Src suppress GJIC, through the Ras/Raf/Erk and other effector pathways. High Src activity was found to correlate with high levels of the Src effector, Signal Transducer and Activator of Transcription-3 (Stat3) in its tyrosine-705 phosphorylated, i.e., transcriptionally activated form, in the majority of Non-Small Cell Lung Cancer lines examined. However, Stat3 inhibition did not restore GJIC in lines with high Src activity. In the contrary, Stat3 inhibition in normal cells or in lines with low Src activity and high GJIC eliminated gap junctional communication. Therefore, despite the fact that Stat3 is growth promoting and in an activated form acts like an oncogene, it is actually required for junctional permeability. Gap junctions are channels linking the interiors of neighboring cells. A reduction in gap junctional intercellular communication (GJIC) correlates with high cell proliferation, while oncogene products such as  Gap junctions are channels linking the interiors of neighboring cells that allow the passage of ions and small metabolites. They consist of integral membrane proteins, the connexin gene family, comprising 21 known members in humans [Connexins are composed of four transmembrane domains, two extracellular loops with six conserved cysteine residues, a cytoplasmic loop and cytoplasmic amino- and carboxy-termini. The carboxy-terminus varies in length and provides sites for protein interactions . ConnexiSrc [Src activation [Src decrease GJIC [A number of oncogene products such as v-Src , the midtivation ,10), thetivation , activattivation , v-mos [tivation  and othease GJIC ,15,16. src is the first oncogene to be discovered, as the tumor gene of the Rous sarcoma virus. src encodes a protein with tyrosine kinase activity (Src), which correlates with tyr-418 phosphorylation (Src418). Src is often activated in cancer. As such, Src is one of the best studied targets for cancer therapy. Results from a number of labs indicated that the Src kinase can affect Cx43 phosphorylation either directly on tyrosine, or through its effector pathways on serine or threonine. At first the Src-homology-3 (SH3) domain of Src binds a proline-rich sequence of Cx43, Pro-274 to Pro-280. The proximity between the two proteins facilitates phosphorylation of Cx43 at tyr-265 by Src. This creates a binding site for the Src, Src-homology-2 (SH2) domain that facilitates phosphorylation of tyr-247 of Cx43, triggering channel closure [Src, as opposed to its effectors, upon GJIC in cancer is unclear. The Src effectors, PLCγ  and Erk1/2 also suppress GJIC in their own right, through phosphorylation at serines 368 and 372, or 255, 279 and 282, respectively. In fact, the Ras/Raf/Erk pathway was shown to transduce Src signals leading to GJIC suppression [ closure . Still, pression .Src effector is the Signal Transducer and Activator of Transcription-3 (Stat3) [Src family, a number of growth factor receptors such as the EGF family including Her2/ErbB2 and receptors for cytokines such as the IL6 family phosphorylate Stat3 at tyr-705 (Stat3-705). This triggers Stat3 dimerisation through a reciprocal interaction between the SH2 domain and ptyr-705 of Stat3, migration to the nucleus and activation of transcription of specific genes involved in cell division and survival, such as myc, Bcl-xL, Mcl-1, survivin, HGF [A prominent  (Stat3) , a key c (Stat3) . Besidesvin, HGF  and othevin, HGF ). Recentvin, HGF ,23,24. Tvin, HGF , reviewevin, HGF ,26). Src/Stat3 axis upon GJIC in cells transformed in culture and in lines established from Non-Small Cell Lung Cancer (NSCLC) tumors. Although in the majority of lines high Src418 correlated with high Stat3-705 and the absence of GJIC, Stat3 inhibition did not restore communication in any of the lines examined. This is in sharp contrast to inhibition of the Ras pathway, which did increase GJIC [Despite the extensive literature on the effect of oncogenes upon GJIC, the effect of Stat3 upon GJIC in cancer cells is unclear. Here, we summarise our recent findings on the effect of the ase GJIC . In the ase GJIC , Stat3 iA reliable method to measure gap junctional permeability is a prerequisite for the investigation of the effect of Stat3 upon GJIC. GJIC examination is usually conducted through the introduction of a fluorescent tracking dye such as Lucifer yellow (LY) by microinjection, scrape-loading  or preloin situ was employed to examine the role of Stat3 upon GJIC, both in immortalised rat liver epithelial T51B [Src [Electroporation ial T51B  or mouseial T51B  cells bo51B [Src ,38. The formation of gap junctions depends upon cell to cell contact, and the engagement of cadherins into adherens junctions . Therefoin vitro transformed, T51B cells where Src was activated through mT expression (T51B-Src cells) [Src, a tyrosine kinase with the ability for GJIC suppression, and an oncogene in its own right [Src signals leading to GJIC suppression. However, the results demonstrated that Stat3 downregulation does not restore GJIC, indicating that the high Stat3 activity in T51B-Src cells cannot be responsible for their lack of junctional communication. This is in sharp contrast to Ras, whose inhibition restored GJIC in Src-transformed rodent fibroblasts, and consistent with findings by Ito et al. [We at first examined the effect of Stat3 upon GJIC in c cells) . Stat3 wc cells) ,41 or 23c cells) ,42, or tc cells) . Given twn right , it was o et al. . We next investigated whether Stat3 might, in fact, play a positive role upon GJIC, by examining the effect of Stat3 inhibition in the parental T51B cells. Interestingly, Stat3 downregulation essentially eliminated GJIC in T51B cells . ConversAs noted above, the half-life of Cx43 is 1–3 h, while cell density (which increases Stat3-705) causes a dramatic increase in Cx43 levels in non-transformed cells. Interestingly, Stat3 downregulation through CPA7 treatment or shRNA expression caused a dramatic reduction in Cx43 levels in rat liver epithelial T51B, mouse lung E10 cells or rat F111 fibroblasts at all densities examined, concomitant with GJIC reduction. These findings indicate that Stat3 activity is required for the maintenance of Cx43 protein levels .i.e., activated Src (Src418) in a number of NSCLC biopsies revealed the presence of higher Src activity than the surrounding, non-tumor lung tissue [Src’s contribution to Stat3 activity in NSCLC lines and primary cells which may express other oncogenes in addition to Src is a matter of controversy. Examination of Stat3 levels in certain NSCLC lines demonstrated that Src is a major Stat3 activator [Src inhibition in different NSCLC lines was found to actually increase Stat3-ptyr705. Since cell density causes a dramatic increase in Stat3-705 [Examination of the levels of tyr-418 phosphorylated, g tissue ,45. Howectivator , while ictivator  Src inhitat3-705 , differeSrc is a potent Stat3 activator, Src418 levels did not increase with density in T51B or E10 cells, or in the NSCLC lines SK-LuCi6 . Moreover, Src inhibition with the inhibitors dasatinib , which were found to correlate with their levels of Stat3-705  had low Stat3-705. In sharp contrast however, line LC-T displayed high Stat3-705 despite the fact that Src418 was undetectable. Similarly, SK-MES cells had intermediate Src418 levels (25% of SK-LuCi6-Src), although Stat3-705 was at 90%, and FR-E cells with Src418 of 25% displayed Stat3-705 of 70%, indicating that other, Src-independent factor(s) must also be responsible for the high Stat3-ptyr705 in these lines  dasatinib caused a dramatic reduction in Stat3-705 (vs. 4 and 2 vs. 5), pointing to Src as a significant Stat3 activator. However, in confluent cultures the reduction was only ~50% (lane 3 vs. 6), which further confirms that the density-induced, Stat3 activation is independent of Src. Similar results were obtained with 11 lines with high Src418  had extensive GJIC , or density plus the Stat3 activation triggered by Src and/or other kinases  . HowE, WT-E) . Interesradation ; apparenradation .Src kinase such as Ras/Raf/Erk, PI3k/Akt, the Crk-associated substrate (Cas) and others [Src-mediated GJIC suppression indicated that inhibition of Ras in Src-transformed, rat fibroblasts reinstated gap junctional communication [Src. It was also shown later that Cas is required for the Src-induced, reduction in gap junctional communication [Src-induced, GJIC suppression in these cells is unlikely, despite the fact that constitutively active Stat3 can act as an oncogene and transform established lines [Several signal transducers besides Stat3 are known to be downstream effectors of the d others . Constitd others ,51. Examnication . Conversnication . Taken tnication . In shared lines .The fact that cell density upregulates Stat3 concomitant with an increase in both Cx43 and GJIC prompted us to explore a potential positive role of Stat3 upon GJIC. Interestingly, Stat3 inhibition in non-neoplastic rodent fibroblasts and epithelial cells, as well as two NSCLC lines which exhibit extensive junctional communication  abolished GJIC, indicating that Stat3 is required for the maintenance of gap junction function. Src, tyr-418 phosphorylation levels and GJIC in a number of lines. Since Src is known to suppress gap junctional communication it is tempting to speculate that Src may be responsible, at least in part, for gap junction closure in these lines. Therefore, since Stat3 is a positive regulator of GJIC and Cx43 levels, it appears that Src has a dual role upon GJIC; as an inhibitor, through Cx43 phosphorylation, but also as a GJIC activator, through Stat3 stimulation. However, the former prevails, with gap junction closure as a result. Examination of the mechanism of GJIC suppression in NSCLC revealed an inverse relationship between Src or the Large Tumor antigen of Simian Virus 40 led to apoptosis [Src/E2F activity may have accentuated gap junction closure. In lines such as LC-T which has low Src418, other oncogenes that activate Stat3, may also be activating the E2F family and induce apoptosis, with gap junction closure as a result. The fact that another major survival pathway, the PI3k/Akt also has a positive effect upon GJIC [Stat3 downregulation caused apoptosis in all lines examined, which was more pronounced at 3 days post-confluence ,57, the poptosis ,33,63, ppon GJIC  tends topon GJIC ,66,67.Src/E2F. In non-transformed cells with low E2F levels, grown to low densities, Stat3 inhibition was previously shown to cause merely a growth retardation. However, at high densities, such as needed for optimal gap junction formation, Stat3 inhibition leads to apoptosis . This coSrc may have been responsible at least in part for GJIC suppression like the majority of NSCLC lines, but also for lines like LC-T where Src levels were found to be low, that is other oncogenes must be responsible for gap junction closure. In the contrary, Stat3 is required for gap junctional communication and the maintenance of Cx43 levels, both in normal epithelial cells and in certain tumor lines that retain GJIC. In cells such as BH-E the gap junction closure may be independent from the Src/Stat3 axis altogether.Although Stat3 is generally growth promoting, and in an activated form it can act as an oncogene, it does not transmit gap junction suppressing signals in any of the NSCLC cell lines examined. This holds true for cells where The role of connexins in cancer is complex. Numerous models support the idea that connexins are tumor suppressors at the early stages of carcinogenesis. However, recent evidence indicated a positive role for connexins in facilitating metastasis (,69,70, r


