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Journal Cover Pharmacological Research
  [SJR: 2.108]   [H-I: 99]   [1 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [3039 journals]
  • The mechanistic role of chemically diverse metal ions in the induction of
           autophagy
    • Authors: Sumit Sahni; Dong-Hun Bae; Patric J. Jansson; Des R. Richardson
      Pages: 118 - 127
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Sumit Sahni, Dong-Hun Bae, Patric J. Jansson, Des R. Richardson
      Autophagy is an evolutionary conserved cellular catabolic degradation process in response to stress which involves lysosomal degradation of unnecessary or damaged organelles and misfolded proteins. This is primarily a pro-survival pathway providing the cell with essential nutrients during stressful conditions. There are number of essential metal ions, which are required for normal physiological functioning of cells. Studies have shown that autophagy can be regulated by cellular metal ion concentrations. On the other hand, autophagy is also shown to regulate intracellular levels of certain metal ions. This review discusses recent advances in the research examining the role of metal ions in the autophagic pathway.
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      PubDate: 2017-02-12T02:13:08Z
      DOI: 10.1016/j.phrs.2017.01.009
      Issue No: Vol. 119 (2017)
       
  • Is bigger still better' Walking on the trail of cancer nanomedicine
    • Authors: Davide Prosperi; Fabio Corsi
      Pages: 149 - 152
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Davide Prosperi, Fabio Corsi


      PubDate: 2017-02-12T02:13:08Z
      DOI: 10.1016/j.phrs.2017.01.030
      Issue No: Vol. 119 (2017)
       
  • Lipoprotein(a) and inflammation: A dangerous duet leading to endothelial
           loss of integrity
    • Authors: Matteo Pirro; Vanessa Bianconi; Francesco Paciullo; Massimo R. Mannarino; Francesco Bagaglia; Amirhossein Sahebkar
      Pages: 178 - 187
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Matteo Pirro, Vanessa Bianconi, Francesco Paciullo, Massimo R. Mannarino, Francesco Bagaglia, Amirhossein Sahebkar
      Lipoprotein(a) [Lp(a)] is an enigmatic lipoprotein whose ancestral useful properties have been gradually obscured by its adverse pro-atherogenic and pro-thrombotic effects, that culminate into an increased risk of ischemic cardiovascular events. Although plasma Lp(a) levels are largely determined on a genetic basis, multiple factors have been reported to interfere with its plasma levels. Inflammation is one of these factors and it is believed to promote pro-atherogenic and pro-thrombotic changes leading to increased cardiovascular disease risk. The influence of inflammation on plasma Lp(a) levels is variable, with studies reporting either increased, reduced or unchanged Lp(a) expression and plasma concentrations following exposure to pro-inflammatory stimuli. The complex association between inflammation and Lp(a) is further amplified by additional findings showing that Lp(a) may promote the expression of a plethora of pro-inflammatory cytokines and induces the endothelium to switch into an activated status which results in adhesion molecules expression and inflammatory cells invasion into the arterial wall. In this picture, it emerges that increased plasma Lp(a) levels and inflammation may coexist and their coexistence may exert a deleterious impact on endothelial integrity both at a functional and structural level. Also, the detrimental duet of inflammation and Lp(a) may interfere with the physiological endothelial repair response, thus further amplifying endothelial loss of integrity and protective functions. A fundamental understanding of the interaction between Lp(a) and inflammation is critical for our comprehension of the mechanisms leading to the derangement of endothelial homeostasis and vascular dysfunction.
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      PubDate: 2017-02-12T02:13:08Z
      DOI: 10.1016/j.phrs.2017.02.001
      Issue No: Vol. 119 (2017)
       
  • Hormonally up-regulated neu-associated kinase: A novel target for breast
           cancer progression
    • Authors: Joelle N. Zambrano; Benjamin A. Neely; Elizabeth S. Yeh
      Pages: 188 - 194
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Joelle N. Zambrano, Benjamin A. Neely, Elizabeth S. Yeh
      Hormonally up-regulated neu-associated Kinase (Hunk) is a protein kinase that was originally identified in the murine mammary gland and has been shown to be highly expressed in Human Epidermal Growth Factor Receptor 2 positive (HER2+/ErbB2+) breast cancer cell lines as well as MMTV-neu derived mammary tumor cell lines. However, the physiological role of Hunk has been largely elusive since its identification. Though Hunk is predicted to be a Serine/Threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK family of protein kinases, there are no known Hunk substrates that have been identified to date. Recent work demonstrates a role for Hunk in HER2+/ErbB2+ breast cancer progression, including drug resistance to HER2/ErbB2 inhibitors, with Hunk potentially acting downstream of HER2/ErbB2 and the PI3K/Akt pathway. These studies have collectively shown that Hunk plays a vital role in promoting mammary tumorigenesis, as Hunk knockdown via shRNA in xenograft tumor models or crossing MMTV-neu or Pten-deficient genetically engineered mouse models into a Hunk knockout (Hunk-/-) background impairs mammary tumor growth in vivo. Because the majority of HER2+/ErbB2+ breast cancer patients acquire drug resistance to HER2/ErbB2 inhibitors, the characterization of novel drug targets like Hunk that have the potential to simultaneously suppress tumorigenesis and potentially enhance efficacy of current therapeutics is an important facet of drug development. Therefore, work aimed at uncovering specific regulatory functions for Hunk that could contribute to this protein kinase’s role in both tumorigenesis and drug resistance will be informative. This review focuses on what is currently known about this under-studied protein kinase, and how targeting Hunk may prove to be a potential therapeutic target for the treatment of breast cancer.
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      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.02.007
      Issue No: Vol. 119 (2017)
       
  • Sex-gender-related therapeutic approaches for cardiovascular complications
           associated with diabetes
    • Authors: Ilaria Campesi; Flavia Franconi; Giuseppe Seghieri; Marco Meloni
      Pages: 195 - 207
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Ilaria Campesi, Flavia Franconi, Giuseppe Seghieri, Marco Meloni
      Diabetes is a chronic disease associated with micro- and macrovascular complications and is a well-established risk factor for cardiovascular disease. Cardiovascular complications associated with diabetes are among the most important causes of death in diabetic patients. Interestingly, several sex-gender differences have been reported to significantly impact in the pathophysiology of diabetes. In particular, sex-gender differences have been reported to affect diabetes epidemiology, risk factors, as well as cardiovascular complications associated with diabetes. This suggests that different therapeutic approaches are needed for managing diabetes-associated cardiovascular complications in men and women. In this review, we will discuss about the sex-gender differences that are known to impact on diabetes, mainly focusing on the cardiovascular complications associated with the disease. We will then discuss the therapeutic approaches for managing diabetes-associated cardiovascular complications and how differences in sex-gender can influence the existing therapeutic approaches.
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      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.01.023
      Issue No: Vol. 119 (2017)
       
  • Effects of curcumin on HDL functionality
    • Authors: Shiva Ganjali; Christopher N. Blesso; Maciej Banach; Matteo Pirro; Muhammed Majeed; Amirhossein Sahebkar
      Pages: 208 - 218
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Shiva Ganjali, Christopher N. Blesso, Maciej Banach, Matteo Pirro, Muhammed Majeed, Amirhossein Sahebkar
      Curcumin, a bioactive polyphenol, is a yellow pigment of the Curcuma longa (turmeric) plant. Curcumin has many pharmacologic effects including antioxidant, anti-carcinogenic, anti-obesity, anti-angiogenic and anti-inflammatory properties. Recently, it has been found that curcumin affects lipid metabolism, and subsequently, may alleviate hyperlipidemia and atherosclerosis. Plasma HDL cholesterol (HDL-C) is an independent negative risk predictor of cardiovascular disease (CVD). However, numerous clinical and genetic studies have yielded disappointing results about the therapeutic benefit of raising plasma HDL-C levels. Therefore, research efforts are now focused on improving HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to heterogeneity in composition. Consistent with its complexity in composition and metabolism, a wide range of biological activities is reported for HDL, including antioxidant, anti-glycation, anti-inflammatory, anti-thrombotic, anti-apoptotic and immune modulatory activities. Protective properties of curcumin may influence HDL functionality; therefore, we reviewed the literature to determine whether curcumin can augment HDL function. In this review, we concluded that curcumin may modulate markers of HDL function, such as apo-AI, CETP, LCAT, PON1, MPO activities and levels. Curcumin may subsequently improve conditions in which HDL is dysfunctional and may have potential as a therapeutic drug in future. Further clinical trials with bioavailability-improved formulations of curcumin are warranted to examine its effects on lipid metabolism and HDL function.
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      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.02.008
      Issue No: Vol. 119 (2017)
       
  • Antibiotics, gut microbiota, environment in early life and type 1 diabetes
    • Authors: Youjia Hu; F. Susan Wong; Li Wen
      Pages: 219 - 226
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Youjia Hu, F. Susan Wong, Li Wen
      The gut microbiota interact with innate immune cells and play an important role in shaping the immune system. Many factors may influence the composition of the microbiota such as mode of birth, diet, infections and medication including antibiotics. In diseases with a multifactorial etiology, like type 1 diabetes, manipulation and alterations of the microbiota in animal models have been shown to influence the incidence and onset of disease. The microbiota are an important part of the internal environment and understanding how these bacteria interact with the innate immune cells to generate immune tolerance may open up opportunities for development of new therapeutic strategies. In this review, we discuss recent findings in relation to the microbiota, particularly in the context of type 1 diabetes.
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      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.01.034
      Issue No: Vol. 119 (2017)
       
