Science.gov

Sample records for glypican-1 potential agents

  1. Glypican-1 nanoliposomes for potentiating growth factor activity in therapeutic angiogenesis.

    PubMed

    Monteforte, Anthony J; Lam, Brian; Das, Subhamoy; Mukhopadhyay, Somshuvra; Wright, Catherine S; Martin, Patricia E; Dunn, Andrew K; Baker, Aaron B

    2016-07-01

    Therapeutic angiogenesis is a highly appealing concept for treating tissues that become ischemic due to vascular disease. A major barrier to the clinical translation of angiogenic therapies is that the patients that are in the greatest need of these treatments often have long term disease states and co-morbidities, such as diabetes and obesity, that make them resistant to angiogenic stimuli. In this study, we identified that human patients with type 2 diabetes have reduced levels of glypican-1 in the blood vessels of their skin. The lack of this key co-receptor in the tissue may make the application of exogenous angiogenic growth factors or cell therapies ineffective. We created a novel therapeutic enhancer for growth factor activity consisting of glypican-1 delivered in a nanoliposomal carrier (a "glypisome"). Here, we demonstrate that glypisomes enhance FGF-2 mediated endothelial cell proliferation, migration and tube formation. In addition, glypisomes enhance FGF-2 trafficking by increasing both uptake and endosomal processing. We encapsulated FGF-2 or FGF-2 with glypisomes in alginate beads and used these to deliver localized growth factor therapy in a murine hind limb ischemia model. Co-delivery of glypisomes with FGF-2 markedly increased the recovery of perfusion and vessel formation in ischemic hind limbs of wild type and diabetic mice in comparison to mice treated with FGF-2 alone. Together, our findings support that glypisomes are effective means for enhancing growth factor activity and may improve the response to local angiogenic growth factor therapies for ischemia. PMID:27101205

  2. Copper-dependent co-internalization of the prion protein and glypican-1.

    PubMed

    Cheng, Fang; Lindqvist, Josefin; Haigh, Cathryn L; Brown, David R; Mani, Katrin

    2006-09-01

    Heparan sulfate chains have been found to be associated with amyloid deposits in a number of diseases including transmissible spongiform encephalopathies. Diverse lines of evidence have linked proteoglycans and their glycosaminoglycan chains, and especially heparan sulfate, to the metabolism of the prion protein isoforms. Glypicans are a family of glycosylphosphatidylinositol-anchored, heparan sulfate-containing, cell-associated proteoglycans. Cysteines in glypican-1 can become nitrosylated by endogenously produced nitric oxide. When glypican-1 is exposed to a reducing agent, such as ascorbate, nitric oxide is released and autocatalyses deaminative cleavage of heparan sulfate chains. These processes take place while glypican-1 recycles via a non-classical, caveolin-associated pathway. We have previously demonstrated that prion protein provides the Cu2+ ions required to nitrosylate thiol groups in the core protein of glypican-1. By using confocal immunofluorescence microscopy and immunomagnetic techniques, we now show that copper induces co-internalization of prion protein and glypican-1 from the cell surface to perinuclear compartments. We find that prion protein is controlling both the internalization of glypican-1 and its nitric oxide-dependent autoprocessing. Silencing glypican-1 expression has no effect on copper-stimulated prion protein endocytosis, but in cells expressing a prion protein construct lacking the copper binding domain internalization of glypican-1 is much reduced and autoprocessing is abrogated. We also demonstrate that heparan sulfate chains of glypican-1 are poorly degraded in prion null fibroblasts. The addition of either Cu2+ ions, nitric oxide donors, ascorbate or ectopic expression of prion protein restores heparan sulfate degradation. These results indicate that the interaction between glypican-1 and Cu2+-loaded prion protein is required both for co-internalization and glypican-1 self-pruning. PMID:16923158

  3. Glypican1 identifies cancer exosomes and facilitates early detection of cancer

    PubMed Central

    Melo, Sonia A.; Luecke, Linda B.; Kahlert, Christoph; Fernandez, Agustin F.; Gammon, Seth T.; Kaye, Judith; LeBleu, Valerie S.; Mittendorf, Elizabeth A.; Weitz, Juergen; Rahbari, Nuh; Reissfelder, Christoph; Pilarsky, Christian; Fraga, Mario F.; Piwnica-Worms, David; Kalluri, Raghu

    2016-01-01

    Summary Exosomes are lipid bilayer-enclosed extracellular vesicles (EVs) that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer cell-derived exosomes in circulation is currently lacking. Using mass spectrometry analyses, we identified a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer cell-derived exosomes. GPC1+ circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of cancer patients and mice with cancer. GPC1+ crExos were detected in the serum of patients with pancreas cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreas disease from patients with early and late stage pancreas cancer. Levels of GPC1+ crExos correlate with tumor burden and survival in patients pre- and post-surgical tumor resection. GPC1+ crExos from patients and from mice with spontaneous pancreas tumors driven by oncogenic KRAS contained RNA with specific KRAS mutation, and it emerges as a reliable biomarker for the detection of PanIN lesions despite negative signal by MRI in mice. GPC1+ crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreas cancer to facilitate possible curative surgical therapy. PMID:26106858

  4. Shear-induced Endothelial NOS Activation and Remodeling via Heparan Sulfate, Glypican-1, and Syndecan-1

    PubMed Central

    Ebong, Eno E; Lopez-Quintero, Sandra V; Rizzo, Victor; Spray, David C; Tarbell, John M

    2014-01-01

    Mammalian epithelial cells are coated with a multifunctional surface glycocalyx (GCX). On vascular endothelial cells (EC), intact GCX is atheroprotective. It is degraded in many vascular diseases. GCX heparan sulfate (HS) is essential for healthy flow-induced EC nitric oxide (NO) release, elongation, and alignment. The HS core protein mechanisms involved in these processes are unknown. We hypothesized that the glypican-1 (GPC1) HS core protein mediates flow-induced EC NO synthase (eNOS) activation because GPC1 is anchored to caveolae where eNOS resides. We also hyphothesized that the HS core protein syndecan-1 (SDC1) mediates flow-induced EC elongation and alignment because SDC1 is linked to the cytoskeleton which impacts cell shape. We tested our hypotheses by exposing EC monolayers treated with HS degrading heparinase III (HepIII), and monolayers with RNA-silenced GPC1, or SDC1, to 3 to 24 hours of physiological shear stress. Shear-conditioned EC with intact GCX exhibited characteristic eNOS activation in short-term flow conditions. After long-term exposure, EC with intact GCX were elongated and aligned in the direction of flow. HS removal and GPC1 inhibition, not SDC1 reduction, blocked shear-induced eNOS activation. EC remodeling in response to flow was attenuated by HS degradation and in the absence of SDC1, but preserved with GPC1 knockdown. These findings clearly demonstrate that HS is involved in both centralized and decentralized GCX-mediated mechanotransduction mechanisms, with GPC1 acting as a centralized mechanotransmission agent and SDC1 functioning in decentralized mechanotransmission. This foundational work demonstrates how EC can transform fluid shear forces into diverse biomolecular and biomechanical responses. PMID:24480876

  5. Improvements in the order, isotropy and electron density of glypican-1 crystals by controlled dehydration

    SciTech Connect

    Awad, Wael; Svensson Birkedal, Gabriel; Thunnissen, Marjolein M. G. M.; Mani, Katrin; Logan, Derek T.

    2013-12-01

    The anisotropy of crystals of glypican-1 was significantly reduced by controlled dehydration using the HC1 device, allowing the building of previously disordered parts of the structure. The use of controlled dehydration for improvement of protein crystal diffraction quality is increasing in popularity, although there are still relatively few documented examples of success. A study has been carried out to establish whether controlled dehydration could be used to improve the anisotropy of crystals of the core protein of the human proteoglycan glypican-1. Crystals were subjected to controlled dehydration using the HC1 device. The optimal protocol for dehydration was developed by careful investigation of the following parameters: dehydration rate, final relative humidity and total incubation time T{sub inc}. Of these, the most important was shown to be T{sub inc}. After dehydration using the optimal protocol the crystals showed significantly reduced anisotropy and improved electron density, allowing the building of previously disordered parts of the structure.

  6. Glypican-1 regulates myoblast response to HGF via Met in a lipid raft-dependent mechanism: effect on migration of skeletal muscle precursor cells

    PubMed Central

    2014-01-01

    Background Via the hepatocyte growth factor receptor (Met), hepatocyte growth factor (HGF) exerts key roles involving skeletal muscle development and regeneration. Heparan sulfate proteoglycans (HSPGs) are critical modulators of HGF activity, but the role of specific HSPGs in HGF regulation is poorly understood. Glypican-1 is the only HSPG expressed in myoblasts that localize in lipid raft membrane domains, controlling cell responses to extracellular stimuli. We determined if glypican-1 in these domains is necessary to stabilize the HGF-Met signaling complex and myoblast response to HGF. Methods C2C12 myoblasts and a derived clone (C6) with low glypican-1 expression were used as an experimental model. The activation of Met, ERK1/2 and AKT in response to HGF was evaluated. The distribution of Met and its activated form in lipid raft domains, as well as its dependence on glypican-1, were characterized by sucrose density gradient fractionation in both cell types. Rescue experiments reexpressing glypican-1 or a chimeric glypican-1 fused to the transmembrane and cytoplasmic domains of mouse syndecan-1 or myoblast pretreatment with MβCD were conducted. In vitro and in vivo myoblast migration assays in response to HGF were also performed. Results Glypican-1 localization in membrane raft domains was required for a maximum cell response to HGF. It stabilized Met and HGF in lipid raft domains, forming a signaling complex where the active phospho-Met receptor was concentrated. Glypican-1 also stabilized CD44 in a HGF-dependent manner. In addition, glypican-1 was required for in vitro and in vivo HGF-dependent myoblast migration. Conclusions Glypican-1 is a regulator of HGF-dependent signaling via Met in lipid raft domains. PMID:24517345

  7. Glypican-1 as a Biomarker for Prostate Cancer: Isolation and Characterization

    PubMed Central

    Truong, Quach; Justiniano, Irene O.; Nocon, Aline L.; Soon, Julie T.; Wissmueller, Sandra; Campbell, Douglas H.; Walsh, Bradley J.

    2016-01-01

    Prostate cancer is the most frequently diagnosed male visceral cancer and the second leading cause of cancer death in the United States. Standard tests such as prostate-specific antigen (PSA) measurement have poor specificity (33%) resulting in a high number of false positive reports. Consequently there is a need for new biomarkers to address this problem. The MIL-38 antibody was first described nearly thirty years ago, however, until now, the identification of the target antigen remained elusive. By a series of molecular techniques and mass spectrometry, the MIL-38 antigen was identified to be the highly glycosylated proteoglycan Glypican-1 (GPC-1). This protein is present in two forms; a membrane bound core protein of 55-60 kDa and secreted soluble forms of 40 kDa and 52 kDa. GPC-1 identification was confirmed by immuno-precipitation, western blots and ELISA. An ELISA platform is currently being developed to assess the levels of GPC-1 in normal, benign prostatic hyperplasia (BPH) and prostate cancer patients to determine whether secreted GPC-1 may represent a clinically relevant biomarker for prostate cancer diagnosis. PMID:27313791

  8. Glypican-1 controls brain size through regulation of fibroblast growth factor signaling in early neurogenesis

    PubMed Central

    Jen, Yi-Huei Linda; Musacchio, Michele; Lander, Arthur D

    2009-01-01

    Background Cell surface heparan sulfate proteoglycans (HSPGs) act as co-receptors for multiple families of growth factors that regulate animal cell proliferation, differentiation and patterning. Elimination of heparan sulfate during brain development is known to produce severe structural abnormalities. Here we investigate the developmental role played by one particular HSPG, glypican-1 (Gpc1), which is especially abundant on neuronal cell membranes, and is the major HSPG of the adult rodent brain. Results Mice with a null mutation in Gpc1 were generated and found to be viable and fertile. The major phenotype associated with Gpc1 loss is a highly significant reduction in brain size, with only subtle effects on brain patterning (confined to the anterior cerebellum). The brain size difference emerges very early during neurogenesis (between embryonic days 8.5 and 9.5), and remains roughly constant throughout development and adulthood. By examining markers of different signaling pathways, and the differentiation behaviors of cells in the early embryonic brain, we infer that Gpc1-/- phenotypes most likely result from a transient reduction in fibroblast growth factor (FGF) signaling. Through the analysis of compound mutants, we provide strong evidence that Fgf17 is the FGF family member through which Gpc1 controls brain size. Conclusion These data add to a growing literature that implicates the glypican family of HSPGs in organ size control. They also argue that, among heparan sulfate-dependent signaling molecules, FGFs are disproportionately sensitive to loss of HSPGs. Finally, because heterozygous Gpc1 mutant mice were found to have brain sizes half-way between homozygous and wild type, the data imply that endogenous HSPG levels quantitatively control growth factor signaling, a finding that is both novel and relevant to the general question of how the activities of co-receptors are exploited during development. PMID:19732411

  9. Bacteriocins as Potential Anticancer Agents

    PubMed Central

    Kaur, Sumanpreet; Kaur, Sukhraj

    2015-01-01

    Cancer remains one of the leading causes of deaths worldwide, despite advances in its treatment and detection. The conventional chemotherapeutic agents used for the treatment of cancer have non-specific toxicity toward normal body cells that cause various side effects. Secondly, cancer cells are known to develop chemotherapy resistance in due course of treatment. Thus, the demand for novel anti-cancer agents is increasing day by day. Some of the experimental studies have reported the therapeutic potential of bacteriocins against various types of cancer cell lines. Bacteriocins are ribosomally-synthesized cationic peptides secreted by almost all groups of bacteria. Some bacteriocins have shown selective cytotoxicity toward cancer cells as compared to normal cells. This makes them promising candidates for further investigation and clinical trials. In this review article, we present the overview of the various cancer cell-specific cytotoxic bacteriocins, their mode of action and efficacies. PMID:26617524

  10. Rapid nuclear transit and impaired degradation of amyloid β and glypican-1-derived heparan sulfate in Tg2576 mouse fibroblasts.

    PubMed

    Cheng, Fang; Fransson, Lars-Åke; Mani, Katrin

    2015-05-01

    Anhydromannose (anMan)-containing heparan sulfate (HS) derived from S-nitrosylated glypican-1 is generated in endosomes by an endogenously or ascorbate induced S-nitrosothiol-catalyzed reaction. Expression and processing of amyloid precursor protein (APP) is required to initiate formation and endosome-to-nucleus translocation of anMan-containing HS in wild-type mouse embryonic fibroblasts (WT MEF). HS is then transported to autophagosomes and finally degraded in lysosomes. To investigate how APP-derived amyloid β (Aβ) peptide affects intracellular trafficking of HS, we have studied nuclear transit as well as autophagosome/lysosome targeting and degradation in transgenic Alzheimer disease mouse (Tg2576) MEF which produce increased amounts of Aβ. Deconvolution immunofluorescence microscopy with an anMan-specific monoclonal antibody showed anMan staining in the nuclei of Tg2576 MEF after 5 min of ascorbate treatment and after 15 min in WT MEF. There was also greater nuclear accumulation of HS in Tg2576 MEF as determined by (35)S-sulfate-labeling experiments. Tg2576 MEF was less sensitive to inhibition of NO production and copper-chelation than WT MEF. By using APP- and Aβ-recognizing antibodies, we observed nuclear translocation of Aβ peptide in Tg2576 MEF but not in WT MEF. HS remained in the nucleus of WT MEF for at least 8 h and was then transported to autophagosomes. By 8 h, HS had disappeared from the nuclei of Tg2576 MEF but colocalized poorly with the autophagosome marker LC3. Aβ also disappeared rapidly from the nuclei of Tg2576 MEF. Initially, it appeared in acidic vesicles and later it accumulated extracellularly. Thus, in Tg2576 MEF there is nuclear accumulation as well as secretion of Aβ and impaired degradation of HS. PMID:25527428

  11. The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo.

    PubMed

    Cappai, Roberto; Cheng, Fang; Ciccotosto, Giuseppe D; Needham, B Elise; Masters, Colin L; Multhaup, Gerd; Fransson, Lars-Ake; Mani, Katrin

    2005-04-01

    Processing of the recycling proteoglycan glypican-1 involves the release of its heparan sulfate chains by copper ion- and nitric oxide-catalyzed ascorbate-triggered autodegradation. The Alzheimer disease amyloid precursor protein (APP) and its paralogue, the amyloid precursor-like protein 2 (APLP2), contain copper ion-, zinc ion-, and heparan sulfate-binding domains. We have investigated the possibility that APP and APLP2 regulate glypican-1 processing during endocytosis and recycling. By using cell-free biochemical experiments, confocal laser immunofluorescence microscopy, and flow cytometry of tissues and cells from wild-type and knock-out mice, we find that (a) APP and glypican-1 colocalize in perinuclear compartments of neuroblastoma cells, (b) ascorbate-triggered nitric oxidecatalyzed glypican-1 autodegradation is zinc ion-dependent in the same cells, (c) in cell-free experiments, APP but not APLP2 stimulates glypican-1 autodegradation in the presence of both Cu(II) and Zn(II) ions, whereas the Cu(I) form of APP and the Cu(II) and Cu(I) forms of APLP2 inhibit autodegradation, (d) in primary cortical neurons from APP or APLP2 knock-out mice, there is an increased nitric oxide-catalyzed degradation of heparan sulfate compared with brain tissue and neurons from wild-type mice, and (e) in growth-quiescent fibroblasts from APLP2 knock-out mice, but not from APP knock-out mice, there is also an increased heparan sulfate degradation. We propose that the rate of autoprocessing of glypican-1 is modulated by APP and APLP2 in neurons and by APLP2 in fibroblasts. These observation identify a functional relationship between the heparan sulfate and copper ion binding activities of APP/APLP2 in their modulation of the nitroxyl anion-catalyzed heparan sulfate degradation in glypican-1. PMID:15677459

  12. Heterocyclic chalcone analogues as potential anticancer agents.

    PubMed

    Sharma, Vikas; Kumar, Vipin; Kumar, Pradeep

    2013-03-01

    Chalcones, aromatic ketones and enones acting as the precursor for flavonoids such as Quercetin, are known for their anticancer effects. Although, parent chalcones consist of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system, various synthetic compounds possessing heterocyclic rings like pyrazole, indole etc. are well known and proved to be effective anticancer agents. In addition to their use as anticancer agents in cancer cell lines, heterocyclic analogues are reported to be effective even against resistant cell lines. In this connection, we hereby highlight the potential of various heterocyclic chalcone analogues as anticancer agents with a brief summary about therapeutic potential of chalcones, mechanism of anticancer action of various chalcone analogues, and current and future prospects related to the chalcones-derived anticancer research. Furthermore, some key points regarding chalcone analogues have been reviewed by analyzing their medicinal properties. PMID:22721390

  13. Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells

    PubMed Central

    Chamorro-Jorganes, Aránzazu; Araldi, Elisa; Rotllan, Noemi; Cirera-Salinas, Daniel; Suárez, Yajaira

    2014-01-01

    ABSTRACT MicroRNA-149 (miR-149) is located within the first intron of the glypican-1 (GPC1) gene. GPC1 is a low affinity receptor for fibroblast growth factor (FGF2) that enhances FGF2 binding to its receptor (FGFR1), subsequently promoting FGF2–FGFR1 activation and signaling. Using bioinformatic approaches, both GPC1 and FGFR1 were identified and subsequently validated as targets for miR-149 (both the mature strand, miR-149, and the passenger strand, miR-149*) in endothelial cells (ECs). As a consequence of their targeting activity towards GPC1 and FGFR1, both miR-149 and miR-149* regulated FGF2 signaling and FGF2-induced responses in ECs, namely proliferation, migration and cord formation. Moreover, lentiviral overexpression of miR-149 reduced in vivo tumor-induced neovascularization. Importantly, FGF2 transcriptionally stimulated the expression of miR-149 independently of its host gene, therefore assuring the steady state of FGF2-induced responses through the regulation of the GPC1–FGFR1 binary complex in ECs. PMID:24463821

  14. Therapeutic potential of chalcones as cardiovascular agents.

    PubMed

    Mahapatra, Debarshi Kar; Bharti, Sanjay Kumar

    2016-03-01

    Cardiovascular diseases are the leading cause of death affecting 17.3 million people across the globe and are estimated to affect 23.3 million people by year 2030. In recent years, about 7.3 million people died due to coronary heart disease, 9.4 million deaths due to high blood pressure and 6.2 million due to stroke, where obesity and atherosclerotic progression remain the chief pathological factors. The search for newer and better cardiovascular agents is the foremost need to manage cardiac patient population across the world. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates to inhibit various cardiovascular, hematological and anti-obesity targets like angiotensin converting enzyme (ACE), cholesteryl ester transfer protein (CETP), diacylglycerol acyltransferase (DGAT), acyl-coenzyme A: cholesterol acyltransferase (ACAT), pancreatic lipase (PL), lipoprotein lipase (LPL), calcium (Ca(2+))/potassium (K(+)) channel, COX-1, TXA2 and TXB2. In this review, a comprehensive study of chalcones, their therapeutic targets, structure activity relationships (SARs), mechanisms of actions (MOAs) have been discussed. Chemically diverse chalcone scaffolds, their derivatives including structural manipulation of both aryl rings, replacement with heteroaryl scaffold(s) and hybridization through conjugation with other pharmacologically active scaffold have been highlighted. Chalcones which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-hypertensive, anti-anginal, anti-arrhythmic and cardioprotective agents. With the knowledge of these molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective chalcone derivatives as potential cardiovascular agents. PMID:26876916

  15. Smallpox: a potential agent of bioterrorism.

    PubMed

    Whitley, Richard J

    2003-01-01

    The events of 11 September 2001, in New York City, and subsequent identification of anthrax in the United States Postal System, have generated a new sense of awareness for the potential of biological terrorism, if not warfare. Among those agents identified by the Centers for Disease Control and Prevention as 'Class A Bioterrorist Threats', smallpox is among the most dangerous. The ease of transmission of this agent, the lack of immunity in the population at large to this agent, and rapidity of its spread, if released, all generate significant concern for its deployment. A vaccine directed against smallpox is available but it is also associated with significant adverse events-some of which are life-threatening. Further, no antiviral drug has proven efficacious for therapy of human disease, although one licensed drug, cidofovir, does have in vitro activity. Regardless, heightened awareness should lead to the development of a vaccine without significant adverse events and safe and efficacious antiviral drugs. The availability of a vaccine and antiviral drugs that are safe would significantly remove any major threat of smallpox deployment by a terrorist. PMID:12615298

  16. Potential of immunosuppressive agents in cerebral ischaemia

    PubMed Central

    Gupta, Yogendra Kumar; Chauhan, Anjali

    2011-01-01

    Ischaemic stroke is a disorder involving multiple mechanisms of injury progression including activation of glutamate receptors, release of proinflammatory cytokines, nitric oxide (NO), free oxygen radicals and proteases. Presently, recombinant tissue plasminogen activator (rtPA) is the only drug approved for the management of acute ischaemic stroke. This drug, however, is associated with limitations like narrow therapeutic window and increased risk of intracranial haemorrhage. A large number of therapeutic agents have been tested including N-methly-D-aspartate (NMDA) receptor antagonist, calcium channel blockers and antioxidants for management of stroke, but none has provided significant neuroprotection in clinical trials. Therefore, searching for other potentially effective drugs for ischaemic stroke management becomes important. Immunosuppressive agents with their wide array of mechanisms have potential as neuroprotectants. Corticosteroids, immunophilin ligands, mycophenolate mofetil and minocycline have shown protective effect on neurons by their direct actions or attenuating toxic effects of mediators of inflammation. This review focuses on the current status of corticosteroids, cyclosporine A, FK506, rapamycin, mycophenolate mofetil and minocycline in the experimental models of cerebral ischaemia. PMID:21321416

  17. Rodents as potential couriers for bioterrorism agents.

    PubMed

    Lõhmus, Mare; Janse, Ingmar; van de Goot, Frank; van Rotterdam, Bart J

    2013-09-01

    Many pathogens that can cause major public health, economic, and social damage are relatively easily accessible and could be used as biological weapons. Wildlife is a natural reservoir for many potential bioterrorism agents, and, as history has shown, eliminating a pathogen that has dispersed among wild fauna can be extremely challenging. Since a number of wild rodent species live close to humans, rodents constitute a vector for pathogens to circulate among wildlife, domestic animals, and humans. This article reviews the possible consequences of a deliberate spread of rodentborne pathogens. It is relatively easy to infect wild rodents with certain pathogens or to release infected rodents, and the action would be difficult to trace. Rodents can also function as reservoirs for diseases that have been spread during a bioterrorism attack and cause recurring disease outbreaks. As rats and mice are common in both urban and rural settlements, deliberately released rodentborne infections have the capacity to spread very rapidly. The majority of pathogens that are listed as potential agents of bioterrorism by the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases exploit rodents as vectors or reservoirs. In addition to zoonotic diseases, deliberately released rodentborne epizootics can have serious economic consequences for society, for example, in the area of international trade restrictions. The ability to rapidly detect introduced diseases and effectively communicate with the public in crisis situations enables a quick response and is essential for successful and cost-effective disease control. PMID:23971813

  18. Tocotrienol as a potential anticancer agent.

    PubMed

    Ling, Ming T; Luk, Sze U; Al-Ejeh, Fares; Khanna, Kum K

    2012-02-01

    Vitamin E is composed of two structurally similar compounds: tocopherols (TPs) and tocotrienols (T3). Despite being overshadowed by TP over the past few decades, T3 is now considered to be a promising anticancer agent due to its potent effects against a wide range of cancers. A growing body of evidence suggests that in addition to its antioxidative and pro-apoptotic functions, T3 possesses a number of anticancer properties that make it superior to TP. These include the inhibition of epithelial-to-mesenchymal transitions, the suppression of vascular endothelial growth factor tumor angiogenic pathway and the induction of antitumor immunity. More recently, T3, but not TP, has been shown to have chemosensitization and anti-cancer stem cell effects, further demonstrating the potential of T3 as an effective anticancer therapeutic agent. With most of the previous clinical studies on TP producing disappointing results, research has now focused on testing T3 as the next generation vitamin E for chemoprevention and cancer treatment. This review will summarize recent developments in the understanding of the anticancer effects of T3. We will also discuss current progress in clinical trials involving T3 as an adjuvant to conventional cancer therapy. PMID:22095072

  19. [Q fever, a potential biowarfare agent].

    PubMed

    Bossi, Philippe; Guihot, Amélie; Bricaire, François

    2003-10-18

    SEVERAL POSSIBLE METHODS OF TRANSFUSION: Q fever is a zoonosis due to Coxiella burnetii. Its interest as a potential biowarfare agent is in its possible transmission by inhalation of sprayed particles. This form of transmission would probably be used: the inhalation of 1 to 10 bacteria could provoke the development of an infection in humans. Another possible method of transmission in the context of a terrorist act would be the intentional introduction of the bacteria into foodstuff. A DISABLING WEAPON: However, C. burnetii has never been used as a biological weapon. The probability that this germ could be used is very low: indeed, the incubation of Q fever is very long, and the majority of the infections is asymptomatic and mortality is low. In fact C. burnetii would more likely be used as a disabling weapon. PMID:14576588

  20. Plants' Metabolites as Potential Antiobesity Agents

    PubMed Central

    Gooda Sahib, Najla; Saari, Nazamid; Ismail, Amin; Khatib, Alfi; Mahomoodally, Fawzi; Abdul Hamid, Azizah

    2012-01-01

    Obesity and obesity-related complications are on the increase both in the developed and developing world. Since existing pharmaceuticals fail to come up with long-term solutions to address this issue, there is an ever-pressing need to find and develop new drugs and alternatives. Natural products, particularly medicinal plants, are believed to harbor potential antiobesity agents that can act through various mechanisms either by preventing weight gain or promoting weight loss amongst others. The inhibition of key lipid and carbohydrate hydrolyzing and metabolizing enzymes, disruption of adipogenesis, and modulation of its factors or appetite suppression are some of the plethora of targeted approaches to probe the antiobesity potential of medicinal plants. A new technology such as metabolomics, which deals with the study of the whole metabolome, has been identified to be a promising technique to probe the progression of diseases, elucidate their pathologies, and assess the effects of natural health products on certain pathological conditions. This has been applied to drug research, bone health, and to a limited extent to obesity research. This paper thus endeavors to give an overview of those plants, which have been reported to have antiobesity effects and highlight the potential and relevance of metabolomics in obesity research. PMID:22666121

  1. Other potentially useful new injectable anesthetic agents.

    PubMed

    Ilkiw, J E

    1992-03-01

    Ultrashort barbiturates are not ideal injectable anesthetic agents, and new agents continue to be released as investigators pursue the goal of finding a more ideal agent. Of the new injectable agents discussed, propofol seems to be the most promising drug. Propofol should find a place in veterinary practice as an outpatient anesthetic agent because it has a rapid, smooth, and complete recovery even after repeated or continuous administration. Midazolam does not induce anesthesia in healthy, small animals and, as such, can only be used in combination with other injectable agents, such as ketamine or the thiobarbiturates. In our practice, Telazol has found a place in the anesthetic management of feral cats and aggressive dogs, where it is used for heavy sedation or to induce anesthesia. The role of flumazenil, as a reversal agent, in veterinary practice remains to be determined; however, the role in small domestic animals is unlikely to be significant. PMID:1585555

  2. Nigella sativa: A Potential Antiosteoporotic Agent

    PubMed Central

    Shuid, Ahmad Nazrun; Mohamed, Norazlina; Mohamed, Isa Naina; Othman, Faizah; Suhaimi, Farihah; Mohd Ramli, Elvy Suhana; Muhammad, Norliza; Soelaiman, Ima Nirwana

    2012-01-01

    Nigella sativa seeds (NS) has been used traditionally for various illnesses. The most abundant and active component of NS is thymoquinone (TQ). Animal studies have shown that NS and TQ may be used for the treatment of diabetes-induced osteoporosis and for the promotion of fracture healing. The mechanism involved is unclear, but it was postulated that the antioxidative, and anti-inflammatory activities may play some roles in the treatment of osteoporosis as this bone disease has been linked to oxidative stress and inflammation. This paper highlights studies on the antiosteoporotic effects of NS and TQ, the mechanisms behind these effects and their safety profiles. NS and TQ were shown to inhibit inflammatory cytokines such as interleukin-1 and 6 and the transcription factor, nuclear factor κB. NS and TQ were found to be safe at the current dosage for supplementation in human with precautions in children and pregnant women. Both NS and TQ have shown potential as antiosteoporotic agent but more animal and clinical studies are required to further assess their antiosteoporotic efficacies. PMID:22973403

  3. Anti-arthritic agents: progress and potential.

    PubMed

    Laev, Sergey S; Salakhutdinov, Nariman F

    2015-07-01

    Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis. Cartilage breakdown is a key feature of both diseases which contributes to the pain and joint deformity experienced by patients. Therefore, anti-arthritis drugs are of great importance. The aim of this review is to present recent progress in studies of various agents against osteoarthritis and rheumatoid arthritis. The structures and activities of anti-arthritic agents, which used in medical practice or are in development, are presented and discussed. The effects and mechanisms of action of opioids, glucocorticoids, non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, natural products derived from plants, nutraceuticals, and a number of new and perspective agents are considered. Various perspective targets for the treatment of osteoarthritis and rheumatoid arthritis are also discussed. Trials of good quality are needed to draw solid conclusions regarding efficacy of many of the studied agents. Unfortunately, to date, there is no pharmacologic agent proven to prevent the progression of both diseases, and there is an urgent need for further development of better anti-arthritic agents. PMID:26014481

  4. Xenon fluorides show potential as fluorinating agents

    NASA Technical Reports Server (NTRS)

    Chernick, C. L.; Shieh, T. C.; Yang, N. C.

    1967-01-01

    Xenon fluorides permit the controlled addition of fluorine across an olefinic double bond. They provide a series of fluorinating agents that permit ready separation from the product at a high purity. The reactions may be carried out in the vapor phase.

  5. Efficient synthesis of benzamide riboside, a potential anticancer agent.

    PubMed

    Bonnac, Laurent F; Gao, Guang-Yao; Chen, Liqiang; Patterson, Steven E; Jayaram, Hiremagalur N; Pankiewicz, Krzysztof W

    2007-01-01

    An efficient five step synthesis of benzamide riboside (BR) amenable for a large scale synthesis has been developed. It allows for extensive pre-clinical studies of BR as a potential anticancer agent. PMID:18066762

  6. Beer constituents as potential cancer chemopreventive agents.

    PubMed

    Gerhäuser, Clarissa

    2005-09-01

    Beer is a complex alcoholic beverage made from barley (malt), hop, water and yeast. Phenolic constituents of beer are derived from malt (70-80%) and hop (20-30%). Structural classes include simple phenols, benzoic- and cinnamic acid derivatives, coumarins, catechins, di-, tri- and oligomeric proanthocyanidins, (prenylated) chalcones and flavonoids as well as alpha- and iso-alpha-acids derived from hop. Compounds belonging to different structural classes have distinct profiles of biological activity in in vitro test systems, and in combination might lead to enhanced effects. Scientific evidence has accumulated over the past 10 years pointing to the cancer preventive potential of selected hop-derived beer constituents, i.e., prenylflavonoids including xanthohumol and isoxanthohumol, and hop bitter acids. Chemopreventive activities observed with these compounds relevant to inhibition of carcinogenesis at the initiation, promotion and progression phases, as well as results from in vivo studies on metabolism, bioavailability and efficacy are summarised in this review. PMID:15953717

  7. Gadolinium oxide nanoparticles as potential multimodal imaging and therapeutic agents.

    PubMed

    Kim, Tae Jeong; Chae, Kwon Seok; Chang, Yongmin; Lee, Gang Ho

    2013-01-01

    Potentials of hydrophilic and biocompatible ligand coated gadolinium oxide nanoparticles as multimodal imaging agents, drug carriers, and therapeutic agents are reviewed. First of all, they can be used as advanced T1 magnetic resonance imaging (MRI) contrast agents because they have r1 larger than those of Gd(III)-chelates due to a high density of Gd(III) per nanoparticle. They can be further functionalized by conjugating other imaging agents such as fluorescent imaging (FI), X-ray computed tomography (CT), positron emission tomography (PET), and single photon emission tomography (SPECT) agents. They can be also useful for drug carriers through morphology modifications. They themselves are also potential CT and ultrasound imaging (USI) contrast and thermal neutron capture therapeutic (NCT) agents, which are superior to commercial iodine compounds, air-filled albumin microspheres, and boron ((10)B) compounds, respectively. They, when conjugated with targeting agents such as antibodies and peptides, will provide enhanced images and be also very useful for diagnosis and therapy of diseases (so called theragnosis). PMID:23432005

  8. 1,2-Dialkyl-4-pyrazolidinethiols as potential antiradiation agents.

    PubMed

    Kornet, M J; Daniels, R

    1979-10-01

    The reaction between 3-chloropropylene sulfide and the 1,2-dialkylhydrazines was employed to prepare a series of 1,2-dialkyl-4-pyrazolidinethiols. Evidence is presented to support the structure proposed for the product. These mercaptoheterocycles are related to the beta-mercaptoethylamines and were prepared as potential radiation protective agents. No significant activity was observed. PMID:512875

  9. Primary screen for potential sheep scab control agents.

    PubMed

    Dunn, J A; Prickett, J C; Collins, D A; Weaver, R J

    2016-07-15

    The efficacy of potential acaricidal agents were assessed against the sheep scab mite Psoroptes ovis using a series of in vitro assays in modified test arenas designed initially to maintain P. ovis off-host. The mortality effects of 45 control agents, including essential oils, detergents, desiccants, growth regulators, lipid synthesis inhibitors, nerve action/energy metabolism disruptors and ecdysteroids were assessed against adults and nymphs. The most effective candidates were the desiccants (diatomaceous earth, nanoclay and sorex), the growth regulators (buprofezin, hexythiazox and teflubenzuron), the lipid synthesis inhibitors (spirodiclofen, spirotetramat and spiromesifen) and the nerve action and energy metabolism inhibitors (fenpyroximate, spinosad, tolfenpyrad, and chlorantraniliprole). PMID:27270393

  10. Polymeric Thioxanthones as Potential Anticancer and Radiotherapy Agents.

    PubMed

    Yilmaz, Gorkem; Guler, Emine; Barlas, Firat Baris; Timur, Suna; Yagci, Yusuf

    2016-07-01

    Thioxanthone (TX) and its derivatives, which are widely used as photoinitiators in UV curing technology, hold promising research interest in biological applications. In particular, the use of TXs as anticancer agent has recently been manifested as an outstanding additional property of this class of molecules. Incorporation of TX molecules into specially designed polymers widens their practical use in such applications. In this study, two water-soluble, biocompatible, and stable polymers, namely poly(vinyl alcohol) and poly(ethylene glycol), possessing TX moieties at the side chains and chain ends, respectively, are prepared and used as anticancer and radiotherapy agents. The findings confirm that both polymers are potential candidates for therapeutic agents as they possess useful features including water-solubility, radiosensitizer effect, and anticancer activity in a polymeric scaffold. PMID:27168378

  11. Modified quaternary ammonium salts as potential antimalarial agents.

    PubMed

    Basilico, Nicoletta; Migotto, Mara; Ilboudo, Denise Patoinewende; Taramelli, Donatella; Stradi, Riccardo; Pini, Elena

    2015-08-01

    A series of new quaternary ammonium salts containing a polyconjugated moiety has been synthesized and characterized; their biological activity as potential antimalarial agents was investigated, as well. All compounds were screened against chloroquine resistant W-2 (CQ-R) and chloroquine sensitive, D-10 (CQ-S) strains of Plasmodium falciparum showing IC50 in the submicromolar range and low toxicity against human endothelial cells. PMID:26081764

  12. Chalcone derivatives as potential antifungal agents: Synthesis, and antifungal activity.

    PubMed

    Gupta, Deepa; Jain, D K

    2015-01-01

    Much research has been carried out with the aim to discover the therapeutic values of chalcone derivatives. Chalcones possess wide range of pharmacological activity such as antibacterial, antimalarial, antiprotozoal, antitubercular, anticancer, and antifungal agents etc. The presence of reactive α,β-unsaturated keto group in chalcones is found to be responsible for their biological activity. The rapid developments of resistance to antifungal agents, led to design, and synthesize the new antifungal agents. The derivatives of chalcones were prepared using Claisen-Schmidt condensation scheme with appropriate tetralone and aldehyde derivatives. Ten derivatives were synthesized and were biologically screened for antifungal activity. The newly synthesized derivatives of chalcone showed antifungal activity against fungal species, Microsporum gypseum. The results so obtained were superior or comparable to ketoconazole. It was observed that none of the compounds tested showed positive results for fungi Candida albicans nor against fungi Aspergillus niger. Chalcone derivatives showed inhibitory effect against M. gypseum species of fungus. It was found that among the chalcone derivatives so synthesized, two of them, that is, 4-chloro derivative, and unsubstituted derivative of chalcone showed antifungal activity superior to ketoconazole. Thus, these can be the potential new molecule as antifungal agent. PMID:26317075

  13. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

    PubMed Central

    Thoppil, Roslin J; Bishayee, Anupam

    2011-01-01

    Despite significant advances in medicine, liver cancer, predominantly hepatocellular carcinoma remains a major cause of death in the United States as well as the rest of the world. As limited treatment options are currently available to patients with liver cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. Several naturally occurring dietary and non-dietary phytochemicals have shown enormous potential in the prevention and treatment of several cancers, especially those of the gastrointestinal tract. Terpenoids, the largest group of phytochemicals, traditionally used for medicinal purposes in India and China, are currently being explored as anticancer agents in clinical trials. Terpenoids (also called “isoprenoids”) are secondary metabolites occurring in most organisms, particularly plants. More than 40 000 individual terpenoids are known to exist in nature with new compounds being discovered every year. A large number of terpenoids exhibit cytotoxicity against a variety of tumor cells and cancer preventive as well as anticancer efficacy in preclinical animal models. This review critically examines the potential role of naturally occurring terpenoids, from diverse origins, in the chemoprevention and treatment of liver tumors. Both in vitro and in vivo effects of these agents and related cellular and molecular mechanisms are highlighted. Potential challenges and future directions involved in the advancement of these promising natural compounds in the chemoprevention and therapy of human liver cancer are also discussed. PMID:21969877

  14. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer.

    PubMed

    Thoppil, Roslin J; Bishayee, Anupam

    2011-09-27

    Despite significant advances in medicine, liver cancer, predominantly hepatocellular carcinoma remains a major cause of death in the United States as well as the rest of the world. As limited treatment options are currently available to patients with liver cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. Several naturally occurring dietary and non-dietary phytochemicals have shown enormous potential in the prevention and treatment of several cancers, especially those of the gastrointestinal tract. Terpenoids, the largest group of phytochemicals, traditionally used for medicinal purposes in India and China, are currently being explored as anticancer agents in clinical trials. Terpenoids (also called "isoprenoids") are secondary metabolites occurring in most organisms, particularly plants. More than 40 000 individual terpenoids are known to exist in nature with new compounds being discovered every year. A large number of terpenoids exhibit cytotoxicity against a variety of tumor cells and cancer preventive as well as anticancer efficacy in preclinical animal models. This review critically examines the potential role of naturally occurring terpenoids, from diverse origins, in the chemoprevention and treatment of liver tumors. Both in vitro and in vivo effects of these agents and related cellular and molecular mechanisms are highlighted. Potential challenges and future directions involved in the advancement of these promising natural compounds in the chemoprevention and therapy of human liver cancer are also discussed. PMID:21969877

  15. Hypoglycemic agents and potential anti-inflammatory activity

    PubMed Central

    Kothari, Vishal; Galdo, John A; Mathews, Suresh T

    2016-01-01

    Current literature shows an association of diabetes and secondary complications with chronic inflammation. Evidence of these immunological changes include altered levels of cytokines and chemokines, changes in the numbers and activation states of various leukocyte populations, apoptosis, and fibrosis during diabetes. Therefore, treatment of diabetes and its complications may include pharmacological strategies to reduce inflammation. Apart from anti-inflammatory drugs, various hypoglycemic agents have also been found to reduce inflammation that could contribute to improved outcomes. Extensive studies have been carried out with thiazolidinediones (peroxisome proliferator-activated receptor-γ agonist), dipeptidyl peptidase-4 inhibitors, and metformin (AMP-activated protein kinase activator) with each of these classes of compounds showing moderate-to-strong anti-inflammatory action. Sulfonylureas and alpha glucosidase inhibitors appeared to exert modest effects, while the injectable agents, insulin and glucagon-like peptide-1 receptor agonists, may improve secondary complications due to their anti-inflammatory potential. Currently, there is a lack of clinical data on anti-inflammatory effects of sodium–glucose cotransporter type 2 inhibitors. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and effects related to intrinsic anti-inflammatory actions of the pharmacological class of compounds. PMID:27114714

  16. Turning on the Radio: Epigenetic Inhibitors as Potential Radiopriming Agents.

    PubMed

    Oronsky, Bryan; Scicinski, Jan; Kim, Michelle M; Cabrales, Pedro; Salacz, Michael E; Carter, Corey A; Oronsky, Neil; Lybeck, Harry; Lybeck, Michelle; Larson, Christopher; Reid, Tony R; Oronsky, Arnold

    2016-01-01

    First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved, clinical problem. Unfortunately, the therapeutic refractoriness of solid tumors is the rule not the exception, and the ubiquity of resistance also extends to standard chemotherapy, molecularly targeted therapy and immunotherapy. Based on extrapolation from recent clinical inroads with epigenetic agents to prime refractory tumors for maximum sensitivity to concurrent or subsequent therapies, the radioresistant phenotype is potentially reversible, since aberrant epigenetic mechanisms are critical contributors to the evolution of resistant subpopulations of malignant cells. Within the framework of a syllogism, this review explores the emerging link between epigenetics and the development of radioresistance and makes the case that a strategy of pre- or co-treatment with epigenetic agents has the potential to, not only derepress inappropriately silenced genes, but also increase reactive oxygen species production, resulting in the restoration of radiosensitivity. PMID:27384589

  17. Suppression of amyloid beta A11 antibody immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, nitric oxide (NO)-catalyzed degradation.

    PubMed

    Cheng, Fang; Cappai, Roberto; Ciccotosto, Giuseppe D; Svensson, Gabriel; Multhaup, Gerd; Fransson, Lars-Åke; Mani, Katrin

    2011-08-01

    Amyloid β (Aβ) is generated from the copper- and heparan sulfate (HS)-binding amyloid precursor protein (APP) by proteolytic processing. APP supports S-nitrosylation of the HS proteoglycan glypican-1 (Gpc-1). In the presence of ascorbate, there is NO-catalyzed release of anhydromannose (anMan)-containing oligosaccharides from Gpc-1-nitrosothiol. We investigated whether these oligosaccharides interact with Aβ during APP processing and plaque formation. anMan immunoreactivity was detected in amyloid plaques of Alzheimer (AD) and APP transgenic (Tg2576) mouse brains by immunofluorescence microscopy. APP/APP degradation products detected by antibodies to the C terminus of APP, but not Aβ oligomers detected by the anti-Aβ A11 antibody, colocalized with anMan immunoreactivity in Tg2576 fibroblasts. A 50-55-kDa anionic, sodium dodecyl sulfate-stable, anMan- and Aβ-immunoreactive species was obtained from Tg2576 fibroblasts using immunoprecipitation with anti-APP (C terminus). anMan-containing HS oligo- and disaccharide preparations modulated or suppressed A11 immunoreactivity and oligomerization of Aβ42 peptide in an in vitro assay. A11 immunoreactivity increased in Tg2576 fibroblasts when Gpc-1 autoprocessing was inhibited by 3-β[2(diethylamino)ethoxy]androst-5-en-17-one (U18666A) and decreased when Gpc-1 autoprocessing was stimulated by ascorbate. Neither overexpression of Gpc-1 in Tg2576 fibroblasts nor addition of copper ion and NO donor to hippocampal slices from 3xTg-AD mice affected A11 immunoreactivity levels. However, A11 immunoreactivity was greatly suppressed by the subsequent addition of ascorbate. We speculate that temporary interaction between the Aβ domain and small, anMan-containing oligosaccharides may preclude formation of toxic Aβ oligomers. A portion of the oligosaccharides are co-secreted with the Aβ peptides and deposited in plaques. These results support the notion that an inadequate supply of vitamin C could contribute to late onset AD

  18. Potential Anti-HIV Agents from Marine Resources: An Overview

    PubMed Central

    Vo, Thanh-Sang; Kim, Se-Kwon

    2010-01-01

    Human immunodeficiency virus (HIV) infection causes acquired immune deficiency syndrome (AIDS) and is a global public health issue. Anti-HIV therapy involving chemical drugs has improved the life quality of HIV/AIDS patients. However, emergence of HIV drug resistance, side effects and the necessity for long-term anti-HIV treatment are the main reasons for failure of anti-HIV therapy. Therefore, it is essential to isolate novel anti-HIV therapeutics from natural resources. Recently, a great deal of interest has been expressed regarding marine-derived anti-HIV agents such as phlorotannins, sulfated chitooligosaccharides, sulfated polysaccharides, lectins and bioactive peptides. This contribution presents an overview of anti-HIV therapeutics derived from marine resources and their potential application in HIV therapy. PMID:21339954

  19. Marine Diterpenoids as Potential Anti-Inflammatory Agents.

    PubMed

    González, Yisett; Torres-Mendoza, Daniel; Jones, Gillian E; Fernandez, Patricia L

    2015-01-01

    The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules. PMID:26538822

  20. Fetal Globin Gene Inducers: Novel Agents & New Potential

    PubMed Central

    Perrine, Susan P.; Castaneda, Serguei A.; Chui, David H.; Faller, Douglas V.; Berenson, Ronald J.; Fucharoen, Suthat

    2013-01-01

    Inducing expression of endogenous fetal globin (γ-globin) gene expression to 60-70% of alpha globin synthesis produces β-thalassemia trait globin synthetic ratios and can reduce anemia to a mild level. Several classes of therapeutics have induced γ-globin expression in beta thalassemia patients and subsequently raised total hemoglobin levels, demonstrating proof-of-concept of the approach. Butyrate treatment eliminated transfusion requirements in formerly transfusion-dependent patients with treatment for as long as 7 years. However, prior generations were not readily applicable for widespread use. Currently, a novel oral dual-action therapeutic sodium 2,2-dimethylbutyrate is in clinical trials, an oral decitabine formulation is under development, and agents with complementary mechanisms of action can be applied in combined regimens. Identification of 3 major genetic trait loci which modulate clinical severity provides avenues for developing tailored regimens. These refinements offer renewed potential to apply fetal globin induction as a treatment approach in patient-friendly regimens that can be used world-wide. PMID:20712788

  1. Honey: A Potential Therapeutic Agent for Managing Diabetic Wounds

    PubMed Central

    Islam, Md. Asiful; Gan, Siew Hua; Khalil, Md. Ibrahim

    2014-01-01

    Diabetic wounds are unlike typical wounds in that they are slower to heal, making treatment with conventional topical medications an uphill process. Among several different alternative therapies, honey is an effective choice because it provides comparatively rapid wound healing. Although honey has been used as an alternative medicine for wound healing since ancient times, the application of honey to diabetic wounds has only recently been revived. Because honey has some unique natural features as a wound healer, it works even more effectively on diabetic wounds than on normal wounds. In addition, honey is known as an “all in one” remedy for diabetic wound healing because it can combat many microorganisms that are involved in the wound process and because it possesses antioxidant activity and controls inflammation. In this review, the potential role of honey's antibacterial activity on diabetic wound-related microorganisms and honey's clinical effectiveness in treating diabetic wounds based on the most recent studies is described. Additionally, ways in which honey can be used as a safer, faster, and effective healing agent for diabetic wounds in comparison with other synthetic medications in terms of microbial resistance and treatment costs are also described to support its traditional claims. PMID:25386217

  2. Potential of Biological Agents in Decontamination of Agricultural Soil.

    PubMed

    Javaid, Muhammad Kashif; Ashiq, Mehrban; Tahir, Muhammad

    2016-01-01

    Pesticides are widely used for the control of weeds, diseases, and pests of cultivated plants all over the world, mainly since the period after the Second World War. The use of pesticides is very extensive to control harm of pests all over the globe. Persistent nature of most of the synthetic pesticides causes serious environmental concerns. Decontamination of these hazardous chemicals is very essential. This review paper elaborates the potential of various biological agents in decontamination of agricultural soils. The agricultural crop fields are contaminated by the periodic applications of pesticides. Biodegradation is an ecofriendly, cost-effective, highly efficient approach compared to the physical and chemical methods which are expensive as well as unfriendly towards environment. Biodegradation is sensitive to the concentration levels of hydrogen peroxide and nitrogen along with microbial community, temperature, and pH changes. Experimental work for optimum conditions at lab scale can provide very fruitful results about specific bacterial, fungal strains. This study revealed an upper hand of bioremediation over physicochemical approaches. Further studies should be carried out to understand mechanisms of biotransformation. PMID:27293964

  3. Astaxanthin: A Potential Therapeutic Agent in Cardiovascular Disease

    PubMed Central

    Fassett, Robert G.; Coombes, Jeff S.

    2011-01-01

    Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail. It is an antioxidant with anti-inflammatory properties and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease. Synthetic forms of astaxanthin have been manufactured. The safety, bioavailability and effects of astaxanthin on oxidative stress and inflammation that have relevance to the pathophysiology of atherosclerotic cardiovascular disease, have been assessed in a small number of clinical studies. No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event. At this stage we do not know whether astaxanthin is of benefit when administered after a cardiovascular event and no clinical cardiovascular studies in humans have been completed and/or reported. Cardiovascular clinical trials are warranted based on the physicochemical and antioxidant properties, the safety profile and preliminary experimental cardiovascular studies of astaxanthin. PMID:21556169

  4. Potential of Biological Agents in Decontamination of Agricultural Soil

    PubMed Central

    Javaid, Muhammad Kashif; Ashiq, Mehrban; Tahir, Muhammad

    2016-01-01

    Pesticides are widely used for the control of weeds, diseases, and pests of cultivated plants all over the world, mainly since the period after the Second World War. The use of pesticides is very extensive to control harm of pests all over the globe. Persistent nature of most of the synthetic pesticides causes serious environmental concerns. Decontamination of these hazardous chemicals is very essential. This review paper elaborates the potential of various biological agents in decontamination of agricultural soils. The agricultural crop fields are contaminated by the periodic applications of pesticides. Biodegradation is an ecofriendly, cost-effective, highly efficient approach compared to the physical and chemical methods which are expensive as well as unfriendly towards environment. Biodegradation is sensitive to the concentration levels of hydrogen peroxide and nitrogen along with microbial community, temperature, and pH changes. Experimental work for optimum conditions at lab scale can provide very fruitful results about specific bacterial, fungal strains. This study revealed an upper hand of bioremediation over physicochemical approaches. Further studies should be carried out to understand mechanisms of biotransformation. PMID:27293964

  5. Marine Diterpenoids as Potential Anti-Inflammatory Agents

    PubMed Central

    González, Yisett; Torres-Mendoza, Daniel; Jones, Gillian E.; Fernandez, Patricia L.

    2015-01-01

    The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules. PMID:26538822

  6. Disulfiram attenuates osteoclast differentiation in vitro: a potential antiresorptive agent.

    PubMed

    Ying, Hua; Qin, An; Cheng, Tak S; Pavlos, Nathan J; Rea, Sarah; Dai, Kerong; Zheng, Ming H

    2015-01-01

    Disulfiram (DSF), a cysteine modifying compound, has long been clinically employed for the treatment of alcohol addiction. Mechanistically, DSF acts as a modulator of MAPK and NF-κB pathways signaling pathways. While these pathways are crucial for osteoclast (OC) differentiation, the potential influence of DSF on OC formation and function has not been directly assessed. Here, we explore the pharmacological effects of DSF on OC differentiation, activity and the modulation of osteoclastogenic signaling cascades. We first analyzed cytotoxicity of DSF on bone marrow monocytes isolated from C57BL/6J mice. Upon the establishment of optimal dosage, we conducted osteoclastogenesis and bone resorption assays in the presence or absence of DSF treatment. Luciferase assays in RAW264.7 cells were used to examine the effects of DSF on major transcription factors activation. Western blot, reverse transcription polymerase chain reaction, intracellular acidification and proton influx assays were employed to further dissect the underlying mechanism. DSF treatment dose-dependently inhibited both mouse and human osteoclastogenesis, especially at early stages of differentiation. This inhibition correlated with a decrease in the expression of key osteoclastic marker genes including CtsK, TRAP, DC-STAMP and Atp6v0d2 as well as a reduction in bone resorption in vitro. Suppression of OC differentiation was found to be due, at least in part, to the blockade of several key receptor activators of nuclear factor kappa-B ligand (RANKL)-signaling pathways including ERK, NF-κB and NFATc1. On the other hand, DSF failed to suppress intracellular acidification and proton influx in mouse and human osteoclasts using acridine orange quenching and microsome-based proton transport assays. Our findings indicate that DSF attenuates OC differentiation via the collective suppression of several key RANKL-mediated signaling cascades, thus making it an attractive agent for the treatment of OC

  7. Potential clinical application of interleukin-27 as an antitumor agent

    PubMed Central

    Yoshimoto, Takayuki; Chiba, Yukino; Furusawa, Jun-Ichi; Xu, Mingli; Tsunoda, Ren; Higuchi, Kaname; Mizoguchi, Izuru

    2015-01-01

    Cancer immunotherapies such as sipuleucel-T and ipilimumab are promising new treatments that harness the power of the immune system to fight cancer and achieve long-lasting remission. Interleukin (IL)-27, a member of the IL-12 heterodimeric cytokine family, has pleiotropic functions in the regulation of immune responses with both pro-inflammatory and anti-inflammatory properties. Evidence obtained using a variety of preclinical mouse models indicates that IL-27 possesses potent antitumor activity against various types of tumors through multiple mechanisms without apparent adverse effects. These mechanisms include those mediated not only by CD8+ T cells, natural killer cells and macrophages, but also by antibody-dependent cell-mediated cytotoxicity, antiangiogenesis, direct antiproliferative effects, inhibition of expression of cyclooxygenase-2 and prostaglandin E2, and suppression of epithelial–mesenchymal transition, depending on the characteristics of individual tumors. However, the endogenous role of IL-27 subunits and one of its receptor subunits, WSX-1, in the susceptibility to tumor development after transplantation of tumor cell lines or endogenously arising tumors seems to be more complicated. IL-27 functions as a double-edged sword: IL-27 increases IL-10 production and the expression of programmed death ligand 1 and T-cell immunoglobulin and mucin domain-3, and promotes the generation of regulatory T cells, and IL-27 receptor α singling enhances transformation; IL-27 may augment protumor effects as well. Here, we review both facets of IL-27, antitumor effects and protumor effects, and discuss the potential clinical application of IL-27 as an antitumor agent. PMID:26132605

  8. Disulfiram Attenuates Osteoclast Differentiation In Vitro: A Potential Antiresorptive Agent

    PubMed Central

    Cheng, Tak S.; Pavlos, Nathan J.; Rea, Sarah; Dai, Kerong; Zheng, Ming H.

    2015-01-01

    Disulfiram (DSF), a cysteine modifying compound, has long been clinically employed for the treatment of alcohol addiction. Mechanistically, DSF acts as a modulator of MAPK and NF-κB pathways signaling pathways. While these pathways are crucial for osteoclast (OC) differentiation, the potential influence of DSF on OC formation and function has not been directly assessed. Here, we explore the pharmacological effects of DSF on OC differentiation, activity and the modulation of osteoclastogenic signaling cascades. We first analyzed cytotoxicity of DSF on bone marrow monocytes isolated from C57BL/6J mice. Upon the establishment of optimal dosage, we conducted osteoclastogenesis and bone resorption assays in the presence or absence of DSF treatment. Luciferase assays in RAW264.7 cells were used to examine the effects of DSF on major transcription factors activation. Western blot, reverse transcription polymerase chain reaction, intracellular acidification and proton influx assays were employed to further dissect the underlying mechanism. DSF treatment dose-dependently inhibited both mouse and human osteoclastogenesis, especially at early stages of differentiation. This inhibition correlated with a decrease in the expression of key osteoclastic marker genes including CtsK, TRAP, DC-STAMP and Atp6v0d2 as well as a reduction in bone resorption in vitro. Suppression of OC differentiation was found to be due, at least in part, to the blockade of several key receptor activators of nuclear factor kappa-B ligand (RANKL)-signaling pathways including ERK, NF-κB and NFATc1. On the other hand, DSF failed to suppress intracellular acidification and proton influx in mouse and human osteoclasts using acridine orange quenching and microsome-based proton transport assays. Our findings indicate that DSF attenuates OC differentiation via the collective suppression of several key RANKL-mediated signaling cascades, thus making it an attractive agent for the treatment of OC

  9. Francisella tularensis as a potential agent of bioterrorism?

    PubMed

    Maurin, Max

    2015-02-01

    Francisella tularensis is a category A bioterrorism agent. It is the etiological agent of tularemia, a zoonotic disease found throughout the northern hemisphere. The intentional spread of F. tularensis aerosols would probably lead to severe and often fatal pneumonia cases, but also secondary cases from contaminated animals and environments. We are not ready to face such a situation. No vaccine is currently available. A few antibiotics are active against F. tularensis, but strains resistant to these antibiotics could be used in the context of bioterrorism. We need new therapeutic strategies to fight against category A bioterrorism agents, including development of new drugs inhibiting F. tularensis growth and/or virulence, or enhancing the host response to infection by this pathogen. PMID:25413334

  10. Occupational exposures to potentially hazardous agents in the petroleum industry.

    PubMed

    Runion, H E

    1988-01-01

    This chapter has been created to acquaint the reader with occupational exposures that are more common in, and somewhat unique to, the petroleum industry. Both highly toxic materials capable of causing acute illness or even death following short-term exposure, and chemical and physical agents that pose risk of chronic and irreversible damage to health during prolonged exposure are addressed. PMID:3043733

  11. Occupational exposures to potentially hazardous agents in the petroleum industry

    SciTech Connect

    Runion, H.E.

    1988-07-01

    This chapter has been created to acquaint the reader with occupational exposures that are more common in, and somewhat unique to, the petroleum industry. Both highly toxic materials capable of causing acute illness or even death following short-term exposure, and chemical and physical agents that pose risk of chronic and irreversible damage to health during prolonged exposure are addressed.

  12. Antioxidants: potential antiviral agents for Japanese encephalitis virus infection.

    PubMed

    Zhang, Yu; Wang, Zehua; Chen, Huan; Chen, Zongtao; Tian, Yanping

    2014-07-01

    Japanese encephalitis (JE) is prevalent throughout eastern and southern Asia and the Pacific Rim. It is caused by the JE virus (JEV), which belongs to the family Flaviviridae. Despite the importance of JE, little is known about its pathogenesis. The role of oxidative stress in the pathogenesis of viral infections has led to increased interest in its role in JEV infections. This review focuses mainly on the role of oxidative stress in the pathogenesis of JEV infection and the antiviral effect of antioxidant agents in inhibiting JEV production. First, this review summarizes the pathogenesis of JE. The pathological changes include neuronal death, astrocyte activation, and microglial proliferation. Second, the relationship between oxidative stress and JEV infection is explored. JEV infection induces the generation of oxidants and exhausts the supply of antioxidants, which activates specific signaling pathways. Finally, the therapeutic efficacy of a variety of antioxidants as antiviral agents, including minocycline, arctigenin, fenofibrate, and curcumin, was studied. In conclusion, antioxidants are likely to be developed into antiviral agents for the treatment of JE. PMID:24780919

  13. Synthesis of alpha-methylenebeutyrolactams as potential antitumor agents.

    PubMed

    Kornet, M J

    1979-03-01

    A series of 1-aryl-3-methylene-2-pyrrolidinones was synthesized via a three-step reaction sequence. 1,4-Bis-[N-(3-methylene-2-oxopyrrolidino)]benzene, which can undergo alkylation at two sites, was also prepared. These compounds are related to the known antitumor agents alpha-methylenebutyrolactones. Attempts to prepare bis-alpha-methylenelactams, in which the heterocyclic rings are joined through their nitrogen atoms by an alkylene bridge, were unsuccessful. All of the alpha-methylenelactams were screened in B16 melanocarcinoma and P-388 lymphocytic leukemia tumor systems but failed to show significant activity. PMID:423127

  14. Investigation of Vietnamese plants for potential anticancer agents

    PubMed Central

    Pérez, Lynette Bueno; Still, Patrick C.; Naman, C. Benjamin; Ren, Yulin; Pan, Li; Chai, Hee-Byung; Carcache de Blanco, Esperanza J.; Ninh, Tran Ngoc; Van Thanh, Bui; Swanson, Steven M.; Soejarto, Djaja D.

    2014-01-01

    Higher plants continue to afford humankind with many new drugs, for a variety of disease types. In this review, recent phytochemical and biological progress is presented for part of a collaborative multi-institutional project directed towards the discovery of new antitumor agents. The specific focus is on bioactive natural products isolated and characterized structurally from tropical plants collected in Vietnam. The plant collection, identification, and processing steps are described, and the natural products isolated from these species are summarized with their biological activities. PMID:25395897

  15. Monocarboxylate Transporter 1 Inhibitors as Potential Anticancer Agents

    PubMed Central

    2015-01-01

    Potent monocarboxylate transporter 1 inhibitors (MCT1) have been developed based on α-cyano-4-hydroxycinnamic acid template. Structure–activity relationship studies demonstrate that the introduction of p-N, N-dialkyl/diaryl, and o-methoxy groups into cyanocinnamic acid has maximal MCT1 inhibitory activity. Systemic toxicity studies in healthy ICR mice with few potent MCT1 inhibitors indicate normal body weight gains in treated animals. In vivo tumor growth inhibition studies in colorectal adenocarcinoma (WiDr cell line) in nude mice xenograft models establish that compound 27 exhibits single agent activity in inhibiting the tumor growth. PMID:26005533

  16. Pyrazoles as potential anti-angiogenesis agents: A contemporary overview

    NASA Astrophysics Data System (ADS)

    Kasiotis, Konstantinos; Tzanetou, Evangelia; Haroutounian, Serkos

    2014-09-01

    Angiogenesis is a mulit-step process by which new blood vessels are formed from preexisting vasculature. It is a key rate limiting factor in tumor growth since new blood vessels are necessary to increase tumor size. In this context it has been shown that anti-angiogenic factors can be used in cancer therapy. Among the plethora of heterocyclic compounds administered as anti-angiogenesis agents, pyrazoles constitute one of the bottlenecks of this category. Currently several pyrazole based compounds are administered or are in Phase II and III trials and new targets emerge. It is highly possible that the advent of the next two decades will lead to the discovery and use of additional pyrazoles whose anti-angiogenic profile will position them in the forefront of the battle of various malignancies. The present review is an attempt to focus on those pyrazoles that arise as anti-angiogenesis agents commenting both on the chemistry and bioactivity that these exhibit aiming to contribute to the perspectives that they hold for future research.

  17. Therapeutic Potential of Hydrazones as Anti-Inflammatory Agents

    PubMed Central

    Bala, Suman; Sharma, Neha; Saini, Vipin

    2014-01-01

    Hydrazones are a special class of organic compounds in the Schiff base family. Hydrazones constitute a versatile compound of organic class having basic structure (R1R2C=NNR3R4). The active centers of hydrazone, that is, carbon and nitrogen, are mainly responsible for the physical and chemical properties of the hydrazones and, due to the reactivity toward electrophiles and nucleophiles, hydrazones are used for the synthesis of organic compound such as heterocyclic compounds with a variety of biological activities. Hydrazones and their derivatives are known to exhibit a wide range of interesting biological activities like antioxidant, anti-inflammatory, anticonvulsant, analgesic, antimicrobial, anticancer, antiprotozoal, antioxidant, antiparasitic, antiplatelet, cardioprotective, anthelmintic, antidiabetic, antitubercular, trypanocidal, anti-HIV, and so forth. The present review summarizes the efficiency of hydrazones as potent anti-inflammatory agents. PMID:25383223

  18. [Chalcones and their heterocyclic analogs as potential antifungal chemotherapeutic agents].

    PubMed

    Opletalová, V; Sedivý, D

    1999-11-01

    Chalcones and their heterocyclic analogues show various biological effects, e.g. anti-inflammatory, antitumour, antibacterial, antituberculous, antiviral, antiprotozoal, gastroprotective, and others. The present review discusses in greater detail the fungistatic and fungicide properties of these compounds and presents also their chemical structures. The mechanism of antifungal effects of chalcones and their analogues has not been investigated in greater detail. Due to the presence of a reactive ketovinyl moiety in the molecule the compounds of this type are able to react with the thiol groups of enzymes. It cannot be excluded that chalcones interfere with the normal function of the membranes of fungi and moulds. Further investigation of chemical, physical, and biological properties of chalcones and their analogues could lead to the elucidation of the mechanism of their action and finding of effective fungicidal and fungistatic agents in this group of organic substances. PMID:10748740

  19. Biomaterials-Potential nucleation agents in blood and possible implications.

    PubMed

    Rohnke, Marcus; Henss, Anja

    2016-01-01

    Blood, simulated body fluids, and many cell culture media are supersaturated solutions with respect to several calcium phosphates. Therefore biomaterials can act as nucleation agents and evoke heterogeneous nucleation of salts on the surface of immersed biomaterials. Depending on the field of application, this can be either beneficial or disadvantageous. Although nucleation from supersaturated solutions is an old and well-known scientific phenomenon it is not standard to test new developed materials with surface analytical methods for their ability to initiate nucleation in vitro. Therefore, this communication aims to review the mineralization effect and to emphasize the possible negative implications, especially to functionalized bone implants. Surface coatings with proteins, growth factors, and, etc., can become ineffective due to deposition of a dense calcium phosphate layer. In the case of drug loaded implants, drug release might be inhibited. PMID:27316221

  20. Biological agents with potential for misuse: a historical perspective and defensive measures.

    PubMed

    Bhalla, Deepak K; Warheit, David B

    2004-08-15

    Biological and chemical agents capable of producing serious illness or mortality have been used in biowarfare from ancient times. Use of these agents has progressed from crude forms in early and middle ages, when snakes and infected cadavers were used as weapons in battles, to sophisticated preparations for use during and after the second World War. Cults and terrorist organizations have attempted the use of biological agents with an aim to immobilize populations or cause serious harm. The reasons for interest in these agents by individuals and organizations include relative ease of acquisition, potential for causing mass casualty or panic, modest financing requirement, availability of technology, and relative ease of delivery. The Centers for Disease Control and Prevention has classified Critical Biological Agents into three major categories. This classification was based on several criteria, which include severity of impact on human health, potential for delivery in a weapon, capacity to cause panic and special needs for development, and stockpiling of medication. Agents that could cause the greatest harm following deliberate use were placed in category A. Category B included agents capable of producing serious harm and significant mortality but of lower magnitude than category A agents. Category C included emerging pathogens that could be developed for mass dispersion in future and their potential as a major health threat. A brief description of the category A bioagents is included and the pathophysiology of two particularly prominent agents, namely anthrax and smallpox, is discussed in detail. The potential danger from biological agents and their ever increasing threat to human populations have created a need for developing technologies for their early detection, for developing treatment strategies, and for refinement of procedures to ensure survival of affected individuals so as to attain the ultimate goal of eliminating the threat from intentional use of

  1. Potential Role of Garcinol as an Anticancer Agent

    PubMed Central

    Saadat, Nadia; Gupta, Smiti V.

    2012-01-01

    Garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Although the fruit has been consumed traditionally over centuries, its biological activities, specifically its anticancer potential is a result of recent scientific investigations. The anticarcinogenic properties of garcinol appear to be moderated via its antioxidative, anti-inflammatory, antiangiogenic, and proapoptotic activities. In addition, garcinol displays effective epigenetic influence by inhibiting histone acetyltransferases (HAT 300) and by possible posttranscriptional modulation by mi RNA profiles involved in carcinogenesis. In vitro as well as some in vivo studies have shown the potential of this compound against several cancers types including breast, colon, pancreatic, and leukemia. Although this is a promising molecule in terms of its anticancer properties, investigations in relevant animal models, and subsequent human trials are warranted in order to fully appreciate and confirm its chemopreventative and/or therapeutic potential. PMID:22745638

  2. Neem components as potential agents for cancer prevention and treatment

    PubMed Central

    Hao, Fang; Kumar, Sandeep; Yadav, Neelu; Chandra, Dhyan

    2016-01-01

    Azadirachta indica, also known as neem, is commonly found in many semi-tropical and tropical countries including India, Pakistan, and Bangladesh. The components extracted from neem plant have been used in traditional medicine for the cure of multiple diseases including cancer for centuries. The extracts of seeds, leaves, flowers, and fruits of neem have consistently shown chemopreventive and antitumor effects in different types of cancer. Azadirachtin and nimbolide are among the few bioactive components in neem that have been studied extensively, but research on a great number of additional bioactive components is warranted. The key anticancer effects of neem components on malignant cells include inhibition of cell proliferation, induction of cell death, suppression of cancer angiogenesis, restoration of cellular reduction/oxidation (redox) balance, and enhancement of the host immune responses against tumor cells. While the underlying mechanisms of these effects are mostly unclear, the suppression of NF-κB signaling pathway is, at least partially, involved in the anticancer functions of neem components. Importantly, the anti-proliferative and apoptosis-inducing effects of neem components are tumor selective as the effects on normal cells are significantly weaker. In addition, neem extracts sensitize cancer cells to immunotherapy and radiotherapy, and enhance the efficacy of certain cancer chemotherapeutic agents. This review summarizes the current updates on the anticancer effects of neem components and their possible impact on managing cancer incidence and treatment. PMID:25016141

  3. Modified polysaccharides as potential (19)F magnetic resonance contrast agents.

    PubMed

    Krawczyk, Tomasz; Minoshima, Masafumi; Sugihara, Fuminori; Kikuchi, Kazuya

    2016-06-16

    The introduction of 3-aminobenzotrifluoride into partially oxidized alginic acid, dextran, and polygalacturonic acid (10-100 kDa) by means of the imine formation and a subsequent reduction resulted in water-soluble materials containing 1-14% of fluorine. They showed a single or split (19)F NMR signal in a narrow range of -63 to -63.5 ppm. The observed T1 and T2 were approximately 1 and 0.2 s at 400 or 500 MHz instruments, respectively. The samples showed low toxicity and uptake toward the HeLa cells similar to native polysaccharides and were preferentially localized in lysosomes. A tail intravenous injection of 5 mg of modified dextran containing 1% of fluorine revealed that the probe was not trapped in liver, spleen or kidneys, but was quickly cleared with urine. The proposed materials can be used for imaging of the gastrointestinal tract or the genitourinary system and act as a material for more complex (19)F MRI agent synthesis. PMID:27148998

  4. Lycopene: a review of its potential as an anticancer agent.

    PubMed

    Bhuvaneswari, V; Nagini, S

    2005-11-01

    Dietary chemoprevention has emerged as a cost effective approach to control most prevalent chronic diseases including cancer. In particular, tomato and tomato products are recognised to confer a wide range of health benefits. Epidemiological studies have provided evidence that high consumption of tomatoes effectively lowers the risk of reactive oxygen species (ROS)-mediated diseases such as cardiovascular disease and cancer by improving the antioxidant capacity. Tomatoes are rich sources of lycopene, an antioxidant carotenoid reported to be a more stable and potent singlet oxygen quenching agent compared to other carotenoids. In addition to its antioxidant properties, lycopene shows an array of biological effects including cardioprotective, anti-inflammatory, antimutagenic and anticarcinogenic activities. The anticancer activity of lycopene has been demonstrated both in in vitro and in vivo tumour models. The mechanisms underlying the inhibitory effects of lycopene on carcinogenesis could involve ROS scavenging, upregulation of detoxification systems, interference with cell proliferation, induction of gap-junctional communication, inhibition of cell cycle progression and modulation of signal transduction pathways. This review outlines the sources, structure, absorption, metabolism, bioavailability and pharmacological properties of lycopene with special reference to its antioxidant and anticarcinogenic effects. PMID:16305484

  5. Evaluation of potential biocontrol agent for aflatoxin in Argentinean peanuts.

    PubMed

    Alaniz Zanon, M S; Chiotta, M L; Giaj-Merlera, G; Barros, G; Chulze, S

    2013-04-01

    Biocontrol by competitive exclusion has been developed as the most promising means of controlling aflatoxins in peanuts. A 2-year study was carried out to determine the efficacy of an Aspergillus flavus strain as biocontrol agent to reduce aflatoxin production in peanuts under field conditions in Argentina. The competitive strain used was a nontoxigenic A. flavus (AFCHG2) naturally occurring in peanut from Córdoba, Argentina. The inoculum was produced through solid-state fermentation on long grain rice and applied at rate of 50kg inoculum/ha. The incidence of the released strain within the A. flavus communities in soil and peanuts was determined using the shift in the ratio toxigenic:nontoxigenic and VCG analysis. During the 2009/2010 growing season, treatments produced significant reductions in the incidence of toxigenic isolates of A. flavus/Aspergillus parasiticus in soil and peanuts. However, no preharvest aflatoxin contamination was observed. In the 2010/2011 growing season, plants were exposed to late season drought conditions that were optimal for aflatoxin contamination. Significant reductions in aflatoxin levels averaging 71% were detected in treated plots with different inoculation treatments. The results suggest that using the strategy of competitive exclusion A. flavus AFCHG2 can be applied to reduce aflatoxin contamination in Argentinean peanuts. PMID:23454811

  6. Neem components as potential agents for cancer prevention and treatment.

    PubMed

    Hao, Fang; Kumar, Sandeep; Yadav, Neelu; Chandra, Dhyan

    2014-08-01

    Azadirachta indica, also known as neem, is commonly found in many semi-tropical and tropical countries including India, Pakistan, and Bangladesh. The components extracted from neem plant have been used in traditional medicine for the cure of multiple diseases including cancer for centuries. The extracts of seeds, leaves, flowers, and fruits of neem have consistently shown chemopreventive and antitumor effects in different types of cancer. Azadirachtin and nimbolide are among the few bioactive components in neem that have been studied extensively, but research on a great number of additional bioactive components is warranted. The key anticancer effects of neem components on malignant cells include inhibition of cell proliferation, induction of cell death, suppression of cancer angiogenesis, restoration of cellular reduction/oxidation (redox) balance, and enhancement of the host immune responses against tumor cells. While the underlying mechanisms of these effects are mostly unclear, the suppression of NF-κB signaling pathway is, at least partially, involved in the anticancer functions of neem components. Importantly, the anti-proliferative and apoptosis-inducing effects of neem components are tumor selective as the effects on normal cells are significantly weaker. In addition, neem extracts sensitize cancer cells to immunotherapy and radiotherapy, and enhance the efficacy of certain cancer chemotherapeutic agents. This review summarizes the current updates on the anticancer effects of neem components and their possible impact on managing cancer incidence and treatment. PMID:25016141

  7. Thymol and eugenol derivatives as potential antileishmanial agents.

    PubMed

    de Morais, Selene Maia; Vila-Nova, Nadja Soares; Bevilaqua, Claudia Maria Leal; Rondon, Fernanda Cristina; Lobo, Carlos Henrique; de Alencar Araripe Noronha Moura, Arlindo; Sales, Antônia Débora; Rodrigues, Ana Paula Ribeiro; de Figuereido, José Ricardo; Campello, Claudio Cabral; Wilson, Mary E; de Andrade, Heitor Franco

    2014-11-01

    In Northeastern Brazil visceral leishmaniasis is endemic with lethal cases among humans and dogs. Treatment is toxic and 5-10% of humans die despite treatment. The aim of this work was to survey natural active compounds to find new molecules with high activity and low toxicity against Leishmania infantum chagasi. The compounds thymol and eugenol were chosen to be starting compounds to synthesize acetyl and benzoyl derivatives and to test their antileishmanial activity in vitro and in vivo against L. i. chagasi. A screening assay using luciferase-expressing promastigotes was used to measure the growth inhibition of promastigotes, and an ELISA in situ was performed to evaluate the growth inhibition of amastigote. For the in vivo assay, thymol and eugenol derivatives were given IP to BALB/c mice at 100mg/kg/day for 30 days. The thymol derivatives demonstrated the greater activity than the eugenol derivatives, and benzoyl-thymol was the best inhibitor (8.67 ± 0.28 μg/mL). All compounds demonstrated similar activity against amastigotes, and acetyl-thymol was more active than thymol and the positive control drug amphotericin B. Immunohistochemistry demonstrated the presence of Leishmania amastigote only in the spleen but not the liver of mice treated with acetyl-thymol. Thus, these synthesized derivatives demonstrated anti-leishmanial activity both in vitro and in vivo. These may constitute useful compounds to generate new agents for treatment of leishmaniasis. PMID:25281268

  8. Influence of potentially remineralizing agents on bleached enamel microhardness.

    PubMed

    Borges, Alessandra Bühler; Samezima, Leticia Yumi; Fonseca, Léila Pereira; Yui, Karen Cristina Kazue; Borges, Alexandre Luiz Souto; Torres, Carlos Rocha Gomes

    2009-01-01

    This study investigated the effect of the addition of calcium and fluoride into a 35% hydrogen peroxide gel on enamel surface and subsurface microhardness. Twenty extracted human third molars were sectioned to obtain enamel fragments and they were divided into four groups (n = 20) according to the bleaching treatment. Group 1 received no bleaching procedure (control). Group 2 was treated with a 35% hydrogen peroxide gel (Total Bleach), Groups 3 and 4 were bleached with Total Bleach modified by the addition of sodium fluoride and calcium chloride, respectively. The microhardness of the enamel surface was assessed using a Vickers microdurometer immediately after the bleaching treatment. The specimens were sectioned in the central portion, polished and evaluated to determine the microhardness of the enamel subsurface to a depth of 125 microm, with an interval of 25 microm between measures. There were significant differences among the groups. In terms of surface microhardness, the bleached group exhibited the lowest means, and the calcium-modified bleached group exhibited the highest means. Regarding subsurface microhardness, there were no significant differences among the groups for the depth and interaction factors. The bleached group exhibited the lowest means, and the calcium-modified bleached group presented the highest means. It was concluded that the bleaching treatment with 35% hydrogen peroxide significantly reduced the surface and subsurface microhardness of the enamel, and the addition of fluoride and calcium in the bleaching agent increased the microhardness means of the bleached enamel. PMID:19830975

  9. ZETA-POTENTIAL OF CONCRETE IN PRESENCE OF CHELATING AGENTS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Contamination of concrete surfaces at Nuclear Power Plants (NPP) and reprocessing facilities by radionuclides/heavy metals is a significant and widespread problem throughout the world’s Nuclear Power Industries. The current study of the zeta-potentials (') of concrete particles in the presence of va...