Pharmaceuticals, took place in November 2015 on the SciForum website. More than 200 authors from 18 countries participated in the event and was attended by 25,000 visitors who had the opportunity to browse among 55 presentations, keynotes, and videos. A short description of some works presented during that scientific meeting is disclosed in this report.The first International Electronic Conference on Medicinal Chemistry, organized and sponsored by MDPI AG, publisher, and the Journal  It took place on the Internet on 2–27 November 2015. The goal of the organizers was to invite researchers involved in the field of drug discovery and drug development to present their recent work to the scientific community and to share their results with academic and industrial groups from all over the world. The procedure selected for this first edition was constituted by four essential steps: (i) online submission of an abstract consisting of a brief description of the topic covered by the authors; (ii) evaluation of the scientific adequacy of the subject with the scope of the conference; (iii) online submission of a full presentation under the form of a slide show; (iv) evaluation of the scientific and general qualities of that presentation. After selection, 55 communications, including 7 keynotes and videos, were posted on the website. A brief summary of some of them is presented hereafter.The first International Electronic Conference on Medicinal Chemistry .etc. In this study, all molecular fragments which do not determine stereochemistry of a molecule are described in terms of 2D molecular representation . Structural elements which determine molecular stereoisomerism are described by respective 3D chiral conformation-independent simplexes.In the SiRMS approach, every molecule is represented as a system of different simplexes (tetratomic fragments with fixed composition and structure). The advantages of that approach are the absence of “molecular alignment” problems, consideration of different physical-chemical properties of atoms , the high adequacy and good interpretability of obtained models, It should be noted that chiral simplexes allow us to describe the molecular system of any stereochemical complexity. In the proposal (2.0+0.X), D-QSAR approach parameter (0.X) is determined by the ratio of 2D achiral and 3D chiral simplexes.1,2,3,*, François Lux 2, Sylvie Montante 1, Luce Vander Elst 1,3, Robert N. Muller 1,3, Olivier Tillement 2 and Sophie Laurent 1,3,*Mario Dentamaro 1 University of Mons, Department of General, Organic and Biomedical Chemistry, Laboratory of NMR and Molecular Imaging, Avenue Maistriau, 19, B-7000 Mons, Belgium2 University Claude Bernard-Lyon 1, Institut Lumière Matière, FENNEC Team, UMR CNRS-5305, F-69622 Villeurbanne Cedex, France3 CMMI-Center of Microscopy and Molecular Imaging, Rue Adrienne Bolland, 8, B-6041 Gosselies, Belgium* Correspondence: mario.dentamaro@umons.ac.be (M.D.); sophie.laurent@umons.ac.be (S.L.)® nanoparticles are small platforms of polysiloxane developed for applications in medical imaging. These nanoparticles present on their surface several amine functions used for the fixation of Gd-DOTA ligands . These paramagnetic platforms have a diameter of less than 5 nm and a low transmetalation . Different studies have been achieved showing that they allow for the combining of multimodal and theranostic properties with a passive tumoral targeting observed by the EPR effect (enhanced permeation effect). Otherwise, their small size allows for a quick elimination by the kidney .AGuIXet al.Technol. J. Biomol. Screen. 2006, 11, 537–545). The targeting of apoptotic cells is interesting for its efficiency of antitumoral therapy and for diagnosis of diseases related to this process. In this work, AGuIX® nanoparticles have thus been grafted with this peptide and characterized.Some studies have shown that a TLVSSL peptide has a high affinity for phosphatidylserine, a phospholipid overexposed on cells in the apoptosis process of death . In a neuroendocrine tumor (NET)-derived cell line study, it was demonstrated that cyclooxygenase-2 (Cox-2) upregulates both CgA expression and bioactivity with implications of this polypeptide in neuroendocrine cancer .The precise biological function of elevated chromogranin A (CgA) in neuroendocrine and nonneuroendocrine neoplasms remains unclear /free metanephrines (MNp) and by a plasma assay of CgA and Cox-2. All four parameters were assayed both in tumoral and normal subjects. We established statistically significant differences between all parameters assayed. Multiple regression showed important correlation coefficients between NMNp/CgA, NMNp/MNp, and CgA/Cox-2. Practically, we proved the traffic control of the noradrenergic metabolite NMNp by CgA and Cox-2. Using relative operating curve analysis (ROC), we were able to compare sensitivity and specificity of all four assayed parameters. Cox-2, CgA, and NMNp were proven to have the best sensitivity and a great specificity.We conclude that Cox-2 can be used as a prediction marker in pheochromocytoma pathology together with CgA/NMNp/MNp.Acknowledgments: This work was financially supported by PNCDI II Grant 42-101/2008.Corinne Fruit *, Julien Godeau, Marine Harari, Sylvain Laclef, Vincent Levacher and Thierry BessonNormandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnière, 76821 Mont Saint Aignan Cedex, France* Correspondence: corinne.fruit@univ-rouen.fret al.ACS Med.Chem.Lett. 2014, 5, 963–967; Dehbi, O.; et al.Eur. J. Med. Chem. 2014, 80, 352–363). Previous biological results inspired us to intensively study thiazoloquinazolin-4-one backbone, especially modulations of positions 1 and 2. Following our effort for the construction of a broad range of substituted thiazoloquinazolin-4-one derivatives as potential kinase inhibitors , modulation of position 3 was further explored. As an efficient and versatile approach in complex molecule synthesis that is palladium-catalyzed, C–H functionalization of heteroarenes represents an extremely attractive approach .Our group was focused on the synthesis of C,N,S- or C,N,O-containing heterocyclic precursors of bioactive molecules able to modulate the activity of kinases involved to some extent in Alzheimer's disease . This innovative methodology tolerates a broad range of heteroaryl and aryl halides substituted by electronically different groups. The scope of substrates was extended to pyridinopyrimidin-4-ones. This method provides an efficient, versatile, and rapid access to 2-arylquinazolin-4-one backbone and will be extended to our thiazoloquinazolin-4-one derivatives.We described the first extensive study of palladium-catalyzed direct C–H (hetero)-arylation of quinazolin-4-ones with aryl iodides, bromides, and chlorides under microwave irradiation  and Labex SynOrg . We gratefully acknowledge the financial support from the MESR (Ministère de l’Enseignement Supérieur et de la Recherche), the “Région Haute-Normandie,” and the CRUNCH network (Centre de Recherche Universitaire Normand de Chimie). We also thank Anton Paar GmbH  for provision of single-mode microwave reactor (Monowave 300) and for technical support.Chhaya Harihar Gadgoli *, Lalit Sali, Mahesh Abhyankar and Prachi PathakSaraswathi Vidya Bhavan's College of Pharmacy, Dombivli East, Thane, Maharashtra 421204, India* Correspondence: chhayahgadgoli@gmail.comVigna species have been known to possess α-amylase inhibitory activity. Therefore, it was thought worthwhile to evaluate the lectins from Vigna radiata for antidiabetic activity. The literature reveals that such studies have not yet been carried out. The principal object of this study was to evaluate antidiabetic activity of the lectins from V. radiata. Another goal of this study was the binding of the zinc with the lectins obtained from V. radiata and an evaluation of its antidiabetic activity.Proteins and phytohemagglutinins from V. radiata seed found contain galactose specific lectin. The MBL-I (Mung Bean Lectin I) may be a tetrameric protein with a molecular weight of 160–180 kDa and may be composed of an identical or nearly identical relative subunit with a molecular weight of 45–50 kDa. Amino acid analysis of purified mung bean lectin by reverse phase HPLC revealed that it contains glutamate in the highest proportion, followed by aspartate and histidine, which indicates that it has good zinc-binding potential. Binding of the lectins with zinc improved the overall stability and efficacy of the lectins. The antidiabetic activity was evaluated in Wistar rats using an alloxan-induced diabetic model, and the studies indicated significant (p < 0.001) reduction in elevated sugar levels. It is probable that the mechanism of antidiabetic action may be insulinomimetic, as it was found to bind with insulin antibodies in an Western blotting analysis.The V. radiata seeds and zinc lectin complexes has good potential to be explored as a safe, natural antidiabetic agent acting with a controlled reduction in blood glucose levels. These findings indicate that the mung bean lectin and zinc lectin complexes have tremendous medicinal potential as a herbal antidiabetic drug which needs to be explored.The lectin obtained from Firuza Tursunkhodjaeva * and Farkhad DzhakhangirovInstitute of the Chemistry of Plant Substances, Uzbek Academy of Sciences, 77, Mirzo Ulugbek street, Tashkent, 100170, Uzbekistan* Correspondence: ftm40438@gmail.comAconitum and Delphinium plants (from the Ranunculaceae family) and their extracts are currently used in Eastern medicine as an antirheumatic, an analgesic, an anti-inflammatory, and other remedies. More than 50 species of Aconitum (300 worlwide) and 100 species of Delphinium (450 worldwide) grow in the territory of Former Soviet countries, including Russia, Central Asia, and Kazakhstan.In different countries in Europe, Asia and America, plants containing diterpenoid alkaloids have been used in folk medicine since ancient times. Aconitum and Delphinium species that are widespread in Central Asia, and revealed 25 promising substances. Antinociceptive activity was investigated with conventional tests for displaying analgesics with central mechanisms of analgesia (hot plate) and peripheral mechanisms . Anti-inflammatory activity was studied with the rat formalin test.We investigated antinociceptive and anti-inflammatory activity of individual diterpenoid alkaloids with lycoctonine, heteratisine and perhydrophenantrene carbon skeletons isolated from + channels of neurons that cause a shifting of the threshold of Na+ currents towards membrane hyperpolarization and that destroy neuronal conductivity; blockers of potentially gated Na+ channels that cause inhibition of fast-intake Na+ currents without changing its activation threshold; and blockers of N-cholinoreceptors.Compared to the antinociceptive activity of investigated alkaloids and underlying mechanisms of their pharmacological action, we divided them by the following types: activators of potentially gated NaAcknowledgments: Salimov B.T., Sultankhodzaev M.N. and Usmanova S.K. , who provided the investigated chemical substances.1,* and Gloria Castellano 2Francisco Torrens 1 Institut Universitari de Ciència Molecular, Universitat de València, Edifici d’Instituts de Paterna, P. O. Box 22085, 46071 València, Spain2 Departamento de Ciencias Experimentales y Matemáticas, Facultad de Veterinaria y Ciencias Experimentales, Universidad Católica de Valencia San Vicente Mártir, Guillem de Castro-94, 46001 València, Spain* Correspondence: torrens@uv.eset al. reported a model of Ebola evading the immune system. What were the factors affecting the emergence, rapid spread, and uncontrolled nature of the 2014 virus outbreak? How is EVD treated? How does the Ebola virus replicate? How have bats evolved to resist fatality in the face of the Ebola virus? Did Ebola in Zaire exist in the African landscape before 1976, or did it evade detection and documentation? How does Ebola evade the immune system? Provisional conclusions follow: (1) Little is known about how viruses interact with the human immune system; (2) transmission among humans occurs via the exchange of blood and bodily secretions.How is Ebola virus disease (EVD) contagious? What happens at the host-pathogen interface? Why are certain viruses capable of jumping into new species? Genetic plasticity is key if the virus is to overcome a host immune attack. Double-stranded ribonucleic acid (dsRNA) triggers the release of cytokines. What is the possibility of an outbreak in Spain? How alert should a country such as Spain be? Does the Law of Labour Risks observe protocol? Does Spain have the equipment and experience needed to treat EVD patients? Why is it difficult to control determined infections or find vaccines against virus-caused diseases? Furthermore, must one be critical of the protocols followed by the Spanish Government? Here, the model of Ebola virus transmission dynamics is reviewed, with the aim of providing a broad sketch of the fundamental human-Ebola-virus biophysical forces that enable and constrain EVD. Akhtar Acknowledgments: F.T. is grateful for the support from the Spanish Ministerio de Economía y Competitividad (Project No. BFU2013-41648-P) and the EU ERDF.1,*, Benoît Menghini 1, Véronique Kruys 2, Nicolas Preyat 2, Simon Lacroix 1 and Serge Goldman 1Michel Monclus 1 PET/Biomedical Cyclotron Unit and Department of Nuclear Medicine, Erasme Hospital, Université Libre de Bruxelles, route de Lennik 808, 1070, Belgium2 Institute for Molecular Biology and Medicine Université Libre de Bruxelles  Rue des Profs Jeener et Brachet 12, 6041 Gosselies, Belgium* Correspondence: mmonclus@ulb.ac.beIn multicellular organisms, homeostasis is maintained by a balance between cell proliferation and apoptosis (programmed cell death). It is a physiological form of cell death responsible for the deletion of non-repairable damaged, mutated, or cells which have lost their function.18F).We describe the synthesis of a series of potential inhibitors of caspases from a modified aspartic acid residue (fluoromethylketone (fmk)). The addition to the entire series of either a 3-cyano-4-fluoro-benzoyl- pattern or of a 4-fluoro-2-thiazolamino pattern will subsequently allow the introduction of a PET isotope  pathways that regulate genes countering the stress. It is noteworthy that mutations in the MAPK signaling system result in fungal tolerance to cell wall disrupting agents or phenylpyrrole.Mycotic infection is becoming a serious health problem since effective antifungal agents for control of pathogenic fungi, especially drug-resistant pathogens, are often very limited. Fungal resistance to antimycotic agents frequently involves mutations caused by environmental stressors. In fungal pathogens, stress signals resulting from oxidative, cell wall stress, Saccharomyces cerevisiae served as a tool for identifying mechanisms of action of redox-active or cell wall disrupting agents. This also enabled the identification of new utility of known compounds or the utilization of natural products/derivatives as chemosensitizing agents to intensify the efficacy of conventional antimycotic agents . Compounds targeting cellular antioxidant, mitochondrial, or cell wall integrity systems effectively inhibited the growth of pathogens and/or overcame fungal tolerance to antimycotic agents. Therefore, chemo-biological approaches lead to the development of novel intervention strategies, such as antifungal chemosensitization, which enhance the drug susceptibility of targeted fungi, and ensure the maintenance of healthy microbiome dynamics.In a chemo-biological platform to achieve targeted antifungal intervention, the model yeast Acknowledgments: This research was conducted under the USDA-ARS CRIS Project 2030-42000-037-00D.1,†, Beatriz Berzal-Herranz 2,†, Pablo Ríos-Marco 2, Cristina Romero-López 2,* and Alfredo Berzal-Herranz 2,*Alba Fernández-Sanlés 1 Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, Barcelona 08003, Spain2 Institute of Parasitology and Biomedicine López-neyra, IPBLN-CSIC, PTS Granada, Av. Conocimiento s/n, 18016, Armilla (Granada), Spain* Correspondence: aberzalh@ipb.csic.es (A.B.-H.); cristina_romero@ipb.csic.es (C.R.-L.)† These authors contributed equally to this workquasi-species structure of the RNA genome population, which favors the emergence of resistant viral variants. Despite the high variability rate, significant sequence and, more importantly, structure conservation can be found in the so-called functional genomic RNA domains, many of which have unknown roles for the consecution of the viral cycle. Such genomic domains are potential therapeutic targets. This study validates the use of RNA-based inhibitors (aptamers) as molecular tools to control the activity of the cis-acting replication element (CRE) within the HCV genome. The CRE is an essential partner for viral replication. Additionally, this structural domain is involved in the regulation of the protein synthesis. A set of 44 RNA aptamers was assayed for the ability to interfere with the viral RNA synthesis in a subgenomic replicon system. Four aptamers emerged as potent inhibitors of HCV replication by direct interaction with specific and well-defined functional RNA domains of the CRE, yielding a decrease in the HCV genomic RNA levels higher than 90%. Concomitantly, one of them also promoted a significant increase in viral translation (>50%), likely by its interaction with the nucleotides surrounding the viral stop translation codon. The three remaining aptamers efficiently competed with the binding of the NS5B protein to the CRE, thus explaining their antiviral activity. Present findings confirm the potential of the CRE as an anti-HCV drug target and support the use of aptamers as molecular tools for challenging the functionality of RNA domains in viral genomes.Hepatitis C virus is an enveloped, ssRNA virus that infects 3% of the world’s population. No fully efficient therapy for treating hepatitis C exists. This is mainly due to the 1, Zoya Orlando 1, Matthias F. Melzig 2, Armin Buschauer 3, Andreas Hensel 4 and Joachim Jose 1,*Isabelle Lengers 1 Institute of Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westfälische Wilhelms-Universität, Corrensstraße 48, 48149 Münster, Germany2 Institute of Pharmacy, Freie Universität Berlin, Königin Luise Str. 2+4, 14195 Berlin, Germany3 Institute of Pharmacy, Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Universitätsstr. 31, 93040 Regensburg, Germany4 Institute of Pharmaceutical Biology and Phytochemistry, PharmaCampus, Westfälische Wilhelms-Universität, Corrensstraße 48, 48149 Münster, Germany* Correspondence: joachim.jose@uni-muenster.deSemin. Cancer Biol. 2008, 18, 275–280). For this reason, Hyal‑1 is an interesting target for drug discovery. The surface display of active Hyal‑1 on Escherichia coli via Autodisplay enables the screening for potential inhibitors in a whole cell system. Based on this technique, we determined the inhibitory effect of different natural substances on human Hyal-1. The IC50 values of the plant extracts Malvae sylvestris flos, Equiseti herba and Ononidis radix were determined to be between 1.4 and 1.7 mg/mL. Furthermore, the IC50 values of four triterpenoid saponines were determined. The obtained IC50 value for glycyrrhizinic acid, a known Hyal-1 inhibitor, was 177 µM. The IC50 values for the newly identified inhibitors gypsophila saponin 2, SA1641, and SA1657 were 108 µM, 296 µM, and 371 µM, respectively . For the synthesis of new small molecule inhibitors targeting human Hyal-1, these extracts and natural compounds can be used as a starting point.The negatively charged polysaccharide hyaluronic acid (HA) has diverse physiological and pathophysiological functions depending on its chain size. Space‑filling, anti‑inflammatory and antiangiogenic effects are triggered by high-molecular-weight HA (HMW HA) (>20 kDa). Hydrolyzation of HMW HA by Hyal‑1 results in low-molecular-weight HA (LMW HA) (<20 kDa), which leads to inflammatory and angiogenic effects . Recent studies have reported that cyclic monoterpenes menthol and thymol also have actions within the CNS  and act as a potent positive allosteric modulator of GABAA receptors . It has been reported that salicylic acid derivatives activate heterologously expressed TRPA1 , a member of the TRP channel family expressed by nociceptors and its potential role as a sensor of noxious cold . In this work, we present the synthesis and pharmacological investigation of some new menthol, thymol, and salicylic acid derivatives designed as GABA- and TRP allosteric modulators.GABAergic and glycinergic systems are the targets of a wide range of drugs active on the CNS, including anxiolytics, sedative-hypnotics, general anesthetics and anticonvulsants  as a compound with anticonvulsant activity over a wide range of doses (87–1350 mg/kg), whereas menthyl ester of glycine 2 (2-isopropyl-5-methylcyclohexyl 2-aminoacetate) shows a significant sedative effect during the six hours after oral administration at 175 mg/kg. Furthermore, orally co-administered gidazepam (1 mg/kg) and compound 1 (175 mg/kg) produce synergistic effect in seizures prevention. Additionally, thymol ester of GABA 3 (20–100 mg/kg) as well as thymol derivative 4 (25–100 mg/kg) exhibits anti-seizure effects during the six hours after oral administration. Complex compounds obtained by SnCl4 interaction with salicyloylhydrazones  have demonstrated anti-inflammatory, anxiolytic, antidepressant and analgesic activities