  • Long term use of metformin in idiopathic cyclic edema, report of thirteen
           cases and review of the literature
    • Authors: S. Soudet; M. Lambert; G. Lefèvre; H. Maillard; D. Huglo; P.Y. Hatron
      Pages: 237 - 239
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): S. Soudet, M. Lambert, G. Lefèvre, H. Maillard, D. Huglo, P.Y. Hatron
      Introduction Idiopathic cyclic edema (ICE) is a rare cause of edema. To date, there is no standard of care. The physiopathology of ICE could be explained by an impairment of capillary permeability. In 1995, a study demonstrated the efficacy of metformin on symptoms and capillary permeability. We evaluated ICE-patients who were treated with metformin in our department. Methods We retrospectively included patients diagnosed for ICE between January 1997 and October 2013. ICE was diagnosed in the presence of edema after excluding other etiologies. LANDIS test was used to support ICE diagnosis in all patients. The absence of edema at follow-up was considered as complete response (CR), partial decreased was considered as partial response (PR). Adverse events were recorded. Results Thirteen patients have accepted to use metformin. The median treatment duration was 28.5 months [8–167] and the median follow-up of treated patients was 40.5 months [14–167]. CR was reached in 10 patients (77%), and PR in 2 patients (15%). Two patients reported side-effects as diarrheas and one of them stopped the treatment due to mild diarrhea. Conclusion We report the interest and tolerance of the long-term use of metformin in ICE. No severe adverse events were noticed. A prospective study is needed to confirm the efficacy of metformin in ICE-patients.
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      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.02.009
      Issue No: Vol. 119 (2017)
       
  • Guidelines for preparing color figures for everyone including the
           colorblind
    • Authors: Robert Roskoski
      Pages: 240 - 241
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Robert Roskoski


      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.02.005
      Issue No: Vol. 119 (2017)
       
  • Deacetylase inhibitors as a novel modality in the treatment of multiple
           myeloma
    • Authors: Paul G. Richardson; Philippe Moreau; Jacob P. Laubach; Michelle E. Maglio; Sagar Lonial; Jesus San-Miguel
      Pages: 185 - 191
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Paul G. Richardson, Philippe Moreau, Jacob P. Laubach, Michelle E. Maglio, Sagar Lonial, Jesus San-Miguel
      Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug. Ricolinostat and ACY-241, which selectively inhibit HDAC6 and the aggresome pathway, are currently being studied in combination with dexamethasone and bortezomib or an immunomodulatory drug for the treatment of relapsed and refractory MM. In this review, we discuss the data from key clinical trials investigating deacetylase inhibitors as novel treatment options for MM.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2016.11.020
      Issue No: Vol. 117 (2017)
       
  • Artemisinin and its derivatives in treating protozoan infections beyond
           malaria
    • Authors: Cecilia Shi Ni Loo; Nelson Siu Kei Lam; Deying Yu; Xin-zhuan Su; Fangli Lu
      Pages: 192 - 217
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Cecilia Shi Ni Loo, Nelson Siu Kei Lam, Deying Yu, Xin-zhuan Su, Fangli Lu
      Parasitic protozoan diseases continue to rank among the world’s greatest global health problems, which are also common among poor populations. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. Artemisinin (ART) and its derivatives are some of the most important classes of antimalarial agents originally derived from Artemisia annua L. However, besides the outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess activities against other parasitic protozoa. In this paper we review the activities of ART and its derivatives against protozoan parasites in vitro and in vivo, including Leishmania spp., Trypanosoma spp., Toxoplasma gondii, Neospora caninum, Eimeria tenella, Acanthamoeba castellanii, Naegleria fowleri, Cryptosporidium parvum, Giardia lamblia, and Babesia spp. We conclude that ART and its derivatives may be good alternatives for treating other non-malarial protozoan infections in developing countries, although more studies are necessary before they can be applied clinically.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2016.11.012
      Issue No: Vol. 117 (2017)
       
  • Pharmacological chaperone approaches for rescuing GPCR mutants: Current
           state, challenges, and screening strategies
    • Authors: Pieter Beerepoot; Reza Nazari; Ali Salahpour
      Pages: 242 - 251
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Pieter Beerepoot, Reza Nazari, Ali Salahpour
      A substantial number of G-protein coupled receptors (GPCRs) genetic disorders are due to mutations that cause misfolding or dysfunction of the receptor product. Pharmacological chaperoning approaches can rescue such mutant receptors by stabilizing protein conformations that behave similar to the wild type protein. For example, this can be achieved by improving folding efficiency and/or interaction with chaperone proteins. Although efficacy of pharmacological chaperones has been demonstrated in vitro for a variety of GPCRs, translation to clinical use has been limited. In this paper we discuss the history of pharmacological chaperones of GPCR’s and other membrane proteins, the challenges in translation to the clinic, and the use of different assays for pharmacological chaperone discovery.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2016.12.036
      Issue No: Vol. 117 (2017)
       
  • Melatonin as a promising agent of regulating stem cell biology and its
           application in disease therapy
    • Authors: Shuo Zhang; Simon Chen; Yuan Li; Yu Liu
      Pages: 252 - 260
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Shuo Zhang, Simon Chen, Yuan Li, Yu Liu
      Stem cells have emerged as an important approach to repair and regenerate damaged tissues or organs and show great therapeutic potential in a variety of diseases. However, the low survival of engrafted stem cells still remains a major challenge for stem cell therapy. As a major hormone from the pineal gland, melatonin has been shown to play an important role in regulating the physiological and pathological functions of stem cells, such as promoting proliferation, migration and differentiation. Thus, melatonin combined with stem cell transplantation displayed promising application potential in neurodegenerative diseases, liver cirrhosis, wound healing, myocardial infarction, kidney ischemia injury, osteoporosis, etc. It exerts its physiological and pathological functions through its anti-oxidant, anti-inflammatory, anti-apoptosis and anti-ageing properties. Here, we summarize recent advances on exploring the biological role of melatonin in stem cells, and discuss its potential applications in stem cell-based therapy.

      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2016.12.035
      Issue No: Vol. 117 (2017)
       
  • [6]-gingerol and [6]-shogaol, active ingredients of the traditional
           Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced
           pain via action on Na+ channels
    • Authors: Suzuro Hitomi; Kentaro Ono; Kiyoshi Terawaki; Chinami Matsumoto; Keita Mizuno; Kiichiro Yamaguchi; Ryota Imai; Yuji Omiya; Tomohisa Hattori; Yoshio Kase; Kiyotoshi Inenaga
      Pages: 288 - 302
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Suzuro Hitomi, Kentaro Ono, Kiyoshi Terawaki, Chinami Matsumoto, Keita Mizuno, Kiichiro Yamaguchi, Ryota Imai, Yuji Omiya, Tomohisa Hattori, Yoshio Kase, Kiyotoshi Inenaga
      The traditional Japanese herbal medicine hangeshashinto (HST) has beneficial effects for the treatment of oral ulcerative mucositis (OUM) in cancer patients. However, the ingredient-based mechanism that underlies its pain-relieving activity remains unknown. In the present study, to clarify the analgesic mechanism of HST on OUM-induced pain, we investigated putative HST ingredients showing antagonistic effects on Na+ channels in vitro and in vivo. A screen of 21 major ingredients using automated patch-clamp recordings in channel-expressing cells showed that [6]-gingerol and [6]-shogaol, two components of a Processed Ginger extract, considerably inhibited voltage-activated Na+ currents. These two ingredients inhibited the stimulant-induced release of substance P and action potential generation in cultured rat sensory neurons. A submucosal injection of a mixture of [6]-gingerol and [6]-shogaol increased the mechanical withdrawal threshold in healthy rats. In a rat OUM model, OUM-induced mechanical pain was alleviated 30min after the swab application of HST despite the absence of anti-bacterial and anti-inflammatory actions in the OUM area. A swab application of a mixture of [6]-gingerol and [6]-shogaol induced sufficient analgesia of OUM-induced mechanical or spontaneous pain when co-applied with a Ginseng extract containing abundant saponin. The Ginseng extract demonstrated an acceleration of substance permeability into the oral ulcer tissue without an analgesic effect. These findings suggest that Na+ channel blockage by gingerol/shogaol plays an essential role in HST-associated analgesia of OUM-induced pain. This pharmacological mechanism provides scientific evidence supporting the use of this herbal medicine in patients suffering from OUM-induced pain.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2016.12.026
      Issue No: Vol. 117 (2017)
       
  • Effects of coenzyme Q10 supplementation on inflammatory markers: a
           systematic review and meta-analysis of randomized controlled trials
    • Authors: Li Fan; Yu Feng; Guo-Chong Chen; Li-Qiang Qin; Chun-ling Fu; Li-Hua Chen
      Abstract: Publication date: Available online 5 February 2017
      Source:Pharmacological Research
      Author(s): Li Fan, Yu Feng, Guo-Chong Chen, Li-Qiang Qin, Chun-ling Fu, Li-Hua Chen
      The aims of this meta-analysis were to evaluate the effects of coenzyme Q10 (CoQ10) supplementation on inflammatory mediators including C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) by analyzing published randomized controlled trials (RCTs). A systematic search in PubMed, Cochrane Library and Clinicaltrials.gov was performed to identify eligible RCTs. Data synthesis was performed using a random- or a fixed-effects model depending on the results of heterogeneity tests, and pooled data were displayed as weighed mean difference (WMD) and 95% confidence interval (CI). Seventeen RCTs were selected for the meta-analysis. CoQ10 supplementation significantly reduced the levels of circulating CRP (WMD: −0.35mg/L, 95% CI: −0.64 to −0.05, P=0.022), IL-6 (WMD: −1.61pg/mL, 95% CI: −2.64 to −0.58, P=0.002) and TNF-α (WMD: −0.49pg/mL, 95% CI: −0.93 to −0.06, P=0.027). The results of meta-regression showed that the changes of CRP were independent of baseline CRP, treatment duration, dosage, and patients characteristics. In the meta-regression analyses, a higher baseline IL-6 level was significantly associated with greater effects of CoQ10 on IL-6 levels (P for interaction=0.006). In conclusion, this meta-analysis of RCTs suggests significant lowering effects of CoQ10 on CRP, IL-6 and TNF-α. However, results should be interpreted with caution because of the evidence of heterogeneity and limited number of studies.
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      PubDate: 2017-02-05T22:57:07Z
      DOI: 10.1016/j.phrs.2017.01.032
       