  10. Radioiodinated fenetylline (captagon): A new potential brain imaging agent

    SciTech Connect

    Biersack, H.J.; Klunenberg, H.; Breuel, H.P.; Reske, S.N.; Reichmann, K.; Winkler, C.

    1984-01-01

    Since about 2 years /sup 123/I-labeled iodamphetamines (IMP) and diamines (HIPDM) have been used for scintigraphic brain investigations. As another possibly useful brain imaging agent we studied radioiodine labeled Fenetylline which is metabolized into amphetamine. Thirty wistar rats were injected 5 ..mu..Ci /sup 125/I-IMP and 2 ..mu..Ci /sup 131/I-Fenetylline each simultaneously. The animals were sacrificed 5,10,15,30,60, and 120 min. p.i. The radioactivity content of tissue specimens (brain, cerebellum, liver, kidney, lung, myocardium, muscle) was measured in a well-counter (% dose/g tissue). In 2 dogs sequential cerebral scintigraphy was performed following the injection of 0.5 mCi /sup 131/I-Fenetylline. Three patients underwent brain SPECT after injection of 6.5 mCi /sup 123/I-Fenetylline. The results can be summarized as follows: after 5/10 min. p.i. Fenetylline-uptake in the brain of rats was 1.0/1.3% compared to 1.3/1.9% (IMP). A fast decrease of cerebral Fenetylline concentration was established after 30 (0.2%) and 60 (0.5%) min. The canine and human sequential scintigraphy revealed a rapid cerebral uptake (maximum after 2-10 min.) suggesting that Fenetylline is concentrated in the brain as a function of cerebral blood flow. From the first clinical findings it appears to be likely that the combined use of /sup 123/I labelled IMP and Fenetylline for SPECT may lead to a more differentiated evaluation of cerebral blood flow and metabolism.

  11. New water soluble pyrroloquinoline derivatives as new potential anticancer agents.

    PubMed

    Ferlin, Maria Grazia; Marzano, Christine; Dalla Via, Lisa; Chilin, Adriana; Zagotto, Giuseppe; Guiotto, Adriano; Moro, Stefano

    2005-08-01

    A new class of water soluble 3H-pyrrolo[3,2-f]quinoline derivatives has been synthesized and investigated as potential anticancer drugs. Water solubility profiles have been used to select the most promising derivatives. The novel compound 10, having two (2-diethylamino-ethyl) side chains linked through positions 3N and 9O, presents a suitable water solubility profile, and it was shown to exhibit cell growth inhibitory properties when tested against the in-house panel of cell lines, in particular those obtained from melanoma. PMID:15936202

  12. Potential Effects of Cannabidiol as a Wake-Promoting Agent

    PubMed Central

    Murillo-Rodríguez, Eric; Sarro-Ramírez, Andrea; Sánchez, Daniel; Mijangos-Moreno, Stephanie; Tejeda-Padrón, Alma; Poot-Aké, Alwin; Guzmán, Khalil; Pacheco-Pantoja, Elda; Arias-Carrión, Oscar

    2014-01-01

    Over the last decades, the scientific interest in chemistry and pharmacology of cannabinoids has increased. Most attention has focused on ∆9-tetrahydrocannabinol (∆9-THC) as it is the psychoactive constituent of Cannabis sativa (C. sativa). However, in previous years, the focus of interest in the second plant constituent with non-psychotropic properties, cannabidiol (CBD) has been enhanced. Recently, several groups have investigated the pharmacological properties of CBD with significant findings; furthermore, this compound has raised promising pharmacological properties as a wake-inducing drug. In the current review, we will provide experimental evidence regarding the potential role of CBD as a wake-inducing drug. PMID:24851090

  13. KETAMINE: A POTENTIAL RAPID-ACTING ANTISUICIDAL AGENT?

    PubMed

    Wilkinson, Samuel T; Sanacora, Gerard

    2016-08-01

    Ketamine has attracted widespread attention as a potential rapid-acting antidepressant. There is also considerable interest in its use for the rapid treatment of patients deemed at risk for suicide. Here, we review the available evidence (open-label and randomized controlled trials) that examine the effects of ketamine on suicidal ideation (SI). Overall, data suggest that ketamine has a rapid albeit transient effect in reducing SI, though some studies had mixed results at different time points or using different assessments. Weaknesses to the existing literature include the small sample sizes of the studies, the exclusion of patients with significant SI at baseline from many of the studies, and the potential functional unblinding when participants are randomized to saline as placebo. The evidence supporting the clinical use of ketamine for SI is very preliminary. Although ketamine appears to a promising therapeutic option in a context where there is a great unmet need (i.e., patients at imminent risk of suicide), further controlled trials are needed to allow for meaningful clinical recommendations. PMID:27082101

  14. New inhibitors of glycogen phosphorylase as potential antidiabetic agents.

    PubMed

    Somsák, L; Czifrák, K; Tóth, M; Bokor, E; Chrysina, E D; Alexacou, K-M; Hayes, J M; Tiraidis, C; Lazoura, E; Leonidas, D D; Zographos, S E; Oikonomakos, N G

    2008-01-01

    The protein glycogen phosphorylase has been linked to type 2 diabetes, indicating the importance of this target to human health. Hence, the search for potent and selective inhibitors of this enzyme, which may lead to antihyperglycaemic drugs, has received particular attention. Glycogen phosphorylase is a typical allosteric protein with five different ligand binding sites, thus offering multiple opportunities for modulation of enzyme activity. The present survey is focused on recent new molecules, potential inhibitors of the enzyme. The biological activity can be modified by these molecules through direct binding, allosteric effects or other structural changes. Progress in our understanding of the mechanism of action of these inhibitors has been made by the determination of high-resolution enzyme inhibitor structures (both muscle and liver). The knowledge of the three-dimensional structures of protein-ligand complexes allows analysis of how the ligands interact with the target and has the potential to facilitate structure-based drug design. In this review, the synthesis, structure determination and computational studies of the most recent inhibitors of glycogen phosphorylase at the different binding sites are presented and analyzed. PMID:19075645

  15. Natural products as a source of potential cancer chemotherapeutic and chemopreventive agents.

    PubMed

    Cassady, J M; Baird, W M; Chang, C J

    1990-01-01

    Recent advances in the chemistry of novel bioactive natural products are reported. This research is directed to the exploration of plants with confirmed activity in bioassays designed to detect potential cancer chemotherapeutic and chemopreventive agents. Structural work and chemical studies are reported for several cytotoxic agents from the plants Annona densicoma, Annona reticulata, Claopodium crispifolium, Polytrichum obioense, and Psorospermum febrifugum. Studies are also reported based on development of a mammalian cell culture benzo[a]pyrene metabolism assay for the detection of potential anticarcinogenic agents from natural products. In this study a number of isoflavonoids and flavonoids with antimutagenic activity have been discovered. PMID:2189947

  16. Potential Antiosteoporotic Agents from Plants: A Comprehensive Review

    PubMed Central

    Jia, Min; Nie, Yan; Cao, Da-Peng; Xue, Yun-Yun; Wang, Jie-Si; Zhao, Lu; Rahman, Khalid; Zhang, Qiao-Yan; Qin, Lu-Ping

    2012-01-01

    Osteoporosis is a major health hazard and is a disease of old age; it is a silent epidemic affecting more than 200 million people worldwide in recent years. Based on a large number of chemical and pharmacological research many plants and their compounds have been shown to possess antiosteoporosis activity. This paper reviews the medicinal plants displaying antiosteoporosis properties including their origin, active constituents, and pharmacological data. The plants reported here are the ones which are commonly used in traditional medical systems and have demonstrated clinical effectiveness against osteoporosis. Although many plants have the potential to prevent and treat osteoporosis, so far, only a fraction of these plants have been thoroughly investigated for their physiological and pharmacological properties including their mechanism of action. An attempt should be made to highlight plant species with possible antiosteoporosis properties and they should be investigated further to help with future drug development for treating this disease. PMID:23365596

  17. Nutraceuticals as potential therapeutic agents for colon cancer: a review

    PubMed Central

    Kuppusamy, Palaniselvam; Yusoff, Mashitah M.; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj

    2014-01-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis. PMID:26579381

  18. Nutraceuticals as potential therapeutic agents for colon cancer: a review.

    PubMed

    Kuppusamy, Palaniselvam; Yusoff, Mashitah M; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj

    2014-06-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis. PMID:26579381

  19. Potential Antiviral Agents from Marine Fungi: An Overview.

    PubMed

    Moghadamtousi, Soheil Zorofchian; Nikzad, Sonia; Kadir, Habsah Abdul; Abubakar, Sazaly; Zandi, Keivan

    2015-07-01

    Biodiversity of the marine world is only partially subjected to detailed scientific scrutiny in comparison to terrestrial life. Life in the marine world depends heavily on marine fungi scavenging the oceans of lifeless plants and animals and entering them into the nutrient cycle by. Approximately 150 to 200 new compounds, including alkaloids, sesquiterpenes, polyketides, and aromatic compounds, are identified from marine fungi annually. In recent years, numerous investigations demonstrated the tremendous potential of marine fungi as a promising source to develop new antivirals against different important viruses, including herpes simplex viruses, the human immunodeficiency virus, and the influenza virus. Various genera of marine fungi such as Aspergillus, Penicillium, Cladosporium, and Fusarium were subjected to compound isolation and antiviral studies, which led to an illustration of the strong antiviral activity of a variety of marine fungi-derived compounds. The present review strives to summarize all available knowledge on active compounds isolated from marine fungi with antiviral activity. PMID:26204947

  20. Potential Antiviral Agents from Marine Fungi: An Overview

    PubMed Central

    Zorofchian Moghadamtousi, Soheil; Nikzad, Sonia; Abdul Kadir, Habsah; Abubakar, Sazaly; Zandi, Keivan

    2015-01-01

    Biodiversity of the marine world is only partially subjected to detailed scientific scrutiny in comparison to terrestrial life. Life in the marine world depends heavily on marine fungi scavenging the oceans of lifeless plants and animals and entering them into the nutrient cycle by. Approximately 150 to 200 new compounds, including alkaloids, sesquiterpenes, polyketides, and aromatic compounds, are identified from marine fungi annually. In recent years, numerous investigations demonstrated the tremendous potential of marine fungi as a promising source to develop new antivirals against different important viruses, including herpes simplex viruses, the human immunodeficiency virus, and the influenza virus. Various genera of marine fungi such as Aspergillus, Penicillium, Cladosporium, and Fusarium were subjected to compound isolation and antiviral studies, which led to an illustration of the strong antiviral activity of a variety of marine fungi-derived compounds. The present review strives to summarize all available knowledge on active compounds isolated from marine fungi with antiviral activity. PMID:26204947

  1. Curcumin: a potential neuroprotective agent in Parkinson's disease.

    PubMed

    Mythri, R B; Bharath, M M Srinivas

    2012-01-01

    Parkinson's disease (PD) is an age-associated neurodegenerative disease clinically characterized as a movement disorder. The motor symptoms in PD arise due to selective degeneration of dopaminergic neurons in the substantia nigra of the ventral midbrain thereby depleting the dopamine levels in the striatum. Most of the current pharmacotherapeutic approaches in PD are aimed at replenishing the striatal dopamine. Although these drugs provide symptomatic relief during early PD, many patients develop motor complications with long-term treatment. Further, PD medications do not effectively tackle tremor, postural instability and cognitive deficits. Most importantly, most of these drugs do not exhibit neuroprotective effects in patients. Consequently, novel therapies involving natural antioxidants and plant products/molecules with neuroprotective properties are being exploited for adjunctive therapy. Curcumin is a polyphenol and an active component of turmeric (Curcuma longa), a dietary spice used in Indian cuisine and medicine. Curcumin exhibits antioxidant, anti-inflammatory and anti-cancer properties, crosses the blood-brain barrier and is neuroprotective in neurological disorders. Several studies in different experimental models of PD strongly support the clinical application of curcumin in PD. The current review explores the therapeutic potential of curcumin in PD. PMID:22211691

  2. Potential New Agents for the Management of Hyperkalemia.

    PubMed

    Packham, David K; Kosiborod, Mikhail

    2016-02-01

    Hyperkalemia is a common electrolyte disturbance with multiple potential etiologies. It is usually observed in the setting of reduced renal function. Mild to moderate hyperkalemia is usually asymptomatic, but is associated with poor prognosis. When severe, hyperkalemia may cause serious acute cardiac arrhythmias and conduction abnormalities, and may result in sudden death. The rising prevalence of conditions associated with hyperkalemia (heart failure, chronic kidney disease, and diabetes) and broad use of renin-angiotensin-aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists (MRAs), which improve patient outcomes but increase the risk of hyperkalemia, have led to a significant rise in hyperkalemia-related hospitalizations and deaths. Current non-invasive therapies for hyperkalemia either do not remove excess potassium or have poor efficacy and tolerability. There is a clear need for safer, more effective potassium-lowering therapies suitable for both acute and chronic settings. Patiromer sorbitex calcium and sodium zirconium cyclosilicate (ZS-9) are two new potassium-lowering compounds currently in development. Although they have not yet been approved by the US FDA, both have demonstrated efficacy and safety in recent trials. Patiromer sorbitex calcium is a polymer resin and sorbitol complex that binds potassium in exchange for calcium; ZS-9, a non-absorbed, highly selective inorganic cation exchanger, traps potassium in exchange for sodium and hydrogen. This review discusses the merits of both novel drugs and how they may help optimize the future management of patients with hyperkalemia. PMID:26156040

  3. Remineralizing potential of various agents on dental erosion

    PubMed Central

    Somani, Rani; Jaidka, Shipra; Singh, Deepti Jawa; Arora, Vanika

    2014-01-01

    Aim The purpose of this study is to compare the effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP, Tooth Mousse) containing and casein phosphopeptide-amorphous calcium phosphate with fluoride (CPP-ACPF, Tooth Mousse Plus) containing pastes on dental erosion. Materials and methods Thirty permanent non-carious premolars indicated for orthodontic extraction were included in this study and were sectioned in mesiodistal direction vertically. After immersion in the carbonated drink for 14 min, samples were treated with various remineralizing pastes which were CPP-ACP containing paste (Tooth Mousse) and CPP-ACPF containing paste (Tooth Mousse Plus) according to the manufacturer's instructions. Vickers Microhardness was recorded at baseline, after exposure to erosive drink and after treatment with remineralizing pastes. Data obtained was statistically analysed using Student t-test with a level of significance set at p < 0.05. Results CPP-ACP (Tooth Mousse) and CPP-ACP with fluoride (Tooth Mousse Plus) resulted in 30.52% and 38.98% increase in post-erosion microhardness values respectively. The remineralizing potential of CPP-ACP with fluoride containing paste (Tooth Mousse Plus) was significantly better than that of CPP-ACP containing paste (Tooth Mousse) (p < 0.05). Conclusion Casein phosphopeptide-amorphous calcium phosphate with fluoride (CPP-ACPF, Tooth Mousse Plus) can be recommended to be used in preventing erosive tooth wear from acidic beverages. PMID:25737926

  4. Characterizing potential heart agents with an isolated perfused heart system

    SciTech Connect

    Pendleton, D.B.; Sands, H.; Gallagher, B.M.; Camin, L.L.

    1984-01-01

    The authors have used an isolated perfused heart system for characterizing potential myocardial perfusion radiopharamaceuticals. Rabbit or guinea pig (GP) hearts are removed and perfused through the aorta with a blood-free buffer. Heart rate and ventricular pressure are monitored as indices of viability. Tc-99m-MAA is 96-100% retained in these hearts, and Tc-99m human serum albumin shows less than 5% extraction. Tl-201 is 30-40% extracted. It is known that in-vivo, Tc-99m(dmpe)/sub 2/Cl/sub 2//sup +/ is taken up by rabbit heart but not by GP or human heart. Analogous results are obtained with the isolated perfused heart model, where the complex is extracted well by the isolated rabbit heart (24%) but not by the GP heart (<5%). Values are unchanged if human, rabbit or GP blood is mixed and co-injected with the complex. Tc-99m)dmpe)/sub 3//sup +/ is also taken up by rabbit but not by GP hearts in-vivo. However, isolated perfused hearts of both species extract this complex well (45-52%). Heart uptake is diminished to <7% if the complex is pre-equilibrated with human blood. GP blood produces a moderate inhibition (in GP hearts only) and rabbit blood has no effect. This suggests that a human or GP blood factor may have a significant effect on heart uptake of this complex. Tc-99m(CN-t-butyl)/sub 6//sup +/ is taken up well by both rabbit and GP hearts in-vivo, and is extracted 100% by both isolated perfused hearts. Heart retention remains high (73-75%) in the presence of human blood.

  5. β-Nitrostyrenes as Potential Anti-leishmanial Agents

    PubMed Central

    Shafi, Syed; Afrin, Farhat; Islamuddin, Mohammad; Chouhan, Garima; Ali, Intzar; Naaz, Faatima; Sharma, Kalicharan; Zaman, Mohammad S.

    2016-01-01

    Development of new therapeutic approach to treat leishmaniasis has become a priority. In the present study, the antileishmanial effect of β-nitrostyrenes was investigated against in vitro promastigotes and amastigotes. A series of β-nitrostyrenes have been synthesized by using Henry reaction and were evaluated for their antimicrobial activities by broth microdilution assay and in vitro antileishmanial activities against Leishmania donovani promastigotes by following standard guidelines. The most active compounds were futher evaluated for their in vitro antileishmanial activities against intracellular amastigotes. Among the tested β-nitrostyrenes, compounds 7, 8, 9, 12, and 17 exhibited potential activities (MICs range, 0.25–8 μg/mL) against clinically significant human pathogenic fungi. However, the microbactericidal concentrations (MBCs) and the microfungicidal concentrations (MFCs) were found to be either similar or only two-fold greater than the MICs. Anti-leishmanial results demonstrated that compounds 9, 12, 14, and 18 were found to be most active among the tested samples and exhibited 50% inhibitory concentration (IC50) by 23.40 ± 0.71, 37.83 ± 3.74, 40.50 ± 1.47, 55.66 ± 2.84 nM against L. donovani promastigotes and 30.5 ± 3.42, 21.46 ± 0.96, 26.43 ± 2.71, and 61.63 ± 8.02 nM respectively against intracellular L. donovani promastigotes amastigotes respectively which are comparable with standard AmB (19.60 ± 1.71 nM against promastigotes and 27.83 ± 3.26 nM against amastigotes). Compounds 9, 12, 14, and 18 were found to have potent in vitro leishmanicidal activity against L. donovani and found to be non-toxic against mammalian macrophages even at a concentration of 25 μM. Nitric oxide (NO) estimation studies reveals that these compounds are moderately inducing NO levels.

  6. Nanomolar cationic dendrimeric sulfadiazine as potential antitoxoplasmic agent.

    PubMed

    Prieto, M J; Bacigalupe, D; Pardini, O; Amalvy, J I; Venturini, C; Morilla, M J; Romero, E L

    2006-12-01

    The high doses of sulfadiazine (SDZ), used in synergistic combination with pyrimethamine, are mainly responsible for severe side effects and discontinuation of toxoplasmosis treatments. In the search for new strategies that improve the efficacy of treatments with reduced doses of SDZ, we have determined the performance of cationic G4 (DG4) and anionic G4.5 (DG4.5) poly(amidoamine) (PAMAM) dendrimers to act as SDZ nanocarriers. Both dendrimers could efficiently load SDZ (SDZ-DG4 and SDZ-DG4.5) up to a ratio of 30 molecules SDZ per dendrimer molecule. The MTT assay on Vero and J774 cells showed no cytotoxicity for DG4.5 and its SDZ complex incubated between 0.03 and 33 microM of dendrimer concentration. On the other hand, DG4 and its SDZ complex resulted cytotoxic when incubated at dendrimer concentrations higher than 3.3 microM. Finally, complexes and empty dendrimers were in vitro tested against Vero cells infected with RH strain of Toxoplasma gondii along 4h of treatment. For SDZ-DG4.5 and DG4.5 to cause an infection decrease between 25 and 40%, respectively, a dendrimer concentration of 33 microM was required; however, SDZ-DG4 produced the highest infection decrease of 60% at 0.03 microM. These preliminary results, achieved with nanomolar doses of SDZ-DG4 as unique active principle, point to this complex as a suitable potential candidate for antitoxoplasmic therapy. PMID:16920292

  7. Hypochlorous Acid as a Potential Wound Care Agent

    PubMed Central

    Wang, L; Bassiri, M; Najafi, R; Najafi, K; Yang, J; Khosrovi, B; Hwong, W; Barati, E; Belisle, B; Celeri, C; Robson, MC

    2007-01-01

    Objective: Hypochlorous acid (HOCl), a major inorganic bactericidal compound of innate immunity, is effective against a broad range of microorganisms. Owing to its chemical nature, HOCl has never been used as a pharmaceutical drug for treating infection. In this article, we describe the chemical production, stabilization, and biological activity of a pharmaceutically useful formulation of HOCl. Methods: Stabilized HOCl is in the form of a physiologically balanced solution in 0.9% saline at a pH range of 3.5 to 4.0. Chlorine species distribution in solution is a function of pH. In aqueous solution, HOCl is the predominant species at the pH range of 3 to 6. At pH values less than 3.5, the solution exists as a mixture of chlorine in aqueous phase, chlorine gas, trichloride (Cl3−), and HOCl. At pH greater than 5.5, sodium hypochlorite (NaOCl) starts to form and becomes the predominant species in the alkaline pH. To maintain HOCl solution in a stable form, maximize its antimicrobial activities, and minimize undesirable side products, the pH must be maintained at 3.5 to 5. Results: Using this stabilized form of HOCl, the potent antimicrobial activities of HOCl are demonstrated against a wide range of microorganisms. The in vitro cytotoxicity profile in L929 cells and the in vivo safety profile of HOCl in various animal models are described. Conclusion: On the basis of the antimicrobial activity and the lack of animal toxicity, it is predicted that stabilized HOCl has potential pharmaceutical applications in the control of soft tissue infection. PMID:17492050

  8. Water-soluble platinum phthalocyanines as potential antitumor agents.

    PubMed

    Bologna, Giuseppina; Lanuti, Paola; D'Ambrosio, Primiano; Tonucci, Lucia; Pierdomenico, Laura; D'Emilio, Carlo; Celli, Nicola; Marchisio, Marco; d'Alessandro, Nicola; Santavenere, Eugenio; Bressan, Mario; Miscia, Sebastiano

    2014-06-01

    Breast cancer represents the second cause of death in the European female population. The lack of specific therapies together with its high invasive potential are the major problems associated to such a tumor. In the last three decades platinum-based drugs have been considered essential constituents of many therapeutic strategies, even though with side effects and frequent generation of drug resistance. These drugs have been the guide for the research, in last years, of novel platinum and ruthenium based compounds, able to overcome these limitations. In this work, ruthenium and platinum based phthalocyanines were synthesized through conventional techniques and their antiproliferative and/or cytotoxic actions were tested. Normal mammary gland (MCF10A) and several models of mammarian carcinoma at different degrees of invasiveness (BT474, MCF-7 and MDA-MB-231) were used. Cells were treated with different concentrations (5-100 μM) of the above reported compounds, to evaluate toxic concentration and to underline possible dose-response effects. The study included growth curves made by trypan blue exclusion test and scratch assay to study cellular motility and its possible negative modulation by phthalocyanine. Moreover, we investigated cell cycle and apoptosis through flow cytometry and AMNIS Image Stream cytometer. Among all the tested drugs, tetrasulfonated phthalocyanine of platinum resulted to be the molecule with the best cytostatic action on neoplastic cell lines at the concentration of 30 μM. Interestingly, platinum tetrasulfophtalocyanine, at low doses, had no antiproliferative effects on normal cells. Therefore, such platinum complex, appears to be a promising drug for mammarian carcinoma treatment. PMID:24699848

  9. Role of sodium tungstate as a potential antiplatelet agent

    PubMed Central

    Fernández-Ruiz, Rebeca; Pino, Marc; Hurtado, Begoña; García de Frutos, Pablo; Caballo, Carolina; Escolar, Ginés; Gomis, Ramón; Diaz-Ricart, Maribel

    2015-01-01

    Purpose Platelet inhibition is a key strategy in the management of atherothrombosis. However, the large variability in response to current strategies leads to the search for alternative inhibitors. The antiplatelet effect of the inorganic salt sodium tungstate (Na2O4W), a protein tyrosine phosphatase 1B (PTP1B) inhibitor, has been investigated in this study. Methods Wild-type (WT) and PTP1B knockout (PTP1B−/−) mice were treated for 1 week with Na2O4W to study platelet function with the platelet function analyzer PFA-100, a cone-and-plate analyzer, a flat perfusion chamber, and thrombus formation in vivo. Human blood aliquots were incubated with Na2O4W for 1 hour to measure platelet function using the PFA-100 and the annular perfusion chamber. Aggregometry and thromboelastometry were also performed. Results In WT mice, Na2O4W treatment prolonged closure times in the PFA-100 and decreased the surface covered (%SC) by platelets on collagen. Thrombi formed in a thrombosis mice model were smaller in animals treated with Na2O4W (4.6±0.7 mg vs 8.9±0.7 mg; P<0.001). Results with Na2O4W were similar to those in untreated PTP1B−/− mice (5.0±0.3 mg). Treatment of the PTP1B−/− mice with Na2O4W modified only slightly this response. In human blood, a dose-dependent effect was observed. At 200 μM, closure times in the PFA-100 were prolonged. On denuded vessels, %SC and thrombi formation (%T) decreased with Na2O4W. Neither the aggregating response nor the viscoelastic clot properties were affected. Conclusion Na2O4W decreases consistently the hemostatic capacity of platelets, inhibiting their adhesive and cohesive properties under flow conditions in mice and in human blood, resulting in smaller thrombi. Although Na2O4W may be acting on platelet PTP1B, other potential targets should not be disregarded. PMID:26060394

  10. Synthetic Ni3S2/Ni hybrid architectures as potential contrast agents in MRI

    NASA Astrophysics Data System (ADS)

    Ma, J.; Chen, K.

    2016-04-01

    Traditional magnetic resonance imaging (MRI) contrast agents mainly include superparamagnetic (SPM) iron oxide nanoparticle as T 2 contrast agent for liver and paramagnetic Gd (III)-chelate as T 1 contrast agent for all organs. In this work, weak ferromagnetic kale-like and SPM cabbage-like Ni3S2@Ni hybrid architectures were synthesized and evaluated as potential T 1 MRI contrast agents. Their relatively small r 2/r 1 ratios of 2.59 and 2.38, and high r 1 values of 11.27 and 4.89 mmol‑1 L s‑1 (for the kale-like and cabbage-like Ni3S2@Ni, respectively) will shed some light on the development of new-type MRI contrast agents.

  11. Draft Genome Sequence of Chromobacterium vaccinii, a Potential Biocontrol Agent against Mosquito (Aedes aegypti) Larvae

    PubMed Central

    Vöing, Kristin; Harrison, Alisha

    2015-01-01

    Chromobacterium vaccinii has been isolated only from cranberry bogs in Massachusetts. While it is unknown what role these bacteria play in their natural environments, they hold potential as biological control agents against the larvae of insect pests. Potential virulence genes were identified, including the violacein synthesis pathway, siderophores, and chitinases. PMID:25999572

  12. Potential organ or tumor imaging agents. 32. A triglyceride ester of p-iodophenyl pentadecanoic acid as a potential hepatic imaging agent.

    PubMed

    Schwendner, S W; Weichert, J P; Longino, M A; Gross, M D; Counsell, R E

    1992-08-01

    A triglyceride analog, glycerol-2-palmitoyl-1,3-di-15-(p-iodophenyl)pentadecanoate (DPPG) was synthesized and radiolabeled for evaluation as a potential functional liver scintigraphic agent. Uptake of DPPG was compared in normal, diabetic, tumor-bearing and heparin pretreated rats, revealing differences in uptake and clearance of radioactivity, correlating with hepatic lipase activity of these groups. Similar results were observed by gamma-camera scintigraphy. Comparing the uptake of DPPG with that of its fatty acid component, 15-(p-iodophenyl)pentadecanoic acid (IPPA), revealed that the peak uptake of IPPA in the liver was about half that of DPPG. Based upon these findings, DPPG warrants further study as a hepatic radiodiagnostic agent. PMID:1522018

  13. Imaging of hemorrhagic fever with renal syndrome: a potential bioterrorism agent of military significance.

    PubMed

    Bui-Mansfield, Liem T; Cressler, Dana K

    2011-11-01

    Hemorrhagic fever with renal syndrome (HFRS) is a potentially fatal infectious disease with worldwide distribution. Its etiologic agents are viruses of the genus Hantavirus of the virus family Bunyaviridae. Hypothetical ease of production and distribution of these agents, with their propensity to incapacitate victims and overwhelm health care resources, lend themselves as significant potential biological agents of terrorism. HFRS has protean clinical manifestations, which may mimic upper respiratory tract infection, nephrolithiasis, and Hantavirus pulmonary syndrome and may delay proper treatment. Sequelae of HFRS, such as hemorrhage, acute renal failure, retroperitoneal edema, pancreatitis, pulmonary edema, and neurologic symptoms, can be detected by different imaging modalities. Medical providers caring for HFRS patients must be aware of its radiologic features, which may help to confirm its clinical diagnosis. In this article, the authors review the epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, and complications of HFRS. PMID:22165665

  14. A potentially artifact-free oral contrast agent for gastrointestinal MRI.

    PubMed

    Liebig, T; Stoupis, C; Ros, P R; Ballinger, J R; Briggs, R W

    1993-11-01

    The combination of diamagnetic barium sulfate and superparamagnetic iron oxide (SPIO) in one suspension produces a macroscopic cancellation of positive and negative magnetic susceptibility components that can potentially eliminate susceptibility artifacts even with gradient echo pulse sequences. The relaxation properties that make the SPIO suspension a useful negative contrast agent are retained. PMID:8259066

  15. In vitro and In vivo Studies on Stilbene Analogs as Potential Treatment Agents for Colon Cancer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Based upon the potential of resveratrol as a cancer chemopreventive agent, 27 stilbenes analogs were synthesized and tested against colon cancer cell line HT-29. Among these compounds, amino derivative (Z)-4-(3,5-dimethoxystyryl) aniline (4), (Z)-methyl 4-(3,5-dimethoxystyryl) benzoate (6) and (Z)-1...

  16. Search for fungi as potential biological control agents of Echinochloa crus-galli

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cockspur dace, Echinochloa crus-galli (family Poaceae), is the most widespread and harmful weed in Russian rice production. Heavy infestations of the weed cause rice-crop losses up to 50 percent. With the purpose of discovering pathogenic fungi as potential agents for biological control of E. crus-g...

  17. Cysteamine-related agents could be potential antidepressants through increasing central BDNF levels.

    PubMed

    Tsai, Shih-Jen

    2006-01-01

    Major depressive disorder (MDD) is a common mental disease, but with an unknown etiology. Antidepressants are the main biological treatment for MDD. However, current antidepressive agents have a slow onset of effect and a substantial proportion of MDD patients do not clinically improve, despite maximal medication. Thus, the exploration for new antidepressants with novel strategies may help to develop faster and more effective antidepressant agents. Studies in the recent decades have demonstrated that antidepressants increase central brain-derived neurotrophic factor (BDNF) levels and activating the BDNF-signaling pathway may play an important role in their therapeutic mechanism. Cysteamine is a natural product of cells and constitutes the terminal region of the CoA molecule. Recent work has found that cysteamine and a related agent, cystamine, have neuroprotective effects in Huntington's disease (HD) mice, through enhancing central BDNF levels. Furthermore, cystamine or cysteamine injection could increase serum BDNF levels in wild-type mice as well as HD mice. Since activation of the BDNF-dependent pathway plays an important role in the mechanism of antidepressant therapeutic action, cystamine or its derivatives could have potential antidepressant therapeutic effects. Among these agents, pantethine may be one of the most promising agents. It is a naturally occurring compound which can be administered orally with negligible side effects, and is metabolized to cysteamine. Further evaluation of the therapeutic and toxic effects of these cysteamine-related antidepressant agents in MDD animal models is needed before any clinical application. PMID:16797865

  18. Intelligent Agents and Their Potential for Future Design and Synthesis Environment

    NASA Technical Reports Server (NTRS)

    Noor, Ahmed K. (Compiler); Malone, John B. (Compiler)

    1999-01-01

    This document contains the proceedings of the Workshop on Intelligent Agents and Their Potential for Future Design and Synthesis Environment, held at NASA Langley Research Center, Hampton, VA, September 16-17, 1998. The workshop was jointly sponsored by the University of Virginia's Center for Advanced Computational Technology and NASA. Workshop attendees came from NASA, industry and universities. The objectives of the workshop were to assess the status of intelligent agents technology and to identify the potential of software agents for use in future design and synthesis environment. The presentations covered the current status of agent technology and several applications of intelligent software agents. Certain materials and products are identified in this publication in order to specify adequately the materials and products that were investigated in the research effort. In no case does such identification imply recommendation or endorsement of products by NASA, nor does it imply that the materials and products are the only ones or the best ones available for this purpose. In many cases equivalent materials and products are available and would probably produce equivalent results.

  19. Molecular effective coverage surface area of optical clearing agents for predicting optical clearing potential

    NASA Astrophysics Data System (ADS)

    Feng, Wei; Ma, Ning; Zhu, Dan

    2015-03-01

    The improvement of methods for optical clearing agent prediction exerts an important impact on tissue optical clearing technique. The molecular dynamic simulation is one of the most convincing and simplest approaches to predict the optical clearing potential of agents by analyzing the hydrogen bonds, hydrogen bridges and hydrogen bridges type forming between agents and collagen. However, the above analysis methods still suffer from some problem such as analysis of cyclic molecule by reason of molecular conformation. In this study, a molecular effective coverage surface area based on the molecular dynamic simulation was proposed to predict the potential of optical clearing agents. Several typical cyclic molecules, fructose, glucose and chain molecules, sorbitol, xylitol were analyzed by calculating their molecular effective coverage surface area, hydrogen bonds, hydrogen bridges and hydrogen bridges type, respectively. In order to verify this analysis methods, in vitro skin samples optical clearing efficacy were measured after 25 min immersing in the solutions, fructose, glucose, sorbitol and xylitol at concentration of 3.5 M using 1951 USAF resolution test target. The experimental results show accordance with prediction of molecular effective coverage surface area. Further to compare molecular effective coverage surface area with other parameters, it can show that molecular effective coverage surface area has a better performance in predicting OCP of agents.

  20. New 1,4-anthracene-9,10-dione derivatives as potential anticancer agents.

    PubMed

    Zagotto, G; Supino, R; Favini, E; Moro, S; Palumbo, M

    2000-01-01

    The amino-substituted anthracene-9,10-dione (9,10-anthraquinone) derivatives represent one of the most important classes of potential anticancer agents. To better understand the basic rules governing DNA sequence specificity, we have recently synthesized a new class of D- and L-aminoacyl-anthraquinone derivatives. We have tested these new compounds as cytotoxic agents, and we have correlated their activity with the configuration of the chiral aminoacyl moiety. Molecular modeling studies have been performed to compare the test drugs in terms of steric overlapping. PMID:10755224

  1. General guidelines for medically screening mixed population groups potentially exposed to nerve or vesicant agents

    SciTech Connect

    Watson, A.P.; Munro, N.B.; Sidell, F.R.; Leffingwell, S.S.

    1992-01-01

    A number of state and local planners have requested guidance on screening protocols and have expressed interest in sampling body fluids from exposed or potentially exposed individuals as a means of estimating agent dose. These guidelines have been developed to provide a clear statement that could be used by state and local emergency response personnel in the event of a nerve or vesicant agent incident resulting in off-post contamination; maximum protection from harm is the goal. The assumption is that any population group so exposed would be heterogeneous for age, gender, reproductive status, and state of health.

  2. Novel Hydrogel Material as a Potential Embolic Agent in Embolization Treatments.

    PubMed

    Zhou, Feng; Chen, Liming; An, Qingzhu; Chen, Liang; Wen, Ying; Fang, Fang; Zhu, Wei; Yi, Tao

    2016-01-01

    We report a novel graphene-oxide (GO) enhanced polymer hydrogel (GPH) as a promising embolic agent capable of treating cerebrovascular diseases and malignant tumors, using the trans-catheter arterial embolization (TAE) technique. Simply composed of GO and generation five poly(amidoamine) dendrimers (PAMAM-5), our rheology experiments reveal that GPH exhibits satisfactory mechanical strength, which resist the high pressures of blood flow. Subcutaneous experiments on Sprague-Dawley (SD) rats demonstrate the qualified biocompatibility of GPH. Finally, our in vivo experiments on New Zealand rabbits, which mix GPH with the X-ray absorbing contrast agent, Iohexol, reveal complete embolization of the artery. We also note that GPH shortens embolization time and exhibits low toxicity in follow-up experiments. Altogether, our study demonstrates that GPH has many advantages over the currently used embolic agents and has potential applications in clinical practice. PMID:27561915

  3. Novel Hydrogel Material as a Potential Embolic Agent in Embolization Treatments

    PubMed Central

    Zhou, Feng; Chen, Liming; An, Qingzhu; Chen, Liang; Wen, Ying; Fang, Fang; Zhu, Wei; Yi, Tao

    2016-01-01

    We report a novel graphene-oxide (GO) enhanced polymer hydrogel (GPH) as a promising embolic agent capable of treating cerebrovascular diseases and malignant tumors, using the trans-catheter arterial embolization (TAE) technique. Simply composed of GO and generation five poly(amidoamine) dendrimers (PAMAM-5), our rheology experiments reveal that GPH exhibits satisfactory mechanical strength, which resist the high pressures of blood flow. Subcutaneous experiments on Sprague-Dawley (SD) rats demonstrate the qualified biocompatibility of GPH. Finally, our in vivo experiments on New Zealand rabbits, which mix GPH with the X-ray absorbing contrast agent, Iohexol, reveal complete embolization of the artery. We also note that GPH shortens embolization time and exhibits low toxicity in follow-up experiments. Altogether, our study demonstrates that GPH has many advantages over the currently used embolic agents and has potential applications in clinical practice. PMID:27561915

  4. Functional Hyperbranched Polylysine as Potential Contrast Agent Probes for Magnetic Resonance Imaging.

    PubMed

    Zu, Guangyue; Liu, Min; Zhang, Kunchi; Hong, Shanni; Dong, Jingjin; Cao, Yi; Jiang, Bin; Luo, Liqiang; Pei, Renjun

    2016-06-13

    Researchers have never stopped questing contrast agents with high resolution and safety to overcome the drawbacks of small-molecule contrast agents in clinic. Herein, we reported the synthesis of gadolinium-based hyperbranched polylysine (HBPLL-DTPA-Gd), which was prepared by thermal polymerization of l-lysine via one-step polycondensation. After conjugating with folic acid, its potential application as MRI contrast agent was then evaluated. This contrast agent had no obvious cytotoxicity as verified by WST assay and H&E analysis. Compared to Gd(III)-diethylenetriaminepentaacetic acid (Gd-DTPA) (r1 = 4.3 mM(-1) s(-1)), the FA-HBPLL-DTPA-Gd exhibited much higher longitudinal relaxivity value (r1 = 13.44 mM(-1) s(-1)), up to 3 times higher than Gd-DTPA. The FA-HBPLL-DTPA-Gd showed significant signal intensity enhancement in the tumor region at various time points and provided a long time window for MR examination. The results illustrate that FA-HBPLL-DTPA-Gd will be a potential candidate for tumor-targeted MRI. PMID:27187578

  5. Total synthesis of plagiochin G and derivatives as potential cancer chemopreventive agents

    PubMed Central

    Li, Rui-Juan; Zhao, Yu; Tokuda, Harukuni; Yang, Xiao-Ming; Wang, Yue-Hu; Shi, Qian; Morris-Natschke, Susan L.; Lou, Hong-Xiang; Lee, Kuo-Hsiung

    2014-01-01

    A new and efficient total synthesis has been developed to obtain plagiochin G (22), a macrocyclic bisbibenzyl, and four derivatives. The key 16-membered ring containing biphenyl ether and biaryl units was closed via an intramolecular SNAr reaction. All synthesized macrocyclic bisbibenzyls inhibited Epstein-Barr virus early antigen (EBVEA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and, thus, are potential cancer chemopreventive agents. PMID:25574060

  6. The use of marine-derived bioactive compounds as potential hepatoprotective agents

    PubMed Central

    Nair, Dileep G; Weiskirchen, Ralf; Al-Musharafi, Salma K

    2015-01-01

    The marine environment may be explored as a rich source for novel drugs. A number of marine-derived compounds have been isolated and identified, and their therapeutic effects and pharmacological profiles are characterized. In the present review, we highlight the recent studies using marine compounds as potential hepatoprotective agents for the treatment of liver fibrotic diseases and discuss the proposed mechanisms of their activities. In addition, we discuss the significance of similar studies in Oman, where the rich marine life provides a potential for the isolation of novel natural, bioactive products that display therapeutic effects on liver diseases. PMID:25500871

  7. Medicinal plants from Peru: a review of plants as potential agents against cancer.

    PubMed

    Gonzales, Gustavo F; Valerio, Luis G

    2006-09-01

    Natural products have played a significant role in drug discovery and development especially for agents against cancer and infectious disease. An analysis of new and approved drugs for cancer by the United States Food and Drug Administration over the period of 1981-2002 showed that 62% of these cancer drugs were of natural origin. Natural compounds possess highly diverse and complex molecular structures compared to small molecule synthetic drugs and often provide highly specific biological activities likely derived from the rigidity and high number of chiral centers. Ethnotraditional use of plant-derived natural products has been a major source for discovery of potential medicinal agents. A number of native Andean and Amazonian medicines of plant origin are used as traditional medicine in Peru to treat different diseases. Of particular interest in this mini-review are three plant materials endemic to Peru with the common names of Cat's claw (Uncaria tomentosa), Maca (Lepidium meyenii), and Dragon's blood (Croton lechleri) each having been scientifically investigated for a wide range of therapeutic uses including as specific anti-cancer agents as originally discovered from the long history of traditional usage and anecdotal information by local population groups in South America. Against this background, we present an evidence-based analysis of the chemistry, biological properties, and anti-tumor activities for these three plant materials. In addition, this review will discuss areas requiring future study and the inherent limitations in their experimental use as anti-cancer agents. PMID:17017852

  8. Cobalt Zinc Ferrite Nanoparticles as a Potential Magnetic Resonance Imaging Agent: An In vitro Study

    PubMed Central

    Ghasemian, Zeinab; Shahbazi-Gahrouei, Daryoush; Manouchehri, Sohrab

    2015-01-01

    Background: Magnetic Nanoparticles (MNP) have been used for contrast enhancement in Magnetic Resonance Imaging (MRI). In recent years, research on the use of ferrite nanoparticles in T2 contrast agents has shown a great potential application in MR imaging. In this work, Co0.5Zn0.5Fe2O4 and Co0.5Zn0.5Fe2O4-DMSA magnetic nanoparticles, CZF-MNPs and CZF-MNPs-DMSA, were investigated as MR imaging contrast agents. Methods: Cobalt zinc ferrite nanoparticles and their suitable coating, DMSA, were investigated under in vitro condition. Human prostate cancer cell lines (DU145 and PC3) with bare (uncoated) and coated magnetic nanoparticles were investigated as nano-contrast MR imaging agents. Results: Using T2-weighted MR images identified that signal intensity of bare and coated MNPs was enhanced with increasing concentration of MNPs in water. The values of 1/T2 relaxivity (r2) for bare and coated MNPs were found to be 88.46 and 28.80 (mM−1 s−1), respectively. Conclusion: The results show that bare and coated MNPs are suitable as T2-weighted MR imaging contrast agents. Also, the obtained r2/r1 values (59.3 and 50) for bare and coated MNPs were in agreement with the results of other previous relevant works. PMID:26140183

  9. Screening a panel of drugs with diverse mechanisms of action yields potential therapeutic agents against neuroblastoma

    PubMed Central

    Gheeya, Jinesh S.; Chen, Qing-Rong; Benjamin, Christopher D.; Cheuk, Adam T.; Tsang, Patricia; Chung, Joon-Yong; Metaferia, Belhu B.; Badgett, Thomas C.; Johansson, Peter; Wei, Jun S.; Hewitt, Stephen M.

    2009-01-01

    Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite current aggressive therapy, the survival rate for high risk NB remains less than 40%. To identify novel effective chemo-agents against NB, we screened a panel of 96 drugs against two NB cell lines, SK-N-AS and SH-SY5Y. We found 30 compounds that were active against NB cell lines at ≤ 10 µM concentration. More interestingly, 17 compounds are active at ≤ 1 µM concentration, and they act through a wide spectrum of diverse mechanisms such as mitotic inhibition, topoisomerase inhibition, targeting various biological pathways, and unknown mechanisms. The majority of these active compounds also induced caspase 3/7 by more than 2-fold. Of these 17 active compounds against NB cell lines at sub-micromolar concentration, 11 compounds are not currently used to treat NB. Among them, 9 are FDA approved compounds, and 3 agents are undergoing clinical trials for various malignancies. Furthermore, we identified 4 agents active against these NB cell lines that have not yet been tested in the clinical setting. Finally we demonstrated that Cucurbitacin I inhibits neuroblastoma cell growth through inhibition of STAT3 pathway. These drugs thus represent potential novel therapeutic agents for patients with NB, and further validation studies are needed to translate them to the clinic. PMID:19946221

  10. Evaluation of boronated EGF as a potential delivery agent for BNCT of brain tumors

    SciTech Connect

    Yang, Weilian; Barth, R.F.; Adams, D.M.

    1996-12-31

    The epidermal growth factor receptor (EGFR) gene is often amplified in human glioblastomas, but, reflecting the cellular heterogeneity of these tumors, the frequency of amplification is variable. Since the number of EGFR has been considered as a potential target for the specific delivery of diagnostic and therapeutic agents to brain tumors. Initially, the focus was on using anti-EGFR monoclonal antibodies or their fragments, but within the past few years there has been increasing interest in using EGF based bioconjugates as targeting agents. Recently, we have described a method for the boronation of EGF and have characterized the resulting bioconjugates in vitro. In the present study, we have investigated the potential usefulness of boronated EGF as a delivery agent for neutron capture therapy in rats bearing intracerebral implants of the C6 glioma, which has been transfected with the gene encoding EGFR. Our results indicate that following intratumoral injection, boronated EGF selectivity targeted the transfected EGFR positive C6 glioma, and that the amount of delivered to the tumor exceeded by 3-4 orders of magnitude that which could be delivered by intravenous injection.

  11. Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs

    PubMed Central

    Shan, T.; Ma, Q.; Guo, K.; Liu, J.; Li, W.; Wang, F.; Wu, E.

    2011-01-01

    Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including anti-oxidant, anti-tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent. PMID:21902651

  12. Synthesis and characterization of iodobenzamide analogues: Potential D-2 dopamine receptor imaging agents

    SciTech Connect

    Murphy, R.A.; Kung, H.F.; Kung, M.P.; Billings, J. )

    1990-01-01

    (S)-N-((1-Ethyl-2-pyrrolidinyl)methyl)-2-hydroxy-3-iodo-6- methoxybenzamide (({sup 123}I)IBZM) is a central nervous system (CNS) D-2 dopamine receptor imaging agent. In order to investigate the versatility of this parent structure in specific dopamine receptor localization and the potential for developing new dopamine receptor imaging agents, a series of new iodinated benzamides with fused ring systems, naphthalene (INAP) and benzofuran (IBF), was synthesized and radiolabeled, and the in vivo and in vitro biological properties were characterized. The best analogue of IBZM is IBF (21). The specific binding of ({sup 125}I)IBF (21) with rat striatal tissue preparation was found to be saturable and displayed a Kd of 0.106 {plus minus} 0.015 nM. Competition data of various receptor ligands for ({sup 125}I)IBF (21) binding show the following rank order of potency: spiperone greater than IBF (21) greater than IBZM greater than (+)-butaclamol greater than ({plus minus})-ADTN,6,7 greater than ketanserin greater than SCH-23390 much greater than propranolol. The in vivo biodistribution results confirm that ({sup 125}I)IBF (21) concentrated in the striatal area after iv injection into rats. The study demonstrates that ({sup 123}I)IBF (21) is a potential agent for imaging CNS D-2 dopamine receptors.

  13. Gd(III) complexes intercalated into hydroxy double salts as potential MRI contrast agents.

    PubMed

    Jin, Miao; Spillane, Dominic E M; Geraldes, Carlos F G C; Williams, Gareth R; Bligh, S W Annie

    2015-12-21

    The ion exchange intercalation of two Gd-based magnetic resonance imaging contrast agents into hydroxy double salts (HDSs) is reported. The presence of Gd(3+) diethylenetriaminepentaacetate and Gd(3+) diethylenetriaminepenta(methylenephosphonate) complexes in the HDS lattice after intercalation was confirmed by microwave plasma-atomic emission spectroscopy. The structural aspects of the HDS-Gd composites were studied by X-ray diffraction, with the intercalates having an interlayer spacing of 14.5-18.6 Å. Infrared spectroscopy confirmed the presence of characteristic vibration peaks associated with the Gd(3+) complexes in the intercalation compounds. The proton relaxivities of the Gd(3+) complex-loaded composites were 2 to 5-fold higher in longitudinal relaxivity, and up to 10-fold higher in transverse relaxivity, compared to solutions of the pure complexes. These data demonstrate that the new composites reported here are potentially potent MRI contrast agents. PMID:26568157

  14. Synthesis and evaluation of novel tropane derivatives as potential PET imaging agents for the dopamine transporter

    PubMed Central

    Qiao, Hongwen; Zhu, Lin; Lieberman, Brian P.; Zha, Zhihao; Plössl, Karl; Kung, Hank F.

    2012-01-01

    A novel series of tropane derivatives containing a fluorinated tertiary amino or amide at the 2β position was synthesized, labeled with the positron-emitter fluorine-18 (T1/2 = 109.8 min), and tested as potential in vivo dopamine transporter (DAT) imaging agents. The corresponding chlorinated analogs were prepared and employed as precursors for radiolabeling leading to the fluorine-18-labeled derivatives via a one-step nucleophilic aliphatic substitution reaction. In vitro binding results showed that the 2β-amino compounds 6b, 6d and 7b displayed moderately high affinities to DAT (Ki < 10 nM). Biodistribution studies of [18F]6b and [18F]6d showed that the brain uptakes in rats were low. This is likely due to their low lipophilicities. Further structural modifications of these tropane derivatives will be needed to improve their in vivo properties as DAT imaging agents. PMID:22658558

  15. Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents.

    PubMed

    Congiu, Cenzo; Onnis, Valentina

    2013-11-01

    We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI50 values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents. PMID:24071449

  16. Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents.

    PubMed

    Luo, Wen; Wang, Ting; Hong, Chen; Yang, Ya-Chen; Chen, Ying; Cen, Juan; Xie, Song-Qiang; Wang, Chao-Jie

    2016-10-21

    A new series of 4-dimethylamine flavonoid derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents. The inhibition of cholinesterase activity, self-induced β-amyloid (Aβ) aggregation, and antioxidant activity by these derivatives was investigated. Most of the compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The derivatives showed potent self-induced Aβ aggregation inhibition and peroxyl radical absorbance activity. Moreover, compound 6d significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Thus, these compounds could become multifunctional agents for further development for the treatment of AD. PMID:27343850

  17. Opportunities for Web-based Drug Repositioning: Searching for Potential Antihypertensive Agents with Hypotension Adverse Events

    PubMed Central

    Wang, Kejian; Wan, Mei; Wang, Rui-Sheng

    2016-01-01

    Background Drug repositioning refers to the process of developing new indications for existing drugs. As a phenotypic indicator of drug response in humans, clinical side effects may provide straightforward signals and unique opportunities for drug repositioning. Objective We aimed to identify drugs frequently associated with hypotension adverse reactions (ie, the opposite condition of hypertension), which could be potential candidates as antihypertensive agents. Methods We systematically searched the electronic records of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) through the openFDA platform to assess the association between hypotension incidence and antihypertensive therapeutic effect regarding a list of 683 drugs. Results Statistical analysis of FAERS data demonstrated that those drugs frequently co-occurring with hypotension events were more likely to have antihypertensive activity. Ranked by the statistical significance of frequent hypotension reporting, the well-known antihypertensive drugs were effectively distinguished from others (with an area under the receiver operating characteristic curve > 0.80 and a normalized discounted cumulative gain of 0.77). In addition, we found a series of antihypertensive agents (particularly drugs originally developed for treating nervous system diseases) among the drugs with top significant reporting, suggesting the good potential of Web-based and data-driven drug repositioning. Conclusions We found several candidate agents among the hypotension-related drugs on our list that may be redirected for lowering blood pressure. More important, we showed that a pharmacovigilance system could alternatively be used to identify antihypertensive agents and sustainably create opportunities for drug repositioning. PMID:27036325

  18. Activation of the chemosensing transient receptor potential channel A1 (TRPA1) by alkylating agents.

    PubMed

    Stenger, Bernhard; Zehfuss, Franziska; Mückter, Harald; Schmidt, Annette; Balszuweit, Frank; Schäfer, Eva; Büch, Thomas; Gudermann, Thomas; Thiermann, Horst; Steinritz, Dirk

    2015-09-01

    The transient receptor potential ankyrin 1 (TRPA1) cation channel is expressed in different tissues including skin, lung and neuronal tissue. Recent reports identified TRPA1 as a sensor for noxious substances, implicating a functional role in the molecular toxicology. TRPA1 is activated by various potentially harmful electrophilic substances. The chemical warfare agent sulfur mustard (SM) is a highly reactive alkylating agent that binds to numerous biological targets. Although SM is known for almost 200 years, detailed knowledge about the pathophysiology resulting from exposure is lacking. A specific therapy is not available. In this study, we investigated whether the alkylating agent 2-chloroethyl-ethylsulfide (CEES, a model substance for SM-promoted effects) and SM are able to activate TRPA1 channels. CEES induced a marked increase in the intracellular calcium concentration ([Ca(2+)]i) in TRPA1-expressing but not in TRPA1-negative cells. The TRP-channel blocker AP18 diminished the CEES-induced calcium influx. HEK293 cells permanently expressing TRPA1 were more sensitive toward cytotoxic effects of CEES compared with wild-type cells. At low CEES concentrations, CEES-induced cytotoxicity was prevented by AP18. Proof-of-concept experiments using SM resulted in a pronounced increase in [Ca(2+)]i in HEK293-A1-E cells. Human A549 lung epithelial cells, which express TRPA1 endogenously, reacted with a transient calcium influx in response to CEES exposure. The CEES-dependent calcium response was diminished by AP18. In summary, our results demonstrate that alkylating agents are able to activate TRPA1. Inhibition of TRPA1 counteracted cellular toxicity and could thus represent a feasible approach to mitigate SM-induced cell damage. PMID:25395009

  19. Metal-oxo containing polymer nanobeads as potential contrast agents for magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Pablico, Michele Huelar

    Magnetic resonance imaging (MRI) has greatly revolutionized the way diseases are detected and treated, as it is a non-invasive imaging modality solely based on the interaction of radiowaves and hydrogen nuclei in the presence of an external magnetic field. It is widely used today for the diagnosis of diseases as it offers an efficient method of mapping structure and function of soft tissues in the body. Most MRI examinations utilize paramagnetic materials known as contrast agents, which enhance the MR signal by decreasing the longitudinal (T1) and transverse (T2) relaxation times of the surrounding water protons in biological systems. This results into increased signal intensity differences thereby allowing better interpretation and analysis of pathological tissues. Contrast agents function by lowering the T1 or lowering the T2, resulting into bright and dark contrasts, respectively. The most common MRI contrast agents that are in clinical use today are gadolinium chelates and superparamagnetic iron oxide nanoparticles, both of which have their own advantages in terms of contrast enhancement properties. In the past few years, however, there has been interest in utilizing metal-containing clusters for MRI contrast enhancement as these materials bridge the gap between the constrained structure and magnetic properties of the gadolinium chelates with the superparamagnetic behavior of the iron oxide nanoparticles. Recently, metallic clusters containing Mn and Fe metal centers have received increased attention mainly because of their potential for high spin states and benign nature. In the quest to further develop novel imaging agents, this research has focused on investigating the use of metal-oxo clusters as potential contrast agents for MRI. The primary goal of this project is to identify clusters that meet the following criteria: high paramagnetic susceptibility, water-soluble, stable, cheap, contain environmentally benign metals, and easily derivatized. This work is

  20. Evaluation of a targeted nanobubble ultrasound contrast agent for potential tumor imaging

    NASA Astrophysics Data System (ADS)

    Li, Chunfang; Shen, Chunxu; Liu, Haijuan; Wu, Kaizhi; Zhou, Qibing; Ding, Mingyue

    2015-03-01

    Targeted nanobubbles have been reported to improve the contrast effect of ultrasound imaging due to the enhanced permeation and retention effects at tumor vascular leaks. In this work, the contrast enhancement abilities and the tumor targeting potential of a self-made VEGFR2-targeted nanobubble ultrasound contrast agent was evaluated in-vitro and in-vivo. Size distribution and zeta potential were assessed. Then the contrast-enhanced ultrasound imaging of the VEGFR2 targeted nanobubbles were evaluated with a custom-made experimental apparatus and in normal Wistar rats. Finally, the in-vivo tumor-targeting ability was evaluated on nude mice with subcutaneous tumor. The results showed that the target nanobubbles had uniform distribution with the average diameter of 208.1 nm, polydispersity index (PDI) of 0.411, and zeta potential of -13.21 mV. Significant contrast enhancement was observed in both in-vitro and in-vivo ultrasound imaging, demonstrating that the self-made target nanobubbles can enhance the contrast effect of ultrasound imaging efficiently. Targeted tumor imaging showed less promising result, due to the fact that the targeted nanobubbles arriving and permeating through tumor vessels were not many enough to produce significant enhancement. Future work will focus on exploring new imaging algorithm which is sensitive to targeted nanobubbles, so as to correctly detect the contrast agent, particularly at a low bubble concentration.

  1. Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents.

    PubMed

    Iwasa, K; Moriyasu, M; Tachibana, Y; Kim, H S; Wataya, Y; Wiegrebe, W; Bastow, K F; Cosentino, L M; Kozuka, M; Lee, K H

    2001-11-01

    Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts. PMID:11597468

  2. Molecules that Mimic Apolipoprotein A-I: Potential Agents for Treating Atherosclerosis

    PubMed Central

    Leman, Luke J.; Maryanoff, Bruce E.; Ghadiri, M. Reza

    2013-01-01

    Certain amphipathic α-helical peptides can functionally mimic many of the properties of full-length apolipoproteins, thereby offering an approach to modulate high-density lipoprotein (HDL) for combating atherosclerosis. In this Perspective, we summarize the key findings and advances over the past 25 years in the development of peptides that mimic apolipoproteins, especially apolipoprotein A-I (apoA-I). This assemblage of information provides a reasonably clear picture of the state of the art in the apolipoprotein mimetic field, an appreciation of the potential for such agents in pharmacotherapy, and a sense of the opportunities for optimizing the functional properties of HDL. PMID:24168751

  3. Synthesis, Antifungal Activities and Qualitative Structure Activity Relationship of Carabrone Hydrazone Derivatives as Potential Antifungal Agents

    PubMed Central

    Wang, Hao; Ren, Shuang-Xi; He, Ze-Yu; Wang, De-Long; Yan, Xiao-Nan; Feng, Jun-Tao; Zhang, Xing

    2014-01-01

    Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents. PMID:24619221

  4. Mustard vesicating agent-induced toxicity in the skin tissue and silibinin as a potential countermeasure.

    PubMed

    Tewari-Singh, Neera; Agarwal, Rajesh

    2016-06-01

    Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of their exposure, edema and erythema develop into blisters, ulceration, necrosis, desquamation, and pigmentation changes, which persist weeks and even years after exposure. Research advances have generated data that have started to explain the probable mechanism of action of vesicant-induced skin toxicity; however, despite these advances, effective and targeted therapies are still deficient. This review highlights studies on two SM analogs, 2-chloroethyl ethyl sulfide (CEES) and NM, and CEES- and NM-induced skin injury mouse models that have substantially added to the knowledge on the complex pathways involved in mustard vesicating agent-induced skin injury. Furthermore, employing these mouse models, studies under the National Institutes of Health Countermeasures Against Chemical Threats program have identified the flavanone silibinin as a novel therapeutic intervention with the potential to be developed as an effective countermeasure against skin injury following exposure to mustard vesicating agents. PMID:27326543

  5. Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals.

    PubMed

    McElroy, Cameron S; Day, Brian J

    2016-01-15

    The continuing horrors of military conflicts and terrorism often involve the use of chemical warfare agents (CWAs) and toxic industrial chemicals (TICs). Many CWA and TIC exposures are difficult to treat due to the danger they pose to first responders and their rapid onset that can produce death shortly after exposure. While the specific mechanism(s) of toxicity of these agents are diverse, many are associated either directly or indirectly with increased oxidative stress in affected tissues. This has led to the exploration of various antioxidants as potential medical countermeasures for CWA/TIC exposures. Studies have been performed across a wide array of agents, model organisms, exposure systems, and antioxidants, looking at an almost equally diverse set of endpoints. Attempts at treating CWAs/TICs with antioxidants have met with mixed results, ranging from no effect to nearly complete protection. The aim of this commentary is to summarize the literature in each category for evidence of oxidative stress and antioxidant efficacy against CWAs and TICs. While there is great disparity in the data concerning methods, models, and remedies, the outlook on antioxidants as medical countermeasures for CWA/TIC management appears promising. PMID:26476351

  6. Mesoporous europo-gadolinosilicate nanoparticles as bimodal medical imaging agents and a potential theranostic platform.

    PubMed

    Tse, Nicholas M K; Kennedy, Danielle F; Kirby, Nigel; Moffat, Bradford A; Muir, Benjamin W; Caruso, Rachel A; Drummond, Calum J

    2013-06-01

    The mesoporous structure of sol-gel prepared gadolinium and europium doped silicate nanoparticles has been found to be highly dependent on the formulated composition, with synthesised samples displaying both disordered and hexagonally ordered mesoporous packing symmetry. The degree of pore ordering within the nanoparticles has a strong correlation with the total lanthanide (Gd(3+) and Eu(3+) ) concentration. The gadolinosilicates are excellent magnetic resonance imaging (MRI) longitudinal (T1 ) agents. The longitudinal relaxivity (r1 ) and transverse (r2 ) relaxivity, a measure of MRI contrast agent efficiency, were up to four times higher than the clinically employed Omniscan (gadodiamide); with r1 up to 20.6 s(-1) mM(-1) and r2 of 66.2 s(-1) mM(-1) compared to 5.53 and 4.64 s(-1) mM(-1) , respectively, for Omniscan. In addition, the europium content of all the samples studied is below the self-quenching limit, which results in a strong luminescence response from the nanoparticles on excitation at 250 nm. The Eu-Gd silicate nanoparticles act as bimodal imaging agents for MRI and luminescence. These mesoporous nanoparticles also have the potential to serve as encapsulation and controlled release matrices for pharmaceuticals. They are therefore a promising multimodal theranostic platform. PMID:23296572

  7. Identification of Aspergillus flavus isolates as potential biocontrol agents of aflatoxin contamination in crops.

    PubMed

    Rosada, L J; Sant'anna, J R; Franco, C C S; Esquissato, G N M; Santos, P A S R; Yajima, J P R S; Ferreira, F D; Machinski, M; Corrêa, B; Castro-Prado, M A A

    2013-06-01

    Aspergillus flavus, a haploid organism found worldwide in a variety of crops, including maize, cottonseed, almond, pistachio, and peanut, causes substantial and recurrent worldwide economic liabilities. This filamentous fungus produces aflatoxins (AFLs) B1 and B2, which are among the most carcinogenic compounds from nature, acutely hepatotoxic and immunosuppressive. Recent efforts to reduce AFL contamination in crops have focused on the use of nonaflatoxigenic A. flavus strains as biological control agents. Such agents are applied to soil to competitively exclude native AFL strains from crops and thereby reduce AFL contamination. Because the possibility of genetic recombination in A. flavus could influence the stability of biocontrol strains with the production of novel AFL phenotypes, this article assesses the diversity of vegetative compatibility reactions in isolates of A. flavus to identify heterokaryon self-incompatible (HSI) strains among nonaflatoxigenic isolates, which would be used as biological controls of AFL contamination in crops. Nitrate nonutilizing (nit) mutants were recovered from 25 A. flavus isolates, and based on vegetative complementation between nit mutants and on the microscopic examination of the number of hyphal fusions, five nonaflatoxigenic (6, 7, 9 to 11) and two nontoxigenic (8 and 12) isolates of A. flavus were phenotypically characterized as HSI. Because the number of hyphal fusions is reduced in HSI strains, impairing both heterokaryon formation and the genetic exchanges with aflatoxigenic strains, the HSI isolates characterized here, especially isolates 8 and 12, are potential agents for reducing AFL contamination in crops. PMID:23726204

  8. Double layered hydroxides as potential anti-cancer drug delivery agents.

    PubMed

    Riaz, Ufana; Ashraf, S M

    2013-04-01

    The emergence of nanotechnology has changed the scenario of the medical world by revolutionizing the diagnosis, monitoring and treatment of cancer. This nanotechnology has been proved miraculous in detecting cancer cells, delivering chemotherapeutic agents and monitoring treatment from non-specific to highly targeted killing of tumor cells. In the past few decades, a number of inorganic materials have been investigated such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide, and layered double hydroxide (LDH) for examining their efficacy in targeting drug delivery. The reason behind the selection of these inorganic materials was their versatile and unique features efficient in drug delivery, such as wide availability, rich surface functionality, good biocompatibility, potential for target delivery, and controlled release of the drug from these inorganic nanomaterials. Although, the drug-LDH hybrids are found to be quite instrumental because of their application as advanced anti-cancer drug delivery systems, there has not been much research on them. This mini review is set to highlight the advancement made in the use of layered double hydroxides (LDHs) as anti-cancer drug delivery agents. Along with the advantages of LDHs as anti-cancer drug delivery agents, the process of interaction of some of the common anti-cancer drugs with LDH has also been discussed. PMID:23170959

  9. Rosemary (Rosmarinus officinalis L.) Extract as a Potential Complementary Agent in Anticancer Therapy.

    PubMed

    González-Vallinas, Margarita; Reglero, Guillermo; Ramírez de Molina, Ana

    2015-01-01

    Cancer remains an important cause of mortality nowadays and, therefore, new therapeutic approaches are still needed. Rosemary (Rosmarinus officinalis L.) has been reported to possess antitumor activities both in vitro and in animal studies. Some of these activities were attributed to its major components, such as carnosic acid, carnosol, ursolic acid, and rosmarinic acid. Initially, the antitumor effects of rosemary were attributed to its antioxidant activity. However, in recent years, a lack of correlation between antioxidant and antitumor effects exerted by rosemary was reported, and different molecular mechanisms were related to its tumor inhibitory properties. Moreover, supported by the U.S. Food and Drug Administration and the European Food and Safety Authority, specific compositions of rosemary extract were demonstrated to be safe for human health and used as antioxidant additive in foods, suggesting the potential easy application of this agent as a complementary approach in cancer therapy. In this review, we aim to summarize the reported anticancer effects of rosemary, the demonstrated molecular mechanisms related to these effects and the interactions between rosemary and currently used anticancer agents. The possibility of using rosemary extract as a complementary agent in cancer therapy in comparison with its isolated components is discussed. PMID:26452641

  10. Nucleic Acid Aptamers as Potential Therapeutic and Diagnostic Agents for Lymphoma

    PubMed Central

    Shum, Ka-To; Zhou, Jiehua; Rossi, John J.

    2014-01-01

    Lymphomas are cancers that arise from white blood cells and usually present as solid tumors. Treatment of lymphoma often involves chemotherapy, and can also include radiotherapy and/or bone marrow transplantation. There is an un-questioned need for more effective therapies and diagnostic tool for lymphoma. Aptamers are single stranded DNA or RNA oligonucleotides whose three-dimensional structures are dictated by their sequences. The immense diversity in function and structure of nucleic acids enable numerous aptamers to be generated through an iterative in vitro selection technique known as Systematic Evolution of Ligands by EXponential enrichment (SELEX). Aptamers have several biochemical properties that make them attractive tools for use as potential diagnostic and pharmacologic agents. Isolated aptamers may directly inhibit the function of target proteins, or they can also be formulated for use as delivery agents for other therapeutic or imaging cargoes. More complex aptamer identification methods, using whole cancer cells (Cell-SELEX), may identify novel targets and aptamers to affect them. This review focuses on recent advances in the use of nucleic acid aptamers as diagnostic and therapeutic agents and as targeted delivery carriers that are relevant to lymphoma. Some representative examples are also discussed. PMID:25057429

  11. The fabrication of novel nanobubble ultrasound contrast agent for potential tumor imaging

    NASA Astrophysics Data System (ADS)

    Xing, Zhanwen; Wang, Jinrui; Ke, Hengte; Zhao, Bo; Yue, Xiuli; Dai, Zhifei; Liu, Jibin

    2010-04-01

    Novel biocompatible nanobubbles were fabricated by ultrasonication of a mixture of Span 60 and polyoxyethylene 40 stearate (PEG40S) followed by differential centrifugation to isolate the relevant subpopulation from the parent suspensions. Particle sizing analysis and optical microscopy inspection indicated that the freshly generated micro/nanobubble suspension was polydisperse and the size distribution was bimodal with large amounts of nanobubbles. To develop a nano-sized contrast agent that is small enough to leak through tumor pores, a fractionation to extract smaller bubbles by variation in the time of centrifugation at 20g (relative centrifuge field, RCF) was suggested. The results showed that the population of nanobubbles with a precisely controlled mean diameter could be sorted from the initial polydisperse suspensions to meet the specified requirements. The isolated bubbles were stable over two weeks under the protection of perfluoropropane gas. The acoustic behavior of the nano-sized contrast agent was evaluated using power Doppler imaging in a normal rabbit model. An excellent power Doppler enhancement was found in vivo renal imaging after intravenous injection of the obtained nanobubbles. Given the broad spectrum of potential clinical applications, the nano-sized contrast agent may provide a versatile adjunct for ultrasonic imaging enhancement and/or treatment of tumors.

  12. The fabrication of novel nanobubble ultrasound contrast agent for potential tumor imaging.

    PubMed

    Xing, Zhanwen; Wang, Jinrui; Ke, Hengte; Zhao, Bo; Yue, Xiuli; Dai, Zhifei; Liu, Jibin

    2010-04-01

    Novel biocompatible nanobubbles were fabricated by ultrasonication of a mixture of Span 60 and polyoxyethylene 40 stearate (PEG40S) followed by differential centrifugation to isolate the relevant subpopulation from the parent suspensions. Particle sizing analysis and optical microscopy inspection indicated that the freshly generated micro/nanobubble suspension was polydisperse and the size distribution was bimodal with large amounts of nanobubbles. To develop a nano-sized contrast agent that is small enough to leak through tumor pores, a fractionation to extract smaller bubbles by variation in the time of centrifugation at 20g (relative centrifuge field, RCF) was suggested. The results showed that the population of nanobubbles with a precisely controlled mean diameter could be sorted from the initial polydisperse suspensions to meet the specified requirements. The isolated bubbles were stable over two weeks under the protection of perfluoropropane gas. The acoustic behavior of the nano-sized contrast agent was evaluated using power Doppler imaging in a normal rabbit model. An excellent power Doppler enhancement was found in vivo renal imaging after intravenous injection of the obtained nanobubbles. Given the broad spectrum of potential clinical applications, the nano-sized contrast agent may provide a versatile adjunct for ultrasonic imaging enhancement and/or treatment of tumors. PMID:20220227

  13. Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression.

    PubMed

    Wargovich, M J; Jimenez, A; McKee, K; Steele, V E; Velasco, M; Woods, J; Price, R; Gray, K; Kelloff, G J

    2000-06-01

    We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis. PMID:10837003

  14. ASSESSING POTENTIAL OF COLLETOTRICHUM ACUTATUM WILD-TYPE AND AUXOTROPHIC MUTANTS AS BIOLOGICAL FRUIT THINNING AGENTS IN CITRUS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Colletotrichum acutatum, causal agent of postbloom fruit drop of citrus, and two induced C. acutatum mutants (3-3 and 3-2) were tested as potential agents for reducing fruit load on Valencia (Citrus sinensis ) and 'Temple' orange (C.reticulata x C. sinensis). Wild-type C. acutatum (RST) and a C. gl...

  15. Antitumoral, antioxidant, and antimelanogenesis potencies of Hawthorn, a potential natural agent in the treatment of melanoma.

    PubMed

    Mustapha, Nadia; Mokdad-Bzéouich, Imèn; Maatouk, Mouna; Ghedira, Kamel; Hennebelle, Thierry; Chekir-Ghedira, Leila

    2016-06-01

    The lack of an efficient agent that does not have the disadvantage of low activity (kojic acid), high cytotoxicity, and mutagenicity (hydroquinone), poor skin penetration (arbutin), or low stability in formulation (glabridin) led us to continue our research on new antipigmentation/skin-lightening agents. Therefore, research of natural products that can modulate the metabolism of pigmentation is of great interest. Otherwise, malignant melanoma is one of the most aggressive forms of skin cancer, with high metastatic potential, and currently, there is no effective chemotherapy against invasive melanoma. Therefore, it is necessary to develop new drugs with potent activity and weak side effects against melanoma. The in-vitro anticancer effect of hawthorn was analyzed against B16F10 melanoma cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of isolated compounds from hawthorn on melanogenesis in B16F10 melanoma cells was investigated by measuring the amounts of melanin and tyrosinase spectrophotometrically at 475 nm. Balb/c mice models inoculated with B16F10 mouse tumor cells were used to evaluate the in-vivo antitumoral potential of hawthorn by assessing its effect on the growth of transplanted tumors. The antioxidant potential of tested samples was evaluated in B16F10 and primary human keratinocyte cells using a cellular antioxidant activity assay. Hawthorn tested samples inhibited effectively the growth of melanoma cells in vitro. Furthermore, it appears that tested samples from hawthorn reduced melanogenesis by inhibiting the tyrosinase activity of B16F10 cells in a dose-dependent manner. In-vivo studies showed that hawthorn total oligomer flavonoids extract treatment at a dose of 150 mg/kg body weight for 21 days in implanted tumor mice resulted in significant inhibition of the tumor growth volume and weight. In addition, tested samples showed significant cellular antioxidant capacity against the reactive oxygen species

  16. Metal chelators coupled with nanoparticles as potential therapeutic agents for Alzheimer's disease

    PubMed Central

    Liu, Gang; Men, Ping; Perry, George; Smith, Mark A.

