis, liver diseases, obesity and type 2 diabetes. In the current review, we present evidence regarding the anti-inflammatory, anti-apoptotic and anti-oxidative potential of irisin pertaining to various pathological conditions. Here, we explore multiple molecular pathways targeted by irisin therapy. Given the promising effects of irisin, many diseases with evident oxidative stress, inflammation and apoptosis can be targeted by irisin.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2018.01.012
      Issue No: Vol. 129 (2018)
       
  • Emerging role of carbon monoxide in regulation of cellular pathways and in
           the maintenance of gastric mucosal integrity
    • Authors: Katarzyna Magierowska; Tomasz Brzozowski; Marcin Magierowski
      Pages: 56 - 64
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Katarzyna Magierowska, Tomasz Brzozowski, Marcin Magierowski
      Heme oxygenase (HO) catalyzes the degradation of toxic free heme to the equimolar amounts of biliverdin, Fe2+ and concurrently releases of carbon monoxide (CO). CO is nowadays increasingly recognized as an important signaling molecule throughout the body that is involved in many physiological processes and shows multidirectional biological activity. Recent evidence indicates that CO exhibits the anti-inflammatory, anti-proliferative, anti-apoptotic, anti-aggregatory and vasodilatory properties. The cellular mechanisms underlying the activity of CO involve stimulation of cGMP-dependent signaling pathway and large conductance calcium activated K+ channels, the activation of mitogen-activated protein kinases and the nuclear factor k-light chain-enhancer of activated B cells transcription factor pathway. Stimulation of endogenous CO production by HO inducers or the inhalation of CO or the delivery of this gaseous molecule by novel pharmaceutical agents have been found in experimental animal models to be promising in the future therapy of various diseases. CO appears to act as a significant component of the complex mechanism of gastrointestinal (GI) mucosal defense. This gaseous molecule plays an important role in diabetic gastroparesis, prevention of the upper GI mucosal damage, post-operative ileus and the healing of ulcerative colitis. This review focuses on the better understanding mechanisms through which CO contributes to the mechanism of protection, resistance to injury and ulcer healing. It is becoming apparent that the pleiotropic effect of this molecule may increase clinical applicability of CO donors and their implementation in many pharmacological research areas, pharmaceutical industry and health-care system.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2018.01.008
      Issue No: Vol. 129 (2018)
       
  • Histamine H4 receptor antagonism prevents the progression of diabetic
           nephropathy in male DBA2/J mice
    • Authors: Alessandro Pini; Cristina Grange; Eleonora Veglia; Monica Argenziano; Roberta Cavalli; Daniele Guasti; Laura Calosi; Corrado Ghè; Roberto Solarino; Robin L. Thurmond; Giovanni Camussi; Paul L. Chazot; Arianna Carolina Rosa
      Pages: 18 - 28
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Alessandro Pini, Cristina Grange, Eleonora Veglia, Monica Argenziano, Roberta Cavalli, Daniele Guasti, Laura Calosi, Corrado Ghè, Roberto Solarino, Robin L. Thurmond, Giovanni Camussi, Paul L. Chazot, Arianna Carolina Rosa
      Due to the incidence of diabetes and the related morbidity of diabetic nephropathy, identification of new therapeutic strategies represents a priority. In the last few decades new and growing evidence on the possible role of histamine in diabetes has been provided. In particular, the histamine receptor H4R is emerging as a new promising pharmacological target for diabetic nephropathy. The aim of this study was to evaluate the efficacy of selective H4R antagonism by JNJ39758979 on the prevention of diabetic nephropathy progression in a murine model of diabetes induced by streptozotocin injection. JNJ39758979 (25, 50, 100 mg/kg/day p.o.) was administered for 15 weeks starting from the onset of diabetes. Functional parameters were monitored throughout the experimental period. JNJ39758979 did not significantly affect glycaemic status or body weight. The urine analysis indicated a dose-dependent inhibitory effect of JNJ39758979 on Albumin-Creatinine-Ratio, the Creatinine Clearance, the 24 h urine volume, and pH urine acidification (P < 0.05). The beneficial effects of JNJ39758979 on renal function paralleled comparable effects on renal morphological integrity. These effects were sustained by a significant immune infiltration and fibrosis reduction. Notably, megalin and sodium-hydrogen-exchanger 3 expression levels were preserved. Our data suggest that the H4R participates in diabetic nephropathy progression through both a direct effect on tubular reabsorption and an indirect action on renal tissue architecture via inflammatory cell recruitment. Therefore, H4R antagonism emerges as a possible new multi-mechanism therapeutic approach to counteract development of diabetic nephropathy development.
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      PubDate: 2018-01-15T23:43:03Z
      DOI: 10.1016/j.phrs.2018.01.002
      Issue No: Vol. 128 (2018)
       
  • Probiotics and antibiotic-associated diarrhea in children: A review and
           new evidence on Lactobacillus rhamnosus GG during and after antibiotic
           treatment
    • Authors: Cecilia Mantegazza; Paola Molinari; Enza D’Auria; Micol Sonnino; Lorenzo Morelli; Gian Vincenzo Zuccotti
      Pages: 63 - 72
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Cecilia Mantegazza, Paola Molinari, Enza D’Auria, Micol Sonnino, Lorenzo Morelli, Gian Vincenzo Zuccotti
      Antibiotic associated diarrhea (AAD) is a common complication in childhood in the outpatient and inpatient settings. This review provides up to date information on the use of probiotics in the prevention and treatment of AAD, including that from Clostridium Difficile, in children. The most recently systematic reviews and subsequently published randomized controlleds trials are considered. Different single and multistrain probiotics are described; a specific recommendation for the use of Lactobacillus Rhamnosus GG (LGG) and Saccharomyces boulardii (Sb) emerges. New information on LGG survival under amoxicillin/clavulanate therapy in children is also provided. This information is relevant in view of the frequent use of this molecule in children, its association with AAD, and LGG’s sensitivity to penicillin that might make this probiotic ineffective. In spite of a demonstrated positive effect of specific strains of probiotics on AAD, safety issues still remain among which the risk of associated severe infections and of antibiotic resistant gene exchange.

      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.08.001
      Issue No: Vol. 128 (2018)
       
  • Epigenetics in osteoarthritis: Potential of HDAC inhibitors as
           therapeutics
    • Authors: Nazir M. Khan; Tariq M. Haqqi
      Pages: 73 - 79
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Nazir M. Khan, Tariq M. Haqqi
      Osteoarthritis (OA) is the most common joint disease and the leading cause of chronic disability in middle-aged and older populations worldwide. The development of disease modifying therapy for OA is in its infancy largely because the regulatory mechanisms for the molecular effectors of OA pathogenesis are poorly understood. Recent studies identified epigenetic events as a critical regulator of molecular players involved in the induction and development of OA. Epigenetic mechanisms include DNA methylation, non-coding RNA and histone modifications. The aim of this review is to briefly highlight the recent advances in the epigenetics of cartilage and potential of HDACs (Histone deacetylases) inhibitors in the therapeutic management of OA. We summarize the recent studies utilizing HDAC inhibitors as potential therapeutics for inhibiting disease progression and preventing the cartilage destruction in OA. HDACs control normal cartilage development and homeostasis and understanding the impact of HDACs inhibitors on the disease pathogenesis is of interest because of its importance in affecting overall cartilage health and homeostasis. These findings also shed new light on cartilage disease pathophysiology and provide substantial evidence that HDACs may be potential novel therapeutic targets in OA.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.08.007
      Issue No: Vol. 128 (2018)
       
  • New perspectives in cancer: Modulation of lipid metabolism and
           inflammation resolution
    • Authors: Nella Prevete; Federica Liotti; Angela Amoresano; Piero Pucci; Amato de Paulis; Rosa Marina Melillo
      Pages: 80 - 87
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Nella Prevete, Federica Liotti, Angela Amoresano, Piero Pucci, Amato de Paulis, Rosa Marina Melillo
      Inflammation is considered an enabling feature of cancer. Besides the persistence of inflammatory stimuli, also defective mechanisms of resolution can lead to chronic inflammation. Inflammation resolution is an active process controlled by lipidic specialized pro-resolving mediators (SPMs), derived from ω-3 or ω-6 essential polyunsaturated fatty acids (PUFA) through the activity of lipoxygenases (ALOX5 and 15). Thus, a lack or defect in resolution mechanisms may affect cancer development and progression by prolonging inflammation. Components of pro-resolving pathways (PUFA, enzymes, or SPMs) have been reported to modulate various cancer features by affecting both cancer cells and cancer-associated stroma. Here, we will review the most important mechanisms by which SPMs, ω-3/6 PUFA, and ALOXs affect cancer biology, paying particular attention to their role in the inhibition of inflammation and angiogenesis, two of the most important hallmarks of cancer. The collection of these results may suggest novel perspectives in cancer management based on the modulation of lipid metabolism and the production of SPMs.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.09.024
      Issue No: Vol. 128 (2018)
       
  • Linking energy sensing to suppression of JAK-STAT signalling: A potential
           route for repurposing AMPK activators'
    • Authors: Claire Speirs; Jamie J.L. Williams; Kirsten Riches; Ian P. Salt; Timothy M. Palmer
      Pages: 88 - 100
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Claire Speirs, Jamie J.L. Williams, Kirsten Riches, Ian P. Salt, Timothy M. Palmer
      Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascular diseases. Mutational activation of JAKs is also responsible for several haematological malignancies, including myeloproliferative neoplasms and acute lymphoblastic leukaemia. Accumulating evidence links adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), an energy sensor and regulator of organismal and cellular metabolism, with the suppression of immune and inflammatory processes. Recent studies have shown that activation of AMPK can limit JAK-STAT-dependent signalling pathways via several mechanisms. These novel findings support AMPK activation as a strategy for management of an array of disorders characterised by hyper-activation of the JAK-STAT pathway. This review discusses the pivotal role of JAK-STAT signalling in a range of disorders and how both established clinically used and novel AMPK activators might be used to treat these conditions.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.10.001
      Issue No: Vol. 128 (2018)
       
