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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  [3049 journals]
  • Targeting Epigenome with Dietary Nutrients in Cancer: Current Advances and
           Future Challenges
    • Abstract: Publication date: Available online 9 December 2017
      Source:Pharmacological Research
      Author(s): Mohammad Imran Khan, Suvasmita Rath, Vaqar Mustafa Adhami, Hasan Mukhtar
      Tumorigenesis and epigenetic are closely linked with each other. Epigenetic changes are potential regulators of gene expression without involving any change in the DNA itself. More interestingly, epigenetic changes are reversible heritable changes which pass through generations. Many dietary bioactive ingredients regulate epigenetic control of cells and influence biochemical processes. Correlation between epigenetic regulation and cancer onset has been well established. Recent studies provide important information on the role of bioactive dietary components in cancer prevention and therapy. Several bioactive components are responsible for modification of the epigenome by affecting DNA methylation, histone modification, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs). This review summarizes recent advancements in this field and describes the role of many bioactive components in regulating human epigenome and how these modifications can be exploited for prevention and treatment of cancer.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Alzheimer’s disease and gut microbiota modifications: the long way
           between preclinical studies and clinical evidence
    • Abstract: Publication date: Available online 9 December 2017
      Source:Pharmacological Research
      Author(s): Cesare Mancuso, Rosaria Santangelo
      Recent studies have suggested the role of an infectious component in the pathogenesis of Alzheimer's disease (AD). In light of this, research has focused on some bacteria constituting the intestinal microbial flora which can produce amyloid. Once generated, the latter hypothetically triggers a systemic inflammatory response which compromises complex brain functions, such as learning and memory. Clinical studies have shown that, in cognitively impaired elderly patients with brain amyloidosis, there is lower abundance in the gut of E. rectale and B. fragilis, two bacterial species which have an anti-inflammatory activity, versus a greater amount of pro-inflammatory genera such as Escherichia/Shigella. According to these findings, some clinical studies have demonstrated that supplementation with Lactobacilli- and Bifidobacteria- based probiotics has improved cognitive, sensory and emotional functions in subjects with AD. Moreover, certain herbal products, in particular dietetic polyphenols, have proved capable of restoring dysbiosis and, therefore, their prebiotic role could be effective in counteracting the onset of AD regardless of their activity of free radical scavenging or enhancement of the cell stress response. One of the recent greatest novelties in the field of neurodegenerative diseases is the chance to prevent or slow down AD progression with agents, such as probiotics and prebiotics, acting outside the central nervous system.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Comparative clinical trial of the variability factors of the exposure
           indices used for the drug monitoring of two tacrolimus formulations in
           kidney transplant recipients
    • Abstract: Publication date: Available online 8 December 2017
      Source:Pharmacological Research
      Author(s): Pierre Marquet, Laetitia Albano, Jean-Baptiste Woillard, Lionel Rostaing, Nassim Kamar, Charlotte Sakarovitch, Philippe Gatault, Matthias Buchler, Bernard Charpentier, Eric Thervet, Elisabeth Cassuto
      Background Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics. Methods 45 adult kidney transplant recipients were randomized to receive either Tac OD or Tac BID. On days 8±1 (D8) and 90±3 (month 3, M3), blood samples were collected over 24h in both groups. Tacrolimus concentrations were determined using HPLC-MS/MS and common CYP3A5, CYP3A4 and ABCB1 genotypes characterized using allelic discrimination assays. Tacrolimus population pharmacokinetics was studied in the two patient groups using the Iterative Two Stage (ITS) technique, considering a one-compartment model with two gamma laws to describe the absorption phase. Bayesian estimation based on the C0, C1h and C3h concentrations was employed to estimate individual Tac AUC0-12h and AUC12-24h (for Tac BID), or AUC0-24h (for Tac OD). Multiple linear regression was used to evaluate the influence of Tac formulation, post-transplantation period, recipient gender, existing glucose metabolism disorders, and CYP3A5, CYP3A4 and ABCB1 genotypes on C0, AUC0-24h and the AUC-to-trough concentration ratios. Results The Full Analysis Set comprised 22 patients on Tac OD and 20 on Tac BID. Tac exposure indices as well as their time evolution were similar in the two groups. Multi-linear modeling analysis showed that the Tac dose was higher with Tac-OD than Tac-BID, on D8 than at M3 and in CYP3A5 expressors (p<0.0001 for all). No such influence was found on C0 or C24h, while the AUC0-24h was significantly higher on D8 than at M3. The AUC0-24h/C0 ratio was not affected by the drug formulation and the polymorphisms studied, but it was significantly lower on D8 than at M3 (p=7.8×10−5). In contrast, both the post-transplantation period (p=1.53×10−4), and CYP3A5 expression (p=0.003) had a significant influence on the AUC0-24h/C24h ratio, explaining 19% and 12% of its variability, respectively. Consistently, for both Tac formulations, the AUC0-24h was better correlated with C24h than C0, and for Tac-BID the AUC0-12h was better correlated with C12h than C0. Conclusions This study confirms that the precisely timed 12h- or 24h-post-dose blood concentration (as opposed to the vaguely defined ‘trough level’) is a convenient surrogate of the 24h-AUC of tacrolimus for the two TAC formulations over the first 3 months post-transplantation. Still, for a given C24h value, AUC0-24h was higher on D8 and in CYP3A5 expressors. Bayesian estimation of AUC0-12h for TAC BID and AUC0-24h for TAC OD is feasible using only 3 time points within the first 3hours, thus giving access to the actual overall exposure.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Novel 1,4-benzothazines obliterate COX-2 mediated JAK-2/STAT-3 signals
           with potential regulation of oxidative and metabolic stress during
           colorectal cancer
    • Abstract: Publication date: Available online 8 December 2017
      Source:Pharmacological Research
      Author(s): Amit Rai, Umesh Kumar, Vinit Raj, Ashok K Singh, Pranesh Kumar, Amit K Keshari, Dinesh Kumar, Biswanath Maity, Arnab De, Amalesh Samanta, Sneha Nath, Anand Prakash, Sunil Babu Gosipatala, Gyan Chand, Sudipta Saha
      1,4-benzothiazines have ameliorative effects through inhibition of COX-2 mediated STAT-3 pathways at G-protein couple receptor site. As per this scenario, we recently prepared and tested novel 1,4-benzothiazine derivatives against HT-29 human colon cancer cell line. Two compounds namely AR13 and AR15 showed higher inhibitions among all the synthesized compounds. In the present context, we conducted the in vivo antiproliferative action and identified the molecular mechanism associated to cytotoxic action of AR13 and AR15 in dimethylhydrazine (DMH) induced colorectal carcinoma (CRC) model. Various physiological, oxidative stress, histopathology, ELISA, qRT-PCR, western blot and NMR-based metabolomics were accomplished to evaluate the anticancer effect of titled compounds. Both compounds were subjected to histological and biochemical tests to observe the protective action of the compounds. ELISA showed potential role of these compounds to normalize increased levels of IL-2, IL-6 and COX-2 mediators. This action was more pronounced for COX-2 rather than IL-2 and IL-6. Gene expression analyses further revealed that both of them attenuated the over-expressed COX-2 gene. Furthermore, it was confirmed that these compounds exerted antitumor potential via preventing COX-2 induced JAK-2 and STAT-3 phosphorylation. This action was substansiated by immunohistochemistry using JAK2, p-JAK2, STAT3 and p-STAT3 targets in colon tissue. Finally, score plots of PLS-DA models exhibited significant metabolic discriminations between the treated and CRC groups, and both compounds showed ability to restore the imbalance of multiple metabolites during CRC. In conclusion, our study provided the evidence towards better antiproliferative effect of AR13 and AR15 in DMH-induced CRC through the blockade of COX-2/JAK-2/STAT-3 signal transduction pathway and could be demonstrated as useful anti-CRC candidate molecules for future anticancer therapy.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Effects of biflavonoids from Garcinia madruno on a triple transgenic mouse
           model of Alzheimer’s disease
    • Abstract: Publication date: Available online 8 December 2017
      Source:Pharmacological Research
      Author(s): Angélica Maria Sabogal-Guáqueta, Luis Carrillo-Hormaza, Edison Osorio, Gloria Patricia Cardona-Gómez
      Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is pathologically characterized by the deposition of β-amyloid (βA) peptides in senile plaques and neurofibrillary tangles in the brain. Flavonoids have recently been used to prevent and treat a variety of neurodegenerative diseases, but little is known about bioflavonoids. In this study, we evaluate whether a biflavonoid fraction (BF) exerts neuroprotective effects on an aged triple transgenic mouse mode of AD (3xTg-AD). Then, 21–24-month-old 3xTg AD mice were i.p. injected with 25mg/kg of a BF from Garcinia madruno composed of morelloflavone (65%), volkensiflavone (12%), GB 2a (11%), fukugiside (6%) and amentoflavone (0.4%) every 48h for 3 months. The BF treatment reduced βA deposition in different regions of the brain (the hippocampus, entorhinal cortex and amygdala), reduced βA1-40 and βA1-42 levels, BACE1-mediated cleavage of APP (CTFβ), tau pathology, astrogliosis and microgliosis in the brains of aged 3xTg-AD mice. Although the BF treatment weakly improved learning, animals treated with BF spent more time in the open arms of the elevated plus maze test and displayed greater risk assessment behavior than the control groups. In summary, the BF reverses histopathological hallmarks and reduces emotional disorders in the 3xTg-AD mouse model, suggesting that the biflavonoids from G. madruno represent a potential natural therapeutic option for AD if its bioavailability is improved.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Exploring the effects of DPP-4 inhibitors on the kidney from the bench to
           clinical trials
    • Abstract: Publication date: Available online 6 December 2017
      Source:Pharmacological Research
      Author(s): Giuseppe Coppolino, Christian Leporini, Laura Rivoli, Francesco Ursini, Eugenio Donato di Paola, Valeria Cernaro, Franco Arturi, Davide Bolignano, Emilio Russo, Giovambattista De Sarro, Michele Andreucci
      Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a relatively new class of non-insulin glucose-lowering agents, belonging to the incretin family, which are able to improve glycemic control with a favorable safety profile, since they are associated with a low risk of hypoglycemia, no weight gain, and good tolerability in patients with chronic renal failure. Some experimental and clinical studies suggest that these drugs may exert significant pleiotropic effects, in particular on chronic kidney disease (CKD) progression, but data from clinical trials are still controversial. In an effort to clarify the effects of DPP-4 inhibitors (DPP-4is) on diabetes-related renal damage, we performed a narrative review of available clinical trials and other experimental studies focusing on renal effects of DPP-4is. Currently, there is no conclusive evidence proving the usefulness of this drug class for improving diabetes-related renal damage. However, our literature review suggests that DPP-4is are safe and well tolerated in type 2 diabetes mellitus (T2DM) patients with CKD. More importantly, results from the reviewed studies indicate that DPP-4 inhibitor therapy may improve two major risk factors for diabetic nephropathy, such as hyperglycemia and albuminuria, resulting in potential renal benefits beyond glycemic control. Despite several limitations, the conclusions of our review corroborate previous evidence on the potential renal benefits of DPP-4is, highlighting the urgent need of future trials adequately powered and designed on hard renal outcomes to ascertain (or contradict) the therapeutic benefit of DPP-4is in T2DM and CKD patients.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Amino acid supplements in critically ill patients
    • Abstract: Publication date: Available online 6 December 2017
      Source:Pharmacological Research
      Author(s): Jan Gunst, Ilse Vanhorebeek, Steven E. Thiessen, Greet Van den Berghe
      Observational studies have associated a low amino acid intake with adverse outcome of critical illness. Although this finding could theoretically be explained by differences in feeding tolerance related to illness severity, guidelines have recommended to administer sufficient amounts of amino acids from early onwards in the disease course. Recently, however, several high quality randomized controlled trials have not shown benefit by early amino acid supplementation and some trials even found potential harm, thus questioning this recommendation. These negative results could be related to amino acid-induced suppression of autophagy, to the inability to suppress bulk catabolism by exogenous amino acids, or to the administration of an amino acid mixture with an inappropriate composition. Currently, there is no evidence supporting administration of individual amino acid supplements during critical illness and glutamine administration may be harmful. The optimal timing, dose and composition of the amino acid mixture for critically ill patients remain unclear.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Functional significance of O-GlcNAc modification in regulating neuronal
           properties
    • Abstract: Publication date: Available online 6 December 2017
      Source:Pharmacological Research
      Author(s): Hongik Hwang, Hyewhon Rhim
      Post-translational modifications (PTMs) covalently modify proteins and diversify protein functions. Along with protein phosphorylation, another common PTM is the addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to serine and/or threonine residues. O-GlcNAc modification is similar to phosphorylation in that it occurs to serine and threonine residues and cycles on and off with a similar time scale. However, a striking difference is that the addition and removal of the O-GlcNAc moiety on all substrates are mediated by the two enzymes regardless of proteins, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. O-GlcNAcylation can interact or potentially compete with phosphorylation on serine and threonine residues, and thus serves as an important molecular mechanism to modulate protein functions and activation. However, it has been challenging to address the role of O-GlcNAc modification in regulating protein functions at the molecular level due to the lack of convenient tools to determine the sites and degrees of O-GlcNAcylation. Studies in this field have only begun to expand significantly thanks to the recent advances in detection and manipulation methods such as quantitative proteomics and highly selective small-molecule inhibitors for OGT and OGA. Interestingly, multiple brain regions, especially hippocampus, express high levels of both OGT and OGA, and a number of neuron-specific proteins have been reported to undergo O-GlcNAcylation. This review aims to discuss the recent updates concerning the impacts of O-GlcNAc modification on neuronal functions at multiple levels ranging from intrinsic neuronal properties to synaptic plasticity and animal behaviors.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Almond, hazelnut and walnut, three nuts for neuroprotection in
           Alzheimer’s disease: a neuropharmacological review of their bioactive
           constituents
    • Abstract: Publication date: Available online 5 December 2017
      Source:Pharmacological Research
      Author(s): Narjes Gorji, Reihaneh Moeini, Zahra Memariani
      An increase in the prevalence of Alzheimer’s disease (AD) as a multifactorial neurodegenerative disorder is an almost obvious issue in the world. Researches on natural products for finding effective drugs to prevent the disease are in progress. There is special attention to the three types of nuts including almond, hazelnut and walnut in manuscripts of traditional Persian medicine (PM) as preventive agents against brain’s atrophy and memory loss. The purpose of this study is a pharmacological review of their bioactive constituents and introducing the value of these nuts as effective supplements and natural medicinal foods in AD patients. Databases including PubMed and ScienceDirect were searched in title, abstract and keywords from year 2000 to present for AD-related researches on these tree nuts, their major phytochemicals and their mechanisms of action. As result, almond, hazelnut and walnut provide macronutrients, micronutrients, and phytochemicals which affect several pathways in AD pathogenesis such as amyloidogenesis, tau phosphorylation, oxidative stress, cholinergic pathways, and some non-target mechanisms including cholesterol lowering and anti-inflammatory properties, as well as effect on neurogenesis. These nuts are recommended in PM for their brain-protective activity and particularly reversing brain atrophy in case of hazelnut. The therapeutical statements of PM scholars mentioned in their books are based on their clinical observations with support of a long history of experiences. Beyond the molecular activities attributed to the phytochemicals, the use of these tree nuts could be more considered in scientific researches as effective nutrients for prevention or even management of AD.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Bleeding in advanced CKD patients on antithrombotic medication – A
           critical appraisal
    • Abstract: Publication date: Available online 5 December 2017
      Source:Pharmacological Research
      Author(s): Alexandru Burlacu, Simonetta Genovesi, David Goldsmith, Patrick Rossignol, Alberto Ortiz, Philip A. Kalra, Jolanta Małyszko, Maciej Banach, Mehmet Kanbay, Adrian Covic
      Patients with advanced chronic kidney disease (CKD) are at an increased risk of bleeding, especially in the context of the complex therapeutic schemes of coronary artery disease (CAD) (from stable angina to acute coronary syndromes), atrial fibrillation or venous thromboembolism. The bleeding issue increases morbidity and mortality, a serious problem in daily medical practice. However, these patients are largely excluded from major randomized clinical trials, which results in the lack of medical evidence-based foundation for specific recommendations regarding antithrombotic treatment in a high bleeding risk setting. Within this framework, the clinician does not benefit from a clear set of algorithms and measures in the exploration and balancing of bleeding and thrombosis risks. We discuss a diversity of scenarios, encompassing all categories of advanced CKD patients with CAD or/and atrial fibrillation, and with various combinations of drugs, such as antiplatelet therapy or/and oral anticoagulation. Our review highlights the most recent research as well as existing gaps in the recommendations of European Society of Cardiology Guidelines. We evaluate the existence or lack of assessment tools for the bleeding risk, strength, reliability and usefulness of the bleeding risk scores. Also, we identify all the measures recommended after risk evaluation, including specific plans, dose adjustments and particular therapeutic approaches. Finally, we provide with suggestions for improving the management of this patient population.
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      PubDate: 2017-12-12T12:23:35Z
       
