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Sample records for chloroquine resistance modulation

  1. High-Dose Chloroquine for Treatment of Chloroquine-Resistant Plasmodium falciparum Malaria

    DEFF Research Database (Denmark)

    Ursing, Johan; Rombo, Lars; Bergqvist, Yngve

    2016-01-01

    BACKGROUND:  Due to development of multidrug-resistant Plasmodium falciparum new antimalarial therapies are needed. In Guinea-Bissau, routinely used triple standard-dose chloroquine remained effective for decades despite the existence of "chloroquine-resistant" P. falciparum. This study aimed...... to determine the in vivo efficacy of higher chloroquine concentrations against P. falciparum with resistance-conferring genotypes. METHODS:  Standard or double-dose chloroquine was given to 892 children aged ...-up. The P. falciparum resistance-conferring genotype (pfcrt 76T) and day 7 chloroquine concentrations were determined. Data were divided into age groups (chloroquine is prescribed according to body weight. RESULTS:  Adequate clinical...

  2. Progressive increase in point mutations associates chloroquine resistance: Even after withdrawal of chloroquine use in India

    Directory of Open Access Journals (Sweden)

    Sabyasachi Das

    2017-12-01

    Full Text Available Chloroquine (CQ is highly effective against P. vivax, due to the rapid spread of CQ resistance in P. falciparum parasites; it is no longer the drug of choice against P. falciparum. This study elucidates the scenario of chloroquine efficacy at times that coincided with a new drug policy and especially assessed the chloroquine resistant molecular markers after withdrawal of chloroquine in Kolkata and Purulia, two malaria endemic zones of West Bengal, India. In vitro CQ susceptibility was tested in 781 patients with P. falciparum mono infections between 2008 and 2013, of which 338 patients had received CQ in 2008–2009. Genotyping of the pfcrt and the pfmdr1 gene was carried out in all isolates. Early treatment failure was detected in 114 patients {43 (31·39% from Kolkata and 71 (35·32% from Purulia} while recrudescence was identified in 13 (9.49% and 17 (8.46% patients from Kolkata and Purulia respectively. In vivo chloroquine resistance was strongly associated with CVMNT-YYSNY (p < 0.01 and SVMNT-YYSNY (p < 0.05 allele in Kolkata. In Purulia chloroquine resistance was associated with CVMNK-YYSNY (P < 0.005, SVMNT-YYSNY (P < 0.01 allele. The proportion of in vitro chloroquine resistance increased in subsequent years to 87.23% and 93·10% in 2013, in Kolkata and Purulia, respectively. Isolates with SVMNT-YFSND, SVMNT-YFSNY, CVIET-YFSND and CVIET-YYSNY haplotypes increased gradually (p < 0.05 from 2010 to 2013, leading to a rise in IC50 (p < 0.05 of chloroquine. An increase in in vitro chloroquine resistance and candidate gene mutations even after five years of chloroquine withdrawal against P. falciparum calls for synchronized research surveillance and proper containment strategies. Keywords: Plasmodium falciparum, ChloroQuine resistance in India, pfcrt polymorphism, pfmdr1 mutation, In vitro chloroquine resistance

  3. Reversal of chloroquine resistance in Plasmodium falciparum by CDR 87/209 and analogues.

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    Walter, R D; Seth, M; Bhaduri, A P

    1993-03-01

    The spreading of resistance towards chloroquine has diminished its value as a potent and safe drug in malaria endemic areas. Recent reports on the reversal of chloroquine resistance in the malaria parasite Plasmodium falciparum in vitro and in vivo by verapamil, desipramine and other Ca(2+)-channel blockers and antidepressants has initiated a strategy for chemotherapy by treatment with chloroquine in combination with a drug resistance modulator. Described here is a class of modulators of distinct structure which reverse chloroquine resistance in a different manner. Contrary to verapamil and desipramine, CDRI 87/209, the most potent compound of this new class and used as a chemical lead, did not restore chloroquine accumulation in the resistant parasites, thereby indicating that besides the proposed blockade of drug efflux other mechanisms are vulnerable targets for a chemotherapeutic approach towards drug resistance. Similar to the former modulators, CDRI 87/209 showed only weak intrinsic plasmodicidal activity and the increase of drug susceptibility was restricted to resistant plasmodia.

  4. Prevalence of the molecular marker of chloroquine resistance (pfcrt ...

    African Journals Online (AJOL)

    Background. In line with the World Health Organization (WHO) guideline on chloroquine (CQ) resistance, CQ was withdrawn as the ... prevention, loss of working hours, etc.1 ... at position 76 being the last in the long process leading to CQ.

  5. Novel short chain chloroquine analogues retain activity against chloroquine resistant K1 Plasmodium falciparum.

    Science.gov (United States)

    Stocks, Paul A; Raynes, Kaylene J; Bray, Patrick G; Park, B Kevin; O'Neill, Paul M; Ward, Stephen A

    2002-11-07

    A series of short chain chloroquine (CQ) derivatives have been synthesized in one step from readily available starting materials. The diethylamine function of CQ is replaced by shorter alkylamine groups (4-9) containing secondary or tertiary terminal nitrogens. Some of these derivatives are significantly more potent than CQ against a CQ resistant strain of Plasmodium falciparum in vitro. We conclude that the ability to accumulate at higher concentrations within the food vacuole of the parasite is an important parameter that dictates their potency against CQ sensitive and the chloroquine resistant K1 P. falciparum.

  6. Development of in-vitro radiometric assay for the rapid assessment of chloroquine resistant plasmodium vivax

    International Nuclear Information System (INIS)

    Myint Oo; Myo Khin; Nwe Nwe Oo

    1997-01-01

    Previously, resistance of malaria parasite to chloroquine has been restricted only to Plasmodium falciparum. Recently, there have been many reports of chloroquine-resistant Plasmodium vivax. One of the mechanisms of chloroquine resistance is the decreased uptake of chloroquine or rapid efflux of the drug from the food vacuole of the parasite. In this study, we have measured the rapid efflux of IH-chloroquine in fifty blood samples from patients with P Vivax infection. All 50 patients were hospitalised for 28 days for the standard treatment with chloroquine. It was found that seven patients who did not respond to the standard regimen of chloroquine have parasites with rapid effluxes of IH-chloroquine. Since rapid effluxes of IH-chloroquine in the resistant parasites showed strong correlation with in vivo 28 days clinical trial, this assay could be used as rapid assessment of chloroquine resistance in patients with P vivax infection

  7. Development of in-vitro radiometric assay for the rapid assessment of chloroquine resistant plasmodium vivax

    Energy Technology Data Exchange (ETDEWEB)

    Oo, Myint; Khin, Myo; Oo, Nwe Nwe [Department of Medical Research, Yangon (Myanmar)

    1997-12-01

    Previously, resistance of malaria parasite to chloroquine has been restricted only to Plasmodium falciparum. Recently, there have been many reports of chloroquine-resistant Plasmodium vivax. One of the mechanisms of chloroquine resistance is the decreased uptake of chloroquine or rapid efflux of the drug from the food vacuole of the parasite. In this study, we have measured the rapid efflux of IH-chloroquine in fifty blood samples from patients with P Vivax infection. All 50 patients were hospitalised for 28 days for the standard treatment with chloroquine. It was found that seven patients who did not respond to the standard regimen of chloroquine have parasites with rapid effluxes of IH-chloroquine. Since rapid effluxes of IH-chloroquine in the resistant parasites showed strong correlation with in vivo 28 days clinical trial, this assay could be used as rapid assessment of chloroquine resistance in patients with P vivax infection.

  8. On the mechanism of chloroquine resistance in Plasmodium falciparum.

    KAUST Repository

    Chinappi, Mauro; Via, Allegra; Marcatili, Paolo; Tramontano, Anna

    2010-01-01

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.

  9. On the mechanism of chloroquine resistance in Plasmodium falciparum.

    KAUST Repository

    Chinappi, Mauro

    2010-11-19

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.

  10. On the Mechanism of Chloroquine Resistance in Plasmodium falciparum

    Science.gov (United States)

    Marcatili, Paolo; Tramontano, Anna

    2010-01-01

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data. PMID:21124966

  11. Prevalence of the molecular marker of chloroquine resistance ( pfcrt ...

    African Journals Online (AJOL)

    In line with the World Health Organization (WHO) guideline on chloroquine (CQ) resistance, CQ was withdrawn as the first-line antimalarial drug in Nigeria in 2005 as a result of ... We monitored the resistance pattern 5 years after withdrawal of CQ, using the pfcrt K76T mutation as a molecular marker for CQ resistance.

  12. Photoaffinity labeling of the Plasmodium falciparum chloroquine resistance transporter with a novel perfluorophenylazido chloroquine.

    Science.gov (United States)

    Lekostaj, Jacqueline K; Natarajan, Jayakumar K; Paguio, Michelle F; Wolf, Christian; Roepe, Paul D

    2008-09-30

    Several models describing how amino acid substitutions in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to chloroquine (CQ) and other antimalarial drugs have been proposed. Further progress requires molecular analysis of interactions between purified reconstituted PfCRT protein and these drugs. We have thus designed and synthesized several perfluorophenyl azido (pfpa) CQ analogues for PfCRT photolabeling studies. One particularly useful probe (AzBCQ) places the pfpa group at the terminal aliphatic N of CQ via a flexible four-carbon ester linker and includes a convenient biotin tag. This probe photolabels PfCRT in situ with high specificity. Using reconstituted proteoliposomes harboring partially purified recombinant PfCRT, we analyze AzBCQ photolabeling versus competition with CQ and other drugs to probe the nature of the CQ binding site. We also inspect how pH, the chemoreversal agent verapamil (VPL), and various amino acid mutations in PfCRT that cause CQ resistance (CQR) affect the efficiency of AzBCQ photolabeling. Upon gel isolation of AzBCQ-labeled PfCRT followed by trypsin digestion and mass spectrometry analysis, we are able to define a single AzBCQ covalent attachment site lying within the digestive vacuolar-disposed loop between putative helices 9 and 10 of PfCRT. Taken together, the data provide important new insight into PfCRT function and, along with previous results, allow us to propose a model for a single CQ binding site in the PfCRT protein.

