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Sample records for active therapeutic agents

  1. Activities of Therapeutic Agents and Myristamidopropyl Dimethylamine against Acanthamoeba Isolates

    PubMed Central

    Kilvington, Simon; Hughes, Reanne; Byas, James; Dart, John

    2002-01-01

    The activities of therapeutic agents and myristamidopropyl dimethylamine (MAPD) against Acanthamoeba strains recalcitrant to medical therapy were studied. MAPD minimum cysticidal concentrations were 6.25 to 25 μg/ml; 10 to 30 μg/ml gave at least a 3-log cyst kill after 6 h, and 50 and 100 μg/ml gave at least a 3-log cyst kill within 2 and 1 h, respectively. PMID:12019127

  2. Activities of therapeutic agents and myristamidopropyl dimethylamine against Acanthamoeba isolates.

    PubMed

    Kilvington, Simon; Hughes, Reanne; Byas, James; Dart, John

    2002-06-01

    The activities of therapeutic agents and myristamidopropyl dimethylamine (MAPD) against Acanthamoeba strains recalcitrant to medical therapy were studied. MAPD minimum cysticidal concentrations were 6.25 to 25 microg/ml; 10 to 30 microg/ml gave at least a 3-log cyst kill after 6 h, and 50 and 100 microg/ml gave at least a 3-log cyst kill within 2 and 1 h, respectively.

  3. Phytonutrients as therapeutic agents.

    PubMed

    Gupta, Charu; Prakash, Dhan

    2014-09-01

    Nutrients present in various foods plays an important role in maintaining the normal functions of the human body. The major nutrients present in foods include carbohydrates, proteins, lipids, vitamins, and minerals. Besides these, there are some bioactive food components known as "phytonutrients" that play an important role in human health. They have tremendous impact on the health care system and may provide medical health benefits including the prevention and/or treatment of disease and various physiological disorders. Phytonutrients play a positive role by maintaining and modulating immune function to prevent specific diseases. Being natural products, they hold a great promise in clinical therapy as they possess no side effects that are usually associated with chemotherapy or radiotherapy. They are also comparatively cheap and thus significantly reduce health care cost. Phytonutrients are the plant nutrients with specific biological activities that support human health. Some of the important bioactive phytonutrients include polyphenols, terpenoids, resveratrol, flavonoids, isoflavonoids, carotenoids, limonoids, glucosinolates, phytoestrogens, phytosterols, anthocyanins, ω-3 fatty acids, and probiotics. They play specific pharmacological effects in human health such as anti-microbial, anti-oxidants, anti-inflammatory, antiallergic, anti-spasmodic, anti-cancer, anti-aging, hepatoprotective, hypolipidemic, neuroprotective, hypotensive, diabetes, osteoporosis, CNS stimulant, analgesic, protection from UVB-induced carcinogenesis, immuno-modulator, and carminative. This mini-review attempts to summarize the major important types of phytonutrients and their role in promoting human health and as therapeutic agents along with the current market trend and commercialization.

  4. Plasmids encoding therapeutic agents

    DOEpatents

    Keener, William K.

    2007-08-07

    Plasmids encoding anti-HIV and anti-anthrax therapeutic agents are disclosed. Plasmid pWKK-500 encodes a fusion protein containing DP178 as a targeting moiety, the ricin A chain, an HIV protease cleavable linker, and a truncated ricin B chain. N-terminal extensions of the fusion protein include the maltose binding protein and a Factor Xa protease site. C-terminal extensions include a hydrophobic linker, an L domain motif peptide, a KDEL ER retention signal, another Factor Xa protease site, an out-of-frame buforin II coding sequence, the lacZ.alpha. peptide, and a polyhistidine tag. More than twenty derivatives of plasmid pWKK-500 are described. Plasmids pWKK-700 and pWKK-800 are similar to pWKK-500 wherein the DP178-encoding sequence is substituted by RANTES- and SDF-1-encoding sequences, respectively. Plasmid pWKK-900 is similar to pWKK-500 wherein the HIV protease cleavable linker is substituted by a lethal factor (LF) peptide-cleavable linker.

  5. Transdermal delivery of therapeutic agent

    NASA Technical Reports Server (NTRS)

    Kwiatkowski, Krzysztof C. (Inventor); Hayes, Ryan T. (Inventor); Magnuson, James W. (Inventor); Giletto, Anthony (Inventor)

    2008-01-01

    A device for the transdermal delivery of a therapeutic agent to a biological subject that includes a first electrode comprising a first array of electrically conductive microprojections for providing electrical communication through a skin portion of the subject to a second electrode comprising a second array of electrically conductive microprojections. Additionally, a reservoir for holding the therapeutic agent surrounding the first electrode and a pulse generator for providing an exponential decay pulse between the first and second electrodes may be provided. A method includes the steps of piercing a stratum corneum layer of skin with two arrays of conductive microprojections, encapsulating the therapeutic agent into biocompatible charged carriers, surrounding the conductive microprojections with the therapeutic agent, generating an exponential decay pulse between the two arrays of conductive microprojections to create a non-uniform electrical field and electrokinetically driving the therapeutic agent through the stratum corneum layer of skin.

  6. Host modulation by therapeutic agents

    PubMed Central

    Elavarasu, Sugumari; Sekar, Santhosh; Murugan, Thamaraiselvan

    2012-01-01

    Periodontal disease susceptible group present advanced periodontal breakdown even though they achieve a high standard of oral hygiene. Various destructive enzymes and inflammatory mediators are involved in destruction. These are elevated in case of periodontal destruction. Host modulation aims at bringing these enzymes and mediators to normal level. Doxycycline, nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, nitrous oxide (NO) synthase inhibitors, recombinant human interleukin-11 (rhIL-11), omega-3 fatty acid, mouse anti-human interleukin-6 receptor antibody (MRA), mitogen-activated protein kinase (MAPK) inhibitors, nuclear factor-kappa B (NF-kb) inhibitors, osteoprotegerin, and tumor necrosis factor antagonist (TNF-α) are some of the therapeutic agents that have host modulation properties. PMID:23066265

  7. Grapefruit-Derived Nanovectors Use an Activated Leukocyte Trafficking Pathway to Deliver Therapeutic Agents to Inflammatory Tumor Sites.

    PubMed

    Wang, Qilong; Ren, Yi; Mu, Jingyao; Egilmez, Nejat K; Zhuang, Xiaoyin; Deng, Zhongbin; Zhang, Lifeng; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

    2015-06-15

    Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory-driven disease mouse models, we show that grapefruit-derived nanovectors (GNV) coated with inflammatory-related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of dextran sulfate sodium-induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that chemokines are overexpressed in diseased human tissue provides the rationale for using IGNVs to more directly deliver therapeutic agents to inflammatory tumor sites and the rationale for the use of IGNVs as treatment for certain cancers in personalized medicine.

  8. Grapefruit-derived nanovectors use an activated leukocyte trafficking pathway to deliver therapeutic agents to inflammatory tumor sites

    PubMed Central

    Wang, Qilong; Ren, Yi; Mu, Jingyao; Egilmez, Nejat; Zhuang, Xiaoyin; Deng, Zhongbin; Zhang, Lifeng; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

    2015-01-01

    Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory driven disease mouse models, we show that grapefruit-derived nanovectors (GNVs) coated with inflammatory related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of DSS induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that there is an overexpression of chemokines in diseased human tissue provides the rationale for using IGNVs to more directed delivery of therapeutic agents to inflammatory tumor sites and the use of IGNVs as personalized medicine for treatment of certain cancers. PMID:25883092

  9. Cobalt Derivatives as Promising Therapeutic Agents

    PubMed Central

    Heffern, Marie C.; Yamamoto, Natsuho; Holbrook, Robert J.; Eckermann, Amanda L.; Meade, Thomas J.

    2013-01-01

    Inorganic complexes are versatile platforms for the development of potent and selective pharmaceutical agents. Cobalt possesses a diverse array of properties that can be manipulated to yield promising drug candidates. Investigations into the mechanism of cobalt therapeutic agents can provide valuable insight into the physicochemical properties that can be harnessed for drug development. This review presents examples of bioactive cobalt complexes with special attention to their mechanisms of action. Specifically, cobalt complexes that elicit biological effects through protein inhibition, modification of drug activity, and bioreductive activation are discussed. Insights gained from these examples reveal features of cobalt that can be rationally tuned to produce therapeutics with high specificity and improved efficacy for the biomolecule or pathway of interest. PMID:23270779

  10. Applications of inorganic nanoparticles as therapeutic agents

    NASA Astrophysics Data System (ADS)

    Kim, Taeho; Hyeon, Taeghwan

    2014-01-01

    During the last decade, various functional nanostructured materials with interesting optical, magnetic, mechanical and chemical properties have been extensively applied to biomedical areas including imaging, diagnosis and therapy. In therapeutics, most research has focused on the application of nanoparticles as potential delivery vehicles for drugs and genes, because nanoparticles in the size range of 2-100 nm can interact with biological systems at the molecular level, and allow targeted delivery and passage through biological barriers. Recent investigations have even revealed that several kinds of nanomaterials are intrinsically therapeutic. Not only can they passively interact with cells, but they can also actively mediate molecular processes to regulate cell functions. This can be seen in the treatment of cancer via anti-angiogenic mechanisms as well as the treatment of neurodegenerative diseases by effectively controlling oxidative stress. This review will present recent applications of inorganic nanoparticles as therapeutic agents in the treatment of disease.

  11. Microbial Content of Nonsterile Therapeutic Agents Containing Natural or Seminatural Active Ingredients

    PubMed Central

    Schiller, I.; Kuntscher, H.; Wolff, A.; Nekola, M.

    1968-01-01

    The relationship was investigated between various chemical or pharmaceutical production processes and the extent of microbial contamination, of natural origin, of the resulting products. The products contained active ingredients of vegetable, enzymatic, or animal origin. It was concluded that (i) vegetable products practically free from microbes can be produced if the proper manufacturing steps are taken; (ii) sterilization of the media used to manufacture antibiotics, etc., produces products with little contamination; and (iii) products containing extracts of animal organs require careful refrigeration and addition of preservatives to produce acceptable levels of microbial contamination. PMID:5726165

  12. Nucleic acids as therapeutic agents.

    PubMed

    Alvarez-Salas, Luis M

    2008-01-01

    Therapeutic nucleic acids (TNAs) and its precursors are applied to treat several pathologies and infections. TNA-based therapy has different rationales and mechanisms and can be classified into three main groups: 1) Therapeutic nucleotides and nucleosides; 2) Therapeutic oligonucleotides; and 3) Therapeutic polynucleotides. This review will focus in those TNAs that have reached clinical trials with anticancer and antiviral protocols, the two most common applications of TNAs. Although therapeutic nucleotides and nucleosides that interfere with nucleic acid metabolism and DNA polymerization have been successfully used as anticancer and antiviral drugs, they often produce toxic secondary effects related to dosage and continuous use. The use of oligonucleotides such as ribozyme and antisense oligodeoxynucleotides (AS-ODNs) showed promise as therapeutic moieties but faced several issues such as nuclease sensitivity, off-target effects and efficient delivery. Nevertheless, immunostimulatory oligodeoxynucleotides and AS-ODNs represent the most successful group of therapeutic oligonucleotides in the clinic. A newer group of therapeutic oligonucleotides, the aptamers, is rapidly advancing towards early detection and treatment alternatives the have reached the commercial interest. Despite the very high in vitro efficiency of small interfering RNAs (siRNAs) they present issues with intracellular target accessibility, specificity and delivery. DNA vaccines showed great promise, but they resulted in very poor responses in the clinic and further development is uncertain. Despite their many issues, the exquisite specificity and versatility of therapeutic oligonucleotides attracts a great deal of research and resources that will certainly convert them in the TNA of choice for treating cancer and viral diseases in the near future.

  13. Potential of peroxisome proliferator-activated receptor gamma antagonist compounds as therapeutic agents for a wide range of cancer types.

    PubMed

    Burton, Jack D; Goldenberg, David M; Blumenthal, Rosalyn D

    2008-01-01

    PPARgamma is a therapeutic target that has been exploited for treatment of type II diabetes mellitus (T2DM) with agonist drugs. Since PPARgamma is expressed by many hematopoietic, mesodermal and epithelial cancers, agonist drugs were tested and shown to have both preclinical and clinical anticancer activities. While preclinical activity has been observed in many cancer types, clinical activity has been observed only in pilot and phase II trials in liposarcoma and prostate cancer. Most studies address agonist compounds, with substantially fewer reports on anticancer effects of PPARgamma antagonists. In cancer model systems, some effects of PPARgamma agonists were not inhibited by PPARgamma antagonists, suggesting noncanonical or PPARgamma-independent mechanisms. In addition, PPARgamma antagonists, such as T0070907 and GW9662, have exhibited antiproliferative effects on a broad range of hematopoietic and epithelial cell lines, usually with greater potency than agonists. Also, additive antiproliferative effects of combinations of agonist plus antagonist drugs were observed. Finally, there are preclinical in vivo data showing that antagonist compounds can be administered safely, with favorable metabolic effects as well as antitumor effects. Since PPARgamma antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment, it is the subject of this review.

  14. Potential of Peroxisome Proliferator-Activated Receptor Gamma Antagonist Compounds as Therapeutic Agents for a Wide Range of Cancer Types

    PubMed Central

    Burton, Jack D.; Goldenberg, David M.; Blumenthal, Rosalyn D.

    2008-01-01

    PPARγ is a therapeutic target that has been exploited for treatment of type II diabetes mellitus (T2DM) with agonist drugs. Since PPARγ is expressed by many hematopoietic, mesodermal and epithelial cancers, agonist drugs were tested and shown to have both preclinical and clinical anticancer activities. While preclinical activity has been observed in many cancer types, clinical activity has been observed only in pilot and phase II trials in liposarcoma and prostate cancer. Most studies address agonist compounds, with substantially fewer reports on anticancer effects of PPARγ antagonists. In cancer model systems, some effects of PPARγ agonists were not inhibited by PPARγ antagonists, suggesting noncanonical or PPARγ-independent mechanisms. In addition, PPARγ antagonists, such as T0070907 and GW9662, have exhibited antiproliferative effects on a broad range of hematopoietic and epithelial cell lines, usually with greater potency than agonists. Also, additive antiproliferative effects of combinations of agonist plus antagonist drugs were observed. Finally, there are preclinical in vivo data showing that antagonist compounds can be administered safely, with favorable metabolic effects as well as antitumor effects. Since PPARγ antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment, it is the subject of this review. PMID:18779871

  15. Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin.

    PubMed Central

    Meruelo, D; Lavie, G; Lavie, D

    1988-01-01

    Two aromatic polycyclic diones hypericin and pseudohypericin have potent antiretroviral activity; these substances occur in plants of the Hypericum family. Both compounds are highly effective in preventing viral-induced manifestations that follow infections with a variety of retroviruses in vivo and in vitro. Pseudohypericin and hypericin probably interfere with viral infection and/or spread by direct inactivation of the virus or by preventing virus shedding, budding, or assembly at the cell membrane. These compounds have no apparent activity against the transcription, translation, or transport of viral proteins to the cell membrane and also no direct effect on the polymerase. This property distinguishes their mode of action from that of the major antiretro-virus group of nucleoside analogues. Hypericin and pseudohypericin have low in vitro cytotoxic activity at concentrations sufficient to produce dramatic antiviral effects in murine tissue culture model systems that use radiation leukemia and Friend viruses. Administration of these compounds to mice at the low doses sufficient to prevent retroviral-induced disease appears devoid of undesirable side effects. This lack of toxicity at therapeutic doses extends to humans, as these compounds have been tested in patients as antidepressants with apparent salutary effects. Our observations to date suggest that pseudohypericin and hypericin could become therapeutic tools against retroviral-induced diseases such as acquired immunodeficiency syndrome (AIDS). Images PMID:2839837

  16. Activity-guided purification identifies lupeol, a pentacyclic triterpene, as a therapeutic agent multiple pathogenic factors of acne.

    PubMed

    Kwon, Hyuck Hoon; Yoon, Ji Young; Park, Seon Yong; Min, Seonguk; Kim, Yong-il; Park, Ji Yong; Lee, Yun-Sang; Thiboutot, Diane M; Suh, Dae Hun

    2015-06-01

    Acne vulgaris is a nearly universal cutaneous disease characterized by multifactorial pathogenic processes. Because current acne medications have various side effects, investigating new pharmacologically active molecules is important for treating acne. As natural products generally provide various classes of relatively safe compounds with medicinal potentials, we performed activity-guided purification after a series of screenings from the extracts of five medicinal plants to explore alternative acne medications. Lupeol, a pentacyclic triterpene, from the hexane extract of Solanum melongena L. (SM) was identified after instrumental analysis. Lupeol targeted most of the major pathogenic features of acne with desired physicochemical traits. It strongly suppressed lipogenesis by modulating the IGF-1R/phosphatidylinositide 3 kinase (PI3K)/Akt/sterol response element-binding protein-1 (SREBP-1) signaling pathway in SEB-1 sebocytes, and reduced inflammation by suppressing the NF-κB pathway in SEB-1 sebocytes and HaCaT keratinocytes. Lupeol exhibited a marginal effect on cell viability and may have modulated dyskeratosis of the epidermis. Subsequently, histopathological analysis of human patients' acne tissues after applying lupeol for 4 weeks demonstrated that lupeol markedly attenuated the levels of both the number of infiltrated cells and major pathogenic proteins examined in vitro around comedones or sebaceous glands, providing solid evidence for suggested therapeutic mechanisms. These results demonstrate the clinical feasibility of applying lupeol for the treatment of acne.

  17. 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

  18. New therapeutic agents in diabetic nephropathy

    PubMed Central

    Kim, Yaeni; Park, Cheol Whee

    2017-01-01

    Studies investigating diabetic nephropathy (DN) have mostly focused on interpreting the pathologic molecular mechanisms of DN, which may provide valuable tools for early diagnosis and prevention of disease onset and progression. Currently, there are few therapeutic drugs for DN, which mainly consist of antihypertensive and antiproteinuric measures that arise from strict renin-angiotensin-aldosterone system inactivation. However, these traditional therapies are suboptimal and there is a clear, unmet need for treatments that offer effective schemes beyond glucose control. The complexity and heterogeneity of the DN entity, along with ambiguous renal endpoints that may deter accurate appraisal of new drug potency, contribute to a worsening of the situation. To address these issues, current research into original therapies to treat DN is focusing on the intrinsic renal pathways that intervene with intracellular signaling of anti-inflammatory, antifibrotic, and metabolic pathways. Mounting evidence in support of the favorable metabolic effects of these novel agents with respect to the renal aspects of DN supports the likelihood of systemic beneficial effects as well. Thus, when translated into clinical use, these novel agents would also address the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease. This review will provide a discussion of the promising and effective therapeutic agents for the management of DN. PMID:28049280

  19. Nicotine: abused substance and therapeutic agent.

    PubMed Central

    Le Houezec, J

    1998-01-01

    Tobacco dependence is a complex phenomenon that is not fully understood. Nicotine is the main alkaloid in tobacco and the addictive compound of tobacco. It can improve both mood and cognitive functioning; these positive effects are strong reinforcements for smokers and contribute to their addiction. Opposite results also have been reported, however, and the effects of nicotine remain controversial. Recent epidemiological and empirical studies have indicated that smoking or nicotine or both may have protective effects against certain diseases. These findings have suggested that nicotine may be used as a therapeutic agent. However, because a variety of nicotinic cholinergic receptors are present in the brain, new agonist compounds may prove to be more effective than nicotine for therapeutic purposes. Studies are reviewed and the suggestion made that nicotine may prove useful as a tool to help us understand normal and pathological brain functioning. PMID:9549250

  20. Improvement of the CuZn-superoxide dismutase enzyme activity and stability as a therapeutic agent by modification with polysialic acids.

    PubMed

    Wu, Jian Rong; Lin, Yi; Zheng, Zhi Yong; Lin, Chi Chung; Zhan, Xiao Bei; Shen, Ying Qiang

    2010-12-01

    The optimal process for the polysialylation reaction was as follows: polysialicacid (PSA) was activated by periodate oxidation, then coupled to CuZn superoxide dismutase (SOD) with a PSA:SOD molar ratio of 40:1 for 24 h. The resulting polysialylated protein contained 3.9 ± 0.3 mol PSA per mol SOD. SDS-PAGE and atomic force microscopy revealed that the molecular weight of polysialylated SOD was about 90-100 kDa. The average size was 10-15 nm, about four-fold of the native enzyme. Compared to the native enzyme, the activity and stability of the polysialylated SOD, as well as resistance to heat, acid, alkali and proteases present in human digestive system such as pepsin and trypsin, were improved significantly as therapeutic agent.

  1. Development and Testing of an In Vitro Assay for Screening of Potential Therapeutic Agents Active against Na Channel Neurotoxins

    DTIC Science & Technology

    1991-04-12

    to produce approximately half-maximal effects mediated through these different sodium channel sites in the assay. Thus, the binding of [3HJBTX-B should...experiments with I3H]STX, yielding the unexpected result that effects of HM-197 are not mediated through the TTX/STX sodium channel binding site. Additional...Scorpion toxin; Screening; nA Pyrethroids; Radioligand binding; Synaptoneurosomes; RA 1 ; nA I ~ I ITherapeutic agents; Sodium channel 19. ABSTRACT

  2. Small molecules as therapeutic agents for inborn errors of metabolism.

    PubMed

    Matalonga, Leslie; Gort, Laura; Ribes, Antonia

    2017-03-01

    Most inborn errors of metabolism (IEM) remain without effective treatment mainly due to the incapacity of conventional therapeutic approaches to target the neurological symptomatology and to ameliorate the multisystemic involvement frequently observed in these patients. However, in recent years, the therapeutic use of small molecules has emerged as a promising approach for treating this heterogeneous group of disorders. In this review, we focus on the use of therapeutically active small molecules to treat IEM, including readthrough agents, pharmacological chaperones, proteostasis regulators, substrate inhibitors, and autophagy inducers. The small molecules reviewed herein act at different cellular levels, and this knowledge provides new tools to set up innovative treatment approaches for particular IEM. We review the molecular mechanism underlying therapeutic properties of small molecules, methodologies used to screen for these compounds, and their applicability in preclinical and clinical practice.

  3. SEAP activity serves for demonstrating ER stress induction by glucolipotoxicity as well as testing ER stress inhibitory potential of therapeutic agents.

    PubMed

    Lenin, Raji; Mohan, Viswanathan; Balasubramanyam, Muthuswamy

    2015-06-01

    Endoplasmic reticulum (ER) stress is emerging as a unifying paradigm and one of the underlying mechanisms in the genesis of diabetes and its complications. While this has prompted the development of ER stress inhibitors, there is a limitation in monitoring of ER stress in vitro and in vivo by reliable methodologies. We validated the secreted alkaline phosphatase (SEAP) activity as a surrogate marker of ER stress in mouse β-TC6 cells exposed to glucolipotoxicity or tunicamycin and studied insulin secretion along with alterations in ER stress markers. SEAP activity assay was measured using the Great EscAPe SEAP kit, insulin levels were determined by Mercodia reagents and mRNA expression of ER stress markers was quantified by real-time PCR. SEAP activity in β-cells was significantly decreased (indicating increased ER stress) on exposure either to glucolipotoxicity or tunicamycin. This was accompanied by an increased mRNA expression of ER stress markers (GRP-78, PERK, IRE1α, ATF6, XBP-1, and CHOP) and decreased insulin secretion. Treating the cells with phenylbutyric acid normalized SEAP activity, decreased mRNA expression of ER stress markers and improved insulin secretion. Interestingly, cells exposed to different classes of anti-diabetes agents or compounds such as resveratrol resisted ER stress. Methylglyoxal also induces ER stress and this was counteracted by aminoguanidine. Out study demonstrates SEAP activity as a novel ER stress monitoring assay to investigate the therapeutic value of agents with ER stress inhibitory potential. Future studies should focus on the exercise of adopting this reporter assay for high-throughput screening mode of drug discovery.

  4. Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases

    PubMed Central

    Bhullar, Khushwant S.; Rupasinghe, H. P. Vasantha

    2013-01-01

    Aging leads to numerous transitions in brain physiology including synaptic dysfunction and disturbances in cognition and memory. With a few clinically relevant drugs, a substantial portion of aging population at risk for age-related neurodegenerative disorders require nutritional intervention. Dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases such as Alzheimer's disease (AD), stroke, multiple sclerosis (MS), Parkinson's disease (PD), and Huntington's disease (HD). Polyphenols exhibit strong potential to address the etiology of neurological disorders as they attenuate their complex physiology by modulating several therapeutic targets at once. Firstly, we review the advances in the therapeutic role of polyphenols in cell and animal models of AD, PD, MS, and HD and activation of drug targets for controlling pathological manifestations. Secondly, we present principle pathways in which polyphenol intake translates into therapeutic outcomes. In particular, signaling pathways like PPAR, Nrf2, STAT, HIF, and MAPK along with modulation of immune response by polyphenols are discussed. Although current polyphenol researches have limited impact on clinical practice, they have strong evidence and testable hypothesis to contribute clinical advances and drug discovery towards age-related neurological disorders. PMID:23840922

  5. Overseas nurses--effective therapeutic agents?

    PubMed

    Shanley, E

    1980-09-01

    Factors affecting the effectiveness of overseas people employed as psychiatric nurses are discussed. Basic cultural influences, especially different value systems between the immigrant and the host population, are seen as unlikely to be greatly altered by the environment in which the immigrant nurses find themselves. In fact a greater divergence would seem more likely to occur. The different experiences of immigrant nurses compared with nurses recruited in Britain are considered under the following headings: expectations of the immigrants on entering nursing, their contact with the host culture, the reaction of the indigenous population to the immigrant, language difficulties, and the insecurity of employment. The conclusion drawn is that the cultural differences, recruitment methods, the immigrants' experiences in employment and lack of contact with the culture of the indigenous population (apart from their deviant members) are likely to adversely affect his/her ability to function as a therapeutic agent. This is particularly important where the form of treatment is based on the social model.

  6. CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP.

    PubMed

    Ju, Wei; Zhang, Meili; Jiang, Jian-kang; Thomas, Craig J; Oh, Unsong; Bryant, Bonita R; Chen, Jing; Sato, Noriko; Tagaya, Yutaka; Morris, John C; Janik, John E; Jacobson, Steven; Waldmann, Thomas A

    2011-02-10

    The retrovirus, human T-cell-lymphotrophic virus-1 (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and the neurological disorder HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-I-encoded protein tax constitutively activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems that in turn activate the Jak3 (Janus kinase 3)/STAT5 (signal transducers and activators of transcription 5) pathway, suggesting a therapeutic strategy that involves targeting Jak3. We evaluated the action of the Jak3 inhibitor CP-690,550 on cytokine dependent ex vivo proliferation that is characteristic of peripheral blood mononuclear cells (PBMCs) from select patients with smoldering or chronic subtypes of ATL, or from those with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve the production of IL-2, IL-9, IL-15, and their receptors. CP-690,550 at 50 nM inhibited the 6-day ex vivo spontaneous proliferation of PBMCs from ATL and HAM/TSP patients by 67.1% and 86.4%, respectively. Furthermore, CP-690,550 inhibited STAT5 phosphorylation in isolated ATL T cells ex vivo. Finally, in an in vivo test of biological activity, CP-690,550 treatment of mice with a CD8 T-cell IL-15-transgenic leukemia that manifests an autocrine IL-15/IL-15Rα pathway prolonged the survival duration of these tumor-bearing mice. These studies support further evaluation of the Jak3 inhibitor CP-690,550 in the treatment of select patients with HTLV-I-associated ATL and HAM/TSP.

  7. Therapeutic interventions in sepsis: current and anticipated pharmacological agents

    PubMed Central

    Shukla, Prashant; Rao, G Madhava; Pandey, Gitu; Sharma, Shweta; Mittapelly, Naresh; Shegokar, Ranjita; Mishra, Prabhat Ranjan

    2014-01-01

    Sepsis is a clinical syndrome characterized by a multisystem response to a pathogenic assault due to underlying infection that involves a combination of interconnected biochemical, cellular and organ–organ interactive networks. After the withdrawal of recombinant human-activated protein C (rAPC), researchers and physicians have continued to search for new therapeutic approaches and targets against sepsis, effective in both hypo- and hyperinflammatory states. Currently, statins are being evaluated as a viable option in clinical trials. Many agents that have shown favourable results in experimental sepsis are not clinically effective or have not been clinically evaluated. Apart from developing new therapeutic molecules, there is great scope for for developing a variety of drug delivery strategies, such as nanoparticulate carriers and phospholipid-based systems. These nanoparticulate carriers neutralize intracorporeal LPS as well as deliver therapeutic agents to targeted tissues and subcellular locations. Here, we review and critically discuss the present status and new experimental and clinical approaches for therapeutic intervention in sepsis. PMID:24977655

  8. Phytocannabinoids as novel therapeutic agents in CNS disorders.

    PubMed

    Hill, Andrew J; Williams, Claire M; Whalley, Benjamin J; Stephens, Gary J

    2012-01-01

    The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB(1) receptors by the major pCB, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ(9)-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ(9)tetrahydrocannabivarin (Δ(9)-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ(9)-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ(9)-THC pCB-based medicines.

  9. Scorpion Toxin Polyptides as Therapeutic Agents: An Overview.

    PubMed

    Bhavya, Janardhan; Francois, Niyonzima N; More, Veena S; More, Sunil S

    2016-01-01

    Scorpions are distributed throughout the world and numerous biological molecules are found in their venom most importantly peptide toxins. These toxins modulate the ion channels either by blocking the pore of the channel or by altering the voltage gating. Molecules which block the pores have been useful in deciphering the structure of the ion channels. Many scorpion toxins have already been used for probing the voltage gated sodium channels and studying their activation and inactivation processes. The specialty of scorpion toxins is to discriminate between vertebrate and invertebrate channels which have led them to applications as pharmacological tools. Most of the scorpion toxin polypeptides were isolated, characterized and were shown to possess vital properties useful in the field of medicine. For instance, they show therapeutic properties such as antimicrobial activity, anticancer activity, used to treat autoimmune diseases and cardiovascular effects. Although the scorpion toxins exhibited good therapeutic effects in vitro and in vivo, no one has reached the market with success up to date. In this mini-review, the scorpion polypeptides, their interactions with ion channels and their uses as therapeutic agents are discussed.

  10. Efficient delivery of therapeutic agents by using targeted albumin nanoparticles.

    PubMed

    Kouchakzadeh, Hasan; Safavi, Maryam Sadat; Shojaosadati, Seyed Abbas

    2015-01-01

    Albumin nanoparticles are one of the most important drug carriers for the delivery of therapeutic drugs, especially for the treatment of malignancies. This potential is due to their high binding capacity for both hydrophobic and hydrophilic drugs and the possibility of surface modification. Accumulation of albumin-bound drugs in the tumor interstitium occurs by the enhanced permeability and retention effect, which is also facilitated by the 60-kDa glycoprotein transcytosis pathway and binding to secreted protein, acidic and rich in cysteine located in the tumor extracellular matrix. In addition, specific ligands such as monoclonal antibodies, folic acid, transferrin, and peptides can be conjugated to the surface of albumin nanoparticles to actively target the drug to its site of action. The albumin-bound paclitaxel, Abraxane, is one of the several therapeutic nanocarriers that have been approved for clinical use. By the development of Abraxane that demonstrates a higher response rate and improved tolerability and therapeutic efficiency in comparison with solvent-based formulation, and with consideration of its commercial success, albumin is attracting the interest of many biotechnological and pharmaceutical companies. This chapter explores the current targeted and nontargeted albumin-based nanoparticles that are in various stages of development for the delivery of therapeutic agents in order to enhance the efficacy of cancer treatment.

  11. Mitochondria targeting nano agents in cancer therapeutics

    PubMed Central

    Zhang, Xiao-Ying; Zhang, Pei-Ying

    2016-01-01

    Mitochondria have emerged as noteworthy therapeutic targets as their physiological functions are often altered in pathological conditions such as cancer. The electronic databases of MEDLINE, EMBASE and PubMed were searched for recent studies reporting the importance of mitochondria targeting nanoagents in cancer therapeutics. The concluding remarks of the above papers mostly confirmed the growing potential of these novel nanoagents in the area of anticancer research. Furthermore, numerous studies demonstrated the immense potential of nanocarriers in delivering mitochondria-acting compounds to their target site. Among the assemblage of nanomaterials, carbon nanotubes (CNTs) are becoming more prominent for drug delivery due to favorable attributes including their unique shape, which promotes cellular uptake, and large aspect ratio that facilitates conjugation of bioactive molecules on their surface. The present review focused on the current view of variable options available in mitochondria-targeting anticancer therapeutics. It may be concluded that improvements are essential for its establishment as a gold standard therapeutic option especially in the clinical setting. PMID:28105197

  12. Calcium antagonists: A new class of therapeutic agents

    PubMed Central

    Gunawan, Antonius; Massumi, Ali; Hall, Robert J.

    1981-01-01

    A new class of therapeutic agents, sharing inhibition of the slow calcium channel, will soon be available to the American patient. Selective action of these agents upon the atrioventricular node, the smooth muscle of coronary and peripheral arteries, and the contractility of cardiac muscle opens new vistas in cardiovascular pharmacology. Early release of these agents by the Federal Drug Administration for general use is urged, based upon the already wide and successful experience in the European and South American continents. PMID:15216199

  13. Novel therapeutic agents for systemic lupus erythematosus.

    PubMed

    Gescuk, Bryan D; Davis, John C

    2002-09-01

    The last significant breakthrough in the treatment of systemic lupus erythematosus (SLE) was the use of cyclophosphamide and methylprednisolone in the treatment of lupus nephritis. Recent advances in immunology, oncology, and endocrinology have resulted in many potential therapies for SLE. These therapies include new immunosuppressants, biologic medications, tolerizing agents, immunoablation techniques, and hormonal medications. Each of these approaches will be discussed in this review. Some therapies are currently in use in clinical rheumatology practice (mycophenolate mofetil) and others are entering phase I trials (anti-BLyS monoclonal antibody). While some of these new therapies target specific inflammatory mechanisms in SLE (anti-CD40L monoclonal antibody), others work by nonspecific inhibition of the immune system (immunoablation).

  14. Recombinant mumps virus as a cancer therapeutic agent

    PubMed Central

    Ammayappan, Arun; Russell, Stephen J; Federspiel, Mark J

    2016-01-01

    Mumps virus belongs to the family of Paramyxoviridae and has the potential to be an oncolytic agent. Mumps virus Urabe strain had been tested in the clinical setting as a treatment for human cancer four decades ago in Japan. These clinical studies demonstrated that mumps virus could be a promising cancer therapeutic agent that showed significant antitumor activity against various types of cancers. Since oncolytic virotherapy was not in the limelight until the beginning of the 21st century, the interest to pursue mumps virus for cancer treatment slowly faded away. Recent success stories of oncolytic clinical trials prompted us to resurrect the mumps virus and to explore its potential for cancer treatment. We have obtained the Urabe strain of mumps virus from Osaka University, Japan, which was used in the earlier human clinical trials. In this report we describe the development of a reverse genetics system from a major isolate of this Urabe strain mumps virus stock, and the construction and characterization of several recombinant mumps viruses with additional transgenes. We present initial data demonstrating these recombinant mumps viruses have oncolytic activity against tumor cell lines in vitro and some efficacy in preliminary pilot animal tumor models. PMID:27556105

  15. A virtual therapeutic environment with user projective agents.

    PubMed

    Ookita, S Y; Tokuda, H

    2001-02-01

    Today, we see the Internet as more than just an information infrastructure, but a socializing place and a safe outlet of inner feelings. Many personalities develop aside from real world life due to its anonymous environment. Virtual world interactions are bringing about new psychological illnesses ranging from netaddiction to technostress, as well as online personality disorders and conflicts in multiple identities that exist in the virtual world. Presently, there are no standard therapy models for the virtual environment. There are very few therapeutic environments, or tools especially made for virtual therapeutic environments. The goal of our research is to provide the therapy model and middleware tools for psychologists to use in virtual therapeutic environments. We propose the Cyber Therapy Model, and Projective Agents, a tool used in the therapeutic environment. To evaluate the effectiveness of the tool, we created a prototype system, called the Virtual Group Counseling System, which is a therapeutic environment that allows the user to participate in group counseling through the eyes of their Projective Agent. Projective Agents inherit the user's personality traits. During the virtual group counseling, the user's Projective Agent interacts and collaborates to recover and increase their psychological growth. The prototype system provides a simulation environment where psychologists can adjust the parameters and customize their own simulation environment. The model and tool is a first attempt toward simulating online personalities that may exist only online, and provide data for observation.

  16. Therapeutic options for herpes labialis, I: Oral agents.

    PubMed

    Elish, Diana; Singh, Fiza; Weinberg, Jeffrey M

    2004-07-01

    Given the prevalence of herpes labialis, effective therapy has the potential to affect the lives of many and presents a challenge for clinicians. Over the last several years, most of the focus of herpes research has been on the treatment of genital herpes. Recently, however, several studies have been published examining the efficacy of therapies specifically for herpes labialis. Several therapeutic agents, both prescription and over-the-counter, are available for controlling and managing the disease. In this series of articles, we review oral and topical therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms. This article will review oral treatment options.

  17. Development of Targeted Therapeutic Agents for Botulism

    DTIC Science & Technology

    2001-02-01

    12.6 ± 1.1 [tmoles/min/mg toxin (mean ± S.D.). Analysis of the results using the Lineweaver - Burke plot revealed that saturation of the enzymes active...performed as detailed in the Materials and Methods. Km and Vmax values were obtained from Lineweaver - Burke plots. TABLE 2. The overall susceptibilities...maximum values recorded (therefore, termed: A A405 nm). Figure 6. Lineweaver - Burke plot of initial rates of proteolysis by reduced BoNT/A for various

  18. Thalidomide-derived immunomodulatory drugs as therapeutic agents.

    PubMed

    Galustian, Christine; Labarthe, Marie-Christine; Bartlett, J Blake; Dalgleish, Angus G

    2004-12-01

    Thalidomide, a drug originally used to treat morning sickness, was removed from the market place in the early 1960s after it was found to cause serious congenital birth defects. However, thalidomide has recently been investigated in a new light following its activity in a number of chronic diseases. Moreover, like thalidomide itself, its second-generation immunomodulatory drug (IMiD) analogues have been shown to act as powerful anticancer agents and are clearly active in the treatment of patients with relapsed multiple myeloma. These new drugs, in particular the second-generation IMiDs, lenalidomide (CC-5013, REVLIMID; Celgene Corp., NJ, USA) and CC-4047 (ACTIMID; Celgene Corp.), offer improvements over thalidomide (a first-generation IMiD) in terms of efficacy and safety in human studies. The key to the therapeutic potential of IMiDs lies in the fact that the drugs have multiple mechanisms of action, which may produce both anti-inflammatory and antitumour effects. These effects are probably contextual, depending both on the cell type and the stimulus involved. Mechanisms associated with IMiD activity include TNF-alpha-inhibitory, T cell costimulatory and antiangiogenic activities. Studies of the mechanisms of action of these drugs are ongoing and will facilitate the continued development of this class of compound in a number of diseases.

  19. Antioxidant Micronutrients: Therapeutic Counter Measures for Chemical Agents

    DTIC Science & Technology

    2011-03-01

    ANSI Std. Z39.18 W81XWH-08-2-0007 1 Mar 2010 - 28 Feb 2011Annual01-03-2011 Antioxidant Micronutrients : Therapeutic Counter Measures for Chemical...Agents Kedar Prasad, Ph.D. Premier Micronutrient Corporation Novato, CA 94949 The results of the first phase of HD study suggested that exposure to

  20. Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent.

    PubMed

    Merchant, Mark; Ma, Xiaolei; Maun, Henry R; Zheng, Zhong; Peng, Jing; Romero, Mally; Huang, Arthur; Yang, Nai-ying; Nishimura, Merry; Greve, Joan; Santell, Lydia; Zhang, Yu-Wen; Su, Yanli; Kaufman, Dafna W; Billeci, Karen L; Mai, Elaine; Moffat, Barbara; Lim, Amy; Duenas, Eileen T; Phillips, Heidi S; Xiang, Hong; Young, Judy C; Vande Woude, George F; Dennis, Mark S; Reilly, Dorothea E; Schwall, Ralph H; Starovasnik, Melissa A; Lazarus, Robert A; Yansura, Daniel G

    2013-08-06

    Binding of hepatocyte growth factor (HGF) to the receptor tyrosine kinase MET is implicated in the malignant process of multiple cancers, making disruption of this interaction a promising therapeutic strategy. However, targeting MET with bivalent antibodies can mimic HGF agonism via receptor dimerization. To address this limitation, we have developed onartuzumab, an Escherichia coli-derived, humanized, and affinity-matured monovalent monoclonal antibody against MET, generated using the knob-into-hole technology that enables the antibody to engage the receptor in a one-to-one fashion. Onartuzumab potently inhibits HGF binding and receptor phosphorylation and signaling and has antibody-like pharmacokinetics and antitumor activity. Biochemical data and a crystal structure of a ternary complex of onartuzumab antigen-binding fragment bound to a MET extracellular domain fragment, consisting of the MET Sema domain fused to the adjacent Plexins, Semaphorins, Integrins domain (MET Sema-PSI), and the HGF β-chain demonstrate that onartuzumab acts specifically by blocking HGF α-chain (but not β-chain) binding to MET. These data suggest a likely binding site of the HGF α-chain on MET, which when dimerized leads to MET signaling. Onartuzumab, therefore, represents the founding member of a class of therapeutic monovalent antibodies that overcomes limitations of antibody bivalency for targets impacted by antibody crosslinking.

  1. Recent Advances on Inorganic Nanoparticle-Based Cancer Therapeutic Agents

    PubMed Central

    Wang, Fenglin; Li, Chengyao; Cheng, Jing; Yuan, Zhiqin

    2016-01-01

    Inorganic nanoparticles have been widely investigated as therapeutic agents for cancer treatments in biomedical fields due to their unique physical/chemical properties, versatile synthetic strategies, easy surface functionalization and excellent biocompatibility. This review focuses on the discussion of several types of inorganic nanoparticle-based cancer therapeutic agents, including gold nanoparticles, magnetic nanoparticles, upconversion nanoparticles and mesoporous silica nanoparticles. Several cancer therapy techniques are briefly introduced at the beginning. Emphasis is placed on how these inorganic nanoparticles can provide enhanced therapeutic efficacy in cancer treatment through site-specific accumulation, targeted drug delivery and stimulated drug release, with elaborations on several examples to highlight the respective strategies adopted. Finally, a brief summary and future challenges are included. PMID:27898016

  2. Multirate delivery of multiple therapeutic agents from metal-organic frameworks

    SciTech Connect

    McKinlay, Alistair C.; Allan, Phoebe K.; Renouf, Catherine L.; Duncan, Morven J.; Wheatley, Paul S.; Warrender, Stewart J.; Dawson, Daniel; Ashbrook, Sharon E.; Gil, Barbara; Marszalek, Bartosz; Düren, Tina; Williams, Jennifer J.; Charrier, Cedric; Mercer, Derry K.; Teat, Simon J.; Morris, Russell E.

    2014-12-01

    The highly porous nature of metal-organic frameworks (MOFs) offers great potential for the delivery of therapeutic agents. Here, we show that highly porous metal-organic frameworks can be used to deliver multiple therapeutic agents—a biologically active gas, an antibiotic drug molecule, and an active metal ion—simultaneously but at different rates. The possibilities offered by delivery of multiple agents with different mechanisms of action and, in particular, variable timescales may allow new therapy approaches. Here, we show that the loaded MOFs are highly active against various strains of bacteria.

  3. Novel therapeutic agents in clinical development for systemic lupus erythematosus

    PubMed Central

    2013-01-01

    Conventional immunosuppressive therapies have radically transformed patient survival in systemic lupus erythematosus (SLE), but their use is associated with considerable toxicity and a substantial proportion of patients remain refractory to treatment. A more comprehensive understanding of the complexity of SLE immunopathogenesis has evolved over the past decade and has led to the testing of several biologic agents in clinical trials. There is a clear need for new therapeutic agents that overcome these issues, and biologic agents offer exciting prospects as future SLE therapies. An array of promising new therapies are currently emerging or are under development including B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anti-cytokine therapies, such as monoclonal antibodies against interleukin-6 and interferon-α. PMID:23642011

  4. Natural Compounds as Therapeutic Agents in the Treatment Cystic Fibrosis

    PubMed Central

    Dey, Isha; Shah, Kalpit; Bradbury, Neil A

    2016-01-01

    The recent FDA approval of two drugs to treat the basic defect in cystic fibrosis has given hope to patients and their families battling this devastating disease. Over many years, with heavy financial investment from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation, pre-clinical evaluation of thousands of synthetic drugs resulted in the production of Kalydeco and Orkambi. Yet, despite the success of this endeavor, many other compounds have been proposed as therapeutic agents in the treatment of CF. Of note, several of these compounds are naturally occurring, and are present in spices from the grocery store and over the counter preparations in health food stores. In this short review, we look at three such compounds, genistein, curcumin, and resveratrol, and evaluate the scientific support for their use as therapeutic agents in the treatment of patients with CF. PMID:27081574

  5. Pituitary Adenylate Cyclase Activating Polypeptide, A Potential Therapeutic Agent for Diabetic Retinopathy in Rats: Focus on the Vertical Information Processing Pathway.

    PubMed

    Szabadfi, K; Reglodi, D; Szabo, A; Szalontai, B; Valasek, A; Setalo, Gy; Kiss, P; Tamas, A; Wilhelm, M; Gabriel, R

    2016-04-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophic and neuroprotective peptide that has been shown to exert protective effects in different neuronal injuries, such as retinal degenerations. Diabetic retinopathy (DR), the most common complication of diabetes, affects the microvasculature and neuronal architecture of the retina. We have proven earlier that PACAP is also protective in a rat model of DR. In this study, streptozotocin-induced DR was treated with intravitreal PACAP administration in order to further analyze the synaptic structure and proteins of PACAP-treated diabetic retinas, primarily in the vertical information processing pathway. Streptozotocin-treated Wistar rats received intravitreal PACAP injection three times into the right eye 2 weeks after the induction of diabetes. Morphological and molecular biological (qRT-PCR; Western blot) methods were used to analyze retinal synapses (ribbons, conventional) and related structures. Electron microscopic analysis revealed that retinal pigment epithelium, the ribbon synapses and other synaptic profiles suffered alterations in diabetes. However, in PACAP-treated diabetic retinas more bipolar ribbon synapses were found intact in the inner plexiform layer than in DR animals. The ribbon synapse was marked with C-terminal binding protein 2/Bassoon and formed horseshoe-shape ribbons, which were more retained in PACAP-treated diabetic retinas than in DR rats. These results are supported by molecular biological data. The selective degeneration of related structures such as bipolar and ganglion cells could be ameliorated by PACAP treatment. In summary, intravitreal administration of PACAP may have therapeutic potential in streptozotocin-induced DR through maintaining synapse integrity in the vertical pathway.

  6. Bioengineering of noncoding RNAs for research agents and therapeutics.

    PubMed

    Ho, Pui Yan; Yu, Ai-Ming

    2016-01-01

    The discovery of functional small noncoding RNAs (ncRNAs), such as microRNAs and small interfering RNAs, in the control of human cellular processes has opened new avenues to develop RNA-based therapies for various diseases including viral infections and cancers. However, studying ncRNA functions and developing RNA-based therapeutics relies on access to large quantities of affordable ncRNA agents. Currently, synthetic RNAs account for the major source of agents for RNA research and development, yet carry artificial modifications on the ribose ring and phosphate backbone in sharp contrast to posttranscriptional modifications present on the nucleobases or unmodified natural RNA molecules produced within cells. Therefore, large efforts have been made in recent years to develop recombinant RNA techniques to cost-effectively produce biological RNA agents that may better capture the structure, function, and safety properties of natural RNAs. In this article, we summarize and compare current in vitro and in vivo methods for the production of RNA agents including chemical synthesis, in vitro transcription, and bioengineering approaches. We highlight the latest recombinant RNA approaches using transfer RNA (tRNA), ribosomal RNA (rRNA), and optimal ncRNA scaffold (OnRS), and discuss the applications of bioengineered ncRNA agents (BERAs) that should facilitate RNA research and development.

  7. [Visceral leishmaniasis: clinical sensitivity and resistance to various therapeutic agents].

    PubMed

    Janvier, F; Morillon, M; Olliaro, P

    2008-02-01

    Visceral leishmaniasis is present in 61 countries but 90% of the 500,000 new cases that arise annually occur in five countries, i.e., India, Bangladesh, Nepal, Sudan, and Brazil. Annual mortality is approximately 59000 cases. Agents based on pentavalent antimony have been the mainstay of treatment for the last 60 years. In recent years, however, clinical resistance to these agents has been reported especially in the state of Bihar in India. Pentamidine and amphotericin B were introduced in the 1950s and 1960s. More recent additions to the therapeutic arsenal include liposomal amphotericin B, miltefosine, and paromomycin. Among these recent molecules, miltefosine, i.e., the only oral agent, appears most vulnerable because it involves long-term treatment and has a long half-life. The main therapeutic problems now being encountered are the emergence of acquired resistance to antimonials, the high cost of treatment, and failure of therapy in immunocompromised patients mainly due to concurrent human immunodeficiency virus (HIV) infection. For eradication initiatives such as the one aimed at eliminating leishmaniasis on the Indian subcontinent, the appearance of drug resistance increases the risk associated to parasite infection and, as for malaria, tuberculosis and HIV infection, raises fears that the problems in the implementation of public health policies will lead to highly refractory forms.

  8. Vaccinia virus, a promising new therapeutic agent for pancreatic cancer

    PubMed Central

    Yaghchi, Chadwan Al; Zhang, Zhongxian; Alusi, Ghassan; Lemoine, Nicholas R; Wang, Yaohe

    2015-01-01

    The poor prognosis of pancreatic cancer patients signifies a need for radically new therapeutic strategies. Tumor-targeted oncolytic viruses have emerged as attractive therapeutic candidates for cancer treatment due to their inherent ability to specifically target and lyse tumor cells as well as induce antitumor effects by multiple action mechanisms. Vaccinia virus has several inherent features that make it particularly suitable for use as an oncolytic agent. In this review, we will discuss the potential of vaccinia virus in the management of pancreatic cancer in light of our increased understanding of cellular and immunological mechanisms involved in the disease process as well as our extending knowledge in the biology of vaccinia virus. PMID:26595180

  9. Nanomaterial-mediated CNS Delivery of Diagnostic and Therapeutic Agents

    PubMed Central

    Biddlestone-Thorpe, Laura; Marchi, Nicola; Guo, Kathy; Ghosh, Chaitali; Janigro, Damir; Valerie, Kristoffer; Yang, Hu

    2011-01-01

    Research into the diagnosis and treatment of central nervous system (CNS) diseases has been enhanced by rapid advances in nanotechnology and an expansion in the library of nanostructured carriers. This review discusses the latest applications of nanomaterials in the CNS with an emphasis on brain tumors. Novel administration routes and transport mechanisms for nanomaterial-mediated CNS delivery of diagnostic and therapeutic agents to bypass or cross the blood brain barrier (BBB) are also discussed. These include temporary disruption of the BBB, use of impregnated polymers (polymer wafers), convection-enhanced delivery (CED), and intranasal delivery. Moreover, an in vitro BBB model capable of mimicking geometrical, cellular and rheological features of the human cerebrovasculature has been developed. This is a useful tool that can be used for screening CNS nanoparticles or therapeutics prior to in vivo and clinical investigation. A discussion of this novel model is included. PMID:22178615

  10. Novel prospects of statins as therapeutic agents in cancer.

    PubMed

    Pisanti, Simona; Picardi, Paola; Ciaglia, Elena; D'Alessandro, Alba; Bifulco, Maurizio

    2014-10-01

    Statins are well known competitive inhibitors of hydroxymethylglutaryl-CoA reductase enzyme (HMG-CoA reductase), thus traditionally used as cholesterol-lowering agents. In recent years, more and more effects of statins have been revealed. Nowadays alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Consequently, much attention has been directed toward the potential of statins as therapeutic agents in the oncological field. Accumulated in vitro and in vivo clinical evidence point out the role of statins in a variety of human malignancies, in regulating tumor cell growth and anti-tumor immune response. Herein, we summarize and discuss, in light of the most recent observations, the anti-tumor effects of statins, underpinning the detailed mode of action and looking for their true significance in cancer prevention and treatment, to determine if and in which case statin repositioning could be really justified for neoplastic diseases.

  11. Optometrist prescribing of therapeutic agents: findings of the AESOP survey.

    PubMed

    Mason, Anne; Mason, James

    2002-05-01

    Throughout the USA and in some parts of Australia and Canada, licensed optometrists may prescribe therapeutic agents for certain eye conditions. However, this role is not currently available to European optometrists. The extension of prescribing rights to new professional groups was the subject of a UK government-commissioned review, which cited optometrists as potential candidates. A recent literature review found limited evidence to assess the appropriateness of eye care delivered by different health care providers. To inform the UK decision, we therefore conducted a national postal survey to explore how optometric practice might change with the introduction of therapeutic prescribing. The Anonymous Enquiry of the Scope for Optometrist Prescribing (AESOP), was sent to a random 10% sample of registered optometrists. Over 80% of respondents indicated that optometrists should be able to train as therapeutic prescribers. Most respondents were willing to undergo training, periodic re-accreditation and continuing education, as well to participate in simple professional audit of their prescribing. Respondents anticipated that referrals to general practitioners (GPs) would be reduced by nearly 40% and to ophthalmologists via a GP by nearly 20%. Optometrist participation could increase patient access to therapeutic ocular care by between 29% and 50%. Authorising UK optometrists to prescribe therapeutically for eye diseases would appear to make good use of their existing skills and improve patient access to eye care, while relieving pressures upon other healthcare providers. Tentative economic analysis suggests that the introduction of independent optometrist prescribing may be cost neutral. However, adequate comparative research on the performance of optometrists as prescribers is needed and the issue of reimbursement will require careful consideration.

  12. Tanshinones as Effective Therapeutic Agents for Prostate Cancer

    DTIC Science & Technology

    2011-06-01

    BW) and the routes of administration (oral gavaging with corn oil or dietary supplementation ) in inhibiting the growth of PC-3 tumors. We found...activity against PC3 tumors. Although dietary supplementation was labor-efficient, the intake of the active agents could not be controlled because the...basis for most modern pharmaceutical drugs. Herbal medicines usually contain multiple bioactive compo- nents with specific biological activities and

  13. Visual perceptions induced by intravitreous injections of therapeutic agents

    PubMed Central

    Charalampidou, S; Nolan, J; Ormonde, G O; Beatty, S

    2011-01-01

    Purpose The purpose of this study was to conduct a questionnaire-based survey of subjective visual perceptions induced by intravitreous (IVT) injections of therapeutic agents. Patients and methods Patients undergoing an IVT injection of ranibizumab, pegaptanib sodium, or triamcinolone acetonide were administered a questionnaire in the immediate post-injection period and at 2 weeks of follow-up. Results In the immediate post-injection period (75 IVT injections, 75 eyes, 75 patients), lights and floaters were reported after 20 (27%) and 24 (32%) IVT injections, respectively. In comparison, at the 2-week follow-up, the incidence of reported lights (11; 15%) was similar (P>0.05), but the incidence of reported floaters was higher (48; 64% P=0.00). Subgroup analysis for various injection subgroups (no previous injection vsprevious injection(s) in the study eye; injections in study eyes with good VA (logarithm of minimal angle of resolution [logMAR] ≤0.3) vsmoderate VA (0.7 0.3) vspoor VA (logMAR ≥0.7); injections according to pharmacological agent (ranibizumab vspegaptanib vstriamcinolone acetonide); injections in study eyes with choroidal neovascularization (of various causes) vsstudy eyes with macular edema (of various causes); and injections in phakic vspseudophakic eyes) did not reveal any statistically significant associations. Visual perceptions experienced following 15% of IVT injections gave cause for concern to the patient (mean visual analog scale score (±SD): 4.5 (±1.7)), and in 64% of cases, the patients believed that preoperative counseling would have averted the concern. Conclusions Lights and floaters are frequent visual perceptions following IVT injections of therapeutic agents. They can give rise to concern that could be alleviated with preinjection counseling. PMID:21274011

  14. The effect of therapeutic drugs and other pharmacologic agents on activity of porphobilinogen deaminase, the enzyme that is deficient in intermittent acute porphyria.

    PubMed

    Tishler, P V

    1999-01-01

    Drugs and toxins precipitate life-threatening acute attacks in patients with intermittent acute porphyria. These materials may act by directly inhibiting enzyme activity, thus further reducing porphobilinogen (PBG) deaminase activity below the ca. 50% level that results from the gene defect. To test this, we studied the effects of drugs that precipitate acute attacks (lead, phenobarbital, griseofulvin, phenytoin, sulfanilamide, sulfisoxazole, 17alpha-ethinyl estradiol, 5beta-pregnan-3alpha-ol-20-one), drugs that are safe (lithium, magnesium, chlorpromazine, promethazine), and those with uncertain effects (ethyl alcohol, imipramine, diazepam, haloperidol) on activity of PBG deaminase in vitro and in vivo. In the in vitro studies, of PBG deaminase from human erythrocytes from normals and individuals with IAP, only lead (> or = .01 mM) inhibited enzyme activity. Chlorpromazine (> or = .01 mM), promethazine (> or = .01 mM) and imipramine (1 mM) seemed to increase enzyme activity. In most in vivo experiments, male rats were injected intraperitoneally with test material twice daily for 3 days and once on day four; and erythrocyte and hepatic PBG deaminase activity was assayed thereafter. Effects on enzyme activity were observed only with 17alpha-ethinyl estradiol (0.05 microg/kg/day; reduction of 11% in erythrocyte enzyme [NS], and of 20% in liver enzyme [P=.02]), and imipramine (12.5 mg/kg/day; reduction in erythrocyte enzyme activity of 13% [P<.001]). Rats given lead acetate in their drinking water (10 mg/ml) for the first 60 days of life, resulting in high blood and liver lead levels, had increased erythrocyte PBG deaminase (167% of control; P=.004). Thus, enzyme inhibition by lead in vitro was not reflected in a similar in vivo inhibition. The only inhibitory effects in vivo, with ethinyl estradiol and imipramine, appear to be mild and biologically inconsequential. We conclude that inhibition of PBG deaminase activity by materials that precipitate acute attacks is an

  15. Phenols, alkaloids and terpenes from medicinal plants with antihypertensive and vasorelaxant activities. A review of natural products as leads to potential therapeutic agents.

    PubMed

    Maione, Francesco; Cicala, Carla; Musciacco, Giulia; De Feo, Vincenzo; Amat, Anibal G; Ialenti, Armando; Mascolo, Nicola

    2013-04-01

    Numerous studies support the cardiovascular effects of medicinal plants. This review examines plants whose antihypertensive and vasorelaxant effects have been scientifically validated. Our study selected only chemically characterized plants whose mode of action had already been investigated. The aim of the paper is to provide a quick way to identify medicinal plants and their constituents with antihypertensive and vasorelaxant activities.

  16. Therapeutic potential of HMGB1-targeting agents in sepsis

    PubMed Central

    Wang, Haichao; Zhu, Shu; Zhou, Rongrong; Li, Wei; Sama, Andrew E.

    2008-01-01

    Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. The inflammatory response is partly mediated by innate immune cells (such as macrophages, monocytes and neutrophils), which not only ingest and eliminate invading pathogens but also initiate an inflammatory response upon recognition of pathogen-associated molecular patterns (PAMPs). The prevailing theories of sepsis as a dysregulated inflammatory response, as manifested by excessive release of inflammatory mediators such as tumour necrosis factor and high-mobility group box 1 protein (HMGB1), are supported by extensive studies employing animal models of sepsis. Here we review emerging evidence that support extracellular HMGB1 as a late mediator of experimental sepsis, and discuss the therapeutic potential of several HMGB1-targeting agents (including neutralising antibodies and steroid-like tanshinones) in experimental sepsis. PMID:18980707

  17. Modulation of pro-inflammatory activation of monocytes and dendritic cells by aza-bis-phosphonate dendrimer as an experimental therapeutic agent

    PubMed Central

    2014-01-01

    Introduction Our objective was to assess the capacity of dendrimer aza-bis-phosphonate (ABP) to modulate phenotype of monocytes (Mo) and monocytes derived dendritic cells (MoDC) activated in response to toll-like receptor 4 (TLR4) and interferon γ (IFN- γ) stimulation. Methods Mo (n = 12) and MoDC (n = 11) from peripheral blood of healthy donors were prepared. Cells were preincubated or not for 1 hour with dendrimer ABP, then incubated with lipopolysaccharide (LPS; as a TLR4 ligand) and (IFN-γ) for 38 hours. Secretion of tumor necrosis factor α (TNFα), interleukin (IL) -1, IL-6, IL-12, IL-10 and IL-23 in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Bead Array. Differentiation and subsequent maturation of MoDC from nine donors in the presence of LPS were analyzed by flow cytometry using CD80, CD86, CD83 and CD1a surface expression as markers. Results Mo and MoDC were orientated to a pro-inflammatory state. In activated Mo, TNFα, IL-1β and IL-23 levels were significantly lower after prior incubation with dendrimer ABP. In activated MoDC, dendrimer ABP promoted IL-10 secretion while decreasing dramatically the level of IL-12. TNFα and IL-6 secretion were significantly lower in the presence of dendrimer ABP. LPS driven maturation of MoDC was impaired by dendrimer ABP treatment, as attested by the significantly lower expression of CD80 and CD86. Conclusion Our data indicate that dendrimer ABP possesses immunomodulatory properties on human Mo and MoDC, in TLR4 + IFN-γ stimulation model, by inducing M2 alternative activation of Mo and promoting tolerogenic MoDC. PMID:24745366

  18. Tackling obesity: new therapeutic agents for assisted weight loss

    PubMed Central

    Karam, JG; McFarlane, SI

    2010-01-01

    The pandemic of overweight and obesity continues to rise in an alarming rate in western countries and around the globe representing a major public health challenge in desperate need for new strategies tackling obesity. In the United States nearly two thirds of the population is overweight or obese. Worldwide the number of persons who are overweight or obese exceeded 1.6 billion. These rising figures have been clearly associated with increased morbidity and mortality. For example, in the Framingham study, the risk of death increases with each additional pound of weight gain even in the relatively younger population between 30 and 42 years of age. Overweight and obesity are also associated with increased co-morbid conditions such as diabetes, hypertension and cardiovascular disease as well as certain types of cancer. In this review we discuss the epidemic of obesity, highlighting the pathophysiologic mechanisms of weight gain. We also provide an overview of the assessment of overweight and obese individuals discussing possible secondary causes of obesity. In a detailed section we discuss the currently approved therapeutic interventions for obesity highlighting their mechanisms of action and evidence of their efficacy and safety as provided in clinical trials. Finally, we discuss novel therapeutic interventions that are in various stages of development with a special section on the weight loss effects of anti-diabetic medications. These agents are particularly attractive options for our growing population of obese diabetic individuals. PMID:21437080

  19. Wasp Venom Toxins as a Potential Therapeutic Agent.

    PubMed

    Dongol, Yashad; Dhananjaya, Bhadrapara L; Shrestha, Rakesh K; Aryal, Gopi

    2016-01-01

    It is high time now to discover novel drugs due to the increasing rate of drug resistance by the pathogen organisms and target cells as well as the dependence or tolerance of the body towards the drug. As it is obvious that significant numbers of the modern day pharmaceuticals are derived from natural products, it is equally astonishing to accept that venoms of various origins have therapeutic potentials. Wasp venoms are also a rich source of therapeutically important toxins which includes short cationic peptides, kinins, polyamines and polyDNA viruses, to name a few indentified. Wasp venom cationic peptides, namely mastoparan and its analogs, show a very important potency as an antimicrobial and anticancer agents of the future. They have proven to be the better candidates due to their lesser toxic effects and higher selectivity upon chemical modification and charge optimization. They also have superiority over the conventional chemical drugs as the target cells very rarely develop resistance against them because these peptides primarily imparts its effect through biophysical interaction with the target cell membrane which is dependent upon the net charge of the peptide, its hydrophobicity and anionicity and fluidity of the target cell membranes. Besides, the other components of wasp venom such as kinins, polyamines and polyDNA viruses show various pharmacological promise in the treatment of pain, inflammatory disease, and neurodegenerative diseases such as epilepsy and aversion.

  20. Cotinine: a potential new therapeutic agent against Alzheimer's disease.

    PubMed

    Echeverria, Valentina; Zeitlin, Ross

    2012-07-01

    Tobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD.

  1. Novel copper-based therapeutic agent for anti-inflammatory: synthesis, characterization, and biochemical activities of copper(II) complexes of hydroxyflavone Schiff bases.

    PubMed

    Joseph, J; Nagashri, K

    2012-07-01

    Four hydroxyflavone derivatives have been synthesized with the aim of obtaining a good model of superoxide dismutase. Better to mimic the natural metalloenzyme, copper complexes have been designed. The Cu(II) complexes of general formulae, [CuL] where L = 5-hydroxyflavone-o-phenylenediamine (L¹H₂)/m-phenylenediamine (L²H₂) and 3-hydroxyflavone-o-phenylenediamine (L³H₂)/m-phenylenediamine (L⁴H₂) have been synthesized. The structural features have been determined from their analytical and spectral data. All the Cu(II) complexes exhibit square planar geometry. Redox behavior of copper complexes was studied and the present ligand systems stabilize the unusual oxidation state of the copper ion during electrolysis. The in vitro antimicrobial activities of the investigated compounds were tested against the bacterial species Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa and fungal species Aspergillus niger, Rhizopus stolonifer, Aspergillus flavus, Rhizoctonia bataicola, and Candida albicans. Superoxide dismutase and anti-inflammatory activities of the copper complexes have also been measured and discussed.