  • Pharmacological intervention of early neuropathy in neurodegenerative
           diseases
    • Authors: Min Jee Kwon; Jeong-Hoon Kim; TaeSoo Kim; Sung Bae Lee
      Abstract: Publication date: Available online 4 February 2017
      Source:Pharmacological Research
      Author(s): Min Jee Kwon, Jeong-Hoon Kim, TaeSoo Kim, Sung Bae Lee
      Extensive studies have reported the significant roles of numerous cellular features and processes in properly maintaining neuronal morphology and function throughout the lifespan of an animal. Any alterations in their homeostasis appear to be strongly associated with neuronal aging and the pathogenesis of various neurodegenerative diseases, even before the occurrence of prominent neuronal death. However, until recently, the primary focus of studies regarding many neurodegenerative diseases has been on the massive cell death occurring at the late stages of disease progression. Thus, our understanding on early neuropathy in these diseases remains relatively limited. The complicated nature of various neuropathic features manifested early in neurodegenerative diseases suggests the involvement of a system-wide transcriptional regulation and epigenetic control. Epigenetic alterations and consequent changes in the neuronal transcriptome are now begun to be extensively studied in various neurodegenerative diseases. Upon the catastrophic incident of neuronal death in disease progression, it is utterly difficult to reverse the deleterious defects by pharmacological treatments, and therefore, therapeutics targeting the system-wide transcriptional dysregulation associated with specific early neuropathy is considered a better option. Here, we review our current understanding on the system-wide transcriptional dysregulation that is likely associated with early neuropathy shown in various neurodegenerative diseases and discuss the possible future developments of pharmaceutical therapeutics.
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      PubDate: 2017-02-05T22:57:07Z
      DOI: 10.1016/j.phrs.2017.02.003
       
  • 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced
           damage via inhibition of p38 MAPK to NF-κB signalling
    • Authors: Yanli Li; Bin Xu; Ming Xu; Dapeng Chen; Yongjian Xiong; Mengqiao Lian; Yuchao Sun; Zeyao Tang; Li Wang; Chunling Jiang; Yuan Lin
      Abstract: Publication date: Available online 4 February 2017
      Source:Pharmacological Research
      Author(s): Yanli Li, Bin Xu, Ming Xu, Dapeng Chen, Yongjian Xiong, Mengqiao Lian, Yuchao Sun, Zeyao Tang, Li Wang, Chunling Jiang, Yuan Lin
      Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1β, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury.
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      PubDate: 2017-02-05T22:57:07Z
      DOI: 10.1016/j.phrs.2017.01.026
       
  • Spinal or supraspinal phosphorylation deficiency at the MOR C-terminus
           does not affect morphine tolerance in vivo
    • Authors: Cherkaouia Kibaly; Hong-Yiou Lin; Horace H. Loh; Ping-Yee Law
      Abstract: Publication date: Available online 4 February 2017
      Source:Pharmacological Research
      Author(s): Cherkaouia Kibaly, Hong-Yiou Lin, Horace H. Loh, Ping-Yee Law
      The development of tolerance to morphine, one of the most potent analgesics, in the management of chronic pain is a significant clinical problem and its mechanisms are poorly understood. Morphine exerts its pharmacological effects via the μ-opioid receptor (MOR). Tolerance is highly connected to G-protein-coupled receptors (GPCR) phosphorylation and desensitization increase. Because morphine desensitization previously has been shown to be MOR phosphorylation- and ß-arrestin2-independent (in contrast to agonists such as fentanyl), we examined the contribution of phosphorylation of the entire C-terminus to the development of antinociceptive tolerance to the partial (morphine) and full (fentanyl) MOR agonists in vivo. In MOR knockout (MORKO) mice, we delivered via lentivirus the genes encoding the wild-type MOR (WTMOR) or a phosphorylation-deficient MOR (Cterm(-S/T)MOR) in which all of the serine and threonine residues were mutated to alanine into the ventrolateral periaqueductal grey matter (vlPAG) or lumbar spinal cord (SC), structures that are involved in nociception. We compared the analgesic ED50 in WTMOR- and Cterm(-S/T)MOR-expressing MORKO mice before and after morphine or fentanyl tolerance was induced. Morphine acute antinociception was partially restored in WTMOR- or Cterm(-S/T)MOR-transferred MORKO mice. Fentanyl acute antinociception was observed only in MORKO mice with the transgenes expressed in the SC. Morphine antinociceptive tolerance was not affected by expressing Cterm(-S/T)MOR in the vlPAG or SC of MORKO mice. Fentanyl-induced tolerance in MORKO mice expressing WTMOR or Cterm(-S/T)MOR, is greater than morphine-induced tolerance. Thus, MOR C-terminus phosphorylation does not appear to be critical for morphine tolerance in vivo.
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      PubDate: 2017-02-05T22:57:07Z
      DOI: 10.1016/j.phrs.2017.01.033
       
  • Acid-sensing ion channel 1a is required for mGlu receptor dependent
           long-term depression in the hippocampus
    • Authors: D. Mango; E. Braksator; G. Battaglia; S. Marcelli; N.B. Mercuri; M. Feligioni; F. Nicoletti; Z.I. Bashir; R. Nisticò
      Abstract: Publication date: Available online 27 January 2017
      Source:Pharmacological Research
      Author(s): D. Mango, E. Braksator, G. Battaglia, S. Marcelli, N.B. Mercuri, M. Feligioni, F. Nicoletti, Z.I. Bashir, R. Nisticò
      Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na+ channel superfamily, are widely distributed in the mammalian nervous system. ASIC1a are highly permeable to Ca2+ and are thought to be important in a variety of physiological processes, including synaptic plasticity, learning and memory. To further understand the role of ASIC1a in synaptic transmission and plasticity, we investigated metabotropic glutamate (mGlu) receptor-dependent long-term depression (LTD) in the hippocampus. We found that ASIC1a channels mediate a component of LTD in P30-40 animals, since the ASIC1a selective blocker psalmotoxin-1 (PcTx1) reduced the magnitude of LTD induced by application of the group I mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) or induced by paired-pulse low frequency stimulation (PP-LFS). Conversely, PcTx1 did not affect LTD in P13-18 animals. We also provide evidence that ASIC1a is involved in group I mGlu receptor-induced increase in action potential firing. However, blockade of ASIC1a did not affect DHPG-induced polyphosphoinositide hydrolysis, suggesting the involvement of some other molecular partners in the functional crosstalk between ASIC1a and group I mGlu receptors. Notably, PcTx1 was able to prevent the increase in GluA1 S845 phosphorylation at the post-synaptic membrane induced by group I mGlu receptor activation. These findings suggest a novel function of ASIC1a channels in the regulation of group I mGlu receptor synaptic plasticity and intrinsic excitability.
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      PubDate: 2017-01-29T22:51:52Z
      DOI: 10.1016/j.phrs.2017.01.028
       
  • GENDER DIFFERENCES IN CARDIOVASCULAR PROPHYLAXIS: FOCUS ON ANTIPLATELET
           TREATMENT
    • Authors: Paolo Di Giosia; Gabriella Passacquale; Marco Petrarca; Paolo Giorgini; Alberto Maria Marra; Albert Ferro
      Abstract: Publication date: Available online 25 January 2017
      Source:Pharmacological Research
      Author(s): Paolo Di Giosia, Gabriella Passacquale, Marco Petrarca, Paolo Giorgini, Alberto Maria Marra, Albert Ferro
      Cardiovascular disease (CVD) represents the leading cause of death worldwide, and equally affects both sexes although women develop disease at an older age than men. A number of clinical evidence has identified the female sex as an independent factor for poor prognosis, with the rate of mortality and disability following an acute cardiovascular (CV) event being higher in women than men. It has been argued that the different level of platelet reactivity between sexes may account for a different responsiveness to anti-platelet therapy, with consequent important implications on clinical outcomes. However, conclusive evidence supporting the concept of a gender-dependent effectiveness of platelet inhibitors are lacking. On the contrary, sex-related dissimilarities have been evidenced in cardiovascular patients in terms of age of presentation, comorbidities such as obesity, diabetes and renal disease, and a different pharmacological approach to and effectiveness in controlling classical cardiovascular risk factors such as hypertension, glucose profile and lipid dysmetabolism. All these factors could place women at an increased level of cardiovascular risk compared to men, and may concur to an enhanced pro-thrombogenic profile. The purpose of this manuscript is to provide an overview of gender-related differences in cardiovascular treatment, in order to highlight the need to improve the pharmacological prophylaxis adopted in women through a more accurate evaluation of the overall cardiovascular risk profile with consequent establishment of a more effective and targeted anti-thrombotic strategy which is not limited to the use of anti-platelet agents.
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      PubDate: 2017-01-29T22:51:52Z
      DOI: 10.1016/j.phrs.2017.01.025
       
  • Modulating the function of ATP-binding cassette subfamily G member 2
           (ABCG2) inhibitor cabozantinib
    • Authors: Guan-Nan Zhang; Yun-Kai Zhang; Yi-Jun Wang; Anna Maria Barbuti; Xi-Jun Zhu; Xin-Yue Yu; Ai-Wen Wen; John N.D. Wurpel; Zhe-Sheng Chen
      Abstract: Publication date: Available online 25 January 2017
      Source:Pharmacological Research
      Author(s): Guan-Nan Zhang, Yun-Kai Zhang, Yi-Jun Wang, Anna Maria Barbuti, Xi-Jun Zhu, Xin-Yue Yu, Ai-Wen Wen, John N.D. Wurpel, Zhe-Sheng Chen
      Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c-Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP-binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug-selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2, and ABCG2-482-T7, which overexpress ABCG2. Cabozantinib, at non-toxic concentrations (3 or 5μM), sensitized the ABCG2-overexpressing cells to mitoxantrone, SN-38, and topotecan. Our results indicate that cabozantinib reverses ABCG2-mediated multidrug resistance by antagonizing the drug efflux function of the ABCG2 transporter instead of downregulating its expression. The molecular docking analysis indicates that cabozantinib binds to the drug-binding site of the ABCG2 transporter. Overall, our findings demonstrate that cabozantinib inhibits the ABCG2 transporter function and consequently enhances the effect of the antineoplastic agents that are substrates of ABCG2. Cabozantinib may be a useful agent in anticancer treatment regimens for patients who are resistant to ABCG2 substrate drugs.
      Graphical abstract image

