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Sample records for clioquinol

  1. Preparation and characterization of gellan gum/glucosamine/clioquinol film as oral cancer treatment patch.

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    Tsai, Wanchi; Tsai, Huifang; Wong, Yinuan; Hong, Juiyen; Chang, Shwujen; Lee, Mingwei

    2018-01-01

    To administer cancer drugs with improved convenience to patients and to enhance the bioavailability of cancer drugs for oral cancer therapy, this study prepared gellan gum/glucosamine/clioquinol (GG/GS/CQ) film as the oral cancer treatment patch. GG/GS/CQ film fabricated through the EDC-mediated coupling reactions (GG/GS/CQ/EDC film). The film of the physicochemical properties and drug release kinetics were studied. The effectiveness of GG/GS/CQ/EDC film as oral cancer treatment patch were evaluated with the animal model. The results confirmed that CQ can be incorporated via EDC-mediated covalent conjugation to gellan gum/glucosamine. Mechanical testing revealed that the maximum tensile strength and elongation percentage at break were 1.91kgf/mm 2 and 5.01% for GG/GS/CQ/EDC film. After a drug release experiment lasting 45days, 86.8% of CQ was released from GG/GS/CQ/EDC film. The Huguchi model fit the GG/GS/CQ/EDC drug release data with high correlation coefficients (R 2 =0.9994, respectively). The effect of the CQ dose on oral cancer cells (OC-2) was tested, and the IC 50 of CQ alone and CQ with 10μM CuCl 2 were 9.59 and 2.22μM, respectively. The animal testing indicated that GG/GS/CQ/EDC film was decreased epidermal growth factor receptor (EGFR) expression and suppress tumor progression. These findings provide insights into a possible use for GG/GS/CQ/EDC film for oral ca in clinical practice. The GG/GS/CQ/EDC film is suitable as the dressing for use in the treatment of early-stage cancer or as wound care after surgery in late-stage of oral cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Quinoline-based clioquinol and nitroxoline exhibit anticancer activity inducing FoxM1 inhibition in cholangiocarcinoma cells

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    Chan-on W

    2015-04-01

    Full Text Available Waraporn Chan-on,1 Nguyen Thi Bich Huyen,2 Napat Songtawee,3 Wilasinee Suwanjang,1 Supaluk Prachayasittikul,3 Virapong Prachayasittikul2 1Center for Research and Innovation, 2Department of Clinical Microbiology and Applied Technology, 3Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand Purpose: Fork head box M1 (FoxM1 is an oncogenic transcription factor frequently elevated in numerous cancers, including cholangiocarcinoma (CCA. A growing body of evidence documents its diverse functions contributing to tumorigenesis and cancer progression. As such, discovery of agents that can target FoxM1 would be valuable for the treatment of CCA. The quinoline-based compounds, namely clioquinol (CQ and nitroxoline (NQ, represent a new class of anticancer drug. However, their efficacy and underlying mechanisms have not been elucidated in CCA. In this study, anticancer activities and inhibitory effects of CQ and NQ on FoxM1 signaling were explored using CCA cells.Methods: The effects of CQ and NQ on cell viability and proliferation were evaluated using the colorimetric 3-(4,5-dimethylthiazol-2yl-5-(3-carboxymethoxyphenyl-(4-sulfophenyl-2H-tetrazolium (MTS assay. Colony formation and cell migration affected by CQ and NQ were investigated using a clonogenic and a wound healing assay, respectively. To demonstrate the agents’ effects on FoxM1 signaling, expression levels of the target genes were quantitatively determined using real-time polymerase chain reaction.Results: CQ and NQ significantly inhibited cell survival of HuCCT1 and Huh28 in a dose- and a time-dependent fashion. Further investigations using the rapidly proliferating HuCCT1 cells revealed significant suppression of cell proliferation and colony formation induced by low doses of the compounds. Treatment of CQ and NQ repressed expression of cyclin D1 but enhanced expression of p21. Most importantly, upon CQ and NQ treatment

  3. Determining the Antifungal Agent Clioquinol by HPLC, the Not so Pure Preparation: A Laboratory-Based Case Study for an Instrumental Analytical Chemistry Course

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    Schaber, Peter M.; Hobika, Geoffrey

    2018-01-01

    The case study approach provides students with a better appreciation of how scientists solve problems and conduct themselves in the "real world". When applied to the undergraduate chemistry laboratory, this approach also challenges critical thinking skills and creativity in ways "cook book" experiments very often do not. This…

  4. Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation

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    Lee, Eun-Jae; Lee, Hyejin; Huang, Tzyy-Nan; Chung, Changuk; Shin, Wangyong; Kim, Kyungdeok; Koh, Jae-Young; Hsueh, Yi-Ping; Kim, Eunjoon