in different models in vivo. All aforementioned compounds can be considered as those that exhibit a combined pharmacological activity due to their simultaneous binding to different receptor types.Our findings identified menthyl ester of GABA 1, Emília Sousa 1,2, Madalena Pinto 1,2 and Marta Correia-da-Silva 1,2,*Ana Rita Neves 1 Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, Portugal2 CIIMAR, Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, 4050-123 Porto, Portugal* Correspondence: m_correiadasilva@ff.up.ptet al. Eur. J. Med. Chem. 2011, 46, 347–2358; Correia-da-Silva, M.; et al.J. Med. Chem. 2011, 54, 5373–5384). However, these polysulfated derivatives showed poor antithrombotic efficacy by in vivo oral administration in mice, predicted to be due to poor absorption in the gastrointestinal (GI) tract . The main aim of this work was to improve the oral bioavailability of these compounds. In order to get new optimized analogues, two strategies were considered: (i) obtaining conjugates with bile acids and (ii) introduction of a triazole ring.According to the World Health Organization, cardiovascular diseases are the most common cause of death worldwide. Although health has improved in the last several decades, lifestyle changes have led to an increased incidence of cardiovascular diseases. Currently, the available antithrombotic drugs are associated with significant drawbacks that limit their use, and the development of more advantageous drugs with less secondary effects is necessary. Our group discovered a new class of polysulfated small-molecules with anticoagulant and antiplatelet activities -1,1,3,3-tetramethyluronium tetrafluoro borate (TBTU) as a coupling reagent. Triazole-linked xanthone glycoside was obtained through a copper(I)-catalyzed alkyne-azide cycloaddition followed by O- and N-deacetylation. Sulfation was successfully achieved with a triethylamine-sulfur trioxide adduct under microwave irradiation.Naringin-deoxycholic acid conjugate was obtained through a cross-linking reaction using 2-(12) in the micromolar range (around 44 µM). These new optimized analogues with anticoagulant activity are expected to cross the GI tract membranes after oral administration.The three sulfated derivatives were screened for anticoagulant activity using the three classic clotting times: activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). All the sulfated compounds prolonged the clotting times and the most active compound was the persulfated naringin-deoxycholic acid conjugate, exhibiting a double concentration value on the APTT . The kinase is composed of two catalytic CK2α subunits and two regulatory CK2β subunits. Most protein–protein interaction (PPI) studies or screening assays are based on fluorescence detection and require the labeling of the target enzyme by a fluorophore. Unfortunately, through labeling by commercial applications, the catalytic subunit CK2α loses activity. Furthermore, the labeling ratio of the protein sample differs and is not exactly reproducible.Human CK2 is a heterotetrameric constitutively active serine/threonine protein kinase and plays an important role in current cancer research . Performing the SPAAC click reaction (Strain-Promoted Alkyne-Azide Cycloaddition) by the use of DBCO 545 (dibenzylcyclooctyne-fluor 545) has led to a specifically labeled human protein kinase CK2 .The solution for this problem was a bioorthogonal click reaction of the protein kinase. By expanding the genetic code, the unnatural amino acid para-acidophenylalanine (pAzF) has been able to be incorporated into CK2 .This site specific labeling does not impair the phosphorylation activity of the kinase, which was evaluated by capillary electrophoresis. The innovatively labeled kinase in combination with the Autodisplay technology could be a significant advancement for inhibitor screening assays by flow cytometry and for CK2α/CK2β interaction studies , Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal3 CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal4 Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal* Correspondence: cfernandes@ff.up.ptet al.Bioorg. Med. Chem. 2014, 22, 1049–1062; Fernandes, C.; et al. Eur. J. Med. Chem. 2012, 55, 1–11). Recently, we have described the ability of CDX to inhibit the growth of different human tumor cell lines . In fact, some of them exhibited interesting dose-dependent growth inhibitory effects being dependent on the stereochemistry.For the last several years, the search for new chiral derivatives of xanthones (CDX) with potential pharmacological properties has remained an area of interest of our group -Whelk-O1® chiral stationary phase under polar-organic elution conditions, achieving values higher than 99%.The enantiomeric excesses for all synthesized CDX were measured by HPLC on  and the European Regional Development Fund (ERDF) in the framework of the programme PT2020 and the Portuguese NMR Network.1,2,*, Agostinho Lemos 1, Ana Gomes 1,3, Sara Cravo 1, Madalena Pinto 1,2Emília Sousa 1 Department of Chemical Sciences, Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Porto, 4050–313 Porto, Portugal2 CIIMAR – Interdisciplinary Centre of Marine and Environmental Research, 4050–123, Porto, Portugal Portugal3 Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, 4169–007 Porto, Portugal.* Correspondence: esousa@ff.up.ptN-containing, and an even higher amount are O-containing. As a consequence, it is not surprising that alkylation and arylation of groups with nitrogen and oxygen emerge as major reactions to obtain bioactive compounds . Xanthones are a class of O-heterocycles characterized by a dibenzo-γ-pyrone nucleus. This scaffold may be considered a “privileged structure” able to provide useful ligands for several types of receptors and/or enzymes targets by judicious structural modifications . In our search for potential anticancer drugs, we pursued a hybridization approach of N-containing xanthones. N-Substitution is typically achieved by one of the following strategies: (i) direct reaction with alkyl-X or aryl-X or (ii) reductive alkylation using an appropriate aldehyde.Typically, about 90% of drug candidates are N-containing xanthones can be reached are shared. The synthesis of new xanthone derivatives proceeds via both strategies, and the respective strengths and weaknesses are presented in a “medchem” perspective. Although chemical route (i) (SN2 reactions and nucleophilic aromatic substitutions) have provided interesting antitumor derivatives , the reductive amination (ii) furnished a library of potential p53:MDM2 inhibitors with noticeable advantages, such as high-yield reactions, one-pot conversions, and aliphatic amines with low potential to form reactive metabolites.Herein, exploiting chemical routes by which bioactive N-transformations, often referred to as the “chemist‘s toolbox” .The use of a variety of (thio)xanthone building blocks with various substituents and different reaction conditions allowed us to develop a repertoire of Acknowledgments: This research was partially supported by ERDF through the COMPETE and national funds through FCT, under the project PEst-C/MAR/LA0015/2013.Dario Donno*, Maria Gabriella Mellano, Alessandro K. Cerutti and Gabriele L. BeccaroDepartment of Agriculture, Forestry and Food Science, University of Torino, 10124 Torino, Italy* Correspondence: dario.donno@unito.itet al. Vegetos 2012, 25, 21–29). In particular, polyphenols, terpenic compounds, organic acids, and vitamins are the most widely occurring groups of phytochemicals . Some endemic species may be used for the production of herbal preparations containing phytochemicals with significant bioactivity such as antioxidant activity and anti-inflammatory capacities, and other health benefits. Blackberry sprouts and blackcurrant buds are known to contain appreciable levels of bioactive compounds, including flavonols, phenolic acids, monoterpenes, vitamin C, and catechins, with several clinical effects .It is well known that plants are important sources for the preparation of natural remedies, as they contain many biologically active compounds . This study allowed for the development of an effective tool for the natural preparation quality control and bioactivity evaluation through the chemical fingerprinting of bud preparations.Chemical, pharmaceutical, and environmental knowledge could be a useful tool for obtaining label certifications for the valorization of specific genotypes, with high clinical and pharmaceutical value .Increasing demands from the pharmaceutical industry for the rapid molecular structure determination of pharmaceutical solids has prompted the development of X-ray diffraction and The intermolecular interactions are crucial in the interpretation of interactions between the biomolecules and macromolecular targets, and their analysis can provide essential information about how they occur.1–7 and the bis-amidines 6a–7a in the solid-state.The objective of the studies was to discuss the structures and the intermolecular interactions of the bis-nitriles et al. Eur. J. Med. Chem. 2012,48, 164–173; Berger, M.L.; et al.Bioorg. Med. Chem. 2015, 23, 4489–4500).The compounds presented in this report can be considered as the pentamidine analogs, which are of interest because they have potential use as the chemotherapeutics against Pneumocystis pneumonia, as potent NMDA receptor inhibitors, or as anticancer and antimicrobial agents  and butyrylcholinesterase (BuChE) inhibitors. For the best compounds of the series, the ICAcknowledgments: This work was partially supported by the University of Santiago de Compostela, University of Cagliari, Portuguese Foundation for Science and Technology (FCT) and QREN (FCUP-CIQ-UP-NORTE-07-0124-FEDER-000065), and FCT, POPH and QREN (SFRH/BPD/95345/2013).1,2, Daniela Häußler 1, Tamara Scheidt 1, Marit Stirnberg 1, Torsten Steinmetzer 3, Jürgen Bajorath 2 and Michael Gütschow 1,*Norbert Furtmann 1 Pharmaceutical Institute, Pharmaceutical Chemistry I, Rheinische Friedrich-Wilhelms-Universität, An der Immenburg 4, Bonn 53121, Germany2 Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstrasse 2, Bonn 53113, Germany3 Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, Marburg 35032, Germany* Correspondence: guetschow@uni-bonn.deIn the absence of X-ray data, the exploration of compound binding modes continues to be a challenging task. For structure-based design, specific features of active sites in different targets play a major role in rationalizing ligand binding characteristics. For example, dibasic compounds have been reported as potent inhibitors of various trypsin-like serine proteases, the active sites of which contain several binding pockets that can be targeted by cationic moieties. This results in several possible orientations within the active site, complicating the binding mode prediction of such compounds by docking tools. Therefore, we introduced symmetry in bi- and tribasic compounds to reduce conformational space in docking calculations and to simplify