  13. Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys

    Science.gov (United States)

    2013-01-01

    Background In vitro evidence indicates that tetrandrine (TT) can potentiate the action of chloroquine 40-fold against choloquine-resistant Plasmodium falciparum. The key question emanating from that study is “would tetrandine and chloroquine be highly effective in a live Aotus monkey model with chloroquine-resistant parasites”. This study was designed to closely mimic the pharmacological/anti-malarial activity in man. Methods The Vietnam Smith/RE strain of P. falciparum, which is chloroquine-resistant was used in this study. Previous experimental procedures were followed. Panamanian owl monkeys (Aotus) were inoculated with 5×106 erythrocytes parasitized with the CQ-resistant strain of P. falciparum. Oral drug treatment was with CQ (20 mg/kg) and/or tetrandrine at 15 mg/Kg, 30 mg/Kg or 60 mg/Kg or 25 mg/Kg depending on experimental conditions. Results and Discussion Parasitaemia was cleared rapidly with CQ and TT while CQ treatment alone was ineffective. Recrudescence of malaria occurred after seven days post-infection. However, four animals were treated orally with TT and CQ parasites were cleared. It is likely that monkeys were cured via a combination of both drug and host immune responses. A single Aotus monkey infected with P. falciparum and untreated with drugs, died. No side effects were observed with these drug treatments. Conclusions This combination of chloroquine and tetrandrine forms the basis of a new attack on chloroquine-resistant malaria - one based upon inhibition of the basis of chloroquine resistance, the multiple drug resistance pump. Previous studies demonstrated that the parasite MDR pump was found on parasite membranes using 3H azidopine photoaffinity labelling. Since MDR-based choloroquine resistance is induced by chloroquine, the basis of the action of tetrandrine is the following: 1) tetrandrine inhibits the MDR pump by stimulating MDR ATPase which limits the energy of the pump by depletion of parasite ATP, 2) tetrandrine blocks the

  14. Plasmodium falciparum genotypes associated with chloroquine and amodiaquine resistance in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia

    2007-01-01

    Chloroquine is the most commonly used antimalarial in Guinea-Bissau and high doses are routinely prescribed. Blood from 497 patients treated with different doses of chloroquine or amodiaquine were genotyped. Pfcrt and pfmdr1 polymorphisms were identified. Pfmsp2 analysis identified recrudescent...... infections. The pfcrt 72-76 haplotypes were CVIET and CVMNK. The pfcrt 76T prevalence was 23% at day 0 and 96%, 83% and 100% at recrudescence following treatment with 25 mg/kg and 50 mg/kg of chloroquine and 15 mg/kg of amodiaquine respectively. When treating pfcrt 76T carrying P. falciparum the efficacy...... of 50 mg/kg and 25 mg/kg of chloroquine was 78% and 34% respectively (P = 0.007). The genetic basis of chloroquine resistance is probably the same in Guinea-Bissau as in the rest of Africa. The low pfcrt 76T prevalence suggests that resistance to normal dose chloroquine does not confer a major advantage...

  15. Patterns of chloroquine use and resistance in sub-Saharan Africa: a systematic review of household survey and molecular data

    Science.gov (United States)

    2011-01-01

    Background As a result of widespread chloroquine and sulphadoxine-pyrimethamine (SP) resistance, 90% of sub-Saharan African countries had adopted policies of artemisinin-based combination therapy (ACT) for treatment of uncomplicated malaria by 2007. In Malawi, cessation of chloroquine use was followed by the re-emergence of chloroquine-susceptible malaria. It was expected that introduction of ACT would lead to a return in chloroquine susceptibility throughout Africa, but this has not yet widely occurred. This observation suggests that there is continuing use of ineffective anti-malarials in Africa and that persistent chloroquine-resistant malaria is due to ongoing drug pressure despite national policy changes. Methods To estimate drug use on a national level, 2006-2007 Demographic Health Survey and Multiple Indicator Cluster Survey data from 21 African countries were analysed. Resistance data were compiled by systematic review of the published literature on the prevalence of the Plasmodium falciparum chloroquine resistance transporter polymorphism at codon 76, which causes chloroquine resistance. Results Chloroquine was the most common anti-malarial used according to surveys from 14 of 21 countries analysed, predominantly in West Africa. SP was most commonly reported in two of 21 countries. Among eight countries with longitudinal molecular resistance data, the four countries where the highest proportion of children treated for fever received chloroquine (Uganda, Burkina Faso, Guinea Bissau, and Mali) also showed no significant declines in the prevalence of chloroquine-resistant infections. The three countries with low or decreasing chloroquine use among children who reported fever treatment (Malawi, Kenya, and Tanzania) had statistically significant declines in the prevalence of chloroquine resistance. Conclusions This study demonstrates that in 2006-2007, chloroquine and SP continued to be used at high rates in many African countries. In countries reporting

  16. No seasonal accumulation of resistant P. falciparum when high-dose chloroquine is used

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia

    2009-01-01

    increase of pfcrt 76T if the high doses of CQ commonly used are effective. METHODS AND FINDINGS: P. falciparum parasite density, age, sex, the proportion of chloroquine resistance associated haplotypes pfcrt 76T and P. falciparum multidrug resistance gene 1 86Y were assessed in 988 samples collected from...... to become the dominant P.falciparum type in Guinea-Bissau. This is most likely due to the efficacy of high-dose chloroquine as used in Guinea-Bissau, combined with a loss of fitness associated with pfcrt 76T.......BACKGROUND: Potentially chloroquine resistant P. falciparum, identified by the 76T haplotype in the chloroquine resistance transporter (pfcrt 76T), are highly prevalent throughout Africa. In Guinea-Bissau, normal and double dose chloroquine have respective efficacies of 34% and 78% against P...

  17. Multiple Origins of Mutations in the mdr1 Gene—A Putative Marker of Chloroquine Resistance in P. vivax

    DEFF Research Database (Denmark)

    Schousboe, Mette L; Ranjitkar, Samir; Rajakaruna, Rupika S

    2015-01-01

    BACKGROUND: Chloroquine combined with primaquine has been the recommended antimalarial treatment of Plasmodium vivax malaria infections for six decades but the efficacy of this treatment regimen is threatened by chloroquine resistance (CQR). Single nucleotide polymorphisms (SNPs) in the multidrug...

  18. Quantitative genome re-sequencing defines multiple mutations conferring chloroquine resistance in rodent malaria

    Science.gov (United States)

    2012-01-01

    Background Drug resistance in the malaria parasite Plasmodium falciparum severely compromises the treatment and control of malaria. A knowledge of the critical mutations conferring resistance to particular drugs is important in understanding modes of drug action and mechanisms of resistances. They are required to design better therapies and limit drug resistance. A mutation in the gene (pfcrt) encoding a membrane transporter has been identified as a principal determinant of chloroquine resistance in P. falciparum, but we lack a full account of higher level chloroquine resistance. Furthermore, the determinants of resistance in the other major human malaria parasite, P. vivax, are not known. To address these questions, we investigated the genetic basis of chloroquine resistance in an isogenic lineage of rodent malaria parasite P. chabaudi in which high level resistance to chloroquine has been progressively selected under laboratory conditions. Results Loci containing the critical genes were mapped by Linkage Group Selection, using a genetic cross between the high-level chloroquine-resistant mutant and a genetically distinct sensitive strain. A novel high-resolution quantitative whole-genome re-sequencing approach was used to reveal three regions of selection on chr11, chr03 and chr02 that appear progressively at increasing drug doses on three chromosomes. Whole-genome sequencing of the chloroquine-resistant parent identified just four point mutations in different genes on these chromosomes. Three mutations are located at the foci of the selection valleys and are therefore predicted to confer different levels of chloroquine resistance. The critical mutation conferring the first level of chloroquine resistance is found in aat1, a putative aminoacid transporter. Conclusions Quantitative trait loci conferring selectable phenotypes, such as drug resistance, can be mapped directly using progressive genome-wide linkage group selection. Quantitative genome-wide short

  19. Chloroquine mediated modulation of Anopheles gambiae gene expression.

    Directory of Open Access Journals (Sweden)

    Patrícia Abrantes

    2008-07-01

    Full Text Available Plasmodium development in the mosquito is crucial for malaria transmission and depends on the parasite's interaction with a variety of cell types and specific mosquito factors that have both positive and negative effects on infection. Whereas the defensive response of the mosquito contributes to a decrease in parasite numbers during these stages, some components of the blood meal are known to favor infection, potentiating the risk of increased transmission. The presence of the antimalarial drug chloroquine in the mosquito's blood meal has been associated with an increase in Plasmodium infectivity for the mosquito, which is possibly caused by chloroquine interfering with the capacity of the mosquito to defend against the infection.In this study, we report a detailed survey of the Anopheles gambiae genes that are differentially regulated by the presence of chloroquine in the blood meal, using an A. gambiae cDNA microarray. The effect of chloroquine on transcript abundance was evaluated separately for non-infected and Plasmodium berghei-infected mosquitoes. Chloroquine was found to affect the abundance of transcripts that encode proteins involved in a variety of processes, including immunity, apoptosis, cytoskeleton and the response to oxidative stress. This pattern of differential gene expression may explain the weakened mosquito defense response which accounts for the increased infectivity observed in chloroquine-treated mosquitoes.The results of the present study suggest that chloroquine can interfere with several putative mosquito mechanisms of defense against Plasmodium at the level of gene expression and highlight the need for a better understanding of the impacts of antimalarial agents on parasite transmission.