    2015-01-01

    Genetic aspects of autism spectrum disorders (ASDs) have recently been extensively explored, but environmental influences that affect ASDs have received considerably less attention. Zinc (Zn) is a nutritional factor implicated in ASDs, but evidence for a strong association and linking mechanism is largely lacking. Here we report that trans-synaptic Zn mobilization rapidly rescues social interaction in two independent mouse models of ASD. In mice lacking Shank2, an excitatory postsynaptic scaffolding protein, postsynaptic Zn elevation induced by clioquinol (a Zn chelator and ionophore) improves social interaction. Postsynaptic Zn is mainly derived from presynaptic pools and activates NMDA receptors (NMDARs) through postsynaptic activation of the tyrosine kinase Src. Clioquinol also improves social interaction in mice haploinsufficient for the transcription factor Tbr1, which accompanies NMDAR activation in the amygdala. These results suggest that trans-synaptic Zn mobilization induced by clioquinol rescues social deficits in mouse models of ASD through postsynaptic Src and NMDAR activation. PMID:25981743

  5. Evaluation of 8-Hydroxyquinoline Derivatives as Hits for Antifungal Drug Design.

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    Pippi, Bruna; Reginatto, Paula; Machado, Gabriella da Rosa Monte; Bergamo, Vanessa Zafaneli; Lana, Daiane Flores Dalla; Teixeira, Mario Lettieri; Franco, Lucas Lopardi; Alves, Ricardo José; Andrade, Saulo Fernandes; Fuentefria, Alexandre Meneghello

    2017-10-01

    Clioquinol is an 8-hydroxyquinoline derivative that was widely used from the 1950s to 1970s as an oral antiparasitic agent. In 1970, the oral forms were withdrawn from the market due to reports of toxicity, but topical formulations for antifungal treatment remained available. Thus, the purpose of this study was to evaluate the toxicity, anti-Candida and antidermatophyte activity and to determine pharmacodynamic characteristics of clioquinol and other 8-hydroxyquinoline derivatives (8-hydroxy-5-quinolinesulfonic acid and 8-hydroxy-7-iodo-5-quinolinesulfonic acid). Antifungal activity was tested by broth microdilution and the fungicidal or fungistatic effect was checked by a time-kill assay. Permeation and histopathological evaluation were performed in Franz diffusion cells with ear skin of pigs and examined under light microscopy. An HET-CAM test was used to determine the potential irritancy. The three compounds were active against all isolates showing anti-Candida and antidermatophyte activity, with MIC ranges of 0.031-2 μg/ml, 1-512 μg/ml, and 2-1024 μg/ml for clioquinol, 8-hydroxy-5-quinolinesulfonic acid, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid, respectively. All compounds showed fungistatic effect for Candida, 8-hydroxy-5-quinolinesulfonic acid, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid showed a fungicidal effect for M. canis and T. mentagrophytes, and clioquinol showed a fungicidal effect only for T. mentagrophytes. Furthermore, they presented a fungicidal effect depending on the time and concentration. The absence of lesions was observed in histopathological evaluation and no compound was irritating. Moreover, clioquinol and 8-hydroxy-5-quinolinesulfonic acid accumulated in the epithelial tissue, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid had a high degree of permeation. In conclusion, 8-hydroxyquinoline derivatives showed antifungal activity and 8-hydroxy-5-quinolinesulfonic acid demonstrated the potential for antifungal drug design.

  6. Blockade of intracellular Zn2+ signaling in the dentate gyrus erases recognition memory via impairment of maintained LTP.

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    Tamano, Haruna; Minamino, Tatsuya; Fujii, Hiroaki; Takada, Shunsuke; Nakamura, Masatoshi; Ando, Masaki; Takeda, Atsushi

    2015-08-01

    There is no evidence on the precise role of synaptic Zn2+ signaling on the retention and recall of recognition memory. On the basis of the findings that intracellular Zn2+ signaling in the dentate gyrus is required for object recognition, short-term memory, the present study deals with the effect of spatiotemporally blocking Zn2+ signaling in the dentate gyrus after LTP induction and learning. Three-day-maintained LTP was impaired 1 day after injection of clioquinol into the dentate gyrus, which transiently reduced intracellular Zn2+ signaling in the dentate gyrus. The irreversible impairment was rescued not only by co-injection of ZnCl2 , which ameliorated the loss of Zn2+ signaling, but also by pre-injection of Jasplakinolide, a stabilizer of F-actin, prior to clioquinol injection. Simultaneously, 3-day-old space recognition memory was impaired 1 day after injection of clioquinol into the dentate gyrus, but not by pre-injection of Jasplakinolide. Jasplakinolide also rescued both impairments of 3-day-maintained LTP and 3-day-old memory after injection of ZnAF-2DA into the dentate gyrus, which blocked intracellular Zn2+ signaling in the dentate gyrus. The present paper indicates that the blockade and/or loss of intracellular Zn2+ signaling in the dentate gyrus coincidently impair maintained LTP and recognition memory. The mechanism maintaining LTP via intracellular Zn2+ signaling in dentate granule cells, which may be involved in the formation of F-actin, may retain space recognition memory. © 2015 Wiley Periodicals, Inc.