  2. Degrasyn-like Symmetrical Compounds: Possible Therapeutic Agents for Multiple Myeloma (MM-I)

    PubMed Central

    Peng, Zhenghong; Maxwell, David; Sun, Duoli; Bhanu Prasad, Basvoju A.; Schuber, Paul T.; Pal, Ashutosh; Ying, Yunming; Han, Dongmei; Gao, Liwei; Wang, Shimei; Levitzki, Alexander; Kapuria, Vaibhav; Talpaz, Moshe; Young, Matthew; Showalter, Hollis D.; Donato, Nicholas J.; Bornmann, William. G.

    2014-01-01

    A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents PMID:24457091

  3. Degrasyn-like symmetrical compounds: possible therapeutic agents for multiple myeloma (MM-I).

    PubMed

    Peng, Zhenghong; Maxwell, David S; Sun, Duoli; Bhanu Prasad, Basvoju A; Schuber, Paul T; Pal, Ashutosh; Ying, Yunming; Han, Dongmei; Gao, Liwei; Wang, Shimei; Levitzki, Alexander; Kapuria, Vaibhav; Talpaz, Moshe; Young, Matthew; Showalter, Hollis D; Donato, Nicholas J; Bornmann, William G

    2014-02-15

    A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.

  4. Novel findings for the development of drug therapy for various liver diseases: Liver microsomal triglyceride transfer protein activator may be a possible therapeutic agent in non-alcoholic steatohepatitis.

    PubMed

    Fujita, Koji; Imajo, Kento; Shinohara, Yoshiyasu; Nozaki, Yuichi; Wada, Koichiro; Yoneda, Masato; Endo, Hiroki; Takahashi, Hirokazu; Abe, Yasunobu; Inamori, Masahiko; Shimamura, Takeshi; Kobayashi, Noritoshi; Kirikoshi, Hiroyuki; Kubota, Kensuke; Saito, Satoru; Nakajima, Atsushi

    2011-01-01

    The factors involved in the progression of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) are not fully understood and thus it is urgently needed to elucidate these factors. Steatosis is not causal in the development of NASH, but rather it sensitizes the liver to the damaging effects of second hits such that stressors innocuous to a healthy liver lead to the development of NASH in the steatotic liver. In the previous study, most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, very-low-density lipoprotein (VLDL) synthesis, especially hepatic microsomal triglyceride transfer protein (MTP) mRNA expression, was impaired in the NASH group. Moreover, NASH showed significantly higher incidence of minor alley appearance compared with NAFL, indicating the possibility of association between NASH pathogenesis and decreased congenital MTP activity. MTP is one of the enzymes that transfer triglycerides to nascent apolipoprotein B, producing VLDL and removing lipid from the hepatocyte. A growing body of literature suggests that the measurement of hepatic MTP expression may be helpful for diagnosis; and moreover, hepatic MTP activator may be a possible therapeutic agent for the treatment of NASH.

  5. Melatonin and Nitrones As Potential Therapeutic Agents for Stroke

    PubMed Central

    Romero, Alejandro; Ramos, Eva; Patiño, Paloma; Oset-Gasque, Maria J.; López-Muñoz, Francisco; Marco-Contelles, José

    2016-01-01

    Stroke is a disease of aging affecting millions of people worldwide, and recombinant tissue-type plasminogen activator (r-tPA) is the only treatment approved. However, r-tPA has a low therapeutic window and secondary effects which limit its beneficial outcome, urging thus the search for new more efficient therapies. Among them, neuroprotection based on melatonin or nitrones, as free radical traps, have arisen as drug candidates due to their strong antioxidant power. In this Perspective article, an update on the specific results of the melatonin and several new nitrones are presented. PMID:27932976

  6. 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

  7. Astaxanthin: a potential therapeutic agent in cardiovascular disease.

    PubMed

    Fassett, Robert G; Coombes, Jeff S

    2011-03-21

    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.

  8. MAD (Multi-Agent-Delivery) Nanolayer: Delivering Multiple Therapeutics from Hierarchical Assembled Surface Coatings

    PubMed Central

    Kim, Byeong-Su; Smith, Renée C.; Poon, Zhiyong; Hammond, Paula T.

    2014-01-01

    We present the hydrolytically degradable polymeric multilayer films that can co-deliver multiple therapeutics of differing chemical characteristics (charged biomacromolecules and neutral hydrophobic small molecules) from a surface. This multi-agent-delivery (MAD) nanolayer system integrates the hydrolytically degradable poly(β-amino ester) as a structural component to control the degradation of the multilayers to release active therapeutic macromolecules, as well as hydrophobic drugs imbedded within amphiphilic block copolymer micellar carriers within layer-by-layer (LbL) films, which would otherwise be difficult to include within the multilayers. By varying the anionic therapeutic agents (heparin and dextran sulfate) within the multilayer, we examine how different structural components can be used to control the release kinetics of multiple therapeutics from MAD nanolayers. Controlled release profiles and the in vitro efficacy of the MAD nanolayers in suppressing the growth of human smooth muscle cell lines were evaluated. The dual delivery of a charged macromolecular heparin and a small hydrophobic drug, paclitaxel, is found to be synergistic and beneficial toward effective therapeutic activity. Furthermore, we compared the classical dipping method we employed here with an automated spray-LbL technique. Spray-LbL significantly facilitates film processing time while preserving the characteristic release profiles of the MAD nanolayers. With the highly versatile and tunable nature of LbL assembly, we anticipate that MAD nanolayers can provide a unique platform for delivering multiple therapeutics from macromolecular to small molecules with distinct release profiles for applications in biological and biomedical surface coatings. PMID:19630389

  9. Surface-active agents from the group of polyoxyethylated glycerol esters of fatty acids. Part III. Surface activity and solubilizing properties of the products of oxyethylation of lard (Adeps suillus, F.P. VIII) in the equilibrium system in relation to lipophilic therapeutic agents (class II and III of BCS).

    PubMed

    Nachajski, Michał J; Piotrowska, Jowita B; Kołodziejczyk, Michał K; Lukosek, Marek; Zgoda, Marian M

    2013-01-01

    Research was conducted into the solubilization processes of diclofenac, ibuprofen, ketoprofen and naproxen in equilibrium conditions in the environment of aqueous solutions of oxyethylated lard's fractions (Adeps suillus, Polish Pharmacopoeia VIII). The determined thermodynamic (cmc, deltaGm(0)) and hydrodynamic (R0, R(obs), omega, M(eta)) parameters characterizing the micelle of the solubilizer and the adduct demonstrate that lipophilic therapeutic agents are adsorbed in a palisade structure of the micelle due to a topologically created so-called "lipophilic adsorption pocket". This shows that the hydrophilicity of the micelle and the adsorption layer decreases at the phase boundary, which is confirmed by the calculated values of coefficients A(m) and r x (a). The results obtained indicate the possibility of making use of the class of non-ionic surfactants which are not ksenobiotics for the modification of the profile of solid oral dosage forms with lipophilic therapeutic agents from the II class of Biopharmaceutics Classification System (BCS).

  10. Effect of therapeutic chemical agents in vitro and on experimental meningoencephalitis due to Naegleria fowleri.

    PubMed

    Kim, Jong-Hyun; Jung, Suk-Yul; Lee, Yang-Jin; Song, Kyoung-Ju; Kwon, Daeho; Kim, Kyongmin; Park, Sun; Im, Kyung-Il; Shin, Ho-Joon

    2008-11-01

    Naegleria fowleri is a ubiquitous, pathogenic free-living amoeba; it is the most virulent Naegleria species and causes primary amoebic meningoencephalitis (PAME) in laboratory animals and humans. Although amphotericin B is currently the only agent available for the treatment of PAME, it is a very toxic antibiotic and may cause many adverse effects on other organs. In order to find other potentially therapeutic agents for N. fowleri infection, the present study was undertaken to evaluate the in vitro and in vivo efficacies of miltefosine and chlorpromazine against pathogenic N. fowleri. The result showed that the growth of the amoeba was effectively inhibited by treatment with amphotericin B, miltefosine, and chlorpromazine. When N. fowleri trophozoites were treated with amphotericin B, miltefosine, and chlorpromazine, the MICs of the drug were 0.78, 25, and 12.5 microg/ml, respectively, on day 2. In experimental meningoencephalitis of mice that is caused by N. fowleri, the survival rates of mice treated with amphotericin B, miltefosine, and chlorpromazine were 40, 55, and 75%, respectively, during 1 month. The average mean time to death for the amphotericin B, miltefosine, and chlorpromazine treatments was 17.9 days. In this study, the effect of drugs was found to be optimal when 20 mg/kg was administered three times on days 3, 7, and 11. Finally, chlorpromazine had the best therapeutic activity against N. fowleri in vitro and in vivo. Therefore, it may be a more useful therapeutic agent for the treatment of PAME than amphotericin B.

  11. Efficacy of Several Therapeutic Agents in a Murine Model of Dry Eye Syndrome

    PubMed Central

    Kilic, Servet; Kulualp, Kadri

    2016-01-01

    In the current study, we used 56 female BALB/c mice with induced dry eye syndrome to evaluate the therapeutic effects of formal saline (FS), sodium hyaluronate (SH), diclofenac sodium (DS), olopatadine (OP), retinoic acid (RA), fluoromethanole (FML), cyclosporine A (CsA), and doxycycline hyclate (DH). All subjects were kept in an evaporative ‘dry eye cabinet’ for the assessment of blink rate, tear production, tear break-up time, and impression cytology prior to (baseline) and during weeks 2, 4, and 6 of the study. The right eyes of all subjects were treated topically with 5 µL of the test agent twice daily during weeks 2 through 6. Impression cytology and tear break-up time differed between time points in all groups and differed between groups at weeks 4 and 6. Blink rate differed by time point only in the FS, FML, and DH groups. Tear production according to the phenol red cotton thread test differed by time point for all groups except RA, CsA, and DH and differed between groups only at week 6. Among the compounds tested in the present study, DS and CsA were the most effective therapeutic agents in our mouse model of dry eye syndrome; these agents likely exert their therapeutic effect through their antiinflammatory activity. PMID:27053565

  12. Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma

    PubMed Central

    Loong, Herbert H; Yeo, Winnie

    2014-01-01

    In mammalian cells, microtubules are present both in interphase and dividing cells. In the latter, microtubules forming the mitotic spindle are highly dynamic and exquisitely sensitive to therapeutic inhibitors. Developed to alter microtubule function, microtubule-binding agents have been proven to be highly active as an anticancer treatment. Significant development of microtubule-binding agents has taken place in recent years, with newer anti-tubulin agents now showing novel properties of enhanced tumor specificity, reduced neurotoxicity, and insensitivity to chemoresistance mechanisms. Hepatocellular carcinoma remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. There is now evidence to suggest that microtubule-binding agents may be effective in the treatment of hepatocellular carcinoma, especially when used in combination with mammalian target of rapamycin inhibitors. Preclinical models have suggested that the latter may be able to overcome resistance to microtubule binding agents. In this review article, recent developments of novel microtubule binding agents and their relevance to the treatment of hepatocellular carcinoma will be discussed. PMID:24790457

  13. Derivatives of human complement component C3 for therapeutic complement depletion: a novel class of therapeutic agents.

    PubMed

    Fritzinger, David C; Hew, Brian E; Lee, June Q; Newhouse, James; Alam, Maqsudul; Ciallella, John R; Bowers, Mallory; Gorsuch, William B; Guikema, Benjamin J; Stahl, Gregory L; Vogel, Carl-Wilhelm

    2008-01-01

    To obtain proteins with the complement-depleting activity of Cobra Venom Factor (CVF), but with less immunogenicity, we have prepared human C3/CVF hybrid proteins, in which the C-terminus of the alpha-chain of human C3 is exchanged with homologous regions of the C-terminus of the beta-chain of CVF. We show that these hybrid proteins are able to deplete complement, both in vitro and in vivo. One hybrid protein, HC3-1496, is shown to be effective in reducing complement-mediated damage in two disease models in mice, collagen-induced arthritis and myocardial ischemia/reperfusion injury. Human C3/CVF hybrid proteins represent a novel class ofbiologicals as potential therapeutic agents in many diseases where complement is involved in the pathogenesis.

  14. 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

  15. Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline.

    PubMed

    Cholo, Moloko C; Mothiba, Maborwa T; Fourie, Bernard; Anderson, Ronald

    2017-02-01

    Drug-resistant (DR)-TB is the major challenge confronting the global TB control programme, necessitating treatment with second-line anti-TB drugs, often with limited therapeutic efficacy. This scenario has resulted in the inclusion of Group 5 antibiotics in various therapeutic regimens, two of which promise to impact significantly on the outcome of the therapy of DR-TB. These are the 're-purposed' riminophenazine, clofazimine, and the recently approved diarylquinoline, bedaquiline. Although they differ structurally, both of these lipophilic agents possess cationic amphiphilic properties that enable them to target and inactivate essential ion transporters in the outer membrane of Mycobacterium tuberculosis. In the case of bedaquiline, the primary target is the key respiratory chain enzyme F1/F0-ATPase, whereas clofazimine is less selective, apparently inhibiting several targets, which may underpin the extremely low level of resistance to this agent. This review is focused on similarities and differences between clofazimine and bedaquiline, specifically in respect of molecular mechanisms of antimycobacterial action, targeting of quiescent and metabolically active organisms, therapeutic efficacy in the clinical setting of DR-TB, resistance mechanisms, pharmacodynamics, pharmacokinetics and adverse events.

  16. Field Agent Activities: Level 1.

    ERIC Educational Resources Information Center

    Gussett, James

    One of a series of monographs providing information about the Delaware Model: A Systems Approach to Science Education (Del Mod System), this monograph describes the role of field agents. These agents are responsible for individual teachers who express a desire for involvement in improving teacher effectiveness and to be involved in the teaching of…

  17. 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.

  18. Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents against Lung Cancer

    DTIC Science & Technology

    2015-12-01

    AWARD NUMBER: W81XWH-13-1-0238 TITLE: Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents against Lung Cancer PRINCIPAL...of Translesion DNA Synthesis as Therapeutic Agents against Lung Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...Oxygen-rich environments can create pro-mutagenic DNA lesions such as 8-oxoguanine (8-oxo-G) that can be misreplicated during translesion DNA synthesis

  19. Emotional Readiness and Music Therapeutic Activities

    ERIC Educational Resources Information Center

    Drossinou-Korea, Maria; Fragkouli, Aspasia

    2016-01-01

    The purpose of this study is to understand the children's expression with verbal and nonverbal communication in the Autistic spectrum. We study the emotional readiness and the music therapeutic activities which exploit the elements of music. The method followed focused on the research field of special needs education. Assumptions on the parameters…

  20. Quercetin as an Emerging Anti-Melanoma Agent: A Four-Focus Area Therapeutic Development Strategy

    PubMed Central

    Harris, Zoey; Donovan, Micah G.; Branco, Gisele Morais; Limesand, Kirsten H.; Burd, Randy

    2016-01-01

    Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase – a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes feasible a target for polyphenol-based therapies. For example, quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables, and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated antiproliferative and proapoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anticancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review, we explore the potential of quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a “four-focus area strategy” to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to (i) modulate cellular bioreduction potential and associated signaling cascades, (ii) affect transcription of relevant genes, (iii) regulate epigenetic processes, and (iv) develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects. PMID:27843913

  1. Cisplatin encapsulated nanoparticle as a therapeutic agent for anticancer treatment

    NASA Astrophysics Data System (ADS)

    Eka Putra, Gusti Ngurah Putu; Huang, Leaf; Hsu, Yih-Chih

    2016-03-01

    The knowledge of manipulating size of biomaterials encapsulated drug into nano-scale particles has been researched and developed in treating cancer. Cancer is the second worldwide cause of death, therefore it is critical to treat cancers challenging with therapeutic modality of various mechanisms. Our preliminary investigation has studied cisplatin encapsulated into lipid-based nanoparticle and examined the therapeutic effect on xenografted animal model. We used mice with tumor volume ranging from 195 to 214 mm3 and then few mice were grouped into three groups including: control (PBS), lipid platinum chloride (LPC) nanoparticles and CDDP (cis-diamminedichloroplatinum(II) at dose of 3mg cisplatin /kg body weight. The effect of the treatment was observed for 12 days post-injection. It showed that LPC NPs demonstrated a better therapeutic effect compared to CDDP at same 3mg cisplatin/kg drug dose of tumor size reduction, 96.6% and 11.1% respectively. In addition, mouse body weight loss of LPC, CDDP and PBS treated group are 12.1%, 24.3% and 1.4%. It means that by compared to CDDP group, LPC group demonstrated less side effect as not much reduction of body weight have found. Our findings have shown to be a potential modality to further investigate as a feasible cancer therapy modality.

  2. Insights into the antimicrobial properties of hepcidins: advantages and drawbacks as potential therapeutic agents.

    PubMed

    Lombardi, Lisa; Maisetta, Giuseppantonio; Batoni, Giovanna; Tavanti, Arianna

    2015-04-10

    The increasing frequency of multi-drug resistant microorganisms has driven research into alternative therapeutic strategies. In this respect, natural antimicrobial peptides (AMPs) hold much promise as candidates for the development of novel antibiotics. However, AMPs have some intrinsic drawbacks, such as partial degradation by host proteases or inhibition by host body fluid composition, potential toxicity, and high production costs. This review focuses on the hepcidins, which are peptides produced by the human liver with a known role in iron homeostasis, as well by numerous other organisms (including fish, reptiles, other mammals), and their potential as antibacterial and antifungal agents. Interestingly, the antimicrobial properties of human hepcidins are enhanced at acidic pH, rendering these peptides appealing for the design of new drugs targeting infections that occur in body areas with acidic physiological pH. This review not only considers current research on the direct killing activity of these peptides, but evaluates the potential application of these molecules as coating agents preventing biofilm formation and critically assesses technical obstacles preventing their therapeutic application.

  3. Nanoparticles as conjugated delivery agents for therapeutic applications

    NASA Astrophysics Data System (ADS)

    Muroski, Megan Elizabeth

    This dissertation explores the use of nanoparticles as conjugated delivery agents. Chapter 1 is a general introduction. Chapter 2 discusses the delivery by a nanoparticle platform provides a method to manipulate gene activation, by taking advantage of the high surface area of a nanoparticle and the ability to selectively couple a desired biological moiety to the NP surface. The nanoparticle based transfection approach functions by controlled release of gene regulatory elements from a 6 nm AuNP (gold nanoparticle) surface. The endosomal release of the regulatory elements from the nanoparticle surface results in endogenous protein knockdown simultaneously with exogenous protein expression for the first 48 h. The use of fluorescent proteins as the endogenous and exogenous signals for protein expression enables the efficiency of co-delivery of siRNA (small interfering RNA) for GFP (green fluorescent protein) knockdown and a dsRed-express linearized plasmid for induction to be optically analyzed in CRL-2794, a human kidney cell line expressing an unstable green fluorescent protein. Delivery of the bimodal nanoparticle in cationic liposomes results in 20% GFP knockdown within 24 h of delivery and continues exhibiting knockdown for up to 48 h for the bimodal agent. Simultaneous dsRed expression is observed to initiate within the same time frame with expression levels reaching 34% after 25 days although cells have divided approximately 20 times, implying daughter cell transfection has occurred. Fluorescence cell sorting results in a stable colony, as demonstrated by Western blot analysis. The simultaneous delivery of siRNA and linearized plasmid DNA on the surface of a single nanocrystal provides a unique method for definitive genetic control within a single cell and leads to a very efficient cell transfection protocol. In Chapter 3, we wanted to understand the NP complex within the cell, and to look at the dynamics of release utilizing nanometal surface energy transfer as

  4. Current therapeutic agents and anesthetic considerations for diabetes mellitus.

    PubMed

    Kang, Hyoseok

    2012-09-01

    As the incidence of diabetes mellitus (DM) continues to increase worldwide, more diabetic patients will be presented for surgery and anesthesia. This increase of DM is a consequence of the rise in new patients of type 2 DM, and is likely attributable to rapid economic development, improved living standards, aging population, obesity, and lack of exercise. The primary goal of management in DM is to delay, or prevent the macro- and microvascular complications by achieving good glycemic control. More understanding of the pathophysiology of DM has contributed to the advance of new pharmacological approaches. In addition to the conventional therapy for DM, glucagon-like peptide-1 (GLP-1) mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and insulin analogues are currently available effective hypoglycemic agents for the management of the patients with DM in the perioperative period and also consider the adverse effects of newly introduced agents that need more clinical observations.

  5. Neuroinflammation in Alzheimer's disease: different molecular targets and potential therapeutic agents including curcumin.

    PubMed

    Ray, Balmiki; Lahiri, Debomoy K

    2009-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. Deposition of amyloid beta plaque and associated neuroinflammation are the major hallmarks of AD. Whereas reactive oxygen species (ROS) and activated microglial cells contribute to neuronal loss, nuclear factor kappaB and apolipoprotein E participate in inflammatory process of AD. Current FDA approved drugs provide only symptomatic relief in AD. For broad spectrum of activity, some natural products are also being tested. Turmeric is used as an anti-inflammatory medicine in various regions of Asia. Curcumin, which is a yellow colored polyphenol compound present in turmeric, showed anti-inflammatory properties. Herein, we discuss the neurobiological and neuroinflammatory pathways of AD, evaluate different molecular targets and potential therapeutic agents, including curcumin, for the treatment of AD.

  6. Activity Recognition for Agent Teams

    DTIC Science & Technology

    2007-07-01

    correspond to a real team, but is rather a visual illusion caused by a coincidental configuration of agents. 50 CHAPTER 4. STABR The behavior...each frame-pair were only classified with 76% accuracy, such a method would hallucinate false action transitions at unacceptable rates). Fortunately

  7. Fibroblast growth factor-21 as a therapeutic agent for metabolic diseases.

    PubMed

    Kharitonenkov, Alexei; Shanafelt, Armen B

    2008-01-01

    Fibroblast growth factor (FGF)-21 is a unique member of the FGF family, with several molecular characteristics that differ from classical FGFs and exhibiting a pharmacologic profile that includes a variety of metabolic responses in vitro and when tested in vivo in animal models. FGF21 represents a novel and attractive therapeutic agent for type 2 diabetes mellitus, because of its ability to modulate disease phenotype in preclinical settings without inducing any apparent adverse effects. Although FGF21 was discovered relatively recently, the understanding of its biology and therapeutic utility is rapidly evolving. A number of key metabolically linked molecules and pathways have been suggested to be involved in the mechanism of action of FGF21, depending on the specific target tissue/organ. Further research into these mechanisms should lead to important advances in the understanding of FGF21 biology and pave the way for novel therapeutic strategies. The specifics of FGF21 activities both in cell culture and in vivo, its potential as a target for diabetes, and insights into the molecular mechanisms of FGF21 metabolic actions will be discussed in this review.

  8. Metformin: A Potential Therapeutic Agent for Recurrent Colon Cancer

    PubMed Central

    Nangia-Makker, Pratima; Yu, Yingjie; Vasudevan, Anita; Farhana, Lulu; Rajendra, Sindhu G.; Levi, Edi; Majumdar, Adhip P. N.

    2014-01-01

    Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties. However, most of the studies to evaluate therapeutic efficacy of metformin have been on primary cancer. No information is available whether metformin could be effectively used for recurrent cancer, specifically colorectal cancer (CRC) that affects up to 50% of patients treated by conventional chemotherapies. Although the reasons for recurrence are not fully understood, it is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs). Therefore, development of non-toxic treatment strategies targeting CSCs would be of significant therapeutic benefit. In the current investigation, we have examined the effectiveness of metformin, in combination with 5-fluorouracil and oxaliplatin (FuOx), the mainstay of colon cancer therapeutics, on survival of chemo-resistant colon cancer cells that are highly enriched in CSCs/CSLCs. Our data show that metformin acts synergistically with FuOx to (a) induce cell death in chemo resistant (CR) HT-29 and HCT-116 colon cancer cells, (b) inhibit colonospheres formation and (c) enhance colonospheres disintegration. In vitro cell culture studies have further demonstrated that the combinatorial treatment inhibits migration of CR colon cancer cells. These changes were associated with increased miRNA 145 and reduction in miRNA 21. Wnt/β-catenin signaling pathway was also down-regulated indicating its pivotal role in regulating the growth of CR colon cancer cells. Data from SCID mice xenograft model of CR HCT-116 and CR HT-29 cells show that the combination of metformin and FuOX is highly effective in inhibiting the growth of colon tumors as evidenced by ∼50% inhibition in growth following 5 weeks of combination treatment, when compared with the vehicle treated controls. Our current data suggest that metformin together with conventional chemotherapy could be an effective treatment

  9. Orexin receptor antagonists as therapeutic agents for insomnia

    PubMed Central

    Equihua, Ana C.; De La Herrán-Arita, Alberto K.; Drucker-Colin, Rene

    2013-01-01

    Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning. Currently, treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed arousal, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia. PMID:24416019

  10. Orexin receptor antagonists as therapeutic agents for insomnia.

    PubMed

    Equihua, Ana C; De La Herrán-Arita, Alberto K; Drucker-Colin, Rene

    2013-12-25

    Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning. Currently, treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed arousal, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

  11. Resveratrol as a Therapeutic Agent for Alzheimer's Disease

    PubMed Central

    Ma, Teng; Tan, Meng-Shan; Yu, Jin-Tai; Tan, Lan

    2014-01-01

    Alzheimer's disease (AD) is the most common cause of dementia, but there is no effective therapy till now. The pathogenic mechanisms of AD are considerably complex, including Aβ accumulation, tau protein phosphorylation, oxidative stress, and inflammation. Exactly, resveratrol, a polyphenol in red wine and many plants, is indicated to show the neuroprotective effect on mechanisms mostly above. Recent years, there are numerous researches about resveratrol acting on AD in many models, both in vitro and in vivo. However, the effects of resveratrol are limited by its pool bioavailability; therefore researchers have been trying a variety of methods to improve the efficiency. This review summarizes the recent studies in cell cultures and animal models, mainly discusses the molecular mechanisms of the neuroprotective effects of resveratrol, and thus investigates the therapeutic potential in AD. PMID:25525597

  12. New therapeutic agents for diabetes mellitus: implications for anesthetic management.

    PubMed

    Chen, Daniel; Lee, Stephanie L; Peterfreund, Robert A

    2009-06-01

    Multiple hormones and transmitter systems contribute to glucose homeostasis and the control of metabolism. Recently, the gastrointestinal peptide hormones glucagon-like peptide 1 and amylin have been shown to significantly contribute to this complex physiology. These advances provide the foundation for new treatments for diabetes mellitus. Therapies based on glucagon-like peptide 1 and amylin have now been introduced into clinical practice. Rimonabant, the selective endocannabinoid receptor antagonist, had been used in European countries for the treatment of obesity; it has recently been withdrawn for this indication. This drug exhibited therapeutic benefits for metabolic variables and for type 2 diabetes mellitus. Anesthesia providers caring for patients with diabetes mellitus will need to understand the implications of these new therapies in perioperative settings, particularly with respect to side effects and interactions.

  13. TRAF6 Activation in Multiple Myeloma: A Potential Therapeutic Target

    PubMed Central

    Liu, Hong; Tamashiro, Samantha; Baritaki, Stavroula; Penichet, Manuel; Yu, Youhua; Chen, Haiming; Berenson, James; Bonavida, Benjamin

    2013-01-01

    Multiple myeloma (MM) is an incurable B-lymphocyte malignancy. New therapeutic options have become available during the past several years; however nearly all patients acquire resistance to currently available therapeutic agents. Mechanisms contributing to the pathogenesis and chemoresistance of MM include genetic abnormalities, chromosomal translocations, gene mutations, the interaction between MM cells and the bone marrow microenvironment, and defects in the apoptotic signaling pathways. Survival signaling pathways associated with the pathogenesis of MM and bone marrow stromal cells play crucial roles in promoting growth, survival, adhesion, immortalization, angiogenesis, and drug resistance. The receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/tumor necrosis factor receptor-associated factor (RANK/RANKL-TRAF6) signal pathway mediates osteolytic bone lesions through the activation of the NF-κB and Janus kinase/signal transducer and activator of transcription (JNK) pathways in osteoclast precursor cells and thus contributes to the main clinical manifestations of bone disease. TRAF6 has also been identified as a ligase for Akt ubiquitination and membrane recruitment and its phosphorylation on growth factor stimulation. The inhibition of TRAF6 by silencing RNA or by decoy peptides decreases MM tumor cell proliferation and increases apoptosis as well as bone resorption. Some proteasome inhibitors and benzoxadiazole derivatives showed inhibitory effects on the activity and function of TRAF6. Overall, we propose that TRAF6 may be considered as a potential therapeutic target for the treatment of MM. PMID:22440007

  14. Antimicrobial Peptides: An Emerging Category of Therapeutic Agents

    PubMed Central

    Mahlapuu, Margit; Håkansson, Joakim; Ringstad, Lovisa; Björn, Camilla

    2016-01-01

    Antimicrobial peptides (AMPs), also known as host defense peptides, are short and generally positively charged peptides found in a wide variety of life forms from microorganisms to humans. Most AMPs have the ability to kill microbial pathogens directly, whereas others act indirectly by modulating the host defense systems. Against a background of rapidly increasing resistance development to conventional antibiotics all over the world, efforts to bring AMPs into clinical use are accelerating. Several AMPs are currently being evaluated in clinical trials as novel anti-infectives, but also as new pharmacological agents to modulate the immune response, promote wound healing, and prevent post-surgical adhesions. In this review, we provide an overview of the biological role, classification, and mode of action of AMPs, discuss the opportunities and challenges to develop these peptides for clinical applications, and review the innovative formulation strategies for application of AMPs. PMID:28083516

  15. Targeted delivery of cancer-specific multimodal contrast agents for intraoperative detection of tumor boundaries and therapeutic margins

    NASA Astrophysics Data System (ADS)

    Xu, Ronald X.; Xu, Jeff S.; Huang, Jiwei; Tweedle, Michael F.; Schmidt, Carl; Povoski, Stephen P.; Martin, Edward W.

    2010-02-01

    Background: Accurate assessment of tumor boundaries and intraoperative detection of therapeutic margins are important oncologic principles for minimal recurrence rates and improved long-term outcomes. However, many existing cancer imaging tools are based on preoperative image acquisition and do not provide real-time intraoperative information that supports critical decision-making in the operating room. Method: Poly lactic-co-glycolic acid (PLGA) microbubbles (MBs) and nanobubbles (NBs) were synthesized by a modified double emulsion method. The MB and NB surfaces were conjugated with CC49 antibody to target TAG-72 antigen, a human glycoprotein complex expressed in many epithelial-derived cancers. Multiple imaging agents were encapsulated in MBs and NBs for multimodal imaging. Both one-step and multi-step cancer targeting strategies were explored. Active MBs/NBs were also fabricated for therapeutic margin assessment in cancer ablation therapies. Results: The multimodal contrast agents and the cancer-targeting strategies were tested on tissue simulating phantoms, LS174 colon cancer cell cultures, and cancer xenograft nude mice. Concurrent multimodal imaging was demonstrated using fluorescence and ultrasound imaging modalities. Technical feasibility of using active MBs and portable imaging tools such as ultrasound for intraoperative therapeutic margin assessment was demonstrated in a biological tissue model. Conclusion: The cancer-specific multimodal contrast agents described in this paper have the potential for intraoperative detection of tumor boundaries and therapeutic margins.

  16. Short AntiMicrobial Peptides (SAMPs) as a class of extraordinary promising therapeutic agents.

    PubMed

    Ramesh, Suhas; Govender, Thavendran; Kruger, Hendrik G; de la Torre, Beatriz G; Albericio, Fernando

    2016-07-01

    The emergence of multidrug resistant bacteria has a direct impact on global public health because of the reduced potency of existing antibiotics against pathogens. Hence, there is a pressing need for new drugs with different modes of action that can kill microorganisms. Antimicrobial peptides (AMPs) can be regarded as an alternative tool for this purpose because they are proven to have therapeutic effects with broad-spectrum activities. There are some hurdles in using AMPs as clinical candidates such as toxicity, lack of stability and high budgets required for manufacturing. This can be overcome by developing shorter and more easily accessible AMPs, the so-called Short AntiMicrobial Peptides (SAMPs) that contain between two and ten amino acid residues. These are emerging as an attractive class of therapeutic agents with high potential for clinical use and possessing multifunctional activities. In this review we attempted to compile those SAMPs that have exhibited biological properties which are believed to hold promise for the future. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  17. Investigation of Stilbenoids as Potential Therapeutic Agents for Rotavirus Gastroenteritis.

    PubMed

    Ball, Judith M; Medina-Bolivar, Fabricio; Defrates, Katelyn; Hambleton, Emily; Hurlburt, Megan E; Fang, Lingling; Yang, Tianhong; Nopo-Olazabal, Luis; Atwill, Richard L; Ghai, Pooja; Parr, Rebecca D

    2015-01-01

    Rotavirus (RV) infections cause severe diarrhea in infants and young children worldwide. Vaccines are available but cost prohibitive for many countries and only reduce severe symptoms. Vaccinated infants continue to shed infectious particles, and studies show decreased efficacy of the RV vaccines in tropical and subtropical countries where they are needed most. Continuing surveillance for new RV strains, assessment of vaccine efficacy, and development of cost effective antiviral drugs remain an important aspect of RV studies. This study was to determine the efficacy of antioxidant and anti-inflammatory stilbenoids to inhibit RV replication. Peanut (A. hypogaea) hairy root cultures were induced to produce stilbenoids, which were purified by high performance countercurrent chromatography (HPCCC) and analyzed by HPLC. HT29.f8 cells were infected with RV in the presence stilbenoids. Cell viability counts showed no cytotoxic effects on HT29.f8 cells. Viral infectivity titers were calculated and comparatively assessed to determine the effects of stilbenoid treatments. Two stilbenoids, trans-arachidin-1 and trans-arachidin-3, show a significant decrease in RV infectivity titers. Western blot analyses performed on the infected cell lysates complemented the infectivity titrations and indicated a significant decrease in viral replication. These studies show the therapeutic potential of the stilbenoids against RV replication.

  18. Indian Herbal Medicines: Possible Potent Therapeutic Agents for Rheumatoid Arthritis

    PubMed Central

    Rathore, Brijesh; Ali Mahdi, Abbas; Nath Paul, Bhola; Narayan Saxena, Prabhu; Kumar Das, Siddharth

    2007-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology and is mainly characterized by the progressive erosion of cartilage leading to chronic polyarthritis and joint distortion. Although the exact pathogenesis of the disease has yet not been elucidated, however, studies suggest that cellular proliferation of synoviocytes result in pannus formation which damages the cartilage and bone. Recent reports also support the role of free radicals in its pathogenesis. Apart from the conventional treatment strategies using nonsteroidal anti-inflammatory drugs, disease modifying antirheumatic drugs and glucocorticoids, newer and safer drugs are continuously being searched, as long term usage of these drugs have resulted in adverse effects. Alternative medicine provides another approach for treatment of RA and currently a number of medicinal plants are under scientific evaluation to develop a novel drug. There is a dire need to investigate the complete therapeutic potential and adverse effects, if any, of these herbals for providing newer and safer treatment options with minimum side effects. In this review we have tried to explore various Indian ancient Ayurvedic, Unani and Tibbi, as also some Chinese and Korean, herbals for their potential to treat RA. PMID:18392103

  19. Molecular imaging agents: impact on diagnosis and therapeutics in oncology

    PubMed Central

    Seaman, Marc E.; Contino, Gianmarco; Bardeesy, Nabeel; Kelly, Kimberly A.

    2011-01-01

    Imaging has become a crucial tool in oncology throughout the course of disease detection and management and is an integral part of clinical trials. Anatomic and functional imaging led the way, providing valuable information used in the diagnosis of disease, including data regarding the size and location of the tumor and on physiologic processes such as blood flow and perfusion. As understanding of cancer pathogenesis has advanced through the identification of genetic, biochemical, and cellular alterations in evolving tumors, emphasis has been made on developing methods to detect and serially monitor such alterations. This class of approaches is referred to as molecular imaging. Molecular imaging offers the potential for increasingly sensitive and specific visualization and quantification of biological processes at the cellular and molecular level. These approaches have become established as essential tools for cancer research, early cancer detection and staging and monitoring and predicting response to targeted therapies. Here, we will discuss recent advances in the development of molecular imaging agents and their implementation in basic cancer research as well as in more rationalized approaches to cancer care. PMID:20633310

  20. Usefulness of selective COX-2 inhibitors as therapeutic agents against canine mammary tumors.

    PubMed

    Saito, Teruyoshi; Tamura, Dai; Asano, Ryuji

    2014-04-01

    Cyclooxygenase-2 (COX-2) is a key enzyme for converting arachidonic acids to prostanoids, which are known to be induced during inflammation and cancer initiation. Previously, it has been reported that COX inhibitors, such as aspirin, reduce the incidence of human colorectal cancer; therefore, it is widely believed that COX-2 is a potential therapeutic and chemoprevention target for several types of human cancer. However, whether selective COX-2 inhibitors have antitumor effects against canine mammary tumor cells remains unclear. In the present study, to elucidate the antitumor effect of selective COX-2 inhibitors against canine mammary tumors, we investigated the antitumor effects of meloxicam, etodolac and celecoxib using COX-2-expressing canine mammary tumor (CF33) cells. We analyzed the effects of selective COX-2 inhibitors on COX-2 protein expression levels in CF33 cells. Celecoxib (100 µM) was found to induce downregulation of COX-2 protein expression. We examined the effect of selective COX-2 inhibitors on CF33 cell proliferation. All the selective COX-2 inhibitors suppressed CF33 cell growth. Specifically, etodolac and celecoxib inhibited cell proliferation via a decrease in S-phase cells and an increase in G0/G1 arrest. We examined the apoptotic effect of selective COX-2 inhibitors on CF33 cells. Our data suggested that etodolac and celecoxib induced apoptosis in CF33 cells. In particular, celecoxib led to apoptosis mediated by the activation of the mitochondrial apoptosis pathway, including the upregulation of BAX expression, downregulation of Bcl-2 expression and activation of caspase-3/7. Furthermore, celecoxib increased the percentages of cells in both early apoptosis and late apoptosis. Our results revealed that celecoxib induced apoptosis and cell cycle arrest in CF33 cells. The data suggested that celecoxib is the most viable candidate as a therapeutic agent for the treatment of canine mammary tumors. Furthermore, our findings provide the first

  1. Development of a Multifaceted Ovarian Cancer Therapeutic and Imaging Agent

    DTIC Science & Technology

    2009-04-01

    a production method for a recombinant disintegrin vicrostatin (VN), whose structure is based on the snake venom disintegrin contortrostatin (CN... venom disintegrin contortrostatin (CN), which has shown impressive antitumor and antiangiogenic activities in models of human ovarian cancer. OC cells...Jararhagin, a metallopreoteinase with a disintegrin domain isolated from Bothrops jararaca, a venomous pit viper found in Brazil, Paraguay and northern

  2. New Therapeutic Strategies for Antibiotic-Resistant Select Agents

    DTIC Science & Technology

    2007-12-31

    experimental model examined the functional activities of the Gram positive Staphylococcus aureus with the Gram negative E. S 1. REPORT DATE (DD-MM-YYYY...4. TITLE AND SUBTITLE 31-12-2007 13. SUPPLEMENTARY NOTES The views, opinions and/or findings contained in this report are those of the author( s ...NAME( S ) AND ADDRESS(ES) 6. AUTHORS 7. PERFORMING ORGANIZATION NAMES AND ADDRESSES U.S. Army Research Office P.O. Box 12211 Research Triangle

  3. New agents with antimycobacterial activity.

    PubMed

    Marco-Contelles, José; Gómez-Sánchez, Elena

    2005-11-01

    In this paper, we report that a series of structurally simple a-halogenoacetamides show potent and excellent antimycobacterial activities against drug-sensitive Mycobacterium tuberculosis H(37)Rv and drug-resistant M. avium.

  4. Bottlenecks in Development of Retinal Therapeutic Post-Transcriptional Gene Silencing Agents

    PubMed Central

    Sullivan, Jack M.; Yau, Edwin H.; Taggart, R. Thomas; Butler, Mark C.; Kolniak, Tiffany A.

    2011-01-01

    Development of post-transcriptional gene silencing (PTGS) agents for therapeutic purposes is an immense challenge in modern biology. Established technologies used to knockdown a specific target RNA and its cognate protein: antisense, ribozyme, RNAi, all conditionally depend upon an initial, critical annealing event of the PTGS ligand to a target RNA. In this review we address the nature of the bottlenecks, emphasizing the biocomplexity of target RNA structure, that currently limit PTGS therapeutic development. We briefly review existing and emerging technologies designed to release these constraints to realize the potential of PTGS agents in gene based therapies. PMID:17976683

  5. Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents.

    PubMed Central

    Dolan, M E; Moschel, R C; Pegg, A E

    1990-01-01

    O6-Alkylguanine-DNA alkyltransferase was rapidly and irreversibly inactivated by exposure to O6-benzylguanine or the p-chlorobenzyl and p-methylbenzyl analogues. This inactivation was much more rapid than with O6-methylguanine: incubation with 2.5 microM O6-benzylguanine led to more than a 90% loss of activity within 10 min, whereas 0.2 mM O6-methylguanine for 60 min was required for the same reduction. O6-Benzylguanine was highly effective in depleting the alkyltransferase activity of cultured human colon tumor (HT29) cells. Complete loss of activity was produced within 15 min after addition of O6-benzylguanine to the culture medium and a maximal effect was obtained with 5 microM. In contrast, at least 100 microM O6-methylguanine for 4 hr was needed to get a maximal effect, and this reduced the alkyltransferase by only 80%. Pretreatment of HT29 cells with 10 microM O6-benzylguanine for 2 hr led to a dramatic increase in the cytotoxicity produced by the chemotherapeutic agents 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) or 2-chloroethyl(methysulfonyl)methanesulfonate (Clomesone). Administration of O6-benzylguanine to mice at a dose of 10 mg/kg reduced alkyltransferase levels by more than 95% in both liver and kidney. These results indicate that depletion of the alkyltransferase by O6-benzylguanine may be used to investigate the role of the DNA repair protein in carcinogenesis and mutagenesis and that this treatment may be valuable to increase the chemotherapeutic effectiveness of chloroethylating agents. PMID:2164681

  6. Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target

    PubMed Central

    Krzyzosiak, Wlodzimierz J.; Sobczak, Krzysztof; Wojciechowska, Marzena; Fiszer, Agnieszka; Mykowska, Agnieszka; Kozlowski, Piotr

    2012-01-01

    This review presents detailed information about the structure of triplet repeat RNA and addresses the simple sequence repeats of normal and expanded lengths in the context of the physiological and pathogenic roles played in human cells. First, we discuss the occurrence and frequency of various trinucleotide repeats in transcripts and classify them according to the propensity to form RNA structures of different architectures and stabilities. We show that repeats capable of forming hairpin structures are overrepresented in exons, which implies that they may have important functions. We further describe long triplet repeat RNA as a pathogenic agent by presenting human neurological diseases caused by triplet repeat expansions in which mutant RNA gains a toxic function. Prominent examples of these diseases include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome, which are triggered by mutant CUG and CGG repeats, respectively. In addition, we discuss RNA-mediated pathogenesis in polyglutamine disorders such as Huntington's disease and spinocerebellar ataxia type 3, in which expanded CAG repeats may act as an auxiliary toxic agent. Finally, triplet repeat RNA is presented as a therapeutic target. We describe various concepts and approaches aimed at the selective inhibition of mutant transcript activity in experimental therapies developed for repeat-associated diseases. PMID:21908410

  7. [Phenibut potentiation of the therapeutic action of antiparkinson agents].

    PubMed

    Gol'dblat, Iu V; Lapin, I P

    1986-01-01

    It was observed in experiments on mice that the central action of phenibut (beta-phenyl-gamma-aminobutyric acid) diminished after destruction of brain dopaminergic neurons by 6-hydroxydopamine and after pretreatment with the dopamine receptor blocker haloperidol which suggests the dopaminergic component in the action of phenibut. In 13 of 16 patients receiving long-term treatment with antiparkinsonic drugs, addition of phenibut (0.25 g thrice daily for 10 days) resulted in marked clinical improvement with a significant increase of motor activity, as well as diminution of both rigidity and tremor. Follow-up showed a significant lowering of muscle tone of rigid muscles, augmentation of their strength and amplitude of movements. In 8 patients receiving phenibut without antiparkinsonic drugs the results were negligible.

  8. 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.

  9. 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

  10. Vanadium compounds as therapeutic agents: some chemical and biochemical studies.

    PubMed

    Faneca, H; Figueiredo, V A; Tomaz, Isabel; Gonçalves, Gisela; Avecilla, Fernando; Pedroso de Lima, M C; Geraldes, Carlos F G C; Pessoa, João Costa; Castro, M Margarida C A

    2009-04-01

    The behaviour of three vanadium(V) systems, namely the pyridinone (V(V)-dmpp), the salicylaldehyde (V(V)-salDPA) and the pyrimidinone (V(V)-MHCPE) complexes, is studied in aqueous solutions, under aerobic and physiological conditions using (51)V NMR, EPR and UV-Visible (UV-Vis) spectroscopies. The speciations for the V(V)-dmpp and V(V)-salDPA have been previously reported. In this work, the system V(V)-MHCPE is studied by pH-potentiometry and (51)V NMR. The results indicate that, at pH ca. 7, the main species present are (V(V)O(2))L(2) and (V(V)O(2))LH(-1) (L=MHCPE(-)) and hydrolysis products, similar to those observed in aqueous solutions of V(V)-dmpp. The latter species is protonated as the pH decreases, originating (V(V)O(2))L and (V(V)O(2))LH. All the V(V)-species studied are stable in aqueous media with different compositions and at physiological pH, including the cell culture medium. The compounds were screened for their potential cytotoxic activity in two different cell lines. The toxic effects were found to be incubation time and concentration dependent and specific for each compound and type of cells. The HeLa tumor cells seem to be more sensitive to drug effects than the 3T3-L1 fibroblasts. According to the IC(50) values and the results on reversibility to drug effects, the V(V)-species resulting from the V(V)-MHCPE system show higher toxicity in the tumor cells than in non-tumor cells, which may indicate potential antitumor activity.

  11. Balancing Antioxidant, Hypolipidemic and Anti-inflammatory Activity in a Single Agent: The Example of 2-Hydroxy-2-Substituted Morpholine, 1,4-Benzoxazine and 1,4-Benzothiazine Derivatives as a Potential Therapeutic Approach against Atherosclerosis.

    PubMed

    Matralis, Alexios N; Bavavea, Eugenia-Ismini; Incerpi, Sandra; Pedersen, Jens Z; Kourounakis, Angeliki P

    2016-08-13

    In line with our previous studies, we have developed through a rational design approach novel morpholine and benzoxa(or thia)zine lead compounds that modulate a multiplicity of targets against atherosclerosis. We have evaluated the most promising compounds for their efficiency to a) interact and scavenge free radicals, b) inhibit the metal ion (Cu2+)-induced LDL oxidation c) act intracellularly as antioxidants in THP- 1 monocytes from a leukemic patient and d) inhibit the pro-inflammatory enzymes cycloxygenase-1 (COX-1) and -2 (COX-2) in vitro. Furthermore, two representative compounds were tested for their potential to decrease lipidemic parameters (TC, LDL and TG) in hyperlipidemic mice. Most derivatives indicated a remarkable antioxidant activity, while at the same time exhibited a significant in vitro anti-inflammatory activity, inhibiting COX-1 or/and COX-2 activity at 20 μΜ. Furthermore, after their long-term administration, compounds 6 and 8 afforded a considerable activity in a chronic experimental animal model of hyperlipidemia (after high fat diet administration). The multifunctional pharmacological profile exhibited by the compounds of this study renders them interesting lead compounds for the development of novel agents against atherosclerosis.

  12. Impact of Absorption and Transport on Intelligent Therapeutics and Nano-scale Delivery of Protein Therapeutic Agents

    PubMed Central

    Peppas, Nicholas A.; Carr, Daniel A

    2009-01-01

    The combination of materials design and advances in nanotechnology has led to the development of new therapeutic protein delivery systems. The pulmonary, nasal, buccal and other routes have been investigated as delivery options for protein therapy, but none result in improved patient compliances and patient quality of life as the oral route. For the oral administration of these new systems, an understanding of protein transport is essential because of the dynamic nature of the gastrointestinal tract and the barriers to transport that exist. Models have been developed to describe the transport between the gastrointestinal lumen and the bloodstream, and laboratory techniques like cell culture provide a means to investigate the absorption and transport of many therapeutic agents. Biomaterials, including stimuli-sensitive complexation hydrogels, have been investigated as promising carriers for oral delivery. However, the need to develop models that accurately predict protein blood concentration as a function of the material structure and properties still exists. PMID:20161384

  13. 77 FR 62521 - Prospective Grant of Exclusive License: The Development of Therapeutic Agents for the Treatment...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-15

    ... Therapeutic Agents for the Treatment of Metastatic Breast Cancer and T- cell Lymphoma AGENCY: National... metastatic breast cancer, or ii) incorporating a p53 isoform antisense oligonucleotide as a single biologic... of a p53 Isoform in Regenerative Medicine, Aging and Cancer'' . The patent rights in these...

  14. The nitric oxide prodrug JS-K and its structural analogues as cancer therapeutic agents.

    PubMed

    Maciag, Anna E; Saavedra, Joseph E; Chakrapani, Harinath

    2009-09-01

    Nitric oxide (NO) prodrugs of the diazeniumdiolate class are routinely used as reliable sources of nitric oxide in chemical and biological laboratory settings. O(2)-(2,4-dinitrophenyl) diazeniumdiolates, which are derivatized forms of ionic diazeniumdiolates, have been found to show potent anti-proliferative activity in a variety of cancer cells, presumably through the effects of NO. One important member of this class of diazeniumdiolates, O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), has shown promise as a novel cancer therapeutic agent in a number of animal models. This review describes the developments in chemical and biochemical characterization and structure-activity relationship of JS-K and its analogues. In addition, some molecular mechanistic insights into the observed anti-proliferative activity of JS-K are discussed. Finally, a structural motif is presented for O(2)-(aryl) diazeniumdiolate nitric oxide prodrugs that show potency comparable with that of JS-K.

  15. Dietary Supplement 4-Methylumbelliferone: An Effective Chemopreventive and Therapeutic Agent for Prostate Cancer

    PubMed Central

    Yates, Travis J.; Lopez, Luis E.; Lokeshwar, Soum D.; Ortiz, Nicolas; Kallifatidis, Georgios; Jordan, Andre; Hoye, Kelly; Altman, Norman

    2015-01-01

    Background: Prevention and treatment of advanced prostate cancer (PCa) by a nontoxic agent can improve outcome, while maintaining quality of life. 4-methylumbelliferone (4-MU) is a dietary supplement that inhibits hyaluronic acid (HA) synthesis. We evaluated the chemopreventive and therapeutic efficacy and mechanism of action of 4-MU. Methods: TRAMP mice (7–28 per group) were gavaged with 4-MU (450mg/kg/day) in a stage-specific treatment design (8–28, 12–28, 22–28 weeks). Efficacy of 4-MU (200–450mg/kg/day) was also evaluated in the PC3-ML/Luc+ intracardiac injection and DU145 subcutaneous models. PCa cells and tissues were analyzed for HA and Phosphoinositide 3-kinase (PI-3K)/Akt signaling and apoptosis effectors. HA add-back and myristoylated Akt (mAkt) overexpression studies evaluated the mechanism of action of 4-MU. Data were analyzed with one-way analysis of variance and unpaired t test or Tukey’s multiple comparison test. All statistical tests were two-sided. Results: While vehicle-treated transgenic adenocarcinoma of the prostate (TRAMP) mice developed prostate tumors and metastases at 28 weeks, both were abrogated in treatment groups, without serum/organ toxicity or weight loss; no tumors developed at one year, even after stopping the treatment at 28 weeks. 4-MU did not alter the transgene or neuroendocrine marker expression but downregulated HA levels. However, 4-MU decreased microvessel density and proliferative index (P < .0001,). 4-MU completely prevented/inhibited skeletal metastasis in the PC3-ML/Luc+ model and DU145-tumor growth (85–90% inhibition, P = .002). 4-MU also statistically significantly downregulated HA receptors, PI-3K/CD44 complex and activity, Akt signaling, and β-catenin levels/activation, but upregulated GSK-3 function, E-cadherin, and apoptosis effectors (P < .001); HA addition or mAkt overexpression rescued these effects. Conclusion: 4-MU is an effective nontoxic, oral chemopreventive, and therapeutic agent that

  16. Socialization Agents and Activities of Young Adolescents

    ERIC Educational Resources Information Center

    Arnon, Sara; Shamai, Shmuel; Ilatov, Zinaida

    2008-01-01

    Research examined the relative importance of peer groups for young adolescents as compared with diverse adult socialization agents--family, school, and community. The factors involved were teenagers' activities, preferences, feelings, and thoughts as to how they spend their leisure time, their preferences for help providers, and their sense of…

  17. Variables and Strategies in Development of Therapeutic Post-Transcriptional Gene Silencing Agents

    PubMed Central

    Sullivan, Jack M.; Yau, Edwin H.; Kolniak, Tiffany A.; Sheflin, Lowell G.; Taggart, R. Thomas; Abdelmaksoud, Heba E.

    2011-01-01

    Post-transcriptional gene silencing (PTGS) agents such as ribozymes, RNAi and antisense have substantial potential for gene therapy of human retinal degenerations. These technologies are used to knockdown a specific target RNA and its cognate protein. The disease target mRNA may be a mutant mRNA causing an autosomal dominant retinal degeneration or a normal mRNA that is overexpressed in certain diseases. All PTGS technologies depend upon the initial critical annealing event of the PTGS ligand to the target RNA. This event requires that the PTGS agent is in a conformational state able to support hybridization and that the target have a large and accessible single-stranded platform to allow rapid annealing, although such platforms are rare. We address the biocomplexity that currently limits PTGS therapeutic development with particular emphasis on biophysical variables that influence cellular performance. We address the different strategies that can be used for development of PTGS agents intended for therapeutic translation. These issues apply generally to the development of PTGS agents for retinal, ocular, or systemic diseases. This review should assist the interested reader to rapidly appreciate critical variables in PTGS development and facilitate initial design and testing of such agents against new targets of clinical interest. PMID:21785698

  18. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology.

    PubMed

    Ashbee, H Ruth; Barnes, Rosemary A; Johnson, Elizabeth M; Richardson, Malcolm D; Gorton, Rebecca; Hope, William W

    2014-05-01

    The burden of human disease related to medically important fungal pathogens is substantial. An improved understanding of antifungal pharmacology and antifungal pharmacokinetics-pharmacodynamics has resulted in therapeutic drug monitoring (TDM) becoming a valuable adjunct to the routine administration of some antifungal agents. TDM may increase the probability of a successful outcome, prevent drug-related toxicity and potentially prevent the emergence of antifungal drug resistance. Much of the evidence that supports TDM is circumstantial. This document reviews the available literature and provides a series of recommendations for TDM of antifungal agents.

  19. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology

    PubMed Central

    Ashbee, H. Ruth; Barnes, Rosemary A.; Johnson, Elizabeth M.; Richardson, Malcolm D.; Gorton, Rebecca; Hope, William W.

    2014-01-01

    The burden of human disease related to medically important fungal pathogens is substantial. An improved understanding of antifungal pharmacology and antifungal pharmacokinetics–pharmacodynamics has resulted in therapeutic drug monitoring (TDM) becoming a valuable adjunct to the routine administration of some antifungal agents. TDM may increase the probability of a successful outcome, prevent drug-related toxicity and potentially prevent the emergence of antifungal drug resistance. Much of the evidence that supports TDM is circumstantial. This document reviews the available literature and provides a series of recommendations for TDM of antifungal agents. PMID:24379304

  20. Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review.

    PubMed

    Zhang, Jia-Sui; Lei, Jie-Ping; Wei, Guo-Qing; Chen, Hui; Ma, Chao-Ying; Jiang, He-Zhong

    2016-09-01

    Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004-2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.

  1. Viral and other cell-penetrating peptides as vectors of therapeutic agents in medicine.

    PubMed

    Durzyńska, Julia; Przysiecka, Łucja; Nawrot, Robert; Barylski, Jakub; Nowicki, Grzegorz; Warowicka, Alicja; Musidlak, Oskar; Goździcka-Józefiak, Anna

    2015-07-01

    Efficient delivery of heterologous molecules for treatment of cells is a great challenge in modern medicine and pharmacology. Cell-penetrating peptides (CPPs) may improve efficient delivery of a wide range of macromolecular cargos, including plasmid DNA, small interfering RNA, drugs, nanoparticulate pharmaceutical carriers, and anticancer drugs. In this paper, we present the history of CPPs' discovery with special attention drawn to sequences of viral origin. We also describe different CPP families with regard to their physicochemical properties and numerous mechanisms of CPP cell uptake by direct penetration and endocytotic pathways. A detailed description is focused on formation of carrier-cargo complexes, which are needed for practical use of CPPs in medicine and biotechnology. Examples of successful application of CPPs in treatment of human diseases are also presented, including decreased tumor growth and induction of cancer cell death. Finally, we review modern design approaches to novel CPPs and prediction of their activity. To sum up, the current review presents a thorough and up-to-date knowledge of CPPs and may be a valuable source of information for researchers in pharmacology designing new therapeutic agents.

  2. Quantum Speedup for Active Learning Agents

    NASA Astrophysics Data System (ADS)

    Paparo, Giuseppe Davide; Dunjko, Vedran; Makmal, Adi; Martin-Delgado, Miguel Angel; Briegel, Hans J.

    2014-07-01

    Can quantum mechanics help us build intelligent learning agents? A defining signature of intelligent behavior is the capacity to learn from experience. However, a major bottleneck for agents to learn in real-life situations is the size and complexity of the corresponding task environment. Even in a moderately realistic environment, it may simply take too long to rationally respond to a given situation. If the environment is impatient, allowing only a certain time for a response, an agent may then be unable to cope with the situation and to learn at all. Here, we show that quantum physics can help and provide a quadratic speedup for active learning as a genuine problem of artificial intelligence. This result will be particularly relevant for applications involving complex task environments.

  3. Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids

    PubMed Central

    Wang, Qilong; Zhuang, Xiaoying; Mu, Jingyao; Deng, Zhong-Bin; Jiang, Hong; Xiang, Xiaoyu; Wang, Baomei; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

    2015-01-01

    Although the use of nanotechnology for the delivery of a wide range of medical treatments has potential to reduce adverse effects associated with drug therapy, tissue-specific delivery remains challenging. Here we show that nanoparticles made of grapefruit-derived lipids, which we call grapefruit-derived nanovectors (GNVs), can transport chemotherapeutic agents, siRNA, DNA expression vectors and proteins to different types of cells. We demonstrate the in vivo targeting specificity of GNVs by co-delivering therapeutic agents with folic acid, which in turn leads to significantly increasing targeting efficiency to cells expressing folate receptors. The therapeutic potential of GNVs was further demonstrated by enhancing the chemotherapeutic inhibition of tumor growth in two tumor animal models. GNVs are less toxic than nanoparticles made of synthetic lipids and, when injected intravenously into pregnant mice, do not pass the placental barrier, suggesting they may be a useful tool for drug delivery. PMID:23695661

  4. AMPK activation: a therapeutic target for type 2 diabetes?

    PubMed

    Coughlan, Kimberly A; Valentine, Rudy J; Ruderman, Neil B; Saha, Asish K

    2014-01-01

    Type 2 diabetes (T2D) is a metabolic disease characterized by insulin resistance, β-cell dysfunction, and elevated hepatic glucose output. Over 350 million people worldwide have T2D, and the International Diabetes Federation projects that this number will increase to nearly 600 million by 2035. There is a great need for more effective treatments for maintaining glucose homeostasis and improving insulin sensitivity. AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase whose activation elicits insulin-sensitizing effects, making it an ideal therapeutic target for T2D. AMPK is an energy-sensing enzyme that is activated when cellular energy levels are low, and it signals to stimulate glucose uptake in skeletal muscles, fatty acid oxidation in adipose (and other) tissues, and reduces hepatic glucose production. There is substantial evidence suggesting that AMPK is dysregulated in animals and humans with metabolic syndrome or T2D, and that AMPK activation (physiological or pharmacological) can improve insulin sensitivity and metabolic health. Numerous pharmacological agents, natural compounds, and hormones are known to activate AMPK, either directly or indirectly - some of which (for example, metformin and thiazolidinediones) are currently used to treat T2D. This paper will review the regulation of the AMPK pathway and its role in T2D, some of the known AMPK activators and their mechanisms of action, and the potential for future improvements in targeting AMPK for the treatment of T2D.

  5. Diagnostic and Therapeutic Radiopharmaceutical Agents for Selective Discrimination of Prostate Cancer

    DTIC Science & Technology

    2009-10-01

    Therapeutic Radiopharmaceutical Agents for Selective Discrimination of Prostate Cancer 5b. GRANT NUMBER W81XWH-05-1-0556 5c. PROGRAM ELEMENT NUMBER 6...Bottenus, Brienne N.∞; Fugate, Glenn A.†; Benny, Paul*. Actinides Separations, Conference Pacific Northwest National Lab 6/2006 In situ formation of...Bottenus, Brienne N.∞; Benny, Paul*. Actinides Separations, Conference Pacific Northwest National Lab 3/12/2006 S-functionalized cysteine ligands

  6. Harnessing the power of cell-penetrating peptides: activatable carriers for targeting systemic delivery of cancer therapeutics and imaging agents.

    PubMed

    MacEwan, Sarah R; Chilkoti, Ashutosh

    2013-01-01

    Targeted delivery of cancer therapeutics and imaging agents aims to enhance the accumulation of these molecules in a solid tumor while avoiding uptake in healthy tissues. Tumor-specific accumulation has been pursued with passive targeting by the enhanced permeability and retention effect, as well as with active targeting strategies. Active targeting is achieved by functionalization of carriers to allow specific interactions between the carrier and the tumor environment. Functionalization of carriers with ligands that specifically interact with overexpressed receptors on cancer cells represents a classic approach to active tumor targeting. Cell-penetrating peptides (CPPs) provide a non-specific and receptor-independent mechanism to enhance cellular uptake that offers an exciting alternative to traditional active targeting approaches. While the non-specificity of CPP-mediated internalization has the intriguing potential to make this approach applicable to a wide range of tumor types, their promiscuity is, however, a significant barrier to their clinical utility for systemically administered applications. Many approaches have been investigated to selectively turn on the function of systemically delivered CPP-functionalized carriers specifically in tumors to achieve targeted delivery of cancer therapeutics and imaging agents.

  7. MULTIFUNCTIONAL SYNTHETIC POLY(L-GLUTAMIC ACID)-BASED CANCER THERAPEUTIC AND IMAGING AGENTS

    PubMed Central

    Melancon, Marites P.

    2012-01-01

    Modern polymer chemistry has led to the generation of a number of biocompatible synthetic polymers have been increasingly studied as efficient carriers for drugs and imaging agents. Synthetic biocompatible polymers have been used to improve the efficacy of both small-molecular-weight therapeutics and imaging agents. Furthermore, multiple targeted anticancer agents and/or imaging reporters can be attached to a single polymer chain, allowing multifunctional and/or multimodality therapy and molecular imaging. Having both an anticancer drug and an imaging reporter in a single polymer chain allows noninvasive real-time visualization of the pharmacokinetics of polymeric drug delivery systems, which can uncover and explain the complicated mechanisms of in vivo drug delivery and their correlation to pharmacodynamics. This review examines use of the synthetic biocompatible polymer poly(L-glutamic acid) (PG) as an efficient carrier of cancer therapeutics and imaging agents. This review will summarize and update our recent research on use of PG as a platform for drug delivery and molecular imaging, including recent clinical findings with respect to PG-paclitaxel (PG-TXL); the combination of PG-TXL with radiotherapy; mechanisms of action of PG-TXL; and noninvasive visualization of in vivo delivery of polymeric conjugates with contrast-enhanced magnetic resonance imaging (MRI), optical imaging, and multimodality imaging. PMID:21303613

  8. Activation of ATM by DNA Damaging Agents

    DTIC Science & Technology

    2005-09-01

    serine 139. Pretreatment of cells with NAC partially, peroxide dismutase and glutathione peroxidase - 1 (37). This but significantly, attenuated the... Gy , concentrations of wortmannin (lanes 3-5) for 30 min prior to the addi- 2 h) (Fig. 4A). tion of 1 gm doxorubicin (lanes 2-5) and further incubation...AD Award Number: DAMD17-02- 1 -0318 TITLE: Activation of ATM by DNA Damaging Agents PRINCIPAL INVESTIGATOR: Ebba U. Kurz, Ph.D. Susan P. Lees-Miller

  9. Transferrin receptors and the targeted delivery of therapeutic agents against cancer

    PubMed Central

    Daniels, Tracy R.; Bernabeu, Ezequiel; Rodríguez, José A.; Patel, Shabnum; Kozman, Maggie; Chiappetta, Diego A.; Holler, Eggehard; Ljubimova, Julia Y.; Helguera, Gustavo; Penichet, Manuel L.