  20. Trends in chloroquine resistance marker, Pfcrt-K76T mutation ten years after chloroquine withdrawal in Tanzania

    DEFF Research Database (Denmark)

    Mohammed, Asia; Ndaro, Arnold; Kalinga, Akili

    2013-01-01

    Plasmodium falciparum resistance to anti-malarial drugs remains a major obstacle to the control of malaria. In 2001 Tanzania replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2006. SP has however......, continued to be used in intermittent preventive treatment of malaria in pregnancy (IPTp) despite reports of high levels of resistance to SP due to the lack of alternatives to SP for IPTp. Recent reports have indicated recovery of CQ-susceptibility in Malawi, Kenya, Mozambique, and Tanzania based...

  1. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes

    DEFF Research Database (Denmark)

    Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia

    2014-01-01

    Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated...... with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized...

  2. Genetics of chloroquine-resistant malaria: a haplotypic view

    Directory of Open Access Journals (Sweden)

    Gauri Awasthi

    2013-12-01

    Full Text Available The development and rapid spread of chloroquine resistance (CQR in Plasmodium falciparum have triggered the identification of several genetic target(s in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76, are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria.

  3. Resistance of infection by Plasmodium vivax to chloroquine in Bolivia.

    Science.gov (United States)

    Añez, Arletta; Moscoso, Manuel; Laguna, Ángel; Garnica, Cecilia; Melgar, Viviana; Cuba, Mauren; Gutierrez, Sonia; Ascaso, Carlos

    2015-07-01

    Chloroquine (CQ) over three days plus primaquine (PQ) for seven days is the treatment of choice of infections by Plasmodium vivax in Bolivia, where 95% of the cases of malaria are attributed to this species. The aim of this study was to evaluate the therapeutic efficacy of CQ in this setting. Patients in the Amazon region of northern Bolivia, were included in the study from May to November 2011 and the therapeutic efficacy of CQ was evaluated over a 28-day follow-up period. Patients with P. vivax mono-infection received 25 mg/Kg body weight of CQ over three days. The concentrations of CQ + desethylchloroquine (DCQ) in blood were determined at days 7 and 28 of follow up; at follow-up and on the day of treatment failure was administered PQ. One hundred patients fulfilled the inclusion criteria, two were lost to follow up and another two were later excluded for protocol violation. Of the 96 patients who completed the follow up 10 showed TF; one presented continued parasitaemia until day 7 of follow up, three on day 21 and six on day 28 of follow up. The geometric mean of CQ + DCQ on day 7 was 321.7 ng/ml (range 197-535 ng/ml). In six patients with TF the CQ + DCQ concentrations in blood on the day of TF were >100 ng/ml. The rate of resistance was 6.5%. The present study demonstrates the presence of resistance to CQ in the treatment of malaria by P. vivax in the Amazon region of Bolivia. New clinical trials are needed to establish alternative treatments against these parasites in this region of South America.

  4. Chloroquine uptake, altered partitioning and the basis of drug resistance: evidence for chloride-dependent ionic regulation.

    Science.gov (United States)

    Martiney, J A; Ferrer, A S; Cerami, A; Dzekunov, S; Roepe, P

    1999-01-01

    The biochemical mechanism of chloroquine resistance in Plasmodium falciparum remains unknown. We postulated that chloroquine-resistant strains could alter ion fluxes that then indirectly control drug accumulation within the parasite by affecting pH and/or membrane potential ('altered partitioning mechanism'). Two principal intracellular pH-regulating systems in many cell types are the amiloride-sensitive Na+/H+ exchanger (NHE), and the sodium-independent, stilbene-sensitive Cl-/HCO3- antiporter (AE). We report that under physiological conditions (balanced CO2 and HCO3-) chloroquine uptake and susceptibility are not altered by amiloride analogues. We also do not detect a significant difference in NHE activity between chloroquine-sensitive and chloroquine-resistant strains via single cell photometry methods. AE activity is dependent on the intracellular and extracellular concentrations of Cl- and HCO3- ions. Chloroquine-resistant strains differentially respond to experimental modifications in chloride-dependent homeostasis, including growth, cytoplasmic pH and pH regulation. Chloroquine susceptibility is altered by stilbene DIDS only on chloroquine-resistant strains. Our results suggest that a Cl(-)-dependent system (perhaps AE) has a significant effect on the uptake of chloroquine by the infected erythrocyte, and that alterations of this biophysical parameter may be part of the mechanism of chloroquine resistance in P. falciparum.

  5. Chloroquine resistant P. falciparum prevalence is low and unchanged between 1990 and 2005 in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Schmidt, Berit Aydin; Lebbad, Marianne

    2007-01-01

    Chloroquine resistant malaria was first reported in Guinea-Bissau in 1990 but chloroquine remains the most commonly used antimalarial in the country. Since 1990, we have conducted nearly annual standardized WHO in vitro micro-tests to assess chloroquine resistance. We have identified pfcrt 76T...... and other genetic polymorphisms in samples from 1992, 1993, 1995, 2004 and 2005. We have also monitored drug prescriptions for febrile illnesses. The mean proportion of in vitro tests indicating chloroquine resistance was 33% (range 14-54%) with the exception of an outlying value year 2000. The proportion...... of chloroquine resistant P. falciparum detected by in vitro testing did not increase over time. Pfcrt 76T was associated with chloroquine resistance but pfmdr1 86Y was not. The mean pfcrt 76T prevalence varied between 13% and 38%. The prevalence of SNPs at Pfcrt positions 76, 271, 326 and pfmdr1 position 86 did...

  6. Chloroquine resistant Plasmodium vivax: in vitro characterisation and association with molecular polymorphisms.

    Directory of Open Access Journals (Sweden)

    Rossarin Suwanarusk

    2007-10-01

    Full Text Available Treatment failure of chloroquine for P. vivax infections has reached high levels in the eastern provinces of Indonesia, however, in vitro characterization of chloroquine resistance and its associated molecular profile have yet to be determined.Using a modified schizont maturation assay we investigated the in vitro chloroquine susceptibility profile and molecular polymorphisms of P. vivax isolates collected from Papua, Indonesia, where high levels of clinical chloroquine treatment failure have been reported, and from Thailand, where chloroquine treatment is generally effective.The geometric mean chloroquine IC(50 for P. vivax isolates from Papua (n = 145 was 312 nM [95%CI: 237-411 nM] compared to 46.8 nM [95%CI: 34.7-63.1 nM] from Thailand (n = 81; p<0.001. Correlating with the known clinical efficacy of the area, a cut off for chloroquine resistance was defined as 220 nM, a level exceeded in 13.6% (11/81 of Thai isolates and 65% (94/145 of Papuan isolates; p<0.001. Several sequence polymorphisms in pvcrt-o and pvmdr1, and difference in pvmdr1 copy number were identified. A Y976F mutation in pvmdr1 was present in 96% (123/128 of Papuan isolates and 25% (17/69 of Thai isolates; p<0.001. Overall, the geometric mean chloroquine IC(50 in isolates with the Y976F mutation was 283 nM [95%CI: 211-379], compared to 44.5 nM [95%CI: 31.3-63.4] in isolates with the wild type; p< 0.001. Pvmdr1 amplification occurred in 23% (15/66 of Thai isolates compared to none (0/104 of Indonesian isolates (p<0.001, but was not associated with increased chloroquine resistance after controlling for geographical location.In vitro susceptibility testing of P. vivax discriminates between populations with differing levels of clinical efficacy of chloroquine. The pvmdr1 polymorphism at Y976F may provide a useful tool to highlight areas of emerging chloroquine resistance, although further studies defining its clinical correlates are needed.

  7. 4-N, 4-S & 4-O Chloroquine Analogues: Influence of Side Chain Length and Quinolyl Nitrogen pKa on Activity vs. Chloroquine Resistant Malaria+, #

    OpenAIRE

    Natarajan, Jayakumar K.; Alumasa, John; Yearick, Kimberly; Ekoue-Kovi, Kekeli A.; Casabianca, Leah B.; de Dios, Angel C.; Wolf, Christian; Roepe, Paul D.

    2008-01-01

    Using predictions from heme – quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure – function principles. We vary side chain length for both monoethyl and diethyl 4N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position, and vary side chain length for these analogues. We introduce an additio...

  8. Assessment of the molecular marker of Plasmodium falciparum chloroquine resistance (Pfcrt) in Senegal after several years of chloroquine withdrawal

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Faye, Babacar; Tine, Roger

    2012-01-01

    Abstract. As a result of widespread antimalarial drug resistance, all African countries with endemic malaria have, in recent years, changed their malaria treatment policy. In Senegal, the health authorities changed from chloroquine (CQ) to a combination of sulfadoxine-pyrimethamine (SP) plus...... at the molecular level in selected sites in Senegal, because the scientific community is interested in using CQ again. Finger prick blood samples were collected from Plasmodium falciparum-positive children below the age of 10 years (N = 474) during cross-sectional surveys conducted in two study sites in Senegal...... with different malaria transmission levels. One site is in central Senegal, and the other site is in the southern part of the country. All samples were analyzed for single nucleotide polymorphisms (SNPs) in the P. falciparum CQ resistance transporter gene (Pfcrt; codons 72-76) using polymerase chain reaction...

  9. Synthesis of New 4-Aminoquinolines and Evaluation of Their In Vitro Activity against Chloroquine-Sensitive and Chloroquine-Resistant Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Chandima S K Rajapakse

    Full Text Available The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-aminoquinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC50, markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound.