  • Nicotine and autoimmunity: The lotus’ flower in tobacco
    • Authors: João Pedro Gomes; Abdulla Watad; Yehuda Shoenfeld
      Pages: 101 - 109
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): João Pedro Gomes, Abdulla Watad, Yehuda Shoenfeld
      Nicotine, the major component of cigarettes, has demonstrated conflicting impact on the immune system: some authors suggest that increases pro-inflammatory cytokines and provokes cellular apoptosis of neutrophils, releasing intracellular components that act as auto-antigens; others claimed that nicotine has a protective and anti-inflammatory effects, especially by binding to α7 subunit of nicotinic acetylcholine receptors. The cholinergic pathway contributes to an anti-inflammatory environment characterized by increasing T regulatory cells response, down-regulating of pro-inflammatory cytokines and a pro-inflammatory cells apoptosis. The effects of nicotine were studied in different autoimmune disease, as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, sarcoidosis, Behçet’s disease and inflammatory bowel diseases. The major problems about nicotine are the addiction and the adverse effects of related to each commercialized formulation. We sought in this review to summarize the knowledge accumulated to date concerning the relationship between nicotine and autoimmunity.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.10.005
      Issue No: Vol. 128 (2018)
       
  • Dendritic spine anomalies and PTEN alterations in a mouse model of
           VPA-induced autism spectrum disorder
    • Authors: Usman Mahmood; Sangzin Ahn; Eun-Jeong Yang; Moonseok Choi; Hyunju Kim; Philip Regan; Kwangwook Cho; Hye-Sun Kim
      Pages: 110 - 121
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Usman Mahmood, Sangzin Ahn, Eun-Jeong Yang, Moonseok Choi, Hyunju Kim, Philip Regan, Kwangwook Cho, Hye-Sun Kim
      Mounting evidence suggests that the etiology of autism spectrum disorders (ASDs) is profoundly influenced by exposure to environmental factors, although the precise molecular and cellular links remain ill-defined. In this study, we examined how exposure to valproic acid (VPA) during pregnancy is associated with an increased incidence of ASD. A mouse model was established by injecting VPA at embryonic day 13, and its behavioral phenotypes including impaired social interaction, increased repetitive behaviors and decreased nociception were observed at postnatal days 21–42. VPA-treated mice showed dysregulation of synaptic structure in cortical neurons, including a reduced proportion of filopodium-type and stubby spines and increased proportions of thin and mushroom-type spines, along with a decreased spine head size. We also found that VPA-treatment led to decreased expression of phosphate and tensin homolog (PTEN) and increased levels of p-AKT protein in the hippocampus and cortex. Our data suggest that there is a correlation between VPA exposure and dysregulation of PTEN with ASD-like behavioral and neuroanatomical changes, and this may be a potential mechanism of VPA-induced ASD.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.08.006
      Issue No: Vol. 128 (2018)
       
  • Single-nucleotide polymorphisms in the genes of CES2, CDA and enzymatic
           activity of CDA for prediction of the efficacy of capecitabine-containing
           chemotherapy in patients with metastatic breast cancer
    • Authors: Siu W. Lam; Vincent van der Noort; Tahar van der Straaten; Aafke H. Honkoop; Godefridus J. Peters; Henk-Jan Guchelaar; Epie Boven
      Pages: 122 - 129
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Siu W. Lam, Vincent van der Noort, Tahar van der Straaten, Aafke H. Honkoop, Godefridus J. Peters, Henk-Jan Guchelaar, Epie Boven
      We examined whether genetic polymorphisms (SNPs) in the capecitabine activation pathway and CDA enzymatic activity were associated with prognosis, benefit from capecitabine-containing treatment or capecitabine-related toxicities. The study population comprised 188 metastatic breast cancer patients of the ATX trial (EudraCT 2006-006058-83) randomized for first-line paclitaxel and bevacizumab with (ATX) or without capecitabine (AT). Cumulative capecitabine dose until grade ≥2 hand-foot syndrome or until first dose reduction were toxicity endpoints. We genotyped CDA c.-451C>T (rs532545), CDA c.-33delC (rs3215400) and CES2 c.-806C>G (rs11075646). CDA activity in baseline serum was measured with a spectrophotometric assay and values were analyzed using a median cut-off or as continuous variable. CDA c.-33delC was prognostic for overall survival (OS) independent of hormone receptor status. For the predictive analysis, progression-free survival benefit from ATX over AT was observed in patients with a CDA c.-33del/del or del/insC genotype, a CDA c.-451CC or CT genotype, and a CES2 c.-806CC genotype compared with their counterparts. There was a higher response rate for ATX over AT in patients with a CDA c.-451CT or TT genotype. Patients with high CDA enzymatic activity had more benefit from capecitabine, while this was marginally observed in the CDA low group. Toxicity endpoints were not associated with any candidate markers. In conclusion, CDA c.-33delC was associated with OS. Since particular SNPs in CDA and CES2 were associated with benefit from the addition of capecitabine to AT, their predictive value should be explored in a higher number of patients.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.08.005
      Issue No: Vol. 128 (2018)
       
  • Effects of coenzyme Q10 supplementation on plasma C-reactive protein
           concentrations: A systematic review and meta-analysis of randomized
           controlled trials
    • Authors: Mohsen Mazidi; Andre Pascal Kengne; Maciej Banach
      Pages: 130 - 136
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Mohsen Mazidi, Andre Pascal Kengne, Maciej Banach
      The aim of this systematic review and meta-analysis of prospective interventional studies was to investigate the effects of coenzyme Q10 (CQ10) on plasma C-reactive protein (CRP) levels. PubMed/Medline, Web of Science (WoS), Cochrane Database and Google Scholar databases were searched (up to December 2016) to identify prospective studies evaluating the impact of CQ10 supplementation on CRP. Random effects models meta-analysis was used for quantitative data synthesis. Sensitivity analysis used the leave-one-out method, and heterogeneity was quantitatively assessed using the I2 index. Systematic review PROSPERO database registration: CRD42016038155. From a total of 119 entries identified via searches, 7 studies were finally included to the analysis. The results of the meta-analysis indicated a non-significant reduction in CRP concentrations following supplementation with CQ10 with a weighted mean difference [WMD] of −0.25mg/l (95% confidence intervals [CI] −0.56 to 0.06, I2 = 42.0%). The WMD for the effects on interleukin 6 (IL6) was −0.72pg/dl, (95% CI −1.24 to −0.24, I2 =51.8%). These findings were robust in sensitivity analyses. Random-effects meta-regression revealed that changes in plasma CRP levels were independent of the dosage of CQ10 (slope: −0.0005; 95% CI: −0.005, 0.004; p =0.832) while duration of supplementation was the dependent mediator (slope: slope: −0.111; 95% CI: −0.21, −0.004; p =0.042). In conclusion, CQ10 supplementation has a borderline favourable effect on CRP levels, and a significant effect on IL-6 level. This suggests that CQ10 supplementation likely attenuates subclinical inflammation.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2017.08.011
      Issue No: Vol. 128 (2018)
       
  • Curcumin or combined curcuminoids are effective in lowering the fasting
           blood glucose concentrations of individuals with dysglycemia: Systematic
           review and meta-analysis of randomized controlled trials
    • Authors: Ingrid Sofia Vieira de Melo; Aldenir Feitosa dos Santos; Nassib Bezerra Bueno
      Pages: 137 - 144
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Ingrid Sofia Vieira de Melo, Aldenir Feitosa dos Santos, Nassib Bezerra Bueno
      Curcuminoids have received considerable attention as therapeutical adjuvants in the treatment of dysglycemia. The purpose of this meta-analysis was to evaluate whether the supplementation of turmeric extract, curcuminoids and/or isolated curcumin is more effective than placebo in decreasing fasting blood glucose (FBG) in adults. MEDLINE, CENTRAL, ScienceDirect and gray literature databases were searched. Randomized controlled trials with the following criteria were included: (1) studied individuals older than 18 years, supplemented with curcumin, curcuminoids and/or turmeric extract (2) had a follow-up ≥4 weeks (3) used a placebo group. Titles and abstracts were screened and potentially eligible articles were retrieved. The primary outcome was FBG. The secondary outcomes were HbA1c and HOMA-IR. Eleven studies were included. In the overall analysis, turmeric, curcuminoids and curcumin supplementation led to a decrease in FBG (−8.88, 95% CI: [−5.04 to −2.72] mg/dL, p = 0.005). Supplementation of curcuminoids and/or curcumin decreased the concentrations of HbA1c (−0.54, 95% CI: [−1.09 to −0.002] %, p = 0.049) but were not able to decrease HOMA-IR (−1.26, 95% CI: [−3.71 to −1.19], p = 0.31). Sensitivity analyses revealed that baseline FBG was an important covariate. Heterogeneity was high in the overall analyses and there was evidence of publication bias. Supplementation of isolated curcumin or combined curcuminoids were both effective in lowering the FBG concentrations of individuals with some degree of dysglycemia, but not in non-diabetic individuals. Isolated curcumin lead to significant decreases of the HbA1c compared to placebo.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.09.010
      Issue No: Vol. 128 (2018)
       
  • Role of tangeretin as a potential bioavailability enhancer for silybin:
           Pharmacokinetic and pharmacological studies
    • Authors: Zhong-Wen Yuan; Ya-Zhuo Li; Zhong-Qiu Liu; Sen-ling Feng; Hua Zhou; Chang-Xiao Liu; Liang Liu; Ying Xie
      Pages: 153 - 166
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Zhong-Wen Yuan, Ya-Zhuo Li, Zhong-Qiu Liu, Sen-ling Feng, Hua Zhou, Chang-Xiao Liu, Liang Liu, Ying Xie
      Biological responses of a variety of naturally occurring compounds in vivo were restrained by their poor oral bioavailability. Silybin, as one of the active ingredients of silymarin, has presented promising bioactivity for the treatment of chronic liver diseases and cancer. However, its exposure in body was limited. In this study, silybin was demonstrated to be substrates of both BCRP and MRP2 by utilizing monolayer Caco-2 cell model and confirmed in MDCK cells overexpressing specific efflux transporter. Of all compounds screened, tangeretin, a potent inhibitor of efflux transporters of BCRP, MRP2 and P-gp, was able to enhance exposure of silybin by inhibiting functions of the barriers mediating transcellular transport. Moreover, study carried out in sandwich-cultured rat hepatocyte (SCH) model showed that the biliary excretion index (BEI) and in vitro biliary clearance of silybin decreased as levels of tangeretin increased, indicating efflux transporters mediating biliary excretion of silybin might be involved. Pharmacokinetic behaviors of silybin in rats were altered by co-administration of tangeretin, in terms of increased AUC and Cmax of silybin by comparing with that of silybin given alone. In addition, results coming from CCl4-induced acute liver injury rat model revealed that protection effect of silybin against liver damage in the presence of tangeretin was significantly enhanced. All these data were evident that efflux transporters play a critical role in transcellular transport of silybin and account for its low bioavailability. Enhanced bioavailability of silybin with co-administration of tangeretin by significantly inhibiting the efflux transporters further boost its bioactivity which is of particular importance in clinical use.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.09.019
      Issue No: Vol. 128 (2018)
       