    2009-01-01

    Alzheimer's disease (AD) is a devastating neuro-degenerative disorder characterized by the progressive and irreversible loss of memory followed by complete dementia. Despite the disease's high prevalence and great economic and social burden, an explicative etiology or viable cure is not available. Great effort has been made to better understand the disease's pathogenesis, and to develop more effective therapeutic agents. However, success is greatly hampered by the presence of the blood-brain barrier that limits a large number of potential therapeutics from entering the brain. Nanoparticle-mediated drug delivery is one of the few valuable tools for overcoming this impediment and its application as a potential AD treatment shows promise. In this review, the current studies on nanoparticle delivery of chelation agents as possible therapeutics for AD are discussed because several metals are found excessive in the AD brain and may play a role in the disease development. Specifically, a novel approach involving transport of iron chelation agents into and out of the brain by nanoparticles is highlighted. This approach may provide a safer and more effective means of simultaneously reducing several toxic metals in the AD brain. It may also provide insights into the mechanisms of AD pathophysiology, and prove useful in treating other iron-associated neurodegenerative diseases such as Friedreich's ataxia, Parkinson's disease, Huntington's disease and Hallervorden-Spatz Syndrome. It is important to note that the use of nanoparticle-mediated transport to facilitate toxicant excretion from diseased sites in the body may advance nanoparticle technology, which is currently focused on targeted drug delivery for disease prevention and treatment. The application of nanoparticle-mediated drug transport in the treatment of AD is at its very early stages of development and, therefore, more studies are warranted. PMID:19936278

  17. Potential Anti-HPV and Related Cancer Agents from Marine Resources: An Overview

    PubMed Central

    Wang, Shi-Xin; Zhang, Xiao-Shuang; Guan, Hua-Shi; Wang, Wei

    2014-01-01

    Recently, the studies on the prevention and treatment of human papillomavirus (HPV) which is closely related to the cervical cancer and other genital diseases are attracting more and more attention all over the world. Marine-derived polysaccharides and other bioactive compounds have been shown to possess a variety of anti-HPV and related cancer activities. This paper will review the recent progress in research on the potential anti-HPV and related cancer agents from marine resources. In particular, it will provide an update on the anti-HPV actions of heparinoid polysaccharides and bioactive compounds present in marine organisms, as well as the therapeutic vaccines relating to marine organisms. In addition, the possible mechanisms of anti-HPV actions of marine bioactive compounds and their potential for therapeutic application will also be summarized in detail. PMID:24705500

  18. Avena sativa (Oat), a potential neutraceutical and therapeutic agent: an overview.

    PubMed

    Singh, Rajinder; De, Subrata; Belkheir, Asma

    2013-01-01

    The aim of the present review article is to summarize the available information related to the availability, production, chemical composition, pharmacological activity, and traditional uses of Avena sativa to highlight its potential to contribute to human health. Oats are now cultivated worldwide and form an important dietary staple for the people in number of countries. Several varieties of oats are available. It is a rich source of protein, contains a number of important minerals, lipids, β-glucan, a mixed-linkage polysaccharide, which forms an important part of oat dietary fiber, and also contains various other phytoconstituents like avenanthramides, an indole alkaloid-gramine, flavonoids, flavonolignans, triterpenoid saponins, sterols, and tocols. Traditionally oats have been in use since long and are considered as stimulant, antispasmodic, antitumor, diuretic, and neurotonic. Oat possesses different pharmacological activities like antioxidant, anti-inflammatory, wound healing, immunomodulatory, antidiabetic, anticholesterolaemic, etc. A wide spectrum of biological activities indicates that oat is a potential therapeutic agent. PMID:23072529

  19. Isolation and characterization of soil Streptomyces species as potential biological control agents against fungal plant pathogens.

    PubMed

    Evangelista-Martínez, Zahaed

    2014-05-01

    The use of antagonist microorganisms against fungal plant pathogens is an attractive and ecologically alternative to the use of chemical pesticides. Streptomyces are beneficial soil bacteria and potential candidates for biocontrol agents. This study reports the isolation, characterization and antagonist activity of soil streptomycetes from the Los Petenes Biosphere Reserve, a Natural protected area in Campeche, Mexico. The results showed morphological, physiological and biochemical characterization of six actinomycetes and their inhibitory activity against Curvularia sp., Aspergillus niger, Helminthosporium sp. and Fusarium sp. One isolate, identified as Streptomyces sp. CACIS-1.16CA showed the potential to inhibit additional pathogens as Alternaria sp., Phytophthora capsici, Colletotrichum sp. and Rhizoctonia sp. with percentages ranging from 47 to 90 %. This study identified a streptomycete strain with a broad antagonist activity that could be used for biocontrol of plant pathogenic fungi. PMID:24310522

  20. Potential Bio-Control Agent from Rhodomyrtus tomentosa against Listeria monocytogenes

    PubMed Central

    Odedina, Grace Fiyinfoluwa; Vongkamjan, Kitiya; Voravuthikunchai, Supayang Piyawan

    2015-01-01

    Listeria monocytogenes is an important foodborne pathogen implicated in many outbreaks of listeriosis. This study aimed at screening for the potential use of Rhodomyrtus tomentosa ethanolic leaf extract as a bio-control agent against L. monocytogenes. Twenty-two L. monocytogenes isolates were checked with 16 commercial antibiotics and isolates displayed resistance to 10 antibiotics. All the tested isolates were sensitive to the extract with inhibition zones ranging from 14 to 16 mm. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values ranged from 16 to 32 µg/mL and 128 to 512 µg/mL, respectively. Time-kill assay showed that the extract had remarkable bactericidal effects on L. monocytogenes. The extract at a concentration of 16 µg/mL reduced tolerance to 10% NaCl in L. monocytogenes in 4 h. Stationary phase L. monocytogenes cells were rapidly inactivated by greater than 3-log units within 30 min of contact time with R. tomentosa extract at 128 µg/mL. Electron microscopy revealed fragmentary bacteria with changes in the physical and morphological properties. Our study demonstrates the potential of the extract for further development into a bio-control agent in food to prevent the incidence of L. monocytogenes contamination. PMID:26371033

  1. Potential water-quality effects from iron cyanide anticaking agents in road salt

    SciTech Connect

    Paschka, M.G.; Ghosh, R.S.; Dzombak, D.A.

    1999-10-01

    Water-soluble iron cyanide compounds are widely used as anticaking agents in road salt, which creates potential contamination of surface and groundwater with these compounds when the salt dissolves and is washed off roads in runoff. This paper presents a summary of available information on iron cyanide use in road salt and its potential effects on water quality. Also, estimates of total cyanide concentrations in snow-melt runoff from roadways are presented as simple mass-balance calculations. Although available information does not indicate a widespread problem, it also is clear that the water-quality effects of cyanide in road salt have not been examined much. Considering the large, and increasing, volume of road salt used for deicing, studies are needed to determine levels of total and free cyanide in surface and groundwater adjacent to salt storage facilities and along roads with open drainage ditches. Results could be combined with current knowledge of the fate and transport of cyanide to assess water-quality effects of iron cyanide anticaking agents used in road salt.

  2. Potential Bio-Control Agent from Rhodomyrtus tomentosa against Listeria monocytogenes.

    PubMed

    Odedina, Grace Fiyinfoluwa; Vongkamjan, Kitiya; Voravuthikunchai, Supayang Piyawan

    2015-09-01

    Listeria monocytogenes is an important foodborne pathogen implicated in many outbreaks of listeriosis. This study aimed at screening for the potential use of Rhodomyrtus tomentosa ethanolic leaf extract as a bio-control agent against L. monocytogenes. Twenty-two L. monocytogenes isolates were checked with 16 commercial antibiotics and isolates displayed resistance to 10 antibiotics. All the tested isolates were sensitive to the extract with inhibition zones ranging from 14 to 16 mm. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values ranged from 16 to 32 µg/mL and 128 to 512 µg/mL, respectively. Time-kill assay showed that the extract had remarkable bactericidal effects on L. monocytogenes. The extract at a concentration of 16 µg/mL reduced tolerance to 10% NaCl in L. monocytogenes in 4 h. Stationary phase L. monocytogenes cells were rapidly inactivated by greater than 3-log units within 30 min of contact time with R. tomentosa extract at 128 µg/mL. Electron microscopy revealed fragmentary bacteria with changes in the physical and morphological properties. Our study demonstrates the potential of the extract for further development into a bio-control agent in food to prevent the incidence of L. monocytogenes contamination. PMID:26371033

  3. Potential use of Folate-appended Methyl-β-Cyclodextrin as an Anticancer Agent

    PubMed Central

    Onodera, Risako; Motoyama, Keiichi; Okamatsu, Ayaka; Higashi, Taishi; Arima, Hidetoshi

    2013-01-01

    To obtain a tumor cell-selectivity of methyl-β-cyclodextrin (M-β-CyD), we newly synthesized folate-appended M-β-CyD (FA-M-β-CyD), and evaluated the potential of FA-M-β-CyD as a novel anticancer agent in vitro and in vivo. Potent antitumor activity and cellular association of FA-M-β-CyD were higher than those of M-β-CyD in KB cells, folate receptor (FR)-positive cells. FA-M-β-CyD drastically inhibited the tumor growth after intratumoral or intravenous injection to FR-positive Colon-26 cells-bearing mice. The antitumor activity of FA-M-β-CyD was comparable and superior to that of doxorubicin after both intratumoral and intravenous administrations, respectively, at the same dose, in the tumor-bearing mice. All of the tumor-bearing mice after an intravenous injection of FA-M-β-CyD survived for at least more than 140 days. Importantly, an intravenous administration of FA-M-β-CyD to tumor-bearing mice did not show any significant change in blood chemistry values. These results strongly suggest that FA-M-β-CyD has the potential as a novel anticancer agent. PMID:23346361

  4. Effect of Hypobaric Hypoxia on Cognitive Functions and Potential Therapeutic Agents

    PubMed Central

    MUTHURAJU, Sangu; PATI, Soumya

    2014-01-01

    High altitude (HA), defined as approximately 3000–5000 m, considerably alters physiological and psychological parameters within a few hours. Chronic HA-mediated hypoxia (5000 m) results in permanent neuronal damage to the human brain that persists for one year or longer, even after returning to sea level. At HA, there is a decrease in barometric pressure and a consequential reduction in the partial pressure of oxygen (PO2), an extreme environmental condition to which humans are occasionally exposed. This condition is referred to as hypobaric hypoxia (HBH), which represents the most unfavourable characteristics of HA. HBH causes the disruption of oxygen availability to tissue. However, no review article has explored the impact of HBH on cognitive functions or the potential therapeutic agents for HBH. Therefore, the present review aimed to describe the impact of HBH on both physiological and cognitive functions, specifically learning and memory. Finally, the potential therapeutic agents for the treatment of HBH-induced cognitive impairment are discussed. PMID:25941462

  5. Synthesis and biological evaluation of oxindole linked indolyl-pyrimidine derivatives as potential cytotoxic agents.

    PubMed

    Prajapti, Santosh Kumar; Nagarsenkar, Atulya; Guggilapu, Sravanthi Devi; Gupta, Keshav Kumar; Allakonda, Lingesh; Jeengar, Manish Kumar; Naidu, V G M; Babu, Bathini Nagendra

    2016-07-01

    In our endeavor towards the development of effective cytotoxic agents, a series of oxindole linked indolyl-pyrimidine derivatives were synthesized and characterized by IR, (1)H NMR, (13)C NMR and Mass spectral analysis. All the newly synthesized target compounds were assessed against PA-1 (ovarian), U-87MG (glioblastoma), LnCaP (prostate), and MCF-7 (Breast) cancer cell lines for their cytotoxic potential, with majority of them showing inhibitory activity at low micro-molar concentrations. Significantly, compound 8e was found to be most potent amongst all the tested compounds with an IC50 value of (2.43±0.29μM) on PA-1 cells. The influence of the most active cytotoxic compound 8e on the cell cycle distribution was assessed on the PA-1 cell line, exhibiting a cell cycle arrest at the G2/M phase. Moreover, acridine orange/ethidium bromide staining and annexin V binding assay confirmed that compound 8e can induce cell apoptosis in PA-1 cells. These preliminary results persuade further investigation on the synthesized compounds aiming to the development of potential cytotoxic agents. PMID:27210438

  6. Effect of hypobaric hypoxia on cognitive functions and potential therapeutic agents.

    PubMed

    Muthuraju, Sangu; Pati, Soumya

    2014-12-01

    High altitude (HA), defined as approximately 3000-5000 m, considerably alters physiological and psychological parameters within a few hours. Chronic HA-mediated hypoxia (5000 m) results in permanent neuronal damage to the human brain that persists for one year or longer, even after returning to sea level. At HA, there is a decrease in barometric pressure and a consequential reduction in the partial pressure of oxygen (PO2), an extreme environmental condition to which humans are occasionally exposed. This condition is referred to as hypobaric hypoxia (HBH), which represents the most unfavourable characteristics of HA. HBH causes the disruption of oxygen availability to tissue. However, no review article has explored the impact of HBH on cognitive functions or the potential therapeutic agents for HBH. Therefore, the present review aimed to describe the impact of HBH on both physiological and cognitive functions, specifically learning and memory. Finally, the potential therapeutic agents for the treatment of HBH-induced cognitive impairment are discussed. PMID:25941462

  7. Effect of reducing agents and uncouplers on the electrical potential generated by mitochondrial ATPase activity.

    PubMed

    Encío, I; de Miguel, C; López-Moratalla, N; Santiago, E

    1989-12-01

    Beef heart submitochondrial particles bound to phospholipids impregnated filters generated an electrical potential upon the addition of ATP. The magnitude of the electrical potential reached depended on the phospholipid mixture composition used for filter impregnation, phosphatidylethanolamine being the active component for the electrical potential generation. Uncoupler FCCP (p-trifluoromethoxy carbonyl cyanide phenylhydrazone) inhibited the transmembrane electrical potential generation by diminishing the electrical resistance of the system as a result of its protonophoric action. However, uncouplers 2, 4-dinitrophenol and dicoumarol did not provoke large modifications of the electrical resistance under the conditions of pH and concentration used, and their action varied with the time elapsed after the submitochondrial particles purification, favouring the idea of the uncoupler interaction with a specific site on the membrane. Addition of sodium dithionite resulted in a higher plateau value for the electrical potential consistent with the promoted increase in ATPase activity. The effect of this agent was reversed by the 2,6-dichlorophenol-indophenol added at equivalent concentrations. PMID:2561021

  8. In vitro assays for assessing the potential for copper complexes to function as radiopharmaceutical agents.

    PubMed

    Barnard, P J; Bayly, S R; Holland, J P; Dilworth, J R; Waghorn, P A

    2008-09-01

    A series of chemical in vitro assays are described to provide a rapid initial assessment of the in vivo stability and biological behaviour of potential new copper(II) based radiopharmaceutical agents. Chemical challenges using an excess of cysteine, glutathione (GSH) and histidine, which are models of S- and N-donor molecules found in vivo, are used to provide a measure of the potential for loss of the copper(II) ion from the radiopharmaceutical as a result of ligand dissociation. In addition, thiol containing molecules such as cysteine and GSH provide a redox challenge, whereby the copper(II) complex may be reduced to give a copper(I) species. The stability of the copper(I) species toward oxidation, protonation, and ligand dissociation may be crucial in determining the biodistribution, the biological half-life and excretion mechanisms of a potential radiopharmaceutical. Further evaluation of the redox stability is assessed using the ubiquitous biological reductant ascorbic acid. The relative stability of a complex with respect to ligand dissociation in human serum provides one of the most important experiments assessing the potential of a complex to be used in vivo. Further challenge experiments with serum proteins such as thioredoxin and serum albumin can be used to provide more detailed information on the probable fate of the complex in serum. Evaluation of complex stability and speciation over a range of pH values may also be used to obtain information on potential biodistribution. PMID:18551094

  9. Correction: Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents

    NASA Astrophysics Data System (ADS)

    Hachani, Roxanne; Lowdell, Mark; Birchall, Martin; Hervault, Aziliz; Mertz, Damien; Begin-Colin, Sylvie; Thanh, Nguy&Ecirtil; N. Thi&Cmb. B. Dot; Kim

    2016-02-01

    Correction for `Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents' by Roxanne Hachani et al., Nanoscale, 2015, DOI: 10.1039/c5nr03867g.

  10. Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

    SciTech Connect

    Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; Ammar, David A.; Agarwal, Chapla; Tyagi, Puneet; Kompella, Uday B.; Enzenauer, Robert W.; Petrash, J. Mark; Agarwal, Rajesh

    2012-10-01

    There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost effective

  11. Bismuth@US-tubes as a Potential Contrast Agent for X-ray Imaging Applications

    PubMed Central

    Rivera, Eladio J.; Tran, Lesa A.; Hernández-Rivera, Mayra; Yoon, Diana; Mikos, Antonios G.; Rusakova, Irene A.; Cheong, Benjamin Y.; Cabreira-Hansen, Maria da Graça; Willerson, James T.; Perin, Emerson C.; Wilson, Lon J.

    2013-01-01

    The encapsulation of bismuth as BiOCl/Bi2O3 within ultra-short (ca. 50 nm) single-walled carbon nanocapsules (US-tubes) has been achieved. The Bi@US-tubes have been characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Bi@US-tubes have been used for intracellular labeling of pig bone marrow-derived mesenchymal stem cells (MSCs) to show high X-ray contrast in computed tomography (CT) cellular imaging for the first time. The relatively high contrast is achieved with low bismuth loading (2.66% by weight) within the US-tubes and without compromising cell viability. X-ray CT imaging of Bi@US-tubes-labeled MSCs showed a nearly two-fold increase in contrast enhancement when compared to unlabeled MSCs in a 100 kV CT clinical scanner. The CT signal enhancement from the Bi@US-tubes is 500 times greater than polymer-coated Bi2S3 nanoparticles and several-fold that of any clinical iodinated contrast agent (CA) at the same concentration. Our findings suggest that the Bi@US-tubes can be used as a potential new class of X-ray CT agent for stem cell labeling and possibly in vivo tracking. PMID:24288589

  12. Understanding Virulence in the Brucellae and Francisellae: Towards Efficacious Treatments for Two Potential Biothreat Agents

    SciTech Connect

    Rasley, A; Parsons, D A; El-Etr, S; Roux, C; Tsolis, R

    2009-12-30

    Francisella tularensis, Yersinia pestis and Brucellae species are highly infectious pathogens classified as select agents by the Centers for Disease Control and Prevention (CDC) with the potential for use in bioterrorism attacks. These organisms are known to be facultative intracellular pathogens that preferentially infect human monocytes. As such, understanding how the host responds to infection with these organisms is paramount in detecting and combating human disease. We have compared the ability of fully virulent strains of each pathogen and their non-pathogenic near neighbors to enter and survive inside the human monocytic cell line THP-1 and have quantified the cellular response to infection with the goal of identifying both unique and common host response patterns. We expanded the scope of these studies to include experiments with pathogenic and non-pathogenic strains of Y. pestis, the causative agent of plague. Nonpathogenic strains of each organism were impaired in their ability to survive intracellularly compared with their pathogenic counterparts. Furthermore, infection of THP-1 cells with pathogenic strains of Y. pestis and F. tularensis resulted in marked increases in the secretion of the inflammatory chemokines IL-8, RANTES, and MIP-1{beta}. In contrast, B. melitensis infection failed to elicit any significant increases in a panel of cytokines tested. These differences may underscore distinct strategies in pathogenic mechanisms employed by these pathogens.

  13. Pseudopterosin A: Protection of Synaptic Function and Potential as a Neuromodulatory Agent.

    PubMed

    Caplan, Stacee Lee; Zheng, Bo; Dawson-Scully, Ken; White, Catherine A; West, Lyndon M

    2016-03-01

    Natural products have provided an invaluable source of inspiration in the drug discovery pipeline. The oceans are a vast source of biological and chemical diversity. Recently, this untapped resource has been gaining attention in the search for novel structures and development of new classes of therapeutic agents. Pseudopterosins are group of marine diterpene glycosides that possess an array of potent biological activities in several therapeutic areas. Few studies have examined pseudopterosin effects during cellular stress and, to our knowledge, no studies have explored their ability to protect synaptic function. The present study probes pseudopterosin A (PsA) for its neuromodulatory properties during oxidative stress using the fruit fly, Drosophila melanogaster. We demonstrate that oxidative stress rapidly reduces neuronal activity, resulting in the loss of neurotransmission at a well-characterized invertebrate synapse. PsA mitigates this effect and promotes functional tolerance during oxidative stress by prolonging synaptic transmission in a mechanism that differs from scavenging activity. Furthermore, the distribution of PsA within mammalian biological tissues following single intravenous injection was investigated using a validated bioanalytical method. Comparable exposure of PsA in the mouse brain and plasma indicated good distribution of PsA in the brain, suggesting its potential as a novel neuromodulatory agent. PMID:26978375

  14. Pseudopterosin A: Protection of Synaptic Function and Potential as a Neuromodulatory Agent

    PubMed Central

    Caplan, Stacee Lee; Zheng, Bo; Dawson-Scully, Ken; White, Catherine A.; West, Lyndon M.

    2016-01-01

    Natural products have provided an invaluable source of inspiration in the drug discovery pipeline. The oceans are a vast source of biological and chemical diversity. Recently, this untapped resource has been gaining attention in the search for novel structures and development of new classes of therapeutic agents. Pseudopterosins are group of marine diterpene glycosides that possess an array of potent biological activities in several therapeutic areas. Few studies have examined pseudopterosin effects during cellular stress and, to our knowledge, no studies have explored their ability to protect synaptic function. The present study probes pseudopterosin A (PsA) for its neuromodulatory properties during oxidative stress using the fruit fly, Drosophila melanogaster. We demonstrate that oxidative stress rapidly reduces neuronal activity, resulting in the loss of neurotransmission at a well-characterized invertebrate synapse. PsA mitigates this effect and promotes functional tolerance during oxidative stress by prolonging synaptic transmission in a mechanism that differs from scavenging activity. Furthermore, the distribution of PsA within mammalian biological tissues following single intravenous injection was investigated using a validated bioanalytical method. Comparable exposure of PsA in the mouse brain and plasma indicated good distribution of PsA in the brain, suggesting its potential as a novel neuromodulatory agent. PMID:26978375

  15. Potential Molecular Targets for Narrow-Spectrum Agents to Combat Mycoplasma pneumoniae Infection and Disease

    PubMed Central

    Balish, Mitchell F.; Distelhorst, Steven L.

    2016-01-01

    As Mycoplasma pneumoniae macrolide resistance grows and spreads worldwide, it is becoming more important to develop new drugs to prevent infection or limit disease. Because other mycoplasma species have acquired resistance to other classes of antibiotics, it is reasonable to presume that M. pneumoniae can do the same, so switching to commonly used antibiotics like fluoroquinolones will not result in forms of therapy with long-term utility. Moreover, broad-spectrum antibiotics can have serious consequences for the patient, as these drugs may have severe impacts on the natural microbiota of the individual, compromising the health of the patient either short-term or long-term. Therefore, developing narrow-spectrum antibiotics that effectively target only M. pneumoniae and no more than a small portion of the microbiota is likely to yield impactful, positive results that can be used perhaps indefinitely to combat M. pneumoniae. Development of these agents requires a deep understanding of the basic biology of M. pneumoniae, in many areas deeper than what is currently known. In this review, we discuss potential targets for new, narrow-spectrum agents and both the positive and negative aspects of selecting these targets, which include toxic molecules, metabolic pathways, and attachment and motility. By gathering this information together, we anticipate that it will be easier for researchers to evaluate topics of priority for study of M. pneumoniae. PMID:26941728

  16. A Novel Potential Positron Emission Tomography Imaging Agent for Vesicular Monoamine Transporter Type 2.

    PubMed

    Huang, Zih-Rou; Tsai, Chia-Ling; Huang, Ya-Yao; Shiue, Chyng-Yann; Tzen, Kai-Yuan; Yen, Ruoh-Fang; Hsin, Ling-Wei

    2016-01-01

    In the early 1990s, 9-(+)-11C-dihydrotetrabenazine (9-(+)-11C-DTBZ) was shown to be a useful positron emission tomography (PET) imaging agent for various neurodegenerative disorders. Here, we described the radiosynthesis and evaluation of the 9-(+)-11C-DTBZ analog, 10-(+)-11C-DTBZ, as a vesicular monoamine transporter 2 (VMAT2) imaging agent and compare it with 9-(+)-11C-DTBZ. 10-(+)-11C-DTBZ was obtained by 11C-MeI methylation with its 10 hydroxy precursor in the presence of 5 M NaOH. It had a slightly better average radiochemical yield of 35.3 ± 3.6% (decay-corrected to end of synthesis (EOS)) than did 9-(+)-11C-DTBZ (30.5 ± 2.3%). MicroPET studies showed that 10-(+)-11C-DTBZ had a striatum-to-cerebellum ratio of 3.74 ± 0.21 at 40 min post-injection, while the ratio of 9-(+)-11C-DTBZ was 2.50 ± 0.33. This indicated that 10-(+)-11C-DTBZ has a higher specific uptake in VMAT2-rich brain regions, and 10-(+)-11C-DTBZ may be a potential VMAT2 radioligand. Our experiment is the first study of 10-(+)-11C-DTBZ to include dynamic brain distribution in rat brains. PMID:27612194

  17. Pharmacophore modeling and in silico toxicity assessment of potential anticancer agents from African medicinal plants

    PubMed Central

    Ntie-Kang, Fidele; Simoben, Conrad Veranso; Karaman, Berin; Ngwa, Valery Fuh; Judson, Philip Neville; Sippl, Wolfgang; Mbaze, Luc Meva’a

    2016-01-01

    Molecular modeling has been employed in the search for lead compounds of chemotherapy to fight cancer. In this study, pharmacophore models have been generated and validated for use in virtual screening protocols for eight known anticancer drug targets, including tyrosine kinase, protein kinase B β, cyclin-dependent kinase, protein farnesyltransferase, human protein kinase, glycogen synthase kinase, and indoleamine 2,3-dioxygenase 1. Pharmacophore models were validated through receiver operating characteristic and Güner–Henry scoring methods, indicating that several of the models generated could be useful for the identification of potential anticancer agents from natural product databases. The validated pharmacophore models were used as three-dimensional search queries for virtual screening of the newly developed AfroCancer database (~400 compounds from African medicinal plants), along with the Naturally Occurring Plant-based Anticancer Compound-Activity-Target dataset (comprising ~1,500 published naturally occurring plant-based compounds from around the world). Additionally, an in silico assessment of toxicity of the two datasets was carried out by the use of 88 toxicity end points predicted by the Lhasa’s expert knowledge-based system (Derek), showing that only an insignificant proportion of the promising anticancer agents would be likely showing high toxicity profiles. A diversity study of the two datasets, carried out using the analysis of principal components from the most important physicochemical properties often used to access drug-likeness of compound datasets, showed that the two datasets do not occupy the same chemical space. PMID:27445461

  18. Design of novel dispirooxindolopyrrolidine and dispirooxindolopyrrolothiazole derivatives as potential antitubercular agents.

    PubMed

    Mhiri, Chourouk; Boudriga, Sarra; Askri, Moheddine; Knorr, Michael; Sriram, Dharmarajan; Yogeeswari, Perumal; Nana, Frédéric; Golz, Christopher; Strohmann, Carsten

    2015-10-01

    With the aim to develop new potent antitubercular agents, a series of novel dispirooxindolopyrrolidines and dispirooxindolopyrrolothiazoles have been synthesized via a three-component 1,3-dipolar cycloaddition of (Z)-3-arylidenebenzofuran-2-ones, substituted isatin derivatives and α-aminoacids. The stereochemistry of the spiroadducts has been confirmed by an X-ray diffraction analysis. All the target heterocycles were evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and the most active compounds were subjected to cytotoxicity studies against (RAW 264.7) cell lines. Among them, twelve compounds showed potent anti-tubercular activity with MIC ranging from 1.56 to 6.25 μg/mL. In particular dispirooxindolopyrrolothiazole derivatives 5c and 5f were found to be the most active (MIC of 1.56 μg/mL) with a good safety profile (27.53% and 20.74% at 50 μM, respectively). This is the first report demonstrating the benzofuranone oxindole hybrids as potential antimycobacterial agents. PMID:26271585

  19. Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent

    PubMed Central

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F. N.; Hamed, Maha I.; Sobreira, Tiago J. P.; Hedrick, Victoria E.; Paul, Lake N.; Seleem, Mohamed N.

    2015-01-01

    The rapid rise of bacterial resistance to traditional antibiotics combined with the decline in discovery of novel antibacterial agents has created a global public health crisis. Repurposing existing drugs presents an alternative strategy to potentially expedite the discovery of new antimicrobial drugs. The present study demonstrates that simvastatin, an antihyperlipidemic drug exhibited broad-spectrum antibacterial activity against important Gram-positive (including methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative pathogens (once the barrier imposed by the outer membrane was permeabilized). Proteomics and macromolecular synthesis analyses revealed that simvastatin inhibits multiple biosynthetic pathways and cellular processes in bacteria, including selective interference of bacterial protein synthesis. This property appears to assist in simvastatin’s ability to suppress production of key MRSA toxins (α-hemolysin and Panton-Valentine leucocidin) that impair healing of infected skin wounds. A murine MRSA skin infection experiment confirmed that simvastatin significantly reduces the bacterial burden and inflammatory cytokines in the infected wounds. Additionally, simvastatin exhibits excellent anti-biofilm activity against established staphylococcal biofilms and demonstrates the ability to be combined with topical antimicrobials currently used to treat MRSA skin infections. Collectively the present study lays the foundation for further investigation of repurposing simvastatin as a topical antibacterial agent to treat skin infections. PMID:26553420

  20. An integrated overview on pyrrolizines as potential anti-inflammatory, analgesic and antipyretic agents.

    PubMed

    Gouda, Ahmed M; Abdelazeem, Ahmed H

    2016-05-23

    Despite the existence of huge number of NSAIDs, the quest for safer drugs is still in the focus of several drug discovery programs. Pyrrolizine heterocyclic system is among the privileged scaffolds utilized in this regard. At least one of these pyrrolizines, ketorolac, has reached the market. The current review represents a collective effort to highlight the reported pyrrolizines with anti-inflammatory and analgesic potential and categorize them into eight different classes. Furthermore, the various synthetic approaches, structure-activity relationship as well as metabolic pathways have been discussed. Taken together, this review sets a base for researchers to design and synthesize novel pyrrolizine-based libraries for further development into safer and efficient anti-inflammatory and analgesic agents. PMID:26994693

  1. Design and evaluation of novel oxadiazole derivatives as potential prostate cancer agents

    PubMed Central

    Qi, Xin; Euynni, Suresh; Sikazwi, Donald; Mateeva, Nelly; Soliman, Karam F.

    2016-01-01

    Various 1,3,4-oxadiazole derivatives have been synthesized and their antiproliferative properties have been studied. The in vitro screening was performed against androgen dependent (LNCaP) and androgen independent (PC-3) prostate cancer cell lines. Most of the compounds showed promising activity. Among them, compounds 2d (IC50 = 0.22 and 1.3 μM) and 2a (IC50 = 8.34 and 2,5 μM) have shown significant activities on PC-3 and LNCaP cell lines respectively. To investigate the mechanism of cell death we performed cell apoptosis staining and cell cycle arrest assay on more sensitive PC-3 cell lines on 2d. The results demonstrated that 2d induced apoptosis and shifted the cells to the sub G0/G1 and S phase. Our study evidently identified the potency of compound 2d as potential anti-prostate cancer agent. PMID:27156770

  2. Potential Use of Phenolic Acids as Anti-Candida Agents: A Review

    PubMed Central

    Teodoro, Guilherme R.; Ellepola, Kassapa; Seneviratne, Chaminda J.; Koga-Ito, Cristiane Y.

    2015-01-01

    There has been a sharp rise in the occurrence of Candida infections and associated mortality over the last few years, due to the growing body of immunocompromised population. Limited number of currently available antifungal agents, undesirable side effects and toxicity, as well as emergence of resistant strains pose a considerable clinical challenge for the treatment of candidiasis. Therefore, molecules that derived from natural sources exhibiting considerable antifungal properties are a promising source for the development of novel anti-candidal therapy. Phenolic compounds isolated from natural sources possess antifungal properties of interest. Particularly, phenolic acids have shown promising in vitro and in vivo activity against Candida species. However, studies on their mechanism of action alone or in synergism with known antifungals are still scarce. This review attempts to discuss the potential use, proposed mechanisms of action and limitations of the phenolic acids in anti-candidal therapy. PMID:26733965

  3. Design and evaluation of novel oxadiazole derivatives as potential prostate cancer agents.

    PubMed

    Mochona, Bereket; Qi, Xin; Euynni, Suresh; Sikazwi, Donald; Mateeva, Nelly; Soliman, Karam F

    2016-06-15

    Various 1,3,4-oxadiazole derivatives have been synthesized and their antiproliferative properties have been studied. The in vitro screening was performed against androgen dependent (LNCaP) and androgen independent (PC-3) prostate cancer cell lines. Most of the compounds showed promising activity. Among them, compounds 2d (IC50=0.22 and 1.3μM) and 2a (IC50=8.34 and 2,5μM) have shown significant activities on PC-3 and LNCaP cell lines respectively. To investigate the mechanism of cell death we performed cell apoptosis staining and cell cycle arrest assay on more sensitive PC-3 cell lines on 2d. The results demonstrated that 2d induced apoptosis and shifted the cells to the sub G0/G1 and S phase. Our study evidently identified the potency of compound 2d as potential anti-prostate cancer agent. PMID:27156770

  4. The potential of antiestrogens as centrally-acting antihostility agents: recent animal data.

    PubMed

    Brain, P F; Simon, V; Hasan, S; Martinez, M; Castano, D

    1988-08-01

    Recent studies suggest that motivations for certain forms of masculine behavior including social aggression are mediated by central estrogen receptors. Two studies using antiestrogens in rodent species were performed. Intact male LH rats were given Tamoxifen or vehicle for 4 or 8 days. The three possible pairings were videotaped for 60 min. Intact male OF1 mice were given CI-680 or vehicle over 25 days. Similar pairings were carried out but some CI-680 or vehicle animals were paired with anosmic opponents. Encounters were videotaped for 10 min. In both experiments evidence was obtained that the antiestrogen markedly reduced time allocated to offense. Any variations in defense were a consequence of the level of attack to which animals were subjected. Neither compound greatly influenced the androgen-dependent sex accessory glands. Antiestrogens consequently have potential as antihostility agents in some forms of attack. PMID:3182180

  5. Design and synthesis of novel 4'-demethyl-4-deoxypodophyllotoxin derivatives as potential anticancer agents.

    PubMed

    Zhu, Xiong; Fu, Junjie; Tang, Yan; Gao, Yuan; Zhang, Shijin; Guo, Qinglong

    2016-02-15

    A group of podophyllotoxin (PPT) derivatives (7a-j) were synthesized by conjugating aryloxyacetanilide moieties to the 4'-hydroxyl of 4'-demethyl-4-deoxypodophyllotoxin (DDPT), and their anticancer activity was evaluated. It was found that the most potent compound 7d inhibited the proliferation of three cancer cell lines with sub to low micromolar IC50 values. Furthermore, it was demonstrated that 7d induced cell cycle arrest in G2/M phase in MGC-803 cells, and regulated the expression of cell cycle check point proteins, such as cyclin A, cyclin B, CDK1, cdc25c, and p21. Finally, 4 mg/kg of 7d reduced the weights and volumes of HepG2 xenografts in mice. Our findings suggest that 7d might be a potential anticancer agent. PMID:26804229

  6. Vibrational spectroscopy of N‧-(Adamantan-2-ylidene)thiophene-2-carbohydrazide, a potential antibacterial agent

    NASA Astrophysics Data System (ADS)

    Gladkov, Lev L.; Gaponenko, Sergey V.; Shabunya-Klyachkovskaya, Elena V.; Shimko, Anna N.; Al-Abdullah, Ebtehal S.; El-Emam, Ali A.

    2014-07-01

    Vibrational states of the newly synthesized molecule N‧-(Adamantan-2-ylidene)thiophene-2-carbohydrazide, a potential antibacterial agent, are examined experimentally for the crystalline phase and analyzed based on quantum chemical modelling of the solitary molecule and of the dimer, and assignment of the observed vibrational frequencies is proposed. Modelling of the title molecule dimer is found to describe better the experimentally observed vibration frequencies for the crystalline phase than calculations performed for a solitary molecule. Contributions from adamantane and thiophene parts within the molecule are identified. Additionally, multiple hydrogen bonds have been revealed both experimentally and computationally, inherent in the crystalline phase contrary to a solitary molecule. The spectroscopic findings correlate with the calculated interatomic distances which were found to change in the dimer versus a single molecule and to correspond better to the X-ray analysis data of the title compound in the crystalline phase.

  7. Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

    PubMed Central

    Ballatore, Carlo; Brunden, Kurt R.; Huryn, Donna M.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Smith, Amos B.

    2012-01-01

    The microtubule (MT)-associated protein tau, which is highly expressed in the axons of neurons, is an endogenous MT-stabilizing agent that plays an important role in the axonal transport. Loss of MT-stabilizing tau function, caused by misfolding, hyperphosphorylation and sequestration of tau into insoluble aggregates, leads to axonal transport deficits with neuropathological consequences. Several in vitro and preclinical in vivo studies have shown that MT-stabilizing drugs can be utilized to compensate for the loss of tau function and to maintain/restore an effective axonal transport. These findings indicate that MT-stabilizing compounds hold considerable promise for the treatment of Alzheimer disease and related tauopathies. The present article provides a synopsis of the key findings demonstrating the therapeutic potential of MT-stabilizing drugs in the context of neurodegenerative tauopathies, as well as an overview of the different classes of MT-stabilizing compounds. PMID:23020671

  8. Sodium arsenite potentiates the clastogenicity and mutagenicity of DNA cross linking agents

    SciTech Connect

    Lee, T.C.; Lee, K.C.; Tzeng, Y.J.; Huang, R.Y.; Jan, K.Y.

    1986-01-01

    To see if sodium arsenite enhances the clastogenicity and the mutagenicity of DNA crosslinking agents, Chinese hamster ovary (CHO) cells and human skin fibroblasts were exposed to cis-diamminedichloroplatinum (II) (cis-Pt(II)) or 8-methoxypsoralen (8-MOP) plus long-wave ultraviolet light (UVA) and then to sodium arsenite. The results indicate that the clastogenicity of cis-Pt(II) and 8-MOP pllus UVA are enhanced by the post-treatment with sodium arsenite. Chromatid breaks and exchanges are predominantly increased in doubly treated cells. Furthermore, the mutagenicity of cis-Pt(II) at the hypoxanthine-guanine phosphoribosyl transferase locus is also potentiated by sodium arsenite in CHO cells

  9. Chitosan as a potential stabilizing agent for titania nanoparticle dispersions for preparation of multifunctional cotton fabric.

    PubMed

    Goyal, Nidhi; Rastogi, Deepali; Jassal, Manjeet; Agrawal, Ashwini K

    2016-12-10

    Titania (TiO2) nanoparticle dispersions in water were prepared using chitosan (CS) as the stabilizing agent. The dispersion stability was evaluated with respect to storage time, hydrodynamic particle size, and zeta potential. The effect of the molecular weight of CS and presence of non-ionic polymers (poly(vinyl alcohol) and poly(ethylene glycol)) as co-dispersants was investigated. Despite the increase in size of dispersed particles, the long-term storage stability of the dispersions improved with increasing concentration and molecular weight of CS. The TiO2/CS dispersions were applied on cotton fabric and characterized. The presence of CS did not seriously affect the photocatalytic self-cleaning activity (SCA) of TiO2; with CS, a SCA of 89% was achieved compared with a value of 96% without CS. In addition, the TiO2/CS-treated cotton fabrics provided UV protection and significant antimicrobial activity. PMID:27577907

  10. 227Th-EDTMP: a potential therapeutic agent for bone metastasis.

    PubMed

    Washiyama, Kohshin; Amano, Ryohei; Sasaki, Jun; Kinuya, Seigo; Tonami, Norihisa; Shiokawa, Yoshinobu; Mitsugashira, Toshiaki

    2004-10-01

    The biodistribution of 227Th-EDTMP and retention of its daughter nuclide 223Ra were examined. 227Th-EDTMP was found to show high uptake and long-term retention in bone. The clearance of 227Th-EDTMP from blood and soft tissues was rapid and the femur-to-tissue uptake ratios reached more than 100 within 30 min for all tissues except the kidney. Seven and 14 days after injection of 227Th-EDTMP, the retention index of 223Ra in bone showed high values, and the differences between these time points were not significant. Therefore, 227Th-EDTMP is a potential radiotherapeutic agent for bone metastasis. PMID:15464392

  11. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential

    PubMed Central

    Zasloff, Michael; Adams, A. Paige; Beckerman, Bernard; Campbell, Ann; Han, Ziying; Luijten, Erik; Meza, Isaura; Julander, Justin; Mishra, Abhijit; Qu, Wei; Taylor, John M.; Weaver, Scott C.; Wong, Gerard C. L.

    2011-01-01

    Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity of squalamine, a cationic amphipathic sterol, to neutralize the negative electrostatic surface charge of intracellular membranes in a way that renders the cell less effective in supporting viral replication. Because squalamine can be readily synthesized and has a known safety profile in man, we believe its potential as a broad-spectrum human antiviral agent should be explored. PMID:21930925

  12. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential.

    PubMed

    Zasloff, Michael; Adams, A Paige; Beckerman, Bernard; Campbell, Ann; Han, Ziying; Luijten, Erik; Meza, Isaura; Julander, Justin; Mishra, Abhijit; Qu, Wei; Taylor, John M; Weaver, Scott C; Wong, Gerard C L

    2011-09-20

    Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity of squalamine, a cationic amphipathic sterol, to neutralize the negative electrostatic surface charge of intracellular membranes in a way that renders the cell less effective in supporting viral replication. Because squalamine can be readily synthesized and has a known safety profile in man, we believe its potential as a broad-spectrum human antiviral agent should be explored. PMID:21930925

  13. New multifunctional ligands for potential use in the design therapeutic or diagnostic radiopharmaceutical imaging agents

    DOEpatents

    Katti, Kattesh V.; Volkert, Wynn A.; Ketring, Alan R.; Singh, Prahlad R.

    1997-01-01

    A class of diagnostic and therapeutic compounds derived from phosphinimines that include ligands containing either a single phosphinimine functionality or both a phosphinimine group and a phosphine or arsine group, or an aminato group, or a second phosphinimine moiety. These phosphinimine ligands are complexed to early transition metal radionuclides (e.g. .sup.99m Tc or .sup.186 Re/.sup.188 Re) or late transition metals (e.g., .sup.105 Rh or .sup.109 Pd). The complexes with these metals .sup.186 Re/.sup.188 Re, .sup.99m Tc and .sup.109 Pd exhibit a high in vitro and high in vivo stability. The complexes are formed in high yields and can be neutral or charged. These ligands can also be used to form stable compounds with paramagnetic transition metals (e.g. Fe and Mn) for potential use as MRI contrast agents. Applications for the use of ligands and making the ligands are also disclosed.

  14. Novel Penicillin Analogues as Potential Antimicrobial Agents; Design, Synthesis and Docking Studies

    PubMed Central

    Ashraf, Zaman; Bais, Abdul; Manir, Md. Maniruzzaman; Niazi, Umar

    2015-01-01

    A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents. PMID:26267242

  15. Biocompatible nanotemplate-engineered nanoparticles containing gadolinium: stability and relaxivity of a potential MRI contrast agent.

    PubMed

    Zhu, Donghua; White, R D; Hardy, Peter A; Weerapreeyakul, Natthida; Sutthanut, Khaetthareeya; Jay, Michael

    2006-04-01

    In this article, we use a nanotemplate engineering approach to prepare biodegradable nanoparticles composed of FDA-approved materials and possessing accessible gadolinium (Gd) atoms and demonstrate their potential as a Magnetic Resonance Imaging (MRI) contrast agent. Nanoparticles containing dimyristoyl phosphoethanolamine diethylene triamine penta acetate (PE-DTPA) were prepared using 3.5 mg of Brij 78, 2.0 mg of emulsifying wax and 0.5 mg of PE-DTPA/ml from a microemulsion precursor. After the addition of GdCl3, the presence of Gd on the surface of nanoparticles was characterized using inductively coupled plasma atomic emission spectroscopy and Scanning Transmission Electron Microscopy (STEM). The in vitro relaxivities of the PE-DTPA-Gd nanoparticles in different media were assessed at different field strengths. The conditional stability constant of Gd binding to the nanoparticles was determined using competitive spectrophotometric titration. Transmetallation kinetics of the gadolinium ion from PE-DTPA-Gd nanoparticles with zinc as the competing ionic was measured using the relaxivity evolution method. Nanoparticles with a diameter of approximately 130 nm possessing surface chelating functions were made from GRAS (Generally Regarded As Safe) materials. STEM demonstrated the uniform distribution of Gd3+ on the surface of the nanoparticles. The thermodynamic binding constant for Gd3+ to the nanoparticles was approximately 10(18) M(-1) and transmetallation studies with Zn2+ yielded kinetic constants K1 and K(-1) of 0.033 and 0.022 1/h, respectively, with an equilibrium constant of 1.5. A payload of approximately 10(5) Gd/nanoparticle was achieved; enhanced relaxivities were observed, including a pH dependence of the transverse relaxivity (r2). Nanoparticles composed of materials that have been demonstrated to be hemocompatible and enzymatically metabolized and possessing accessible Gd ions on their surface induce relaxivities in the bulk water signal that make them

  16. Enhancing Potentially Plant-Available Lead Concentrations in Contaminated Residential Soils Using a Biodegradable Chelating Agent

    NASA Astrophysics Data System (ADS)

    Andra, S.; Datta, R.; Sarkar, D.; Saminathan, S.

    2007-12-01

    Chelation of heavy metals is an important factor in enhancing metal solubility and, hence, metal availability to plants to promote phytoremediation. In the present study, we compared the effects of application of a biodegradable chelating agent, namely, ethylenediaminedisuccinic acid (EDDS) on enhancing plant available form of lead (Pb) in Pb-based paint contaminated residential soils compared to that of a more commonly used, but non-biodegradable chelate, i.e., ethylenediaminetetraacetic acid (EDTA). Development of a successful phytoremediation model for metals such as Pb depends on a thorough understanding of the physical and chemical properties of the soil, along with the optimization of a chelate treatment to mobilize Pb from `unavailable' pools to potentially plant available fraction. In this context, we set out to perform batch incubation experiments to investigate the effectiveness of the two aforementioned chelates in enhancing plant available Pb at four different concentrations (0, 5, 10 and 15 mM/kg soil) and three treatment durations (0, 10 and 30 days). We selected 12 contaminated residential soils from two major metropolitan areas (San Antonio, TX and Baltimore, MD) with varying soil physico-chemical properties - the soils from San Antonio were primarily alkaline and those from Baltimore were typically acidic. Total soil Pb concentrations ranged between 256 mg/kg and 4,182 mg/kg. Our results show that both chelates increased the solubility of Pb, otherwise occluded in the complex soil matrix. For both EDTA and EDDS, the exchangeable concentrations of soil Pb also increased with increase in chelate concentration and incubation time. The most effective treatment was 15 mM chelate kg-1 soil incubated for 30 days, which caused many fold increase in potentially plant available Pb (a combination of the soluble and exchangeable fractions) relative to the unamended controls. Step wise multiple linear regression analysis using chelate-extractable Pb and soil

  17. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer

    PubMed Central

    Bishayee, Anupam; Ahmed, Shamima; Brankov, Nikoleta; Perloff, Marjorie

    2010-01-01

    Breast cancer remains a major cause of death in the United States as well as the rest of the world. In view of the limited treatment options for patients with advanced breast cancer, preventive and novel therapeutic approaches play an important role in combating this disease. The plant-derived triterpenoids, commonly used for medicinal purposes in many Asian countries, posses various pharmacological properties. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells as well as anticancer efficacy in preclinical animal models. Numerous triterpenoids have been synthesized by structural modification of natural compounds. Some of these analogs are considered to be the most potent antiinflammatory and anticarcinogenic triterpenoids known. This review examines the potential role of natural triterpenoids and their derivatives in the chemoprevention and treatment of mammary tumors. Both in vitro and in vivo effects of these agents and related molecular mechanisms are presented. Potential challenges and future directions involved in the advancement of these promising compounds in the prevention and therapy of human breast cancer are also identified. PMID:21196213

  18. Screening for potential anti-infective agents towards Burkholderia pseudomallei infection

    NASA Astrophysics Data System (ADS)

    Eng, Su Anne; Nathan, Sheila

    2014-09-01

    The established treatment for melioidosis is antibiotic therapy. However, a constant threat to this form of treatment is resistance development of the causative agent, Burkholderia pseudomallei, towards antibiotics. One option to circumvent this threat of antibiotic resistance is to search for new alternative anti-infectives which target the host innate immune system and/or bacterial virulence. In this study, 29 synthetic compounds were evaluated for their potential to increase the lifespan of an infected host. The nematode Caenorhabditis elegans was adopted as the infection model as its innate immune pathways are homologous to humans. Screens were performed in a liquid-based survival assay containing infected worms exposed to individual compounds and survival of untreated and compound-treated worms were compared. A primary screen identified nine synthetic compounds that extended the lifespan of B. pseudomallei-infected worms. Subsequently, a disc diffusion test was performed on these selected compounds to delineate compounds into those that enhanced the survival of worms via antimicrobial activity i.e. reducing the number of infecting bacteria, or into those that did not target pathogen viability. Out of the nine hits selected, two demonstrated antimicrobial effects on B. pseudomallei. Therefore, the findings from this study suggest that the other seven identified compounds are potential anti-infectives which could protect a host against B. pseudomallei infection without developing the risk of drug resistance.

  19. Identification of (-)-epigallocatechin-3-gallate as a potential agent for blocking infection by grass carp reovirus.

    PubMed

    Wang, Hao; Liu, Weisha; Yu, Fei; Lu, Liqun

    2016-04-01

    Grass carp reovirus (GCRV), the representative strain of the species Aquareovirus C, serves as a model for studying the pathogenesis of aquareoviruses. Previously, epigallocatechin gallate (EGCG) was shown to inhibit orthoreovirus infection. The aim of this study was to test its potential in blocking infection by GCRV. We show that adhesion to the CIK (Ctenopharyngodon idellus kidney) cell surface by GCRV particles is inhibited in a dose-dependent manner by EGCG, as well as by a crude extract of green tea. We also evaluated the safety of EGCG and green tea extract using CIK cells, and the results suggest that EGCG is a promising compound that may be developed as a plant-derived small molecular therapeutic agent against grass carp hemorrhagic disease caused by GCRV infection. As the ligand for the 37/67-kDa laminin receptor (LamR), EGCG's blocking effect on GCRV attachment was associated with the binding potential of GCRV particles to LamR, which was inferred from a VOPBA assay. PMID:26758731

  20. Recent developments in L-asparaginase discovery and its potential as anticancer agent.

    PubMed

    Shrivastava, Abhinav; Khan, Abdul Arif; Khurshid, Mohsin; Kalam, Mohd Abul; Jain, Sudhir K; Singhal, Pradeep K

    2016-04-01

    L-Asparaginase (EC3.5.1.1) is an enzyme, which is used for treatment of acute lymphoblastic leukaemia (ALL) and other related blood cancers from a long time. This enzyme selectively hydrolyzes the extracellular amino acid L-asparagine into L-aspartate and ammonia, leading to nutritional deficiencies, protein synthesis inhibition, and ultimately death of lymphoblastic cells by apoptosis. Currently, bacterial asparaginases are used for treatment purpose but offers scepticism due to a number of toxicities, including thrombosis, pancreatitis, hyperglycemia, and hepatotoxicity. Resistance towards bacterial asparaginase is another major disadvantage during cancer management. This situation attracted attention of researchers towards alternative sources of L-asparaginase, including plants and fungi. Present article discusses about potential of L-asparaginase as an anticancer agent, its mechanism of action, and adverse effects related to current asparaginase formulations. This article also provides an outlook for recent developments in L-asparaginase discovery from alternative sources and their potential as a less toxic alternative to current formulations. PMID:25630663

  1. Synthesis and evaluation of new 3-phenylcoumarin derivatives as potential antidepressant agents.

    PubMed

    Sashidhara, Koneni V; Rao, K Bhaskara; Singh, Seema; Modukuri, Ram K; Aruna Teja, G; Chandasana, Hardik; Shukla, Shubha; Bhatta, Rabi S

    2014-10-15

    A series of amine substituted 3-phenyl coumarin derivatives were designed and synthesized as potential antidepressant agents. In preliminary screening, all compounds were evaluated in forced swimming test (FST), a model to screen antidepressant activity in rodents. Among the series, compounds 5c and 6a potentially decreased the immobility time by 73.4% and 79.7% at a low dose of 0.5 mg/kg as compared to standard drug fluoxetine (FXT) which reduced the immobility time by 74% at a dose of 20 mg/kg, ip. Additionally, these active compounds also exhibited significant efficacy in tail suspension test (TST) (another model to screen antidepressant compounds). Interestingly, rotarod and locomotor activity tests confirmed that these two compounds do not have any motor impairment effect and neurotoxicity in mice. Our studies demonstrate that the new 3-phenylcoumarin derivatives may serve as a promising antidepressant lead and hence pave the way for further investigation around this chemical space. PMID:25239852

  2. Genomic identification of potential targets unique to Candida albicans for the discovery of antifungal agents.

    PubMed

    Tripathi, Himanshu; Luqman, Suaib; Meena, Abha; Khan, Feroz

    2014-01-01

    Despite of modern antifungal therapy, the mortality rates of invasive infection with human fungal pathogen Candida albicans are up to 40%. Studies suggest that drug resistance in the three most common species of human fungal pathogens viz., C. albicans, Aspergillus fumigatus (causing mortality rate up to 90%) and Cryptococcus neoformans (causing mortality rate up to 70%) is due to mutations in the target enzymes or high expression of drug transporter genes. Drug resistance in human fungal pathogens has led to an imperative need for the identification of new targets unique to fungal pathogens. In the present study, we have used a comparative genomics approach to find out potential target proteins unique to C. albicans, an opportunistic fungus responsible for severe infection in immune-compromised human. Interestingly, many target proteins of existing antifungal agents showed orthologs in human cells. To identify unique proteins, we have compared proteome of C. albicans [SC5314] i.e., 14,633 total proteins retrieved from the RefSeq database of NCBI, USA with proteome of human and non-pathogenic yeast Saccharomyces cerevisiae. Results showed that 4,568 proteins were identified unique to C. albicans as compared to those of human and later when these unique proteins were compared with S. cerevisiae proteome, finally 2,161 proteins were identified as unique proteins and after removing repeats total 1,618 unique proteins (42 functionally known, 1,566 hypothetical and 10 unknown) were selected as potential antifungal drug targets unique to C. albicans. PMID:24102473

  3. Mn-54 DTPA distribution in dogs: Evaluation as a potential NMR contrast agent

    SciTech Connect

    Boudreau, R.J.; Frick, M.P.; Levy, R.M.; Sirr, S.A.; Lund, G.; Loken, M.K.

    1985-05-01

    Several paramagnetic ions are currently being evaluated as potential contrast agents for NMR imaging. To date the most successful of these appears to be Gd-DTPA. The authors recently undertook an investigation into the kinetics of biodistribution of Mn-DTPA to determine if this agent showed any tissue specific uptake, and if so, to optimize the time for imaging. In order to obviate the need for repetitive quantitative NMR imaging they have substituted tracer amounts of Mn-54 for the stable ion. Following intravenous injection into three mongrel dogs, samples of blood, bowel, liver, and pancreas were obtained at 3, 15, 30 and 60 minutes and 2, 4 and 6 hours post-injection. Radioactivity, and thus tissue concentration, was then determined in a gamma counter. Urine was also collected throughout the study. At six hours 58.4 +- 7.1% of the injected dose had been excreted in the urine. Peak liver accumulation occurred within 30 minutes (0.503 +- 0.144% injected dose/gm x kg body weight). The pancreas also showed a relatively high accumulation of tracer (0.247 +- 0.039%/gram x kg body weight) by four hours. The pancreas to liver ratios were highest at six hours (.73). The blood concentration fell very rapidly with little tracer remaining in the blood at one hour. The results of these experiments indicate that a significant portion of the injected material was concentrated by liver and pancreas. Unlike MnCl/sub 2/, most of the Mn-DTPA is excreted in the urine. This excretion is expected to reduce the toxicity of the injected material. These results are being used to establish the optimal protocols for NMR imaging with Mn-DTPA.

  4. A Novel Bacteriophage Targeting Cronobacter sakazakii Is a Potential Biocontrol Agent in Foods

    PubMed Central

    Lee, Ju-Hoon; Bai, Jaewoo; Shin, Hakdong; Kim, Yeran; Park, Bookyung; Heu, Sunggi

    2015-01-01

    Cronobacter sakazakii is an important pathogen that causes high mortality in infants. Due to its occasional antibiotic resistance, a bacteriophage approach might be an alternative effective method for the control of this pathogen. To develop a novel biocontrol agent using bacteriophages, the C. sakazakii-infecting phage CR5 was newly isolated and characterized. Interestingly, this phage exhibited efficient and relatively durable host lysis activity. In addition, a specific gene knockout study and subsequent complementation experiment revealed that this phage infected the host strain using the bacterial flagella. The complete genome sequence analysis of phage CR5 showed that its genome contains 223,989 bp of DNA, including 231 predicted open reading frames (ORFs), and it has a G+C content of 50.06%. The annotated ORFs were classified into six functional groups (structure, packaging, host lysis, DNA manipulation, transcription, and additional functions); no gene was found to be related to virulence or toxin or lysogen formation, but >80% of the predicted ORFs are unknown. In addition, a phage proteomic analysis using SDS-PAGE and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) revealed that seven phage structural proteins are indeed present, supporting the ORF predictions. To verify the potential of this phage as a biocontrol agent against C. sakazakii, it was added to infant formula milk contaminated with a C. sakazakii clinical isolate or food isolate, revealing complete growth inhibition of the isolates by the addition of phage CR5 when the multiplicity of infection (MOI) was 105. PMID:26497465

  5. A Novel Bacteriophage Targeting Cronobacter sakazakii Is a Potential Biocontrol Agent in Foods.

    PubMed

    Lee, Ju-Hoon; Bai, Jaewoo; Shin, Hakdong; Kim, Yeran; Park, Bookyung; Heu, Sunggi; Ryu, Sangryeol

    2016-01-01

    Cronobacter sakazakii is an important pathogen that causes high mortality in infants. Due to its occasional antibiotic resistance, a bacteriophage approach might be an alternative effective method for the control of this pathogen. To develop a novel biocontrol agent using bacteriophages, the C. sakazakii-infecting phage CR5 was newly isolated and characterized. Interestingly, this phage exhibited efficient and relatively durable host lysis activity. In addition, a specific gene knockout study and subsequent complementation experiment revealed that this phage infected the host strain using the bacterial flagella. The complete genome sequence analysis of phage CR5 showed that its genome contains 223,989 bp of DNA, including 231 predicted open reading frames (ORFs), and it has a G+C content of 50.06%. The annotated ORFs were classified into six functional groups (structure, packaging, host lysis, DNA manipulation, transcription, and additional functions); no gene was found to be related to virulence or toxin or lysogen formation, but >80% of the predicted ORFs are unknown. In addition, a phage proteomic analysis using SDS-PAGE and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) revealed that seven phage structural proteins are indeed present, supporting the ORF predictions. To verify the potential of this phage as a biocontrol agent against C. sakazakii, it was added to infant formula milk contaminated with a C. sakazakii clinical isolate or food isolate, revealing complete growth inhibition of the isolates by the addition of phage CR5 when the multiplicity of infection (MOI) was 10(5). PMID:26497465

  6. Synthesis and evaluation of 18F labeled alanine derivatives as potential tumor imaging agents

    PubMed Central

    Wang, Limin; Zha, Zhihao; Qu, Wenchao; Qiao, Hongwen; Lieberman, Brian P.; Plössl, Karl; Kung, Hank F.

    2012-01-01

    Introduction This paper reports the synthesis and labeling of 18F alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents mediated by alanine-serine-cysteine preferring (ASC) transporter system. Methods Three new 18F alanine derivatives were prepared from corresponding tosylate-precursors through a two-step labelling reaction. In vitro uptake studies to evaluate and to compare these three analogs were carried out in 9L glioma and PC-3 prostate cancer cell lines. Potential transport mechanisms, protein incorporation and stability of 3-(1-[18F]fluoromethyl)-L-alanine (L[18F]FMA) were investigated in 9L glioma cells. Its biodistribution was determined in a rat-bearing 9L tumor model. PET imaging studies were performed on rat bearing 9L glioma tumors and transgenic mouse carrying spontaneous generated M/tomND tumor (mammary gland adenocarcinoma). Results New 18F alanine derivatives were prepared with 7–34% uncorrected radiochemical yields, excellent enantiomeric purity (>99%) and good radiochemical purity (>99%). In vitro uptake of the L-[18F]FMA in 9L glioma and PC-3 prostate cancer cells was higher than those observed for other two alanine derivatives and [18F]FDG in first 1 h. Inhibition of cell uptake studies suggested that L-[18F]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L-[18F]FMA remained stable and was not incorporated into protein within 2 h. In vivo biodistribution studies demonstrated that L-[18F]FMA had relatively high uptake in liver and kidney. Tumor uptake was fast, reaching a maximum within 30 min. The tumor-to-muscle, tumor-to-blood and tumor-to-brain ratios at 60 min post injection were 2.2, 1.9 and 3.0, respectively. In PET imaging studies, tumors were visualized with L-[18F]FMA in both 9L rat and transgenic mouse. Conclusion L-[18F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor

  7. Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents

    NASA Astrophysics Data System (ADS)

    Hachani, Roxanne; Lowdell, Mark; Birchall, Martin; Hervault, Aziliz; Mertz, Damien; Begin-Colin, Sylvie; Thanh, Nguy&Ecirtil; N. Thi&Cmb. B. Dot; Kim

    2016-02-01

    Iron oxide nanoparticles (IONPs) of low polydispersity were obtained through a simple polyol synthesis in high pressure and high temperature conditions. The control of the size and morphology of the nanoparticles was studied by varying the solvent used, the amount of iron precursor and the reaction time. Compared with conventional synthesis methods such as thermal decomposition or co-precipitation, this process yields nanoparticles with a narrow particle size distribution in a simple, reproducible and cost effective manner without the need for an inert atmosphere. For example, IONPs with a diameter of ca. 8 nm could be made in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high saturation magnetization value (84.5 emu g-1). The surface of the IONPs could be tailored post synthesis with two different ligands which provided functionality and stability in water and phosphate buffer saline (PBS). Their potential as a magnetic resonance imaging (MRI) contrast agent was confirmed as they exhibited high r1 and r2 relaxivities of 7.95 mM-1 s-1 and 185.58 mM-1 s-1 respectively at 1.4 T. Biocompatibility and viability of IONPs in primary human mesenchymal stem cells (hMSCs) was studied and confirmed.Iron oxide nanoparticles (IONPs) of low polydispersity were obtained through a simple polyol synthesis in high pressure and high temperature conditions. The control of the size and morphology of the nanoparticles was studied by varying the solvent used, the amount of iron precursor and the reaction time. Compared with conventional synthesis methods such as thermal decomposition or co-precipitation, this process yields nanoparticles with a narrow particle size distribution in a simple, reproducible and cost effective manner without the need for an inert atmosphere. For example, IONPs with a diameter of ca. 8 nm could be made in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high

  8. Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action.

    PubMed

    Dutt, Vikas; Gupta, Sanjeev; Dabur, Rajesh; Injeti, Elisha; Mittal, Ashwani

    2015-09-01

    Over the last two decades, new insights into the etiology of skeletal muscle wasting/atrophy under diverse clinical settings including denervation, AIDS, cancer, diabetes, and chronic heart failure have been reported in the literature. However, the treatment of skeletal muscle wasting remains an unresolved challenge to this day. About nineteen potential drugs that can regulate loss of muscle mass have been reported in the literature. This paper reviews the mechanisms of action of all these drugs by broadly classifying them into six different categories. Mechanistic data of these drugs illustrate that they regulate skeletal muscle loss either by down-regulating myostatin, cyclooxygenase2, pro-inflammatory cytokines mediated catabolic wasting or by up-regulating cyclic AMP, peroxisome proliferator-activated receptor gamma coactivator-1α, growth hormone/insulin-like growth factor1, phosphatidylinositide 3-kinases/protein kinase B(Akt) mediated anabolic pathways. So far, five major proteolytic systems that regulate loss of muscle mass have been identified, but the majority of these drugs control only two or three proteolytic systems. In addition to their beneficial effect on restoring the muscle loss, many of these drugs show some level of toxicity and unwanted side effects such as dizziness, hypertension, and constipation. Therefore, further research is needed to understand and develop treatment strategies for muscle wasting. For successful management of skeletal muscle wasting either therapeutic agent which regulates all five known proteolytic systems or new molecular targets/proteolytic systems must be identified. PMID:26048279

  9. Plant foods in the management of diabetes mellitus: vegetables as potential hypoglycaemic agents.

    PubMed

    Platel, K; Srinivasan, K

    1997-04-01

    Vegetables are among the numerous plant adjuncts tried for the treatment of diabetes mellitus. A few vegetables that are commonly consumed in India have been claimed to possess antidiabetic potency. In recent years, there has been a renewed interest to screen such plant food materials, for a possible beneficial use. Considerable amount of work has been carried out in this regard with bitter gourd (Momordica charantia) and ivy gourd (Coccinia indica) both in experimental animals and human diabetic subjects. Majority of these studies have documented the beneficial effect of the fruit of bitter gourd and leaf of ivy gourd when administered orally as a single dose. The hypoglycaemic influence is claimed to be mediated through an insulin secretagogue effect or through an influence on enzymes involved in glucose metabolism. The limited number of studies on other vegetables such as cabbage (Brassica oleracia), green leafy vegetables, beans and tubers have shown the beneficial hypoglycaemic influence in both experimental animals and humans. There is scope for more extensive research in this area, especially to examine the long term beneficial effect of dietary vegetables, to identify the active principle, and to understand the mechanism of action, which is at present unclear. Since diet forms the mainstay in the management of diabetes mellitus, there is scope for exploiting the antidiabetic potency of vegetables to the maximum extent. Such plant food adjuncts possessing hypoglycaemic activity appear to hold promise as potential antidiabetic agents. PMID:9188186

  10. Child as change agent. The potential of children to increase healthy food purchasing.

    PubMed

    Wingert, Katherine; Zachary, Drew A; Fox, Monica; Gittelsohn, Joel; Surkan, Pamela J

    2014-10-01

    Shoppers make many food choices while buying groceries. Children frequently accompany caregivers, giving them the potential to influence these choices. We aimed to understand low-income shoppers' perceptions of how children influence caregivers' purchasing decisions and how the supermarket environment could be manipulated to allow children to serve as change agents for healthy food purchasing in a primarily African-American community. We conducted thirty in-depth interviews, five follow-up interviews, one supermarket walk-through interview, and four focus groups with adult supermarket shoppers who were regular caregivers for children under age 16. We conducted one focus group with supermarket employees and one in-depth interview with a supermarket manager. Qualitative data were analyzed using iterative thematic coding and memo writing. Caregivers approached grocery shopping with efforts to save money, prevent waste and purchase healthy food for their families, but described children as promoting unplanned, unhealthy food purchases. This influence was exacerbated by the supermarket environment, which participants found to promote unhealthy options and provide limited opportunities for children to interact with healthier foods. Caregivers' suggestions for promoting healthy purchasing for shoppers with children included manipulating the placement of healthy and unhealthy foods and offering opportunities for children to taste and interact with healthy options. PMID:24996593

  11. Potential of immunomodulatory agents as adjunct host-directed therapies for multidrug-resistant tuberculosis.

    PubMed

    Zumla, Alimuddin; Rao, Martin; Dodoo, Ernest; Maeurer, Markus

    2016-01-01

    Treatment of multidrug-resistant tuberculosis (MDR-TB) is extremely challenging due to the virulence of the etiologic strains of Mycobacterium tuberculosis (M. tb), the aberrant host immune responses and the diminishing treatment options with TB drugs. New treatment regimens incorporating therapeutics targeting both M. tb and host factors are urgently needed to improve the clinical management outcomes of MDR-TB. Host-directed therapies (HDT) could avert destructive tuberculous lung pathology, facilitate eradication of M. tb, improve survival and prevent long-term functional disability. In this review we (1) discuss the use of HDT for cancer and other infections, drawing parallels and the precedent they set for MDR-TB treatment, (2) highlight preclinical studies of pharmacological agents commonly used in clinical practice which have HDT potential, and (3) outline developments in cellular therapy to promote clinically beneficial immunomodulation to improve treatment outcomes in patients with pulmonary MDR-TB. The use of HDTs as adjuncts to MDR-TB therapy requires urgent evaluation. PMID:27301245

  12. Potential of Submergedly Cultivated Mycelia of Ganoderma spp. as Antioxidant and Antimicrobial Agents.

    PubMed

    Ćilerdžić, Jasmina; Stajic, Mirjana; Vukojevic, Jelena

    2016-01-01

    The study aimed to evaluate the antiradical and antimicrobial (antibacterial and antifungal) potentials of ethanol mycelial extracts of selected Ganoderma species and strains and to define interand intraspecies diversity among Ganoderma species and strains. Ganoderma lucidum strains were good DPPH• scavengers (neutralizing up to 57.12% radicals), contrary to G. applanatum (20.35%) and G. carnosum (17.04%). High correlations between the activities and contents of total phenols in the extracts showed that these compounds were carriers of the activity. Results obtained by both discdiffusion and microdilution methods indicated that the extract of G. lucidum BEOFB 433 was the most potent antibacterial agent that inhibited growth of almost all bacterial species at a concentration of 1.0 mg/mL. Salmonella typhimurium was the most sensitive species to the mycelium extracts. Extracts of G. lucidum BEOFB 431 and BEOFB 434 showed the best antifungal activity since in concentration of 0.5 mg/mL inhibited the growth of Aspergillus glaucus (BEOFB 431) and the growth of A. glaucus and Trichoderma viride (BEOFB 434). Extracts of G. applanatum and G. lucidum BEOFB 431 had the strongest fungicidal effects, with lethal outcomes for A. glaucus and T. viride, respectively, being noted at a concentration of 1.17 mg/mL. Aspergillus niger was proved as the most resistant species. PMID:26420047

  13. Pyrolysis mass spectrometry for distinguishing potential hoax materials from bioterror agents.

    PubMed

    Wilkes, Jon G; Rafii, Fatemeh; Sutherland, John B; Rushing, Larry G; Buzatu, Dan A

    2006-01-01

    Pyrolysis mass spectrometry (PyMS) was investigated as a rapid tool to distinguish potential bioterror hoax materials from samples containing pathogenic bacteria. A pyrolysis time-of-flight (TOF) mass spectrometer equipped with an alternative ionization technique, metastable atom bombardment (MAB), was used to produce sample spectra. These spectra were analyzed by principal component and discriminant analysis for pattern recognition. Materials investigated were two strains of Vibrio parahaemolyticus, one of which produced the tdh toxin, two Salmonella enterica serotypes, a biological mosquito control product containing spores of Bacillus thuringiensis, and several white to off-white powders (which could be used as hoax materials), such as flour, corn starch, methyl cellulose, and xanthan gum. PyMS distinguished bacterial samples from hoax materials. Furthermore, pattern analysis differentiated Vibrios from Salmonellae, Salmonella enterica Anatum from S. enterica Heidelberg, and the two V. parahaemolyticus strains from each other. The B. thuringiensis mixture was distinguished from other bacteria and powders, suggesting that PyMS with pattern recognition may differentiate samples containing pathogens, including Bacillus spp., from nonbiological agents and that it can be a rapid method for detection of bacteria. MS data acquisition took only 7 min for each sample. PMID:16841357

  14. Recent Development of Multifunctional Agents as Potential Drug Candidates for the Treatment of Alzheimer's Disease

    PubMed Central

    Guzior, Natalia; ckowska,, Anna Wię; Panek, Dawid; Malawska, Barbara

    2015-01-01

    Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β anti-aggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NO-releasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD. PMID:25386820

  15. Natural flavonoids as potential multifunctional agents in prevention of diabetic cataract

    PubMed Central

    Stefek, Milan

    2011-01-01

    Cataract is one of the earliest secondary complications of diabetes mellitus. The lens is a closed system with limited capability to repair or regenerate itself. Current evidence supports the view that cataractogenesis is a multifactorial process. Mechanisms related to glucose toxicity, namely oxidative stress, processes of non-enzymatic glycation and enhanced polyol pathway significantly contribute to the development of eye lens opacity under conditions of diabetes. There is an urgent need for inexpensive, non-surgical approaches to the treatment of cataract. Recently, considerable attention has been devoted to the search for phytochemical therapeutics. Several pharmacological actions of natural flavonoids may operate in the prevention of cataract since flavonoids are capable of affecting multiple mechanisms or etiological factors responsible for the development of diabetic cataract. In the present paper, natural flavonoids are reviewed as potential agents that could reduce the risk of cataract formation via affecting multiple pathways pertinent to eye lens opacification. In addition, the bioavailability of flavonoids for the lens is considered. PMID:21753902

  16. Diversity-oriented synthesis of α-aminophosphonates: a new class of potential anticancer agents.

    PubMed

    Bhattacharya, Asish K; Raut, Dnyaneshwar S; Rana, Kalpeshkumar C; Polanki, Innaiah K; Khan, Mohd Sajid; Iram, Sana

    2013-08-01

    A small library of structurally diverse α-aminophosphonates has been synthesized by reacting alkyl/aryl aldehydes, alkyl/aryl amines and alkyl/aryl phosphites in one-pot catalyzed by Amberlite-IR 120 resin (acidic). All the synthesized α-aminophosphonates were assayed for their in vitro cytotoxic activities against a panel of five human cancer cell lines including A-549, NCI-H23 (Lung), Colo 320DM (Colon), MG-63 (Bone marrow) and Jurkat (Blood T lymphocytes). Compound 4n having (R)-1-phenylethanamine was found to be the most active amongst all the synthesized α-aminophosphonates against all the five cancer cell lines, most prominent being against Jurkat cell line with an IC50 value of 4 μM. Surprisingly, compound 4o having (S)-1-phenylethanamine was found to be devoid of any cytotoxicity. Our finding suggests that these chemical entities could further serve as interesting template for the design of potential anticancer agents. PMID:23792352

  17. Animals living in polluted environments are potential source of antimicrobials against infectious agents

    PubMed Central

    Lee, Simon; Siddiqui, Ruqaiyyah; Khan, Naveed Ahmed

    2012-01-01

    The antimicrobials crisis is a ticking time bomb which could lead to millions of people dying from untreatable infections. With the worsening trends of antimicrobial resistance, we are heading towards a pre-antibiotic era. Thus, there is a need for newer and more powerful antibiotic agents. The search for new antibiotic compounds originating from natural resources is a promising research area. Animals living in germ-infested environments are a potent source of antimicrobials. Under polluted milieus, organisms such as cockroaches encounter different types of bacteria, including superbugs. Such creatures survive the onslaught of superbugs and are able to ward off disease by producing antimicrobial substances which show potent activity in the nervous system. We hope that the discovery of antimicrobial activity in the cockroach brain will stimulate research in finding antimicrobials from unusual sources, and has potential for the development of novel antibiotics. Nevertheless, intensive research in the next few years will be required to approach or realize these expectations. PMID:23265422

  18. Preparation of Amyloid Immuno-Nanoparticles as Potential MRI Contrast Agents for Alzheimer's Disease Diagnosis.

    PubMed

    Yin, Zhenyu; Yul, Tingting; Xu, Yun

    2015-09-01

    Alzheimer's disease (AD) is the most common form of dementia which is caused by accumulation in the brain of plaques made up of amyloid beta-peptide (Abeta). Research on nanosized systems indicated that nanoparticles (NPs) could pass across the blood-brain barrier (BBB) and improve the visibility of internal body structures in magnetic resonance imaging (MRI), which made it possible to aid the early diagnosis of AD. In this research study we synthesized magnetite nanoparticles by high-temperature solution-phase reaction, transferred into water based on a ligand exchange process and coated with meso-2,3-dimercaptosuccinic (DMSA). Subsequently, the anti-amyloid Abeta immunomagnetic nanoparticles (IMNPs) were prepared by grafting anti-amyloid antibodies on the surface of the DMSA-coated magnetic nanoparticles (MNPs). The enzyme linked immunosorbent assay (ELISA) method was introduced to evaluate the IMNPs activity and conjugation amount of antibodies. The biocompatibility of the IMNPs was tested by colony-forming assay. The results showed that the anti-amyloid Abeta IMNPs were biocompatible and biologically active, as well as effective in enhancing MRI solution, indicating that the IMNPs could be used as potential MRI contrast agents and targeted carriers for AD early diagnosis and therapy. PMID:26716196

  19. Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents.

    PubMed

    Chen, Jia-Nian; Wang, Xian-Fu; Li, Ting; Wu, De-Wen; Fu, Xiao-Bo; Zhang, Guang-Ji; Shen, Xing-Can; Wang, Heng-Shan

    2016-01-01

    Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7 g, 7 m, 7 o, 8 e, 8 g, and 8 m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8 g exhibited the strongest activity. In particular, compound 8 g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure-activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8 g may be a potent antitumor agent, representing a promising lead for further optimization. PMID:26560049

  20. N-( sup 18 F)fluoroacetyl-D-glucosamine: A potential agent for cancer diagnosis

    SciTech Connect

    Fujiwara, T.; Kubota, K.; Sato, T.; Matsuzawa, T.; Tada, M.; Iwata, R.; Itoh, M.; Hatazawa, J.; Sato, K.; Fukuda, H. )

    1990-10-01

    Positron labeled substrates such as sugars, amino acids, and nucleosides have been investigated for the in-vivo evaluation of biochemical processes in cancerous tissue. Hexosamines are obligatory structural components of many biologically important macromolecules, including membrane glycoproteins and mucopolysaccharide. We evaluated a new synthesized pharmaceutical, N-({sup 18}F)fluoroacetyl-D-glucosamine ({sup 18}F-FAG), which is a structural analog of N-acetyl-D-glucosamine. C3H/HeMsNRS mice bearing spontaneous hepatomas were used for the tissue distribution study. At 60 min after injection, high uptakes were found in tumor (5.16, mean value of %dose/g), liver (3.71), and kidney (3.27). The tumor uptake of 18F-FAG showed the highest value in all tissue. In the PET study, VX-2 carcinoma of the rabbit was clearly visualized. Our preliminary results suggest that {sup 18}F-FAG has potential as a new agent for tumor imaging.

  1. Sonorensin: A new bacteriocin with potential of an anti-biofilm agent and a food biopreservative

    PubMed Central

    Chopra, Lipsy; Singh, Gurdeep; Kumar Jena, Kautilya; Sahoo, Debendra K.