  10. Polymorphism in the Plasmodium falciparum chloroquine-resistance transporter protein links verapamil enhancement of chloroquine sensitivity with the clinical efficacy of amodiaquine

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    Warhurst David C

    2003-09-01

    Full Text Available Abstract Background Chloroquine accumulates in the acidic digestive vacuole of the intraerythrocytic malaria parasite, and prevents the detoxication of haematin released during haemoglobin digestion. Changes in protein PfCRT in the digestive vacuole membrane of growing intra-erythrocytic stages of Plasmodium falciparum are crucial for resistance. Expressed in yeast, PfCRT resembles an anion channel. Depressed anion channel function could increase intralysosomal pH to reduce entry of basic drug, or enhanced function could reduce drug interaction with target haematin. The most important resistance-associated change is from positively-charged lysine-76 to neutral threonine which could facilitate drug efflux through a putative channel. It has been proposed that the resistance-reversing effect of verapamil is due to hydrophobic binding to the mutated PfCRT protein, and replacement of the lost positive charge, which repels the access of 4-aminoquinoline cations, thus partially restoring sensitivity. Desethylamodiaquine, the active metabolite of amodiaquine, which has significant activity in chloroquine-resistance, may also act similarly on its own. Methods Changes in physicochemical parameters in different CQ-resistant PfCRT sequences are analysed, and correlations with drug activity on lines transfected with different alleles of the pfcrt gene are examined. Results and conclusions The results support the idea that PfCRT is a channel which, in resistant parasites, can allow efflux of chloroquine from the digestive vacuole. Activity of the chloroquine/verapamil combination and of desethylamodiaquine both correlate with the mean hydrophobicity of PfCRT residues 72-76. This may partly explain clinical-resistance to amodiaquine found in the first chloroquine-resistant malaria cases from South America and enables tentative prediction of amodiaquine's clinical activity against novel haplotypes of PfCRT.

  11. Genetic polymorphisms in Plasmodium falciparum chloroquine resistance genes, pfcrt and pfmdr1, in North Sulawesi, Indonesia

    OpenAIRE

    Reteng, Patrick; Vrisca, Visia; Sukarno, Inka; Djarkoni, Ilham Habib; Kalangi, Jane Angela; Jacobs, George Eduardo; Runtuwene, Lucky Ronald; Eshita, Yuki; Maeda, Ryuichiro; Suzuki, Yutaka; Mongan, Arthur Elia; Warouw, Sarah Maria; Yamagishi, Junya; Tuda, Josef

    2017-01-01

    Background Malaria still poses one of the major threats to human health. Development of effective antimalarial drugs has decreased this threat; however, the emergence of drug-resistant Plasmodium falciparum, a cause of Malaria, is disconcerting. The antimalarial drug chloroquine has been effectively used, but resistant parasites have spread worldwide. Interestingly, the withdrawal of the drug reportedly leads to an increased population of susceptible parasites in some cases. We examined the p...

  12. A four-year surveillance program for detection of Plasmodium falciparum chloroquine resistance in Honduras

    Directory of Open Access Journals (Sweden)

    Gustavo A Fontecha

    2014-07-01

    Full Text Available Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt “CVMNK” genotype in codons 72-76.

  13. A four-year surveillance program for detection of Plasmodium falciparum chloroquine resistance in Honduras.

    Science.gov (United States)

    Fontecha, Gustavo A; Sanchez, Ana L; Mendoza, Meisy; Banegas, Engels; Mejía-Torres, Rosa E

    2014-07-01

    Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt "CVMNK" genotype in codons 72-76.

  14. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites.

    Science.gov (United States)

    Hunt, Paul; Afonso, Ana; Creasey, Alison; Culleton, Richard; Sidhu, Amar Bir Singh; Logan, John; Valderramos, Stephanie G; McNae, Iain; Cheesman, Sandra; do Rosario, Virgilio; Carter, Richard; Fidock, David A; Cravo, Pedro

    2007-07-01

    Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed.

  15. Microsatellite analysis of chloroquine resistance associated alleles and neutral loci reveal genetic structure of Indian Plasmodium falciparum.

    Science.gov (United States)

    Mallick, Prashant K; Sutton, Patrick L; Singh, Ruchi; Singh, Om P; Dash, Aditya P; Singh, Ashok K; Carlton, Jane M; Bhasin, Virendra K

    2013-10-01

    Efforts to control malignant malaria caused by Plasmodium falciparum are hampered by the parasite's acquisition of resistance to antimalarial drugs, e.g., chloroquine. This necessitates evaluating the spread of chloroquine resistance in any malaria-endemic area. India displays highly variable malaria epidemiology and also shares porous international borders with malaria-endemic Southeast Asian countries having multi-drug resistant malaria. Malaria epidemiology in India is believed to be affected by two major factors: high genetic diversity and evolving drug resistance in P. falciparum. How transmission intensity of malaria can influence the genetic structure of chloroquine-resistant P. falciparum population in India is unknown. Here, genetic diversity within and among P. falciparum populations is analyzed with respect to their prevalence and chloroquine resistance observed in 13 different locations in India. Microsatellites developed for P. falciparum, including three putatively neutral and seven microsatellites thought to be under a hitchhiking effect due to chloroquine selection were used. Genetic hitchhiking is observed in five of seven microsatellites flanking the gene responsible for chloroquine resistance. Genetic admixture analysis and F-statistics detected genetically distinct groups in accordance with transmission intensity of different locations and the probable use of chloroquine. A large genetic break between the chloroquine-resistant parasite of the Northeast-East-Island group and Southwest group (FST=0.253, Pstructure for Indian P. falciparum population. Overall, the study suggests that transmission intensity can be an efficient driver for genetic differentiation at both neutral and adaptive loci across India. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Microsatellite analysis of chloroquine resistance associated alleles and neutral loci reveal genetic structure of Indian Plasmodium falciparum

    Science.gov (United States)

    Mallick, Prashant K.; Sutton, Patrick L.; Singh, Ruchi; Singh, Om P.; Dash, Aditya P.; Singh, Ashok K.; Carlton, Jane M.; Bhasin, Virendra K.

    2013-01-01

    Efforts to control malignant malaria caused by Plasmodium falciparum are hampered by the parasite’s acquisition of resistance to antimalarial drugs, e.g., chloroquine. This necessitates evaluating the spread of chloroquine resistance in any malaria-endemic area. India displays highly variable malaria epidemiology and also shares porous international borders with malaria-endemic Southeast Asian countries having multi-drug resistant malaria. Malaria epidemiology in India is believed to be affected by two major factors: high genetic diversity and evolving drug resistance in P. falciparum. How transmission intensity of malaria can influence the genetic structure of chloroquine-resistant P. falciparum population in India is unknown. Here, genetic diversity within and among P. falciparum populations is analyzed with respect to their prevalence and chloroquine resistance observed in 13 different locations in India. Microsatellites developed for P. falciparum, including three putatively neutral and seven microsatellites thought to be under a hitchhiking effect due to chloroquine selection were used. Genetic hitchhiking is observed in five of seven microsatellites flanking the gene responsible for chloroquine resistance. Genetic admixture analysis and F-statistics detected genetically distinct groups in accordance with transmission intensity of different locations and the probable use of chloroquine. A large genetic break between the chloroquine-resistant parasite of the Northeast-East-Island group and Southwest group (FST = 0.253, P<0.001) suggests a long period of isolation or a possibility of different origin between them. A pattern of significant isolation by distance was observed in low transmission areas (r = 0.49, P=0.003, N = 83, Mantel test). An unanticipated pattern of spread of hitchhiking suggests genetic structure for Indian P. falciparum population. Overall, the study suggests that transmission intensity can be an efficient driver for genetic differentiation

  17. Return of chloroquine sensitivity to Africa? Surveillance of African Plasmodium falciparum chloroquine resistance through malaria imported to China.

    Science.gov (United States)

    Lu, Feng; Zhang, Meihua; Culleton, Richard L; Xu, Sui; Tang, Jianxia; Zhou, Huayun; Zhu, Guoding; Gu, Yaping; Zhang, Chao; Liu, Yaobao; Wang, Weiming; Cao, Yuanyuan; Li, Julin; He, Xinlong; Cao, Jun; Gao, Qi

    2017-07-26

    Chloroquine (CQ) was the cornerstone of anti-malarial treatment in Africa for almost 50 years, but has been widely withdrawn due to the emergence and spread of resistance. Recent reports have suggested that CQ-susceptibility may return following the cessation of CQ usage. Here, we monitor CQ sensitivity and determine the prevalence of genetic polymorphisms in the CQ resistance transporter gene (pfcrt) of Plasmodium falciparum isolates recently imported from Africa to China. Blood samples were collected from falciparum malaria patients returning to China from various countries in Africa. Isolates were tested for their sensitivity to CQ using the SYBR Green I test ex vivo, and for a subset of samples, in vitro following culture adaptation. Mutations at positions 72-76 and codon 220 of the pfcrt gene were analyzed by sequencing and confirmed by PCR-RFLP. Correlations between drug sensitivity and pfcrt polymorphisms were investigated. Of 32 culture adapted isolates assayed, 17 (53.1%), 6 (18.8%) and 9 (28.1%) were classified as sensitive, moderately resistant, and highly resistant, respectively. In vitro CQ susceptibility was related to point mutations in the pfcrt gene, the results indicating a strong association between pfcrt genotype and drug sensitivity. A total of 292 isolates were typed at the pfcrt locus, and the prevalence of the wild type (CQ sensitive) haplotype CVMNK in isolates from East, South, North, West and Central Africa were 91.4%, 80.0%, 73.3%, 53.3% and 51.7%, respectively. The only mutant haplotype observed was CVIET, and this was almost always linked to an additional mutation at A220S. Our results suggest that a reduction in drug pressure following withdrawal of CQ as a first-line drug may lead to a resurgence in CQ sensitive parasites. The prevalence of wild-type pfcrt CQ sensitive parasites from East, South and North Africa was higher than from the West and Central areas, but this varied greatly between countries. Further surveillance is

  18. Potentiation of Artemisinin Activity against Chloroquine-Resistant Plasmodium falciparum Strains by Using Heme Models

    Science.gov (United States)

    Benoit-Vical, Françoise; Robert, Anne; Meunier, Bernard

    1999-01-01

    The influence of different metalloporphyrin derivatives on the antimalarial activity of artemisinin was studied with two chloroquine-resistant strains of Plasmodium falciparum (FcB1-Colombia and FcM29-Cameroon) cultured in human erythrocytes. This potentiation study indicates that the manganese complex of meso-tetrakis(4-sulfonatophenyl)porphyrin has a significant synergistic effect on the activity of artemisinin against both Plasmodium strains. PMID:10508044

  19. Assessment of the molecular marker of Plasmodium falciparum chloroquine resistance (Pfcrt) in Senegal after several years of chloroquine withdrawal.