  7. A rapid and efficient preparation of [{sup 123}I]radiopharmaceuticals using a small HPLC Rocket[reg] column

    Energy Technology Data Exchange (ETDEWEB)

    Katsifis, Andrew [Radiopharmaceuticals Division R and D, Australian Nuclear Science and Technology, Organisation, Menai, NSW 2234, Sydney (Australia)]. E-mail: akx@ansto.gov.au; Papazian, Vahan [Radiopharmaceuticals Division R and D, Australian Nuclear Science and Technology, Organisation, Menai, NSW 2234, Sydney (Australia); Jackson, Timothy [Radiopharmaceuticals Division R and D, Australian Nuclear Science and Technology, Organisation, Menai, NSW 2234, Sydney (Australia); Loc' h, Christian [Radiopharmaceuticals Division R and D, Australian Nuclear Science and Technology, Organisation, Menai, NSW 2234, Sydney (Australia)

    2006-01-01

    A simplified method for the rapid and efficient preparation of [{sup 123}I]radiopharmaceuticals is described. Three radiopharmaceuticals, [{sup 123}I]{beta}-CIT, [{sup 123}I]MIBG and [{sup 123}I]clioquinol, were synthesised and purified as model compounds. The radiotracers were labelled with iodine-123 using electrophilic oxidative conditions and purified by a compact semi-preparative reverse phase column (C-18, 3 {mu}m, 7x53 mm, Alltima Rocket[reg, Alltech] using aqueous-ethanol as HPLC solvents that were directly used for radiopharmaceutical formulation. The radiochemical purity of the radioiodinated tracers as assessed by analytical HPLC was higher than 99% with specific activity higher than 3 GBq/nmol. The total preparation time of a radiotracer ranged from 40 to 60 min and, starting from 3.7 GBq of iodine-123, more than 2.5 GBq of formulated radiopharmaceuticals were available for clinical investigations.

  8. Involvement of glucocorticoid-mediated Zn2+ signaling in attenuation of hippocampal CA1 LTP by acute stress.

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    Takeda, Atsushi; Suzuki, Miki; Tamano, Haruna; Takada, Shunsuke; Ide, Kazuki; Oku, Naoto

    2012-03-01

    Glucocorticoid-glutamatergic interactions have been proposed as a potential model to explain stress-mediated impairment of cognition. However, it is unknown whether glucocorticoid-zincergic interactions are involved in this impairment. Histochemically reactive zinc (Zn(2+)) is co-released with glutamate from zincergic neurons. In the present study, involvement of synaptic Zn(2+) in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30s, which significantly increased serum corticosterone. Stress-induced attenuation of CA1 LTP was ameliorated by administration of clioquinol, a membrane permeable zinc chelator, to rats prior to exposure to stress, implying that the reduction of synaptic Zn(2+) by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn(2+) signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn(2+) was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn(2+) levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca(2+) levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn(2+) release from the neuron terminals. Intracellular Zn(2+) levels measured with ZnAF-2DA were also increased dose-dependently, but not in the coexistence of CaEDTA, a membrane-impermeable zinc chelator, suggesting that intracellular Zn(2+) levels is increased by the influx of extracellular Zn(2+). Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn(2+) signal in the cytosolic compartment is involved in the attenuation of CA1 LTP after exposure to acute stress. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Interventions for skin changes caused by nerve damage in leprosy

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    Liv Merete Reinar

    Full Text Available BACKGROUND More than three million persons are disabled by leprosy worldwide. The main complication of sensory nerve damage is neuropathic ulceration, particularly of the feet. In this review we explored interventions that can prevent and treat secondary damage to skin and limbs. OBJECTIVE To assess the effects of self-care, dressings and footwear in preventing and healing secondary damage to the skin in persons affected by leprosy. METHODS Search methods: We searched the Cochrane Skin Group Specialised Register (April 2008, the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2008, MEDLINE (from 2003 to April 2008, EMBASE (from 2005 to April 2008, CINAHL (1982-2006 and LILACS (1982- April 2008 as well as online registers of ongoing trials (April 2008. Selection criteria: Randomised controlled trials involving anyone with leprosy and damage to peripheral nerves treated with any measures designed to prevent damage with the aim of healing existing ulcers and preventing development of new ulcers. Data collection and analysis: Two authors assessed trial quality and extracted data. MAIN RESULTS Eight trials with a total of 557 participants were included. The quality of the trials was generally poor. The interventions and outcome measures were diverse. Although three studies that compared zinc tape to more traditional dressings found some benefit, none of these showed a statistically significant effect. One trial indicated that topical ketanserin had a better effect on wound healing than clioquinol cream or zinc paste, RR was 6.00 (95% CI 1.45 to 24.75. We did not combine the results of the two studies that compared topical phenytoin to saline dressing, but both studies found statistically significant effects in favour of phenytoin for healing of ulcer (SMD -2.34; 95% CI -3.30 to -1.39; and SMD -0.79; 95% CI -1.20 to 0.39. Canvas shoes were not much better than PVC-boots, and double rocker shoes did not promote healing