  • N-3 PUFA diet enrichment prevents amyloid beta-induced depressive-like
           phenotype
    • Abstract: Publication date: Available online 5 December 2017
      Source:Pharmacological Research
      Author(s): M.G. Morgese, S. Schiavone, E. Mhillaj, M. Bove, P. Tucci, L. Trabace
      Among neuropsychiatric diseases, depression is one of the most prevalent. Many pathologies have been indicated as comorbid with depression and in particular, neurodegenerative disorders such as Alzheimer’s diseases (AD). In this regard, several evidences endorse a strong relationship between depression and AD, so much that this mental illness has been proposed either as a risk factor for AD or as a prodromic AD phase. Furthermore, amyloid beta (Aβ) peptide, the main constituent of amyloid plaques commonly considered the principal hallmark of AD brains, has been shown to be increased, in its soluble form, in depressed patients. Accordingly, we have previously found that Aβ, intracerebroventricularly (i.c.v.) injected, is able to evoke a depressive-like profile in rats accompanied by low cortical serotonin and reduced neurotrophin content. Taking into account the great increase in AD and depression prevalence, many environmental factors have been under study, particularly dietary factors, and the role of polyunsaturated fatty acids (PUFA) is becoming central in this field of research. Thus, aim of the present study was to evaluate the neurobehavioral effects of lifelong exposure to either n-3 PUFA rich or n-3 PUFA poor diet after Aβ central administration. Results showed that n-3 PUFA enriched diet prevented the Aβ- induced depressive-like behaviors, as reveled by the reduction in the immobility time in the FST test. Furthermore, n-3 PUFA rich diet exposure reverted also serotonin and neurotrophin level reduction in prefrontal cortex of Aβ treated rats. Taken together, our data support the concept that supplementation of diet with n-3 PUFA represents a valid approach to reduce the risk of developing depressive symptoms, as well as reducing the risk of Aβ-related pathologies, such as AD.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Functional histamine H3 and adenosine A2A receptor heteromers in
           recombinant cells and rat striatum
    • Abstract: Publication date: Available online 5 December 2017
      Source:Pharmacological Research
      Author(s): Ricardo Márquez-Gómez, Meridith T. Robins, Citlaly Gutiérrez-Rodelo, Juan-Manuel Arias, Jesús-Alberto Olivares-Reyes, Richard M.van Rijn, José-Antonio Arias-Montaño
      In the striatum, histamine H3 receptors (H3Rs) are co-expressed with adenosine A2A receptors (A2ARs) in the cortico-striatal glutamatergic afferents and the GABAergic medium-sized spiny neurons that originate the indirect pathway of the basal ganglia. This location allows H3Rs and A2ARs to regulate the striatal GABAergic and glutamatergic transmission. However, whether these receptors can physically interact has not yet been assessed. To test this hypothesis, a heteromer-selective in vitro assay was used to detect functional complementation between a chimeric A2AR302-Gαqi4 and wild-type H3Rs in transfected HEK-293T cells. H3R activation with the agonist RAMH resulted in Ca2+ mobilization (pEC50 7.31±0.23; maximal stimulation, Emax 449±25% of basal) indicative of receptor heterodimerization. Functional H3R-A2AR heteromers were confirmed by co-immunoprecipitation and observations of differential cAMP signaling when both receptors were co-expressed in the same cells. In membranes from rat striatal synaptosomes, H3R activation decreased A2AR affinity for the agonist CGS-21680 (pKi values 8.10±0.04 and 7.70±0.04). Moreover, H3Rs and A2ARs co-immunoprecipitated in protein extracts from striatal synaptosomes. These results support the existence of a H3R-A2AR heteromer with possible physiological implications for the modulation of the intra-striatal transmission.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Therapeutic targeting of oncogenic transcription factors by natural
           products in eye cancer
    • Abstract: Publication date: Available online 2 December 2017
      Source:Pharmacological Research
      Author(s): Michelle G. Zhang, John Y. Lee, Ryan A. Gallo, Wensi Tao, David Tse, Ravi Doddapaneni, Daniel Pelaez
      Carcinogenesis has a multifactorial etiology, and the underlying molecular pathogenesis is still not entirely understood, especially for eye cancers. Primary malignant intraocular neoplasms are relatively rare, but delayed detection and inappropriate management contribute to poor outcomes. Conventional treatment, such as orbital exenteration, chemotherapy, or radiotherapy, alone results in high mortality for many of these malignancies. Recent sequential multimodal therapy with a combination of high-dose chemotherapy, followed by appropriate surgery, radiotherapy, and additional adjuvant chemotherapy has helped dramatically improve management. Transcription factors are proteins that regulate gene expression by modulating the synthesis of mRNA. Since transcription is a dominant control point in the production of many proteins, transcription factors represent key regulators for numerous cellular functions, including proliferation, differentiation, and apoptosis, making them compelling targets for drug development. Natural compounds have been studied for their potential to be potent yet safe chemotherapeutic drugs. Since the ancient times, plant-derived bioactive molecules have been used to treat dreadful diseases like cancer, and several refined pharmaceutics have been developed from these compounds. Understanding targeting mechanisms of oncogenic transcription factors by natural products can add to our oncologic management toolbox. This review summarizes the current findings of natural products in targeting specific oncogenic transcription factors in various types of eye cancer.
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      PubDate: 2017-12-12T12:23:35Z
       