  • The effect of lipophilicity and dose on the frequency of statin-associated
           muscle symptoms: A systematic review and meta-analysis
    • Authors: Jordon C. Irwin; Saman Khalesi; Andrew S. Fenning; Rebecca K. Vella
      Pages: 264 - 273
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Jordon C. Irwin, Saman Khalesi, Andrew S. Fenning, Rebecca K. Vella
      Addressing the factors which lead to the development of statin-associated muscle symptoms (SAMS) is vital for maintaining patient compliance with these pharmaceuticals, and thus improving patient outcomes. This study aimed to clarify the relationship between statin lipophilicity, or dose, and the frequency of adverse muscle symptoms using a systematic review of randomised controlled trials (RCTs). RCTs, including statin monotherapy and placebo groups, which reported data on muscle adverse events were identified through the PubMed and Scopus databases. Risk ratios (RRs) and 95% confidence intervals (CI) were pooled using a random-effects meta-analysis. A total of 135 RCTs were included in this review. Statin therapy was associated with a significant, but modest, increase in the risk of adverse muscle symptoms compared to placebo (RR=1.050; 95% CI=1.014–1.089; P =0.007; I2 =3.291%). This significant association was primarily due to the inclusion of RCTs recruiting participants with a history of statin intolerance. Lipophilic statins had no appreciable impact on the development of SAMS compared to hydrophilic formulations. A univariate meta-regression of dose (standardised to atorvastatin dose equivalents) and the risk of musculoskeletal complaints also showed no significant association. The results obtained from this meta-analysis indicate that there is a slight increase in the risk of SAMS, especially in individuals with a history of statin intolerance. There is limited evidence to suggest that the risk of SAMS would differ between the use of lipophilic and hydrophilic statins, or high- and low-dose therapy.

      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.09.013
      Issue No: Vol. 128 (2018)
       
  • Circulating miRNAs in nontumoral liver diseases
    • Authors: Alex Evangelista do Amaral; Júlia Cisilotto; Tânia Beatriz Creczynski-Pasa; Leonardo de Lucca Schiavon
      Pages: 274 - 287
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Alex Evangelista do Amaral, Júlia Cisilotto, Tânia Beatriz Creczynski-Pasa, Leonardo de Lucca Schiavon
      In recent years, there has been increasing interest in finding new biomarkers for diagnosis and prognostication of liver diseases. MicroRNAs (miRNAs) are small noncoding RNA molecules involved in the regulation of gene expression and have been studied in relation to several conditions, including liver disease. Mature miRNAs can reach the bloodstream by passive release or by incorporation into lipoprotein complexes or microvesicles, and have stable and reproducible concentrations among individuals. In this review, we summarize studies involving circulating miRNAs sourced from the serum or plasma of patients with nontumoral liver diseases in attempt to bring insights in the use of miRNAs as biomarkers for diagnosis, as well as for prognosis of such diseases. In addition, we present pre-analytical aspects involving miRNA analysis and strategies for normalization of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) data related to the studies evaluated.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.10.002
      Issue No: Vol. 128 (2018)
       
  • Antimicrobial peptides as an alternative to anti-tuberculosis drugs
    • Authors: Manaf AlMatar; Essam A. Makky; Gülfer Yakıcı; Işıl Var; Begüm Kayar; Fatih Köksal
      Pages: 288 - 305
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Manaf AlMatar, Essam A. Makky, Gülfer Yakıcı, Işıl Var, Begüm Kayar, Fatih Köksal
      Tuberculosis (TB) presently accounts for high global mortality and morbidity rates, despite the introduction four decades ago of the affordable and efficient four-drugs (isoniazid, rifampicin, pyrazinamide and ethambutol). Thus, a strong need exists for new drugs with special structures and uncommon modes of action to effectively overcome M. tuberculosis. Within this scope, antimicrobial peptides (AMPs), which are small, cationic and amphipathic peptides that comprise a section of the innate immune system, are currently the leading potential agents for the treatment of TB. Many studies have recently illustrated the capability of anti-mycobacterial peptides to disrupt the normal mycobacterial cell wall function through various modes, thereby interacting with the intracellular targets, as well as encompassing nucleic acids, enzymes and organelles. This review presents a wide array of antimicrobial activities, alongside the associated properties of the AMPs that could be utilized as potential agents in therapeutic tactics for TB treatment.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.10.011
      Issue No: Vol. 128 (2018)
       
  • Transitioning from first- to second-generation biosimilars: An appraisal
           of regulatory and post-marketing challenges
    • Authors: Corrado Blandizzi; Mauro Galeazzi; Guido Valesini
      Pages: 306 - 314
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Corrado Blandizzi, Mauro Galeazzi, Guido Valesini
      Second-generation biosimilars (i.e. monoclonal antibodies or proteins generated by fusion of antibody and receptor moieties) differ in several respects as compared to first-generation ones (e.g. epoetins, bone marrow stimulating factors, somatotropins). In this respect, as second-generation biosimilars are endowed with much greater structural and molecular complexity, which might translate into a number of pharmacological and therapeutic issues, they raise new challenges for manufacturers and regulatory authorities as well as new concerns for clinicians. Based on these arguments, the present article was intended to review information on the main differences between first- and second-generation biosimilars for treatment of immune-mediated inflammatory diseases, as well as their impact on immunogenicity, the design of clinical trials and the critical issue of extrapolation of therapeutic indications. The positions taken by relevant medical associations and the crucial role of pharmacovigilance are also reviewed. According to current knowledge, the initial post-marketing clinical experience with second-generation biosimilars is providing encouraging results, though their long-term safety and efficacy as well as the scientific basis underlying the extrapolation of therapeutic indications are still matter of discussion. There is some consensus that marketing applications should rely on studies supporting the clinical use of biosimilars in their different target diseases and patient populations. In parallel, clinical safety must be ensured by a strict control of the manufacturing processes and a solid pharmacovigilance program. It remains then a responsibility of the physician to drive a proper use of second-generation biosimilars into clinical practice, in accordance with guidelines issued by scientific societies.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.10.015
      Issue No: Vol. 128 (2018)
       
  • Targeting immune-driven opioid analgesia by sigma-1 receptors: opening the
           door to novel perspectives for the analgesic use of sigma-1 antagonists
    • Authors: Miguel Á. Tejada; Ángeles Montilla-García; Rafael González-Cano; Inmaculada Bravo-Caparrós; M. Carmen Ruiz-Cantero; Francisco R. Nieto; Enrique J. Cobos
      Abstract: Publication date: Available online 15 February 2018
      Source:Pharmacological Research
      Author(s): Miguel Á. Tejada, Ángeles Montilla-García, Rafael González-Cano, Inmaculada Bravo-Caparrós, M. Carmen Ruiz-Cantero, Francisco R. Nieto, Enrique J. Cobos
      Immune cells have a known role in pronociception, since they release a myriad of inflammatory algogens which interact with neurons to facilitate pain signaling. However, these cells also produce endogenous opioid peptides with analgesic potential. The sigma-1 receptor is a ligand-operated chaperone that modulates neurotransmission by interacting with multiple protein partners, including the μ-opioid receptor. We recently found that sigma-1 antagonists are able to induce opioid analgesia by enhancing the action of endogenous opioid peptides of immune origin during inflammation. This opioid analgesia is seen only at the inflamed site, where immune cells naturally accumulate. In this article we review the difficulties of targeting the opioid system for selective pain relief, and discuss the dual role of immune cells in pain and analgesia. Our discussion creates perspectives for possible novel therapeutic uses of sigma-1 antagonists as agents able to maximize the analgesic potential of the immune system.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.008
       
  • OPA1: how much do we know to approach therapy'
    • Authors: Valentina Del Dotto; Mario Fogazza; Guy Lenaers; Michela Rugolo; Valerio Carelli; Claudia Zanna
      Abstract: Publication date: Available online 15 February 2018
      Source:Pharmacological Research
      Author(s): Valentina Del Dotto, Mario Fogazza, Guy Lenaers, Michela Rugolo, Valerio Carelli, Claudia Zanna
      OPA1 is a GTPase that controls several functions, such as mitochondrial dynamics and energetics, mtDNA maintenance and cristae integrity. In the last years, there have been described other cellular pathways and mechanisms involving OPA1 directly or through its interaction. All this new information, by implementing our knowledge on OPA1 is instrumental to elucidating the pathogenic mechanisms of OPA1 mutations. Indeed, these are associated with dominant optic atrophy (DOA), one of the most common inherited optic neuropathies, and with an increasing number of heterogeneous neurodegenerative disorders. In this review, we overview all recent findings on OPA1 protein functions, on its dysfunction and related clinical phenotypes, focusing on the current therapeutic options and future perspectives to treat DOA and the other associated neurological disorders due to OPA1 mutations.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.018
       