  10. Interventions for skin changes caused by nerve damage in leprosy.

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    Reinar, Liv Merete; Forsetlund, Louise; Bjørndal, Arild; Lockwood, Diana

    2008-07-16

    More than three million persons are disabled by leprosy worldwide. The main complication of sensory nerve damage is neuropathic ulceration, particularly of the feet. In this review we explored interventions that can prevent and treat secondary damage to skin and limbs. To assess the effects of self-care, dressings and footwear in preventing and healing secondary damage to the skin in persons affected by leprosy. We searched the Cochrane Skin Group Specialised Register (April 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2008), MEDLINE (from 2003 to April 2008), EMBASE (from 2005 to April 2008), CINAHL (1982-2006) and LILACS (1982- April 2008 ) as well as online registers of ongoing trials (April 2008). Randomised controlled trials involving anyone with leprosy and damage to peripheral nerves treated with any measures designed to prevent damage with the aim of healing existing ulcers and preventing development of new ulcers. Two authors assessed trial quality and extracted data. Eight trials with a total of 557 participants were included. The quality of the trials was generally poor. The interventions and outcome measures were diverse. Although three studies that compared zinc tape to more traditional dressings found some benefit, none of these showed a statistically significant effect. One trial indicated that topical ketanserin had a better effect on wound healing than clioquinol cream or zinc paste, RR was 6.00 (95% CI 1.45 to 24.75). We did not combine the results of the two studies that compared topical phenytoin to saline dressing, but both studies found statistically significant effects in favour of phenytoin for healing of ulcer (SMD -2.34; 95% CI -3.30 to -1.39; and SMD -0.79; 95% CI -1.20 to 0.39). Canvas shoes were not much better than PVC-boots, and double rocker shoes did not promote healing much more than below-knee plasters. One study suggested that topical ketanserin is more effective than clioquinol cream

  11. Zinc signaling in the hippocampus and its relation to pathogenesis of depression.

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    Takeda, Atsushi

    2012-06-01

    Histochemically reactive zinc (Zn(2+)) is co-released with glutamate from zincergic neurons, a subclass of glutamatergic neurons. Zn(2+) serves as a signal factor in both the extracellular and intracellular compartments. Glucocorticoid-glutamatergic interactions have been proposed as a potential model to explain stress-mediated impairment of hippocampal function, i.e., cognition. However, it is unknown whether glucocorticoid-zincergic interactions are involved in this impairment. In the present study, involvement of synaptic Zn(2+) in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30s, which significantly increased serum corticosterone. Stress-induced attenuation of CA1 LTP was ameliorated by administration of clioquinol, a membrane permeable zinc chelator, to rats prior to exposure to stress, implying that the reduction of synaptic Zn(2+) by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn(2+) signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn(2+) was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn(2+) levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca(2+) levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn(2+) release from the neuron terminals. Intracellular Zn(2+) levels measured with ZnAF-2DA were also increased dose-dependently, but not in the coexistence of CaEDTA, a membrane-impermeable zinc chelator, suggesting that intracellular Zn(2+) levels is increased by the influx of extracellular Zn(2+). Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn(2+) signal in the cytosolic compartment is involved in the attenuation

  12. The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo.

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    Xie, Zhongcong; Culley, Deborah J; Dong, Yuanlin; Zhang, Guohua; Zhang, Bin; Moir, Robert D; Frosch, Matthew P; Crosby, Gregory; Tanzi, Rudolph E

    2008-12-01

    An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed. We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction. Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo. Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation.

  13. New record of Scedosporium dehoogii from Chile: Phylogeny and susceptibility profiles to classic and novel putative antifungal agents.

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    Alvarez, Eduardo; Sanhueza, Camila

    Scedosporium species are considered emerging agents causing illness in immunocompromised patients. In Chile, only Scedosporium apiospermum, Scedosporium boydii and Lomentospora prolificans haven been reported previously. The study aimed to characterize genetically Scedosporium dehoogii strains from Chilean soil samples, and assessed the antifungal susceptibility profile to classic and novel putative antifungal molecules. In 2014, several samples were obtained during a survey of soil fungi in urban areas from Chile. Morphological and phylogenetic analyses of the internal transcribed spacer region (ITS), tubulin (TUB), and calmodulin (CAL) sequences were performed. In addition, the susceptibility profiles to classic antifungal and new putative antifungal molecules were determined. Four strains of Scedosporium dehoogii were isolated from soil samples. The methodology confirmed the species (reported here as a new record for Chile). Antifungal susceptibility testing demonstrates the low activity of terpenes (α-pinene and geraniol) against this species. Voriconazole (VRC), posaconazole (PSC), and the hydroxyquinolines (clioquinol, and 5,7-dibromo-8-hydroxyquinoline) showed the best antifungal activity. Our results demonstrate that Scedosporium dehoogii is present in soil samples from Chile. This study shows also that hydroxyquinolines have potential as putative antifungal molecules. Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. Intra-antral application of an anti-fungal agent for recurrent maxillary fungal rhinosinusitis: a case report