  • A promising natural product, pristimerin, results in cytotoxicity against
           breast cancer stem cells in vitro and xenografts in vivo through apoptosis
           and an incomplete autopaghy in breast cancer
    • Abstract: Publication date: Available online 2 December 2017
      Source:Pharmacological Research
      Author(s): Buse Cevatemre, Merve Erkısa, Nazlihan Aztopal, Didem Karakas, Pınar Alper, Chrisiida Tsimplouli, Evangelia Sereti, Konstantinos Dimas, Elif I. Ikitimur Armutak, Ebru Gurel Gurevin, Ayca Uvez, Mattia Mori, Simone Berardozzi, Cinzia Ingallina, Ilaria D’Acquarica, Bruno Botta, Bulent Ozpolat, Engin Ulukaya
      Several natural products have been suggested as effective agents for the treatment of cancer. Given the important role of CSCs (Cancer Stem Cells) in cancer, which is a trendy hypothesis, it is worth investigating the effects of pristimerin on CSCs as well as on the other malignant cells (MCF-7 and MDA-MB-231) of breast cancer. The anti-growth activity of pristimerin against MCF-7 and MCF-7s (cancer stem cell enriched population) cells was investigated by real time viability monitorization (xCELLigence System®) and ATP assay, respectively. Mode of cell death was evaluated using electron and fluorescence microscopies, western blotting (autophagy, apoptosis and ER-stress related markers) and flow cytometry (annexin-V staining, caspase 3/7 activity, BCL-2 and PI3K expressions). Pristimerin showed an anti-growth effect on cancer cells and cancer stem cells with IC50 values ranging at 0.38–1.75μM. It inhibited sphere formation at relatively lower doses (<1.56μM). Apoptosis was induced in MCF-7 and MCF-7s cells. In addition, extensive cytoplasmic vacuolation was observed, implying an incompleted autophagy as evidenced by the increase of autophagy-related proteins (p62 and LC3-II) with an unfolded protein response (UPR). Pristimerin inhibited the growth of MCF-7 and MDA-MB-231-originated xenografts in NOD.CB17-Prkdcscid/J mice. In mice, apoptosis was further confirmed by cleavage of PARP, activation of caspase 3 and/or 7 and TUNEL staining. Taken together, pristimerin shows cytotoxic activity on breast cancer both in vitro and in vivo. It seems to represent a robust promising agent for the treatment of breast cancer. Pristimerin’s itself or synthetic novel derivatives should be taken into consideration for novel potent anticancer agent(s).
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      PubDate: 2017-12-12T12:23:35Z
       
  • Editorial
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126


      PubDate: 2017-12-12T12:23:35Z
       
  • MDR in cancer: Addressing the underlying cellular alterations with the use
           of nanocarriers
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126
      Author(s): Manu S. Singh, Salma N. Tammam, Maryam A. Shetab Boushehri, Alf Lamprecht
      Multidrug resistance (MDR) is associated with a wide range of pathological changes at different cellular and intracellular levels. Nanoparticles (NPs) have been extensively exploited as the carriers of MDR reversing payloads to resistant tumor cells. However, when properly formulated in terms of chemical composition and physicochemical properties, NPs can serve as beyond delivery systems and help overcome MDR even without carrying a load of chemosensitizers or MDR reversing molecular cargos. Whether serving as drug carriers or beyond, a wise design of the nanoparticulate systems to overcome the cellular and intracellular alterations underlying the resistance is imperative. Within the current review, we will initially discuss the cellular changes occurring in resistant cells and how such changes lead to chemotherapy failure and cancer cell survival. We will then focus on different mechanisms through which nanosystems with appropriate chemical composition and physicochemical properties can serve as MDR reversing units at different cellular and intracellular levels according to the changes that underlie the resistance. Finally, we will conclude by discussing logical grounds for a wise and rational design of MDR reversing nanoparticulate systems to improve the cancer therapeutic approaches.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Nanomedicine as a potent strategy in melanoma tumor microenvironment
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126
      Author(s): Vincent Pautu, Daniela Leonetti, Elise Lepeltier, Nicolas Clere, Catherine Passirani
      Melanoma originated from melanocytes is the most aggressive type of skin cancer. Despite considerable progresses in clinical treatment with the discovery of BRAF or MEK inhibitors and monoclonal antibodies, the durability of response to treatment is often limited to the development of acquired resistance and systemic toxicity. The limited success of conventional treatment highlights the importance of understanding the role of melanoma tumor microenvironment in tumor developement and drug resistance. Nanoparticles represent a promising strategy for the development of new cancer treatments able to improve the bioavailability of drugs and increase their penetration by targeting specifically tumors cells and/or tumor environment. In this review, we will discuss the main influence of tumor microenvironment in melanoma growth and treatment outcome. Furthermore, third generation loaded nanotechnologies represent an exciting tool for detection, treatment, and escape from possible mechanism of resistance mediated by tumor microenvironment, and will be highlighted in this review.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Efficient ferrocifen anticancer drug and Bcl-2 gene therapy using lipid
           nanocapsules on human melanoma xenograft in mouse
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126
      Author(s): Pauline Resnier, Natacha Galopin, Yann Sibiril, Anne Clavreul, Jérôme Cayon, Alessandro Briganti, Pierre Legras, Anne Vessières, Tristan Montier, Gérard Jaouen, Jean-Pierre Benoit, Catherine Passirani
      Metastatic melanoma has been described as a highly aggressive cancer with low sensibility to chemotherapeutic agents. New types of drug, such as metal-based drugs (ferrocifens) have emerged and could represent an alternative for melanoma treatment since they show interesting anticancer potential. Furthermore, molecular analysis has evidenced the role of apoptosis in the low sensibility of melanomas and especially of the key regulator, Bcl-2. The objective of this study was to combine two strategies in the same lipid nanocapsules (LNCs): i) gene therapy to modulate anti-apoptotic proteins by the use of Bcl-2 siRNA, and ii) ferrocifens as a new type of anticancer agent. The efficient gene silencing with LNCs was verified by the specific extinction of Bcl-2 in melanoma cells. The cellular toxicity of ferrocifens (ferrociphenol (FcDiOH) or Ansa-FcDiOH) was demonstrated, showing higher efficacy than dacarbazine. Interestingly, the association of siBcl-2 LNCs with Ansa-FcDiOH demonstrated a significant effect on melanoma cell viability. Moreover, the co-encapsulation of siRNA and ferrocifens was successfully performed into LNCs for animal experiments. A reduction of tumor volume and mass was proved after siBcl-2 LNC treatment and Ansa-FcDiOH LNC treatment, individually (around 25%). Finally, the association of both components into the same LNCs increased the reduction of tumor volume to about 50% compared to the control group. In conclusion, LNCs appeared to provide a promising tool for the co-encapsulation of a metal-based drug and siRNA.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Recombinant EGFR/MMP-2 bi-targeted fusion protein markedly binding to
           non-small-cell lung carcinoma and exerting potent therapeutic efficacy
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126
      Author(s): Jian Xu, Yue Du, Xiu-Jun Liu, Bing-Yan Zhu, Sheng-Hua Zhang, Liang Li, Yi Li, Xiao-Fei Wang, Chuan-Kun Shan, Rui-Qi Wang, Yong-Su Zhen
      Overexpression of EGFR and MMP-2 plays an essential role in the initiation and progression of non-small-cell lung carcinoma (NSCLC). In this study, a novel format of EGFR/MMP-2 bi-targeted fusion protein Ec-LDP-TIMP2 and its enediyne-integrated analogue Ec-LDP(AE)-TIMP2 have been prepared by genetic engineering and molecular reconstitution. The Ec-LDP(AE)-TIMP2 comprises endogenous inhibitor of matrix metalloproteinase 2 (TIMP2), EGF-derived oligopeptide (Ec), lidamycin apoprotein (LDP), and the extremely potent cytotoxic enediyne (AE). By tissue microarray, Ec-LDP-TIMP2 showed high binding intensity and selectivity to human NSCLC specimens as compared with the matched non-cancerous tissues. By in vivo imaging, Ec-LDP-TIMP2 displayed prominent tumor-specific distribution in human NSCLC H460 xenograft. Particularly, Ec-LDP(AE)-TIMP2 inhibited tumor growth of H460 xenograft in athymic mice more striking. At doses of 0.2 and 0.4mg/kg, Ec-LDP(AE)-TIMP2 suppressed tumor growth by 74% and 89%, respectively. No histopathological changes were found in various organs of treated animals, suggesting that the effective dosage was tolerated. In summary, the ligand-based and enediyne-integrated fusion protein displaying extremely potent cytotoxicity might be highly effective for NSCLC therapy and useful as a carrier for drug delivery.
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      PubDate: 2017-12-12T12:23:35Z
       