  • Gut microbiota and probiotics intervention: A potential therapeutic target
           for management of cardiometabolic disorders and chronic kidney
           disease'
    • Authors: Marinaldo Pacífico Cavalcanti Neto; Jailane de Souza Aquino; Larissa de Fátima Romão da Silva; Ruanniere de Oliveira Silva; Keyth Sulamitta de Lima Guimarães; Yohanna de Oliveira; Evandro Leite de Souza; Marciane Magnani; Hubert Vidal; José Luiz de Brito Alves
      Abstract: Publication date: Available online 14 February 2018
      Source:Pharmacological Research
      Author(s): Marinaldo Pacífico Cavalcanti Neto, Jailane de Souza Aquino, Larissa de Fátima Romão da Silva, Ruanniere de Oliveira Silva, Keyth Sulamitta de Lima Guimarães, Yohanna de Oliveira, Evandro Leite de Souza, Marciane Magnani, Hubert Vidal, José Luiz de Brito Alves
      The gut microbiota plays an important role in host metabolism and its dysregulation have been related to cardiometabolic disorders (CMD), such as type 2 diabetes mellitus (T2D), dyslipidemia and arterial hypertension, as well as to chronic kidney diseases (CKD). The implication of the gut microbiota on systemic disorders has been associated with changes in its composition (dysbiosis) as a result of the oxidative unbalance in the body. This alteration may be the result of the adoption of unhealthy lifestyle behavior, including lack of physical activity and fat- or sugar-rich diets, which are largely associated with increased incidence of CMD and CKD. In last years, a number of clinical trials and experimental studies have demonstrated that probiotics can modulate the host metabolism, resulting in amelioration of systemic disease phenotypes by the improvement of dyslipidemia, glycemic profile and blood pressure or CKD parameters. The beneficial effects of probiotics consumption have been associated with their anti-inflammatory, antioxidant and gut-modulating properties. Despite of some mechanistic evidence, these effects are not totally elucidated. The present review summarizes and clarifies the effects of probiotics administration on CMD and CKD using combined evidence from clinical and experimental studies. Considering that the microbiota dysregulation has been associated with inflammation and oxidative stress and consequently with CMD and CKD, supplementation with probiotics is discussed as a strategy for management of CMD and CKD.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.01.020
       
  • Early Alteration of Distribution and Activity of Hippocampal Type-1
           Cannabinoid Receptor in Alzheimer's Disease-like Mice Overexpressing the
           Human Mutant Amyloid Precursor Protein
    • Authors: Mauro Maccarrone; Antonio Totaro; Alessandro Leuti; Giacomo Giacovazzo; Lucia Scipioni; Dalila Mango; Roberto Coccurello; Robert Nisticò; Sergio Oddi
      Abstract: Publication date: Available online 14 February 2018
      Source:Pharmacological Research
      Author(s): Mauro Maccarrone, Antonio Totaro, Alessandro Leuti, Giacomo Giacovazzo, Lucia Scipioni, Dalila Mango, Roberto Coccurello, Robert Nisticò, Sergio Oddi
      Besides its involvement in Alzheimer's disease (AD) as precursor of the neurotoxic amyloid peptides, the pathophysiological impact of brain accumulation of amyloid precursor protein (APP) is not yet well understood. Recent studies reported that APP interacts with other membrane proteins, including G protein coupled receptors, affecting their biological functions. Here, we focused on the study of the potential impact of human mutant APP on expression, distribution and activity of type-1 cannabinoid (CB1) receptor in the hippocampus of Tg2576 mice, an AD-like mice model. By using biochemical and electrophysiological measures, we found that in a presymptomatic phase, when amyloid plaques have not yet formed and there is no sign of cognitive deficits, the over-expression of full-length APP in the hippocampus of Tg2576 mice altered membrane localization and inhibitory signalling activity of CB1 receptor, possibly by binding to the receptor and reducing its specific interaction with caveolin-1 and G proteins.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.009
       
  • Pharmacokinetic models to assist the prescriber in choosing the best
           tacrolimus dose
    • Authors: Jean-Baptiste Woillard; Franck Saint-Marcoux; Jean Debord; Anders Åsberg
      Abstract: Publication date: Available online 13 February 2018
      Source:Pharmacological Research
      Author(s): Jean-Baptiste Woillard, Franck Saint-Marcoux, Jean Debord, Anders Åsberg
      Due to a high inter-individual variability in its pharmacokinetics, tacrolimus dose individualization is mandatory. Even though the expert opinion has defined the area under the curve (AUC) as the best marker to use when performing dose adjustment of tacrolimus, most centres only use trough levels. Multiple targets have been proposed for this parameter and physicians rely largely on their personal experience when making a decision about dose adjustment. Several population pharmacokinetics models (POPPK) allowing AUC determination have been developed, but only a few are actually used in routine practice for dose individualization. These POPPK models can also be used to perform Monte Carlo simulations that help to establish different dosing rules or to anticipate the pharmacokinetics of tacrolimus in particular populations, without conducting clinical trials. Various available applications of POPPK models to assist the prescriber in choosing the best tacrolimus dose are discussed in this paper as well as the difficulties in introducing them into routine therapeutic drug monitoring.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.016
       
  • Lean body weight is the best scale for venous thromboprophylaxis algorithm
           in severely obese patients undergoing bariatric surgery
    • Authors: Bénédicte Gaborit; Pierre-Antoine Moulin; Thierry Bege; Sandrine Boullu; Clara Vincentelli; Olivier Emungania; Pierre-Emmanuel Morange; Stéphane Berdah; Joe-Elie Salem; Anne Dutour; Corinne Frere
      Abstract: Publication date: Available online 13 February 2018
      Source:Pharmacological Research
      Author(s): Bénédicte Gaborit, Pierre-Antoine Moulin, Thierry Bege, Sandrine Boullu, Clara Vincentelli, Olivier Emungania, Pierre-Emmanuel Morange, Stéphane Berdah, Joe-Elie Salem, Anne Dutour, Corinne Frere
      Severely obese patients undergoing bariatric surgery (BS) are at increased risk for venous thromboembolism (VTE). How standard low molecular weight heparin (LMWH) regimen should be adapted to provide both sufficient efficacy and safety in this setting is unclear. We aimed to compare the influence of four body size descriptors (BSD) on peak anti-Xa levels in BS obese patients receiving LMWH fixed doses to identify which one had the greatest impact. One hundred and thirteen BS obese patients [median body mass index (BMI), 43.3 kg/m2 (IQR, 40.6-48.7 kg/m2)] receiving subcutaneous dalteparin 5000 IU twice daily were included in this prospective monocenter study. Peak steady-state anti-Xa levels were measured peri-operatively following thromboprophylaxis initiation. Only 48% of patients achieved target anti-Xa levels (0.2-0.5 IU/ml). In univariate analysis, age, gender, total body-weight (TBW), lean body-weight (LBW), ideal body-weight (IBW), BMI and estimated glomerural filtration rate (eGFR) were associated with anti-Xa levels. The strongest negative association was observed with LBW (r = −0.56, p<0.0001). Receiver operating characteristic curves indicated that among BSD, LBW (cut-off >55.8 Kg) had the highest sensitivity (73%) and specificity (69%) to predict sub-prophylactic anti-Xa levels. In multivariate analysis, LBW and eGFR remained associated with anti-Xa levels (β=-0.47 ± 0.08, p < 0.0001 and β=-0.19 ± 0.08; p = 0.02, respectively). In BS morbidly obese patients receiving LMWH for thromboprophylaxis after BS, LBW and eGFR are the main determinants of anti-Xa level, and could be proposed in LMWH-based thromboprophylaxis dosing algorithms. The efficacy of a LBW-scale based dosing algorithm for optimal VTE prevention deserves further prospective randomized trials. (245 words)
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.012
       
  • Calcium Channel Blockers as Drug Repurposing Candidates for Gestational
           Diabetes: Mining large scale genomic and electronic health records data to
           repurpose medications
    • Authors: Jeffery A. Goldstein; Lisa A. Bastarache; Joshua C. Denny; Dan M. Roden; Jill M. Pulley; David M. Aronoff
      Abstract: Publication date: Available online 12 February 2018
      Source:Pharmacological Research
      Author(s): Jeffery A. Goldstein, Lisa A. Bastarache, Joshua C. Denny, Dan M. Roden, Jill M. Pulley, David M. Aronoff
      New therapeutic approaches are needed for gestational diabetes mellitus (GDM), but must show safety and efficacy in a historically understudied population. We studied associations between electronic medical record (EMR) phenotypes and genetic variants to uncover drugs currently considered safe in pregnancy that could treat or prevent GDM. We identified 129 systemically active drugs considered safe in pregnancy targeting the proteins produced from 196 genes. We tested for associations between GDM and/or type 2 diabetes (DM2) and 306 SNPs in 130 genes represented on the Illumina Infinium Human Exome Bead Chip (DM2 was included due to shared pathophysiological features with GDM). In parallel, we tested the association between drugs and glucose tolerance during pregnancy as measured by the glucose recorded during a routine 50-gram glucose tolerance test (GTT). We found an association between GDM/DM2 and the genes targeted by 11 drug classes. In the EMR analysis, 6 drug classes were associated with changes in GTT. Two classes were identified in both analyses. L-type calcium channel blocking antihypertensives (CCBs), were associated with a 3.18 mg/dL (95% CI −6.18 to −0.18) decrease in glucose during GTT, and Serotonin receptor type 3 (5HT-3) antagonist antinausea medications were associated with a 3.54 mg/dL (95% CI 1.86 to 5.23) increase in glucose during GTT. CCBs were identified as a class of drugs considered safe in pregnancy could have efficacy in treating or preventing GDM. 5HT-3 antagonists may be associated with worse glucose tolerance.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.013
       
  • The microbiome in chronic kidney disease patients undergoing hemodialysis
           and peritoneal dialysis
    • Authors: Liliana Simões-Silva; Ricardo Araujo; Manuel Pestana; Isabel Soares-Silva; Benedita Sampaio-Maia
      Abstract: Publication date: Available online 11 February 2018
      Source:Pharmacological Research
      Author(s): Liliana Simões-Silva, Ricardo Araujo, Manuel Pestana, Isabel Soares-Silva, Benedita Sampaio-Maia
      Chronic kidney disease (CKD) is associated with an imbalanced human microbiome due not only to CKD-associated factors such as uremia, increased inflammation and immunosuppression, but also to pharmacological therapies and dietary restrictions. End-stage renal disease patients require renal replacement therapies commonly in the form of hemodialysis (HD) or peritoneal dialysis (PD). HD implies the existence of a vascular access, such as an arteriovenous fistula/graft or a venous catheter, whereas PD implies a long-term peritoneal catheter and the constant inflow of peritoneal dialysate. Also, dietary adaptations are mandatory in both therapies. This revision explores the impact of HD or PD therapies on human microbiome. HD and PD appear to be associated with different changes in the gut microbiome, for example a decrease in Proteobacteria relative abundance in HD patients and increase in PD patients. Both therapies may also have an impact on the human microbiome beyond the gut, leading to increased relative abundance of specific bacteria in the blood microbiome of HD patients and increased relative abundance of other bacteria in the peritoneal microbiome of PD patients. HD and PD catheter biofilms may also play an important role in the changes observed in these microbiomes. A more interdisciplinary approach is needed to further clarify the role of microbial groups other than bacteria in all body habitats to allow the complete understanding of the impact of HD or PD on the microbiome of CKD patients. Moreover, strategies that promote a healthy balance of the human microbiome on these patients should be explored.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.011
       