    2012-01-01

    Background Traditional cancer therapy can be successful in destroying tumors, but can also cause dangerous side effects. Therefore, many targeted therapies are in development. The transferrin receptor (TfR) functions in cellular iron uptake through its interaction with transferrin. This receptor is an attractive molecule for the targeted therapy of cancer since it is upregulated on the surface of many cancer types and is efficiently internalized. This receptor can be targeted in two ways: 1) for the delivery of therapeutic molecules into malignant cells or 2) to block the natural function of the receptor leading directly to cancer cell death. Scope of review In the present article we discuss the strategies used to target the TfR for the delivery of therapeutic agents into cancer cells. We provide a summary of the vast types of anti-cancer drugs that have been delivered into cancer cells employing a variety of receptor binding molecules including Tf, anti-TfR antibodies, or TfR-binding peptides alone or in combination with carrier molecules including nanoparticles and viruses. Major conclusions Targeting the TfR has been shown to be effective in delivering many different therapeutic agents and causing cytotoxic effects in cancer cells in vitro and in vivo. General significance The extensive use of TfR for targeted therapy attests to the versatility of targeting this receptor for therapeutic purposes against malignant cells. More advances in this area are expected to further improve the therapeutic potential of targeting the TfR for cancer therapy leading to an increase in the number of clinical trials of molecules targeting this receptor. PMID:21851850

  10. Strategies for transformation of naturally-occurring amphibian antimicrobial peptides into therapeutically valuable anti-infective agents.

    PubMed

    Conlon, J Michael; Al-Ghaferi, Nadia; Abraham, Bency; Leprince, Jérôme

    2007-08-01

    The emergence of strains of pathogenic microorganisms with resistance to commonly used antibiotics has necessitated a search for novel types of antimicrobial agents. Many frog species produce amphipathic alpha-helical peptides with broad spectrum antimicrobial activity in the skin but their therapeutic potential is limited by varying degrees of cytolytic activity towards eukaryotic cells. Methods for development of such peptides into anti-infective drugs are illustrated by the example of temporin-1DRa (HFLGTLVNLAK KIL.NH(2)). Studies with model alpha-helical peptides have shown that increase in cationicity promotes antimicrobial activity whereas increases in hydrophobicity, helicity and amphipathicity promote hemolytic activity and loss of selectivity for microorganisms. Analogs of temporin-1DRa in which each amino acid is replaced by L-lysine and D-lysine were synthesized and their cytolytic activities tested against a range of microorganisms and human erythrocytes. Small changes in structure produced marked changes in conformation, as determined by retention time on reversed-phase HPLC, and in biological activity. However, peptides containing the substitutions (Val(7) -->L-Lys), (Thr(5)-->D-Lys) and (Asn(8)-->D-Lys) retained the high solubility and potent, broad spectrum antimicrobial activity of the naturally occurring peptide but were appreciably (up to 10-fold) less hemolytic. In contrast, analogs in which Leu(9) and Ile(13) were replaced by the more hydrophobic cyclohexylglycine residue showed slightly increased antimicrobial potencies (up to 2-fold) but a 4-fold increase in hemolytic activity. The data suggest a strategy of selective increases in cationicity concomitant with decreases in helicity and hydrophobicity in the transformation of naturally-occurring antimicrobial peptides into non-toxic therapeutic agents.

  11. The impact of DeltaG on the oral bioavailability of low bioavailable therapeutic agents.

    PubMed

    Salama, Noha N; Fasano, Alessio; Thakar, Manjusha; Eddington, Natalie D

    2005-01-01

    Low oral bioavailability continues to drive research toward identifying novel approaches to enhance drug delivery. Over the past few years, emphasis on the use of absorption enhancers has been overwhelming despite their major adverse effects. Zonula occludens toxin (Zot) was recently established as a safe and effective absorption enhancer, reversibly opening the tight junctions for hydrophilic markers and hydrophobic drugs across the small intestine and the blood brain barrier. DeltaG, the biologically active fragment of Zot, was isolated and shown to increase the in vitro transport and in vivo absorption of paracellular markers. The objective of this study was to examine the effect of DeltaG on the oral bioavailability of low bioavailable therapeutic agents. Jugular vein cannulated Sprague-Dawley rats were randomly assigned to receive the following treatments intraduodenally (ID): [(3)H]cyclosporin A, [(3)H]ritonavir, [(3)H]saquinavir, or [(3)H]acyclovir at (120 microCi/kg) alone, with protease inhibitors (PIs), or with DeltaG (720 microg/kg)/PI. Serial blood samples were collected, and plasma was analyzed for radioactivity. After ID administration with DeltaG/PI, C(max) significantly (p < 0.05) increased over a range of 197 to 5700%, whereas area under the plasma concentration time curve displayed significant increases extending over a range of 123.8 to 4990.3% for the investigated drugs. DeltaG significantly increased the in vivo oral absorption of some low bioavailable drugs in the presence of PI. This study suggests that DeltaG-mediated tight junction modulation, combined with metabolic protection, may be used to enhance the low oral bioavailability of certain drugs when administered concurrently.

  12. Nanoceria: a rare-earth nanoparticle as a novel anti-angiogenic therapeutic agent in ovarian cancer.

    PubMed

    Giri, Shailendra; Karakoti, Ajay; Graham, Rondell P; Maguire, Jacie L; Reilly, Christopher M; Seal, Sudipta; Rattan, Ramandeep; Shridhar, Viji

    2013-01-01

    Ovarian cancer (OvCa) is the fifth most common cause of death from all cancers among women in United Sates and the leading cause of death from gynecological malignancies. While most OvCa patients initially respond to surgical debulking and chemotherapy, 75% of patients later succumb to the disease. Thus, there is an urgent need to test novel therapeutic agents to counteract the high mortality rate associated with OvCa. In this context, we have developed and engineered Nanoceria (NCe), nanoparticles of cerium oxide, possessing anti-oxidant properties, to be used as a therapeutic agent in OvCa. We show for the first time that NCe significantly inhibited production of reactive oxygen species (ROS) in A2780 cells, attenuated growth factor (SDF1, HB-EGF, VEGF(165) and HGF) mediated cell migration and invasion of SKOV3 cells, without affecting the cell proliferation. NCe treatment also inhibited VEGF(165) induced proliferation, capillary tube formation, activation of VEGFR2 and MMP2 in human umbilical vascular endothelial cells (HUVEC). NCe (0.1 mg/kg body weigh) treatment of A2780 ovarian cancer cells injected intra-peritoneally in nude mice showed significant reduction (p<0.002) in tumor growth accompanied by decreased tumor cell proliferation as evident from reduced tumor size and Ki67 staining. Accumulation of NCe was found in tumors isolated from treated group using transmission electron microscopy (TEM) and inductively coupled plasma mass spectroscopy (ICP-MS). Reduction of the tumor mass was accompanied by attenuation of angiogenesis, as observed by reduced CD31 staining and specific apoptosis of vascular endothelial cells. Collectively, these results indicate that cerium oxide based NCe is a novel nanoparticle that can potentially be used as an anti-angiogenic therapeutic agent in ovarian cancer.

  13. Real-time, aptamer-based tracking of circulating therapeutic agents in living animals

    PubMed Central

    Ferguson, B. Scott; Hoggarth, David A.; Maliniak, Dan; Ploense, Kyle; White, Ryan J.; Woodward, Nick; Hsieh, Kuangwen; Bonham, Andrew J.; Eisenstein, Michael; Kippin, Tod; Plaxco, Kevin W.; Soh, H. Tom

    2014-01-01

    A sensor capable of continuously measuring specific molecules in the bloodstream in vivo would give clinicians a valuable window into patients’ health and their response to therapeutics. Such technology would enable truly personalized medicine, wherein therapeutic agents could be tailored with optimal doses for each patient to maximize efficacy and minimize side effects. Unfortunately, continuous, real-time measurement is currently only possible for a handful of targets, such as glucose, lactose, and oxygen, and the few existing platforms for continuous measurement are not generalizable for the monitoring of other analytes, such as small-molecule therapeutics. In response, we have developed a real-time biosensor capable of continuously tracking a wide range of circulating drugs in living subjects. Our microfluidic electrochemical detector for in vivo continuous monitoring (MEDIC) requires no exogenous reagents, operates at room temperature, and can be reconfigured to measure different target molecules by exchanging probes in a modular manner. To demonstrate the system's versatility, we measured therapeutic in vivo concentrations of doxorubicin (a chemotherapeutic) and kanamycin (an antibiotic) in live rats and in human whole blood for several hours with high sensitivity and specificity at sub-minute temporal resolution. Importantly, we show that MEDIC can also obtain pharmacokineticparameters for individual animals in real-time. Accordingly, just as continuous glucose monitoring technology is currently revolutionizing diabetes care, we believe MEDIC could be a powerful enabler for personalized medicine by ensuring delivery of optimal drug doses for individual patients based on direct detection of physiological parameters. PMID:24285484

  14. Core-shell-type magnetic mesoporous silica nanocomposites for bioimaging and therapeutic agent delivery.

    PubMed

    Wang, Yao; Gu, Hongchen

    2015-01-21

    Advances in nanotechnology and nanomedicine offer great opportunities for the development of nanoscaled theranostic platforms. Among various multifunctional nanocarriers, magnetic mesoporous silica nanocomposites (M-MSNs) attract prominent research interest for their outstanding properties and potential biomedical applications. This Research News article highlights recent progress in the design of core-shell-type M-MSNs for both diagnostic and therapeutic applications. First, an overview of synthetic strategies for three representative core-shell-type M-MSNs with different morphologies and structures is presented. Then, the diagnostic functions of M-MSNs is illustrated for magnetic resonance imaging (MRI) applications. Next, magnetic targeted delivery and stimuli-responsive release of drugs, and effective package of DNA/siRNA inside mesopores using M-MSNs as therapeutic agent carriers are discussed. The article concludes with some important challenges that need to be overcome for further practical applications of M-MSNs in nanomedicine.

  15. Molecular predictors of therapeutic response to specific anti-cancer agents

    DOEpatents

    Spellman, Paul T.; Gray, Joe W.; Sadanandam, Anguraj; Heiser, Laura M.; Gibb, William J.; Kuo, Wen-lin; Wang, Nicholas J.

    2016-11-29

    Herein is described the use of a collection of 50 breast cancer cell lines to match responses to 77 conventional and experimental therapeutic agents with transcriptional, proteomic and genomic subtypes found in primary tumors. Almost all compounds produced strong differential responses across the cell lines produced responses that were associated with transcriptional and proteomic subtypes and produced responses that were associated with recurrent genome copy number abnormalities. These associations can now be incorporated into clinical trials that test subtype markers and clinical responses simultaneously.

  16. Spherical Nucleic Acids as Intracellular Agents for Nucleic Acid Based Therapeutics

    NASA Astrophysics Data System (ADS)

    Hao, Liangliang

    Recent functional discoveries on the noncoding sequences of human genome and transcriptome could lead to revolutionary treatment modalities because the noncoding RNAs (ncRNAs) can be applied as therapeutic agents to manipulate disease-causing genes. To date few nucleic acid-based therapeutics have been translated into the clinic due to challenges in the delivery of the oligonucleotide agents in an effective, cell specific, and non-toxic fashion. Unmodified oligonucleotide agents are destroyed rapidly in biological fluids by enzymatic degradation and have difficulty crossing the plasma membrane without the aid of transfection reagents, which often cause inflammatory, cytotoxic, or immunogenic side effects. Spherical nucleic acids (SNAs), nanoparticles consisting of densely organized and highly oriented oligonucleotides, pose one possible solution to circumventing these problems in both the antisense and RNA interference (RNAi) pathways. The unique three dimensional architecture of SNAs protects the bioactive oligonucleotides from unspecific degradation during delivery and supports their targeting of class A scavenger receptors and endocytosis via a lipid-raft-dependent, caveolae-mediated pathway. Owing to their unique structure, SNAs are able to cross cell membranes and regulate target genes expression as a single entity, without triggering the cellular innate immune response. Herein, my thesis has focused on understanding the interactions between SNAs and cellular components and developing SNA-based nanostructures to improve therapeutic capabilities. Specifically, I developed a novel SNA-based, nanoscale agent for delivery of therapeutic oligonucleotides to manipulate microRNAs (miRNAs), the endogenous post-transcriptional gene regulators. I investigated the role of SNAs involving miRNAs in anti-cancer or anti-inflammation responses in cells and in in vivo murine disease models via systemic injection. Furthermore, I explored using different strategies to construct

  17. Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells

    NASA Astrophysics Data System (ADS)

    Geninatti Crich, S.; Cadenazzi, M.; Lanzardo, S.; Conti, L.; Ruiu, R.; Alberti, D.; Cavallo, F.; Cutrin, J. C.; Aime, S.

    2015-04-01

    In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation.In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation. Electronic supplementary information (ESI) available: Competition studies with free apoferritin, Fig. S1; APO-FITC intracellular distribution by

  18. Is there potential for therapeutic drug monitoring of biologic agents in rheumatoid arthritis?

    PubMed

    Bastida, Carla; Ruíz, Virginia; Pascal, Mariona; Yagüe, Jordi; Sanmartí, Raimon; Soy, Dolors

    2016-12-19

    The use of biologics has significantly changed the management of rheumatoid arthritis over the last decade, becoming the cornerstone treatment for many patients. The current therapeutic arsenal consists of just under 10 biologic agents, with four different mechanisms of action. Several studies have demonstrated a large interindividual pharmacokinetic variability, which translates to unpredictability in clinical response among individuals. The present review focuses on the pharmacokinetics and pharmacodynamics of biologic agents approved for rheumatoid arthritis. The literature relating to their concentration-effect relationship and the use of pharmacokinetic-pharmacodynamic modelling to optimize drug regimens is analysed. Due to the scarcity and complexity of these studies, the current dosing strategy is based on clinical indexes/aspects. In general, dose individualization for biologics should be implemented increasingly in clinical practice as there is a direct benefit for treated rheumatoid arthritis patients. Moreover, there is an indirect benefit in terms of cost-effectiveness.

  19. 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

    2016-06-17

    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.

  20. Silibinin, Dexamethasone, and Doxycycline as Potential Therapeutic Agents for Treating Vesicant-Inflicted Ocular Injuries

    PubMed Central

    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

    2014-01-01

    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. PMID:22841772

  1. 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

  2. Poly-S-Nitrosated Albumin as a Safe and Effective Multifunctional Antitumor Agent: Characterization, Biochemistry and Possible Future Therapeutic Applications

    PubMed Central

    Ishima, Yu; Kragh-Hansen, Ulrich; Maruyama, Toru; Otagiri, Masaki

    2013-01-01

    Nitric oxide (NO) is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated human serum albumin (Mono-SNO-HSA), and that is why we are testing whether this albumin form can be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA) which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA possesses very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In this review, we forward the possibility that Poly-SNO-HSA can be used as a safe and effective multifunctional antitumor agent. PMID:24490156

  3. 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

  4. L-Ferritin targets breast cancer stem cells and delivers therapeutic and imaging agents

    PubMed Central

    Ruiu, Roberto; Cadenazzi, Marta; Cavallo, Federica; Aime, Silvio; Crich, Simonetta Geninatti

    2016-01-01

    A growing body of evidence suggests that cancer stem cells (CSC) have the unique biological properties necessary for tumor maintenance and spreading, and function as a reservoir for the relapse and metastatic evolution of the disease by virtue of their resistance to radio- and chemo-therapies. Thus, the efficacy of a therapeutic approach relies on its ability to effectively target and deplete CSC. In this study, we show that CSC-enriched tumorspheres from breast cancer cell lines display an increased L-Ferritin uptake capability compared to their monolayer counterparts as a consequence of the upregulation of the L-Ferritin receptor SCARA5. L-Ferritin internalization was exploited for the simultaneous delivery of Curcumin, a natural therapeutic molecule endowed with antineoplastic action, and the MRI contrast agent Gd-HPDO3A, both entrapped in the L-Ferritin cavity. This theranostic system was able to impair viability and self-renewal of tumorspheres in vitro and to induce the regression of established tumors in mice. In conclusion, here we show that Curcumin-loaded L-Ferritin has a strong therapeutic potential due to the specific targeting of CSC and the improved Curcumin bioavailability, opening up the possibility of its use in a clinical setting. PMID:27579532

  5. Cosmetic Preservatives as Therapeutic Corneal and Scleral Tissue Cross-Linking Agents

    PubMed Central

    Babar, Natasha; Kim, MiJung; Cao, Kerry; Shimizu, Yukari; Kim, Su-Young; Takaoka, Anna; Trokel, Stephen L.; Paik, David C.

    2015-01-01

    Purpose. Previously, aliphatic β-nitroalcohols (BNAs) have been studied as a means to chemically induce tissue cross-linking (TXL) of cornea and sclera. There are a number of related and possibly more potent agents, known as formaldehyde releasers (FARs), that are in commercial use as preservatives in cosmetics and other personal care products. The present study was undertaken in order to screen such compounds for potential clinical utility as therapeutic TXL agents. Methods. A chemical registry of 62 FARs was created from a literature review and included characteristics relevant to TXL such as molecular weight, carcinogenicity/mutagenicity, toxicity, hydrophobicity, and commercial availability. From this registry, five compounds [diazolidinyl urea (DAU), imidazolidinyl urea (IMU), sodium hydroxymethylglycinate (SMG), DMDM hydantoin (DMDM), 5-Ethyl-3,7-dioxa-1-azabicyclo [3.3.0] octane (OCT)] were selected for efficacy screening using two independent systems, an ex vivo rabbit corneal cross-linking simulation setup and incubation of cut scleral tissue pieces. Treatments were conducted at pH 7.4 or 8.5 for 30 minutes. Efficacy was evaluated using thermal denaturation temperature (Tm), and cell toxicity was studied using the trypan blue exclusion method. Results. Cross-linking effects in the five selected FARs were pH and concentration dependent. Overall, the Tm shifts were in agreement with both cornea and sclera. By comparison with BNAs previously reported upon, the FARs identified in this study were significantly more potent but with similar or better cytotoxicity. Conclusions. The FARs, a class of compounds well known to the cosmetic industry, may have utility as therapeutic TXL agents. The compounds studied thus far show promise and will be further tested. PMID:25634979

  6. THIOCYANATE: A potentially useful therapeutic agent with host defense and antioxidant properties✩

    PubMed Central

    Chandler, Joshua D.; Day, Brian J.

    2014-01-01

    Thiocyanate (SCN) functions in host defense as part of the secreted lactoperoxidase (LPO) microbicidal pathway. SCN is the preferred substrate for LPO-driven catalytic reduction of hydrogen peroxide (H2O2) forming hypothiocyanous acid (HOSCN). HOSCN is selectively generated by many peroxidase enzymes that can utilize SCN including: eosinophil peroxidase (EPO), gastric peroxidase (GPO), myeloperoxidase (MPO), salivary peroxidase (SPO), and thyroid peroxidase (TPO). These enzymes generate HOSCN through a two-electron halogenation reaction. HOSCN is a potent microbicidal agent that kills or nullifies invading pathogens but is better tolerated by host tissue. Some controversy exists as to whether physiologic levels of HOSCN are non-toxic to host tissue, but the disagreement appears to be based on results of enzymatic generation (yielding moderate steady-state exposure) versus direct high level acute exposure in mammalian cell lines. This apparent duality is also true of other endogenous oxidants such as hydrogen peroxide and relates to the difference between physiologically relevant oxidant production versus supra-physiologic bolus dosing approaches. SCN has antioxidant properties that include the ability to protect cells against oxidizing agents such as hypochlorous acid (HOCl) and repair protein chloramines. SCN is an important endogenous molecule that has the potential to interact in complex and elegant ways with its host environment and foreign organisms. SCN’s diverse properties as both host defense and antioxidant agent make it a potentially useful therapeutic. PMID:22968041

  7. Therapeutic potential of the chemokine receptor CXCR4 antagonists as multifunctional agents.

    PubMed

    Tsutsumi, Hiroshi; Tanaka, Tomohiro; Ohashi, Nami; Masuno, Hiroyuki; Tamamura, Hirokazu; Hiramatsu, Kenichi; Araki, Takanobu; Ueda, Satoshi; Oishi, Shinya; Fujii, Nobutaka

    2007-01-01

    The chemokine receptor CXCR4 possesses multiple critical functions in normal and pathologic physiology. CXCR4 is a G-protein-coupled receptor that transduces signals of its endogenous ligand, the chemokine CXCL12 (stromal cell-derived factor-1, SDF-1). The interaction between CXCL12 and CXCR4 plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems, and so on. This interaction is also known to be involved in several intractable disease processes, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA), and pulmonary fibrosis. It is conjectured that this interaction may be a critical therapeutic target in all of these diseases, and several CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogues, were previously developed in our laboratory as specific CXCR4 antagonists that were identified as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents, and anti-RA agents. Cyclic pentapeptides, such as FC131 [cyclo(D-Tyr-Arg-Arg-L-3-(2-naphthyl)alanine-Gly)], were also previously found as CXCR4 antagonist leads based on pharmacophores of T140. This review article describes the elucidation of multiple functions of CXCR4 antagonists and the development of a number of low-molecular weight CXCR4 antagonists involving FC131 analogues and other compounds with different scaffolds including linear-type structures.

  8. Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

    PubMed Central

    Inamdar, Arati A.; Goy, Andre; Ayoub, Nehad M.; Attia, Christen; Oton, Lucia; Taruvai, Varun; Costales, Mark; Lin, Yu-Ting; Pecora, Andrew; Suh, Stephen K.

    2016-01-01

    Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL. PMID:27119356

  9. Biological Activity of Coumarin Derivatives as Anti-Leishmanial Agents

    PubMed Central

    Mandlik, Vineetha; Patil, Sohan; Bopanna, Ramanamurthy; Basu, Sudipta; Singh, Shailza

    2016-01-01

    Cutaneous leishmaniasis affects nearly 0.7 to 1.3 million people annually. Treatment of this disease is difficult due to lack of appropriate medication and the growing problem of drug resistance. Natural compounds such as coumarins serve as complementary therapeutic agents in addition to the current treatment modalities. In this study, we have performed an in-silico screening of the coumarin derivatives and their anti-leishmanial properties has been explored both in-vitro and in-vivo. One of the compounds (compound 2) exhibited leishmanicidal activity and to further study its properties, nanoliposomal formulation of the compound was developed. Treatment of cutaneous lesions in BALB/c mice with compound 2 showed significantly reduced lesion size as compared to the untreated mice (p<0.05) suggesting that compound 2 may possess anti-leishmanial properties. PMID:27768694

  10. Laboratory activities involving transmissible spongiform encephalopathy causing agents

    PubMed Central

    Leunda, Amaya; Van Vaerenbergh, Bernadette; Baldo, Aline; Roels, Stefan; Herman, Philippe

    2013-01-01

    Since the appearance in 1986 of epidemic of bovine spongiform encephalopathy (BSE), a new form of neurological disease in cattle which also affected human beings, many diagnostic and research activities have been performed to develop detection and therapeutic tools. A lot of progress was made in better identifying, understanding and controlling the spread of the disease by appropriate monitoring and control programs in European countries. This paper reviews the recent knowledge on pathogenesis, transmission and persistence outside the host of prion, the causative agent of transmissible spongiform encephalopathies (TSE) in mammals with a particular focus on risk (re)assessment and management of biosafety measures to be implemented in diagnostic and research laboratories in Belgium. Also, in response to the need of an increasing number of European diagnostic laboratories stopping TSE diagnosis due to a decreasing number of TSE cases reported in the last years, decontamination procedures and a protocol for decommissioning TSE diagnostic laboratories is proposed. PMID:24055928

  11. The emerging role of nitrite as an endogenous modulator and therapeutic agent of cardiovascular function.

    PubMed

    Tota, B; Quintieri, A M; Angelone, T

    2010-01-01

    Recently, the circulating anion nitrite (NO2-), the largest physiological reservoir of nitric oxide (NO) in the body, has revealed itself as a signalling molecule mediating numerous biological responses. Since it was estimated that as much as 70% of plasma nitrite originates from nitric oxide synthases (NOSs), mainly in the endothelium by endothelial NOS, nitrite is considered an index of NOSs activity. Exogenous sources, principally environmental pollutants and intake of vegetables, also contribute to this NO reserve. In mammalian blood, nitrite, present at nanomolar concentrations, can be reduced to bioactive NO along a physiological oxygen and pH gradient either non-enzymatically (acidic disproportionation) or by a number of enzymes including xanthine oxidoreductase, NOS, mitochondrial cytochromes and deoxygenated haemoglobin and myoglobin. The various NO-dependent nitrite-induced biological responses include hypoxic vasodilation, inhibition of mitochondrial respiration, cytoprotection following ischemia/reperfusion, and regulation of protein and gene expression. Since NO is a major paracrine-autocrine cardiovascular modulator and nitrite acts mainly as an endocrine store of NO, it is not surprising that NO2 - exerts important cardiovascular actions both under normal and physio-pathological conditions. In the interdisciplinary framework of the NO cycle concept, this review illustrates the actions exerted by nitrite on the cardiovascular system. Since the majority of the NO2 - -oriented studies focused on the systemic and regional control of blood flow both under physiological and ischemia/reperfusion conditions, we will firstly consider this issue. Secondly, the nitrite- induced effects on myocardial contractile and relaxation processes will be discussed, emphasizing the biomedical interest of nitrite as a new therapeutic agent. The importance of cardiac myoglobin as nitrite-reductase able to exert cardioprotection through a novel function, in addition to its

  12. The effects of physical therapeutic agents on serum levels of stress hormones in patients with osteoarthritis

    PubMed Central

    Tönük, Şükrü Burak; Serin, Erdinc; Ayhan, Fikriye Figen; Yorgancioglu, Zeynep Rezan

    2016-01-01

    Abstract To investigate the effects of physical agents on the levels of stress hormones in patients with osteoarthritis (OA). Transcutaneous electrical nerve stimulation, hot packs, and therapeutic ultrasound were applied to the lumbar region and knees of patients with OA. Blood samples were taken for the measurement of the serum levels of glucose, insulin (INS), growth hormone (GH), prolactin (PRL), cortisol (COR), and plasma adrenocorticotropic hormone (ACTH) immediately before and after the 1st session, to investigate the acute effects of those physical agents on the endocrine system. The hormone levels were also measured every 5 sessions in a total of 10 sessions. The treatment response was also evaluated by using the visual analogue scale (VAS), Roland Morris Disability Questionnaire (RMDQ), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) throughout the therapy period. After the 1st session, there was a decrease in INS levels and a mild decrease in PRL levels (P = 0.001 and P < 0.05, respectively). Throughout the 10-session therapy period, the INS levels increased, whereas the ACTH and COR levels decreased (P < 0.05 for all). The VAS-spine, RMDQ, VAS-knee, and WOMAC scores decreased (P = 0.001 for VAS-spine and P < 0.001 for all others). A positive correlation was detected between the changes in serum COR and WOMAC-pain score (P < 0.05). Although the combination therapy caused changes in INS level accompanied with steady glucose levels, the application of physical agents did not adversely affect the hormone levels. The decrease in ACTH and COR levels may be attributed to the analgesic effect of agents and may be an indicator of patient comfort through a central action. PMID:27583888

  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. Pancreatic Cancer Therapy Review: from classic therapeutic agents to modern nanotechnologies.

    PubMed

    Rebelo, Ana; Molpeceres, Jesús; Rijo, Patrícia; Reis, Catarina Pinto

    2017-02-01

    Pancreatic cancer remains one of the most lethal cancers worldwide, with an extremely poor prognosis. This cancer is considered the 5th leading cause of cancer related death. The median survival after diagnosis is generally 2-8 months and five-year survival rate is less than 5%. In recent years, nanotechnology is emerging as a rising approach for drug delivery since it has opened up new landscapes in medicine through introduction of smart nanocarrier systems that can selectively deliver the therapeutic agent in a specific region and in appropriate levels, reducing the adverse side effects. This review covers the main delivery systems developed so far for anticancer drug delivery to the pancreas over a period of 20 years, from polymeric to lipidic-based nanosystems, with a particular emphasis on albumin as core material.

  15. Near Infrared Resonant Gold / Gold Sulfide Nanoparticles as a Photothermal Cancer Therapeutic Agent

    PubMed Central

    Gobin, André M.; Watkins, Emily M.; Quevedo, Elizabeth; Colvin, Vicki L.; West, Jennifer L.

    2010-01-01

    The development and optimization of near-infrared (nIR) absorbing nanoparticles for use as photothermal cancer therapeutic agents has been ongoing. We have previously reported on larger layered gold / silica nanoshells (~140 nm) for combined therapy and imaging applications. This work exploits the properties of smaller gold / gold sulfide (GGS) nIR absorbing nanoparticles (~35–55 nm) that provide higher absorption (98% absorption & 2% scattering for GGS versus 70% absorption & 30% scattering for gold/silica nanoshells) as well as potentially better tumor penetration. In this work we demonstrate ability to ablate tumor cells in vitro, and efficacy for photothermal cancer therapy, where in an in vivo model we show significantly increased long-term, tumor-free survival. Further, enhanced circulation and bio-distribution is observed in vivo. This class of nIR absorbing nanoparticles has potential to improve upon photothermal tumor ablation for cancer therapy. PMID:20183810

  16. Tumor spheroid-based migration assays for evaluation of therapeutic agents.

    PubMed

    Vinci, Maria; Box, Carol; Zimmermann, Miriam; Eccles, Suzanne A

    2013-01-01

    Cell migration is a key hallmark of malignant cells that contributes to the progression of cancers from a primary, localized mass to an invasive and/or metastatic phenotype. Traditional methods for the evaluation of tumor cell migration in vitro generally employ two-dimensional (2D), homogeneous cultures that do not take into account tumor heterogeneity, three-dimensional (3D) cell-cell contacts between tumor and/or host cells or interactions with extracellular matrix proteins. Here we describe a 3D tumor spheroid-based migration assay which more accurately reflects the solid tumor microenvironment and can accommodate both extracellular matrix and host cell interactions. It is a rapid and highly reproducible 96-well plate-based technique and we demonstrate its utility for the evaluation of therapeutic agents/drugs with anti-migratory properties.

  17. Oxidative stress and Alzheimer's disease: dietary polyphenols as potential therapeutic agents.

    PubMed

    Darvesh, Altaf S; Carroll, Richard T; Bishayee, Anupam; Geldenhuys, Werner J; Van der Schyf, Cornelis J

    2010-05-01

    Oxidative stress has been strongly implicated in the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). In recent years, antioxidants - especially those of dietary origin - have been suggested as possible agents useful for the prevention and treatment of AD. This article reviews the role of oxidative stress and the contribution of free radicals in the development of AD, and also discusses the use of antioxidants as a therapeutic strategy in the amelioration of this illness. The antioxidant potential of polyphenolic compounds obtained from dietary sources, such as anthocyanins from berries, catechins and theaflavins from tea, curcumin from turmeric, resveratrol from grapes and peanuts, the dihydrochalcones aspalathin and nothofagin from rooibos and the xanthone mangiferin from honeybush, are discussed in this review. The neuroprotective effects of these phytochemicals in preclinical models of AD are highlighted. Finally, innovative concepts, novel hypotheses, current challenges and future directions in the use of dietary polyphenols for the treatment of AD are discussed.

  18. Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies

    PubMed Central

    Zhang, Qingchun; Jin, Bo; Shi, Zhaotao; Wang, Xiaofang; Liu, Qiangqiang; Lei, Shan; Peng, Rufang

    2016-01-01

    A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents. PMID:27671769

  19. Lipid-based cochleates: a promising formulation platform for oral and parenteral delivery of therapeutic agents.

    PubMed

    Rao, Ravi; Squillante, Emilio; Kim, Kwon H

    2007-01-01

    Cochleates are lipid-based supramolecular assemblies that display great potential as delivery systems for systemic delivery of drugs, including peptides, proteins, vaccines, oligonucleotides, and genes. This is mainly attributed to their high stability and biocompatibility and their ability to deliver both hydrophilic and lipophilic drugs. Cochleates have a unique multilayered spiral structure, which is composed of a negatively charged phospholipid and a divalent cation, and can encapsulate diverse drug molecules of various shapes and sizes while minimizing toxicity associated with polymeric materials present in micro- and nanoparticle systems. This review describes current technological advances in the preparation methods, physicochemical characterization, and potential applications of cochleates as a drug delivery system for systemic delivery of various types of therapeutic agents.

  20. Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies

    NASA Astrophysics Data System (ADS)

    Zhang, Qingchun; Jin, Bo; Shi, Zhaotao; Wang, Xiaofang; Liu, Qiangqiang; Lei, Shan; Peng, Rufang

    2016-09-01

    A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents.

  1. Antiendotoxin activity of cationic peptide antimicrobial agents.

    PubMed

    Gough, M; Hancock, R E; Kelly, N M

    1996-12-01

    The endotoxin from gram-negative bacteria consists of a molecule lipopolysaccharide (LPS) which can be shed by bacteria during antimicrobial therapy. A resulting syndrome, endotoxic shock, is a leading cause of death in the developed world. Thus, there is great interest in the development of antimicrobial agents which can reverse rather than promote sepsis, especially given the recent disappointing clinical performance of antiendotoxin therapies. We describe here two small cationic peptides, MBI-27 and MBI-28, which have both antiendotoxic and antibacterial activities in vitro and in vivo in animal models. We had previously demonstrated that these peptides bind to LPS with an affinity equivalent to that of polymyxin B. Consistent with this, the peptides blocked the ability of LPS and intact cells to induce the endotoxic shock mediator, tumor necrosis factor (TNF), upon incubation with the RAW 264.7 murine macrophage cell line. MBI-28 was equivalent to polymyxin B in its ability to block LPS induction of TNF by this cell line, even when added 60 min after the TNF stimulus. Furthermore, MBI-28 offered significant protection in a galactosamine-sensitized mouse model of lethal endotoxic shock. This protection correlated with the ability of MBI-28 to reduce LPS-induced circulating TNF by nearly 90% in this mouse model. Both MBI-27 and MBI-28 demonstrated antibacterial activity against gram-negative bacteria in vitro and in vivo against Pseudomonas aeruginosa infections in neutropenic mice.

  2. Antiendotoxin activity of cationic peptide antimicrobial agents.

    PubMed Central

    Gough, M; Hancock, R E; Kelly, N M

    1996-01-01

    The endotoxin from gram-negative bacteria consists of a molecule lipopolysaccharide (LPS) which can be shed by bacteria during antimicrobial therapy. A resulting syndrome, endotoxic shock, is a leading cause of death in the developed world. Thus, there is great interest in the development of antimicrobial agents which can reverse rather than promote sepsis, especially given the recent disappointing clinical performance of antiendotoxin therapies. We describe here two small cationic peptides, MBI-27 and MBI-28, which have both antiendotoxic and antibacterial activities in vitro and in vivo in animal models. We had previously demonstrated that these peptides bind to LPS with an affinity equivalent to that of polymyxin B. Consistent with this, the peptides blocked the ability of LPS and intact cells to induce the endotoxic shock mediator, tumor necrosis factor (TNF), upon incubation with the RAW 264.7 murine macrophage cell line. MBI-28 was equivalent to polymyxin B in its ability to block LPS induction of TNF by this cell line, even when added 60 min after the TNF stimulus. Furthermore, MBI-28 offered significant protection in a galactosamine-sensitized mouse model of lethal endotoxic shock. This protection correlated with the ability of MBI-28 to reduce LPS-induced circulating TNF by nearly 90% in this mouse model. Both MBI-27 and MBI-28 demonstrated antibacterial activity against gram-negative bacteria in vitro and in vivo against Pseudomonas aeruginosa infections in neutropenic mice. PMID:8945527

  3. Hepcidin as a predictive factor and therapeutic target in erythropoiesis-stimulating agent treatment for anemia of chronic disease in rats.

    PubMed

    Theurl, Milan; Nairz, Manfred; Schroll, Andrea; Sonnweber, Thomas; Asshoff, Malte; Haschka, David; Seifert, Markus; Willenbacher, Wolfgang; Wilflingseder, Doris; Posch, Wilfried; Murphy, Anthony T; Witcher, Derrick R; Theurl, Igor; Weiss, Günter

    2014-09-01

    Anemia of chronic disease is a multifactorial disorder, resulting mainly from inflammation-driven reticuloendothelial iron retention, impaired erythropoiesis, and reduced biological activity of erythropoietin. Erythropoiesis-stimulating agents have been used for the treatment of anemia of chronic disease, although with varying response rates and potential adverse effects. Serum concentrations of hepcidin, a key regulator of iron homeostasis, are increased in patients with anemia of chronic disease and linked to the pathogenesis of this disease, because hepcidin blocks cellular iron egress, thus limiting availability of iron for erythropoiesis. We tested whether serum hepcidin levels can predict and affect the therapeutic efficacy of erythropoiesis-stimulating agent treatment using a well-established rat model of anemia of chronic disease. We found that high pre-treatment hepcidin levels correlated with an impaired hematologic response to an erythropoiesis-stimulating agent in rats with anemia of chronic disease. Combined treatment with an erythropoiesis-stimulating agent and an inhibitor of hepcidin expression, LDN-193189, significantly reduced serum hepcidin levels, mobilized iron from tissue stores, increased serum iron levels and improved hemoglobin levels more effectively than did the erythropoiesis-stimulating agent or LDN-193189 monotherapy. In parallel, both the erythropoiesis-stimulating agent and erythropoiesis-stimulating agent/LDN-193189 combined reduced the expression of cytokines known to inhibit erythropoiesis. We conclude that serum hepcidin levels can predict the hematologic responsiveness to erythropoiesis-stimulating agent therapy in anemia of chronic disease. Pharmacological inhibition of hepcidin formation improves the erythropoiesis-stimulating agent's therapeutic efficacy, which may favor a reduction of erythropoiesis-stimulating agent dosages, costs and side effects.

  4. The adsorption of sympathomimetic agents by activated carbon hemoperfusion.

    PubMed

    Horres, C R; Hill, J B; Ellis, F W

    1976-01-01

    Sympathomimetic agents with mixed and pure alpha and beta adrenergic activity are adsorbed by coconut shell activated carbon from blood, sufficiently rapidly to markedly reduce the activity of these agents. The results of this study suggest that the site of injection of sympathomimetic agents being considered for correcting hypotension during activated carbon hemoperfusion be selected to permit systemic mixing before circulation into the adsorption device.

  5. Application of disposable bag bioreactors in tissue engineering and for the production of therapeutic agents.

    PubMed

    Eibl, R; Eibl, D

    2009-01-01

    In order to increase process efficiency, many pharmaceutical and biotechnology companies have introduced disposable bag technology over the last 10 years. Because this technology also greatly reduces the risk of cross-contamination, disposable bags are preferred in applications in which an absolute or improved process safety is a necessity, namely the production of functional tissue for implantation (tissue engineering), the production of human cells for the treatment of cancer and immune system diseases (cellular therapy), the production of viruses for gene therapies, the production of therapeutic proteins, and veterinary as well as human vaccines.Bioreactors with a pre-sterile cultivation bag made of plastic material are currently used in both development and manufacturing processes primarily operating with animal and human cells at small- and middle-volume scale. Because of their scalability, hydrodynamic expertise and the convincing results of oxygen transport efficiency studies, wave-mixed bioreactors are the most used, together with stirred bag bioreactors and static bags, which have the longest tradition.Starting with a general overview of disposable bag bioreactors and their main applications, this chapter summarizes the working principles and engineering aspects of bag bioreactors suitable for cell expansion, formation of functional tissue and production of therapeutic agents. Furthermore, results from selected cultivation studies are presented and discussed.

  6. Lipopeptides as the Antifungal and Antibacterial Agents: Applications in Food Safety and Therapeutics

    PubMed Central

    Meena, Khem Raj; Kanwar, Shamsher S.

    2015-01-01

    A lot of crops are destroyed by the phytopathogens such as fungi, bacteria, and yeast leading to economic losses to the farmers. Members of the Bacillus genus are considered as the factories for the production of biologically active molecules that are potential inhibitors of growth of phytopathogens. Plant diseases constitute an emerging threat to global food security. Many of the currently available antimicrobial agents for agriculture are highly toxic and nonbiodegradable and thus cause extended environmental pollution. Moreover, an increasing number of phytopathogens have developed resistance to antimicrobial agents. The lipopeptides have been tried as potent versatile weapons to deal with a variety of phytopathogens. All the three families of Bacillus lipopeptides, namely, Surfactins, Iturins and Fengycins, have been explored for their antagonistic activities towards a wide range of phytopathogens including bacteria, fungi, and oomycetes. Iturin and Fengycin have antifungal activities, while Surfactin has broad range of potent antibacterial activities and this has also been used as larvicidal agent. Interestingly, lipopeptides being the molecules of biological origin are environmentally acceptable. PMID:25632392

  7. Ultrananocrystalline diamond thin films functionalized with therapeutically active collagen networks.

    SciTech Connect

    Huang, H.; Chen, M.; Bruno, P.; Lam, R.; Robinson, E.; Gruen, D.; Ho, D.; Materials Science Division; Northwestern Univ.

    2009-01-01

    The fabrication of biologically amenable interfaces in medicine bridges translational technologies with their surrounding biological environment. Functionalized nanomaterials catalyze this coalescence through the creation of biomimetic and active substrates upon which a spectrum of therapeutic elements can be delivered to adherent cells to address biomolecular processes in cancer, inflammation, etc. Here, we demonstrate the robust functionalization of ultrananocrystalline diamond (UNCD) with type I collagen and dexamethasone (Dex), an anti-inflammatory drug, to fabricate a hybrid therapeutically active substrate for localized drug delivery. UNCD oxidation coupled with a pH-mediated collagen adsorption process generated a comprehensive interface between the two materials, and subsequent Dex integration, activity, and elution were confirmed through inflammatory gene expression assays. These studies confer a translational relevance to the biofunctionalized UNCD in its role as an active therapeutic network for potent regulation of cellular activity toward applications in nanomedicine.

  8. Is pimecrolimus cream (1%) an appropriate therapeutic agent for the treatment of external ear atopic dermatitis?

    PubMed Central

    Beriat, Güçlü Kaan; Akmansu, Şefik Halit; Doğan, Cem; Taştan, Eren; Topal, Ferda; Sabuncuoğlu, Bizden

    2012-01-01

    Summary Background In recent years, pimecrolimus 1% cream has been demonstrated to reduce symptoms of atopic dermatitis in patients when applied topically. Material/Methods In our study we compared the therapeutic effects of local 1% pimecrolimus to 1% hydrocortisone, and to a control group in a mouse model with atopic dermatitis in the external ear canals. Atopic dermatitis was created by application of Dinitrochlorobenzene in the external ear canals of mice. The development of atopic dermatitis was detected by clinical observation score and determination of total serum IgE levels. Pimecrolimus and hydrocortisone cream were topically applied to the external ear canal skin once a day for 14 days. Results There was no significant difference between the hydrocortisone and the pimecrolimus therapy groups, while there was a statistically significant difference between these 2 groups and the control group (p<0.05) Assessment of the clinical observation scoring carried out on the 14th day of therapy revealed that there was no difference between the hydrocortisone and pimecrolimus groups. Biopsies were taken on the 14th day following treatment. Tissue samples were histologically evaluated; contact dermatitis was observed microscopically in the control group, but in the therapy groups only minimal evidence of contact dermatitis was found. Conclusions The results of our study reveal that the therapeutic efficacy of 1% pimecrolimus was equivalent to 1% hydrocortisone treatment in the artificially developed atopic dermatitis model in external ear canals of mice. These results clearly demonstrate that 1% pimecrolimus cream can be an effective alternative therapeutic agent in cases where steroid treatment proves to be insufficient or in cases where treatment must be discontinued due to its adverse effects. PMID:22460087

  9. BK channel activators and their therapeutic perspectives

    PubMed Central

    Bentzen, Bo H.; Olesen, Søren-Peter; Rønn, Lars C. B.; Grunnet, Morten

    2014-01-01

    The large conductance calcium- and voltage-activated K+ channel (KCa1.1, BK, MaxiK) is ubiquitously expressed in the body, and holds the ability to integrate changes in intracellular calcium and membrane potential. This makes the BK channel an important negative feedback system linking increases in intracellular calcium to outward hyperpolarizing potassium currents. Consequently, the channel has many important physiological roles including regulation of smooth muscle tone, neurotransmitter release and neuronal excitability. Additionally, cardioprotective roles have been revealed in recent years. After a short introduction to the structure, function and regulation of BK channels, we review the small organic molecules activating BK channels and how these tool compounds have helped delineate the roles of BK channels in health and disease. PMID:25346695

  10. Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis.

    PubMed

    Yamada, Masahito; Ono, Kenjiro; Hamaguchi, Tsuyoshi; Noguchi-Shinohara, Moeko

    2015-01-01

    Epidemiological studies have suggested that diets rich in phenolic compounds may have preventive effects on the development of dementia or Alzheimer's disease (AD). We investigated the effects of natural phenolic compounds, such as myricetin (Myr), rosmarinic acid (RA), ferulic acid (FA), curcumin (Cur) and nordihydroguaiaretic acid (NDGA) on the aggregation of amyloid β-protein (Aβ), using in vitro and in vivo models of cerebral Aβ amyloidosis. The in vitro studies revealed that these phenolic compounds efficiently inhibit oligomerization as well as fibril formation of Aβ through differential binding, whilst reducing Aβ oligomer-induced synaptic and neuronal toxicity. Furthermore, a transgenic mouse model fed orally with such phenolic compounds showed significant reduction of soluble Aβ oligomers as well as of insoluble Aβ deposition in the brain. These data, together with an updated review of the literature, indicate that natural phenolic compounds have anti-amyloidogenic effects on Aβ in addition to well-known anti-oxidative and anti-inflammatory effects, hence suggesting their potential as therapeutic and/or preventive agents for cerebral Aβ amyloidosis, including AD and cerebral amyloid angiopathy (CAA). Well-designed clinical trials or preventive interventions with natural phenolic compounds are necessary to establish their efficacy as disease-modifying agents.

  11. Effects of Potential Therapeutic Agents on Copper Accumulations in Gill of Crassostrea virginica

    PubMed Central

    Luxama, Juan D.; Carroll, Margaret A.; Catapane, Edward J.

    2010-01-01

    Copper is an essential trace element for organisms, but when in excess, copper’s redox potential enhances oxyradical formation and increases cellular oxidative stress. Copper is a major pollutant in Jamaica Bay and other aquatic areas. Bivalves are filter feeders that accumulate heavy metals and other pollutants from their environment. Previously it was determined that seed from the bivalve Crassostrea virginica, transplanted from an oyster farm to Jamaica Bay readily accumulated copper and other pollutants into their tissues. In the present study we utilized Atomic Absorption Spectrometry to measure the uptake of copper into C. virginica gill in the presence and absence of three potential copper -blocking agents: diltiazem, lanthanum, and p-aminosalicyclic acid. Diltiazem and lanthanum are known calcium-channel blockers and p-aminosalicylic acid is an anti-infammarory agent with possible metal chelating properties. We also used the DMAB-Rhodanine histochemistry staining technique to confirm that copper was entering gill cells. Our result showed that diltiazem and p-aminosalicyclic acid reduced copper accumulations in the gill, while lanthanum did not. DMAB-Rhodanine histochemistry showed enhanced cellular copper staining in copper-treated samples and further demonstrated that diltiazem was able to reduce copper uptake. The accumulation of copper into oyster gill and its potential toxic effects could be of physiological significance to the growth and long term health of oysters and other marine animals living in a copper polluted environment. Identifying agents that block cellular copper uptake will further the understanding of metal transport mechanisms and may be beneficial in the therapeutic treatment of copper toxicity in humans. PMID:21841975

  12. Exploring DNA topoisomerases as targets of novel therapeutic agents in the treatment of infectious diseases.

    PubMed

    Tse-Dinh, Y-C

    2007-03-01

    DNA topoisomerases are ubiquitous enzymes needed to overcome topological problems encountered during DNA replication, transcription, recombination and maintenance of genomic stability. They have proved to be valuable targets for therapy, in part because some anti-topoisomerase agents act as poisons. Bacterial DNA gyrase and topoisomerase IV (type IIA topoisomerases) are targets of fluoroquinolones while human topoisomerase I (a type IB topoisomerase) and topoisomerase II are targets of various anticancer drugs. Bacterial type IA topoisomerase share little sequence homology to type IB or type IIA topoisomerases, but all topoisomerases have the potential of having the covalent phosphotyrosine DNA cleavage intermediate trapped by drug action. Recent studies have demonstrated that stabilization of the covalent complex formed by bacterial topoisomerase I and cleaved DNA can lead to bacterial cell death, supporting bacterial topoisomerase I as a promising target for the development of novel antibiotics. For current antibacterial therapy, the prevalence of fluoroquinolone-resistant bacterial pathogens has become a major public health concern, and efforts are directed towards identifying novel inhibitors of bacterial type IIA topoisomerases that are not affected by fluoroquinolone resistant mutations on the gyrase or topoisomerase IV genes. For anti-viral therapy, poxviruses encode their own type IB topoisomerases; these enzymes differ in drug sensitivity from human topoisomerase I. To confront potential threat of small pox as a weapon in terrorist attacks, vaccinia virus topoisomerase I has been targeted for discovery of anti-viral agents. These new developments of DNA topoisomerases as targets of novel therapeutic agents being reviewed here represent excellent opportunities for drug discovery in the treatment of infectious diseases.

  13. Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases

    PubMed Central

    Zhang, Yuan; Tang, Zhi-Han; Ren, Zhong; Qu, Shun-Lin; Liu, Mi-Hua; Liu, Lu-Shan

    2013-01-01

    Hydrogen sulfide (H2S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide. It is physiologically generated by cystathionine-γ-lyase, cystathionine-β-synthase, and 3-mercaptopyruvate sulfurtransferase. H2S has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems. Substantial evidence shows that H2S is involved in aging by inhibiting free-radical reactions, activating SIRT1, and probably interacting with the age-related gene Klotho. Moreover, H2S has been shown to have therapeutic potential in age-associated diseases. This article provides an overview of the physiological functions and effects of H2S in aging and age-associated diseases, and proposes the potential health and therapeutic benefits of H2S. PMID:23297346

  14. An Active Learning Exercise for Introducing Agent-Based Modeling

    ERIC Educational Resources Information Center

    Pinder, Jonathan P.

    2013-01-01

    Recent developments in agent-based modeling as a method of systems analysis and optimization indicate that students in business analytics need an introduction to the terminology, concepts, and framework of agent-based modeling. This article presents an active learning exercise for MBA students in business analytics that demonstrates agent-based…

  15. Novel compounds in the treatment of lung cancer: current and developing therapeutic agents

    PubMed Central

    Bao, Rudi; Chan, Pokman

    2011-01-01

    Lung cancer is the leading cause of cancer-related death in the United States. Though incremental advances have been made in the treatment of this devastating disease during the past decade, new therapies are urgently needed. Traditional cytotoxic agents have been combined with other modalities with improved survival for early-stage patients. Newer cytotoxic agents targeting the same or different mechanisms have been developed at different stages. Optimization of various chemotherapy regimens in different settings is one of the aims of current clinical trials. Some predictive biomarkers (eg, excision repair cross-complementing 1, ERCC1) and histotypes (eg, adenocarcinoma) are found to be associated with resistance/response to some cytotoxic drugs. Another notable advance is the addition of targeted therapy to lung cancer treatment. Targeted agents such as erlotinib and bevacizumab have demonstrated clinical benefits and gained Food and Drug Administration approval for lung cancer. More agents targeting various signaling pathways critical to lung cancer are at different stages of development. Along with the effort of new targeted drug discovery, biomarkers such as epidermal growth factor receptor and anaplastic lymphoma kinase mutations have proven useful for patient selection, and more predictive biomarkers have been actively evaluated in non-small cell lung cancer. The paradigm of lung cancer treatment has shifted towards biomarker-based personalized medicine. PMID:27186107

  16. Therapeutic perspectives of epigenetically active nutrients.

    PubMed

    Remely, M; Lovrecic, L; de la Garza, A L; Migliore, L; Peterlin, B; Milagro, F I; Martinez, A J; Haslberger, A G

    2015-06-01

    Many nutrients are known for a wide range of activities in prevention and alleviation of various diseases. Recently, their potential role in regulating human health through effects on epigenetics has become evident, although specific mechanisms are still unclear. Thus, nutriepigenetics/nutriepigenomics has emerged as a new and promising field in current epigenetics research in the past few years. In particular, polyphenols, as part of the central dynamic interaction between the genome and the environment with specificity at physiological concentrations, are well known to affect mechanisms underlying human health. This review summarizes the effects of dietary compounds on epigenetic mechanisms in the regulation of gene expression including expression of enzymes and other molecules responsible for drug absorption, distribution, metabolism and excretion in cancer, metabolic syndrome, neurodegenerative disorders and hormonal dysfunction.

  17. Therapeutic perspectives of epigenetically active nutrients

    PubMed Central

    Remely, M; Lovrecic, L; de la Garza, A L; Migliore, L; Peterlin, B; Milagro, F I; Martinez, A J; Haslberger, A G

    2015-01-01

    Many nutrients are known for a wide range of activities in prevention and alleviation of various diseases. Recently, their potential role in regulating human health through effects on epigenetics has become evident, although specific mechanisms are still unclear. Thus, nutriepigenetics/nutriepigenomics has emerged as a new and promising field in current epigenetics research in the past few years. In particular, polyphenols, as part of the central dynamic interaction between the genome and the environment with specificity at physiological concentrations, are well known to affect mechanisms underlying human health. This review summarizes the effects of dietary compounds on epigenetic mechanisms in the regulation of gene expression including expression of enzymes and other molecules responsible for drug absorption, distribution, metabolism and excretion in cancer, metabolic syndrome, neurodegenerative disorders and hormonal dysfunction. PMID:25046997

  18. Potential therapeutic applications of multifunctional host-defense peptides from frog skin as anti-cancer, anti-viral, immunomodulatory, and anti-diabetic agents.

    PubMed

    Conlon, J Michael; Mechkarska, Milena; Lukic, Miodrag L; Flatt, Peter R

    2014-07-01

    Frog skin constitutes a rich source of peptides with a wide range of biological properties. These include host-defense peptides with cytotoxic activities against bacteria, fungi, protozoa, viruses, and mammalian cells. Several hundred such peptides from diverse species have been described. Although attention has been focused mainly on antimicrobial activity, the therapeutic potential of frog skin peptides as anti-infective agents remains to be realized and no compound based upon their structures has yet been adopted in clinical practice. Consequently, alternative applications are being explored. Certain naturally occurring frog skin peptides, and analogs with improved therapeutic properties, show selective cytotoxicity against tumor cells and viruses and so have potential for development into anti-cancer and anti-viral agents. Some peptides display complex cytokine-mediated immunomodulatory properties. Effects on the production of both pro-inflammatory and anti-inflammatory cytokines by peritoneal macrophages and peripheral blood mononuclear cells have been observed so that clinical applications as anti-inflammatory, immunosuppressive, and immunostimulatory agents are possible. Several frog skin peptides, first identified on the basis of antimicrobial activity, have been shown to stimulate insulin release both in vitro and in vivo and so show potential as incretin-based therapies for treatment of patients with Type 2 diabetes mellitus. This review assesses the therapeutic possibilities of peptides from frogs belonging to the Ascaphidae, Alytidae, Pipidae, Dicroglossidae, Leptodactylidae, Hylidae, and Ranidae families that complement their potential role as anti-infectives for use against multidrug-resistant microorganisms.

  19. Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate.

    PubMed

    Deal, C L; Moskowitz, R W

    1999-05-01

    There are a sufficient number of short-term studies with these agents suggesting efficacy equal to that seen in the symptomatic treatment of OA using NSAIDs. Two recent meta-analyses by McAlindon and colleagues and Towheed et al reviewed clinical trials of glucosamine and chondroitin in the treatment of osteoarthritis. The study by McAlindon and co-workers included all double-blind placebo-controlled trials of greater than 4 weeks' duration, testing oral or parenteral glucosamine or chondroitin for treatment of hip or knee osteoarthritis. Thirteen trials (six with glucosamine, seven with chondroitin) met eligibility criteria. The authors used global pain score or the Lequesne index in the index joint as the primary outcome measure and considered the trial positive if improvement in the treatment group was equal to or greater than 25% compared with the placebo group, and was significant (P < or = .05). All 13 studies reviewed were classified as positive, demonstrating large effects, compared with placebo (39.5% [S.D. 21.9] for glucosamine, 40.2% [S.D. 6.4] for chondroitin). The authors concluded that clinical trials of these two agents showed substantial benefit in the treatment of osteoarthritis but provided insufficient information about study design and conduct to allow definitive evaluation. Towheed and colleagues reviewed nine randomized, controlled trials of glucosamine sulfate in osteoarthritis. In seven of the randomized controlled trials, in which they compared glucosamine with placebo, glucosamine was always superior. In two randomized controlled trials comparing glucosamine to ibuprofen, glucosamine was superior in one and equivalent in one. Methodologic problems, including lack of standardized case definition of osteoarthritis and lack of standardized outcome assessment led the authors to conclude that further studies are needed to determine if route of administration is important and whether the therapeutic effect is site specific. A meta-analysis of

  20. Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury

    PubMed Central

    Lee, Dongwon; Park, Seunggyu; Bae, Soochan; Jeong, Dahee; Park, Minhyung; Kang, Changsun; Yoo, Wooyoung; Samad, Mohammed A.; Ke, Qingen; Khang, Gilson; Kang, Peter M.

    2015-01-01

    Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries. PMID:26563741

  1. Coordinating Learning Agents for Active Information Collection

    DTIC Science & Technology

    2011-06-30

    ranging from robocup soccer [26, 27], to rover coordination [19], to trading agents [25, 43], to air traffic management [32]. What makes this problem...Bazzan, A. and Ossowski, S. (eds.), Applications of Agent Technology in Traffic and Transportation ( Springer , 2005). [19] Mataric, M. J., Coordination...of Complex Systems ( Springer , 2004). September 16, 2009 16:40 WSPC/169-ACS 00230 472 K. Tumer and N. Khani [24] Pynadath, D. and Tambe, M., The

  2. [Weighing use and safety of therapeutic agents and feed additives (author's transl)].

    PubMed

    van der Wal, P

    1982-02-01

    (1) The pros and cons of using feed additives and therapeutic agents may be successfully weighed in the light of carefully considered consumer requirements. (2) The socio-economic interests of the producer and the welfare of the animal will also determine the response of the production apparatus to consumer requirements. (3) Consumption of the current amounts of products of animal origin and maintenance of price and quality will only be feasible in the event of rational large-scale production in which constituents used in nutrition, prophylaxis and therapeutics are highly important factors. (4) Using these ingredients should be preceded by accurate evaluation of their use and safety. Testing facilities, conduct of studies and reporting should be such as to make the results nationally and internationally acceptable to all those concerned. (5) In deciding whether feed constituents are acceptable in view of the established use and safety, compliance will have to be sought with those standards which are accepted in other fields of society. Measures which result in raising the price of food without actually helping to reduce the risks to the safety of man, animals and environment, are likely to be rejected by any well-informed consumer who is aware of the facts. (6) For accurate weighing of use and safety at a national level, possibilities are hardly adequate in Europe. Decisions reached within the framework of the European Community, also tuned to U.S.A.- conditions are rightly encouraged. A centrally managed professionally staffed and equipped test system in the European Community would appear to be indispensable.

  3. Novel therapeutic strategies using hypomethylating agents in the treatment of myelodysplastic syndrome.

    PubMed

    Ishikawa, Takayuki

    2014-02-01

    Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm with high rates of leukemic transformation. MDS had been an intractable disease for which the mainstream of therapeutic approach was best supportive care. Recently, however, treatment of hematological malignancies has benefited from advances in molecular targeted drug discovery such as the revolutionary drug imatinib for chronic myeloid leukemia, and from the reappraisal of forgotten drugs such as thalidomide for multiple myeloma. Two azanucleotide drugs, azacitidine (AZA) and decitabine, were created as anti-neoplastic drugs in the 1960s with little success. In the 1980s, they were reassessed as hypomethylating agents (HMAs), and the introduction of low-dose schedules of them has shown dramatic effects in the delay of leukemic evolution for high-risk MDS. AZA was approved in Japan in March 2011 and has become a standard drug of choice in the treatment of high-risk MDS. Its position as a treatment for low-risk MDS remains to be established. Only half of patients with high-risk MDS can gain benefit from AZA. For example, those with complex karyotypes experience only a limited extension in survival. In addition, AZA resistance develops sooner or later. To achieve a more sustained disease control of high-risk MDS, the combined use of HMAs with other therapeutic approaches will be inevitable. Clinical trials of histone deacetylase inhibitors, lenalidomide, thrombopoietin agonists, or anticancer drugs in combination with HMAs are ongoing. In addition, HMAs are being used as a bridging therapy prior to allogeneic stem cell transplantation (AHSCT) and the salvage therapy of relapsed disease after AHSCT. Thus, HMAs will continue to be key drugs for the management of MDS.

  4. Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity?

    PubMed

    Shah, Rashmi R

    2017-03-01

    Signalling pathways involving protein kinase, insulin-like growth factor 1, insulin receptors and the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) system are critical in promoting oncogenesis. The use of anticancer agents that inhibit these pathways frequently results in hyperglycaemia, an on-target effect of these drugs. Hyperglycaemia induced by these agents denotes optimal inhibition of the desired pharmacological target. As hyperglycaemia can be treated successfully and effectively with metformin, managing this complication by reducing the dose of or discontinuing the anticancer drug may be counterproductive, especially if it is otherwise effective and clinically tolerated. The use of metformin to treat hyperglycaemia induced by anticancer drugs provides a valuable therapeutic opportunity of potentiating their clinical anticancer effects. Although evidence from randomised controlled trials is awaited, extensive preclinical evidence and clinical observational studies suggest that metformin has anticancer properties that improve overall survival in patients with diabetes and a variety of cancers. Metformin has also been reported to reverse resistance to epidermal growth factor receptor (EGFR)-inhibiting tyrosine kinase inhibitors. This review summarises briefly the role of the above signalling pathways in oncogenesis, the causal association between inhibition of these pathways and hyperglycaemia, and the effect of metformin on clinical outcomes resulting from its anticancer properties. The evidence reviewed herein, albeit almost exclusively from observational studies, provides support for a greater use of metformin not only in patients with cancer and diabetes or drug-induced hyperglycaemia but also potentially as an anticancer drug. However, prospective randomised controlled studies are needed in all these settings to better assess the effect on clinical outcomes of adding metformin to ongoing anticancer therapy.

  5. Image-guided robotic delivery system for precise placement of therapeutic agents.

    PubMed

    Cleary, K; Freedman, M; Clifford, M; Lindisch, D; Onda, S; Jiang, L

    2001-07-06

    The effectiveness of conventional solid tumor treatment is limited by the systemic toxicity and lack of specificity of chemotherapeutic agents. Present treatment modalities are frequently insufficient to eliminate competent cancer cells without exceeding the limits of toxicity to normal tissue. The coming generation of cancer therapeutics depends on the precise targeting and sustained release of antitumor agents to overcome these limitations. We are developing an image-guided, robotic system for precise intratumoral placement of anticancer drugs and sustained release devices to advance this new treatment paradigm. The robotic system will use intraoperatively obtained computed tomographic (CT) images from a mobile CT scanner for guidance. The concept is to track patient anatomy and localize instruments using currently available optical tracking technology. Tracking will also be used to register patient anatomy with the images. The physician can then use the registered image to select an appropriate tumor target and entry location and to plan the instrument path. This path will then be transmitted to the robot, which orients and drives the instrument to the desired target under physician control. Achievement of the target is confirmed via intraoperative CT. This system will provide instrument guidance that is precise, direct, and controllable. Error due to poor target visualization and hand unsteadiness should be reduced greatly. The basic components of the system (robot, mobile CT, tracking) have been demonstrated in our laboratory, and the integration of the components is in progress. In future work, we plan to fuse preoperative PET imaging with intraoperative CT to allow functional as well as anatomic image guidance.

  6. Low molecular weight compounds with transition metals as free radical scavengers and novel therapeutic agents.

    PubMed

    Bencini, Andrea; Failli, Paola; Valtancoli, Barbara; Bani, Daniele

    2010-07-01

    Molecules able to modulate the levels of endogenous free radicals, such as reactive oxygen species (ROS) and nitric oxide (NO), are of pivotal interest for pharmacological and pharmaceutical sciences because of their potential therapeutic relevance. In fact, ROS and NO, which are normal products of cell metabolism, may play a dual beneficial/deleterious role, depending on local concentration and mode of generation. As such, they have been identified as key pathogenic factors for many inflammatory, vascular dysfunctional and degenerative disorders, including atherosclerosis, hypertension, cardiovascular and neurodegenerative diseases, cancer, diabetes mellitus, and ageing. Therefore, the identification and characterization of novel antioxidant/free radical scavenger molecules may expand the current therapeutic implements for the treatment and prevention of the above diseases. In this perspective, low molecular weight complexes of transition metals with organic scaffolds are viewed and investigated as promising pharmaceutical agents. These complexes take advantage of the known principles of inorganic chemistry, i.e. the ability of transition metals, Fe(II), Co(II), Mn(II) and Ru(II), to bind to and react with NO and/or ROS, to counterbalance excessive endogenous free radical generation in biological systems. Among NO scavengers, representative examples are iron complexes with dithiocarbamates or ruthenium compounds with polyamine-polycarboxylate scaffolds; on the other hand, manganese-based molecules appear effective as ROS scavengers. Of note, Mn(II)-containing molecules, currently under study as ROS scavengers, have major functional similarities to Mn-superoxide dismutase (SOD), a Mn-containing enzyme acting as potent endogenous anti-oxidant. In this article, we briefly summarize the state-of-the-art concerning the chemical and biological properties of transition metal ion complexes with low molecular weight synthetic ligands as ROS/NO scavengers provided with

  7. Development of RNAi technology for targeted therapy--a track of siRNA based agents to RNAi therapeutics.

    PubMed

    Zhou, Yinjian; Zhang, Chunling; Liang, Wei

    2014-11-10

    RNA interference (RNAi) was intensively studied in the past decades due to its potential in therapy of diseases. The target specificity and universal treatment spectrum endowed siRNA advantages over traditional small molecules and protein drugs. However, barriers exist in the blood circulation system and the diseased tissues blocked the actualization of RNAi effect, which raised function versatility requirements to siRNA therapeutic agents. Appropriate functionalization of siRNAs is necessary to break through these barriers and target diseased tissues in local or systemic targeted application. In this review, we summarized that barriers exist in the delivery process and popular functionalized technologies for siRNA such as chemical modification and physical encapsulation. Preclinical targeted siRNA delivery and the current status of siRNA based RNAi therapeutic agents in clinical trial were reviewed and finally the future of siRNA delivery was proposed. The valuable experience from the siRNA agent delivery study and the RNAi therapeutic agents in clinical trial paved ways for practical RNAi therapeutics to emerge early.