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    Dunmade Adekunle D

    2012-08-01

    Full Text Available Abstract Introduction Fungal infection of the paranasal sinuses is an increasingly recognized entity both in immunocompetent and immunocompromised individuals. Treatment has been via use of either surgical or medical modalities, or a combination of the two. Here, we present a case of utilization of intra-antral application of an anti-fungal agent in the management of recurrent fungal sinusitis in an indigent Nigerian patient. Case presentation We present the case of a 30-year-old West African Yoruba man, an indigent Nigerian clergyman, who presented to our facility with a history of recurrent nasal discharge (about one year, recurrent nasal blockage (about five months, and right facial swelling (about one week. After intra-nasal antrostomy for debulking with a systemic anti-fungal agent, our patient had a recurrence after four months. Our patient subsequently had an intra-antral application of flumetasone and clioquinol (Locacorten®-Vioform® weekly for six weeks with improvement of symptoms and no recurrence after six months of follow-up. Conclusions We conclude that topical intra-antral application of anti-fungal agents is effective in patients with recurrent fungal maxillary sinusitis after surgical debulking.

  15. A proposal to create an extension to the European baseline series.

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    Wilkinson, Mark; Gallo, Rosella; Goossens, An; Johansen, Jeanne D; Rustemeyer, Thomas; Sánchez-Pérez, Javier; Schuttelaar, Marie L; Uter, Wolfgang

    2018-02-01

    The current European baseline series consists of 30 allergens, and was last updated in 2015. To use data from the European Surveillance System on Contact Allergies (ESSCA) to propose an extension to the European baseline series in response to changes in environmental exposures. Data from departmental and national extensions to the baseline series, together with some temporary additions from departments contributing to the ESSCA, were collated during 2013-2014. In total, 31689 patients were patch tested in 46 European departments. Many departments and national groups already consider the current European baseline series to be a suboptimal screen, and use their own extensions to it. The haptens tested are heterogeneous, although there are some consistent themes. Potential haptens to include in an extension to the European baseline series comprise sodium metabisulfite, formaldehyde-releasing preservatives, additional markers of fragrance allergy, propolis, Compositae mix, and 2-hydroxyethyl methacrylate. In combination with other published work from the ESSCA, changes to the current European baseline series are proposed for discussion. As well as addition of the allergens listed above, it is suggested that primin and clioquinol should be deleted from the series, owing to reduced environmental exposure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease

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    Su, Tao; Zhang, Tianhua; Xie, Shishun; Yan, Jun; Wu, Yinuo; Li, Xingshu; Huang, Ling; Luo, Hai-Bin

    2016-02-01

    Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer’s disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ1-42 aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu2+-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.

  17. Intracellular Zn(2+) signaling in the dentate gyrus is required for object recognition memory.

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    Takeda, Atsushi; Tamano, Haruna; Ogawa, Taisuke; Takada, Shunsuke; Nakamura, Masatoshi; Fujii, Hiroaki; Ando, Masaki

    2014-11-01

    The role of perforant pathway-dentate granule cell synapses in cognitive behavior was examined focusing on synaptic Zn(2+) signaling in the dentate gyrus. Object recognition memory was transiently impaired when extracellular Zn(2+) levels were decreased by injection of clioquinol and N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylendediamine. To pursue the effect of the loss and/or blockade of Zn(2+) signaling in dentate granule cells, ZnAF-2DA (100 pmol, 0.1 mM/1 µl), an intracellular Zn(2+) chelator, was locally injected into the dentate molecular layer of rats. ZnAF-2DA injection, which was estimated to chelate intracellular Zn(2+) signaling only in the dentate gyrus, affected object recognition memory 1 h after training without affecting intracellular Ca(2+) signaling in the dentate molecular layer. In vivo dentate gyrus long-term potentiation (LTP) was affected under the local perfusion of the recording region (the dentate granule cell layer) with 0.1 mM ZnAF-2DA, but not with 1-10 mM CaEDTA, an extracellular Zn(2+) chelator, suggesting that the blockade of intracellular Zn(2+) signaling in dentate granule cells affects dentate gyrus LTP. The present study demonstrates that intracellular Zn(2+) signaling in the dentate gyrus is required for object recognition memory, probably via dentate gyrus LTP expression. Copyright © 2014 Wiley Periodicals, Inc.