  • Detection of drug safety signals from clinical trials data: role of SUSARs
    • Authors: Christelle Perez; Pascale Olivier; Barbara Lortal; Sophie Duranton; Jean-Louis Montastruc; Anne-Laurène Colin; Emilie Toulza; Madlyne Becker; Laura Hamy; Sabrina Crepin; Caroline Roussillon; Anne Gimbert; Nadine Petitpain; Francesco Salvo
      Abstract: Publication date: Available online 11 February 2018
      Source:Pharmacological Research
      Author(s): Christelle Perez, Pascale Olivier, Barbara Lortal, Sophie Duranton, Jean-Louis Montastruc, Anne-Laurène Colin, Emilie Toulza, Madlyne Becker, Laura Hamy, Sabrina Crepin, Caroline Roussillon, Anne Gimbert, Nadine Petitpain, Francesco Salvo
      One of the main goals of safety management in clinical trials is to detect suspected unexpected serious adverse reactions (SUSARs). The unexpectedness concerns the nature, frequency or severity of an adverse reaction. Drug safety signals could thus be retrieved, and a study was performed to investigate whether SUSARs allow signal detection in pharmacovigilance. Data from six academic safety units were collected from 2005 to 2016. Characteristics of SUSARs were analysed and signals were identified i) by evaluating the presence of other causes, ii) by assessing the summary of product characteristics (SPC), iii) by searching for specific safety information in Pubmed and health agencies, and iv) by investigating the narrative of each case. Pharmacological plausibility was evaluated by compatible mechanism of reaction and time-to-onset. During the study period, 211 SUSARs were collected. They mostly concerned general disorders (26.1%) and protein kinase inhibitors (24.6%). After eliminating SUSARs with other causes or those considered as expected, 50 SUSARs (23.7%), involving a total of 115 drug-reaction pairs, concerned potential safety signals. Among these pairs, 12 (10.4%) were considered as pharmacologically plausible. This study indicates that one quarter of SUSARs collected in academic clinical trials refers to potential safety signals, especially for oncologic drugs. One tenth of drug-reaction pairs was considered to have a pharmacological plausibility and could merit further evaluation. This is the first study suggesting that SUSARs could be a source of safety signals and that their routine analysis should be complementary to spontaneous reporting.

      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.010
       
  • Neurobiological links between depression and AD: The role of TGF-β1
           signaling as a new pharmacological target
    • Authors: Filippo Caraci; Simona Federica Spampinato; Maria Grazia Morgese; Fabio Tascedda; Maria Grazia Salluzzo; Maria Concetta Giambirtone; Giuseppe Caruso; Antonio Munafò; Sebastiano Alfio Torrisi; Gian Marco Leggio; Luigia Trabace; Ferdinando Nicoletti; Filippo Drago; Maria Angela Sortino; Agata Copani
      Abstract: Publication date: Available online 10 February 2018
      Source:Pharmacological Research
      Author(s): Filippo Caraci, Simona Federica Spampinato, Maria Grazia Morgese, Fabio Tascedda, Maria Grazia Salluzzo, Maria Concetta Giambirtone, Giuseppe Caruso, Antonio Munafò, Sebastiano Alfio Torrisi, Gian Marco Leggio, Luigia Trabace, Ferdinando Nicoletti, Filippo Drago, Maria Angela Sortino, Agata Copani
      In the last several years a large number of studies have demonstrated the neurobiological and clinical continuum between depression and Alzheimer’s disease (AD). Depression is a risk factor for the development of AD, and the presence of depressive symptoms significantly increases the conversion of Mild Cognitive Impairment (MCI) into AD. Common pathophysiological events have been identified in depression and AD, including neuroinflammation with an aberrant Tumor Necrosis Factor-α (TNF-α) signaling, and an impairment of Brain-Derived Neurotrophic Factor (BDNF) and Transforming-Growth-Factor-β1 (TGF-β1) signaling. TGF-β1 is an anti-inflammatory cytokine that exerts neuroprotective effects against amyloid-β (Aβ)-induced neurodegeneration, and it has a key role in memory formation and synaptic plasticity. TGF-β1 plasma levels are reduced in major depressed patients (MDD), correlate with depression severity, and significantly contribute to treatment resistance in MDD. The deficit of Smad-dependent TGF-β1 signaling is also an early event in AD pathogenesis, which contributes to inflammaging and cognitive decline in AD. A long-term treatment with antidepressants such as selective-serotonin-reuptake inhibitors (SSRIs) is known to reduce the risk of AD in patients with depression and, SSRIs, such as fluoxetine, increase the release of TGF-β1 from astrocytes and exert relevant neuroprotective effects in experimental models of AD. We propose the TGF-β1 signaling pathway as a common pharmacological target in depression and AD, and discuss the potential rescue of TGF-β1 signaling by antidepressants as a way to prevent the transition from depression to AD.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.007
       
  • Analgesic effects of the novel semicarbazide-sensitive amine oxidase
           inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms:
           involvement of transient receptor potential vanilloid 1 and ankyrin 1
           receptors
    • Authors: Ádám Horváth; Valéria Tékus; Noémi Bencze; Nikolett Szentes; Bálint Scheich; Kata Bölcskei; Éva Szőke; Attila Mócsai; Éva Tóth-Sarudy; Péter Mátyus; Erika Pintér; Zsuzsanna Helyes
      Abstract: Publication date: Available online 10 February 2018
      Source:Pharmacological Research
      Author(s): Ádám Horváth, Valéria Tékus, Noémi Bencze, Nikolett Szentes, Bálint Scheich, Kata Bölcskei, Éva Szőke, Attila Mócsai, Éva Tóth-Sarudy, Péter Mátyus, Erika Pintér, Zsuzsanna Helyes
      Semicarbazide-sensitive amine oxidase (SSAO) produces tissue irritants by deamination of primary amines, which activate transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly on nociceptors. Since there are no data about its functions in pain, we studied the effects and mechanisms of action of our novel SSAO inhibitor and dual TRPA1/TRPV1 antagonist multi-target drug SZV 1287 in different pain models. Acute chemonociception was induced by TRPV1 and TRPA1 activation (resiniferatoxin and formalin, respectively), chronic arthritis by K/BxN serum transfer, traumatic mononeuropathy by sciatic nerve ligation. SZV 1287 (20 mg/kg i.p.) was investigated in C57Bl/6J wildtype (WT), TRPA1- (TRPA1−/−) and TRPV1-deficient (TRPV1−/−) mice. Paw mechanonociception was measured by aesthesiometry, thermonociception by hot plate, nocifensive behavior by licking duration, volume by plethysmometry, myeloperoxidase activity by luminescence and plasma extravasation by fluorescence imaging, glia activation in pain-related brain regions by immunohistochemistry. SZV 1287 significantly inhibited both TRPA1 and TRPV1 activation-induced acute chemonociception and hyperalgesia. In K/BxN arthritis, daily SZV 1287 injections significantly decreased hyperalgesia, L4-L6 spinal dorsal horn microgliosis, edema and myeloperoxidase activity. SZV 1287-evoked antihyperalgesic and anti-edema effects were absent in TRPV1−/−, and remarkably reduced in TRPA1−/− mice. In contrast, myeloperoxidase-inhibitory effect was absent in TRPA1−/−, but not in TRPV1−/− animals. Acute SZV 1287 administration resulted in approximately 50% significant reduction of neuropathic hyperalgesia 7 days after nerve ligation, which was not observed in either TRPA1−/− or TRPV1−/− mice. SZV 1287 inhibits chronic inflammatory and neuropathic pain via TRPV1 and TRPA1/TRPV1 activation, respectively, highlighting its drug developmental potential.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.006
       
  • Impact of SLC22A1 and CYP3A5 genotypes on imatinib response in chronic
           myeloid leukemia: A systematic review and meta-analysis
    • Authors: Sarah Cargnin; Gloria Ravegnini; Simona Soverini; Sabrina Angelini; Salvatore Terrazzino
      Abstract: Publication date: Available online 7 February 2018
      Source:Pharmacological Research
      Author(s): Sarah Cargnin, Gloria Ravegnini, Simona Soverini, Sabrina Angelini, Salvatore Terrazzino
      Contrasting results have been reported on the role of rs628031 and rs683369 polymorphisms of SLC22A1 and rs776746 of CYP3A5 on imatinib treatment response in patients with chronic myeloid leukemia (CML). In the present study, we conducted a systematic review and meta-analysis of published studies to estimate the impact of the above-mentioned gene variants on major molecular response (MMR) or complete cytogenetic response (CCyR) in imatinib-treated CML patients. We performed a comprehensive search through PubMed, Web of Knowledge, and Cochrane databases up to September 2017. The pooled analyses showed association between carriers of SLC22A1 rs628031A allele (GA + AA vs GG, OR: 0.58, 95% CI: 0.38–0.88, P = 0.011) or rs683369G allele (CG + GG vs CC, OR: 0.64, 95% CI: 0.42–0.96, P = 0.032) and a lower MMR rate. The combined analyses also revealed a correlation between the dominant (GG + AG vs AA, OR: 2.43, 95%CI: 1.12–5.27, P = 0.024) or the allelic model (G vs A, OR: 1.72, 95% CI: 1.09–2.72, P = 0.020) of CYP3A5 rs776746 with higher CCyR rates. The subsequent sensitivity analysis confirmed the statistical significance of CYP3A5 rs776746 among Asian CML patients (dominant model OR: 3.90; 95%CI: 2.47–6.14, P < 0.001; allelic model OR: 2.08; 95% CI: 1.47–2.95, P < 0.001). In conclusion, the present meta-analysis supports the association of SLC22A1 and CYP3A5 genotypes with clinical imatinib response rates of CML patients, nevertheless further large studies, particularly in Caucasians, are still warranted to provide conclusive evidences.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.005
       