      PubDate: 2017-01-29T22:51:52Z
      DOI: 10.1016/j.phrs.2017.01.024
       
  • Caveolin1/Protein Arginine Methyltransferase1/Sirtuin1 Axis as a Potential
           Target Against Endothelial Dysfunction
    • Authors: Soniya Charles; Vijay Raj; Jesu Arokiaraj; Kanchana Mala
      Abstract: Publication date: Available online 23 January 2017
      Source:Pharmacological Research
      Author(s): Soniya Charles, Vijay Raj, Jesu Arokiaraj, Kanchana Mala
      Endothelial dysfunction (ED), an established response to cardiovascular risk factors, is characterized by increased levels of soluble molecules secreted by endothelial cells (EC). Evidence suggest that ED is an independent predictor of cardiac events and that it is associated with a deficiency in production or bioavailability of nitric oxide (NO) and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors. ED can be reversed by treating cardiovascular risk factors, hence, beyond ambiguity, ED contributes to initiation and progression of atherosclerotic disease. Majority of cardiovascular risk factors act by a common pathway, oxidative stress (OS), characterized by an imbalance in bioavailability of NO and reactive oxygen species (ROS). Enhanced ROS, through several mechanisms, alters competence of EC that leads to ED, reducing its potential to maintain homeostasis and resulting in development of cardiovascular disease (CVD). Influential mechanisms that have been implicated in the development of ED include (i) presence of elevated levels of NOS inhibitor, asymmetric dimethylarginine (ADMA) due to augmented enzyme activity of protein arginine methyl transferase-1 (PRMT1); (ii) decrease in NO generation by endothelial nitric oxide synthase (eNOS) uncoupling, or by reaction of NO with free radicals and (iii) impaired post translational modification of protein (PTM) such as eNOS, caveolin-1 (cav1) and sirtuin-1 (SIRT1). However, the inter-related mechanisms that concur to developing ED is yet to be understood. The events that possibly overlay include OS-induced sequestration of SIRT1 to caveolae facilitating cav1-SIRT1 association; potential increase in lysine acetylation of enzymes such as eNOS and PRMT1 leading to enhanced ADMA formation; imbalance in acetylation-methylation ratio (AMR); diminished NO generation and ED. Here we review current literature from research showing interdependent association between cav1-PRMT1-SIRT1 to the outcomes of experimental and clinical research aiming to preserve endothelial function with gene- or pharmaco-therapy.
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      PubDate: 2017-01-29T22:51:52Z
      DOI: 10.1016/j.phrs.2017.01.022
       
  • Targeted basic research to highlight the role of estrogen and estrogen
           receptors in the cardiovascular system
    • Authors: Elke Dworatzek; Shokoufeh Mahmoodzadeh
      Abstract: Publication date: Available online 21 January 2017
      Source:Pharmacological Research
      Author(s): Elke Dworatzek, Shokoufeh Mahmoodzadeh
      Epidemiological, clinical and animal studies revealed that sex differences exist in the manifestation and outcome of cardiovascular disease (CVD). The underlying molecular mechanisms implicated in these sex differences are not fully understood. The reasons for sex differences in CVD are definitely multifactorial, but major evidence points to the contribution of sex steroid hormone, 17β-estradiol (E2), and its receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). In this review, we summarize past and present studies that implicate E2 and ER as important determinants of sexual dimorphism in the physiology and pathophysiology of the heart. In particular, we give an overview of studies aimed to reveal the role of E2 and ER in the physiology of the observed sex differences in CVD using ER knock-out mice. Finally, we discuss recent findings from novel transgenic mouse models, which have provided new information on the sexual dimorphic roles of ER specifically in cardiomyocytes under pathological conditions.
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      PubDate: 2017-01-22T22:46:48Z
      DOI: 10.1016/j.phrs.2017.01.019
       
  • P-gp/ABCB1 Exerts Differential Impacts On Brain and Fetal Exposure to
           Norbuprenorphine
    • Authors: Michael Z. Liao; Chunying Gao; Laura M. Shireman; Brian Phillips; Linda J. Risler; Naveen K. Neradugomma; Prachi Choudhari; Bhagwat Prasad; Danny D. Shen; Qingcheng Mao
      Abstract: Publication date: Available online 19 January 2017
      Source:Pharmacological Research
      Author(s): Michael Z. Liao, Chunying Gao, Laura M. Shireman, Brian Phillips, Linda J. Risler, Naveen K. Neradugomma, Prachi Choudhari, Bhagwat Prasad, Danny D. Shen, Qingcheng Mao
      Norbuprenorphine is the major active metabolite of buprenorphine which is commonly used to treat opiate addiction during pregnancy. Norbuprenorphine produces marked respiratory depression and was 10 times more potent than buprenorphine. Therefore, it is important to understand the mechanism that controls fetal exposure to norbuprenorphine, as exposure to this compound may pose a significant risk to the developing fetus. P-gp/ABCB1 and BCRP/ABCG2 are two major efflux transporters regulating tissue distribution of drugs. Previous studies have shown that norbuprenorphine, but not buprenorphine, is a P-gp substrate. In this study, we systematically examined and compared the roles of P-gp and BCRP in determining maternal brain and fetal distribution of norbuprenorphine using transporter knockout mouse models. We administered 1mg/kg norbuprenorphine by retro-orbital injection to pregnant FVB wild-type, Abcb1a −/−/1b −/−, and Abcb1a −/−/1b −/−/Abcg2 −/− mice on gestation day 15. The fetal AUC of norbuprenorphine was ∼64% of the maternal plasma AUC in wild-type mice, suggesting substantial fetal exposure to norbuprenorphine. The maternal plasma AUCs of norbuprenorphine in Abcb1a −/−/1b −/− and Abcb1a −/−/1b −/−/Abcg2 −/− mice were ∼2 times greater than that in wild-type mice. Fetal AUCs in Abcb1a −/−/1b −/− and Abcb1a −/−/1b −/−/Abcg2 −/− mice were also increased compared to wild-type mice; however, the fetal-to-maternal plasma AUC ratio remained relatively unchanged by the knockout of Abcb1a/1b or Abcb1a/1b/Abcg2. In contrast, the maternal brain-to-maternal plasma AUC ratio in Abcb1a −/−/1b −/− or Abcb1a −/−/1b −/−/Abcg2 −/− mice was increased ∼30-fold compared to wild-type mice. Protein quantification by LC-MS/MS proteomics revealed significantly higher amounts of P-gp protein in the wild-type mice brain than that in the placenta. These results indicate that fetal exposure to norbuprenorphine is substantial and that P-gp has a minor impact on fetal exposure to norbuprenorphine, but plays a significant role in restricting its brain distribution. The differential impacts of P-gp on norbuprenorphine distribution into the brain and fetus are likely, at least in part, due to the differences in amounts of P-gp protein expressed in the blood-brain and blood-placental barriers. BCRP is not as important as P-gp in determining both the systemic and tissue exposure to norbuprenorphine. Finally, fetal AUCs of the metabolite norbuprenorphine-β-D-glucuronide were 3-7 times greater than maternal plasma AUCs, while the maternal brain AUCs were <50% of maternal plasma AUCs, suggesting that a reversible pool of conjugated metabolite in the fetus may contribute to the high fetal exposure to norbuprenorphine.
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      PubDate: 2017-01-22T22:46:48Z
      DOI: 10.1016/j.phrs.2017.01.018
       
  • An update on the assessment and management of Metabolic Syndrome, a
           growing medical emergency in paediatric populations
    • Authors: Chiara Mameli; Gian Vincenzo Zuccotti; Carla Carnovale; Erica Galli; Pilar Nannini; Davide Cervia; Cristiana Perrotta
      Abstract: Publication date: Available online 19 January 2017
      Source:Pharmacological Research
      Author(s): Chiara Mameli, Gian Vincenzo Zuccotti, Carla Carnovale, Erica Galli, Pilar Nannini, Davide Cervia, Cristiana Perrotta
      In the last decades the increasing rate of obesity in children and adolescent worldwide has led to the onset in paediatric age of metabolic syndrome a disease commonly associated to adulthood. Central obesity, dyslipidaemia, hyperglycaemia, and hypertension are typical features of metabolic syndrome that seem to hesitate often in type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and many other clinical conditions. Thus preventing and curing metabolic syndrome in paediatric patients is becoming an urgent need for public health. While diagnostic criteria and therapy of metabolic syndrome in adults are very well defined, there is no consensus on the definition of metabolic syndrome in children and adolescents as well as on healing approaches. The aim of this review is to describe the recent advances on the pathogenesis and clinical outcomes of paediatric metabolic syndrome. We then detail the therapeutic strategies (i.e. dietary regimens, physical exercise, nutraceuticals, and medications) employed to manage the disease. Finally, we analyse the safety profile of the drugs used in children and adolescents by performing a retrospective review of paediatric adverse reactions reported in the FDA’s Adverse Event Reporting System database.
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      PubDate: 2017-01-22T22:46:48Z
      DOI: 10.1016/j.phrs.2017.01.017
       
  • The 35-year odyssey of beta blockers in cirrhosis: any gender difference
           in sight?
    • Authors: Maria Antonella Burza; Hanns-Ulrich Marschall; Laura Napoleone; Antonio Molinaro
      Abstract: Publication date: Available online 15 January 2017
      Source:Pharmacological Research
      Author(s): Maria Antonella Burza, Hanns-Ulrich Marschall, Laura Napoleone, Antonio Molinaro
      Cirrhosis is the end-stage of chronic liver disease and leads to the development of portal hypertension and its complications such as esophagogastric varices. Non-selective beta blockers (NSBB) are the keystone for the treatment of portal hypertension since the 1980s and, over the decades, several studies have confirmed their beneficial effect on the prevention of variceal (re)bleeding. Pharmacological studies showed effects of gender, sex hormones, oral contraceptives, and pregnancy on cytochrome P450 (CYPs) enzymes that metabolise NSBB, suggesting that gender differences might exist in the effect of NSBB. In this review, we focused on the 35-year knowledge about the use of beta blockers in cirrhosis and potential gender differences. We specifically examined the role of NSBB in pre-primary, primary and secondary prophylaxis of variceal bleeding, compared two commonly used NSBB (i.e., Propranolol and Carvedilol), and present the current controversies about the window of treatment in advanced cirrhosis with a specific focus on gender differences in NSBB effects. NSBB are not currently recommended in pre-primary prophylaxis of varices mainly because of lack of proven efficacy. On the other hand, NSBB are strongly recommended in patient with cirrhosis as primary (as alternative to endoscopic band ligation, EBL) and secondary prophylaxis (in addition to EBL) of variceal bleeding. To date, no studies have focused specifically on the effect of gender on NSBB treatment. Data extrapolated from clinical studies show that gender was neither a risk factor for the development of varices nor associated with a different response to treatment in primary or secondary prophylaxis. According to the available guidelines, no different, gender-based treatment for portal hypertension is recommended.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.015
       