    Science.gov (United States)

    Ndiaye, Magatte; Faye, Babacar; Tine, Roger; Ndiaye, Jean Louis; Lo, Aminata; Abiola, Annie; Dieng, Yemou; Ndiaye, Daouda; Hallett, Rachel; Alifrangis, Michael; Gaye, Oumar

    2012-10-01

    As a result of widespread antimalarial drug resistance, all African countries with endemic malaria have, in recent years, changed their malaria treatment policy. In Senegal, the health authorities changed from chloroquine (CQ) to a combination of sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) in 2003. Since 2006, the artemisinin combination therapies (ACTs) artemether-lumefantrine (AL) and artesunate plus amodiaquine (AS/AQ) were adopted for uncomplicated malaria treatment. After several years of CQ withdrawal, the current study wished to determine the level of CQ resistance at the molecular level in selected sites in Senegal, because the scientific community is interested in using CQ again. Finger prick blood samples were collected from Plasmodium falciparum-positive children below the age of 10 years (N = 474) during cross-sectional surveys conducted in two study sites in Senegal with different malaria transmission levels. One site is in central Senegal, and the other site is in the southern part of the country. All samples were analyzed for single nucleotide polymorphisms (SNPs) in the P. falciparum CQ resistance transporter gene (Pfcrt; codons 72-76) using polymerase chain reaction (PCR) sequence-specific oligonucleotide probe (SSOP) enzyme-linked immunosorbent assay (ELISA) and real-time PCR methods. In total, the 72- to 76-codon region of Pfcrt was amplified in 449 blood samples (94.7%; 285 and 164 samples from the central and southern sites of Senegal, respectively). In both study areas, the prevalence of the Pfcrt wild-type single CVMNK haplotype was very high; in central Senegal, the prevalence was 70.5% in 2009 and 74.8% in 2010, and in southern Senegal, the prevalence was 65.4% in 2010 and 71.0% in 2011. Comparing data with older studies in Senegal, a sharp decline in the mutant type Pfcrt prevalence is evident: from 65%, 64%, and 59.5% in samples collected from various sites in 2000, 2001, and 2004 to approximately 30% in our study. A similar

  20. Antiplasmodial activity of new 4-aminoquinoline derivatives against chloroquine resistant strain.

    Science.gov (United States)

    Sinha, Manish; Dola, Vasanth R; Agarwal, Pooja; Srivastava, Kumkum; Haq, Wahajul; Puri, Sunil K; Katti, Seturam B

    2014-07-15

    Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β(3)- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI=5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Diversity of Plasmodium falciparum chloroquine resistance transporter (pfcrt exon 2 haplotypes in the Pacific from 1959 to 1979.

    Directory of Open Access Journals (Sweden)

    Chim W Chan

    Full Text Available Nearly one million deaths are attributed to malaria every year. Recent reports of multi-drug treatment failure of falciparum malaria underscore the need to understand the molecular basis of drug resistance. Multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt are involved in chloroquine resistance, but the evolution of complex haplotypes is not yet well understood. Using over 4,500 archival human serum specimens collected from 19 Pacific populations between 1959 and 1979, the period including and just prior to the appearance of chloroquine treatment failure in the Pacific, we PCR-amplified and sequenced a portion of the pfcrt exon 2 from 771 P. falciparum-infected individuals to explore the spatial and temporal variation in falciparum malaria prevalence and the evolution of chloroquine resistance. In the Pacific, the prevalence of P. falciparum varied considerably across ecological zones. On the island of New Guinea, the decreases in prevalence of P. falciparum in coastal, high-transmission areas over time were contrasted by the increase in prevalence during the same period in the highlands, where transmission was intermittent. We found 78 unique pfcrt haplotypes consisting of 34 amino acid substitutions and 28 synonymous mutations. More importantly, two pfcrt mutations (N75D and K76T implicated in chloroquine resistance were present in parasites from New Hebrides (now Vanuatu eight years before the first report of treatment failure. Our results also revealed unexpectedly high levels of genetic diversity in pfcrt exon 2 prior to the historical chloroquine resistance selective sweep, particularly in areas where disease burden was relatively low. In the Pacific, parasite genetic isolation, as well as host acquired immune status and genetic resistance to malaria, were important contributors to the evolution of chloroquine resistance in P. falciparum.

  2. Activity of two chlorinated lincomycin analogues against chloroquine-resistant falciparum malaria in owl monkeys.

    Science.gov (United States)

    Powers, K G; Jacobs, R L

    1972-01-01

    The chloroquine-resistant Oak Knoll strain of Plasmodium falciparum, recently adapted to the owl monkey (Aotus trivirgatus), was insusceptible to chloroquine therapy. Two chlorinated lincomycin analogues tested in this host-parasite system cured blood-induced infections. Acute infections were treated orally for 7 consecutive days with either 15 or 75 mg of clindamycin hydrochloride (U-21) per kg per day, 10 or 50 mg of N-demethyl-4'-pentyl clindamycin hydrochloride (U-24) per kg per day, or 20 mg of chloroquine base per kg per day. These lincomycin analogues cleared trophozoites from the peripheral blood by the end of the 7-day treatment period. The speed of clearance of parasites was not dose-related, but curative activity appeared dependent upon the amount of drug given as well as the number of daily treatments. The efficacy of U-21 and U-24 is of particular interest since they represent major structural departures from compounds commonly used in the treatment of malaria.

  3. Activity of Two Chlorinated Lincomycin Analogues Against Chloroquine-Resistant Falciparum Malaria in Owl Monkeys1

    Science.gov (United States)

    Powers, Kendall G.; Jacobs, Richard L.

    1972-01-01

    The chloroquine-resistant Oak Knoll strain of Plasmodium falciparum, recently adapted to the owl monkey (Aotus trivirgatus), was insusceptible to chloroquine therapy. Two chlorinated lincomycin analogues tested in this host-parasite system cured blood-induced infections. Acute infections were treated orally for 7 consecutive days with either 15 or 75 mg of clindamycin hydrochloride (U-21) per kg per day, 10 or 50 mg of N-demethyl-4′-pentyl clindamycin hydrochloride (U-24) per kg per day, or 20 mg of chloroquine base per kg per day. These lincomycin analogues cleared trophozoites from the peripheral blood by the end of the 7-day treatment period. The speed of clearance of parasites was not dose-related, but curative activity appeared dependent upon the amount of drug given as well as the number of daily treatments. The efficacy of U-21 and U-24 is of particular interest since they represent major structural departures from compounds commonly used in the treatment of malaria. PMID:4207758

  4. 4-N-, 4-S-, and 4-O-chloroquine analogues: influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria.

    Science.gov (United States)

    Natarajan, Jayakumar K; Alumasa, John N; Yearick, Kimberly; Ekoue-Kovi, Kekeli A; Casabianca, Leah B; de Dios, Angel C; Wolf, Christian; Roepe, Paul D

    2008-06-26

    Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4-O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4-N, 4-S, and 4-O derivatives vs mu-oxo dimeric heme, measure binding constants for monomeric vs dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs CQR malaria.

  5. 4-N, 4-S & 4-O Chloroquine Analogues: Influence of Side Chain Length and Quinolyl Nitrogen pKa on Activity vs. Chloroquine Resistant Malaria+, #

    Science.gov (United States)

    Natarajan, Jayakumar K.; Alumasa, John; Yearick, Kimberly; Ekoue-Kovi, Kekeli A.; Casabianca, Leah B.; de Dios, Angel C.; Wolf, Christian; Roepe, Paul D.

    2009-01-01

    Using predictions from heme – quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure – function principles. We vary side chain length for both monoethyl and diethyl 4N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position, and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4N, 4S and 4O derivatives vs. μ-oxo dimeric heme, measure binding constants for monomeric vs. dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs. CQR malaria. PMID:18512900

  6. Characterization of the commercially-available fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a marker for chloroquine resistance and uptake in a 96-well plate assay.

    Directory of Open Access Journals (Sweden)

    Cheryl C Y Loh

    Full Text Available Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a proxy for chloroquine accumulation. This compound localized to the digestive vacuole of the parasite as observed under confocal microscopy, and inhibited growth of chloroquine-sensitive strain 3D7 more extensively than in the resistant strains 7G8 and K1. Microplate reader measurements indicated suppression of LynxTag-CQGREEN efflux after pretreatment of parasites with known reversal agents. Microsomes carrying either sensitive- or resistant-type PfCRT were assayed for uptake; resistant-type PfCRT exhibited increased accumulation of LynxTag-CQGREEN, which was suppressed by pretreatment with known chemosensitizers. Eight laboratory strains and twelve clinical isolates were sequenced for PfCRT and Pgh1 haplotypes previously reported to contribute to drug resistance, and pfmdr1 copy number and chloroquine IC50s were determined. These data were compared with LynxTag-CQGREEN uptake/fluorescence by multiple linear regression to identify genetic correlates of uptake. Uptake of the compound correlated with the logIC50 of chloroquine and, more weakly, a mutation in Pgh1, F1226Y.