    2015-01-01

    The emergence of antibiotic resistant bacteria has led to exploration of alternative therapeutic agents such as ribosomally synthesized bacterial peptides known as bacteriocins. Biofilms, which are microbial communities that cause serious chronic infections, form environments that enhance antimicrobial resistance. Bacteria in biofilm can be upto thousand times more resistant to antibiotics than the same bacteria circulating in a planktonic state. In this study, sonorensin, predicted to belong to the heterocycloanthracin subfamily of bacteriocins, was found to be effectively killing active and non-multiplying cells of both Gram-positive and Gram-negative bacteria. Sonorensin showed marked inhibition activity against biofilm of Staphylococcus aureus. Fluorescence and electron microscopy suggested that growth inhibition occurred because of increased membrane permeability. Low density polyethylene film coated with sonorensin was found to effectively control the growth of food spoilage bacteria like Listeria monocytogenes and S. aureus. The biopreservative effect of sonorensin coated film showing growth inhibition of spoilage bacteria in chicken meat and tomato samples demonstrated the potential of sonorensin as an alternative to current antibiotics/ preservatives. PMID:26292786

  2. Phyllanthus wightianus Müll. Arg.: a potential source for natural antimicrobial agents.

    PubMed

    Natarajan, D; Srinivasan, R; Shivakumar, M S

    2014-01-01

    Phyllanthus wightianus belongs to Euphorbiaceae family having ethnobotanical importance. The present study deals with validating the antimicrobial potential of solvent leaf extracts of P. wightianus. 11 human bacterial pathogens (Bacillus subtilis, Streptococcus pneumoniae, Staphylococcus epidermidis, Proteus vulgaris, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhimurium, Escherichia coli, Shigella flexneri, Proteus vulgaris, and Serratia marcescens) and 4 fungal pathogens (Candida albicans, Cryptococcus neoformans, Mucor racemosus, and Aspergillus niger) were also challenged with solvent leaf extracts usingagar well and disc diffusion methods. Further, identification of the active component present in the bioactive extract was done using GC-MS analysis. Results show that all extracts exhibited broad spectrum (6-29 mm) of antibacterial activity on most of the tested organisms. The results highlight the fact that the well in agar method was more effective than disc diffusion method. Significant antimicrobial activity was detected in methanol extract against S. pneumoniae (29 mm) with MIC and MBC values of 15.62 μg/mL. GC-MS analysis revealed that 29 bioactive constituents were present in methanolic extract of P. wightianus, of which 9,12-octadecaenioic acid (peak area 22.82%; RT-23.97) and N-hexadecanoic acid (peak area 21.55% RT-21.796) are the major compounds. The findings of this study show that P. wightianus extracts may be used as an anti-infective agent in folklore medicine. PMID:24883301

  3. Evaluation of Se-75 BISTAES as a potential articular cartilage imaging agent

    SciTech Connect

    Yu, S.W.K.

    1987-01-01

    The potential of Se-75 bis (..beta..-N,N,N-trimethylamino)-ethyl) selenide diiodide (Se-75 BISTAES) as an articular cartilage imaging agent for the early diagnosis of osteoarthritis was evaluated. The compound was synthesized and the identity was established. The radiochemical purity and stability were determined initially and over a two-month period of storage at three temperatures. The biodistribution of Se-75 BISTAES in rabbits and guinea pigs was studied. A high concentration of radioactivity was found in the knee and shoulder cartilage. The radioactivity in the cartilage was the highest at 15 minutes to one hour post-injection. In rabbits, the highest ratio of radioactivity in the cartilage to the surrounding tissues was about 30. A minimal ratio of 10 is required for nuclear medicine imaging. Nuclear medicine imaging conducted on rabbits demonstrated increased radioactivity in the articular cartilage in the knee and shoulder. The impression from the nuclear medicine images and the findings of the biodistribution study indicated that the route of excretion of Se-75 BISTAES was the urine. The in vitro binding between Se-75 BISTAES and chondroitin sulfate was determined by an equilibrium dialysis technique.

  4. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease.

    PubMed

    Guzior, Natalia; Wieckowska, Anna; Panek, Dawid; Malawska, Barbara

    2015-01-01

    Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β antiaggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NOreleasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD. PMID:25386820

  5. Human recombinant truncated RNASET2, devoid of RNase activity; A potential cancer therapeutic agent.

    PubMed

    Nesiel-Nuttman, Liron; Schwartz, Betty; Shoseyov, Oded

    2014-11-30

    Human RNASET2 has been implicated in antitumorigenic and antiangiogenic activities, independent of its ribonuclease capacities. We constructed a truncated version of human RNASET2, starting at E50 (trT2-50) and devoid of ribonuclease activity. trT2-50 maintained its ability to bind actin and to inhibit angiogenesis and tumorigenesis. trT2-50 binds to cell surface actin and formed a complex with actin in vitro. The antiangiogenic effect of this protein was demonstrated in human umbilical vein endothelial cells (HUVECs) by its ability to arrest tube formation on Matrigel, induced by angiogenic factors. Immunofluorescence staining of HUVECs showed nuclear and cytosolic RNASET2 protein that was no longer detectable inside the cell following trT2-50 treatment. This effect was associated with disruption of the intracellular actin network. trT2-50 co-localized with angiogenin, suggesting that both molecules bind (or compete) for similar cellular epitopes. Moreover, trT2-50 led to a significant inhibition of tumor development. Histological analysis demonstrated abundant necrotic tissue and a substantial loss of endothelial structure in trT2-50-treated tumors. Collectively, the present results indicate that trT2-50, a molecule engineered to be deficient of its catalytic activity, still maintained its actin binding and anticancer-related biological activities. We therefore suggest that trT2-50 may serve as a potential cancer therapeutic agent. PMID:25426551

  6. Human recombinant truncated RNASET2, devoid of RNase activity; A potential cancer therapeutic agent

    PubMed Central

    Nesiel-Nuttman, Liron; Schwartz, Betty; Shoseyov, Oded

    2014-01-01

    Human RNASET2 has been implicated in antitumorigenic and antiangiogenic activities, independent of its ribonuclease capacities. We constructed a truncated version of human RNASET2, starting at E50 (trT2-50) and devoid of ribonuclease activity. trT2-50 maintained its ability to bind actin and to inhibit angiogenesis and tumorigenesis. trT2-50 binds to cell surface actin and formed a complex with actin in vitro. The antiangiogenic effect of this protein was demonstrated in human umbilical vein endothelial cells (HUVECs) by its ability to arrest tube formation on Matrigel, induced by angiogenic factors. Immunofluorescence staining of HUVECs showed nuclear and cytosolic RNASET2 protein that was no longer detectable inside the cell following trT2-50 treatment. This effect was associated with disruption of the intracellular actin network. trT2-50 co-localized with angiogenin, suggesting that both molecules bind (or compete) for similar cellular epitopes. Moreover, trT2-50 led to a significant inhibition of tumor development. Histological analysis demonstrated abundant necrotic tissue and a substantial loss of endothelial structure in trT2-50-treated tumors. Collectively, the present results indicate that trT2-50, a molecule engineered to be deficient of its catalytic activity, still maintained its actin binding and anticancer-related biological activities. We therefore suggest that trT2-50 may serve as a potential cancer therapeutic agent. PMID:25426551

  7. Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents.

    PubMed

    Hachani, Roxanne; Lowdell, Mark; Birchall, Martin; Hervault, Aziliz; Mertz, Damien; Begin-Colin, Sylvie; Thanh, Nguyen Thi Kim

    2016-02-14

    Iron oxide nanoparticles (IONPs) of low polydispersity were obtained through a simple polyol synthesis in high pressure and high temperature conditions. The control of the size and morphology of the nanoparticles was studied by varying the solvent used, the amount of iron precursor and the reaction time. Compared with conventional synthesis methods such as thermal decomposition or co-precipitation, this process yields nanoparticles with a narrow particle size distribution in a simple, reproducible and cost effective manner without the need for an inert atmosphere. For example, IONPs with a diameter of ca. 8 nm could be made in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high saturation magnetization value (84.5 emu g(-1)). The surface of the IONPs could be tailored post synthesis with two different ligands which provided functionality and stability in water and phosphate buffer saline (PBS). Their potential as a magnetic resonance imaging (MRI) contrast agent was confirmed as they exhibited high r1 and r2 relaxivities of 7.95 mM(-1) s(-1) and 185.58 mM(-1) s(-1) respectively at 1.4 T. Biocompatibility and viability of IONPs in primary human mesenchymal stem cells (hMSCs) was studied and confirmed. PMID:26460932

  8. Biorelevant reactions of the potential anti-tumor agent vanadocene dichloride.

    PubMed

    Sanna, Daniele; Serra, Maria; Ugone, Valeria; Manca, Laura; Pirastru, Monica; Buglyó, Péter; Bíró, Linda; Micera, Giovanni; Garribba, Eugenio

    2016-05-01

    The interaction of the potential anti-tumor agent vanadocene dichloride ([Cp2VCl2] or VDC) with some relevant bioligands of the cytosol such as proteins (Hb), amino acids (glycine and histidine), NADH derivatives (NADH, NADPH, NAD(+) and NADP(+)), reductants (GSH and ascorbic acid), phosphates (HPO4(2-), P2O7(4-), cAMP, AMP, ADP and ATP) and carboxylate derivatives (lactate) and its uptake by red blood cells were studied. The results indicated that [Cp2VCl2] transforms at physiological pH into [Cp2V(OH)2] and that only HPO4(2-), P2O7(4-), lactate, ATP and ADP form mixed species with the [Cp2V](2+) moiety replacing the two hydroxide ions. EPR and electronic absorption spectroscopy, agarose gel electrophoresis and spin trapping measurements allow excluding any direct interaction and/or intercalation with DNA and the formation of reactive oxygen species (ROS) in Fenton-like reactions. Uptake experiments by erythrocytes suggested that VDC crosses the membrane and enters inside the cells, whereas 'bare' V(IV) transforms into V(IV)O species with loss of the two cyclopentadienyl rings. This transformation in the cellular environment could be related to the mechanism of action of VDC. PMID:27121101

  9. New multifunctional ligands for potential use in the design therapeutic or diagnostic radiopharmaceutical imaging agents

    DOEpatents

    Katti, K.V.; Volkert, W.A.; Ketring, A.R.; Singh, P.R.

    1997-02-11

    A class of diagnostic and therapeutic compounds are derived from phosphinimines that include ligands containing either a single phosphinimine functionality or both a phosphinimine group and a phosphine or arsine group, or an aminato group, or a second phosphinimine moiety. These phosphinimine ligands are complexed to early transition metal radionuclides (e.g., {sup 99m}Tc or {sup 186}Re/{sup 188}Re) or late transition metals (e.g., {sup 105}Rh or {sup 109}Pd). The complexes with these metals {sup 186}Re/{sup 188}Re, {sup 99m}Tc and {sup 109}Pd exhibit a high in vitro and high in vivo stability. The complexes are formed in high yields and can be neutral or charged. These ligands can also be used to form stable compounds with paramagnetic transition metals (e.g., Fe and Mn) for potential use as MRI contrast agents. Applications for the use of ligands and making the ligands are also disclosed.

  10. Hydroxychalcone inhibitors of Streptococcus mutans glucosyl transferases and biofilms as potential anticaries agents.

    PubMed

    Nijampatnam, Bhavitavya; Casals, Luke; Zheng, Ruowen; Wu, Hui; Velu, Sadanandan E

    2016-08-01

    Streptococcus mutans has been implicated as the major etiological agent in the initiation and the development of dental caries due to its robust capacity to form tenacious biofilms. Ideal therapeutics for this disease will aim to selectively inhibit the biofilm formation process while preserving the natural bacterial flora of the mouth. Several studies have demonstrated the efficacies of flavonols on S. mutans biofilms and have suggested the mechanism of action through their effect on S. mutans glucosyltransferases (Gtfs). These enzymes metabolize sucrose into water insoluble and soluble glucans, which are an integral measure of the dental caries pathogenesis. Numerous studies have shown that flavonols and polyphenols can inhibit Gtf and biofilm formation at millimolar concentrations. We have screened a group of 14 hydroxychalcones, synthetic precursors of flavonols, in an S. mutans biofilm assay. Several of these compounds emerged to be biofilm inhibitors at low micro-molar concentrations. Chalcones that contained a 3-OH group on ring A exhibited selectivity for biofilm inhibition. Moreover, we synthesized 6 additional analogs of the lead compound and evaluated their potential activity and selectivity against S. mutans biofilms. The most active compound identified from these studies had an IC50 value of 44μM against biofilm and MIC50 value of 468μM against growth displaying >10-fold selectivity inhibition towards biofilm. The lead compound displayed a dose dependent inhibition of S. mutans Gtfs. The lead compound also did not affect the growth of two commensal species (Streptococcus sanguinis and Streptococcus gordonii) at least up to 200μM, indicating that it can selectively inhibit cariogenic biofilms, while leaving commensal and/or beneficial microbes intact. Thus non-toxic compounds have the potential utility in public oral health regimes. PMID:27371109

  11. Volatile Organic Compounds from Native Potato-associated Pseudomonas as Potential Anti-oomycete Agents

    PubMed Central

    De Vrieze, Mout; Pandey, Piyush; Bucheli, Thomas D.; Varadarajan, Adithi R.; Ahrens, Christian H.; Weisskopf, Laure; Bailly, Aurélien

    2015-01-01

    The plant kingdom represents a prominent biodiversity island for microbes that associate with the below- or aboveground organs of vegetal species. Both the root and the leaf represent interfaces where dynamic biological interactions influence plant life. Beside well-studied communication strategies based on soluble compounds and protein effectors, bacteria were recently shown to interact both with host plants and other microbial species through the emissions of volatile organic compounds (VOCs). Focusing on the potato late blight-causing agent Phytophthora infestans, this work addresses the potential role of the bacterial volatilome in suppressing plant diseases. In a previous study, we isolated and identified a large collection of strains with anti-Phytophthora potential from both the phyllosphere and the rhizosphere of potato. Here we report the characterization and quantification of their emissions of biogenic volatiles, comparing 16 Pseudomonas strains differing in (i) origin of isolation (phyllosphere vs. rhizosphere), (ii) in vitro inhibition of P. infestans growth and sporulation behavior, and (iii) protective effects against late blight on potato leaf disks. We systematically tested the pharmacological inhibitory activity of core and strain-specific single compounds against P. infestans mycelial growth and sporangial behavior in order to identify key effective candidate molecules present in the complex natural VOCs blends. We envisage the plant bacterial microbiome as a reservoir for functional VOCs and establish the basis for finding the primary enzymatic toolset that enables the production of active components of the volatile bouquet in plant-associated bacteria. Comprehension of these functional interspecies interactions will open perspectives for the sustainable control of plant diseases in forthcoming agriculture. PMID:26635763

  12. Novel glyoxalase-I inhibitors possessing a “zinc-binding feature” as potential anticancer agents

    PubMed Central

    Al-Balas, Qosay A; Hassan, Mohammad A; Al-Shar’i, Nizar A; Mhaidat, Nizar M; Almaaytah, Ammar M; Al-Mahasneh, Fatima M; Isawi, Israa H

    2016-01-01

    Background The glyoxalase system including two thiol-dependent enzymes, glyoxalase I (Glo-I) and glyoxalase II, plays an important role in a ubiquitous metabolic pathway involved in cellular detoxification of cytotoxic 2-oxoaldehydes. Tumor cells have high glycolytic activity, leading to increased cellular levels of these toxic metabolites. The increased activity of the detoxification system in cancerous cells makes this pathway a viable target for developing novel anticancer agents. In this study, we examined the potential utility of non-glutathione-based inhibitors of the Glo-I enzyme as novel anticancer drugs. Methods Computer-aided drug design techniques, such as customized pharmacophoric features, virtual screening, and flexible docking, were used to achieve the project goals. Retrieved hits were extensively filtered and subsequently docked into the active site of the enzyme. The biological activities of retrieved hits were assessed using an in vitro assay against Glo-I. Results Since Glo-I is a zinc metalloenzyme, a customized Zn-binding pharmacophoric feature was used to search for selective inhibitors via virtual screening of a small-molecule database. Seven hits were selected, purchased, and biologically evaluated. Three of the seven hits inhibited Glo-I activity, the most effective of which exerted 76.4% inhibition at a concentration of 25 µM. Conclusion We successfully identified a potential Glo-I inhibitor that can serve as a lead compound for further optimization. Moreover, our in silico and experimental results were highly correlated. Hence, the docking protocol adopted in this study may be efficiently employed in future optimization steps. PMID:27574401

  13. Volatile Organic Compounds from Native Potato-associated Pseudomonas as Potential Anti-oomycete Agents.

    PubMed

    De Vrieze, Mout; Pandey, Piyush; Bucheli, Thomas D; Varadarajan, Adithi R; Ahrens, Christian H; Weisskopf, Laure; Bailly, Aurélien

    2015-01-01

    The plant kingdom represents a prominent biodiversity island for microbes that associate with the below- or aboveground organs of vegetal species. Both the root and the leaf represent interfaces where dynamic biological interactions influence plant life. Beside well-studied communication strategies based on soluble compounds and protein effectors, bacteria were recently shown to interact both with host plants and other microbial species through the emissions of volatile organic compounds (VOCs). Focusing on the potato late blight-causing agent Phytophthora infestans, this work addresses the potential role of the bacterial volatilome in suppressing plant diseases. In a previous study, we isolated and identified a large collection of strains with anti-Phytophthora potential from both the phyllosphere and the rhizosphere of potato. Here we report the characterization and quantification of their emissions of biogenic volatiles, comparing 16 Pseudomonas strains differing in (i) origin of isolation (phyllosphere vs. rhizosphere), (ii) in vitro inhibition of P. infestans growth and sporulation behavior, and (iii) protective effects against late blight on potato leaf disks. We systematically tested the pharmacological inhibitory activity of core and strain-specific single compounds against P. infestans mycelial growth and sporangial behavior in order to identify key effective candidate molecules present in the complex natural VOCs blends. We envisage the plant bacterial microbiome as a reservoir for functional VOCs and establish the basis for finding the primary enzymatic toolset that enables the production of active components of the volatile bouquet in plant-associated bacteria. Comprehension of these functional interspecies interactions will open perspectives for the sustainable control of plant diseases in forthcoming agriculture. PMID:26635763

  14. Oligonucleotide n3'-->p5' phosphoramidates and thio-phoshoramidates as potential therapeutic agents.

    PubMed

    Gryaznov, Sergei M

    2010-03-01

    and thus inhibits its activity. This compound is currently in multiple Phase-I and Phase-I/II clinical trials as potential broad-spectrum anticancer agent. PMID:20232321

  15. Characterization and Functionalization of Iron-Oxide Nanoparticles for Use as Potential Agents for Cancer Thermotherapy

    NASA Astrophysics Data System (ADS)

    O'Reilly, Nora

    This thesis presents experimental studies of iron oxide nanoparticle synthesis, functionalization, and intracellular hyperthermal effects on murine macrophages as a model in vitro system. Colloidal suspensions of magnetic nanoparticles (MNPs) are of particular interest in Magnetic Fluid Hyperthermia (MFH). Iron oxide nanoparticles (IONPs) have garnered great interest as economical, biocompatible hyperthermia agents due to their superparamagnetic activity. Here we seek to optimize the synthetic reproducibility and in vitro utilization of IONPs for application in MFH. We compared aqueous synthetic protocols and various protective coating techniques using various analytical techniques and in vitro assays to assess the biocompatibility and feasibility of the various preparations of nanoparticles. Using a co-precipitation of iron salts methodology, iron oxide nanoparticles (IONPs) with an average diameter of 6-8nm were synthesized and stabilized with carboxylates. By performing calorimetry measurements in an oscillating magnetic field (OMF) with a frequency of 500 kHz and field strength of 0.008Tesla the superparamagnetic behavior of these particles was confirmed. To further investigate these IONPs in a biological application, citric acid-stabilized particles, in conjunction with heat generated by these IONPs when exposed to an OMF, were assessed to determine their effects on cell viability in a RAW 267.4 murine macrophage model system. Our results show that 91.5-97% of cells that have ingested IONPs die follow exposure to an OMF. Importantly, neither the IONPs (at applicable concentrations) nor the OMF show cytotoxic effects. These particular particles have promising preliminary results as hyperthermic agents in both the current literature and simple, proof-of-concept experiments in our laboratory setting. We present experimental results for the synthesis, characterization, and utilization of iron oxide nanoparticles in MFH. Our results show that while IONPs have

  16. Entomopathogenic marine actinomycetes as potential and low-cost biocontrol agents against bloodsucking arthropods.

    PubMed

    Loganathan, Karthik; Kumar, Gaurav; Kirthi, Arivarasan Vishnu; Rao, Kokati Venkata Bhaskara; Rahuman, Abdul Abdul

    2013-11-01

    A novel approach to control strategies for integrated blood-feeding parasite management is in high demand, including the use of biological control agents. The present study aims to determine the efficacy of optimized crude extract of actinomycetes strain LK1 as biological control agent against the fourth-instar larvae of Anopheles stephensi and Culex tritaeniorhynchus (Diptera: Culicidae) and adults of Haemaphysalis bispinosa, Rhipicephalus (Boophilus) microplus (Acari: Ixodidae), and Hippobosca maculata (Diptera: Hippoboscidae). Antiparasitic activity was optimized using the Plackett-Burman method, and the design was developed using the software Design-Expert version 8.0.7.1. The production of the optimized crude actinomycetes LK1 strain extract was performed using response surface methodology to optimize the process parameters of protease inhibitor activity of marine actinobacteria for the independent variables like pH, temperature, glucose, casein, and NaCl at two levels (-1 and +1). The potential actinomycetes strain was identified as Saccharomonas spp., and the metamodeling surface simulation procedure was followed. It was studied using a computer-generated experimental design, automatic control of simulation experiments, and sequential optimization of the metamodels fitted to a simulation response surface function. The central composite design (CCD) used for the analysis of treatment showed that a second-order polynomial regression model was in good agreement with the experimental results at R (2) = 0.9829 (p < 0.05). The optimized values of the variables for antioxidant production were pH 6.00, glucose 1.3%, casein 0.09%, temperature 31.23 °C, and NaCl 0.10%. The LK1 strain-optimized crude extract was purified using reversed-phase high-pressure liquid chromatography, and the isolated protease inhibitor showed antiparasitic activity. The antiparasitic activity of optimized crude extract of LK1 was tested against larvae of A. stephensi (LC₅₀ = 31.82 ppm

  17. Antitumor Agents 250.† Design and Synthesis of New Curcumin Analogs as Potential Anti-Prostate Cancer Agents

    PubMed Central

    Lin, Li; Shi, Qian; Nyarko, Alexander K.; Bastow, Kenneth F.; Wu, Chin-Chung; Su, Ching-Yuan; Shih, Charles C.-Y; Lee, Kuo-Hsiung

    2008-01-01

    In a continuing study of curcumin analogs as potential drug candidates to treat prostate cancer at both androgen-dependent and androgen-refractory stages, we designed and synthesized over 40 new analogs classified into four series: monophenyl analogs (series A), heterocycle-containing analogs (series B), analogs bearing various substituents on the phenyl rings (series C) and analogs with various linkers (series D). These new compounds were tested for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Antiandrogenic activity was also evaluated in LNCaP cells and PC-3 cells transfected with wild-type androgen receptor. Ten compounds possessed potent cytotoxicity against both LNCaP and PC-3 cells; seven only against LNCaP; and one solely against PC-3. This study established an advanced structure-activity relationship (SAR), and these correlations will guide the further design of new curcumin analogs with better anti-prostate cancer activity. PMID:16789753

  18. Potential of Microbispora sp. V2 as biocontrol agent against Sclerotium rolfsii, the causative agent of southern blight of Zea mays L (Baby corn)--in vitro studies.

    PubMed

    Patil, N N; Waghmode, M S; Gaikwad, P S; Gajbhiye, M H; Gunjal, A B; Nawani, N N; Kapadnis, B P

    2014-11-01

    The study was undertaken with the aim of exploring novel and beneficial agro activities of rare actinomycetes like Microbispora sp. V2. The antagonistic activity of Microbispora sp. V2 was evaluated as a biocontrol agents against Sclerotium rolfsii, a soil-borne fungal plant pathogen. The methodology performed for evaluation of biocontrol agent was in vitro evaluation assay which comprised of three tests viz., cellophane overlay technique, seed germination test and Thiram (fungicide) tolerance of Microbispora sp. V2. The isolate was found to inhibit the fungal pathogen Sclerotium rolfsii to 91.43% in cellophane assay. In seed germination assay, Microbispora sp. V2 treated seeds resulted in 25.75% increased germination efficiency, as compared to seeds infected by Sclerotium rolfsii. The isolate Microbispora sp. V2 could tolerate 1000 microg mL(-1) of Thiram (fungicide). The in vitro assay studies proved that Microbispora sp. V2 can be used as antifungal antagonist and thus posses' great potential as biocontrol agent against southern blight caused by Sclerotium rolfsii in Zea mays L (Baby corn) which causes large economical losses. PMID:25434111

  19. MATING BIOLOGY OF AUSTROMUSOTIMA CAMPTOZONALE (LEPIDOPTERA: CRAMBIDAE) - A POTENTIAL BIOLOGICAL CONTROL AGENT OF OLD WORLD CLIMBING FERN, LYGODIUM MICROPHYLLUM (SCHIZAEACEAE)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Austromusotima camptozonale (Hampson) is under investigation as a potential biological control agent of Old World Climbing fern, Lygodium microphyllum (Cav.) R. Br., which is a serious invasive weed in southern Florida. Studies were conducted to investigate aspects of the mating biology of A. campto...

  20. Potential biological control agents for management of cogongrass [Imperata cylindrica 15 (Cyperales: Poaceae)] in the southeastern USA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cogongrass, Imperata cylindrica (L.) Palisot de Beauvois (Cyperales: Poaceae), is a noxious invasive weed in the southeastern USA. Surveys for potential biological control agents of cogongrass were conducted in Asia and East Africa from 2013 to 2016. Several insect herbivores were found that may hav...

  1. Characterization of Novel Diaryl Oxazole-Based Compounds as Potential Agents to Treat Pancreatic Cancer

    PubMed Central

    Shaw, Arthur Y.; Henderson, Meredith C.; Flynn, Gary; Samulitis, Betty; Han, Haiyong; Stratton, Steve P.; Chow, H.-H. Sherry; Hurley, Laurence H.

    2009-01-01

    A series of diaryl- and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of >3 μM were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases. PMID:19657049

  2. Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents.

    PubMed

    Chakka, Sai Kumar; Kalamuddin, Mohammad; Sundararaman, Srividhya; Wei, Lianhu; Mundra, Sourabh; Mahesh, Radhakrishnan; Malhotra, Pawan; Mohmmed, Asif; Kotra, Lakshmi P

    2015-05-01

    Falcipain-2 is a papain family cysteine protease and an emerging antimalarial drug target. A pseudo-tripeptide scaffold I was designed using in silico screening tools and the three dimensional structures of falcipain-2, falcipain-3, and papain. This scaffold was investigated at four positions, T1, T2, T3, and T3', with various targeted substitutions to understand the structure-activity relationships. Inhibitor synthesis was accomplished by first obtaining the appropriate dipeptide precursors with common structural components. The pyrrolidine moiety introduced interesting rotamers in a number of synthesized molecules, which was confirmed using high-temperature (1)H NMR spectroscopy. Among the synthesized compounds, 61, 62, and 66 inhibited falcipain-2 activity with inhibition constants (Ki) of 1.8 ± 1.1, 0.2 ± 0.1 and 7.0 ± 2.3 μM, respectively. A group of molecules with a pyrrolidine moiety at the T2 position (68, 70, 71, 72, and 73) also potently inhibited falcipain-2 activity (Ki=0.4 ± 0.1, 2.5 ± 0.5, 3.3 ± 1.1, 7.5 ± 1.9, and 4.6 ± 0.7 μM, respectively). Overall, compound 74 exhibited potent anti-parasitic activity (IC₅₀=0.9 ± 0.1 μM), corresponding with its inhibitory activity against falcipain-2, with a Ki of 1.1 ± 0.1 μM. Compounds 62 and 67 inhibited the growth of the drug resistant parasite Dd2 with better efficacy, and compound 74 exhibited a 7- to 12-fold higher potency against Dd2 and MCamp isolates, than the laboratory strain (3D7). These data suggest that this novel series of compounds should be further investigated as potential antimalarial agents. PMID:25840796

  3. Bioinformatics prediction of siRNAs as potential antiviral agents against dengue viruses

    PubMed Central

    Villegas-Rosales, Paula M; Méndez-Tenorio, Alfonso; Ortega-Soto, Elizabeth; Barrón, Blanca L

    2012-01-01

    Dengue virus (DENV 1-4) represents the major emerging arthropod-borne viral infection in the world. Currently, there is neither an available vaccine nor a specific treatment. Hence, there is a need of antiviral drugs for these viral infections; we describe the prediction of short interfering RNA (siRNA) as potential therapeutic agents against the four DENV serotypes. Our strategy was to carry out a series of multiple alignments using ClustalX program to find conserved sequences among the four DENV serotype genomes to obtain a consensus sequence for siRNAs design. A highly conserved sequence among the four DENV serotypes, located in the encoding sequence for NS4B and NS5 proteins was found. A total of 2,893 complete DENV genomes were downloaded from the NCBI, and after a depuration procedure to identify identical sequences, 220 complete DENV genomes were left. They were edited to select the NS4B and NS5 sequences, which were aligned to obtain a consensus sequence. Three different servers were used for siRNA design, and the resulting siRNAs were aligned to identify the most prevalent sequences. Three siRNAs were chosen, one targeted the genome region that codifies for NS4B protein and the other two; the region for NS5 protein. Predicted secondary structure for DENV genomes was used to demonstrate that the siRNAs were able to target the viral genome forming double stranded structures, necessary to activate the RNA silencing machinery. PMID:22829722

  4. Photoactive metal carbonyl complexes as potential agents for targeted CO delivery.

    PubMed

    Gonzales, Margarita A; Mascharak, Pradip K

    2014-04-01

    The surprising discovery of carbon monoxide (CO) as a signaling molecule in mammalian physiology has recently raised interest in this toxic gas among researchers in biochemical and pharmaceutical community. CO is endogenously produced mainly from catabolism of heme by the enzyme heme oxygenase (HO) and participates in a myriad of anti-inflammatory, anti-proliferative, and vasoregulatory pathways. In animal models, low doses of CO have exhibited beneficial effects in suppression of organ graft rejection and safeguarding the heart during reperfusion after cardiopulmonary bypass surgery. The salutary effects of CO have naturally drawn attention of the pharmaceutical industry for its use as a cytoprotective agent. Safety-related concerns of the use of this noxious gas have prompted research in the area of syntheses of CO-releasing molecules (CORMs) and to date, several metal carbonyls (metal complexes of CO) have been employed as CORMs in promoting prolonged (and safe) delivery of low doses of CO to cellular targets. Because many carbonyl complexes release CO upon illumination, investigators have recently began to explore the possibility of "controlled CO delivery" through the use of light. During the past few years, a number of photoactive CORMs or "photoCORMs" have been synthesized that release CO upon illumination with UV or visible light. The utility of these photoCORMs in CO delivery has also been confirmed. Novel design principles for isolation of photoCORMs have started to appear in recent reports. Scrutiny of the literature reveals the emergence of a new exciting area of drug development in such efforts. The potential of photoCORMs as CO-donating pharmaceuticals along with a brief overview of the physiological roles of CO is presented in this review. PMID:24287103

  5. Pharmacological characterization of a novel gastrodin derivative as a potential anti-migraine agent.

    PubMed

    Wang, Ping-Han; Zhao, Li-Xue; Wan, Jing-Yu; Zhang, Liang; Mao, Xiao-Na; Long, Fang-Yi; Zhang, Shuang; Chen, Chu; Du, Jun-Rong

    2016-03-01

    Migraine is a highly prevalent neurovascular disorder in the brain. An optimal therapy for migraine has not yet been developed. Gastrodin (Gas), the main effective constitute from Gastrodiae Rhizoma (Tianma in Chinese), has been indicated for migraine treatment and prophylaxis more than 30 years, with demonstrated safety. However, Gas is a phenolic glycoside, with relatively low concentrations and weak efficacy in the central nervous system. To develop more effective anti-migraine agents, we synthesized a novel Gas derivative (Gas-D). In the present study, comparative pharmacodynamic evaluations of Gas and Gas-D were performed in a model of nitroglycerin (NTG)-induced migraine in rats and the hot-plate test in mice. Following behavioral testing in this migraine model, external jugular vein blood and the trigeminal nucleus caudalis (TNC) were collected to analyze plasma nitric oxide (NO) and calcitonin gene-related peptide (CGRP) concentrations and c-Fos expression in the TNC. The acute oral toxicity of Gas and Gas-D was also examined. We found that Gas-D had potent anti-migraine effects, likely attributable to inhibition of both trigeminal nerve activation at central sites and the peripheral release of CGRP following NO scavenging. Additionally, Gas-D exerted significant anti-nociceptive effect in response to thermal pain compared with Gas. Furthermore, a single dose of 2.048 g/kg Gas or Gas-D presented no acute oral toxicity in mice. Altogether, the potent anti-migraine and anti-hyperalgesic effects of Gas-D suggest that it might be a potentially novel drug candidate for migraine treatment or prophylaxis. PMID:26704993

  6. Monascus Pigment Rubropunctatin: A Potential Dual Agent for Cancer Chemotherapy and Phototherapy.

    PubMed

    Zheng, Yunquan; Zhang, Yun; Chen, Deshan; Chen, Haijun; Lin, Ling; Zheng, Chengzhuo; Guo, Yanghao

    2016-03-30

    The Monascus pigment, rubropunctatin, was extracted and purified from red mold rice (RMR), and its cytotoxic activities against human cervical carcinoma HeLa cells were studied under the conditions with or without light irradiation. The IC50 value of rubropunctatin against HeLa cells in the dark was 93.71 ± 1.96 μM (24 h), while the cytotoxic activity was enhanced more than 3 times (IC50 = 24.02 ± 2.17 μM) under light irradiation (halogen lamp, 500 W; wavelength, 597-622 nm; and fluence rate, 15 mW cm(-2), for 30 min). However, the IC50 value of rubropunctatin against the immortalized human cervical epithelial H8 cells was more than 300 μM, even under light irradiation, indicating that rubropunctatin has a favorable selectivity index (SI). Treatment of HeLa cells with rubropunctatin in the dark or under light irradiation resulted in a dose-dependent apoptosis, as validated by the increase in the percentage of cells in the sub-G1 phase and phosphatidylserine externalization, and the inductive effect on HeLa cell apoptosis was boosted by the light irradiation. In addition, treatment with rubropunctatin alone or under light irradiation was found to induce apoptosis in HeLa cells via the mitochondrial pathway, including loss of mitochondrial membrane potential, activation of caspase-3, caspase-8, and caspase-9, and increase of the level of intracellular reactive oxygen species (ROS). It was suggested that rubropunctatin could be a promising natural dual anticancer agent for photodynamic therapy and chemotherapy. PMID:26953890

  7. Balancing stealth and echogenic properties in an ultrasound contrast agent with drug delivery potential.

    PubMed

    Jablonowski, Lauren J; Alfego, David; Andorko, James I; Eisenbrey, John R; Teraphongphom, Nutte; Wheatley, Margaret A

    2016-10-01

    Contrast agents are currently being modified to combine diagnostic and therapeutic capabilities. For ultrasound (US) imaging with polymeric contrast agents, it is necessary to modify the shell to create "stealth" microbubbles but without these modifications sacrificing the agent's ability to interact with the focused US beam. We hypothesize that addition of the classic immune shielding molecule polyethylene glycol (PEG) to a polylactide (PLA) microbubble shell will affect the acoustic and physical properties of the resulting agents. In an effort to determine the best formulation to achieve a balance between stealth and acoustic activity, we compared two PEGylation techniques; addition of increasing amounts of PEG-PLA copolymer and employing incorporation of a PEG lipid (LipidPEG) into the shell. Loss of acoustic enhancement occurred in a dose-dependent manner for both types of PEGylated agents (loss of signal occurred at >5 wt% PEG-PLA and >1 wt% LipidPEG), while immune activation was also reduced in a dose-dependent manner for the PEG-PLA agents. This study shows that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with both PEGylation methods, and was best achieved using for PEG-PLA at 5 wt% and for LipidPEG at 1 wt%. Studies are ongoing to evaluate the best method for the targeting and drug delivery capabilities of these agents for applications in cancer treatment. This study represents the basis for understanding the consequences of making modifications to the native polymeric shell. PMID:27388945

  8. Organometallic Palladium Complexes with a Water-Soluble Iminophosphorane Ligand as Potential Anticancer Agents

    PubMed Central

    Carreira, Monica; Calvo-Sanjuán, Rubén; Sanaú, Mercedes; Marzo, Isabel; Contel, María

    2012-01-01

    The synthesis and characterization of a new water-soluble iminophosphorane ligand TPA=N-C(O)-2BrC6H4 (C,N-IM; TPA = 1,3,5-triaza-7-phosphaadamantane) 1 is reported. Oxidative addition of 1 to Pd2(dba)3 affords the orthopalladated dimer [Pd(μ-Br){C6H4(C(O)N=TPA-kC,N)-2}]2 (2) as a mixture of cis and trans isomers (1:1 molar ratio) where the iminophosphorane moeity behaves as a C,N-pincer ligand. By addition of different neutral or monoanionic ligands to 2, the bridging bromide can be cleaved and a variety of hydrophilic or water-soluble mononuclear organometallic palladium(II) complexes of the type [Pd{C6H4(C(O)N=TPA-kC,N)-2}(L-L)] (L-L = acac (3); S2CNMe2 (4); 4,7-Diphenyl-1,10-phenanthrolinedisulfonic acid disodium salt C12H6N2(C6H4SO3Na)2 (5)); [Pd{C6H4(C(O)N=TPA-kC,N)-2}(L)Br] (L = P(mC6H4SO3Na)3 (6); P(3-Pyridyl)3 (7)) and, [Pd(C6H4(C(O)N=TPA)-2}(TPA)2Br] (8) are obtained as single isomers. All new complexes were tested as potential anticancer agents and their cytotoxicity properties were evaluated in vitro against human Jurkat-T acute lymphoblastic leukemia cells, normal T-lymphocytes (PBMC) and DU-145 human prostate cancer cells. Compounds [Pd(μ-Br){C6H4(C(O)N=TPA-kC,N)-2}]2 (2) and [Pd{C6H4(C(O)N=TPA-kC,N)-2}(acac)] 3 (which has been crystallographically characterized) display the higher cytotoxicity against the above mentioned cancer cell lines while being less toxic to normal T-lymphocytes (peripheral blood mononuclear cells: PBMC). In addition, 3 is very toxic to cisplatin resistant Jurkat shBak indicating a cell death pathway that may be different to that of cisplatin. The interaction of 2 and 3 with plasmid (pBR322) DNA is much weaker than that of cisplatin pointing to an alternative biomolecular target for these cytotoxic compounds. All the compounds show an interaction with human serum albumin (HSA) faster than that of cisplatin. PMID:23066172

  9. The potential bioproduction of the pharmaceutical agent sakuranetin, a flavonoid phytoalexin in rice.

    PubMed

    Shimizu, Takafumi; Lin, Fengqiu; Hasegawa, Morifumi; Nojiri, Hideaki; Yamane, Hisakazu; Okada, Kazunori

    2012-01-01

    Sakuranetin, the major flavonoid phytoalexin in rice, can be induced by ultraviolet (UV) irradiation, treatment with CuCl 2 or jasmonic acid (JA), or phytopathogenic infection. In addition to sakuranetin's biological significance on disease resistance in rice, its broad bioactivities have recently been described. Results from these studies have shown that sakuranetin is a useful compound as a plant antibiotic and a potential pharmaceutical agent. Sakuranetin is biosynthesized from naringenin, a precursor of sakuranetin, by naringenin 7-O-methyltransferase (NOMT), but the relevant gene has not yet been identified in rice. Recently, we identified the OsNOMT gene, which is involved in the final step of sakuranetin biosynthesis in rice. In previous studies, OsNOMT was purified to apparent homogeneity from UV-treated wild-type rice leaves; however, the purified protein, termed OsCOMT1, exhibited caffeic acid 3-O-methyltransferase (COMT) activity, but not NOMT activity. Based on the analysis of an oscomt1 T-DNA tagged mutant, we determined that OsCOMT1 did not contribute to sakuranetin production in rice in vivo. Therefore, we took advantage of the oscomt1 mutant to purify OsNOMT. A crude protein preparation from UV-treated oscomt1 leaves was subjected to three sequential purification steps resulting in a 400-fold purification from the crude enzyme preparation with a minor band at an apparent molecular mass of 40 kDa in the purest enzyme preparation. Matrix-assisted laser desorption/ionization time of flight/time of flight analysis showed that the 40 kDa protein band included two O-methyltransferase-like proteins, but one of the proteins encoded by Os12g0240900 exhibited clear NOMT activity; thus, this gene was designated OsNOMT. Gene expression was induced by treatment with jasmonic acid in rice leaves prior to sakuranetin accumulation, and the recombinant protein showed reasonable kinetic properties to NOMT. Identification of the OsNOMT gene enables the production of

  10. 99Tcm-LL1: a potential new bone marrow imaging agent.

    PubMed

    Juweid, M; Dunn, R M; Sharkey, R M; Rubin, A D; Hansen, H J; Goldenberg, D M

    1997-02-01

    LL1, a monoclonal antibody (MAb) to HLA Class-II-like antigen (li determinant) on the surface of B-lymphocytes, monocytes and histiocytes, was evaluated as an agent for bone marrow imaging. Six patients with diverse diseases (non-Hodgkin's lymphoma, n = 2; multiple myeloma, n = 1; polycythaemia vera, n = 1; lung cancer, n = 1; breast cancer, n = 1) were given low protein doses (< 1 mg) of 99Tcm (30 mCi) labelled Fab' of LL1. 99Tcm-sulphur colloid (SC) imaging was performed in three patients for comparison. Both planar and single photon emission tomographic images were acquired using Sopha gamma cameras. As early as 2 h post-MAb injection, excellent bone marrow images were achieved in all patients, demonstrating both normal or hyperproliferative marrow, as well as 'cold' bone marrow abnormalities such as radiation defects or cancer metastases. Similar to SC, relatively high uptake of LL1 was found in the liver and spleen. However, the bone marrow-to-liver and -spleen uptake ratios were approximately 19-fold higher (0.75 vs 0.04) and 6-fold higher (1.23 vs 0.22), respectively, with LL1 than with SC. The higher bone marrow uptake allowed clearly superior visualization of the thoracic spine when compared to SC. The mean T1/2 of blood and whole-body clearance were 0.4 and 66 h, respectively. The highest radiation absorbed doses (in cGy mCi-1) were observed in the spleen (0.47 +/- 0.24), kidneys (0.25 +/- 0.09) and liver (0.14 +/- 0.04). The bone marrow dose was only 0.05 +/- 0.02 cGy mCi-1. These results indicate that bone marrow imaging with 99Tcm-LL1 is feasible, and that LL1 may be a suitable alternative to SC because of better visualization of the lower thoracic spine. Potential applications include the improved detection of bone marrow metastases of solid tumours and the assessment of haematological disorders. PMID:9076770

  11. Potential of Pest and Host Phenological Data in the Attribution of Regional Forest Disturbance Detection Maps According to Causal Agent

    NASA Technical Reports Server (NTRS)

    Spruce, Joseph; Hargrove, William; Norman Steve; Christie, William

    2014-01-01

    Near real time forest disturbance detection maps from MODIS NDVI phenology data have been produced since 2010 for the conterminous U.S., as part of the on-line ForWarn national forest threat early warning system. The latter has been used by the forest health community to identify and track many regional forest disturbances caused by multiple biotic and abiotic damage agents. Attribution of causal agents for detected disturbances has been a goal since project initiation in 2006. Combined with detailed cover type maps, geospatial pest phenology data offer a potential means for narrowing the candidate causal agents responsible for a given biotic disturbance. U.S. Aerial Detection Surveys (ADS) employ such phenology data. Historic ADS products provide general locational data on recent insect-induced forest type specific disturbances that may help in determining candidate causal agents for MODIS-based disturbance maps, especially when combined with other historic geospatial disturbance data (e.g., wildfire burn scars and drought maps). Historic ADS disturbance detection polygons can show severe and extensive regional forest disturbances, though they also can show polygons with sparsely scattered or infrequent disturbances. Examples will be discussed that use various historic disturbance data to help determine potential causes of MODIS-detected regional forest disturbance anomalies.

  12. POTENTIAL OF ENTOMOPATHOGENIC FUNGI AS BIOLOGICAL CONTROL AGENTS AGAINST THE FORMOSAN SUBTERRANEAN TERMITE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tolerance, pathogenicity and transmission studies of the fungi Metarhizium and Beauveria, show that biological control agents can enhance termite treatment flexibility. Subterranean termites cause significant damage to wood structures and trees, especially in the Gulf of Mexico region of the United ...

  13. Synthesis and biological evaluation of novel gigantol derivatives as potential agents in prevention of diabetic cataract

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As a continuation of our efforts directed towards the development of natural anti-diabetic cataract agents, gigantol was isolated from Herba dendrobii and was found to inhibit both aldose reductase (AR) and inducible nitric oxide synthase (iNOS) activity, which play a significant role in the develop...

  14. Anticholinesterase (DFP) toxicity antagonism by chronic donepezil: a potential nerve agent treatment.

    PubMed

    Janowsky, David S; Davis, John M; Overstreet, David H

    2005-08-01

    Animal studies exploring the antagonism of irreversible cholinesterase inhibitors (i.e. nerve agents) such as soman and sarin have shown that pretreatment with the reversible centrally acting cholinesterase inhibitor, physostigmine, alone or in conjunction with the centrally acting anticholinergic drug, scopolamine, antagonizes the lethality and toxicity of these agents. This study evaluated the effects of pretreatment with the oral cholinesterase inhibitor and anti-Alzheimer's agent, donepezil (Aricept) on the hypokinetic, hypothermic and diarrhea-inducing effects of the irreversible long-acting cholinesterase inhibitor, diisopropylfluorophosphate (DFP) in adult Sprague-Dawley rats. Donepezil (2 mg/kg), given acutely (30 min pretreatment) or chronically (10 daily treatments), significantly antagonized the hypothermia, hypoactivity and diarrhea induced by DFP (1.25 mg/kg) administration. The effects were most prominent 4 and 6 h after the injection of DFP and some protection was observed even when the last treatment of the chronic donepezil protocol was given 24 h before the DFP injection. Although these phenomena are not the same as lethality, they may be parallel phenomena, and our results may have therapeutic implications for the treatment of nerve agent toxicity. PMID:16054679

  15. Synthesis and biological evaluation of quinoline derivatives as potential anti-prostate cancer agents and Pim-1 kinase inhibitors.

    PubMed

    Li, Kun; Li, Ying; Zhou, Di; Fan, Yinbo; Guo, Hongye; Ma, Tianyi; Wen, Jiachen; Liu, Dan; Zhao, Linxiang

    2016-04-15

    In this work, a series of quinoline derivatives were designed and synthesized as antitumor agents. Most quinolines showed potent anti-proliferative activity against human prostatic cancer PC-3 cell line. Among which, 9d, 9f and 9g were the most effective compounds with GI50 values of 2.60, 2.81 and 1.29μM, respectively. Structure-activity relationship analysis indicated that the secondary amine linked quinoline and pyridine ring played an important role in the anti-proliferative effects. Mechanistic studies revealed that 9g was a potential Pim-1 kinase inhibitor with abilities of cell cycle arrest and apoptosis induction. Considering of the increased activity of Pim-1 in prostate cancer, such compounds have potential to be developed as anti-prostate cancer agents. PMID:26979485

  16. Microtubule S-glutathionylation as a potential approach for antimitotic agents

    PubMed Central

    2012-01-01

    Background Microtubules have been one of the most effective targets for the development of anticancer agents. Cancer cells treated by these agents are characterized by cell arrest at G2/M phase. Microtubule-targeting drugs are, therefore, referred to as antimitotic agents. However, the clinical application of the current antimitotic drugs is hampered by emerging drug resistance which is the major cause of cancer treatment failure. The clinical success of antimitotic drugs and emerging drug resistance has prompted a search for new antimitotic agents, especially those with novel mechanisms of action. The aim of this study was to determine whether microtubules can be S-glutathionylated in cancer cells and whether the glutathionylation will lead to microtubule dysfunction and cell growth inhibition. The study will determine whether microtubule S-glutathionylation can be a novel approach for antimitotic agents. Methods 2-Acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)phenyl carbamoylsulfanyl]propionic acid (2-AAPA) was used as a tool to induce microtubule S-glutathionylation. UACC-62 cells, a human melanoma cell line, were used as a cancer cell model. A pull-down assay with glutathione S-transferase (GST)-agarose beads followed by Western blot analysis was employed to confirm microtubule S-glutathionylation. Immunofluorescence microscopy using a mouse monoclonal anti-α-tubulin-FITC was used to study the effect of the S-glutathionylation on microtubule function; mainly polymerization and depolymerization. Flow cytometry was employed to examine the effect of the S-glutathionylation on cell cycle distribution and apoptosis. Cell morphological change was followed through the use of a Zeiss AXIO Observer A1 microscope. Cancer cell growth inhibition by 2-AAPA was investigated with ten human cancer cell lines. Results Our investigation demonstrated that cell morphology was changed and microtubules were S-glutathionylated in the presence of 2-AAPA in UACC

  17. Non-aflatoxigenic Aspergillus flavus as potential biocontrol agents to reduce aflatoxin contamination in peanuts harvested in Northern Argentina.

    PubMed

    Alaniz Zanon, María Silvina; Barros, Germán Gustavo; Chulze, Sofía Noemí

    2016-08-16

    Biological control is one of the most promising strategies for preventing aflatoxin contamination in peanuts at field stage. A population of 46 native Aspergillus flavus nonaflatoxin producers were analysed based on phenotypic, physiological and genetic characteristics. Thirty-three isolates were characterized as L strain morphotype, 3 isolates as S strain morphotype, and 10 isolates did not produce sclerotia. Only 11 of 46 non-aflatoxigenic isolates did not produce cyclopiazonic acid. The vegetative compatibility group (VCG) diversity index for the population was 0.37. For field trials we selected the non-aflatoxigenic A. flavus AR27, AR100G and AFCHG2 strains. The efficacy of single and mixed inocula as potential biocontrol agents in Northern Argentina was evaluated through a 2-year study (2014-2015). During the 2014 peanut growing season, most of the treatments reduced the incidence of aflatoxigenic strains in both soil and peanut kernel samples, and no aflatoxin was detected in kernels. During the 2015 growing season, there was a reduction of aflatoxigenic strains in kernel samples from the plots treated with the potential biocontrol agents. Reductions of aflatoxin contamination between 78.36% and 89.55% were observed in treated plots in comparison with the un-inoculated control plots. This study provides the first data on aflatoxin biocontrol based on competitive exclusion in the peanut growing region of Northern Argentina, and proposes bioproducts with potential use as biocontrol agents. PMID:27220011

  18. Hydroxy double salts intercalated with Mn(II) complexes as potential contrast agents

    NASA Astrophysics Data System (ADS)

    Jin, Miao; Li, Wanjing; Spillane, Dominic E. M.; Geraldes, Carlos F. G. C.; Williams, Gareth R.; Bligh, S. W. Annie

    2016-03-01

    A series of Mn(II) aminophosphonate complexes were successfully synthesized and intercalated into the hydroxy double salt [Zn5(OH)8]Cl2·yH2O. Complex incorporation led to an increase in the interlayer spacing from 7.8 to 10-12 Å. Infrared spectroscopy showed the presence of the characteristic vibration peaks of the Mn(II) complexes in the intercalates' spectra, indicating successful incorporation. The complex-loaded composites had somewhat lower proton relaxivities than the pure complexes. Nevertheless, these intercalates may have use as MRI contrast agents for patients with poor kidney function, where traditional Gd(III)-based contrast agents cause severe renal failure.

  19. Evaluation of Degradation Properties of Polyglycolide and Its Potential as Delivery Vehicle for Anticancer Agents

    SciTech Connect

    Noorsal, K.; Ghani, S. M.; Yunos, D. M.; Mohamed, M. S. W.; Yahya, A. F.

    2010-03-11

    Biodegradable polymers offer a unique combination of properties that can be tailored to suit nearly any controlled drug delivery application. The most common biodegradable polymers used for biomedical applications are semicrystalline polyesters and polyethers which possess good mechanical properties and have been used in many controlled release applications. Drug release from these polymers may be controlled by several mechanisms and these include diffusion of drug through a matrix, dissolution of polymer matrix and degradation of the polymer. This study aims to investigate the degradation and drug release properties of polyglycolide (1.03 dL/g), in which, cis platin, an anticancer agent was used as the model drug. The degradation behaviour of the chosen polymer is thought to largely govern the release of the anticancer agent in vitro.

  20. Synthesis and mechanisms of action of novel harmine derivatives as potential antitumor agents.

    PubMed

    Zhang, Xiao-Fei; Sun, Rong-Qin; Jia, Yi-Fan; Chen, Qing; Tu, Rong-Fu; Li, Ke-Ke; Zhang, Xiao-Dong; Du, Run-Lei; Cao, Ri-Hui

    2016-01-01

    A series of novel harmine derivatives bearing a benzylindine substituent in position-1 of β-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated β-carboline derivatives 3a-g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment. PMID:27625151

  1. Synthesis and biological evaluation of a fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain and imaging agent

    PubMed Central

    Walls, Thomas H.; Grindrod, Scott C.; Beraud, Dawn; Zhang, Li; Baheti, Aparna R.; Dakshanamurthy, Sivanesan; Patel, Manoj K.; Brown, Milton L.; MacArthur, Linda H.

    2013-01-01

    Here we report on a novel fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain with potential use as an imaging agent. Compound 2 incorporated a heptyl side chain and dansyl moiety onto the parent compound phenytoin and produced greater displacement of BTX from sodium channels and greater functional blockade with greatly reduced toxicity. Compound 2 reduced mechano-allodynia in a rat model of neuropathic pain and was visualized ex vivo in sensory neuron axons with two-photon microscopy. These results suggest a promising strategy for developing novel sodium channel inhibitors with imaging capabilities. PMID:22863530

  2. Synthesis and Biological Evaluation of Novel Gigantol Derivatives as Potential Agents in Prevention of Diabetic Cataract.

    PubMed

    Wu, Jie; Lu, Chuanjun; Li, Xue; Fang, Hua; Wan, Wencheng; Yang, Qiaohong; Sun, Xiaosheng; Wang, Meiling; Hu, Xiaohong; Chen, C-Y Oliver; Wei, Xiaoyong

    2015-01-01

    As a continuation of our efforts directed towards the development of natural anti-diabetic cataract agents, gigantol was isolated from Herba dendrobii and was found to inhibit both aldose reductase (AR) and inducible nitric oxide synthase (iNOS) activity, which play a significant role in the development and progression of diabetic cataracts. To improve its bioefficacy and facilitate use as a therapeutic agent, gigantol (compound 14f) and a series of novel analogs were designed and synthesized. Analogs were formulated to have different substituents on the phenyl ring (compounds 4, 5, 8, 14a-e), substitute the phenyl ring with a larger steric hindrance ring (compounds 10, 17c) or modify the carbon chain (compounds 17a, 17b, 21, 23, 25). All of the analogs were tested for their effect on AR and iNOS activities and on D-galactose-induced apoptosis in cultured human lens epithelial cells. Compounds 5, 10, 14a, 14b, 14d, 14e, 14f, 17b, 17c, 23, and 25 inhibited AR activity, with IC50 values ranging from 5.02 to 288.8 μM. Compounds 5, 10, 14b, and 14f inhibited iNOS activity with IC50 ranging from 432.6 to 1188.7 μM. Compounds 5, 8, 10, 14b, 14f, and 17c protected the cells from D-galactose induced apoptosis with viability ranging from 55.2 to 76.26%. Of gigantol and its analogs, compound 10 showed the greatest bioefficacy and is warranted to be developed as a therapeutic agent for diabetic cataracts. PMID:26517726

  3. Synthesis and Biological Evaluation of Novel Gigantol Derivatives as Potential Agents in Prevention of Diabetic Cataract

    PubMed Central

    Li, Xue; Fang, Hua; Wan, Wencheng; Yang, Qiaohong; Sun, Xiaosheng; Wang, Meiling; Hu, Xiaohong; Chen, C.-Y. Oliver; Wei, Xiaoyong

    2015-01-01

    As a continuation of our efforts directed towards the development of natural anti-diabetic cataract agents, gigantol was isolated from Herba dendrobii and was found to inhibit both aldose reductase (AR) and inducible nitric oxide synthase (iNOS) activity, which play a significant role in the development and progression of diabetic cataracts. To improve its bioefficacy and facilitate use as a therapeutic agent, gigantol (compound 14f) and a series of novel analogs were designed and synthesized. Analogs were formulated to have different substituents on the phenyl ring (compounds 4, 5, 8, 14a-e), substitute the phenyl ring with a larger steric hindrance ring (compounds 10, 17c) or modify the carbon chain (compounds 17a, 17b, 21, 23, 25). All of the analogs were tested for their effect on AR and iNOS activities and on D-galactose-induced apoptosis in cultured human lens epithelial cells. Compounds 5, 10, 14a, 14b, 14d, 14e, 14f, 17b, 17c, 23, and 25 inhibited AR activity, with IC50 values ranging from 5.02 to 288.8 μM. Compounds 5, 10, 14b, and 14f inhibited iNOS activity with IC50 ranging from 432.6 to 1188.7 μM. Compounds 5, 8, 10, 14b, 14f, and 17c protected the cells from D-galactose induced apoptosis with viability ranging from 55.2 to 76.26%. Of gigantol and its analogs, compound 10 showed the greatest bioefficacy and is warranted to be developed as a therapeutic agent for diabetic cataracts. PMID:26517726

  4. Tunable release of chemotherapeutic and vascular disrupting agents from injectable fiber fragments potentiates combination chemotherapy.

    PubMed

    Luo, Xiaoming; Xu, Guisen; Wei, Jiaojun; Chen, Maohua; Zhang, Hong; Li, Xiaohong

    2016-06-15

    Cancer progression and metastasis relies much on vasculature networks in tumor microenvironment, and the combination treatment with chemotherapeutic drugs and vascular disrupting agents represents apparent clinical benefits. In the current study, fiber fragments with loadings of hydroxycamptothecin (HCPT) or combretastatin A-4 (CA4) were proposed for tumor inhibition and blood vessel disruption after local administration in tumors. To address challenges in balancing the disruption of tumor vessels and intratumoral uptake of chemotherapeutic agents, this study is focus on release tuning of HCPT and CA4 from the fiber fragment mixtures. Hydroxypropyl-β-cyclodextrin (HPCD) was blended at ratios from 0 to 10% into CA4-loaded fiber fragments (Fc) to modulate CA4 release durations from 0.5 to 24days, and HCPT-loaded fiber fragments (Fh) indicated a sustained release for over 35days. In vitro cytotoxicity tests indicated a sequential inhibition on the endothelial and tumor cell growth, and the growth inhibition of tumor cells was more significant after treatment with mixtures of Fh and Fc containing 2% HPCD (Fc2) than that of other mixtures. In an orthotopic breast tumor model, compared with those of free CA4, or Fc with a fast or slow release of CA4, Fh/Fc mixtures with CA4 release durations from 2 to 12days indicated a lower tumor growth rate, a prolonged animal survival, a lower vessel density in tumors, and a less significant tumor metastasis. In addition, the tumor cell proliferation rate, hypoxia-inducible factor-1α expression within tumors, and the number of surface metastatic nodules in lungs were significantly lower after treatment with Fh/Fc2 mixtures with a CA4 release duration of 5days than those of other mixtures. It demonstrates the advantages of fiber fragment mixtures in independently modulating the release of multiple drugs and the essential role of release tuning of chemotherapeutic drugs and vascular disrupting agents in improving the therapeutic

  5. Synthesis of fluorine-18 labeled rhodamine B: A potential PET myocardial perfusion imaging agent

    PubMed Central

    Heinrich, Tobias K.; Gottumukkala, Vijay; Snay, Erin; Dunning, Patricia; Fahey, Frederic H; Treves, S. Ted; Packard, Alan B.

    2009-01-01

    There is considerable interest in developing an 18F-labeled PET myocardial perfusion agent. Rhodamine dyes share several properties with 99mTc-MIBI, the most commonly used single-photon myocardial perfusion agent, suggesting that an 18F-labeled rhodamine dye might prove useful for this application. In addition to being lipophilic cations, like 99mTc-MIBI, rhodamine dyes are known to accumulate in the myocardium and are substrates for Pgp, the protein implicated in MDR1 multidrug resistance. As the first step in determining whether 18F-labeled rhodamines might be useful as myocardial perfusion agents for PET, our objective was to develop synthetic methods for preparing the 18F-labeled compounds so that they could be evaluated in vivo. Rhodamine B was chosen as the prototype compound for development of the synthesis because the ethyl substituents on the amine moieties of rhodamine B protect them from side reactions, thus eliminating the need to include (and subsequently remove) protecting groups. The 2′-[18F]fluoroethyl ester of rhodamine B was synthesized by heating rhodamine B lactone with [18F]fluoroethyltosylate in acetonitrile at 165°C for 30 min.using [18F]fluoroethyl tosylate, which was prepared by the reaction of ethyleneglycol ditosylate with Kryptofix 2.2.2, K2CO3, and [18F]NaF in acetonitrile for 10 min. at 90°C. The product was purified by semi-preparative HPLC to produce the 2′-[18F]-fluoroethylester in >97% radiochemical purity with a specific activity of 1.3 GBq/μmol, an isolated decay corrected yield of 35%, and a total synthesis time of 90 min. PMID:19783150

  6. Synthesis, analysis and biological evaluation of novel indolquinonecryptolepine analogues as potential anti-tumour agents.

    PubMed

    Le Gresley, A; Gudivaka, V; Carrington, S; Sinclair, A; Brown, J E

    2016-03-21

    A small library of cryptolepine analogues were synthesised incorporating halogens and/or nitrogen containing side chains to optimise their interaction with the sugar-phosphate backbone of DNA to give improved binding, interfering with topoisomerase II hence enhancing cytotoxicity. Cell viability, DNA binding and Topoisomerase II inhibition is discussed for these compounds. Fluorescence microscopy was used to investigate the uptake of the synthesised cryptolepines into the nucleus. We report the synthesis and anti-cancer biological evaluation of nine novel cryptolepine analogues, which have greater cytotoxicity than the parent compound and are important lead compounds in the development of novel potent and selective indoloquinone anti-neoplastic agents. PMID:26893255

  7. Glycans in pathogenic bacteria – potential for targeted covalent therapeutics and imaging agents

    PubMed Central

    Tra, Van N.; Dube, Danielle H.

    2014-01-01

    A substantial obstacle to the existing treatment of bacterial diseases is the lack of specific probes that can be used to diagnose and treat pathogenic bacteria in a selective manner while leaving the microbiome largely intact. To tackle this problem, there is an urgent need to develop pathogen-specific therapeutics and diagnostics. Here, we describe recent evidence that indicates distinctive glycans found exclusively on pathogenic bacteria could form the basis of targeted therapeutic and diagnostic strategies. In particular, we highlight the use of metabolic oligosaccharide engineering to covalently deliver therapeutics and imaging agents to bacterial glycans. PMID:24647371

  8. Lepidopterans as Potential Agents for the Biological Control of the Invasive Plant, Miconia calvescens

    PubMed Central

    Morais, Elisangela G.F.; Picanço, Marcelo C.; Semeão, Altair A.; Barreto, Robert W.; Rosado, Jander F.; Martins, Julio C.

    2012-01-01

    This work investigated eight species of Lepidoptera associated with Miconia calvescens DC. (Myrtales: Melastomataceae) in Brazil, including six defoliators, Salbia lotanalis Druce (Lepidoptera: Pyralidae), Druentia inscita Schaus (Mimallonidae), Antiblemma leucocyma Hampson (Noctuidae), three Limacodidae species, a fruit borer Carposina cardinata Meyrick (Carposinidae), and a damager of flowers Pleuroprucha rudimentaria Guenée (Geometridae). Based on host specificity and the damage caused to plants, S. lotanalis and D. inscita are the most promising species for biological control of M. calvescens. Furthermore, if C. cardinata and P. rudimentaria have host specificity in future tests, these caterpillars could also be considered as appropriate biocontrol agents. PMID:22938203

  9. (Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents)

    SciTech Connect

    Not Available

    1991-01-01

    Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

  10. [Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents

    SciTech Connect

    Not Available

    1991-12-31

    Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

  11. Gadolinium(III) Complexes with N-Alkyl-N-methylglucamine Surfactants Incorporated into Liposomes as Potential MRI Contrast Agents

    PubMed Central

    Silva, Simone Rodrigues; Duarte, Érica Correia; Ramos, Guilherme Santos; Kock, Flávio Vinícius Crizóstomo; Andrade, Fabiana Diuk; Frézard, Frédéric; Colnago, Luiz Alberto; Demicheli, Cynthia

    2015-01-01

    Complexes of gadolinium(III) with N-octanoyl-N-methylglucamine (L8) and N-decanoyl-N-methylglucamine (L10) with 1 : 2 stoichiometry were synthesized and characterized by elemental analysis, electrospray ionization-tandem mass spectrometry (ESI-MS), infrared (IR) spectroscopy, and molar conductivity measurements. The transverse (r2) and longitudinal (r1) relaxivity protons were measured at 20 MHz and compared with those of the commercial contrasts. These complexes were incorporated in liposomes, resulting in the increase of the vesicle zeta potential. Both the free and liposome-incorporated gadolinium complexes showed high relaxation effectiveness, compared to commercial contrast agent gadopentetate dimeglumine (Magnevist). The high relaxivity of these complexes was attributed to the molecular rotation that occurs more slowly, because of the elevated molecular weight and incorporation in liposomes. The results establish that these paramagnetic complexes are highly potent contrast agents, making them excellent candidates for various applications in molecular MR imaging. PMID:26347596

  12. Clinical Features and Laboratory Diagnosis of Infection with the Potential Bioterrorism Agents Burkholderia Mallei and Burkholderia Pseudomallei

    PubMed Central

    Gilad, Jacob; Schwartz, David; Amsalem, Yoram

    2007-01-01

    Burkholderia mallei and Burkholderia pseudomallei are the causative organisms of Glanders and Melioidosis, respectively. Although now rare in Western countries, both organisms have recently gained much interest because of their unique potential as bioterrorism agents. These organisms are less familiar to medical and laboratory personnel than other select bioterrorism bacterial agents and thus heightened awareness of Glanders and Melioidosis is crucial in order to enable adequate emergency preparedness and response to deliberate release of B. mallei and B. pseudomallei. The microbiological diagnosis of both species in the clinical laboratory is complicated. This paper reviews the various challenges and pitfalls associated with the diagnosis of Melioidosis and Glanders in the clinical setting, with emphasis on the role of sentinel laboratories. PMID:23675037

  13. Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400).

    PubMed

    Lv, Peng-Cheng; Elsayed, Mohamed S A; Agama, Keli; Marchand, Christophe; Pommier, Yves; Cushman, Mark

    2016-05-26

    Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents with two compounds in clinical trials. Recent metabolism studies of indotecan (LMP400) led to the discovery of the biologically active 2-hydroxylated analogue and 3-hydroxylated metabolite, thus providing strategically placed functional groups for the preparation of a variety of potential ester prodrugs of these two compounds. The current study details the design and synthesis of two series of indenoisoquinoline prodrugs, and it also reveals how substituents on the O-2 and O-3 positions of the A ring, which are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage complex, affect Top1 inhibitory activity and cytotoxicity. Many of the indenoisoquinoline prodrugs were very potent antiproliferative agents with GI50 values below 10 nM in a variety of human cancer cell lines. PMID:27097152

  14. N,N-dimethylhexadecyl carboxymethyl chitosan as a potential carrier agent for rotenone.

    PubMed

    Kamari, A; Aljafree, N F A; Yusoff, S N M

    2016-07-01

    In this study, an amphiphilic chitosan derivative namely N,N-dimethylhexadecyl carboxymethyl chitosan (DCMC) was synthesised and applied for the first time as a carrier agent for rotenone. The physical and chemical properties of DCMC were characterised by using Fourier Transform Infrared Spectrometer (FTIR), Proton Nuclear Magnetic Resonance Spectrometer ((1)H NMR), CHN-O Elemental Analyser, Thermogravimetric Analyser (TGA) and Differential Scanning Calorimeter (DSC). DCMC was soluble in acidic (except pH 4), neutral and basic media with percent of transmittance (%T) values ranged from 67.2 to 99.4%. The critical micelle concentration (CMC) was determined as 0.095mg/mL. Transmission Electron Microscopy (TEM) analysis confirmed that DCMC has formed self-aggregates and exhibited spherical shape with the size of 65.5-137.0nm. The encapsulation efficiency (EE) and loading capacity (LC) of DCMC micelles with different weight ratios (DCMC:rotenone; 5:1, 50:1 and 100:1) were determined by using High Performance Liquid Chromatography (HPLC). The weight ratio of 100:1 gave the best EE with the value of more than 95.0%. DCMC micelles performed an excellent ability to control the release of rotenone, of which 99.0% of rotenone was released within 48h. Overall, DCMC has several key features to be an effective carrier agent for pesticide formulations. PMID:27041651

  15. Synthesis and evaluation of paeonol derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

    PubMed

    Zhou, An; Wu, Hongfei; Pan, Jian; Wang, Xuncui; Li, Jiaming; Wu, Zeyu; Hui, Ailing

    2015-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder characterized by memory loss, language impairment, personality changes and intellectual decline. Taking into account the key pathological features of AD, such as low levels of acetylcholine, beta-amyloid (Aβ) aggregation, oxidative stress and dyshomeostasis of biometals, a new series of paeonol derivatives 5a-5d merging three different functions, i.e., antioxidant, anti-acetylcholinesterase (AChE) activity, metal chelating agents for AD treatment have been synthesized and characterized. Biological assays revealed that compared with paeonol (309.7 μM), 5a-5d had a lower DPPH IC50 value (142.8-191.6 μM). 5a-5d could significantly inhibit hydrogen peroxide-induced neuronal PC12 cell death assessed by MTT assay in the concentration range of 5-40 μM. AChE activity was effectively inhibited by 5a-5d, with IC50 values in the range of 0.61-7.04 μM. 5a-5d also exhibited good metal-chelating ability. All the above results suggested that paeonol derivatives may be promising multifunctional agents for AD treatment. PMID:25594344

  16. New candidate therapeutic agents for endometrial cancer: potential for clinical practice (review).

    PubMed

    Umene, Kiyoko; Banno, Kouji; Kisu, Iori; Yanokura, Megumi; Nogami, Yuya; Tsuji, Kosuke; Masuda, Kenta; Ueki, Arisa; Kobayashi, Yusuke; Yamagami, Wataru; Tominaga, Eiichiro; Susumu, Nobuyuki; Aoki, Daisuke

    2013-03-01

    Cases of endometrial cancer have increased in recent years, but the prognosis of patients with this disease has also been improved by combined modality therapy with surgery, radiotherapy and chemotherapy. However, the development of new therapy is required from the perspectives of conservation of fertility and efficacy for recurrent and intractable cancer. New candidate therapeutic agents for endometrial cancer include fourth-generation progestins for inhibition of growth and differentiation of endometrial glands; metformin for reduction of hTERT expression in the endometrium and inhibition of the mTOR pathway by activation of AMPK, with consequent inhibition of the cell cycle; mTOR inhibitors for supressing growth of cancer cells by G1 cell cycle arrest; microRNAs involved in the molecular mechanisms of oncogenesis and progression; and HDAC inhibitors that block the growth of cancer cells by transcriptional elevation of tumor-suppressor genes, cell cycle arrest and induction of apoptosis. In this study, we review the background and early clinical evidence for these agents as new therapeutic candidates for endometrial cancer. PMID:23291663

  17. Functionality study of santalin as tyrosinase inhibitor: A potential depigmentation agent.

    PubMed

    Hridya, Hemachandran; Amrita, Anantharaman; Mohan, Sankari; Gopalakrishnan, Mohan; Dakshinamurthy, Thirumal Kumar; Doss, George Priya; Siva, Ramamoorthy

    2016-05-01

    Excessive melanin production leads to hyperpigmentation disorders which results in distressing aesthetic values. Though there are some synthetic depigmentation agents available it has been reported to possess cytotoxic and mutagenic effects. Hence there is a need for the development of safe and non toxic natural tyrosinase inhibitors. Here we report the role of santalin, the chief constituent of Pterocarpus santalinus in inhibition of tyrosinase and melanin synthesis. Santalin inhibited tyrosinase activity dose dependently. Inhibitory kinetic studies revealed mixed type of inhibition with reversible mechanism. Santalin was found to interact with the fluorophore amino acid residue of tyrosinase. Analysis of circular dichroism spectra showed the binding of santalin to tyrosinase which induced the loss of secondary helical structure. Molecular docking result suggested that santalin interact with the catalytic core of tyrosinase through strong hydrogen and hydrophobic bonding. The results of in vitro studies showed santalin inhibited melanogenesis through down regulation of MITF, tyrosinase, TRP-1 and TRP-2 without any cytotoxic effects towards B16F0 melanoma cells. Therefore, our results suggested that santalin possesses anti-tyrosinase activity, which could be utilized as a safe depigmentation agent in the cosmetic field for the treatment of hyperpigmentation disorder. PMID:26828288

  18. Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery

    PubMed Central

    Brunstein, F; Rens, J; van Tiel, S T; Eggermont, A M M; ten Hagen, T L M

    2006-01-01

    Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents. PMID:17106443

  19. Novel C6-substituted 1,3,4-oxadiazinones as potential anti-cancer agents

    PubMed Central

    Jung, Yujin; Yun, Hye Jeong; Min, Hye-Young; Lee, Ho Jin; Pham, Phuong Chi; Moon, Jayoung; Kwon, Dah In; Lim, Bumhee; Suh, Young-Ger; Lee, Jeeyeon; Lee, Ho-Young

    2015-01-01

    The insulin-like growth factor 1 receptor (IGF-1R) is a membrane receptor tyrosine kinase over-expressed in a number of tumors. However, combating resistance is one of the main challenges in the currently available IGF-1R inhibitor-based cancer therapies. Increased Src activation has been reported to confer resistance to anti-IGF-1R therapeutics in various tumor cells. An urgent unmet need for IGF-1R inhibitors is to suppress Src rephosphorylation induced by current anti-IGF-1R regimens. In efforts to develop effective anticancer agents targeting the IGF-1R signaling pathway, we explored 2-aryl-1,3,4-oxadiazin-5-ones as a novel scaffold that is structurally unrelated to current tyrosine kinase inhibitors (TKIs). The compound, LL-2003, exhibited promising antitumor effects in vitro and in vivo; it effectively suppressed IGF-1R and Src and induced apoptosis in various non-small cell lung cancer cells. Further optimizations for enhanced potency in cellular assays need to be followed, but our strategy to identify novel IGF-1R/Src inhibitors may open a new avenue to develop more efficient anticancer agents. PMID:26515601

  20. Synthesis and Evaluation of Ester Derivatives of 10-Hydroxycanthin-6-one as Potential Antimicrobial Agents.

    PubMed

    Zhao, Fei; Dai, Jiang-Kun; Liu, Dan; Wang, Shi-Jun; Wang, Jun-Ru

    2016-01-01

    As part of our continuing research on canthin-6-one antimicrobial agents, a new series of ester derivatives of 10-hydroxycanthin-6-one were synthesized using a simple and effective synthetic route. The structure of each compound was characterized by NMR, ESI-MS, FT-IR, UV, and elemental analysis. The antimicrobial activity of these compounds against three phytopathogenic fungi (Alternaria solani, Fusarium graminearum, and Fusarium solani) and four bacteria (Bacillus cereus, Bacillus subtilis, Ralstonia solanacearum, and Pseudomonas syringae) were evaluated using the mycelium linear growth rate method and micro-broth dilution method, respectively. The structure-activity relationship is discussed. Of the tested compounds, 4 and 7s displayed significant antifungal activity against F. graminearum, with inhibition rates of 100% at a concentration of 50 μg/mL. Compounds 5, 7s, and 7t showed the best inhibitory activity against all the tested bacteria, with minimum inhibitory concentrations (MICs) between 3.91 and 31.25 μg/mL. Thus, 7s emerged as a promising lead compound for the development of novel canthine-6-one antimicrobial agents. PMID:27007362

  1. Discovery of novel diaryl urea derivatives bearing a triazole moiety as potential antitumor agents.

    PubMed

    Qin, Mingze; Yan, Shuang; Wang, Lei; Zhang, Haotian; Zhao, Yanfang; Wu, Shasha; Wu, Di; Gong, Ping

    2016-06-10

    Herein, we report a novel series of diaryl urea derivatives bearing a triazole moiety, from which potent antitumor agents have been identified. With a modified triazole, most compounds showed high level activity in both cellular and enzymatic assays, accompanied with a suitable ClogD7.4 value. The most active compound, 13i, effectively suppressed proliferation of HT-29, H460 and MDA-MB-231 cancer cells, with IC50 values of 0.90, 0.85 and 1.54 μM, respectively. Compound 13i also exhibited significant inhibition of tyrosine kinases including c-Kit, RET and FLT3. Furthermore, compound 13i could obviously induce apoptosis of HT-29 cells in a concentration-dependent manner. The study of structure-activity relationships also revealed that a hydrophilic tail at the 4-position of the triazole was crucial for high activity of the compound. PMID:26991938

  2. Potentials and limits for the use of ozone as a fish disease control agent

    USGS Publications Warehouse

    Wedemeyer, Gary A.; Nelson, Nancy C.; Yasutake, Wm. T.

    1979-01-01

    Ozone and chlorine inactivation curves were determined in three types of freshwater at 20 C for the destruction of the fish pathogens Aeromonas salmonicida the etiologic agent of furunculosis, and Yersinia ruckeri the enteric redmouth bacterium (ERM). Ozone and chlorine inactivation curves were also obtained in the same water types at 10 C for the fish pathogenic viruses infectious hematopoietic necrosis (IHNV), and infectious pancreatic necrosis (IPNV). Acute toxicity tests using the rainbow trout as a representative salmonid revealed that ozone was highly toxic at the dose levels used. Partial chronic (3. mo.) testing revealed that ozone exposure at 2 μg/L causes only minimal physiological changes, none of which would be expected to compromise biological function.