  • Synaptic plasticity modulation by circulating peptides and metaplasticity:
           involvement in Alzheimer’s disease
    • Authors: Stéphane Peineau; Kevin Rabiant; Olivier Pierrefiche; Brigitte Potier
      Abstract: Publication date: Available online 6 February 2018
      Source:Pharmacological Research
      Author(s): Stéphane Peineau, Kevin Rabiant, Olivier Pierrefiche, Brigitte Potier
      Synaptic plasticity is a cellular process involved in learning and memory whose alteration in its two main forms (Long Term Depression (LTD) and Long Term Potentiation (LTP)), is observed in most brain pathologies, including neurodegenerative disorders such as Alzheimer’s disease (AD). In humans, AD is associated at the cellular level with neuropathological lesions composed of extracellular deposits of β-amyloid (Aβ) protein aggregates and intracellular neurofibrillary tangles, cellular loss, neuroinflammation and a general brain homeostasis dysregulation. Thus, a dramatic synaptic environment perturbation is observed in AD patients, involving changes in brain neuropeptides, cytokines, growth factors or chemokines concentration and diffusion. Studies performed in animal models demonstrate that these circulating peptides strongly affect synaptic functions and in particular synaptic plasticity. Besides this neuromodulatory action of circulating peptides, other synaptic plasticity regulation mechanisms such as metaplasticity are altered in AD animal models. Here, we will review new insights into the study of synaptic plasticity regulatory/modulatory mechanisms which could influence the process of synaptic plasticity in the context of AD with a particular attention to the role of metaplasticity and peptide dependent neuromodulation.
      Graphical abstract image

      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.01.018
       
  • Does poor fetal growth influence the extent of fetal exposure to maternal
           medications'
    • Authors: Jia Yin Soo; Michael D. Wiese; Mary J. Berry; Janna L. Morrison
      Abstract: Publication date: Available online 6 February 2018
      Source:Pharmacological Research
      Author(s): Jia Yin Soo, Michael D. Wiese, Mary J. Berry, Janna L. Morrison
      A large proportion of women are prescribed a medication during pregnancy, and the conditions requiring treatment with these medicines are often also associated with placental dysfunction and abnormal fetal growth. For the fetus, exposure to maternal illness or medications can alter fetal growth trajectory, which is a key indicator of fetal and postnatal wellbeing. There is a large amount of human and animal evidence highlighting the hormonal and/or metabolic changes that occur in both the mother and the fetus as a result of maternal illness or either excessive or restricted fetal growth. These changes can affect the expression of drug metabolising enzymes and drug transporters in the both the mother and her fetus, and may ultimately alter fetal drug exposure. This review aims to explore the complex and multidirectional interplay between maternal illness, fetal growth trajectory, maternal drug treatment, and fetal drug exposure.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.001
       
  • What are the chances that resveratrol will be the drug of tomorrow'
    • Authors: Lasse Gliemann
      Abstract: Publication date: Available online 6 February 2018
      Source:Pharmacological Research
      Author(s): Lasse Gliemann


      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.004
       
  • The tip link protein Cadherin-23: from hearing loss to cancer
    • Authors: Paridhy Vanniya. S; C.R. Srikumari Srisailapathy; Ramkumar Kunka Mohanram
      Abstract: Publication date: Available online 5 February 2018
      Source:Pharmacological Research
      Author(s): Paridhy Vanniya. S, C.R. Srikumari Srisailapathy, Ramkumar Kunka Mohanram
      Cadherin-23 is an atypical member of the cadherin superfamily, with a particularly long extracellular domain. It has been known to be a part of the tip links of the inner ear mechanosensory hair cells. Several studies have been carried out to understand the role of Cadherin-23 in the hearing mechanism and defects in the CDH23 have been associated with hearing impairment resulting from defective or absence of tip links. Recently, studies have reported the role of Cadherin-23 in several pathological conditions, including cancer, suggesting the presence of several unknown functions. Initially, it was proposed that Cadherin-23 represents a yet unspecified subtype of Cadherins; however, no other proteins with similar characteristics have been identified, till date. It has a unique cytoplasmic domain that does not bear a β-catenin binding region, but has been demonstrated to mediate cell-cell adhesions. Several protein interacting partners have been identified for Cadherin-23 and the roles of their interactions and in various cellular mechanisms are yet to be explored. This review summarizes the characteristics of Cadherin-23 and its roles in several pathologies including cancer.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.01.026
       
  • Therapies for gestational diabetes and their implications for maternal and
           offspring health: Evidence from human and animal studies
    • Authors: Gabriel M. Brawerman; Vernon W. Dolinsky
      Abstract: Publication date: Available online 5 February 2018
      Source:Pharmacological Research
      Author(s): Gabriel M. Brawerman, Vernon W. Dolinsky
      Obesity prior to and during pregnancy is associated with an increased risk of complications during pregnancy. One of the most common complications of pregnancy is gestational diabetes mellitus (GDM), a condition characterized by hyperglycemia and insulin resistance that is diagnosed in the third trimester of pregnancy. GDM predisposes both mothers and their children to increased obesity and cardiometabolic disorders, namely type 2 diabetes and cardiovascular disease. Current treatments include lifestyle changes and insulin injections, but oral anti-diabetic drugs such as metformin and glyburide are increasingly prescribed as they do not require injections. However, the long-term implications of therapies for diabetes during pregnancy on mothers and their offspring are not fully understood. In this review, we describe current treatments for GDM, including the first line lifestyle interventions such as exercise as well as insulin, glyburides and metformin. We also review selected natural health products that are sometimes used by individuals during pregnancy that could also be an effective therapeutic in pregnancies characterized by obesity or GDM. We focus on both the short- and long-term effects of treatments on the health of mothers and their offspring. We review the current literature from clinical research and animal studies.
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      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.002
       
  • A chlorogenic acid-phospholipid complex ameliorates post-myocardial
           infarction inflammatory response mediated by mitochondrial reactive oxygen
           species in SAMP8 mice
    • Authors: Yi Li; Xuecong Ren; Chonkit Lio; Wenxia Sun; Ke Lai; Yuan Liu; Zhifeng Zhang; Jie Liang; Hua Zhou; Liang Liu; Hui Huang; Jing Ren; Pei Luo
      Abstract: Publication date: Available online 4 February 2018
      Source:Pharmacological Research
      Author(s): Yi Li, Xuecong Ren, Chonkit Lio, Wenxia Sun, Ke Lai, Yuan Liu, Zhifeng Zhang, Jie Liang, Hua Zhou, Liang Liu, Hui Huang, Jing Ren, Pei Luo
      Mitochondrial reactive oxygen species (mtROS) directly stimulate the inflammatory cytokines cascades and participate in age-related changes of cardiovascular diseases. Application of small molecule targeting the mtROS is significant towards development of better therapy to combat inflammatory response after myocardial infarction (MI) in the aging heart. Chlorogenic acid (CGA) is a well-known natural compound while the clinical potential is largely stifled by its poor oral absorption. In the present study, we tested the protective effect of a novel chlorogenic acid-phospholipid complex (CGA-PC) against acute post-MI inflammation in aged senescence accelerated mouse model. 10-month-old SAMP8 mice were treated with CGA-PC (equivalent of CGA 10 or 20 mg/kg body weight) or phospholipid randomly by gavage on a daily basis for 2 weeks. mtROS, lipid peroxidation, H2O2 production and oxygen consumption were evaluated in hearts subjected to ischemia reperfusion (I/R) induced by left anterior descending artery ligation. CGA-PC significantly reduced pro-inflammatory cytokines and myocardial necrosis, accompanied by decreased oxidative stress and mitochondrial respiratory deficits. p-JNK, MnSOD and soluble cytochrome c were up-regulated in the necrotic heart tissue, while CGA-PC treatment increased the expression of MKP-1 and inhibited the downstream activation of JNK. Our study indicated that CGA-PC ameliorated post-MI inflammatory response in aging heart and that it might be a promising candidate for the clinical development of CGA.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2018.01.006
       
  • Melatonin as an endogenous regulator of diseases: The role of autophagy
    • Authors: Ali Roohbakhsh; Ali Shamsizadeh; A.Wallace Hayes; Russel J. Reiter; Gholamreza Karimi
      Abstract: Publication date: Available online 3 February 2018
      Source:Pharmacological Research
      Author(s): Ali Roohbakhsh, Ali Shamsizadeh, A.Wallace Hayes, Russel J. Reiter, Gholamreza Karimi
      Melatonin has long been known for its apparent effects on sleep and circadian rhythm. It may participate as a possible therapeutic agent in neurodegenerative, cardiovascular, and endocrine disorders as well. Autophagy is a lysosomal degradation process that occurs in response to starvation and other stresses. Recent studies have reported that melatonin may modulate the autophagy process. We reviewed the current literature that has reported on how different diseases and/or experimental models change autophagy parameters. We also discussed the effect of melatonin on autophagy parameters in the central nervous, cardiovascular, gastrointestinal and endocrine systems as reported in nonclinical studies. Moreover, the molecular targets for melatonin are discussed in details. In summary, melatonin has been reported to enhance significant protective effects in different in vitro and in vivo studies either through enhancement or inhibition of the autophagy process. Melatonin holds promise in the treatment of several major diseases. Regulation of autophagy by melatonin is a determinant parameter that should be considered in the future studies.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2018.01.022
       