  7. Evolution of malaria mortality and morbidity after the emergence of chloroquine resistance in Niakhar, Senegal

    Science.gov (United States)

    2009-01-01

    Background Recently, it has been assumed that resistance of Plasmodium to chloroquine increased malaria mortality. The study aimed to assess the impact of chemoresistance on mortality attributable to malaria in a rural area of Senegal, since the emergence of resistance in 1992, whilst chloroquine was used as first-line treatment of malaria, until the change in national anti-malarial policy in 2003. Methods The retrospective study took place in the demographic surveillance site (DSS) of Niakhar. Data about malaria morbidity were obtained from health records of three health care facilities, where diagnosis of malaria was based on clinical signs. Source of data concerning malaria mortality were verbal autopsies performed by trained fieldworkers and examined by physicians who identified the probable cause of death. Results From 1992 to 2004, clinical malaria morbidity represented 39% of total morbidity in health centres. Mean malaria mortality was 2.4‰ and 10.4‰ among total population and children younger than five years, respectively, and was highest in the 1992-1995 period. It tended to decline from 1992 to 2003 (Trend test, total population p = 0.03, children 0-4 years p = 0.12 - children 1-4 years p = 0.04- children 5-9 years p = 0.01). Conclusion Contrary to what has been observed until 1995, mortality attributable to malaria did not continue to increase dramatically in spite of the growing resistance to chloroquine and its use as first-line treatment until 2003. Malaria morbidity and mortality followed parallel trends and rather fluctuated accordingly to rainfall. PMID:19943921

  8. Investigating the activity of quinine analogues versus chloroquine resistant Plasmodium falciparum.

    Science.gov (United States)

    Dinio, Theresa; Gorka, Alexander P; McGinniss, Andrew; Roepe, Paul D; Morgan, Jeremy B

    2012-05-15

    Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide a well-tolerated therapy with improved activity versus CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC(50) values relative to QN. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Chlorpheniramine Analogues Reverse Chloroquine Resistance in Plasmodium falciparum by Inhibiting PfCRT.

    Science.gov (United States)

    Deane, Karen J; Summers, Robert L; Lehane, Adele M; Martin, Rowena E; Barrow, Russell A

    2014-05-08

    The emergence and spread of malaria parasites that are resistant to chloroquine (CQ) has been a disaster for world health. The antihistamine chlorpheniramine (CP) partially resensitizes CQ-resistant (CQR) parasites to CQ but possesses little intrinsic antiplasmodial activity. Mutations in the parasite's CQ resistance transporter (PfCRT) confer resistance to CQ by enabling the protein to transport the drug away from its site of action, and it is thought that resistance-reversers such as CP exert their effect by blocking this CQ transport activity. Here, a series of new structural analogues and homologues of CP have been synthesized. We show that these compounds (along with other in vitro CQ resistance-reversers) inhibit the transport of CQ via a resistance-conferring form of PfCRT expressed in Xenopus laevis oocytes. Furthermore, the level of PfCRT-inhibition was found to correlate well with both the restoration of CQ accumulation and the level of CQ resensitization in CQR parasites.

  10. Iron is a substrate of the Plasmodium falciparum chloroquine resistance transporter PfCRT in Xenopus oocytes.

    Science.gov (United States)

    Bakouh, Naziha; Bellanca, Sebastiano; Nyboer, Britta; Moliner Cubel, Sonia; Karim, Zoubida; Sanchez, Cecilia P; Stein, Wilfred D; Planelles, Gabrielle; Lanzer, Michael

    2017-09-29

    The chloroquine resistance transporter of the human malaria parasite Plasmodium falciparum , PfCRT, is an important determinant of resistance to several quinoline and quinoline-like antimalarial drugs. PfCRT also plays an essential role in the physiology of the parasite during development inside erythrocytes. However, the function of this transporter besides its role in drug resistance is still unclear. Using electrophysiological and flux experiments conducted on PfCRT-expressing Xenopus laevis oocytes, we show here that both wild-type PfCRT and a PfCRT variant associated with chloroquine resistance transport both ferrous and ferric iron, albeit with different kinetics. In particular, we found that the ability to transport ferrous iron is reduced by the specific polymorphisms acquired by the PfCRT variant as a result of chloroquine selection. We further show that iron and chloroquine transport via PfCRT is electrogenic. If these findings in the Xenopus model extend to P. falciparum in vivo , our data suggest that PfCRT might play a role in iron homeostasis, which is essential for the parasite's development in erythrocytes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Effect of selected local medicinal plants on the asexual blood stage of chloroquine resistant Plasmodium falciparum.

    Science.gov (United States)

    Mohd Abd Razak, Mohd Ridzuan; Afzan, Adlin; Ali, Rosnani; Amir Jalaluddin, Nur Fasihah; Wasiman, Mohd Isa; Shiekh Zahari, Siti Habsah; Abdullah, Noor Rain; Ismail, Zakiah

    2014-12-15

    The development of resistant to current antimalarial drugs is a major challenge in achieving malaria elimination status in many countries. Therefore there is a need for new antimalarial drugs. Medicinal plants have always been the major source for the search of new antimalarial drugs. The aim of this study was to screen selected Malaysian medicinal plants for their antiplasmodial properties. Each part of the plants were processed, defatted by hexane and sequentially extracted with dichloromethane, methanol and water. The antiplasmodial activities of 54 plant extracts from 14 species were determined by Plasmodium falciparum Histidine Rich Protein II ELISA technique. In order to determine the selectivity index (SI), all plant extracts demonstrating a good antiplasmodial activity were tested for their cytotoxicity activity against normal Madin-Darby Bovine Kidney (MDBK) cell lines by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Twenty three extracts derived from Curcuma zedoaria (rhizome), Curcuma aeruginosa (rhizome), Alpinia galanga (rhizome), Morinda elliptica (leaf), Curcuma mangga (rhizome), Elephantopus scaber (leaf), Vitex negundo (leaf), Brucea javanica (leaf, root and seed), Annona muricata (leaf), Cinnamomun iners (leaf) and Vernonia amygdalina (leaf) showed promising antiplasmodial activities against the blood stage chloroquine resistant P. falciparum (EC50 toxicity effect to MDBK cells in vitro (SI ≥10). The extracts belonging to eleven plant species were able to perturb the growth of chloroquine resistant P. falciparum effectively. The findings justified the bioassay guided fractionation on these plants for the search of potent antimalarial compounds or formulation of standardized extracts which may enhance the antimalarial effect in vitro and in vivo.

  12. Photoaffinity Labeling of the Plasmodium falciparum Chloroquine Resistance Transporter with a Novel Perfluorophenylazido Chloroquine†

    Science.gov (United States)

    Lekostaj, Jacqueline K.; Natarajan, Jayakumar K.; Paguio, Michelle F.; Wolf, Christian; Roepe, Paul D.

    2009-01-01

    Several models describing how amino acid substitutions in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to chloroquine (CQ) and other antimalarial drugs have been proposed. Further progress requires molecular analysis of interactions between purified reconstituted PfCRT protein and these drugs. We have thus designed and synthesized several perfluorophenyl azido (pfpa) CQ analogues for PfCRT photolabeling studies. One particularly useful probe (AzBCQ) places the pfpa group at the terminal aliphatic N of CQ via a flexible four-carbon ester linker and includes a convenient biotin tag. This probe photolabels PfCRT in situ with high specificity. Using reconstituted proteoliposomes harboring partially purified recombinant PfCRT, we analyze AzBCQ photolabeling versus competition with CQ and other drugs to probe the nature of the CQ binding site. We also inspect how pH, the chemoreversal agent verapamil (VPL), and various amino acid mutations in PfCRT that cause CQ resistance (CQR) affect the efficiency of AzBCQ photolabeling. Upon gel isolation of AzBCQ-labeled PfCRT followed by trypsin digestion and mass spectrometry analysis, we are able to define a single AzBCQ covalent attachment site lying within the digestive vacuolar-disposed loop between putative helices 9 and 10 of PfCRT. Taken together, the data provide important new insight into PfCRT function and, along with previous results, allow us to propose a model for a single CQ binding site in the PfCRT protein. PMID:18767816

  13. Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

    Science.gov (United States)

    Sá, Juliana Martha; Twu, Olivia; Hayton, Karen; Reyes, Sahily; Fay, Michael P.; Ringwald, Pascal; Wellems, Thomas E.

    2009-01-01

    Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum originated from at least six foci in South America, Asia, and Oceania. Malaria parasites from these locations exhibit contrasting resistance phenotypes that are distinguished by point mutations and microsatellite polymorphisms in and near the CQR transporter gene, pfcrt, and the multidrug resistance transporter gene, pfmdr1. Amodiaquine (AQ), a 4-aminoquinoline related to CQ, is recommended and often used successfully against CQ-resistant P. falciparum in Africa, but it is largely ineffective across large regions of South America. The relationship of different pfcrt and pfmdr1 combinations to these drug-resistant phenotypes has been unclear. In two P. falciparum genetic crosses, particular pfcrt and pfmdr1 alleles from South America interact to yield greater levels of resistance to monodesethylamodiaquine (MDAQ; the active metabolite of AQ) than to CQ, whereas a pfcrt allele from Southeast Asia and Africa is linked to greater CQ than MDAQ resistance with all partner pfmdr1 alleles. These results, together with (i) available haplotype data from other parasites; (ii) evidence for an emerging focus of AQ resistance in Tanzania; and (iii) the persistence of 4-aminoquinoline-resistant parasites in South America, where CQ and AQ use is largely discontinued, suggest that different histories of drug use on the two continents have driven the selection of distinct suites of pfcrt and pfmdr1 mutations. Increasing use of AQ in Africa poses the threat of a selective sweep of highly AQ-resistant, CQ-resistant parasites with pfcrt and pfmdr1 mutations that are as advantaged and persistent as in South America. PMID:19884511

  14. Chloroquine-resistant falciparum malaria from Irian Jaya (Indonesian New Guinea).

    Science.gov (United States)

    Clyde, D F; McCarthy, V C; Miller, R M; Hornick, R B

    1976-02-01

    A strain of Plasmodium falciparum, transmitted in Irian Jaya (Indonesian New Guinea) was isolated in 1974 and sent to the University of Maryland for characterization in nonimmune volunteers. At Maryland the Indonesia (Whit.) strain, as it has been designated, was transmitted to colonized Anopheles stephensi. Prophylactically, it was not suppressed by proguanil hydrochloride 100 mg. daily. Curatively, parasitaemia was not cleared by treatment with 1-5 g. (base) in three days of chloroquine or amodiaquine (RII responses), nor by treatment with 150 mg. of pyrimethamine in three days (RIII), and some resistance was also shown to quinine. A single dose of 1-5 g. of mefloquine (WR 142,490) produced radical cure in the two patients treated with this new 4-quinolinemethanol compound.