  3. Potent and Orally Bioavailable Antiplatelet Agent, PLD-301, with the Potential of Overcoming Clopidogrel Resistance

    PubMed Central

    Chen, Jingyu; Wang, Michael Zhiyan

    2016-01-01

    PLD-301, a phosphate prodrug of clopidogrel thiolactone discovered by Prelude Pharmaceuticals with the aim to overcome clopidogrel resistance, was evaluated for its in vivo inhibitory effect on ADP-induced platelet aggregation in rats. The potency of PLD-301 was similar to that of prasugrel, but much higher than that of clopidogrel. The results of pharmacokinetic analysis showed that the oral bioavailability of clopidogrel thiolactone converted from PLD-301 was 4- to 5-fold higher than that of the one converted from clopidogrel, suggesting that in comparison with clopidogrel, lower doses of PLD-301 could be used clinically. In summary, PLD-301 presents a potent and orally bioavailable antiplatelet agent that might have some advantages over clopidogrel, such as overcoming clopidogrel resistance for CYP2C19-allele loss-of-function carriers, and lowering dose-related toxicity due to a much lower effective dose.

  4. Potential of medicinal plants as antimicrobial and antioxidant agents in food industry: a hypothesis.

    PubMed

    Ortega-Ramirez, Luis Alberto; Rodriguez-Garcia, Isela; Leyva, Juan Manuel; Cruz-Valenzuela, Manuel Reynaldo; Silva-Espinoza, Brenda Adriana; Gonzalez-Aguilar, Gustavo A; Siddiqui, Wasim; Ayala-Zavala, Jesus Fernando

    2014-02-01

    Many food preservation strategies can be used for the control of microbial spoilage and oxidation; however, these quality problems are not yet controlled adequately. Although synthetic antimicrobial and antioxidant agents are approved in many countries, the use of natural safe and effective preservatives is a demand of food consumers and producers. This paper proposes medicinal plants, traditionally used to treat health disorders and prevent diseases, as a source of bioactive compounds having food additive properties. Medicinal plants are rich in terpenes and phenolic compounds that present antimicrobial and antioxidant properties; in addition, the literature revealed that these bioactive compounds extracted from other plants have been effective in food systems. In this context, the present hypothesis paper states that bioactive molecules extracted from medicinal plants can be used as antimicrobial and antioxidant additives in the food industry. PMID:24446991

  5. Assessment of oligogalacturonide from citrus pectin as a potential antibacterial agent against foodborne pathogens.

    PubMed

    Wu, Ming-Chang; Li, Hui-chin; Wu, Po-Hua; Huang, Ping-Hsiu; Wang, Yuh-Tai

    2014-08-01

    Foodborne diseases are an important public health problem in the world. The bacterial resistance against presently used antibiotics is becoming a public health issue; hence, the discovery of new antimicrobial agents from natural sources attracts a lot of attention. Antibacterial activities of oligogalacturonide from commercial microbial pectic enzyme (CPE) treated citrus pectin, which exhibits antioxidant and antitumor activities, against 4 foodborne pathogens including Salmonella Typhimurium, Staphylococcus aureus, Listeria monocytogenes, and Pseudomonas aeruginosa was assessed. Pectin hydrolysates from CPE hydrolysis exhibited antibacterial activities. However, no antibacterial activity of pectin was observed. Citrus oligogalacturonide from 24-h hydrolysis exhibited bactericidal effect against all selected foodborne pathogens and displayed minimal inhibitory concentration at 37.5 μg/mL for P. aeruginosa, L. monocytogenes, and S. Typhimurium, and at 150.0 μg/mL for S. aureus. PMID:25048440

  6. Novel hederagenin-triazolyl derivatives as potential anti-cancer agents.

    PubMed

    Rodríguez-Hernández, Diego; Demuner, Antonio J; Barbosa, Luiz C A; Heller, Lucie; Csuk, René

    2016-06-10

    A series of novel aryl-1H-1,2,3-triazol-4-yl methylester and amide derivatives of the natural product hederagenin was synthesized aiming to develop new antitumor agents, using Huisgen 1,3-dipolar cycloaddition reactions, with yields between 35% and 95%. The structures of all derivatives (2-31) were confirmed by MS, IR, (1)H NMR and (13)C NMR spectroscopic data. The cytotoxic activities of all compounds were screened against a panel of six human cancer cell lines using SRB assay. It was found that most of the compounds displayed higher levels of antitumor activities as compared to parent hederagenin. Compounds 4, 8 and 15 were the most potent against all human cancer cell lines. Furthermore, compound 11 was the most cytotoxic against cell HT29 showing EC50 = 1.6 μM and a selectivity index of 5.4. PMID:27017553

  7. Potential new approaches for the development of brain imaging agents for single-photon applications

    SciTech Connect

    Knapp, F.F. Jr.; Srivastava, P.C.

    1984-01-01

    This paper describes new strategies for the brain-specific delivery of radionuclides that can be used to evaluate regional cerebral perfusion by single photon imaging techniques. A description of several examples of interesting new strategies that have recently been reported is presented. A new approach at this institution for the brain-specific delivery of radioiodinated iodophenylalkyl-substituted dihyronicotinamide systems is described which shows good brain uptake and retention in preliminary studies in rats. Following transport into the brain these agents appear to undergo facile intracerebral oxidation to the quaternized analogues which do not recross the intact blood-brain barrier and so are effectively trapped in the brain. 49 refs., 9 figs., 1 tab.

  8. Novel capsaicin analogues as potential anticancer agents: synthesis, biological evaluation, and in silico approach.

    PubMed

    Damião, Mariana C F C B; Pasqualoto, Kerly F M; Ferreira, Adilson K; Teixeira, Sarah F; Azevedo, Ricardo A; Barbuto, José A M; Palace-Berl, Fanny; Franchi-Junior, Gilberto C; Nowill, Alexandre E; Tavares, Maurício T; Parise-Filho, Roberto

    2014-12-01

    A novel class of benzo[d][1,3]dioxol-5-ylmethyl alkyl/aryl amide and ester analogues of capsaicin were designed, synthesized, and evaluated for their cytotoxic activity against human and murine cancer cell lines (B16F10, SK-MEL-28, NCI-H1299, NCI-H460, SK-BR-3, and MDA-MB-231) and human lung fibroblasts (MRC-5). Three compounds (5f, 6c, and 6e) selectively inhibited the growth of aggressive cancer cells in the micromolar (µM) range. Furthermore, an exploratory data analysis pointed at the topological and electronic molecular properties as responsible for the discrimination process regarding the set of investigated compounds. The findings suggest that the applied designing strategy, besides providing more potent analogues, indicates the aryl amides and esters as well as the alkyl esters as interesting scaffolds to design and develop novel anticancer agents. PMID:25283529

  9. Complete Genome Sequence Analysis of Two Pseudomonas plecoglossicida Phages, Potential Therapeutic Agents

    PubMed Central

    Yasuike, Motoshige; Nakamura, Yoji; Shigenobu, Yuya; Fujiwara, Atushi; Sano, Motohiko; Nakai, Toshihiro

    2014-01-01

    Pseudomonas plecoglossicida is a lethal pathogen of ayu (Plecoglossus altivelis) in Japan and is responsible for substantial economic costs to ayu culture. Previously, we demonstrated the efficacy of phage therapy against P. plecoglossicida infection using two lytic phages (PPpW-3 and PPpW-4) (S. C. Park, I. Shimamura, M. Fukunaga, K. Mori, and T. Nakai, Appl Environ Microbiol 66:1416–1422, 2000, http://dx.doi.org/10.1128/AEM.66.4.1416-1422.2000; S. C. Park and T. Nakai, Dis Aquat Org 53:33–39, 2003, http://dx.doi.org/10.3354/dao053033). In the present study, the complete genome sequences of these therapeutic P. plecoglossicida phages were determined and analyzed for deleterious factors as therapeutic agents. The genome of PPpW-3 (myovirus) consisted of 43,564 bp with a GC content of 61.1% and 66 predicted open reading frames (ORFs). Approximately half of the genes were similar to the genes of the Escherichia coli phage vB_EcoM_ECO1230-10 (myovirus). The genome of PPpW-4 (podovirus) consisted of 41,386 bp with a GC content of 56.8% and 50 predicted ORFs. More than 70% of the genes were similar to the genes of Pseudomonas fluorescens phage ϕIBB-PF7A and Pseudomonas putida phage ϕ15 (podoviruses). The whole-genome analysis revealed that no known virulence genes were present in PPpW-3 and PPpW-4. An integrase gene was found in PPpW-3, but other factors used for lysogeny were not confirmed. The PCR detection of phage genes in phage-resistant variants provided no evidence of lysogenic activity in PPpW-3 and PPpW-4. We conclude that these two lytic phages qualify as therapeutic agents. PMID:25416766

  10. Complete genome sequence analysis of two Pseudomonas plecoglossicida phages, potential therapeutic agents.

    PubMed

    Kawato, Yasuhiko; Yasuike, Motoshige; Nakamura, Yoji; Shigenobu, Yuya; Fujiwara, Atushi; Sano, Motohiko; Nakai, Toshihiro

    2015-02-01

    Pseudomonas plecoglossicida is a lethal pathogen of ayu (Plecoglossus altivelis) in Japan and is responsible for substantial economic costs to ayu culture. Previously, we demonstrated the efficacy of phage therapy against P. plecoglossicida infection using two lytic phages (PPpW-3 and PPpW-4) (S. C. Park, I. Shimamura, M. Fukunaga, K. Mori, and T. Nakai, Appl Environ Microbiol 66:1416-1422, 2000, http://dx.doi.org/10.1128/AEM.66.4.1416-1422.2000; S. C. Park and T. Nakai, Dis Aquat Org 53:33-39, 2003, http://dx.doi.org/10.3354/dao053033). In the present study, the complete genome sequences of these therapeutic P. plecoglossicida phages were determined and analyzed for deleterious factors as therapeutic agents. The genome of PPpW-3 (myovirus) consisted of 43,564 bp with a GC content of 61.1% and 66 predicted open reading frames (ORFs). Approximately half of the genes were similar to the genes of the Escherichia coli phage vB_EcoM_ECO1230-10 (myovirus). The genome of PPpW-4 (podovirus) consisted of 41,386 bp with a GC content of 56.8% and 50 predicted ORFs. More than 70% of the genes were similar to the genes of Pseudomonas fluorescens phage ϕIBB-PF7A and Pseudomonas putida phage ϕ15 (podoviruses). The whole-genome analysis revealed that no known virulence genes were present in PPpW-3 and PPpW-4. An integrase gene was found in PPpW-3, but other factors used for lysogeny were not confirmed. The PCR detection of phage genes in phage-resistant variants provided no evidence of lysogenic activity in PPpW-3 and PPpW-4. We conclude that these two lytic phages qualify as therapeutic agents. PMID:25416766

  11. Potentiating effects of caffeine on teratogenicity of alkylating agents in mice

    SciTech Connect

    Fujii, T.; Nakatsuka, T.

    1983-08-01

    Teratogenic to subteratogenic doses of x-ray, mitomycin C, MNNG, thio-TEPA, cyclophosphamide, and chlorambucil were administered to pregnant ICR mice together with caffeine at doses of 12.5, 25, or 50 mg/kg on day 11 of gestation. Fetuses were examined for gross malformations on day 18 of gestation. The teratogenicity of mitomycin C was significantly potentiated by caffeine at a dose as low as 12.5 mg/kg. The teratogenicity of chlorambucil was also significantly potentiated by caffeine at 50 mg/kg, but similar potentiation was not observed for x-ray, MNNG, thio-TEPA, and cyclophosphamide.

  12. Tert-butyl benzoquinone: mechanism of biofilm eradication and potential for use as a topical antibiofilm agent

    PubMed Central

    Ooi, N.; Eady, E. A.; Cove, J. H.; O'Neill, A. J.

    2016-01-01

    Objectives Tert-butyl benzoquinone (TBBQ) is the oxidation product of tert-butyl hydroquinone (TBHQ), an antimicrobial food additive with >40 years of safe use. TBBQ displays potent activity against Staphylococcus aureus biofilms in vitro. Here, we report on studies to further explore the action of TBBQ on staphylococcal biofilms, and provide a preliminary preclinical assessment of its potential for use as a topical treatment for staphylococcal infections involving a biofilm component. Methods The antibacterial properties of TBBQ were assessed against staphylococci growing in planktonic culture and as biofilms in the Calgary Biofilm Device. Established assays were employed to measure the effects of TBBQ on biofilm structure and bacterial membranes, and to assess resistance potential. A living-skin equivalent was used to evaluate the effects of TBBQ on human skin. Results TBBQ eradicated biofilms of S. aureus and other staphylococcal species at concentrations ≤64 mg/L. In contrast to other redox-active agents exhibiting activity against biofilms, TBBQ did not cause substantial destructuring of the biofilm matrix; instead, the antibiofilm activity of the compound was attributed to its ability to kill slow- and non-growing cells via membrane perturbation. TBBQ acted synergistically with gentamicin, did not damage a living-skin equivalent following topical application and exhibited low resistance potential. Conclusions The ability of TBBQ to eradicate biofilms appears to result from its ability to kill bacteria regardless of growth state. Preliminary evaluation suggests that TBBQ represents a promising candidate for development as a topical antibiofilm agent. PMID:27121399

  13. Synthesis and in vitro evaluation of 4-substituted furano[3,2-c] tetrahydroquinolines as potential anti-cancer agents.

    PubMed

    Chen, Can; Zingales, Sarah; Wang, Ting; Yuan, Mingyong; Wang, Dan; Cai, Lulu; Jiang, Qinglin

    2016-10-01

    A convenient and mild method for the synthesis of substituted furano [3,2-c]tetrahydroquinoline derivatives was developed, using the multi-component Povarov reaction. Of the synthesized tetrahydroquinoline derivatives, compound 10a displayed the greatest cellular proliferation inhibitory activities with IC50 values of 2.5-16.7 μmol/l. In addition, 10a induced murine C6 glioma cell apoptosis in a dose-dependent manner by up-regulating the expression of Bax, caspase-3, and caspase-9, and by down-regulating Bcl-2. Our findings suggest that these novel compounds have potential as therapeutic agents via inducing mitochondrial apoptosis. PMID:26207511

  14. Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

    PubMed

    Bajda, Marek; Jończyk, Jakub; Malawska, Barbara; Czarnecka, Kamila; Girek, Małgorzata; Olszewska, Paulina; Sikora, Joanna; Mikiciuk-Olasik, Elżbieta; Skibiński, Robert; Gumieniczek, Anna; Szymański, Paweł

    2015-09-01

    A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4-dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid β aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases (EeAChE, EqBChE) with IC50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC50 = 19 nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced Aβ 1-42 aggregation (80.6% and 91.3% at 50 μM and 100 μM screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD. PMID:26242241

  15. Anti-Heparanase Aptamers as Potential Diagnostic and Therapeutic Agents for Oral Cancer

    PubMed Central

    Silva, Dilson; Cortez, Celia M.; McKenzie, Edward A.; Bitu, Carolina C.; Salo, Sirpa; Nurmenniemi, Sini; Nyberg, Pia; Risteli, Juha; deAlmeida, Carlos E. B.; Brenchley, Paul E. C.; Salo, Tuula; Missailidis, Sotiris

    2014-01-01

    Heparanase is an endoglycosidase enzyme present in activated leucocytes, mast cells, placental tissue, neutrophils and macrophages, and is involved in tumour metastasis and tissue invasion. It presents a potential target for cancer therapies and various molecules have been developed in an attempt to inhibit the enzymatic action of heparanase. In an attempt to develop a novel therapeutic with an associated diagnostic assay, we have previously described high affinity aptamers selected against heparanase. In this work, we demonstrated that these anti-heparanase aptamers are capable of inhibiting tissue invasion of tumour cells associated with oral cancer and verified that such inhibition is due to inhibition of the enzyme and not due to other potentially cytotoxic effects of the aptamers. Furthermore, we have identified a short 30 bases aptamer as a potential candidate for further studies, as this showed a higher ability to inhibit tissue invasion than its longer counterpart, as well as a reduced potential for complex formation with other non-specific serum proteins. Finally, the aptamer was found to be stable and therefore suitable for use in human models, as it showed no degradation in the presence of human serum, making it a potential candidate for both diagnostic and therapeutic use. PMID:25295847

  16. Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents.

    PubMed

    Grover, Gaurav; Kini, Suvarna G

    2006-02-01

    In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H(2)SO(4) and fuming HNO(3). Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, (1)H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative

  17. The evidence for natural therapeutics as potential anti-scarring agents in burn-related scarring.

    PubMed

    Mehta, M; Branford, O A; Rolfe, K J

    2016-01-01

    Though survival rate following severe thermal injuries has improved, the incidence and treatment of scarring have not improved at the same speed. This review discusses the formation of scars and in particular the formation of hypertrophic scars. Further, though there is as yet no gold standard treatment for the prevention or treatment of scarring, a brief overview is included. A number of natural therapeutics have shown beneficial effects both in vivo and in vitro with the potential of becoming clinical therapeutics in the future. These natural therapeutics include both plant-based products such as resveratrol, quercetin and epigallocatechin gallate as examples and includes the non-plant-based therapeutic honey. The review also includes potential mechanism of action for the therapeutics, any recorded adverse events and current administration of the therapeutics used. This review discusses a number of potential 'treatments' that may reduce or even prevent scarring particularly hypertrophic scarring, which is associated with thermal injuries without compromising wound repair. PMID:27574685

  18. Preclinical evaluation of perifosine as a potential promising anti-rhabdomyosarcoma agent.

    PubMed

    Shen, Jie; Hong, Yue; Zhao, Qiong; Zhang, Jian-Li

    2016-01-01

    Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer that arises from the skeletal muscle. Recent studies have identified an important role of AKT signaling in RMS progression. In the current study, we investigated the activity of perifosine, an oral alkylphospholipid AKT inhibitor, against human RMS cells (RD and Rh-30 lines) both in vivo and in vitro, and studied the underlying mechanisms. We showed that perifosine significantly inhibited RMS cell growth in concentration- and time-dependent manners. Meanwhile, perifosine induced dramatic apoptosis in RMS cells. At the signaling level, perifosine blocked AKT activation, while inducing reactive oxygen species (ROS) production as well as JNK and P38 phosphorylations in RMS cells. Restoring AKT activation by introducing a constitutively active-AKT (CA-AKT) only alleviated (not abolished) perifosine-induced cytotoxicity in RD cells. Yet, the ROS scavenger N-acetyl cysteine (NAC) as well as pharmacological inhibitors against JNK (SP-600125) or P38 (SB-203580) suppressed perifosine-induced cytotoxicity in RMS cells. Thus, perifosine induces growth inhibition and apoptosis in RMS cells through mechanisms more than just blocking AKT. In vivo, oral administration of perifosine significantly inhibited growth of Rh-30 xenografts in severe combined immunodeficient (SCID) mice. Our data indicate that perifosine might be further investigated as a promising anti-RMS agent. PMID:26269112

  19. The preliminary evaluation of Mn DTPA as a potential contrast agent for nuclear magnetic resonance imaging.

    PubMed

    Boudreau, R J; Frick, M P; Levey, R M; Lund, G; Sirr, S A; Loken, M K

    1986-01-01

    The pharmacokinetics of 54Mn administered as Mn-diethylenetriamine pentaacetic acid (DTPA) are being investigated to determine if tissue-specific uptake of manganese could be observed while increasing urinary excretion. This chelation and increased excretion should reduce toxicity. In order to obviate the need for repetitive quantitative nuclear magnetic resonance imaging (NMR) we have substituted tracer amounts of a radioisotope of manganese, Mn-54, for the stable ion. By 6 hours, 58 +/- 7% of the injected dose had been excreted in the urine. Peak liver accumulation occurred within 30 minutes (0.50 +/- 0.14% injected dose/g X kg body weight). The pancreas also showed a relatively high accumulation of tracer (0.25 +/- 0.04%/g X kg body weight), reaching a peak at 4 hours. The pancreas to liver ratios were highest at 6 hours (0.7). There was also a substantial accumulation of the manganese in bile. The blood concentration fell very rapidly with little tracer remaining in the blood at 1 hour. Based on these pharmacokinetics, imaging experiments were conducted before, immediately after, and 9 or 24 hours postinjection. These images showed enhanced kidneys and, later (at 9 hours), an excellent parenchymal-collecting system differentiation. The gallbladder was negatively enhanced. The liver showed either increased or decreased signal strength relative to skeletal muscle depending on the pulse sequence used. We conclude that Mn++, administered as Mn-DTPA, merits further investigation as an NMR contrast agent. PMID:3451753

  20. Recombinant L-Asparaginase from Zymomonas mobilis: A Potential New Antileukemic Agent Produced in Escherichia coli

    PubMed Central

    Pereira, Juliana Christina Castanheira Vicente; Costa-Amaral, Isabele Campos; da Costa, Elaine Sobral; Ribeiro, Maria Cecília Menks; Land, Marcelo Gerardin Poirot; Alves, Tito Lívio Moitinho; Larentis, Ariane Leites; Almeida, Rodrigo Volcan

    2016-01-01

    L-asparaginase is an enzyme used as a chemotherapeutic agent, mainly for treating acute lymphoblastic leukemia. In this study, the gene of L-asparaginase from Zymomonas mobilis was cloned in pET vectors, fused to a histidine tag, and had its codons optimized. The L-asparaginase was expressed extracellularly and intracellularly (cytoplasmically) in Escherichia coli in far larger quantities than obtained from the microorganism of origin, and sufficient for initial cytotoxicity tests on leukemic cells. The in silico analysis of the protein from Z. mobilis indicated the presence of a signal peptide in the sequence, as well as high identity to other sequences of L-asparaginases with antileukemic activity. The protein was expressed in a bioreactor with a complex culture medium, yielding 0.13 IU/mL extracellular L-asparaginase and 3.6 IU/mL intracellular L-asparaginase after 4 h of induction with IPTG. The cytotoxicity results suggest that recombinant L-asparaginase from Z. mobilis expressed extracellularly in E.coli has a cytotoxic and cytostatic effect on leukemic cells. PMID:27253887

  1. Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001

    PubMed Central

    Ning, Shoucheng; Sekar, Thillai Veerapazham; Scicinski, Jan; Oronsky, Bryan; Peehl, Donna M.; Knox, Susan J.; Paulmurugan, Ramasamy

    2015-01-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulatory transcription factor that plays an important role in the antioxidant response pathway against anticancer drug-induced cytotoxic effects. RRx-001 is a new anticancer agent that generates reactive oxygen and nitrogen species, and leads to epigenetic alterations in cancer cells. Here we report the RRx-001 mediated nuclear translocation of Nrf2 and the activation of expression of its downstream enzymes HO-1 and NQO1 in tumor cells. Inhibition of intrinsic Nrf2 expression by Nrf2-specific siRNA increased cell sensitivity to RRx-001. Molecular imaging of tumor cells co-expressing pARE-Firefly luciferase and pCMV-Renilla luciferase-mRFP in vitro and in vivo in mice revealed that RRx-001 significantly increased ARE-FLUC signal in cells in a dose- and time-dependent manner, suggesting that RRx-001 is an effective activator of the Nrf2-ARE signaling pathway. The pre-treatment level of ARE-FLUC signal in cells, reflecting basal activity of Nrf2, negatively correlated with the tumor response to RRx-001. The results support the concept that RRx-001 activates Nrf2-ARE antioxidant signaling pathways in tumor cells. Hence measurement of Nrf2-mediated activation of downstream target genes through ARE signaling may constitute a useful molecular biomarker for the early prediction of response to RRx-001 treatment, and thereby guide therapeutic decision-making. PMID:26280276

  2. The potential role of antiplatelet agents in modulating inflammatory markers in atherothrombosis.

    PubMed

    Yeh, E T H; Khan, B V

    2006-11-01

    Atherothrombosis is the process that links atherosclerotic lesion development with unpredictable and life-threatening ischemic vascular events such as angina, myocardial infarction, transient ischemic attack, and stroke. Atherothrombosis is triggered when an unstable atherosclerotic lesion is ruptured, leading to platelet activation and thrombus formation. Inflammatory mediators are responsible for lesion instability leading to rupture, and in recent years atherothrombosis and its underlying condition of atherosclerosis have come to be recognized as manifestations of inflammatory disease. Inflammatory mediators may therefore serve as early markers of atherothrombosis. Measurement of early markers may be used to predict future ischemic events and improve risk stratification in patients following diagnosis of atherothrombotic disease. In addition, detection of such markers may help to optimize the use of current therapies to manage atherothrombosis. Molecules that may serve as early markers of atherothrombotic disease include C-reactive protein, CD40 ligand, myeloperoxidase, pregnancy-associated plasma protein and plasminogen activator inhibitor-1. Early indications are that levels of these markers are influenced by therapies currently in use in the treatment of atherothrombotic conditions, including antiplatelet agents. Ongoing studies will provide further insight into routine assessment of inflammatory markers as a guide to the management of patients with atherothrombosis. PMID:16961584

  3. Psoralea glandulosa as a Potential Source of Anticancer Agents for Melanoma Treatment

    PubMed Central

    Madrid, Alejandro; Cardile, Venera; González, César; Montenegro, Ivan; Villena, Joan; Caggia, Silvia; Graziano, Adriana; Russo, Alessandra

    2015-01-01

    With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on melanoma cancer, the present study was undertaken to investigate the biological activity of the resinous exudate of aerial parts from Psoralea glandulosa, and its active components (bakuchiol (1), 3-hydroxy-bakuchiol (2) and 12-hydroxy-iso-bakuchiol (3)) against melanoma cells (A2058). In addition, the effect in cancer cells of bakuchiol acetate (4), a semi-synthetic derivative of bakuchiol, was examined. The results obtained show that the resinous exudate inhibited the growth of cancer cells with IC50 value of 10.5 μg/mL after 48 h of treatment, while, for pure compounds, the most active was the semi-synthetic compound 4. Our data also demonstrate that resin is able to induce apoptotic cell death, which could be related to an overall action of the meroterpenes present. In addition, our data seem to indicate that the apoptosis correlated to the tested products appears, at least in part, to be associated with an increase of reactive oxygen species (ROS) production. In summary, our study provides the first evidence that P. glandulosa may be considered a source of useful molecules in the development of analogues with more potent efficacy against melanoma cells. PMID:25860949

  4. Recombinant L-Asparaginase from Zymomonas mobilis: A Potential New Antileukemic Agent Produced in Escherichia coli.

    PubMed

    Einsfeldt, Karen; Baptista, Isis Cavalcante; Pereira, Juliana Christina Castanheira Vicente; Costa-Amaral, Isabele Campos; Costa, Elaine Sobral da; Ribeiro, Maria Cecília Menks; Land, Marcelo Gerardin Poirot; Alves, Tito Lívio Moitinho; Larentis, Ariane Leites; Almeida, Rodrigo Volcan

    2016-01-01

    L-asparaginase is an enzyme used as a chemotherapeutic agent, mainly for treating acute lymphoblastic leukemia. In this study, the gene of L-asparaginase from Zymomonas mobilis was cloned in pET vectors, fused to a histidine tag, and had its codons optimized. The L-asparaginase was expressed extracellularly and intracellularly (cytoplasmically) in Escherichia coli in far larger quantities than obtained from the microorganism of origin, and sufficient for initial cytotoxicity tests on leukemic cells. The in silico analysis of the protein from Z. mobilis indicated the presence of a signal peptide in the sequence, as well as high identity to other sequences of L-asparaginases with antileukemic activity. The protein was expressed in a bioreactor with a complex culture medium, yielding 0.13 IU/mL extracellular L-asparaginase and 3.6 IU/mL intracellular L-asparaginase after 4 h of induction with IPTG. The cytotoxicity results suggest that recombinant L-asparaginase from Z. mobilis expressed extracellularly in E.coli has a cytotoxic and cytostatic effect on leukemic cells. PMID:27253887

  5. EDTA as a potential agent preventing formation of Staphylococcus epidermidis biofilm on polichloride vinyl biomaterials.

    PubMed

    Juda, Marek; Paprota, Katarzyna; Jałoza, Dariusz; Malm, Anna; Rybojad, Paweł; Goździuk, Kazimierz

    2008-01-01

    Polichloride vinyl (PCV) is a widely used thermoplastic polymer, also in the production of medical devices. In the present study we assess the influence of EDTA in vitro on the biofilm structure formed by Staphylococcus epidermidis isolates on PCV biomaterials (Nelaton and Thorax catheters). The 6 strains of S. epidermidis were isolated from nasopharynx of hospitalised patients. It was found that all isolates were able to form the biofilm on both PCV biomaterials, irrespective of adhesion properties (cell surface properties, ability to slime production, minimal time needed for adhesion). The EDTA showed bacteriostatic effect against planktonic cells of the isolates (MIC = 0.25-0.5 mmol/l; MBC = 10.0- >25.0 mmol/l; MBC/MIC = 20, 30, 40, >50). The adhesion process and also formation of the biofilm was inhibited by EDTA at concentrations 1.0-2.0 mmol/l (2-8 x MIC). The eradication of the mature biofilm was achieved at 2.0-4.0 mmol/l EDTA (4-8 x MIC ) for two strains, while for the other four isolates, concentration of EDTA needed for eradication effect was >32 mmol/l (> 128 x MIC ). Data obtained in this paper suggest that EDTA may be regarded as a useful agent preventing formation of the S. epidermidis biofilm on PCV biomaterials. PMID:19118444

  6. Purification of an antifungal endochitinase from a potential biocontrol Agent Streptomyces griseus.

    PubMed

    Rabeeth, M; Anitha, A; Srikanth, Geetha

    2011-08-15

    Streptomyces griseus (MTCC 9723) is a chitinolytic bacterium isolated from prawn cultivated pond soil of Peddapuram Village; East Godavari District was studied in detailed. Chitinase (EC 3.2.1.14) was extracted from the culture filtrate of Streptomyces griseus and purified by ammonium sulfate precipitation, DEAE-cellulose ionexchange chromatography, Sephadex G-100 and Sephadex G-200 gel filtration chromatography. The molecular mass of the purified chitinase was estimated to be 34, 32 kDa by SDS gel electrophoresis and confirmed by activity staining with Calcofluor White M2R. Chitinase was optimally active at pH of 6.0 and at 40 degrees C. The enzyme was stable from pH 5-9 and up to 20-50 degrees C. The chitinase exhibited Km and Vmax values of 400 mg and 180 IU mL(-1) for colloidal chitin. Among the metals and inhibitors that were tested, the Hg+, Hg2+ and P-chloromercuribenzoic acid completely inhibited the chitinase activity at 1 mM concentration. The purified chitinase showed high activity on colloidal chitin, chitobiose, and chitooligosaccharide. An in vitro assay proved that the crude chitinase, actively growing cells of S. griseus having antifungal activity against all studied fungal pathogen. This result implies that characteristics of S. griseus producing endochitinase made them suitable for biotechnological purpose such as for degradation of chitin containing waste and it might be a promising biocontrol agent for plant pathogens. PMID:22545353

  7. Aptamer-conjugated, fluorescent gold nanorods as potential cancer theradiagnostic agents.

    PubMed

    Gallina, Maria Elena; Zhou, Yu; Johnson, Christopher J; Harris-Birtill, David; Singh, Mohan; Zhao, Hailin; Ma, Daqing; Cass, Tony; Elson, Daniel S

    2016-02-01

    GNRs are emerging as a new class of probes for theradiagnostic applications thanks to their unique optical properties. However, the achievement of proper nanoconstructs requires the synthesis of highly pure GNRs with well-defined aspect ratio (AR), in addition to extensive surface chemistry modification to provide them with active targeting and, possibly, multifunctionality. In this work, we refined the method of the seed mediated growth and developed a robust procedure for the fabrication of GNRs with specific AR. We also revealed and characterized unexplored aging phenomena that follow the synthesis and consistently alter GNRs' final AR. Such advances appreciably improved the feasibility of GNRs fabrication and offered useful insights on the growth mechanism. We next produced fluorescent, biocompatible, aptamer-conjugated GNRs by performing ligand exchange followed by bioconjugation to anti-cancer oligonucleotide AS1411. In vitro studies showed that our nanoconstructs selectively target cancer cells while showing negligible cytotoxicity. As a result, our aptamer-conjugated GNRs constitute ideal cancer-selective multifunctional probes and promising candidates as photothermal therapy agents. PMID:26652380

  8. Plant growth-promoting rhizobacteria (PGPR): Their potential as antagonists and biocontrol agents

    PubMed Central

    Beneduzi, Anelise; Ambrosini, Adriana; Passaglia, Luciane M.P.

    2012-01-01

    Bacteria that colonize plant roots and promote plant growth are referred to as plant growth-promoting rhizobacteria (PGPR). PGPR are highly diverse and in this review we focus on rhizobacteria as biocontrol agents. Their effects can occur via local antagonism to soil-borne pathogens or by induction of systemic resistance against pathogens throughout the entire plant. Several substances produced by antagonistic rhizobacteria have been related to pathogen control and indirect promotion of growth in many plants, such as siderophores and antibiotics. Induced systemic resistance (ISR) in plants resembles pathogen-induced systemic acquired resistance (SAR) under conditions where the inducing bacteria and the challenging pathogen remain spatially separated. Both types of induced resistance render uninfected plant parts more resistant to pathogens in several plant species. Rhizobacteria induce resistance through the salicylic acid-dependent SAR pathway, or require jasmonic acid and ethylene perception from the plant for ISR. Rhizobacteria belonging to the genera Pseudomonas and Bacillus are well known for their antagonistic effects and their ability to trigger ISR. Resistance-inducing and antagonistic rhizobacteria might be useful in formulating new inoculants with combinations of different mechanisms of action, leading to a more efficient use for biocontrol strategies to improve cropping systems. PMID:23411488

  9. Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents.

    PubMed

    Dar, Bilal Ahmad; Lone, Ali Mohd; Shah, Wajaht Amin; Qurishi, Mushtaq Ahmad

    2016-03-23

    Ursolic acid present abundantly in plant kingdom is a well-known compound with various promising biological activities including, anti-cancer, anti-inflammatory, hepatoprotective, antiallergic and anti-HIV properties. Herein, a library of ursolic acid-benzylidine derivatives have been designed and synthesized using Claisen Schmidt condensation of ursolic acid with various aromatic aldehydes in an attempt to develop potent antitumor agents. The compounds were evaluated against a panel of four human carcinoma cell lines including, A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2). The results from MTT assay revealed that all the compounds displayed high level of antitumor activities compared with the triazole analogs (previously reported) and the parent ursolic acid. However, compound 3b, the most active derivative was subjected to mechanistic studies to understand the underlying mechanism. The results revealed that compound 3b induced apoptosis in HCT-116 cell lines, arrest cell cycle in the G1 phase, caused accumulation of cytochrome c in the cytosol and increased the expression levels of caspase-9 and caspase-3 proteins. Therefore, compound 3b induces apoptosis in HCT-116 cells through mitochondrial pathway. PMID:26854375

  10. 75 FR 43184 - Transport of Laboratory Personnel Potentially Exposed to Infectious Agents From Fort Detrick...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-23

    ... the Federal Register (73 FR 35145) announcing its intent to prepare the NIH Transportation EIS and... Register on May 22, 2009 (74 FR 24006). The formal comment period for the Draft NIH Transportation EIS.... Potential impacts on air quality and noise levels are all within government standards (Federal, state,...

  11. Heterapoderopsis bicallosicollis (Coleoptera: Attelabidae): A Potential Biological Control Agent for Triadeca sebifera

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Native to China, Chinese tallow, Triadica sebifera (L.) Small (Euphorbiaceae), is an invasive plant in the southeastern United States of America. The leaf-rolling weevil, Apoderus bicallosicollis Voss is a common herbivore attacking the plant in China. To evaluate its potential as a biological contr...

  12. Gadolinium(III)-loaded nanoparticulate zeolites as potential high-field MRI contrast agents: relationship between structure and relaxivity.

    PubMed

    Csajbók, Eva; Bányai, István; Vander Elst, Luce; Muller, Robert N; Zhou, Wuzong; Peters, Joop A

    2005-08-01

    The effects of dealumination, pore size, and calcination on the efficiency (as expressed in the relaxivity) of Gd3+-loaded zeolites for potential application as magnetic resonance imaging (MRI) contrast agents were studied. Partial dealumination of zeolites NaY or NaA by treatment with (NH4)2SiF6 or diluted HCl resulted in materials that, upon loading with Gd3+, had a much higher relaxivity than the corresponding non-dealuminated materials. Analysis of the 1H NMR dispersion profiles of the various zeolites showed that this can be mainly ascribed to an increase of the amount of water inside the zeolite cavities as a result of the destruction of walls between cavities. However, the average residence time of water inside the Gd3+-loaded cavities did not change significantly, which suggests that the windows of the Gd3+-loaded cavities are not affected by the dealumination. Upon calcination, the Gd3+ ions moved to the small sodalite cavities and became less accessible for water, resulting in a decrease in relaxivity. The important role of diffusion for the relaxivity was demonstrated by a comparison of the relaxivity of Gd3+-loaded zeolite NaY and NaA samples. NaA had much lower relaxivities due to the smaller pore sizes. The transversal relaxivities of the Gd3+-doped zeolites are comparable in magnitude to the longitudinal ones at low magnetic fields (<60 MHz). However at higher fields, the transversal relaxivities steeply increased, whereas the longitudinal relaxivities decreased as field strength increased. Therefore, these materials have potential as T1 MRI contrast agents at low field, and as T2 agents at higher fields. PMID:15929138

  13. Monoclonal antibody-targeted PEGylated liposome-ICG encapsulating doxorubicin as a potential theranostic agent.

    PubMed

    Lozano, Neus; Al-Ahmady, Zahraa S; Beziere, Nicolas S; Ntziachristos, Vasilis; Kostarelos, Kostas

    2015-03-30

    Indocyanine green (ICG) is an FDA-approved, strongly photo-absorbent/fluorescent probe that has been incorporated into a clinically-relevant PEGylated liposome as a flexible optoacoustic contrast agent platform. This study describes the engineering of targeted PEGylated liposome-ICG using the anti-MUC-1 "humanized" monoclonal antibody (MoAb) hCTM01 as a tumour-specific theranostic system. We aimed to visualise non-invasively the tumour accumulation of these MoAb-targeted liposomes over time in tumour-bearing mice using multispectral optoacoustic tomography (MSOT). Preferential accumulation of targeted PEGylated liposome-ICG was studied after intravenous administration in comparison to non-targeted PEGylated liposome-ICG using both fast growing (4T1) and slow growing (HT-29) MUC-1 positive tumour models. Monitoring liposomal ICG in the tumour showed that both targeted and non-targeted liposome-ICG formulations preferentially accumulated into the tumour models studied. Rapid accumulation was observed for targeted liposomes at early time points mainly in the periphery of the tumour volume suggesting binding to available MUC-1 receptors. In contrast, non-targeted PEGylated liposomes showed accumulation at the centre of the tumour at later time points. In an attempt to take this a step further, we successfully encapsulated the anticancer drug, doxorubicin (DOX) into both targeted and non-targeted PEGylated liposome-ICG. The engineering of DOX-loaded targeted ICG liposome systems present a novel platform for combined tumour-specific therapy and diagnosis. This can open new possibilities in the design of advanced image-guided cancer therapeutics. PMID:25445515

  14. Purpureocillium lilacinum, potential agent for biological control of the leaf-cutting ant Acromyrmex lundii.

    PubMed

    Goffré, D; Folgarait, P J

    2015-09-01

    Many leaf-cutter ant species are well known pests in Latin America, including species of the genera Acromyrmex and Atta. An environmentally friendly strategy to reduce the number of leafcutter ants and avoid indiscriminate use of chemical pesticides is biological control. In this work we evaluated the effectiveness of a strain of the entomopathogen Purpureocillium lilacinum, against worker ants from six Acromyrmex lundii field colonies, after immersions in pure suspensions at a concentration of 1×10(6)conidiaml(-1). Survival of ants treated with P. lilacinum was significantly lower than that recorded in controls, and median lethal time (LT50) was 6-7days. P. lilacinum was responsible for 85.6% (80.6-89.7) of the mortality in inoculated ants, in which we found that the percentage of other entomopathogens that naturally infected ants decreased also, suggesting a good competitive capability of the fungus. Horizontal transmission to non-inoculated ants was also evidenced, given that 58.5% (41.9-64.2) of them died because of P. lilacinum. Moreover, we tested pathogenicity for three concentrations of this strain (1.0×10(4), 10(6) and 10(8)conidiaml(-1)) and found a significantly faster mortality of ants and greater median percentage of infection at 10(8)conidiaml(-1) of P. lilacinum. CL50 value was 2.8×10(5)conidiaml(-1). We thus propose the use of P. lilacinum as a biological control agent of leafcutter ants in crops and plantations. PMID:26205173

  15. Novel quinolines carrying pyridine, thienopyridine, isoquinoline, thiazolidine, thiazole and thiophene moieties as potential anticancer agents.

    PubMed

    Ghorab, Mostafa M; Alsaid, Mansour S; Al-Dosari, Mohammed S; Ragab, Fatma A; Al-Mishari, Abdullah A; Almoqbil, Abdulaziz N

    2016-06-01

    As a part of ongoing studies in developing new anticancer agents, novel 1,2-dihydropyridine 4, thienopyridine 5, isoquinolines 6-20, acrylamide 21, thiazolidine 22, thiazoles 23-29 and thiophenes 33-35 bearing a biologically active quinoline nucleus were synthesized. The structure of newly synthesized compounds was confirmed on the basis of elemental analyses and spectral data. All the newly synthesized compounds were evaluated for their cytotoxic activity against the breast cancer cell line MCF7. 2,3-Dihydrothiazole-5-carboxamides 27, 25, 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (34), 1,2-dihydroisoquinoline-7-carbonitrile (7), 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (35), 1,2-dihydroisoquinoline-7-carbonitrile (6), 2-cyano-3-(dimethylamino)-N-(quinolin-3-yl)acrylamide (21), 1,2-dihydroisoquinoline-7-carbonitriles (11) and (8) exhibited higher activity (IC50 values of 27-45 μmol L-1) compared to doxorubicin (IC50 47.9 μmol L-1). LQ quinolin-3-yl)-1,2-dihydroisoquinoline-7-carbonitrile (12), 2-thioxo-2,3-dihydrothiazole-5-carboxamide (28) and quinolin-3-yl)-1,2-dihydroisoquinoline-7-carbonitrile (15) show activity comparable to doxorubicin, while (quinolin-3-yl)-1,2-dihydroisoquinoline-7-carbonitrile (9), 2,3-dihydrothiazole-5-carboxamide (24), thieno [3,4-c] pyridine-4(5H)-one (5), cyclopenta[b]thiophene-3-carboxamide (33) and (quinolin-3-yl)-6-stryl-1,2-dihydroisoquinoline-7-carbonitrile (10) exhibited moderate activity, lower than doxorubicin. PMID:27279061

  16. Potential spawn induction and suppression agents in Caribbean Acropora cervicornis corals of the Florida Keys

    PubMed Central

    Than, John T.

    2016-01-01

    The enhanced ability to direct sexual reproduction may lead to improved restoration outcomes for Acropora cervicornis. Gravid fragments of A. cervicornis were maintained in a laboratory for two sequential trials in the seven days prior to natural spawning in the Florida Keys. Ten replicates of five chemicals known to affect spawning in various invertebrate taxa were tested. Hydrogen peroxide at 2 mM (70%) and L-5-hydroxytryptophan (5-HTP) at 5 (40%) and 20 µM (30%) induced spawning within 15.4 h, 38.8 h and 26.9 h of dosing at or above the rate of release of the control (30%) within 14.6 h. Serotonin acetate monohydrate at 1 µM (20%) and 10 µM (20%), naloxone hydrochloride dihydrate at 0.01 µM (10%) and potassium phosphate monobasic at 0.25 µM (0%) induced spawning at rates less than the control. Although the greatest number of fragments spawned using hydrogen peroxide, it was with 100% mortality. There was a significantly higher induction rate closer to natural spawn (Trial 2) compared with Trial 1 and no genotype effect. Mechanisms of action causing gamete release were not elucidated. In Caribbean staghorn corals, 5-HTP shows promise as a spawning induction agent if administered within 72 h of natural spawn and it will not result in excessive mortality. Phosphate chemicals may inhibit spawning. This is the first study of its kind on Caribbean acroporid corals and may offer an important conservation tool for biologists currently charged with restoring the imperiled Acropora reefs of the Florida Keys. PMID:27168990

  17. Manganese(II) complexes with thiosemicarbazones as potential anti-Mycobacterium tuberculosis agents.

    PubMed

    Oliveira, Carolina G; da S Maia, Pedro Ivo; Souza, Paula C; Pavan, Fernando R; Leite, Clarice Q F; Viana, Rommel B; Batista, Alzir A; Nascimento, Otaciro R; Deflon, Victor M

    2014-03-01

    Through a systematic variation on the structure of a series of manganese complexes derived from 2-acetylpyridine-N(4)-R-thiosemicarbazones (Hatc-R), structural features have been investigated with the aim of obtaining complexes with potent anti-Mycobacterium tuberculosis activity. The analytical methods used for characterization included FTIR, EPR, UV-visible, elemental analysis, cyclic voltammetry, magnetic susceptibility measurement and single crystal X-ray diffractometry. Density functional theory (DFT) calculations were performed in order to evaluate the contribution of the thiosemicarbazonate ligands on the charge distribution of the complexes by changing the peripheral groups as well as to verify the Mn-donor atoms bond dissociation predisposition. The results obtained are consistent with the monoanionic N,N,S-tridentate coordination of the thiosemicarbazone ligands, resulting in octahedral complexes of the type [Mn(atc-R)2], paramagnetic in the extension of 5 unpaired electrons, whose EPR spectra are consistent for manganese(II). The electrochemical analyses show two nearly reversible processes, which are influenced by the peripheral substituent groups at the N4 position of the atc-R(1-) ligands. The minimal inhibitory concentration (MIC) of these compounds against M. tuberculosis as well as their in vitro cytotoxicity on VERO and J774A.1 cells (IC50) was determined in order to find their selectivity index (SI) (SI=IC50/MIC). The results evidenced that the compounds described here can be considered as promising anti-M. tuberculosis agents, with SI values comparable or better than some commercial drugs available for the tuberculosis treatment. PMID:24188534

  18. Potential spawn induction and suppression agents in Caribbean Acropora cervicornis corals of the Florida Keys.

    PubMed

    Flint, Mark; Than, John T

    2016-01-01

    The enhanced ability to direct sexual reproduction may lead to improved restoration outcomes for Acropora cervicornis. Gravid fragments of A. cervicornis were maintained in a laboratory for two sequential trials in the seven days prior to natural spawning in the Florida Keys. Ten replicates of five chemicals known to affect spawning in various invertebrate taxa were tested. Hydrogen peroxide at 2 mM (70%) and L-5-hydroxytryptophan (5-HTP) at 5 (40%) and 20 µM (30%) induced spawning within 15.4 h, 38.8 h and 26.9 h of dosing at or above the rate of release of the control (30%) within 14.6 h. Serotonin acetate monohydrate at 1 µM (20%) and 10 µM (20%), naloxone hydrochloride dihydrate at 0.01 µM (10%) and potassium phosphate monobasic at 0.25 µM (0%) induced spawning at rates less than the control. Although the greatest number of fragments spawned using hydrogen peroxide, it was with 100% mortality. There was a significantly higher induction rate closer to natural spawn (Trial 2) compared with Trial 1 and no genotype effect. Mechanisms of action causing gamete release were not elucidated. In Caribbean staghorn corals, 5-HTP shows promise as a spawning induction agent if administered within 72 h of natural spawn and it will not result in excessive mortality. Phosphate chemicals may inhibit spawning. This is the first study of its kind on Caribbean acroporid corals and may offer an important conservation tool for biologists currently charged with restoring the imperiled Acropora reefs of the Florida Keys. PMID:27168990

  19. Synthesis and characterization of a new retinoic acid ECPIRM as potential chemotherapeutic agent for human cutaneous squamous carcinoma.

    PubMed

    Zhang, Mengli; Tao, Yue; Ma, Pengcheng; Wang, Dechuan; He, Chundi; Cao, Yuping; Wei, Jun; Li, Lingjun; Tao, Lei

    2015-01-01

    Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers worldwide, requiring effective therapeutic interventions. Retinoids are important chemopreventive and therapeutic agents for a variety of human cancers including CSCC. In this study we synthesized a novel retinoic derivative N-(4-ethoxycarbonylphenyl) isoretinamide (ECPIRM) and evaluated its biological activities and possible mechanisms in human cutaneous squamous cell lines. ECPIRM had better inhibitory effect on the proliferation of squamous carcinoma cells SCL-1 and colo-16, compared with All-trans retinoic acid and 13-cis retinoic acid. ECPIRM had less toxicity to normal keratinocyte cell line HaCaT. Mechanistically, ECPIRM induced G1 cell cycle arrest in SCL-1 cells, via the downregulation of CDK2, CDK4, cycling D1 and cyclin E expression and upregulation of p21. In addition, these effects were at least partially due to the inhibition of JNK/ ERK-AP-1 signaling pathway by ECPIRM. Importantly, these effects of ECPIRM are independent of the classical retinoid receptor pathway, suggesting that the novel compound will have less side-effects in chemotherapy. These findings demonstrate that ECPIRM is a potential inhibitor of MPAK-AP-1 pathway, and is a potential therapeutic agent against CSCC. PMID:25991427

  20. Dropwort (Filipendula hexapetala Gilib.): potential role as antioxidant and antimicrobial agent

    PubMed Central

    Katanic, Jelena; Mihailovic, Vladimir; Stankovic, Nevena; Boroja, Tatjana; Mladenovic, Milan; Solujic, Slavica; Stankovic, Milan S.; Vrvic, Miroslav M.

    2015-01-01

    The aim of this study was to investigate the antioxidant activity of the methanolic extracts of Filipendula hexapetala Gilib. aerial parts (FHA) and roots (FHR) and their potential in different model systems, as well as antimicrobial activity. According to this, a number of assays were employed to evaluate the antioxidant and antimicrobial potential of F. hexapetala extracts. In addition, the antioxidant activity assays in different model systems were carried out, as well as pH, thermal and gastrointestinal stability studies. The phenolic compounds contents in FHA and FHR were also determined. The results showed that F. hexapetala extracts had considerable antioxidant activity in vitro and a great stability in different conditions. The extracts exhibited antimicrobial activity against most of the tested bacterial and fungal species. Also, the extracts contain high level of phenolic compounds, especially aerial parts extract. PMID:26417349

  1. Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense.

    PubMed

    Suganuma, Keisuke; Sarwono, Albertus Eka Yudistira; Mitsuhashi, Shinya; Jąkalski, Marcin; Okada, Tadashi; Nthatisi, Molefe; Yamagishi, Junya; Ubukata, Makoto; Inoue, Noboru

    2016-07-01

    This study aimed to evaluate the trypanocidal activity of mycophenolic acid (MPA) and its derivatives for Trypanosoma congolense The proliferation of T. congolense was completely inhibited by adding <1 μM MPA and its derivatives. In addition, the IMP dehydrogenase in T. congolense was molecularly characterized as the target of these compounds. The results suggest that MPA and its derivatives have the potential to be new candidates as novel trypanocidal drugs. PMID:27139487

  2. Marine macro- and microalgae as potential agents for the prevention of asthma: hyperresponsiveness and inflammatory subjects.

    PubMed

    Senevirathne, Mahinda; Kim, Se-Kwon

    2011-01-01

    Asthma is a variable disease and various factors are affected to increase the asthmatic symptoms and level of asthma control. It is believed that the cause for this disease is a combination of genetic and environmental factors. Numerous medications are available at present to treat this disease but it has been failed to control number of incidences successfully. Hence, recently many researchers have paid their interest to identify potential drugs from marine-based resources such as marine algae. In vitro and in vivo experiments have been conducted with extracts or compounds from algae and found that they showed significant activities against asthma. Accordingly, many marine macro- and microalgae have been reported to have potential to ameliorate the effect of asthma. However, detailed studies are needed in relation to identify the molecular mechanism of this disease to apply those marine resources against asthma effectively. In this chapter, an attempt has been taken to discuss the potential antiasthmatic activity of marine macro- and microalgae. PMID:22054955

  3. Sugar-borate esters--potential chemical agents in prostate cancer chemoprevention.

    PubMed

    Scorei, Romulus Ion; Popa, Radu

    2013-07-01

    The potential value of sugar-borate esters (SBEs) in the chemo-preventive therapy of prostate cancer has been reviewed. We propose that SBEs act as boron (B) vehicles, increasing the concentration of borate inside cancer cells relative to normal cells. Increased intracellular concentration of borate activates borate transporters, but also leads to growth inhibition and apoptosis. The effects of SBEs on normal cells are less dramatic because SBEs are naturally-occurring biochemicals, common and abundant in some fruits and vegetables, and also because borate dissociated from SBEs in natural diet doses is easily exported from normal cells. Cancer cell lines that over-express sugar transporters or under-express borate export are potential targets for SBE-based therapy. With regard to efficiency against cancer cells and drug preparation requirements, trigonal cis-diol boric monoesters will be one of the most effective class of SBEs. Because negative correlation exists between borate intake and the incidence of prostate cancer, and because most cancer cells overexpress sugar transporters, SBEs are proposed as a potential chemopreventive avenue in the fight against primary and recurrent prostate cancer. PMID:23293883

  4. Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning

    SciTech Connect

    Auerbach, Scott S.; Shah, Ruchir R.; Mav, Deepak; Smith, Cynthia S.; Walker, Nigel J.; Vallant, Molly K.; Boorman, Gary A.; Irwin, Richard D.

    2010-03-15

    Identification of carcinogenic activity is the primary goal of the 2-year bioassay. The expense of these studies limits the number of chemicals that can be studied and therefore chemicals need to be prioritized based on a variety of parameters. We have developed an ensemble of support vector machine classification models based on male F344 rat liver gene expression following 2, 14 or 90 days of exposure to a collection of hepatocarcinogens (aflatoxin B1, 1-amino-2,4-dibromoanthraquinone, N-nitrosodimethylamine, methyleugenol) and non-hepatocarcinogens (acetaminophen, ascorbic acid, tryptophan). Seven models were generated based on individual exposure durations (2, 14 or 90 days) or a combination of exposures (2 + 14, 2 + 90, 14 + 90 and 2 + 14 + 90 days). All sets of data, with the exception of one yielded models with 0% cross-validation error. Independent validation of the models was performed using expression data from the liver of rats exposed at 2 dose levels to a collection of alkenylbenzene flavoring agents. Depending on the model used and the exposure duration of the test data, independent validation error rates ranged from 47% to 10%. The variable with the most notable effect on independent validation accuracy was exposure duration of the alkenylbenzene test data. All models generally exhibited improved performance as the exposure duration of the alkenylbenzene data increased. The models differentiated between hepatocarcinogenic (estragole and safrole) and non-hepatocarcinogenic (anethole, eugenol and isoeugenol) alkenylbenzenes previously studied in a carcinogenicity bioassay. In the case of safrole the models correctly differentiated between carcinogenic and non-carcinogenic dose levels. The models predict that two alkenylbenzenes not previously assessed in a carcinogenicity bioassay, myristicin and isosafrole, would be weakly hepatocarcinogenic if studied at a dose level of 2 mmol/kg bw/day for 2 years in male F344 rats; therefore suggesting that these

  5. History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents.

    PubMed

    Preti, Delia; Baraldi, Pier Giovanni; Moorman, Allan R; Borea, Pier Andrea; Varani, Katia

    2015-07-01

    Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD. PMID:25821194

  6. Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review.

    PubMed

    Owusu-Ansah, Amma; Choi, Sung Hee; Petrosiute, Agne; Letterio, John J; Huang, Alex Yee-Chen

    2015-03-01

    Sickle cell disease (SCD) is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vasoocclusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived-2 related factor 2 (Nrf2) controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD. PMID:25511620

  7. Wheat enolase demonstrates potential as a non-toxic cryopreservation agent for liver and pancreatic cells.

    PubMed

    Grondin, Mélanie; Chow-Shi-Yée, Mélanie; Ouellet, François; Averill-Bates, Diana A

    2015-05-01

    Cryopreservation is essential for long-term storage of cells and tissues, which can be used for clinical applications such as drug toxicity testing, human transplantation, reproductive, regenerative and transfusion medicine. It requires use of cryoprotectants (e.g. dimethyl disulfoxide (DMSO), glycerol) that protect cells and tissues from dehydration and damage caused by formation of intracellular ice during freezing. As an alternative to these cytotoxic cryoprotectants, we are developing new technology using natural substances produced by plants that survive freezing conditions. We previously showed that soluble protein extracts such as wheat protein extract (WPE) prepared from winter wheat plants can substitute for DMSO as a cryoprotectant for certain mammalian cell types. To identify novel cryoactive proteins, WPE was separated using different chromatographic procedures and cryoactive fractions were analyzed by mass spectrometry. The analysis revealed enolase as a potential wheat protein candidate. A recombinant enolase protein was prepared and was able to successfully cryopreserve rat hepatocytes and insulin-secreting INS832/13 pancreatic cells. Post-thaw cells had high viability and levels of metabolic activities. Cryopreserved cells were plateable and had good adherence and morphological properties. These results indicate that individual plant proteins such as enolase have promising potential as new, non-toxic technology for cryopreservation protocols used for clinical applications. PMID:25740431

  8. Inhibition of endothelial cell functions by novel potential cancer chemopreventive agents.

    PubMed

    Bertl, Elisabeth; Becker, Hans; Eicher, Theophil; Herhaus, Christian; Kapadia, Govind; Bartsch, Helmut; Gerhäuser, Clarissa

    2004-12-01

    Endothelial cells (EC) play a major role in tumor-induced neovascularization and bridge the gap between a microtumor and growth factors such as nutrients and oxygen supply required for expansion. Immortalized human microvascular endothelial cells (HMEC-1) were utilized to assess anti-endothelial effects of 10 novel potential cancer chemopreventive compounds from various sources that we have investigated previously in a human in vitro anti-angiogenic assay. These include the monoacylphloroglucinol isoaspidinol B, 1,2,5,7-tetrahydroxy-anthraquinone, peracetylated carnosic acid (PCA), isoxanthohumol, 2,2',4'-trimethoxychalcone, 3'-bromo-2,4-dimethoxychalcone as well as four synthetic derivatives of lunularic acid, a bibenzyl found in mosses [Int. J. Cancer Prev. 1 (2004) 47]. EC proliferation was inhibited with half-maximal inhibitory concentrations from 0.3 to 49.6muM, whereas EC migration was affected by most compounds at sub-micromolar concentrations. PCA and the bibenzyl derivative EC 1004 potently prevented differentiation of HMEC-1 into tubule-like structures. Overall, our data indicate that inhibition of endothelial cell function contributes to various extents to the chemopreventive or anti-angiogenic potential of these lead compounds. PMID:15522231

  9. Poly (ADP-ribose) polymerases inhibitor, Zj6413, as a potential therapeutic agent against breast cancer.

    PubMed

    Zhou, Qin; Ji, Ming; Zhou, Jie; Jin, Jing; Xue, Nina; Chen, Ju; Xu, Bailing; Chen, Xiaoguang

    2016-05-01

    Poly (ADP-ribose) polymerases (PARPs) facilitate repairing of cancer cell DNA damage as a mean to promote cancer proliferation and metastasis. Inhibitors of PARPs which interfering DNA repair, in context of defects in other DNA repair mechanisms, can thus be potentially exploited to inhibit or even kill cancer cells. However, nondiscriminatory inhibition of PARPs, such as PARP2, may lead to undesired consequences. Here, we demonstrated the design and development of the Zj6413 as a potent and selective PARP1 catalytic inhibitor. It trapped PARP1/2 at damaged sites of DNA. As expected, the Zj6413 showed notable anti-tumor activity against breast cancer gene (BRCA) deficient triple negative breast cancers (TNBCs). Zj6413 treated breast cancers (BCs) showed an elevated level of DNA damage evidenced by the accumulation of γ-H2AX foci and DNA damaged related proteins. Zj6413 also induced G2/M arrest and cell death in the MX-1, MDA-MB-453 BC cells, exerted chemo-sensitizing effect on BRCA proficient cancer cells and potentiated Temozolomide (TMZ)'s cytotoxicity in MX-1 xenograft tumors mice. In conclusion, our study provided evidence that a new PARP inhibitor strongly inhibited the catalytic activity of PARPs, trapped them on nicked DNA and damaged the cancer cells, eventually inhibiting the growth of breast tumor cells in vitro and in vivo. PMID:26920250

  10. New antibacterial agents: Hybrid bioisoster derivatives as potential E. coli FabH inhibitors.

    PubMed

    Segretti, Natanael D; Serafim, Ricardo A M; Segretti, Mariana C F; Miyata, Marcelo; Coelho, Fernando R; Augusto, Ohara; Ferreira, Elizabeth I

    2016-08-15

    The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new antibiotics. In this regard, we propose the design, synthesis and biological evaluation of hybrid sulfonylhydrazone bioisosters/furoxans with potential antibacterial (Escherichia coli) activity. The most active compound of the series, (E)-3-methyl-4-((2-tosylhydrazono)methyl)-1,2,5-oxadiazole 2-oxide, with a MIC=0.36μM, was not cytotoxic when tested on Vero cells (IC50>100μM). To complement the in vitro screening, we also studied the interaction of the test compounds with β-ketoacyl acyl carrier protein synthase (FabH), the target for the parent compounds, and we observed three important hydrogen-bonding interactions with two important active site residues in the catalytic site of the enzyme, providing complementary evidence to support the target of the new hybrid molecules. PMID:27426865

  11. Redox-active compounds with a history of human use: antistaphylococcal action and potential for repurposing as topical antibiofilm agents

    PubMed Central

    Ooi, N.; Eady, E. A.; Cove, J. H.; O'Neill, A. J.

    2015-01-01

    Objectives To investigate the antistaphylococcal/antibiofilm activity and mode of action (MOA) of a panel of redox-active (RA) compounds with a history of human use and to provide a preliminary preclinical assessment of their potential for topical treatment of staphylococcal infections, including those involving a biofilm component. Methods Antistaphylococcal activity was evaluated by broth microdilution and by time–kill studies with growing and slow- or non-growing cells. The antibiofilm activity of RA compounds, alone and in combination with established antibacterial agents, was assessed using the Calgary Biofilm Device. Established assays were used to examine the membrane-perturbing effects of RA compounds, to measure penetration into biofilms and physical disruption of biofilms and to assess resistance potential. A living skin equivalent model was used to assess the effects of RA compounds on human skin. Results All 15 RA compounds tested displayed antistaphylococcal activity against planktonic cultures (MIC 0.25–128 mg/L) and 7 eradicated staphylococcal biofilms (minimum biofilm eradication concentration 4–256 mg/L). The MOA of all compounds involved perturbation of the bacterial membrane, whilst selected compounds with antibiofilm activity caused destructuring of the biofilm matrix. The two most promising agents [celastrol and nordihydroguaiaretic acid (NDGA)] in respect of antibacterial potency and selective toxicity against bacterial membranes acted synergistically with gentamicin against biofilms, did not damage artificial skin following topical application and exhibited low resistance potential. Conclusions In contrast to established antibacterial drugs, some RA compounds are capable of eradicating staphylococcal biofilms. Of these, celastrol and NDGA represent particularly attractive candidates for development as topical antistaphylococcal biofilm treatments. PMID:25368206

  12. Agent based modeling of the effects of potential treatments over the blood-brain barrier in multiple sclerosis.

    PubMed

    Pennisi, Marzio; Russo, Giulia; Motta, Santo; Pappalardo, Francesco

    2015-12-01

    Multiple sclerosis is a disease of the central nervous system that involves the destruction of the insulating sheath of axons, causing severe disabilities. Since the etiology of the disease is not yet fully understood, the use of novel techniques that may help to understand the disease, to suggest potential therapies and to test the effects of candidate treatments is highly advisable. To this end we developed an agent based model that demonstrated its ability to reproduce the typical oscillatory behavior observed in the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis. The model has then been used to test the potential beneficial effects of vitamin D over the disease. Many scientific studies underlined the importance of the blood-brain barrier and of the mechanisms that influence its permeability on the development of the disease. In the present paper we further extend our previously developed model with a mechanism that mimics the blood-brain barrier behavior. The goal of our work is to suggest the best strategies to follow for developing new potential treatments that intervene in the blood-brain barrier. Results suggest that the best treatments should potentially prevent the opening of the blood-brain barrier, as treatments that help in recovering the blood-brain barrier functionality could be less effective. PMID:26343337

  13. Evaluating the potential of IL-27 as a novel therapeutic agent in HIV-1 infection

    PubMed Central

    Swaminathan, Sanjay; Dai, Lue; Lane, H. Clifford; Imamichi, Tomozumi

    2013-01-01

    Interleukin 27 (IL-27) is an immunomodulatory cytokine with important roles in both the innate and adaptive immune systems. In the last five years, the addition of exogenous IL-27 to primary cell cultures has been demonstrated to decrease HIV-1 replication in a number of cell types including peripheral blood mononuclear cells (PBMCs), CD4+ T cells, macrophages and dendritic cells. These in-vitro findings suggest that IL-27 may have therapeutic value in the setting of HIV-1 infection. In this review, we describe the current knowledge of the biology of IL-27, its effects primarily on HIV-1 replication but also in other viral infections and explore its potential role as a therapeutic cytokine for the treatment of patients with HIV-1 infection. PMID:23962745

  14. Design, synthesis and biological evaluation of C6-modified celastrol derivatives as potential antitumor agents.

    PubMed

    Tang, Kaiyong; Huang, Qingqing; Zeng, Jafeng; Wu, Guangming; Huang, Jinwen; Pan, Junfang; Lu, Wei

    2014-01-01

    New six C6-celastrol derivatives were designed, synthesized, and evaluated for their in vitro cytotoxic activities against nine human cancer cell lines (BGC-823, H4, Bel7402, H522, Colo 205, HepG2 and MDA-MB-468). The results showed that most of the compounds displayed potent inhibition against BGC823, H4, and Bel7402, with IC50s of 1.84-0.39 μM. The best compound NST001A was tested in an in vivo antitumor assay on nude mice bearing Colo 205 xenografts, and showed significant inhibition of tumor growth at low concentrations. Therefore, celastrol C-6 derivatives are potential drug candidates for treating cancer. PMID:25025148

  15. Synthesis and Cytotoxic Evaluation of Monocarbonyl Analogs of Curcumin as Potential Anti‐Tumor Agents

    PubMed Central

    Pan, Zheer; Chen, Chengwei; Zhou, Yeli; Xu, Feng

    2016-01-01

    Abstract Preclinical Research A series of mono‐carbonyl curcumin analogs with different substituents at the 4/4’‐position of the phenyl group were synthesized and screened for in vitro cytotoxicity against a panel of human cancer cell lines using a methyl thiazolyl tetrazolium assay. Several of the curcumin analogs, especially B114, exhibited a wide‐spectrum of anti‐tumor properties in all tested cell lines, indicating their potential in as anti‐cancer lead compounds. Further toxicity testing in the NRK‐52E kidney cell line revealed that the analogs A111, A113, and B114 had comparable or higher safety than curcumin. These data suggested that the introduction of appropriate substituents in the 4/4’‐positions could be a promising approach for curcumin‐based drug design. Drug Dev Res 77 : 43–49, 2016. © 2016 Wiley Periodicals, Inc. PMID:26846154

  16. X-ray photoelectron spectroscopy of potential technetium-based organ imaging agents

    SciTech Connect

    Thompson, M.; Nunn, A.D.; Treher, E.N.

    1986-12-01

    Technetium-99 3d binding energies were measured for a set of 12 compounds which included model species and several potential radiopharmaceuticals. The range of compounds from the free metal to the technetium(VII) valence state gave a span of 4.9 eV. Anionic and coordinated halogen was distinguished in the chlorine 2p and bromine 3d spectra of a number of phosphine complexes. Similar spectra of two dioxime complexes indicated significantly more electron density on the halogen than is the case for a coordinated species. The result is indicative of weakening of the metal-chlorine bond. Analogous spectra were obtained when bromine was substituted for chlorine. The boron 1s binding energy for boronic acid present in the dioxime complexes was in agreement with the proposed oxygen population on the boron atom.

  17. Livestock as a potential biological control agent for an invasive wetland plant

    PubMed Central

    Mozdzer, Thomas; Angelini, Christine; Brundage, Jennifer E.; Esselink, Peter; Bakker, Jan P.; Gedan, Keryn B.; van de Koppel, Johan; Baldwin, Andrew H.

    2014-01-01

    Invasive species threaten biodiversity and incur costs exceeding billions of US$. Eradication efforts, however, are nearly always unsuccessful. Throughout much of North America, land managers have used expensive, and ultimately ineffective, techniques to combat invasive Phragmites australis in marshes. Here, we reveal that Phragmites may potentially be controlled by employing an affordable measure from its native European range: livestock grazing. Experimental field tests demonstrate that rotational goat grazing (where goats have no choice but to graze Phragmites) can reduce Phragmites cover from 100 to 20% and that cows and horses also readily consume this plant. These results, combined with the fact that Europeans have suppressed Phragmites through seasonal livestock grazing for 6,000 years, suggest Phragmites management can shift to include more economical and effective top-down control strategies. More generally, these findings support an emerging paradigm shift in conservation from high-cost eradication to economically sustainable control of dominant invasive species. PMID:25276502

  18. Cyclin-dependent kinases inhibitors as potential anticancer, antineurodegenerative, antiviral and antiparasitic agents.

    PubMed

    Meijer, Laurent

    2000-04-01

    Cyclin-dependent kinases (CDKs) play a key role in the cell division cycle, in neuronal functions, in transcription and in apoptosis. Intensive screening with these kinases as targets has lead to the identification of highly selective and potent small - molecule inhibitors. Co-crystallization with CDK2 shows that these flat heterocyclic hydrophobic compounds bind through two or three hydrogen bonds with the side chains of two amino acids located in the ATP-binding pocket of the kinase. These inhibitors are anti-proliferative; they arrest cells in G1 and in G2/M phase. Furthermore they facilitate or even trigger apoptosis in proliferating cells while they protect neuronal cells and thymocytes from apoptosis. The potential use of these inhibitors is being extensively evaluated for cancer chemotherapy and also in other therapeutic areas: neurology (Alzheimer's disease), cardiovascular (restenosis, angiogenesis), nephrology (glomerulonephritis), parasitology (Plasmodium, Trypanosoma, Toxoplasma, etc.) and virology (cytomegalovirus, HIV, herpes virus). Copyright 2000 Harcourt Publishers Ltd. PMID:11498372

  19. Natural products as anti-glycation agents: possible therapeutic potential for diabetic complications.

    PubMed

    Elosta, Abdulhakim; Ghous, Tahseen; Ahmed, Nessar

    2012-03-01

    Diabetes mellitus is characterised by hyperglycaemia, lipidaemia and oxidative stress and predisposes affected individuals to long-term complications afflicting the eyes, skin, kidneys, nerves and blood vessels. Increased protein glycation and the subsequent build-up of tissue advanced glycation endproducts (AGEs) contribute towards the pathogenesis of diabetic complications. Protein glycation is accompanied by generation of free radicals through autoxidation of glucose and glycated proteins and via interaction of AGEs with their cell surface receptors (referred to as RAGE). Glycationderived free radicals can damage proteins, lipids and nucleic acids and contribute towards oxidative stress in diabetes. There is interest in compounds with anti-glycation activity as they may offer therapeutic potential in delaying or preventing the onset of diabetic complications. Although many different compounds are under study, only a few have successfully entered clinical trials but none have yet been approved for clinical use. Whilst the search for new synthetic inhibitors of glycation continues, little attention has been paid to anti-glycation compounds from natural sources. In the last few decades the traditional system of medicine has become a topic of global interest. Various studies have indicated that dietary supplementation with combined anti-glycation and antioxidant nutrients may be a safe and simple complement to traditional therapies targeting diabetic complications. Data for forty two plants/constituents studied for anti-glycation activity is presented in this review and some commonly used medicinal plants that possess anti-glycation activity are discussed in detail including their active ingredients, mechanism of action and therapeutic potential. PMID:22268395

  20. Three dimensional pharmacophore modeling of human CYP17 inhibitors. Potential agents for prostate cancer therapy.

    PubMed

    Clement, Omoshile O; Freeman, Clive M; Hartmann, Rolf W; Handratta, Venkatesh D; Vasaitis, Tadas S; Brodie, Angela M H; Njar, Vincent C O

    2003-06-01

    We report here a molecular modeling investigation of steroidal and nonsteroidal inhibitors of human cytochrome P450 17alpha-hydroxylase-17,20-lyase (CYP17). Using the pharmacophore perception technique, we have generated common-feature pharmacophore model(s) to explain the putative binding requirements for two classes of human CYP17 inhibitors. Common chemical features in the steroid and nonsteroid human CYP17 enzyme inhibitors, as deduced by the Catalyst/HipHop program, are one to two hydrogen bond acceptors (HBAs) and three hydrophobic groups. For azole-steroidal ligands, the 3beta-OH group of ring A and the N-3 of the azole ring attached to ring D at C-17 act as hydrogen bond acceptors. A model that permits hydrogen bond interaction between the azole functionality on ring D and the enzyme is consistent with experimental deductions for type II CYP17 inhibitors where a sixth ligating atom interacts with Fe(II) of heme. In general, pharmacophore models derived for steroid and nonsteroidal compounds bear striking similarities to all azole sites mapping the HBA functionality and to three hydrophobic features describing the hydrophobic interactions between the ligands and the enzyme. Using the pharmacophore model derived for azole-steroidal inhibitors as a 3D search query against several 3D multiconformational Catalyst formatted databases, we identified several steroidal compounds with potential inhibition of this enzyme. Biological testing of some of these compounds show low to high inhibitory potency against the human CYP17 enzyme. This shows the potential of our pharmacophore model in identifying new and potent CYP17 inhibitors. Further refinement of the model is in progress with a view to identifying and optimizing new leads. PMID:12773039

  1. A Review of Potential Harmful Interactions between Anticoagulant/Antiplatelet Agents and Chinese Herbal Medicines

    PubMed Central

    Tsai, Hsin-Hui; Lin, Hsiang-Wen; Lu, Ying-Hung; Chen, Yi-Ling; Mahady, Gail B.

    2013-01-01

    Background The risks attributed to drug-herb interactions, even when known, are often ignored or underestimated, especially for those involving anti-clotting drugs and Chinese medicines. The aim of this study was to structurally search and evaluate the existing evidence-based data associated with potential drug interactions between anticoagulant/antiplatelet drugs and Chinese herbal medicines (CHMs) and evaluate the documented mechanisms, consequences, and/or severity of interactions. Methodology and Findings Information related to anticoagulant/antiplatelet drug-CHM interactions was retrieved from eight interaction-based textbooks, four web resources and available primary biomedical literature. The primary literature searches were conducted in English and/or Chinese from January 2000 through December 2011 using the secondary databases (e.g., PubMed, Airiti Library, China Journal full-text database). The search terms included the corresponding medical subject headings and key words. Herbs or natural products not used as a single entity CHM or in Chinese Medicinal Prescriptions were excluded from further review. The corresponding mechanisms and severity ratings of interactions were retrieved using MicroMedex®, Lexicomp® and Natural Medicines Comprehensive Database®. Finally, we found 90 single entity CHMs contributed to 306 documented drug-CHM interactions. A total of 194 (63.4%) interactions were verified for its evidence describing possible mechanisms and severity. Of them, 155 interactions (79.9%) were attributable to pharmacodynamic interactions, and almost all were rated as moderate to severe interactions. The major consequences of these interactions were increased bleeding risks due to the additive anticoagulant or antiplatelet effects of the CHMs, specifically danshen, dong quai, ginger, ginkgo, licorice, and turmeric. Conclusions/Significance Conventional anticoagulants and antiplatelet drugs were documented to have harmful interactions with some commonly

  2. Structure based medicinal chemistry-driven strategy to design substituted dihydropyrimidines as potential antileishmanial agents.

    PubMed

    Rashid, Umer; Sultana, Riffat; Shaheen, Nargis; Hassan, Syed Fahad; Yaqoob, Farhana; Ahmad, Muhammad Jawad; Iftikhar, Fatima; Sultana, Nighat; Asghar, Saba; Yasinzai, Masoom; Ansari, Farzana Latif; Qureshi, Naveeda Akhter

    2016-06-10

    In an attempt to explore novel and more potent antileishmanial compounds to diversify the current inhibitors, we pursued a medicinal chemistry-driven strategy to synthesize novel scaffolds with common pharmacophoric features of dihydropyrimidine and chalcone as current investigational antileishmanial compounds. Based on the reported X-ray structure of Pteridine reductase 1 (PTR1) from Leishmania major, we have designed a number of dihydropyrimidine-based derivatives to make specific interactions in PTR1 active site. Our lead compound 8i has shown potent in vitro antileishmanial activity against promastigotes of L. Major and Leishmania donovani with IC50 value of 0.47 μg/ml and 1.5 μg/ml respectively. The excellent in vitro activity conclusively revealed that our lead compound is efficient enough to eradicate both visceral and topical leishmaniasis. In addition, docking analysis and in silico ADMET predictions were also carried out. Predicted molecular properties supported our experimental analysis that these compounds have potential to eradicate both visceral and topical leishmaniasis. PMID:27017551

  3. Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents.