  • A transcriptomic analysis of turmeric: curcumin represses the expression
           of cholesterol biosynthetic genes and synergizes with simvastatin
    • Authors: Linda Saxe Einbond; Fabiana Manservisi; Hsan-au Wu; Michael Balick; Victoria Antonetti; Andrea Vornoli; Ilaria Menghetti; Fiorella Belpoggi; Stephen Redenti; Alan Roter
      Abstract: Publication date: Available online 3 February 2018
      Source:Pharmacological Research
      Author(s): Linda Saxe Einbond, Fabiana Manservisi, Hsan-au Wu, Michael Balick, Victoria Antonetti, Andrea Vornoli, Ilaria Menghetti, Fiorella Belpoggi, Stephen Redenti, Alan Roter
      The spice turmeric (Curcuma longa L.) has a long history of use as an anti-inflammatory agent. The active component curcumin induces a variety of diverse biological effects and forms a series of degradation and metabolic products in vivo. Our hypothesis is that the field of toxicogenomics provides tools that can be used to characterize the mode of action and toxicity of turmeric components and to predict turmeric-drug interactions. Male Sprague-Dawley rats were treated for 4 days with turmeric root containing about 3% curcumin (comparable to what people consume in the fresh or dried root) or a fraction of turmeric enriched for curcumin (∼74%) and liver tissue collected for gene expression analysis. Two doses of each agent were added to the diet, corresponding to 540 and 2700 mg/kg body weight/day of turmeric. The transcriptomic effects of turmeric on rat liver tissue were examined using 3 programs, ToxFx, in the context of a large drug database, Ingenuity and Nextbio analysis. ToxFx analysis indicates that turmeric containing about 3% or 74% curcumin represses the expression of cholesterol biosynthetic genes. The dose of 400 mg/kg b.w./day curcumin induced the Drug Signature associated with hepatic inflammatory infiltrate. Ingenuity confirmed that all 4 turmeric treatments had a significant effect on cholesterol biosynthesis, specifically the Cholesterol biosynthesis superpathway and Cholesterol biosynthesis 1 and 2. Among the top 10 up or downregulated genes, all 4 treatments downregulated PDK4; while 3 treatments downregulated Angptl4 or Fasn. These findings suggest curcumin may enhance the anticancer effects of certain classes of statins, which we confirmed with biological assays. Given this enhancement, lower levels of statins may be required, and even be desirable. Our findings also warn of possible safety issues, such as potential inflammatory liver effects, for patients who ingest a combination of certain classes of statins and curcumin. Transcriptomic analysis suggests that turmeric is worthwhile to study to prevent and treat cancer and lipid disorders. Our approach lays new groundwork for studies of the mode of action and safety of herbal medicines and can also be used to develop a methodology to standardize herbal medicines.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2018.01.023
       
  • The role of small molecule platelet-derived growth factor receptor (PDGFR)
           inhibitors in the treatment of neoplastic disorders
    • Authors: Robert Roskoski
      Abstract: Publication date: Available online 3 February 2018
      Source:Pharmacological Research
      Author(s): Robert Roskoski
      Platelet-derived growth factor (PDGF) was discovered as a serum-derived component necessary for the growth of smooth muscle cells, fibroblasts, and glial cells. The PDGF family is a product of four gene products and consists of five dimeric isoforms: PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD, and the PDGF-AB heterodimer. This growth factor family plays an essential role in embryonic development and in wound healing in the adult. These growth factors mediate their effects by binding to and activating their receptor protein-tyrosine kinases, which are encoded by two genes: PDGFRA and PDGFRB. The functional receptors consist of the PDGFRα/α and PDGFRβ/β homodimers and the PDGFRα/β heterodimer. Although PDGF signaling is most closely associated with mesenchymal cells, PDGFs and PDGF receptors are widely expressed in the mammalian central nervous system. The PDGF receptors contain an extracellular domain that is made up of five immunoglobulin-like domains (Ig-D1/2/3/4/5), a transmembrane segment, a juxtamembrane segment, a protein-tyrosine kinase domain that contains an insert of about 100 amino acid residues, and a carboxyterminal tail. Although uncommon, activating mutations in the genes for PDGF or PDGF receptors have been documented in various neoplasms including dermatofibrosarcoma protuberans (DFSP) and gastrointestinal stromal tumors (GIST). In most neoplastic diseases, PDGF expression and action appear to involve the tumor stroma. Moreover, this family is pro-angiogenic. More than ten PDGFRα/β multikinase antagonists have been approved by the FDA for the treatment of several neoplastic disorders and interstitial pulmonary fibrosis (www.brimr.org/PKI/PKIs.htm). Type I protein kinase inhibitors interact with the active enzyme form with DFG-D of the proximal activation segment directed inward toward the active site (DFG-Din). In contrast, type II inhibitors bind to their target with the DFG-D pointing away from the active site (DFG-Dout). We used the Schrödinger induced-fit docking protocol to model the interaction of several antagonists with PDGFRα including imatinib, sorafenib, and sunitinib. The results indicate that these antagonists are able to bind to the DFG-Dout conformation of the receptor and are thus classified as type II inhibitors. Owing to the multiplicity of less active protein kinase conformations when compared with the canonical more active conformation, it was hypothesized that type II drugs would be less promiscuous than type I drugs which bind to the typical active conformation. Although type II inhibitors may be more selective, most – if not all – inhibit more than one target protein kinase and the differences are a matter of degree only.
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      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2018.01.021
       
  • Glucocorticoids and Toll-like receptor 2 cooperatively induce acute-phase
           serum amyloid A
    • Authors: Weindl
      Abstract: Publication date: February 2018
      Source:Pharmacological Research, Volume 128
      Author(s): Qi Su, Günther Weindl
      Serum amyloid A (SAA) is a highly conserved acute-phase protein and extrahepatic produced SAA1/2 contributes to cutaneous inflammation. Prolonged systemic or topical treatment with glucocorticoids can provoke skin diseases such as steroid-induced acne. Glucocorticoids increase Toll-like receptor 2 (TLR2) expression, however, an inflammatory mediator linked to this side effect remains elusive. We report that TLR2 agonists in combination with dexamethasone substantially increase SAA expression and production in human keratinocytes and epithelial cells. Dexamethasone-mediated SAA1 induction depends on the glucocorticoid receptor (GR). In response to Propionibacterium acnes, TLR2-activated signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB (NF-κB) signaling pathways are critically involved in dexamethasone-induced SAA1 production. The formation of transcription factor complexes between GR or p300 and phospho-STAT3 was confirmed by co-immunoprecipitation in dexamethasone- and P. acnes-stimulated keratinocytes. Furthermore, dexamethasone and P. acnes-increased TLR2 and mitogen-activated protein kinase phosphatase-1 (MKP-1) contribute to induction of SAA1 and 2. Likewise, tumor necrosis factor (TNF) induces SAA1 in combination with dexamethasone. GR, transcription factors STAT3 and NF-κB, but not MKP-1, mediate TNF- and dexamethasone-induced SAA1. Conclusively, we provide evidence that glucocorticoids promote SAA1 production under infectious and sterile inflammatory conditions which may provide significant insights to the pathogenesis of steroid-induced acne.
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      PubDate: 2018-02-05T05:25:09Z
       
  • HIV Infection and its effects on the development of autoimmune disorders
    • Authors: Luis E. Vega; Luis R. Espinoza
      Abstract: Publication date: Available online 10 January 2018
      Source:Pharmacological Research
      Author(s): Luis E. Vega, Luis R. Espinoza
      More than 35 years have elapsed since the initial outbreak of the HIV/AIDS epidemic and the status of a considerable number of patients has changed from a fatal disorder to a chronic one where comorbidities including sarcoidosis and autoimmune diseases have become relevant and dominant. HIV targets the immune system leading to a state of immunodeficiency in a setting of immune activation in which CD4+ T cell depletion plays a critical role. The onset, natural history and course of HIV-associated autoimmune disease has dramatically changed according to the stage of HIV infection and since the introduction of combined anti-retroviral therapy. There are some issues that need further study regarding therapy, especially when immunosuppressive drugs and biologic agents are under consideration. Currently, biologic agents and others immunosuppressive agents are recommended when patients have CD4+ T cell counts above 200 cells/mm3 and the HIV viral activity is completely suppressed.
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      PubDate: 2018-01-15T23:43:03Z
      DOI: 10.1016/j.phrs.2018.01.005
       
  • Understanding Melanocortin-4 Receptor Control of Neuronal Circuits: Toward
           Novel Therapeutics for Obesity Syndrome
    • Authors: Sang Hyeon Ju; Gyu-Bon Cho; Jong-Woo Sohn
      Abstract: Publication date: Available online 9 January 2018
      Source:Pharmacological Research
      Author(s): Sang Hyeon Ju, Gyu-Bon Cho, Jong-Woo Sohn
      It is well known that melanocortin-4 receptors (MC4Rs) and central melanocortin pathways regulate food intake, energy expenditure, and glucose homeostasis. Importantly, MC4R deficiency is the most common monogenic cause of human obesity. Interestingly, MC4Rs expressed by distinct central nuclei are responsible for the different physiological function of MC4R stimulation. In addition, MC4Rs activate multiple intracellular and/or synaptic signaling molecules for the regulation of neuronal circuits. Therefore, MC4Rs and the downstream signal molecules are plausible targets for development of novel therapeutics against obesity and obesity-related metabolic disorders. In this review, we discuss recent findings on the neuronal circuits and signaling molecules that are responsible for MC4R control energy balance and autonomic function. Further, we review status of MC4R agonists as novel therapeutics for obesity syndrome. We believe that comprehensive understanding of signaling molecules involved in MC4R control of neuronal circuits will help to design MC4R agonists as safe and effective anti-obesity drugs.
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      PubDate: 2018-01-15T23:43:03Z
      DOI: 10.1016/j.phrs.2018.01.004
       