  • Resveratrol supplementation and plasma adipokines concentrations? A
           systematic review and meta-analysis of randomized controlled trials
    • Authors: Mohsen Mohammadi Sartang; Zohreh Mazloom; Zahra Sohrabi; Saeed Sherafatmanesh; Reza Barati Boldaji
      Abstract: Publication date: Available online 13 January 2017
      Source:Pharmacological Research
      Author(s): Mohsen Mohammadi Sartang, Zohreh Mazloom, Zahra Sohrabi, Saeed Sherafatmanesh, Reza Barati Boldaji
      The results of human clinical trials have revealed that the effects of resveratrol on adipokines are inconsistent. Our objective was to elucidate the role of resveratrol supplementation on adipokines through a systematic review and a meta-analysis of available randomized placebo-controlled trials (RCTs). 1 1 RCTs: randomized placebo-controlled trials. The search included PubMed-MEDLINE, SCOPUS and ISI web of sciences database till up to 6th November 2016. Weight mean differences (WMD) 2 2 WMD: weight mean difference. were calculated for net changes in adipokines using fixed-effects or random-effects models; meta-regression analysis and publication bias were conducted in accordance with standard methods. Nine RCTs with 11 treatment arms were eligible for inclusion in this systematic review and meta-analysis. Meta-analysis of data from 10 treatment arms showed a significant change in plasma adiponectin concentrations following resveratrol supplementation (WMD: 1.10μg/ml, 95%CI: 0.88, 1.33, p < 0.001); Q =11.43, I2 =21.29%, p=0.247). There was a significant greater adiponectin-reducing effect in trials with higher than or equal to 100mg/day (WMD: 1.11 ug/ml, 95%CI: 0.88, 1.34, p < 0.001), versus those with less than 100 mg/day dosage (WMD: 0.84 ug/ml, 95%CI: −0.62, 2.31, p = 0.260). Meta-analysis of data from 5 treatment arms did not find any significant change in plasma leptin concentrations following resveratrol supplementation (WMD: 3.77ng/ml, 95% CI: −2.28, 9.83, p =0.222; Q =8.00, I2 =50.01%). Resveratrol significantly improves adiponectin but does not affect leptin concentrations. Additional studies are required to further evaluate the potential benefits of resveratrol on adipokines in humans.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.012
       
  • An Update on the Physiological and Therapeutic Relevance of GPCR Oligomers
    • Authors: Batoul Farran
      Abstract: Publication date: Available online 11 January 2017
      Source:Pharmacological Research
      Author(s): Batoul Farran
      The traditional view on GPCRs held that they function as single monomeric units composed of identical subunits. This notion was overturned by the discovery that GPCRs can form homo- and hetero-oligomers, some of which are obligatory, and can further assemble into receptor mosaics consisting of three or more protomers. Oligomerisation exerts significant impacts on receptor function and physiology, offering a platform for the diversification of receptor signalling, pharmacology, regulation, crosstalk, internalization and trafficking. Given their involvement in the modulation of crucial physiological processes, heteromers could constitute important therapeutic targets for a wide range of diseases, including schizophrenia, Parkinson’s disease, substance abuse or obesity. This review aims at depicting the current developments in GPCR oligomerisation research, documenting various class A, B and C GPCR heteromers detected in vitro and in vivo using biochemical and biophysical approaches, as well as recently identified higher-order oligomeric complexes. It explores the current understanding of dimerization dynamics and the possible interaction interfaces that drive oligomerisation. Most importantly, it provides an inventory of the wide range of physiological processes and pathophysiological conditions to which GPCR oligomers contribute, surveying some of the oligomers that constitute potential drug targets. Finally, it delineates the efforts to develop novel classes of ligands that specifically target and tether to receptor oligomers instead of a single monomeric entity, thus ameliorating their ability to modulate GPCR function.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.008
       
  • Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven
           lung cancers
    • Authors: Robert Roskoski
      Abstract: Publication date: Available online 8 January 2017
      Source:Pharmacological Research
      Author(s): Robert Roskoski
      Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large-cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result in dimerization and subsequent activation of the ALK protein kinase domain that plays a key role in the pathogenesis of various tumors. Downstream signaling from the ALK fusion protein leads to the activation of the Ras/Raf/MEK/ERK1/2 cell proliferation module and the JAK/STAT cell survival pathways. Moreover, nearly two dozen ALK activating mutations are involved in the pathogenesis of childhood neuroblastomas. The occurrence of oncogenic ALK-fusion proteins, particularly in non-small cell lung cancer, has fostered considerable interest in the development of ALK inhibitors. Crizotinib was the first such inhibitor approved by the US Food and Drug Administration for the treatment of ALK-positive non-small cell lung cancer in 2011. The median time for the emergence of crizotinib drug resistance is 10.5 months after the initiation of therapy. Such resistance prompted the development of second-generation drugs including ceritinib and alectinib, which are approved for the treatment of non-small cell lung cancer. Unlike the single gatekeeper mutation that occurs in drug-resistant epidermal growth factor receptor in lung cancer, nearly a dozen different mutations in the catalytic domain of ALK fusion proteins have been discovered that result in crizotinib resistance. Crizotinib, ceritinib, and alectinib form a complex within the front cleft between the small and large lobes of an inactive ALK protein-kinase domain with a compact activation segment. These drugs are classified as type I½ B inhibitors because they bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.007
       
  • DREAM as a novel therapeutic target for anti-thrombotic agents
    • Authors: Jaehyung Cho
      Abstract: Publication date: Available online 5 January 2017
      Source:Pharmacological Research
      Author(s): Jaehyung Cho
      Circulating platelets participate in the process of numerous diseases including thrombosis, inflammation, and cancer. Thus, it is of great importance to understand the underlying mechanisms mediating platelet activation under disease conditions. Emerging evidence indicates that despite the lack of a nucleus, platelets possess molecules involved in gene transcription occurring in nucleated cells. This review will summarize downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor, and highlight recent findings suggesting its novel non-transcriptional role in hemostasis and thrombosis.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2017.01.002
       
  • Dysregulation of cytokine mediated chemotherapy induced cognitive
           impairment
    • Authors: Xiaojia Ren; Daret K.St. Clair; D.Allan Butterfield
      Abstract: Publication date: Available online 4 January 2017
      Source:Pharmacological Research
      Author(s): Xiaojia Ren, Daret K.St. Clair, D.Allan Butterfield
      One of the major complaints patients who survive cancer often make is chemotherapy induced cognitive impairment (CICI), which survivors often call “chemo brain.” CICI is a side effect of chemotherapy due to the cytotoxicity and neurotoxicity of anti-cancer drugs causing structural and functional changes in brain, even when drugs that do not cross the blood brain barrier (BBB) are used. Diminished cognitive functions including diminution of learning and memory, concentration and attention, processing speed and executive functions that reduce quality of life and ability to work are common signs and symptoms of CICI. There still is not a clarified and complete mechanism for CICI, but researchers have pointed to several biochemical candidates. Chemotherapy-induced, cytokine-mediated involvement in CICI will be mainly discussed in this review paper with emphasis on different types of cytokines, correlated with BBB and epigenetic changes. Mechanisms of ROS-generating, anti-cancer drugs and their relation to cytokine-mediated CICI will be emphasized.
      Graphical abstract image

      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2017.01.001
       
  • Paradoxical sleep deprivation in rats causes a selective reduction in the
           expression of type-2 metabotropic glutamate receptors in the hippocampus
    • Authors: Isabella Panaccione; Luisa Iacovelli; Luigi di Nuzzo; Francesca Nardecchia; Gianluca Mauro; Delfina Janiri; Antonio De Blasi; Gabriele Sani; Ferdinando Nicoletti; Rosamaria Orlando
      Pages: 46 - 53
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Isabella Panaccione, Luisa Iacovelli, Luigi di Nuzzo, Francesca Nardecchia, Gianluca Mauro, Delfina Janiri, Antonio De Blasi, Gabriele Sani, Ferdinando Nicoletti, Rosamaria Orlando
      Paradoxical sleep deprivation in rats is considered as an experimental animal model of mania endowed with face, construct, and pharmacological validity. We induced paradoxical sleep deprivation by placing rats onto a small platform surrounded by water. This procedure caused the animal to fall in the water at the onset of REM phase of sleep. Control rats were either placed onto a larger platform (which allowed them to sleep) or maintained in their home cage. Sleep deprived rats showed a substantial reduction in type-2 metabotropic glutamate (mGlu2) receptors mRNA and protein levels in the hippocampus, but not in the prefrontal cortex or corpus striatum, as compared to both groups of control rats. No changes in the expression of mGlu3 receptor mRNA levels or mGlu1α and mGlu5 receptor protein levels were found with exception of an increase in mGlu1α receptor levels in the striatum of SD rats. Moving from these findings we treated SD and control rats with the selective mGlu2 receptor enhancer, BINA (30mg/kg, i.p.). SD rats were also treated with sodium valproate (300mg/kg, i.p.) as an active comparator. Both BINA and sodium valproate were effective in reversing the manic-like phenotype evaluated in an open field arena in SD rats. BINA treatment had no effect on motor activity in control rats, suggesting that our findings were not biased by a non-specific motor-lowering activity of BINA. These findings suggest that changes in the expression of mGlu2 receptors may be associated with the enhanced motor activity observed with mania.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.11.029
      Issue No: Vol. 117 (2016)
       