  8. Vitamin B12: a tunable, long wavelength, light-responsive platform for launching therapeutic agents.

    PubMed

    Shell, Thomas A; Lawrence, David S

    2015-11-17

    Light-responsive agents offer the promise of targeted therapy, whose benefits include (i) prolonged action at the target site, (ii) overall reduced systemic dosage, (iii) reduced adverse effects, and (iv) localized delivery of multiple agents. Although photoactivated prodrugs have been reported, these species generally require short wavelengths (<450 nm) for activation. However, maximal tissue penetrance by light occurs within the "optical window of tissue" (600-900 nm), well beyond the wavelength range of most existing photocleavable functional groups. Furthermore, since multidrug therapy holds promise for the treatment of complex diseases, from cancer to neurological disorders, controlling the action of multiple drugs via wavelength modulation would take advantage of a property that is unique to light. However, discrimination between existing photoresponsive moieties has thus far proven to be limited. We have developed a vitamin B12/light-facilitated strategy for controlling drug action using red, far-red, and NIR light. The technology is based on a light-triggered reaction displayed by a subset of B12 derivatives: alkyl-cob(III)alamins suffer photohomolysis of the C-Co(III) bond. The C-Co(III) bond is weak (<30 kcal/mol), and therefore all wavelengths absorbed by the corrin ring (330-580 nm) induce photocleavage. In addition, by appending fluorophores to the corrin ring, long wavelength light (>600 nm) is readily captured and used to separate the Co-appended ligand (e.g., a drug) from B12. Consequently, it is now feasible to preassign the wavelength of homolysis by simply installing a fluorescent antenna with the desired photophysical properties. The wavelength malleability inherent within this strategy has been used to construct photoresponsive compounds that launch different drugs by simply modulating the wavelength of illumination. In addition, these phototherapeutics have been installed on the surface and interior of cells, such as erythrocytes or neural

  9. Reactivation of Brain Acetylcholinesterase by Monoisonitrosoacetone Increases the Therapeutic Efficacy Against Nerve Agents in Guinea Pigs

    DTIC Science & Technology

    2010-01-01

    reactivated ChE in the brain, educed toxic signs, improved survival, and prevented or termi- ated seizures following GB intoxication in guinea pigs [15,16...nerve agent intox - cation more effectively than peripherally acting reversible ChE nhibitors, such as pyridostigmine [17–19]. The present study was...cumulative score was categorized as mild intoxication [0–3.0], moderate intoxication [3.1–6.0] and severe intoxication [6.1–9.0]. 2.3.2. ChE activity

  10. 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.

  11. Ethosomes: versatile vesicular carriers for efficient transdermal delivery of therapeutic agents.

    PubMed

    Pandey, Vikas; Golhani, Dilip; Shukla, Rajesh

    2015-12-01

    Delivery across skin is attractive due to its easy accessibility. However, drug delivery across skin is still a challenge in biomedical sciences. Over the past few decades, various successful novel devices and techniques have emerged to optimize drug delivery across skin whose obstructing behavior constricts entry of most of the therapeutic agents. Inability of various conventional vesicular formulations, e.g. liposomes to pass through the tapered (>30 nm) intercellular channels of stratum corneum, rendered invention of some lipid based vesicular carrier systems such as ethosomes which consist of phospholipid, ethanol and water. Ethosomes are non-invasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. In spite of their sophistication in conceptuality, they are exemplified by easiness in their preparation, safety and efficacy - a combination that can highly inflate their application. This review attempts to describe all aspects of ethosomes including roles and upshots of different excipients, various methods of preparation and characterizations, research reports on various drug deliveries, patent reports and future prospects.

  12. Statin derivatives as therapeutic agents for castration-resistant prostate cancer.

    PubMed

    Ingersoll, Matthew A; Miller, Dannah R; Martinez, October; Wakefield, C Brent; Hsieh, Kuan-Chan; Simha, M Vijaya; Kao, Chai-Lin; Chen, Hui-Ting; Batra, Surinder K; Lin, Ming-Fong

    2016-12-01

    Despite recent advances in modern medicine, castration-resistant prostate cancer remains an incurable disease. Subpopulations of prostate cancer cells develop castration-resistance by obtaining the complete steroidogenic ability to synthesize androgens from cholesterol. Statin derivatives, such as simvastatin, inhibit cholesterol biosynthesis and may reduce prostate cancer incidence as well as progression to advanced, metastatic phenotype. In this study, we demonstrate novel simvastatin-related molecules SVA, AM1, and AM2 suppress the tumorigenicity of prostate cancer cell lines including androgen receptor-positive LNCaP C-81 and VCaP as well as androgen receptor-negative PC-3 and DU145. This is achieved through inhibition of cell proliferation, colony formation, and migration as well as induction of S-phase cell-cycle arrest and apoptosis. While the compounds effectively block androgen receptor signaling, their mechanism of inhibition also includes suppression of the AKT pathway, in part, through disruption of the plasma membrane. SVA also possess an added effect on cell growth inhibition when combined with docetaxel. In summary, of the compounds studied, SVA is the most potent inhibitor of prostate cancer cell tumorigenicity, demonstrating its potential as a promising therapeutic agent for castration-resistant prostate cancer.

  13. The pigment epithelium-derived factor (PEDF): an important potential therapeutic agent for infantile hemangioma.

    PubMed

    Li, Ming; Chen, Yanru; Guo, Zhihui; Xie, Yide; Zhou, Yakuan; Jiang, Chenghong; Chen, Xiaosong

    2017-04-01

    In previous studies, the expression and the role of proangiogenic factors in infantile hemangiomas have been well studied. However, the role of angiogenic inhibitors has been revealed rarely. The expression of PEDF, as the strongest and safe endogenous inhibitor, is still unrecognized until the current study. In order to investigate the expression and significance of the pigment epithelium-derived factor (PEDF) in the proliferating and regressing phases of infantile hemangiomas, the expression of PEDF, VEGF, Ki-67, and CD34 protein in hemangioma tissues was examined with immunohistochemical polymer HRP method in 42 cases during the proliferative phase, 40 cases during the regressing phase, and 11 cases of non-involuting congenital hemangiomas (NICHs). Meanwhile, the mRNA expression of these factors was detected with quantitative realtime RT-PCR. We found the protein and mRNA expression of PEDF in regressing phase was significantly higher than those in proliferative phase and NICHs (P < 0.001), while the protein and mRNA expression of VEGF were much lower (P < 0.001). The microvessel density (MVD), Ki-67 changes, and the expression of PEDF and VEGF were found significantly correlated. These results indicated that the reduction of VEGF and increase in PEDF are causative to the evolution of infantile hemangioma. PEDF may play a key role in the spontaneous regression of infantile hemangioma and may become an important potential therapeutic agent for infantile hemangioma.

  14. Tumor therapeutics by design: targeting and activation of death receptors.

    PubMed

    Wajant, Harald; Gerspach, Jeannette; Pfizenmaier, Klaus

    2005-02-01

    Due to their strong apoptosis-inducing capacity, the death receptor ligands CD95L, TNF and TRAIL have been widely viewed as potential cancer therapeutics. While clinical data with CD95L and TRAIL are not yet available, TNF is a registered drug, albeit only for loco-regional application in a limited number of indications. The TNF experience has told us that specific delivery and restricted action is a major challenge in the development of multifunctional, pleiotropically acting cytokines into effective cancer therapeutics. Thus, gene-therapeutic approaches and new cytokine variants have been designed over the last 10 years with the aim of increasing anti-tumoral activity and reducing systemic side effects. Here, we present our current view of the therapeutic potential of the death receptor ligands TNF, CD95L and TRAIL and of the progress made towards improving their efficacy by tumor targeting, use of gene therapy and genetic engineering. Results generated with newly designed fusion proteins suggest that enhanced tumor-directed activity and prevention of undesirable actions of death receptor ligands is possible, thereby opening up a useful therapeutic window for all of the death receptor ligands, including CD95L.

  15. Mesoporous silica nanoparticles with organo-bridged silsesquioxane framework as innovative platforms for bioimaging and therapeutic agent delivery.

    PubMed

    Du, Xin; Li, Xiaoyu; Xiong, Lin; Zhang, Xueji; Kleitz, Freddy; Qiao, Shi Zhang

    2016-06-01

    Mesoporous silica material with organo-bridged silsesquioxane frameworks is a kind of synergistic combination of inorganic silica, mesopores and organics, resulting in some novel or enhanced physicochemical and biocompatible properties compared with conventional mesoporous silica materials with pure Si-O composition. With the rapid development of nanotechnology, monodispersed nanoscale periodic mesoporous organosilica nanoparticles (PMO NPs) and organo-bridged mesoporous silica nanoparticles (MSNs) with various organic groups and structures have recently been synthesized from 100%, or less, bridged organosilica precursors, respectively. Since then, these materials have been employed as carrier platforms to construct bioimaging and/or therapeutic agent delivery nanosystems for nano-biomedical application, and they demonstrate some unique and/or enhanced properties and performances. This review article provides a comprehensive overview of the controlled synthesis of PMO NPs and organo-bridged MSNs, physicochemical and biocompatible properties, and their nano-biomedical application as bioimaging agent and/or therapeutic agent delivery system.

  16. Terpinen-4-ol: A Novel and Promising Therapeutic Agent for Human Gastrointestinal Cancers

    PubMed Central

    Shapira, Shiran; Pleban, Shlomo; Kazanov, Diana; Tirosh, Peter; Arber, Nadir

    2016-01-01

    Background Terpinen-4-ol, a naturally occurring monoterpene is the main bioactive component of tea-tree oil and has been shown to have many biological activities. Aim To study the antitumor effects of terpinen-4-ol and its mechanism of action in prostate and GI malignancies, alone and in combination with chemotherapeutic and biological agents. Methods Terpinen-4-ol was administrated alone or combined with standard chemotherapy (Oxaliplatin, Fluorouracil, Gemcitabine, Tarceva) and biological agent (Cetuximab). It was also combined with humanized anti-CD24 mAbs (was developed by us). Killing effects were measured qualitatively by light microscopy and quantitatively using the MTT and FACS analysis, following treatment of colorectal, pancreatic, gastric and prostate cancer cells. Terpinen-4-ol effect on tumor development was evaluated in xenograft model. Results Terpinen-4-ol induces a significant growth inhibition of colorectal, pancreatic, prostate and gastric cancer cells in a dose-dependent manner (10–90% in 0.005–0.1%). Terpinen-4-ol and various anti-cancer agents (0.2μM oxaliplatin and 0.5μM fluorouracil) demonstrated a synergistic inhibitory effect (83% and 91%, respectively) on cancer cell proliferation. In KRAS mutated colorectal cancer cells, which are resistant to anti-EGFR therapy, combining of terpinen-4-ol with cetuximab (1 μM) resulted in impressive efficacy of 80–90% growth inhibition. Sub-toxic concentrations of terpinen-4-ol potentiate anti-CD24 mAb (150μg/ml)-induced growth inhibition (90%). Considerable reduction in tumor volume was seen following terpinen-4-ol (0.2%) treatment alone and with cetuximab (10mg/kg) (40% and 63%, respectively) as compare to the control group. Conclusion Terpinen-4-ol significantly enhances the effect of several chemotherapeutic and biological agents. The possible molecular mechanism for its activity involves induction of cell-death rendering this compound as a potential anti-cancer drug alone and in

  17. Methylselenocysteine - a Promising Antiangiogenic Agent for Overcoming Drug Delivery Barriers in Solid Malignancies for Therapeutic Synergy with Anticancer Drugs

    PubMed Central

    Bhattacharya, Arup

    2011-01-01

    Introduction Despite progress, chemotherapeutic response in solid malignancies has remained limited. While initial results of the use of antiangiogenic agents in combination chemotherapy indicated an enhanced therapeutic response, recent data indicates that the surviving cancer is not only able to surmount therapy, but is actually able to adapt a more aggressive metastatic phenotype. Thus, selecting an antiangiogenic agent that is less likely to lead to tumor resurgence is a key to future therapeutic success of antiangiogenic agents, in a combinatorial setting. Areas covered Against the broad spectrum of currently used antiangiogenic agents in the clinic, the putative benefits of the use of organo selenium (Se) compounds, such as methylselenocysteine (MSC), are discussed in this reiew. Expert opinion MSC, being part of the mammalian physiology, is a well tolerated, versatile and economical antiangiogenic agent. It down regulates multiple key upstream tumor survival markers, and enhances tumor drug delivery, at a given systemic dose of an anticancer agent, while protecting normal tissue from cytotoxic adverse effects. Further clinical trials, especially in poorly differentiated cancers, are warranted. PMID:21473705

  18. Plasma Membrane Calcium ATPases as Novel Candidates for Therapeutic Agent Development

    PubMed Central

    Strehler, Emanuel E.

    2013-01-01

    Plasma membrane Ca2+ ATPases (PMCAs) are highly regulated transporters responsible for Ca2+ extrusion from all eukaryotic cells. Different PMCA isoforms are implicated in various tasks of Ca2+ regulation including bulk Ca2+ transport and localized Ca2+ signaling in specific membrane microdomains. Accumulating evidence shows that loss, mutation or inappropriate expression of different PMCAs is associated with pathologies ranging from hypertension, low bone density and male infertility to hearing loss and cerebellar ataxia. Compared to Ca2+ influx channels, PMCAs have lagged far behind as targets for drug development, mainly due to the lack of detailed understanding of their structure and specific function. This is rapidly changing thanks to integrated efforts combining biochemical, structural, cellular and physiological studies suggesting that selective modulation of PMCA isoforms may be of therapeutic value in the management of different and complex diseases. Both structurally informed rational design and high-throughput small molecule library screenings are promising strategies that are expected to lead to specific and isoform-selective modulators of PMCA function. This short review will provide an overview of the diverse roles played by PMCA isoforms in different cells and tissues and their emerging involvement in pathophysiological processes, summarize recent progress in obtaining structural information on the PMCAs, and discuss current and future strategies to develop specific PMCA inhibitors and activators for potential therapeutic applications. PMID:23958189

  19. Erythropoiesis stimulating agents: approaches to modulate activity

    PubMed Central

    Sinclair, Angus M

    2013-01-01

    Recombinant human erythropoietin (rHuEPO), such as the approved agents epoetin alfa and epoetin beta, has been used successfully for over 20 years to treat anemia in millions of patients. However, due to the relatively short half-life of the molecule (approximately 8 hours), frequent dosing may be required to achieve required hemoglobin levels. Therefore, a need was identified in some anemic patient populations for erythropoiesis stimulating agents with longer half-lives that required less frequent dosing. This need led to the development of second generation molecules which are modified versions of rHuEPO with improved pharma-cokinetic and pharmacodynamic properties such as darbepoetin alfa, a hyperglycosylated analog of rHuEPO, and pegzyrepoetin, a pegylated rHuEPO. Third generation molecules, such as peginesatide, which are peptide mimetics that have no sequence homology to rHuEPO have also recently been developed. The various molecular, pharmacokinetic, and pharmacodynamic properties of these and other erythropoiesis stimulating agents will be discussed in this review. PMID:23847411

  20. Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment.

    PubMed Central

    Huang, L.; Pardee, A. B.

    2000-01-01

    BACKGROUND: Suberoylanilide hydroxamic acid (SAHA) is a prototype of the newly developed, second-generation, hybrid polar compounds. It is a novel histone deacetylase inhibitor with high potency for inducing cell differentiation of cultured murine erythroleukemia cells. Studies with SAHA have primarily been performed with hematopoietic tumor cells. Here we extent these studies with SAHA to human breast cancer cell lines in an attempt to find better therapeutic agents for breast cancer treatment. MATERIALS AND METHODS: Human breast cancer cell lines, MCF7, MDA-MB-231, and MDA-MB-435, as well as normal cells, including the normal breast epithelial cell line MCF-10A, and fibroblasts, were treated with SAHA. Cells assayed for cell survival by using trypan blue exclusion assay, colony formation assay, and cell cycle and apoptosis analysis. The effects of SAHA on cell cycle and apoptosis regulatory proteins were examined by Western blots analysis. The identification of additional target genes was carried out by differential display (DD) and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: SAHA inhibited clonogenic growth of MCF7, MDA-MB-231, and MDA-MB-435 breast cancer cells. These cells were more sensitive to SAHA-mediated cytotoxic effects than normal breast epithelial cells and fibroblasts. The cytotoxic effects of SAHA on breast cancer cells were manifested by G1 and G2/M cell cycle arrest and eventual apoptosis. The pan-caspase inhibitor, Z-VAD.fmk, blocked SAHA-induced cell death, DNA laddering, and cleavage of poly(ADP-ribose) polymerase, indicating the involvement of caspases in SAHA-mediated apoptosis. In addition, SAHA modulated cell cycle and apoptosis regulatory proteins. For example, cyclin-dependent kinase (CDK) inhibitors p21WAF1/Cip1 and p27Kip1 were induced, and retinoblastoma protein pRb was hypophosphorylated. Moreover, SAHA induced several genes associated with differentiation and/ or growth inhibition. These genes encode gelsolin

  1. Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein

    PubMed Central

    Zhu, Hao-Jie; Wang, Jun-Sheng; Donovan, Jennifer L.; Jiang, Yan; Gibson, Bryan B.; DeVane, C. Lindsay; Markowitz, John S.

    2009-01-01

    The objective of this study was to assess the potential interactions of the drug transporter P-glycoprotein with attention-deficit/hyperactivity disorder (ADHD) therapeutic agents atomoxetine — and the individual isomers of methylphenidate, amphetamine, and modafinil utilizing established in vitro assay. An initial ATPase assay indicated that both d- and l-methylphenidate have weak affinity for P-glycoprotein. The intracellular accumulation of P-glycoprotein substrates doxorubicin and rhodamine123 in the P-glycoprotein overexpressing cell line LLC-PK1/MDR1 was determined to evaluate potential inhibitory effects on P-glycoprotein. The results demonstrated that all compounds, except both modafinil isomers, significantly increased doxorubicin and rhodamine123 accumulation in LLC-PK1/MDR1 cells at higher concentrations. To investigate the P-glycoprotein substrate properties, the intracellular concentrations of the tested compounds in LLC-PK1/MDR1 and P-glycoprotein negative LLC-PK1 cells were measured in the presence and absence of the P-glycoprotein inhibitor PSC833. The results indicate that the accumulation of d-methylphenidate in LLC-PK1 cells was 32.0% higher than in LLC-PK1/MDR1 cells. Additionally, coadministration of PSC833 leads to 52.9% and 45.6% increases in d-modafinil and l-modafinil accumulation, respectively, in LLC-PK1/MDR1 cells. Further studies demonstrated that l-modafinil transport across LLC-PK1/MDR1 cell monolayers in the basolateral-to-apical (B–A) direction was significantly higher than in the apical-to-basolateral (A–B) direction. PSC833 treatment significantly decreased the transport of l-modafinil in B–A direction. In conclusion, our results suggest that all tested agents with the exception of modafinil isomers are relatively weak P-glycoprotein inhibitors. Furthermore, P-glycoprotein may play a minor role in the transport of d-methylphenidate, d-modafinil, and l-modafinil. PMID:17963743

  2. Cynaropicrin: A Comprehensive Research Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent

    PubMed Central

    Elsebai, Mahmoud F.; Mocan, Andrei; Atanasov, Atanas G.

    2016-01-01

    The different pharmacologic properties of plants-containing cynaropicrin, especially artichokes, have been known for many centuries. More recently, cynaropicrin exhibited a potential activity against all genotypes of hepatitis C virus (HCV). Cynaropicrin has also shown a wide range of other pharmacologic properties such as anti-hyperlipidemic, anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, and anti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatory properties (e.g., associated with the suppression of the key pro-inflammatory NF-κB pathway). These pharmacological effects are very supportive factors to its outstanding activity against HCV. Structurally, cynaropicrin might be considered as a potential drug candidate, since it has no violations for the rule of five and its water-solubility could allow formulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that can be easily synthesized and as the major constituent of the edible plant artichoke, which has a history of safe dietary use. In summary, cynaropicrin is a promising bioactive natural product that, with minor hit-to-lead optimization, might be developed as a drug for HCV. PMID:28008316

  3. Caffeic Acid Phenethyl Ester Is a Potential Therapeutic Agent for Oral Cancer

    PubMed Central

    Kuo, Ying-Yu; Jim, Wai-Tim; Su, Liang-Cheng; Chung, Chi-Jung; Lin, Ching-Yu; Huo, Chieh; Tseng, Jen-Chih; Huang, Shih-Han; Lai, Chih-Jen; Chen, Bo-Chih; Wang, Bi-Juan; Chan, Tzu-Min; Lin, Hui-Ping; Chang, Wun-Shaing Wayne; Chang, Chuang-Rung; Chuu, Chih-Pin

    2015-01-01

    Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% of oral cancers are oral and oropharyngeal squamous cell carcinoma (OSCC). The overall five-year survival rate of OSCC patients is approximately 63%, which is due to the low response rate to current therapeutic drugs. In this review we discuss the possibility of using caffeic acid phenethyl ester (CAPE) as an alternative treatment for oral cancer. CAPE is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment can effectively suppress the proliferation, survival, and metastasis of oral cancer cells. CAPE treatment inhibits Akt signaling, cell cycle regulatory proteins, NF-κB function, as well as activity of matrix metalloproteinase (MMPs), epidermal growth factor receptor (EGFR), and Cyclooxygenase-2 (COX-2). Therefore, CAPE treatment induces cell cycle arrest and apoptosis in oral cancer cells. According to the evidence that aberrations in the EGFR/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling, NF-κB function, COX-2 activity, and MMPs activity are frequently found in oral cancers, and that the phosphorylation of Akt, EGFR, and COX-2 correlates to oral cancer patient survival and clinical progression, we believe that CAPE treatment will be useful for treatment of advanced oral cancer patients. PMID:25984601

  4. Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties.

    PubMed

    Wang, Yan-Yang; Yang, Yin-Xue; Zhe, Hong; He, Zhi-Xu; Zhou, Shu-Feng

    2014-01-01

    Triterpenoids have been used for medicinal purposes in many Asian countries because of their anti-inflammatory, antioxidant, antiproliferative, anticancer, and anticarcinogenic properties. Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. CDDO-Me has been used for the treatment of chronic kidney disease, cancer (including leukemia and solid tumors), and other diseases. In this review, we will update our knowledge of the clinical pharmacokinetics and pharmacodynamics of CDDO-Me, highlighting its clinical benefits and the underlying mechanisms involved. The role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)/the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the therapeutic activities of CDDO-Me will be discussed. CDDO-Me contains α,β-unsaturated carbonyl groups on rings A and C that can generate reversible adducts with the thiol groups of Cys residues in target proteins such as Keap1 and IκB kinase. At low nanomolar concentrations, CDDO-Me protects the cells against oxidative stress via inhibition of reactive oxygen species generation, while CDDO-Me at low micromolar concentrations induces apoptosis by increasing reactive oxygen species and decreasinging intracellular glutathione levels. Through Keap1/Nrf2 and nuclear factor-κB pathways, this agent can modulate the activities of a number of important proteins that regulate inflammation, redox balance, cell proliferation and programmed cell death. In a Phase I trial in cancer patients, CDDO-Me was found to have a slow and saturable oral absorption, a relatively long terminal phase half-life (39 hours at 900 mg/day), nonlinearity (dose-dependent) at high doses (600-1,300 mg/day), and high interpatient variability. As a multifunctional agent, CDDO-Me has improved the renal function in patients with chronic kidney disease

  5. Heterocyclic N-Oxides – An Emerging Class of Therapeutic Agents

    PubMed Central

    Mfuh, Adelphe M.; Larionov, Oleg V.

    2016-01-01

    Heterocyclic N-oxides have emerged as potent compounds with anticancer, antibacterial, antihypertensive, antiparasitic, anti-HIV, anti-inflammatory, herbicidal, neuroprotective, and procognitive activities. The N-oxide motif has been successfully employed in a number of recent drug development projects. This review surveys the emergence of this scaffold in the mainstream medicinal chemistry with a focus on the discovery of the heterocyclic N-oxide drugs, N-oxide-specific mechanisms of action, drug-receptor interactions and synthetic avenues to these compounds. As the first review on this subject that covers the developments since 1950s to date, it is expected that it will inspire wider implementation of the heterocyclic N-oxide motif in the rational design of new medicinal agents. PMID:26087764

  6. STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma

    PubMed Central

    Oi, Toru; Asanuma, Kunihiro; Matsumine, Akihiko; Matsubara, Takao; Nakamura, Tomoki; Iino, Takahiro; Asanuma, Yumiko; Goto, Mikinobu; Okuno, Kazuma; Kakimoto, Takuya; Yada, Yuki; Sudo, Akihiro

    2016-01-01

    The development of clinical agents remains a costly and time-consuming process. Although identification of new uses of existing drugs has been recognized as a more efficient approach for drug discovery than development of novel drugs, little screening of drugs that might be used for a rare malignant tumor such as osteosarcoma (OS) has been performed. In this study, we attempted to identify new molecular targeted agents for OS by employing Screening Committee of Anticancer Drugs (SCADS) kits. To screen compounds for OS treatment, their effect on cell viability of the OS cell lines 143B, MG63, HOS, SAOS-2, and HUO9 were evaluated. Candidate drugs were narrowed down based on a global anti-proliferative effect against these five OS cell lines. After excluding cytotoxic compounds and compounds unsuitable for in vivo administration, cucurbitacin I was extracted. Cucurbitacin I has been found to have cytotoxic and anti-proliferative properties against several tumors through inhibition of signal transducer and activator of transcription 3 (STAT3) activation. Cucurbitacin I dose- and time-dependently inhibited the proliferation of all five OS cell lines. Following cucurbitacin I treatment, STAT3 was inactivated and analysis of Mcl-1, cleaved PARP and caspase-3 indicated apoptosis induction. Expression of cell cycle regulator proteins, such as phospho-cyclin D1, c-Myc and survivin, were suppressed. Finally, cucurbitacin I potently inhibited the tumor growth of human OS 143B cells in nude mice. Our in vitro and in vivo results suggest that STAT3 inhibition by cucurbitacin I will be an effective and new approach for the treatment of OS. PMID:27840900

  7. Therapeutic activity of modified U1 core spliceosomal particles

    PubMed Central

    Rogalska, Malgorzata Ewa; Tajnik, Mojca; Licastro, Danilo; Bussani, Erica; Camparini, Luca; Mattioli, Chiara; Pagani, Franco

    2016-01-01

    Modified U1 snRNAs bound to intronic sequences downstream of the 5′ splice site correct exon skipping caused by different types of mutations. Here we evaluate the therapeutic activity and structural requirements of these exon-specific U1 snRNA (ExSpeU1) particles. In a severe spinal muscular atrophy, mouse model, ExSpeU1, introduced by germline transgenesis, increases SMN2 exon 7 inclusion, SMN protein production and extends life span. In vitro, RNA mutant analysis and silencing experiments show that while U1A protein is dispensable, the 70K and stem loop IV elements mediate most of the splicing rescue activity through improvement of exon and intron definition. Our findings indicate that precise engineering of the U1 core spliceosomal RNA particle has therapeutic potential in pathologies associated with exon-skipping mutations. PMID:27041075

  8. 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.; 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

  9. 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.

  10. Synthetic Curcumin Analogs as Inhibitors of β -Amyloid Peptide Aggregation: Potential Therapeutic and Diagnostic Agents for Alzheimer's Disease.

    PubMed

    Bukhari, Syed Nasir Abbas; Jantan, Ibrahim

    2015-01-01

    There is a crucial need to develop new effective drugs for Alzheimer's disease (AD) as the currently available AD treatments provide only momentary and incomplete symptomatic relief. Amongst natural products, curcumin, a major constituent of turmeric, has been intensively investigated for its neuroprotective effect against β-amyloid (Aβ)-induced toxicity in cultured neuronal cells. The ability of curcumin to attach to Aβ peptide and prevent its accumulation is attributed to its three structural characteristics such as the presence of two aromatic end groups and their co-planarity, the length and rigidity of the linker region and the substitution conformation of these aromatics. However, curcumin failed to reach adequate brain levels after oral absorption in AD clinical trials due to its low water solubility and poor oral bioavailability. A number of new curcumin analogs that mimic the active site of the compound along with analogs that mimic the curcumin anti-amyloid effect combined with anticholinesterase effect have been developed to enhance the bioavailability, pharmacokinetics, water solubility, stability at physiological conditions and delivery of curcumin. In this article, we have summarized all reported synthetic analogs of curcumin showing effects on β-amyloid and discussed their potential as therapeutic and diagnostic agents for AD.

  11. A Small Molecule Inhibitor of Human RAD51 Potentiates Breast Cancer Cell Killing by Therapeutic Agents in Mouse Xenografts

    PubMed Central

    Huang, Fei; Mazin, Alexander V.

    2014-01-01

    The homologous recombination pathway is responsible for the repair of DNA double strand breaks. RAD51, a key homologous recombination protein, promotes the search for homology and DNA strand exchange between homologous DNA molecules. RAD51 is overexpressed in a variety of cancer cells. Downregulation of RAD51 by siRNA increases radio- or chemo-sensitivity of cancer cells. We recently developed a specific RAD51 small molecule inhibitor, B02, which inhibits DNA strand exchange activity of RAD51 in vitro. In this study, we used human breast cancer cells MDA-MB-231 to investigate the ability of B02 to inhibit RAD51 and to potentiate an anti-cancer effect of chemotherapeutic agents including doxorubicin, etoposide, topotecan, and cisplatin. We found that the combination of B02 with cisplatin has the strongest killing effect on the cancer cells. We then tested the effect of B02 and cisplatin on the MDA-MB-231 cell proliferation in mouse xenografts. Our results showed that B02 significantly enhances the therapeutic effect of cisplatin on tumor cells in vivo. Our current data demonstrate that use of RAD51-specific small molecule inhibitor represents a feasible strategy of a combination anti-cancer therapy. PMID:24971740

  12. 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.

  13. In Vivo Application of Bacteriophage as a Potential Therapeutic Agent To Control OXA-66-Like Carbapenemase-Producing Acinetobacter baumannii Strains Belonging to Sequence Type 357

    PubMed Central

    Jeon, Jongsoo; Ryu, Choong-Min; Lee, Jun-Young; Park, Jong-Hwan; Lee, Kyungwon

    2016-01-01

    ABSTRACT The increasing prevalence of carbapenem-resistant Acinetobacter baumannii (CRAB) strains in intensive care units has caused major problems in public health worldwide. Our aim was to determine whether this phage could be used as an alternative therapeutic agent against multidrug-resistant bacterial strains, specifically CRAB clinical isolates, using a mouse model. Ten bacteriophages that caused lysis in CRAB strains, including blaOXA-66-like genes, were isolated. YMC13/01/C62 ABA BP (phage Bϕ-C62), which showed the strongest lysis activity, was chosen for further study by transmission electron microscopy (TEM), host range test, one-step growth and phage adsorption rate, thermal and pH stability, bacteriolytic activity test, genome sequencing and bioinformatics analysis, and therapeutic effect of phage using a mouse intranasal infection model. The phage Bϕ-C62 displayed high stability at various temperatures and pH values and strong cell lysis activity in vitro. The phage Bϕ-C62 genome has a double-stranded linear DNA with a length of 44,844 bp, and known virulence genes were not identified in silico. In vivo study showed that all mice treated with phage Bϕ-C62 survived after intranasal bacterial challenge. Bacterial clearance in the lung was observed within 3 days after bacterial challenge, and histologic damage also improved significantly; moreover, no side effects were observed. IMPORTANCE In our study, the novel A. baumannii phage Bϕ-C62 was characterized and evaluated in vitro, in silico, and in vivo. These results, including strong lytic activities and the improvement of survival rates, showed the therapeutic potential of the phage Bϕ-C62 as an antimicrobial agent. This study reports the potential of a novel phage as a therapeutic candidate or nontoxic disinfectant against CRAB clinical isolates in vitro and in vivo. PMID:27208124

  14. [Design and study of new agents having antitubercular activity: the original compound perchlosone as a potent agent of etiotropic therapy for tuberculosis].

    PubMed

    Vinogradova, T I; Aleksandrova, A E; Antonenkova, E V; Elokhina, V N; Nakhmanovich, A S

    1999-01-01

    Studies dealing with the design of new antituberculous agents based on goal-oriented synthesis have provided the agent Perchlosone which is similar to isoniazid and rifampicin, produces in tuberculostatic activity against sensitive laboratory cultured mycobacteria, produces an inhibitory action on polyresistant clinical strains. Experiments on animals (mice, rabbits) with experimental tuberculosis have established that Perchlosone and isoniazid have equal therapeutical properties, and the former shows a synergist interaction with rifampicin, has neither mutagenic activity nor negative effects on immunity and the surfactant system of the lung.

  15. In vitro antimicrobial activity of peroxide-based bleaching agents.

    PubMed

    Napimoga, Marcelo Henrique; de Oliveira, Rogério; Reis, André Figueiredo; Gonçalves, Reginaldo Bruno; Giannini, Marcelo

    2007-06-01

    Antibacterial activity of 4 commercial bleaching agents (Day White, Colgate Platinum, Whiteness 10% and 16%) on 6 oral pathogens (Streptococcus mutans, Streptococcus sobrinus, Streptococcus sanguinis, Candida albicans, Lactobacillus casei, and Lactobacillus acidophilus) and Staphylococcus aureus were evaluated. A chlorhexidine solution was used as a positive control, while distilled water was the negative control. Bleaching agents and control materials were inserted in sterilized stainless-steel cylinders that were positioned under inoculated agar plate (n = 4). After incubation according to the appropriate period of time for each microorganism, the inhibition zones were measured. Data were analyzed by 2-way analysis of variance and Tukey test (a = 0.05). All bleaching agents and the chlorhexidine solution produced antibacterial inhibition zones. Antimicrobial activity was dependent on peroxide-based bleaching agents. For most microorganisms evaluated, bleaching agents produced inhibition zones similar to or larger than that observed for chlorhexidine. C albicans, L casei, and L acidophilus were the most resistant microorganisms.

  16. 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

  17. Activities of Antimicrobial Agents against Intracellular Pneumococci

    PubMed Central

    Mandell, Gerald L.; Coleman, Elizabeth J.

    2000-01-01

    Pneumococci can enter and survive inside human lung alveolar carcinoma cells. We examined the activity of azithromycin, gentamicin, levofloxacin, moxifloxacin, penicillin G, rifampin, telithromycin, and trovafloxacin against pneumococci inside and outside cells. We found that moxifloxacin, trovafloxacin, and telithromycin were the most active, but only telithromycin killed all intracellular organisms. PMID:10952618

  18. Synthesis and activities of antitumor agents.

    PubMed

    Suami, T; Machinami, T; Hisamatsu, T

    1979-03-01

    N-(2-Chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines have been prepared. Six N-(2-chloroethyl)-N-nitrosoureas, including three disaccharide derivatives, were submitted to a determination of antitumor activity. All the compounds tested exhibited strong antitumor activity against leukemia L1210 in mice.

  19. Novel 2-Aminobenzamides as Potential Orally Active Antithrombotic Agents

    PubMed Central

    2012-01-01

    In an effort to develop potent antithrombotic agents, a series of novel 2-aminobenzamide derivatives were synthesized and screened for their in vivo antithrombotic activity. Among the 23 compounds tested, compound (8g) showed the most promising antithrombotic activity, which was comparable with clinically used aspirin or warfarin, but at variance with these standard drugs, 8g did not exhibit the increased bleeding time, suggesting its potential as a novel antithrombotic agent. PMID:24900559

  20. Evaluation of (1-Sarcosine, 8-Isoleucine) Angiotensin II as a Therapeutic Agent for OLEIC Acid-Induced Pulmonary Edema

    DTIC Science & Technology

    1986-02-01

    experiment. The direct REFERENCES effect of the drug on cardiac function is uncertain. 1. Ogihara T, Yamamoto T, Kumahara Y : Clinical applications These...study we 13. Ogihara T, Hata T, Mikami 1t, Nakamuru M, Maruyama A, Mandai T, Kumahara Y : Sodium depletion and blood pressurefound no depressive...circulation when 1974 2. ()gihara T, Yamamoto T, Kumahara Y : Angiotensin blockade used as a therapeutic agent for ARDS. (letter). Lancet 1:219, 1974

  1. Migraine Preventive Treatment and Its Influence on the Change in Therapeutic Intensity with Disease-Specific Abortive Agents

    DTIC Science & Technology

    2006-01-09

    the headache allowing a return to normal function. Despite availability of effective abortive medication, several problems with this treatment have...Working Title: MIGRAINE PREVENTIVE TREATMENT AND ITS INFLUENCE ON THE CHANGE IN THERAPEUTIC INTENSITY WITH DISEASE-SPECIFIC ABORTIVE AGENTS ABSTRACT...Objective: To (1) examine prescribing patterns of migraine-specific abortive medication among new users and non-users of migraine preventive therapy

  2. The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems

    PubMed Central

    Wu, Min; Frieboes, Hermann B.; Chaplain, Mark A.J.; McDougall, Steven R.; Cristini, Vittorio; Lowengrub, John

    2014-01-01

    Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but leads to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the

  3. A new photothermal therapeutic agent: core-free nanostructured Au x Ag1-x dendrites.

    PubMed

    Hu, Kuo-Wei; Huang, Chih-Chia; Hwu, Jih-Ru; Su, Wu-Chou; Shieh, Dar-Bin; Yeh, Chen-Sheng

    2008-01-01

    A new class of Au(x)Ag(1-x) nanostructures with dendrite morphology and a hollow interior were synthesized by using a replacement reaction between Ag dendrites and an aqueous solution of HAuCl(4). The Ag nanostructured dendrites were generated by the reaction of AgNO(3) with ascorbic acid in a methanol/water system. The dendrites resemble a coral shape and are built up of many stems with an asymmetric arrangement. Each stem is approximately 400 nm in length and 65 nm in diameter. The bimetallic composition of Au(x)Ag(1-x) can be tuned by the addition of different amounts of HAuCl(4) to the Ag dendritic solution. The hollowing process resulted in tubular structures with a wall thickness of 10.5 nm in Au(0.3)Ag(0.7) dendrites. The UV/Vis spectra indicate that the strongest NIR absorption among the resulting hollow Au(x)Ag(1-x) dendrites was in Au(0.3)Ag(0.7). The MTT assay was conducted to evaluate the cytotoxicity of Ag dendrites, hollow Au(0.06)Ag(0.94) and Au(0.3)Ag(0.7) dendrites, and Au nanorods. It was found that hollow Au(0.06)Ag(0.94) and Au(0.3)Ag(0.7) dendrites exhibited good biocompatibility, while both Ag dendrites and Au nanorods showed dose-dependent toxicity. Because of absorption in the NIR region, hollow Au(0.3)Ag(0.7) dendrites were used as photothermal absorbers for destroying A549 lung cancer cells. Their photothermal performance was compared to that of Au nanorod photothermal therapeutic agents. As a result, the particle concentration and laser power required for efficient cancer cell damage were significantly reduced for hollow Au(0.3)Ag(0.7) dendrites relative to those used for Au nanorods. The hollow Au(0.3)Ag(0.7) nanostructured dendrites show potential in photothermolysis for killing cancer cells.

  4. Intramuscular Temperature Rises With Topical Analgesics Used as Coupling Agents During Therapeutic Ultrasound

    PubMed Central

    Measom, Gary J.; Fellingham, Gilbert W.

    2001-01-01

    Objective: To compare the effectiveness of Nature's Chemist as an ultrasound coupling agent with the effectiveness of another topical analgesic (Biofreeze), Aquasonic 100, and a sham treatment in producing intramuscular (IM) temperature increase during a typical therapeutic ultrasound treatment. Design and Setting: Subjects were randomly assigned to 1 of 4 treatment groups (n = 10 in each group). Groups 1 through 3 received continuous ultrasound at 1.0 W/cm2 for 10 minutes at a frequency of 3 MHz over the posterior calf. Group 4 received a sham treatment. In group 1, we used Aquasonic 100 alone; in group 2, we used a 1:1 (wt/wt) mixture of Biofreeze and Aquasonic 100; in group 3, we used a 1:1 mixture of Nature's Chemist and Aquasonic 100; and in group 4, we used a 1:1 mixture of Aquasonic 100 and Nature's Chemist. In all groups, IM temperature was recorded during the treatment and for 15 minutes posttreatment. We used a modified visual analogue scale to measure each subject's perception of heat at the treatment area during and after treatment. Subjects: Forty college students (age, 22.5 ± 2.0 years; height, 175.5 ± 8.0 cm; weight, 71.6 ± 13.1 kg; calf skinfold thickness, 17.8 ± 7.2 mm) volunteered to become subjects. Measurements: The IM temperature was recorded at 15-second intervals for 25 minutes at 1 cm below the subcutaneous fat with a thermocouple. Differences were analyzed within and among groups at the beginning of the treatment (T0), the end of the treatment (T10), and 15 minutes posttreatment (T25). Results: The IM temperature increases in groups 1 through 3 were significantly different from those in group 4 (sham), but they were not significantly different from each other. Temperatures increased in group 1 (Aquasonic 100) by 7.47° ± 1.8°C, in group 2 (Biofreeze and Aquasonic 100) by 6.52° ± 1.6°C, and in group 3 (Nature's Chemist and Aquasonic 100) by 6.99° ± 1.1°C. Temperatures decreased in group 4 (sham) by 0.56° ± 0.3°C. There were no

  5. Garcinia xanthones as orally active antitumor agents.

    PubMed

    Zhang, Xiaojin; Li, Xiang; Sun, Haopeng; Wang, Xiaojian; Zhao, Li; Gao, Yuan; Liu, Xiaorong; Zhang, Shenglie; Wang, Yanyan; Yang, Yingrui; Zeng, Su; Guo, Qinglong; You, Qidong

    2013-01-10

    Using a newly developed strategy whose key step is the regioselective propargylation of hydroxyxanthone substrates, 99 structurally diverse Garcinia natural-product-like xanthones based on gambogic acid were designed and synthesized and their in vitro antitumor activity was evaluated. A set of 40 related compounds was chosen for determination of their physicochemical properties including polar surface area, log D₇.₄, aqueous solubility, and permeability at pH 7.4. In the light of the in vitro antitumor activity and the physicochemical properties, two compounds were advanced into in vivo efficacy experiments. The antitumor activity of compound 112, administered po, showed more potent in vivo oral antitumor activity than gambogic acid.

  6. Ozone: A Multifaceted Molecule with Unexpected Therapeutic Activity.

    PubMed

    Zanardi, I; Borrelli, E; Valacchi, G; Travagli, V; Bocci, V

    2016-01-01

    A comprehensive outline for understanding and recommending the therapeutic use of ozone in combination with established therapy in diseases characterized by a chronic oxidative stress is currently available. The view of the absolute ozone toxicity is incorrect, because it has been based either on lung or on studies performed in artificial environments that do not correspond to the real antioxidant capacity of body compartments. In fact, ozone exerts either a potent toxic activity or it can stimulate biological responses of vital importance, analogously to gases with prospective therapeutic value such as NO, CO, H2S, H2, as well as O2 itself. Such a crucial difference has increasingly become evident during the last decade. The purpose of this review is to explain the aspects still poorly understood, highlighting the divergent activity of ozone on the various biological districts. It will be clarified that such a dual effect does not depend only upon the final gas concentration, but also on the particular biological system where ozone acts. The real significance of ozone as adjuvant therapeutic treatment concerns severe chronic pathologies among which are cardiovascular diseases, chronic obstructive pulmonary diseases, multiple sclerosis, and the dry form of age-related macular degeneration. It is time for a full insertion of ozone therapy within pharmaceutical sciences, responding to all the requirements of quality, efficacy and safety, rather than as either an alternative or an esoteric approach.

  7. Potential use of biaromatic L-phenylalanyl derivatives as therapeutic agents in the treatment of sickle cell disease.

    PubMed Central

    Votano, J R; Altman, J; Wilchek, M; Gorecki, M; Rich, A

    1984-01-01

    N-Phenylacetyl-L-phenylalanine (PAP) and L-phenylalanyl-3-aminopyridine ( PAPA ) are biaromatic agents with properties that make them suitable candidates for the development of a useful therapeutic agent for the treatment of sickle cell disease. PAP and PAPA are taken up by the erythrocyte to give intra-/extracellular concentration ratios of 2.2 and 1.5, respectively, after a 2-hr exposure period. The intracellular buildup of PAP and PAPA produces moderate decreases in the mean corpuscular hemoglobin concentration (MCHC) of 6 and 10%, respectively, at 3 mM and a further decline in MCHC with increased concentration. Both PAP and PAPA increase the deoxy-Hb S solubility, CS. If the solubility in the absence of the agent is COS, PAP and PAPA have CS/COS values of 1.21 and 1.14 at 20 mM, respectively, compared with a value of 1.06 for L-phenylalanine itself. Filterability assays of partially dexygenated homozygous sickle cells shows an increase in cell flexibility of 7 to 16 times more than that of untreated cells when these agents are present at 3-6 mM. These results are largely due to the reduction in the Hb S polymer content of the treated cells. At 3 mM or less, both PAP and PAPA delay the onset of gelation in reversible sickle cells for time periods that are likely to be therapeutically useful. PMID:6587344

  8. Ferrous iron-dependent delivery of therapeutic agents to the malaria parasite

    PubMed Central

    Mahajan, Sumit S; Gut, Jiri; Rosenthal, Philip J; Renslo, Adam R

    2013-01-01

    Background The malaria parasites Plasmodium falciparum and Plasmodium vivax generate significant concentrations of free unbound ferrous iron heme as a side product of hemoglobin degradation. The presence of these chemically reactive forms of iron, rare in healthy cells, presents an opportunity for parasite-selective drug delivery. Accordingly, our group is developing technologies for the targeted delivery of therapeutics to the intra-erythrocytic malaria parasite. These so-called ‘fragmenting hybrids’ employ a 1,2,4-trioxolane ring system as an iron(II)-sensing ‘trigger’ moiety and a ‘traceless’ retro-Michael linker to which a variety of partner drug species may be attached. After ferrous iron-promoted activation in the parasite, the partner drug is released via a β-elimination reaction. Methods In this report, we describe three orthogonal experimental approaches that were explored in order to generate in vitro proof-of-concept for ferrous iron-dependent drug delivery from a prototypical fragmenting hybrid. Conclusion Studies of two fragmenting hybrids by orthogonal approaches confirm that a partner drug species can be delivered to live P. falciparum parasites. A key advantage of this approach is the potential to mask a partner drug’s intrinsic bioactivity prior to release in the parasite. PMID:23234548

  9. Therapeutic and prophylactic activity of itraconazole against human rhinovirus infection in a murine model

    PubMed Central

    Shim, Aeri; Song, Jae-Hyoung; Kwon, Bo-Eun; Lee, Jeong-Jun; Ahn, Jae-Hee; Kim, Yeon-Jeong; Rhee, Ki-Jong; Chang, Sun-Young; Cha, Younggil; Lee, Yong-Soo; Kweon, Mi-Na; Park, Kwi Sung; Kim, Dong-Eun; Cho, Sungchan; Cho, Hyun-Jong; Ko, Hyun-Jeong

    2016-01-01

    Human rhinovirus (HRV) is the most common viral infectious agent in humans and is the predominant cause of the common cold. There is a need for appropriate vaccines or therapeutic agents to treat HRV infection. In this study, we investigated whether itraconazole (ICZ) can protect cells from HRV-induced cytotoxicity. Replication of HRV1B was reduced by ICZ treatment in the lungs of HRV1B- as compared to vehicle-treated mice. The numbers of immune cells, including granulocytes and monocytes, were reduced in bronchoalveolar lavage fluid (BALF) by ICZ administration after HRV1B infection, corresponding to decreased pro-inflammatory cytokine and chemokine levels in BALF. A histological analysis of lung tissue showed that ICZ suppressed inflammation caused by HRV1B infection. Interestingly, pretreatment of mice with ICZ in the form of a nasal spray had potent prophylactic antiviral activity. Cholesterol accumulation in the plasma membrane was observed upon HRV infection; ICZ blocked cholesterol trafficking to the plasma membrane, as well as resulted in its accumulation in subcellular compartments near the nucleus. These findings suggest that ICZ is a potential antiviral agent for the treatment of HRV infection, which can be adopted preventatively as well as therapeutically. PMID:26976677

  10. Molecular combo of photodynamic therapeutic agent silicon(iv) phthalocyanine and anticancer drug cisplatin.

    PubMed

    Mao, Jiafei; Zhang, Yangmiao; Zhu, Jianhui; Zhang, Changli; Guo, Zijian

    2009-02-28

    The combination of a red light PDT agent and a Pt(ii)-based chemotherapeutic drug at the molecular level maintains the intrinsic functions of each unit; the conjugated complexes exhibit remarkable photocytoxicity and demonstrate potential to serve as agents for DNA-targeting PDT as well as red light photochemotherapy.

  11. Antimicrobial Dendrimeric Peptides: Structure, Activity and New Therapeutic Applications.

    PubMed

    Scorciapino, Mariano A; Serra, Ilaria; Manzo, Giorgia; Rinaldi, Andrea C

    2017-03-03

    Microbial resistance to conventional antibiotics is one of the most outstanding medical and scientific challenges of our times. Despite the recognised need for new anti-infective agents, however, very few new drugs have been brought to the market and to the clinic in the last three decades. This review highlights the properties of a new class of antibiotics, namely dendrimeric peptides. These intriguing novel compounds, generally made of multiple peptidic sequences linked to an inner branched core, display an array of antibacterial, antiviral and antifungal activities, usually coupled to low haemolytic activity. In addition, several peptides synthesized in oligobranched form proved to be promising tools for the selective treatment of cancer cells.

  12. New drugs from old natural compounds: scarcely investigated sesquiterpenes as new possible therapeutic agents.

    PubMed

    Suta, Stefania; Maggi, Filippo; Nicoletti, Marcello; Baldan, Valeria; Dall Acqua, Stefano

    2017-04-04

    Sesquiterpene are natural products that have been extensively studied for their bioactivities, evidencing their potentiality as useful scaffolds for the development of drugs. Considering the different derivatives, the sesquiterpene lactones have been evaluated, especially on cancer cell and antineoplastic efficacy in in vivo studies. Their bioactivity is strictly related to the presence of the reactive α-methylene-γ-lactone group (αMγL). Nevertheless, several other sesquiterpene lacking of the αMγL are known and have been studied for their biological effects and potential usefulness in the development of new drugs. In this review, we focused on several sesquiterpenes that are not presenting the αMγL moiety and may have future potential as scaffold for the development of new drugs, namely the bicyclic compounds belonging to the carotane type (daucanes) that present significant effect as antiproliferative and estrogenic agents. The monocyclic humulane derivatives correlated to zerumbone, and the bicyclic compound beta-caryophyllene and its derivatives that have been considered in the field of cancer and inflammation. It is noteworthy that published studies on sesquiterpenes, reported in this review, concern on pathologies of increasing importance, like estrogen, anti-proliferative, bone loos, immunity deficiency and anti-tumour activities. Some of the natural "old" sesquiterpenes can be considered for their possible role in drug discovery and in counteracting these "new" challenges.

  13. Asphaltenes as a surface active agent

    SciTech Connect

    Sheu, E.Y.; Shields, M.B.; Storm, D.A.

    1995-12-31

    Asphaltene represents the heavy-end materials of the crude oil, conventionally defined via solvent solubility (either heptane or pentane). Chemically, it consists of polynuclear aromatics with the H/C ratio close to unity. Additionally, it contains a great deal of heteroatoms, such as sulfur, nitrogen, nickel, vanadium, etc. Several experiments have revealed the surface activity of asphaltenes in some selected solvents through measurements of their rheology or critical micelle concentrations in these solvents. The asphaltene micelles were found thermodynamically reversible. In a two phase asphaltene/water system, asphaltenes appear to vary their surface activities depending upon the polarity of the aqueous phase. Our recent experiment further showed that asphaltene/water/toluene may form, water-in-oil emulsion under certain conditions.

  14. Activity-Based Protein Profiling Reveals Broad Reactivity of the Nerve Agent Sarin.

    PubMed

    Tuin, Adriaan W; Mol, Marijke A E; van den Berg, Roland M; Fidder, A; van der Marel, Gijs A; Overkleeft, Herman S; Noort, Daan

    2009-04-01

    Elucidation of noncholinesterase protein targets of organophosphates, and nerve agents in particular, may reveal additional mechanisms for their high toxicity as well as clues for novel therapeutic approaches toward intoxications with these agents. Within this framework, we here describe the synthesis of the activity-based probe 3, which contains a phosphonofluoridate moiety, a P-Me moiety, and a biotinylated O-alkyl group, and its use in activity-based protein profiling with two relevant biological samples, that is, rhesus monkey liver and cultured human A549 lung cells. In this way, we have unearthed eight serine hydrolases (fatty acid synthase, acylpeptide hydrolase, dipeptidyl peptidase 9, prolyl oligopeptidase, carboxylesterase, long-chain acyl coenzyme A thioesterase, PAF acetylhydrolase 1b, and esterase D/S-formyl glutathione hydrolase) as targets that are modified by the nerve agent sarin. It is also shown that the newly developed probe 3 might find its way into the development of alternative, less laborious purification protocols for human butyrylcholinesterase, a potent bioscavenger currently under clinical investigation as a prophylactic/therapeutic for nerve agent intoxications.

  15. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy.

    PubMed

    Siemann, Dietmar W; Mercer, Emma; Lepler, Sharon; Rojiani, Amyn M

    2002-05-01

    The utility of combining the vascular targeting agents 5,6-dimethyl-xanthenone-4 acetic acid (DMXAA) and combretastatin A-4 disodium phosphate (CA4DP) with the anticancer drugs cisplatin and cyclophosphamide (CP) was evaluated in experimental rodent (KHT sarcoma), human breast (SKBR3) and ovarian (OW-1) tumor models. Doses of the vascular targeting agents that led to rapid vascular shutdown and subsequent extensive central tumor necrosis were identified. Histologic evaluation showed morphologic damage of tumor cells within a few hours after treatment, followed by extensive hemorrhagic necrosis and dose-dependent neoplastic cell death as a result of prolonged ischemia. Whereas these effects were induced by a range of CA4DP doses (10-150 mg/kg), the dose response to DMXAA was extremely steep; doses < or = 15 mg/kg were ineffective and doses > or = 20 mg/kg were toxic. DMXAA also enhanced the tumor cell killing of cisplatin, but doses > 15 mg/kg were required. In contrast, CA4DP increased cisplatin-induced tumor cell killing at all doses studied. This enhancement of cisplatin efficacy was dependent on the sequence and interval between the agents. The greatest effects were achieved when the vascular targeting agents were administered 1-3 hr after cisplatin. When CA4DP (100 mg/kg) or DMXAA (17.5 mg/kg) were administered 1 hr after a range of doses of cisplatin or CP, the tumor cell kill was 10-500-fold greater than that seen with chemotherapy alone. In addition, the inclusion of the antivascular agents did not increase bone marrow stem cell toxicity associated with these anticancer drugs, thus giving rise to a therapeutic gain.

  16. In Vitro Sensitivity Profiling Of Neuroblastoma Cells Against A Comprehensive Small Molecule Kinase Inhibitor Library To Identify Agents For Future Therapeutic Studies.

    PubMed

    Singh, Anjali; Meier-Stephenson, Vanessa; Jayanthan, Aarthi; Narendran, Aru

    2016-11-22

    Solid tumors represent one of the most widespread causes of death in children across the world. Neuroblastoma (NB) constitutes about 8% of all childhood tumors, yet accounts for more than 15% of death, with an unacceptable overall survival rate. Despite the current multimodal therapeutic approaches involving surgery, radiation, chemotherapy with myeloablative therapy and hematopoietic stem cell rescue, there is growing realization of the limitations of conventional agents to improve the outcome in high risk metastatic disease. Hence, efforts have intensified to identify new targets and novel therapeutic approaches to improve cure rates in these children. Among the significant number of new therapeutics that are being evaluated for cancer each year, the agents that have been developed for common adult malignancies have the added advantage of having usable toxicity data already available for consideration. To identify potential therapeutic targets, we screened a small molecule library of 151 small kinase inhibitors against NB cell lines. Based on our initial screening data, we further examined the potential of Bcr-Abl targeting small molecule inhibitors to affect the growth and survival of NB cells. Our findings confirm the diversity in activity among the currently available Bcr-Abl inhibitors, possibly reflecting the molecular heterogeneity and off-target activity in each combination. In depth analyses of ponatinib, an orally bioavailable multi-target kinase inhibitor and an effective agent in the treatment of refractory Philadelphia chromosome (Ph) positive leukemia, show growth inhibition at sub-micromolar concentrations. In addition, we also identified the potential of this agent to interfere with insulin-like growth factor-1 receptor (IGF-1R) signaling pathways and Src activity. Ponatinib also induced apoptosis, indicated by caspase-9 and PARP cleavage. Furthermore, at sub-lethal conditions ponatinib significantly inhibited the ability of these cells to migrate

  17. The presence of Estrogen Receptor β modulates the response of breast cancer cells to therapeutic agents.

    PubMed

    Pons, Daniel Gabriel; Torrens-Mas, Margalida; Nadal-Serrano, Mercedes; Sastre-Serra, Jorge; Roca, Pilar; Oliver, Jordi

    2015-09-01

    Breast cancer is a leading cause of death for women. The estrogen receptors (ERs) ratio is important in the maintenance of mitochondrial redox status, and higher levels of ERβ increases mitochondrial functionality, decreasing ROS production. Our aim was to determine the interaction between the ERα/ERβ ratio and the response to cytotoxic treatments such as cisplatin (CDDP), paclitaxel (PTX) and tamoxifen (TAM). Cell viability, apoptosis, autophagy, ROS production, mitochondrial membrane potential, mitochondrial mass and mitochondrial functionality were analyzed in MCF-7 (high ERα/ERβ ratio) and T47D (low ERα/ERβ ratio) breast cancer cell lines. Cell viability decreased more in MCF-7 when treated with CDDP and PTX. Apoptosis was less activated after cytotoxic treatments in T47D than in MCF-7 cells. Nevertheless, autophagy was increased more in CDDP-treated MCF-7, but less in TAM-treated cells than in T47D. CDDP treatment produced a raise in mitochondrial mass in MCF-7, as well as the citochrome c oxidase (COX) and ATP synthase protein levels, however significantly reduced COX activity. In CDDP-treated cells, the overexpression of ERβ in MCF-7 caused a reduction in apoptosis, autophagy and ROS production, leading to higher cell survival; and the silencing of ERβ in T47D cells promoted the opposite effects. In TAM-treated cells, ERβ-overexpression led to less cell viability by an increment in autophagy; and the partial knockdown of ERβ in T47D triggered an increase in ROS production and apoptosis, leading to cell death. In conclusion, ERβ expression plays an important role in the response of cancer cells to cytotoxic agents, especially for cisplatin treatment.

  18. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  19. Anti-Androgen Receptor RNA Enzyme as a Novel Therapeutic Agent for Prostate Cancer in Vivo

    DTIC Science & Technology

    2007-08-01

    No Primary Field of Research: (Please check only one box) Cancer biomarkers, prevention & control Cancer genetics Carcinogenesis Cancer ... immunology Cell or molecular biology Clinical interventions DNA repair/genomic integrity Drug development/experimental therapeutics

  20. Ultrasound Delivery of an Anti-Aβ Therapeutic Agent to the Brain in a Mouse Model of Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Jordão, Jessica F.; Ayala-Grosso, Carlos A.; Chopra, Rajiv; McLaurin, JoAnne; Aubert, Isabelle; Hynynen, Kullervo

    2009-04-01

    Plaques composed of amyloid-beta (Aβ) peptides represent a pathological hallmark in the brain of patients with Alzheimer's disease. Aβ oligomers are considered cytotoxic and several therapeutic approaches focus on reducing Aβ load in the brain of Alzheimer's patients. The efficacy of most anti-Aβ agents is significantly limited because they do not cross the blood-brain-barrier. Innovative technologies capable of enhancing the permeability of the blood-brain barrier, thereby allowing entry of therapeutic agents into the brain, show great promise in circumventing this problem. The application of low-intensity focused ultrasound in the presence of an ultrasound contrast agent causes localized and transient permeability of the blood-brain barrier. We demonstrate the value of this technology for the delivery of anti-Aβ antibodies to the brain of TgCRND8 mice, a mouse model of Alzheimer's disease exhibiting Aβ plaques. BAM-10, an anti-Aβ antibody, was injected into the tail vein simultaneously with exposure to MRI-guided, low-intensity focused ultrasound (FUS) to one hemisphere of TgCNRD8 mice. Four hours after treatment, antibodies were detected at significant amounts only in the brain of mice receiving FUS in addition to BAM-10. This data provides a proof-of-concept that FUS allows anti-Aβ therapeutics to efficiently enter the brain and target Aβ plaques. Four days following a single treatment with BAM-10 and MRI-guided FUS, a significant decrease in the number of Aβ plaques on the side of the treated hemisphere was observed in TgCRND8 mice. In conclusion low-intensity, focused ultrasound is effective in delivering Aβ antibodies to the brain. This technology has the potential to enhance current anti-Aβ treatments by allowing increased exposure of amyloid plaques to treatment agents.

  1. Effects of exogenous agents on brain development: stress, abuse and therapeutic compounds.

    PubMed

    Archer, Trevor

    2011-10-01

    The range of exogenous agents likely to affect, generally detrimentally, the normal development of the brain and central nervous system defies estimation although the amount of accumulated evidence is enormous. The present review is limited to certain types of chemotherapeutic and "use-and-abuse" compounds and environmental agents, exemplified by anesthetic, antiepileptic, sleep-inducing and anxiolytic compounds, nicotine and alcohol, and stress as well as agents of infection; each of these agents have been investigated quite extensively and have been shown to contribute to the etiopathogenesis of serious neuropsychiatric disorders. To greater or lesser extent, all of the exogenous agents discussed in the present treatise have been investigated for their influence upon neurodevelopmental processes during the period of the brain growth spurt and during other phases uptill adulthood, thereby maintaining the notion of critical phases for the outcome of treatment whether prenatal, postnatal, or adolescent. Several of these agents have contributed to the developmental disruptions underlying structural and functional brain abnormalities that are observed in the symptom and biomarker profiles of the schizophrenia spectrum disorders and the fetal alcohol spectrum disorders. In each case, the effects of the exogenous agents upon the status of the affected brain, within defined parameters and conditions, is generally permanent and irreversible.

  2. Botulinum Toxin Type A as a Therapeutic Agent against Headache and Related Disorders

    PubMed Central

    Luvisetto, Siro; Gazerani, Parisa; Cianchetti, Carlo; Pavone, Flaminia

    2015-01-01

    Botulinum neurotoxin A (BoNT/A) is a toxin produced by the naturally-occurring Clostridium botulinum that causes botulism. The potential of BoNT/A as a useful medical intervention was discovered by scientists developing a vaccine to protect against botulism. They found that, when injected into a muscle, BoNT/A causes a flaccid paralysis. Following this discovery, BoNT/A has been used for many years in the treatment of conditions of pathological muscle hyperactivity, like dystonias and spasticities. In parallel, the toxin has become a “glamour” drug due to its power to ward off facial wrinkles, particularly frontal, due to the activity of the mimic muscles. After the discovery that the drug also appeared to have a preventive effect on headache, scientists spent many efforts to study the potentially-therapeutic action of BoNT/A against pain. BoNT/A is effective at reducing pain in a number of disease states, including cervical dystonia, neuropathic pain, lower back pain, spasticity, myofascial pain and bladder pain. In 2010, regulatory approval for the treatment of chronic migraine with BoNT/A was given, notwithstanding the fact that the mechanism of action is still not completely elucidated. In the present review, we summarize experimental evidence that may help to clarify the mechanisms of action of BoNT/A in relation to the alleviation of headache pain, with particular emphasis on preclinical studies, both in animals and humans. Moreover, we summarize the latest clinical trials that show evidence on headache conditions that may obtain benefits from therapy with BoNT/A. PMID:26404377

  3. Activity of 10 antimicrobial agents against intracellular Rhodococcus equi.

    PubMed

    Giguère, Steeve; Berghaus, Londa J; Lee, Elise A

    2015-08-05

    Studies with facultative intracellular bacterial pathogens have shown that evaluation of the bactericidal activity of antimicrobial agents against intracellular bacteria is more closely associated with in vivo efficacy than traditional in vitro susceptibility testing. The objective of this study was to determine the relative activity of 10 antimicrobial agents against intracellular Rhodococcus equi. Equine monocyte-derived macrophages were infected with virulent R. equi and exposed to erythromycin, clarithromycin, azithromycin, rifampin, ceftiofur, gentamicin, enrofloxacin, vancomycin, imipenem, or doxycycline at concentrations achievable in plasma at clinically recommended dosages in foals. The number of intracellular R. equi was determined 48h after infection by counting colony forming units (CFUs). The number of R. equi CFUs in untreated control wells were significantly higher than those of monolayers treated with antimicrobial agents. Numbers of R. equi were significantly lower in monolayers treated with enrofloxacin followed by those treated with gentamicin, and vancomycin, when compared to monolayers treated with other antimicrobial agents. Numbers of R. equi in monolayers treated with doxycycline were significantly higher than those of monolayers treated with other antimicrobial agents. Differences in R. equi CFUs between monolayers treated with other antimicrobial agents were not statistically significant. Enrofloxacin, gentamicin, and vancomycin are the most active drugs in equine monocyte-derived macrophages infected with R. equi. Additional studies will be needed to determine if these findings correlate with in vivo efficacy.