binding mode selection by limiting the number of possible pocket occupations.et al. Chem. Eur. J. 2016, 22, 610–625).Herein, asymmetric bisbenzamidines were used as starting points for a multistage and structure-guided optimization. A series of compounds with either two or three benzamidine substructures was ultimately synthesized and evaluated as inhibitors of five serine proteases, leading to potent symmetric inhibitors for the pharmaceutical drug targets matriptase, matriptase-2, thrombin, and factor Xa . M.S. was supported by the German Research Foundation (STI 660/1-1) and the Maria von Linden-Program of the University of Bonn. The authors thank Dr. Matthias D. Mertens for support in building block synthesis and Dr. Eva Maurer and Anna-Madeleine Beckmann for providing matriptase-2.Mohamed Jawed Ahsan * and Sunil ShastriDepartment of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy Ambabri Circle, Jaipur, Rajasthan 302 039, India* Correspondence: jawedpharma@gmail.comin vitro anticancer activity against NCI-60 human cell lines of nine different panels including leukemia, non-small lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer, according to the National Cancer Institute (NCI US) Protocol at 10 µM . The compounds N-{methyl}pyridin-2-amine (1c), N-{methyl}pyridin-2-amine (1f) and N-{methyl}pyridin-2-amine (1g) showed anticancer with higher selectivity towards HOP-92 . N-{methyl}pyridin-2-amine (1b) showed maximum antibacterial activity with a minimum inhibitory concentration (MIC) of 4–8 µg/mL, while N-{methyl}pyridin-2-amine (1f) showed maximum antifungal activity with MIC 4 µg/mL.A new series of oxadiazole analogues was synthesized starting from 2-aminopyridine. The compounds were characterized by infrared (IR), nuclear magnetic resonance (NMR) and mass spectral analyses followed by their anticancer and antimicrobial activities. Three compounds were tested for Acknowledgments: This work was partially supported by Department of Science and Technology (DST), Rajasthan (1156/2015). The authors are thankful to the National Cancer Institute (NCI), US for carrying out in vitro anticancer activity.1, Annie Mayence 2, Madhusoodanan Mottamal 3, Cyrus J. Bacchi 4, Nigel Yarlett 4, Marcel Kaiser 5, Reto Brun 5 and Tien L. Huang 3,*Jean Jacques Vanden Eynde 1 University of Mons-Umons, department of organic chemistry, B-7000 Mons, Belgium2 Haute Ecole Provinciale de Hainaut Condorcet, B-7730 Saint-Ghislain, Belgium3 Xavier University of Louisiana, College of Pharmacy, New Orleans, LA 70125, USA4 Pace University, Haskins Laboratories, New York, NY 10038, USA5 Parasite Chemotherapy, Swiss Tropical institute, 4051 Basel, Switzerland* Correspondence: thuang@xula.eduin vitro against two Trypanosoma brucei (Tb) strains: T. b. brucei (Tbb) and T. b. rhodesiense (Tbr); two Plasmodium falciparum (Pf) strains: a chloroquine-sensitive strain (NF54) and a chloroquine-resistant strain (K1); Trypanosoma cruzi (Tc); and Leishmania donovani (Ld). The in vitro cytotoxicity was determined against rat myoblast cells (L6). Seven compounds showed high potency toward both strains of Tb and Pf with the inhibitory concentrations for 50% (IC50) in the nanomolar range (IC50 = 1–96 nM). None of the tested derivatives was significantly active against Tc or Ld. Three of the more potent compounds were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002) or drug-resistant (KETRI 2538 and KETRI 1992) clinical isolates of T. brucei. Compounds 1 and 2 were highly effective in curing 100% mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences in the minor grove as possible binding sites for these compounds.A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested 1,*, Rita Yadav 1 and Surender Singh Jadav 2Mohamed Jawed Ahsan 1 Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy Ambabri Circle, Jaipur, Rajasthan 302 039, India2 Department of Pharmaceutical Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835 215, India* Correspondence: jawedpharma@gmail.com50, TGI, and GI50 were calculated . 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-(4-methoxylphenyl)-urea (1) showed maximum anticancer activity with a GI50 of 35.1 µM against HeLa (cervix cancer cell line) and 60.4 µM against MDA-MB-435 (breast cancer cell line), respectively. A molecular docking study implying epidermal growth factor receptor tyrosine kinase (EGFR-TK) was carried out to observe the binding mode of new quinoline analogues on the active site of EGFR-TK. Compound 1 showed a maximum docking score among the series of compounds. The amino acid residues Met793 showed backbone H-bonding with the hydroxyl group, while Asp855 showed side chain H-bonding with aryl NH group.A series of new quinoline analogues was prepared in two steps. All the synthesized compounds were characterized by IR, NMR, and mass spectral data. The anticancer activity was carried out as per the standard protocol, and LCAcknowledgments: This work was partially supported by the Department of Science and Technology (DST), Rajasthan (1156/2015). The authors are thankful to the Anticancer Drug Screening Facility (ACTREC), Navi Mumbai, India for carrying out in vitro anticancer activity.1, Annie Mayence 2, Tien L. Huang 3 and Jean Jacques Vanden Eynde 1,*Honoré Térence 1 University of Mons-UMons, Department of Organic Chemistry, B-7000 Mons, Belgium2 Haute Ecole Provinciale de Hainaut Condorcet, B-7730 Saint-Ghislain, Belgium3 Xavier University of Louisiana, College of Pharmacy, New Orleans, LA 70125, USA.* Correspondence: jean-jacques.vandeneynde@ex.umons.ac.beet al. Bioorg. Med. Chem. 2011, 19, 7493–7500), but they are characterized by a high lipophilic character. To circumvent that drawback, two series of structural analogs have been prepared. In the first series, oxygen atoms have been introduced in the linker separating both pharmacophores. In the second series, the heterocyclic skeletons have been replaced by imidazopyridine moieties. The antiplasmodial activity of the newly synthesized compounds has been evaluated against the chloroquine-sensitive strain NF-54. Their cytotoxicity in the presence of L6 rat skeletal muscle cells has also been determined.Recently, we have demonstrated that some bis(oxyphenylene)benzimidazoles constituted potential antiplasmodial candidates ]bis-1Natalya I. Vasilevich *, Elena A. Aksenova, Denis N. Kazyulkin and Ilya I. AfanasyevNovie Nauchnie Tekhnologii Ltd. (ASINEX company group), 20 Geroev Panfilovtsev Str., Moscow 125480, Russia* Correspondence: nvasilevich@asinex.comBased on the data of compounds known from the literature to be active against various types of Ser/Thr kinases, a general pharmachophore model for these types of kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against such Ser/Thr kinases as Aurora A, Aurora B, and Haspin.Our work on optimization of these molecules to Aurora A kinase allowed us to achieve several hits in the 3–5 nM range of activity, with rather good selectivity and ADME properties.Thus, we showed the possibility of performing the fine-tuning of the general Ser/Thr pharmacophore designed for desired types of kinase to get active and selective compounds.Acknowledgments: The authors gratefully acknowledge support from the Ministry of Education and Science of the Russian Federation for funding .1,2, Nobert Furtmann 1,3, Moritz Ponert 1, Ulrike Bartz 2, Jürgen Bajorath 3 and Michael Gütschow 1,*Janina Schmitz 1 University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An der Immenburg 4, Bonn 53121, Germany2 Bonn-Rhein-Sieg University of Applied Sciences, von-Liebig-Str. 20, Rheinbach 53359, Germany3 Department of Life Science Informatics, B-IT, Dahlmannstr. 2, Bonn 53113, Germany* Correspondence: guetschow@uni-bonn.deet al.J. Exp. Med. 2000, 191, 1177–1186). Low molecular weight inhibitors for cathepsin F have not been investigated so far. We have chosen the dipeptide nitrile chemotype to develop covalent-reversible inhibitors for this target .Cysteine cathepsins are lysosomal cysteine proteases which play roles in many physiological processes. Cathepsin F is predominantly expressed in macrophages. Major histocompatibility complex class II molecules (MHC-II) are expressed by antigen-presenting cell types including macrophages, B cells, and dendritic cells. The cleavage of the invariant chain is the key event in the pathway of MHC-II complexes. Cathepsin S was described as the major processing enzyme of the invariant chain, but it was shown that cathepsin F can adopt its role in cathepsin S deficient mice .An active site mapping with a library of 52 nitrile-based cathepsin inhibitors was performed at human cathepsin F to draw structure-activity relationships. With the kinetic data in hand, new compounds with optimized residues in the P1, P2, and P3 positions were synthesized and evaluated. With all dipeptide nitriles including the newly synthesized derivatives, a 3D activity landscape was generated to visualize similarity-activity relationships of this series of cathepsin F inhibitors .Casein kinase 2 (CK2) is a ubiquitous kinase protein emerging as a target for several human diseases including cancer. Several active CK2 inhibitors have been developed in the last few years; most of them have an ATP-competitive type of inhibition, and only one inhibitor is in a clinical trial as an anticancer drug. Here, we report on the synthesis of two derivatives of 2,6-diaryl-anthracene-9,10-dione. One of them, 2,6-di(furan-3-yl)anthracene-9,10-dione compound 3, turned out to be active towards CK2 and ATP-competitive with an IC1,2,*, Arnaud Petit 1, Joséphine Conti 1 and Joël De Coninck 1,2Emmanuel Gosselin 1 Laboratory of Surface and Interfacial Physics, University of Mons, Place du Parc 20, Mons 7000, Belgium2 Biosciences Institute, University of Mons, avenue Maistriau 19, Mons 7000, Belgium* Correspondence: Emmanuel.gosselin@umons.ac.beSensors based on the molecular recognition of biomolecules have already attracted intensive interest in many different fields. Different surface sensitive techniques can be applied to detect these biomolecular interactions. We proposed an assessment of the utility of Fourier transform infrared (FTIR) spectroscopy in studying biomolecules attachment to inorganic surfaces in a variety of biosensing applications. We have designed a new generic device suitable for the investigation of ligand–receptor interactions based on the successive grafting of a novel silanization reagent and a bifunctional molecular clip directly at the surface of an internal reflection element.These molecular constructions lead to an activated transducer substrate ready for the covalent binding of any bioreceptor molecules. Contrary to SPR or quartz crystal microbalance (QCM) sensors, FTIR sensors provide useful spectroscopic information concerning the chemical nature of the interacting molecules and the amount of bound receptors and ligands. It is even possible that conformational transitions of the receptor during the interaction with the ligand can also be monitored. Currently, this information is not usually accessible using standard sensors that are limited to measuring physical modifications on the surface. We will illustrate the attachment of biomolecules to such organic surfaces through various systems commonly used in the biosensing field.Acknowledgments: This work was financially supported by the F.R.S.