  • Sigma-2 receptor and progesterone receptor membrane component 1 (PGRMC1)
           are two different proteins: Proofs by fluorescent labeling and binding of
           sigma-2 receptor ligands to PGRMC1
    • Authors: Maria Laura Pati; Diana Groza; Chiara Riganti; Joanna Kopecka; Mauro Niso; Francesco Berardi; Sonja Hager; Petra Heffeter; Miwa Hirai; Hitoshi Tsugawa; Yasuaki Kabe; Makoto Suematsu; Carmen Abate
      Pages: 67 - 74
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Maria Laura Pati, Diana Groza, Chiara Riganti, Joanna Kopecka, Mauro Niso, Francesco Berardi, Sonja Hager, Petra Heffeter, Miwa Hirai, Hitoshi Tsugawa, Yasuaki Kabe, Makoto Suematsu, Carmen Abate
      A controversial relationship between sigma-2 and progesterone receptor membrane component 1 (PGRMC1) proteins, both representing promising targets for the therapy and diagnosis of tumors, exists since 2011, when the sigma-2 receptor was reported to be identical to PGRMC1. Because a misidentification of these proteins will lead to biased future research hampering the possible diagnostic and therapeutic exploitation of the two targets, there is the need to solve the debate on their identity. With this aim, we have herein investigated uptake and distribution of structurally different fluorescent sigma-2 receptor ligands by flow cytometry and confocal microscopy in MCF7 cells, where together with intrinsic sigma-2 receptors, PGRMC1 was constitutively present or alternatively silenced or overexpressed. HCT116 cells, with constitutive or silenced PGRMC1, were also studied. These experiments showed that the fluorescent sigma-2 ligands bind to their receptor irrespective of PGRMC1 expression. Furthermore, isothermal titration calorimetry was conducted to examine if DTG and PB28, two structurally distinct nanomolar affinity sigma-2 ligands, bind to purified PGRMC1 proteins that have recently been revealed to form both apo-monomeric and heme-mediated dimeric forms. While no binding to apo-PGRMC1 monomer was detected, a micromolar affinity to heme-mediated dimerized PGRMC1 was demonstrated in DTG but not in PB28. The current data provide evidence that sigma-2 receptor and PGRMC1 are not identical, paving the pathway for future unbiased research in which these two attractive targets are treated as different proteins while the identification of the true sigma-2 protein further needs to be pursued.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.023
      Issue No: Vol. 117 (2016)
       
  • Dysfunctional oleoylethanolamide signaling in a mouse model of
           Prader-Willi syndrome
    • Authors: Miki Igarashi; Vidya Narayanaswami; Virginia Kimonis; Pietro M. Galassetti; Fariba Oveisi; Kwang-Mook Jung; Daniele Piomelli
      Pages: 75 - 81
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Miki Igarashi, Vidya Narayanaswami, Virginia Kimonis, Pietro M. Galassetti, Fariba Oveisi, Kwang-Mook Jung, Daniele Piomelli
      Prader-Willi syndrome (PWS), the leading genetic cause of obesity, is characterized by a striking hyperphagic behavior that can lead to obesity, type-2 diabetes, cardiovascular disease and death. The molecular mechanism underlying impaired satiety in PWS is unknown. Oleoylethanolamide (OEA) is a lipid mediator involved in the control of feeding, body weight and energy metabolism. OEA produced by small-intestinal enterocytes during dietary fat digestion activates type-α peroxisome proliferator-activated receptors (PPAR-α) to trigger an afferent signal that causes satiety. Emerging evidence from genetic and human laboratory studies suggests that deficits in OEA-mediated signaling might be implicated in human obesity. In the present study, we investigated whether OEA contributes to feeding dysregulation in Magel2 m+/p− (Magel2 KO) mice, an animal model of PWS. Fasted/refed male Magel2 KO mice eat more than do their wild-type littermates and become overweight with age. Meal pattern analyses show that hyperphagia in Magel2 KO is due to increased meal size and meal duration rather than to lengthening of the intermeal interval, which is suggestive of a defect in mechanisms underlying satiation. Food-dependent OEA accumulation in jejunum and fasting OEA levels in plasma are significantly greater in Magel2 KO mice than in wild-type controls. Together, these findings indicate that deletion of the Magel2 gene is accompanied by marked changes in OEA signaling. Importantly, intraperitoneal administration of OEA (10mg/kg) significantly reduces food intake in fasted/refed Magel2 KO mice, pointing to a possible use of this natural compound to control hunger in PWS.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.024
      Issue No: Vol. 117 (2016)
       
  • Potentiation of hepatic stellate cell activation by extracellular ATP is
           dependent on P2X7R-mediated NLRP3 inflammasome activation
    • Authors: Shuang Jiang; Yu Zhang; Jin-Hua Zheng; Xia Li; You-Li Yao; Yan-Ling Wu; Shun-Zong Song; Peng Sun; Ji-Xing Nan; Li-Hua Lian
      Pages: 82 - 93
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Shuang Jiang, Yu Zhang, Jin-Hua Zheng, Xia Li, You-Li Yao, Yan-Ling Wu, Shun-Zong Song, Peng Sun, Ji-Xing Nan, Li-Hua Lian
      Purinergic receptor P2x7 (P2x7R) is a key modulator of liver inflammation and fibrosis. The present study aimed to investigate the role of P2x7R in hepatic stellate cells activation. Lipopolysaccharide (LPS) or the conditioned medium (CM) from LPS-stimulated RAW 264.7 mouse macrophages was supplemented to human hepatic stellate cells, LX-2 for 24h and P2x7R selective antagonist A438079 (10μM) was supplemented to LX-2 cells 1h before LPS or CM stimulation. In addition LX-2 cells were primed with LPS for 4h and subsequently stimulated for 30min with 3mM of adenosine 5′-triphosphate (ATP). A438079 was supplemented to LX-2 cells 10min prior to ATP. Directly treated with LPS on LX-2 cells, mRNA expressions of interleukin (IL)-1β, IL-18 and IL-6 were increased, as well as mRNA expressions of P2x7R, caspase-1, apoptosis-associated speck-like protein containing CARD (ASC) and NOD-like receptor family, pyrin domain containing 3 (NLRP3) mRNA. LPS also increased α-smooth muscle actin (α-SMA) and type I collagen mRNA expressions, as well as collagen deposition. Interestingly treatment of LX-2 cells with LPS-activated CM exhibited the greater increase of above factors than those in LX-2 cells directly treated with LPS. Pretreatment of A438079 on LX-2 cells stimulated by LPS or LPS-activated CM both suppressed IL-1β mRNA expression. LPS combined with ATP dramatically increased protein synthesis and cleavage of IL-1β and its mRNA level than those in HSC treated with LPS or ATP alone. Additionally LX-2 cells primed with LPS and subsequently stimulated for 30min with ATP greatly increased mRNA and protein expression of caspase-1, NLRP3 and P2x7R, as well as liver fibrosis markers, α-SMA and type I collagen. These events were remarkably suppressed by A438079 pretreatment. siRNA against P2x7R reduced protein expression of NLRP3 and α-SMA, and suppressed deposition and secretion of type I collagen. The involvement of P2X7R-mediated NLRP3 inflammasome activation in IL-1β production of HSC might contribute to ECM deposition and suggests that blockade of the P2x7R-NLRP3 inflammasome axis represents a potential therapeutic target to liver fibrosis.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.11.040
      Issue No: Vol. 117 (2016)
       
  • Passive drug permeation through membranes and cellular distribution
    • Authors: D.O. Scott; A. Ghosh; L. Di; T.S. Maurer
      Pages: 94 - 102
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): D.O. Scott, A. Ghosh, L. Di, T.S. Maurer
      Although often overlooked, passive mechanisms can lead to significant accumulation or restriction of drugs to intracellular sites of drug action. These mechanisms include lipoidal diffusion of ionized species and pH partitioning according to the electrochemical potential and to pH gradients that exist across subcellular compartments, respectively. These mechanisms are increasingly being exploited in the design of safe and effective drugs for the treatment of a wide variety of diseases. In this work, the authors review these efforts and the associated passive mechanisms of cellular drug permeation. A generic mathematical model of the cell is provided and used to illustrate concepts relevant to steady-state intracellular distribution. Finally, the authors review methods for estimating determinant parameters and measuring the net effect at the level of unbound intracellular drug concentrations.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.11.028
      Issue No: Vol. 117 (2016)
       
  • A story of metformin-butyrate synergism to control various pathological
           conditions as a consequence of gut microbiome modification: Genesis of a
           wonder drug?
    • Authors: Kunal Maniar; Amal Moideen; Ankur Mittal; Amol Patil; Amitava Chakrabarti; Dibyajyoti Banerjee
      Pages: 103 - 128
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Kunal Maniar, Amal Moideen, Ankur Mittal, Amol Patil, Amitava Chakrabarti, Dibyajyoti Banerjee
      The most widely prescribed oral anti-diabetic agent today in the world today is a member of the biguanide class of drugs called metformin. Apart from its use in diabetes, it is currently being investigated for its potential use in many diseases such as cancer, cardiovascular diseases, Alzheimer's disease, obesity, comorbidities of diabetes such as retinopathy, nephropathy to name a few. Numerous in-vitro and in-vivo studies as well as clinical trials have been and are being conducted with a vast amount of literature being published every day. Numerous mechanisms for this drug have been proposed, but they have been unable to explain all the actions observed clinically. It is of interest that insulin has a stimulatory effect on cellular growth. Metformin sensitizes the insulin action but believed to be beneficial in cancer. Like -wise metformin is shown to have beneficial effects in opposite sets of pathological scenario looking from insulin sensitization point of view. This requires a comprehensive review of the disease conditions which are claimed to be affected by metformin therapy. Such a comprehensive review is presently lacking. In this review, we begin by examining the history of metformin before it became the most popular anti-diabetic medication today followed by a review of its relevant molecular mechanisms and important clinical trials in all areas where metformin has been studied and investigated till today. We also review novel mechanistic insight in metformin action in relation to microbiome and elaborate implications of such aspect in various disease states. Finally, we highlight the quandaries and suggest potential solutions which will help the researchers and physicians to channel their research and put this drug to better use.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.12.003
      Issue No: Vol. 117 (2016)
       