  15. Rapid selection of Plasmodium falciparum chloroquine resistance transporter gene and multidrug resistance gene-1 haplotypes associated with past chloroquine and present artemether-lumefantrine use in Inhambane District, southern Mozambique

    DEFF Research Database (Denmark)

    Thomsen, Thomas T; Madsen, Laura B; Hansson, Helle H

    2013-01-01

    Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living...... in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P = 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246...... haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased...

  16. Active case detection, treatment of falciparum malaria with combined chloroquine and sulphadoxine/pyrimethamine and vivax malaria with chloroquine and molecular markers of anti-malarial resistance in the Republic of Vanuatu

    Directory of Open Access Journals (Sweden)

    Rogers William O

    2010-04-01

    Full Text Available Abstract Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study

  17. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites§

    Science.gov (United States)

    Hunt, Paul; Afonso, Ana; Creasey, Alison; Culleton, Richard; Sidhu, Amar Bir Singh; Logan, John; Valderramos, Stephanie G; McNae, Iain; Cheesman, Sandra; do Rosario, Virgilio; Carter, Richard; Fidock, David A; Cravo, Pedro

    2007-01-01

    Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed. PMID:17581118

  18. Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites.

    Directory of Open Access Journals (Sweden)

    Anna Caroline Campos Aguiar

    Full Text Available Chloroquine (CQ is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index. However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ and compared with a previously synthesized bisquinoline (BAQ, both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.

  19. Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites.

    Science.gov (United States)

    Aguiar, Anna Caroline Campos; Santos, Raquel de Meneses; Figueiredo, Flávio Júnior Barbosa; Cortopassi, Wilian Augusto; Pimentel, André Silva; França, Tanos Celmar Costa; Meneghetti, Mario Roberto; Krettli, Antoniana Ursine

    2012-01-01

    Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.

  20. Plasmodium falciparum chloroquine resistance transporter (PfCRT) isoforms PH1 and PH2 perturb vacuolar physiology

    OpenAIRE

    Callaghan, Paul S.; Siriwardana, Amila; Hassett, Matthew R.; Roepe, Paul D.

    2016-01-01

    Background Recent work has perfected yeast-based methods for measuring drug transport by the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT). Methods The approach relies on inducible heterologous expression of PfCRT in Saccharomyces cerevisiae yeast. In these experiments selecting drug concentrations are not toxic to the yeast, nor is expression of PfCRT alone toxic. Only when PfCRT is expressed in the presence of CQ is the growth of yeast impaired, due to inward transpo...

  1. The antiplasmodium effects of a traditional South American remedy: Zanthoxylum chiloperone var. angustifolium against chloroquine resistant and chloroquine sensitive strains of Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Gerardo Cebrian-Torrejon

    2011-06-01

    Full Text Available Zanthoxylum chiloperone var. angustifolium Engl., Rutaceae, is used in traditional medicine to treat fungal and protozoal infections in the central area of South America. Considering the increasing resistance of Plasmodium falciparum in malarial ridden areas, we explored the anti-plasmodial effects of three compounds isolated from Z. chiloperone. The pyranocoumarin transavicennol and the canthinone alkaloids, canthin-6-one and 5-methoxycanthin-6-one, were found to have IC50 on chloroquine/mefloquine resistant and sensitive strains of P. falciparum of 0.5-2.7, 2.0-5.3 and 5.1-10.4 ƒÊg/mL, respectively. Moreover, the formation of heme adducts by these compounds is described by a novel alternative method based on MS-CID methods. The alkylamide sanshool was also identified, for first time in this plant, in the dichloromethanic and ethanolic extracts and the extracts were found to be notably non-toxic and displayed good anti-plasmodial effects.

  2. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance.

    Science.gov (United States)

    Warhurst, David C; Craig, John C; Raheem, K Saki

    2016-01-01

    Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications.

  3. Survey of chloroquine-resistant mutations in the Plasmodium falciparum pfcrt and pfmdr-1 genes in Hadhramout, Yemen.

    Science.gov (United States)

    Bamaga, Omar A A; Mahdy, Mohammed A K; Lim, Yvonne A L

    2015-09-01

    Malaria is still a major public health problem in Yemen. More than 95% of the malaria cases are due to Plasmodium ‎falciparum‎. Recently in Yemen, the antimalarial treatment policy was changed from chloroquine (CQ) to artemisinin combination therapy (ACTs). However, CQ is still available and prescribed in the Yemeni market. The persistence of CQ resistance will be prolonged if the shift to ACT and the simultaneous withdrawal of CQ are not rigorously implemented. The aim of the current survey is to detect chloroquine-resistant mutations in P. falciparum chloroquine-resistance transporter (pfcrt) and P. falciparum multi-drug resistance-1 (pfmdr1) genes. These data will be important for future monitoring and assessment of antimalarial drug policy in Yemen. Blood specimens were collected from 735 individuals from different districts of the Hadhramout province, Yemen by house-to-house visit. Mutation-specific nested polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) methods were used to investigate the mutations in the pfmdr1(codons 86 and 1246) and pfcrt (codons 76, 271, 326, 356 and 371) genes. The overall prevalence of pfcrt mutations at codons 76, 271, 326 and 371 were 50.4%, 58.7%, 54.3% and 44.9%, respectively. All isolates had wild-type pfcrt 356 allele. The majority of pfmdr1 86 alleles (83.3%) and all pfmdr1 1246 alleles were wild type. There was no association between pfcrt mutations and symptomatology, gender and age groups. In conclusion, point mutations in codons 76, 271, 326 and 371 of pfcrt of P. falciparum are high suggesting a sustained high CQ resistance even after 4 years of shifting to ACTs. These findings warrant complete withdrawal of CQ use from the Yemeni market for P. falciparum and careful usage of CQ for treating Plasmodium vivax. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Carriers, channels and chloroquine efficacy in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Rombo, Lars; Kofoed, Poul-Erik

    2008-01-01

    Recent studies suggest that chloroquine resistance is mediated by an energy-dependent saturable chloroquine efflux carrier. An alternative explanation is that resistance is mediated by a channel. In Guinea-Bissau high doses of chloroquine are effective, well-tolerated and commonly used....... This suggests that chloroquine resistance can be overcome by higher doses. Research on the mechanism of chloroquine resistance is of utmost importance and should include the effect of higher doses....

  5. Large-scale survey for novel genotypes of Plasmodium falciparum chloroquine-resistance gene pfcrt

    Directory of Open Access Journals (Sweden)

    Takahashi Nobuyuki

    2012-03-01

    Full Text Available Abstract Background In Plasmodium falciparum, resistance to chloroquine (CQ is conferred by a K to T mutation at amino acid position 76 (K76T in the P. falciparum CQ transporter (PfCRT. To date, at least 15 pfcrt genotypes, which are represented by combinations of five amino acids at positions 72-76, have been described in field isolates from various endemic regions. To identify novel mutant pfcrt genotypes and to reveal the genetic relatedness of pfcrt genotypes, a large-scale survey over a wide geographic area was performed. Methods Sequences for exon 2 in pfcrt, including known polymorphic sites at amino acid positions 72, 74, 75 and 76, were obtained from 256 P. falciparum isolates collected from eight endemic countries in Asia (Bangladesh, Cambodia, Lao P.D.R., the Philippines and Thailand, Melanesia (Papua New Guinea and Vanuatu and Africa (Ghana. A haplotype network was constructed based on six microsatellite markers located -29 kb to 24 kb from pfcrt in order to examine the genetic relatedness among mutant pfcrt genotypes. Results In addition to wild type (CVMNK at positions 72-76, four mutant pfcrt were identified; CVIET, CVIDT, SVMNT and CVMNT (mutated amino acids underlined. Haplotype network revealed that there were only three mutant pfcrt lineages, originating in Indochina, Philippines and Melanesia. Importantly, the Indochina lineage contained two mutant pfcrt genotypes, CVIET (n = 95 and CVIDT (n = 14, indicating that CVIDT shares a common origin with CVIET. Similarly, one major haplotype in the Melanesian lineage contained two pfcrt genotypes; SVMNT (n = 71 and CVMNT (n = 3. In Africa, all mutant pfcrt genotypes were the CVIET of the Indochina lineage, probably resulting from the intercontinental migration of CQ resistance from Southeast Asia. Conclusions The number of CQ-mutant lineages observed in this study was identical to that found in previous studies. This supports the hypothesis that the emergence of novel CQ resistance

  6. Molecular interaction of selected phytochemicals under the charged environment of Plasmodium falciparum chloroquine resistance transporter (PfCRT) model.

    Science.gov (United States)

    Patel, Saumya K; Khedkar, Vijay M; Jha, Prakash C; Jasrai, Yogesh T; Pandya, Himanshu A; George, Linz-Buoy; Highland, Hyacinth N; Skelton, Adam A

    2016-01-01

    Phytochemicals of Catharanthus roseus Linn. and Tylophora indica have been known for their inhibition of malarial parasite, Plasmodium falciparum in cell culture. Resistance to chloroquine (CQ), a widely used antimalarial drug, is due to the CQ resistance transporter (CRT) system. The present study deals with computational modeling of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein and development of charged environment to mimic a condition of resistance. The model of PfCRT was developed using Protein homology/analogy engine (PHYRE ver 0.2) and was validated based on the results obtained using PSI-PRED. Subsequently, molecular interactions of selected phytochemicals extracted from C. roseus Linn. and T. indica were studied using multiple-iterated genetic algorithm-based docking protocol in order to investigate the translocation of these legends across the PfCRT protein. Further, molecular dynamics studies exhibiting interaction energy estimates of these compounds within the active site of the protein showed that compounds are more selective toward PfCRT. Clusters of conformations with the free energy of binding were estimated which clearly demonstrated the potential channel and by this means the translocation across the PfCRT is anticipated.