  4. THREE-DIMENSIONAL MODELING OF THE DYNAMICS OF THERAPEUTIC ULTRASOUND CONTRAST AGENTS

    PubMed Central

    Hsiao, Chao-Tsung; Lu, Xiaozhen; Chahine, Georges

    2010-01-01

    A 3-D thick-shell contrast agent dynamics model was developed by coupling a finite volume Navier-Stokes solver and a potential boundary element method flow solver to simulate the dynamics of thick-shelled contrast agents subjected to pressure waves. The 3-D model was validated using a spherical thick-shell model validated by experimental observations. We then used this model to study shell break-up during nonspherical deformations resulting from multiple contrast agent interaction or the presence of a nearby solid wall. Our simulations indicate that the thick viscous shell resists the contrast agent from forming a re-entrant jet, as normally observed for an air bubble oscillating near a solid wall. Instead, the shell thickness varies significantly from location to location during the dynamics, and this could lead to shell break-up caused by local shell thinning and stretching. PMID:20950929

  5. Melatonin, a potential therapeutic agent for smooth muscle-related pathological conditions and aging.

    PubMed

    Pozo, M J; Gomez-Pinilla, P J; Camello-Almaraz, C; Martin-Cano, F E; Pascua, P; Rol, M A; Acuña-Castroviejo, D; Camello, P J

    2010-01-01

    Increases or decreases in the contractile response of smooth muscle underlie important pathological conditions such as hypertension, incontinence and altered gastrointestinal transit. These disorders are also frequently encountered in the aged population. Oxidative stress and inflammation are key features in the initiation, progression, and clinical manifestations of smooth muscle disorders. Melatonin, the major secretory product of the pineal gland, has free radical scavenging and antioxidative properties and protects against oxidative insult. Recently, widespread interest has grown regarding the apparent protective effects of melatonin on smooth muscle dysfunction. "In vitro" studies have shown that melatonin decreased vascular tone of vascular beds from control, hypertensive or aged animals, through the reduction of adrenergic contraction and the increase in acetylcholine-induced relaxation. "In vivo", melatonin also attenuates sympathetic tone by direct activation of melatonin receptors, scavenging free radicals or increasing NO availability in the central nervous system. In the gastrointestinal tract, melatonin treatment improves age-related impairments in gallbladder contractility and prevents deleterious effects of cholecystitis on smooth muscle and the enteric nervous system through suppression of oxidative stress. In addition, melatonin improves colonic transit time in constipation-predominant IBS patients. Melatonin is also able to restore impaired contractility of the detrusor muscle from old animals through normalization of Ca(2+) dependent and independent contraction, mitochondrial polarity, neuromuscular function and oxidative stress, which would explain the effects of melatonin counteracting cystometric changes in senescent animals. It also reverses bladder damage following ischemia/reperfusion. In conclusion, melatonin may be a promising candidate for future research of agents that modulate smooth muscle motility.

  6. pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents.

    PubMed

    Malik, Erum; Dennison, Sarah R; Harris, Frederick; Phoenix, David A

    2016-11-01

    Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel

  7. pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

    PubMed Central

    Malik, Erum; Dennison, Sarah R.; Harris, Frederick; Phoenix, David A.

    2016-01-01

    Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel

  8. Antidote control of aptamer therapeutics: the road to a safer class of drug agents.

    PubMed

    Bompiani, K M; Woodruff, R S; Becker, R C; Nimjee, S M; Sullenger, B A

    2012-08-01

    Aptamers, or nucleic acid ligands, have gained clinical interest over the past 20 years due to their unique characteristics, which are a combination of the best facets of small molecules and antibodies. The high binding affinity and specificity of aptamers allows for isolation of an artificial ligand for theoretically any therapeutic target of interest. Chemical manipulations of aptamers also allow for fine-tuning of their bioavailability, and antidote control greatly expands their clinical use. Here we review the various methods of antidote control of aptamer therapeutics--matched oligonucleotide antidotes and universal antidotes. We also describe the development, recent progress, and potential future therapeutic applications of these types of aptamer-antidote pairs.

  9. Pomalidomide shows significant therapeutic activity against CNS lymphoma with a major impact on the tumor microenvironment in murine models.

    PubMed

    Li, Zhimin; Qiu, Yushi; Personett, David; Huang, Peng; Edenfield, Brandy; Katz, Jason; Babusis, Darius; Tang, Yang; Shirely, Michael A; Moghaddam, Mehran F; Copland, John A; Tun, Han W

    2013-01-01

    Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti-lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1-polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS

  10. Therapeutic Uses of Active Videogames: A Systematic Review

    PubMed Central

    Flynn, Rachel

    2014-01-01

    Abstract Background: Active videogames (AVGs) may be useful for promoting physical activity for therapeutic uses, including for balance, rehabilitation, and management of illness or disease. The literature from 64 peer-reviewed publications that assessed health outcomes of AVGs for therapeutic purposes was synthesized. Materials and Methods: PubMed, Medline, and PyschInfo were queried for original studies related to the use of AVGs to improve physical outcomes in patients who were ill or undergoing rehabilitation related to balance, burn treatment, cancer, cerebral palsy, Down's syndrome, extremity dysfunction or amputation, hospitalization, lupus, Parkinson's disease, spinal injury, or stroke. The following inclusion criteria were used: (1) human subjects; (2) English language; (3) not duplicates; (4) new empirical data; and (5) tests an AVG, including commercially available or custom-designed. Studies were included regardless of participants' age or the study design. Results and Limitations: Overall, the vast majority of studies demonstrated promising results for improved health outcomes related to therapy, including significantly greater or comparable effects of AVG play versus usual care. However, many studies were pilot trials with small, homogeneous samples, and many studies lacked a control or comparison group. Some trials tested multiweek or multimonth interventions, although many used a single bout of gameplay, and few included follow-up assessments to test sustainability of improved health. Conclusions and Implications: AVGs were acceptable and enjoyable to the populations examined and appear as a promising tool for balance, rehabilitation, and illness management. Future research directions and implications for clinicians are discussed. PMID:26192642

  11. C60 Fullerene as Promising Therapeutic Agent for the Prevention and Correction of Skeletal Muscle Functioning at Ischemic Injury

    NASA Astrophysics Data System (ADS)

    Nozdrenko, D. M.; Zavodovskyi, D. O.; Matvienko, T. Yu.; Zay, S. Yu.; Bogutska, K. I.; Prylutskyy, Yu. I.; Ritter, U.; Scharff, P.

    2017-02-01

    The therapeutic effect of pristine C60 fullerene aqueous colloid solution (C60FAS) on the functioning of the rat soleus muscle at ischemic injury depending on the time of the general pathogenesis of muscular system and method of administration C60FAS in vivo was investigated. It was found that intravenous administration of C60FAS is the optimal for correction of speed macroparameters of contraction for ischemic muscle damage. At the same time, intramuscular administration of C60FAS shows pronounced protective effect in movements associated with the generation of maximum force responses or prolonged contractions, which increase the muscle fatigue level. Analysis of content concentration of creatine phosphokinase and lactate dehydrogenase enzymes in the blood of experimental animals indicates directly that C60FAS may be a promising therapeutic agent for the prevention and correction of ischemic-damaged skeletal muscle function.

  12. A High-Throughput Biophotonics Instrument to Screen for Novel Ocular Photosensitizing Therapeutic Agents

    PubMed Central

    Butler, Mark C.; Itotia, Patrick N.

    2010-01-01

    Purpose. High-throughput techniques are needed to identify and optimize novel photodynamic therapy (PDT) agents with greater efficacy and to lower toxicity. Novel agents with the capacity to completely ablate pathologic angiogenesis could be of substantial utility in diseases such as wet age-related macular degeneration (AMD). Methods. An instrument and approach was developed based on light-emitting diode (LED) technology for high-throughput screening (HTS) of libraries of potential chemical and biological photosensitizing agents. Ninety-six-well LED arrays were generated at multiple wavelengths and under rigorous intensity control. Cell toxicity was measured in 96-well culture arrays with the nuclear dye SYTOX Green (Invitrogen-Molecular Probes, Eugene, OR). Results. Rapid screening of photoactivatable chemicals or biological molecules has been realized in 96-well arrays of cultured human cells. This instrument can be used to identify new PDT agents that exert cell toxicity on presentation of light of the appropriate energy. The system is further demonstrated through determination of the dose dependence of model compounds having or lacking cellular phototoxicity. Killer Red (KR), a genetically encoded red fluorescent protein expressed from transfected plasmids, is examined as a potential cellular photosensitizing agent and offers unique opportunities as a cell-type–specific phototoxic protein. Conclusions. This instrument has the capacity to screen large chemical or biological libraries for rapid identification and optimization of potential novel phototoxic lead candidates. KR and its derivatives have unique potential in ocular gene therapy for pathologic angiogenesis or tumors. PMID:19834043

  13. 78 FR 77471 - Prospective Grant of Exclusive License for: Convection Enhanced Delivery of a Therapeutic Agent...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-23

    ... HUMAN SERVICES National Institutes of Health Prospective Grant of Exclusive License for: Convection... inventions embodied in: HHS Ref. No E-202-2002/0 ``Method for Convection Enhanced Delivery of Therapeutic... that express IL-4 receptor on their cell surface by administering cpIL4- PE38KDEL by...

  14. 77 FR 26772 - Prospective Grant of Exclusive License: Ocular Therapeutics Agent Delivery Devices and Methods...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-07

    ... HUMAN SERVICES National Institutes of Health Prospective Grant of Exclusive License: Ocular Therapeutics... Health, Public Health Service, HHS. ACTION: Notice. SUMMARY: This is notice, in accordance with 35 U.S.C... Health and Human Services, is contemplating the grant of an exclusive patent license to practice...

  15. Chitosan oligosaccharide: Biological activities and potential therapeutic applications.

    PubMed

    Muanprasat, Chatchai; Chatsudthipong, Varanuj

    2017-02-01

    Chitosan oligosaccharide (COS) is an oligomer of β-(1➔4)-linked d-glucosamine. COS can be prepared from the deacetylation and hydrolysis of chitin, which is commonly found in the exoskeletons of arthropods and insects and the cell walls of fungi. COS is water soluble, non-cytotoxic, readily absorbed through the intestine and mainly excreted in the urine. Of particular importance, COS and its derivatives have been demonstrated to possess several biological activities including anti-inflammation, immunostimulation, anti-tumor, anti-obesity, anti-hypertension, anti-Alzheimer's disease, tissue regeneration promotion, drug and DNA delivery enhancement, anti-microbial, anti-oxidation and calcium-absorption enhancement. The mechanisms of actions of COS have been found to involve the modulation of several important pathways including the suppression of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) and the activation of AMP-activated protein kinase (AMPK). This review summarizes the current knowledge of the preparation methods, pharmacokinetic profiles, biological activities, potential therapeutic applications and safety profiles of COS and its derivatives. In addition, future research directions are discussed.

  16. Antimicrobial Dendrimeric Peptides: Structure, Activity and New Therapeutic Applications

    PubMed Central

    Scorciapino, Mariano A.; Serra, Ilaria; Manzo, Giorgia; Rinaldi, Andrea C.

    2017-01-01

    Microbial resistance to conventional antibiotics is one of the most outstanding medical and scientific challenges of our times. Despite the recognised need for new anti-infective agents, however, very few new drugs have been brought to the market and to the clinic in the last three decades. This review highlights the properties of a new class of antibiotics, namely dendrimeric peptides. These intriguing novel compounds, generally made of multiple peptidic sequences linked to an inner branched core, display an array of antibacterial, antiviral and antifungal activities, usually coupled to low haemolytic activity. In addition, several peptides synthesized in oligobranched form proved to be promising tools for the selective treatment of cancer cells. PMID:28273806

  17. Circulatory therapeutics: use of antihypertensive agents and their effects on the vasculature

    PubMed Central

    Schiffrin, Ernesto L

    2010-01-01

    Abstract This review addresses the use of the different antihypertensive agents currently available and some in development, and their effects on the vasculature. The different classes of agents used in the treatment of hypertension, and the results of recent large clinical trials, dosing protocols and adverse effects are first briefly summarized. The consequences on blood vessels of the use of antihypertensive drugs and the differential effects on the biology of large and small arteries resulting in modulation of vascular remodelling and dysfunction in hypertensive patients are then described. Large elastic conduit arteries exhibit outward hypertrophic remodelling and increased stiffness, which contributes to raise systolic blood pressure and afterload on the heart. Small resistance arteries undergo eutrophic or hypertrophic inward remodelling, and impair tissue perfusion. By these mechanisms both large and small arteries may contribute to trigger cardiovascular events. Some antihypertensive agents correct these changes, which could contribute to improved outcome. The mechanisms that at the level of the vascular wall lead to remodelling and can be beneficially affected by antihypertensive agents will also be addressed. These include vasoconstriction, growth and inflammation. The molecular pathways contributing to growth and inflammation will be summarily described. Further identification of these signalling pathways should allow identification of novel targets leading to development of new and improved medications for the treatment of hypertension and cardiovascular disease. PMID:20345850

  18. Vulnerable families as active agents of their own change process: a bidirectional perspective.

    PubMed

    Goh, Esther C L

    2015-04-01

    The literature on successful practice with vulnerable families reports social workers' efforts in forging therapeutic bonds with clients, their ability to both recognize clients' strengths and pain and support them as they work through adversity. Vulnerable families' own contribu- tions to their change process, however, have remained largely opaque. This article offers concrete conceptual tools to consider both social workers and clients from vulnerable families as active agents in the change process. Empirical evidence collected by practitioner-researchers through in-depth discussions with 10 vulnerable families illustrates clients' agentic capacities for autonomy, construction, and action as well as joint construction and maintenance of the helping relationships with social workers, thereby illustrating their active contribution to the process of change.

  19. Activation of a photosensitive pharmaceutical agent by a triboluminescent material

    SciTech Connect

    Yuen, Stacey; Schreyer, Magdalena; Finlay, W.H.; Loebenberg, R.; Moussa, W.

    2006-03-20

    Given the recent emphasis on applications of triboluminescent materials, we investigate the ability of a triboluminescent material to activate a photosensitive pharmaceutical agent. Using compressed sucrose doped with wintergreen, which luminesces when fractured, we demonstrate the activation of riboflavin (vitamin B2), a photosensitizer. A product of activation is the highly reactive singlet oxygen. We add ascorbic acid (vitamin C), an antioxidant, and measure the amount of ascorbic acid oxidation to correlate with the amount of riboflavin activation. Up to 17% ascorbic acid oxidation is observed, indicating triboluminescence is worth exploring as a mechanism for activation of photosensitizers in photodynamic therapy.

  20. Alternative matrices for therapeutic drug monitoring of immunosuppressive agents using LC-MS/MS.

    PubMed

    Ghareeb, Mwlod; Akhlaghi, Fatemeh

    2015-01-01

    Immunosuppressive drugs used in solid organ transplants typically have narrow therapeutic windows and high intra- and intersubject variability. To ensure satisfactory exposure, therapeutic drug monitoring (TDM) plays a pivotal role in any successful posttransplant maintenance therapy. Currently, recommendations for optimum immunosuppressant concentrations are based on blood/plasma measurements. However, they introduce many disadvantages, including poor prediction of allograft survival and toxicity, a weak correlation with drug concentrations at the site of action and the invasive nature of the sample collection. Thus, alternative matrices have been investigated. This paper reviews tandem-mass spectrometry (LC-MS/MS) methods used for the quantification of immunosuppressant drugs utilizing nonconventional matrices, namely oral fluids, fingerprick blood and intracellular and intratissue sampling. The advantages, disadvantages and clinical application of such alternative mediums are discussed. Additionally, sample extraction techniques and basic chromatography information regarding these methods are presented in tabulated form.

  1. Phytochemical Modulators of Mitochondria: The Search for Chemopreventive Agents and Supportive Therapeutics

    PubMed Central

    Grabacka, Maja M.; Gawin, Malgorzata; Pierzchalska, Malgorzata

    2014-01-01

    Mitochondria are crucially important for maintaining not only the energy homeostasis, but the proper cellular functions in a general sense. Impairment of mitochondrial functions is observed in a broad variety of pathological states such as neoplastic transformations and cancer, neurodegenerative diseases, metabolic disorders and chronic inflammation. Currently, in parallel to the classical drug design approaches, there is an increasing interest in the screening for natural bioactive substances, mainly phytochemicals, in order to develop new therapeutic solutions for the mentioned pathologies. Dietary phytochemicals such as resveratrol, curcumin and sulforaphane are very well tolerated and can effectively complement classical pharmacological therapeutic regimens. In this paper we disscuss the effect of the chosen phytochemicals (e.g., resveratrol, curcumin, sulforaphane) on various aspects of mitochondrial biology, namely mitochondrial biogenesis, membrane potential and reactive oxygen species production, signaling to and from the nucleus and unfolded protein response. PMID:25192192

  2. Keratin sponge/hydrogel II, active agent delivery

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Keratin sponge/hydrogels from oxidation and reduction hydrolysis of fine and coarse wool fibers were formed to behave as cationic hydrogels to swell and release active agents in the specific region of the gastro-intestinal (GI) tract. Their porous, interpenetrating networks (IPN) were effective for...

  3. Supplemental substances derived from foods as adjunctive therapeutic agents for treatment of neurodegenerative diseases and disorders.

    PubMed

    Bigford, Gregory E; Del Rossi, Gianluca

    2014-07-01

    Neurodegenerative disorders and diseases (NDDs) that are either chronically acquired or triggered by a singular detrimental event are a rapidly growing cause of disability and/or death. In recent times, there have been major advancements in our understanding of various neurodegenerative disease states that have revealed common pathologic features or mechanisms. The many mechanistic parallels discovered between various neurodegenerative diseases suggest that a single therapeutic approach may be used to treat multiple disease conditions. Of late, natural compounds and supplemental substances have become an increasingly attractive option to treat NDDs because there is growing evidence that these nutritional constituents have potential adjunctive therapeutic effects (be it protective or restorative) on various neurodegenerative diseases. Here we review relevant experimental and clinical data on supplemental substances (i.e., curcuminoids, rosmarinic acid, resveratrol, acetyl-L-carnitine, and ω-3 (n-3) polyunsaturated fatty acids) that have demonstrated encouraging therapeutic effects on chronic diseases, such as Alzheimer's disease and neurodegeneration resulting from acute adverse events, such as traumatic brain injury.

  4. 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

  5. Erythrocyte-derived photo-theranostic agents: hybrid nano-vesicles containing indocyanine green for near infrared imaging and therapeutic applications

    PubMed Central

    Bahmani, Baharak; Bacon, Danielle; Anvari, Bahman

    2013-01-01

    Development of theranostic nano-constructs may enable diagnosis and treatment of diseases at high spatial resolution. Some key requirements for clinical translation of such constructs are that they must be non-toxic, non-immunogenic, biodegradable, with extended circulating lifetime. Cell-based structures, particularly those derived from erythrocytes, are promising candidate carrier systems to satisfy these requirements. One particular type of theranostic materials utilize light-sensitive agents that once photo-activated can provide diagnostic imaging capability, and elicit therapeutic effects. Here we demonstrate the first successful engineering of hybrid nano-scale constructs derived from membranes of hemoglobin-depleted erythrocytes that encapsulate the near infrared chromophore, indocyanine green. We show the utility of the constructs as photo-theranostic agents in fluorescence imaging and photothermal destruction of human cells. These erythrocyte-mimicking nano-structures can be derived autologously, and may have broad applications in personal nanomedicine ranging from imaging and photo-destruction of cancerous tissues to vascular abnormalities, and longitudinal evaluations of therapeutic interventions. PMID:23846447

  6. Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: Crossing the blood-brain-barrier divide

    PubMed Central

    Chacko, Ann-Marie; Li, Chunsheng; Pryma, Daniel A.; Brem, Steven; Coukos, George; Muzykantov, Vladimir R.

    2014-01-01

    Introduction Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. Areas covered This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. Expert Opinion Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes. PMID:23751126

  7. Nanoscaled boron-containing delivery systems and therapeutic agents for cancer treatment.

    PubMed

    Wang, Jing; Wu, Wei; Jiang, Xiqun

    2015-01-01

    Significant efforts have recently been made to develop nanoscaled boron-containing delivery systems for improving drug delivery in cancer therapy. On one hand, borate ester chemistry has shown importance in ligand-mediated tumor targeting owing to the recognition ability of boronic acid to polyol residues in cell membranes. In particular, the phenylboronic acid-functionalized nanocarriers for specific targeting to sialic acid groups which are overexpressed on tumor cells have made great achievements. On the other hand, nanoscaled boron neutron capture therapy agents show growing potential in efficiently transporting boron to tumor. The current review outlines the recent developments in the application of borate ester chemistry in tumor targeting by nanoparticles, then summarizes recent work on the development of boron-based nanomaterials as boron neutron capture therapy agents.

  8. Possible Role of Common Spices as a Preventive and Therapeutic Agent for Alzheimer's Disease

    PubMed Central

    Mirmosayyeb, Omid; Tanhaei, Amirpouya; Sohrabi, Hamid R.; Martins, Ralph N.; Tanhaei, Mana; Najafi, Mohammad Amin; Safaei, Ali; Meamar, Rokhsareh

    2017-01-01

    For centuries, spices have been consumed as food additives or medicinal agents. However, there is increasing evidence indicating the plant-based foods in regular diet may lower the risk of neurodegenerative diseases including Alzheimer disease. Spices, as one of the most commonly used plant-based food additives may provide more than just flavors, but as agents that may prevent or even halt neurodegenerative processes associated with aging. In this article, we review the role and application of five commonly used dietary spices including saffron turmeric, pepper family, zingiber, and cinnamon. Besides suppressing inflammatory pathways, these spices may act as antioxidant and inhibit acetyl cholinesterase and amyloid β aggregation. We summarized how spice-derived nutraceuticals mediate such different effects and what their molecular targets might be. Finally, some directions for future research are briefly discussed. PMID:28250905

  9. Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents Against Lung Cancer

    DTIC Science & Technology

    2014-10-01

    effectively and accurately replicate crosslinked DNA lesions such as thymine dimers and cisplatinated DNA (19-21). A third group of DNA polymerases...lines correlates with resistance to chemotherapeutic agents such as cisplatin which damage DNA (38). Furthermore, pol  overexpression is a poor... cisplatinated GG adduct (33). In this model, dCTP is properly paired with the first templating nucleobase via conventional hydrogen bonds. In general, our

  10. Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis

    PubMed Central

    González-García, C; Bravo, B; Ballester, A; Gómez-Pérez, R; Eguiluz, C; Redondo, M; Martínez, A; Gil, C; Ballester, S

    2013-01-01

    BACKGROUND AND PURPOSE PDE4 inhibition suppresses experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, side effects hinder PDE4 inhibitors clinical use. PDE7 inhibition might constitute an alternative therapeutic strategy, but few data about the anti-inflammatory potential of PDE7 inhibitors are currently available. We have used the EAE model to perform a comparative evaluation of PDE4 and PDE7 inhibition as strategies for MS treatment. EXPERIMENTAL APPROACH Two PDE7 inhibitors, the sulfonamide derivative BRL50481 and the recently described quinazoline compound TC3.6, were assayed to modulate EAE in SJL mice, in comparison with the well-known PDE4 inhibitor Rolipram. We evaluated clinical signs, presence of inflammatory infiltrates in CNS and anti-inflammatory markers. We also analysed the effect of these inhibitors on the inflammatory profile of spleen cells in vitro. KEY RESULTS TC3.6 prevented EAE with efficacy similar to Rolipram, while BRL50481 had no effect on the disease. Differences between both PDE7 inhibitors are discussed. Data from Rolipram and TC3.6 showed that PDE4 and PDE7 inhibition work through both common and distinct pathways. Rolipram administration caused an increase in IL-10 and IL-27 expression which was not found after TC3.6 treatment. On the other hand, both inhibitors reduced IL-17 levels, prevented infiltration in CNS and increased the expression of the T regulator cell marker Foxp3. CONCLUSIONS AND IMPLICATIONS These results provide new information about the effects of Rolipram on EAE, underline PDE7 inhibition as a new therapeutic target for inflammatory diseases and show the value of TC3.6 to prevent EAE, with possible consequences for new therapeutic tools in MS. PMID:23869659

  11. Identification of therapeutic targets in ovarian cancer through active tyrosine kinase profiling

    PubMed Central

    Ocaña, Alberto; Pandiella, Atanasio

    2015-01-01

    The activation status of a set of pro-oncogenic tyrosine kinases in ovarian cancer patient samples was analyzed to define potential therapeutic targets. Frequent activation of HER family receptor tyrosine kinases, especially HER2, was observed. Studies in ovarian cancer cell lines confirmed the activation of HER2. Moreover, knockdown of HER2 caused a strong inhibition of their proliferation. Analyses of the action of agents that target HER2 indicated that the antibody drug conjugate trastuzumab-emtansine (T-DM1) caused a substantial antitumoral effect in vivo and in vitro, and potentiated the action of drugs used in the therapy of ovarian cancer. T-DM1 provoked cell cycle arrest in mitosis, and caused the appearance of aberrant mitotic spindles in cells treated with the drug. Biochemical experiments confirmed accumulation of the mitotic markers phospho-Histone H3 and phospho-BUBR1 in cells treated with the drug. Prolonged treatment of ovarian cancer cells with T-DM1 provoked the appearance of multinucleated cells which later led to cell death. Together, these data indicate that HER2 represents an important oncogene in ovarian cancer, and suggest that targeting this tyrosine kinase with T-DM1 may be therapeutically effective, especially in ovarian tumors with high content of HER2. PMID:26336133

  12. Modulation of Adult Mesenchymal Stem Cells Activity by Toll-Like Receptors: Implications on Therapeutic Potential

    PubMed Central

    DelaRosa, Olga; Lombardo, Eleuterio

    2010-01-01

    Mesenchymal stem cells (MSCs) are of special interest as therapeutic agents in the settings of both chronic inflammatory and autoimmune diseases. Toll-like receptors (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases due to the permanent exposure of the immune system to TLR-specific stimuli. Therefore, MSCs employed in therapy can be potentially exposed to TLR ligands, which may modulate MSC therapeutic potential in vivo. Recent results demonstrate that MSCs are activated by TLR ligands leading to modulation of the differentiation, migration, proliferation, survival, and immunosuppression capacities. However inconsistent results among authors have been reported suggesting that the source of MSCs, TLR stimuli employed or culture conditions play a role. Notably, activation by TLR ligands has not been reported to modulate the “immunoprivileged” phenotype of MSCs which is of special relevance regarding the use of allogeneic MSC-based therapies. In this review, we discuss the available data on the modulation of MSCs activity through TLR signalling. PMID:20628526

  13. Application of Disposable Bag Bioreactors in Tissue Engineering and for the Production of Therapeutic Agents

    NASA Astrophysics Data System (ADS)

    Eibl, R.; Eibl, D.

    In order to increase process efficiency, many pharmaceutical and biotechnology companies have introduced disposable bag technology over the last 10 years. Because this technology also greatly reduces the risk of cross-contamination, disposable bags are preferred in applications in which an absolute or improved process safety is a necessity, namely the production of functional tissue for implantation (tissue engineering), the production of human cells for the treatment of cancer and immune system diseases (cellular therapy), the production of viruses for gene therapies, the production of therapeutic proteins, and veterinary as well as human vaccines.

  14. Halloysite clay nanotubes for controlled delivery of chemically active agents

    NASA Astrophysics Data System (ADS)

    Abdullayev, Elshard

    In this work we explored the capabilities of halloysite nanotubes as capsules for encapsulation and controlled delivery of the chemically and biologically active substances. Halloysite is a two-layered aluminosilicate which has a predominantly hollow tubular structure in the submicron range and is chemically similar to kaolinite [1, 2]. In the first section of this work, we analyzed the structure of the halloysite nanotubes as well as its capability to encapsulate and deliver biologically and chemically active agents, similarities and differences between release characteristics of different agents and how these differences relate with their chemical structure. Models were used to describe the release characteristics of the active agents. Study of the interaction between loaded agents and halloysite nanotubes provides better understanding of the release characteristics of the loaded agents and how halloysite can be implemented for technological and medical applications. The second part of the work deals with self-healing coatings produced on the basis of halloysite nanotubes loaded with corrosion inhibitors. Self-healing coatings are one of the effective methods to protect metals from corrosion and deterioration. The difference between self-healing coatings and the usual coatings is the ability of the first to recover after the formation of the damages due to external or internal stresses. High efficiency of the self- healing coatings produced by halloysite nanotubes were demonstrated on 110 Copper alloys and 2024 aluminum alloys. Controlled delivery of the corrosion inhibitors with additional encapsulation of the halloysite nanotubes by synthesizing stoppers at tube endings was also demonstrated. Additional encapsulation of the halloysite nanotubes may be necessary when slow release of the loaded agents is required or rapid convection of the liquid in the surrounding environment takes place (since this may cause rapid release of the loaded agents without additional

  15. Lactic Acid as a New Therapeutic Peeling Agent in the Treatment of Lifa Disease (Frictional Dermal Melanosis)

    PubMed Central

    Sharquie, Khalifa E; Al-Dhalimi, Muhsin A; Noaimi, Adil A; Al-Sultany, Hussein A

    2012-01-01

    Background: Lifa disease (frictional dermal melanosis) is a common dermatological problem. Full strength lactic acid has been proved to be effective and safe peeling agent in the treatment of melasma. Objective: To assess the effectiveness and the safety of lactic acid chemical peeling in the treatment of lifa disease. Materials and Methods: This open label therapeutic trial was conducted in Department of Dermatology in Najaf and Baghdad Teaching Hospitals, from March 2007-October 2008. Full strength lactic acid (92%, pH 3.5) was used as a peeling agent. The treatment sessions were done every 2 weeks until the desired response was achieved (but not more than 6 sessions). The response to therapy was evaluated by objective and subjective methods. All patients were followed monthly for 3 months after the last treatment session. Results: 52 patients with typical clinical features of lifa disease were included. All patients were slim with prominent bones and low body mass index, and gave history of using the lifa (washing agent) during bathing. The number of sessions ranged from 2-6 sessions. The pigmentation was improved in all patients as revealed by objective and subjective methods, and this response was statistically highly significant. No significant side effects were recorded in all treated patients. The improvement has been sustained without any obvious relapse throughout the follow-up period. Conclusion: Lactic acid peel is a new, non-costly mode of therapy in treating dermal melanosis in patients with lifa disease. PMID:23248362

  16. Novel and emerging drugs for systemic lupus erythematosus: mechanism of action and therapeutic activity.

    PubMed

    Robak, E; Robak, T

    2012-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity and defective T-cell function, and several cytokine aberrations, with high titer production of autoantibodies and clinical involvement in multiple organ systems. It can present with a wide variety of symptoms, most commonly involving the skin, joints, kidneys, and blood vessels. Patients with mild SLE can be treated with non-steroidal antiinflammatory drugs and antimalarials. Corticosteroids, azathioprine and cyclophosphamide, remain important for long term management of most patients with active disease. In recent years, significant progress in molecular and cellular biology of SLE has resulted in a better characterization and understanding of the biology and prognosis of this disease. These achievements have provided new opportunities for the development of innovative, more effective, therapies. Novel agents potentially useful in the treatment of patients with SLE include tolerogens, monoclonal antibodies and other agents. Tolerogens are synthetic molecules that can bind and cross-link autoantibodies on reactive B-cell surface, promoting B-cell depletion or inactivity. An anti-DNA antibody based peptide, pCons, might have also therapeutic efficacy in SLE patients who are positive for anti-DNA antibodies. In addition, prasterone, a proprietary synthetic dehydroepiandrosterone product is under investigation for the treatment of SLE. Blockade of TLR9 with specific G-rich DNAoligonucleotids also suppresses lupus activity. Several newer mAbs have been developed and are being evaluated in phase I/II clinical trials. These include newer anti-CD20 mAbs, anti-cytokine therapies, anti-BLys mAbs and anti-C5 mAbs. Most of the new agents which could be potentially useful in the treatment of patients with SLE need further laboratory investigations and clinical trials. In this review, promising new agents, potentially useful in SLE, are presented.

  17. Novel Browning Agents, Mechanisms, and Therapeutic Potentials of Brown Adipose Tissue

    PubMed Central

    Shen, Michael; Yadav, Hariom; Thakali, Keshari M.

    2016-01-01

    Nonshivering thermogenesis is the process of biological heat production in mammals and is primarily mediated by brown adipose tissue (BAT). Through ubiquitous expression of uncoupling protein 1 (Ucp1) on the mitochondrial inner membrane, BAT displays uncoupling of fuel combustion and ATP production in order to dissipate energy as heat. Because of its crucial role in regulating energy homeostasis, ongoing exploration of BAT has emphasized its therapeutic potential in addressing the global epidemics of obesity and diabetes. The recent appreciation that adult humans possess functional BAT strengthens this prospect. Furthermore, it has been identified that there are both classical brown adipocytes residing in dedicated BAT depots and “beige” adipocytes residing in white adipose tissue depots that can acquire BAT-like characteristics in response to environmental cues. This review aims to provide a brief overview of BAT research and summarize recent findings concerning the physiological, cellular, and developmental characteristics of brown adipocytes. In addition, some key genetic, molecular, and pharmacologic targets of BAT/Beige cells that have been reported to have therapeutic potential to combat obesity will be discussed. PMID:28105413

  18. Diagnostic and therapeutic potential of new radiopharmaceutical agents in medullary thyroid carcinoma

    SciTech Connect

    Troncone, L.; Rufini, V.; De Rosa, G.; Testa, A.

    1989-01-01

    Recently developed radiopharmaceuticals have been proposed for imaging medullary thyroid carcinoma (MTC) with some having therapeutic potential. This study compares the imaging results obtained with radioiodinated meta-iodo-benzylguanidine (MIBG), {sup 99m}Tc (V) DMSA, and {sup 131}I F(ab')2 anti-carcinoembryonic antigen (anti-CEA) in a group of MTC patients. In 23 patients {sup 131}I MIBG imaging showed a high specificity (no false-positive results) but a less satisfactory sensitivity (50%). In 12 patients {sup 99m}Tc (V) DMSA revealed a better sensitivity (77%) but a lower specificity (three false-positive results). Positive results were obtained in two of three patients studied with {sup 131}I F(ab')2 anti-CEA. These data suggest that the highly sensitive {sup 99m}Tc (V) DMSA should be considered as a first choice procedure followed by the highly specific radioiodinated MIBG to confirm the initial results. Since radioiodinated MIBG imaging may have therapeutic usefulness, {sup 131}I MIBG was evaluated in an integrated treatment protocol in four cases of proven MTC. The preliminary results obtained were encouraging.

  19. New potential antimalarial agents: therapeutic-index evaluation of pyrroloquinazolinediamine and its prodrugs in a rat model of severe malaria.

    PubMed

    Xie, Lisa H; Li, Qigui; Lin, Ai J; Smith, Kirsten; Zhang, Jing; Skillman, Donald S

    2006-05-01

    Tetra-acetamide pyrroloquinazolinediamine (PQD-A4) and bis-ethylcarbamyl pyrroloquinazolinediamine (PQD-BE) are new derivatives of pyrroloquinazolinediamine (PQD) and are being investigated as potential chemotherapeutic agents for the treatment of malaria. Comparative studies to assess the therapeutic indices of PQD-A4, PQD-BE, and PQD were conducted in Plasmodium berghei-infected rats following daily intragastric dosing for three consecutive days. Artesunate (AS), a standard drug for treatment of severe malaria, was used as a comparator. The minimum doses required to clear malaria parasitemia were 156 micromol/kg of body weight for AS and 2.4 micromol/kg for PQD, PQD-4A, and PQD-BE. The maximum tolerated dose (MTD) of AS was 625 micromol/kg, and its therapeutic index was calculated to be 4. The MTDs of PQD-A4, PQD-BE, and PQD were found to be 190, 77, and 24 micromol/kg, respectively, yielding therapeutic indices of 80, 32, and 10, respectively. Although PQD-A4 and PQD-BE are only half as potent as PQD based on their curative effects, the two new derivatives, PQD-4A and PQD-BE, are 8.0-fold and 3.2-fold safer, respectively, than their parent compound when they are dosed for three consecutive days. Oral PQD-A4 and PQD-BE are 44 to 70 times more potent on an mg basis than intravenous AS. As assessed from the therapeutic index over 3 days, PQD-A4, PQD-BE, and PQD administered orally are 20.0, 8.0, and 2.5 times safer than AS given intravenously. The results indicate that PQD-4A is a promising candidate for antimalarial treatment.

  20. Engineering a Therapeutic Lectin by Uncoupling Mitogenicity from Antiviral Activity

    PubMed Central

    Swanson, Michael D.; Boudreaux, Daniel M.; Salmon, Loïc; Chugh, Jeetender; Winter, Harry C.; Meagher, Jennifer L.; André, Sabine; Murphy, Paul V.; Oscarson, Stefan; Roy, René; King, Steven; Kaplan, Mark H.; Goldstein, Irwin J.; Tarbet, E. Bart; Hurst, Brett L.; Smee, Donald F.; de la Fuente, Cynthia; Hoffmann, Hans-Heinrich; Xue, Yi; Rice, Charles M.; Schols, Dominique; Garcia, J. Victor; Stuckey, Jeanne A.; Gabius, Hans-Joachim; Al-Hashimi, Hashim M.; Markovitz, David M.

    2015-01-01

    Summary A key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a single amino acid substitution in a banana lectin, replacing histidine 84 with a threonine, significantly reduces its mitogenicity while preserving its broad-spectrum antiviral potency. X-ray crystallography, NMR spectroscopy, and glycocluster assays reveal that loss of mitogenicity is strongly correlated with loss of pi-pi stacking between aromatic amino acids H84 and Y83, which removes a wall separating two carbohydrate binding sites, thus diminishing multivalent interactions. On the other hand, monovalent interactions and antiviral activity are preserved by retaining other wild-type conformational features and possibly through unique contacts involving the T84 side chain. Through such fine-tuning, target selection and downstream effects of a lectin can be modulated so as to knock down one activity while preserving another, thus providing tools for therapeutics and for understanding the Sugar Code. PMID:26496612

  1. Bypassing the blood-brain barrier: delivery of therapeutic agents by macrophages

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Baek, Seung-Kuk; Kwon, Young Jik; Sun, Chung-Ho; Madsen, Steen J.

    2010-02-01

    Introduction: Failure to eradicate infiltrating glioma cells using conventional treatment regimens results in tumor recurrence and is responsible for the dismal prognosis of patients with glioblastoma multiforme (GBM). This is due to the fact that these migratory cells are protected by the blood-brain barrier (BBB) and the blood brain tumor barrier (BBTB) which prevents the delivery of most anti-cancer agents. We have evaluated the ability of monocytes/macrophages (Mo/Ma) to cross the BBB in rats. This will permit access of anti-cancer agents such as nanoparticles to effectively target the infiltrating tumor cells, and potentially improve the treatment effectiveness for malignant gliomas. Materials and Methods: The infiltration of Mo/Ma into brain tumor spheroids in vitro was determined using fluorescent stained Mo/Ma. Tumors were also established in the brains of inbred rats and ALA-PDT was given 18 days following tumor induction. The degredation of the BBTB and quantification of the number of infiltrating Mo/Ma was examined on histological sections from removed brains. Results & Conclusion: PDT was highly effective in locally opening the BBTB and inducing macrophage migration into the irradiated portions of brain tumors.

  2. Nonlinear behaviors of contrast agents relevant to diagnostic and therapeutic applications.

    PubMed

    Wu, Junru; Pepe, Jason; Dewitt, William

    2003-04-01

    The nonlinear properties of an encapsulated microbubble of a contrast agent were studied theoretically and experimentally. A modified nonlinear differential equation (Herring equation) was used to describe the radial oscillation of the microbubble and solved numerically. It was found that the nonlinear resonance frequency, at which the peak radial oscillation amplitude occurs, was a decreasing function of the acoustic amplitude of a driving ultrasonic pulse. Optical images of the contrast agent microbubbles under various ultrasonic exposure conditions: 1. sham exposure; 2. 2-MHz spatial peak acoustic pressure = 200 kPa, I(SATA) = 260 mW/cm(2), duty cycle = 7.5%, repetition period = 0.0266 ms; 3. 0.5-MHz spatial peak acoustic pressure = 200 kPa, I(SATA) = 130 mW/cm(2), duty cycle = 7.5%, repetition period = 0.1067 ms; have also shown that the lower-frequency ultrasound (US) excitation (0.5 MHz) is more effective in disruption of the microbubbles due to acoustic inertial cavitation than the higher frequency US (2 MHz).

  3. Recent advances in metamaterial split-ring-resonator circuits as biosensors and therapeutic agents.

    PubMed

    RoyChoudhury, Sohini; Rawat, Vaishali; Jalal, Ahmed Hasnain; Kale, S N; Bhansali, Shekhar

    2016-12-15

    Potential applications of thin film metamaterials are diverse and their realization to offer miniaturized waveguides, antennas and shielding patterns are on anvil. These artificially engineered structures can produce astonishing electromagnetic responses because of their constituents being engineered at much smaller dimensions than the wavelength of the incident electromagnetic wave, hence behaving as artificial materials. Such micro-nano dimensions of thin film metamaterial structures can be customized for various applications due to their exclusive responses to not only electromagnetic, but also to acoustic and thermal waves that surpass the natural materials' properties. In this paper, the recent major advancements in the emerging fields of diagnostics (sensors) and therapeutics involving thin film metamaterials have been reviewed and underlined; discussing their edge over conventional counterpart techniques; concentrating on their design considerations and feasible ways of achieving them. Challenges faced in sensitivity, precision, accuracy and factors that interfere with the degree of performance of the sensors are also dealt with, herein.

  4. Immunomodulators as Therapeutic Agents in Mitigating the Progression of Parkinson’s Disease

    PubMed Central

    Grimmig, Bethany; Morganti, Josh; Nash, Kevin; Bickford, Paula C

    2016-01-01

    Parkinson’s disease (PD) is a common neurodegenerative disorder that primarily afflicts the elderly. It is characterized by motor dysfunction due to extensive neuron loss in the substantia nigra pars compacta. There are multiple biological processes that are negatively impacted during the pathogenesis of PD, and are implicated in the cell death in this region. Neuroinflammation is evidently involved in PD pathology and mitigating the inflammatory cascade has been a therapeutic strategy. Age is the number one risk factor for PD and thus needs to be considered in the context of disease pathology. Here, we discuss the role of neuroinflammation within the context of aging as it applies to the development of PD, and the potential for two representative compounds, fractalkine and astaxanthin, to attenuate the pathophysiology that modulates neurodegeneration that occurs in Parkinson’s disease. PMID:27669315

  5. Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia.

    PubMed

    Roecker, Anthony J; Cox, Christopher D; Coleman, Paul J

    2016-01-28

    Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist for the treatment of insomnia.

  6. 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

  7. Thiazole: a promising heterocycle for the development of potent CNS active agents.

    PubMed

    Mishra, Chandra Bhushan; Kumari, Shikha; Tiwari, Manisha

    2015-03-06

    Thiazole is a valuable scaffold in the field of medicinal chemistry and has accounted to display a variety of biological activities. Thiazole and its derivatives have attracted continuing interest to design various novel CNS active agents. In the past few decades, thiazoles have been widely used to develop a variety of therapeutic agents against numerous CNS targets. Thiazole containing drug molecules are currently being used in treatment of various CNS disorders and a number of thiazole derivatives are also presently in clinical trials. A lot of research has been carried out on thiazole and their analogues, which has proved their efficacy to overcome several CNS disorders in rodent as well as primate models. The aim of present review is to highlights diverse CNS activities displayed by thiazole and their derivatives. SAR of this nucleus has also been well discussed. This review covers the recent updates present in literature and will surely provide a greater insight for the designing and development of potent thiazole based CNS active agents in future.

  8. Activity of quinone alkylating agents in quinone-resistant cells.

    PubMed

    Begleiter, A; Leith, M K

    1990-05-15

    The role of the quinone group in the antitumor activity of quinone alkylating agents, such as mitomycin C and 2,5-diaziridinyl-3,5-bis(carboethoxyamino)-1,4-benzoquinone, is still uncertain. The quinone group may contribute to antitumor activity by inducing DNA strand breaks through the formation of free radicals and/or by influencing the alkylating activity of the quinone alkylators. The cytotoxic activity and DNA damage produced by the model quinone alkylating agents, benzoquinone mustard and benzoquinone dimustard, were compared in L5178Y murine lymphoblasts sensitive and resistant to the model quinone antitumor agent, hydrolyzed benzoquinone mustard. The resistant cell lines, L5178Y/HBM2 and L5178Y/HBM10, have increased concentrations of glutathione and elevated catalase, superoxide dismutase, glutathione S-transferase, and DT-diaphorase activity. L5178Y/HBM2 and L5178Y/HBM10 cells were 7.4- and 8.5-fold less sensitive to benzoquinone mustard and 1.7- and 4.3-fold less sensitive to benzoquinone dimustard, respectively, compared with sensitive cells, but showed no resistance to the non-quinone alkylating agent, aniline mustard. The formation of DNA double strand breaks by benzoquinone mustard was reduced by 2- and 8-fold in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, while double strand break formation by benzoquinone dimustard was reduced only in the L5178Y/HBM10 cells. The number of DNA-DNA cross-links produced by benzoquinone mustard was 3- and 6-fold lower, and the number produced by benzoquinone dimustard was 35% and 2-fold lower in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, compared with L5178Y parental cells. In contrast, cross-linking by aniline mustard was unchanged in sensitive and resistant cells. Dicoumarol, an inhibitor of DT-diaphorase, increased the cytotoxic activity of both benzoquinone mustard and benzoquinone dimustard in L5178Y/HBM10 cells. This study provides evidence that elevated DT-diaphorase activity in the resistant cells

  9. Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents

    PubMed Central

    Krauze, Michal T.; Saito, Ryuta; Noble, Charles; Tamas, Matyas; Bringas, John; Park, John W.; Berger, Mitchel S.; Bankiewicz, Krystof

    2013-01-01

    Object Clinical application of the convection-enhanced delivery (CED) technique is currently limited by low infusion speed and reflux of the delivered agent. The authors developed and evaluated a new step-design cannula to overcome present limitations and to introduce a rapid, reflux-free CED method for future clinical trials. Methods The CED of 0.4% trypan blue dye was performed in agarose gel to test cannula needles for distribution and reflux. Infusion rates ranging from 0.5 to 50 μl/minute were used. Agarose gel findings were translated into a study in rats and then in cynomolgus monkeys (Macaca fascicularis) by using trypan blue and liposomes to confirm the efficacy of the reflux-free step-design cannula in vivo. Results of agarose gel studies showed reflux-free infusion with high flow rates using the step-design cannula. Data from the study in rats confirmed the agarose gel findings and also revealed increasing tissue damage at a flow rate above 5-μl/minute. Robust reflux-free delivery and distribution of liposomes was achieved using the step-design cannula in brains in both rats and nonhuman primates. Conclusions The authors developed a new step-design cannula for CED that effectively prevents reflux in vivo and maximizes the distribution of agents delivered in the brain. Data in the present study show reflux-free infusion with a constant volume of distribution in the rat brain over a broad range of flow rates. Reflux-free delivery of liposomes into nonhuman primate brain was also established using the cannula. This step-design cannula may allow reflux-free distribution and shorten the duration of infusion in future clinical applications of CED in humans. PMID:16304999

  10. Interview: glycolipid antigen presentation by CD1d and the therapeutic potential of NKT cell activation.

    PubMed

    Kronenberg, Mitchell

    2007-01-01

    Natural Killer T cells (NKT) are critical determinants of the immune response to cancer, regulation of autioimmune disease, clearance of infectious agents, and the development of artheriosclerotic plaques. In this interview, Mitch Kronenberg discusses his laboratory's efforts to understand the mechanism through which NKT cells are activated by glycolipid antigens. Central to these studies is CD1d--the antigen presenting molecule that presents glycolipids to NKT cells. The advent of CD1d tetramer technology, a technique developed by the Kronenberg lab, is critical for the sorting and identification of subsets of specific glycolipid-reactive T cells. Mitch explains how glycolipid agonists are being used as therapeutic agents to activate NKT cells in cancer patients and how CD1d tetramers can be used to assess the state of the NKT cell population in vivo following glycolipid agonist therapy. Current status of ongoing clinical trials using these agonists are discussed as well as Mitch's prediction for areas in the field of immunology that will have emerging importance in the near future.

  11. Inhibiting NF-κB Activation by Small Molecules As a Therapeutic Strategy

    PubMed Central

    Gupta, Subash C; Sundaram, Chitra; Reuter, Simone; Aggarwal, Bharat B

    2010-01-01

    Because nuclear factor-κB (NF-κB) is a ubiquitously expressed proinflammatory transcription factor that regulates the expression of over 500 genes involved in cellular transformation, survival, proliferation, invasion, angiogenesis, metastasis, and inflammation, the NF-κB signaling pathway has become a potential target for pharmacological intervention. A wide variety of agents can activate NF-κB through canonical and noncanonical pathways. Canonical pathway involves various steps including the phosphorylation, ubiquitnation, and degradation of the inhibitor of NF-κB (IκBα), which leads to the nuclear translocation of the p50- p65 subunits of NF-κB followed by p65 phosphorylation, acetylation and methylation, DNA binding, and gene transcription. Thus, agents that can inhibit protein kinases, protein phosphatases, proteasomes, ubiquitnation, acetylation, methylation, and DNA binding steps have been identified as NF-κB inhibitors. Here, we review the small molecules that suppress NF-κB activation and thus may have therapeutic potential. PMID:20493977

  12. Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

    PubMed Central

    Rathbun, R. Chris; Liedtke, Michelle D.

    2011-01-01

    Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide). The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed. PMID:24309307

  13. Eugenol nanocapsule for enhanced therapeutic activity against periodontal infections.

    PubMed

    Pramod, Kannissery; Aji Alex, M R; Singh, Manisha; Dang, Shweta; Ansari, Shahid H; Ali, Javed

    2016-01-01

    Eugenol is a godsend to dental care due to its analgesic, local anesthetic, and anti-inflammatory and antibacterial effects. The aim of the present research work was to prepare, characterize and evaluate eugenol-loaded nanocapsules (NCs) against periodontal infections. Eugenol-loaded polycaprolactone (PCL) NCs were prepared by solvent displacement method. The nanometric size of the prepared NCs was confirmed by transmission electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM). The in vitro drug release was found to follow a biphasic pattern and followed Michaelis-Menten like model. The percentage cell viability values near to 100 in the cell viability assay indicated that the NCs are not cytotoxic. In the in vivo studies, the eugenol NC group displayed significant difference in the continuity of epithelium of the interdental papilla in comparison to the untreated, pure eugenol and placebo groups. The in vivo performance of the eugenol-loaded NCs using ligature-induced periodontitis model in rats indicated that eugenol-loaded NCs could prevent septal bone resorption in periodontitis. On the basis of our research findings it could be concluded that eugenol-loaded PCL NCs could serve as a novel colloidal drug delivery system for enhanced therapeutic activity of eugenol in the treatment of periodontal infections.

  14. Preparation and standardization of a herbal agent for the therapeutic management of asthma.

    PubMed

    Emeje, Martins; Izuka, Amaka; Isimi, Christiana; Ofoefule, Sabinus; Kunle, Olobayo

    2011-04-01

    This study aims to develop a suitable single tablet dosage form containing a mixture of hot water stem back extracts of Anogeissus leiocarpus and Prosopis africana (AA1), suitable for use in the therapeutic management of asthma. The compaction characteristics of the oven-dried hot water extract (HWE) were studied using the Heckel equation. The mechanical properties as well as disintegration and dissolution profile of the compacts were also assessed. The results showed that AA1 exhibited high densification due to dye filling while the subsequent rearrangement of the granules did not contribute, significantly, to their densification. The granules had enhanced plasticity as shown by the low yield point, Py. The tablets produced from the extract had good mechanical properties, with hardness increasing with compression pressure while the friability decreased. Of the four disintegrants tested, tablets containing Explotab had the shortest disintegration time of 11 min while tablets containing Prosolv had the longest disintegration time of 40 min. The order of disintegrant property is Explotab > Cellactose > Emcocel > Maize starch > Prosolv. Dissolution results (t(90%)) show that tablets containing Explotab released 100% of the drug in 20 min proving to be the most suitable in acute asthma attack. The order of dissolution is Explotab > Cellactose > Maize starch > Prosolv > Emcocel. It is concluded that incorporation of Explotab (10%w/w) as a disintegrant in AA1 preparation produced tablets of suitable compressional properties and ensured adequate drug release for the management of acute asthma.

  15. NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents.

    PubMed

    Babalola, Olubukola; Mamalis, Andrew; Lev-Tov, Hadar; Jagdeo, Jared

    2014-05-01

    Fibrosis is characterized by the excessive deposition of extracellular matrix components eventually resulting in organ dysfunction and failure. In dermatology, fibrosis is the hallmark component of many skin diseases, including systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy and other conditions. Fibrotic skin disorders may be debilitating and impair quality of life. There are few FDA-approved anti-fibrotic drugs; thus, research in this area is crucial in addressing this deficiency. Recent investigations elucidating the pathogenesis of skin fibrosis have implicated endogenous reactive oxygen species produced by the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex. In this review, we discuss Nox enzymes and their role in skin fibrosis. An overview of the Nox enzyme family is presented and their role in the pathogenesis of skin fibrosis is discussed. The mechanisms by which Nox enzymes influence specific fibrotic skin disorders are also reviewed. Finally, we describe the therapeutic approaches to ameliorate skin fibrosis by directly targeting Nox enzymes with the use of statins, p47phox subunit modulators, or GKT137831, a competitive inhibitor of Nox enzymes. Nox enzymes can also be targeted indirectly via scavenging ROS with antioxidants. We believe that Nox modulators are worthy of further investigation and have the potential to transform the management of skin fibrosis by dermatologists.

  16. microRNAs as neuroregulators, biomarkers and therapeutic agents in neurodegenerative diseases.

    PubMed

    Basak, Indranil; Patil, Ketan S; Alves, Guido; Larsen, Jan Petter; Møller, Simon Geir

    2016-02-01

    The last decade has experienced the emergence of microRNAs as a key molecular tool for the diagnosis and prognosis of human diseases. Although the focus has mostly been on cancer, neurodegenerative diseases present an exciting, yet less explored, platform for microRNA research. Several studies have highlighted the significance of microRNAs in neurogenesis and neurodegeneration, and pre-clinical studies have shown the potential of microRNAs as biomarkers. Despite this, no bona fide microRNAs have been identified as true diagnostic or prognostic biomarkers for neurodegenerative disease. This is mainly due to the lack of precisely defined patient cohorts and the variability within and between individual cohorts. However, the discovery that microRNAs exist as stable molecules at detectable levels in body fluids has opened up new avenues for microRNAs as potential biomarker candidates. Furthermore, technological developments in microRNA biology have contributed to the possible design of microRNA-mediated disease intervention strategies. The combination of these advancements, with the availability of well-defined longitudinal patient cohort, promises to not only assist in developing invaluable diagnostic tools for clinicians, but also to increase our overall understanding of the underlying heterogeneity of neurodegenerative diseases. In this review, we present a comprehensive overview of the existing knowledge of microRNAs in neurodegeneration and provide a perspective of the applicability of microRNAs as a basis for future therapeutic intervention strategies.

  17. Mesenchymal Stem Cells as Therapeutics Agents: Quality and Environmental Regulatory Aspects

    PubMed Central

    Sabata, Roger; Verges, Josep; Zugaza, José L.; Ruiz, Adolfina; Clares, Beatriz

    2016-01-01

    Mesenchymal stem cells (MSCs) are one of the main stem cells that have been used for advanced therapies and regenerative medicine. To carry out the translational clinical application of MSCs, their manufacturing and administration in human must be controlled; therefore they should be considered as medicine: stem cell-based medicinal products (SCMPs). The development of MSCs as SCMPs represents complicated therapeutics due to their extreme complex nature and rigorous regulatory oversights. The manufacturing process of MSCs needs to be addressed in clean environments in compliance with requirements of Good Manufacturing Practice (GMP). Facilities should maintain these GMP conditions according to international and national medicinal regulatory frameworks that introduce a number of specifications in order to produce MSCs as safe SCMPs. One of these important and complex requirements is the environmental monitoring. Although a number of environmental requirements are clearly defined, some others are provided as recommendations. In this review we aim to outline the current issues with regard to international guidelines which impact environmental monitoring in cleanrooms and clean areas for the manufacturing of MSCs. PMID:27999600

  18. NADPH Oxidase Enzymes in Skin Fibrosis: Molecular Targets and Therapeutic Agents

    PubMed Central

    Lev-Tov, Hadar; Jagdeo, Jared

    2013-01-01

    Fibrosis is characterized by the excessive deposition of extracellular matrix components eventually resulting in organ dysfunction and failure. In dermatology, fibrosis is the hallmark component of many skin diseases, including systemic sclerosis, graft versus host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy and other conditions. Fibrotic skin disorders may be debilitating and impair quality of life. There are few FDA-approved anti-fibrotic drugs; thus, research in this area is crucial in addressing this deficiency. Recent investigations elucidating the pathogenesis of skin fibrosis have implicated endogenous reactive oxygen species produced by the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex. In this review we discuss Nox enzymes and their role in skin fibrosis. An overview of the Nox enzyme family is presented and their role in the pathogenesis of skin fibrosis is discussed. The mechanisms that Nox enzymes influence specific skin fibrotic disorders are also reviewed. Finally, we describe the therapeutic approaches to ameliorate skin fibrosis by directly targeting Nox enzymes with the use of statins, p47phox subunit modulators, or GKT137831, a competitive inhibitor of Nox enzymes. Nox enzymes can also be targeted indirectly via scavenging ROS with antioxidants. We believe that Nox modulators are worthy of further investigation and have the potential to transform the management of skin fibrosis by dermatologists. PMID:24155025

  19. Singing as a Therapeutic Agent, inThe Etude, 1891-1949.

    PubMed

    Hunter

    1999-01-01

    The Etude music magazine, founded by Theodore Presser, was one of a number of popular music magazines published in the years prior to the establishment of the music therapy profession in 1950. During its publication run from 1883 to 1957, over 100 music therapy related articles appeared, including 13 on the health benefits of singing published between 1891 and 1949. Written by authors with diverse backgrounds, such as the famous Battle Creek, Michigan physician John Harvey Kellogg and Boston music critic Louis C. Elson, the articles contained consistent and adamant support regarding the health benefits of singing. The advantages described were both physical and psychological, and were recommended prophylactically for well persons and therapeutically for ill persons. Although the articles varied in perspective, from philosophical to theoretical to pedagogical, there is a consistent holistic medicine theme that appeared almost ahead of its time and no doubt linked to the push for vocal music education in that era. The importance of The Etude in promulgating ideas that helped shape the early practice of music therapy should not be underestimated. For much of its publication run The Etude was the largest music periodical in print, reaching its peak circulation of 250,000 copies per month in 1924.

  20. Surveillance of antimicrobial resistance in bacteria isolated from food animals to antimicrobial growth promoters and related therapeutic agents in Denmark.

    PubMed

    Aarestrup, F M; Bager, F; Jensen, N E; Madsen, M; Meyling, A; Wegener, H C

    1998-06-01

    This study was conducted to describe the occurrence of acquired resistance to antimicrobials used for growth promotion among bacteria isolated from swine, cattle and poultry in Denmark. Resistance to structurally related therapeutic agents was also examined. Three categories of bacteria were tested: 1) indicator bacteria (Escherichia coli, Enterococcus faecalis, Enterococcus faecium), 2) zoonotic bacteria (Campylobacter, Salmonella, Yersinia enterocolitica), and 3) animal pathogens (E. coli, Staphylococcus aureus, coagulase-negative staphylococci (CNS), Staphylococcus hyicus, Actinobacillus pleuropneumoniae). All antimicrobials used as growth promoters in Denmark and some structurally related therapeutic agents (in brackets) were included: Avilamycin, avoparcin (vancomycin), bacitracin, carbadox, flavomycin, monensin, olaquindox, salinomycin, spiramycin (erythromycin, lincomycin), tylosin (erythromycin, lincomycin), and virginiamycin (pristinamycin). Bacterial species intrinsically resistant to an antimicrobial were not tested towards that antimicrobial. Breakpoints for growth promoters were established by population distribution of the bacteria tested. A total of 2,372 bacterial isolates collected during October 1995 to September 1996 were included in the study. Acquired resistance to all currently used growth promoting antimicrobials was found. A frequent occurrence of resistance were observed to avilamycin, avoparcin, bacitracin, flavomycin, spiramycin, tylosin and virginiamycin, whereas resistance to carbadox, monensin, olaquindox and salinomycin was less frequent. The occurrence of resistance varied by animal origin and bacterial species. The highest levels of resistance was observed among enterococci, whereas less resistance was observed among zoonotic bacteria and bacteria pathogenic to animals. The association between the occurrence of resistance and the consumption of the antimicrobial is discussed. The results show the present level of resistance to

  1. Erythrocytes and microbubble contrast agents, improve the therapeutic efficiency of high intensity focused ultrasound

    NASA Astrophysics Data System (ADS)

    Takegami, Kenji; Kaneko, Yukio; Watanabe, Toshiaki; Maruyama, Toshiyuki; Matsumoto, Yoichiro; Nagawa, Hirokazu

    2005-03-01

    Erythrocytes, an well as Levovist microbubble contrast agent, enhance the heating effect of high intensity focused ultrasound (HIFU) and increase the coagulation volume produced by HIFU irradiation. In vitro experiments used human plasma with various concentrations of human erythrocytes in combination with or without Levovist. In vivo experiments used eight Japan white rabbits with three levels of anaemia. Using a 2.17 MHz transducer, HIFU was applied for 60 seconds, and the temperature rise and the volume of coagulation necrosis was evaluated. There was a significant correlation between the HIFU-induced temperature rise and hematocrit, with a correlation coefficient of 0.998 (p=0.0001). Although the temperature rise was smaller at low hematocrit, it was significantly increased by adding Levovist to the suspension (p<0.01). The mean volume of coagulation necrosis was significantly higher in the rabbits with higher hematocrit (p<0.01), and that in the moderate anaemia group was significantly increased by using Levovist (p<0.01).

  2. A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins.

    PubMed

    Rosenberg, A S; Pariser, A R; Diamond, B; Yao, L; Turka, L A; Lacana, E; Kishnani, P S

    2016-04-01

    Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology.

  3. UCP2 inhibition sensitizes breast cancer cells to therapeutic agents by increasing oxidative stress.

    PubMed

    Pons, Daniel Gabriel; Nadal-Serrano, Mercedes; Torrens-Mas, Margalida; Valle, Adamo; Oliver, Jordi; Roca, Pilar

    2015-09-01

    Modulation of oxidative stress in cancer cells plays an important role in the study of the resistance to anticancer therapies. Uncoupling protein 2 (UCP2) may play a dual role in cancer, acting as a protective mechanism in normal cells, while its overexpression in cancer cells could confer resistance to chemotherapy and a higher survival through downregulation of ROS production. Thus, our aim was to check whether the inhibition of UCP2 expression and function increases oxidative stress and could render breast cancer cells more sensitive to cisplatin (CDDP) or tamoxifen (TAM). For this purpose, we studied clonogenicity, mitochondrial membrane potential (ΔΨm), cell viability, ROS production, apoptosis, and autophagy in MCF-7 and T47D (only the last four determinations) breast cancer cells treated with CDDP or TAM, in combination or without a UCP2 knockdown (siRNA or genipin). Furthermore, survival curves were performed in order to check the impact of UCP2 expression in breast cancer patients. UCP2 inhibition and cytotoxic treatments produced a decrease in cell viability and clonogenicity, in addition to an increase in ΔΨm, ROS production, apoptosis, and autophagy. It is important to note that CDDP decreased UCP2 protein levels, so that the greatest effects produced by the UCP2 inhibition in combination with a cytotoxic treatment, with regard to treatment alone, were observed in TAM+UCP2siRNA-treated cells. Moreover, this UCP2 inhibition caused autophagic cell death, since apoptosis parameters barely increased after UCP2 knockdown. Finally, survival curves revealed that higher UCP2 expression corresponded with a poorer prognosis. In conclusion, UCP2 could be a therapeutic target in breast cancer, especially in those patients treated with tamoxifen.

  4. Anti-microRNAs as Novel Therapeutic Agents in the Clinical Management of Alzheimer's Disease.

    PubMed

    Zhao, Yuhai; Alexandrov, Peter N; Lukiw, Walter J

    2016-01-01

    Overview- One hundred and ten years since its first description Alzheimer's disease (AD) still retains its prominent status: (i) as the industrialized world's number one cause of age-related intellectual impairment and cognitive decline; (ii) as this country's most rapidly expanding socioeconomic and healthcare concern; and (iii) as an insidious, progressive and lethal neurological disorder of the human central nervous system (CNS) for which there is currently no adequate treatment or cure (Alzheimer, 1991; Alzheimer et al., 1991, 1995) [https://www.alz.org/facts/downloads/facts_figures_2015.pdf (2015)]. The concept of small non-coding RNAs (ncRNAs) as being involved in the etiopathogenesis of AD and age-related human neurodegenerative disease was first proposed about 25 years ago, however it was not until 2007 that specific microRNA (miRNA) abundance, speciation and localization to the hippocampal CA1 region (an anatomical area of the human CNS specifically targeted by the AD process) was shown to strongly associate with AD-type change when compared to age-matched controls (Lukiw et al., 1992; Lukiw, 2007; Schipper et al., 2007; Cogswell et al., 2008; Guerreiro et al., 2012). Currently about 400 reports address the potential link between disruptions in miRNA signaling and the development of various features associated with AD neuropathology (http://www.ncbi.nlm.nih.gov/pubmed/?term=micro+RNA+alzheimer's+disease). In this "Perspectives" paper we will highlight some of the most recent literature on anti-miRNA (AM; antagomir) therapeutic strategies and some very recent technological advances in the analysis and characterization of defective miRNA signaling pathways in AD compared to neurologically normal age-matched controls.