-FNRS, CDR J.0116.14. We thank J.J. Vanden Eynde for helpful scientific discussions.Liubov Biliavska *, Olga Povnitsa, Svitlana Zagorodnya, Sergei Voychuk, Liubov Zelena, Yulia Shamara and Nadiya NesterovaInstitute of Microbiology and Virology, National Academy of Sciences of Ukraine, Zabolotnogo str., 154, Kyiv, 03143, Ukraine* Correspondence:bilyavskal@ukr.net1Human adenovirus and herpes simplex virus cause infectious diseases of the eyes, respiratory, enteric, and urogenital tracts, and of the central and peripheral nervous system, are capable of persisting in a latent form, and are activated under the influence of endogenous and exogenous factors.A high spread of infections caused by herpes virus and adenovirus, as well as their mixed infections, are a problems in modern medicine. During mixed infections, an absence of virus interaction as well as a mutual influence of viruses may originate.The search for drugs that have relatively high activity against co-associated viruses through the inhibition of their reproduction and transmission is an important task. The activity of antiviral drugs under the condition of co-infection is not studied enough. Change in the nature of pathological processes were found as a result of the interference of the viruses and of the differences between drug activities against the co-associated viruses in conditions of the mono and mixed infections of MDBK cells. Both an increase in, and an inhibition of, drug activities were detected, which may lead to the formation of resistant strains of viruses.1, Corinne Fruit 1, Anne-Sophie Casagrande 2, Laurent Désiré 2, Bertrand Leblond 2, Laurent Meijer 3 and Thierry Besson1 1,*Damien Hédou 1 Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen. CNRS, IRCOF, 1 Rue Tesnière, 76821 Mont St Aignan Cedex, France2 Diaxonhit, 65 boulevard Masséna, 75013 Paris, France3 Manros Therapeutics, Centre de Perharidy, 29680 Roscoff, France* Correspondence: thierry.besson@univ-rouen.frf]quinazolines were particularly studied . The chemical highlight of this work was the use of Appel salt  for the conception of a 6-amino-2-cyanobenzo[d]thiazole-7-carbonitrile derivative as a versatile molecular platform from 5-nitroanthranilonitrile. Thus, introduction of various aliphatic, aromatic, or amino substituents at position 8 was best achieved via one-pot DMFDMA-mediated cyclization . Transformation of the carbonitrile group into various chemical functions  allowed for the efficient preparation of a library of novel thiazoloquinazoline derivatives .In our continuous efforts to prepare novel heterocyclic scaffolds that are able to modulate the activity of kinases in signal transduction, synthetic routes to functionalized thiazolo-labeled positron emission tomography (PET) tracer to realize the early diagnostic or to validate the efficiency of therapies in clinical trials for AD is indubitably crucial.The neurotransmitter acetylcholine (ACh) exerts its effects on the central nervous system (CNS) through two distinct muscarinic mAChRs and nicotinic nAChRs receptors types: nAChRs belong to the superfamily of ligand-gated ion channels, possessing a pentameric structure , we also endeavored to design novel α7 nAChR ligands and their transformation into a [18F] PET tracer. We synthesized a library of potent α7 nAChR ligands containing a quinuclidine, a tropane or a 8H-quinolizine moiety. We present herein chemistry  SAR studies, molecular modeling docking studies, which confirmed the binding mode of the developed ligands, in vitro efficiency (SAR), radiolabeling, and in vivo results in rats.With this aim, based on our expertise in heterocyclic bio-mimetic development , the Région Centre (IMAD), the FEDER, and Cyclopharma Laboratories.Azhidhack Hadjipour, Rena-Jean Palmer, Mohamed Zarara and Amal Ali Elkordy*Sunderland School of Pharmacy, Faculty of Applied Sciences, University of Sunderland, Sunderland, SR1 3SD, UK* Correspondence: amal.elkordy@sunderland.ac.uk2 when tablets come in contact with the acidic medium. Tablets without drugs were characterized for their floatability properties in a simulated gastric fluid (SGF) without enzymes at 37 °C. The successful formulations regarding floatability were incorporated with Nizatidine (50 mg/tablet) or Piracetam (30 mg/tablet). The powder admixtures were characterized for flow properties, and tablets containing drugs were evaluated via British Pharmacopeia quality control tests. All batches with Nizatidine that contain xanthan gum alone or in combination with Eudragit-RS PO showed good flow and compaction properties and also yielded significant (p < 0.05) swelling and floating results. However, Piracetam batches prepared with Lubritose SD showed poor compaction; therefore, granulation of the powders was applied to enhance floating tablet properties such as friability, floatability, and sustainability of the drug release of more than 6 hours. In conclusion, xanthan gum, Eudragit-RS PO (used with Nizatidine), and Lubritose SD (applied with Piracetam) could be promising excipients to formulate floating tablets.The aims of this study were to prepare and investigate the dissolution and floatability profiles of Nizatidine and Piracetam effervescent floating tablets and to study the effect of xanthan gum, Eudragit-RS PO, or Lubritose SD on tablet compression properties with or without granulation of the powder admixtures. Sodium bicarbonate was used to release CO1,2, Alla Fedchuk 1,2, Tetyana Grydina 2,3, Larysa Shytikova 2, Lyubov Mudryk 2, Lidiya Socheslo 2, Mikhailo Lebediuk 1,3, Oleksandr Voronkov 4, Volodymir Trykhlib 5, Arkadyi Frolov 6, Victoria Zadorozhna 6, Vira Buiko 3 and Sergyi Tkachuk 7Viktor Lozitsky 1 Research Center “Biomedical Testing of Preparations and Products”, Odessa 65003, Ukraine2 I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of Health, Odessa 65003, Ukraine3 Odessa National Medical University, Odessa, 65000 Ukraine4 State Enterprise “Research Enterprise Institute of Chemical Technology “Chemtechnology”, Sevtodonetsk 93400, Ukraine5 Ukrainian Military Medical Academy, Kyiv 03049, Ukraine6 L.V.Gromashevsky Institute of Epidemiology and Infectious Diseases of NAMS of Ukraine, Kyiv 03680, Ukraine7 Military Medical Clinical Center of the Western Region, Lviv 79010, Ukraine* Correspondence: lorevit@ukr.netS. aureus strains with different sensitivity to antibiotics. ACA inhibits all these strains, and the combined use of ACA with antibiotics magnifies the antibacterial effect.We have established the efficacy of proteolysis inhibitor (PI) aminocaproic acid (ACA) in viral infections as a result of its impact on the etiological factor and pathogenesis of the infection. The Ministry of Health of Ukraine, on the basis of our studies and clinical trials, allowed for the use of ACA for prophylaxix and treatment of influenza and other acute respiratory viral infections (ARVIs). Including ACA to therapeutic complex for the treatment of influenza and other ARVI in children and neonates led to a decrease in the duration of symptoms of intoxication, catarrhal phenomena, and fever as well as to a decrease in the number of complications. The prevention effectiveness of ACA has also been established. In light of the results, we recommend the use of ACA for the efficient prophylaxix of ARVIs and pneumonia in organized collectivities in any period of increased incidence of these infections. Our research has shown that the combined use of drugs with different mechanisms of action—PI ACA and neuraminidase inhinbitor Tamiflu—causes a synergetic effect. We also studied the antibacterial action of ACA on 1, Bart I. Roman 1, Sophie L. K. W. Roelants 2,3, Inge N. A. Van Bogaert 2, Guy B. Marin 4, Kevin M. Van Geem 4 and Christian V. Stevens 1,*Elisabeth I. P. Delbeke 1 SynBioC, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.2 Department of Biochemical and Microbial Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium3 Bio Base Europe Pilot Plant (BBEU), Rodenhuizekaai 1, 9042 Ghent (Desteldonk), Belgium4 LCT, Department of Chemical Engineering and Technical Chemistry, Ghent University, Technologiepark 914, 9052 Ghent, Belgium.* Correspondence: Chris.Stevens@UGent.be1) and sophorolipid quaternary ammonium salts (2). These sophorolipid quaternary ammonium salts were evaluated for their antimicrobial activity against Gram-negative and Gram-positive bacterial test strains. Minimum inhibitory concentration (MIC) values were determined for the active compounds. Values of 5–8 µM results were obtained for the derivatives containing an octadecyl chain attached to the nitrogen atom, compared to values of 10–52 µM for the antibiotic gentamicin sulfate. These results show great promise for modified sophorolipids in the medical sector, for example, for the inhibition of biofilm formation.In the European chemical industry, there is a strong drive to shift from fossil to renewable resources in the pursuit of sustainability. Sophorolipids, a class of biosurfactants, are interesting renewable resources, since they combine a complex structure with divergent biological and physico-chemical properties. The microbially produced lactonic sophorolipids were used for the production of a broad range of innovative sophorolipid amines . The authors gratefully acknowledge the company Ecover  and the InBio research group  for the delivery of the sophorolipid starting compound, and the Laboratory for Microbiology  for the evaluation of the antimicrobial activities. Bart I. Roman is a fellow of the fund for Scientific Research—Flanders (FWO-Vlaanderen).1,*, Viktor Lozitsky 2,*, Regina Lozytska 2 and Vitalyi Larionov 1Iryna Kravchenko 1 Odessa National University, Odessa 65000, Ukraine2 Bogatsky Physico-Chemical Institute of NAS of Ukraine, Odessa 65080, Ukraine* Correspondence: kravchenko.pharm@gmail.com; lorevit@ukr.neta prolonging of the drug action;an absence of the drug concentration hopping; anda decrease in the side effect risk.Transdermal delivery of drugs is a novel method of pharmacotherapy for many diseases. The main advantages of this method of administration are:This method of administration has to be viewed for preventive actions and therapy of viral respiratory infections. The aim of this work was to study the possibility of transdermal rimantadine delivery for influenza A prophylaxis and treatment in experimental animals. Rimantadine was administrated in the hydrogel matrix  in doses of 1–2 mg/mouse applied on the shaved back of mice one day before infection. Mice of experimental and control groups were infected intranasally with a highly pathogenic influenza virus A/PR/8/34 (H1N1). Challenge was carried out using for animals for each virus dilution within the range of 10–1 to 