  • A combination of nanosystems for the delivery of cancer
           chemoimmunotherapeutic combinations: 1-Methyltryptophan nanocrystals and
           paclitaxel nanoparticles
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126
      Author(s): P. Calleja, J.M. Irache, C. Zandueta, C. Martínez-Oharriz, S. Espuelas
      IDO is an enzyme that tumors use to create a state of immunosupression. 1-d-methyltryptophan (1-MT) is an IDO pathway inhibitor. After being successfully evaluated in preclinical studies, current clinical trials are actually analyzing its efficacy as monotherapy or in combination with multiple chemotherapeutic agents such as paclitaxel. 1-MT very poor solubility in water and many other solvents precludes its ease parenteral administration. It is currently administered by oral route because high daily doses were well-tolerated and effectively inhibited the IDO activity although only 25% of dose was recovered in plasma. The present work describes the preparation and characterization of 1-MT nanocrystals in order to enhance its solubility, dissolution rate, biodisponibility as well as facilitate its administration by parenteral route. A bottom-down approach of nanoprecipitation with an antisolvent was used for the fabrication of the nanocrystals and the choice of stabilizers was critical for reducing the size. Thermal analysis and x-ray diffraction indicated modifications in the drug crystalline state by the process. Through the reduction size and crystalline state modifications the dissolution characteristics of raw material were significantly increased. In a Lewis Lung cancer mice model, the nanocrystals strategy facilitated the sc administration and its antitumoral activity was similar to that of i.v. paclitaxel. The best efficacy was achieved when sc 1-MT nanocrystals were administered in combination with oral paclitaxel loaded in poly(anhydride) nanoparticles. Take together, 1-MT nanocrystals delivery performs a nanotechnological strategy suitable to modify the current route and schedule for its administration.
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      PubDate: 2017-12-12T12:23:35Z
       
  • The reversion of anti-cancer drug antagonism of tamoxifen and docetaxel by
           the hyaluronic acid-decorated polymeric nanoparticles
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126
      Author(s): Zhihong Zhu, Yuenan Li, Xinggang Yang, Weisan Pan, Hao Pan
      Docetaxel (DTX) and tamoxifen (TMX) are first-line drugs used to treat breast cancer. However when used in combination, they produce antagonism because of their differential metabolic pathways. In order to prevent this antagonism, an amphiphilic copolymer, cholesterol modified hyaruronic acid (HA-CHOL), was synthesized for investigating the co-delivery of TMX and DTX. In vitro drug release experiment of the Co-encapsulated (encapsulated DTX+TMX) nanoparticles (Co-NPs) revealed that NPs with unique release mechanism can markedly reduce the release of these drugs in the circulatory system. However, when reaching in cell, TMX can release rapidly to prevent DTX from coming into contact with metabolizing enzymes. In vitro cytotoxicity experiment revealed that the Co-NPs exhibited a significant synergistic effect for inhibiting the proliferation of the cancer cell lines A549, MCF7 and S180. NPs carrying Coumarin-6(Cou6) exhibited increased cellular uptake compared with Cou6 solution at similar drug concentrations. As an in vivo treatment of xenograft tumors involving 180 cells, the Co-NPs displayed a clear tumor-inhibiting effect. This led us to conclude that the reversion of drug antagonism by NPs was attributed to the increased stability of the nanoparticles in the blood circulation, the efficient cellular uptake, the hierarchical drug metabolism in the tumor and the good and orderly delivery of the drugs to the tumor tissue.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Nanoparticles for modulating tumor microenvironment to improve drug
           delivery and tumor therapy
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126
      Author(s): Shu Yang, Huile Gao
      Tumor microenvironment (TME) plays a critical role in tumorigenesis, tumor invasion and metastasis. TME is composed of stroma, endothelial cells, pericytes, fibroblasts, smooth muscle cells, and immune cells, which is characterized by hypoxia, acidosis, and high interstitial fluid pressure. Due to the important role of TME, we firstly reviewed the composition of TME and discussed the impact of TME on tumor progression, drug and nanoparticle delivery. Next, we reviewed current strategies developed to modulate TME, including modulating tumor vasculature permeability, tumor associated macrophage phenotypes, tumor associated fibroblasts, tumor stroma components, tumor hypoxia, and multiple interventions simultaneously. Also, potential problems and future directions of TME modulation strategy have been discussed.

      PubDate: 2017-12-12T12:23:35Z
       
  • Exploring the Potential of Nanotherapeutics in Targeting Tumor
           Microenvironment for Cancer Therapy
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126
      Author(s): Eameema Muntimadugu, Nagavendra Kommineni, Wahid Khan
      Advanced research in the field of cancer biology clearly demonstrated the key role of tumor microenvironment (TME) in cancer development and metastasis particularly in solid tumors. Components of TME, being non-neoplastic in nature provide supportive and permissive conditions for the growth of cancer cells. Hence it is important to modify TME in cancer therapy and this would be achieved by better understanding of TME morphological features and functioning of stromal components. Nanotechnology based drug delivery offers various advantages such as prolonged circulation time, delivery of cargo at desired site, improved bioavailability, reduced toxicity etc. over conventional chemotherapeutics. Abnormal characteristic features of TME play a paradoxical role in nanoparticulate drug delivery. Leaky vasculature, acidic and hypoxic conditions of TME helps in the accumulation of tailored nanoparticles whereas high interstitial pressure and dense stroma restrict the extravasation, homogenous distribution of nanocarriers in TME. This review mainly discusses the potential of nanotherapeutics in targeting TME by briefly discussing stromal components, therapeutic opportunities and barriers offered by TME for nanoparticulate drug delivery. Updated information on TME remodeling strategies for improved drug delivery and specific targeting of individual stromal components are also outlined.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Nanoparticle-based hyperthermia, a local treatment modulating the tumor
           extracellular matrix
    • Abstract: Publication date: December 2017
      Source:Pharmacological Research, Volume 126
      Author(s): Jelena Kolosnjaj-Tabi, Iris Marangon, Alba Nicolas-Boluda, Amanda K.A. Silva, Florence Gazeau
      The structural complexity and physical properties of the tumor microenvironment negatively affect the penetration and efficiency of conventional anticancer drugs. While previously underestimated, the tumor microenvironment now becomes a potential target for cancer treatment. This microenvironment can be modulated either systemically by pharmacological means, or locally, through physical effects mediated by certain nanoparticles. Some of them, such as magnetic, plasmonic or carbon-based nanoparticles, can generate heat on demand in a spatially and temporally controlled manner. In addition, the nanoparticles can be either activated by light or magnetic stimuli. The impact of the resulting local heating can be observed on the ultrastructural level, as it strongly affects the organization of collagen fibers, and on the macroscopic level, since the thermal damages alter the mechanical properties of the tumor. Nanoparticle-based hyperthermia thus improves the effect of conventional anticancer drugs, as it allows their better penetration through the altered extracellular matrix. Here we suggest the use of nanoparticle-generated hyperthermia, obtained after magnetic or light activation, as an adjuvant treatment to prime the tumor microenvironment and improve the efficacy of chemotherapy.
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      PubDate: 2017-12-12T12:23:35Z
       