  5. Nanodiscs as a therapeutic delivery agent: inhibition of respiratory syncytial virus infection in the lung.

    PubMed

    Numata, Mari; Grinkova, Yelena V; Mitchell, James R; Chu, Hong Wei; Sligar, Stephen G; Voelker, Dennis R

    2013-01-01

    There is increasing interest in the application of nanotechnology to solve the difficult problem of therapeutic administration of pharmaceuticals. Nanodiscs, composed of a stable discoidal lipid bilayer encircled by an amphipathic membrane scaffold protein that is an engineered variant of the human Apo A-I constituent of high-density lipoproteins, have been a successful platform for providing a controlled lipid composition in particles that are especially useful for investigating membrane protein structure and function. In this communication, we demonstrate that nanodiscs are effective in suppressing respiratory syncytial viral (RSV) infection both in vitro and in vivo when self-assembled with the minor pulmonary surfactant phospholipid palmitoyloleoylphosphatidylglycerol (POPG). Preparations of nanodiscs containing POPG (nPOPG) antagonized interleukin-8 production from Beas2B epithelial cells challenged by RSV infection, with an IC50 of 19.3 μg/mL. In quantitative in vitro plaque assays, nPOPG reduced RSV infection by 93%. In vivo, nPOPG suppressed inflammatory cell infiltration into the lung, as well as IFN-γ production in response to RSV challenge. nPOPG also completely suppressed the histopathological changes in lung tissue elicited by RSV and reduced the amount of virus recovered from lung tissue by 96%. The turnover rate of nPOPG was estimated to have a halftime of 60-120 minutes (m), based upon quantification of the recovery of the human Apo A-I constituent. From these data, we conclude that nPOPG is a potent antagonist of RSV infection and its inflammatory sequelae both in vitro and in vivo.

  6. Insect-gene-activity detection system for chemical and biological warfare agents and toxic industrial chemicals

    NASA Astrophysics Data System (ADS)

    Mackie, Ryan S.; Schilling, Amanda S.; Lopez, Arturo M.; Rayms-Keller, Alfredo

    2002-02-01

    Detection of multiple chemical and biological weapons (CBW) agents and/or complex mixtures of toxic industrial chemicals (TIC) is imperative for both the commercial and military sectors. In a military scenario, a multi-CBW attack would create confusion, thereby delaying decontamination and therapeutic efforts. In the commercial sector, polluted sites invariably contain a mixture of TIC. Novel detection systems capable of detecting CBW and TIC are sorely needed. While it may be impossible to build a detector capable of discriminating all the possible combinations of CBW, a detection system capable of statistically predicting the most likely composition of a given mixture is within the reach of current emerging technologies. Aquatic insect-gene activity may prove to be a sensitive, discriminating, and elegant paradigm for the detection of CBW and TIC. We propose to systematically establish the expression patterns of selected protein markers in insects exposed to specific mixtures of chemical and biological warfare agents to generate a library of biosignatures of exposure. The predicting capabilities of an operational library of biosignatures of exposures will allow the detection of emerging novel or genetically engineered agents, as well as complex mixtures of chemical and biological weapons agents. CBW and TIC are discussed in the context of war, terrorism, and pollution.

  7. Coordinating the activities of a planner and an execution agent

    NASA Technical Reports Server (NTRS)

    Tate, Austin

    1989-01-01

    A research program was defined that will explore the link between planning and execution systems. A simple scenario was defined in which a very capable off-line planning system interacts with the user and a smaller, less capable, on-line real-time system executing plans and reacting to faults. However, the on-line execution system may have a more flexible representation of the plans it is executing. This imbalance in the capabilities of the two agents involved should clarify some of the research objectives and give an experimental framework for the work. The task is to investigate the knowledge representations and communication protocols needed to link a user stating some requirements for a task to be carried out through a planning system to the (remote) execution agent that can carry out the user's wishes. The notion that a single representation can encapsulate the expression of the user's requirements, the capabilities for action, the communication to the execution agent, the successful or faulty response from the execution agent and the means of keeping the user informed, is examined. Methods of creating plan patches to update the plans separately held by each of the parties involved to keep them in step as they each react to changing circumstances in real-time is investigated. This involves the specification of plan patch attachment points that can be understood by the recipient. Transaction based methods are also investigated for coordinating the activities of the planner with those of the execution agent and user. The trial application area for the research is in the command and control of an advanced Earth Observation Space Platform.

  8. Anti-angiogenic activity of a novel synthetic agent, 9alpha-fluoromedroxyprogesterone acetate.

    PubMed

    Yamaji, T; Tsuboi, H; Murata, N; Uchida, M; Kohno, T; Sugino, E; Hibino, S; Shimamura, M; Oikawa, T

    1999-10-18

    9Alpha-fluoromedroxyprogesterone acetate (FMPA) is a novel synthetic analog of medroxyprogesterone acetate (MPA), widely used as therapeutic agent for breast and endometrium cancers. FMPA showed almost the same binding affinities to the progesterone and glucocorticoid receptors as MPA. In the rabbit corneal assay, FMPA, MPA and fumagillin significantly inhibited the angiogenic response induced by rat mammary tumor at doses of 0. 1, 1 and 50 microg/pellet, respectively, so FMPA showed greater anti-angiogenic activity than MPA and fumagillin. In the mouse dorsal air sac method, FMPA inhibited the mouse sarcoma 180 cell-induced angiogenesis by oral administration at a dose of 200 mg/kg. FMPA inhibited the activity of plasminogen activator (PA) in bovine endothelial cells. These results suggest that FMPA may be useful for diseases associated with angiogenesis by oral administration.

  9. Fabrication of Highly Uniform Nanoparticles from Recombinant Silk-Elastinlike Protein Polymers for Therapeutic Agent Delivery

    PubMed Central

    Anumolu, Rajasekhar; Gustafson, Joshua A.; Magda, Jules J.; Cappello, Joseph; Ghandehari, Hamidreza; Pease, Leonard F.

    2011-01-01

    Here we generate silk-elastinlike protein (SELP) polymeric nanoparticles and demonstrate precise control over their dimensions using an electrospray differential mobility analyzer (ES-DMA). Electrospray produces droplets encompassing several polymer strands. Evaporation ensues, leading polymer strands to accumulate at the droplet interface forming a hollow nanoparticle. The resulting nanoparticle size distributions which govern particle yield, depend on buffer concentration to the −1/3 power, polymer concentration to the 1/3 power, and ratio of silk to elastin blocks. Three recombinantly tuned ratios of silk to elastin blocks, 8:16, 4:8, and 4:16, respectively named SELP-815K, SELP-47K, and SELP-415K, are employed with the latter ratio resulting in a thinner shell and larger diameter for the nanoparticles than the former. The DMA narrows the size distribution by electrostatically classifying the aerosolized nanoparticles. These highly uniform nanoparticles have variations of 1.2 nm and 1.4 nm for 24.0 nm and 36.0 nm particles, respectively. Transmission electron microscopy reveals the nanoparticles to be faceted, as a buckling instability releases compression energy arising from evaporation after the shell has formed by bending it. A thermodynamic equilibrium exists between compression and bending energies, where the facet length is 1/2 the particle diameter, in agreement with experiments. Rod-like particles also formed from polymer stabilized filaments when the viscous length exceeds the jet radius at higher solution viscosities. The unusual uniformity in composition and dimension indicates the potential of these nanoparticles to deliver bioactive and imaging agents. PMID:21696150

  10. Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells.

    PubMed

    Kenlan, Dasha E; Rychahou, Piotr; Sviripa, Vitaliy M; Weiss, Heidi L; Liu, Chunming; Watt, David S; Evers, B Mark

    2017-03-03

    Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality in the United States. Over 50% of patients with CRC will develop local recurrence or distant organ metastasis. Cancer stem cells play a major role in the survival and metastasis of cancer cells. In this study, we examined the effects of novel AMP-activated protein kinase (AMPK) activating compounds on CRC metastatic and stem cell lines as potential candidates for chemotherapy. We found that activation of AMPK by all fluorinated N,N-diarylureas (FND) compounds at micromolar levels significantly inhibited the cell cycle progression and subsequent cellular proliferation. Additionally, we demonstrated that select FNDs significantly increased apoptosis in CRC metastatic and cancer stem cells. Therefore, FNDs hold considerable promise in the treatment of metastatic CRC, through elimination of both regular cancer cells and cancer stem cells.

  11. Iron Chelators as Potential Therapeutic Agents for Parkinson’s Disease

    PubMed Central

    Perez, Carlos A.; Tong, Yong; Guo, Maolin

    2009-01-01

    Parkinson’s disease (PD) is a neurological disorder characterized by the progressive impairment of motor skills in patients. Growing evidence suggests that abnormal redox-active metal accumulation, caused by dysregulation, plays a central role in the neuropathology of PD. Redox-active metals (e.g. Fe and Cu) catalyze essential reactions for brain function. However, these metals can also participate in the generation of highly toxic free radicals that can cause oxidative damage to cells and ultimately lead to the death of dopamine-containing neurons. The emergence of redox-active metals as key players in the pathogenesis of PD strongly suggests that metal-chelators could be beneficial in the treatment of this condition. This mini-review summarizes major recent developments on natural, synthetic iron chelating compounds and hydrogen peroxide-triggered prochelators as potential candidates for PD treatment. PMID:19809592

  12. Synthesis, characterization and preclinical studies of two-photon-activated targeted PDT therapeutic triads

    NASA Astrophysics Data System (ADS)

    Spangler, C. W.; Starkey, J. R.; Rebane, A.; Meng, F.; Gong, A.; Drobizhev, M.

    2006-02-01

    Photodynamic therapy (PDT) continues to evolve into a mature clinical treatment of a variety of cancer types as well as age-related macular degeneration of the eye. However, there are still aspects of PDT that need to be improved in order for greater clinical acceptance. While a number of new PDT photo-sensitizers, sometimes referred to as second- or third- generation therapeutic agents, are currently under clinical investigation, the direct treatment through the skin of subcutaneous tumors deeper than 5 mm remains problematic. Currently approved PDT porphyrin photo-sensitizers, as well as several modified porphyrins (e.g. chlorins, bacteriochlorins, etc.) that are under clinical investigation can be activated at 630-730 nm, but none above 800 nm. It would be highly desirable if new PDT paradigms could be developed that would allow photo-activation deep in the tissue transparency window in the Near-infrared (NIR) above 800 nm to reduce scattering and absorption phenomena that reduce deep tissue PDT efficacy. Rasiris and MPA Technologies have developed new porphyrins that have greatly enhanced two-photon absorption ( P A ) cross-sections and can be activated deep in the NIR (ca. 780-850 nm). These porphyrins can be incorporated into a therapeutic triad that also employs an small molecule targeting agent that directs the triad to over-expressed tumor receptor sites, and a NIR onephoton imaging agent that allows tracking the delivery of the triad to the tumor site, as well as clearance of excess triad from healthy tissue prior to the start of PDT treatment. We are currently using these new triads in efficacy studies with a breast cancer cell line that has been transfected with luciferase genes that allow implanted tumor growth and post- PDT treatment efficacy studies in SCID mouse models by following the rise and decay of the bioluminescence signal. We have also designed highly absorbing and scattering collagen breast cancer phantoms in which we have demonstrated

  13. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents.

    PubMed

    Miyamoto, S; Miyake, N; Jarskog, L F; Fleischhacker, W W; Lieberman, J A

    2012-12-01

    Since the introduction of chlorpromazine and throughout the development of the new-generation antipsychotic drugs (APDs) beginning with clozapine, the D(2) receptor has been the target for the development of APDs. Pharmacologic actions to reduce neurotransmission through the D(2) receptor have been the only proven therapeutic mechanism for psychoses. A number of novel non-D(2) mechanisms of action of APDs have been explored over the past 40 years but none has definitively been proven effective. At the same time, the effectiveness of treatments and range of outcomes for patients are far from satisfactory. The relative success of antipsychotics in treating positive symptoms is limited by the fact that a substantial number of patients are refractory to current medications and by their lack of efficacy for negative and cognitive symptoms, which often determine the level of functional impairment. In addition, while the newer antipsychotics produce fewer motor side effects, safety and tolerability concerns about weight gain and endocrinopathies have emerged. Consequently, there is an urgent need for more effective and better-tolerated antipsychotic agents, and to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. In recent years, a variety of new experimental pharmacological approaches have emerged, including compounds acting on targets other than the dopamine D(2) receptor. However, there is still an ongoing debate as to whether drugs selective for singe molecular targets (that is, 'magic bullets') or drugs selectively non-selective for several molecular targets (that is, 'magic shotguns', 'multifunctional drugs' or 'intramolecular polypharmacy') will lead to more effective new medications for schizophrenia. In this context, current and future drug development strategies can be seen to fall into three categories: (1) refinement of precedented mechanisms of action to provide drugs

  14. Pharmacological activity of metal binding agents that alter copper bioavailability

    PubMed Central

    Helsel, Marian E.

    2015-01-01

    Iron, copper and zinc are required nutrients for many organisms but also potent toxins if misappropriated. An overload of any of these metals can be cytotoxic and ultimately lead to organ failure, whereas deficiencies can result in anemia, weakened immune system function, and other medical conditions. Cellular metal imbalances have been implicated in neurodegenerative diseases, cancer and infection. It is therefore critical for living organisms to maintain careful control of both the total levels and subcellular distributions of these metals to maintain healthy function. This perspective explores several strategies envisioned to alter the bioavailability of metal ions by using synthetic metal-binding agents targeted for diseases where misappropriated metal ions are suspected of exacerbating cellular damage. Specifically, we discuss chemical properties that influence the pharmacological outcome of a subset of metal-binding agents known as ionophores, and review several examples that have shown multiple pharmacological activities in metal-related diseases, with a specific focus on copper. PMID:25797044

  15. Discovery and development of anticancer agents from marine sponges: perspectives based on a chemistry-experimental therapeutics collaborative program.

    PubMed

    Valeriote, Frederick A; Tenney, Karen; Media, Joseph; Pietraszkiewicz, Halina; Edelstein, Matthew; Johnson, Tyler A; Amagata, Taro; Crews, Phillip

    2012-01-01

    A collaborative program was initiated in 1990 between the natural product chemistry laboratory of Dr. Phillip Crews at the University of California Santa Cruz and the experimental therapeutics laboratory of Dr. Fred Valeriote at the Henry Ford Hospital in Detroit. The program focused on the discovery and development of anticancer drugs from sponge extracts. A novel in vitro disk diffusion, solid tumor selective assay was used to examine 2,036 extracts from 683 individual sponges. The bioassay-directed fractionation discovery component led to the identification of active pure compounds from many of these sponges. In most cases, pure compound was prepared in sufficient quantities to both chemically identify the active compound(s) as well as pursue one or more of the biological development components. The latter included IC50, clonogenic survival-concentration exposure, maximum tolerated dose, pharmacokinetics and therapeutic assessment studies. Solid tumor selective compounds included fascaplysin and 10-bromofascaplysin (Fascaplysinopsis), neoamphimedine, 5-methoxyneoamphimedine and alpkinidine (Xestospongia), makaluvamine C and makaluvamine H (Zyzzya), psymberin (Psammocinia and Ircinia), and ethylplakortide Z and ethyldidehydroplakortide Z (Plakortis). These compounds or analogs thereof continue to have therapeutic potential.

  16. Therapeutic journey of 2,4-thiazolidinediones as a versatile scaffold: An insight into structure activity relationship.

    PubMed

    Naim, Mohd Javed; Alam, Md Jahangir; Ahmad, Shujauddin; Nawaz, Farah; Shrivastava, Neelima; Sahu, Meeta; Alam, Ozair

    2017-03-31

    Thiazolidinedione is an important heterocyclic ring system, a pharmacophore and a privileged scaffold in medicinal chemistry; is a derivative of thiazolidine ring which came into existence for its role as antihyperglycemic agent and a specific ligand of PPAR's (Peroxisome proliferator activated receptor). Exhaustive research has led to determination of its vast biological profile with wide range of therapeutic applications. This review covers recent pharmacological advancements of thiazolidinedione moiety along with structure activity relationship so as to provide better correlation among different structures and their receptor interactions.

  17. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis.

    PubMed

    Bruyere, Olivier; Reginster, Jean-Yves

    2007-01-01

    Osteoarthritis (OA), the most common form of arthritis, is a public health problem throughout the world. Several entities have been carefully investigated for the symptomatic and structural management of OA. This review evaluates published studies of the effect of glucosamine salts and chondroitin sulfate preparations on the progression of knee or hip OA. Despite multiple double-blind, controlled clinical trials of the use of glucosamine and chondroitin sulfate in OA, controversy regarding the efficacy of these agents with respect to symptomatic improvement remains. Several potential confounders, including placebo response, use of prescription medicines versus over-the-counter pills or food supplements, or use of glucosamine sulfate versus glucosamine hydrochloride, may have relevance when attempting to interpret the seemingly contradictory results of different clinical trials. The National Institutes of Health-sponsored GAIT (Glucosamine/chondroitin Arthritis Intervention Trial) compared placebo, glucosamine hydrochloride, chondroitin sulfate, a combination of glucosamine and chondroitin sulfate and celecoxib in a parallel, blinded 6-month multicentre study of patients with knee OA. This trial showed that glucosamine hydrochloride and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with OA of the knee. However, exploratory analyses suggest that the combination of glucosamine hydrochloride and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. For decades, the traditional pharmacological management of OA has been mainly symptomatic. However, in recent years, several randomised controlled studies have assessed the structure-modifying effect of glucosamine sulfate and chondroitin sulfate using plain radiography to measure joint space narrowing over years. There is some evidence to suggest a structure-modifying effect of glucosamine sulfate and chondroitin

  18. Formulation and dosage of therapeutic nanosuspension for active targeting of docetaxel (WO 2014210485A1).

    PubMed

    Pooja, Deep; Kulhari, Hitesh; Adams, David J; Sistla, Ramakrishna

    2016-07-01

    Non-specificity and drug resistance are two major limitations of all chemotherapeutic agents. Ligand-conjugated nanomedicine is the most versatile approach for targeted cancer therapy. Attaching a targeting ligand to the nanoparticle surface increases drug concentration at the desired sites, decreases the dose needed and lessens side effects. The subject of this patent evaluation describes the preparation of a therapeutic nanosuspension of an anticancer drug, docetaxel (DTX). The nanoparticle matrix comprised a polylactic acid-polyethylene glycol block copolymer (PLA-PEG). The nanoparticles were actively directed towards prostate-specific membrane antigen (PSMA) over-expressing cancer cells using a targeting ligand S,S-2-{3-[1-carboxy-5-amino-pentyl-]ureido}-pantanedioic acid (GL2). The dose-limiting toxicity and maximum tolerated dose were determined for GL2-conjugated and DTX-loaded polymeric nanosuspensions. The efficacy of nanosuspensions was evaluated in people with various cancer types. The investigators claim the method of preparation of therapeutic nanosuspension, optimized composition of the formulation and dosage regimen for the clinical studies to effectively treat gastroesophageal and breast cancers.

  19. Role of organic cation transporters in the renal handling of therapeutic agents and xenobiotics

    SciTech Connect

    Wright, Stephen H. . E-mail: shwright@u.arizona.edu

    2005-05-01

    Organic cations (OCs) constitute a diverse array of compounds of physiological, pharmacological, and toxicological importance. Renal secretion of these compounds, which occurs principally along the proximal portion of the nephron, plays a critical role in regulating the concentration of OCs in the plasma and in clearing the body of potentially toxic xenobiotic OCs. Transepithelial OC transport in the kidney involves separate entry and exit steps at the basolateral and luminal aspects of renal tubular cells. It is increasingly apparent that basolateral and luminal OC transport reflects the concerted activity of a suite of separate transport processes arranged in parallel in each pole of proximal tubule cells. Most of the transporters that appear to dominate renal secretion of OCs belong to a single family of transport proteins: the OCT Family. The characterization of their activity, and their localization within distinct regions of the kidney, has permitted development of models describing the molecular and cellular basis of the renal secretion of OCs.

  20. Isoprenoid-phospholipid conjugates as potential therapeutic agents: Synthesis, characterization and antiproliferative studies

    PubMed Central

    Gliszczyńska, Anna; Niezgoda, Natalia; Gładkowski, Witold; Świtalska, Marta; Wietrzyk, Joanna

    2017-01-01

    The aim of this research was to extend application field of isoprenoid compounds by their introduction into phospholipid structure as the transport vehicle. The series of novel isoprenoid phospholipids were synthesized in high yields (24–97%), their structures were fully characterized and its anticancer activity was investigated in vitro towards several cell lines of different origin. Most of synthesized compounds showed a significantly higher antiproliferative effect on tested cell lines than free terpene acids. The most active phosphatidylcholine analogue, containing 2,3-dihydro-3-vinylfarnesoic acids instead of fatty acids in both sn-1 and sn-2 position, inhibits the proliferation of colon cancer cells at 13.6 μM. PMID:28196124

  1. Anti-inflammatory glycosylated flavonoids as therapeutic agents for treatment of diabetes-impaired wounds.

    PubMed

    Antunes-Ricardo, Marilena; Gutiérrez-Uribe, Janet; Serna-Saldívar, Sergio O

    2015-01-01

    Diabetes is a chronic disease that affects more than 387 million people worldwide. About 20% of patients diagnosed with diabetes develop diabetic foot ulcerations (DFU). Standard treatment of DFU includes wound debridement, infection control, revascularization and, in general, the acceleration of the healing process. Topical ointments containing flavonoids exert beneficial effects in wound healing process. Flavonoids increase the migration and proliferation of fibroblasts and collagen synthesis. Furthermore, most flavonoids exert antibacterial and astringent activities that help in infection control. Additionally, flavonoids possess antioxidant and anti-inflammatory activities reducing the reactive oxygen species and modulating the inflammatory pathways, respectively. Bioactivity of flavonoids can vary according to source, chemical structure and glycosylation pattern. In summary, topical application of flavonoids reduces epithelialization and wound closure time of DFU in diabetic patients.

  2. Searching therapeutic agents for treatment of Alzheimer disease using the Monte Carlo method.

    PubMed

    Toropova, Mariya A; Toropov, Andrey A; Raška, Ivan; Rašková, Mária

    2015-09-01

    Quantitative structure - activity relationships (QSARs) for the pIC50 (binding affinity) of gamma-secretase inhibitors can be constructed with the Monte Carlo method using CORAL software (http://www.insilico.eu/coral). The considerable influence of the presence of rings of various types with respect to the above endpoint has been detected. The mechanistic interpretation and the domain of applicability of the QSARs are discussed. Methods to select new potential gamma-secretase inhibitors are suggested.

  3. Percutaneous penetration, melanin activation and toxicity evaluation of a phytotherapic formulation for vitiligo therapeutic.

    PubMed

    Truite, Cecília Valente Rodrigues; Philippsen, Gisele Strieder; Ueda-Nakamura, Tânia; Natali, Maria Raquel Marçal; Dias Filho, Benedito Prado; Bento, Antonio Carlos; Baesso, Mauro Luciano; Nakamura, Celso Vataru

    2007-01-01

    The aim of this work was to apply photoacoustic spectroscopy for the ex vivo determination of the penetration rate of a phytotherapic formulation for vitiligo therapeutic, with or without salicylic acid as the promoter agent. In addition, the compound toxicity and morphophysiology effects were evaluated for different concentrations of salicylic acid. The experiments were performed as a function of the period of time of treatment in a well-controlled group of rabbits. Toxic effects were not observed with any of the tested products. All formulations containing salicylic acid induced cutaneous reaction which was dose dependent. The histological analysis showed that the use of the medication was associated with an increased comedogenic effect in relation to the control group, regardless of salicylic acid concentration. Inflammatory reactions and acanthosis were observed only in the animals treated with formulations containing higher concentrations of salicylic acid, while none of these effects were detected with the use of the formulation containing 2.5% (wt/vol) of salicylic acid. Photoacoustic depth monitoring showed that both formulations, with or without salicylic acid, propagated through the skin up to the melanocytes region, suggesting that the transport of the active agent may occur through the epithelial structure without the need of using queratinolitic substances, which are known to induce side effects in the animals.

  4. Chicken cathelicidin-2-derived peptides with enhanced immunomodulatory and antibacterial activities against biological warfare agents.

    PubMed

    Molhoek, E Margo; van Dijk, Albert; Veldhuizen, Edwin J A; Dijk-Knijnenburg, Helma; Mars-Groenendijk, Roos H; Boele, Linda C L; Kaman-van Zanten, Wendy E; Haagsman, Henk P; Bikker, Floris J

    2010-09-01

    Host defence peptides (HDPs) are considered to be excellent candidates for the development of novel therapeutic agents. Recently, it was demonstrated that the peptide C1-15, an N-terminal segment of chicken HDP cathelicidin-2, exhibits potent antibacterial activity while lacking cytotoxicity towards eukaryotic cells. In the present study, we report that C1-15 is active against bacteria such as Bacillus anthracis and Yersinia pestis that may potentially be used by bioterrorists. Substitution of single and multiple phenylalanine (Phe) residues to tryptophan (Trp) in C1-15 resulted in variants with improved antibacterial activity against B. anthracis and Y. pestis as well as decreased salt sensitivity. In addition, these peptides exhibited enhanced neutralisation of lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs). The antibacterial and LPS-neutralising activities of these C1-15-derived peptides are exerted at concentrations far below the concentrations that are toxic to human PBMCs. Taken together, we show that Phe-->Trp substitutions in C1-15 variants enhances the antibacterial and LPS-neutralising activities against pathogenic bacteria, including those that may potentially be used as biological warfare agents.

  5. miR-181b as a therapeutic agent for chronic lymphocytic leukemia in the Eµ-TCL1 mouse model.

    PubMed

    Bresin, Antonella; Callegari, Elisa; D'Abundo, Lucilla; Cattani, Caterina; Bassi, Cristian; Zagatti, Barbara; Narducci, M Grazia; Caprini, Elisabetta; Pekarsky, Yuri; Croce, Carlo M; Sabbioni, Silvia; Russo, Giandomenico; Negrini, Massimo

    2015-08-14

    The involvement of microRNAs (miRNAs) in chronic lymphocytic leukemia (CLL) pathogenesis suggests the possibility of anti-CLL therapeutic approaches based on miRNAs. Here, we used the Eµ-TCL1 transgenic mouse model, which reproduces leukemia with a similar course and distinct immunophenotype as human B-CLL, to test miR-181b as a therapeutic agent.In vitro enforced expression of miR-181b mimics induced significant apoptotic effects in human B-cell lines (RAJI, EHEB), as well as in mouse Eµ-TCL1 leukemic splenocytes. Molecular analyses revealed that miR-181b not only affected the expression of TCL1, Bcl2 and Mcl1 anti-apoptotic proteins, but also reduced the levels of Akt and phospho-Erk1/2. Notably, a siRNA anti-TCL1 could similarly down-modulate TCL1, but exhibited a reduced or absent activity in other relevant proteins, as well as a reduced effect on cell apoptosis and viability. In vivo studies demonstrated the capability of miR-181b to reduce leukemic cell expansion and to increase survival of treated mice.These data indicate that miR-181b exerts a broad range of actions, affecting proliferative, survival and apoptotic pathways, both in mice and human cells, and can potentially be used to reduce expansion of B-CLL leukemic cells.

  6. Urokinase type plasminogen activator receptor (uPAR) as a new therapeutic target in cancer

    PubMed Central

    Montuori, Nunzia; Pesapane, Ada; Rossi, Francesca W; Giudice, Valentina; De Paulis, Amato; Selleri, Carmine; Ragno, Pia

    2016-01-01

    The urokinase (uPA)-type plasminogen activator receptor (uPAR) is a GPI-anchored receptor that focuses urokinase (uPA) proteolytic activity on the cell surface. uPAR also regulates cell adhesion, migration and proliferation, protects from apoptosis and contributes to epithelial mesenchymal transition (EMT), independently of uPA enzymatic activity. Indeed, uPAR interacts with beta1, beta2 and beta3 integrins, thus regulating their activities. uPAR cross-talks with receptor tyrosine kinases through integrins and regulates cancer cell dormancy, proliferation and angiogenesis. Moreover, uPAR mediates uPA-dependent cell migration and chemotaxis induced by fMet-Leu-Phe (fMLF), through its association with fMLF-receptors (fMLF-Rs). Further, uPAR is an adhesion receptor because it binds vitronectin (VN), a component of provisional extracellular matrix. High uPAR expression predicts for more aggressive disease in several cancer types for its ability to increase invasion and metastasis. In fact, uPAR has been hypothesized to be the link between tumor cell dormancy and proliferation that usually precedes the onset of metastasis. Thus, inhibiting uPAR could be a feasible approach to affect tumor growth and metastasis. Here, we review the more recent advances in the development of uPAR-targeted anti-cancer therapeutic agents suitable for further optimization or ready for the evaluation in early clinical trials. PMID:27896223

  7. Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease.

    PubMed

    González-Naranjo, Pedro; Pérez-Macias, Natalia; Campillo, Nuria E; Pérez, Concepción; Arán, Vicente J; Girón, Rocio; Sánchez-Robles, Eva; Martín, María Isabel; Gómez-Cañas, María; García-Arencibia, Moisés; Fernández-Ruiz, Javier; Páez, Juan A

    2014-02-12

    Designing drugs with a specific multi-target profile is a promising approach against multifactorial illnesses as Alzheimer's disease. In this work, new indazole ethers that possess dual activity as both cannabinoid agonists CB2 and inhibitors of BuChE have been designed by computational methods. On the basis of this knowledge, the synthesis, pharmacological evaluation and docking studies of a new class of indazoles has been performed. Pharmacological evaluation includes radioligand binding assays with [(3)H]-CP55940 for CB1R and CB2R and functional activity for cannabinoid receptors on isolated tissue. Additionally, in vitro inhibitory assays of AChE/BuChE and the corresponding competition studies have been carried out. The results of pharmacological tests have revealed that three of these derivatives behave as CB2 cannabinoid agonists and simultaneously show BuChE inhibition. In particular, compounds 3 and 24 have emerged as promising candidates as novel cannabinoids that inhibit BuChE by a non-competitive or mixed mechanism, respectively. On the other hand, both molecules show antioxidant properties.

  8. 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

  9. Silver Nanoforms as a Therapeutic Agent for Killing Escherichia coli and Certain ESKAPE Pathogens.

    PubMed

    Kedziora, A; Korzekwa, K; Strek, W; Pawlak, A; Doroszkiewicz, W; Bugla-Ploskonska, G

    2016-07-01

    The scope of this study included the preparation of silver nanoforms with high antimicrobial efficacy, low cost, and ease of application. The term 'silver nanoforms' refers to silver located on the amorphous or crystalline titanium dioxide (TiO2). Silver nanoforms may be used as an alternative to antibiotics in killing bacteria. Pure and silver-incorporated titanium (used as a carrier) was prepared using the sol-gel-modified method. Physical and chemical properties of the samples were described, and the antibacterial activity was indicated using the following strains of bacteria: Staphylococcus aureus, Klebsiella pneumoniae (ESKAPE pathogens), and Escherichia coli. The results have shown that the antibacterial activity of silver nanoforms with amorphous TiO2 is much better than that in the samples based on anatase (crystalline TiO2). The sensitivity of the tested bacteria to silver nanoforms depends on physical and chemical properties of the nanoforms and individual characteristics of the bacteria. For the first time, significant participation of amorphous TiO2 in antibacterial compounds has been described through this study.

  10. Mechanistic investigation of beta-galactosidase-activated MR contrast agents.

    PubMed

    Urbanczyk-Pearson, Lauren M; Femia, Frank J; Smith, Jeffrey; Parigi, Giacomo; Duimstra, Joseph A; Eckermann, Amanda L; Luchinat, Claudio; Meade, Thomas J

    2008-01-07

    We report a mechanistic investigation of an isomeric series of beta-galactosidase-activated magnetic resonance contrast agents. Our strategy focuses on the synthesis of macrocyclic caged-complexes that coordinatively saturate a chelated lanthanide. Enzyme cleavage of the complex results in an open coordination site available for water that creates a detectable MR contrast agent. The complexes consist of a DO3A Gd(III) chelator modified with a galactopyranose at the N-10 position of the macrocycle. We observed significant differences in relaxometric properties and coordination geometry that can be correlated to subtle variations of the linker between the macrocycle and the galactopyranose. After synthesis and purification of the R, S, and racemic mixtures of complexes 1 and 3 and measurement of the hydration number, water residence lifetime, and longitudinal relaxation rates, we propose mechanisms for water exclusion from the lanthanide in the precleavage state. While the stereochemistry of the linker does not influence the agents' properties, the mechanism of water exclusion for each isomer is significantly influenced by the position of modification. Data for one series with a methyl group substituted on the sugar-macrocycle linker at the alpha-position suggests a steric mechanism where the galactopyranose sugar blocks water from the Gd(III) center. In contrast, our observations for a second series with methyl substitution at the beta position of the sugar-macrocycle linker are consistent with a mechanism in which a bidentate anion occupies two available coordination sites of Gd(III) in the precleavage state.

  11. Information theoretic entropy for molecular classification: oxadiazolamines as potential therapeutic agents.

    PubMed

    Torrens, Francisco; Castellano, Gloria

    2013-06-01

    In this review we present algorithms for classification and taxonomy based on information entropy, followed by structure-activity relationship (SAR) models for the inhibition of human prostate carcinoma cell line DU-145 by 26 derivatives of N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines (NNAs). The NNAs are classified using two characteristic chemical properties based on different regions of the molecules. A table of periodic properties of inhibitors of DU-145 human prostate carcinoma cell line is obtained based on structural features from the amine moiety and from the oxadiazole ring. Inhibitors in the same group and period of the periodic table are predicted to have highly similar properties, and those located only in the same group will present moderate similarity. The results of a virtual screening campaign are presented.

  12. The myosin activator omecamtiv mecarbil: a promising new inotropic agent.

    PubMed

    Nánási, Péter; Váczi, Krisztina; Papp, Zoltán

    2016-10-01

    Heart failure became a leading cause of mortality in the past few decades with a progressively increasing prevalence. Its current therapy is restricted largely to the suppression of the sympathetic activity and the renin-angiotensin system in combination with diuretics. This restrictive strategy is due to the potential long-term adverse effects of inotropic agents despite their effective influence on cardiac function when employed for short durations. Positive inotropes include inhibitors of the Na(+)/K(+) pump, β-receptor agonists, and phosphodiesterase inhibitors. Theoretically, Ca(2+) sensitizers may also increase cardiac contractility without resulting in Ca(2+) overload; nevertheless, their mechanism of action is frequently complicated by other pleiotropic effects. Recently, a new positive inotropic agent, the myosin activator omecamtiv mecarbil, has been developed. Omecamtiv mecarbil binds directly to β-myosin heavy chain and enhances cardiac contractility by increasing the number of the active force-generating cross-bridges, presumably without major off-target effects. This review focuses on recent in vivo and in vitro results obtained with omecamtiv mecarbil, and discusses its mechanism of action at a molecular level. Based on clinical data, omecamtiv mecarbil is a promising new tool in the treatment of systolic heart failure.

  13. Perspective of surface active agents in baking industry: an overview.

    PubMed

    Ahmad, Asif; Arshad, Nazish; Ahmed, Zaheer; Bhatti, Muhammad Shahbaz; Zahoor, Tahir; Anjum, Nomana; Ahmad, Hajra; Afreen, Asma

    2014-01-01

    Different researchers have previously used surfactants for improving bread qualities and revealed that these compounds result in improving the quality of dough and bread by influencing dough strength, tolerance, uniform crumb cell size, and improve slicing characteristics and gas retention. The objective of this review is to highlight the areas where surfactants are most widely used particularly in the bread industries, their role and mechanism of interaction and their contribution to the quality characteristics of the dough and bread. This review reveals some aspects of surface-active agents regarding its role physiochemical properties of dough that in turn affect the bread characteristics by improving its sensory quality and storage stability.

  14. Molluscicidal properties and selective toxicity of surface-active agents

    PubMed Central

    Visser, S. A.

    1965-01-01

    Of over 100 commercially produced surface-active agents tested against the bilharziasis vector snail Biomphalaria sudanica, 13 were found to possess considerable and highly selective molluscicidal properties at concentrations of less than 1 ppm for exposures of 48 hours. Against crustacea, fish, water plants, mosquito larvae, mice, and the eggs of B. sudanica, the toxicities of the 13 surfactants were slight. The chemicals did not appear to be absorbed by organic matter to any appreciable extent. It is thought that the toxicity to B. sudanica is of both a chemical and a physical nature. PMID:5294185

  15. Synthesis of Arylpiperazine Derivatives As Protease Activated Receptor 1 Antagonists And Their Evaluation As Antiproliferative Agents.

    PubMed

    Zotti, Andrea Ilaria; Di Gennaro, Elena; Corvino, Angela; Frecentese, Francesco; Magli, Elisa; Perissutti, Elisa; Cirino, Giuseppe; Roviezzo, Fiorentina; Terranova-Barberio, Manuela; Iannelli, Federica; Caliendo, Giuseppe; Santagada, Vincenzo; Fiorino, Ferdinando; Budillon, Alfredo; Severino, Beatrice

    2016-09-26

    Protease activated receptor-1 (PAR1) is a G-coupled receptor activated by α-thrombin and other proteases. Several reports demonstrate PAR1 involvement in tumorigenesis and tumor progression. In order to investigate on potential use of PAR1 antagonists as antiproliferative agents, we have identified a series of arylpiperazine derivatives acting as PAR1 antagonists; the selected molecules have been evaluated for their antiproliferative properties. All the compounds inhibited the growth of a panel of cell lines expressing PAR1; two of them, compounds 13 and 15, were able to inhibit, in a dose dependent manner, the growth of the selected cell lines with the lowest IC50 values, and were further characterized to define the mechanism responsible for the observed antiproliferative effect. This study directed us to the identification of two interesting leads that may help to further validate PAR1 as an important therapeutic target for cancer treatment.

  16. How Native and Alien Metal Cations Bind ATP: Implications for Lithium as a Therapeutic Agent

    NASA Astrophysics Data System (ADS)

    Dudev, Todor; Grauffel, Cédric; Lim, Carmay

    2017-02-01

    Adenosine triphosphate (ATP), the major energy currency of the cell, exists in solution mostly as ATP-Mg. Recent experiments suggest that Mg2+ interacts with the highly charged ATP triphosphate group and Li+ can co-bind with the native Mg2+ to form ATP-Mg-Li and modulate the neuronal purine receptor response. However, it is unclear how the negatively charged ATP triphosphate group binds Mg2+ and Li+ (i.e. which phosphate group(s) bind Mg2+/Li+) and how the ATP solution conformation depends on the type of metal cation and the metal-binding mode. Here, we reveal the preferred ATP-binding mode of Mg2+/Li+ alone and combined: Mg2+ prefers to bind ATP tridentately to each of the three phosphate groups, but Li+ prefers to bind bidentately to the terminal two phosphates. We show that the solution ATP conformation depends on the cation and its binding site/mode, but it does not change significantly when Li+ binds to Mg2+-loaded ATP. Hence, ATP-Mg-Li, like Mg2+-ATP, can fit in the ATP-binding site of the host enzyme/receptor, activating specific signaling pathways.

  17. How Native and Alien Metal Cations Bind ATP: Implications for Lithium as a Therapeutic Agent.

    PubMed

    Dudev, Todor; Grauffel, Cédric; Lim, Carmay

    2017-02-14

    Adenosine triphosphate (ATP), the major energy currency of the cell, exists in solution mostly as ATP-Mg. Recent experiments suggest that Mg(2+) interacts with the highly charged ATP triphosphate group and Li(+) can co-bind with the native Mg(2+) to form ATP-Mg-Li and modulate the neuronal purine receptor response. However, it is unclear how the negatively charged ATP triphosphate group binds Mg(2+) and Li(+) (i.e. which phosphate group(s) bind Mg(2+)/Li(+)) and how the ATP solution conformation depends on the type of metal cation and the metal-binding mode. Here, we reveal the preferred ATP-binding mode of Mg(2+)/Li(+) alone and combined: Mg(2+) prefers to bind ATP tridentately to each of the three phosphate groups, but Li(+) prefers to bind bidentately to the terminal two phosphates. We show that the solution ATP conformation depends on the cation and its binding site/mode, but it does not change significantly when Li(+) binds to Mg(2+)-loaded ATP. Hence, ATP-Mg-Li, like Mg(2+)-ATP, can fit in the ATP-binding site of the host enzyme/receptor, activating specific signaling pathways.

  18. Delonix regia Leaf Extract (DRLE): A Potential Therapeutic Agent for Cardioprotection

    PubMed Central

    Su, Wei-Lieh; Huang, Shih-Che; Wang, Shu-Chi

    2016-01-01

    Delonix regia (Boj. Ex. Hook) is a flowering plant in the pea family found in tropical areas and its leaves are used informally to treat diseases in folk medicine. However, the cardioprotective effects in this plant are still unclear. In this study, we found that the Delonix regia leaf extract (DRLE) (400 mg/kg/d) can reduce the mortality rate in an isoproterenol (ISO)-induced heart injury and hypertrophy mouse model. Decreased serum levels of creatine phosphokinase, LDH, GOT, TNF-alpha and increased nitric oxide levels were found in DRLE-treated ISO-injured mice. In the in vitro study, the porcine coronary artery exhibited vasodilation effect induced by DRLE in a dose-dependent manner. In the DRLE toxic test, overdose of DRLE showed the high safety in normal mice and may have the ability to remove the metabolic wastes in blood. In conclusion, we demonstrated for the first time that DRLE has the cardioprotective effects by activating the vasodilation through NO pathway and preventing the myocyte injury via inhibition of TNF-alpha pathway. We suggest that DRLE may act as a promising novel herbal medicine for cardioprotection. PMID:27936072

  19. How Native and Alien Metal Cations Bind ATP: Implications for Lithium as a Therapeutic Agent

    PubMed Central

    Dudev, Todor; Grauffel, Cédric; Lim, Carmay

    2017-01-01

    Adenosine triphosphate (ATP), the major energy currency of the cell, exists in solution mostly as ATP-Mg. Recent experiments suggest that Mg2+ interacts with the highly charged ATP triphosphate group and Li+ can co-bind with the native Mg2+ to form ATP-Mg-Li and modulate the neuronal purine receptor response. However, it is unclear how the negatively charged ATP triphosphate group binds Mg2+ and Li+ (i.e. which phosphate group(s) bind Mg2+/Li+) and how the ATP solution conformation depends on the type of metal cation and the metal-binding mode. Here, we reveal the preferred ATP-binding mode of Mg2+/Li+ alone and combined: Mg2+ prefers to bind ATP tridentately to each of the three phosphate groups, but Li+ prefers to bind bidentately to the terminal two phosphates. We show that the solution ATP conformation depends on the cation and its binding site/mode, but it does not change significantly when Li+ binds to Mg2+-loaded ATP. Hence, ATP-Mg-Li, like Mg2+-ATP, can fit in the ATP-binding site of the host enzyme/receptor, activating specific signaling pathways. PMID:28195155

  20. A Clinico-analytical Study on Seed of Wrightia antidysenterica Linn. as a Therapeutic Emetic Agent (Vamaka Yoga) in the Management of Psoriasis

    PubMed Central

    Bhattacharyya, Nirupam; Pujar, Muralidhar P.; Chaturvedi, Ashutosh; Kumar, M. Ashvini; Lohith, B. A.; Kumar, K. N. Sunil

    2016-01-01

    Objectives: Wrightia antidysenterica Linn. (WA) is male variety Kutaja stated to be potent therapeutic emetic agent in skin disorders. Expulsion of doshas through oral route is termed as Vamana Karma (VK) (therapeutic emesis). However, so far, its utility for Vamana is not explored in detail, therefore there is a need to revalidate the utility of WA for Vamana. Hence, the above study was conducted to ascertain the efficacy as a therapeutic emetic agent (vamaka yoga) in the management of psoriasis along with quality control and standardization of this herb. Materials and Methods: The drug was standardized as per analytical procedures in Pharmacopeias. Thirty patients of psoriasis fulfilling inclusion criteria were taken for the study and Vamana with WA was conducted. Criteria were prepared to assess the signs and Symptoms of psoriasis. VK was assessed using the classical Lakshanas (features) such as Anthiki shudhi (Ending symptoms of emesis), Vaigiki shudhi (features of vomiting bouts), Maniki shudhi (Quantitative and qualitative purification), complications. Result: VK with WA showed significant relief in parameters of psoriasis such as scaling, itching, candle grease sign (P < 0.001), and psoriasis area and severity index score (P = 0.001). In VK with WA, mean number of Vegas (vomiting bouts) was 6.91. 66% patients showing quantitative purification between 301 and 600 ml. 73.33% showed all Symptoms of purification. 73.33% patients showed Kaphanta vamana (Moderate expulsion of desire humor). In the level of biopurification, 66.66% patients showed moderated purification. No complication was noted with moderate drug palatability. Conclusion: Pharmacopeial analytical study showed its standardized values for testing the drug used for the study. It is proved as potent therapeutic emetic agent with no complication showed its clinical benefits over skin disorder like psoriasis. SUMMARY Seeds of Wrightia antidysenterica (WA) Linn. free from any foreign matter were selected

  1. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain.

    PubMed

    Costa, Barbara; Trovato, Anna Elisa; Comelli, Francesca; Giagnoni, Gabriella; Colleoni, Mariapia

    2007-02-05

    Cannabidiol, the major psycho-inactive component of cannabis, has substantial anti-inflammatory and immunomodulatory effects. This study investigated its therapeutic potential on neuropathic (sciatic nerve chronic constriction) and inflammatory pain (complete Freund's adjuvant intraplantar injection) in rats. In both models, daily oral treatment with cannabidiol (2.5-20 mg/kg to neuropathic and 20 mg/kg to adjuvant-injected rats) from day 7 to day 14 after the injury, or intraplantar injection, reduced hyperalgesia to thermal and mechanical stimuli. In the neuropathic animals, the anti-hyperalgesic effect of cannabidiol (20 mg/kg) was prevented by the vanilloid antagonist capsazepine (10 mg/kg, i.p.), but not by cannabinoid receptor antagonists. Cannabidiol's activity was associated with a reduction in the content of several mediators, such as prostaglandin E(2) (PGE(2)), lipid peroxide and nitric oxide (NO), and in the over-activity of glutathione-related enzymes. Cannabidiol only reduced the over-expression of constitutive endothelial NO synthase (NOS), without significantly affecting the inducible form (iNOS) in inflamed paw tissues. Cannabidiol had no effect on neuronal and iNOS isoforms in injured sciatic nerve. The compound's efficacy on neuropathic pain was not accompanied by any reduction in nuclear factor-kappaB (NF-kappaB) activation and tumor necrosis factor alpha (TNFalpha) content. The results indicate a potential for therapeutic use of cannabidiol in chronic painful states.

  2. Evaluating cardiovascular safety of novel therapeutic agents for the treatment of type 2 diabetes mellitus.

    PubMed

    Azim, Sidra; Baker, William L; White, William B

    2014-11-01

    Type 2 diabetes increases the risk of developing cardiovascular (CV) complications such as myocardial infarction, heart failure, stroke, peripheral vascular disease, and CV-associated mortality. Strict glycemic control in diabetics has shown improvement in microvascular complications related to diabetes but has been unable to demonstrate major effects on macrovascular complications including myocardial infarction and stroke. Conventional therapies for diabetes that include insulin, metformin, sulfonylureas (SU), and alpha-glucosidase inhibitors have limited and/or controversial data on CV safety based on observational studies not designed or powered to assess CV safety of these medications. In 2008, the US Food and Drug Administration (FDA) revised regulations for the approval of medications for type 2 diabetes by requiring that enough CV events are accrued prior to approval to rule out an upper 95 % confidence interval (95 % CI) for HR of 1.8 for CV events, followed by ruling out an upper 95 % CI for HR of 1.3 in the post-approval period. To date, novel diabetes therapies including peroxisome proliferator-activated receptor (PPAR) gamma agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP 1) analogs, and sodium-glucose transporter-2 (SGL2) inhibitors have been evaluated in CV safety trials. Results from the first major CV outcome studies in type 2 diabetes, SAVOR-TIMI 53 and EXAMINE, have shown that neither saxagliptin nor alogliptin had increases in major CV events relative to placebo in high-risk patients. Ongoing and future trials will elucidate the CV safety for other DPP-4 inhibitors compared to SUs and the GLP-1 agonists versus placebo.

  3. Curcuma longa L. as a Therapeutic Agent in Intestinal Motility Disorders. 2: Safety Profile in Mouse

    PubMed Central

    Micucci, Matteo; Aldini, Rita; Cevenini, Monica; Colliva, Carolina; Spinozzi, Silvia; Roda, Giulia; Montagnani, Marco; Camborata, Cecilia; Camarda, Luca; Chiarini, Alberto; Mazzella, Giuseppe; Budriesi, Roberta

    2013-01-01

    Background Curcuma extract exerts a myorelaxant effect on the mouse intestine. In view of a possible use of curcuma extract in motor functional disorders of the gastrointestinal tract, a safety profile study has been carried out in the mouse. Methods Thirty mice were used to study the in vitro effect of curcuma on gallbladder, bladder, aorta and trachea smooth muscular layers and hearth inotropic and chronotropic activity. The myorelaxant effect on the intestine was also thoroughly investigated. Moreover, curcuma extract (200 mg/Kg/day) was orally administered to twenty mice over 28 days and serum liver and lipids parameters were evaluated. Serum, bile and liver bile acids qualitative and quantitative composition was were also studied. Results In the intestine, curcuma extract appeared as a not competitive inhibitor through cholinergic, histaminergic and serotoninergic receptors and showed spasmolytic effect on K+ induced contraction at the level of L type calcium channels. No side effect was observed on bladder, aorta, trachea and heart when we used a dose that is effective on the intestine. An increase in gallbladder tone and contraction was observed. Serum liver and lipids parameters were normal, while a slight increase in serum and liver bile acids concentration and a decrease in bile were observed. Conclusions Although these data are consistent with the safety of curcuma extract as far as its effect on the smooth muscular layers of different organs and on the heart, the mild cholestatic effect observed in absence of alteration of liver function tests must be further evaluated and the effective dose with minimal side effects considered. PMID:24260512

  4. Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions

    PubMed Central

    Mendizábal, V E; Adler-Graschinsky, E

    2007-01-01

    In addition to their classical known effects, such as analgesia, impairment of cognition and learning and appetite enhancement, cannabinoids have also been related to the regulation of cardiovascular responses and implicated in cardiovascular pathology. Elevated levels of endocannabinoids have been related to the extreme hypotension associated with various forms of shock as well as to the cardiovascular abnormalities that accompany cirrhosis. In contrast, cannabinoids have also been associated with beneficial effects on the cardiovascular system, such as a protective role in atherosclerosis progression and in cerebral and myocardial ischaemia. In addition, it has also been suggested that the pharmacological manipulation of the endocannabinoid system may offer a novel approach to antihypertensive therapy. During the last decades, the tremendous increase in the understanding of the molecular basis of cannabinoid activity has encouraged many pharmaceutical companies to develop more potent synthetic cannabinoid analogues and antagonists, leading to an explosion of basic research and clinical trials. Consequently. not only the synthetic THC dronabinol (Marinol) and the synthetic THC analogue nabilone (Cesamet) have been approved in the United States, but also the standardized cannabis extract (Sativex) in Canada. At least three strategies can be foreseen in the future clinical use of cannabinoid-based drugs: (a) the use of CB1 receptor antagonists, such as the recently approved rimonabant (b) the use of CB2-selective agonists, and (c) the use of inhibitors of endocannabinoid degradation. In this context, the present review examines the effects of cannabinoids and of the pharmacological manipulation of the endocannabinoid system, in cardiovascular pathophysiology. PMID:17450170

  5. Surface modification of medical implant materials with hydrophilic polymers for enhanced biocompatibility and delivery of therapeutic agents

    NASA Astrophysics Data System (ADS)

    Urbaniak, Daniel J.

    2004-11-01

    In the research reported here, the surface modification of medical grade poly(dimethyl siloxane), polyetherurethane, and stainless steel through gamma-radiation grafting of hydrophilic polymers was investigated. Emphasis was placed on developing improved and simplified surface modification methods that produce more stable and more bioacceptible hydrophilic graft surfaces. As a result of this research, new surface modification techniques were developed that yield significantly improved surface stability unachievable using previous surface modification techniques. The surface modification of poly(dimethyl siloxane) with hydrophilic polymers was carried out using gamma radiation initiated graft polymerization. The addition of alkali metal hydroxides afforded a unique way to enhance the grafting of N-vinyl-2 pyrrolidone, dimethylacryamide, 2-methacryloyloxyethyl phosphoryl choline, N,N-dimethyl-N-(methacryloyloxyethyl)-N-(3-sulfopropyl)-ammonium-betaine, N,N-dimethyl-N-(methacrylamidopropyl)-N-(3-sulfopropyl)-ammonium-betaine, and copolymers thereof to silicones. Ethanolamine was found to further enhance the grafting of some hydrophilic polymers to silicone. The resulting hydrophilic surface grafts were resistant to hydrophobic surface rearrangement. This process overcomes previous problems inherent in silicone surface modification. The technique was also found to moderately enhance the grafting of hydrophilic monomers to polyetherurethane and to 316-L stainless steel. The surface modification of 316-L stainless steel was further enhanced by treating the substrates with a chromium III methacrylate bonding agent prior to irradiation. The coatings were evaluated for their potential use as depots for delivering therapeutic agents. The release of ofloxacin from surface-modified poly(dimethyl siloxane) and dexamethasone from surface-modified 316-L stainless steel was evaluated by in-vitro experiments. Therapeutic levels of drugs were released from surface-modified specimens

  6. Latest treatment for lower urinary tract dysfunction: therapeutic agents and mechanism of action.

    PubMed

    Yamaguchi, Osamu

    2013-01-01

    Recent studies suggest that antimuscarinics might suppress bladder afferent activity by blocking muscarinic receptors in the urothelium, myofibroblasts and detrusor, thereby improving overactive bladder symptoms. β(3)-Adrenoceptors are predominantly expressed in the human bladder and mediate relaxation of detrusor muscle. β(3)-Adrenoceptor agonists increase bladder capacity and prolong micturition interval. It is assumed that β(3)-adrenoceptor agonists could exert an inhibitory effect on bladder afferent through β(3)-adrenoceptors in the urothelium and detrusor, which eventually improve the symptom of urgency. Mirabegron is a potent and selective β(3)-adrenoceptor agonist. A Japanese phase 3 study showed that mirabegron has excellent efficacy and safety for treating overactive bladder. α(1)-Adrenoceptor antagonists (α(1)-blockers) have become a mainstay of male lower urinary tract symptoms treatment. The α(1)(A) subtype is known to mediate functional obstruction as a result of benign prostatic enlargement. Recent studies have suggested that α(1)(A)-adrenoceptors are additionally involved in the generation of storage symptoms. The α(1)(D) subtype is thought to play a role in the facilitation of voiding reflex; that is; storage symptoms. α(1)-Blockers often fail to alleviate overactive bladder symptoms. In this context, combination therapy with α(1)-blockers and antimuscarinics has been recommended. Treatment with 5α-reductase inhibitor for 1 year improves urinary symptoms and flow rate by reducing prostatic volume in men with benign prostatic enlargement. A pooled analysis showed that the long-term (2 or 4 years) treatment with 5α-reductase inhibitor reduced the rate of progression to acute urinary retention and surgery. Combination therapy with 5α-reductase inhibitor and α(1)-blocker was shown to provide a rapid improvement in lower urinary tract symptoms, and reduce the relative risk of acute urinary retention and benign prostatic hyperplasia

  7. Wet deposition of the seeding agent after weather modification activities.

    PubMed

    Curić, Mladjen; Janc, Dejan

    2013-09-01

    Weather modification activities are performed mostly by cloud seeding. Some operational projects have been conducted for more than a half century and cover planetary scales. These activities have led to large amounts of seeding agents being deposited on the ground in precipitation. The main intent of this paper is to identify the spatial pattern of silver iodide deposits after hail suppression. The spatial pattern of silver iodide deposits is determined using the weather modification project measurements from seeding agent reports, two weather radars and 316 launching sites during a 5-year period. The estimated spatial distribution of the deposits is not uniform, with the maximum silver iodide amount located in the southern part of the study area (up to 140 μg m(-2)). Our results are comparable with the measurements performed by chemical analyses during other cloud seeding experiments. The maximum location coincides well with that of the maximum seeded hailstorm precipitation frequency. A new method for identifying the spatial pattern of wet-deposited material has been established. The location with the maximum amount is found. This method would be important as a means of placing samplers and monitoring at the representative sites because those are where most weather modification projects would be performed in the future.

  8. Reactive oxygen species-activated nanomaterials as theranostic agents

    PubMed Central

    Kim, Kye S; Lee, Dongwon; Song, Chul Gyu; Kang, Peter M

    2015-01-01

    Reactive oxygen species (ROS) are generated from the endogenous oxidative metabolism or from exogenous pro-oxidant exposure. Oxidative stress occurs when there is excessive production of ROS, outweighing the antioxidant defense mechanisms which may lead to disease states. Hydrogen peroxide (H2O2) is one of the most abundant and stable forms of ROS, implicated in inflammation, cellular dysfunction and apoptosis, which ultimately lead to tissue and organ damage. This review is an overview of the role of ROS in different diseases. We will also examine ROS-activated nanomaterials with emphasis on hydrogen peroxide, and their potential medical implications. Further development of the biocompatible, stimuli-activated agent responding to disease causing oxidative stress, may lead to a promising clinical use. PMID:26328770

  9. Sales of veterinary antimicrobial agents for therapeutic use in food-producing animal species in Japan between 2005 and 2010.

    PubMed

    Hosoi, Y; Asai, T; Koike, R; Tsuyuki, M; Sugiura, K

    2014-12-01

    The use of veterinary antimicrobial agents in animals can result in the emergence and selection of resistant bacteria in food-producing animals. This study elucidated the use of veterinary antimicrobial agents in Japan in terms of milligrams of active ingredient sold per kilogram of biomass between 2005 and 2010. Data on sales of antimicrobial agents and on the biomass of the target animal species were compiled from statistics published bythe Japanese Ministry of Agriculture, Forestry and Fisheries. The quantities of antimicrobials used varied between animal species: the highest usage was observed in pigs (392 to 423 mg/ kg), followed by beef cattle (45 to 67 mg/kg), broiler chickens (44 to 63 mg/kg) and dairy cattle (33 to 49 mg/kg). For the animal species combined, usage of third- and fourth-generation cefalosporins, fluoroquinolones and macrolides ranged from 0.10 to 0.14 mg/kg biomass, 1.1 to 1.3 mg/kg biomass and 7.8 to 10.6 mg/kg biomass, respectively.

  10. Introducing Cichorium Pumilum as a potential therapeutical agent against drug-induced benign breast tumor in rats.

    PubMed

    Al-Akhras, M-Ali H; Aljarrah, Khaled; Al-Khateeb, Hasan; Jaradat, Adnan; Al-Omari, Abdelkarim; Al-Nasser, Amjad; Masadeh, Majed M; Amin, Amr; Hamza, Alaaeldin; Mohammed, Karima; Al Olama, Mohammad; Daoud, Sayel

    2012-12-01

    Cichorium Pumilum (chicory) is could be a promising cancer treatment in which a photosensitizing drug concentrates in benign tumor cells and activated by quanta at certain wavelength. Such activated extracts could lead to cell death and tumor ablation. Previous studies have shown that Cichorium Pumilum (chicory) contains photosensitive compounds such as cichoriin, anthocyanins, lactucin, and Lactucopicrin. In the present study, the protective effect of sun light-activated Cichorium against the dimethylbenz[a]anthracene (DMBA) induced benign breast tumors to female Sprague-Dawley rats was investigated. Chicory's extract has significantly increase P.carbonyl (PC) and malondialdehyde (MDA) and decreases the hepatic levels of total antioxidant capacity (TAC) and superoxide dismutase (SOD) in benign breast tumors-induced group compared to control. It also significantly decrease the number of estrogen receptors ER-positive cells in tumor masses. These results suggest that chicory extracts could be used as herbal photosensitizing agent in treating benign breast tumor in rats.

  11. 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

  12. 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.

  13. Quantitative structure-activity relationship studies on nitrofuranyl antitubercular agents

    PubMed Central

    Hevener, Kirk E.; Ball, David M.; Buolamwini, John K.

    2008-01-01

    A series of nitrofuranylamide and related aromatic compounds displaying potent activity against M. tuberculosis has been investigated utilizing 3-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) techniques. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to produce 3D-QSAR models that correlated the Minimum Inhibitory Concentration (MIC) values against M. tuberculosis with the molecular structures of the active compounds. A training set of 95 active compounds was used to develop the models, which were then evaluated by a series of internal and external cross-validation techniques. A test set of 15 compounds was used for the external validation. Different alignment and ionization rules were investigated as well as the effect of global molecular descriptors including lipophilicity (cLogP, LogD), Polar Surface Area (PSA), and steric bulk (CMR), on model predictivity. Models with greater than 70% predictive ability, as determined by external validation, and high internal validity (cross validated r2 > .5) have been developed. Incorporation of lipophilicity descriptors into the models had negligible effects on model predictivity. The models developed will be used to predict the activity of proposed new structures and advance the development of next generation nitrofuranyl and related nitroaromatic anti-tuberculosis agents. PMID:18701298

  14. Curcumin as therapeutics for the treatment of head and neck squamous cell carcinoma by activating SIRT1.

    PubMed

    Hu, An; Huang, Jing-Juan; Li, Rui-Lin; Lu, Zhao-Yang; Duan, Jun-Li; Xu, Wei-Hua; Chen, Xiao-Ping; Fan, Jing-Ping

    2015-08-24

    SIRT1 is one of seven mammalian homologs of Sir2 that catalyzes NAD(+)-dependent protein deacetylation. The aim of the present study is to explore the effect of SIRT1 small molecule activator on the anticancer activity and the underlying mechanism. We examined the anticancer activity of a novel oral agent, curcumin, which is the principal active ingredient of the traditional Chinese herb Curcuma Longa. Treatment of FaDu and Cal27 cells with curcumin inhibited growth and induced apoptosis. Mechanistic studies showed that anticancer activity of curcumin is associated with decrease in migration of HNSCC and associated angiogenesis through activating of intrinsic apoptotic pathway (caspase-9) and extrinsic apoptotic pathway (caspase-8). Our data demonstrating that anticancer activity of curcumin is linked to the activation of the ATM/CHK2 pathway and the inhibition of nuclear factor-κB. Finally, increasing SIRT1 through small molecule activator curcumin has shown beneficial effects in xenograft mouse model, indicating that SIRT1 may represent an attractive therapeutic target. Our studies provide the preclinical rationale for novel therapeutics targeting SIRT1 in HNSCC.

  15. Therapeutic antibody gene transfer: an active approach to passive immunity.

    PubMed

    Bakker, Joost M; Bleeker, Wim K; Parren, Paul W H I

    2004-09-01

    Advances in gene transfer approaches are enabling the possibility of applying therapeutic antibodies using DNA. In particular gene transfer in combination with electroporation is promising and can result in generating in vivo antibody concentrations in the low therapeutic range. However, several important problems need to be dealt with before antibody gene transfer can become a valuable supplement to the current therapies. As antibody production following gene transfer is difficult to control, the danger of inducing autoimmune conditions or uncontrollable side effects occurs in cases in which autologous antigens are targeted. It is suggested that the most promising area of application therefore appears to be infectious disease in which heterologous antigens are targeted and concerns for long-term antibody exposure are minimal. Finally, genes encoding fully human antibodies will enhance long-term expression and decrease problems linked to immunogenicity.

  16. ActivitySim: large-scale agent based activity generation for infrastructure simulation

    SciTech Connect

    Gali, Emmanuel; Eidenbenz, Stephan; Mniszewski, Sue; Cuellar, Leticia; Teuscher, Christof

    2008-01-01

    The United States' Department of Homeland Security aims to model, simulate, and analyze critical infrastructure and their interdependencies across multiple sectors such as electric power, telecommunications, water distribution, transportation, etc. We introduce ActivitySim, an activity simulator for a population of millions of individual agents each characterized by a set of demographic attributes that is based on US census data. ActivitySim generates daily schedules for each agent that consists of a sequence of activities, such as sleeping, shopping, working etc., each being scheduled at a geographic location, such as businesses or private residences that is appropriate for the activity type and for the personal situation of the agent. ActivitySim has been developed as part of a larger effort to understand the interdependencies among national infrastructure networks and their demand profiles that emerge from the different activities of individuals in baseline scenarios as well as emergency scenarios, such as hurricane evacuations. We present the scalable software engineering principles underlying ActivitySim, the socia-technical modeling paradigms that drive the activity generation, and proof-of-principle results for a scenario in the Twin Cities, MN area of 2.6 M agents.