  • sec-Butylpropylacetamide (SPD), a new amide derivative of valproic acid
           for the treatment of neuropathic and inflammatory pain
    • Authors: Dan Kaufmann; Peter J. West; Misty D. Smith; Boris Yagen; Meir Bialer; Marshall Devor; H. Steve White; K.C. Brennan
      Pages: 129 - 139
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Dan Kaufmann, Peter J. West, Misty D. Smith, Boris Yagen, Meir Bialer, Marshall Devor, H. Steve White, K.C. Brennan
      Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect ∼20% of the world’s population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study, we defined the pharmacokinetic parameters of SPD in rat and mouse, and then evaluated its antinociceptive potential in neuropathic and acute inflammatory pain models. In the sciatic nerve ligation (SNL) model of neuropathic pain, SPD was equipotent to gabapentin and more potent than its parent compound VPA. SPD also showed either higher or equal potency to VPA in the formalin, carrageenan, and writhing tests of inflammatory pain. SPD showed no effects on compound action potential properties in a sciatic nerve preparation, suggesting that its mechanism of action is distinct from local anesthetics and membrane stabilizing drugs. SPD’s activity in both neuropathic and inflammatory pain warrants its development as a potential broad-spectrum anti-nociceptive drug.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.11.030
      Issue No: Vol. 117 (2016)
       
  • Effect of lysosomotropic molecules on cellular homeostasis
    • Authors: Omer F. Kuzu; Mesut Toprak; M. Anwar Noory; Gavin P. Robertson
      Pages: 177 - 184
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Omer F. Kuzu, Mesut Toprak, M. Anwar Noory, Gavin P. Robertson
      Weak bases that readily penetrate through the lipid bilayer and accumulate inside the acidic organelles are known as lysosomotropic molecules. Many lysosomotropic compounds exhibit therapeutic activity and are commonly used as antidepressant, antipsychotic, antihistamine, or antimalarial agents. Interestingly, studies also have shown increased sensitivity of cancer cells to certain lysosomotropic agents and suggested their mechanism of action as a promising approach for selective destruction of cancer cells. However, their chemotherapeutic utility may be limited due to various side effects. Hence, understanding the homeostatic alterations mediated by lysosomotropic compounds has significant importance for revealing their true therapeutic potential as well as toxicity. In this review, after briefly introducing the concept of lysosomotropism and classifying the lysosomotropic compounds into two major groups according to their cytotoxicity on cancer cells, we focused on the subcellular alterations mediated by class-II lysosomotropic compounds. Briefly, their effect on intracellular cholesterol homeostasis, autophagy and lysosomal sphingolipid metabolism was discussed. Accordingly, class-II lysosomotropic molecules inhibit intracellular cholesterol transport, leading to the accumulation of cholesterol inside the late endosomal-lysosomal cell compartments. However, the accumulated lysosomal cholesterol is invisible to the cellular homeostatic circuits, hence class-II lysosomotropic molecules also upregulate cholesterol synthesis pathway as a downstream event. Considering the fact that Niemann-Pick disease, a lysosomal cholesterol storage disorder, also triggers similar pathologic abnormalities, this review combines the knowledge obtained from the Niemann-Pick studies and lysosomotropic compounds. Taken together, this review is aimed at allowing readers a better understanding of subcellular alterations mediated by lysosomotropic drugs, as well as their potential therapeutic and/or toxic activities.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.12.021
      Issue No: Vol. 117 (2016)
       
  • Curcumin: a potentially powerful tool to reverse cisplatin-induced
           toxicity
    • Authors: Ramin Rezaee; Amir Abbas Momtazi; Alireza Monemi; Amirhossein Sahebkar
      Abstract: Publication date: Available online 29 December 2016
      Source:Pharmacological Research
      Author(s): Ramin Rezaee, Amir Abbas Momtazi, Alireza Monemi, Amirhossein Sahebkar
      Curcumin is a naturally occurring polyphenol isolated from Curcuma longa that has gained considerable interest over the last decades due to its beneficial effects for human health. Moreover, the usage of cisplatin, a platinum-based chemotherapeutic, is associated with several adverse effects affecting the quality of life of the patients. Also, cisplatin therapy is jeopardized by a great challenge of resistance which reduces the efficacy of this drug. In order to conquer these dark sides of cisplatin therapy, curcumin has been widely used to fight against cisplatin-resistant cancer cells and decrease its unwanted side effects (e.g. ototoxicity, nephrotoxicity and neurotoxicity). In this review, we provide a summary of the studies done to show the protective effects of curcumin against cisplatin failure and toxicity.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.12.037
       
  • Prolonged infusion of sedatives and analgesics in adult intensive care
           patients: a systematic review of pharmacokinetic data reporting and
           quality of evidence
    • Authors: Andrew H.W. Tse; Lowell Ling; Gavin M. Joynt; Anna Lee
      Abstract: Publication date: Available online 21 December 2016
      Source:Pharmacological Research
      Author(s): Andrew H.W. Tse, Lowell Ling, Gavin M. Joynt, Anna Lee
      Although pharmacokinetic (PK) data for prolonged sedative and analgesic agents in intensive care unit (ICU) has been described, the number of publications in this important area appear relatively few, and PK data presented is not comprehensive. Known pathophysiological changes in critically ill patients result in altered drug PK when compared with non-critically ill patients. ClinPK Statement was recently developed to promote consistent reporting in PK studies, however, its applicability to ICU specific PK studies is unclear. In this systematic review, we assessed the overall ClinPK Statement compliance rate, determined the factors affecting compliance rate, graded the level of PK evidence and assessed the applicability of the ClinPK Statement to future ICU PK studies. Of the 33 included studies (n=2016), 22 (67%) were low evidence quality descriptive studies (Level 4). Included studies had a median compliance rate of 80% (IQR 66% to 86%) against the ClinPK Statement. Overall pooled compliance rate (78%, 95% CI 73% to 83%) was stable across time (P=0.38), with higher compliance rates found in studies fitting three compartments models (88%, P<0.01), two compartments models (83%, P<0.01) and one compartment models (77%, P=0.17) than studies fitting noncompartmental or unspecified models (69%) (P<0.01). Data unique to the interpretation of PK data in critically ill patients, such as illness severity (48%), organ dysfunction (36%) and renal replacement therapy use (32%), were infrequently reported. Discrepancy between the general compliance rate with ClinPK Statement and the under-reporting of ICU specific parameters suggests that the applicability of the ClinPK Statement to ICU PK studies may be limited in its current form.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.028
       
  • Gender related differences in treatment and response to statins in primary
           and secondary cardiovascular prevention: the never-ending debate
    • Authors: Roberto Cangemi; Giulio Francesco Romiti; Giuseppe Campolongo; Eleonora Ruscio; Susanna Sciomer; Daniele Gianfrilli; Valeria Raparelli
      Abstract: Publication date: Available online 21 December 2016
      Source:Pharmacological Research
      Author(s): Roberto Cangemi, Giulio Francesco Romiti, Giuseppe Campolongo, Eleonora Ruscio, Susanna Sciomer, Daniele Gianfrilli, Valeria Raparelli
      Statins are a main curbstone in the prevention of cardiovascular disease (CVD), pandemic in 21st century. CVD displays evident sex and gender differences, not only in clinical manifestation and outcomes but also in pharmacological treatment. Whether statin therapy should be differentially prescribed according to sex is a matter of debate. Aside a different pharmacological action, statins are not proven to be less effective in one gender comparing to the other, nor to be less safe. Nevertheless, up to date evidence shows that statins have not been adequately tested in women, especially in primary prevention trials. Since data-lacking, making a treatment decision on women is potentially harmful, although female individuals represent the majority of the population and they have a greater lifetime CVD risk. Therefore, adequately powered randomized control trials with longer follow-up are warranted to establish if a benefit on CV events and mortality prevention exists in both sexes. The aim of the present review is to summarize the sex and gender differences in statin use: it raises concerns and updates perspectives towards an evidence-based and sex-tailored prevention of CVD management.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.027
       
  • Resveratrol regulates gene transcription via activation of
           stimulus-responsive transcription factors
    • Authors: Gerald Thiel; Oliver G. Rössler
      Abstract: Publication date: Available online 21 December 2016
      Source:Pharmacological Research
      Author(s): Gerald Thiel, Oliver G. Rössler
      Resveratrol (trans-3,4′,5-trihydroxystilbene), a polyphenolic phytoalexin of grapes and other fruits and plants, is a common constituent of our diet and of dietary supplements. Many health-promoting benefits have been connected with resveratrol in the treatment of cardiovascular diseases, cancer, diabetes, inflammation, neurodegeneration, and diseases connected with aging. To explain the pleiotropic effects of resveratrol, the molecular targets of this compound have to be identified on the cellular level. Resveratrol induces intracellular signal transduction pathways which ultimately lead to changes in the gene expression pattern of the cells. Here, we review the effect of resveratrol on the activation of the stimulus-responsive transcription factors CREB, AP-1, Egr-1, Elk-1, and Nrf2. Following activation, these transcription factors induce transcription of delayed response genes. The gene products of these delayed response genes are ultimately responsible for the changes in the biochemistry and physiology of resveratrol-treated cells. The activation of stimulus-responsive transcription factors may explain many of the intracellular activities of resveratrol. However, results obtained in vitro may not easily be transferred to in vivo systems.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.029
       