  18. Patch test results in patients with allergic contact dermatitis in Yozgat

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    Emine Çölgeçen Özel

    2013-09-01

    Full Text Available Background and Design: Patch testing is valuable in the diagnosis of allergic contact dermatitis (ACD as well as in determining the causative agent and thus is helpful in prevention of the disease and also provides information for the patient Material and Method: Hundred and sixty-eight patients (94 female and 74 male with ACD were patch tested with European standard series. Patch test result were assessed according to suggestion of International Contact Dermatitis Research Group at 48 and 72 hours after initial application. Results: Of the patients, 64.3% were between 16-45 years of age and majority of the lesions (57.1% were localized on the hands. A total of 86 (51.1% patients had one or more positive patch test reactions. The most common allergens were nickel sulfate (20.2% followed by potassium dichromate (8.3%, cobalt chloride (7.1%, fragrance mix (7.1%, paraphenylendiamine base (6%, paraben mix 3.6%, N-isopropyl-N-phenyl-p-phenylenediamine (3.6%, wool alcohols (3.6%, formaldehyde (3.6%, quaternium-15 (3.6%. Positive reactions to nickel sulfate were more common among women, especially those in younger group. Frequency of contact allergy to neomycin sulfate, epoxy resin, 4-tert-butylphenolformaldehyde resin, sesquiterpenelactone mix, primin, 5-chloro-2-methyl-4-isothiazolin-3-1, budesonide, lyral were relatively low (1.2%, while no positive reaction was obtained to clioquinol and methyldibromoglutaronitrile in any case. Conclusion: Since no similar study has been previously performed in our area, this study provides information about contact allergen profile in patients underwent skin patch test with a diagnosis of AKD at Yozgat. The most frequent allergens detected with ASS and frequency rates may vary among different facilities at various cities of Turkey. A standard series for our country may be created after assessment of regional variability by new studies conducted in same time zone.

  19. Cardiac Light Chain Amyloidosis: The Role of Metal Ions in Oxidative Stress and Mitochondrial Damage.

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    Diomede, Luisa; Romeo, Margherita; Rognoni, Paola; Beeg, Marten; Foray, Claudia; Ghibaudi, Elena; Palladini, Giovanni; Cherny, Robert A; Verga, Laura; Capello, Gian Luca; Perfetti, Vittorio; Fiordaliso, Fabio; Merlini, Giampaolo; Salmona, Mario

    2017-09-20

    The knowledge of the mechanism underlying the cardiac damage in immunoglobulin light chain (LC) amyloidosis (AL) is essential to develop novel therapies and improve patients' outcome. Although an active role of reactive oxygen species (ROS) in LC-induced cardiotoxicity has already been envisaged, the actual mechanisms behind their generation remain elusive. This study was aimed at further dissecting the action of ROS generated by cardiotoxic LC in vivo and investigating whether transition metal ions are involved in this process. In the absence of reliable vertebrate model of AL, we used the nematode Caenorhabditis elegans, whose pharynx is an "ancestral heart." LC purified from patients with severe cardiac involvement intrinsically generated high levels of ROS and when administered to C. elegans induced ROS production, activation of the DAF-16/forkhead transcription factor (FOXO) pathway, and expression of proteins involved in stress resistance and survival. Profound functional and structural ROS-mediated mitochondrial damage, similar to that observed in amyloid-affected hearts from AL patients, was observed. All these effects were entirely dependent on the presence of metal ions since addition of metal chelator or metal-binding 8-hydroxyquinoline compounds (chelex, PBT2, and clioquinol) permanently blocked the ROS production and prevented the cardiotoxic effects of amyloid LC. Innovation and Conclusion: Our findings identify the key role of metal ions in driving the ROS-mediated toxic effects of LC. This is a novel conceptual advance that paves the way for new pharmacological strategies aimed at not only counteracting but also totally inhibiting the vicious cycle of redox damage. Antioxid. Redox Signal. 27, 567-582.

  20. Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution

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    Denoyer, Delphine; Pearson, Helen B.; Clatworthy, Sharnel A.S.; Smith, Zoe M.; Francis, Paul S.; Llanos, Roxana M.; Volitakis, Irene; Phillips, Wayne A.; Meggyesy, Peter M.; Masaldan, Shashank; Cater, Michael A.

    2016-01-01

    Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mouse prostate epithelial cells (PrECs). Our results provide a basis for the pharmacological activity of copper-ionophores and suggest they are amendable for treatment of patients with prostate cancer. Additionally, recent in vitro and mouse xenograft studies have suggested an increased copper requirement by prostate cancer cells. We demonstrated that prostate adenocarcinoma development in TRAMP mice requires a functional supply of copper and is significantly impeded by altered systemic copper distribution. The presence of a mutant copper-transporting Atp7b protein (tx mutation: A4066G/Met1356Val) in TRAMP mice changed copper-integration into serum and caused a remarkable reduction in prostate cancer burden (64% reduction) and disease severity (grade), abrogating adenocarcinoma development. Implications for current clinical trials are discussed. PMID:27175597