  17. Activity of catalytic silver nanoparticles modulated by capping agent hydrophobicity.

    PubMed

    Janani, Seralathan; Stevenson, Priscilla; Veerappan, Anbazhagan

    2014-05-01

    In this paper, a facile in situ method is reported for the preparation of catalytic silver nanoparticles (AgNPs) using N-acyl tyramine (NATA) with variable hydrophobic acyl length. Scanning electron microscopic analysis shows that NATA exists initially as larger aggregates in alkaline aqueous solution. The addition of AgNO3 dissociates these larger aggregate and subsequently promotes the formation of self-assembled NATA and AgNPs. Characterization of AgNPs using UV-vis spectroscopy, scanning electron microscope and transmission electron microscope revealed that the hydrophobic acyl chain length of NATA does not influence the particle size, shape and morphology. All NATA-AgNPs yielded relatively identical values in full width at half-maximum (FWHM) analysis, indicating that the AgNPs prepared with NATA are relatively polydispersed at all tested acyl chain lengths. These nanoparticles are able to efficiently catalyze the reduction of 4-nitro phenol to 4-amino phenol, 2-nitro aniline to 1,2-diamino benzene, 2,4,6-trinitro phenol to 2,4,6-triamino phenol by NaBH4 in an aqueous environment. The reduction reaction rate is determined to be pseudo-first order and the apparent rate constant is linearly dependent on the hydrophobic acyl chain length of the NATA. All reaction kinetics presented an induction period, which is dependent on the N-acyl chain length, indicating that the hydrophobic effects play a critical role in bringing the substrate to the metal nanoparticle surface to induce the catalytic reaction. In this study, however, the five catalytic systems have similar size and polydispersity, differing only in terms of capping agent hydrophobicity, and shows different catalytic activity with respect to the alkyl chain length of the capping agent. As discussed, the ability to modulate the metal nanoparticles catalytic property, by modifying the capping agent hydrophobicity represents a promising future for developing an efficient nanocatalyst without altering the size

  18. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl...

  19. Bifunctional Therapeutic High-Valence Silver-Pyridoxine Nanoparticles with Proliferative and Antibacterial Wound-Healing Activities.

    PubMed

    Rangasamy, Sabarinathan; Tak, Yu Kyung; Kim, Sunhee; Paul, Avijit; Song, Joon Myong

    2016-01-01

    The antibacterial and moisturizing effects inherent to silver nanoparticles contribute greatly to their use as a topical antibacterial agent. The antibacterial property of silver nanoparticles provides topical wounds with an indirect environment for healing through the prevention of pathogenic infection. However, the direct wound-healing effects of silver nanoparticles have not been previously explored. In this work, we report a bimodal therapeutic silver nanoparticle that possesses both direct wound-healing and antibacterial properties. The nanoparticles consist of high-valence silver-pyridoxine complexes. The wound-healing efficacy was verified in diabetic mice, as well as in vitro assays. A MAPK pathway study demonstrated that silver-pyridoxine nanoparticles induced the proliferation and migration of keratinocyte and fibroblast cells. Antibacterial activities in 8 different pathogenic bacteria responsible for the infection of burn wounds were tested. The rapid wound healing occurring on skin wounds of diabetic mice attests to the utility of bimodal therapeutic silver nanoparticles as a next-generation topical therapeutic agent.

  20. SEQUESTERING AGENTS FOR ACTIVE CAPS - REMEDIATION OF METALS AND ORGANICS

    SciTech Connect

    Knox, A; Michael Paller, M; Danny D. Reible, D; Xingmao Ma, X; Ioana G. Petrisor, I

    2007-05-10

    This research evaluated organoclays, zeolites, phosphates, and a biopolymer as sequestering agents for inorganic and organic contaminants. Batch experiments were conducted to identify amendments and mixtures of amendments for metal and organic contaminants removal and retention. Contaminant removal was evaluated by calculating partitioning coefficients. Metal retention was evaluated by desorption studies in which residue from the removal studies was extracted with 1 M MgCl{sub 2} solution. The results indicated that phosphate amendments, some organoclays, and the biopolymer, chitosan, were very effective sequestering agents for metals in fresh and salt water. Organoclays were very effective sorbents for phenanthrene, pyrene, and benzo(a)pyrene. Partitioning coefficients for the organoclays were 3000-3500 ml g{sup -1} for benzo(a)pyrene, 400-450 ml g{sup -1} for pyrene, and 50-70 ml g{sup -1} for phenanthrene. Remediation of sites with a mixture of contaminants is more difficult than sites with a single contaminant because metals and organic contaminants have different fate and transport mechanisms in sediment and water. Mixtures of amendments (e.g., organoclay and rock phosphate) have high potential for remediating both organic and inorganic contaminants under a broad range of environmental conditions, and have promise as components in active caps for sediment remediation.

  1. Therapeutic Uses and Pharmacological Properties of Garlic, Shallot, and Their Biologically Active Compounds

    PubMed Central

    Mikaili, Peyman; Maadirad, Surush; Moloudizargari, Milad; Aghajanshakeri, Shahin; Sarahroodi, Shadi

    2013-01-01

    Objective(s): Garlic (Allium sativum L. family Liliaceae) is well known in Iran and its leaves, flowers, and cloves have been used in traditional medicine for a long time. Research in recent decades has shown widespread pharmacological effects of A. sativum and its organosulfur compounds especially Allicin. Studies carried out on the chemical composition of the plant show that the most important constituents of this plant are organosulfur compounds such as allicin, diallyl disulphide, S-allylcysteine, and diallyl trisulfide. Allicin represents one of the most studied among these naturally occurring compounds. In addition to A. sativum, these compounds are also present in A. hirtifolium (shallot) and have been used to treat various diseases. This article reviews the pharmacological effects and traditional uses of A. sativum, A. hirtifolium, and their active constituents to show whether or not they can be further used as potential natural sources for the development of novel drugs. Materials and Methods: For this purpose, the authors went through a vast number of sources and articles and all needed data was gathered. The findings were reviewed and classified on the basis of relevance to the topic and a summary of all effects were reported as tables. Conclusion: Garlic and shallots are safe and rich sources of biologically active compounds with low toxicity. Further studies are needed to confirm the safety and quality of the plants to be used by clinicians as therapeutic agents. PMID:24379960

  2. Therapeutic Activity of Lenalidomide in Mantle Cell Lymphoma and Indolent Non-Hodgkin's Lymphomas.

    PubMed

    Gunnellini, Marco; Falchi, Lorenzo

    2012-01-01

    Mantle cell lymphoma (MCL) comprises 3-10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper.

  3. Therapeutic Activity of Lenalidomide in Mantle Cell Lymphoma and Indolent Non-Hodgkin's Lymphomas

    PubMed Central

    Gunnellini, Marco; Falchi, Lorenzo

    2012-01-01

    Mantle cell lymphoma (MCL) comprises 3–10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper. PMID:22761620

  4. Activation of latent HIV-1 expression by protein kinase C agonists. A novel therapeutic approach to eradicate HIV-1 reservoirs.

    PubMed

    Sánchez-Duffhues, Gonzalo; Vo, Minh Q; Pérez, Moisés; Calzado, Marco A; Moreno, Santiago; Appendino, Giovanni; Muñoz, Eduardo

    2011-03-01

    The persistence of latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication in patients treated with highly active antiretroviral therapy. The molecular mechanisms by which integrated HIV-1 is repressed during latency have been partially identified in different models of HIV-1 latency, and the involvement of multiple processes has been demonstrated. Therefore, several molecular targets amenable to pharmacological manipulation have emerged to antagonize HIV-1 latency in the viral reservoirs. In this context, it has been suggested that successful depletion of such latent reservoirs will require a combination of therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. HIV-1 reactivation therapy is a potential therapeutic option to purge the viral reservoirs. The goal of this therapy is to enhance the transcriptional activity of the latent HIV-1 without inducing the polyclonal activation of non-infected cells. In this sense natural or semisynthetic protein kinase C agonists lacking tumour-promoter activities clearly fulfil this criterion, thereby opening new research avenues to purge HIV-1 reservoirs. In this review article, we have succinctly summarized the known effects of "natural products", focusing on phorboids like prostratin and ingenols, macrolides like bryostatin 1, and macrocyclic polyesters like ingols and jatrophanes. A comprehensive view on the molecular mechanisms underlying the principle of HIV-1 reactivation from latency is provided, discussing the combination of "natural products" with other experimental or conventional therapeutics.

  5. BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models

    PubMed Central

    Ambati, Srikanth R.; Shieh, Jae-Hung; Pera, Benet; Lopes, Eloisi Caldas; Chaudhry, Anisha; Wong, Elissa W.P.; Saxena, Ashish; Su, Tsann-Long; Moore, Malcolm A.S.

    2016-01-01

    DNA damaging agents cause rapid shrinkage of tumors and form the basis of chemotherapy for sarcomas despite significant toxicities. Drugs having superior efficacy and wider therapeutic windows are needed to improve patient outcomes. We used cell proliferation and apoptosis assays in sarcoma cell lines and benign cells; γ-H2AX expression, comet assay, immunoblot analyses and drug combination studies in vitro and in patient derived xenograft (PDX) models. BO-1055 caused apoptosis and cell death in a concentration and time dependent manner in sarcoma cell lines. BO-1055 had potent activity (submicromolar IC50) against Ewing sarcoma and rhabdomyosarcoma, intermediate activity in DSRCT (IC50 = 2-3μM) and very weak activity in osteosarcoma (IC50 >10μM) cell lines. BO-1055 exhibited a wide therapeutic window compared to other DNA damaging drugs. BO-1055 induced more DNA double strand breaks and γH2AX expression in cancer cells compared to benign cells. BO-1055 showed inhibition of tumor growth in A673 xenografts and caused tumor regression in cyclophosphamide resistant patient-derived Ewing sarcoma xenografts and A204 xenografts. Combination of BO-1055 and irinotecan demonstrated synergism in Ewing sarcoma PDX models. Potent activity on sarcoma cells and its relative lack of toxicity presents a strong rationale for further development of BO-1055 as a therapeutic agent. PMID:27248664

  6. Toward Constructing the Therapeutic System.

    ERIC Educational Resources Information Center

    Andolfi, Maurizio; Angelo, Claudio

    1988-01-01

    Describes the therapist as an active participant in the construction of the therapeutic system, explaining how the therapist constructs complex relationships within the evolving therapeutic process. Reevaluates the importance of the individual in the family as an agent of change and as a mediator of triangular relational messages. (Author/NB)

  7. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

    PubMed

    Wang, Hui; Liu, Xiufei; Long, Min; Huang, Yi; Zhang, Linlin; Zhang, Rui; Zheng, Yi; Liao, Xiaoyu; Wang, Yuren; Liao, Qian; Li, Wenjie; Tang, Zili; Tong, Qiang; Wang, Xiaocui; Fang, Fang; Rojo de la Vega, Montserrat; Ouyang, Qin; Zhang, Donna D; Yu, Shicang; Zheng, Hongting

    2016-04-13

    Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.

  8. Laboratory activities involving transmissible spongiform encephalopathy causing agents: risk assessment and biosafety recommendations in Belgium.

    PubMed

    Leunda, Amaya; Van Vaerenbergh, Bernadette; Baldo, Aline; Roels, Stefan; Herman, Philippe

    2013-01-01

    Since the appearance in 1986 of epidemic of bovine spongiform encephalopathy (BSE), a new form of neurological disease in cattle which also affected human beings, many diagnostic and research activities have been performed to develop detection and therapeutic tools. A lot of progress was made in better identifying, understanding and controlling the spread of the disease by appropriate monitoring and control programs in European countries. This paper reviews the recent knowledge on pathogenesis, transmission and persistence outside the host of prion, the causative agent of transmissible spongiform encephalopathies (TSE) in mammals with a particular focus on risk (re)assessment and management of biosafety measures to be implemented in diagnostic and research laboratories in Belgium. Also, in response to the need of an increasing number of European diagnostic laboratories stopping TSE diagnosis due to a decreasing number of TSE cases reported in the last years, decontamination procedures and a protocol for decommissioning TSE diagnostic laboratories is proposed.

  9. Potential use of G protein-coupled receptor-blocking monoclonal antibodies as therapeutic agents for cancers.

    PubMed

    Herr, Deron R

    2012-01-01

    The therapeutic use of monoclonal antibodies (mAbs) is the fastest growing area of pharmaceutical development and has enjoyed significant clinical success since approval of the first mAb drug in1984. However, despite significant effort, there are still no approved therapeutic mAbs directed against the largest and most attractive family of drug targets: G protein-coupled receptors (GPCRs). GPCRs regulate essentially all cellular processes, including those that are fundamental to cancer pathology, such as proliferation, survival/drug resistance, migration, differentiation, tissue invasion, and angiogenesis. Many different GPCR isoforms are enhanced or dysregulated in multiple tumor types, and several GPCRs have known oncogenic activity. With approximately 350 distinct GPCRs in the genome, these receptors provide a rich landscape for the design of effective, targeted therapies for cancer, a uniquely heterogeneous disease family. While the generation of selective, efficacious mAbs has been problematic for these structurally complex integral membrane proteins, progress in the development of immunotherapeutics has been made by several independent groups. This chapter provides an overview of the roles of GPCRs in cancer and describes the current state of the art of GPCR-targeted mAb drugs.

  10. 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

  11. Synthesis, biological evaluation and structure-activity relationship of 2-styrylquinazolones as anti-tubercular agents.

    PubMed

    Jadhavar, Pradeep S; Dhameliya, Tejas M; Vaja, Maulikkumar D; Kumar, Dinesh; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Sriram, Dharmarajan; Chakraborti, Asit K

    2016-06-01

    2-Styrylquinazolones are reported as a novel class of potent anti-mycobacterial agents. Forty-six target compounds have been synthesized using one pot reaction involving isatoic anhydride, amine, and triethyl orthoacetate followed by aldehyde to construct the 2-styrylquinazolone scaffold. The anti-mycobacterial potency of the compounds was determined against H37Rv strain. Twenty-six compounds exhibited anti-Mtb activity in the range of 0.40-6.25μg/mL. Three compounds 8c, 8d and 8ab showed MIC of 0.78μg/mL and were found to be non-toxic (<50% inhibition at 50μg/mL) to HEK 293T cell lines with the therapeutic index >64. The most potent compound 8ar showed MIC of 0.40μg/mL with the therapeutic index >125. An early structure activity relationship for this class of compounds has been established. The computational studies indicate the possibility of these compounds binding to the penicillin binding proteins (PBPs).

  12. Agents that activate the High Osmolarity Glycerol pathway as a means to combat pathogenic molds.

    PubMed

    Wiedemann, Annegret; Spadinger, Anja; Löwe, Axel; Seeger, Allison; Ebel, Frank

    2016-12-01

    Treatment of invasive fungal infections often fails due to the limited number of therapeutic options. In this study, we have analyzed the impact of agents activating the High Osmolarity Glycerol (HOG) pathway on molds that cause infections in humans and livestock. We found that agents like fludioxonil and iprodione, have a clear anti-fungal activity against pathogenic Aspergillus, Lichtheimia, Rhizopus and Scedosporium species. Only A. terreus turned out to be resistant to fludioxonil, even though it is sensitive to iprodione and able to adapt to hyperosmotic conditions. Moreover, the A. terreus tcsC gene can fully complement an A. fumigatus ΔtcsC mutant, thereby also restoring its sensitivity to fludioxonil. The particular phenotype of A. terreus is therefore likely to be independent of its TcsC kinase. In a second part of this study, we further explored the impact of fludioxonil using A. fumigatus as a model organism. When applied in concentrations of 1-2μg/ml, fludioxonil causes an immediate growth arrest and, after longer exposure, a quantitative killing. Hyphae respond to fludioxonil by the formation of new septa and closure of nearly all septal pores. Mitosis occurs in all compartments and is accompanied by a re-localization of the NimA kinase to the cytoplasm. In the swollen compartments, the massive extension of the cell wall triggers a substantial reorganization resulting in an enhanced incorporation of chitin and, most strikingly, a massive loss of galactomannan. Hence, HOG-activating agents have dramatic cell biological consequences and may represent a valuable, future element in the armory that can be used to combat mold infections.

  13. Therapeutic Care. Technology Learning Activity. Teacher Edition. Technology Education Series. Level 2.

    ERIC Educational Resources Information Center

    Oklahoma State Dept. of Vocational and Technical Education, Stillwater. Curriculum and Instructional Materials Center.

    This Technology Learning Activity (TLA) for exploring therapeutic care careers is designed for use in eight class periods. It exposes students to the different types of therapeutic care and helps them understand how they can be used to treat and heal. This teacher's edition begins with an overview of technology education. The second section…

  14. Assessing the adherence to and the therapeutic effectiveness of hypolipidemic agents in a population of patients in Brazil: a retrospective cohort study

    PubMed Central

    Cunico, Cássia; Picheth, Geraldo; Correr, Cassyano J.; Scartezini, Marileia

    2013-01-01

    Objective to evaluate the relation between patient adherence and therapeutic effectiveness of hypolipidemic agents in clinical practice. Methods A retrospective cohort study of 417 patients using hypolipidemic drugs (simvastatin, atorvastatin) between 2003 and 2010 was performed. The population studied consists of patients assisted by the Public Health Service in the far-west region of the State of Santa Catarina, Brazil. The Medication Possession Ratio obtained from pharmacy refill data was used to measure patient adherence. Therapeutic effectiveness was evaluated based on the difference obtained in the serum levels of total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides, before and after taking the drug, in an average time of 8.3 months. Results Following the treatment with hypolipidemic agents, it has been observed a reduction of 14.3% for total cholesterol, 19.6% for LDL-cholesterol, and 14.4% for triglycerides. HDL-cholesterol increased by an 8.0% average. The major changes in lipid profile were promoted by atorvastatin 20 mg daily. The medication adherence rate decreased over the monitoring period. Adherence rates below 60% were associated with therapeutic failure, while rates equal to 80% or higher were associated with the best response to the lipid-lowering drugs. Conclusion Adherence to hypolipidemic agents is higher at the beginning of the treatment, but it decreases over time, affecting the achievement of therapeutic goals. PMID:25035713

  15. Acanthamoeba polyphaga Strain Age and Method of Cyst Production Influence the Observed Efficacy of Therapeutic Agents and Contact Lens Disinfectants

    PubMed Central

    Hughes, Reanne; Heaselgrave, Wayne; Kilvington, Simon

    2003-01-01

    The effects of age in culture and the type of medium used for induction of Acanthamoeba polyphaga (Ros) cysts on susceptibilities to polyhexamethylene biguanide (PHMB; 3 μg/ml), chlorhexidine digluconate (30 μg/ml), myristamidopropyl dimethylamine (20 μg/ml), H2O2 (3%), and two multipurpose contact lens solutions (MPS-1 and MPS-2, based on 1 μg of PHMB per ml) were examined. Strain Ros-02 was cryopreserved on isolation in 1991, while strain Ros-91 had been in continuous axenic culture. Significant differences in susceptibilities to the disinfectants were found depending on the medium used for cyst preparation and the age of the test strain, with Ros-02 generally being more resistant. For example, the killing of Ros-91 cysts produced from an axenic culture of trophozoites in the presence of 50 mM MgCl2 by MPS-2 was 4 logs, but the killing of Ros-02 by MPS-2 was only 2 logs (P < 0.05) and killing of both strains with cysts obtained from monoxenic cultures with Escherichia coli was only 1 log (P < 0.001). Assays repeated with different batches of the various cyst types gave consistent results. A batch of Ros-91 cysts stored at 4°C and tested over an 8-week period with MPS-1 showed progressively increasing susceptibility to disinfection, although there was no loss of viability during storage (P < 0.01). These observations have important implications for the standardization and interpretation of Acanthamoeba disinfectant and therapeutic agent testing. PMID:14506012

  16. Synthesis, antifungal activities and qualitative structure activity relationship of carabrone hydrazone derivatives as potential antifungal agents.

    PubMed

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

    2014-03-11

    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.

  17. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...

  18. Occurrence of Surface Active Agents in the Environment

    PubMed Central

    Olkowska, Ewa; Ruman, Marek; Polkowska, Żaneta

    2014-01-01

    Due to the specific structure of surfactants molecules they are applied in different areas of human activity (industry, household). After using and discharging from wastewater treatment plants as effluent stream, surface active agents (SAAs) are emitted to various elements of the environment (atmosphere, waters, and solid phases), where they can undergo numerous physic-chemical processes (e.g., sorption, degradation) and freely migrate. Additionally, SAAs present in the environment can be accumulated in living organisms (bioaccumulation), what can have a negative effect on biotic elements of ecosystems (e.g., toxicity, disturbance of endocrine equilibrium). They also cause increaseing solubility of organic pollutants in aqueous phase, their migration, and accumulation in different environmental compartments. Moreover, surfactants found in aerosols can affect formation and development of clouds, which is associated with cooling effect in the atmosphere and climate changes. The environmental fate of SAAs is still unknown and recognition of this problem will contribute to protection of living organisms as well as preservation of quality and balance of various ecosystems. This work contains basic information about surfactants and overview of pollution of different ecosystems caused by them (their classification and properties, areas of use, their presence, and behavior in the environment). PMID:24527257

  19. Rapid test for distinguishing membrane-active antibacterial agents.

    PubMed

    Prakash Singh, Maya

    2006-10-01

    In the search for antibacterial agents with a novel mode-of-action (MOA) many targeted cellular and cell-free assays are developed and used to screen chemical and natural product libraries. Frequently, hits identified by the primary screens include compounds with nonspecific activities that can affect the integrity and function of bacterial membrane. For a rapid dereplication of membrane-active compounds, a simple method was established using a commercially available Live/Dead(R) Bacterial Viability Kit. This method utilized two fluorescent nucleic acid stains, SYTO9 (stains all cells green) and propidium iodide (stains cells with damaged membrane red) for the drug-treated bacterial cells. The cells were then either examined visually by fluorescence microscopy or their fluorescence emissions were recorded using a multi-label plate reader set to measure emissions at two different wavelengths. The ratio of green versus red was compared to a standard curve indicating the percentage of live versus dead bacteria. Nine known antibiotics and 14 lead compounds from various antibacterial screens were tested with results consistent with their MOA.

  20. 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

  1. Aloe vera Gel: Effective Therapeutic Agent against Multidrug-Resistant Pseudomonas aeruginosa Isolates Recovered from Burn Wound Infections.

    PubMed

    Goudarzi, Mehdi; Fazeli, Maryam; Azad, Mehdi; Seyedjavadi, Sima Sadat; Mousavi, Reza

    2015-01-01

    Objective. Aloe vera is an herbal medicinal plant with biological activities, such as antimicrobial, anticancer, anti-inflammatory, and antidiabetic ones, and immunomodulatory properties. The purpose of this study was investigation of in vitro antimicrobial activity of A. vera gel against multidrug-resistant (MDR) Pseudomonas aeruginosa isolated from patients with burn wound infections. Methods. During a 6-month study, 140 clinical isolates of P. aeruginosa were collected from patients admitted to the burn wards of a hospital in Tehran, Iran. Antimicrobial susceptibility test was carried out against the pathogens using the A. vera gel and antibiotics (imipenem, gentamicin, and ciprofloxacin). Results. The antibiogram revealed that 47 (33.6%) of all isolates were MDR P. aeruginosa. The extract isolated from A. vera has antibacterial activity against all of isolates. Also, 42 (89.4%) isolates were inhibited by A. vera gel extract at minimum inhibitory concentration (MIC) ≤ 200 µg/mL. MIC value of A. vera gel for other isolates (10.6%) was 800 µg/mL. All of MDR P. aeruginosa strains were inhibited by A. vera at similar MIC50 and MIC90 200 µg/mL. Conclusion. Based on our results, A. vera gel at various concentrations can be used as an effective antibacterial agent in order to prevent wound infection caused by P. aeruginosa.

  2. A new insight into viral proteins as Immunomodulatory therapeutic agents: KSHV vOX2 a homolog of human CD200 as a potent anti-inflammatory protein

    PubMed Central

    Mousavinezhad-Moghaddam, Maryam; Amin, Abbas Ali; Rafatpanah, Houshang; Rezaee, Seyed Abdol Rahim

    2016-01-01

    The physiologic function of the immune system is defense against infectious microbes and internal tumour cells, Therefore, need to have precise modulatory mechanisms to maintain the body homeostasis. The mammalian cellular CD200 (OX2)/CD200R interaction is one of such modulatory mechanisms in which myeloid and lymphoid cells are regulated. CD200 and CD200R molecules are membrane proteins that their immunomodulatory effects are able to suppress inflammatory responses, particularly in the privilege sites such as CNS and eyes. Kaposi’s sarcoma-associated herpesvirus (KSHV), encodes a wide variety of immunoregulatory proteins which play central roles in modulating inflammatory and anti-inflammatory responses in favour of virus dissemination. One such protein is a homologue of the, encoded by open reading frame (ORF) K14 and therefore called vOX2. Based on its gene expression profile during the KSHV life cycle, it is hypothesised that vOX2 modulates host inflammatory responses. Moreover, it seems that vOX2 involves in cell adhesion and modulates innate immunity and promotes Th2 immune responses. In this review the activities of mammalian CD200 and KSHV CD200 in cell adhesion and immune system modulation are reviewed in the context of potential therapeutic agents. PMID:27096058

  3. Doxorubicin Conjugated to Glutathione Stabilized Gold Nanoparticles (Au-GSH-Dox) as an Effective Therapeutic Agent for Feline Injection-Site Sarcomas-Chick Embryo Chorioallantoic Membrane Study.

    PubMed

    Zabielska-Koczywąs, Katarzyna; Dolka, Izabella; Król, Magdalena; Żbikowski, Artur; Lewandowski, Wiktor; Mieczkowski, Józef; Wójcik, Michał; Lechowski, Roman

    2017-02-08

    Feline injection-site sarcomas are malignant skin tumours with a high local recurrence rate, ranging from 14% to 28%. The treatment of feline injection-site sarcomas includes radical surgery, radiotherapy and/or chemotherapy. In our previous study it has been demonstrated that doxorubicin conjugated to glutathione-stabilized gold nanoparticles (Au-GSH-Dox) has higher cytotoxic effects than free doxorubicin for feline fibrosarcoma cell lines with high glycoprotein P activity (FFS1, FFS3). The aim of the present study was to assess the effectiveness of intratumoural injection of Au-GSH-Dox on the growth of tumours from the FFS1 and FFS3 cell lines on chick embryo chorioallantoic membrane. This model has been utilized both in human and veterinary medicine for preclinical oncological studies. The influence of intratumoural injections of Au-GSH-Dox, glutathione-stabilized gold nanoparticles and doxorubicin alone on the Ki-67 proliferation marker was also checked. We demonstrated that the volume ratio of tumours from the FFS1 and FFS3 cell lines was significantly (p < 0.01) decreased after a single intratumoural injection of Au-GSH-Dox, which confirms the positive results of in vitro studies and indicates that Au-GSH-Dox may be a potent new therapeutic agent for feline injection-site sarcomas.

  4. 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.

  5. Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells.

    PubMed

    Gray, Lachlan R; On, Hung; Roberts, Emma; Lu, Hao K; Moso, Michael A; Raison, Jacqueline A; Papaioannou, Catherine; Cheng, Wan-Jung; Ellett, Anne M; Jacobson, Jonathan C; Purcell, Damian F J; Wesselingh, Steve L; Gorry, Paul R; Lewin, Sharon R; Churchill, Melissa J

    2016-08-01

    Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.

  6. The Structure Activity Relationship of Urea Derivatives as Anti-Tuberculosis Agents

    PubMed Central

    Brown, Joshua R.; North, Elton J.; Hurdle, Julian G.; Morisseau, Christophe; Scarborough, Jerrod S.; Sun, Dianqing; Korduláková, Jana; Scherman, Michael S.; Jones, Victoria; Grzegorzewicz, Anna; Crew, Rebecca M.; Jackson, Mary; McNeil, Michael R.; Lee, Richard E.

    2011-01-01

    The treatment of tuberculosis is becoming more difficult due to the ever increasing prevalence of drug resistance. Thus, it is imperative that novel anti-tuberculosis agents, with unique mechanisms of action, be discovered and developed. The direct anti-tubercular testing of a small compound library led to discovery of adamantyl urea hit compound 1. In this study, the hit was followed up through the synthesis of an optimization library. This library was generated by systematically replacing each section of the molecule with a similar moiety until a clear structure activity relationship was obtained with respect to anti-tubercular activity. The best compounds in this series contained a 1-adamantyl-3-phenyl urea core and had potent activity against Mycobacterium tuberculosis plus an acceptable therapeutic index. It was noted that the compounds identified and the pharmacophore developed is consistent with inhibitors of epoxide hydrolase family of enzymes. Consequently, the compounds were tested for inhibition of representative epoxide hydrolases: M. tuberculosis EphB and EphE; and human soluble epoxide hydrolase. Many of the optimized inhibitors showed both potent EphB and EphE inhibition suggesting the antitubercular activity is through inhibition of multiple epoxide hydrolyase enzymes. The inhibitors also showed potent inhibition of humans soluble expoxide hydrolyase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolyase inhibition towards the M. tuberculosis enzymes. PMID:21840723

  7. Large-scale field trials of active immunizing agents

    PubMed Central

    Cockburn, W. Charles

    1955-01-01

    In this discussion of the methods to be used in large-scale field trials of active immunizing agents and of the results to be expected from such trials, special emphasis is laid on pertussis vaccine trials in Great Britain. After a review of the criteria for strictly controlled field studies and of the investigation of typhoid vaccines conducted in 1904-08 by the Antityphoid Committee of the British Army, the author describes the pertussis vaccine studies which have been and are now being carried by the Whooping-Cough Immunization Committee of the Medical Research Council of Great Britain. The original strictly controlled trials have been completed and the results published. Studies are now being made of vaccines prepared by different methods and evaluated both in the field and in the laboratory. Each vaccine is given to some 2000-3000 children of 4-6 months to 4 years of age. By the end of the studies 30 000-40 000 children will have been followed up for a period of two years. Since in the current studies all the children are vaccinated and none are left as unvaccinated controls, the relative and not the absolute protective value of the vaccines will be measured. PMID:13270079

  8. Potential Therapeutic Agents for the Treatment of Fatty Degeneration of Liver and Atheromatous Plaques: An Experimental Study in Rats

    PubMed Central

    Sangi, Sibghatullah Muhammad Ali

    2016-01-01

    Background: Since long high fat diet (HFD) is being blamed for causing fatty degeneration of liver and formation of atheromatous plaques. At present, no proper pharmacotherapy is available for both the conditions. In this study, different substances containing monounsaturated fatty acids were used to observe their protective effects in the HFD induced damage to liver and coronary vessels. Objectives: To discover effective therapeutic agents for HFD induced fatty degeneration of liver and atheromatous plaques. Materials and Methods: The study was conducted from September 2015 to April 2016. In this study, rats were divided into nine groups according to dietary regimen. Each group comprised six rats. Saturated fat was given in the form of butter, and unsaturated fat was given in the form of corn oil, olive oil, Nigella sativa oil, and crushed garlic. Serum samples were taken to estimate lipid profile, liver functions, cardiac functions, and kidney functions. Visceras were removed after animal sacrifice, and histopathological examination was done. Results and Conclusion: During the study period, the weight of animals changed significantly in some groups. Those animals which were given crushed garlic along with high saturated fat diet, showed protection against accumulation of lipids in the hepatocytes. Olive oil and Nigella sativa oil were comparatively less effective. SUMMARY Consumption of Garlic, Nigella Sativa and Olive oil significantly improved/revised the Fatty Degeneration of liver induced by intake of High Fat Diet.No fat deposition was found in the liver when Garlic, Nigella Sativa and Olive oil, were given concomitantly with HFD.Hepatocytes functioned better even in comparison to control and a decrease in liver enzymes was found with use of Garlic.Use of Garlic, Nigella Sativa and Olive oil, prevented the plaque formation in the vessels and decreased serum lipids.Beneficial effects of Garlic were significant in comparison to Nigella Sativa and Olive oil

  9. Therapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis.

    PubMed

    Ribeiro, R; Yu, F; Wen, J; Vana, A; Zhang, Y

    2013-12-19

    Multiple Sclerosis (MS) is a demyelinating disease which causes inflammation, demyelination, and axonal injury. Currently, there is no cure for the disease. The endocannabinoid system has recently emerged as a promising therapeutic target for MS. The protective mechanisms of cannabinoids are thought to be mediated by the activation of the cannabinoid type 1 (CB1) and type 2 (CB2) receptors expressed primarily in neurons and immune cells, respectively. However, the molecular mechanisms and the contribution of each receptor in ameliorating disease progression are still debatable. Although CB1 and CB2 receptors are expressed in oligodendrocytes, the myelin producing cells in the central nervous system, the role of cannabinoids in oligodendrocyte survival has not been well investigated. Using primary cultures of mature oligodendrocytes, we tested the effect of a novel synthetic cannabinoid CB52 on oligodendrocyte toxicity induced by peroxynitrite, the primary toxic species released by microglia. Interestingly, we found that CB52 is more potent than a number of broad and selective CB1 and CB2 agonists in protecting oligodendrocytes against peroxynitrite-induced toxicity. The protection provided by CB52 is likely due to its reduction of ERK1/2 phosphorylation and reactive oxygen species (ROS) generation in these cells. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found that CB52 reduces microglia activation, nitrotyrosine formation, T cell infiltration, oligodendrocyte toxicity, myelin loss and axonal damage in the mouse spinal cord white matter and alleviates the clinical scores when given either before or after disease onset. These effects are reversed by the CB1 receptor antagonist, but not by the CB2 receptor antagonist, suggesting that the activation of CB1 receptors contributes significantly to the anti-inflammatory and neuroprotective effects of cannabinoids on MS.

  10. Histatin 5-spermidine conjugates have enhanced fungicidal activity and efficacy as a topical therapeutic for oral candidiasis.

    PubMed

    Tati, Swetha; Li, Rui; Puri, Sumant; Kumar, Rohitashw; Davidow, Peter; Edgerton, Mira

    2014-01-01

    Oropharyngeal candidiasis (OPC) is caused by the opportunistic fungi Candida albicans and is prevalent in immunocompromised patients, individuals with dry mouth, or patients with prolonged antibiotic therapies that reduce oral commensal bacteria. Human salivary histatins, including histatin 5 (Hst 5), are small cationic proteins that are the major source of fungicidal activity of saliva. However, Hsts are rapidly degraded in vivo, limiting their usefulness as therapeutic agents despite their lack of toxicity. We constructed a conjugate peptide using spermidine (Spd) linked to the active fragment of Hst 5 (Hst 54-15), based upon our findings that C. albicans spermidine transporters are required for Hst 5 uptake and fungicidal activity. We found that Hst 54-15-Spd was significantly more effective in killing C. albicans and Candida glabrata than Hst 5 alone in both planktonic and biofilm growth and that Hst 54-15-Spd retained high activity in both serum and saliva. Hst 54-15-Spd was not bactericidal against streptococcal oral commensal bacteria and had no hemolytic activity. We tested the effectiveness of Hst 54-15-Spd in vivo by topical application to tongue surfaces of immunocompromised mice with OPC. Mice treated with Hst 54-15-Spd had significant clearance of candidal tongue lesions macroscopically, which was confirmed by a 3- to 5-log fold reduction of C. albicans colonies recovered from tongue tissues. Hst 54-15-Spd conjugates are a new class of peptide-based drugs with high selectivity for fungi and potential as topical therapeutic agents for oral candidiasis.

  11. Histatin 5-Spermidine Conjugates Have Enhanced Fungicidal Activity and Efficacy as a Topical Therapeutic for Oral Candidiasis

    PubMed Central

    Tati, Swetha; Li, Rui; Puri, Sumant; Kumar, Rohitashw; Davidow, Peter

    2014-01-01

    Oropharyngeal candidiasis (OPC) is caused by the opportunistic fungi Candida albicans and is prevalent in immunocompromised patients, individuals with dry mouth, or patients with prolonged antibiotic therapies that reduce oral commensal bacteria. Human salivary histatins, including histatin 5 (Hst 5), are small cationic proteins that are the major source of fungicidal activity of saliva. However, Hsts are rapidly degraded in vivo, limiting their usefulness as therapeutic agents despite their lack of toxicity. We constructed a conjugate peptide using spermidine (Spd) linked to the active fragment of Hst 5 (Hst 54–15), based upon our findings that C. albicans spermidine transporters are required for Hst 5 uptake and fungicidal activity. We found that Hst 54–15-Spd was significantly more effective in killing C. albicans and Candida glabrata than Hst 5 alone in both planktonic and biofilm growth and that Hst 54–15-Spd retained high activity in both serum and saliva. Hst 54–15-Spd was not bactericidal against streptococcal oral commensal bacteria and had no hemolytic activity. We tested the effectiveness of Hst 54–15-Spd in vivo by topical application to tongue surfaces of immunocompromised mice with OPC. Mice treated with Hst 54–15-Spd had significant clearance of candidal tongue lesions macroscopically, which was confirmed by a 3- to 5-log fold reduction of C. albicans colonies recovered from tongue tissues. Hst 54–15-Spd conjugates are a new class of peptide-based drugs with high selectivity for fungi and potential as topical therapeutic agents for oral candidiasis. PMID:24247141

  12. Antibacterial activity of bee honey and its therapeutic usefulness against Escherichia coli O157:H7 and Salmonella typhimurium infection.

    PubMed

    Badawy, O F H; Shafii, S S A; Tharwat, E E; Kamal, A M

    2004-12-01

    The authors studied the effect of storage period and heat on the physical and chemical properties of honey and proceeded to study the antibacterial effect of honey on Escherichia coli and Salmonella typhimurium. In samples of honey (Egyptian clover honey) that were heat-treated and stored over a long period of time, water content decreased, hydroxymethyl furfural (HMF) was produced and increased in concentration, and enzyme activity decreased. Colour, measured in optical density, was markedly affected in honey samples stored over long periods of time, as was the refractive index, but electrical conductivity remained unaffected by storage or heating. Similarly, the storage period had no effect on pH value. To study the therapeutic effect of honey on E.coli and S. typhimurium, 25 isolates of E. coil O157:H7 (18.5%) and 49 isolates of S. typhimurium (36.2%) were isolated from 135 samples taken from children and calves (30 stool samples from children and 105 samples from calf organs and faecal swabs). Most E. coli O157:H7 and S. typhimurium isolates were highly resistant to most antibiotic discs. In vitro, the antibacterial effect of honey was more pronounced on E. coil O157:H7 than on S. typhimurium. Water content, pH value, HMF and the presence of H2O, all played an important role in the potency of olover honey as an antibacterial agent. In vivo, mice were used as a model for studying the parenteral usefulness of honey as an antibacterial agent against both pathogens. The antibacterial activity of honey that had been stored over a long period of time decreased and high concentrations of honey proved more effective as antibacterial agents. In this study there was lower mortality among mice treated with honey but the parenteral application of honey and its therapeutic properties require further investigation.

  13. pH-Sensitive Microparticles with Matrix-Dispersed Active Agent

    NASA Technical Reports Server (NTRS)

    Li, Wenyan (Inventor); Buhrow, Jerry W. (Inventor); Jolley, Scott T. (Inventor); Calle, Luz M. (Inventor)

    2014-01-01

    Methods to produce pH-sensitive microparticles that have an active agent dispersed in a polymer matrix have certain advantages over microcapsules with an active agent encapsulated in an interior compartment/core inside of a polymer wall. The current invention relates to pH-sensitive microparticles that have a corrosion-detecting or corrosion-inhibiting active agent or active agents dispersed within a polymer matrix of the microparticles. The pH-sensitive microparticles can be used in various coating compositions on metal objects for corrosion detecting and/or inhibiting.

  14. Identification of endoplasmic reticulum stress-inducing agents by antagonizing autophagy: a new potential strategy for identification of anti-cancer therapeutics in B-cell malignancies

    PubMed Central

    Mahoney, Emilia; Maddocks, Kami; Flynn, Joseph; Jones, Jeffrey; Cole, Sara L.; Zhang, Xiaoli; Byrd, John C.; Johnson, Amy J.

    2013-01-01

    The endoplasmic reticulum (ER) plays a vital function in multiple cellular processes. There is a growing interest in developing therapeutic agents that can target the ER in cancer cells, inducing a stress response that leads to cell death. However, ER stress-inducing agents can also induce autophagy, a survival strategy of cancer cells. Therefore, by inhibiting autophagy we can increase the efficacy of the ER stress-inducing agents. Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor with anti-cancer properties, can induce ER stress. Nelfinavir’s effects on chronic lymphocytic leukemia (CLL) are yet to be elucidated. Herein we demonstrate that nelfinavir induces ER morphological changes and stress response, along with an autophagic protective strategy. Our data reveal that chloroquine, an autophagy inhibitor, significantly increases nelfinavir cytotoxicity. These results identify a novel strategy potentially effective in CLL treatment, by repositioning two well-known drugs as a combinatorial therapy with anti-cancer properties. PMID:23469959

  15. Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance

    PubMed Central

    Kwatra, Deep; Venugopal, Anand; Standing, David; Ponnurangam, Sivapriya; Dhar, Animesh; Mitra, Ashim; Anant, Shrikant

    2014-01-01

    Recently we demonstrated that extracts of bitter melon (BME) can be used as a preventive/therapeutic agent in colon cancers. Here, we determined BME effects on anticancer activity and bioavailability of doxorubicin (DOX) in colon cancer cells. BME enhanced the effect of DOX on cell proliferation and sensitized the cells towards DOX upon pretreatment. Furthermore, there was both increased drug uptake and reduced drug efflux. We also observed a reduction in the expression of Multidrug resistance conferring proteins (MDRCP) P-glycoprotein, MRP-2 and BCRP. Further BME suppressed DOX efflux in MDCK cells overexpressing the three efflux proteins individually, suggesting that BME is a potent inhibitor of MDR function. Next, we determined the effect of BME on PXR, a xenobiotic sensing nuclear receptor and a transcription factor that controls the expression of the three MDR genes. BME suppressed PXR promoter activity thereby suppressing its expression. Finally, we determined the effect of AMPK pathway on drug efflux because we have previously demonstrated that BME affects the pathway. However, inhibiting AMPK did not affect drug resistance, suggesting that BME may use different pathways for the anticancer and MDR modulating activities. Together, these results suggest that BME can enhance the bioavailability and efficacy of conventional chemotherapy. PMID:24129966

  16. Development of a theoretical model describing sonoporation activity of cells exposed to ultrasound in the presence of contrast agents

    PubMed Central

    Forbes, Monica M.; O’Brien, William D.

    2012-01-01

    Sonoporation uses ultrasound, with the aid of ultrasound contrast agents (UCAs), to enhance cell permeabilization, thereby allowing delivery of therapeutic compounds noninvasively into specific target cells. The objective of this study was to determine if a computational model describing shear stress on a cell membrane due to microstreaming would successfully reflect sonoporation activity with respect to the peak rarefactional pressure. The theoretical models were compared to the sonoporation results from Chinese hamster ovary cells using Definity® at 0.9, 3.15, and 5.6 MHz and were found to accurately describe the maximum sonoporation activity, the pressure where a decrease in sonoporation activity occurs, and relative differences between maximum activity and the activity after that decrease. Therefore, the model supports the experimental findings that shear stress on cell membranes secondary to oscillating UCAs results in sonoporation. PMID:22501051

  17. NRF2 Activation as Target to Implement Therapeutic Treatments

    NASA Astrophysics Data System (ADS)

    Bocci, Velio; Valacchi, Giuseppe

    2015-02-01

    A chronic increase of oxidative stress is typical of serious pathologies such as myocardial infarction, stroke, chronic limb ischemia, chronic obstructive pulmonary disease (COPD), type II-diabetes, age-related macular degeneration leads to an epic increase of morbidity and mortality in all countries of the world. The initial inflammation followed by an excessive release of reactive oxygen species (ROS) implies a diffused cellular injury that needs to be corrected by an inducible expression of the innate detoxifying and antioxidant system. The transcription factor Nrf2, when properly activated, is able to restore a redox homeostasis and possibly improve human health.

  18. Nrf2 activation as target to implement therapeutic treatments

    PubMed Central

    Bocci, Velio; Valacchi, Giuseppe

    2015-01-01

    A chronic increase of oxidative stress is typical of serious pathologies such as myocardial infarction, stroke, chronic limb ischemia, chronic obstructive pulmonary disease (COPD), type II-diabetes, age-related macular degeneration leads to an epic increase of morbidity and mortality in all countries of the world. The initial inflammation followed by an excessive release of reactive oxygen species (ROS) implies a diffused cellular injury that needs to be corrected by an inducible expression of the innate detoxifying and antioxidant system. The transcription factor Nrf2, when properly activated, is able to restore a redox homeostasis and possibly improve human health. PMID:25699252

  19. Atomic basis for therapeutic activation of neuronal potassium channels

    PubMed Central

    Kim, Robin Y.; Yau, Michael C.; Galpin, Jason D.; Seebohm, Guiscard; Ahern, Christopher A.; Pless, Stephan A.; Kurata, Harley T.

    2015-01-01

    Retigabine is a recently approved anticonvulsant that acts by potentiating neuronal M-current generated by KCNQ2–5 channels, interacting with a conserved Trp residue in the channel pore domain. Using unnatural amino-acid mutagenesis, we subtly altered the properties of this Trp to reveal specific chemical interactions required for retigabine action. Introduction of a non-natural isosteric H-bond-deficient Trp analogue abolishes channel potentiation, indicating that retigabine effects rely strongly on formation of a H-bond with the conserved pore Trp. Supporting this model, substitution with fluorinated Trp analogues, with increased H-bonding propensity, strengthens retigabine potency. In addition, potency of numerous retigabine analogues correlates with the negative electrostatic surface potential of a carbonyl/carbamate oxygen atom present in most KCNQ activators. These findings functionally pinpoint an atomic-scale interaction essential for effects of retigabine and provide stringent constraints that may guide rational improvement of the emerging drug class of KCNQ channel activators. PMID:26333338

  20. Curcumin derivatives as metal-chelating agents with potential multifunctional activity for pharmaceutical applications.

    PubMed

    Ferrari, Erika; Benassi, Rois; Sacchi, Stefania; Pignedoli, Francesca; Asti, Mattia; Saladini, Monica

    2014-10-01

    Curcuminoids represent new perspectives for the development of novel therapeutics for Alzheimer's disease (AD), one probable mechanism of action is related to their metal complexing ability. In this work we examined the metal complexing ability of substituted curcuminoids to propose new chelating molecules with biological properties comparable with curcumin but with improved stability as new potential AD therapeutic agents. The K2T derivatives originate from the insertion of a -CH2COOC(CH3)3 group on the central atom of the diketonic moiety of curcumin. They retain the diketo-ketoenol tautomerism which is solvent dependent. In aqueous solution the prevalent form is the diketo one but the addition of metal ion (Ga(3+), Cu(2+)) causes the dissociation of the enolic proton creating chelate complexes and shifting the tautomeric equilibrium towards the keto-enol form. The formation of metal complexes is followed by both NMR and UV-vis spectroscopy. The density functional theory (DFT) calculations on K2T21 complexes with Ga(3+) and Cu(2+) are performed and compared with those on curcumin complexes. [Ga(K2T21)2(H2O)2](+) was found more stable than curcumin one. Good agreement is detected between calculated and experimental (1)H and (13)C NMR data. The calculated OH bond dissociation energy (BDE) and the OH proton dissociation enthalpy (PDE), allowed to predict the radical scavenging ability of the metal ion complexed with K2T21, while the calculated electronic affinity (EA) and ionization potential (IP) represent yardsticks of antioxidant properties. Eventually theoretical calculations suggest that the proton-transfer-associated superoxide-scavenging activity is enhanced after binding metal ions, and that Ga(3+) complexes display possible superoxide dismutase (SOD)-like activity.

  1. VDAC1-based peptides: novel pro-apoptotic agents and potential therapeutics for B-cell chronic lymphocytic leukemia.

    PubMed

    Prezma, T; Shteinfer, A; Admoni, L; Raviv, Z; Sela, I; Levi, I; Shoshan-Barmatz, V

    2013-09-19

    The voltage-dependent anion channel 1 (VDAC1), localized in the outer mitochondrial membrane, mediates metabolic cross-talk between the mitochondrion and the cytoplasm and thus serves a fundamental role in cell energy metabolism. VDAC1 also plays a key role in mitochondria-mediated apoptosis, interacting with anti-apoptotic proteins. Resistance of cancer cells to apoptosis involves quenching the mitochondrial apoptotic pathway by over-expression of anti-apoptotic/pro-survival hexokinase (HK) and Bcl-2 family proteins, proteins that mediate their anti-apoptotic activities via interaction with VDAC1. Using specifically designed VDAC1-based cell-penetrating peptides, we targeted these anti-apoptotic proteins to prevent their pro-survival/anti-apoptotic activities. Anti-apoptotic proteins are expressed at high levels in B-cell chronic lymphocytic leukemia (CLL), an incurable disease requiring innovative new approaches to improve therapeutic outcome. CLL is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Specifically, we demonstrate that the VDAC1-based peptides (Antp-LP4 and N-Terminal-Antp) selectively kill peripheral blood mononuclear cells (PBMCs) obtained from CLL patients, yet spare those obtained from healthy donors. The cell death induction competence of the peptides was well correlated with the amount of double positive CD19/CD5 cancerous CLL PBMCs, further illustrating their selectivity toward cancer cells. Moreover, these VDAC1-based peptides induced apoptosis by activating the mitochondria-mediated pathway, reflected in membrane blebbing, condensation of nuclei, DNA fragmentation, release of mitochondrial cytochrome c, loss of mitochondrial membrane potential, decreased cellular ATP levels and detachment of HK, all leading to apoptotic cell death. Thus, the mode of action of the peptides involves decreasing energy production and inducing apoptosis. Over 27 versions of cell-penetrating VDAC1-based peptides

  2. Phytochemical composition, protective and therapeutic effect on gastric ulcer and α-amylase inhibitory activity of Achillea biebersteinii Afan.

    PubMed

    Abd-Alla, Howaida I; Shalaby, Nagwa M M; Hamed, Manal A; El-Rigal, Nagy Saba; Al-Ghamdi, Samira N; Bouajila, Jalloul

    2016-01-01

    Three sesquiterpene lactones [two germacranolides (micranthin and sintenin) and one guaianolide (4β,10α-dihydroxy-5β,7β,8βH-guaia-1,11(13)dien-12,8α-olide)] and four derivatives of 3-methoxy flavones (santin, quercetagetin-3,6,3'-trimethyl ether, quercetagetin-3,6-dimethyl ether, and 5,7 dihydroxy 3,3',4'-trimethoxy flavone) were isolated from the ethyl acetate extract (EAE) of the aerial parts of Achillea biebersteinii Afan. (Asteraceae). Evaluation of protective and therapeutic effects of EAE against ethanol-induced gastric ulcer in rats was carried. Antiulcer activity evaluation was done through measuring ulcer indices, stomach acidity, gastric volume and lesion counts. Oxidative stress markers; malondialdehyde, glutathione and superoxide dismutase were also estimated. The work was extended to determine the histopathological assessment of the stomach. Gastric ulcer exhibited a significant elevation of the ulcer index and oxidative stress markers. The extract attenuated these increments and recorded protective and therapeutic effects against gastric ulcer. Hyperglycaemia increases the mucosal susceptibility to ulcerogenic stimuli and predisposes gastric ulceration. In vitro α-amylase inhibitory assay was applied to evaluate the post prandial antihyperglycaemia activity. The result showing that the EAE has the ability to reduce starch-induced postprandial glycaemic excursions by virtue of potent intestinal α-amylase inhibitory activity. These findings demonstrated the remarkable potential of A. biebersteinii as valuable source of antiulcer agent with post prandial hyperglycaemia lowering effect.

  3. Comparison of status epilepticus models induced by pilocarpine and nerve agents - a systematic review of the underlying aetiology and adopted therapeutic approaches.

    PubMed

    Tang, F R; Loke, W K; Ling, E A

    2011-01-01

    Among potential radiological, nuclear, biological and chemical weapons, cholinergic nerve agents from chemical weapons remain a realistic terrorist threat due to its combination of high lethality, demonstrated use and relative abundance of un-destroyed stockpiles in various militaries around the world. While current fielded antidotes are able to mitigate acute poisoning, effective neuroprotection in the field remains a challenge amongst subjects with established status epilepticus following nerve agent intoxication. Due to ethical, safety and surety issues, extensive preclinical and clinical research on cholinergic nerve agents is not possible. This may have been a contributory factor for the slow progress in uncovering new neuroprotectants for nerve agent casualties with established status epilepticus. To overcome this challenge, comparative research with surrogate chemicals that produce similar hypercholinergic toxicity but with less security concerns would be a useful approach forward. In this paper, we will systemically compare the mechanism of seizure generation, propagation and the subsequent clinical, hematologic, and metabolic, biochemical, neuroinflammatory changes and current therapeutic approaches reported in pilocarpine, soman, and sarin models of seizures. This review will be an important first step in closing this knowledge gap among different closely related models of seizures and neurotoxicity. Hopefully, it will spur further efforts in using surrogate cholinergic models by the wider scientific community to expedite the development of a new generation of antidotes that are better able to protect against delayed neurological effects inflicted by nerve agents.

  4. The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines

    NASA Astrophysics Data System (ADS)

    Beaufils, Damien; Jepaul, Sandra; Liu, Ziwei; Boiteau, Laurent; Pascal, Robert

    2016-03-01

    The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behaviour was explained by the fast formation of a 5(4 H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was observed when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were observed to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as additional evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equilibrium processes.

  5. The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines.

    PubMed

    Beaufils, Damien; Jepaul, Sandra; Liu, Ziwei; Boiteau, Laurent; Pascal, Robert

    2016-03-01

    The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behaviour was explained by the fast formation of a 5(4H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was observed when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were observed to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as additional evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equilibrium processes.

  6. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease.

    PubMed

    Hanson, Leah R; Frey, William H

    2008-12-10

    Intranasal delivery provides a practical, non-invasive method of bypassing the blood-brain barrier (BBB) to deliver therapeutic agents to the brain and spinal cord. This technology allows drugs that do not cross the BBB to be delivered to the central nervous system within minutes. It also directly delivers drugs that do cross the BBB to the brain, eliminating the need for systemic administration and its potential side effects. This is possible because of the unique connections that the olfactory and trigeminal nerves provide between the brain and external environment. Intranasal delivery does not necessarily require any modification to therapeutic agents. A wide variety of therapeutics, including both small molecules and macromolecules, can be targeted to the olfactory system and connected memory areas affected by Alzheimer's disease. Using the intranasal delivery system, researchers have reversed neurodegeneration and rescued memory in a transgenic mouse model of Alzheimer's disease. Intranasal insulin-like growth factor-I, deferoxamine, and erythropoietin have been shown to protect the brain against stroke in animal models. Intranasal delivery has been used to target the neuroprotective peptide NAP to the brain to treat neurodegeneration. Intranasal fibroblast growth factor-2 and epidermal growth factor have been shown to stimulate neurogenesis in adult animals. Intranasal insulin improves memory, attention, and functioning in patients with Alzheimer's disease or mild cognitive impairment, and even improves memory and mood in normal adult humans. This new method of delivery can revolutionize the treatment of Alzheimer's disease, stroke, and other brain disorders.

  7. Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat.

    PubMed

    Broca, Christophe; Breil, Vincent; Cruciani-Guglielmacci, Céline; Manteghetti, Michèle; Rouault, Christine; Derouet, Michel; Rizkalla, Salwa; Pau, Bernard; Petit, Pierre; Ribes, Gérard; Ktorza, Alain; Gross, René; Reach, Gérard; Taouis, Mohammed

    2004-09-01

    ID-1101 (4-hydroxyisoleucine), an amino acid extracted from fenugreek seeds, exhibits an interesting glucose-dependent insulin-stimulating activity. The present study was undertaken to investigate a possible extrapancreatic effect of ID-1101 on insulin signaling and action besides its previously described insulinotropic action. Insulin-sensitizing effects of ID-1101 were investigated in rat in vivo by three different approaches: 1) using euglycemic hyperinsulinemic clamps in two different rat models of insulin resistance, i.e., Zucker fa/fa rats and rats fed a sucrose-lipid diet; 2) measuring liver and muscle phosphatidylinositol (PI) 3-kinase activity after an acute injection of ID-1101 in normal and insulin-resistant diabetic rats; and 3) after chronic treatment in two rat models of insulin resistance. Euglycemic hyperinsulinemic clamp experiments revealed that ID-1101 can improve insulin resistance through an increase of peripheral glucose utilization rate in sucrose-lipid-fed rats and by decreasing hepatic glucose production in Zucker fa/fa rats. Moreover, we demonstrated that a single injection of ID-1101 activates the PI 3-kinase activity in liver and muscle from normal rats but also in muscle from diabetic rats. Finally, chronic ID-1101 treatment significantly reduced insulinemia in type 2 diabetic rats and reduced the progression of hyperinsulinemia in insulin-resistant obese Zucker fa/fa rats. These findings clearly demonstrate that ID-1101 can reduce insulin resistance through activation of the early steps of insulin signaling in peripheral tissues and in liver. In summary, ID-1101, besides its insulinotropic effect, directly improves insulin sensitivity, making it a potentially very valuable therapeutic agent for diabetes treatment.

  8. Metallic ions as therapeutic agents in tissue engineering scaffolds: an overview of their biological applications and strategies for new developments

    PubMed Central

    Mouriño, Viviana; Cattalini, Juan Pablo; Boccaccini, Aldo R.

    2012-01-01

    This article provides an overview on the application of metallic ions in the fields of regenerative medicine and tissue engineering, focusing on their therapeutic applications and the need to design strategies for controlling the release of loaded ions from biomaterial scaffolds. A detailed summary of relevant metallic ions with potential use in tissue engineering approaches is presented. Remaining challenges in the field and directions for future research efforts with focus on the key variables needed to be taken into account when considering the controlled release of metallic ions in tissue engineering therapeutics are also highlighted. PMID:22158843

  9. Chemopreventive and therapeutic efficacy of orally active tyrosine kinase inhibitors in a transgenic mouse model of gallbladder carcinoma.

    PubMed

    Kiguchi, Kaoru; Ruffino, Lynnsie; Kawamoto, Toru; Ajiki, Tetsuo; Digiovanni, John

    2005-08-01

    Biliary tract cancer (BTC) is the second most common primary hepatobiliary cancer after hepatocellular cancer. At the time of diagnosis, most BTC are at an advanced stage and are unresectable. There is presently no effective curative treatment of the advanced disease nor is there any effective clinical therapy that will prevent the development of BTC. All of these factors render gallbladder cancer nearly incurable with a poor survival rate. The aim of our study was to provide a better understanding of the mechanisms involved in the development of gallbladder carcinoma as the advancement of more effective treatment options would significantly improve prognosis. In the present study, we examined the effect of gefitinib, a selective epidermal growth factor receptor/tyrosine kinase inhibitor (EGFR/TKI), on the development of gallbladder carcinoma in BK5.erbB2 mice. In addition, we examined the effect of another quinazoline derivative, GW2974, which is able to block the activation of both the EGFR and erbB2, in this model. Animals were treated with either 400 ppm gefitinib or 200 ppm GW2974 as a supplement in the diet using either a chemopreventive or therapeutic protocol. The results show that both compounds were potent chemopreventive and therapeutic agents in this mouse model of human BTC. The results also suggest that activation of the EGFR plays an important role in development of BTC in this model and that targeting both the EGFR and erbB2 may be an effective strategy for treatment of this disease.

  10. Combinatorial therapeutic activation with heparin and AICAR stimulates additive effects on utrophin A expression in dystrophic muscles.

    PubMed

    Péladeau, Christine; Ahmed, Aatika; Amirouche, Adel; Crawford Parks, Tara E; Bronicki, Lucas M; Ljubicic, Vladimir; Renaud, Jean-Marc; Jasmin, Bernard J

    2016-01-01

    Upregulation of utrophin A is an attractive therapeutic strategy for treating Duchenne muscular dystrophy (DMD). Over the years, several studies revealed that utrophin A is regulated by multiple transcriptional and post-transcriptional mechanisms, and that pharmacological modulation of these pathways stimulates utrophin A expression in dystrophic muscle. In particular, we recently showed that activation of p38 signaling causes an increase in the levels of utrophin A mRNAs and protein by decreasing the functional availability of the destabilizing RNA-binding protein called K-homology splicing regulatory protein, thereby resulting in increases in the stability of existing mRNAs. Here, we treated 6-week-old mdx mice for 4 weeks with the clinically used anticoagulant drug heparin known to activate p38 mitogen-activated protein kinase, and determined the impact of this pharmacological intervention on the dystrophic phenotype. Our results show that heparin treatment of mdx mice caused a significant ∼1.5- to 3-fold increase in utrophin A expression in diaphragm, extensor digitorum longus and tibialis anterior (TA) muscles. In agreement with these findings, heparin-treated diaphragm and TA muscle fibers showed an accumulation of utrophin A and β-dystroglycan along their sarcolemma and displayed improved morphology and structural integrity. Moreover, combinatorial drug treatment using both heparin and 5-amino-4-imidazolecarboxamide riboside (AICAR), the latter targeting 5' adenosine monophosphate-activated protein kinase and the transcriptional activation of utrophin A, caused an additive effect on utrophin A expression in dystrophic muscle. These findings establish that heparin is a relevant therapeutic agent for treating DMD, and illustrate that combinatorial treatment of heparin with AICAR may serve as an effective strategy to further increase utrophin A expression in dystrophic muscle via activation of distinct signaling pathways.

  11. Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity.

    PubMed

    Miyamoto, Yukiko; Kalisiak, Jaroslaw; Korthals, Keith; Lauwaet, Tineke; Cheung, Dae Young; Lozano, Ricardo; Cobo, Eduardo R; Upcroft, Peter; Upcroft, Jacqueline A; Berg, Douglas E; Gillin, Frances D; Fokin, Valery V; Sharpless, K Barry; Eckmann, Lars

    2013-10-22

    Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis, and the bacterial pathogens Helicobacter pylori, Clostridium difficile, and Bacteroides fragilis. Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.

  12. OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells

    PubMed Central

    Liu, Ta-Ming; Ling, Yonghua; Woyach, Jennifer A.; Beckwith, Kyle; Yeh, Yuh-Ying; Hertlein, Erin; Zhang, Xiaoli; Lehman, Amy; Awan, Farrukh; Jones, Jeffrey A.; Andritsos, Leslie A.; Maddocks, Kami; MacMurray, Jessica; Salunke, Santosh B.; Chen, Ching-Shih; Phelps, Mitch A.; Byrd, John C.

    2015-01-01

    Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL. PMID:25293770

  13. OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells.

    PubMed

    Liu, Ta-Ming; Ling, Yonghua; Woyach, Jennifer A; Beckwith, Kyle; Yeh, Yuh-Ying; Hertlein, Erin; Zhang, Xiaoli; Lehman, Amy; Awan, Farrukh; Jones, Jeffrey A; Andritsos, Leslie A; Maddocks, Kami; MacMurray, Jessica; Salunke, Santosh B; Chen, Ching-Shih; Phelps, Mitch A; Byrd, John C; Johnson, Amy J

    2015-01-08

    Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.

  14. Methods for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, Eric A.; Fisher, Walter G.; Dees, H. Craig

    2008-03-18

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method comprises the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention also provides a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent.

  15. Method for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, E.A.; Fisher, W.G.; Dees, H.C.

    1998-11-10

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method includes the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention is also a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent. 13 figs.

  16. Method for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, Eric A.; Fisher, Walter G.; Dees, H. Craig

    1998-01-01

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method includes the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention is also a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent.

  17. [Preparation and optimum process of walnut peel activated carbon by zinc chloride as activating agent].

    PubMed

    Liu, Xiao-hong; Wang, Xing-wei; Zhao, Bo; Lü, Jun-fang; Kang, Ni-na; Zhang, Yao-jun

    2014-12-01

    Walnut peel as raw material, zinc chloride was used as activating agent for preparation walnut peel activated carbon in the muffle furnace in this experiment, using orthogonal design. Yield, the specific surface area and iodine number of walnut peel activated carbon were determined at all designed experimental conditions and the optimum technological condition of preparation was obtained. By analysis of aperture, infrared spectra and the content of acidic group in surface with Boehm, walnut peel activated carbon of prepared at the optimum condition was characterized. The results showed the optimum technological parameters of preparation: activation temperature (600 °C), activation time (1 h), the concentration of zinc chloride (50%), the particle size (60 mesh). The specific surface area of walnut peel activated carbon obtained at optimum condition was mounting to 1258.05 m2 · g(-1), the ratio of medium porous 32.18%. Therefore, walnut peel can be used in the preparation of the high-quality activated carbon of large surface area. Agricultural wastes, as walnut peel, not only were implemented recycle, but also didn't make any pollution. Meanwhile, a cheap adsorbent was provided and it was of great significance to open a new source of activated carbon.

  18. The therapeutic value of natural agents to treat miRNA targeted breast cancer in African-American and Caucasian-American women.

    PubMed

    Rahman, K M Wahidur; Sakr, Wael A

    2012-12-01

    Breast cancer is the most common cancer in women in the United States, with African-American (AA) women showing significantly higher rates than Caucasian-American (CA) women do. The reason for this racial disparity remains unknown, and factors that might be responsible for the differences in incidence and mortality have not been identified. One possible factor could be microRNAs (miRs), which are small noncoding regulatory RNAs involved intimately in cancer, and the expression of certain miRs may be decreased or increased in the breast tumors of AA and CA women. Therefore, modulation of miRs using natural agents could lead to the development of a novel therapeutic strategy to treat aggressive forms of breast cancer in women of different racial backgrounds. The function of natural agents in the regulation of miRs has not been investigated extensively. In this review, we will discuss the potential role of naturally occurring agents as potent antitumor agents thought to function by targeting miRs as contributing factors to the disparity in breast cancer between AA and CA women.