10–7. Deaths of animals were recorded for 14 days. The results of our investigations had shown high anti-influenza efficacy of rimantadine under transdermal delivery. Differences of LD50 between control and experimental groups consist 1.7–1.75 log10 when the dose of rimantadine was 1 mg/mouse, and 2.25 log10 when preparation was administrated in dose 2mg/mouse. In this study, the anti-influenza efficacy of rimantadine after its transdermal administration was established for the first time.Hannah J. Winfield, Kevin D. O'Shea and Florence O. McCarthy *Department of Chemistry and ABCRF, University College Cork, Western Road, Cork, Ireland* Correspondence: f.mccarthy@ucc.iehttp://globocan.iarc.fr). Although chemotherapy is increasingly prescribed, it is not without side effects; therefore, new, more selective remedies for cancer sufferers must be found.Cancer causes about 13% of all human deaths and at least one fifth of all deaths in Europe and North America  et al. J. Med. Chem. 2006, 49, 1271–1281; Pierce, L.T.; et al., Tetrahedron 2011, 67, 4601–4611; Pierce, L.T.; et al. Tetrahedron 2010, 66, 9754–9761).Since the discovery of the anticancer properties of the indolocarbazole Staurosporine 1, many analogues have been synthesized in order to obtain compounds that have a higher potency with respect to anticancer mechanisms  . Biological evaluation via the NCI 60 cell line screen has been completed for a number of these compounds, and some show significant selectivity towards individual leukemia and melanoma cell lines.The overall objective of this project was to produce selective and highly potent novel anticancer agents through modification of the indolocarbazole structure, and one focus of this work was the replacement of the lactam/maleimide heretocycle to form a series of novel indolocarbazole derivatives including the first reported synthesis of a series of novel substituted indolocarbazole uracils . While ellipticine itself is not a suitable candidate for therapeutic use, derivatives including 2-methyl-9-hydroxyellipticinium acetate and 2-(2-(diethylamino)ethyl)-9-hydroxyellipticinium chloride have progressed to clinical trials .Ellipticine is a natural product possessing multimodal cytotoxic activity including DNA intercalation, topoisomerase II inhibition, c-Kit kinase inhibition, and restoration of function to mutant p53 protein .The effect of derivatization on the isoellipticine is uncharted and structural diversification of isoellipticine could lead to drug candidates with a better clinical profile due to enhanced target specificity. Our initial approach was to use substitutent modification at positions 10, 7 and 2 . A number of novel derivatives of isoellipticine have been synthesized and further derivatized. Preliminary biological testing of novel compounds was performed using a topoisomerase II decatenation assay and via assessment of the anticancer profile using the National Cancer Institute 60 cell line screen for cellular activity  was given to the group of C. Nienberg, A. Retterath, K.S. Becher, H.D. Mootz, and J. Jose for the work entitled “Click Chemistry for Advanced Drug Discovery Applications of Human Protein Kinase CK2” (A020). Members of the scientific advisory committee elected as the best presentation the research topic of K. Zhu and M. Kai, entitled “Convenient Drug-Resistance Testing of HIV Mutants” (A030).www.sciforum.net/conference/ecmc-2. All of us hope that you will have the opportunity to attend, as authors or visitors.Thanks to the support of the organizers and the confidence of the participants, we are proud to announce that the Second International Conference on Medicinal Chemistry will be held in November 2016 on


Streptococcus pyogenes emm28 strain M28PF1, isolated from a patient with postpartum endometritis. The M28 protein is smaller than that of MGAS6180 (NC_007296.1). Furthermore, the 1,896,976-bp-long chromosome presents, compared to that of MGAS6180, an inversion between the two comX genes.We report the sequence of the  Streptococcus pyogenes (group A Streptococcus [GAS]), an important Gram-positive human pathogen, causes varied clinical manifestations, ranging from noninvasive to invasive diseases and poststreptococcal sequelae, with an estimated 517,000 deaths yearly  between 2006 and 2009 in France.nd emm89 . A tissuemm type , 5, and metritis . To studChromosomal DNA was extracted using the MasterPure Gram-positive DNA purification kit (Tebu-Bio) and sequenced using Illumina technology, with read length of 100 nucleotides (nt) and coverage over 200-fold. Libraries were constructed using the Illumina TrueSeq kit. Illumina short reads were assembled using the Velvet software . The iniOverall, in comparison with the MGAS6180 chromosome, there are 30 indels : 7 in-frame, 7 yielding modified proteins, and 16 intergenic; and 137 single-nucleotide polymorphisms: 40 synonymous, 73 nonsynonymous, and 24 intergenic. The M28PF1 M28 protein lacks one 35 amino-acid repeat.One failing PCR overlaps the M28_Spy1336 gene encoding the R28 protein, most certainly due to the large number of repetitions. The R28 repetition number varies, yielding proteins of different sizes (comX–ribosomal operon regions which may be chromosomal crossover points (comX-proximal primers; DNA fragments were then obtained that comigrated with those produced by the initial primer couples on MGAS6180 DNA, demonstrating that a chromosomal inversion occurred in the M28PF1 genome relative to MGAS6180. This may influence the level of expression of some genes (The other two PCRs that failed encompass the two r points , 10. PCRCP011535.This genome sequence has been deposited in GenBank under the accession number


In the present review, we summarize recent findings in signaling underlying MAMP-induced stomatal movement by comparing with other signalings.Stomata, formed by pairs of guard cells in the epidermis of terrestrial plants, regulate gas exchange, thus playing a critical role in plant growth and stress responses. As natural openings, stomata are exploited by microbes as an entry route. Recent studies reveal that plants close stomata upon guard cell perception of molecular signatures from microbes, microbe associated molecular patterns (MAMPs), to prevent microbe invasion. The perception of MAMPs induces signal transduction including recruitment of second messengers, such as Ca As natural openings, stomata are exploited as a major entry route by a wide range of microbes including bacteria, oomycetes, and fungi  and phosphorylation events, which are critical for plant innate immunity (Pseudomonas syringae pv tomato (Pst) strain DC3000, Pst DC3118  are molecular signatures that are highly conserved in whole classes of microbes but are absent from the host, such as chitin for fungi and flagellin for bacteria . Recogniimmunity . Recent immunity . Furthert DC3118 . As a reis topic . In the Arabidopsis guard cells. For details on this topic, we refer readers to excellent reviews , and salicylic acid (SA) are believed to induce stomatal closure in various plants . Particu reviews .2+-independent protein kinase and an essential positive regulator in ABA signaling in Arabidopsis guard cells. In resting condition, OST1 kinase activity is inhibited by clade A Type 2C protein phosphatases (PP2Cs). Upon ABA perception, the interaction of ABA receptors, PYR/PYL/RCAR, and PP2Cs releases the inhibition of OST1, resulting in increment of OST1 kinase activity  KAT1 , CPK3, CPK4, CPK5, CPK6, CPK10, CPK11, and CPK23  KAT1 , K+ upta 6 KUP6; , vacuola 6 KUP6;  and Plas 6 KUP6; . Downstrnd CPK23 , and mitnd CPK23 . The regA wide range of MAMPs from bacteria, fungi and oomycetes have been identified and characterized . New typP. syringae pv. tabaci 6605, and induces stomatal closure and inhibits light-trigged stomatal opening in Arabidopsis , Flagellin-sensitive 2 , which induces stomatal closure in tomato , which is also an LRR-RLK expressed in guard cells  family, among which Brassinosteroid insensitive1-associated kinase1/SERK3 (BAK1/SERK3) plays a dominant role . StructuP. aeruginosa. The LPS induces stomatal closure in Arabidopsis and tomato  that can have variable composition, length, and branching of its carbohydrate subunits. Due to variety in structure and easy contamination during preparation, LPS used in many of the plant researches can be consider a mixture of MAMPs and is derived from human pathogen d tomato . Lipopolbidopsis . The PRRbidopsis . Recent f plants . Interest manner . These rN-acetylglucosamineone and one of the major components of fungal cell wall. Chitosan is the deacetylated form of chitin. Caution has to be paid that commercially available chitosan can be only partially deacetylated. For example, some chitosan from Sigma is 75 to 85% deacetylated. Chitin induces stomatal closure in Arabidopsis (Arabidopsis (Arabidopsis involves three lysin motif type RLKs (LysM-RLKs), Lysin motif receptor kinase 5 (LYK5), LYK4 and chitin elicitor receptor kinase 1 (CERK1)  . It has  (CERK1) . These r (CERK1) . For the (CERK1) . Chitosa (CERK1) . It is f (CERK1) .Mixtures of β-1→3-linked glucans with different DP have been shown to induce stomatal closure and inhibits stomatal opening in grapevine and tobacco . The strArabidopsis (Elicitors from baker’s yeast (YEL) extracted by ethanol precipitation mainly contains fungal cell wall fraction including mannan, β-1→3-linked glucans, chitin, and glycopeptides, and has been widely used as a fungal MAMP to induce plant immune response including stomatal responses . YEL indbidopsis , 2015.2O2, NO, and Ca2+, phosphorylation events mediated by CDPKs, OST1, and MAPKs, and changes of transporter activity. In this section, we review the main signaling events upon perception of MAMPs with focus on findings from Arabidopsis guard cells.Guard cell signaling induced by MAMPs involves in recruitment of second messengers, such as H2O2, are important second messengers in guard cell signaling induced by abiotic and biotic factors H oxidases, RBOHD and RBOHF. NAD(P)H oxidases transfer electrons from cytosolic NAD(P)H to apoplastic oxygen, leading to superoxide production. The superoxide can be converted to H2O2 through dismutation by unknown superoxide dismutase . Regarding the activation of NAD(P)H oxidases, studies have shown that elevation of free cytosolic Ca2+ concentration ([Ca2+]cyt) and phosphorylation by CDPKs are important for flg22- and elf18-induced H2O2 production in leaf disks H oxidases. In ABA signaling, the Ca2+-independent protein kinase, OST1, phosphorylates RBOHF at Ser13 and Ser174 and interacts with RBOHD . Both internal factors, such as SA -sensitive PRXs but not RBOHD or RBOHF are essential for stomatal closure and H2O2 production in guard cells induced by SA, ITCs, methylglyoxal, chitosan and YEL , and flg22 , 2011. Frd cells . It is loduction . Pharmacchitosan ,b. Howevoduction . Enzymatoduction . Pharmacoduction . Howeveroduction . Two Ara closure . Further2+ has long been considered as an important second messenger in guard cell