    PubMed

    Min, Jaeki; Guo, Kexiao; Suryadevara, Praveen K; Zhu, Fangyi; Holbrook, Gloria; Chen, Yizhe; Feau, Clementine; Young, Brandon M; Lemoff, Andrew; Connelly, Michele C; Kastan, Michael B; Guy, R Kiplin

    2016-01-28

    We previously reported a novel inhibitor of the ataxia-telangiectasia mutated (ATM) kinase, which is a target for novel radiosensitizing drugs. While our initial lead, compound 4, was relatively potent and nontoxic, it exhibited poor stability to oxidative metabolism and relatively poor selectivity against other kinases. The current study focused on balancing potency and selectivity with metabolic stability through structural modification to the metabolized site on the quinazoline core. We performed extensive structure-activity and structure-property relationship studies on this quinazoline ATM kinase inhibitor in order to identify structural variants with enhanced selectivity and metabolic stability. We show that, while the C-7-methoxy group is essential for potency, replacing the C-6-methoxy group considerably improves metabolic stability without affecting potency. Promising analogues 20, 27g, and 27n were selected based on in vitro pharmacology and evaluated in murine pharmacokinetic and tolerability studies. Compound 27g possessed significantly improve pharmacokinetics relative to that of 4. Compound 27g was also significantly more selective against other kinases than 4. Therefore, 27g is a good candidate for further development as a potential radiosensitizer. PMID:26632965

  4. Newcastle Disease Virus Hemagglutinin Neuraminidase as a Potential Cancer Targeting Agent

    PubMed Central

    Baradaran, Ali; Yusoff, Khatijah; Shafee, Norazizah; Rahim, Raha Abdul

    2016-01-01

    The hemagglutinin-neuraminidase (HN) protein of Newcastle disease virus (NDV) with its immunotherapeutic activities and sialic acid binding abilities is a promising cancer adjuvant. The HN was surfaced displayed on Lactococcus lactis and its cancer targeting ability was investigated via attachment to the MDA-MB231 breast cancers. To surface display the HN protein on the bacterial cell wall, HN was fused to N-acetylmuraminidase (AcmA) anchoring motif of L. lactis and expressed in Chinese hamster ovary cells. The expressed recombinant fusion proteins were purified and mixed with a culture of L. lactis and Lactobacillus plantarum. Immunofluorescence assay showed the binding of the recombinant HN-AcmA protein on the surface of the bacterial cells. The bacterial cells carrying the HN-AcmA protein interacted with the MDA-MB231 breast cancer cells. Direct and fluorescent microscopy confirmed that L. lactis and Lb. plantarum surface displaying the recombinant HN were attached to the breast cancer MDA-MB231 cells, providing evidence for the potential ability of HN in targeting to cancer cells. PMID:26918060

  5. Synthesis and Evaluation of Novel Triterpene Analogues of Ursolic Acid as Potential Antidiabetic Agent

    PubMed Central

    Wu, Panpan; Zheng, Jie; Huang, Tianming; Li, Dianmeng; Hu, Qingqing; Cheng, Anming; Jiang, Zhengyun; Jiao, Luoying; Zhao, Suqing; Zhang, Kun

    2015-01-01

    Ursolic acid (UA) is a naturally bioactive compound that possesses potential anti-diabetic activity. The relatively safe and effective molecule intrigued us to further explore and to improve its anti-diabetic activity. In the present study, a series of novel UA analogues was synthesized and their structures were characterized. Their bioactivities against the α-glucosidase from baker's yeast were determined in vitro. The results suggested that most of the analogues exhibited significant inhibitory activity, especially analogues 8b and 9b with the IC50 values of 1.27 ± 0.27 μM (8b) and 1.28 ± 0.27 μM (9b), which were lower than the other analogues and the positive control. The molecular docking and 2D-QSAR studies were carried out to prove that the C-3 hydroxyl could interact with the hydrophobic region of the active pocket and form hydrogen bonds to increase the binding affinity of ligand and the homology modelling protein. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from UA analogues. PMID:26406581

  6. Benzylpiperidine-Linked Diarylthiazoles as Potential Anti-Alzheimer's Agents: Synthesis and Biological Evaluation.

    PubMed

    Shidore, Mahesh; Machhi, Jatin; Shingala, Kaushik; Murumkar, Prashant; Sharma, Mayank Kumar; Agrawal, Neetesh; Tripathi, Ashutosh; Parikh, Zalak; Pillai, Prakash; Yadav, Mange Ram

    2016-06-23

    A novel series of hybrid molecules were designed and synthesized by fusing the pharmacophoric features of cholinesterase inhibitor donepezil and diarylthiazole as potential multitarget-directed ligands for the treatment of Alzheimer's disease (AD). The compounds showed significant in vitro anticholinesterase (anti-ChE) activity, the most potent compound (44) among them showing the highest activity (IC50 value of 0.30 ± 0.01 μM) for AChE and (1.84 ± 0.03 μM) for BuChE. Compound 44 showed mixed inhibition of AChE in the enzyme kinetic studies. Some compounds exhibited moderate to high inhibition of AChE-induced Aβ1-42 aggregation and noticeable in vitro antioxidant and antiapoptotic properties. Compound 44 showed significant in vivo anti-ChE and antioxidant activities. Furthermore, compound 44 demonstrated in vivo neuroprotection by decreasing Aβ1-42-induced toxicity by attenuating abnormal levels of Aβ1-42, p-Tau, cleaved caspase-3, and cleaved PARP proteins. Compound 44 exhibited good oral absorption and was well tolerated up to 2000 mg/kg, po, dose without showing toxic effects. PMID:27253679

  7. Radioiodinated aza-diphenylacetylenes as potential SPECT imaging agents for β-amyloid plaque detection

    PubMed Central

    Qu, Wenchao; Kung, Mei-Ping; Hou, Catherine; Jin, Lee-Way; Kung, Hank F.

    2007-01-01

    Two new iodinated fluoro- and hydroxy-pegylated aza-diphenylacetylene derivatives, 1 and 2, targeting β-amyloid (Aβ) plaques have been successfully prepared. In vitro binding carried out in tissue homogenates prepared from postmortem AD brains with [125I]IMPY (6-iodo-2-(4′-dimethylamino-)phenyl-imidazo[1,2-a]pyridine) as the radioligand indicated good binding affinities (Ki = 9.2 and 16.8 nM for 1 and 2, respectively). Brain penetrations of the corresponding radioiodinated ligands, evaluated in the normal mice, showed good initial brain penetrations (3.55 and 5.67% ID/g for [125I]1 and [125I]2 at 2 min post-injection). The washout from normal mice brain was relatively fast (0.33 and 0.91% ID/g at 2 hr post-injection). The specific binding of these radioiodinated ligands to β-amyloid plaques was clearly demonstrated using film autoradiography of AD brain sections. Taken together, these preliminary results strongly suggest that these novel iodinated aza-diphenylacetylenes may be potentially useful for imaging Aβ plaques in the living human brain. PMID:17502139

  8. Recombinant l-phenylalanine ammonia lyase from Rhodosporidium toruloides as a potential anticancer agent.

    PubMed

    Babich, Olga O; Pokrovsky, Vadim S; Anisimova, Natalia Yu; Sokolov, Nikolai N; Prosekov, Alexander Yu

    2013-01-01

    The recombinant producer strain expressing Rhodosporidium toruloides l-phenylalanine ammonia lyase (PAL) has been obtained, and a purification procedure of PAL has been developed. The purified enzyme, PAL, has the following biochemical and catalytic characteristics: Km for l-Phe of 0.49 mM, pH optimum at 8.5, and temperature optimum at 50°C. PAL exhibited a significant cytotoxic effect toward the following cell lines: MCF7 (IC50 = 1.97 U/mL), DU145 (IC50 = 7.3 U/mL), which are comparable with E. coli l-asparaginase type-II cytotoxicity in vitro. Administration of PAL (200-400 U/kg) to L5178y-bearing mice for five times (a total dose of 1000-2000 U/kg) was well tolerated and showed the increase of life span (ILS) = 12-16%, P < 0.05. Data obtained suggest that PAL from R. toruloides has a potential for cancer treatment. PMID:23718781

  9. Scutellarin as a Potential Therapeutic Agent for Microglia-Mediated Neuroinflammation in Cerebral Ischemia.

    PubMed

    Yuan, Yun; Fang, Ming; Wu, Chun-Yun; Ling, Eng-Ang

    2016-09-01

    The cerebral ischemia is one of the most common diseases in the central nervous system that causes progressive disability or even death. In this connection, the inflammatory response mediated by the activated microglia is believed to play a central role in this pathogenesis. In the event of brain injury, activated microglia can clear the cellular debris and invading pathogens, release neurotrophic factors, etc., but in chronic activation microglia may cause neuronal death through the release of excessive inflammatory mediators. Therefore, suppression of microglial over-reaction and microglia-mediated neuroinflammation is deemed to be a therapeutic strategy of choice for cerebral ischemic damage. In the search for potential herbal extracts that are endowed with the property in suppressing the microglial activation and amelioration of neuroinflammation, attention has recently been drawn to scutellarin, a Chinese herbal extract. Here, we review the roles of activated microglia and the effects of scutellarin on activated microglia in pathological conditions especially in ischemic stroke. We have further extended the investigation with special reference to the effects of scutellarin on Notch signaling, one of the several signaling pathways known to be involved in microglial activation. Furthermore, in light of our recent experimental evidence that activated microglia can regulate astrogliosis, an interglial "cross-talk" that was amplified by scutellarin, it is suggested that in designing of a more effective therapeutic strategy for clinical management of cerebral ischemia both glial types should be considered collectively. PMID:27103430

  10. Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease

    PubMed Central

    Barreto, George E.; Iarkov, Alexander; Moran, Valentina Echeverria

    2015-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disorder, which is characterized by neuroinflammation, dopaminergic neuronal cell death and motor dysfunction, and for which there are no proven effective treatments. The negative correlation between tobacco consumption and PD suggests that tobacco-derived compounds can be beneficial against PD. Nicotine, the more studied alkaloid derived from tobacco, is considered to be responsible for the beneficial behavioral and neurological effects of tobacco use in PD. However, several metabolites of nicotine, such as cotinine, also increase in the brain after nicotine administration. The effect of nicotine and some of its derivatives on dopaminergic neurons viability, neuroinflammation, and motor and memory functions, have been investigated using cellular and rodent models of PD. Current evidence shows that nicotine, and some of its derivatives diminish oxidative stress and neuroinflammation in the brain and improve synaptic plasticity and neuronal survival of dopaminergic neurons. In vivo these effects resulted in improvements in mood, motor skills and memory in subjects suffering from PD pathology. In this review, we discuss the potential benefits of nicotine and its derivatives for treating PD. PMID:25620929

  11. Phenylpropiophenone derivatives as potential anticancer agents: synthesis, biological evaluation and quantitative structure-activity relationship study.

    PubMed

    Ivković, Branka M; Nikolic, Katarina; Ilić, Bojana B; Žižak, Željko S; Novaković, Radmila B; Čudina, Olivera A; Vladimirov, Sote M

    2013-05-01

    Series of twelve chalcone and propafenone derivatives has been synthesized and evaluated for anticancer activities against HeLa, Fem-X, PC-3, MCF-7, LS174 and K562 cell lines. The 2D-QSAR and 3D-QSAR studies were performed for all compounds with cytotoxic activities against each cancer cell line. Partial least squares (PLS) regression has been applied for selection of the most relevant molecular descriptors and QSAR models building. Predictive potentials of the created 2D-QSAR and 3D-QSAR models for each cell line were compared, by use of leave-one-out cross-validation and external validation, and optimal QSAR models for each cancer cell line were selected. The QSAR studies have selected the most significant molecular descriptors and pharmacophores of the chalcone and propafenone derivatives and proposed structures of novel chalcone and propafenone derivatives with enhanced anticancer activity on the HeLa, Fem-X, PC-3, MCF-7, LS174 and K562 cells. PMID:23501110

  12. Synthesis and Evaluation of Selected Benzimidazole Derivatives as Potential Antimicrobial Agents.

    PubMed

    Alasmary, Fatmah A S; Snelling, Anna M; Zain, Mohammed E; Alafeefy, Ahmed M; Awaad, Amani S; Karodia, Nazira

    2015-01-01

    A library of 53 benzimidazole derivatives, with substituents at positions 1, 2 and 5, were synthesized and screened against a series of reference strains of bacteria and fungi of medical relevance. The SAR analyses of the most promising results showed that the antimicrobial activity of the compounds depended on the substituents attached to the bicyclic heterocycle. In particular, some compounds displayed antibacterial activity against two methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentrations (MICs) comparable to the widely-used drug ciprofloxacin. The compounds have some common features; three possess 5-halo substituents; two are derivatives of (S)-2-ethanaminebenzimidazole; and the others are derivatives of one 2-(chloromethyl)-1H-benzo[d]imidazole and (1H-benzo[d]imidazol-2-yl)methanethiol. The results from the antifungal screening were also very interesting: 23 compounds exhibited potent fungicidal activity against the selected fungal strains. They displayed equivalent or greater potency in their MIC values than amphotericin B. The 5-halobenzimidazole derivatives could be considered promising broad-spectrum antimicrobial candidates that deserve further study for potential therapeutic applications. PMID:26307956

  13. Exploring a natural MDR reversal agent: potential of medicinal food supplement Nerium oleander leaf distillate

    PubMed Central

    Kars, Meltem Demirel; Gündüz, Ufuk; Üney, Kamil; Baş, Ahmet Levent

    2013-01-01

    Objective To investigate the molecular effects of Nerium oleander leaf distillate on paclitaxel and vincristine resistant (MCF-7/Pac and MCF-7/Vinc) cells and sensitive (MCF-7/S) cell lines. Methods Nerium oleander (N. oleander) leaf extract was obtained by hydrodistillation method. The toxicological effects of N. oleander distillate, previously suggested as medicinal food supplement, on drug resistant cells were evaluated by XTT tests. MDR modulation potential of the plant material was evaluated by flow cytometry and fluorescent microscopy. Paclitaxel and vincristine were applied to the sublines in combination with N. oleander distillate. Results Fractional inhibitory indices show that N. oleander distillate did not increase the antiproliferative effects of anticancer drugs. N. oleander treatment in to MCF-7/Pac and MCF-7/Vinc did not inhibit P-gp activity and MDR1 gene expression level. Conclusions As a result it may be suggested that although N. oleander distillate has some medicinal effects as food supplement it may not be suitable as an MDR modulator for drug resistant breast cancer cells. PMID:23905023

  14. Interleukin-1 receptor associated kinase inhibitors: potential therapeutic agents for inflammatory- and immune-related disorders.

    PubMed

    Bahia, Malkeet Singh; Kaur, Maninder; Silakari, Pragati; Silakari, Om

    2015-06-01

    The various cells of innate immune system quickly counter-attack invading pathogens, and mount up "first line" defense through their trans-membrane receptors including Toll-like receptors (TLRs) and interleukin receptors (IL-Rs) that result in the secretion of pro-inflammatory cytokines. Albeit such inflammatory responses are beneficial in pathological conditions, their overstimulation may cause severe inflammatory damage; thus, make this defense system a "double edged sword". IRAK-4 has been evaluated as an indispensable element of IL-Rs and TLR pathways that can regulate the abnormal levels of cytokines, and therefore could be employed to manage immune- and inflammation-related disorders. Historically, the identification of selective and potent inhibitors has been challenging; thus, a limited number of small molecule IRAK-4 inhibitors are available in literature. Recently, IRAK-4 achieved great attention, when Ligand® pharmaceutical and Nimbus Discovery® reported the beneficial potentials of IRAK-4 inhibitors in the pre-clinical evaluation for various inflammatory- and immune-related disorders, but not limited to, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, gout, asthma and cancer. PMID:25728511

  15. Synthesis and Evaluation of Novel Triterpene Analogues of Ursolic Acid as Potential Antidiabetic Agent.

    PubMed

    Wu, Panpan; Zheng, Jie; Huang, Tianming; Li, Dianmeng; Hu, Qingqing; Cheng, Anming; Jiang, Zhengyun; Jiao, Luoying; Zhao, Suqing; Zhang, Kun

    2015-01-01

    Ursolic acid (UA) is a naturally bioactive compound that possesses potential anti-diabetic activity. The relatively safe and effective molecule intrigued us to further explore and to improve its anti-diabetic activity. In the present study, a series of novel UA analogues was synthesized and their structures were characterized. Their bioactivities against the α-glucosidase from baker's yeast were determined in vitro. The results suggested that most of the analogues exhibited significant inhibitory activity, especially analogues 8b and 9b with the IC50 values of 1.27 ± 0.27 μM (8b) and 1.28 ± 0.27 μM (9b), which were lower than the other analogues and the positive control. The molecular docking and 2D-QSAR studies were carried out to prove that the C-3 hydroxyl could interact with the hydrophobic region of the active pocket and form hydrogen bonds to increase the binding affinity of ligand and the homology modelling protein. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from UA analogues. PMID:26406581

  16. Brominated and radioiodinated derivatives of methylphenidate (MP): Potential imaging agents for the dopamine (DA) transporter

    SciTech Connect

    Pan, D.; Gatley, S.J.; Dewey, S.L.

    1994-05-01

    MP (Ritalin) is a psychomotor stimulant used in the treatment of attention-deficit hyperactivity disorder. The therapeutic properties of MP are thought to be mediated by its binding to a site on the DA transporter, resulting in inhibition of DA reuptake and enhanced levels of synaptic dopamine. MP also inhibits reuptake of norepinephrine (NE) in vitro. MP has two chiral centers, but its pharmacological activity is believed due solely to the d-threo isomer. We have found that d,l-threo-C-11 MP has favorable properties for PET studies, and therefore examined the effects of incorporating halogen atoms into the phenyl ring of MP, with a view to preparing C-11 and I-123 MP analogs as potential PET/SPECT tracers. We synthesized the 2-, 3- and 4-bromo MP analogs from the corresponding bromophenylacetonitriles by modification of the original synthesis of MP. In in vitro binding assays all three d,l-threo bromo compounds had higher affinities than MP for DA transporter sites labeled with tritiated WIN 35,428 (3->4-, 2->MP). They also showed high activity with NE reuptake sites labeled with tritiated nisoxetine. They were active in vivo as demonstrated by inhibition of heart uptake of tritiated NE in the mouse, and elevation of striatal extracellular DA (microdialysis) and stimulation of locomotor activity in the rat.

  17. Conjugation of Uridine with Oleanolic Acid Derivatives as Potential Antitumor Agents.

    PubMed

    Cheng, Ke-Guang; Su, Chun-Hua; Huang, Jia-Yan; Liu, Jun; Zheng, Yuan-Ting; Chen, Zhen-Feng

    2016-09-01

    According to fused two bioactive moieties together by bonds covalently and available as a new single hybrid entity known as pharmacophore hybridization, a total of 10 targeted uridine-oleanolic acid hybrids were synthesized. Most of these hybrids showed excellent proliferation inhibition against tested Hep-G2, A549, BGC-823, MCF-7, and PC-3 tumor cell lines (IC50 < 8 μm), even with some IC50 values under 0.1 μm. The detection of cytotoxicity selectivity revealed that hybrids 5 and 18 exhibited low cytotoxicity toward normal human liver cell HL-7702. Further studies revealed that selected hybrid 5 could induce apoptosis in Hep-G2 cells through the investigation of acridine orange/ethidium bromide, Hoechst 33258 fluorescence stainings, and annexin V/propidium iodide assay. It was also found that hybrid 5 could induce mitochondrial membrane potential disruption, arrest Hep-G2 cell line at G1 phase, and activate effector caspase-3/9 to trigger cell apoptosis. PMID:26990000

  18. Advancements in Non-steroidal Antiandrogens as Potential Therapeutic Agents for the Treatment of Prostate Cancer.

    PubMed

    Kaur, Paranjeet; Khatik, Gopal L

    2016-01-01

    Prostate cancer (PCa) is a leading cause of death in men worldwide. The main reason for the progression of prostate cancer is identified as over activation of androgen receptor (AR) through androgens. Its development can be diagnosed by monitoring the prostate specific antigen (PSA). Treatment of PCa includes prostatectomy, radiotherapy, and chemotherapy, among them chemotherapy is normally employed in early and advanced prostate cancer. Chemotherapy mainly includes two classes of drugs which are steroidal and non-steroidal antiandrogens. The non-steroidal classes of compounds are preferred over steroidal because they are relatively safe, cost effective and diverse. Non-steroidal drugs are commonly used for the treatment of PCa, however these drugs are associated with serious side effects and acquired resistance. So researchers are working in the direction to develop better analogue which can address the issue related to resistant type of prostate cancer. This review discusses the advancement in the non-steroidal antiandrogens which offers a better potential in the treatment of prostate cancer. PMID:26776222

  19. Small Molecule Modulators of Keap1-Nrf2-ARE Pathway as Potential Preventive and Therapeutic Agents$

    PubMed Central

    Magesh, Sadagopan; Chen, Yu; Hu, Longqin

    2012-01-01

    Keap1-Nrf2-ARE pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, over-activation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction. PMID:22549716

  20. Synthesis and characterization of novel organocobaloximes as potential catecholase and antimicrobial activity agents.

    PubMed

    Erdem-Tuncmen, Mukadder; Karipcin, Fatma; Sariboga, Bahtiyar

    2013-10-01

    An asymmetric, potentially bidentate dioxime ligand (H₂L) was formed by condensation of 4-biphenylchloroglyoxime and napthyl-1-amine. Two equivalents of H₂L were reacted with CoCl₂  · 6H₂O under appropriate conditions with deprotonation of the dioxime ligand. A series of new organocobaloxime derivatives of the type [CoR(HL)₂Py], [CoRL₂PyB₂F₄], and [CoRL₂Py(Cu(phen))₂] (H₂L = 4-(napthyl-1-amino)biphenylglyoxime; phen = 1,10-phenathroline; R = izopropyl and benzyl; Py = pyridine) were synthesized. The products were characterized by elemental analysis, molar conductance, FT-IR, ¹H NMR, and magnetic susceptibility measurements. Catecholase-like activity properties of all complexes were also studied. All complexes are catalysts for the oxidation of 3,5-di-tert-butylcatechol to 3,5-di-tert-butyl-1,2-benzoquinone in methanol. Antimicrobial activity studies of H₂L and the six complexes were carried out on standard strains (human pathogenic) of bacteria (Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Bacillus cereus, Enterococcus faecalis, Streptococcus pneumoniae, Listeria monocytogenes, Bacillus subtilis, Escherichia coli, Pseudominas aeruginosa, Salmonella typhi) and the yeast Candida albicans. The compounds showed a significant inhibition of the growth of the Gram-positive bacteria tested. Among the tested microorganisms, S. aureus was the most sensitive strain, especially to H₂L and its complexes. PMID:24003018

  1. Autotrophic, hydrogen-oxidizing, denitrifying bacteria in groundwater, potential agents for bioremediation of nitrate contamination

    USGS Publications Warehouse

    Smith, R.L.; Ceazan, M.L.; Brooks, M.H.

    1994-01-01

    Addition of hydrogen or formate significantly enhanced the rate of consumption of nitrate in slurried core samples obtained from an active zone of denitrification in a nitrate-contaminated sand and gravel aquifer (Cape Cod, Mass.). Hydrogen uptake by the core material was immediate and rapid, with an apparent K(m) of 0.45 to 0.60 ??M and a V(max) of 18.7 nmol cm-3 h-1 at 30??C. Nine strains of hydrogen-oxidizing denitrifying bacteria were subsequently isolated from the aquifer. Eight of the strains grew autotrophically on hydrogen with either oxygen or nitrate as the electron acceptor. One strain grew mixotrophically. All of the isolates were capable of heterotrophic growth, but none were similar to Paracoccus denitrificans, a well-characterized hydrogen-oxidizing denitrifier. The kinetics for hydrogen uptake during denitrification were determined for each isolate with substrate depletion progress curves; the K(m)s ranged from 0.30 to 3.32 ??M, with V(max)s of 1.85 to 13.29 fmol cell-1 h-1. Because these organisms appear to be common constituents of the in situ population of the aquifer, produce innocuous end products, and could be manipulated to sequentially consume oxygen and then nitrate when both were present, these results suggest that these organisms may have significant potential for in situ bioremediation of nitrate contamination in groundwater.

  2. Solid-phase synthesis of libraries of ethynylated aminosteroid derivatives as potential antileukemic agents.

    PubMed

    Talbot, Amélie; Maltais, René; Kenmogne, Lucie Carolle; Roy, Jenny; Poirier, Donald

    2016-03-01

    Steroids possessing an ethynyl group at position 17α (tertiary alcohols) are well known to be more stable than their non-ethynyl analogs (secondary alcohols). To facilitate the development of new drugs with better metabolic stability, we developed a new diethylsilyl acetylenic linker allowing us to rapidly synthesize libraries of ethynylated steroid derivatives using a solid-phase strategy. To illustrate its usefulness, this linker was used to expand the molecular diversity of a lead compound having a hydroxy acetylenic pattern and to potentially find new compounds with interesting cytotoxic activity against leukemia cell lines. Herein, we report the chemical synthesis and the characterization of three libraries of ethynylated aminosteroid derivatives using the diethylacetylenic linker. We discuss their antiproliferative activities obtained in 2 leukemia cell lines (HL-60 and Jurkat), which results provided new structure-activity relationships. We also identified a new promising aminosteroid derivative with an azetidine moiety (compound B1) inhibiting 60% and 75% of HL-60 and Jurkat cell proliferation, respectively, at 1 μM. More generally, these results validate the use of a diethylsilyl acetylenic linker for researchers interested in generating libraries of alcohol derivatives with better stability and drug profile. PMID:26742630

  3. Boric acid: a potential chemoprotective agent against aflatoxin b1 toxicity in human blood

    PubMed Central

    Geyikoglu, Fatime

    2010-01-01

    Aflatoxin B1 is the most potent pulmonary and hepatic carcinogen. Since the eradication of Aflatoxin B1 contamination in agricultural products has been difficult, the use of natural or synthetic free radical scavengers could be a potential chemopreventive strategy. Boric acid is the major component of industry and its antioxidant role has recently been reported. The present study assessed, for the first time, the effectiveness of boric acid following exposure to Aflatoxin B1 on human whole blood cultures. The biochemical characterizations of glutathione and some enzymes have been carried out in erythrocytes. Alterations in malondialdehyde level were determined as an index of oxidative stress. The sister-chromatid exchange and micronucleus tests were performed to assess DNA damages in lymphocytes. Aflatoxin B1 treatment significantly reduced the activities of antioxidants by increasing malondialdehyde level (30.53 and 51.43%) of blood, whereas, the boric acid led to an increased resistance of DNA to oxidative damage induced by Aflatoxin B1 in comparison with control values (P < 0.05). In conclusion, the support of boric acid was especially useful in Aflatoxin-toxicated blood. Thus the risk on tissue targeting of Aflatoxin B1 could be reduced ensuring early recovery from its toxicity. PMID:20431944

  4. Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents.

    PubMed

    Abed, Dhulfiqar Ali; Goldstein, Melanie; Albanyan, Haifa; Jin, Huijuan; Hu, Longqin

    2015-07-01

    The Keap1-Nrf2-ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1-Nrf2 protein-protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1-Nrf2 PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1׳s cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1-Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1-Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions. PMID:26579458

  5. Potentiation activity of multiple antibacterial agents by Salvianolate from the Chinese medicine Danshen against methicillin-resistant Staphylococcus aureus (MRSA).

    PubMed

    Liu, Qing-Qing; Han, Jun; Zuo, Guo-Ying; Wang, Gen-Chun; Tang, Hua-Shu

    2016-05-01

    Salvianolate (SAL) is a prescribed medicine from the Chinese herb Danshen (Salvia miltiorrhiza Bunge). It has been widely used in treatment of coronary and other diseases with significant effects. The in vitro antimicrobial activities of SAL against infectious pathogens were assayed and its combined effects on 10 clinical isolates of SCCmec III type methicillin-resistant Staphylococcus aureus (MRSA) with ten antibiotics were evaluated. Susceptibility to each agent alone was tested using a broth microdilution method, and the chequerboard and time-kill experiments were used for the combined activities. The results showed MIC was 128-256 mg/L for SAL used alone against MRSA. Significant synergies were observed for SAL/Ampicillin (Fosfomycin, Erythromycin, Piperacillin-tazobactam or Clindamycin) combination against over half of the isolates, with their MICs reduced by times of dilution (TOD) to 4-32 (FICIs 0.375-0.5), respectively. SAL/AMP combination showed the best combined effect of synergy on bacteriostatic and bactericidal activities, while SAL/AMK combination reversed the resistance of MRSA to AMK. The results demonstrated that SAL enhanced widely the in vitro anti-MRSA efficacy of the ten antibacterial agents, which had potential for combinatory therapy of patients infected with MRSA and warrants further investigations. PMID:26639445

  6. A case of ecological specialization in ladybirds: Iberorhyzobius rondensis (Coleoptera: Coccinellidae), potential biocontrol agent of Matsucoccus feytaudi (Hemiptera: Matsucoccidae).

    PubMed

    Tavares, C; Jactel, H; van Halder, I; Mendel, Z; Branco, M

    2014-06-01

    Specialization is an important attribute of a biological control agent. The maritime pine bast scale, Matsucoccus feytaudi Ducasse (Hemiptera Matsucoccidae), is an invasive species in Southeast France and the North of Italy. Iberorhyzobius rondensis Eizaguirre (Coleoptera: Coccinellidae), is a recently described ladybird species. Both adults and larvae are predaceous, feeding on egg masses of M. feytaudi, and are strongly attracted to M. feytaudi's sex pheromone. To evaluate the potential of I. rondensis as a biocontrol agent of the scale, we studied its niche breadth and prey range with emphasis on pine forests and hemipterans as tested prey. In this study, I. rondensis was found to achieve complete development only when fed on M. feytaudi egg masses (92.9% survival) and an artificial prey: eggs of Ephestia kuehniella Zeller (27.6% survival). From the 2nd instar onwards, complete development could be achieved using other prey species, although larvae had significantly higher mortality and slower development. In choice tests, M. feytaudi was the preferred prey. Surveys of the ladybird populations in the Iberian Peninsula revealed that it was found exclusively on Pinus pinaster Aiton, the sole host of M. feytaudi. The unusual specialization of I. rondensis, among other predaceous ladybirds, makes it an appropriate candidate for classical biological control of M. feytaudi. PMID:24666751

  7. A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers.

    PubMed

    Bishop, J B; Phillips, L G; Mustoe, T A; VanderZee, A J; Wiersema, L; Roach, D E; Heggers, J P; Hill, D P; Taylor, E L; Robson, M C

    1992-08-01

    Chronic wounds such as venous stasis ulcers have become a socioeconomic problem. Even with successful initial management, the recurrence rate approaches 70%. With the advent of new wound healing agents, nonoperative attempts to heal these wounds appear indicated. This study reports a prospective randomized evaluator-blinded trial comparing two potential wound healing agents to an inert vehicle placebo. Eighty-six evaluable patients completed the trial. Silver sulfadiazine 1% in a cream proved to statistically reduce the ulcer size compared with a biologically active tripeptide copper complex 0.4% cream formulation or the placebo. There was no difference between the latter two treatments. Silver sulfadiazine has been shown to allow keratinocyte replication and to have antiinflammatory properties. In this trial its antibacterial action was not used since all ulcers had comparable bacterial levels (less than or equal to 10(5)/gm of tissue) before treatment. These results suggest that the silver sulfadiazine cream used in this study may facilitate healing in wounds healing largely by the process of epithelialization. PMID:1495150

  8. Potential Therapeutic Effects of Curcumin, the Anti-inflammatory Agent, Against Neurodegenerative, Cardiovascular, Pulmonary, Metabolic, Autoimmune and Neoplastic Diseases

    PubMed Central

    Aggarwal, Bharat B.; Harikumar, Kuzhuvelil B.

    2009-01-01

    Although safe in most cases, ancient treatments are ignored because neither their active component nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. For centuries it has been known that turmeric exhibits anti-inflammatory activity, but extensive research performed within the past two decades has shown that the this activity of turmeric is due to curcumin, a diferuloylmethane. This agent has been shown to regulate numerous transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that have been linked to inflammation. The process of inflammation has been shown to play a major role in most chronic illnesses, including neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. In the current review, we provide evidence for the potential role of curcumin in the prevention and treatment of various pro-inflammatory chronic diseases. These features, combined with the pharmacological safety and negligible cost, render curcumin an attractive agent to explore further. PMID:18662800

  9. Coumarin carboxylic acids as monocarboxylate transporter 1 inhibitors: In vitro and in vivo studies as potential anticancer agents.

    PubMed

    Gurrapu, Shirisha; Jonnalagadda, Sravan K; Alam, Mohammad A; Ronayne, Conor T; Nelson, Grady L; Solano, Lucas N; Lueth, Erica A; Drewes, Lester R; Mereddy, Venkatram R

    2016-07-15

    Novel N,N-dialkyl carboxy coumarins have been synthesized as potential anticancer agents via inhibition of monocarboxylate transporter 1 (MCT1). These coumarin carboxylic acids have been evaluated for their in vitro MCT1 inhibition, MTT cancer cell viability, bidirectional Caco-2 cell permeability, and stability in human and liver microsomes. These results indicate that one of the lead candidate compounds 4a has good absorption, metabolic stability, and a low drug efflux ratio. Systemic toxicity studies with lead compound 4a in healthy mice demonstrate that this inhibitor is well tolerated based on zero animal mortality and normal body weight gains compared to the control group. In vivo tumor growth inhibition studies in mice show that the candidate compound 4a exhibits significant single agent activity in MCT1 expressing GL261-luc2 syngraft model but doesn't show significant activity in MCT4 expressing MDA-MB-231 xenograft model, indicating the selectivity of 4a for MCT1 expressing tumors. PMID:27241692

  10. Potential of high-Z contrast agents in clinical contrast-enhanced computed tomography

    SciTech Connect

    Nowak, Tristan; Hupfer, Martin; Brauweiler, Robert; Eisa, Fabian; Kalender, Willi A.

    2011-12-15

    Purpose: Currently, only iodine- and barium-based contrast media (CM) are used in clinical contrast-enhanced computed tomography (CE-CT). High-Z metals would produce a higher contrast at equal mass density for the x-ray spectra used in clinical CT. Using such materials might allow for significant dose reductions in CE-CT. The purpose of this study was to quantify the potential for dose reduction when using CM based on heavy metals. Methods: The contrast-to-noise ratio weighted by dose (CNRD) was determined as a function of scan protocol by means of measurements and simulations on a clinical CT scanner. For simulations, water cylinders with diameters 160, 320, 480, and 640 mm were used to cover a broad range of patient sizes. Measurements were conducted with 160 and 320 mm water-equivalent plastic cylinders. A central bore of 13 mm diameter was present in all phantoms. The tube voltage was varied from 80 to 140 kV for measurements and from 60 to 180 kV for simulations. Additional tin filtration of thicknesses 0.4, 0.8, and 1.2 mm was applied in the simulation to evaluate a range of spectral hardness. The bore was filled with a mixture of water and 10 mg/ml of pure iodine, holmium, gadolinium, ytterbium, osmium, tungsten, gold, and bismuth for the simulations and with aqueous solutions of ytterbium, tungsten, gold, and bismuth salts as well as Iopromid containing 10 mg/ml of the pure materials for the measurements. CNRDs were compared to iodine at phantom size-dependent reference voltages for all high-Z materials and the resulting dose reduction was calculated for equal contrast-to-noise ratio. Results: Dose reduction potentials strongly depended on phantom size, spectral hardness, and tube voltage. Depending on the added filtration, a dose reduction of 19%-60% could be reached at 80 kV with gadolinium for the 160 mm phantom, 52%-69% at 100 kV with holmium for the 320 mm phantom, 62%-78% with 120 kV for hafnium and the 480 mm phantom and 74%-86% with 140 kV for gold

  11. Biodistribution and Stability Studies of [18F]Fluoroethylrhodamine B, a Potential PET Myocardial Perfusion Agent

    PubMed Central

    Gottumukkala, Vijay; Heinrich, Tobias K.; Baker, Amanda; Dunning, Patricia; Fahey, Frederick H; Treves, S. Ted; Packard, Alan B.

    2010-01-01

    Introduction Fluorine-18-labeled rhodamine B was developed as a potential PET tracer for the evaluation of myocardial perfusion, but preliminary studies in mice showed no accumulation in the heart suggesting that it was rapidly hydrolyzed in vivo in mice. A study was, therefore, undertaken to further evaluate this hypothesis. Methods [18F]Fluoroethylrhodamine B was equilibrated for 2 h at 37 °C in human, rat and mouse serum and in PBS. Samples were removed periodically and assayed by HPLC. Based on the results of the stability study, microPET imaging and a biodistribution study were carried out in rats. Results In vitro stability studies demonstrated that [18F]fluoroethylrhodamine B much more stable in rat and human sera than in mouse serum. After 2 h, the compound was >80% intact in rat serum but <30% intact in mouse serum. The microPET imaging and biodistribution studies in rats confirmed this result showing high and persistent tracer accumulation in the myocardium compared with the absence of uptake by the myocardium in mice thereby validating our original hypothesis that 18F-labeled rhodamines should accumulate in the heart. Conclusions [18F]Fluoroethyl rhodamine B is more stable in rat and human sera than it is in mouse serum. This improved stability is demonstrated by the high uptake of the tracer in the rat heart in comparison to the absence of visible uptake in the mouse heart. These observations suggest that 18F-labeled rhodamines are promising candidates for more extensive evaluation as PET tracers for the evaluation of myocardial perfusion. PMID:20346876

  12. Iron oxide nanoparticles functionalized with novel hydrophobic and hydrophilic porphyrins as potential agents for photodynamic therapy.

    PubMed

    Penon, Oriol; Marín, María J; Amabilino, David B; Russell, David A; Pérez-García, Lluïsa

    2016-01-15

    The preparation of novel porphyrin derivatives and their immobilization onto iron oxide nanoparticles to build up suitable nanotools for potential use in photodynamic therapy (PDT) has been explored. To achieve this purpose, a zinc porphyrin derivative, ZnPR-COOH, has been synthesized, characterized at the molecular level and immobilized onto previously synthesized iron oxide nanoparticles covered with oleylamine. The novel nanosystem (ZnPR-IONP) has been thoroughly characterized by a variety of techniques such as UV-Vis absorption spectroscopy, fluorescence spectroscopy, X-ray photoloectron spectroscopy (XPS) and transmission electron microscopy (TEM). In order to probe the capability of the photosensitizer for PDT, the singlet oxygen production of both ZnPR-IONP and the free ligand ZnPR-COOH have been quantified by measuring the decay in absorption of the anthracene derivative 9,10-anthracenedipropionic acid (ADPA), showing an important increase on singlet oxygen production when the porphyrin is incorporated onto the IONP (ZnPR-IONP). On the other hand, the porphyrin derivative PR-TRIS3OH, incorporating several polar groups (TRIS), was synthesized and immobilized with the intention of obtaining water soluble nanosystems (PR-TRIS-IONP). When the singlet oxygen production ability was evaluated, the values obtained were similar to ZnPR-COOH/ZnPR-IONP, again much higher in the case of the nanoparticles PR-TRIS-IONP, with more than a twofold increase. The efficient singlet oxygen production of PR-TRIS-IONP together with their water solubility, points to the great promise that these new nanotools represent for PDT. PMID:26454374

  13. Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders.

    PubMed

    Ganie, Showkat Ahmad; Dar, Tanveer Ali; Bhat, Aashiq Hussain; Dar, Khalid B; Anees, Suhail; Zargar, Mohammad Afzal; Masood, Akbar

    2016-02-01

    Mitochondria play a central role in cellular physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions, including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis, and control of apoptosis. Simultaneously, mitochondria are the main producer and target of ROS with the result that multiple mitochondrial diseases are related to ROS-induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide synthase (iNOS) activity, enhanced nitric oxide (NO) production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pores have all been suggested as factors responsible for impaired mitochondrial function. Because of these, neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and aging, are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an anti-oxidant and as a regulator of mitochondrial bioenergetic function. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other anti-oxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. With these functions in mind, this article reviews the protective role of melatonin with mechanistic insights against mitochondrial diseases and suggests new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights are also discussed. PMID:26087000

  14. Dendrimer-entrapped gold nanoparticles as potential CT contrast agents for blood pool imaging

    PubMed Central

    2012-01-01

    The purpose of this study was to evaluate dendrimer-entrapped gold nanoparticles [Au DENPs] as a molecular imaging [MI] probe for computed tomography [CT]. Au DENPs were prepared by complexing AuCl4- ions with amine-terminated generation 5 poly(amidoamine) [G5.NH2] dendrimers. Resulting particles were sized using transmission electron microscopy. Serial dilutions (0.001 to 0.1 M) of either Au DENPs or iohexol were scanned by CT in vitro. Based on these results, Au DENPs were injected into mice, either subcutaneously (10 μL, 0.007 to 0.02 M) or intravenously (300 μL, 0.2 M), after which the mice were imaged by micro-CT or a standard mammography unit. Au DENPs prepared using G5.NH2 dendrimers as templates are quite uniform and have a size range of 2 to 4 nm. At Au concentrations above 0.01 M, the CT value of Au DENPs was higher than that of iohexol. A 10-μL subcutaneous dose of Au DENPs with [Au] ≥ 0.009 M could be detected by micro-CT. The vascular system could be imaged 5 and 20 min after injection of Au DENPs into the tail vein, and the urinary system could be imaged after 60 min. At comparable time points, the vascular system could not be imaged using iohexol, and the urinary system was imaged only indistinctly. Findings from this study suggested that Au DENPs prepared using G5.NH2 dendrimers as templates have good X-ray attenuation and a substantial circulation time. As their abundant surface amine groups have the ability to bind to a range of biological molecules, Au DENPs have the potential to be a useful MI probe for CT. PMID:22429280

  15. S-equol: a potential nonhormonal agent for menopause-related symptom relief.

    PubMed

    Utian, Wulf H; Jones, Michelle; Setchell, Kenneth D R

    2015-03-01

    Many women suffering from vasomotor symptoms (VMS) are now seeking nonpharmaceutical treatments for symptom relief. Recently, S-equol, an intestinal bacterial metabolite of the soybean isoflavone daidzein has received attention for its ability to alleviate VMS and provide other important health benefits to menopausal women. S-equol is found in very few foods and only in traces. About 50% of Asians and 25% of non-Asians host the intestinal bacteria that convert daidzein into S-equol. Clinical trials that evaluated the efficacy of an S-equol-containing product found that VMS were alleviated but these trials were limited in scope and primarily involved Japanese women for whom hot flashes are a minor complaint. The only trial in the United States evaluating hot flashes found symptoms were significantly reduced by S-equol, but the study lacked a placebo group, although it did include a positive control. The daily dose of S-equol used in most trials was 10 mg, and because the half-life of S-equol is 7-10 hours, to maximize efficacy, it was taken twice daily. Subanalysis of epidemiologic studies suggests that equol producers are more likely to benefit from soyfood consumption than nonproducers with respect to both cardiovascular disease and osteoporosis, although the data are inconsistent. The limited safety data for S-equol do not suggest cause for concern, especially with regard to its effects on breast and endometrial tissue. Further studies are needed before definitive conclusions of its effectiveness for VMS can be made, but the preliminary evidence warrants clinicians discussing the potential of S-equol for the alleviation of VMS with patients. PMID:25692726

  16. Multi-Functional Roles of Chitosan as a Potential Protective Agent against Obesity

    PubMed Central

    Walsh, Ann M.; Sweeney, Torres; Bahar, Bojlul; O’Doherty, John V.

    2013-01-01

    Chitosan, a natural polysaccharide comprising copolymers of glucosamine and N-acetylglucosamine, has been shown to have anti-obesity properties. Two experiments (Exp. 1 and Exp. 2) were performed to determine the role of chitosan on dietary intake, body weight gain, and fat deposition in a pig model, as well as identifying potential mechanisms underlying the anti-obesity effect of chitosan. In Exp. 1, the nutrient digestibility experiment, 16 pigs (n = 4/treatment) were randomly allocated to one of four dietary treatments as follows: 1) basal diet; 2) basal diet plus 300 ppm chitosan; 3) basal diet plus 600 ppm chitosan; 4) basal diet plus 1200 ppm chitosan. The main observation was that crude fat digestibility was lower in the 1200 ppm chitosan group when compared with the control group (P<0.05). In Exp. 2, a total of 80 pigs (n = 20/treatment) were offered identical dietary treatments to that offered to animals in Exp. 1. Blood samples were collected on day 0, day 35 and at the end of the experiment (day 57). Animals offered diets containing 1200 ppm chitosan had a lower daily dietary intake (P<0.001) and body weight gain (P<0.001) from day 35 to 57 when compared with all the other treatment groups. Animals offered diets containing 1200 ppm chitosan had a significantly lower final body weight (P<0.01) when compared with all the other treatment groups. The decreased dietary intake observed in the 1200 ppm chitosan group was associated with increased serum leptin concentrations (P<0.001) and a decrease in serum C-reactive protein (CRP) concentrations (P<0.05). In conclusion, the results of this study highlight novel endocrine mechanisms involving the modulation of serum leptin and CRP concentrations by which chitosan exhibits anti-obesity properties in vivo. PMID:23342013

  17. Fundamental Host Range of Leptoypha hospita (Hemiptera: Tingidae), a Potential Biological Control Agent of Chinese Privet.

    PubMed

    Zhang, Yanzhuo; Hanula, James L; Horn, Scott; Jones, Cera; Kristine Braman, S; Sun, Jianghua

    2016-08-01

    Chinese privet, Ligustrum sinense Lour., is an invasive shrub within riparian areas of the southeastern United States. Biological control is considered the most suitable management option for Chinese privet. The potential host range of the lace bug, Leptoypha hospita Drake et Poor, was evaluated on the basis of adult feeding and oviposition, combined oviposition-nymphal development no-choice tests, nymphal development no-choice tests, multiple generation comparison on Forestiera pubescens Nutt. and L. sinense no-choice tests, and multiple-choice tests with 45 plant species in 13 families. No-choice tests showed that the host range of L. hospita was restricted to the tribe Oleeae. In adult feeding and oviposition no-choice tests, the bug fed and oviposited significantly more on Chinese privet than all other test plant species except for three native Forestiera spp., two nonnative Syringa spp., and another exotic Ligustrum sp. Among those, only F. pubescens supported complete development in numbers comparable to Chinese privet. However, when reared for multiple generations lace bugs reared on F. pubescens were smaller and had lower fecundity than those reared on L. sinense, suggesting F. pubescens is not an optimal host. In multiple-choice tests, L. hospita displayed a strong preference for feeding and ovipositing on Chinese privet over other test plant species, with the exception of the closely related nonnative Syringa spp. and its congenic species Ligustrum vulgare. The results of this study suggest that the risk to nontarget plant species in North America is minimal, and L. hospita would be a promising candidate for Chinese privet biological control. PMID:27325627

  18. Novel amphiphilic cationic porphyrin and its Ag(II) complex as potential anticancer agents

    PubMed Central

    Tovmasyan, Artak; Babayan, Nelli; Poghosyan, David; Margaryan, Kristine; Harutyunyan, Boris; Grigoryan, Rusanna; Sarkisyan, Natalia; Spasojevic, Ivan; Mamyan, Suren; Sahakyan, Lida; Aroutiounian, Rouben; Ghazaryan, Robert; Gasparyan, Gennadi

    2015-01-01

    In the present study we have synthesized a novel amphiphilic porphyrin and its Ag(II) complex through modification of water-soluble porphyrinic structure in order to increase its lipophilicity and in turn pharmacological potency. New cationic non-symmetrical meso-substituted porphyrins were characterized by UV–visible, electrospray ionization mass spectrometry (ESI-MS), 1H NMR techniques, lipophilicity (thin-layer chromatographic retention factor, Rf), and elemental analysis. The key toxicological profile (i.e. cytotoxicity and cell line-(cancer type-) specificity; genotoxicity; cell cycle effects) of amphiphilic Ag porphyrin was studied in human normal and cancer cell lines of various tissue origins and compared with its water-soluble analog. Structural modification of the molecule from water-soluble to amphiphilic resulted in a certain increase in the cytotoxicity and a decrease in cell line-specificity. Importantly, Ag(II) porphyrin showed less toxicity to normal cells and greater toxicity to their cancerous counterparts as compared to cisplatin. The amphiphilic complex was also not genotoxic and demonstrated a slight cytostatic effect via the cell cycle delay due to the prolongation of S-phase. As expected, the performed structural modification affected also the photocytotoxic activity of metal-free amphiphilic porphyrin. The ligand tested on cancer cell line revealed a dramatic (more than 70-fold) amplification of its phototoxic activity as compared to its water-soluble tetracationic metal-free analog. The compound combines low dark cytotoxicity with 5 fold stronger phototoxicity relative to Chlorin e6 and could be considered as a potential photosensitizer for further development in photodynamic therapy. PMID:25086237

  19. Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents

    PubMed Central

    Russo, Francesco; Gising, Johan; Åkerbladh, Linda; Roos, Annette K; Naworyta, Agata; Mowbray, Sherry L; Sokolowski, Anders; Henderson, Ian; Alling, Torey; Bailey, Mai A; Files, Megan; Parish, Tanya; Karlén, Anders; Larhed, Mats

    2015-01-01

    This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure–activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs. PMID:26246997

  20. Biological activity of N(4)-boronated derivatives of 2'-deoxycytidine, potential agents for boron-neutron capture therapy.

    PubMed

    Nizioł, Joanna; Uram, Łukasz; Szuster, Magdalena; Sekuła, Justyna; Ruman, Tomasz

    2015-10-01

    Boron-neutron capture therapy (BNCT) is a binary anticancer therapy that requires boron compound for nuclear reaction during which high energy alpha particles and lithium nuclei are formed. Unnatural, boron-containing nucleoside with hydrophobic pinacol moiety was investigated as a potential BNCT boron delivery agent. Biological properties of this compound are presented for the first time and prove that boron nucleoside has low cytotoxicity and that observed apoptotic effects suggest alteration of important functions of cancer cells. Mass spectrometry analysis of DNA from cancer cells proved that boron nucleoside is inserted into nucleic acids as a functional nucleotide derivative. NMR studies present very high degree of similarity of natural dG-dC base pair with dG-boron nucleoside system. PMID:26344594

  1. Design, synthesis and biological evaluation of 5-fluorouracil-derived benzimidazoles as novel type of potential antimicrobial agents.

    PubMed

    Fang, Xue-Jie; Jeyakkumar, Ponmani; Avula, Srinivasa Rao; Zhou, Qian; Zhou, Cheng-He

    2016-06-01

    A series of 5-fluorouracil benzimidazoles as novel type of potential antimicrobial agents were designed and synthesized for the first time. Bioactive assay manifested that some of the prepared compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains in comparison with reference drugs norfloxacin, chloromycin and fluconazole. Noticeably, 3-fluorobenzyl benzimidazole derivative 5c gave remarkable antimicrobial activities against Saccharomyces cerevisiae, MRSA and Bacillus proteus with MIC values of 1, 2 and 4μg/mL, respectively. Experimental research revealed that compound 5c could effectively intercalate into calf thymus DNA to form compound 5c-DNA complex which might block DNA replication and thus exert antimicrobial activities. Molecular docking indicated that compound 5c should bind with DNA topoisomerase IA through three hydrogen bonds by the use of fluorine atom and oxygen atoms in 5-fluorouracil with the residue Lys 423. PMID:27117429

  2. Raman, infrared and DFT studies of N‧-(adamantan-2-ylidene)benzohydrazide, a potential antibacterial agent

    NASA Astrophysics Data System (ADS)

    Shundalau, Maksim B.; Al-Abdullah, Ebtehal S.; Shabunya-Klyachkovskaya, Elena V.; Hlinisty, Anton V.; Al-Deeb, Omar A.; El-Emam, Ali A.; Gaponenko, Sergey V.

    2016-07-01

    The Raman and Fourier transform infrared spectra of the N‧-(adamantan-2-ylidene)benzohydrazide molecule (C17H20N2O), a potential antibacterial agent, were examined in the ranges of 3500-300 cm-1 and 3500-650 cm-1, respectively. The density functional theory calculations were performed for the geometric structures and vibrational spectra for the two conformers (cis- and trans-) and for the dimer of the title molecule. On the basis of full geometry optimization at the B3LYP/cc-pVDZ level of the theory, the equilibrium configurations were determined; Raman and IR vibrational spectra were calculated and compared with the experimental ones. The experimental vibrational Raman and infrared spectra were interpreted. The calculations for the trans-conformer were found to describe better the experimentally observed vibrational modes for the crystalline phase than the calculations which were performed for the cis-conformer and for the dimer.

  3. NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragile X syndrome.

    PubMed

    Deacon, Robert M J; Glass, Larry; Snape, Mike; Hurley, Michael J; Altimiras, Francisco J; Biekofsky, Rodolfo R; Cogram, Patricia

    2015-03-01

    Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, and many agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. In the present work, a novel pharmacological approach for FXS is investigated. NNZ-2566, a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1), was administered to fmr1 knockout mice correcting learning and memory deficits, abnormal hyperactivity and social interaction, normalizing aberrant dendritic spine density, overactive ERK and Akt signaling, and macroorchidism. Altogether, our results indicate a unique disease-modifying potential for NNZ-2566 in FXS. Most importantly, the present data implicate the IGF-1 molecular pathway in the pathogenesis of FXS. A clinical trial is under way to ascertain whether these findings translate into clinical effects in FXS patients. PMID:25613838

  4. Honey – a potential agent against Porphyromonas gingivalis: an in vitro study

    PubMed Central

    2014-01-01

    Background Honey has been discussed as a therapeutic option in wound healing since ancient time. It might be also an alternative to the commonly used antimicrobials in periodontitis treatment. The in-vitro study was aimed to determine the antimicrobial efficacy against Porphyromonas gingivalis as a major periodontopathogen. Methods One Manuka and one domestic beekeeper honey have been selected for the study. As a screening, MICs of the honeys against 20 P. gingivalis strains were determined. Contents of methylglyoxal and hydrogen peroxide as the potential antimicrobial compounds were determined. These components (up to 100 mg/l), propolis (up to 200 mg/l) as well as the two honeys (up to 10% w/v) were tested against four P. gingivalis strains in planktonic growth and in a single-species biofilm. Results 2% of Manuka honey inhibited the growth of 50% of the planktonic P. gingivalis, the respective MIC50 of the German beekeeper honey was 5%. Manuka honey contained 1.87 mg/kg hydrogen peroxide and the domestic honey 3.74 mg/kg. The amount of methylglyoxal was found to be 2 mg/kg in the domestic honey and 982 mg/kg in the Manuka honey. MICs for hydrogen peroxide were 10 mg/l - 100 mg/l, for methylglyoxal 5 – 20 mg/l, and for propolis 20 mg/l – 200 mg/l. 10% of both types of honey inhibited the formation of P. gingivalis biofilms and reduced the numbers of viable bacteria within 42 h-old biofilms. Neither a total prevention of biofilm formation nor a complete eradication of a 42 h-old biofilm by any of the tested compounds and the honeys were found. Conclusions Honey acts antibacterial against P. gingivalis. The observed pronounced effects of Manuka honey against planktonic bacteria but not within biofilm can be attributed to methylglyoxal as the characteristic antimicrobial component. PMID:24666777

  5. Rhodomyrtone as a potential anti-proliferative and apoptosis inducing agent in HaCaT keratinocyte cells.

    PubMed

    Chorachoo, Julalak; Saeloh, Dennapa; Srichana, Teerapol; Amnuaikit, Thanaporn; Musthafa, Khadar Syed; Sretrirutchai, Somporn; Voravuthikunchai, Supayang P

    2016-02-01

    Psoriasis is a skin disease associated with hyperproliferation and abnormal differentiation of keratinocytes. Available approaches using synthetic drugs for the treatment of severe psoriasis may cause side effects. Alternatively, plant-derived compounds are now receiving much attention as alternative candidates for the treatment of psoriasis. In this study, the effects of rhodomyrtone, a bioactive plant extract isolated from Rhodomyrtus tomentosa leaves on the proliferation, growth arrest, and apoptosis of HaCaT keratinocytes were investigated. Percentage anti-proliferative activity of rhodomyrtone on HaCaT cells at concentrations of 2-32µg/ml after 24, 48, and 72h ranged from 13.62-61.61%, 50.59-80.16%, and 61.82-85.34%, respectively. In a scratch assay, rhodomyrtone at 2 and 4µg/ml significantly delayed closure of a wound by up to 61.78%, and 71.65%, respectively, after 24h incubation. HaCaT keratinocytes treated with rhodomyrtone showed chromatin condensation and fragmentation of nuclei when stained with Hoechst 33342. This indicated that rhodomyrtone induced apoptosis in the keratinocytes. In addition, flow cytometric analysis demonstrated an increase in the percentage of apoptosis of keratinocytes after treatment with rhodomyrtone at 2-32µg/ml from 1.2-10%, 8.2-35.4%, and 21.0-77.8% after 24, 48, and 72h, respectively, compared with the control. To further develop the compound as a potential anti-psoriasis agent, a rhodomyrtone formulation was prepared and subjected to skin irritation tests in rabbits. The formulation caused no skin irritation including such as erythema and edema. The results indicated that rhodomyrtone had the potential as a promising candidate for further development as a natural anti-psoriasis agent. PMID:26687635

  6. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 1

    PubMed Central

    Sagar, S.M.; Yance, D.; Wong, R.K.

    2006-01-01

    An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose–response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or

  7. Bioprospecting the Curculigoside-Cinnamic Acid-Rich Fraction from Molineria latifolia Rhizome as a Potential Antioxidant Therapeutic Agent.

    PubMed

    Ooi, Der Jiun; Chan, Kim Wei; Sarega, Nadarajan; Alitheen, Noorjahan Banu; Ithnin, Hairuszah; Ismail, Maznah

    2016-01-01

    Increasing evidence from both experimental and clinical studies depicts the involvement of oxidative stress in the pathogenesis of various diseases. Specifically, disruption of homeostatic redox balance in accumulated body fat mass leads to obesity-associated metabolic syndrome. Strategies for the restoration of redox balance, potentially by exploring potent plant bioactives, have thus become the focus of therapeutic intervention. The present study aimed to bioprospect the potential use of the curculigoside-cinnamic acid-rich fraction from Molineria latifolia rhizome as an antioxidant therapeutic agent. The ethyl acetate fraction (EAF) isolated from M. latifolia rhizome methanolic extract (RME) contained the highest amount of phenolic compounds, particularly curculigoside and cinnamic acid. EAF demonstrated glycation inhibitory activities in both glucose- and fructose-mediated glycation models. In addition, in vitro chemical-based and cellular-based antioxidant assays showed that EAF exhibited high antioxidant activities and a protective effect against oxidative damage in 3T3-L1 preadipocytes. Although the efficacies of individual phenolics differed depending on the structure and concentration, a correlational study revealed strong correlations between total phenolic contents and antioxidant capacities. The results concluded that enriched phenolic contents in EAF (curculigoside-cinnamic acid-rich fraction) contributed to the overall better reactivity. Our data suggest that this bioactive-rich fraction warrants therapeutic potential against oxidative stress-related disorders. PMID:27322226

  8. Computational Investigations of Potential Energy Function Development for Metal--Organic Framework Simulations, Metal Carbenes, and Chemical Warfare Agents

    NASA Astrophysics Data System (ADS)

    Cioce, Christian R.

    Metal-Organic Frameworks (MOFs) are three-dimensional porous nanomaterials with a variety of applications, including catalysis, gas storage and separation, and sustainable energy. Their potential as air filtration systems is of interest for designer carbon capture materials. The chemical constituents (i.e. organic ligands) can be functionalized to create rationally designed CO2 sequestration platforms, for example. Hardware and software alike at the bleeding edge of supercomputing are utilized for designing first principles-based molecular models for the simulation of gas sorption in these frameworks. The classical potentials developed herein are named PHAST --- Potentials with High Accuracy, Speed, and Transferability, and thus are designed via a "bottom-up" approach. Specifically, models for N2 and CH4 are constructed and presented. Extensive verification and validation leads to insights and range of applicability. Through this experience, the PHAST models are improved upon further to be more applicable in heterogeneous environments. Given this, the models are applied to reproducing high level ab initio energies for gas sorption trajectories of helium atoms in a variety of rare-gas clusters, the geometries of which being representative of sorption-like environments commonly encountered in a porous nanomaterial. This work seeks to push forward the state of classical and first principles materials modeling. Additionally, the characterization of a new type of tunable radical metal---carbene is presented. Here, a cobalt(II)---porphyrin complex, [Co(Por)], was investigated to understand its role as an effective catalyst in stereoselective cyclopropanation of a diazoacetate reagent. Density functional theory along with natural bond order analysis and charge decomposition analysis gave insight into the electronics of the catalytic intermediate. The bonding pattern unveiled a new class of radical metal---carbene complex, with a doublet cobalt into which a triplet carbene

  9. Spectroscopic and electronic structure calculation of a potential antibacterial agent incorporating pyrido-dipyrimidine-dione moiety using first principles

    NASA Astrophysics Data System (ADS)

    Fatma, Shaheen; Bishnoi, Abha; Singh, Vineeta; Al-Omary, Fatmah A. M.; El-Emam, Ali A.; Pathak, Shilendra; Srivastava, Ruchi; Prasad, Onkar; Sinha, Leena

    2016-04-01

    Quantum chemical calculations of geometrical structure, energy and vibrational wavenumbers of a novel functionalized pyrido-pyrimidine compound (a prospective antibacterial agent), chemically known as 6-Methyl,13,14,15-Trihydro-14-(4-Nitrophenyl)pyrido[1,2-a:1‧,2‧-a‧] pyrido[2″,3″-d:6″,5″-d‧]dipyrimidine-13,15-dione (C24H16N6O4), were carried out, using B3LYP/6311++G(d,p) method. Comprehensive interpretation of the infrared and Raman spectra of the compound under study is based on potential energy distribution. A good coherence between experimental and theoretical wavenumbers shows the preciseness of the assignments. NLO properties like the dipole moment, polarizability, first static hyperpolarizability and molecular electrostatic potential surface have been calculated to get a better cognizance of the properties of the title compound. Molecular docking results reveal that the title compound exhibit inhibitory activity against Staphylococcus aureus.

  10. Systematic review of herbals as potential anti-inflammatory agents: Recent advances, current clinical status and future perspectives

    PubMed Central

    Beg, Sarwar; Swain, Suryakanta; Hasan, Hameed; Barkat, M Abul; Hussain, Md Sarfaraz

    2011-01-01

    Many synthetic drugs reported to be used for the treatment of inflammatory disorders are of least interest now a days due to their potential side effects and serious adverse effects and as they are found to be highly unsafe for human assistance. Since the last few decades, herbal drugs have regained their popularity in treatment against several human ailments. Herbals containing anti-inflammatory activity (AIA) are topics of immense interest due to the absence of several problems in them, which are associated with synthetic preparations. The primary objective of this review is to provide a deep overview of the recently explored anti-inflammatory agents belonging to various classes of phytoconstituents like alkaloids, glycosides, terpenoids, steroids, polyphenolic compounds, and also the compounds isolated from plants of marine origin, algae and fungi. Also, it enlists a distended view on potential interactions between herbals and synthetic preparations, related adverse effects and clinical trials done on herbals for exploring their AIA. The basic aim of this review is to give updated knowledge regarding plants which will be valuable for the scientists working in the field of anti-inflammatory natural chemistry. PMID:22279370

  11. Novel R-roscovitine NO-donor hybrid compounds as potential pro-resolution of inflammation agents

    PubMed Central

    Montanaro, Gabriele; Bertinaria, Massimo; Rolando, Barbara; Fruttero, Roberta; Lucas, Christopher D.; Dorward, David A.; Rossi, Adriano G.; Megson, Ian L.; Gasco, Alberto

    2013-01-01

    Neutrophils play a pivotal role in the pathophysiology of multiple human inflammatory diseases. Novel pharmacological strategies which drive neutrophils to undergo programmed cell death (apoptosis) have been shown to facilitate the resolution of inflammation. Both the cyclin-dependent kinase inhibitor (CDKi) R-roscovitine and nitric oxide (NO) have been shown to enhance apoptosis of neutrophils and possess pro-resolution of inflammation properties. In order to search for new multi-target pro-resolution derivatives, here we describe the design, synthesis and investigation of the biological potential of a small series of hybrid compounds obtained by conjugating R-roscovitine with two different NO-donor moieties (compounds 2, 9a, 9c). The synthesized compounds were tested as potential pro-resolution agents, with their ability to promote human neutrophil apoptosis evaluated. Both compound 9a and 9c showed an increased pro-apoptotic activity when compared with either R-roscovitine or structurally related compounds devoid of the ability to release NO (des-NO analogues). Inhibition of either NO-synthase or soluble guanylate cyclase did not affect the induction of apoptosis by the R-roscovitine derivatives, similar to that reported for other classes of NO-donors. In contrast the NO scavenger PTIO prevented the enhanced apoptosis seen with compound 9a over R-roscovitine. These data show that novel compounds such as CDKi–NO-donor hybrids may have additive pro-resolution of inflammation effects. PMID:23394865

  12. Synthesis and Biological Evaluation of Novel N-phenyl-5-carboxamidyl Isoxazoles as Potential Chemotherapeutic Agents for Colon Cancer.

    PubMed

    Shaw, Jiajiu; Chen, Ben; Bourgault, Jean P; Jiang, Hao; Kumar, Narendra; Mishra, Jayshree; Valeriote, Frederick A; Media, Joe; Bobbitt, Kevin; Pietraszkiewicz, Halina; Edelstein, Matthew; Andreana, Peter R

    2012-01-01

    A new series of isoxazole derivatives, N-phenyl-5-carboxamidyl isoxazoles, was investigated for their anticancer activity with solid tumor selectivity. Six N-phenyl-5-carboxamidylisoxazoles were chemically synthesized and evaluated by the in vitro disk-diffusion assay and IC50 cytotoxicity determination. The results showed that one of the derivatives, compound 3, N-(4-chlorophenyl)-5-carboxamidyl isoxazole, was the most active against colon 38 and CT-26 mouse colon tumor cells with an IC50 of 2.5 μg/mL for both cell lines. Western blot analysis showed that compound 3 significantly down-regulated the expression of phosphorylated STAT3 in both human and mouse colon cancer cells indicating that the mechanism of action for compound 3 may involve the inhibition of JAK3/STAT3 signaling pathways. Flow cytometric analysis with Annexin V staining showed that the death induced by compound 3 is mediated through cell necrosis and not apoptotic pathway. In summary, our results show that compound 3 is a new N-phenyl-5-carboxamidyl isoxazole with potential anticancer activity. Compound 3 inhibits the phosphorylation of STAT3, a novel target for chemotherapeutic drugs, and is worthy of further investigation as a potential chemotherapeutic agent for treating colon cancer. PMID:25285182

  13. Rapid, potentially automatable, method extract biomarkers for HPLC/ESI/MS/MS to detect and identify BW agents

    SciTech Connect

    White, D.C. |; Burkhalter, R.S.; Smith, C.; Whitaker, K.W.

    1997-12-31

    The program proposes to concentrate on the rapid recovery of signature biomarkers based on automated high-pressure, high-temperature solvent extraction (ASE) and/or supercritical fluid extraction (SFE) to produce lipids, nucleic acids and proteins sequentially concentrated and purified in minutes with yields especially from microeukaryotes, Gram-positive bacteria and spores. Lipids are extracted in higher proportions greater than classical one-phase, room temperature solvent extraction without major changes in lipid composition. High performance liquid chromatography (HPLC) with or without derivatization, electrospray ionization (ESI) and highly specific detection by mass spectrometry (MS) particularly with (MS){sup n} provides the detection, identification and because the signature lipid biomarkers are both phenotypic as well as genotypic biomarkers, insights into potential infectivity of BW agents. Feasibility has been demonstrated with detection, identification, and determination of infectious potential of Cryptosporidium parvum at the sensitivity of a single oocyst (which is unculturable in vitro) and accurate identification and prediction, pathogenicity, and drug-resistance of Mycobacteria spp.

  14. Caspase-3 short hairpin RNAs: a potential therapeutic agent in neurodegeneration of aluminum-exposed animal model.

    PubMed

    Zhang, Qinli; Li, Na; Jiao, Xia; Qin, Xiujun; Kaur, Ramanjit; Lu, Xiaoting; Song, Jing; Wang, Linping; Wang, Junming; Niu, Qiao

    2014-01-01

    There is abundant evidence supporting the role of caspases in the development of neurodegenerative disease, including Alzheimer's disease (AD). Therefore, regulating the activity of caspases has been considered as a therapeutic target. However, all the efforts on AD therapy using pan-caspase inhibitors have failed because of uncontrolled adverse effects. Alternatively, the specific knockdown of caspase-3 gene through RNA interference (RNAi) could serve as a future potential therapeutic strategy. The aim of the present study is to down-regulate the expression of caspase-3 gene using lentiviral vector-mediated caspase-3 short hairpin RNA (LV-Caspase-3 shRNA). The effect of LV-Caspase-3 shRNA on apoptosis induced by aluminum (Al) was investigated in primary cultured cortical neurons and validated in C57BL/6J mice. The results indicated an increase in apoptosis and caspase-3 expression in primary cultured neurons and the cortex ofmice exposed to Al, which could be down-regulated by LV-Caspase-3 shRNA. Furthermore, LV-Caspase-3 shRNA reduced neural cell death and improved learning and memory in C57BL/6J mice treated with Al. Our results suggest that LV-caspase-3 shRNA is a potential therapeutic agent to prevent neurodegeneration and cognitive dysfunction in aluminum- exposed animal models. The findings provide a rational gene therapy strategy for AD. PMID:25387335

  15. Climate variability and change in the United States: potential impacts on water- and foodborne diseases caused by microbiologic agents.

    PubMed

    Rose, J B; Epstein, P R; Lipp, E K; Sherman, B H; Bernard, S M; Patz, J A

    2001-05-01

    Exposure to waterborne and foodborne pathogens can occur via drinking water (associated with fecal contamination), seafood (due to natural microbial hazards, toxins, or wastewater disposal) or fresh produce (irrigated or processed with contaminated water). Weather influences the transport and dissemination of these microbial agents via rainfall and runoff and the survival and/or growth through such factors as temperature. Federal and state laws and regulatory programs protect much of the U.S. population from waterborne disease; however, if climate variability increases, current and future deficiencies in areas such as watershed protection, infrastructure, and storm drainage systems will probably increase the risk of contamination events. Knowledge about transport processes and the fate of microbial pollutants associated with rainfall and snowmelt is key to predicting risks from a change in weather variability. Although recent studies identified links between climate variability and occurrence of microbial agents in water, the relationships need further quantification in the context of other stresses. In the marine environment as well, there are few studies that adequately address the potential health effects of climate variability in combination with other stresses such as overfishing, introduced species, and rise in sea level. Advances in monitoring are necessary to enhance early-warning and prevention capabilities. Application of existing technologies, such as molecular fingerprinting to track contaminant sources or satellite remote sensing to detect coastal algal blooms, could be expanded. This assessment recommends incorporating a range of future scenarios of improvement plans for current deficiencies in the public health infrastructure to achieve more realistic risk assessments. PMID:11359688

  16. Inhibitory potential of three zinc chelating agents against the proteolytic, hemorrhagic, and myotoxic activities of Echis carinatus venom.

    PubMed

    Nanjaraj Urs, Ankanahalli N; Yariswamy, Manjunath; Ramakrishnan, Chandrasekaran; Joshi, Vikram; Suvilesh, Kanve Nagaraj; Savitha, Mysore Natarajan; Velmurugan, Devadasan; Vishwanath, Bannikuppe Sannanayak

    2015-01-01

    Viperbites undeniably cause local manifestations such as hemorrhage and myotoxicity involving substantial degradation of extracellular matrix (ECM) at the site of envenomation and lead to progressive tissue damage and necrosis. The principle toxin responsible is attributed to snake venom metalloproteases (SVMPs). Treatment of such progressive tissue damage induced by SVMPs has become a challenging task for researchers and medical practitioners who are in quest of SVMPs inhibitors. In this study, we have evaluated the inhibitory potential of three specific zinc (Zn(2+)) chelating agents; N,N,N',N'-tetrakis (2-pyridylmethyl) ethane-1,2-diamine (TPEN), diethylene triamine pentaacetic acid (DTPA), tetraethyl thiuram disulfide (TTD) on Echis carinatus venom (ECV) induced hemorrhage and myotoxicity. Amongst them, TPEN has high affinity for Zn(2+) and revealed potent inhibition of ECV metalloproteases (ECVMPs) in vitro (IC50: 6.7 μM) compared to DTPA and TTD. The specificity of TPEN towards Zn(2+) was confirmed by spectral and docking studies. Further, TPEN, DTPA, and TTD completely blocked the hemorrhagic and myotoxic activities of ECV in a dose dependent manner upon co-injection; whereas, only TPEN successfully neutralized hemorrhage and myotoxicity following independent injection. Histological examinations revealed that TPEN effectively prevents degradation of dermis and basement membrane surrounding the blood vessels in mouse skin sections. TPEN also prevents muscle necrosis and accumulation of inflammatory cells at the site of ECV injections. In conclusion, a high degree of structural and functional homology between mammalian MMPs and SVMPs suggests that specific Zn(2+) chelators currently in clinical practice could be potent first aid therapeutic agents in snakebite management, particularly for local tissue damage. PMID:25447774

  17. Efficacy of a novel mucolytic agent on pseudomyxoma peritonei mucin, with potential for treatment through peritoneal catheters.

    PubMed

    Akhter, Javed; Pillai, Krishna; Chua, Terence C; Alzarin, Naeef; Morris, David Lawson

    2014-01-01

    Compared to current treatment for pseudomyxoma peritonei (PMP), the extraction of solubilised mucin through peritoneal catheter can be minimally invasive. However, mucin has variable appearance that may influence mucolysis. Hence, we investigated the mucolysis of 36 mucin samples with a novel agent. Using visual inspection and hardness index, PMP mucin was classified into three grades. The mucin pathological category was identified from patient record. Subsequently, the dissolution of the samples was tested. For in vitro, 1 g of mucin was treated to the mucolytic agent in 10 ml TRIS buffer at 37 deg. Celsius for 3 hours, with weighing of residual mucin. Control treatment was similar but received TRIS buffer. For in vivo, 2 g of implanted intra-peritoneal mucin in nude rats was treated to mucolytic (2 X 500 ul/24 hr, over 48 hours, plus another treatment before sacrifice at 56 hours, with weighing of residual mucin. Controls were treated but only with TRIS buffer. Six animals were used for each mucin grade (3 mucolytic treated & and 3 controls). Grades of mucin were soft mucin (62%), semi hard (20%) and hard mucin (18%). Diffuse peritoneal adenomucinosis had 50% of soft mucin and peritoneal mucinous carcinoma had 11% (P = 0.0382). In vitro and in vivo absolute disintegration was 100% for soft, 57.38% and 48.67% for semi hard, 50% and 28.67% for hard mucin. Majority of mucin were soft with complete disintegration, the rest showed variable disintegration, suggesting that the mucolytic has potential for treating PMP. PMID:25232491

  18. Benefits of a European Project on Diagnostics of Highly Pathogenic Agents and Assessment of Potential “Dual Use” Issues

    PubMed Central

    Grunow, Roland; Ippolito, G.; Jacob, D.; Sauer, U.; Rohleder, A.; Di Caro, A.; Iacovino, R.

    2014-01-01

    Quality assurance exercises and networking on the detection of highly infectious pathogens (QUANDHIP) is a joint action initiative set up in 2011 that has successfully unified the primary objectives of the European Network on Highly Pathogenic Bacteria (ENHPB) and of P4-laboratories (ENP4-Lab) both of which aimed to improve the efficiency, effectiveness, and response capabilities of laboratories directed at protecting the health of European citizens against high consequence bacteria and viruses of significant public health concern. Both networks have established a common collaborative consortium of 37 nationally and internationally recognized institutions with laboratory facilities from 22 European countries. The specific objectives and achievements include the initiation and establishment of a recognized and acceptable quality assurance scheme, including practical external quality assurance exercises, comprising living agents, that aims to improve laboratory performance, accuracy, and detection capabilities in support of patient management and public health responses; recognized training schemes for diagnostics and handling of highly pathogenic agents; international repositories comprising highly pathogenic bacteria and viruses for the development of standardized reference material; a standardized and transparent Biosafety and Biosecurity strategy protecting healthcare personnel and the community in dealing with high consequence pathogens; the design and organization of response capabilities dealing with cross-border events with highly infectious pathogens including the consideration of diagnostic capabilities of individual European laboratories. The project tackled several sensitive issues regarding Biosafety, Biosecurity and “dual use” concerns. The article will give an overview of the project outcomes and discuss the assessment of potential “dual use” issues. PMID:25426479

  19. Efficacy of a novel mucolytic agent on pseudomyxoma peritonei mucin, with potential for treatment through peritoneal catheters

    PubMed Central

    Akhter, Javed; Pillai, Krishna; Chua, Terence C; Alzarin, Naeef; Morris, David Lawson

    2014-01-01

    Compared to current treatment for pseudomyxoma peritonei (PMP), the extraction of solubilised mucin through peritoneal catheter can be minimally invasive. However, mucin has variable appearance that may influence mucolysis. Hence, we investigated the mucolysis of 36 mucin samples with a novel agent. Using visual inspection and hardness index, PMP mucin was classified into three grades. The mucin pathological category was identified from patient record. Subsequently, the dissolution of the samples was tested. For in vitro, 1 g of mucin was treated to the mucolytic agent in 10 ml TRIS buffer at 37 deg. Celsius for 3 hours, with weighing of residual mucin. Control treatment was similar but received TRIS buffer. For in vivo, 2 g of implanted intra-peritoneal mucin in nude rats was treated to mucolytic (2 X 500 ul/24 hr, over 48 hours, plus another treatment before sacrifice at 56 hours, with weighing of residual mucin. Controls were treated but only with TRIS buffer. Six animals were used for each mucin grade (3 mucolytic treated & and 3 controls). Grades of mucin were soft mucin (62%), semi hard (20%) and hard mucin (18%). Diffuse peritoneal adenomucinosis had 50% of soft mucin and peritoneal mucinous carcinoma had 11% (P = 0.0382). In vitro and in vivo absolute disintegration was 100% for soft, 57.38% and 48.67% for semi hard, 50% and 28.67% for hard mucin. Majority of mucin were soft with complete disintegration, the rest showed variable disintegration, suggesting that the mucolytic has potential for treating PMP. PMID:25232491

  20. Climate variability and change in the United States: potential impacts on water- and foodborne diseases caused by microbiologic agents.

    PubMed Central

    Rose, J B; Epstein, P R; Lipp, E K; Sherman, B H; Bernard, S M; Patz, J A

    2001-01-01

    Exposure to waterborne and foodborne pathogens can occur via drinking water (associated with fecal contamination), seafood (due to natural microbial hazards, toxins, or wastewater disposal) or fresh produce (irrigated or processed with contaminated water). Weather influences the transport and dissemination of these microbial agents via rainfall and runoff and the survival and/or growth through such factors as temperature. Federal and state laws and regulatory programs protect much of the U.S. population from waterborne disease; however, if climate variability increases, current and future deficiencies in areas such as watershed protection, infrastructure, and storm drainage systems will probably increase the risk of contamination events. Knowledge about transport processes and the fate of microbial pollutants associated with rainfall and snowmelt is key to predicting risks from a change in weather variability. Although recent studies identified links between climate variability and occurrence of microbial agents in water, the relationships need further quantification in the context of other stresses. In the marine environment as well, there are few studies that adequately address the potential health effects of climate variability in combination with other stresses such as overfishing, introduced species, and rise in sea level. Advances in monitoring are necessary to enhance early-warning and prevention capabilities. Application of existing technologies, such as molecular fingerprinting to track contaminant sources or satellite remote sensing to detect coastal algal blooms, could be expanded. This assessment recommends incorporating a range of future scenarios of improvement plans for current deficiencies in the public health infrastructure to achieve more realistic risk assessments. PMID:11359688

  1. Influence of promoter/enhancer region haplotypes on MGMT transcriptional regulation: a potential biomarker for human sensitivity to alkylating agents

    PubMed Central

    Abdel-Rahman, Sherif Z.