  • DACT2, an epigenetic stimulator, exerts dual efficacy for colorectal
           cancer prevention and treatment
    • Abstract: Publication date: Available online 1 December 2017
      Source:Pharmacological Research
      Author(s): Linlin Lu, Ying Wang, Rilan Ou, Qian Feng, Liyan Ji, Hongming Zheng, Yue Guo, Xiaoxiao Qi, Ah-Ng Tony Kong, Zhongqiu Liu
      DACT2, a tumor suppressor gene in various tumors, is frequently down-regulated via hypermethylation. We found DACT2 gene expressions were dramatically silenced (P =0.002, n=8) in our clinical colorectal cancer (CRC) tissues, and TCGA data revealed DACT2 hypermethylation correlated to CRC poor prognosis (P =0.0129, HR=0.2153, n=248). Thus, by screening twelve nutritional compounds, we aim to find out an effective DACT2 epigenetic stimulator to determine whether DACT2 epigenetic restoration could reverse CRC tumorigenesis. We found that kaempferol significantly increased DACT2 expressions up to 3.47-fold in three CRC cells (HCT116, HT29, and YB5). Furthermore, kaempferol remarkably decreased DACT2 methylation (range: 19.58%-67.00%, P< 0.01), while increased unmethylated DACT2 by 13.72-fold (P< 0.01) via directly binding to DNA methyltransferases DNMT1. By epigenetic reactivating DACT2 transcription, kaempferol notably inhibited nuclear β-catenin expression to inactivate Wnt/β-catenin pathway, which consequently restricted CRC cells proliferation and migration. Moreover, in AOM/DSS-induced CRC tumorigenesis, kaempferol-demethylated DACT2 effectively decreased tumor load (range: 50.00%-73.52%, P< 0.05). By determining the chemopreventive and chemotherapeutic efficacy of a novel DACT2 demethylating stimulator, we demonstrated that DACT2 epigenetic restoration could successfully slow down and reverse CRC tumorigenesis.
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      PubDate: 2017-12-12T12:23:35Z
       
  • CAR-T cells and combination therapies: What’s next in the
           immunotherapy revolution'
    • Abstract: Publication date: Available online 1 December 2017
      Source:Pharmacological Research
      Author(s): Maria C. Ramello, Eric B. Haura, Daniel Abate-Daga
      Cancer immunotherapies are dramatically reshaping the clinical management of oncologic patients. For many of these therapies, the guidelines for administration, monitoring, and management of associated toxicities are still being established. This is especially relevant for adoptively transferred, genetically-modified T cells, which have unique pharmacokinetic properties, due to their ability to replicate and persist long-term, following a single administration. Furthermore, in the case of CAR-T cells, the use of synthetic immune receptors may impact signaling pathways involved in T cell function and survival in unexpected ways. We, herein, comment on the most salient aspects of CAR-T cell design and clinical experience in the treatment of solid tumors. In addition, we discuss different possible scenarios for combinations of CAR-T cells and other treatment modalities, with a special emphasis on kinase inhibitors, elaborating on the strategies to maximize synergism. Finally, we discuss some of the technologies that are available to explore the molecular events governing the success of these therapies. The young fields of synthetic and systems biology are likely to be major players in the advancement of CAR-T cell therapies, providing the tools and the knowledge to engineer patients’ T lymphocytes into intelligent cancer-fighting micromachines.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Cardiovascular and renal interactions between cyclosporine and NSAIDs:
           Underlying mechanisms and clinical relevance
    • Abstract: Publication date: Available online 26 November 2017
      Source:Pharmacological Research
      Author(s): Ahmed F. El-Yazbi, Ali H. Eid, Mahmoud M. El-Mas
      Cyclosporine, the prototype calcineurin inhibitor, transformed immunosuppressant regimens and practices post-organ transplantation. Therapeutic uses of cyclosporine branched out to include management of different autoimmune disorders. However, multiple additional effects posed significant clinical challenges in face of the prolonged nature of cyclosporine use. Significantly, cyclosporine produced nephrotoxic, cardiotoxic and neurotoxic effects in addition to alteration of hemodynamic function. These adverse effects are shared with other drug groups further complicating the therapeutic situation to include potential exacerbation in case of drug interactions. The potential for detrimental outcomes increases with commonly used drugs such as non-steroidal anti-inflammatory drugs also notorious for their deleterious renal and cardiovascular effects. Herein, we review the available experimental and clinical evidence describing the mechanisms and the outcomes of interactions between the two drug classes. Special attention is given to the divergent toxic effects of co-administration of cyclosporine with selective vs. non-selective cyclooxygenase inhibiting non-steroidal drugs.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Nutraceuticals: An emerging therapeutic approach against the pathogenesis
           of Alzheimer’s disease
    • Abstract: Publication date: Available online 26 November 2017
      Source:Pharmacological Research
      Author(s): Pritam Sadhukhan, Sukanya Saha, Sayanta Dutta, Sushweta Mahalanobish, Parames C. Sil
      Alzheimer’s disease (AD) is regarded as a progressive and devastating neurodegenerative disorder. In aged individuals, it is the most prevalent cause of dementia and is characterized by gradual loss of cognitive functions. In the last decade, numerous research works were undertaken to investigate the pathogenesis of AD. Although the etiology of AD is still not clear, several histopathological studies confirm prominent changes in the AD affected brains. The major changes include the formation of senile plaques and neurofibrillary tangles primarily owing to the deposition of amyloid β plaques (Aβ) and hyper-phosphorylation of tau protein. Disruption of the redox homeostasis in the brain is a major triggering factor for the development of such pathophysiological conditions. Chemical formulations usually act by inhibiting activities of the enzymes responsible for the development of AD. But with time, these pharmacotherapies develop many side effects including toxicity in different organs. Recent researches are henceforth focused on the identification of novel therapeutic molecules from the nature’s basket. This review aims to emphasize the therapeutic effects and regulation of molecular targets of different natural products such as curcumin, resveratrol, genistein and others. These prophylactic multipotent natural compounds have the potency to interfere with the formation as well as deposition of the Aβ peptides. These natural compounds have also been found in modulating different intracellular signalling molecules and enzymes including β-secretase and γ-secretase. This review article is expected to be helpful in understanding the recent progress in natural product research as a therapeutic approach in amelioration and/or delaying the detrimental effects of AD.
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      PubDate: 2017-12-12T12:23:35Z
       
  • TPL2 kinase action and control of inflammation
    • Abstract: Publication date: Available online 26 November 2017
      Source:Pharmacological Research
      Author(s): Daqi Xu, Marissa L. Matsumoto, Brent S. McKenzie, Ali A. Zarrin
      Tumor progression locus 2 (TPL2, also known as COT or MAP3K8) is a mitogen-activated protein kinase kinase (MAP3K) activated downstream of TNFαR, IL1R, TLR, CD40, IL17R, and some GPCRs. TPL2 regulates the MEK1/2 and ERK1/2 pathways to regulate a cascade of inflammatory responses. In parallel to this, TPL2 also activates p38α and p38δ to drive the production of various inflammatory mediators in neutrophils. We discuss the implications of this finding in the context of various inflammatory diseases.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Phytochemicals as inhibitors of NF-κB for treatment of
           Alzheimer’s disease
    • Abstract: Publication date: Available online 24 November 2017
      Source:Pharmacological Research
      Author(s): Ean-Jeong Seo, Nicolas Fischer, Thomas Efferth
      Alzheimer’s disease (AD) is the most prevalent form of dementia. The exact pathophysiology of this disease remains incompletely understood and safe and effective therapies are required. AD is highly correlated with neuroinflammation and oxidative stress in brain causing neuronal loss. Nuclear factor of activated B-cells (NF-κB) is involved in physiological inflammatory processes and thus representing a promising target for inflammation-based AD therapy. Phytochemicals are able to interfere with the NF-κB pathway. They inhibit the phosphorylation or the ubiquitination of signaling molecules, and thus, inhibit the degradation of IκB. The translocation of NF-κB to the nucleus and subsequent transcription of pro-inflammatory cytokines are inhibited by the actions of phytochemicals. Additionally, natural compounds preventing the interaction of NF-κB can block NF-κB’s transcriptional activity by inhibiting its binding to target DNA. Many polyphenols including curcumin, resveratrol, pterostilbene, punicalagin, macranthoin G, salidroside, 4-O-methylhonokiol, lycopene, genistein, obovatol and gallic acid were reported as potent NF-κB inhibitors for AD treatment. Several alkaloids such as galantamine, glaucocalyxin B, tetrandrine, berberine, oridonin, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in vivo. Besides, vitamins, tanshinone IIA, artemisinin, dihydroasparagusic acid, geniposide, xanthoceraside, l-theranine, 1,8-cineole and paeoniflorin were described as promising NF-κB inhibitors. In conclusion, natural products from plants represent interesting candidates for AD treatment. They may qualify as promising compounds for the development of derivatives providing enhanced pharmacological features.