  • Ischemia/reperfusion-associated tubular cells injury in renal
           transplantation: Can metabolomics inform about mechanisms and help
           identify new therapeutic targets'
    • Authors: Chantal Barin-Le Guellec; Bérenger Largeau; Delphine Bon; Pierre Marquet; Thierry Hauet
      Abstract: Publication date: Available online 6 January 2018
      Source:Pharmacological Research
      Author(s): Chantal Barin-Le Guellec, Bérenger Largeau, Delphine Bon, Pierre Marquet, Thierry Hauet
      Tubular cells are central targets of ischemia-reperfusion (I/R) injury in kidney transplantation. Inflammation and metabolic disturbances occurring within these cells are deleterious by themselves but also favor secondary events, such as activation of immune response. It is critical to have an in depth understanding of the mechanisms governing tubular cells response to I/R if one wants to define pertinent biomarkers or to elaborate targeted therapeutic interventions. As oxidative damage was shown to be central in the patho-physiological mechanisms, the impact of I/R on proximal tubular cells metabolism has been widely studied, contrary to its effects on expression and activity of membrane transporters of the proximal tubular cells. Yet, temporal modulation of transporters over ischemia and reperfusion periods appears to play a central role, not only in the induction of cells injury but also in graft function recovery. Metabolomics in cell models or diverse biofluids has the potential to provide large pictures of biochemical consequences of I/R. Metabolomic studies conducted in experimental models of I/R or in transplanted patients indeed retrieved metabolites belonging to the pathways known to be particularly affected. Interestingly, they also revealed that metabolic disturbances and transporters activities are in very close mutual interplay. As well as helping to select diagnostic biomarkers, such analyses could also contribute to identify new pharmacological targets and to set up innovative nephroprotective strategies for the future. Even if various therapeutic approaches have been evaluated for a long time to prevent or treat I/R injuries, metabolomics has helped identifying new ones, those related to membrane transporters seeming to be of particular interest. However, considering the very complex and multifactorial effects of I/R in the context of kidney transplantation, all tracks must be followed if one wants to prevent or limit its deleterious consequences.
      Graphical abstract image

      PubDate: 2018-01-15T23:43:03Z
      DOI: 10.1016/j.phrs.2017.12.032
       
  • Highlighting the Endoplasmic Reticulum-Mitochondria connection: focus on
           Mitofusin 2
    • Authors: Riccardo Filadi; Elisa Greotti; Paola Pizzo
      Abstract: Publication date: Available online 5 January 2018
      Source:Pharmacological Research
      Author(s): Riccardo Filadi, Elisa Greotti, Paola Pizzo
      The endoplasmic reticulum (ER) and the mitochondrial network are two highly interconnected cellular structures. By proteinaceous tethers, specialized membrane domains of the ER are tightly associated with the outer membrane of mitochondria, allowing the assembly of signaling platforms where different cell functions take place or are modulated, such as lipid biosynthesis, Ca2+ homeostasis, inflammation, autophagy and apoptosis. The ER-mitochondria coupling is highly dynamic and contacts between the two organelles can be modified in their number, extension and thickness by different stimuli. Importantly, several pathological conditions, such as cancer, neurodegenerative diseases and metabolic syndromes show alterations in this feature, underlining the key role of ER-mitochondria crosstalk in cell physiology. In this contribution, we will focus on one of the major modulator of ER-mitochondria apposition, Mitofusin 2, discussing the structure of the protein and its debated role on organelles tethering. Moreover, we will critically describe different techniques commonly used to investigate this crucial issue, highlighting their advantages, drawbacks and limits.
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      PubDate: 2018-01-05T16:40:25Z
      DOI: 10.1016/j.phrs.2018.01.003
       
  • PRESENT THERAPEUTIC ROLE OF CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS
    • Authors: Nicola Ferri; Alberto Corsini; Cesare R. Sirtori; Massimiliano Ruscica
      Abstract: Publication date: Available online 26 December 2017
      Source:Pharmacological Research
      Author(s): Nicola Ferri, Alberto Corsini, Cesare R. Sirtori, Massimiliano Ruscica
      Therapeutic interventions aimed at increasing high-density lipoprotein (HDL) levels, in order to reduce the residual cardiovascular (CV) risk of optimally drug treated patients have not provided convincing results, so far. Transfer of cholesterol from extrahepatic tissues to the liver appears to be the major atheroprotective function of HDL, and an elevation of HDL levels could represent an effective strategy. Inhibition of the cholesteryl ester transfer protein (CETP), raising HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, reduces low-density lipoprotein-cholesterol (LDL-C) and apoB levels, thus offering a promising approach. Despite the beneficial influence on cholesterol metabolism, off-target effects and lack of reduction in CV events and mortality (with torcetrapib, dalcetrapib and evacetrapib) highlighted the complex mechanism of CETP inhibition. After the failure of the above mentioned inhibitors in phase III clinical development, possibly due to the short duration of the trials masking benefit, the secondary prevention REVEAL trial has recently shown that the inhibitor anacetrapib significantly raised HDL-C (+104%), reduced LDL-C (-18%), with a protective effect on major coronary events (RR, 0.91; 95%CI, 0.85 to 0.97; p = 0.004). Whether LDL-C lowering fully accounts for the CV benefit, or if HDL-C-rise is a crucial factor, still needs to be determined, although the reduction of non-HDL (-18%) and Lp(a) (-25%), should be also taken into account. In spite of the positive results of the REVEAL Study, Merck decided not to proceed in asking regulatory approval for anacetrapib. Dalcetrapib (Dal-GenE study) and CKD-519 remain the two molecules within this area still in clinical development.
      Graphical abstract image

      PubDate: 2018-01-05T16:40:25Z
      DOI: 10.1016/j.phrs.2017.12.028
       
  • Implication of STARD5 and cholesterol homeostasis disturbance in the
           endoplasmic reticulum stress-related response induced by pro-apoptotic
           aminosteroid RM-133
    • Authors: Martin Perreault; René Maltais; Lucie-Carole Kenmogne; Danny Létourneau; Jean-Guy LeHoux; Stéphane Gobeil; Donald Poirier
      Abstract: Publication date: Available online 26 December 2017
      Source:Pharmacological Research
      Author(s): Martin Perreault, René Maltais, Lucie-Carole Kenmogne, Danny Létourneau, Jean-Guy LeHoux, Stéphane Gobeil, Donald Poirier
      The aminosteroid derivative RM-133 is an effective anticancer molecule for which proof of concept has been achieved in several mouse xenograph models (HL-60, MCF-7, PANC-1 and OVCAR-3). To promote this new family of molecules toward a clinical phase 1 trial, the mechanism of action governing the anticancer properties of the representative candidate RM-133 needs to be characterized. In vitro experiments were first used to determine that RM-133 causes apoptosis in cancer cells. Then, using proteomic and transcriptomic experiments, RM-133 cytotoxicity was proven to be achieved via the endoplasmic reticulum (ER)-related apoptosis, which characterizes RM-133 as an endoplasmic reticulum stress aggravator (ERSA) anticancer drug. Furthermore, an shRNA-genome-wide screening has permitted to identify the steroidogenic acute regulator-related lipid transfer protein 5 (STARD5) as a major player in the RM-133 ER-related apoptosis mechanism, which was validated by an in vitro binding experiment. Altogether, the results presented herein suggest that RM-133 provokes a disturbance of cholesterol homeostasis via the implication of STARD5, which delivers an ERSA molecule to the ER. These results will be a springboard for RM-133 in its path toward clinical use.
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      PubDate: 2017-12-26T18:27:46Z
      DOI: 10.1016/j.phrs.2017.12.024
       
  • Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven
           thyroid and lung cancers
    • Authors: Robert Roskoski; Abdollah Sadeghi-Nejad
      Abstract: Publication date: Available online 25 December 2017
      Source:Pharmacological Research
      Author(s): Robert Roskoski, Abdollah Sadeghi-Nejad
      RET is a transmembrane receptor protein-tyrosine kinase that is required for the development of the nervous system and several other tissues. The mechanism of activation of RET by its glial-cell derived neurotrophic factor (GDNF) ligands differs from that of all other receptor protein-tyrosine kinases owing to the requirement for additional GDNF family receptor-α (GFRα) co-receptors (GFRα1/2/3/4). RET point mutations have been reported in multiple endocrine neoplasia (MEN2A, MEN2B) and medullary thyroid carcinoma. In contrast, RET fusion proteins have been reported in papillary thyroid and non-small cell lung adenocarcinomas. More than a dozen fusion partners of RET have been described in papillary thyroid carcinomas, most frequently CCDC6-RET and NCOA4-RET. RET-fusion proteins, commonly KIF5B-RET, have also been found in non-small cell lung cancer (NSCLC). Several drugs targeting RET have been approved by the FDA for the treatment of cancer: (i) cabozantinib and vandetanib for medullary thyroid carcinoma and (ii) lenvatinib and sorafenib for differentiated thyroid cancers. In addition, alectinib and sunitinib are approved for the treatment of other neoplasms. Each of these drugs is a multikinase inhibitor that has activity against RET. Previous X-ray studies indicated that vandetanib binds within the ATP-binding pocket and forms a hydrogen bond with A807 within the RET hinge and it makes hydrophobic contact with L881 of the catalytic spine which occurs in the floor of the adenine-binding pocket. Our molecular modeling studies indicate that the other antagonists bind in a similar fashion. All of these antagonists bind to the active conformation of RET and are therefore classified as type I inhibitors. The drugs also make variable contacts with other residues of the regulatory and catalytic spines. None of these drugs was designed to bind preferentially to RET and it is hypothesized that RET-specific antagonists might produce even better clinical outcomes. Currently the number of new cases of neoplasms bearing RET mutations or RET-fusion proteins is estimated to be about 10,000 per year in the United States. This is about the same as the incidence of chronic myelogenous leukemia for which imatinib and second and third generation BCR-Abl non-receptor protein-tyrosine kinase antagonists have proven clinically efficacious and which are commercially successful. These findings warrant the continued development of specific antagonists targeting RET-driven neoplasms.
      Graphical abstract image

      PubDate: 2017-12-26T18:27:46Z
      DOI: 10.1016/j.phrs.2017.12.021
       
  • Iron deficiency and iron deficiency anemia in children aged 6-36 months:
           is there room for improvement of screening, prophylaxis and treatment'
           
    • Authors: Francesca Penagini; Luisa Abbattista; Barbara Borsani; Giulia Ramponi; Enza D’Auria; Gian Vincenzo Zuccotti
      Abstract: Publication date: Available online 16 December 2017
      Source:Pharmacological Research
      Author(s): Francesca Penagini, Luisa Abbattista, Barbara Borsani, Giulia Ramponi, Enza D’Auria, Gian Vincenzo Zuccotti


      PubDate: 2017-12-17T18:08:08Z
      DOI: 10.1016/j.phrs.2017.12.012
       
 
 
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