    2014-01-01

    The O 6-methylguanine-DNA methyltransferase gene (MGMT) encodes the direct reversal DNA repair protein that removes alkyl adducts from the O 6 position of guanine. Several single-nucleotide polymorphisms (SNPs) exist in the MGMT promoter/enhancer (P/E) region. However, the haplotype structure encompassing these SNPs and their functional/biological significance are currently unknown. We hypothesized that MGMT P/E haplotypes, rather than individual SNPs, alter MGMT transcription and can thus alter human sensitivity to alkylating agents. To identify the haplotype structure encompassing the MGMT P/E region SNPs, we sequenced 104 DNA samples from healthy individuals and inferred the haplotypes using the data generated. We identified eight SNPs in this region, namely T7C (rs180989103), T135G (rs1711646), G290A (rs61859810), C485A (rs1625649), C575A (rs113813075), G666A (rs34180180), C777A (rs34138162) and C1099T (rs16906252). Phylogenetics and Sequence Evolution analysis predicted 21 potential haplotypes that encompass these SNPs ranging in frequencies from 0.000048 to 0.39. Of these, 10 were identified in our study population as 20 paired haplotype combinations. To determine the functional significance of these haplotypes, luciferase reporter constructs representing these haplotypes were transfected into glioblastoma cells and their effect on MGMT promoter activity was determined. Compared with the most common (reference) haplotype 1, seven haplotypes significantly upregulated MGMT promoter activity (18–119% increase; P < 0.05), six significantly downregulated MGMT promoter activity (29–97% decrease; P < 0.05) and one haplotype had no effect. Mechanistic studies conducted support the conclusion that MGMT P/E haplotypes, rather than individual SNPs, differentially regulate MGMT transcription and could thus play a significant role in human sensitivity to environmental and therapeutic alkylating agents. PMID:24163400

  2. Synthesis, Characterization, and Evaluation of cis-Diphenyl Pyridineamine Platinum(II) Complexes as Potential Anti-Breast Cancer Agents

    PubMed Central

    Guevara, Priscilla; Ramirez, Verenice; Metta-Magaña, Alejandro J.; Villagrán, Dino; Varela-Ramirez, Armando; Das, Siddhartha; Nuñez, Jose E.

    2015-01-01

    Although cisplatin is considered as an effective anti-cancer agent, it has shown limitations and may produce toxicity in patients. Therefore, we synthesized two cis-dichlorideplatinum(II) compounds (13 and 14) composed of meta- and para-N,N-diphenyl pyridineamine ligands through a reaction of the amine precursors and PtCl2 with respective yields of 16% and 47%. We hypothesized that compounds 13 and 14, with lipophilic ligands, should transport efficiently in cancer cells and demonstrate more effectiveness than cisplatin. When tested for biological activity, compounds 13 and 14 were found to inhibit the growth of MCF 7 and MDA-MB-231 cells (IC50s 1 ± 0.4 μM and 1 ± 0.2 μM for 13 and 14, respectively, and IC50 7.5 ± 1.3 μM for compound 13 and 1 ± 0.3 μM for compound 14). Incidentally, these doses were found to be lower than cisplatin doses (IC50 5 ± 0.7 μM for MCF 7 and 10 ± 1.1 μM for MDA-MB-231). Similar to cisplatin, 13 and 14 interacted with DNA and induced apoptosis. However, unlike cisplatin, they blocked the migration of MDA-MB-231 cells suggesting that in addition to apoptotic and DNA-binding capabilities, these compounds are useful in blocking the metastatic migration of breast cancer cells. To delineate the mechanism of action, computer-aided analyses (DFT calculations) were conducted for compound 13. Results indicate that in vivo, the pyridineamine ligands are likely to dissociate from the complex, forming a platinum DNA adduct with anti-proliferative activity. These results suggest that complexes 13 and 14 hold promise as potential anti-cancer agents. PMID:24737042

  3. Non-carrier-added 186, 188Re labeled 17a-ethynylestradiol : a potential breast cancer imaging and therapy agent

    SciTech Connect

    Fassbender, M. E.; Phillips, Dennis R.; Peterson, E. J.; Ott, K. C.; Arterburn, J. B.

    2001-01-01

    Receptor-targeted radiopharmaceuticals constitute potential agents for the diagnosis and therapy of cancer. Breast cancer is the most prevalent form of diagnosed cancer in women in the United States, and it accounts for the second highest number of cases of cancer fatalities (1). In Approximately two-thirds of the breast tumors, estrogen and progesterone steroid hormone receptors can be found. Such tumors can often be treated successfully with anti-estrogen hormone therapy (2). Hence, the ability to determine the estrogen receptor (ER) contend of the breast tumor is essential for making the most appropriate choice of treatment for the patient. Along with this diagnostic aspect, steroid-based radiopharmaceuticals with high specific activity offer an encouraging prospect for therapeutic applications: {sup 186,188}Re labeled steroids binding to receptors expressed by cancer cells appear to be potential agents for the irradiation of small to medium-sized tumors. {sup 186}Re has been regarded as an ideal radionuclide for radiotherapy due to its appropriate half-live of 90 h and {beta}-energy of 1.07 MeV. Moreover, the {gamma}-emission of 137 keV that allows in vivo imaging while in therapy is an additional bonus. {sup 188}Re is obtained from a {sup 188}W/{sup 188}Re radionuclide generator system, representing an advantage for availability at radiopharmacy laboratory by daily elution. In addition, {sup 188}Re emits high energy beta particles with an average energy of 769 keV, and the emission of the 155 keV allows simultaneous imaging for biodistribution evaluation in vivo. In order to avoid competitive saturation of the binding sites of the ligand receptor, Re labeled steroids with high specific activity are required, and the removal of all excess unlabeled ligands is mandatory. {sup 188}Re is eluted from a {sup 188}W/{sup 188}Re generator produced and provided by Oak Ridge National Laboratory (3). This paper outlines the solid phase-supported preparation of an n

  4. Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents

    PubMed Central

    Leitch, AE; Haslett, C; Rossi, AG

    2009-01-01

    The cyclin-dependent kinase inhibitor (CDKi) drugs such as R-roscovitine have emerged as potential anti-inflammatory, pharmacological agents that can influence the resolution of inflammation. Usually, once an inciting inflammatory stimulus has been eliminated, resolution proceeds by prompt, safe removal of dominant inflammatory cells. This is accomplished by programmed cell death (apoptosis) of prominent effector, inflammatory cells typified by the neutrophil. Apoptosis of neutrophils ensures that toxic neutrophil granule contents are securely packaged in apoptotic bodies and expedites phagocytosis by professional phagocytes such as macrophages. A panel of CDKi drugs have been shown to promote neutrophil apoptosis in a concentration- and time-dependent manner and the archetypal CDKi drug, R-roscovitine, overrides the anti-apoptotic effects of powerful survival factors [including lipopolysaccharide (LPS) and granulocyte macrophage-colony stimulating factor (GM-CSF)]. Inflammatory cell longevity and survival signalling is integral to the inflammatory process and any putative anti-inflammatory agent must unravel a complex web of redundancy in order to be effective. CDKi drugs have also been demonstrated to have significant effects on other cell types including lymphocytes and fibroblasts indicating that they may have pleiotropic anti-inflammatory, pro-resolution activity. In keeping with this, CDKi drugs like R-roscovitine have been reported to be efficacious in resolving established animal models of neutrophil-dominant and lymphocyte-driven inflammation. However, the mechanism of action behind these powerful effects has not yet been fully elucidated. CDKs play an integral role in the regulation of the cell cycle but are also recognized as participants in processes such as apoptosis and transcriptional regulation. Neutrophils have functional CDKs, are transcriptionally active and demonstrate augmented apoptosis in response to CDKi drugs, while lymphocyte proliferation

  5. In Vitro Metabolism and Drug-Drug Interaction Potential of UTL-5g, a Novel Chemo- and Radioprotective Agent

    PubMed Central

    Wu, Jianmei; Shaw, Jiajiu; Dubaisi, Sarah; Valeriote, Frederick

    2014-01-01

    N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g), a potential chemo- and radioprotective agent, acts as a prodrug requiring bioactivation to the active metabolite 5-methylisoxazole-3-carboxylic acid (ISOX). UTL-5g hydrolysis to ISOX and 2,4-dichloroaniline (DCA) has been identified in porcine and rabbit liver esterases. The purpose of this study was to provide insights on the metabolism and drug interaction potential of UTL-5g in humans. The kinetics of UTL-5g hydrolysis was determined in human liver microsomes (HLM) and recombinant human carboxylesterases (hCE1b and hCE2). The potential of UTL-5g and its metabolites for competitive inhibition and time-dependent inhibition of microsomal cytochrome P450 (P450) was examined in HLM. UTL-5g hydrolysis to ISOX and DCA in HLM were NADPH-independent, with a maximum rate of reaction (Vmax) of 11.1 nmol/min per mg and substrate affinity (Km) of 41.6 µM. Both hCE1b and hCE2 effectively catalyzed UTL-5g hydrolysis, but hCE2 exhibited ∼30-fold higher catalytic efficiency (Vmax/Km) than hCE1b. UTL-5g and DCA competitively inhibited microsomal CYP1A2, CYP2B6, and CYP2C19 (IC50 values <50 µM), and exhibited time-dependent inhibition of microsomal CYP1A2 with the inactivation efficiency (kinact/KI) of 0.68 and 0.51 minute−1·mM−1, respectively. ISOX did not inhibit or inactivate any tested microsomal P450. In conclusion, hCE1b and hCE2 play a key role in the bioactivation of UTL-5g. Factors influencing carboxylesterase activities may have a significant impact on the pharmacological and therapeutic effects of UTL-5g. UTL-5g has the potential to inhibit P450-mediated metabolism through competitive inhibition or time-dependent inhibition. Caution is particularly needed for potential drug interactions involving competitive inhibition or time-dependent inhibition of CYP1A2 in the future clinical development of UTL-5g. PMID:25249693

  6. Concanavalin A: A potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics

    SciTech Connect

    Li, Wen-wen; Yu, Jia-ying; Xu, Huai-long; Bao, Jin-ku

    2011-10-22

    Highlights: {yields} ConA induces cancer cell death targeting apoptosis and autophagy. {yields} ConA inhibits cancer cell angiogenesis. {yields} ConA is utilized in pre-clinical and clinical trials. -- Abstract: Concanavalin A (ConA), a Ca{sup 2+}/Mn{sup 2+}-dependent and mannose/glucose-binding legume lectin, has drawn a rising attention for its remarkable anti-proliferative and anti-tumor activities to a variety of cancer cells. ConA induces programmed cell death via mitochondria-mediated, P73-Foxo1a-Bim apoptosis and BNIP3-mediated mitochondrial autophagy. Through IKK-NF-{kappa}B-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK anti-angiogenic pathways, ConA would inhibit cancer cell survival. In addition, ConA stimulates cell immunity and generates an immune memory, resisting to the same genotypic tumor. These biological findings shed light on new perspectives of ConA as a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis in pre-clinical or clinical trials for cancer therapeutics.

  7. Reproductive Requirements and Life Cycle of Iberorhyzobius rondensis (Coleoptera: Coccinellidae), Potential Biological Control Agent of Matsucoccus feytaudi (Hemiptera: Matsucoccidae).

    PubMed

    Tavares, C; Jactel, H; van Halder, I; Branco, M

    2015-06-01

    Several pine bast scales (Hemiptera: Matsucoccidae) are important pests of pine trees in the Northern Hemisphere. Some species are invasive and cause significant economic and environmental impacts. Such is the case with Matsucoccus feytaudi Ducasse, an invasive pest of maritime pine forests in Southeastern France, Italy, and Corsica. The ladybird Iberorhyzobius rondensis (Eizaguirre) is a recently described species that is endemic to the Iberian Peninsula and is a potential candidate for the biological control of M. feytaudi. However, little is known of the biology of I. rondensis. As part of the risk assessment study for a classical biological control program, the phenology and reproductive mechanisms of the beetle were analyzed. I. rondensis is univoltine and is seasonally synchronized with the phenology of the prey M. feytaudi, which is also univoltine. An obligatory reproductive diapause of 5-6 mo and the need to feed on the eggs of the prey to begin oviposition emerged as the two primary mechanisms that assure life cycle synchronization of the ladybird with its prey. Female fecundity was also higher when the ladybirds were fed M. feytaudi eggs. Life cycle synchronization with M. feytaudi and reproduction triggered by consumption of prey eggs indicate that I. rondensis is a promising biological control agent of the pine bast scale. PMID:26313991

  8. Exposure to the Riot Control Agent CS and Potential Health Effects: A Systematic Review of the Evidence

    PubMed Central

    Dimitroglou, Yiannis; Rachiotis, George; Hadjichristodoulou, Christos

    2015-01-01

    o-Chlorobenzylidene malononitrile (CS) is one of the most extensively used riot control agents. Our aim was to conduct a systematic review of the potential health effects related to CS exposure. We searched for papers in English between 1991 and 2014. Thirty five (35) studies (25 case reports, seven descriptive studies and three analytical studies) were included in the review. In the twenty five case reports/series 90 cases of exposure to CS and their clinical effects are presented. Their mean age was 25.7 years and 62.0% were males. In addition, 61% of the cases described dermal, 40% respiratory, 57% ocular clinical effects. Life threatening situations as well as long-term health effects were found and were related with exposure to confined/enclosed space. Descriptive and analytical studies have shown attack rates ranging from 12% to 40%. Subjects who were sprayed by the police more often needed special treatment and reported adverse health effects. Apart from transient clinical effects, CS could have lasting and serious effects on human health. Better surveillance of the subjects exposed to CS and completion of cohort studies among exposed populations will illuminate the spectrum of the health effects of exposure to CS. PMID:25633030

  9. The potential of a fluorescent-based approach for bioassay of antifungal agents against chili anthracnose disease in Thailand.

    PubMed

    Chutrakul, Chanikul; Khaokhajorn, Pratoomporn; Auncharoen, Patchanee; Boonruengprapa, Tanapong; Mongkolporn, Orarat

    2013-01-01

    Severe chili anthracnose disease in Thailand is caused by Colletotrichum gloeosporioides and C. capsici. To discover anti-anthracnose substances we developed an efficient dual-fluorescent labeling bioassay based on a microdilution approach. Indicator strains used in the assay were constructed by integrating synthetic green fluorescent protein (sGFP) and Discosoma sp. red fluorescent protein (DsRedExp) genes into the genomes of C. gloeosporioides or C. capsici respectively. Survival of co-spore cultures in the presence of inhibitors was determined by the expression levels of these fluorescent proteins. This developed assay has high potential for utilization in the investigation of selective inhibition activity to either one of the pathogens as well as the broad-range inhibitory effect against both pathogens. The value of using the dual-fluorescent assay is rapid, reliable, and consistent identification of anti-anthracnose agents. Most of all, the assay enables the identification of specific inhibitors under the co-cultivation condition. PMID:23391904

  10. Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics

    PubMed Central

    Goytia, Maira M.; Donnelly, Paul S.; Schembri, Mark A.; Shafer, William M.

    2015-01-01

    There is increasing interest in the use of lipophilic copper (Cu)-containing complexes to combat bacterial infections. In this work, we showed that Cu complexes with bis(thiosemicarbazone) ligands [Cu(btsc)] exert antibacterial activity against a range of medically significant pathogens. Previous work using Neisseria gonorrhoeae showed that Cu(btsc) complexes may act as inhibitors of respiratory dehydrogenases in the electron transport chain. We now show that these complexes are also toxic against pathogens that lack a respiratory chain. Respiration in Escherichia coli was slightly affected by Cu(btsc) complexes, but our results indicate that, in this model bacterium, the complexes act primarily as agents that deliver toxic Cu ions efficiently into the cytoplasm. Although the chemistry of Cu(btsc) complexes may dictate their mechanism of action, their efficacy depends heavily on bacterial physiology. This is linked to the ability of the target bacterium to tolerate Cu and, additionally, the susceptibility of the respiratory chain to direct inhibition by Cu(btsc) complexes. The physiology of N. gonorrhoeae, including multidrug-resistant strains, makes it highly susceptible to damage by Cu ions and Cu(btsc) complexes, highlighting the potential of Cu(btsc) complexes (and Cu-based therapeutics) as a promising treatment against this important bacterial pathogen. PMID:26239980

  11. Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer

    PubMed Central

    Heo, Tae-Hwe; Wahler, Joseph; Suh, Nanjoo

    2016-01-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine with known multiple functions in immune regulation, inflammation, and oncogenesis. Binding of IL-6 to the IL-6 receptor (IL-6R) induces homodimerization and recruitment of glycoprotein 130 (gp130), which leads to activation of downstream signaling. Emerging evidence suggests that high levels of IL-6 are correlated with poor prognosis in breast cancer patients. IL-6 appears to play a critical role in the growth and metastasis of breast cancer cells, renewal of breast cancer stem cells (BCSCs), and drug resistance of BCSCs, making anti–IL-6/IL-6R/gp130 therapies promising options for the treatment and prevention of breast cancers. However, preclinical and clinical studies of the applications of anti–IL-6/IL-6R/gp130 therapy in breast cancers are limited. In this review, we summarize the structures, preclinical and clinical studies, mechanisms of action of chemical and biological blockers that directly bind to IL-6, IL-6R, or gp130, and the potential clinical applications of these pharmacological agents as breast cancer therapies. PMID:26840088

  12. Synthesis, physicochemical characterization, and biological activities of new carnosine derivatives stable in human serum as potential neuroprotective agents.

    PubMed

    Bertinaria, Massimo; Rolando, Barbara; Giorgis, Marta; Montanaro, Gabriele; Guglielmo, Stefano; Buonsanti, M Federica; Carabelli, Valentina; Gavello, Daniela; Daniele, Pier Giuseppe; Fruttero, Roberta; Gasco, Alberto

    2011-01-27

    The synthesis and the physicochemical and biological characterization of a series of carnosine amides bearing on the amido group alkyl substituents endowed with different lipophilicity are described. All synthesized products display carnosine-like properties differentiating from the lead for their high serum stability. They are able to complex Cu(2+) ions at physiological pH with the same stoichiometry as carnosine. The newly synthesized compounds display highly significant copper ion sequestering ability and are capable of protecting LDL from oxidation catalyzed by Cu(2+) ions, the most active compounds being the most hydrophilic ones. All the synthesized amides show quite potent carnosine-like HNE quenching activity; in particular, 7d, the member of the series selected for this kind of study, is able to cross the blood-brain barrier (BBB) and to protect primary mouse hippocampal neurons against HNE-induced death. These products can be considered metabolically stable analogues of carnosine and are worthy of additional investigation as potential neuroprotective agents. PMID:21182325

  13. First In Vivo Evaluation of Liposome-encapsulated 223Ra as a Potential Alpha-particle-emitting Cancer Therapeutic Agent

    SciTech Connect

    Jonasdottir, Thora J.; Fisher, Darrell R.; Borrebaek, Jorgen; Bruland, Oyvind S.; Larsen, Roy H.

    2006-09-13

    Liposomes carrying chemotherapeutics have had some success in cancer treatment and may be suitable carriers for therapeutic radionuclides. This study was designed to evaluate the biodistribution of and to estimate the radiation doses from the alpha emitter 223Ra loaded into pegylated liposomes in selected tissues. 223Ra was encapsulated in pegylated liposomal doxorubicin by ionophore-mediated loading. The biodistribution of liposomal 223Ra was compared to free cationic 223Ra in Balb/C mice. We showed that liposomal 223 Ra circulated in the blood with an initial half-time in excess of 24 hours, which agreed well with that reported for liposomal doxorubicin in rodents, while the blood half-time of cationic 223Ra was considerably less than one hour. When liposomal 223 Ra was catabolized, the released 223Ra was either excreted or taken up in the skeleton. This skeletal uptake increased up to 14 days after treatment, but did not reach the level seen with free 223Ra. Pre-treatment with non-radioactive liposomal doxorubicin 4 days in advance lessened the liver uptake of liposomal 223 Ra. Dose estimates showed that the spleen, followed by bone surfaces, received the highest absorbed doses. Liposomal 223 Ra was relatively stable in vivo and may have potential for radionuclide therapy and combination therapy with chemotherapeutic agents.

  14. In vitro characterization of 211 At-labeled antibody A33--a potential therapeutic agent against metastatic colorectal carcinoma.

    PubMed

    Almqvist, Ylva; Orlova, Anna; Sjöström, Anna; Jensen, Holger J; Lundqvist, Hans; Sundin, Anders; Tolmachev, Vladimir

    2005-10-01

    The humanized antibody A33 binds to the A33 antigen, expressed in 95% of primary and metastatic colorectal carcinomas. The restricted pattern of expression in normal tissue makes this antigen a possible target for radioimmunotherapy of colorectal micrometastases. In this study, the A33 antibody was labeled with the therapeutic nuclide (211)At using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB). The in vitro characteristics of the (211)At-benzoate-A33 conjugate ((211)At-A33) were investigated and found to be similar to those of (125)I-benzoate-A33 ((125)I-A33) in different assays. Both conjugates bound with high affinity to SW1222 cells (K(d) = 1.7 +/- 0.2 nM, and 1.8 +/- 0.1 nM for (211)At-A33 and (125)I-A33, respectively), and both showed good intracellular retention (70% of the radioactivity was still cell associated after 20 hours). The cytotoxic effect of (211)At-A33 was also confirmed. After incubation with (211)At-A33, SW1222 cells had a survival of approximately 0.3% when exposed to some 150 decays per cell (DPC). The cytotoxic effect was found to be dose-dependent, as cells exposed to only 56 DPC had a survival of approximately 5%. The (211)At-A33 conjugate shows promise as a potential radioimmunotherapy agent for treatment of micrometastases originating from colorectal carcinoma. PMID:16248767

  15. Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics.

    PubMed

    Djoko, Karrera Y; Goytia, Maira M; Donnelly, Paul S; Schembri, Mark A; Shafer, William M; McEwan, Alastair G

    2015-10-01

    There is increasing interest in the use of lipophilic copper (Cu)-containing complexes to combat bacterial infections. In this work, we showed that Cu complexes with bis(thiosemicarbazone) ligands [Cu(btsc)] exert antibacterial activity against a range of medically significant pathogens. Previous work using Neisseria gonorrhoeae showed that Cu(btsc) complexes may act as inhibitors of respiratory dehydrogenases in the electron transport chain. We now show that these complexes are also toxic against pathogens that lack a respiratory chain. Respiration in Escherichia coli was slightly affected by Cu(btsc) complexes, but our results indicate that, in this model bacterium, the complexes act primarily as agents that deliver toxic Cu ions efficiently into the cytoplasm. Although the chemistry of Cu(btsc) complexes may dictate their mechanism of action, their efficacy depends heavily on bacterial physiology. This is linked to the ability of the target bacterium to tolerate Cu and, additionally, the susceptibility of the respiratory chain to direct inhibition by Cu(btsc) complexes. The physiology of N. gonorrhoeae, including multidrug-resistant strains, makes it highly susceptible to damage by Cu ions and Cu(btsc) complexes, highlighting the potential of Cu(btsc) complexes (and Cu-based therapeutics) as a promising treatment against this important bacterial pathogen. PMID:26239980

  16. 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation.

    PubMed

    Abou-Seri, Sahar M; Eldehna, Wagdy M; Ali, Mamdouh M; Abou El Ella, Dalal A

    2016-01-01

    In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 ± 0.03 and 0.40 ± 0.04 μM, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 μM, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 μM, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode. PMID:26590508

  17. FePt nanoparticles as a potential X-ray activated chemotherapy agent for HeLa cells

    PubMed Central

    Zheng, Yanhong; Tang, Yunlan; Bao, Zhirong; Wang, Hui; Ren, Feng; Guo, Mingxiong; Quan, Hong; Jiang, Changzhong

    2015-01-01

    Nanomaterials have an advantage in “personalized” therapy, which is the ultimate goal of tumor treatment. In order to investigate the potential ability of FePt nanoparticles (NPs) in the diagnosis and chemoradiotherapy treatment of malignant tumors, superparamagnetic, monodispersed FePt (~3 nm) alloy NPs were synthesized, using cysteamine as a capping agent. The NPs were characterized by means of X-ray diffraction; transmission electron microscopy, Physical Property Measurement System, and Fourier transform infrared spectroscopy. The cytotoxicity of FePt NPs on Vero cells was assessed using an MTT assay, and tumor cell proliferation inhibited by individual FePt NPs and FePt NPs combined with X-ray beams were also collected using MTT assays; HeLa human cancer cell lines were used as in vitro models. Further confirmation of the combined effect of FePt NPs and X-rays was verified using HeLa cells, after which, the cellular uptake of FePt NPs was captured by transmission electron microscopy. The results indicated that the growth of HeLa cells was significantly inhibited by FePt NPs in a concentration-dependent manner, and the growth was significantly more inhibited by FePt NPs combined with a series of X-ray beam doses; the individual NPs did not display any remarkable cytotoxicity on Vero cells at a concentration <250 μg/mL. Meanwhile, the FePt NPs showed negative/positive contrast enhancement for MRI/CT molecule imaging at the end of the study. Therefore, the combined results implied that FePt NPs might potentially serve as a promising nanoprobe for the integration of tumor diagnosis and chemoradiotherapy. PMID:26604740

  18. FePt nanoparticles as a potential X-ray activated chemotherapy agent for HeLa cells.

    PubMed

    Zheng, Yanhong; Tang, Yunlan; Bao, Zhirong; Wang, Hui; Ren, Feng; Guo, Mingxiong; Quan, Hong; Jiang, Changzhong

    2015-01-01

    Nanomaterials have an advantage in "personalized" therapy, which is the ultimate goal of tumor treatment. In order to investigate the potential ability of FePt nanoparticles (NPs) in the diagnosis and chemoradiotherapy treatment of malignant tumors, superparamagnetic, monodispersed FePt (~3 nm) alloy NPs were synthesized, using cysteamine as a capping agent. The NPs were characterized by means of X-ray diffraction; transmission electron microscopy, Physical Property Measurement System, and Fourier transform infrared spectroscopy. The cytotoxicity of FePt NPs on Vero cells was assessed using an MTT assay, and tumor cell proliferation inhibited by individual FePt NPs and FePt NPs combined with X-ray beams were also collected using MTT assays; HeLa human cancer cell lines were used as in vitro models. Further confirmation of the combined effect of FePt NPs and X-rays was verified using HeLa cells, after which, the cellular uptake of FePt NPs was captured by transmission electron microscopy. The results indicated that the growth of HeLa cells was significantly inhibited by FePt NPs in a concentration-dependent manner, and the growth was significantly more inhibited by FePt NPs combined with a series of X-ray beam doses; the individual NPs did not display any remarkable cytotoxicity on Vero cells at a concentration <250 μg/mL. Meanwhile, the FePt NPs showed negative/positive contrast enhancement for MRI/CT molecule imaging at the end of the study. Therefore, the combined results implied that FePt NPs might potentially serve as a promising nanoprobe for the integration of tumor diagnosis and chemoradiotherapy. PMID:26604740

  19. Enhanced gastric retention of solid resin beads as a marker for emetic potential of agents in rats.

    PubMed

    Ando, Kentaro; Takagi, Kan; Tsubone, Hirokazu

    2012-01-01

    Whereas nausea and emesis are burdensome side effects that lead to poor treatment compliance especially in chemotherapy, it is difficult to predict the emetic potential of agents in rats and mice because rodents do not vomit. We examined the effect of emetics on gastric retention and role of serotonin (5-hydroxytryptamine, 5-HT)3 receptor in chemotherapeutic-induced enhancement of gastric retention in rats. The gastric retention of solid material was determined using resin beads, which were suitable to beads made with metals or glasses in size, hardness and weight. Each rat was orally given distilled water (0.5 ml/rat) containing 40 resin beads via a plastic feeding tube. The stomach was removed at 1 hr post-dose and cut along the greater curvature under carbon dioxide anesthesia. Beads were given immediately after administration of the drugs except with cisplatin, when there was a 1 hr delay. Cancer chemotherapeutics including cisplatin(0.1-3 mg/kg i.v.) and doxorubicin(0.3-10 mg/kg i.v.) and a nauseant, copper sulfate(1-30 mg/kg p.o.) enhanced gastric retention of beads. Ondansetron, a 5-HT3 receptor antagonist, dose-dependently antagonized the enhanced gastric retention by cisplatin and doxorubicin. The copper sulfate-induced enhancement was also reversed by ondansetron. Our results suggest that 5-HT3 receptors mediate the cancer chemotherapeutic-enhanced gastric retention of solid material in rats. This implicates that the gastric retention of solid material is a useful marker to predict the potential of compounds to induce nausea and/or emesis in non-vomiting rodents. PMID:22687994

  20. Single Agents with Designed Combination Chemotherapy Potential: Synthesis and Evaluation of Substituted Pyrimido[4,5-b]indoles as Receptor Tyrosine Kinase and Thymidylate Synthase Inhibitors and as Antitumor Agents

    PubMed Central

    Gangjee, Aleem; Zaware, Nilesh; Raghavan, Sudhir; Ihnat, Michael; Shenoy, Satyendra; Kisliuk, Roy L.

    2010-01-01

    Combinations of antiangiogenic agents (AAs) with cytotoxic agents have shown significant promise and several such clinical trials are currently underway. We have designed, synthesized and evaluated two compounds that each inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor-beta (PDGFR-β) for antiangiogenic effects and also inhibit human thymidylate synthase (hTS) for cytotoxic effects in single agents. The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate benzenethiols. The inhibitory potency of both these single agents against VEGFR-2, PDGFR-β and hTS is better than or close to standards. In a COLO-205 xenograft mouse model one of the analogs significantly decreased tumor growth (TGI = 76% at 35 mg/kg), liver metastases and tumor blood vessels compared to a standard drug and to control and thus demonstrated potent tumor growth inhibition, inhibition of metastasis and antiangiogenic effects in vivo. These compounds afford combination chemotherapeutic potential in single agents. PMID:20092323

  1. THE POTENTIAL OF THE ENDOPHYTIC FUNGUS, MUSCODOR ALBUS, AS A BIO-CONTROL AGENT AGAINST ECONOMICALLY IMPORTANT PLANT PARASITIC NEMATODES OF VEGETABLE CROPS IN WASHINGTON STATE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The fungus Muscodor albus produces a mixture of antimicrobial volatile organic chemicals with activity against post-harvest disease causing organisms, insect pests of harvested fruit and tubers, and soil-borne disease causing agents and plant parasitic nematodes. M. albus was tested for its potenti...

  2. Behavioral and antioxidant activity of a tosylbenz[g]indolamine derivative. A proposed better profile for a potential antipsychotic agent

    PubMed Central

    Zika, Chara A; Nicolaou, Ioannis; Gavalas, Antonis; Rekatas, George V; Tani, Ekaterini; Demopoulos, Vassilis J

    2004-01-01

    Background Tardive dyskinesia (TD) is a major limitation of older antipsychotics. Newer antipsychotics have various other side effects such as weight gain, hyperglycemia, etc. In a previous study we have shown that an indolamine molecule expresses a moderate binding affinity at the dopamine D2 and serotonin 5-HT1A receptors in in vitro competition binding assays. In the present work, we tested its p-toluenesulfonyl derivative (TPBIA) for behavioral effects in rats, related to interactions with central dopamine receptors and its antioxidant activity. Methods Adult male Fischer-344 rats grouped as: i) Untreated rats: TPBIA was administered i.p. in various doses ii) Apomorphine-treated rats: were treated with apomorphine (1 mg kg-1, i.p.) 10 min after the administration of TPBIA. Afterwards the rats were placed individually in the activity cage and their motor behaviour was recorded for the next 30 min The antioxidant potential of TPBIA was investigated in the model of in vitro non enzymatic lipid peroxidation. Results i) In non-pretreated rats, TPBIA reduces the activity by 39 and 82% respectively, ii) In apomorphine pretreated rats, TPBIA reverses the hyperactivity and stereotype behaviour induced by apomorphine. Also TPBIA completely inhibits the peroxidation of rat liver microsome preparations at concentrations of 0.5, 0.25 and 0.1 mM. Conclusion TPBIA exerts dopamine antagonistic activity in the central nervous system. In addition, its antioxidant effect is a desirable property, since TD has been partially attributed, to oxidative stress. Further research is needed to test whether TPBIA may be used as an antipsychotic agent. PMID:14711381

  3. siRNA Against KIR3DL1 as a Potential Gene Therapeutic Agent in Controlling HIV-1 Infection

    PubMed Central

    Fu, Geng-Feng; Pan, Ji-Cheng; Lin, Nan; Hu, Hai-Yang; Tang, Wei-Ming; Xu, Jin-Shui; Wang, Xiao-Liang; Xu, Xiao-Qin; Qiu, Tao; Liu, Xiao-Yan; Chen, Guo-Hong; Mahapatra, Tanmay; Huan, Xi-Ping

    2014-01-01

    Abstract Objectives: The aim of this study was to develop a small interfering RNA (siRNA) against the expression of KIR3DL1 receptor on natural killer (NK) cells, in order to promote the ability of NK cells to destroy human immunodeficiency virus (HIV)-infected cells and thus prevent failure of siRNA therapy targeting human immunodeficiency virus type 1 (HIV-1) virus among HIV-1 infected patients in vitro. Methods: A siRNA targeting KIR3DL1 was synthesized and then modified with cholesterol, methylene, and sulfate. The inhibitory action of the siRNAs on primary cultured NK cells was detected. The amount of IFN-γ and TNF-α secretions in NK cells was measured. The intended functions of NK cells in vitro were analyzed by CFSE and PI methods. Results: There were no significant differences in inhibiting the expression of KIR3DL1 on NK cells between the modified and unmodified siRNAs, while inhibition by each of them differed significantly from controls. The amount of IFN-γ and TNF-α secretions in the NK cells was abundant due to unsuccessful expression of KIR3DL1 on NK cells, which further promoted function of the NK cells. Conclusion: The siRNA against KIR3DL1 could enhance the ability of the NK cells to kill the HIV-1 infected cells in vitro and successfully prevented the failure of siRNA therapy targeting the HIV-1 virus. Therefore, it can act as a potential gene therapeutic agent among HIV-1 infected people. PMID:24834927

  4. Synthesis, uptake mechanism characterization and biological evaluation of 18F labeled fluoroalkyl phenylalanine analogs as potential PET imaging agents

    PubMed Central

    Wang, Limin; Qu, Wenchao; Lieberman, Brian P.; Plössl, Karl; Kung, Hank F.

    2010-01-01

    Introduction Amino acids based tracers represent a promising class of tumor metabolic imaging agents with successful clinical applications. Two new phenylalanine derivatives, p-(2-[18F]fluoroethyl)-L-phenylalanine (FEP, [18F]2) and p-(3-[18F]fluoropropyl)-L-phenylalanine (FPP, [18F]3) were synthesized and evaluated in comparison to clinically utilized O-(2-[18F]fluoroethyl)-L-tyrosine (FET, [18F]1). Methods FEP ([18F]2) and FPP ([18F]3) were successfully synthesized by a rapid and efficient two-step nucleophilic fluorination of tosylate precursors and deprotection reaction. In vitro cell uptake studies were carried out in 9L glioma cells. In vivo studies, 9L tumor xenografts were implanted in Fisher 344 rats. Results FEP ([18F]2) and FPP ([18F]3) could be efficiently labeled within 90 min with good enantiomeric purity (>95%), good yield (11–37%) and high specific activity (21–69 GBq/μmol). Cell uptake studies showed FEP had higher uptake than FPP as well as reference ligand FET ([18F]1). Uptake mechanism studies suggested that FEP is a selective substrate for system L and prefers its subtype LAT1. In vivo biodistribution studies demonstrated FEP had specific accumulation in tumor cells and tumor to background ratio reached 1.45 at 60 min. Small animal PET imaging studies showed FEP was comparable to FET for imaging rats bearing 9L tumor model. FEP had high uptake in 9L tumor compared to surrounding tissue and was quickly excreted through urinary tract. Conclusion Biological evaluations indicate that FEP ([18F]2) is a potential useful tracer for tumor imaging with PET. PMID:21220129

  5. Gadolinium Nanoparticles Conjugated with Therapeutic Bifunctional Chelate as a Potential T1 Theranostic Magnetic Resonance Imaging Agent.

    PubMed

    Kang, Min-Kyoung; Lee, Gang Ho; Jung, Ki-Hye; Jung, Jae-Chang; Kim, Hee-Kyung; Kim, Yeon-Hee; Lee, Jongmin; Ryeom, Hun-Kyu; Kim, Tae-Jeong; Chang, Yongmin

    2016-05-01

    This work is directed toward the synthesis of two types of gadolinium oxide nanoparticles (Gd-oxide NPs), abbreviated as Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA, with diameters of 50-60 nm. The synthesis involves sequential coating of Gd-oxide NPs with tetraethyl orthosilicate (TEOS) and (3-aminopropyl) triethoxysilane (APTES), followed by functionalization of the aminopropylsilane group with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid conjugates of benzothiazoles (DO3A-BTA). Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA exhibit high water solubility and colloidal stability. The r1 relaxivities of both Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA are higher than those of the corresponding low-molecular-weight magnetic resonance imaging contrast agents (MRI CAs), and their r2/r1 ratios are close to 1, indicating that both can be used as potential T1 MRI CAs. Biodistribution studies demonstrated that Gd@SiO2-DO2A-BTA was excreted via both hepatobiliary and renal pathways. Gd@SiO2-DO2A-BTA exhibits a strong intracellular uptake property in a series of tumor cell lines, and has significant anticancer characteristics against cell lines such as SK-HEP-1, MDA-MB-231, HeLa, and Hep-3B. PMID:27305813

  6. α-Santalol, a skin cancer chemopreventive agent with potential to target various pathways involved in photocarcinogenesis.

    PubMed

    Santha, Sreevidya; Dwivedi, Chandradhar

    2013-01-01

    This study is designed to investigate the chemopreventive effect and molecular mechanisms of α-santalol on UVB-induced skin tumor development in SKH-1 hairless mouse, a widely used model for human photocarcinogenesis. A dose of UVB radiation (30 mJ cm(-2) day(-1)) that is in the range of human sunlight exposure was used for the initiation and promotion of tumor. Topical treatment of mice with α-santalol (10%, wt/vol in acetone) caused reduction in tumor incidence, multiplicity and volume. In our study, the anticarcinogenic action of α-santalol against UVB-induced photocarcinogenesis was found to be associated with inhibition of inflammation and epidermal cell proliferation, cell cycle arrest and induction of apoptosis. α-Santalol pretreatment strongly inhibited UVB-induced epidermal hyperplasia and thickness of the epidermis, expression of proliferation and inflammation markers proliferating cell nuclear antigen (PCNA), Ki-67 and cyclooxygenase 2 (Cox-2). Significant decrease in the expression of cyclins A, B1, D1 and D2 and cyclin-dependent kinases (Cdk)s Cdk1 (Cdc2), Cdk2, Cdk4 and Cdk6 and an upregulated expression of cyclin-dependent kinase (CDK) inhibitor Cip1/p21 were found in α-santalol pretreated group. Furthermore, an elevated level of cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) were observed in α-santalol-treated group. Our data suggested that α-santalol is a safer and promising skin cancer chemopreventive agent with potential to target various pathways involved in photocarcinogenesis. PMID:23480292

  7. Interactions between nematophagous fungi and consequences for their potential as biological agents for the control of potato cyst nematodes.

    PubMed

    Jacobs, Helen; Gray, Simon N; Crump, David H

    2003-01-01

    The efficacies of three nematophagous fungi, Paecilomyces lilacinus, Plectosphaerella cucumerina and Pochonia chlamydosporia, for controlling potato cyst nematodes (PCN) as part of an Integrated Pest Management (IPM) regime were studied. The compatibility of the nematophagous fungi with commonly used chemical pesticides and their ability to compete with the soil fungi Rhizoctonia solani, Chaetomium globosum, Fusarium oxysporum, Penicillium bilaii and Trichoderma harzianum were tested in vitro. Paecilomyces lilacinus was the most successful competitor when the ability to grow and inhibit growth of an opposing colony at both 10 and 20 degrees C was considered. P. lilacinus also showed potential for control of the soil-borne fungal pathogen R. solani, releasing a diffusable substance in vitro which inhibited its growth and caused morphological abnormalities in its hyphae. Pochonia chlamydosporia was least susceptible to growth inhibition by other fungi at 20 degrees in vitro, but the isolate tested did not grow at 10 degrees. Plectosphaerella cucumerina was a poor saprophytic competitor. Radial growth of Paecilomyces lilacinus and Plectosphaerella cucumerina was slowed, but not prevented, when grown on potato dextrose agar incorporating the fungicides fenpiclonil and tolclofos-methyl, and was not inhibited by the addition of pencycuron or the nematicide oxamyl. Radial growth of Pochonia chlamydosporia was partially inhibited by all the chemical pesticides tested. The efficacy of Paecilomyces lilacinus as a control agent for R. solani was further investigated in situ. Treatment with P. lilacinus significantly reduced the symptoms of Rhizoctonia disease on potato stems in a pot trial. The effectiveness of P. lilacinus and P. cucumerina against PCN was also tested in situ. Three application methods were compared; incorporating the fungi into alginate pellets, Terra-Green inoculated with the fungi and applying conidia directly to the tubers. Both formulations containing P

  8. Host plant oviposition preference of Ceratapion basicorne (Coleoptera:Apionidae), a potential biological control agent of yellow starthistle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ceratapion basicorne (Coleoptera: Apionidae) is a weevil native to Europe and western Asia that is being evaluated as a prospective classical biological control agent of Centaurea solstitialis (yellow starthistle) in the United States. Choice oviposition experiments were conducted under laboratory ...

  9. Design, synthesis, and evaluation of cisplatin-containing EGFR targeting bioconjugates as potential therapeutic agents for brain tumors

    PubMed Central

    Barth, Rolf F; Wu, Gong; Meisen, W Hans; Nakkula, Robin J; Yang, Weilian; Huo, Tianyao; Kellough, David A; Kaumaya, Pravin; Turro, Claudia; Agius, Lawrence M; Kaur, Balveen

    2016-01-01

    The aim of this study was to evaluate four different platinated bioconjugates containing a cisplatin (cis-diamminedichloroplatinum [cis-DDP]) fragment and epidermal growth factor receptor (EGFR)-targeting moieties as potential therapeutic agents for the treatment of brain tumors using a human EGFR-expressing transfectant of the F98 rat glioma (F98EGFR) to assess their efficacy. The first two bioconjugates employed the monoclonal antibody cetuximab (C225 or Erbitux®) as the targeting moiety, and the second two used genetically engineered EGF peptides. C225-G5-Pt was produced by reacting cis-DDP with a fifth-generation polyamidoamine dendrimer (G5) and then linking it to C225 by means of two heterobifunctional reagents. The second bioconjugate (C225-PG-Pt) employed the same methodology except that polyglutamic acid was used as the carrier. The third and fourth bioconjugates used two different EGF peptides, PEP382 and PEP455, with direct coordination to the Pt center of the cis-DDP fragment. In vivo studies with C225-G5-Pt failed to demonstrate therapeutic activity following intracerebral (ic) convection-enhanced delivery (CED) to F98EGFR glioma-bearing rats. The second bioconjugate, C225-PG-Pt, failed to show in vitro cytotoxicity. Furthermore, because of its high molecular weight, we decided that lower molecular weight peptides might provide better targeting and microdistribution within the tumor. Both PEP382-Pt and PEP455-Pt bioconjugates were cytotoxic in vitro and, based on this, a pilot study was initiated using PEP455-Pt. The end point for this study was tumor size at 6 weeks following tumor cell implantation and 4 weeks following ic CED of PEP455-Pt to F98 glioma-bearing rats. Neuropathologic examination revealed that five of seven rats were either tumor-free or only had microscopic tumors at 42 days following tumor implantation compared to a mean survival time of 20.5 and 26.3 days for untreated controls. In conclusion, we have succeeded in reformatting the

  10. Synthesis of silver nanoparticles using Dioscorea bulbifera tuber extract and evaluation of its synergistic potential in combination with antimicrobial agents

    PubMed Central

    Ghosh, Sougata; Patil, Sumersing; Ahire, Mehul; Kitture, Rohini; Kale, Sangeeta; Pardesi, Karishma; Cameotra, Swaranjit S; Bellare, Jayesh; Dhavale, Dilip D; Jabgunde, Amit; Chopade, Balu A

    2012-01-01

    . Conclusion This is the first report on the synthesis of silver nanoparticles using D. bulbifera tuber extract followed by an estimation of its synergistic potential for enhancement of the antibacterial activity of broad spectrum antimicrobial agents. PMID:22334779

  11. Caffeic acid: potential applications in nanotechnology as a green reducing agent for sustainable synthesis of gold nanoparticles.

    PubMed

    Seo, Yu Seon; Cha, Song-Hyun; Yoon, Hye-Ran; Kang, Young-Hwa; Park, Youmie

    2015-04-01

    The sustainable synthesis of gold nanoparticles from gold ions was conducted with caffeic acid as a green reducing agent. The formation of gold nanoparticles was confirmed by spectroscopic and microscopic methods. Spherical nanoparticles with an average diameter of 29.99 ± 7.43 nm were observed in high- resolution transmission electron microscopy and atomic force microscopy images. The newly prepared gold nanoparticles exhibited catalytic activity toward the reduction of 4-nitrophenol to 4-aminophenol in the presence of sodium borohydride. This system enables the preparation of green catalysts using plant natural products as reducing agents, which fulfills the growing need for sustainability initiatives. PMID:25973494

  12. Repositioning of Endonuclear Receptors Binders as Potential Antibacterial and Antifungal Agents. Eptyloxìm: A Potential and Novel Gyrase B and Cytochrome Cyp51 Inhibitor.

    PubMed

    Carrieri, Antonio; L'Abbate, Maria; Di Chicco, Mariangela; Rosato, Antonio; Carbonara, Giuseppe; Fracchiolla, Giuseppe

    2016-09-01

    A novel class of antibacterial and antifungal agents is here identified by means of dockings and virtual screening techniques. Biological data proved the initial effort, formulated on the structure similarity of nuclear receptors binders with known quinolones or thiazole derivatives, to reposition PPARs agonists as likely bacterial type II topoisomerases inhibitors. PMID:27546036

  13. Evaluation of kappa carrageenan as potential carrier for floating drug delivery system: Effect of pore forming agents.

    PubMed

    Selvakumaran, Suguna; Muhamad, Ida Idayu; Abd Razak, Saiful Izwan

    2016-01-01

    Floating hydrogels were prepared from kappa carrageenan containing CaCO3 and NaHCO3 as pore forming agents. The effects of CaCO3 and NaHCO3 on hydrogel characterizations were investigated and compared. Amoxicillin trihydrate was used as a model drug. Characterizations of the hydrogels were carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and field emission scanning electron microscope (FESEM). As pore forming agents concentration increases, the porosity (%) and floating properties increased. NaHCO3 incorporated hydrogels showed higher porosity with shorter floating lag time (FLT) than CaCO3. Hydrogel which contained CaCO3 exhibited better gel stability over the control and NaHCO3 containing gel. Incorporation of CaCO3 into kappa carrageenan hydrogel showed smoother surface gels compared to those produced with NaHCO3. CaCO3 also showed higher drug entrapment efficiency and sustained drug release profile than NaHCO3. The results of these studies showed that, CaCO3 is an effective pore forming agents in κC hydrogels preparation as compare to NaHCO3. Thus, CaCO3 can be an excellent pore forming agent for an effective floating drug delivery system. PMID:26453870

  14. Phenology and temperature-dependent development of Ceutorhynchus assimilis, a potential biological control agent for Lepidium draba

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Heart-podded hoary cress (Lepidium draba) is an alien weed that has invaded rangeland in the northwestern USA. A host race (i;e; host-specific biotype) of the weevil, Ceutorhynchus assimilis, is being evaluated as a prospective biological control agent. This biotype is only known from southern Eur...

  15. Potentiation of cytotoxicity by 3-aminobenzamide in DNA repair-deficient human tumor cell lines following exposure to methylating agents or anti-neoplastic drugs.

    PubMed

    Babich, M A; Day, R S

    1988-04-01

    We studied the potentiation by 3-aminobenzamide (3AB) of killing of nine human cell lines exposed to alkylating agents. Cell lines included normal, transformed and DNA repair-proficient and -deficient phenotypes. 3AB potentiated cell killing by the methylating agents methylmethanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in all lines tested. The degree of potentiation ranged from 1.7- to 3.8-fold, based on the LD99. The average potentiation observed with MMS (2.7-fold) was greater than with MNNG (2.2-fold). On average the potentiation of MMS and MNNG killing of repair-deficient Mer- lines (2.4-fold) was similar to that of repair-proficient Mer+ lines. The degree of 3AB potentiation of MNNG killing (2.0-fold) was similar in Mer+ Rem- lines and in Mer+ Rem+ lines. Mer+ Rem+, Mer+ Rem-, Mer- Rem+, and Mer- Rem- strains all appeared proficient in a 3AB-sensitive DNA repair pathway. Within experimental error, 20 mM 3AB did not inhibit the removal of the MNNG-induced methylpurines 7-methylguanine, O6-methylguanine and 3-methyladenine from the DNA of repair-proficient Mer+ Rem+ HT29 cells, consistent with evidence that 3AB inhibits the ligation step of excision repair. 3AB potentiated cell killing by the bifunctional alkylating agents 1-(2-chlorethyl)-1-nitrosourea or busulfan, two anti-neoplastic drugs, by only 0.9- to 1.5-fold. These drugs therefore produce DNA damage which is not efficiently repaired by the pathways that repair methylated bases. PMID:3356063

  16. 1α,25-Dihydroxyvitamin D3-3β-bromoacetate, a potential cancer therapeutic agent: synthesis and molecular mechanism of action

    PubMed Central

    Ray, Rahul; Lambert, James R.

    2011-01-01

    Synthesis of 1α,25-dihydroxyvitamin D3-3β-bromoacetate (1,25(OH)2D3-3-BE), a potential anti-cancer agent is presented. We also report that mechanism of action of 1,25(OH)2D3-3-BE may involve reduction of its catabolism, as evidenced by the reduced and delayed expression of 1α,25-dihydroxyvitamin D3-24-hydroxylase (CYP24) gene in cellular assays. PMID:21392983

  17. Synthesis of a thiol-β-cyclodextrin, a potential agent for controlling enzymatic browning in fruits and vegetables.

    PubMed

    Manta, Carmen; Peralta-Altier, Gabriela; Gioia, Larissa; Méndez, María F; Seoane, Gustavo; Ovsejevi, Karen

    2013-11-27

    A thiol-β-cyclodextrin was synthesized by a simple and environmentally friendly three-step method comprising epoxy activation of β-cyclodextrin, thiosulfate-mediated oxirane opening, and further reduction of the S-alkyl thiosulfate to a thiol group. The final step was optimized by using thiopropyl-agarose, a solid phase reducing agent with many advantages over soluble ones. β-Cyclodextrin thiolation was confirmed by titration with a thiol-reactive reagent, NMR studies, and MALDI-TOF/TOF. Thiolated cyclodextrin had an average value of one thiol group per molecule. Thiol-β-cyclodextrin proved to be an excellent agent for controlling polyphenol oxidase activity. This copper-containing enzyme is responsible for browning in fruits and vegetables. Under the same conditions, thiol-β-cyclodextrin generated a reductive microenvironment that increased the antibrowning effect on Red Delicious apples compared to unmodified β-cyclodextrin. PMID:24215568

  18. 18-Methoxycoronaridine, a potential anti-obesity agent, does not produce a conditioned taste aversion in rats.

    PubMed

    Taraschenko, Olga D; Maisonneuve, Isabelle M; Glick, Stanley D

    2010-09-01

    18-Methoxycoronaridine (18-MC), a selective antagonist of alpha3beta4 nicotinic receptors, has been shown to reduce the self-administration of several drugs of abuse. Recently, this agent has also been shown to attenuate sucrose reward, decrease sucrose intake and prevent the development of sucrose-induced obesity in rats. The present experiments were designed to determine whether the latter effect was due to an 18-MC-induced conditioned taste aversion to sucrose. Both 18-MC (20mg/ kg, i.p.) and control agent, lithium chloride (100mg/kg, i.p.), reduced sucrose intake 24h after association with sucrose; however, only lithium chloride reduced sucrose intake 72h later. Consistent with previous data, 18-MC appears to have proactive effect for 24h and it does not induce a conditioned taste aversion. PMID:20457177

  19. Synthesis and evaluation of gallocyanine dyes as potential agents for the treatment of Alzheimer's disease and related neurodegenerative tauopathies.

    PubMed

    Mpousis, Spyros; Thysiadis, Savvas; Avramidis, Nicolaos; Katsamakas, Sotirios; Efthimiopoulos, Spiros; Sarli, Vasiliki

    2016-01-27

    In search of safe and effective anti-Alzheimer disease agents a series of gallocyanine dyes have been synthesized and evaluated for their ability to inhibit LRPs/DKK1 interactions. Modulation of the interactions between LRPS and DKK1, regulate Wnt signaling pathway and affect Tau phosphorylation. The current efforts resulted in the identification of potent DKK1 inhibitors which are able to inhibit prostaglandin J2-induced tau phosphorylation at serine 396. PMID:26629858

  20. Design, synthesis and evaluation of redox radiopharmaceuticals: a potential new approach for the development of brain imaging agents

    SciTech Connect

    Srivastava, P.C.; Knapp, F.F. Jr.

    1986-01-01

    The fabrication and complete evaluation are described of a dihydropyridine in equilibrium pyridinium salt type redox system for the delivery of radioiodinated agents to the brain. The pivotal intermediate, N-succinimidyl (1-methylpyridinium iodide)-3-carboxylate was prepared by condensation of nicotinic acid and N-hydroxysuccinimide in the presence of dicyclohexylcarbodimide, followed by quaternization of III with methyl iodide. Tissue distribution studies of /sup 125/I-labeled 4-iodoaniline and the redox agents were performed in rats. (/sup 125/I)Iodoaniline initially showed moderate (0.58% dose/gm) brain uptake with subsequent release of the radioactivity from the brain. (/sup 125/I)Iodoaniline, when coupled to a dihydropyridine carrier showed higher uptake and retention in the brain. The (/sup 125/I)iodophenylethyl analogue showed uptake and retention in the brain to be very similar. Apparently the lipophilic agents cross the blood-brain barrier and are oxidized (quaternized) within the brain. The blood-brain barrier then prevents their release resulting in high uptake and retention in the brain and high brain:blood ratios. 11 refs., 3 figs.

  1. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort.

    PubMed

    Lewis, J M; Stott, K E; Monnery, D; Seden, K; Beeching, N J; Chaponda, M; Khoo, S; Beadsworth, M B J

    2016-02-01

    Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety. PMID:25721922

  2. Indomethacin/ibuprofen-like anti-inflammatory agents selectively potentiate the gamma-aminobutyric acid-antagonistic effects of several norfloxacin-like quinolone antibacterial agents on [35S]t-butylbicyclophosphorothionate binding.

    PubMed

    Squires, R F; Saederup, E

    1993-05-01

    Four piperazinoquinolone antibacterial drugs (norfloxacin, ciprofloxacin, enoxacin, and pipemidic acid), known to be gamma-aminobutyric acid (GABA) antagonists, fully reversed the inhibitory effect of GABA on [35S]t-butylbicyclophosphorothionate ([35S] TBPS) binding to rat brain membranes in vitro. Twelve indomethacin/ibuprofen-like arylalkanoic acid (AAA) anti-inflammatory drugs alone had no effect on [35S]TBPS binding, or on its inhibition by GABA, but potentiated the GABA-antagonistic effects of the four quinolones. Felbinac (4-biphenylacetic acid) was most potent in this respect (EC50 = 110 nM, together with 5 microM norfloxacin), followed by flurbiprofen > anirolac > metiazinic acid > tolmetin = ketoprofen = fenbufen = indomethacin > fenoprofen > ibuprofen = (+)-naproxen = sulindac. Other anti-inflammatory analgesic drugs, including aspirin, diclofenac, diflunisal, meclofenamic acid, mefenamic acid, nambumetone, phenacetin, piroxicam, and phenylbutazone, failed to potentiate the GABA-antagonistic effect of norfloxacin. Felbinac (1 microM) increased the GABA-antagonistic potencies of norfloxacin and enoxacin about 26-fold, while increasing those of ciprofloxacin and pipemidic acid 7-fold and 2.3-fold, respectively. Using subsaturating concentrations of the four quinolones, concentration-response curves for felbinac yielded EC50 values ranging from 110 nM with 5 microM norfloxacin to 1.3 microM with 100 microM pipemidic acid. Three other piperazinoquinolone antibacterial agents (amifloxacin, difloxacin, and fleroxacin) and four nonpiperazinoquinolone anti-bacterial agents (oxolinic acid, cinoxacin, nalidixic acid, and piromidic acid) were much weaker GABA antagonists and were not significantly potentiated by felbinac. All other known GABAA receptor blockers tested, including R 5135, pitrazepin, bicuculline, SR 95531, strychnine, D-tubocurarine, thebaine, securinine, theophylline, and caffeine, were not potentiated by felbinac. Our results suggest that

  3. Neoadjuvant and conversion treatment of patients with colorectal liver metastasis: the potential role of bevacizumab and other antiangiogenic agents.

    PubMed

    García-Alfonso, Pilar; Ferrer, Ana; Gil, Silvia; Dueñas, Rosario; Pérez, María Teresa; Molina, Raquel; Capdevila, Jaume; Safont, María José; Castañón, Carmen; Cano, Juana María; Lara, Ricardo

    2015-12-01

    More than 50 % of patients with colorectal cancer develop liver metastases. Surgical resection is the only available treatment that improves survival in patients with colorectal liver metastases (CRLM). New antiangiogenic targeted therapies, such as bevacizumab, aflibercept, and regorafenib, in combination with neoadjuvant and conversion chemotherapy may lead to improved response rates in this population of patients and increase the proportion of patients eligible for surgical resection. The present review discusses the available data for antiangiogenic targeted agents in this setting. One of these therapies, bevacizumab, which targets the vascular endothelial growth factor (VEGF) has demonstrated good results in this setting. In patients with initially unresectable CRLM, the combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab has led to high response and resection rates. This combination is also effective for patients with unresectable CRLM. Moreover, the addition of bevacizumab to chemotherapy in the neoadjuvant setting of liver metastasis has a higher impact on pathological response rate. This drug also has a manageable safety profile, and according to recent data, bevacizumab may protect against the sinusoidal dilation provoked in the liver by certain cytotoxic agents. In phase II trials, antiangiogenic therapy has demonstrated benefits in the presurgical treatment of CRLM and may represent a new treatment pathway for these patients. PMID:25752908

  4. N-(/sup 11/C)-methyl-p-substituted phentermine analogs as potential brain blood flow agents for positron tomography

    SciTech Connect

    Kizuka, H.; Elmaleh, D.R.; Boudreaux, G.J.; Anderton, K.D.; Strauss, H.W.; Ackerman, R.H.; Brownell, G.L.

    1984-01-01

    The addition of a methyl group to the ..cap alpha..-position of amphetamine increases both the lipophilicity of the agent and its resistance to metabolism by monoamine oxidase. In addition, since tritium substituted phenteramine analog studies suggested that the p-halo phentermines had a greater concentration in the brain and prolonged retention time, the authors evaluated the biological behavior of positron labeled ..cap alpha..-methylamphetamine (phenteramine) in rats, dogs and monkeys. The N-(/sup 11/C) methyl analogs of p-chloro (I) and p-fluoro (II) phentermines were prepared by methylation of their primary amines using /sup 11/Ch/sub 3/I. Biodistribution studies in rats shows brain uptake is in the range of 1% dose/gr at 5 and 15 min for both agents. The activity in blood and eyes is low. Sequential images of the dogs' brain over 1 hour revealed a clearance of <15%. Images of the monkey brain were also obtained using a MGH positron camera PCR-I.

  5. Non-Lethal Control of the Cariogenic Potential of an Agent-Based Model for Dental Plaque

    PubMed Central

    Head, David A.; Marsh, Phil D.; Devine, Deirdre A.

    2014-01-01

    Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments. PMID:25144538

  6. NIR and visible investigation of some potential SERS-active substrates for studying antitumour agent all- trans retinoic acid

    NASA Astrophysics Data System (ADS)

    Beljebbar, A.; Sockalingum, G. D.; Morjani, H.; Angiboust, J. F.; Manfait, M.

    1997-01-01

    Red and near-infrared excited Fourier transform surface-enhanced Raman spectra of an anticancer agent, all- trans retinoic acid (ATRA), adsorbed on gold island films are reported. Best results have been obtained with plates 80 Å and 40 Å thick respectively in the red and near-infrared and at concentrations of 10 -5 and 5 × 10 -6 M with a spinning system. The use of near-infrared laser excitation with low photon energy, allows us to overcome the problems of isomerisation when the sample is exposed for a long time to the laser radiation. Comparison between the Raman and SERS spectra in the visible shows that the adsorption on the surface does not perturb the structure of ATRA and confirms the long range enhancement of the island films with this type of molecule. Spectral data show that while gold island films and colloids are appropriate substrates for use with red excitation, silver and gold colloids as well as gold island films exhibit satisfactory enhancement levels in the near-infrared. This study will in the future allow us to choose the appropriate system that will serve to investigate the interaction of ATRA with its target in vitro and the effect of this differentiating agent in human leukaemia cell lines such as K562 and HL60.

  7. Non-lethal control of the cariogenic potential of an agent-based model for dental plaque.

    PubMed

    Head, David A; Marsh, Phil D; Devine, Deirdre A

    2014-01-01

    Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments. PMID:25144538

  8. Profilin potentiates chemotherapeutic agents mediated cell death via suppression of NF-κB and upregulation of p53.

    PubMed

    Zaidi, Adeel H; Raviprakash, Nune; Mokhamatam, Raveendra B; Gupta, Pankaj; Manna, Sunil K

    2016-04-01

    The molecular mechanism by which Profilin acts as a tumor suppressor is still unclear. Several chemotherapeutic agents, used till date either have unfavorable side effects or acquired resistance in tumor cells. Our findings show that Profilin enhances cell death mediated by several chemotherapeutic-agents. The activation of NF-κB and its dependent genes, mediated by paclitaxel and vinblastine, was completely inhibited in Profilin overexpressing cells. This inhibition was due to the Profilin mediated attenuation of IκBα degradation, thereby preventing p65 nuclear translocation and low NF-κB DNA binding activity.Moreover, Profilin increases level of p53 in the presence of known inducers, such as doxorubicin, vinblastine, and benzofuran. This increased p53 level leads to enhanced cell death as indicated by activation of caspases 3, 8, 9, which results in cleavage of PARP.Furthermore, knocking down of p53 in Profilin overexpressing cells leads to decreased cell death. Ectopic expression of Profilin in HCT116 p53 knock out cells showed lesser cell death as compared to the HCT116 p53 wild type cells. For the first time, we provide evidences, which suggest that Profilin synergizes with chemotherapeutic drugs to induce tumor cell death by regulating NF-κB and p53. Thus, modulation of Profilin may be a useful strategy for effective combination therapy. PMID:26842845

  9. Imatinib Analogs as Potential Agents for PET Imaging of Bcr-Abl/c-KIT Expression at a Kinase Level

    PubMed Central

    Peng, Zhenghong; Maxwell, David S.; Sun, Duoli; Bhanu Prasad, Basvoju A.; Pal, Ashutosh; Wang, Shimei; Balatoni, Julius; Ghosh, Pradip; Lim, Seok T.; Volgin, Andrei; Shavrin, Aleksander; Alauddin, Mian M.; Gelovani, Juri G.; Bornmann, William G.

    2014-01-01

    We synthesized two series of imatinib mesylate (STI-571) analogs to develop a Bcr-Abl and c-KIT receptor-specific labeling agent for positron emission tomography (PET) imaging to measure Bcr-Abl and c-KIT expression levels in a mouse model. The methods of molecular modeling, synthesis of STI-571 and its analogs, in vitro kinase assays, and radiolabeling are described. Molecular modeling revealed that these analogs bind the same Bcr-Abl and c-KIT binding sites as those bound by STI-571. The analogs potently inhibit the tyrosine kinase activity of Bcr-Abl and c-KIT, similarly to STI-571. [18F]-labeled STI-571 was prepared with high specific activity (75 GBq/μmol) by nucleophilic displacement and an average radiochemical yield of 12%. [131I]-labeled STI-571 was prepared with high purity (>95%) and an average radiochemical yield of 23%. The uptake rates of [18F]-STI-571 in K562 cells expressing Abl and in U87WT cells overexpressing c-KIT were significantly higher than those in the U87 cell and could be inhibited by STI-71 (confirming the specificity of uptake). PET scans of K562 and U87WT tumor-bearing mice with [18F]-STI-571 as a contrast agent showed visible tumor uptake and tumor-to-non-target contrast. PMID:24280068

  10. Wonder world of phages: potential biocontrol agents safeguarding biosphere and health of animals and humans- current scenario and perspectives.

    PubMed

    Tiwari, Ruchi; Chakraborty, Sandip; Dhama, Kuldeep; Wani, Mohd Yaqoob; Kumar, Amit; Kapoor, Sanjay

    2014-02-01

    Darwin's theory of natural selection and concept of survival of fittest of Wallace is a universal truth which derives the force of life among all live entities on this biosphere. Issues regarding food safety along with increased drug resistance and emerging zoonotic infections have proved that multidisciplinary efforts are in demand for human and animal welfare. This has led to development of various novel therapies the list of which remains incomplete without mentioning about phages. Homologous and non-homologous recombination along with point mutation and addition of new genes play role in their evolution. The rapid emergence of the antibiotic resistant strains of bacteria have created keen interest in finding necessary alternatives to check microbial infections and there comes the importance of phages. Phages kill the bacteria either by lysis or by releasing holins. Bacteriophages; the viruses that live on bacteria are nowadays considered as the best biocontrol agents. They are used as replacers of antibiotics; food industry promoter; guard of aquatic life as well as of plants; pre-slaughter treatment agents; Generally Recognized As Safe (GRAS) food additives; Typing agent of bacteria; active tool of super bug therapy; in post harvest crops and food and during post infection and also to combat intracellular pathogens viz. Mycobacteria and Mycoplasma. Cyanophages/phycophages are particularly useful in controlling blooms produced by various genera of algae and cyanobacteria. By performing centrifugation studies and based on electron microscopy certain virus like particles containing ds RNA have been confirmed as mycophages. They are well proven as threat to pathogenic fungi (both fungal hyphae and yeast). Those that infect yeasts are called zymophages. Virophages have exquisite specificity for their viral host, hence can extensively be used for genetic studies and can also act as evolutionary link. After the discovery of very first virophage till now, a total of 3

  11. Anesthetic agents modulate ECoG potentiation after spreading depression, and insulin-induced hypoglycemia does not modify this effect.

    PubMed

    de Souza, Thays Kallyne Marinho; E Silva-Gondim, Mariana Barros; Rodrigues, Marcelo Cairrão Araújo; Guedes, Rubem Carlos Araújo

    2015-04-10

    Cortical spreading depression (CSD) is characterized by reversible reduction of spontaneous and evoked electrical activity of the cerebral cortex. Experimental evidence suggests that CSD may modulate neural excitability and synaptic activity, with possible implications for long-term potentiation. Systemic factors like anesthetics and insulin-induced hypoglycemia can influence CSD propagation. In this study, we examined whether the post-CSD ECoG potentiation can be modulated by anesthetics and insulin-induced hypoglycemia. We found that awake adult rats displayed increased ECoG potentiation after CSD, as compared with rats under urethane+chloralose anesthesia or tribromoethanol anesthesia. In anesthetized rats, insulin-induced hypoglycemia did not modulate ECoG potentiation. Comparison of two cortical recording regions in awake rats revealed a similarly significant (p<0.05) potentiation effect in both regions, whereas in the anesthetized groups the potentiation was significant only in the recording region nearer to the stimulating point. Our data suggest that urethane+chloralose and tribromoethanol anesthesia modulate the post-CSD potentiation of spontaneous electrical activity in the adult rat cortex, and insulin-induced hypoglycemia does not modify this effect. Data may help to gain a better understanding of excitability-dependent mechanisms underlying CSD-related neurological diseases. PMID:25681772

  12. Synthesis, in vitro, and in vivo evaluation of novel functionalized quaternary ammonium curcuminoids as potential anti-cancer agents.

    PubMed

    Solano, Lucas N; Nelson, Grady L; Ronayne, Conor T; Lueth, Erica A; Foxley, Melissa A; Jonnalagadda, Sravan K; Gurrapu, Shirisha; Mereddy, Venkatram R

    2015-12-15

    Novel functionalized quaternary ammonium curcuminoids have been synthesized from piperazinyl curcuminoids and Baylis-Hillman reaction derived allyl bromides. These molecules are found to be highly water soluble with increased cytotoxicity compared to native curcumin against three cancer cell lines MIAPaCa-2, MDA-MB-231, and 4T1. Preliminary in vivo toxicity evaluation of a representative curcuminoid 5a in healthy mice indicates that this molecule is well tolerated based on normal body weight gains compared to control group. Furthermore, the efficacy of 5a has been tested in a pancreatic cancer xenograft model of MIAPaCa-2 and has been found to exhibit good tumor growth inhibition as a single agent and also in combination with clinical pancreatic cancer drug gemcitabine. PMID:26561365

  13. Design and synthesis of novel hydroxyanthraquinone nitrogen mustard derivatives as potential anticancer agents via a bioisostere approach

    PubMed Central

    Zhao, Li-Ming; Ma, Feng-Yan; Jin, Hai-Shan; Zheng, Shilong; Zhong, Qiu; Wang, Guangdi

    2016-01-01

    A series of hydroxyanthraquinones having an alkylating N-mustard pharmacophore at 1′-position were synthesized via a bioisostere approach to evaluate their cytotoxicity against four tumor cell lines (MDA-MB-231, HeLa, MCF-7 and A549). These compounds displayed significant in vitro cytotoxicity against MDA-MB-231 and MCF-7 cells, reflecting the excellent selectivity for the human breast cancer. Among them, compound 5k was the most cytotoxic with IC50 value of 0.263 nM and is more potent than DXR (IC50 = 0.294 nM) in inhibiting the growth of MCF-7 cells. The excellent cytotoxicity and good selectivity of compound 5k suggest that it could be a promising lead for further design and development of anticancer agents, especially for breast cancer. PMID:26291039

  14. Manganese doped-iron oxide nanoparticle clusters and their potential as agents for magnetic resonance imaging and hyperthermia.

    PubMed

    Casula, Maria F; Conca, Erika; Bakaimi, Ioanna; Sathya, Ayyappan; Materia, Maria Elena; Casu, Alberto; Falqui, Andrea; Sogne, Elisa; Pellegrino, Teresa; Kanaras, Antonios G

    2016-06-22

    A simple, one pot method to synthesize water-dispersible Mn doped iron oxide colloidal clusters constructed of nanoparticles arranged into secondary flower-like structures was developed. This method allows the successful incorporation and homogeneous distribution of Mn within the nanoparticle iron oxide clusters. The formed clusters retain the desired morphological and structural features observed for pure iron oxide clusters, but possess intrinsic magnetic properties that arise from Mn doping. They show distinct performance as imaging contrast agents and excellent characteristics as heating mediators in magnetic fluid hyperthermia. It is expected that the outcomes of this study will open up new avenues for the exploitation of doped magnetic nanoparticle assemblies in biomedicine. PMID:27282828

  15. Design, synthesis and evaluation of 2-deoxy-2-iodovinyl-branched carbohydrates as potential brain imaging agents

    SciTech Connect

    Goodman, M.M.; Callahan, A.P.; Knapp, F.F. Jr.

    1986-01-01

    Radioiodinated carbohydrates such as 2-deoxy-2-iodo-D-glucose and 3-deoxy-3-iodo-D-glucose undergo facile chemical or in vivo deiodination which precludes their use as radiotracers of glucose metabolism in tissues. To overcome the problems resulting from in vivo deiodination, we explored the concept of stabilizing radioiodide on a model carbohydrate, (E)-C-3-iodovinyl-D-allose (10) as an iodovinyl moiety. This agent did not exhibit brain specificity but showed low in vivo deiodination which demonstrated for the first time that radioiodide can be stabilized on a carbohydrate. The goal of this study was to develop a deoxy-branched carbohydrate with radioiodide stabilized as a vinyliodide with the objective of achieving high brain uptake. 10 refs., 1 fig., 1 tab.

  16. Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints.

    PubMed

    Wahid, Mohd; Mandal, Raju K; Dar, Sajad A; Jawed, Arshad; Lohani, Mohtashim; Areeshi, Mohammad Y; Akhter, Naseem; Haque, Shafiul

    2016-08-01

    Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies. PMID:27357488

  17. G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status.

    PubMed

    Agarwal, Pallavi; Jackson, Stephen P

    2016-10-01

    Cancer cells often exhibit altered epigenetic signatures that can misregulate genes involved in processes such as transcription, proliferation, apoptosis and DNA repair. As regulation of chromatin structure is crucial for DNA repair processes, and both DNA repair and epigenetic controls are deregulated in many cancers, we speculated that simultaneously targeting both might provide new opportunities for cancer therapy. Here, we describe a focused screen that profiled small-molecule inhibitors targeting epigenetic regulators in combination with DNA double-strand break (DSB) inducing agents. We identify UNC0638, a catalytic inhibitor of histone lysine N-methyl-transferase G9a, as hypersensitising tumour cells to low doses of DSB-inducing agents without affecting the growth of the non-tumorigenic cells tested. Similar effects are also observed with another, structurally distinct, G9a inhibitor A-366. We also show that small-molecule inhibition of G9a or siRNA-mediated G9a depletion induces tumour cell death under low DNA damage conditions by impairing DSB repair in a p53 independent manner. Furthermore, we establish that G9a promotes DNA non-homologous end-joining in response to DSB-inducing genotoxic stress. This study thus highlights the potential for using G9a inhibitors as anti-cancer therapeutic agents in combination with DSB-inducing chemotherapeutic drugs such as etoposide. PMID:27431310

  18. Inhibition of platelet aggregation by vanilloid-like agents is not mediated by transient receptor potential vanilloid-1 channels or cannabinoid receptors.

    PubMed

    Almaghrabi, Safa; Geraghty, Dominic; Ahuja, Kiran; Adams, Murray

    2016-06-01

    Vanilloid-like agents, including capsaicin, N-arachidonoyl-dopamine and N-oleoyldopamine inhibit platelet aggregation, however little is known about the precise mechanism(s) of action. The authors have previously shown that blocking of the capsaicin receptor, transient receptor potential vanilloid-1 (TRPV1), does not interfere with capsaicin action during adenosine diphosphate (ADP)-induced aggregation. This research is extended to investigate the effect of these vanilloid-like-agents on platelet count, and to test whether the effect of these agents is mediated through TRPV1 and/or cannabinoid (CB1 and CB2) receptors in the presence of other agonists, including collagen and arachidonic acid. Incubation of platelets with each of the individual vanilloids, or with receptor antagonists of TRPV1 (SB452533), CB1 (AM251) and CB2 (AM630), for up to 2 h did not significantly affect the platelet count. Similarly, the effect of individual vanilloids on the inhibition of platelet aggregation was not significantly different in the presence of receptor agonists compared to control, irrespective of the agonist used, suggesting that the inhibitory effect of vanilloids on platelet aggregation is independent of TRPV1, CB1 and CB2 receptors. Further research on the antiplatelet activity of vanilloids should focus on mechanisms other than those associated with vanilloid receptors. PMID:26991025

  19. A polyphasic approach for studying the interaction between Ralstonia solanacearum and potential control agents in the tomato phytosphere.

    PubMed

    van Overbeek, Leo S; Cassidy, Mike; Kozdroj, Jacek; Trevors, Jack T; van Elsas, Jan D

    2002-01-01

    Ralstonia solanacearum biovar 2, the causative agent of brown rot in potato, has been responsible for large crop losses in Northwest Europe during the last decade. Knowledge on the ecological behaviour of R. solanacearum and its antagonists is required to develop sound procedures for its control and eradication in infested fields.A polyphasic approach was used to study the invasion of plants by a selected R. solanacearum biovar 2 strain, denoted 1609, either or not in combination with the antagonistic strains Pseudomonas corrugata IDV1 and P. fluorescens UA5-40. Thus, this study combined plating (spread and drop plate methods), reporter gene technology (gfp mutants) and serological (imunofluorescence colony staining [IFC]) and molecular techniques (fluorescent in situ hybridization [FISH], PCR with R. solanacearum specific primers and PCR-DGGE on plant DNA extracts). The behaviour of R. solanacearum 1609 and the two control strains was studied in bulk and (tomato) rhizosphere soil and the rhizoplane and stems of tomato plants. The results showed that an interaction between the pathogen and the control strains at the root surface was likely. In particular, R. solanacearum 1609 CFU numbers were significantly reduced on tomato roots treated with P. corrugata IDV1(chr:gfp1) cells as compared to those on untreated roots. Concomitant with the presence of P. corrugata IDV1(chr:gfp1), plant invasion by the pathogen was hampered, but not abolished.PCR-DGGE analyses of the tomato rhizoplane supported the evidence for antagonistic activity against the pathogen; as only weak R. solanacearum 1609 specific bands were detected in profiles derived from mixed systems versus strong bands in profiles from systems containing only the pathogen. Using FISH, a difference in root colonization was demonstrated between the pathogen and one of the two antagonists, i.e. P. corrugata IDV1(chr:gfp1); R. solanacearum strain 1609 was clearly detected in the vascular cylinder of tomato plants

  20. Genetic toxicology and preliminary in vivo studies of nitric oxide donor tocopherol analogs as potential new class of antiatherogenic agents.