signaling induced by various internal and external stimuli , which are activated by hyperpolarization  are involved in elevation of [Ca2+]cyt in seedlings induced by flg22, elf18, and chitin , other proteins containing EF-hand are CDPKs, CaM-like proteins (CML) and calcineurin B-like protein (CBL). CBLs can form complexes with CBL-interacting protein kinases (CIPKs) to convert the Ca2+ signal to phosphorylation events  represents a Ca2+ sensor of low Ca2+ affinity/high-capacity that does not contain EF-hand motif and is associated with thylakoid membranes . Further research is needed to validate this possibility.To our knowledge, there is no evidence that kinase activity of OST1 is increased by stimuli other than ABA in guard cells. On the other hand, recent studies have shown that flg22 does not increase OST1 kinase in rd cells . OST1 isrd cells . Flg22 drd cells , suggestPst DC3000, in which flg22 is the dominant MAMP sensed by guard cells H-free solution . Further studies reveal that CPK6 is required for activation of ICa channels induced by ABA, MeJA, and YEL , and R-type channels, ALMT12. However, SLAC1 shows the most prominent role in regulation of stomatal closure induced by various stimuli, such as ABA, CO2, darkness and high extracellular Ca2+  as positive regulators and PP2Cs as negative regulators .In channels . These rchannels . Since tgulators . Howevergulators . In casegulators . These rgulators . CPK6 dod by YEL . These rin vitro, which are probably dephosphorylated by PP2Cs  function as the main gate for K+ eﬄux to the apoplast. Both Kin channels and Kout channels are voltage-dependent and do not inactivate with time . On the other hand, YEL and chitosan induced stomatal closure in ABA-deficient mutant , such as 4-hydroxy-2-nonenal and acrolein, is produced by both enzymatic and non-enzymatic mechanisms and regulates guard cell signalings . Recent 2O2 accumulation in guard cells induced by flg22, LPS, elf26 and ABA , LecRK-V.5, and Cysteine-rich receptor-like kinases (CRKs), which are involved in guard cell MAMP signaling. LecRK-V.5 has been reported to negatively regulate stomatal closure and H and ABA . LecRK-V and ABA . Furthercificity . For the2O2 production, sensing of Ca2+, MAPK function and regulation of anion channels. However, these mechanisms do have their own specificity. For example, CPK3 and CPK6 have different Ca2+ sensitivity, with CPK6 activated at lower Ca2+ concentration, but both can phosphorylate SLAC1 . Future research is needed to unravel new Ca2+-dependent mechanisms. Emergent challenge is to elucidate how Ca2+-independent mechanisms, such as the ones mediated by OST1 and MAPKs, are involved in MAMP signaling in guard cells. Signaling specificity provided by RLCKs and CRKs has been observed in MAMP-induced stomatal response. Further elucidation of these specificities is essential for dissecting MAMP signaling in guard cells.Though plasma membrane-localized PRRs in guard cells are widely accepted to function to perceive MAMPs, MAMP signaling also happens in the cell wall. It remains unknown whether the apoplast signaling is regulated by the plasm membrane-localized PRRs or there are PRRs in the apoplasts. Upon binding of PRRs and ligands, co-receptors are immediately recruited to form receptor complexes, which determine the specificity of signalings. The core signaling downstream to induce stomatal closure is that MAMP perception induces CaThe roles of phytohormones in guard cell MAMP signaling are still unclear. Though increase of phytohormone by methods such as direct application can induce stomatal movement, it is less likely that MAMPs increase the level of phytohormone to trigger stomatal movement, as seen in the case that flg22 does not increase ABA content. Therefore, it is important to note that the function of elevating level of phytohormone can be different from that of phytohormone in unstressed plants. An emerging role is that phytohormones, such as ethylene and SA, in unstressed plants regulate the level of PRRs. A possible role is that phytohormones, such as ABA, are important for providing basal activity of important signaling components. The future challenge is to elucidate the roles of endogenous phytohormones in guard cell MAMP signaling.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Eryptosis is triggered by a wide variety of xenobiotics. It is inhibited by several xenobiotics and endogenous molecules including NO and erythropoietin. The susceptibility of erythrocytes to eryptosis increases with erythrocyte age. Phosphatidylserine exposing erythrocytes adhere to the vascular wall by binding to endothelial CXC-Motiv-Chemokin-16/Scavenger-receptor for phosphatidylserine and oxidized low density lipoprotein (CXCL16). Phosphatidylserine exposing erythrocytes are further engulfed by phagocytosing cells and are thus rapidly cleared from circulating blood. Eryptosis eliminates infected or defective erythrocytes thus counteracting parasitemia in malaria and preventing detrimental hemolysis of defective cells. Excessive eryptosis, however, may lead to anemia and may interfere with microcirculation. Enhanced eryptosis contributes to the pathophysiology of several clinical disorders including metabolic syndrome and diabetes, malignancy, cardiac and renal insufficiency, hemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose 6-phosphate dehydrogenase deficiency, and Wilson's disease. Facilitating or inhibiting eryptosis may be a therapeutic option in those disorders.Suicidal erythrocyte death or eryptosis is characterized by erythrocyte shrinkage, cell membrane blebbing, and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca The lifespan of circulating erythrocytes is limited by senescence to 100–120 days . In seneThe present paper lists triggers and inhibitors or eryptosis, the mechanisms involved in the regulation of eryptosis, and the (patho-) physiological significance of eryptosis. The reader is encouraged to study earlier reviews on further aspects of eryptosis –12.As listed in The susceptibility to stimulation of eryptosis increases with erythrocyte age . The enhErythrocytes from newborns are relatively resistant to several triggers of eryptosis but are highly susceptible to eryptosis following oxidative stress –24. The 2+ activity ([Ca2+]i) [2+]i mainly results from Ca2+ entry through Ca2+-permeable unselective cation channels i and eryptosis following Cl− removal were thus blunted in erythrocytes from gene-targeted mice lacking TRPC6 [A major trigger of eryptosis is the increase of cytosolic Ca[Ca2+]i) . The incchannels , 27, whiand Ca2+ . The cha2 (PGE2) , 30. Phaic shock . The Ca2sorbitol  and by s or SCN− . They ar or SCN− –34, whicryptosis , 28. Actryptosis . Accordiryptosis –37 glutaryptosis , salidroryptosis , 7-monohryptosis , trolox ryptosis , or N-acryptosis , 20. Theryptosis . The incng TRPC6 .2+]i following activation of the cation channels is followed by cell shrinkage due to activation of Ca2+-sensitive K+ channels i further stimulates cell membrane scrambling with breakdown of phosphatidylserine asymmetry of the erythrocyte cell membrane and translocation of phosphatidylserine to the erythrocyte surface i and subsequent stimulation of eryptosis upon exposure of erythrocytes to oxidative stress or following energy depletion [α opens cation channels and thus triggers Ca2+ influx into erythrocytes [Pharmacological evidence points to a role of casein kinase 1epletion . Pharmachrocytes . Osmotichrocytes  and pharhrocytes . Eryptoshrocytes  and sunihrocytes  sensitiv2+]i [2+ as it protects against eryptosis induced by the Ca2+ ionophore ionomycin without appreciably affecting the ionomycin-induced increase of [Ca2+]i. NO blunts apoptosis of nucleated cells in part by caspase inhibition [2+]i [Eryptosis is further inhibited by cGMP-dependent protein kinase (cGKI) . cGKI de2+]i . The kin2+]i –233, a p2+]i . NO is s2+]i –236. Ery2+]i  at conce2+]i , 238. NOhibition , 240. Hoon [2+]i –245 NO ion [2+]i . Converson [2+]i , 242. Ason [2+]i . The effon [2+]i . In conton [2+]i , excession [2+]i –248. NO on [2+]i , 250. Inon [2+]i  and pres2+]i, ceramide, oxidative stress, caspases, nitroxide, and a variety of kinases. Most triggers of eryptosis are mainly effective by increasing [Ca2+]i and/or enhancing ceramide abundance in the cell membrane. Unlike in apoptosis of nucleated cells, caspases do not play a dominant role in the triggering of eryptosis. Survival of erythrocytes does require the activity of several kinases including AMPK and cGKI. Activation of other kinases, such as CK1α and JAK3, triggers eryptosis. The phosphorylation targets of the kinases required for the stimulation or inhibition of eryptosis are still ill-defined. Clearly, tremendous additional experimental effort is required for full understanding of the eryptotic machinery.Collectively erythrocyte survival and eryptosis are regulated by an amazingly complex cellular machinery involving i results from activation of the Ca2+ permeable unselective cation channels i i . The pat [Ca2+]i . Plasmodylserine , 299 andylserine , 301. Thylserine . Adherenhrocytes . P. falciparum, however, the formation of PGE2, Ca2+ permeability, phosphatidylserine exposure at the cell surface, and removal by macrophages are all augmented in HbA/S carriers [Upon infection, eryptosis is accelerated in erythrocytes from heterozygous carriers of the sickle-cell trait (HbA/S), beta-thalassemia-trait, homozygous Hb-C, and G6PD-deficiency thus leading to early clearance of infected erythrocytes, decreased parasitemia, and a relatively mild course of the disease , 300. Ascarriers . The acccarriers . Moreovecarriers , chlorprcarriers , and inhcarriers . Importa2+-permeable unselective cation channels, ceramide, caspases, and a variety of kinases including Janus-activated kinase 3, AMP-activated kinase, cGMP-dependent protein kinase, casein kinase 1α, p38 kinase, protein kinase C, and p21-activated kinase 2. The sensitivity to eryptosis is enhanced in aged erythrocytes. Fetal erythrocytes are particularly sensitive to oxidative stress. Eryptosis is triggered by a wide variety of xenobiotics and enhanced eryptosis is observed in several clinical conditions including dehydration, diabetes, cardiac and renal insufficiency, hemolytic uremic syndrome, sepsis, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose 6-phosphate dehydrogenase deficiency, and Wilson's disease. Drugs and nutrients inhibiting eryptosis may open novel therapeutic options in the treatment of anemia and deranged microcirculation. Eryptosis stimulating xenobiotics may at least in theory accelerate removal of Plasmodium infected erythrocytes and thus favourably influence the clinical course of malaria.Similar to apoptosis of nucleated cells, eryptosis is a physiological mechanism eliminating defective erythrocytes in order to prevent hemolysis and subsequent release of hemoglobin into circulating blood. Excessive eryptosis may, however, cause anemia and impede microcirculation. Orchestration of eryptosis involves Ca