  1. Patch testing for allergic contact dermatitis: Three years retrospective results in Tekirdağ

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    Gamze Erfan

    2015-06-01

    Full Text Available Background and Design: Allergic contact dermatitis is a delayed type hypersensitivity reaction to allergens in individuals who were sensitized with same allergens before. The causative allergens may change in time as well as vary among geographical and population based differences. Materials and Methods: The characteristics of 169 patients-107 (63.3% male, 62 (36.7% female, who patch tested between 2011- 2014 with allergic contact dermatitis diagnosis and test results were retrospectively analysed. Results: The mean age of all patients who had the most frequent occupation as service sector/house wife (26.6% were 41.06 years and the mean disease duration of all patients was 19.5 months. The most frequent localization of disease was hands (n: 105,%73 and %50.3 of patients had positivity with at least one allergen. The most frequent seven allergens with positivity were nickel sulfate (n: 50, %29.6, cobalt chloride (n: 23, %13.6, potassium dichromate (n: 22, %13, sesquiterpene lactone mix (n: 18, %10.7, thiuram (n: 10, %5.9, clioquinol mix (n: 10, %5.9 and 4-tert-butilfenol formaldehyde resin (n: 10, %5.9, respectively. On the other hand in all patients there were no positivity with N-Isopropyl-N-phenyl-4-phenylenediamine, epoxy resin, balsam of peru, formaldehyde, quaternium-15, primin, tixocortol-21-pivalate, fragrance mix-2. Conclusion: In comparison of this study which first reports patch test results of patients in Tekirdağ-a city in Trakya region and other studies that report patch test results of different regions of our country; the mean age of patients of present study were older and there were similar results for occupations and localization of disease in between eastern region and present study. We believe that further studies are needed to specify allergen characteristics of Trakya region using multicenter studies, which include other cities as well.

  2. Profound morphological changes in the erythrocytes and fibrin networks of patients with hemochromatosis or with hyperferritinemia, and their normalization by iron chelators and other agents.

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    Etheresia Pretorius

    Full Text Available It is well-known that individuals with increased iron levels are more prone to thrombotic diseases, mainly due to the presence of unliganded iron, and thereby the increased production of hydroxyl radicals. It is also known that erythrocytes (RBCs may play an important role during thrombotic events. Therefore the purpose of the current study was to assess whether RBCs had an altered morphology in individuals with hereditary hemochromatosis (HH, as well as some who displayed hyperferritinemia (HF. Using scanning electron microscopy, we also assessed means by which the RBC and fibrin morphology might be normalized. An important objective was to test the hypothesis that the altered RBC morphology was due to the presence of excess unliganded iron by removing it through chelation. Very striking differences were observed, in that the erythrocytes from HH and HF individuals were distorted and had a much greater axial ratio compared to that accompanying the discoid appearance seen in the normal samples. The response to thrombin, and the appearance of a platelet-rich plasma smear, were also markedly different. These differences could largely be reversed by the iron chelator desferal and to some degree by the iron chelator clioquinol, or by the free radical trapping agents salicylate or selenite (that may themselves also be iron chelators. These findings are consistent with the view that the aberrant morphology of the HH and HF erythrocytes is caused, at least in part, by unliganded ('free' iron, whether derived directly via raised ferritin levels or otherwise, and that lowering it or affecting the consequences of its action may be of therapeutic benefit. The findings also bear on the question of the extent to which accepting blood donations from HH individuals may be desirable or otherwise.

  3. [India: an expensive and dangerous drug].

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    Astrup, N

    1992-12-16

    India has launched a liberalization of its economy with restructuring, privatization, and increased imports in order to achieve higher economic performance. This drive also affected the pharmaceutical industry and drug distribution, but in a negative manner. In the 1980s there were 9000 drug manufacturers that together produced up to 60,000 different preparations. In 1992, only 20,000 drugs were produced. The Voluntary Health Organization of India (VHAI) has fought for 10 years for a rational policy on medicines to halt the production of worthless or outright harmful products. For instance, anabolic steroids are sold as nutritional supplements to children, and the banned clioquinol is regularly used against diarrhea despite an international boycott. In recent years unscrupulous manufacturers have sold contaminated water as glucose for infusion bags and anti-D-immunoglobulin which was contaminated with HIV-infected blood. In northern India, a criminal organization bought up used cannulas from hospitals and repacked them for resale as new supplies. While a new medicine policy is formulated, there is a serious shortage of life-saving drugs such as insulin and rifampicin. In the last years, prices have exploded as some products have become six times more expensive. The whole national health system has undergone cost cuts to comply with an ultimatum from the World Bank and the International Monetary Fund; otherwise, sorely needed dollar loans would not be forthcoming. Funds for fighting tuberculosis and malaria have been trimmed, although AIDS and family planning budgets have been increased. One-fourth of the state health expenditures go to combat AIDS, since about 1 million people are infected with HIV. The pharmaceutical industry has also been embroiled in a patent protection wrangle with American drug exporters who claim that Retrovir or AZT (developed by Burroughs Wellcome) was pirated by the Cipla firm, whereas Cipla countered that it was ferreted out from

  4. Copper (II) complexes of bidentate ligands exhibit potent anti-cancer activity regardless of platinum sensitivity status.