      PubDate: 2017-12-12T12:23:35Z
       
  • Chalcones as putative hepatoprotective agents: Preclinical evidence and
           molecular mechanisms
    • Abstract: Publication date: Available online 23 November 2017
      Source:Pharmacological Research
      Author(s): Elham Karimi-Sales, Gisou Mohaddes, Mohammad Reza Alipour
      Chalcones form an important group of natural compounds and flavonoid precursors which are abundant in fruits, vegetables, and edible plants. These compounds have many beneficial properties including anti-inflammatory, anti-microbial, antioxidant, anti-cancer, anti-amyloid, anti-diabetic, anti-obesity, hypolipidemic, and cytoprotective. Chalcone derivatives have protective effects on the liver in nonalcoholic fatty liver disease, alcoholic fatty liver, drug- and toxicant-induced liver injury, and liver cancer through several mechanisms. Chalcones improve adipocytes function and adiponectin secretion. They inhibit triglyceride synthesis, activating factors of hepatic stellate cells and extracellular matrix deposition and also elevate fatty acid oxidation. These effects of chalcones lead to liver injury improvement. In conclusion, chalcones with antioxidant, anti-fibrotic, and anti-inflammatory properties decrease liver injury markers and histological abnormality in liver injury.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Phytochemical portfolio and anticancer activity of Murraya koenigii and
           its primary active component, mahanine
    • Abstract: Publication date: Available online 23 November 2017
      Source:Pharmacological Research
      Author(s): Suman Kumar Samanta, Raghuram Kandimalla, Bhaskarjyoti Gogoi, Krishna Nayani Dutta, Paramita Choudhury, Prashanta Kumar Deb, Rajlakshmi Devi, Bikas Chandra Pal, Narayan Chandra Talukdar
      Murraya koenigii, a plant belonging to the Rutaceae family is widely distributed in Eastern-Asia and its medicinal properties are well documented in Ayurveda, the traditional Indian system of medicine. Through systematic research and pharmacological evaluation of different parts of the plant extracts has been shown to possess antiviral, anti-inflammatory, antioxidant, antidiabetic, antidiarrhoeal, antileishmanial, and antitumor activity. In the plant extracts, carbazole alkaloid, mahanine has been identified as the principle bioactive component among several other chemical constituents. Scientific evidence derived not only from in vitro cellular experiments but also from in vivo studies in various cancer models is accumulating for the pronounced anticancer effects of mahanine. The primary objective of this review is to summarize research data on cytotoxic chemical constituents present in different parts of Murraya koenigii and the anticancer activity of mahanine along with the recent understanding on the mechanism of its action in diverse cancer models. The information on its bioavailability and the toxicity generated from the recent studies have also been incorporated in the review.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Molecular adjuvants that modulate regulatory T cell function in
           vaccination: A critical appraisal
    • Abstract: Publication date: Available online 22 November 2017
      Source:Pharmacological Research
      Author(s): Alexander Batista-Duharte, Damiana Téllez-Martínez, Deivys Leandro Portuondo Fuentes, Iracilda Zeppone Carlos
      Adjuvants are substances used to enhance the efficacy of vaccines. They influence the magnitude and alter the quality of the adaptive immune response to vaccine antigens by amplifying or modulating different signals involved in the innate immune response. The majority of known adjuvants have been empirically identified. The limited immunogenicity of new vaccine antigens and the need for safer vaccines have increased the importance of identifying single, well-defined adjuvants with known cellular and molecular mechanisms for rational vaccine design. Depletion or functional inhibition of CD4+CD25+FoxP3+ regulatory T cells (Tregs) by molecular adjuvants has become an emergent approach in this field. Different successful results have been obtained for specific vaccines, but there are still unresolved issues such as the risk of autoimmune disease induction, the involvement of cells other than Tregs and optimization for different conditions. This work provides a comprehensive analysis of current approaches to inhibit Tregs with molecular adjuvants for vaccine improvement, highlights the progress being made, and describes ongoing challenges.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Molecular modeling study on resistance of WT/D473H SMO to antagonists
           LDE-225 and LEQ-506
    • Abstract: Publication date: Available online 21 November 2017
      Source:Pharmacological Research
      Author(s): Jing Tu, Jiao Jiao Li, Li Ting Song, Hong Lin Zhai, Juan Wang, Xiao Yun Zhang
      The smoothened (SMO) receptor, an essential signal transducer in the Hedgehog pathway, was targeted with antagonists to suppress the tumor. It is interesting that SMO D473H mutation confers resistance on inhibitor LDE-225 rather than LEQ-506. In this paper, the binding modes of them against the wild type and mutant SMO receptors were identified to gain insights into the resistant and non-resistant factors, based on a comprehensive protocol involving molecular docking, molecular dynamic simulations, free energy calculation and decomposition. A comparison of resistant LDE-225 and non-resistant LEQ-506 indicates that the volume of the binding cavity decreases seriously in the mutant complex with resistant LDE-225. In addition, the D473H mutation disrupts the hydrogen bond network with residues R400 and Q477, which results in the TM6 conformation inward. Owing to the absence of the hydrogen bond, residues R400 and Q477 make weak contributions to LDE-225. However, the D473H mutation along with TM6 conformational change has no effect on non-resistant LEQ-506. Finally, the resistance ascribes to adverse interaction between the greater polarity of mutant residue H473 and the nonpolar phenmethyl of LDE-225. The elaborate insights into structural and energetic mechanism of drug resistance provide an effective strategy to design rationally non-resistant antagonists.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Modulation of diverse oncogenic transcription factors by thymoquinone, an
           essential oil compound isolated from the seeds of Nigella sativa Linn
    • Abstract: Publication date: Available online 21 November 2017
      Source:Pharmacological Research
      Author(s): Muthu K. Shanmugam, Frank Arfuso, Alan Prem Kumar, Lingzhi Wang, Boon Cher Goh, Kwang Seok Ahn, Anupam Bishayee, Gautam Sethi
      Thymoquinone (TQ), isolated almost fifty years ago, is the main bioactive constituent of black seed essential oil extracted from the seed of Nigella sativa. TQ has been shown to have promising effects against a variety of inflammatory diseases and cancer. Cancer development is a multistep process where normal cells acquire qualities that enable the cells to proliferate continuously and migrate to distant sites in the human body. Drugs that interfere with this process are considered potential anti-cancer therapeutics, which may ultimately result in their clinical usage. TQ is once such compound which has been reported to modulate several major signaling pathways and key oncogenic molecules that play a prominent role in cancer initiation, progression, invasion, metastasis, and angiogenesis. Various studies have reported that TQ can enhance the anti-cancer potential when co-administered with several chemotherapeutic agents while reducing their toxic side effects. In addition, TQ has been shown to inhibit the growth of breast, prostate, pancreatic, colon, lung, and hematological malignancies in different mouse models of cancer. This review focuses on TQ’s chemical and pharmacological properties, its diverse molecular targets and also provides clear evidence on its promising potential under preclinical and clinical settings.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Mild cognitive impairment due to Alzheimer disease: Contemporary
           approaches to diagnostics and pharmacological intervention
    • Abstract: Publication date: Available online 21 November 2017
      Source:Pharmacological Research
      Author(s): Sergey O. Bachurin, Svetlana I. Gavrilova, Anna Samsonova, George E. Barreto, Gjumrakch Aliev
      Alzheimer disease (AD) and related forms of dementia are among the main medical and social problems in the economically developed countries. It is connected with significant increase in human life span in these regions and with the absence of efficient medicines for treatment and prevention of such diseases. Lack of positive results in the developing of novel drugs for AD treatment stimulates special attention on problem of early diagnosis and drug discovery for pharmacotherapy on the very early stages of dementia, in particular, on mild cognitive impairments (MCI) due to AD. Here we review the state of art in the field of MCI diagnostics and analyze the data on the pharmacological agents developed for MCI treatment, which currently are in preclinical and clinical trials. The conclusion was made that only the agents that act on the very early pathogenetic stages of the disease, when the damage of cholinergic neurons is not observed, can be efficient for pharmacotherapeutic intervention of MCI. Therefore, the focused search and design of “disease-modifying” medicines should be accepted as the most (and may be the only) efficient strategy for treatment and prevention of MCI.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Metformin promotes the proliferation and differentiation of murine
           preosteoblast by regulating the expression of sirt6 and oct4
    • Abstract: Publication date: Available online 21 November 2017
      Source:Pharmacological Research
      Author(s): Wei Mu, Zhuoran Wang, Chuanyu Ma, Yunyun Jiang, Nannan Zhang, Kaiqiang Hu, Liyuan Li, Zhao Wang
      Osteopenia, osteoporosis and bone salt metabolism disorder are common diseases in the aged and diabetics. From case reports of patients with T2DM, we have observed that metformin can decrease risk of bone fracture and promote bone formation. However, the underlying mechanism of metformin’s effect on bone metabolism remains unknown. In our research, we show that metformin can promote proliferation of murine preosteoblast by regulating AMPK-mTORC2 and AKT-mTORC1 signaling axis. Furthermore, we have observed that metformin can promote SIRT6 expression before and during differentiation of murine preosteoblast. The interaction between SIRT6 and NF-κB is highly important in osteoblast differentiation just as the relationship between OPG and RANKL in the process of bone formation. During differentiation, we show that SIRT6 inhibits phosphorylation of NF-κB and that OPG increases while RANKL decrease in HG groups. In addition, ablation of sirt6 in mice causes phosphorylation of NF-κB at high-levels and RANKL increases slightly in femur bone cells. However, other bone formation marker proteins such as RUNX2, OSTERIX and OPG appear at low-levels in sirt6 KO mice. It has been confirmed that downregulation of OCT4 is critical incident in the differentiation of embryonic stem cells. Fortunately, we observe that SIRT6 can suppress OCT4 expression in murine preosteoblast and the expression of OCT4 is at high-level in sirt6 KO mice. Taken together, this study’s results illuminate metformin’s effect on bone metabolism under HG condition and help to elucidate why metformin can promote bone fracture healing of patients with T2DM.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Enantiomer-specific positive allosteric modulation of CB1 signaling in
           autaptic hippocampal neurons
    • Abstract: Publication date: Available online 20 November 2017
      Source:Pharmacological Research
      Author(s): Jose Mitjavila, Danielle Yin, Pushkar M. Kulkarni, Chiara Zanato, Ganesh A. Thakur, Ruth Ross, Iain Greig, Ken Mackie, Alex Straiker
      The cannabinoid signaling system is found throughout the CNS and its involvement in several pathological processes makes it an attractive therapeutic target. Because orthosteric CB1 cannabinoid receptor ligands have undesirable adverse effects there has been great interest in the development of allosteric modulators – both negative (NAMs) and positive (PAMs) – of these receptors. NAMs of CB1 appeared first on the scene, followed more recently by PAMs. Because allosteric modulation can vary depending on the orthosteric ligand it is important to study their function in a system that employs endogenous cannabinoids. We have recently surveyed first generation NAMs using cultured autaptic hippocampal neurons. These neurons express depolarization induced suppression of excitation (DSE), a form of synaptic plasticity that is mediated by CB1 and 2-arachidonoyl glycerol (2-AG); they are therefore an excellent neuronal model of endogenous cannabinoid signaling in which to test CB1 modulators. In this study we find that while two related compounds, GAT211 and ZCZ011, each show PAM-like responses in autaptic hippocampal neurons, they also exhibit complex pharmacology. Notably we were able to separate the PAM- and agonist-like responses of GAT211 by examining the enantiomers of this racemic compound: GAT228 and GAT229. We find that GAT229 exhibits PAM-like behavior while GAT228 appears to directly activate the CB1 receptor. Both GAT229 and ZCZ011 represent the first PAMs that we have found to be effective in using this 2-AG utilizing neuronal model system. Because these compounds may exhibit both probe selectivity and biased signaling it will be important to test them with anandamide as well as other signaling pathways.
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      PubDate: 2017-12-12T12:23:35Z
       