  19. Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity.

    PubMed

    Gilson, Paul R; Tan, Cyrus; Jarman, Kate E; Lowes, Kym N; Curtis, Joan M; Nguyen, William; Di Rago, Adrian E; Bullen, Hayley E; Prinz, Boris; Duffy, Sandra; Baell, Jonathan B; Hutton, Craig A; Jousset Subroux, Helene; Crabb, Brendan S; Avery, Vicky M; Cowman, Alan F; Sleebs, Brad E

    2017-02-09

    Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.

  20. [Ajoene the main active compound of garlic (Allium sativum): a new antifungal agent].

    PubMed

    Ledezma, Eliades; Apitz-Castro, Rafael

    2006-06-01

    The curative properties of garlic in medicine have been known for a long time. But, it was only in the last three decades when garlic properties were seriously investigated confirming its potential as therapeutic agent. Allicin, ajoene, thiosulfinates and a wide range of other organosulphurate compounds, are known to be the constituents linked to the garlic properties. Regarding the biochemical properties of these compounds, ajoene [(E,Z)-4,5,9 Trithiadodeca 1,6,11 Triene 9-oxide] is stable in water, and it can be obtained by chemical synthesis. There is evidence that some of the garlic constituents exert a wide variety of effects on different biological systems. However, ajoene is the garlic compound related to more biological activities, as showed in in vitro and in vivo systems. Those studies found that ajoene has antithrombotic, anti-tumoral,antifungal, and antiparasitic effects. This study deals with a recently described antifungal property of ajoene, and its potential use in clinical trails to treat several fungal infections.

  1. Solubilizing properties of new surface-active agents, products of catalytic oxyethylation of cholic acid.

    PubMed

    Kołodziejczyk, Michał Krzysztof; Nachajski, Michal Jakub; Lukosek, Marek; Zgoda, Marian Mikołaj

    2013-01-01

    Solubilizing properties of aqueous solutions of a series of surface-active agents, products of oxyethylation of cholic acid, were examined in the present study. The content of oxyethylated segments determined by means of the 1H NMR method enabled the verification of the molecular mass of surfactants along with the calculation of the structural hydrophilic-lipophilic balance (HLB), the solubility parameter delta1/2, and the required solubility level of balance HLB(R). Viscosimetric measurements enabled the calculation of the limiting viscosity number, the content-average molecular mass, the effective volume, the hydrodynamic radius of the surfactant micelle and their equilibrium adducts with rutin, diclofenac and loratadine (BCS Class II and III). By means of the spectrophotometric method (UV) the amount of the solubilized diclofenac, loratadine and rutin (rutoside) was determined in the equilibrium system (saturated solution) in the environment of aqueous solutions of cholic acid derivatives of n(TE) = 20-70. The obtained results serve as a basis for determining the solubilization mechanism of lipophilic therapeutic products and indirectly for estimating the influence of the above process on pharmaceutical as well as biological availability of a micellar adduct from model drug forms (Lindbladt lithogenolitic index).

  2. Novel activity-dependent approaches to therapeutic hypnosis and psychotherapy: the general waking trance.

    PubMed

    Rossi, Ernest; Erickson-Klein, Roxanna; Rossi, Kathryn

    2008-10-01

    This paper presents a highly edited version of a videotape made in 1980 by Marion Moore, M.D., showing Milton H. Erickson and Moore demonstrating novel, activity-dependent approaches to hand-levitation and therapeutic hypnosis on their subject, Ernest Rossi. Erickson's naturalistic and utilization approach is described in his very direct and surprising induction in a trance challenged patient. These novel, and surprising inductions are examples of how Erickson was prescient in developing activity-dependent approaches to therapeutic hypnosis and psychotherapy several generations before modern neuroscience documented the activity-dependent molecular-genomic mechanisms of memory, learning, and behavior change. Erickson describes a case where he utilized what he called, "The General Waking Trance" when he "dared" not use an obvious hypnotic induction. It is proposed that the states of intense mental absorption and response attentiveness that are facilitated by the general waking trance are functionally related to the three conditions neuroscientists have identified as novelty, enrichment, and exercise (both mental and physical), which can turn on activity-dependent gene expression and activity-dependent brain plasticity, that are the molecular-genomic and neural basis ofmemory, learning, consciousness, and behavior change. We recommend that the next step in investigating the efficacy of therapeutic hypnosis will be in partnering with neuroscientists to explore the possibilities and limitations of utilizing the activity-dependent approaches to hypnotic induction and the general waking trance in facilitating activity-dependent gene expression and brain plasticity.

  3. Therapeutic administration of plasminogen activator inhibitor-1 prevents hypoxic-ischemic brain injury in newborns.

    PubMed

    Yang, Dianer; Nemkul, Niza; Shereen, Ahmed; Jone, Alice; Dunn, R Scott; Lawrence, Daniel A; Lindquist, Diana; Kuan, Chia-Yi

    2009-07-08

    Disruption of the integrity of the blood-brain barrier (BBB) is an important mechanism of cerebrovascular diseases, including neonatal cerebral hypoxia-ischemia (HI). Although both tissue-type plasminogen activator (tPA) and matrix metalloproteinase-9 (MMP-9) can produce BBB damage, their relationship in neonatal cerebral HI is unclear. Here we use a rodent model to test whether the plasminogen activator (PA) system is critical for MMP-9 activation and HI-induced brain injury in newborns. To test this hypothesis, we examined the therapeutic effect of intracerebroventricular injection of plasminogen activator inhibitor-1 (PAI-1) in rat pups subjected to unilateral carotid artery occlusion and systemic hypoxia. We found that the injection of PAI-1 greatly reduced the activity of both tPA and urokinase-type plasminogen activator after HI. It also blocked HI-induced MMP-9 activation and BBB permeability at 24 h of recovery. Furthermore, magnetic resonance imaging and histological analysis showed the PAI-1 treatment reduced brain edema, axonal degeneration, and cortical cell death at 24-48 h of recovery. Finally, the PAI-1 therapy provided a dose-dependent decrease of brain tissue loss at 7 d of recovery, with the therapeutic window at 4 h after the HI insult. Together, these results suggest that the brain PA system plays a pivotal role in neonatal cerebral HI and may be a promising therapeutic target in infants suffering hypoxic-ischemic encephalopathy.

  4. Supplemental Substances Derived from Foods as Adjunctive Therapeutic Agents for Treatment of Neurodegenerative Diseases and Disorders12

    PubMed Central

    Bigford, Gregory E.; Del Rossi, Gianluca

    2014-01-01

    Neurodegenerative disorders and diseases (NDDs) that are either chronically acquired or triggered by a singular detrimental event are a rapidly growing cause of disability and/or death. In recent times, there have been major advancements in our understanding of various neurodegenerative disease states that have revealed common pathologic features or mechanisms. The many mechanistic parallels discovered between various neurodegenerative diseases suggest that a single therapeutic approach may be used to treat multiple disease conditions. Of late, natural compounds and supplemental substances have become an increasingly attractive option to treat NDDs because there is growing evidence that these nutritional constituents have potential adjunctive therapeutic effects (be it protective or restorative) on various neurodegenerative diseases. Here we review relevant experimental and clinical data on supplemental substances (i.e., curcuminoids, rosmarinic acid, resveratrol, acetyl-l-carnitine, and ω-3 (n–3) polyunsaturated fatty acids) that have demonstrated encouraging therapeutic effects on chronic diseases, such as Alzheimer’s disease and neurodegeneration resulting from acute adverse events, such as traumatic brain injury. PMID:25022989

  5. Methods, microfluidic devices, and systems for detection of an active enzymatic agent

    DOEpatents

    Sommer, Gregory J; Hatch, Anson V; Singh, Anup K; Wang, Ying-Chih

    2014-10-28

    Embodiments of the present invention provide methods, microfluidic devices, and systems for the detection of an active target agent in a fluid sample. A substrate molecule is used that contains a sequence which may cleave in the presence of an active target agent. A SNAP25 sequence is described, for example, that may be cleaved in the presence of Botulinum Neurotoxin. The substrate molecule includes a reporter moiety. The substrate molecule is exposed to the sample, and resulting reaction products separated using electrophoretic separation. The elution time of the reporter moiety may be utilized to identify the presence or absence of the active target agent.

  6. A review of current murine models of multiple myeloma used to assess the efficacy of therapeutic agents on tumour growth and bone disease.

    PubMed

    Paton-Hough, J; Chantry, A D; Lawson, M A

    2015-08-01

    Pre-clinical in vivo models of multiple myeloma are essential tools for investigating the pathophysiology of multiple myeloma and for testing new therapeutic agents and strategies prior to their potential use in clinical trials. Over the last five decades, several different types of murine models of multiple myeloma have been developed ranging from immunocompetent syngeneic models, e.g. the 5 T series of myeloma cells, to immunocompromised models including the SCID xenograft models, which use human myeloma cell lines or patient-derived cells. Other models include hybrid models featuring the implantation of SCID mice with bone chips (SCID-hu or SCID-rab) or 3-D bone scaffolds (SCID-synth-hu), and mice that have been genetically engineered to develop myeloma. Bearing in mind the differences in these models, it is not surprising that they reflect to varying degrees different aspects of myeloma. Here we review the past and present murine models of myeloma, with particular emphasis on their advantages and limitations, characteristics, and their use in testing therapeutic agents to treat myeloma tumour burden and bone disease.

  7. Impact of the direct application of therapeutic agents to the terminal recta of experimentally colonized calves on Escherichia coli O157:H7 shedding.

    PubMed

    Naylor, Stuart W; Nart, Pablo; Sales, Jill; Flockhart, Allen; Gally, David L; Low, J Christopher

    2007-03-01

    Enterohemorrhagic Escherichia coli O157:H7 is an important intestinal pathogen of humans with a main reservoir of domesticated ruminants, particularly cattle. It is anticipated that the risk of human infection can be reduced by controlling the organism within its reservoir hosts. Several options for the control of E. coli O157:H7 in cattle have been proposed, but none have been demonstrated to be successful in the field. Here we describe a novel experimental method, based on the terminal-rectum-restricted colonization described previously, to eliminate fecal carriage of E. coli O157:H7. In experimentally challenged calves, direct application to the rectal mucosa of either of two therapeutic agents, polymyxin B or chlorhexidine, greatly reduced bacterial shedding levels in the immediate posttreatment period. The most efficacious therapeutic agent, chlorhexidine, was compared in orally and rectally challenged calves. The treatment eliminated high-level shedding and reduced low-level shedding by killing bacteria at the terminal rectum. A rapid-detection system based on the ability to identify E. coli O157:H7 from swabs of the rectal mucosa was also assessed. This test was sufficiently sensitive to identify high-level bacterial carriage. Thus, a combination of the detection method and treatment regimens could be used in the field to eliminate high-level fecal excretion of E. coli O157:H7, so greatly reducing its prevalence within this host and the risk of human infection.

  8. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    2000-01-01

    An apparatus for the treatment of a particular volume of plant or animal tissue by treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue.

  9. Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX.

    PubMed

    Kuca, Kamil; Musilek, Kamil; Jun, Daniel; Karasova, Jana; Soukup, Ondrej; Pejchal, Jaroslav; Hrabinova, Martina

    2013-08-01

    Nerve agents such as sarin, VX and tabun are organophosphorus compounds able to inhibit an enzyme acetylcholinesterase (AChE). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None from the known AChE reactivators is able to reactivate AChE inhibited by all kinds of nerve agents. In this work, reactivation potency of seventeen structurally different AChE reactivators was tested in vitro and subsequently, relationship between their chemical structure and biological activity was outlined. VX was chosen as appropriate member of the nerve agent family.

  10. Plasma-activated medium suppresses choroidal neovascularization in mice: a new therapeutic concept for age-related macular degeneration

    PubMed Central

    Ye, Fuxiang; Kaneko, Hiroki; Nagasaka, Yosuke; Ijima, Ryo; Nakamura, Kae; Nagaya, Masatoshi; Takayama, Kei; Kajiyama, Hiroaki; Senga, Takeshi; Tanaka, Hiromasa; Mizuno, Masaaki; Kikkawa, Fumitaka; Hori, Masaru; Terasaki, Hiroko

    2015-01-01

    Choroidal neovascularization (CNV) is the main pathogenesis of age-related macular degeneration (AMD), which leads to severe vision loss in many aged patients in most advanced country. CNV compromises vision via hemorrhage and retinal detachment on account of pathological neovascularization penetrating the retina. Plasma medicine represents the medical application of ionized gas “plasma” that is typically studied in the field of physical science. Here we examined the therapeutic ability of plasma-activated medium (PAM) to suppress CNV. The effect of PAM on vascularization was assessed on the basis of human retinal endothelial cell (HREC) tube formation. In mice, laser photocoagulation was performed to induce CNV (laser-CNV), followed by intravitreal injection of PAM. N-Acetylcysteine was used to examine the role of reactive oxygen species in PAM-induced CNV suppression. Fundus imaging, retinal histology examination, and electroretinography (ERG) were also performed to evaluate PAM-induced retinal toxicity. Interestingly, HREC tube formation and laser-CNV were both reduced by treatment with PAM. N-acetylcysteine only partly neutralized the PAM-induced reduction in laser-CNV. In addition, PAM injection had no effect on regular retinal vessels, nor did it show retinal toxicity in vivo. Our findings indicate the potential of PAM as a novel therapeutic agent for suppressing CNV. PMID:25573059

  11. Chaperone Activity of Small Heat Shock Proteins Underlies Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis*

    PubMed Central

    Kurnellas, Michael P.; Brownell, Sara E.; Su, Leon; Malkovskiy, Andrey V.; Rajadas, Jayakumar; Dolganov, Gregory; Chopra, Sidharth; Schoolnik, Gary K.; Sobel, Raymond A.; Webster, Jonathan; Ousman, Shalina S.; Becker, Rachel A.; Steinman, Lawrence; Rothbard, Jonathan B.

    2012-01-01

    To determine whether the therapeutic activity of αB crystallin, small heat shock protein B5 (HspB5), was shared with other human sHsps, a set of seven human family members, a mutant of HspB5 G120 known to exhibit reduced chaperone activity, and a mycobacterial sHsp were expressed and purified from bacteria. Each of the recombinant proteins was shown to be a functional chaperone, capable of inhibiting aggregation of denatured insulin with varying efficiency. When injected into mice at the peak of disease, they were all effective in reducing the paralysis in experimental autoimmune encephalomyelitis. Additional structure activity correlations between chaperone activity and therapeutic function were established when linear regions within HspB5 were examined. A single region, corresponding to residues 73–92 of HspB5, forms amyloid fibrils, exhibited chaperone activity, and was an effective therapeutic for encephalomyelitis. The linkage of the three activities was further established by demonstrating individual substitutions of critical hydrophobic amino acids in the peptide resulted in the loss of all of the functions. PMID:22955287

  12. Current state of evidence on 'off-label' therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland--a consensus report.

    PubMed

    Aringer, M; Burkhardt, H; Burmester, G R; Fischer-Betz, R; Fleck, M; Graninger, W; Hiepe, F; Jacobi, A M; Kötter, I; Lakomek, H J; Lorenz, H M; Manger, B; Schett, G; Schmidt, R E; Schneider, M; Schulze-Koops, H; Smolen, J S; Specker, C; Stoll, T; Strangfeld, A; Tony, H P; Villiger, P M; Voll, R; Witte, T; Dörner, T

    2012-04-01

    Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.

  13. The Big Book of Therapeutic Activity Ideas for Children and Teens: Inspiring Arts-Based Activities and Character Education Curricula

    ERIC Educational Resources Information Center

    Joiner, Lindsey

    2011-01-01

    For difficult or challenging children and teenagers in therapeutic or school settings, creative activities can be an excellent way of increasing enjoyment and boosting motivation, making the sessions more rewarding and successful for everyone involved. This resource provides over one hundred tried-and-tested fun and imaginative therapeutic…

  14. Efficacy of buparvaquone as a therapeutic and clearing agent of Babesia equi of European origin in horses.

    PubMed

    Zaugg, J L; Lane, V M

    1992-08-01

    We evaluated the efficacy of buparvaquone in eliminating infection with Babesia equi of European origin in carrier horses and in splenectomized horses with experimentally induced acute infection. When administered at the rate of 5 mg/kg of body weight, IV, 4 times at 48-hour intervals, buparvaquone prompted rapid abatement of parasitemia. However, secondary and tertiary recrudescent parasitemias invariably returned with establishment of the carrier state. Buparvaquone, at the dosage evaluated, had transitory therapeutic efficacy against acute B equi infection in splenectomized horses, but was unable alone to clear carrier infection.

  15. Kras mutations increase telomerase activity and targeting telomerase is a promising therapeutic strategy for Kras-mutant NSCLC

    PubMed Central

    Shi, Bowen; Zhang, Lianmin; Qian, Dong; Li, Chenguang; Zhang, Hua; Wang, Shengguang; Zhu, Jinfang; Gao, Liuwei; Zhang, Qiang; Jia, Bin; Hao, Ligang; Wang, Changli; Zhang, Bin

    2017-01-01

    As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3). MEK inhibition led to reduced TERT expression and telomerase activity. Furthermore, telomerase inhibitor BIBR1532 shortened telomere length and inhibited mutant Kras-induced long-term proliferation, colony formation and migration capabilities of BEAS-2B and Calu-3 cells. Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. In addition, higher TERT expression was seen in Kras-mutant NSCLC than that with wild-type Kras. Our data suggest that Kras mutations increase telomerase activity and telomere length by activating the RAS/MEK pathway, which contributes to an aggressive phenotype of NSCLC. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. PMID:27329725

  16. Ca(2+)-activated K(+) channels as therapeutic targets for myocardial and vascular protection.

    PubMed

    Clements, Richard T; Terentyev, Dmitry; Sellke, Frank W

    2015-01-01

    Small- and large-conductance Ca(2+)-activated K(+)channels (SKCa and BKCa, respectively) may be important targets for therapeutic interventions in a variety of cardiac conditions. In cardiomyocytes, BKCa channels are localized to mitochondria where they beneficially modulate reactive oxygen species, mitochondrial Ca(2+), and respiration. In vascular smooth muscle cells, BKCa channels regulate vascular tone and promote vasodilation. Activation of BKCa channels has demonstrated significant cardioprotection following ischemic injury, including improved function and reduced infarct size. SKCa channels are expressed in both the membrane and mitochondria of cardiomyocytes. Modulation of cardiomyocyte SKCa channels may be beneficial for arrhythmia, heart failure, and ischemia. Mitochondrial SKCa channels may provide similar benefit to BKCa channels. In addition, activation of SKCa channels on the endothelium promotes vasodilation. This mini-review focuses on the modulation of cardiomyocyte BKCa and SKCa channels for cardioprotection and briefly address associated potential therapeutic benefits in the coronary circulation.

  17. Cellular Delivery and Photochemical Activation of Antisense Agents through a Nucleobase Caging Strategy

    PubMed Central

    Govan, Jeane M.; Uprety, Rajendra; Thomas, Meryl; Lusic, Hrvoje; Lively, Mark O.; Deiters, Alexander

    2013-01-01

    Antisense oligonucleotides are powerful tools to regulate gene expression in cells and model organisms. However, a transfection or microinjection is needed for efficient delivery of the antisense agent. We report the conjugation of multiple HIV TAT peptides to a hairpin-protected antisense agent through a light-cleavable nucleobase caging group. This conjugation allows for the facile delivery of the antisense agent without a transfection reagent and photochemical activation offers precise control over gene expression. The developed approach is highly modular, as demonstrated by the conjugation of folic acid to the caged antisense agent. This enabled targeted cell delivery through cell-surface folate receptors followed by photochemical triggering of antisense activity. Importantly, the presented strategy delivers native oligonucleotides after light-activation, devoid of any delivery functionalities or modifications that could otherwise impair their antisense activity. PMID:23915424

  18. 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.

  19. Chlorin e6 Conjugated Poly(dopamine) Nanospheres as PDT/PTT Dual-Modal Therapeutic Agents for Enhanced Cancer Therapy.

    PubMed

    Zhang, Da; Wu, Ming; Zeng, Yongyi; Wu, Lingjie; Wang, Qingtang; Han, Xiao; Liu, Xiaolong; Liu, Jingfeng

    2015-04-22

    Photodynamic therapy (PDT), using a combination of chemical photosensitizers (PS) and light, has been successfully applied as a noninvasive therapeutic procedure to treat tumors by inducing apoptosis or necrosis of cancer cells. However, most current clinically used PS have suffered from the instability in physiological conditions which lead to low photodynamic therapy efficacy. Herein, a highly biocompatible poly(dopamine) (PDA) nanoparticle conjugated with Chlorin e6 (referenced as the PDA-Ce6 nanosphere) was designed as a nanotherapeutic agent to achieve simultaneous photodynamic/photothermal therapy (PDT/PTT). Compared to the free Ce6, the PDA-Ce6 nanosphere exhibited significantly higher PDT efficacy against tumor cells, because of the enhanced cellular uptake and subsequently greater reactive oxygen species (ROS) production upon laser irradiation at 670 nm. Meanwhile, the PDA-Ce6 nanosphere could be also used as a photoabsorbing agent for PTT, because of the excellent photothermal conversion ability of PDA nanoparticle under laser irradiation at 808 nm. Moreover, our prepared nanosphere had extremely low dark toxicity, while excellent phototoxicity under the combination laser irradiation of 670 and 808 nm, both in vitro and in vivo, compared to any single laser irradiation alone. Therefore, our prepared PDA-Ce6 nanosphere could be applied as a very promising dual-modal phototherapeutic agent for enhanced cancer therapy in future clinical applications.

  20. Becoming Therapeutic Agents: A Grounded Theory of Mothers' Process When Implementing Cognitive Behavioural Therapy at Home with an Anxious Child.

    PubMed

    Pishva, Rana

    2016-09-29

    The premise of parent-centred programmes for parents of anxious children is to educate and train caregivers in the sustainable implementation of cognitive behaviour therapy (CBT) in the home. The existing operationalization of parent involvement, however, does not address the systemic, parent or child factors that could influence this process. The qualitative approach of grounded theory was employed to examine patterns of action and interaction involved in the complex process of carrying out CBT with one's child in one's home. A grounded theory goes beyond the description of a process, offering an explanatory theory that brings taken-for-granted meanings and processes to the surface. The theory that emerged from the analysis suggests that CBT implementation by mothers of anxious children is characterized by the evolution of mothers' perception of their child and mothers' perception of their role as well as a shift from reacting with emotion to responding pragmatically to the child. Changes occur as mothers recognize the crisis, make links between the treatment rationale, child's symptoms and their own parenting strategies, integrate tenets of CBT for anxiety and eventually focus on sustaining therapeutic gains through natural life transitions. The theory widens our understanding of mothers' role, therapeutic engagement, process, and decision-making. The theory also generates new hypotheses regarding parent involvement in the treatment of paediatric anxiety disorders and proposes novel research avenues that aim to maximize the benefits of parental involvement in the treatment of paediatric anxiety disorders. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Effects of surface active agents on DNAPL migration and distribution in saturated porous media.

    PubMed

    Cheng, Zhou; Gao, Bin; Xu, Hongxia; Sun, Yuanyuan; Shi, Xiaoqing; Wu, Jichun

    2016-11-15

    Dissolved surface active agents such as surfactant and natural organic matter can affect the distribution and fate of dense nonaqueous liquids (DNAPLs) in soil and groundwater systems. This work investigated how two common groundwater surface active agents, humic acid (HA) and Tween 80, affected tetrachloroethylene (PCE) migration and source zone architecture in saturated porous media under environmentally relevant conditions. Batch experiments were first conducted to measure the contact angles and interfacial tensions (IFT) between PCE and quartz surface in water containing different amount of surface active agents. Results showed that the contact angle increased and IFT decreased with concentration of surface active agent increasing, and Tween 80 was much more effective than HA. Five 2-D flow cell experiments were then conducted. Correspondingly, Tween 80 showed strong effects on the migration and distribution of PCE in the porous media due to its ability to change the medium wettability from water-wet into intermediate/NAPL-wet. The downward migration velocities of the PCE in three Tween 80 cells were slower than those in the other two cells. In addition, the final saturation of the PCE in the cells containing surface active agents was higher than that in the water-only cell. Results from this work indicate that the presence of surface active agents in groundwater may strongly affect the fate and distribution of DNAPL through altering porous medium wettability.

  2. Chlorogenic Acid Activates CFTR-Mediated Cl- Secretion in Mice and Humans: Therapeutic Implications for Chronic Rhinosinusitis

    PubMed Central

    Illing, Elisa; Cho, Do-Yeon; Zhang, Shaoyan; Skinner, Daniel F.; Dunlap, Quinn A.; Sorscher, Eric J.; Woodworth, Bradford A.

    2016-01-01

    Objectives Salubrious effects of the green coffee bean are purportedly secondary to high concentrations of chlorogenic acid. Chlorogenic acid has a molecular structure similar to bioflavonoids that activate transepithelial Cl- transport in sinonasal epithelia. In contrast to flavonoids, the drug is freely soluble in water. The objective of this study is to evaluate the Cl- secretory capability of chlorogenic acid and its potential as a therapeutic activator of mucus clearance in sinus disease. Study Design Basic research Setting Laboratory Subjects and Methods Chlorogenic acid was tested on primary murine nasal septal epithelial(MNSE)[CFTR+/+ and transgenic CFTR-/-] and human sinonasal epithelial(HSNE)[CFTR+/+ and F508del/F508del] cultures under pharmacologic conditions in Ussing chambers to evaluate effects on transepithelial Cl- transport. Cellular cAMP, phosphorylation of the CFTR regulatory domain(R-D), and CFTR mRNA transcription were also measured. Results Chlorogenic acid stimulated transepithelial Cl- secretion [(change in short-circuit current(ΔISC=μA/cm2)] in MNSE(13.1+/-0.9 vs. 0.1+/-0.1, p<0.05) and HSNE(34.3+/-0.9 vs. 0.0+/-0.1, p<0.05). The drug had a long duration until peak effect at 15-30 minutes after application. Significant inhibition with INH-172, as well as absent stimulation in cultures lacking functional CFTR, suggests effects are dependent on CFTR-mediated pathways. However, the absence of elevated cellular cAMP and phosphorylation the CFTR R-D indicates chlorogenic acid does not work through a PKA-dependent mechanism. Conclusion Chlorogenic acid is a water soluble agent that promotes CFTR-mediated Cl- transport in mouse and human sinonasal epithelium. Translating activators of mucociliary transport to clinical use provides a new therapeutic approach to sinus disease. Further in vivo evaluation is planned. PMID:26019132

  3. Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property.

    PubMed

    Azmi, Asfar S; Sarkar, Fazlul H; Hadi, S M

    2013-01-01

    " Let food be thy medicine and medicine be thy food" was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating) behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents.

  4. The pharmacological mechanisms and therapeutic activities of hydroxychloroquine in rheumatic and related diseases.

    PubMed

    Hu, Changfeng; Lu, Lu; Wan, Jie-Ping; Wen, Chengping

    2017-03-16

    Hydroxychloroquine (HCQ) is known as one of the most fascinating synthetic antimalarial drugs during the last 50 years. It is currently among the most commonly employed medicines for the clinical treatment of rheumatic diseases, especially systemic lupus erythematosus and rheumatoid arthritis. In related mechanism studies, it has been found that HCQ possesses various immunomodulatory and anti-inflammatory activities. In addition, the effects of HCQ on anti-platelet, metabolic pathways, and antineoplasticity have also been disclosed in more recent studies. These significant findings on HCQ suggest the potential therapeutic applications of HCQ for treatment of many diseases, such as cancers, skin disease, antiphospholipid syndrome, etc. This review focuses on recent in vitro and clinical trials on its pharmacological mechanisms, therapeutic activities, and potential adverse effects.

  5. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice

    PubMed Central

    Welford, Abigail F.; Biziato, Daniela; Coffelt, Seth B.; Nucera, Silvia; Fisher, Matthew; Pucci, Ferdinando; Di Serio, Clelia; Naldini, Luigi; De Palma, Michele; Tozer, Gillian M.; Lewis, Claire E.

    2011-01-01

    Vascular-disrupting agents (VDAs) such as combretastatin A4 phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment with such compounds. Here, we show that CA4P-induced vessel narrowing, hypoxia, and hemorrhagic necrosis in murine mammary tumors were accompanied by elevated tumor levels of the chemokine CXCL12 and infiltration by proangiogenic TIE2-expressing macrophages (TEMs). Inhibiting TEM recruitment to CA4P-treated tumors either by interfering pharmacologically with the CXCL12/CXCR4 axis or by genetically depleting TEMs in tumor-bearing mice markedly increased the efficacy of CA4P treatment. These data suggest that TEMs limit VDA-induced tumor injury and represent a potential target for improving the clinical efficacy of VDA-based therapies. PMID:21490397

  6. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice.

    PubMed

    Welford, Abigail F; Biziato, Daniela; Coffelt, Seth B; Nucera, Silvia; Fisher, Matthew; Pucci, Ferdinando; Di Serio, Clelia; Naldini, Luigi; De Palma, Michele; Tozer, Gillian M; Lewis, Claire E

    2011-05-01

    Vascular-disrupting agents (VDAs) such as combretastatin A4 phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment with such compounds. Here, we show that CA4P-induced vessel narrowing, hypoxia, and hemorrhagic necrosis in murine mammary tumors were accompanied by elevated tumor levels of the chemokine CXCL12 and infiltration by proangiogenic TIE2-expressing macrophages (TEMs). Inhibiting TEM recruitment to CA4P-treated tumors either by interfering pharmacologically with the CXCL12/CXCR4 axis or by genetically depleting TEMs in tumor-bearing mice markedly increased the efficacy of CA4P treatment. These data suggest that TEMs limit VDA-induced tumor injury and represent a potential target for improving the clinical efficacy of VDA-based therapies.

  7. Engineering Neprilysin Activity and Specificity to Create a Novel Therapeutic for Alzheimer’s Disease

    PubMed Central

    Webster, Carl I.; Burrell, Matthew; Olsson, Lise-Lotte; Fowler, Susan B.; Digby, Sarah; Sandercock, Alan; Snijder, Arjan; Tebbe, Jan; Haupts, Ulrich; Grudzinska, Joanna; Jermutus, Lutz; Andersson, Christin

    2014-01-01

    Neprilysin is a transmembrane zinc metallopeptidase that degrades a wide range of peptide substrates. It has received attention as a potential therapy for Alzheimer’s disease due to its ability to degrade the peptide amyloid beta. However, its broad range of peptide substrates has the potential to limit its therapeutic use due to degradation of additional peptides substrates that tightly regulate many physiological processes. We sought to generate a soluble version of the ectodomain of neprilysin with improved activity and specificity towards amyloid beta as a potential therapeutic for Alzheimer’s disease. Extensive amino acid substitutions were performed at positions surrounding the active site and inner surface of the enzyme and variants screened for activity on amyloid beta 1–40, 1–42 and a variety of other physiologically relevant peptides. We identified several mutations that modulated and improved both enzyme selectivity and intrinsic activity. Neprilysin variant G399V/G714K displayed an approximately 20-fold improved activity on amyloid beta 1–40 and up to a 3,200-fold reduction in activity on other peptides. Along with the altered peptide substrate specificity, the mutant enzyme produced a markedly altered series of amyloid beta cleavage products compared to the wild-type enzyme. Crystallisation of the mutant enzyme revealed that the amino acid substitutions result in alteration of the shape and size of the pocket containing the active site compared to the wild-type enzyme. The mutant enzyme offers the potential for the more efficient degradation of amyloid beta in vivo as a therapeutic for the treatment of Alzheimer’s disease. PMID:25089527

  8. Chemopreventive and therapeutic activity of dietary blueberry against estrogen-mediated breast cancer.

    PubMed

    Jeyabalan, Jeyaprakash; Aqil, Farrukh; Munagala, Radha; Annamalai, Lakshmanan; Vadhanam, Manicka V; Gupta, Ramesh C

    2014-05-07

    Berries are gaining increasing importance lately for their chemopreventive and therapeutic potential against several cancers. In earlier studies, a blueberry-supplemented diet has shown protection against 17β-estradiol (E2)-mediated mammary tumorigenesis. This study tested both preventive and therapeutic activities of diet supplemented with whole blueberry powder (50:50 blend of Tifblue and Rubel). Animals received 5% blueberry diet, either 2 weeks prior to or 12 weeks after E2 treatment in preventive and therapeutic groups, respectively. Both interventions delayed the tumor latency for palpable mammary tumors by 28 and 37 days, respectively. Tumor volume and multiplicity were also reduced significantly in both modes. The effect on mammary tumorigenesis was largely due to down-regulation of CYP 1A1 and ER-α gene expression and also favorable modulation of microRNA (miR-18a and miR-34c) levels. These data suggest that the blueberry blend tested is effective in inhibiting E2-mediated mammary tumorigenesis in both preventive and therapeutic modes.

  9. PSMA-Activated Imaging Agents for Prostate Cancer

    DTIC Science & Technology

    2009-07-01

    media and the cell extract were run on the LCMS . Figure 3. MTT assay evaluating varying concentrations of I-PD...Society 62, 2422-2423. 7. Fujii, A., Tanaka, K., Tsuchiya, Y., Cook, E.S., 1971. Antistaphylococcal and Antifibrinolytic Activities of Omega- Amino ... Acids and Their L-Histidine Dipeptides. Journal of Medicinal Chemistry 14, 354-&.

  10. Assessing the therapeutic efficacy of oxime therapies against percutaneous organophosphorus pesticide and nerve agent challenges in the Hartley guinea pig

    PubMed Central

    Snider, Thomas H.; Wilhelm, Christina M.; Babin, Michael C.; Platoff, Gennady E.; Yeung, David T.

    2016-01-01

    Given the rapid onset of symptoms from intoxication by organophosphate (OP) compounds, a quick-acting, efficacious therapeutic regimen is needed. A primary component of anti-OP therapy is an oxime reactivator to rescue OP-inhibited acetylcholinesterases. Male guinea pigs, clipped of hair, received neat applications of either VR, VX, parathion, or phorate oxon (PHO) at the 85th percentile lethal dose, and, beginning with presentation of toxicosis, received the human equivalent dose therapy by intramuscular injection with two additional follow-on treatments at 3-hr intervals. Each therapy consisted of atropine free base at 0.4 mg/kg followed by one of eight candidate oximes. Lethality rates were obtained at 24 hr after VR, VX and PHO challenges, and at 48 hr after challenge with parathion. Lethality rates among symptomatic, oxime-treated groups were compared with that of positive control (OP-challenged and atropine-only treated) guinea pigs composited across the test days. Significant (p ≤ 0.05) protective therapy was afforded by 1,1-methylene bis(4(hydroxyimino- methyl)pyridinium) dimethanesulfonate (MMB4 DMS) against challenges of VR (p ≤ 0.001) and VX (p ≤ 0.05). Lethal effects of VX were also significantly (p ≤ 0.05) mitigated by treatments with oxo-[[1-[[4-(oxoazaniumylmethylidene)pyridin-1-yl] methoxymethyl]pyridin-4-ylidene]methyl]azanium dichloride (obidoxime Cl2) and 1-(((4-(aminocarbonyl) pyridinio)methoxy)methyl)-2,4-bis((hydroxyimino)methyl)pyridinium dimethanesulfonate (HLö-7 DMS). Against parathion, significant protective therapy was afforded by obidoxime dichloride (p ≤ 0.001) and 1,1′-propane-1,3-diylbis{4-[(E)-(hydroxyimino)methyl]pyridinium} dibromide (TMB-4, p ≤ 0.01). None of the oximes evaluated was therapeutically effective against PHO. Across the spectrum of OP chemicals tested, the oximes that offered the highest level of therapy were MMB4 DMS and obidoxime dichloride. PMID:26558457

  11. An amphiphilic ruthenium(II)-polypyridyl appended porphyrin as potential bifunctional two-photon tumor-imaging and photodynamic therapeutic agent.

    PubMed

    Poon, Chun-Ting; Chan, Pui-Shan; Man, Cornelia; Jiang, Feng-Lei; Wong, Ricky Ngok Shun; Mak, Nai-Ki; Kwong, Daniel W J; Tsao, Sai-Wah; Wong, Wai-Kwok

    2010-01-01

    An amphiphilic porphyrin appended with a Ru(II)-polypyridyl complex (Ru-P) showing a moderate two-photon absorption cross-section (178.0+/-26.8GM), high singlet oxygen quantum yield and rapid cellular uptake was synthesized. In vitro study using human nasopharyngeal carcinoma cells showed that Ru-P exhibited a strong two-photon induced fluorescence upon uptake, lysosomal localization and potent two-photon induced cytotoxicity. These results show that Ru-P, which was designed to enhance its cellular uptake, can potentially be used as an efficacious bifunctional two-photon tumor-imaging and photodynamic therapeutic agent despite its moderate two-photon absorption cross-section.

  12. Flavones Inhibit the Activity of AKR1B10, a Promising Therapeutic Target for Cancer Treatment.

    PubMed

    Zemanova, Lucie; Hofman, Jakub; Novotna, Eva; Musilek, Kamil; Lundova, Tereza; Havrankova, Jana; Hostalkova, Anna; Chlebek, Jakub; Cahlikova, Lucie; Wsol, Vladimír

    2015-11-25

    AKR1B10 is an NADPH-dependent reductase that plays an important function in several physiological reactions such as the conversion of retinal to retinol, reduction of isoprenyl aldehydes, and biotransformation of procarcinogens and drugs. A growing body of evidence points to the important role of the enzyme in the development of several types of cancer (e.g., breast, hepatocellular), in which it is highly overexpressed. AKR1B10 is regarded as a therapeutic target for the treatment of these diseases, and potent and specific inhibitors may be promising therapeutic agents. Several inhibitors of AKR1B10 have been described, but the area of natural plant products has been investigated sparingly. In the present study almost 40 diverse phenolic compounds and alkaloids were examined for their ability to inhibit the recombinant AKR1B10 enzyme. The most potent inhibitors-apigenin, luteolin, and 7-hydroxyflavone-were further characterized in terms of IC50, selectivity, and mode of action. Molecular docking studies were also conducted, which identified putative binding residues important for the interaction. In addition, cellular studies demonstrated a significant inhibition of the AKR1B10-mediated reduction of daunorubicin in intact cells by these inhibitors without a considerable cytotoxic effect. Although these compounds are moderately potent and selective inhibitors of AKR1B10, they constitute a new structural type of AKR1B10 inhibitor and may serve as a template for the development of better inhibitors.

  13. Therapeutic activity of a Saccharomyces cerevisiae-based probiotic and inactivated whole yeast on vaginal candidiasis.

    PubMed

    Pericolini, Eva; Gabrielli, Elena; Ballet, Nathalie; Sabbatini, Samuele; Roselletti, Elena; Cayzeele Decherf, Amélie; Pélerin, Fanny; Luciano, Eugenio; Perito, Stefano; Jüsten, Peter; Vecchiarelli, Anna

    2017-01-02

    Vulvovaginal candidiasis is the most prevalent vaginal infection worldwide and Candida albicans is its major agent. Vulvovaginal candidiasis is characterized by disruption of the vaginal microbiota composition, as happens following large spectrum antibiotic usage. Recent studies support the effectiveness of oral and local probiotic treatment for prevention of recurrent vulvovaginal candidiasis. Saccharomyces cerevisiae is a safe yeast used as, or for, the production of ingredients for human nutrition and health. Here, we demonstrate that vaginal administration of probiotic Saccharomyces cerevisiae live yeast (GI) and, in part, inactivated whole yeast Saccharomyces cerevisiae (IY), used as post-challenge therapeutics, was able to positively influence the course of vaginal candidiasis by accelerating the clearance of the fungus. This effect was likely due to multiple interactions of Saccharomyces cerevisiae with Candida albicans. Both live and inactivated yeasts induced coaggregation of Candida and consequently inhibited its adherence to epithelial cells. However, only the probiotic yeast was able to suppress some major virulence factors of Candida albicans such as the ability to switch from yeast to mycelial form and the capacity to express several aspartyl proteases. The effectiveness of live yeast was higher than that of inactivated whole yeast suggesting that the synergy between mechanical effects and biological effects were dominant over purely mechanical effects. The protection of epithelial cells to Candida-induced damage was also observed. Overall, our data show for the first time that Saccharomyces cerevisiae-based ingredients, particularly the living cells, can exert beneficial therapeutic effects on a widespread vaginal mucosal infection.

  14. Rostral anterior cingulate activity generates posterior versus anterior theta activity linked to agentic extraversion.

    PubMed

    Chavanon, Mira-Lynn; Wacker, Jan; Stemmler, Gerhard

    2011-06-01

    Recent research using the resting electroencephalogram (EEG) showed that posterior versus anterior theta activity (around 4-8 Hz) is consistently associated with agency, reflecting the dopaminergic core of extraversion (i.e., incentive motivation, positive emotion). Neuroimaging studies using various methodologies and experimental paradigms have converged on the anterior cingulate cortex (ACC) as a neurophysiological correlate of extraversion. The aim of the present study is integrate these lines of research by testing the hypothesis that posterior versus anterior EEG theta is at least partly based on ACC theta activity. Resting EEG data were analyzed in N = 78 healthy, male participants extremely high or low in agentic extraversion (aE). Using the low-resolution electromagnetic tomography algorithm, we localized the sources of aE-dependent intracerebral theta activity within rostral subdivisions of the ACC. The posterior versus anterior index and theta current density within the rostral ACC were significantly correlated (r = -.52), and both displayed high retest stability across 5 hr and were associated with traits from the aE spectrum. These neurophysiological correlates of aE and their possible functional significance are discussed.

  15. New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients

    PubMed Central

    Gerotziafas, Grigoris T; Mahé, Isabelle; Elalamy, Ismail

    2014-01-01

    Patients with cancer have a 6–7-fold higher risk of venous thromboembolism (VTE) as compared with non-cancer patients. Effective and safe anticoagulation for the prevention and treatment of VTE is the cornerstone of the management of patients with cancer, aiming to decrease morbidity and mortality and to improve quality of life. Unfractionated heparin, low molecular weight heparins, fondaparinux and vitamin K antagonists (VKAs) are used in the prevention and treatment of VTE in cancer patients. Heparins and fondaparinux are administered subcutaneously. VKAs are orally active, but they have a narrow therapeutic window, numerous food and drug interactions, and treatment requires regular laboratory monitoring and dose adjustment. These limitations among others have important negative impact on the quality of life of patients and decrease adherence to the treatment. New orally active anticoagulant (NOAC) agents are specific inhibitors of activated factor Xa (FXa) (rivaroxaban and apixaban) or thrombin (dabigatran). It is expected that NOACs will improve antithrombotic treatment. Cancer patients are a particular group that could benefit from treatment with NOACs. However, NOACs present some significant interactions with drugs frequently used in cancer patients, which might influence their pharmacokinetics, compromising their efficacy and safety. In the present review, we analyzed the available data from the subgroups of patients with active cancer who were included in Phase III clinical trials that assessed the efficacy and safety of NOACs in the prevention and treatment of VTE. The data from the Phase III trials in prophylaxis of VTE by rivaroxaban or apixaban highlight that these two agents, although belonging to the same pharmacological group (direct inhibitors of factor Xa), have substantially different profiles of efficacy and safety, especially in hospitalized acutely ill medical patients with active cancer. A limited number of patients with VTE and active

  16. The Role of Guanfacine as a Therapeutic Agent to Address Stress-related Pathophysiology in Cocaine Dependent Individuals

    PubMed Central

    Fox, Helen; Sinha, Rajita

    2014-01-01

    The pathophysiology of cocaine addiction is linked to changes within neural systems and brain regions that are critical mediators of stress system sensitivity as well as behavioral processes associated with the regulation of adaptive goal-directed behavior. This is characterized by the up-regulation of core adrenergic and corticotrophin releasing factor (CRF) mechanisms which sub-serve negative affect and anxiety and impinge upon intracellular pathways in the prefrontal cortex underlying cognitive regulation of stress and negative emotional state. Not only are these mechanisms essential to the severity of cocaine withdrawal symptoms, and hence the trajectory of clinical outcome, but they may also be particularly pertinent to the demography of cocaine dependence. The ability of guanfacine to target overlapping stress, reward and anxiety pathophysiology suggests that it may be a useful agent for attenuating the stress and cue-induced craving state in women especially, but also in men. This is supported by recent research findings from our own laboratory. Additionally, the ability of guanfacine to improve regulatory mechanisms that are key to exerting cognitive and emotional control over drug seeking behavior also suggest that guanfacine may be an effective medication for reducing craving and relapse vulnerability in many drugs of abuse. As cocaine dependent individuals are typically polydrug abusers, and women may be at a greater disadvantage for compulsive drug use than men, it is plausible that medications which target catecholaminergic fronto-striatal inhibitory circuits and simultaneously reduce stress system arousal may provide added benefits for attenuating cocaine dependence. PMID:24484979

  17. Mitigating the antimicrobial activities of selected organic acids and commercial sanitizers with various neutralizing agents.

    PubMed

    Park, Yoen Ju; Chen, Jinru

    2011-05-01

    This study was conducted to evaluate the abilities of five neutralizing agents, Dey-Engley (DE) neutralizing broth (single or double strength), morpholinepropanesulfonic acid (MOPS) buffer, phosphate-buffered saline (PBS), and sodium thiosulfate buffer, in mitigating the activities of acetic or lactic acid (2%) and an alkaline or acidic sanitizer (a manufacturer-recommended concentration) againt the cells of Shiga toxin-producing Escherichia coli (STEC; n = 9). To evaluate the possible toxicity of the neutralizing agents to the STEC cells, each STEC strain was exposed to each of the neutralizing agents at room temperature for 10 min. Neutralizing efficacy was evaluated by placing each STEC strain in a mixture of sanitizer and neutralizer under the same conditions. The neutralizing agents had no detectable toxic effect on the STEC strains. PBS was least effective for neutralizing the activity of selected organic acids and sanitizers. Single-strength DE and sodium thiosulfate neutralized the activity of both acetic and lactic acids. MOPS buffer neutralized the activity of acetic acid and lactic acid against six and five STEC strains, respectively. All neutralizing agents, except double-strength DE broth, had a limited neutralizing effect on the activity of the commercial sanitizers used in the study. The double-strength DE broth effectively neutralized the activity of the two commercial sanitizers with no detectable toxic effects on STEC cells.

  18. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, W.G.; Wachter, E.A.; Dees, H.C.

    1998-11-03

    A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material. 23 figs.

  19. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    1999-01-01

    A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material.

  20. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    1998-01-01

    A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material.

  1. Antimicrobial agents from plants: antibacterial activity of plant volatile oils.

    PubMed

    Dorman, H J; Deans, S G

    2000-02-01

    The volatile oils of black pepper [Piper nigrum L. (Piperaceae)], clove [Syzygium aromaticum (L.) Merr. & Perry (Myrtaceae)], geranium [Pelargonium graveolens L'Herit (Geraniaceae)], nutmeg [Myristica fragrans Houtt. (Myristicaceae), oregano [Origanum vulgare ssp. hirtum (Link) Letsw. (Lamiaceae)] and thyme [Thymus vulgaris L. (Lamiaceae)] were assessed for antibacterial activity against 25 different genera of bacteria. These included animal and plant pathogens, food poisoning and spoilage bacteria. The volatile oils exhibited considerable inhibitory effects against all the organisms under test while their major components demonstrated various degrees of growth inhibition.

  2. Antianaerobic activity of sulopenem compared to six other agents.

    PubMed

    Ednie, Lois M; Appelbaum, Peter C

    2009-05-01

    Agar dilution MIC methodology was used to compare the activity of sulopenem with those of amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 431 anaerobes. Overall, MIC(50)/(90) values were as follows: sulopenem, 0.25/1.0 microg/ml; amoxicillin/clavulanate, 0.5/2.0 microg/ml; ampicillin/sulbactam, 0.5/4.0 microg/ml; piperacillin/tazobactam, 0.25/8.0 microg/ml; imipenem, 0.06/1.0 microg/ml; clindamycin, 0.25/16.0 microg/ml; and metronidazole, 1.0/4.0 microg/ml.

  3. A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse

    SciTech Connect

    Brim, Remy L.; Nance, Mark R.; Youngstrom, Daniel W.; Narasimhan, Diwahar; Zhan, Chang-Guo; Tesmer, John J.G.; Sunahara, Roger K.; Woods, James H.

    2010-09-03

    Rhodococcal cocaine esterase (CocE) is an attractive potential treatment for both cocaine overdose and cocaine addiction. CocE directly degrades cocaine into inactive products, whereas traditional small-molecule approaches require blockade of the inhibitory action of cocaine on a diverse array of monoamine transporters and ion channels. The usefulness of wild-type (wt) cocaine esterase is hampered by its inactivation at 37 C. Herein, we characterize the most thermostable form of this enzyme to date, CocE-L169K/G173Q. In vitro kinetic analyses reveal that CocE-L169K/G173Q displays a half-life of 2.9 days at 37 C, which represents a 340-fold improvement over wt and is 15-fold greater than previously reported mutants. Crystallographic analyses of CocE-L169K/G173Q, determined at 1.6-{angstrom} resolution, suggest that stabilization involves enhanced domain-domain interactions involving van der Waals interactions and hydrogen bonding. In vivo rodent studies reveal that intravenous pretreatment with CocE-L169K/G173Q in mice provides protection from cocaine-induced lethality for longer time periods before cocaine administration than wt CocE. Furthermore, intravenous administration (pretreatment) of CocE-L169K/G173Q prevents self-administration of cocaine in a time-dependent manner. Termination of the in vivo effects of CoCE seems to be dependent on, but not proportional to, its clearance from plasma as its half-life is approximately 2.3 h and similar to that of wt CocE (2.2 h). Taken together these data suggest that CocE-L169K/G173Q possesses many of the properties of a biological therapeutic for treating cocaine abuse but requires additional development to improve its serum half-life.

  4. Therapeutic polymers for dental adhesives: Loading resins with bio-active components

    PubMed Central

    Imazato, Satoshi; Ma, Sai; Chen, Ji-hua; Xu, Hockin H.K.

    2014-01-01

    Objectives Many recent adhesives on the market exhibit reasonable clinical performance. Future innovations in adhesive materials should therefore seek out novel properties rather than simply modifying existing technologies. It is proposed that adhesive materials that are “bio-active” could contribute to better prognosis of restorative treatments. Methods This review examines the recent approaches used to achieve therapeutic polymers for dental adhesives by incorporating bio-active components. A strategy to maintain adhesive restorations is the focus of this paper. Results Major trials on therapeutic dental adhesives have looked at adding antibacterial activities or remineralization effects. Applications of antibacterial resin monomers based on quaternary ammonium compounds have received much research attention, and the loading of nano-sized bioactive particles or multiple ion-releasing glass fillers have been perceived as advantageous since they are not expected to influence the mechanical properties of the carrier polymer. Significance The therapeutic polymer approaches described here have the potential to provide clinical benefits. However, not many technological applications in this category have been successfully commercialized. Clinical evidence as well as further advancement of these technologies can be a driving force to make these new types of materials clinically available. PMID:23899387

  5. The Synthesis and Study of Azole Carboxamide Nucleosides as Agents Active Against RNA Viruses.

    DTIC Science & Technology

    1986-09-15

    5012 62770A 62770A8,1. AH 355 11. TITLE (Include Security Classification) The Synthesis and Study of Azole Carboxamide Nucleosides as Agents Active...broad-spectrum antiviral agent has stimulated a great deal of effort toward the chemical synthesis of nucleosides of other azole heterocycles. During the...4 II. Chemistry and Discussion . . .. .. . 6 1. Synthesis of Certain 5’-Substituted Derivatives of Ribavirin and Tiazofurin . . .. . 6 2

  6. Targeting the kinase activities of ATR and ATM exhibits therapeutic potential in a mouse model of MLL-rearranged AML

    PubMed Central

    Lafarga, Vanesa; Anton, Marta Elena; Tubbs, Anthony; Chen, Hua Tang; Ergan, Aysegul; Anderson, Rhonda; Bhandoola, Avinash; Pike, Kurt G.; Barlaam, Bernard; Cadogan, Elaine; Wang, Xi; Pierce, Andrew J.; Hubbard, Chad; Armstrong, Scott A.; Nussenzweig, André; Fernandez-Capetillo, Oscar

    2016-01-01

    Among the various subtypes of Acute Myeloid Leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies due to an attenuated response by p53, which induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AMLMLL cells (with an MLL-ENL fusion and a constitutively active N-RAS) independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AMLMLL and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AMLMLL mice. Collectively, these data indicated that ATR and ATM inhibition represent potential alternative therapeutic strategies for the treatment of AML, especially MLL-driven leukemias. PMID:27625305

  7. Biological properties and therapeutic activities of honey in wound healing: A narrative review and meta-analysis.

    PubMed

    Oryan, Ahmad; Alemzadeh, Esmat; Moshiri, Ali

    2016-05-01

    For thousands of years, honey has been used for medicinal applications. The beneficial effects of honey, particularly its anti-microbial activity represent it as a useful option for management of various wounds. Honey contains major amounts of carbohydrates, lipids, amino acids, proteins, vitamin and minerals that have important roles in wound healing with minimum trauma during redressing. Because bees have different nutritional behavior and collect the nourishments from different and various plants, the produced honeys have different compositions. Thus different types of honey have different medicinal value leading to different effects on wound healing. This review clarifies the mechanisms and therapeutic properties of honey on wound healing. The mechanisms of action of honey in wound healing are majorly due to its hydrogen peroxide, high osmolality, acidity, non-peroxide factors, nitric oxide and phenols. Laboratory studies and clinical trials have shown that honey promotes autolytic debridement, stimulates growth of wound tissues and stimulates anti-inflammatory activities thus accelerates the wound healing processes. Compared with topical agents such as hydrofiber silver or silver sulfadiazine, honey is more effective in elimination of microbial contamination, reduction of wound area, promotion of re-epithelialization. In addition, honey improves the outcome of the wound healing by reducing the incidence and excessive scar formation. Therefore, application of honey can be an effective and economical approach in managing large and complicated wounds.

  8. Treatment Algorithm for Chronic Idiopathic Constipation and Constipation-Predominant Irritable Bowel Syndrome Derived from a Canadian National Survey and Needs Assessment on Choices of Therapeutic Agents

    PubMed Central

    Tse, Yvonne; Andrews, Christopher N.; Bitton, Alain

    2017-01-01

    Background. Chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) are common functional lower gastrointestinal disorders that impair patients' quality of life. In a national survey, we aimed to evaluate (1) Canadian physician practice patterns in the utilization of therapeutic agents listed in the new ACG and AGA guidelines; (2) physicians satisfaction with these agents for their CIC and IBS-C patients; and (3) the usefulness of these new guidelines in their clinical practice. Methods. A 9-item questionnaire was sent to 350 Canadian specialists to evaluate their clinical practice for the management of CIC and IBS-C. Results. The response rate to the survey was 16% (n = 55). Almost all (96%) respondents followed a standard, stepwise approach for management while they believed that only 24% of referring physicians followed the same approach. Respondents found guanylyl cyclase C (GCC) agonist most satisfying when treating their patients. Among the 69% of respondents who were aware of published guidelines, only 50% found them helpful in prioritizing treatment choices and 69% of respondents indicated that a treatment algorithm, applicable to Canadian practice, would be valuable. Conclusion. Based on this needs assessment, a treatment algorithm was developed to provide clinical guidance in the management of IBS-C and CIC in Canada. PMID:28271055

  9. Treatment Algorithm for Chronic Idiopathic Constipation and Constipation-Predominant Irritable Bowel Syndrome Derived from a Canadian National Survey and Needs Assessment on Choices of Therapeutic Agents.

    PubMed

    Tse, Yvonne; Armstrong, David; Andrews, Christopher N; Bitton, Alain; Bressler, Brian; Marshall, John; Liu, Louis W C

    2017-01-01

    Background. Chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) are common functional lower gastrointestinal disorders that impair patients' quality of life. In a national survey, we aimed to evaluate (1) Canadian physician practice patterns in the utilization of therapeutic agents listed in the new ACG and AGA guidelines; (2) physicians satisfaction with these agents for their CIC and IBS-C patients; and (3) the usefulness of these new guidelines in their clinical practice. Methods. A 9-item questionnaire was sent to 350 Canadian specialists to evaluate their clinical practice for the management of CIC and IBS-C. Results. The response rate to the survey was 16% (n = 55). Almost all (96%) respondents followed a standard, stepwise approach for management while they believed that only 24% of referring physicians followed the same approach. Respondents found guanylyl cyclase C (GCC) agonist most satisfying when treating their patients. Among the 69% of respondents who were aware of published guidelines, only 50% found them helpful in prioritizing treatment choices and 69% of respondents indicated that a treatment algorithm, applicable to Canadian practice, would be valuable. Conclusion. Based on this needs assessment, a treatment algorithm was developed to provide clinical guidance in the management of IBS-C and CIC in Canada.

  10. Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells.

    PubMed

    Tanimura, Susumu; Uchiyama, Aya; Watanabe, Kazushi; Yasunaga, Masahiro; Inada, Yoshiyuki; Kawabata, Takumi; Iwashita, Ken-Ichi; Noda, Sinji; Ozaki, Kei-Ichi; Kohno, Michiaki

    2009-01-16

    The extracellular signal-regulated kinase (ERK) signaling pathway is constitutively activated in many human tumor cell types. Given the cytoprotective role of this pathway, we examined whether its specific blockade might sensitize human tumor cells to the induction of apoptosis by various anticancer drugs. Although blockade of ERK signaling alone did not induce substantial cell death, it resulted in marked and selective enhancement of the induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the ERK pathway is constitutively activated. The synergistic activation of c-Jun NH(2)-terminal kinase by the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent appeared to be responsible, at least in part, for this effect. These results suggest that administration of the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent is a potential chemotherapeutic strategy for the treatment of tumor cells with constitutive activation of the ERK pathway.

  11. Novel Oxidatively Activated Agents Modify DNA and are Enhanced by Ercc1 Silencing

    PubMed Central

    Jones, Amy R.; Bell-Horwath, Tiffany R.; Li, Guorui; Rollmann, Stephanie M.; Merino, Edward J.

    2012-01-01

    Agents that chemically modify DNA form a backbone of many cancer treatments. A key problem for DNA modifying agents is lack of specificity. To address this issue, we designed novel molecular scaffolds, termed An-Hq and An-Hq2, which are activated by a hallmark of some cancers: elevated concentrations of reactive oxygen species. Elevated reactive oxygen species are linked to oncogenesis and is found to increase in several aggressive cancers. The agents are quinones that, upon oxidation, form highly electrophilic species. In vitro studies identified the mode of addition to DNA. The aniline portion of An-Hq serves to enhance nucleophilic addition to the ethyl phenyl ether instead of forming common Michael additions. Structural characterization showed the agents add to 2′-deoxyguanosine at the N2,N3-positions. The product formed is a bulky hydroxy-N2,3-benzetheno-2′-deoxyguanosine adduct. In addition, the oxidatively activated agents added to 2′-deoxyadenosine and 2′-deoxycytidine, but not thymidine or 2′-deoxyinosine. These findings are confirmed by primer extension analysis of a 392 base pair DNA. The full-length primer extension product was reduced by 69.0 ± 0.6% upon oxidative activation of An-Hq2 compared to controls. Little sequence dependence was observed with 76% of guanine, adenine, and cytosine residues showing an increase in extension stops between two and four fold above controls. Benzetheno-nucleobase addition to double stranded DNA was confirmed by LC/MS of a self-complementary oligonucletide. Experiments were carried out to confirm in vivo DNA damage. Because of the lesion identified in vitro, we reasoned that nucleotide excision repair should be involved in reversing the effects of these oxidatively activated agents and enhance toxicity in Drosophila melanogaster. Using an RNAi based approach, Ercc1 was silenced and survival monitored after injection of an agent. As expected, bulky cross-linking DNA modifying agents, cisplatin and

  12. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity.

    PubMed

    Johansen, Lisa M; DeWald, Lisa Evans; Shoemaker, Charles J; Hoffstrom, Benjamin G; Lear-Rooney, Calli M; Stossel, Andrea; Nelson, Elizabeth; Delos, Sue E; Simmons, James A; Grenier, Jill M; Pierce, Laura T; Pajouhesh, Hassan; Lehár, Joseph; Hensley, Lisa E; Glass, Pamela J; White, Judith M; Olinger, Gene G

    2015-06-03

    Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration-approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections.

  13. Emerging therapeutic strategies to prevent infection-related microvascular endothelial activation and dysfunction

    PubMed Central

    Darwish, Ilyse; Liles, W Conrad

    2013-01-01

    Recent evidence suggests that loss of endothelial barrier function and resulting microvascular leak play important mechanistic roles in the pathogenesis of infection-related end-organ dysfunction and failure. Several distinct therapeutic strategies, designed to prevent or limit infection-related microvascular endothelial activation and permeability, thereby mitigating end-organ injury/dysfunction, have recently been investigated in pre-clinical models. In this review, these potential therapeutic strategies, namely, VEGFR2/Src antagonists, sphingosine-1-phosphate agonists, fibrinopeptide Bβ15–42, slit2N, secinH3, angiopoietin-1/tie-2 agonists, angiopoietin-2 antagonists, statins, atrial natriuretic peptide, and mesenchymal stromal (stem) cells, are discussed in terms of their translational potential for the management of clinical infectious diseases. PMID:23863603

  14. Antianaerobic Activity of Sulopenem Compared to Six Other Agents

    PubMed Central

    Ednie, Lois M.; Appelbaum, Peter C.

    2009-01-01

    Agar dilution MIC methodology was used to compare the activity of sulopenem with those of amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 431 anaerobes. Overall, MIC50/90 values were as follows: sulopenem, 0.25/1.0 μg/ml; amoxicillin/clavulanate, 0.5/2.0 μg/ml; ampicillin/sulbactam, 0.5/4.0 μg/ml; piperacillin/tazobactam, 0.25/8.0 μg/ml; imipenem, 0.06/1.0 μg/ml; clindamycin, 0.25/16.0 μg/ml; and metronidazole, 1.0/4.0 μg/ml. PMID:19223615

  15. [Cytotoxic and genotoxic activity of certain preservative agents in cosmetics].

    PubMed

    Jantová, S; Hojerová, J; Hanusová, B; Mikulásová, M

    2001-09-01

    Cytotoxic effects of the preservative compounds for cosmetics JMAC TD, Bronopol, CA 24, and Euxyl K100 were studied. Bronopol demonstrated the highest cytotoxic effect on the proliferation of V79 and VH10 fibroblast cell lines--the IC100 values being 10 mg/l during the whole experiment. The preservatives CA 24 and Euxyl K100 showed 4-times and 5-times smaller cytotoxic activity than Bronopol IC100 = 42 or 50.3 mg/l). The preservative compounds on silver chloride ions JMAC TD manifested the lowest cytotoxicity of the preservatives tested (IC100 = 150 mg/l); 15-times smaller than Bronopol, 3.5-times smaller than CA 24 and 3-times smaller than Euxyl K100. The biocide JMAC TD did not exhibit mutagenic effects on the bacteria Salmonella typhimurium TA 98 and TA 100.

  16. Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand.

    PubMed

    Amoury, Manal; Bauerschlag, Dirk; Zeppernick, Felix; von Felbert, Verena; Berges, Nina; Di Fiore, Stefano; Mintert, Isabell; Bleilevens, Andreas; Maass, Nicolai; Bräutigam, Karen; Meinhold-Heerlein, Ivo; Stickeler, Elmar; Barth, Stefan; Fischer, Rainer; Hussain, Ahmad Fawzi

    2016-08-23

    Triple-negative breast cancer (TNBC) is a heterogeneous disease in which the tumors do not express estrogen receptor (ER), progesterone receptor (PgR) or human epidermal growth factor receptor 2 (HER2). Classical receptor-targeted therapies such as tamoxifen or trastuzumab are therefore unsuitable and combinations of surgery, chemotherapy and/or radiotherapy are required. Photoimmunotheranostics is a minimally invasive approach in which antibodies deliver nontoxic photosensitizers that emit light to facilitate diagnosis and produce cytotoxic reactive oxygen species to induce apoptosis and/or necrosis in cancer cells. We developed a panel of photoimmunotheranostic agents against three TNBC-associated cell surface antigens. Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye®700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50values of 62-165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4. A combination of all three reagents increased the therapeutic activity against TNBC cells by up to 40%.

  17. Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand

    PubMed Central

    Zeppernick, Felix; von Felbert, Verena; Berges, Nina; Di Fiore, Stefano; Mintert, Isabell; Bleilevens, Andreas; Maass, Nicolai; Bräutigam, Karen; Meinhold-Heerlein, Ivo; Stickeler, Elmar

    2016-01-01

    Triple-negative breast cancer (TNBC) is a heterogeneous disease in which the tumors do not express estrogen receptor (ER), progesterone receptor (PgR) or human epidermal growth factor receptor 2 (HER2). Classical receptor-targeted therapies such as tamoxifen or trastuzumab are therefore unsuitable and combinations of surgery, chemotherapy and/or radiotherapy are required. Photoimmunotheranostics is a minimally invasive approach in which antibodies deliver nontoxic photosensitizers that emit light to facilitate diagnosis and produce cytotoxic reactive oxygen species to induce apoptosis and/or necrosis in cancer cells. We developed a panel of photoimmunotheranostic agents against three TNBC-associated cell surface antigens. Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye®700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50values of 62–165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4. A combination of all three reagents increased the therapeutic activity against TNBC cells by up to 40%. PMID:27448975

  18. Chelating agents inhibit activity and prevent expression of streptococcal glucan-binding lectins.

    PubMed Central

    Lü-Lü; Singh, J S; Galperin, M Y; Drake, D; Taylor, K G; Doyle, R J

    1992-01-01</