    PubMed

    Cabrera, Mauricio; López, Gloria V; Gómez, Luis E; Breijo, Martín; Pintos, Cristina; Botti, Horacio; Raymondo, Stella; Vettorazzi, Ariane; Ceráin, Adela López de; Monge, Antonio; Rubbo, Homero; González, Mercedes; Cerecetto, Hugo

    2011-07-01

    Nitric oxide donor tocopherol analogs were found to be incorporated in low-density lipoprotein to release nitric oxide into the hydrophobic core of the lipoprotein, thus inhibiting lipid oxidation processes associated with atheroma plaque formation. Previously, we studied their cytotoxicity against human and murine macrophages as first selection for in vivo studies. Herein, we examined both the in vitro mutagenic and DNA-damage effects of selected compounds to further evaluate drug potential. While the compounds of interest were nongenotoxics in both experimental tests (Ames and alkaline comet), one of the potential blood metabolites exhibited genotoxicity (alkaline comet test), and the furazan derivative was mutagenic (Ames test). Two selected (nitrooxy and furoxan) compounds were studied in long- and short-term in vivo treatment, and in these conditions, animal toxicity was not evidenced, suggesting the possibility of these compounds as potential antiatherogenic drugs. PMID:21649483

  1. The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models.

    PubMed

    Foster, Paul; Yamaguchi, Kyoko; Hsu, Pin P; Qian, Fawn; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yu, Peiwen; Jaeger, Christopher T; Zhang, Wentao; Marlowe, Charles K; Keast, Paul; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Artur; Yakes, F Michael; Chu, Felix; Engell, Kelly; Bentzien, Frauke; Lam, Sanh T; Dale, Stephanie; Yturralde, Olivia; Matthews, David J; Lamb, Peter; Laird, A Douglas

    2015-04-01

    Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents. PMID:25637314

  2. Synthesis and biological evaluation of cyclic analogs of L-carnitine as potential agents in the treatment of myocardial ischemia

    SciTech Connect

    Woster, P.M.

    1987-01-01

    The purpose of this research was to synthesize a number of cyclic, rigid analogs of L-carnitine, having a variety of predetermined positional and stereochemical orientations, to be used as probes into the spatial and conformational requirements of the enzyme known as carnitine/acylcarnitine translocase. The ability of these analogs to serve as substrates for this enzyme was to be determined by assessing the degree to which they initiate efflux of {sup 14}C-L-carnitine from isolated heart mitochondria. Toward this end, synthesis of several such analogs was attempted, resulting in the isolation and characterization of 9 cyclic analogs of carnitine, 5 of which are previously unreported. Bioevaluation of these synthetic carnitine analogs was conducted in a previously described assay system. Rat heart mitochondria were isolated by differential centrifugation and prepared for the study by incubation with {sup 14}C-L-carnitine. Efflux of radiolabeled carnitine was then monitored in the presence of the compound being evaluated. This represents the first instance in which non-naturally occurring analogs of L-carnitine have been shown to undergo transport via this mitochondrial translocase, suggesting the possibility that cyclic carnitine analogs may find utility as agents in the treatment of myocardial ischemia.

  3. Inhibition of cell adhesion by anti–P-selectin aptamer: a new potential therapeutic agent for sickle cell disease

    PubMed Central

    Gutsaeva, Diana R.; Parkerson, James B.; Yerigenahally, Shobha D.; Kurz, Jeffrey C.; Schaub, Robert G.; Ikuta, Tohru

    2011-01-01

    Adhesive interactions between circulating sickle red blood cells (RBCs), leukocytes, and endothelial cells are major pathophysiologic events in sickle cell disease (SCD). To develop new therapeutics that efficiently inhibit adhesive interactions, we generated an anti–P-selectin aptamer and examined its effects on cell adhesion using knockout-transgenic SCD model mice. Aptamers, single-stranded oligonucleotides that bind molecular targets with high affinity and specificity, are emerging as new therapeutics for cardiovascular and hematologic disorders. In vitro studies found that the anti–P-selectin aptamer exhibits high specificity to mouse P-selectin but not other selectins. SCD mice were injected with the anti–P-selectin aptamer, and cell adhesion was observed under hypoxia. The anti–P-selectin aptamer inhibited the adhesion of sickle RBCs and leukocytes to endothelial cells by 90% and 80%, respectively. The anti–P-selectin aptamer also increased microvascular flow velocities and reduced the leukocyte rolling flux. SCD mice treated with the anti–P-selectin aptamer demonstrated a reduced mortality rate associated with the experimental procedures compared with control mice. These results demonstrate that anti–P-selectin aptamer efficiently inhibits the adhesion of both sickle RBCs and leukocytes to endothelial cells in SCD model mice, suggesting a critical role for P-selectin in cell adhesion. Anti–P-selectin aptamer may be useful as a novel therapeutic agent for SCD. PMID:20926770

  4. In vivo phase II-enzymes inducers, as potential chemopreventive agents, based on the chalcone and furoxan skeletons.

    PubMed

    Cabrera, Mauricio; Mastandrea, Ignacio; Otero, Gabriel; Cerecetto, Hugo; González, Mercedes

    2016-04-15

    Cancer chemoprevention involves prevention/delay/reverse of the carcinogenic process through administration of cancer chemopreventive agents (CCA). Compounds which are able to induce detoxification-enzymes, especially monofunctional phase II enzymes, have become in excellent approaches for new CCA. Herein, we report the synthesis of new furoxanyl chalcone-like hybrid compounds as CCA. In vitro studies showed that phenylfuroxanyl derivatives 6 and 9 displayed the best activities being 9 the greatest monofunctional-inducer. Additionally, compounds were non-mutagenic against TA98 Salmonella typhimurium strain (Ames test) and could be used in the prevention of the progression of pre-malignant lesions for their cytotoxic activity against tumoral cells. In vivo proof of concept showed increment on phase II-enzymes activities in liver, colon and mammary gland having derivative 9 the best induction profiles. We probed Nrf2 nuclear translocation is operative for both compounds allowing to exert protective effects via expression of downstream phase-II enzymes. PMID:26970663

  5. Novel synthesis and initial preclinical evaluation of (18)F-[FDG] labeled rhodamine: a potential PET myocardial perfusion imaging agent.

    PubMed

    AlJammaz, Ibrahim; Al-Otaibi, Basim; AlHindas, Hussein; Okarvi, Subhani M

    2015-10-01

    Myocardial perfusion imaging is one of the most commonly performed investigations in nuclear medicine studies. Due to the clinical importance of [(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]-FDG) and its availability in almost every PET center, a new radiofluorinated [(18)F]-FDG-rhodamine conjugate was synthesized using [(18)F]-FDG as a prosthetic group. In a convenient and simple one-step radiosynthesis, [(18)F]-FDG-rhodamine conjugate was prepared in quantitative radiochemical yields, with total synthesis time of nearly 20 min and radiochemical purity of greater than 98%, without the need for HPLC purification, which make these approaches amenable for automation. Biodistribution studies in normal rats at 60 min post-injection demonstrated a high uptake in the heart (>11% ID/g) and favorable pharmacokinetics. Additionally, [(18)F]-FDG-rhodamine showed an extraction value of 27.63%±5.12% in rat hearts. These results demonstrate that [(18)F]-FDG-rhodamine conjugate may be useful as an imaging agent for the positron emission tomography evaluation of myocardial perfusion. PMID:26160144

  6. New Oxidovanadium Complexes Incorporating Thiosemicarbazones and 1, 10-Phenanthroline Derivatives as DNA Cleavage, Potential Anticancer Agents, and Hydroxyl Radical Scavenger.

    PubMed

    Ying, Peng; Zeng, Pengfei; Lu, Jiazheng; Chen, Hongyuan; Liao, Xiangwen; Yang, Ning

    2015-10-01

    Four novel oxidovanadium(IV) complexes, [VO(hntdtsc)(PHIP)] (1) (hntdtsc = 2-hydroxy-1-naphthaldehyde thiosemicarbazone, PHIP= 2-phenyl-imidazo[4,5-f]1,10-phenanthroline), [VO(hntdtsc)(DPPZ)](2)(DPPZ= dipyrido[3,2-a:2',3'-c]phenazine), [VO(satsc)(PHIP)](3) (satsc=salicylaldehyde thiosemicarbazone), and [VO(satsc)(DPPZ)](4), have been prepared and characterized. The chemical nuclease activities and photocleavage reactions of the complexes were tested. All four complexes can efficiently cleave pBR322 DNA, and complex 1 has the best cleaving ability. The antitumor properties of these complexes were examined with three different tumor cell lines using MTT assay. Their antitumor mechanism has been analyzed using cell cycle analysis, fluorescence microscopy of apoptosis, and Annexin V-FITC/PI assay. The results showed that the growth of human neuroblastoma (SH-SY5Y, SK-N-SH) and human breast adenocarcinoma (MCF-7) cells were inhibited significantly with very low IC50 values. Complex 1 was found to be the most potent antitumor agent among the four complexes. It can cause G0/G1 phase arrest of the cell cycle and exhibited significant induced apoptosis in SK-N-SH cells and displayed typical morphological apoptotic characteristics. In addition, they all displayed reasonable abilities to scavenge hydroxyl radical, and complex 1 was the best inhibitor. PMID:25659415

  7. HS-133, a novel fluorescent phosphatidylinositol 3-kinase inhibitor as a potential imaging and anticancer agent for targeted therapy

    PubMed Central

    Lee, Hyunseung; Son, Mi Kwon; Yun, Sun-Mi; Ahn, Sung-Hoon; Lee, Kyeong-Ryoon; Lee, Soyoung; Kim, Donghee; Hong, Sungwoo; Hong, Soon-Sun

    2014-01-01

    As PI3K/Akt signaling is frequently deregulated in a wide variety of human tumors, PI3K inhibitors are an emerging class of drugs for cancer treatment. The monitoring of the drug behavior and distribution in the biological system can play an important role for targeted therapy and provide information regarding the response or resistance to available therapies. In this study, therefore, we have developed a family of xanthine derivatives, serving as a dual function exhibiting fluorescence, as well as inhibiting PI3K. Among them, HS-133 showed anti-proliferative effects and was monitored for its subcellular localization by a fluorescence microscopy. HS-133 suppressed the PI3K/Akt pathway and induced cell cycle arrest at the G0/G1 phase. The induction of apoptosis by HS-133 was confirmed by the increases of the cleaved PARP, caspase-3, and caspase-8. Furthermore, HS-133 decreased the protein expression of HIF-1α and VEGF, as well inhibited the tube formation and migration of the human umbilical vein endothelial cells. In vivo imaging also showed that tumors were visualized fluorescent with HS-133, and its oral administration significantly inhibited the growth of tumor in SkBr3 mouse xenograft models. Thus, we suggest that HS-133 may be used as a fluorescent anticancer agent against human breast cancer. PMID:25338206

  8. Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

    PubMed Central

    Humphreys, Hilary; Greene, Catherine M.; Fitzgerald-Hughes, Deirdre; Devocelle, Marc

    2014-01-01

    Host defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities of Pseudomonas aeruginosa to parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates of P. aeruginosa. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 μg/ml). Cytotoxic effects on CFBE41o- cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme at in vivo concentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung. PMID:24277028

  9. Synthesis and characterization of N-acylaniline derivatives as potential chemical hybridizing agents (CHAs) for wheat (Triticum aestivum L.).

    PubMed

    Chakraborty, Kajal; Devakumar, C

    2006-09-01

    Induction of male sterility by deployment of chemical hybridizing agents (CHAs) are important in heterosis breeding of self-pollinated crops like wheat, wherein the male and female organs are in the same flower. Taking a lead from the earlier work on rice, a total of 25 N-acylanilines comprising of malonanilates, acetoacetanilides, and acetanilides (including halogenated acetanilides) were synthesized and screened as CHAs on three genotypes of wheat, viz., PBW 343, HD 2046, and HD 2733 at 1500 ppm in the winter of 2001-2002. The N-acylanilines containing variations at the acyl and aromatic domain were synthesized by condensation of substituted anilines with appropriate diesters, acid chlorides, or monoesters. The test compounds with highly electronegative groups such as F/Br at the para position of the aryl ring were identified as the most potent CHAs, causing higher induction of male sterility. A variation of N-substitution at the side chain generally furnished analogues like 4'-fluoroacetoacetanilide (7) and ethyl 4'-fluoromalonanilate (1), which induced 89.12 and 84.66% male sterility, respectively, in PBW 343. Among halogenated acetanilides, the increasing number of chlorine atoms in the side chain led to an increase in the activity of 4'-fluoro (23) and 4'-bromo (24) derivatives of trichoroacetanilides, which induced >87% male sterility. Quantitative structure-activity relationship (QSAR) models indicated the positive contributions of the field effect exemplified by the Swain-Lupton constant (Fp) and negative contributions of the Swain-Lupton resonance constant (R) for the aromatic substitution. The positive influences of parachor (P) for the acyl domain have been underlined. These leads will be significant in explaining the CHA fit in the macromolecular receptor site. The CHAs appeared to act by causing an imbalance in the acid-base equilibrium in pollen mother cells resulting in dissolution of the callose wall by premature callase secretion. PMID:16939342

  10. Antispasmodic and myorelaxant effects of the flavoring agent methyl cinnamate in gut: potential inhibition of tyrosine kinase.

    PubMed

    Lima, Francisco J B; Cosker, François; Brito, Teresinha S; Ribeiro-Filho, Hélder V; Silva, Camila M S; Aragão, Karoline S; Lahlou, Saad; Souza, Marcellus H L P; Santos, Armênio A; Magalhães, Pedro J C

    2014-10-01

    Methyl cinnamate (MC) is a safe flavoring agent useful to food industry. Although chemically analog to tyrosine kinase inhibitors, there is little information regarding its biological actions. Here, we aimed at assessing the MC effects on gastrointestinal contractility and the putative involvement of tyrosine kinase in the mediation of these effects. Isometric contractions were recorded in rat isolated strips from stomach, duodenum and colon segments. In gastric strips, MC (3-3000 µM) showed antispasmodic effects against carbachol-induced contractions, which remained unchanged by either l-NAME or tetraethylammonium pretreatment and occurred with potency similar to that obtained against contractions evoked by potassium or U-46619. In colon strips, MC was four times more potent than in gastric ones. MC and the positive control genistein inhibited phasic contractions induced by acetylcholine in Ca2+-free medium, an effect fully prevented by sodium orthovanadate. Both MC and genistein decreased the spontaneous contractions of duodenal strips and shortened the time necessary for gastric fundic tissues to reach 50% of maximal relaxation. In freshly isolated colon myocytes, MC decreased the basal levels of cytoplasmic Ca2+, but not the potassium-elicited cytoplasmic Ca2+ elevation. Colon strips obtained from rats subjected to intracolonic acetic acid instillation showed reduced contractility to potassium, which was partially recovered in MC-treated rats. Inhibitory effect of nifedipine against cholinergic contractions, blunted in acetic acid-induced colitis, was also recovered in MC-treated rats. In conclusion, MC inhibited the gastrointestinal contractility with a probable involvement of tyrosine kinase pathways. In vivo, it was effective to prevent the deleterious effects of colitis resulting from acetic acid injury. PMID:25046838

  11. Low-density lipoprotein as a potential vehicle for chemotherapeutic agents and radionucleotides in the management of gynecologic neoplasms

    SciTech Connect

    Gal, D.; Ohashi, M.; MacDonald, P.C.; Buchsbaum, H.J.; Simpson, E.R.

    1981-04-15

    Cholesterol metabolism was studied in cells from two established gynecologic cancer cell lines which were maintained in monolayer cultures. The cell lines were derived and established from poorly differentiated epidermoid cervical carcinoma and endometrial adenocarcinoma. The specific activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol de novo synthesis, in AC-258 cells was three times higher than that found in EC-50 cells. However, epidermoid cervical cancer cells metabolized low-density lipoprotein, the major transport vehicle for cholesterol in plasma, at a very high rate. This rate is fifteen times greater than the rate observed in fetal adrenal tissue and fifty times greater than the rate observed in nonneoplastic gynecologic tissue, each in organ culture. Both cancer cells in monolayer culture were shown to have specific receptors for LDL. These cancer cells demonstrate no defect in LDL metabolism, and lysosomal degradation of LDL was blocked by chloroquine. From the results of studies of specific binding of LDL in tissues obtained from nude mice it was demonstrated that membrane fractions prepared from EC-50 cells, after propagation in the mice, contained fifteen to thirty times more specific binding capacity for (125I)iodo-LDL than vital organs of the mouse, such as the liver, heart, lung, kidney, or brain. The results of these studies are suggestive that certain tumor cells might have a higher affinity for LDL than normal tissues and cytotoxic drugs or radionucleotides ligated to the LDL macromolecule may be utilized for the specific delivery of these agents.

  12. Low-density lipoprotein as a potential vehicle for chemotherapeutic agents and radionucleotides in the management of gynecologic neoplasms

    SciTech Connect

    Gal, D.; Ohashi, M.; MacDonald, P.C.; Buchsbaum, H.J.; Simpson, E.R.

    1981-04-15

    Cholesterol metabolism was studied in cells from two established gynecologic cancer cell lines which were maintained in monolayer cultures. The cell lines were derived and established from poorly differentiated epidermoid cervical carcinoma (EC-50) and endometrial adenocarcinoma (AC-258). The specific activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme of cholesterol de novo synthesis, in AC-258 cells (1700 pmoles x mg-1 microsomal protein x min-1) was three times higher than that found in EC-50 cells (550 pmoles x mg-1 microsomal protein x min-1). However, epidermoid cervical cancer cells (EC-50) metabolized low-density lipoprotein (LDL), the major transport vehicle for cholesterol in plasma, at a very high rate (14,000 ng x mg-1 cell protein x 6 hours). This rate is fifteen times greater than the rate observed in fetal adrenal tissue and fifty times greater than the rate observed in nonneoplastic gynecologic tissue, each in organ culture. Both cancer cells (EC-50 and AC-258) in monolayer culture were shown to have specific receptors for LDL. These cancer cells demonstrate no defect in LDL metabolism, and lysosomal degradation of LDL was blocked by chloroquine. From the results of studies of specific binding of LDL in tissues obtained from nude mice it was demonstrated that membrane fractions prepared from EC-50 cells, after propagation in the mice, contained fifteen to thirty times more specific binding capacity for (125I)iodo-LDL than vital organs of the mouse, such as the liver, heart, lung, kidney, or brain. The results of these studies are suggestive that certain tumor cells might have a higher affinity for LDL than normal tissues and cytotoxic drugs or radionucleotides ligated to the LDL macromolecule may be utilized for the specific delivery of these agents.

  13. Design, synthesis, and molecular docking studies of 2-(furan-2-yl)quinazolin-4-one derivatives as potential antiproliferative agents.

    PubMed

    Ahmed, Marwa F; Belal, Amany

    2015-07-01

    Fifteen new derivatives of quinazolin-4-one bearing the 2-furyl moiety at position 2 and a substituted phenyl moiety at position 3 were designed and synthesized to be evaluated as cytotoxic agents. Their chemical structures were confirmed by spectral and elemental analysis; cytotoxic activity evaluation was performed against HEPG2, HCT116, and MCF7 cancer cell lines using the sulforhodamine-B assay. All the tested compounds except 6a showed high potency against the HEPG2 cancer cell line (IC50 8-101  nM/mL); 11 compounds out of 15 proved to be potent against HCT116 cells (IC50 3-49 nM/mL), also 11 of the tested compounds showed high potency against MCF7 cells with IC50 values ranging from 7 to 63 nM/mL. The rest of the tested compounds showed IC50 values of more than 100 nM/mL. Compounds 3e and 4d are the most active compounds against HEPG2 cells; in addition, 3e is the most active compound against MCF7 cells. Also, compounds 4a, 3a, and 3b are the most active compounds against HCT116 cells. Compounds 3a, 3b, 3e, 4a, and 4d were also evaluated for their inhibitory activity against the EGFR tyrosine kinase (EGFR-TK) and showed a percentage inhibitory activity ranging from 53 to 84%. The most potent EGFR-TK inhibitors, 3a (84%), 3b (75%), and 3e (60%), were docked into the ATP binding site of the EGFR to explore their binding mode and possible interactions. PMID:25921702

  14. Design, synthesis and evaluation of novel 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids as potential multifunctional agents for the treatment of Alzheimer's disease.

    PubMed

    Liao, Shixian; Deng, Hui; Huang, Shengbin; Yang, Jingyuan; Wang, Siqian; Yin, Baodi; Zheng, Tieli; Zhang, Dafeng; Liu, Jinsong; Gao, Guohui; Ma, Jianfeng; Deng, Zhennan

    2015-04-01

    A series of 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that the target compounds exhibited good acetylcholinesterase (AChE) inhibitory potencies, high selectivity toward AChE over butyrylcholinesterase (BuChE), potential antioxidant activities and significant inhibitory potencies of self-induced beta-amyloid peptide (Aβ) aggregation. In particular, compound 14c had the strongest AChE inhibitory activity with IC50 value of 12.8 nM, potent inhibition of self-induced Aβ1-42 aggregation with inhibition ratio of 33.8% at 25 μM. Moreover, compound 14c acted as an antioxidant, as well as a neuroprotectant. Furthermore, 14c could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 14c might be a potential multifunctional candidate for the treatment of AD. PMID:25724825

  15. Preparation and characterization of ferrofluid stabilized with biocompatible chitosan and dextran sulfate hybrid biopolymer as a potential magnetic resonance imaging (MRI) T2 contrast agent.

    PubMed

    Tsai, Zei-Tsan; Tsai, Fu-Yuan; Yang, Wei-Cheng; Wang, Jen-Fei; Liu, Chao-Lin; Shen, Chia-Rui; Yen, Tzu-Chen

    2012-11-01

    Chitosan is the deacetylated form of chitin and used in numerous applications. Because it is a good dispersant for metal and/or oxide nanoparticle synthesis, chitosan and its derivatives have been utilized as coating agents for magnetic nanoparticles synthesis, including superparamagnetic iron oxide nanoparticles (SPIONs). Herein, we demonstrate the water-soluble SPIONs encapsulated with a hybrid polymer composed of polyelectrolyte complexes (PECs) from chitosan, the positively charged polymer, and dextran sulfate, the negatively charged polymer. The as-prepared hybrid ferrofluid, in which iron chloride salts (Fe³⁺ and Fe²⁺) were directly coprecipitated inside the hybrid polymeric matrices, was physic-chemically characterized. Its features include the z-average diameter of 114.3 nm, polydispersity index of 0.174, zeta potential of −41.5 mV and iron concentration of 8.44 mg Fe/mL. Moreover, based on the polymer chain persistence lengths, the anionic surface of the nanoparticles as well as the high R2/R1 ratio of 13.5, we depict the morphology of SPIONs as a cluster because chitosan chains are chemisorbed onto the anionic magnetite surfaces by tangling of the dextran sulfate. Finally, the cellular uptake and biocompatibility assays indicate that the hybrid polymer encapsulating the SPIONs exhibited great potential as a magnetic resonance imaging T2 contrast agent for cell tracking. PMID:23203267

  16. Quantification of the biocontrol agent Trichoderma harzianum with real-time TaqMan PCR and its potential extrapolation to the hyphal biomass.

    PubMed

    López-Mondéjar, Rubén; Antón, Anabel; Raidl, Stefan; Ros, Margarita; Pascual, José Antonio

    2010-04-01

    The species of the genus Trichoderma are used successfully as biocontrol agents against a wide range of phytopathogenic fungi. Among them, Trichoderma harzianum is especially effective. However, to develop more effective fungal biocontrol strategies in organic substrates and soil, tools for monitoring the control agents are required. Real-time PCR is potentially an effective tool for the quantification of fungi in environmental samples. The aim of this study consisted of the development and application of a real-time PCR-based method to the quantification of T. harzianum, and the extrapolation of these data to fungal biomass values. A set of primers and a TaqMan probe for the ITS region of the fungal genome were designed and tested, and amplification was correlated to biomass measurements obtained with optical microscopy and image analysis, of the hyphal length of the mycelium of the colony. A correlation of 0.76 between ITS copies and biomass was obtained. The extrapolation of the quantity of ITS copies, calculated based on real-time PCR data, into quantities of fungal biomass provides potentially a more accurate value of the quantity of soil fungi. PMID:19897358

  17. Therapeutic potential of new B cell-targeted agents in the treatment of elderly and unfit patients with chronic lymphocytic leukemia.

    PubMed

    Rai, Kanti R

    2015-01-01

    Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is primarily a disease of the elderly, with most patients ≥65 years of age and having at least one major comorbidity. Aggressive chemoimmunotherapy regimens recommended to achieve remission and improve survival in young, fit patients are often poorly tolerated in elderly and/or less physiologically fit ("unfit") patients, necessitating alternative treatment options. Although patient age, fitness, and comorbidities are key considerations in the selection of a treatment regimen, historically, clinical trials have been limited to young, fit patients by virtue of the ethical concerns associated with potential end organ toxic effects that could worsen comorbidities. However, the availability of new therapies promises a shift to a research paradigm that encompasses the identification of optimal treatments for elderly and unfit patients. Anti-CD20 monoclonal antibody therapy, which overall has improved response rates and survival in patients with CLL, has only recently been evaluated elderly and unfit patients. B cell-targeted agents such as the Bruton's tyrosine kinase inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib are the first of a new generation of oral agents for CLL. Available clinical data suggest that these therapies have the potential to address the unmet need in elderly and unfit patients with CLL and result in clinical remission, and not merely symptom palliation and improved quality of life, which, by themselves, are also a reasonable goal. PMID:26170206

  18. Amalgamation of complex iron(III) ions and iron nanoclusters with MWCNTs as a route to potential T2 MRI contrast agents

    PubMed Central

    Kuźnik, Nikodem; Tomczyk, Mateusz M; Wyskocka, Marzena; Przypis, Łukasz; Herman, Artur P; Jędrysiak, Rafał; Koziol, Krzysztof K; Boncel, Sławomir

    2015-01-01

    Iron-filled multiwall carbon nanotubes (Fe@MWCNTs) were functionalized toward a variety of potential magnetic resonance imaging contrast agents. Oxidized Fe@MWNCTs were covered with PEG5000 via direct esterification or using acyl chloride derivatives. Alternatively, the latter were functionalized with an aminophenol ligand (Fe@O-MWCNT-L). Moreover, pristine Fe@MWCNTs were functionalized with N-phenylaziridine groups (Fe@f-MWCNT) via [2+1] cycloaddition of nitrene. All of these chemically modified nanotubes served as a vehicle for anchoring Fe3+ ions. The new hybrids – Fe(III)/Fe@(f-/O-)MWCNTs – containing 6%–14% of the “tethered” Fe3+ions were studied in terms of the acceleration of relaxation of water protons in nuclear magnetic resonance. The highest transverse relaxivity r2=63.9±0.9 mL mg−1 s−1 was recorded for Fe(III)/Fe@O-MWCNT-L, while for Fe(III)/Fe@f-MWCNT, with r2=57.9±2.9 mL mg−1 s−1, the highest impact of the anchored Fe(III) ions was observed. The T1/T2 ratio of 30–100 found for all of the nanotube hybrids presented in this work is a very important factor for their potential application as T2 contrast agents. Increased stability of the hybrids was confirmed by ultraviolet–visible spectrophotometry. PMID:25999719

  19. TiO2 nanotube arrays deposited on Ti substrate by anodic oxidation and their potential as a long-term drug delivery system for antimicrobial agents

    NASA Astrophysics Data System (ADS)

    Moseke, Claus; Hage, Felix; Vorndran, Elke; Gbureck, Uwe

    2012-05-01

    Nanotube arrays on medical titanium surfaces were fabricated by two different anodization methods and their potential for storage and release of antimicrobial substances was evaluated. The treatment of the Ti surfaces in fluoride containing electrolytes on water as well as on polyethylene glycol basis led to the formation of TiO2 nanotubes with up to 6.54 μm length and average diameters of up to 160 nm. Drug release experiments with the model antibiotic vancomycin and with antibacterial silver ions showed that the increased surface area of the anodized samples enabled them to be loaded with up to 450% more active agent than the untreated Ti surfaces. Significant surface-dependent differences in the release kinetics of vancomycin were observed. In comparison to surfaces anodized in an aqueous electrolyte, the release of the antibiotic from surfaces anodized in an electrolyte based on ethylene glycol was significantly retarded, with a release of noticeable amounts over a period of more than 300 days. Loading of nanotube surfaces fabricated in aqueous electrolyte with silver ions revealed increased amounts of adsorbed silver by up to 230%, while the release kinetics showed significant differences in comparison to untreated Ti. It was concluded that nanotube arrays on favored medical implant materials have a high potential for loading with antimicrobial agents and also provide the possibility of tailored release kinetics by variation of anodization parameters.

  20. Molecular analysis of faecal samples from birds to identify potential crop pests and useful biocontrol agents in natural areas.

    PubMed

    King, R A; Symondson, W O C; Thomas, R J

    2015-06-01

    Wild habitats adjoining farmland are potentially valuable sources of natural enemies, but also of pests. Here we tested the utility of birds as 'sampling devices', to identify the diversity of prey available to predators and particularly to screen for pests and natural enemies using natural ecosystems as refugia. Here we used PCR to amplify prey DNA from three sympatric songbirds foraging on small invertebrates in Phragmites reedbed ecosystems, namely the Reed Warbler (Acrocephalus scirpaceus), Sedge Warbler (Acrocephalus schoenobaenus) and Cetti's Warbler (Cettia cetti). A recently described general invertebrate primer pair was used for the first time to analyse diets. Amplicons were cloned and sequenced, then identified by reference to the Barcoding of Life Database and to our own sequences obtained from fresh invertebrates. Forty-five distinct prey DNA sequences were obtained from 11 faecal samples, of which 39 could be identified to species or genus. Targeting three warbler species ensured that species-specific differences in prey choice broadened the range of prey taken. Amongst the prey found in reedbeds were major pests (including the tomato moth Lacanobia oleracea) as well as many potentially valuable natural enemies including aphidophagous hoverflies and braconid wasps. Given the mobility of birds, this approach provides a practical way of sampling a whole habitat at once, providing growers with information on possible invasion by locally resident pests and the colonization potential of natural enemies from local natural habitats. PMID:25572526

  1. Discovery of isoalloxazine derivatives as a new class of potential anti-Alzheimer agents and their synthesis.

    PubMed

    Kanhed, Ashish M; Sinha, Anshuman; Machhi, Jatin; Tripathi, Ashutosh; Parikh, Zalak S; Pillai, Prakash P; Giridhar, Rajani; Yadav, Mange Ram

    2015-08-01

    This article describes discovery of a novel and new class of cholinesterase inhibitors as potential therapeutics for Alzheimer's disease. A series of novel isoalloxazine derivatives were synthesized and biologically evaluated for their potential inhibitory outcome for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds exhibited high activity against both the enzymes AChE as well as BuChE. Of the synthesized compounds, the most potent isoalloxazine derivatives (7m and 7q) showed IC50 values of 4.72 μM and 5.22 μM respectively against AChE; and, 6.98 μM and 5.29 μM respectively against BuChE. These two compounds were further evaluated for their anti-aggregatory activity for β-amyloid (Aβ) in presence and absence of AChE by performing Thioflavin-T (ThT) assay and Congo red (CR) binding assay. In order to evaluate cytotoxic profile of these two potential compounds, cell viability assay of SH-SY5Y human neuroblastoma cells was performed. Further, to understand the binding behavior of these two compounds with AChE and BuChE enzymes, docking studies have been reported. PMID:26042530

  2. DDPH, a novel antihypertensive agent, is a potential dual inhibitor of hepatic CYP2D and CYP3A.

    PubMed

    Zhu, Yinsong; Hu, Jiong; He, Wenjuan; Gao, Xiujuan; Ren, Ping; Chen, Hui

    2016-03-01

    DDPH (1-(2, 6-dimethylphenoxy)-2-(3, 4-dimethoxyphenylethylamino) propane hydrochloride) is a promising novel antihypertensive agent, with potent antihypertensive, neuroprotective and cardioprotective effects. This study aimed to investigate the effects of DDPH on the expression and activity of hepatic cytochrome P450 (CYP) isoforms and evaluate the metabolic drug-drug interactions of DDPH with propafenone. Our results showed that orally administered DDPH (12.5-50 mg/kg/d) for 7 days significantly inhibited CYP2D1 and CYP3A1 activity and mRNA and protein expression but weakly increased CYP1A2 activity and expression in rats. Enzyme kinetics studies showed that DDPH was a competitive inhibitor of CYP2D1 and mixed inhibitor of CYP3A1 in rat liver microsomes with Ki values of 3.70 ± 0.42 μM and 4.79 ± 1.10 μM respectively. With human liver microsomes, DDPH was a noncompetitive inhibitor of CYP2D6 (Ki = 0.85 ± 0.06 μM) and mixed inhibitor of CYP3A (Ki = 2.15 ± 0.41 μM). Further in vivo study showed that oral administration of DDPH (12.5-50 mg/kg/d) for 7 days in rats significantly increased the area under the plasma concentration-time curve (AUC) of propafenone by 25.4%-63.9%, with a concomitant decrease in the plasma clearance. In conclusion, the results indicated that DDPH inhibited CYP2D and CYP3A activities and down-regulated their protein expression and mRNA transcription. DDPH might cause metabolic drug-drug interactions through modulation of the activity and expression of CYP2D and CYP3A. This information could be important in the prediction of possible drug-drug interactions as well as for the effective therapy and the limitation of toxicity of DDPH in clinical practice. PMID:26827781

  3. Green synthesis of silver nanoparticles using Ganoderma neo-japonicum Imazeki: a potential cytotoxic agent against breast cancer cells

    PubMed Central

    Gurunathan, Sangiliyandi; Raman, Jegadeesh; Malek, Sri Nurestri Abd; John, Priscilla A; Vikineswary, Sabaratnam

    2013-01-01

    Background Silver nanoparticles (AgNPs) are an important class of nanomaterial for a wide range of industrial and biomedical applications. AgNPs have been used as antimicrobial and disinfectant agents due their detrimental effect on target cells. The aim of our study was to determine the cytotoxic effects of biologically synthesized AgNPs using hot aqueous extracts of the mycelia of Ganoderma neo-japonicum Imazeki on MDA-MB-231 human breast cancer cells. Methods We developed a green method for the synthesis of water-soluble AgNPs by treating silver ions with hot aqueous extract of the mycelia of G. neo-japonicum. The formation of AgNPs was characterized by ultraviolet-visible absorption spectroscopy, X-ray diffraction, dynamic light scattering, and transmission electron microscopy. Furthermore, the toxicity of synthesized AgNPs was evaluated using a series of assays: such as cell viability, lactate dehydrogenase leakage, reactive oxygen species generation, caspase 3, DNA laddering, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling in human breast cancer cells (MDA-MB-231). Results The ultraviolet-visible absorption spectroscopy results showed a strong resonance centered on the surface of AgNPs at 420 nm. The X-ray diffraction analysis confirmed that the synthesized AgNPs were single-crystalline, corresponding with the result of transmission electron microscopy. Treatment of MDA-MB-231 breast cancer cells with various concentrations of AgNPs (1–10 μg/mL) for 24 hours revealed that AgNPs could inhibit cell viability and induce membrane leakage in a dose-dependent manner. Cells exposed to AgNPs showed increased reactive oxygen species and hydroxyl radical production. Furthermore, the apoptotic effects of AgNPs were confirmed by activation of caspase 3 and DNA nuclear fragmentation. Conclusion The results indicate that AgNPs possess cytotoxic effects with apoptotic features and suggest that the reactive oxygen species generated by

  4. Potential tuberculostatic agents. Topliss application on benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazide series.

    PubMed

    Rando, Daniela G; Sato, Dayse N; Siqueira, Leonardo; Malvezzi, Alberto; Leite, Clarice Q F; do Amaral, Antonia T; Ferreira, Elizabeth I; Tavares, Leoberto C

    2002-03-01

    Nitroaromatic compounds such as nifuroxazide are used in many human enteropathogenic bacteria infections without causing an increase in the plasmidial antibiotic resistance of the aerobic Gram-negative intestinal Enterobacteriaceae. For these reasons, these compounds have been synthesized using the rational approach of Topliss' decision tree. Generally, this approach allows us to obtain the most active derivative from the series in a few steps. These compounds were tested against Mycobacterium tuberculosis in vitro and the most active of the series identified. A new lead for potential tuberculostatic activity has been predicted and will be used in further QSAR studies. PMID:11814842

  5. Draft Genome Sequence of a Natural Root Isolate, Bacillus subtilis UD1022, a Potential Plant Growth-Promoting Biocontrol Agent.

    PubMed

    Bishnoi, Usha; Polson, Shawn W; Sherrier, D Janine; Bais, Harsh P

    2015-01-01

    Bacillus subtilis, which belongs to the phylum Firmicutes, is the most widely studied Gram-positive model organism. It is found in a wide variety of environments and is particularly abundant in soils and in the gastrointestinal tracts of ruminants and humans. Here, we present the complete genome sequence of the newly described B. subtilis strain UD1022. The UD1022 genome consists of a 4.025-Mbp chromosome, and other major findings from our analysis will provide insights into the genomic basis of it being a plant growth-promoting rhizobacterium (PGPR) with biocontrol potential. PMID:26159522

  6. Synthesis and Evaluation of [(18) F]-Ammonium BODIPY Dyes as Potential Positron Emission Tomography Agents for Myocardial Perfusion Imaging.

    PubMed

    Chansaenpak, Kantapat; Wang, Hui; Wang, Mengzhe; Giglio, Benjamin; Ma, Xiaofeng; Yuan, Hong; Hu, Shuo; Wu, Zhanhong; Li, Zibo

    2016-08-16

    Recently, we demonstrated the potential of a [(18) F]-trimethylammonium BODIPY dye for cardiac imaging. This is the first example of the use of the [(18) F]-ammonium BODIPY dye for positron emission tomography (PET) myocardial perfusion imaging (MPI). In this report, we extend our study to other ammonium BODIPY dyes with different nitrogen substituents. These novel ammonium BODIPY dyes were successfully prepared and radiolabeled by the SnCl4 -assisted (18) F-(19) F isotopic exchange method. The microPET results and the biodistribution data reveal that nitrogen substituent changes have a significant effect on the in vivo and pharmacological properties of the tracers. Of the novel [(18) F]-ammonium BODIPY dyes prepared in this work, the [(18) F]-dimethylethylammonium BODIPY is superior in terms of myocardium uptake and PET imaging contrast. These results support our hypothesis that the ammonium BODIPY dyes have a great potential for use as PET/optical dual-modality MPI probes. PMID:27405398

  7. Exploring the Potential of Venom from Nasonia vitripennis as Therapeutic Agent with High-Throughput Screening Tools

    PubMed Central

    Danneels, Ellen L.; Formesyn, Ellen M.; de Graaf, Dirk C.

    2015-01-01

    The venom from the ectoparasitoid wasp Nasonia vitripennis (Hymenoptera: Pteromalidae) contains at least 80 different proteins and possibly even more peptides or other small chemical compounds, demonstrating its appealing therapeutic application. To better understand the dynamics of the venom in mammalian cells, two high-throughput screening tools were performed. The venom induced pathways related to an early stress response and activated reporters that suggest the involvement of steroids. Whether these steroids reside from the venom itself or show an induced release/production caused by the venom, still remains unsolved. The proinflammatory cytokine IL-1β was found to be down-regulated after venom and LPS co-treatment, confirming the anti-inflammatory action of N. vitripennis venom. When analyzing the expression levels of the NF-κB target genes, potentially not only the canonical but also the alternative NF-κB pathway can be affected, possibly explaining some counterintuitive results. It is proposed that next to an NF-κB binding site, the promoter of the genes tested by the PCR array may also contain binding sites for other transcription factors, resulting in a complex puzzle to connect the induced target gene with its respective transcription factor. Interestingly, Nasonia venom altered the expression of some drug targets, presenting the venom with an exciting therapeutical potential. PMID:26046700

  8. Grain dust originating from organic and conventional farming as a potential source of biological agents causing respiratory diseases in farmers

    PubMed Central

    Cholewa, Grażyna; Krasowska, Ewelina; Chmielewska-Badora, Jolanta; Zwoliński, Jacek; Sobczak, Paweł

    2013-01-01

    Introduction Agricultural producers are exposed to a number of different health risks associated with their work environment. Aim The objective of the study was to assess the degree of colonization by fungi in terms of quantity and in terms of variety of species the samples taken from the settled dust from combine threshing of rye cultivation from organic and conventional farms in the Province of Lublin. Material and methods This paper is a preliminary quantitative assessment of the species of fungi colonizing the samples of settled dust collected during combine threshing from organic and conventional farms in the Province of Lublin. One of the stages of the project was the classification of biosafety BSL (biosafety level) of selected isolates and API ZYM tests to evaluate the potential ability of isolates to cause adverse health effects. To determine the concentration and composition of fungi in collected samples plate dilution method was used with two media: Malt Agar and Potato Dextrose Agar. Results Most commonly isolated fungi in settled dust samples collected during combine threshing from organic farms, on PDA medium were: Alternaria alternata and Aureobasidium pullulans. Cultures on MA medium were dominated by Alternaria alternata, Mycelia sterilia and Fusarium poae. In samples of dust from conventional crops, the predominant species was Alternaria alternata on PDA medium and on MA medium. Conclusions The obtained results show a potential risk of people involved in agricultural work. PMID:24493998

  9. Cryptolepis sanguinolenta: an ethnobotanical approach to drug discovery and the isolation of a potentially useful new antihyperglycaemic agent.

    PubMed

    Luo, J; Fort, D M; Carlson, T J; Noamesi, B K; nii-Amon-Kotei, D; King, S R; Tsai, J; Quan, J; Hobensack, C; Lapresca, P; Waldeck, N; Mendez, C D; Jolad, S D; Bierer, D E; Reaven, G M

    1998-05-01

    Evidence has been published that a wide array of plant-derived active principles, representing numerous classes of chemical compounds, demonstrate activity consistent with their possible use in the treatment of patients with Type 2 diabetes mellitus (DM). Despite these interesting observations, to date, metformin is the only ethical drug approved for treatment of Type 2 DM derived from a medicinal plant. Why is this so, given the fact that higher plants are such a potential source of new drugs? The answer to this rhetorical question may lie in the reliance of most pharmaceutical companies on random, in vitro, mechanism-based, high throughput screening in the initial phases of plant drug research. In this article we describe an alternative pathway to discovery of drugs for the treatment of Type 2 DM: on based on an ethnomedical approach, involving ethnobotany and traditional medicine. In particular, we present evidence that cryptolepine, an indoloquinolone alkaloid isolated from Cryptolepis sanguinolenta, significantly lowers glucose when given orally to a mouse model of diabetes. The antihyperglycaemic effect of cryptolepine leads to a significant decline in plasma insulin concentration, associated with evidence of an enhancement in insulin-mediated glucose disposal. Finally, cryptolepine increases glucose uptake by 3T3-L1 cells. These data permit us to conclude that an ethnobotanical approach to drug discovery can identify a potentially useful drug for the treatment of Type 2 DM. PMID:9609357

  10. Agent Orange

    MedlinePlus

    ... Index Agent Orange Agent Orange Home Facts about Herbicides Veterans' Diseases Birth Defects Benefits Exposure Locations Provider ... millions of gallons of Agent Orange and other herbicides on trees and vegetation during the Vietnam War. ...

  11. Bromine-75-labeled 1,4-benzodiazepines: potential agents for the mapping of benzodiazepine receptors in vivo: concise communication

    SciTech Connect

    Scholl, H.; Kloster, G.; Stoecklin, G.

    1983-05-01

    We have prepared four different 1,4-benzodiazepines, labeled at C-7 with the 1.6-hr positron emitter Br-75 or the 57-hr gamma emitter Br-77, as potential radio-pharmaceuticals for the mapping of cerebral benzodiazepine receptor areas. The triazene method was used and optimized. Yields at the no-carrier-added level were 20%. (7-/sup 75/Br)-5-(2-flophenyl)-1-methyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one (Br-75 BFB) was isolated with a minimum specific activity of 20,000 Ci/mmole. Biodistribution in mice shows that BFB is taken up rapidly by the brain and is retained there at useful concentrations for significant periods of time. The maximum uptake is observed at 0.25 min. Brain-to-blood concentration ratios are larger than 2 during the interval (0.25 to 10 min) investigated.

  12. Synthesis and evaluation of novel N-fluoropyridyl derivatives of tropane as potential PET imaging agents for the dopamine transporter

    PubMed Central

    Liu, Jingying; Zhu, Lin; Plössl, Karl; Lieberman, Brian P.; Kung, Hank F.

    2011-01-01

    A series of novel N-fluoropyridyl-containing tropane derivatives were synthesized and their binding affinities for the dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine (NET) were determined via competitive radioligand binding assays. Among these derivatives, compound 6d showed the highest binding affinity to DAT (Ki = 4.1 nM), and selectivity for DAT over SERT (5 fold) and NET (16 fold). Compound 6d was radiolabeled with Fluorine-18 in two steps. Regional brain distribution and ex vivo autoradiography studies of [18F]6d demonstrated that the ligand was selectively localized in the striatum region, where DAT binding sites are highly expressed. [18F]6d may be useful as a potential radioligand for imaging DATs with PET. PMID:21458259

  13. Phthalimide-Derived N-Benzylpyridinium Halides Targeting Cholinesterases: Synthesis and Bioactivity of New Potential Anti-Alzheimer's Disease Agents.

    PubMed

    Saeedi, Mina; Golipoor, Maedeh; Mahdavi, Mohammad; Moradi, Alireza; Nadri, Hamid; Emami, Saeed; Foroumadi, Alireza; Shafiee, Abbas

    2016-04-01

    In order to develop potent dual-binding cholinesterase inhibitors as potential drugs for the treatment of Alzheimer's disease, we designed and synthesized phthalimide-based acetylcholinesterase (AChE) inhibitors (7) containing a substituted N-benzylpyridinium residue. The in vitro anti-cholinesterase assay employing the target compounds against AChE and butyrylcholinesterase (BChE) revealed the 2-fluorobenzylpyridinium derivative 7d as the most potent compound against both enzymes, with IC50 values of 0.77 and 8.71 μM. The docking study of compound 7d into the active site of AChE showed the gorge-spanning binding mode, in which the compound spans the narrow hydrophobic gorge from the bottom to the rim. PMID:26898241

  14. Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance.

    PubMed

    Pape, Veronika F S; Tóth, Szilárd; Füredi, András; Szebényi, Kornélia; Lovrics, Anna; Szabó, Pál; Wiese, Michael; Szakács, Gergely

    2016-07-19

    There is a constant need for new therapies against multidrug resistant (MDR) cancer. An attractive strategy is to develop chelators that display significant antitumor activity in multidrug resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein. In this study we used a panel of sensitive and MDR cancer cell lines to evaluate the toxicity of picolinylidene and salicylidene thiosemicarbazone, arylhydrazone, as well as picolinylidene and salicylidene hydrazino-benzothiazole derivatives. Our results confirm the collateral sensitivity of MDR cells to isatin-β-thiosemicarbazones, and identify several chelator scaffolds with a potential to overcome multidrug resistance. Analysis of structure-activity-relationships within the investigated compound library indicates that NNS and NNN donor chelators show superior toxicity as compared to ONS derivatives regardless of the resistance status of the cells. PMID:27161177

  15. In vitro evaluation of 2-hydroxyalkylated β-cyclodextrins as potential therapeutic agents for Niemann-Pick Type C disease.

    PubMed

    Kondo, Yuki; Tokumaru, Hiroko; Ishitsuka, Yoichi; Matsumoto, Tomoko; Taguchi, Makiko; Motoyama, Keiichi; Higashi, Taishi; Arima, Hidetoshi; Matsuo, Muneaki; Higaki, Katsumi; Ohno, Kousaku; Irie, Tetsumi

    2016-07-01

    This study was conducted to evaluate the attenuating potential of 2-hydroxypropyl-β-cyclodextrin (HPBCD) against Niemann-Pick Type C (NPC) disease, as well as the physical and chemical properties, particularly the cholesterol-solubilizing ability, in an NPC disease model in vitro. As parameters of NPC abnormalities, intracellular free and esterified cholesterol levels and lysosome volume were measured in Npc1 null Chinese hamster ovary cells. HPBCD showed dose-dependent effects against dysfunctional intracellular cholesterol trafficking, such as the accumulation and shortage of free and esterified cholesterols, respectively, in Npc1 null cells. However, the effectiveness was gradually offset by exposure to ≥8mM HPBCD. The same effect was also observed for increasing lysosome volume in Npc1 null cells. The degree of substitution of the hydroxypropyl group had little influence on the attenuating effects of HPBCD against the NPC abnormalities, at least in the range between 2.8 and 7.4. Next, we compared the effects of other hydroxyalkylated β-cyclodextrin derivatives with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-β-cyclodextrin (HEBCD) and 2-hydroxybutyl-β-cyclodextrin (HBBCD). The cholesterol solubilizing potential, attenuating effects against NPC abnormalities and cytotoxicity induction were HBBCD≫HPBCD>HEBCD, HBBCD=HPBCD>HEBCD and HBBCD≫HPBCD=HEBCD, respectively. HPBCD may be superior in terms of safety and efficacy in Npc1 null cells compared with HEBCD and HBBCD. The results of this study will provide a rationale for the optimization of HPBCD therapy for NPC disease. PMID:27184436

  16. Synthesis of Rapamycin Derivatives Containing the Triazole Moiety Used as Potential mTOR-Targeted Anticancer Agents.

    PubMed

    Xie, Lijun; Huang, Jie; Chen, Xiaoming; Yu, Hui; Li, Kualiang; Yang, Dan; Chen, Xiaqin; Ying, Jiayin; Pan, Fusheng; Lv, Youbing; Cheng, Yuanrong

    2016-06-01

    Rapamycin, a potent antifungal antibiotic, was approved as immunosuppressant, and lately its derivatives have been developed into mTOR targeting anticancer drugs. Structure modification was performed at the C-42 position of rapamycin, and a novel series of rapamycin triazole hybrids (4a-d, 5a-e, 8a-e, and 9a-e) was facilely synthesized via Huisgen's reaction. The anticancer activity of these compounds was evaluated against the Caski, H1299, MGC-803, and H460 human cancer cell lines. Some of the derivatives (8a-e, 9a-e) appeared to have stronger activity than that of rapamycin; however, 4a-d and 5a-e failed to show potential anticancer activity. Compound 9e with a (2,4-dichlorophenylamino)methyl moiety on the triazole ring was the most active anticancer compound, which showed IC50 values of 6.05 (Caski), 7.89 (H1299), 25.88 (MGC-803), and 8.60 μM (H460). In addition, research on the mechanism showed that 9e was able to cause cell morphological changes and to induce apoptosis in the Caski cell line. Most importantly, 9e can decrease the phosphorylation of mTOR and of its downstream key proteins, S6 and P70S6K1, indicating that 9e can effectively inhibit the mTOR signaling pathway. Thus, it may have the potential to become a new mTOR inhibitor against various cancers. PMID:27150260

  17. Potentiation of treosulfan toxicity by the glutathione-depleting agent buthionine sulfoximine in human malignant glioma cells: the role of bcl-2.

    PubMed

    Reber, U; Wüllner, U; Trepel, M; Baumgart, J; Seyfried, J; Klockgether, T; Dichgans, J; Weller, M

    1998-02-01

    Median survival of human malignant glioma patients is less than one year even with cytoreductive surgery and postoperative radiotherapy. Adjuvant chemotherapy has been rather ineffective. Here, we studied the potentiation by L-buthionine-[S,R]-sulfoximine (BSO), a glutathione-depleting agent, of anticancer drug actions on two human malignant glioma cell lines, LN-229 and T98G. LN-229 has wild-type p53 status, T98G is mutant for p53. Glutathione levels were depleted by BSO with similar kinetics in both cell lines. Only LN-229 cells were growth-inhibited by BSO. BSO had minor effects on the toxicity of doxorubicin, ACNU (1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosou rea, nimustine) and vincristine. BSO failed to alter teniposide or cytarabine toxicity. BSO induced prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides. In the absence of BSO, treosulfan had little acute cytotoxic and moderate antiproliferative effects. Synergistic glioma cell cytotoxicity induced by treosulfan and BSO was not associated with reactive oxygen species formation. Ectopic expression of bcl-2 did not alter basal glutathione levels but attenuated glutathione depletion induced by BSO. Bcl-2 provided only moderate protection from synergistic induction of glioma cell death by treosulfan and BSO. Glutathione depletion may play a role in BSO-mediated chemosensitization, but other mechanisms are probably involved as well. BSO may be a useful agent for glioma cell sensitization to specific chemotherapeutic drugs such as treosulfan. PMID:9484802

  18. Data Mining in the U.S. National Toxicology Program (NTP) Database Reveals a Potential Bias Regarding Liver Tumors in Rodents Irrespective of the Test Agent

    PubMed Central

    Ring, Matthias; Eskofier, Bjoern M.

    2015-01-01

    Long-term studies in rodents are the benchmark method to assess carcinogenicity of single substances, mixtures, and multi-compounds. In such a study, mice and rats are exposed to a test agent at different dose levels for a period of two years and the incidence of neoplastic lesions is observed. However, this two-year study is also expensive, time-consuming, and burdensome to the experimental animals. Consequently, various alternatives have been proposed in the literature to assess carcinogenicity on basis of short-term studies. In this paper, we investigated if effects on the rodents’ liver weight in short-term studies can be exploited to predict the incidence of liver tumors in long-term studies. A set of 138 paired short- and long-term studies was compiled from the database of the U.S. National Toxicology Program (NTP), more precisely, from (long-term) two-year carcinogenicity studies and their preceding (short-term) dose finding studies. In this set, data mining methods revealed patterns that can predict the incidence of liver tumors with accuracies of over 80%. However, the results simultaneously indicated a potential bias regarding liver tumors in two-year NTP studies. The incidence of liver tumors does not only depend on the test agent but also on other confounding factors in the study design, e.g., species, sex, type of substance. We recommend considering this bias if the hazard or risk of a test agent is assessed on basis of a NTP carcinogenicity study. PMID:25658102

  19. Comparison of the Lonidamine Potentiated Effect of Nitrogen Mustard Alkylating Agents on the Systemic Treatment of DB-1 Human Melanoma Xenografts in Mice

    PubMed Central

    Nath, Kavindra; Nelson, David S.; Putt, Mary E.; Leeper, Dennis B.; Garman, Bradley; Nathanson, Katherine L.; Glickson, Jerry D.

    2016-01-01

    Previous NMR studies demonstrated that lonidamine (LND) selectively diminishes the intracellular pH (pHi) of DB-1 melanoma and mouse xenografts of a variety of other prevalent human cancers while decreasing their bioenergetic status (tumor βNTP/Pi ratio) and enhancing the activities of melphalan and doxorubicin in these cancer models. Since melphalan and doxorubicin are highly toxic agents, we have examined three other nitrogen (N)-mustards, chlorambucil, cyclophosphamide and bendamustine, to determine if they exhibit similar potentiation by LND. As single agents LND, melphalan and these N-mustards exhibited the following activities in DB-1 melanoma xenografts; LND: 100% tumor surviving fraction (SF); chlorambucil: 100% SF; cyclophosphamide: 100% SF; bendamustine: 79% SF; melphalan: 41% SF. When combined with LND administered 40 min prior to administration of the N-mustard (to maximize intracellular acidification) the following responses were obtained; chlorambucil: 62% SF; cyclophosphamide: 42% SF; bendamustine: 36% SF; melphalan: 10% SF. The effect of LND on the activities of these N-mustards is generally attributed to acid stabilization of the aziridinium active intermediate, acid inhibition of glutathione-S-transferase, which acts as a scavenger of aziridinium, and acid inhibition of DNA repair by O6-alkyltransferase. Depletion of ATP by LND may also decrease multidrug resistance and increase tumor response. At similar maximum tolerated doses, our data indicate that melphalan is the most effective N-mustard in combination with LND when treating DB-1 melanoma in mice, but the choice of N-mustard for coadministration with LND will also depend on the relative toxicities of these agents, and remains to be determined. PMID:27285585

  20. Gas and Gas Hydrate Potential Offshore Amasra,Bartin and Zonguldak and Possible Agent for Multiple BSR Occurrence

    NASA Astrophysics Data System (ADS)

    Mert Küçük, Hilmi; Dondurur, Derman; Özel, Özkan; Sınayuç, Çağlar; Merey, Şükrü; Parlaktuna, Mahmut; Çifçi, Günay

    2015-04-01

    Gas hydrates, shallow gases and mud volcanoes have been studied intensively in the Black Sea in recent years. Researches have shown that the Black Sea region has an important potential about hydrocarbon. BSR reflections in the seismic sections and seabed sampling studies also have proven the formations of hydrates clearly. In this respect, total of 2400 km multichannel seismic reflection, chirp and multibeam bathymetry data were collected along shelf to abyssal plain in 2010 and 2012 offshore Amasra, Bartın, Zonguldak-Kozlu in the central Black Sea.. Collected data represent BSRs, bright spots and transparent zones. It has been clearly observed that possible gas chimneys cross the base of gas hydrate stability zones as a result of possible weak zones in the gas hydrate bearing sediments. Seabed samples were collected closely to possible gas chimneys due to shallow gas anomalies in the data. Head space gas cromatography was applied to seabed samples to observe gas composition and the gas cromatography results represented hydrocarbon gases such as Methane, Ethane, Propane, i-Butane, n-Butane, i-Pentane, n-Pentane and Hexane. Thermogenic gas production by Turkish Petroleum Corp. from Akçakoca-1 and Ayazlı-1 well is just located at the southwest of the study area and the observations of the study area point out there is also thermogenic gas potential at the eastern side of the Akçakoca. In addition, multiple-BSRs were observed in the study area and it is thought the key point of the multiple-BSRs are different gas compositions. This suggests that hydrate formations can be formed by gas mixtures. Changing of the thermobaric conditions can trigger dissociation of the gas hydrates in the marine sediments due to sedimentary load and changing of the water temperature around seabed. Our gas hydrate modelling study suggest that gas hydrates are behaving while their dissociation process if the gas hydrates are generated by gas mixture. Monitoring of our gas hydrate

  1. Antifungal agents.

    PubMed

    Ryder, N S

    1999-12-01

    At this year's ICAAC Meeting, new data on approximately 20 different antifungal agents were presented, while no new agents were disclosed. Drugs in late development include the triazoles, voriconazole (Pfizer Ltd) and Sch-56592 (Schering-Plough Corp), and the echinocandins, caspofungin (Merck & Co Inc) and FK-463 (Fujisawa Pharmaceutical Co Ltd). In contrast to previous years, presentations on these and earlier developmental compounds were relatively modest in scope, with few significant new data. Little new information appeared on the most recent novel class of agents, the sordarins (Glaxo Wellcome plc). Early clinical results were presented for FK-463, showing acceptable tolerability and dose-dependent efficacy in AIDS-associated esophageal candidiasis. A new liposomal formulation of nystatin (Nyotran; Aronex Pharmaceuticals Inc) was shown to be equivalent to conventional amphotericin B in empiric therapy of presumed fungal infection in neutropenic patients, but with reduced toxicity. Intravenous itraconazole (Janssen Pharmaceutica NV) was an effective prophylactic therapy in invasive pulmonary aspergillosis, while oral itraconazole was discussed as a treatment for fungal infection in heart and liver transplant patients. The allylamine compound, terbinafine (Novartis AG), showed good clinical efficacy against fungal mycetoma, a serious tropical infection. A major highlight was the first presentation of inhibitors of fungal efflux pumps as a strategy for overcoming resistance. MC-510027 (milbemycin alpha-9; Microcide Pharmaceuticals Inc) and its derivatives, potentiated the antifungal activity of triazoles and terbinafine in a number of Candida spp. Another pump inhibitor, MC-005172 (Microcide Pharmaceuticals Inc) showed in vivo potentiation of fluconazole in a mouse kidney infection model. Microcide Pharmaceuticals Inc also presented inhibitors of bacterial efflux pumps. PMID:16113946

  2. Human Anti-Oxidation Protein A1M—A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy

    PubMed Central

    Ahlstedt, Jonas; Tran, Thuy A.; Strand, Sven-Erik; Gram, Magnus; Åkerström, Bo

    2015-01-01

    Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α1-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies. PMID:26694383

  3. Human Anti-Oxidation Protein A1M--A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy.

    PubMed

    Ahlstedt, Jonas; Tran, Thuy A; Strand, Sven-Erik; Gram, Magnus; Åkerström, Bo

    2015-01-01

    Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies. PMID:26694383

  4. Technetium-99m bis (aminoethanethiol) complexes with amine sidechains--potential brain perfusion imaging agents for SPECT

    SciTech Connect

    Efange, S.M.; Kung, H.F.; Billings, J.; Guo, Y.Z.; Blau, M.

    1987-06-01

    In an effort to develop new clinically useful technetium-99m bis(aminoethanethiol) ((/sup 99m/Tc)BAT) complexes for the evaluation of regional cerebral perfusion, two new BAT ligands containing amines in the sidechain were synthesized and subsequently complexed with /sup 99m/Tc to yield the target complexes: (/sup 99m/Tc)DEA and (/sup 99m/Tc)TMPDA. Each complex was obtained as mixtures of two isomers, syn and anti, which were separated chromatographically. In biodistribution studies, both isomers of (/sup 99m/Tc)TMPDA showed little uptake in the brain. In contrast, the brain uptake values at 2 and 15 min for (/sup 99m/Tc)DEA-anti were 0.99 and 0.26, whereas, the corresponding values for DEA-syn were 2.27, 0.64% dose/organ, respectively. Autoradiographic studies (in rats) using both isomers of (/sup 99m/Tc)DEA show a fixed regional distribution and a higher concentration of radioactivity in the gray matter relative to the white matter. Planar imaging using (/sup 99m/Tc)DEA-syn clearly demonstrates localization of the complex in the brain with a T 1/2 of 41 min, suggesting some potential for use with single photon emission computed tomography.

  5. Potential Application of Biohydrogen Production Liquid Waste as Phosphate Solubilizing Agent-A Study Using Soybean Plants.

    PubMed

    Sarma, Saurabh Jyoti; Brar, Satinder Kaur; LeBihan, Yann; Buelna, Gerardo

    2016-03-01

    With CO2 free emission and a gravimetric energy density higher than gasoline, diesel, biodiesel, and bioethanol, biohydrogen is a promising green renewable energy carrier. During fermentative hydrogen production, 60-70 % of the feedstock is converted to different by-products, dominated by organic acids. In the present investigation, a simple approach for value addition of hydrogen production liquid waste (HPLW) containing these compounds has been demonstrated. In soil, organic acids produced by phosphate solubilizing bacteria chelate the cations of insoluble inorganic phosphates (e.g., Ca3 (PO4)2) and make the phosphorus available to the plants. Organic acid-rich HPLW, therefore, has been evaluated as soil phosphate solubilizer. Application of HPLW as soil phosphate solubilizer was found to improve the phosphorus uptake of soybean plants by 2.18- to 2.74-folds. Additionally, 33-100 % increase in seed germination rate was also observed. Therefore, HPLW has the potential to be an alternative for phosphate solubilizing biofertilizers available in the market. Moreover, the strategy can be useful for phytoremediation of phosphorus-rich soil. PMID:26541163

  6. Evaluating the potential of marine Bacteriovorax sp. DA5 as a biocontrol agent against vibriosis in Litopenaeus vannamei larvae.

    PubMed

    Wen, Chongqing; Xue, Ming; Liang, Huafang; Zhou, Shining

    2014-09-17

    The potential application of Bdellovibrio-and-like organisms (BALOs) for the biocontrol of bacterial diseases has been widely recognized. However, no marine BALOs have been reported for Vibrio-related infections in penaeid shrimp. In the present study, the bacteriolytic ability of the marine Bacteriovorax strain DA5 against Vibrio alginolyticus zouA was examined by cocultivation and electron microscopy, and optimal lysis was observed at 30-35°C and 20-30‰ salinity along with a high multiplicity of infection. Then, we showed that experimentally infected Litopenaeus vannamei larvae exhibited significantly higher survival with incremental DA5 levels. Finally, variation in the bacterial counts and the bacterial community in larval rearing water was investigated after prophylactic application of DA5. The elimination effect of DA5 on vibrios was visible at early time points, whereas only a few non-dominant bacteria, rather than the predominant populations, were affected through analysis of denaturing gradient gel electrophoresis of the 16S rDNA V3 region. Accordingly, the prophylactic and therapeutic efficacies of DA5 on vibriosis associated with L. vannamei could markedly enhance larval survivability, and these results will facilitate the application of marine Bacteriovorax to control vibriosis in shrimp larviculture. PMID:25139659

  7. Ethephon As a Potential Abscission Agent for Table Grapes: Effects on Pre-Harvest Abscission, Fruit Quality, and Residue.

    PubMed

    Ferrara, Giuseppe; Mazzeo, Andrea; Matarrese, Angela M S; Pacucci, Carmela; Trani, Antonio; Fidelibus, Matthew W; Gambacorta, Giuseppe

    2016-01-01

    Some plant growth regulators, including ethephon, can stimulate abscission of mature grape berries. The stimulation of grape berry abscission reduces fruit detachment force (FDF) and promotes the development of a dry stem scar, both of which could facilitate the production of high quality stemless fresh-cut table grapes. The objective of this research was to determine how two potential abscission treatments, 1445 and 2890 mg/L ethephon, affected FDF, pre-harvest abscission, fruit quality, and ethephon residue of Thompson Seedless and Crimson Seedless grapes. Both ethephon treatments strongly induced abscission of Thompson Seedless berries causing >90% pre-harvest abscission. Lower ethephon rates, a shorter post-harvest interval, or berry retention systems such as nets, would be needed to prevent excessive pre-harvest losses. The treatments also slightly affected Thompson Seedless berry skin color, with treated fruit being darker, less uniform in color, and with a more yellow hue than non-treated fruit. Ethephon residues on Thompson Seedless grapes treated with the lower concentration of ethephon were below legal limits at harvest. Ethephon treatments also promoted abscission of Crimson Seedless berries, but pre-harvest abscission was much lower (≅49%) in Crimson Seedless compared to Thompson Seedless. Treated fruits were slightly darker than non-treated fruits, but ethephon did not affect SSC, acidity, or firmness of Crimson Seedless, and ethephon residues were below legal limits. PMID:27303407

  8. Selection and evaluation of Debaryomyces hansenii isolates as potential bioprotective agents against toxigenic penicillia in dry-fermented sausages.

    PubMed

    Núñez, Félix; Lara, María S; Peromingo, Belén; Delgado, Josué; Sánchez-Montero, Lourdes; Andrade, María J

    2015-04-01

    Biocontrol using autochthonous Debaryomyces hansenii isolates is a potentially suitable strategy for inhibiting toxigenic moulds in dry-cured meat products. The antifungal activity of 280 D. hansenii isolated from dry-cured meat products as well as the mode of action of the most active isolates against toxigenic penicillia were evaluated in this work. A 13.9% of the D. hansenii isolates showed inhibitory activity in a radial inhibition assay. The effects on penicillia growth of both the cell-free culture filtrate and volatile compounds from active yeast isolates were analysed. Penicillia growth inhibition by D. hansenii was probably based on additive or synergistic effects of several inhibiting factors such as competition for nutrient and space, and production of soluble or volatile compounds. When four D. hansenii isolates were tested on dry-fermented sausage, two of them produced a significantly growth reduction of the ochratoxigenic Penicillium verrucosum, keeping its counts under the level considered as hazardous for the mycotoxin presence. Therefore, the use of these two D. hansenii isolates during the processing of dry-fermented meat product could be a promising tool to control toxigenic moulds in the meat industry. PMID:25475274

  9. Potential of olive oil phenols as chemopreventive and therapeutic agents against cancer: a review of in vitro studies.

    PubMed

    Casaburi, Ivan; Puoci, Francesco; Chimento, Adele; Sirianni, Rosa; Ruggiero, Carmen; Avena, Paola; Pezzi, Vincenzo

    2013-01-01

    Olive oil is a common component of Mediterranean dietary habits. Epidemiological studies have shown how the incidence of various diseases, including certain cancers, is relatively low in the Mediterranean basin compared to that of other European or North America countries. Current knowledge indicates that the phenolic fraction of olive oil has antitumor effects. In addition to the ability to be chemopreventive, with its high antioxidant activity, the antitumor effects of olive oil phenols (OO-phenols) has been studied because of their capacity to inhibit proliferation and promote apoptosis in several tumor cell lines, by diverse mechanisms. This review will summarize and discuss the most recent relevant results on the antitumor effect of OO-phenols on leukemia tumor cells, colorectal carcinoma cells, and breast cancer (BC) cells. In particular, very recent data will be reported and discussed showing the molecular signaling pathways activated by OO-phenols in different histopathological BC cell types, suggesting the potential use of OO-phenols as adjuvant treatment against several subsets of BC. Data summarized here represent a good starting point for more extensive studies for better insight into the molecular mechanisms induced by OO-phenols and to increase the availability of chemopreventive or therapeutic drugs to fight cancer. PMID:23193056

  10. Magnetic nanoscale metal organic frameworks for potential targeted anticancer drug delivery, imaging and as an MRI contrast agent.

    PubMed

    Ray Chowdhuri, Angshuman; Bhattacharya, Dipsikha; Sahu, Sumanta Kumar

    2016-02-21

    The development of a novel multifunctional porous nanoplatform for targeted anticancer drug delivery with cell imaging and magnetic resonance imaging has been realised in the current work. Here we have developed a magnetic nanoscale metal organic frameworks (NMOF) for potential targeted drug delivery. These magnetic NMOFs were fabricated by incorporation of Fe3O4 nanoparticles into porous isoreticular metal organic frameworks (IRMOF-3). To achieve targeted drug delivery towards cancer cells specifically, folic acid was conjugated to the NMOF surface. Then, the fluorescent molecule rhodamine B isothiocyanate (RITC) was conjugated to the NMOFs for biological imaging applications. The synthesized magnetic NMOFs were fully characterised by FTIR, powder XRD, XPS, SQUID, TGA, TEM, FESEM, and DLS. The synthesized magnetic NMOFs were observed to be smaller than 100 nm and were found to be nontoxic towards human cervix adenocarcinoma (HeLa) and murine fibroblast (NIH3T3) cells according to cell viability assays. The cancer chemotherapy drug paclitaxel was conjugated to the magnetic NMOFs through hydrophobic interactions with a relatively high loading capacity. Moreover, these folic acid-conjugated magnetic NMOFs showed stronger T2-weighted MRI contrast towards the cancer cells, justifying their possible significance in imaging. PMID:26754449

  11. Ethephon As a Potential Abscission Agent for Table Grapes: Effects on Pre-Harvest Abscission, Fruit Quality, and Residue

    PubMed Central

    Ferrara, Giuseppe; Mazzeo, Andrea; Matarrese, Angela M. S.; Pacucci, Carmela; Trani, Antonio; Fidelibus, Matthew W.; Gambacorta, Giuseppe

    2016-01-01

    Some plant growth regulators, including ethephon, can stimulate abscission of mature grape berries. The stimulation of grape berry abscission reduces fruit detachment force (FDF) and promotes the development of a dry stem scar, both of which could facilitate the production of high quality stemless fresh-cut table grapes. The objective of this research was to determine how two potential abscission treatments, 1445 and 2890 mg/L ethephon, affected FDF, pre-harvest abscission, fruit quality, and ethephon residue of Thompson Seedless and Crimson Seedless grapes. Both ethephon treatments strongly induced abscission of Thompson Seedless berries causing >90% pre-harvest abscission. Lower ethephon rates, a shorter post-harvest interval, or berry retention systems such as nets, would be needed to prevent excessive pre-harvest losses. The treatments also slightly affected Thompson Seedless berry skin color, with treated fruit being darker, less uniform in color, and with a more yellow hue than non-treated fruit. Ethephon residues on Thompson Seedless grapes treated with the lower concentration of ethephon were below legal limits at harvest. Ethephon treatments also promoted abscission of Crimson Seedless berries, but pre-harvest abscission was much lower (≅49%) in Crimson Seedless compared to Thompson Seedless. Treated fruits were slightly darker than non-treated fruits, but ethephon did not affect SSC, acidity, or firmness of Crimson Seedless, and ethephon residues were below legal limits. PMID:27303407

  12. Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders

    PubMed Central

    Leopoldo, Marcello; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto; Hedlund, Peter B.

    2010-01-01

    Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented. PMID:20923682

  13. Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders

    PubMed Central

    Butelman, Eduardo R.; Kreek, Mary Jeanne

    2015-01-01

    Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A. PMID:26441647

  14. Size and CT density of iodine-containing ethosomal vesicles obtained by membrane extrusion: potential for use as CT contrast agents.

    PubMed

    Na, Bomin; Choi, Byoung Wook; Kim, Bumsang

    2013-11-01

    Computed tomography (CT) is the primary non-invasive imaging technique used for most patients with suspected liver disease. In order to improve liver-specific imaging properties and prevent toxic effects in patients with compromised renal function, we investigated the encapsulation of iodine within ethosomal vesicles. As a first step in the development of novel contrast agents using ethosomes for CT imaging applications, iodine was entrapped within ethosomes and iodine-containing ethosomes of the desired size were obtained by extrusion using a polycarbonate membrane with a defined pore size. Ethosomes containing iodine showed a relatively high CT density, which decreased when they were extruded, due to the rupture and re-formation of the lipid bilayer of the ethosome. However, when a solution with a high iodine concentration was used as a dispersion media during the extrusion process, the decrease in CT density could be prevented. In addition, ethosomes containing iodine were taken up efficiently by macrophages, which are abundant in the liver, and these ethosomes exhibited no cellular toxicity. These results demonstrate that iodine could be entrapped within ethosomal vesicles, giving the ethosomes a relatively high CT density, and that the extrusion technique used in this study could conveniently and reproducibly produce ethosomal vesicles with a desired size. Therefore, ethosomes containing iodine, as prepared in this study, have potential as contrast agents with applications in CT imaging. PMID:23857905

  15. 'A child is also a teacher': exploring the potential for children as change agents in the context of a school-based WASH intervention in rural Eastern Zambia.

    PubMed

    Bresee, S; Caruso, B A; Sales, J; Lupele, J; Freeman, M C

    2016-08-01

    As part of water, sanitation and hygiene interventions in low-income settings, it is frequently assumed that pupils can disseminate information and catalyze change at home, yet this assumption has not been rigorously assessed. We employed qualitative research methods in two phases to assess the potential for children to be change agents in five schools in rural Zambia. Phase 1 included role-play and focus group discussions among pupils on their percieved ability to serve as change agents. Children were then given 'homework' that included information on health messages and on how to build a handwashing station, and were encouraged to engage their family. In Phase 2, we conducted separate focus group discussions with pupils and mothers on their experiences with the 'homework'. We found that, in general, pupils were enthusiastic about engaging with parents-typically male heads of household-and were successful at constructing handwashing stations. Mothers reported high levels of trust in children to relay health information learned at school. Pupils were able to enact small changes to behavior, but not larger infrastructure changes, such as construction of latrines. Pupils are capable of communicating knowledge and behaviors to family members; however, discrete activities and guidance is required. PMID:27206442

  16. Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents

    PubMed Central

    Abed, Dhulfiqar Ali; Goldstein, Melanie; Albanyan, Haifa; Jin, Huijuan; Hu, Longqin

    2015-01-01

    The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1–Nrf2 PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1׳s cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1–Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions. PMID:26579458

  17. In vitro and in vivo evaluation of (/sup 123/I)IBZM: a potential CNS D-2 dopamine receptor imaging agent

    SciTech Connect

    Kung, H.F.; Pan, S.; Kung, M.P.; Billings, J.; Kasliwal, R.; Reilley, J.; Alavi, A.

    1989-01-01

    In vitro binding characteristics of a CNS dopamine D-2 receptor imaging agent, (S)-N-((1-ethyl-2-pyrrolidinyl)) methyl-2-hydroxy-3-iodo-6-methoxybenzamide ((/sup 125/I)IBZM), was carried out in rats. Also brain images, as well as organ biodistribution were determined in a monkey following the administration of /sup 123/I-labeled compound. The S-(-)-I(/sup 125/I)IBZM showed high specific dopamine D-2 receptor binding in rat striatum (Kd = 0.426 +/- 0.082 nM, Bmax = 480 +/- 22 fmol/mg of protein). Competition of various ligands for the IBZM binding displayed the following rank order of potency: spiperone greater than S(-)IBZM much greater than R(+)IBZM greater than or equal to S(-)BZM greater than dopamine greater than ketanserin greater than SCH-23390 much greater than propranolol, norepinephrine, serotonin. In vivo planar images of a monkey injected with (/sup 123/I)IBZM demonstrated a high concentration in basal ganglia of brain. The ratios of activity in the basal ganglia to cerebellum and the cortex to cerebellum in monkey brain were 4.93 and 1.44, respectively, at 120 min postinjection. These preliminary results indicate that (/sup 123/I)IBZM is a potentially promising imaging agent for the investigation of dopamine D-2 receptors in humans.

  18. Polyglycerol-grafted superparamagnetic iron oxide nanoparticles: highly efficient MRI contrast agent for liver and kidney imaging and potential scaffold for cellular and molecular imaging.

    PubMed

    Arsalani, Nasser; Fattahi, Hassan; Laurent, Sophie; Burtea, Carmen; Vander Elst, Luce; Muller, Robert N

    2012-01-01

    Polyglycerol as a water-soluble and biocompatible hyperbranched polymer was covalently grafted on the surface of superparamagnetic iron oxide nanoparticles. With this aim, superparamagnetic magnetite nanoparticles were prepared by coprecipitation in aqueous media, then the surface of nanoparticles was modified to introduce the reactive groups on the surface of nanoparticles. After that, polyglycerol was grafted on the surface of nanoparticles by ring-opening anionic polymerization of glycidol using n-bulyllithium as initiator. The magnetometry, relaxometry and phantom MRI experiments of this highly stable ferrofluid showed its high potential as a negative MRI contrast agent. Calculated r(1) and r(2) relaxivities at different magnetic fields were higher than the values reported for commercially available iron oxide contrast agents. The in vivo MRI studies showed that, after intravenous injection into mice, the particles produced a strong negative contrast in liver and kidneys, which persisted for 80 min (in liver) to 110 min (in kidneys). The negative contrast of the liver and kidneys weakened over the time, suggesting that polyglycerol coating renders the nanoparticles stealth and possibly optimal for renal excretion. PMID:22434631