  • Multiple Nickel-Sensitive Targets Elicit Cardiac Arrhythmia in Isolated
           Mouse Hearts after Pituitary Adenylate Cyclase-Activating
           Polypeptide-Mediated Chronotropy
    • Authors: Etienne E. Tevoufouet; Erastus N. Nembo; Fabian Distler; Felix Neumaier; Jürgen Hescheler; Filomain Nguemo; Toni Schneider
      Abstract: Publication date: Available online 19 December 2016
      Source:Pharmacological Research
      Author(s): Etienne E. Tevoufouet, Erastus N. Nembo, Fabian Distler, Felix Neumaier, Jürgen Hescheler, Filomain Nguemo, Toni Schneider
      The pituitary adenylate cyclase-activating polypeptide (PACAP)-27 modulates various biological processes, from the cellular level to function specification. However, the cardiac actions of this neuropeptide are still under intense studies. Using control (+ +) and mice lacking (− −) either R-type (Cav2.3) or T-type (Cav3.2) Ca2+ channels, we investigated the effects of PACAP-27 on cardiac activity of spontaneously beating isolated perfused hearts. Superfusion of PACAP-27 (20nM) caused a significant increase of baseline heart frequency in Cav2.3(+ +) (156.9±10.8 to 239.4±23.4 bpm; p<0.01) and Cav2.3(− −) (190.3±26.4 to 270.5±25.8 bpm; p<0.05) hearts. For Cav3.2, the heart rate was significantly increased in Cav3.2(− −) (133.1±8.5 bpm to 204.6±27.9 bpm; p<0.05) compared to Cav3.2(+ +) hearts (185.7±11.2 bpm to 209.3±22.7 bpm). While the P wave duration and QTc interval were significantly increased in Cav2.3(+ +) and Cav2.3(− −) hearts following PACAP-27 superfusion, there was no effect in Cav3.2(+ +) and Cav3.2(− −) hearts. The positive chronotropic effect observed in the four study groups, as well as the effect on P wave duration and QTc interval were abolished in the presence of Ni2+ (50μM) and PACAP-27 (20nM) in hearts from Cav2.3(+ +) and Cav2.3(− −) mice. In addition to suppressing PACAP’s response, Ni2+ also induced conduction disturbances in investigated hearts. In conclusion, the most Ni2+-sensitive Ca2+ channels (R- and T-type) may modulate the PACAP signaling cascade during cardiac excitation in isolated mouse hearts, albeit to a lesser extent than other Ni2+-sensitive targets.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.025
       
  • Therapeutic Potential and Limitations of Cholinergic Anti-Inflammatory
           Pathway in Sepsis
    • Authors: Alexandre Kanashiro; Fabiane Sônego; Raphael G. Ferreira; Fernanda V.S. Castanheira; Caio A. Leite; Vanessa F. Borges; Daniele C. Nascimento; David F. Cólon; José Carlos Alves-Filho; Luis Ulloa; Fernando Q. Cunha
      Abstract: Publication date: Available online 12 December 2016
      Source:Pharmacological Research
      Author(s): Alexandre Kanashiro, Fabiane Sônego, Raphael G. Ferreira, Fernanda V.S. Castanheira, Caio A. Leite, Vanessa F. Borges, Daniele C. Nascimento, David F. Cólon, José Carlos Alves-Filho, Luis Ulloa, Fernando Q. Cunha
      Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called “cholinergic anti-inflammatory pathway”, suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.
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      PubDate: 2016-12-14T14:01:00Z
      DOI: 10.1016/j.phrs.2016.12.014
       
  • A2B adenosine receptors stimulate IL-6 production in primary murine
           microglia through p38 MAPK kinase pathway
    • Authors: Stefania Merighi; Serena Bencivenni; Fabrizio Vincenzi; Katia Varani; Pier Andrea Borea; Stefania Gessi
      Abstract: Publication date: Available online 11 December 2016
      Source:Pharmacological Research
      Author(s): Stefania Merighi, Serena Bencivenni, Fabrizio Vincenzi, Katia Varani, Pier Andrea Borea, Stefania Gessi
      The hallmark of neuroinflammation is the activation of microglia, the immunocompetent cells of the CNS, releasing a number of proinflammatory mediators implicated in the pathogenesis of neuronal diseases. Adenosine is an ubiquitous autacoid regulating several microglia functions through four receptor subtypes named A1, A2A, A2B and A3 (ARs), that represent good targets to suppress inflammation occurring in CNS. Here we investigated the potential role of ARs in the modulation of IL-6 secretion and cell proliferation in primary microglial cells. The A2BAR agonist 2-[[6-Amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide (BAY60-6583) stimulated IL-6 increase under normoxia and hypoxia, in a dose- and time-dependent way. In cells incubated with the blockers of phospholipase C (PLC), protein kinase C epsilon (PKC-ε) and PKC delta (PKC-δ) the IL-6 increase due to A2BAR activation was strongly reduced, whilst it was not affected by the inhibitor of adenylyl cyclase (AC). Investigation of cellular signalling involved in the A2BAR effect revealed that only the inhibitor of p38 mitogen activated protein kinase (MAPK) was able to block the agonist’s effect on IL-6 secretion, whilst inhibitors of pERK1/2, JNK1/2 MAPKs and Akt were not. Stimulation of p38 by BAY60-6583 was A2BAR-dependent, through a pathway affecting PLC, PKC-ε and PKC-δ but not AC, in both normoxia and hypoxia. Finally, BAY60-6583 increased microglial cell proliferation involving A2BAR, PLC, PKC-ε, PKC-δ and p38 signalling. In conclusion, A2BARs activation increased IL-6 secretion and cell proliferation in murine primary microglial cells, through PLC, PKC-ε, PKC-δ and p38 pathways, thus suggesting their involvement in microglial activation and neuroinflammation.
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      PubDate: 2016-12-14T14:01:00Z
      DOI: 10.1016/j.phrs.2016.11.024
       
  • Advanced technologies charting a new path for Traditional Chinese Medicine
           drug discovery
    • Authors: Elaine Lai-Han Leung; Emilio Clementi; W.S. Fred Wong
      Abstract: Publication date: Available online 10 December 2016
      Source:Pharmacological Research
      Author(s): Elaine Lai-Han Leung, Emilio Clementi, W.S. Fred Wong


      PubDate: 2016-12-14T14:01:00Z
      DOI: 10.1016/j.phrs.2016.12.010
       
  • Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the
           treatment of cutaneous melanomas
    • Authors: Robert Roskoski
      Abstract: Publication date: Available online 9 December 2016
      Source:Pharmacological Research
      Author(s): Robert Roskoski
      The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer. Mutations that activate the Map kinase pathway occur in more than 90% of these melanomas. This has led to the development of the combination of dabrafenib and trametinib or vemurafenib and cobimetanib for the treatment of BRAF V600E mutant melanomas. Dabrafenib and vemurafenib target V600E/K BRAF mutants while trametinib and cobimetanib target MEK1/2. The latter two agents bind to MEK1/2 at a site that is adjacent to, but separate from, the ATP-binding site and are therefore classified as type III allosteric protein kinase inhibitors. These agents form a hydrogen bond with a conserved β3-lysine and they make numerous hydrophobic contacts with residues within the αC-helix, the β5 strand, and within the activation segment, regions of the protein kinase domain that exhibit greater diversity than those found within the ATP-binding site. One advantage of such allosteric inhibitors is that they do not have to compete with millimolar concentrations of cellular ATP, which most FDA-approved small molecule competitive inhibitors such as imatinib must do. Owing to the wide spread activation of this pathway in numerous neoplasms, trametinib and cobimetinib are being studied in combination with other targeted and cytotoxic drugs in a variety of clinical situations. Except for BRAF and NRAS mutations, there are no other biomarkers correlated with treatment responses following MEK1/2 inhibition and the discovery of such biomarkers would represent an important therapeutic breakthrough.
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      PubDate: 2016-12-14T14:01:00Z
      DOI: 10.1016/j.phrs.2016.12.009
       
  • Hydroxytyrosol ameliorates metabolic, cardiovascular and liver changes in
           a rat model of diet-induced metabolic syndrome: pharmacological and
           metabolism-based investigation
    • Authors: Hemant Poudyal; Nikolaos Lemonakis; Panagiotis Efentakis; Evangelos Gikas; Maria Halabalaki; Ioanna Andreadou; Leandros Skaltsounis; Lindsay Brown
      Abstract: Publication date: Available online 8 December 2016
      Source:Pharmacological Research
      Author(s): Hemant Poudyal, Nikolaos Lemonakis, Panagiotis Efentakis, Evangelos Gikas, Maria Halabalaki, Ioanna Andreadou, Leandros Skaltsounis, Lindsay Brown
      Metabolic syndrome is a clustering of interrelated risk factors for cardiovascular disease and diabetes. The Mediterranean diet has been proposed as an important dietary pattern to confer cardioprotection by attenuating risk factors of metabolic syndrome. Hydroxytyrosol (HT) is present in olive fruit and oil, which are basic constituents of the Mediterranean diet. In this study, we have shown that treatment with HT (20mg/kg/d for 8 weeks) decreased adiposity, improved impaired glucose and insulin tolerance, improved endothelial function with lower systolic blood pressure, decreased left ventricular fibrosis and resultant diastolic stiffness and reduced markers of liver damage in a diet-induced rat model of metabolic syndrome. These results were accompanied by reduced infiltration of monocytes/macrophages into the heart and liver and reduced biomarkers of oxidative stress in heart. Furthermore, in an HRMS-based metabolism study of HT, we have identified 24 HT phase I and II metabolites, six of them being over-produced in high-starch, low-fat diet fed rats treated with HT compared to obese rats on high-fructose, high-fat diet. These results provide direct evidence for cardioprotective effects of hydroxytyrosol by attenuation of metabolic risk factors. The implications of altered metabolism of HT in high-fructose, high-fat diet fed obese rats warrant further investigation.
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      PubDate: 2016-12-08T10:14:50Z
      DOI: 10.1016/j.phrs.2016.12.002
       
  • Title: Re-calculating! Navigating through the osteosarcoma treatment
           roadblock
    • Authors: J.M. McGuire; T.J. Utset-Ward; D.M. Reed; C.C. Lynch
      Abstract: Publication date: Available online 7 December 2016
      Source:Pharmacological Research
      Author(s): J.M. McGuire, T.J. Utset-Ward, D.M. Reed, C.C. Lynch
      The survival rates for patients with osteosarcoma has remained almost static for the past three decades. Current standard of care therapy includes chemotherapies such as doxorubicin, cisplatin, and methotrexate along with complete surgical resection and surgery with or without ifosfamide and etoposide for relapse, though outcomes are hoped to be improved through clinical trials. Additionally, increased understanding of the genetics, signaling pathways and microenvironmental factors driving the disease has led to the identification of promising agents and potential paths towards translation of an exciting array of novel targeted therapies. Here, we review the mechanism of action of these emerging therapies and how, with clinical translation, they can potentially improve the survival rates for osteosarcoma patients in the near future.
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      PubDate: 2016-12-08T10:14:50Z
      DOI: 10.1016/j.phrs.2016.12.004
       
 
 
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