  • Down regulation of pro-inflammatory pathways by tanshinone IIA and
           cryptotanshinone in a non-genetic mouse model of Alzheimer’s disease
    • Abstract: Publication date: Available online 20 November 2017
      Source:Pharmacological Research
      Author(s): Francesco Maione, Marialuisa Piccolo, Simona De Vita, Maria Giovanna Chini, Claudia Cristiano, Carmen De Caro, Pellegrino Lippiello, Maria Concetta Miniaci, Rita Santamaria, Carlo Irace, Vincenzo De Feo, Antonio Calignano, Nicola Mascolo, Giuseppe Bifulco
      Alzheimer's disease (AD) is a common form of dementia mainly characterized by the deposition of neurofibrillary tangles and β-amyloid (Aβ) peptides in the brain. Additionally, increasing evidence demonstrates that a neuro-inflammatory state plays a key role in the development of this disease. Beside synthetic drugs, the use of natural compounds represents an alternative for the development of new potential drugs for the treatment of AD. Among these, the root of Salvia miltiorhiza Bunge (also known as Danshen) used for the treatment of cardiovascular, cerebrovascular disease and CNS functional decline in Chinese traditional medicine is one of the most representative examples. We therefore evaluated the effects of tanshinone IIA (TIIA) and cryptotanshinone (CRY) (the two major lipophilic compounds of Danshen) in a non-genetic mouse model of β-amyloid (Aβ)-induced AD, which is mainly characterized by reactive gliosis and neuro-inflammation in the brain. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aβ1–42 peptide (3μg/3μl) and after with TIIA and CRY (1, 3, or 10mg/kg) intraperitoneally (i.p.) 3 times weekly for 21days following the induction of experimental AD. Spatial working memory was assessed as a measure of short-term memory in mice, whereas the level of GFAP, S100β, COX-2, iNOS and NF-kBp65 monitored by western blot and ELISA assay, were selected as markers of reactive gliosis and neuro-inflammation. Finally, by docking studies, the modulation of key pro-inflammatory enzymes and pathways involved in the AD-related neuro-inflammation were also investigated. Results indicate that TIIA and CRY alleviate memory decline in Aβ1-42-injected mice, in a dose dependent manner. Moreover, the analysis of gliosis-related and neuro-inflammatory markers in the hippocampal tissues reveal a remarkable reduction in the expression of GFAP, S100β, COX-2, iNOS and NF-kBp65 after CRY (10mg/kg) treatment. These effects were less evident, but still significant, after TIIA (10mg/kg). Finally, in silico analysis also revealed that both compounds were able to interact with the binding sites of NF-kBp65 endorsing the data from biochemical analysis. We conclude that TIIA and CRY display anti-inflammatory and neuroprotective effect in a non-genetic mouse model of AD, thus playing a role in slowing down the course and onset of AD.
      Graphical abstract image

      PubDate: 2017-12-12T12:23:35Z
       
  • Targeting bromodomain and extraterminal proteins in breast cancer
    • Abstract: Publication date: Available online 16 November 2017
      Source:Pharmacological Research
      Author(s): Jennifer M. Sahni, Ruth A. Keri
      Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expression profiles. These transcriptomes are controlled by various epigenetic marks that dictate which genes are expressed and suppressed. During carcinogenesis, extensive restructuring of the epigenome occurs, including aberrant acetylation, alteration of methylation patterns, and accumulation of epigenetic readers at oncogenes. As epigenetic alterations are reversible, epigenome-modulating drugs could provide a mechanism to silence numerous oncogenes simultaneously. Here, we review the impact of inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers in breast cancer. These agents, including the prototypical BET inhibitor JQ1, have been shown to suppress a variety of oncogenic pathways while inducing minimal, if any, toxicity in models of several subtypes of breast cancer. BET inhibitors also synergize with multiple approved anti-cancer drugs, providing a greater response in breast cancer cell lines and mouse models than either single agent. The combined findings of the studies discussed here provide an excellent rationale for the continued investigation of the utility of BET inhibitors in breast cancer.
      Graphical abstract image

      PubDate: 2017-12-12T12:23:35Z
       
  • Role of toll-like receptors in inflammatory bowel disease
    • Abstract: Publication date: Available online 16 November 2017
      Source:Pharmacological Research
      Author(s): Nastaran Kordjazy, Arvin Haj-Mirzaian, Arya Haj-Mirzaian, Mohammad Mojtaba Rohani, Erwin W. Gelfand, Nima Rezaei, Amir Hossein Abdolghaffari
      Inflammatory bowel disease (IBD) is the chronic inflammation of the gastrointestinal tract. Recently, studies of the interplay between the adaptive and innate immune responses have provided a better understanding of the immunopathogenesis of inflammatory disorders such as IBD, as well as identification of novel targets for more potent interventions. Toll-like receptors (TLRs) are a class of proteins that play a significant role in the innate immune system and are involved in inflammatory processes. Activation of TLR signal transduction pathways lead to the induction of numerous genes that function in host defense, including those for inflammatory cytokines, chemokines, and antigen presenting molecules. It was proposed that TLR mutations and dysregulation are major contributing factors to the predisposition and susceptibility to IBD. Thus, modulating TLRs represent an innovative immunotherapeutic approach in IBD therapy. This article outlines the role of TLRs in IBD, focusing on both animal and human studies; the role of TLR-targeted agonists or antagonists as potential therapeutic agents in the different stages of the disease is discussed.
      Graphical abstract image

      PubDate: 2017-12-12T12:23:35Z
       
  • Role of p-MKK7 in myricetin-induced protection against intestinal
           ischemia/reperfusion injury
    • Abstract: Publication date: Available online 15 November 2017
      Source:Pharmacological Research
      Author(s): Yuchao Sun, Mengqiao Lian, Yuan Lin, Bin Xu, Yanli Li, Jin Wen, Dapeng Chen, Ming Xu, Marwan Almoiliqy, Li Wang
      Intestinal ischemia reperfusion (I/R) may cause inflammation-, oxidative stress-, and apoptosis-related tissue injuries and facilitate bacterial infection, leading to multiple organ failure. Myricetin, a flavonoid, is found to have diverse biological effects including anti-inflammatory, anti-oxidative, and anti-bacterial effects. Based on our pre-experiment, we proposed that myricetin pretreatment (25, 50mg/kg) could ameliorate intestinal I/R injury and myricetin-induced modulation on MKK7/JNK signal pathway might play a key role in the amelioration. The present study was designed to verify the proposal by using both rat intestinal I/R model in vivo and hypoxia/reoxygenation (H/R)-injured intestinal epithelial cell line (IEC-6 cells) model in vitro. The results confirmed our proposal. Myricetin selectively ameliorated I/R- and H/R-induced injuries in vivo and in vitro respectively without significantly affecting the corresponding normal controls. Myricetin significantly alleviated I/R-induced rat intestinal injury by reducing the generation of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 and by reducing MPO activity. Myricetin significantly reduced oxidative stress through decreasing MDA level and increasing the levels of SOD and GSH in the intestinal tissues compared with I/R control rats. Myricetin significantly decreased apoptosis by selectively down-regulating the expression of p-MKK7 and p-JNK without affecting MKK7 and JNK, inhibiting Bax, caspase-3 protein expression, and up-regulating Bcl-2 protein expression in I/R-injured jejunum of rats. In vitro study indicated that MKK7 siRNA transfection significantly decreased both MKK7 and p-MKK7 and other apoptosis-related proteins, partially simulating myricetin-induced anti-apoptotic effects. MKK7 siRNA transfection+myricetin could not further decrease MKK7, p-MKK7, and other apoptosis-related proteins, suggesting that inhibition of MKK7/JNK pathway plays a key role in myricetin-induced protection against intestinal I/R. MKK7 overexpression by cDNA transfection abrogated myricetin-reduced apoptosis-related protein expression, confirming that the MKK7/JNK signal pathway is the key target for myricetin-induced amelioration. The present study indicated that pretreatment of myricetin induced selective protection against intestinal I/R injury without significantly affecting corresponding normal controls and p-MKK7 was the key target, suggesting that myricetin is worth further translational studies.
      Graphical abstract image