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    Wehbe, Mohamed; Lo, Cody; Leung, Ada W Y; Dragowska, Wieslawa H; Ryan, Gemma M; Bally, Marcel B

    2017-12-01

    Insensitivity to platinum, either through inherent or acquired resistance, is a major clinical problem in the treatment of many solid tumors. Here, we explored the therapeutic potential of diethyldithiocarbamate (DDC), pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ), clioquinol (CQ) copper complexes in a panel of cancer cell lines that differ in their sensitivity to platins (cisplatin/carboplatin) using a high-content imaging system. Our data suggest that the copper complexes were effective against both platinum sensitive (IC 50  ~ 1 μM platinum) and insensitive (IC 50  > 5 μM platinum) cell lines. Furthermore, copper complexes of DDC, Pyr and 8-HQ had greater therapeutic activity compared to the copper-free ligands in all cell lines; whereas the copper-dependent activities of Plum and CQ were cell-line specific. Four of the copper complexes (Cu(DDC) 2 , Cu(Pyr) 2 , Cu(Plum) 2 and Cu(8-HQ) 2 ) showed IC 50 values less than that of cisplatin in all tested cell lines. The complex copper DDC (Cu(DDC) 2 ) was selected for in vivo evaluation due to its low nano-molar range activity in vitro and the availability of an injectable liposomal formulation. Liposomal (Cu(DDC) 2 ) was tested in a fast-growing platinum-resistant A2780-CP ovarian xenograft model and was found to achieve a statistically significant reduction (50%; p < 0.05) in tumour size. This work supports the potential use of copper-based therapeutics to treat cancers that are insensitive to platinum drugs.

  5. Transient increase in Zn2+ in hippocampal CA1 pyramidal neurons causes reversible memory deficit.

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    Atsushi Takeda

    Full Text Available The translocation of synaptic Zn(2+ to the cytosolic compartment has been studied to understand Zn(2+ neurotoxicity in neurological diseases. However, it is unknown whether the moderate increase in Zn(2+ in the cytosolic compartment affects memory processing in the hippocampus. In the present study, the moderate increase in cytosolic Zn(2+ in the hippocampus was induced with clioquinol (CQ, a zinc ionophore. Zn(2+ delivery by Zn-CQ transiently attenuated CA1 long-term potentiation (LTP in hippocampal slices prepared 2 h after i.p. injection of Zn-CQ into rats, when intracellular Zn(2+ levels was transiently increased in the CA1 pyramidal cell layer, followed by object recognition memory deficit. Object recognition memory was transiently impaired 30 min after injection of ZnCl(2 into the CA1, but not after injection into the dentate gyrus that did not significantly increase intracellular Zn(2+ in the granule cell layer of the dentate gyrus. Object recognition memory deficit may be linked to the preferential increase in Zn(2+ and/or the preferential vulnerability to Zn(2+ in CA1 pyramidal neurons. In the case of the cytosolic increase in endogenous Zn(2+ in the CA1 induced by 100 mM KCl, furthermore, object recognition memory was also transiently impaired, while ameliorated by co-injection of CaEDTA to block the increase in cytosolic Zn(2+. The present study indicates that the transient increase in cytosolic Zn(2+ in CA1 pyramidal neurons reversibly impairs object recognition memory.

  6. Transient increase in Zn2+ in hippocampal CA1 pyramidal neurons causes reversible memory deficit.

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    Takeda, Atsushi; Takada, Shunsuke; Nakamura, Masatoshi; Suzuki, Miki; Tamano, Haruna; Ando, Masaki; Oku, Naoto

    2011-01-01

    The translocation of synaptic Zn(2+) to the cytosolic compartment has been studied to understand Zn(2+) neurotoxicity in neurological diseases. However, it is unknown whether the moderate increase in Zn(2+) in the cytosolic compartment affects memory processing in the hippocampus. In the present study, the moderate increase in cytosolic Zn(2+) in the hippocampus was induced with clioquinol (CQ), a zinc ionophore. Zn(2+) delivery by Zn-CQ transiently attenuated CA1 long-term potentiation (LTP) in hippocampal slices prepared 2 h after i.p. injection of Zn-CQ into rats, when intracellular Zn(2+) levels was transiently increased in the CA1 pyramidal cell layer, followed by object recognition memory deficit. Object recognition memory was transiently impaired 30 min after injection of ZnCl(2) into the CA1, but not after injection into the dentate gyrus that did not significantly increase intracellular Zn(2+) in the granule cell layer of the dentate gyrus. Object recognition memory deficit may be linked to the preferential increase in Zn(2+) and/or the preferential vulnerability to Zn(2+) in CA1 pyramidal neurons. In the case of the cytosolic increase in endogenous Zn(2+) in the CA1 induced by 100 mM KCl, furthermore, object recognition memory was also transiently impaired, while ameliorated by co-injection of CaEDTA to block the increase in cytosolic Zn(2+). The present study indicates that the transient increase in cytosolic Zn(2+) in CA1 pyramidal neurons reversibly impairs object recognition memory.

  7. Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases.

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    Lanza, Valeria; Milardi, Danilo; Di Natale, Giuseppe; Pappalardo, Giuseppe

    2018-02-12

    There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration. Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs. Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease. In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since