      PubDate: 2017-12-12T12:23:35Z
       
  • Topical administration of reversible SAHH inhibitor ameliorates
           imiquimod-induced psoriasis-like skin lesions in mice via suppression of
           TNF-α/IFN-γ-induced inflammatory response in keratinocytes and T
           cell-derived IL-17
    • Abstract: Publication date: Available online 14 November 2017
      Source:Pharmacological Research
      Author(s): Ze-Min Lin, Meng Ma, Heng Li, Qing Qi, Yu-Ting Liu, Yu-Xi Yan, Yun-Fu Shen, Xiao-Qian Yang, Feng-Hua Zhu, Shi-Jun He, Wei Tang, Jian-Ping Zuo
      DZ2002, a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. The present study was designed to characterize the potential therapeutic effects of DZ2002 on murine model of psoriasis and reveal the correlated mechanisms. In this report, we demonstrated that in vitro, DZ2002 significantly decreased the expression of pro-inflammatory cytokines and adhesion molecule including IL-1α, IL-1β, IL-6, IL-8, TNF-α and ICAM-1 by inhibiting the phosphorylation of p38 MAPK, ERK and JNK in TNF-α/IFN-γ-stimulated HaCaT human keratinocytes. Topical administration of DZ2002 alleviated the imiquimod (IMQ)-induced psoriasis-like skin lesions and inflammation in mice, the therapeutic effect was comparable with the Calcipotriol. Moreover, the inflammatory skin disorder was restored by DZ2002 treatment characterized by reducing both of the CD3+ T cell accumulation and the psoriasis-specific cytokines expression. Further, we found that DZ2002 improved IMQ-induced splenomegaly and decreased the frequency of splenic IL-17-producing T cells. Our finding offered the convincing evidence that SAHH inhibitor DZ2002 might attenuate psoriasis by simultaneously interfering the abnormal activation and differentiation of keratinocytes and accumulation of IL-17-producing T cells in skin lesions.
      Graphical abstract image

      PubDate: 2017-12-12T12:23:35Z
       
  • P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein
           (BCRP/ABCG2) affect brain accumulation and intestinal disposition of
           encorafenib in mice
    • Abstract: Publication date: Available online 14 November 2017
      Source:Pharmacological Research
      Author(s): Jing Wang, Changpei Gan, Rolf W. Sparidans, Els Wagenaar, Stéphanie van Hoppe, Jos H. Beijnen, Alfred H. Schinkel
      Encorafenib (LGX818) is a promising BRAFV600E inhibitor that has efficacy against metastatic melanoma. To better understand its pharmacokinetics, we studied its interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A. In polarized MDCK-II cells, encorafenib was efficiently transported by canine and human ABCB1 and ABCG2 and by mouse Abcg2. Upon oral administration to wild-type, Abcb1a/1b−/− , Abcg2−/− , and Abcb1a/1b;Abcg2−/− mice, encorafenib was absorbed very quickly and to very high plasma levels, but without clear changes in oral availability between the strains. Upon oral or intravenous administration, encorafenib brain accumulation was markedly increased in Abcb1a/1b;Abcg2−/− mice and to a lesser extent in Abcb1a/1b−/− mice. However, absolute brain concentrations and brain-to-plasma ratios remained very low in all strains, indicating intrinsically poor brain penetration of encorafenib. Upon intravenous administration, Abcb1a/1b;Abcg2−/− mice showed somewhat reduced plasma elimination of encorafenib compared to wild-type mice, and lower accumulation of the drug in the intestinal tract, suggesting a limited role for these transporters in intestinal elimination of the drug. In Cyp3a−/− mice plasma levels of encorafenib were not markedly increased, suggesting a limited impact of Cyp3a on encorafenib oral availability. The low brain penetration of encorafenib might limit its efficacy against malignancies positioned behind a functional blood-brain barrier, but its oral bioavailability and distribution to other tested organs (liver, kidney, spleen, testis) was high.
      Graphical abstract image

      PubDate: 2017-12-12T12:23:35Z
       
  • Resveratrol dimer trans-ε-viniferin prevents rotaviral diarrhea in mice
           by inhibition of the intestinal calcium-activated chloride channel
    • Abstract: Publication date: Available online 14 November 2017
      Source:Pharmacological Research
      Author(s): Bo Yu, Yu Jiang, Bo Zhang, Hong Yang, Tonghui Ma
      We previously identified, by a natural-product screen, resveratrol oligomers as inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Here, we report the resveratrol dimer trans-ε-viniferin (TV) and tetramer r-2-viniferin (RV) as inhibitors of the intestinal calcium-activated chloride channel (CaCC) and demonstrate their antisecretory efficacy in a neonatal mouse model of rotaviral diarrhea. Short-circuit measurements show inhibition of CaCC current in the human colonic cell line HT-29 by TV and RV with IC50 ∼1 and 20μM, respectively. TV primarily inhibited the physiologically relevant, long-term CaCC current following agonist stimulation, without effect on cytoplasmic Ca2+ signaling. TV and RV inhibited short-circuit current in mouse colon as well. In a neonatal mouse model of rotaviral secretory diarrhea produced by oral inoculation with rotavirus, 2μg TV or 11μg RV inhibited secretory diarrhea by >50%, without effect on the rotaviral infection. Our results support the antisecretory efficacy of non-toxic, natural-product resveratrol oligomers for diarrheas produced by CaCC activation. Because these compounds also inhibit the CFTR chloride channel, they may be useful for antisecretory therapy of a wide range of diarrheas.
      Graphical abstract image

      PubDate: 2017-12-12T12:23:35Z
       
  • Optimized lentiviral transduction of human amniotic mesenchymal stromal
           cells
    • Abstract: Publication date: Available online 14 November 2017
      Source:Pharmacological Research
      Author(s): Federica Pisano, Manuela Mura, Maria Chiara Ciuffreda, Federica Calabrò, Nicola Lanzo, Massimiliano Gnecchi
      Mesenchymal stromal cells are excellent candidates for regenerative medicine since they are multipotent, easy to isolate, can be expanded to obtain clinically relevant numbers and are immunoprivileged. Stable genetic modification with viral vectors can improve mesenchymal stromal cell function and enhance their therapeutic potential. However, standard viral vectors achieve sub-optimal transduction efficiency with a single infection. On the other hand, multiple transduction cycles or antibiotic-based selection methods may alter the stem cell phenotype. We hypothesized that the use of lentiviral vectors containing specific regulatory sequences may result in improved transduction efficiency. Thus, we compared two types of third generation lentiviral vectors, one of which, the pLenti7.3 vector, contains the optimized sequences for Polypurine Tract and Woodchuck Post-transcriptional Regulatory Element. We demonstrated that with the pLenti7.3 it is possible to efficiently transduce human mesenchymal stromal cells with a single transduction cycle. Additionally, we successfully showed that by using the pLenti7.3 vector it is possible to efficiently over-express different growth factors, particularly relevant for cardiac protection and differentiation, in human mesenchymal stromal cells.
      Graphical abstract image

      PubDate: 2017-12-12T12:23:35Z
       
  • The Blood Brain Barrier and BRAF inhibitors: Implications for patients
           with melanoma brain metastases
    • Abstract: Publication date: Available online 13 November 2017
      Source:Pharmacological Research
      Author(s): Keiran S.M. Smalley, Peter A. Forsyth


      PubDate: 2017-12-12T12:23:35Z
       
  • Anti-cancer effects of naturally derived compounds targeting histone
           deacetylase 6-related pathways
    • Authors: Manon Lernoux; Michael Schnekenburger; Mario Dicato; Marc Diederich
      Abstract: Publication date: Available online 11 November 2017
      Source:Pharmacological Research
      Author(s): Manon Lernoux, Michael Schnekenburger, Mario Dicato, Marc Diederich
      Alterations of the epigenetic machinery, affecting multiple biological functions, represent a major hallmark enabling the development of tumors. Among epigenetic regulatory proteins, histone deacetylase (HDAC)6 has emerged as an interesting potential therapeutic target towards a variety of diseases including cancer. Accordingly, this isoenzyme regulates many vital cellular regulatory processes and pathways essential to physiological homeostasis, as well as tumor multistep transformation involving initiation, promotion, progression and metastasis. In this review, we will consequently discuss the critical implications of HDAC6 in distinct mechanisms relevant to physiological and cancerous conditions, as well as the anticancer properties of synthetic, natural and natural-derived compounds through the modulation of HDAC6-related pathways.
      Graphical abstract image

      PubDate: 2017-11-12T01:54:39Z
      DOI: 10.1016/j.phrs.2017.11.004
       
  • Strengths, weaknesses and future challenges of biosimilars’ development.
           An opinion on how to improve the knowledge and use of biosimilars in
           clinical practice
    • Authors: Cristina Scavone; Concetta Rafaniello; Liberato Berrino; Francesco Rossi; Annalisa Capuano
      Abstract: Publication date: Available online 4 November 2017
      Source:Pharmacological Research
      Author(s): Cristina Scavone, Concetta Rafaniello, Liberato Berrino, Francesco Rossi, Annalisa Capuano
      Biosimilars started receiving the marketing authorization by European Medicine Agency since 2006. The development of biosimilars follows a well-defined step-wise approach, the so-called comparability exercise, which aims to compare non-clinical (mainly quality features and biological activity) and clinical (efficacy and safety profiles) features of new biosimilars with their respective reference products. Despite the undeniable advantages of such procedure, some concerns (such as the absence of switching studies or the evaluation of efficacy and safety in all therapeutic indications) still exist about its. In particular, the European regulatory framework on biosimilars approval does not include the conduction of switching studies demonstrating the interchangeability to be carried out before marketing authorization. This is one of the main aspects that negatively affects healthcare professionals’ clinical decisions on switch. In order to achieve a better knowledge on safety and efficacy of biosimilar drugs, real world data should be collected and post-marketing efficacy and safety clinical studies (including those evaluating specific endpoints, therapeutic regimens and patients population), should be planned. also the conduction of well-designed switching studies is highly advisable, especially in the case of biosimilar drugs used in oncology settings. Lastly, considering the critical role of antidrug antibodies on efficacy/safety profile of biologic drugs, studies based on therapeutic drug monitoring would be useful in order to achieve treatment optimization. Implementing the above strategies could be helpful to fill the gap in knowledge observed in the present European biosimilar regulatory framework.
      Graphical abstract image

      PubDate: 2017-11-12T01:54:39Z
      DOI: 10.1016/j.phrs.2017.11.002
       
 
 
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