  7. Nonradioactive heteroduplex tracking assay for the detection of minority-variant chloroquine-resistant Plasmodium falciparum in Madagascar

    Science.gov (United States)

    Juliano, Jonathan J; Randrianarivelojosia, Milijaona; Ramarosandratana, Benjamin; Ariey, Frédéric; Mwapasa, Victor; Meshnick, Steven R

    2009-01-01

    Background Strains of Plasmodium falciparum genetically resistant to chloroquine (CQ) due to the presence of pfcrt 76T appear to have been recently introduced to the island of Madagascar. The prevalence of such resistant genotypes is reported to be low (chloroquine resistant parasites were described in Malawian patients using an isotopic heteroduplex tracking assay (HTA), which can detect pfcrt 76T-bearing P. falciparum minority variants in individual patients that were undetectable by conventional PCR. However, as this assay required a radiolabeled probe, it could not be used in many resource-limited settings. Methods This study describes a digoxigenin (DIG)-labeled chemiluminescent heteroduplex tracking assay (DIG-HTA) to detect pfcrt 76T-bearing minority variant P. falciparum. This assay was compared to restriction fragment length polymorphism (RFLP) analysis and to the isotopic HTA for detection of genetically CQ-resistant parasites in clinical samples. Results Thirty one clinical P. falciparum isolates (15 primary isolates and 16 recurrent isolates) from 17 Malagasy children treated with CQ for uncomplicated malaria were genotyped for the pfcrt K76T mutation. Two (11.7%) of 17 patients harboured genetically CQ-resistant P. falciparum strains after therapy as detected by HTA. RFLP analysis failed to detect any pfcrt K76T-bearing isolates. Conclusion These findings indicate that genetically CQ-resistant P. falciparum are more common than previously thought in Madagascar even though the fitness of the minority variant pfcrt 76T parasites remains unclear. In addition, HTAs for malaria drug resistance alleles are promising tools for the surveillance of anti-malarial resistance. The use of a non-radioactive label allows for the use of HTAs in malaria endemic countries. PMID:19291288

  8. Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms.

    Science.gov (United States)

    Salas, Paloma F; Herrmann, Christoph; Cawthray, Jacqueline F; Nimphius, Corinna; Kenkel, Alexander; Chen, Jessie; de Kock, Carmen; Smith, Peter J; Patrick, Brian O; Adam, Michael J; Orvig, Chris

    2013-02-28

    Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ∼26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.

  9. Distribution of Mutations Associated with Antifolate and Chloroquine Resistance among Imported Plasmodium vivax in the State of Qatar.

    Science.gov (United States)

    Bansal, Devendra; Acharya, Anushree; Bharti, Praveen K; Abdelraheem, Mohamed H; Elmalik, Ashraf; Abosalah, Salem; Khan, Fahmi Y; ElKhalifa, Mohamed; Kaur, Hargobinder; Mohapatra, Pradyumna K; Sehgal, Rakesh; Idris, Mohammed A; Mahanta, Jagadish; Singh, Neeru; Babiker, Hamza A; Sultan, Ali A

    2017-12-01

    Plasmodium vivax is the most prevalent parasite worldwide, escalating by spread of drug resistance. Currently, in Qatar, chloroquine (CQ) plus primaquine are recommended for the treatment of P. vivax malaria. The present study examined the prevalence of mutations in dihydrofolate reductase ( dhfr ), dihydropteroate synthase ( dhps ) genes and CQ resistance transporter ( crt-o ) genes, associated with sulphadoxine-pyrimethamine (SP) and chloroquine resistance, among imported P. vivax cases in Qatar. Blood samples were collected from patients positive for P. vivax and seeking medical treatment at Hamad General Hospital, Doha, during 2013-2016. The Sanger sequencing method was performed to examine the single nucleotide polymorphisms in Pvdhfr , Pvdhps , and Pvcrt-o genes. Of 314 examined P. vivax isolates, 247 (78.7%), 294 (93.6%) and 261 (83.1%) were successfully amplified and sequenced for Pvdhfr , Pvdhps , and Pvcrt-o , respectively. Overall, 53.8% ( N = 133) carried mutant alleles (58R/117N) in Pvdhfr , whereas 77.2% ( N = 227) and 90% ( N = 235) isolates possessed wild type allele in Pvdhps and Pvcrt-o genes, respectively. In addition, a total of eleven distinct haplotypes were detected in Pvdhfr / Pvdhps genes. Interestingly, K10 insertion in the Pvcrt-o gene was observed only in patients originating from the Indian subcontinent. The results suggested that CQ remains an acceptable treatment regimen but further clinical data are required to assess the effectiveness of CQ and SP in Qatar to support the current national treatment guidelines. In addition, limited distribution of genetic polymorphisms associated with CQ and SP resistance observed in imported P. vivax infections, necessitates regular monitoring of drug resistant P. vivax malaria in Qatar.

  10. Identification of chloroquine resistance Pfcrt-K76T and determination of Pfmdr1-N86Y copy number by SYBR Green I qPCR

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    Addimas Tajebe

    2015-03-01

    Conclusions: The study showed high prevalence level and fixation of Pfcrt, 76T mutation after chloroquine withdrawal. The prevalence of Pfmdr1 copy number variant suggested that the presence of modulating factor for emergence of Plasmodium falciparum strains with higher copy numbers. However, the prevalence level was not statistically significant.

  11. Molecular analysis demonstrates high prevalence of chloroquine resistance but no evidence of artemisinin resistance in Plasmodium falciparum in the Chittagong Hill Tracts of Bangladesh.

    Science.gov (United States)

    Alam, Mohammad Shafiul; Ley, Benedikt; Nima, Maisha Khair; Johora, Fatema Tuj; Hossain, Mohammad Enayet; Thriemer, Kamala; Auburn, Sarah; Marfurt, Jutta; Price, Ric N; Khan, Wasif A

    2017-08-15

    Artemisinin resistance is present in the Greater Mekong region and poses a significant threat for current anti-malarial treatment guidelines in Bangladesh. The aim of this molecular study was to assess the current status of drug resistance in the Chittagong Hill Tracts of Bangladesh near the Myanmar border. Samples were obtained from patients enrolled into a Clinical Trial (NCT02389374) conducted in Alikadam, Bandarban between August 2014 and January 2015. Plasmodium falciparum infections were confirmed by PCR and all P. falciparum positive isolates genotyped for the pfcrt K76T and pfmdr1 N86Y markers. The propeller region of the kelch 13 (k13) gene was sequenced from isolates from patients with delayed parasite clearance. In total, 130 P. falciparum isolates were available for analysis. The pfcrt mutation K76T, associated with chloroquine resistance was found in 81.5% (106/130) of cases and the pfmdr1 mutation N86Y in 13.9% (18/130) cases. No single nucleotide polymorphisms were observed in the k13 propeller region. This study provides molecular evidence for the ongoing presence of chloroquine resistant P. falciparum in Bangladesh, but no evidence of mutations in the k13 propeller domain associated with artemisinin resistance. Monitoring for artemisinin susceptibility in Bangladesh is needed to ensure early detection and containment emerging anti-malarial resistance.

  12. Plasmodium falciparum chloroquine resistance transporter (PfCRT) isoforms PH1 and PH2 perturb vacuolar physiology.

    Science.gov (United States)

    Callaghan, Paul S; Siriwardana, Amila; Hassett, Matthew R; Roepe, Paul D

    2016-03-31

    Recent work has perfected yeast-based methods for measuring drug transport by the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT). The approach relies on inducible heterologous expression of PfCRT in Saccharomyces cerevisiae yeast. In these experiments selecting drug concentrations are not toxic to the yeast, nor is expression of PfCRT alone toxic. Only when PfCRT is expressed in the presence of CQ is the growth of yeast impaired, due to inward transport of chloroquine (CQ) via the transporter. During analysis of all 53 known naturally occurring PfCRT isoforms, two isoforms (PH1 and PH2 PfCRT) were found to be intrinsically toxic to yeast, even in the absence of CQ. Additional analysis of six very recently identified PfCRT isoforms from Malaysia also showed some toxicity. In this paper the nature of this yeast toxicity is examined. Data also show that PH1 and PH2 isoforms of PfCRT transport CQ with an efficiency intermediate to that catalyzed by previously studied CQR conferring isoforms. Mutation of PfCRT at position 160 is found to perturb vacuolar physiology, suggesting a fitness cost to position 160 amino acid substitutions. These data further define the wide range of activities that exist for PfCRT isoforms found in P. falciparum isolates from around the globe.

  13. High frequency of Plasmodium falciparum CICNI/SGEAA and CVIET haplotypes without association with resistance to sulfadoxine/pyrimethamine and chloroquine combination in the Daraweesh area, in Sudan

    DEFF Research Database (Denmark)

    A-Elbasit, I E; Khalil, I F; Elbashir, M I

    2008-01-01

    Estimation of the prevalence of the molecular markers of sulfadoxine/pyrimethamine (SP) and chloroquine (CQ) resistance and validation of the association of mutations with resistance in different settings is needed for local policy guidance and for contributing to a global map for anti-malarial d......Estimation of the prevalence of the molecular markers of sulfadoxine/pyrimethamine (SP) and chloroquine (CQ) resistance and validation of the association of mutations with resistance in different settings is needed for local policy guidance and for contributing to a global map for anti......-malarial drug resistance. In this study, malaria patients treated with SP alone (60) and SP with CQ (194) had a total treatment failure (TF) of 35.4%, with no difference between the two arms. The polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA) method was used to identify polymorphisms...

  14. Low Prevalence of Pfcrt Resistance Alleles among Patients with Uncomplicated Falciparum Malaria in Niger Six Years after Chloroquine Withdrawal

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    Adamou Salissou

    2014-01-01

    Full Text Available Chloroquine (CQ resistance is widespread in Africa, but few data are available for Niger. Pfcrt haplotypes (aa 56–118 and ex vivo responses to CQ and amodiaquine were characterized for 26 isolates collected in South Niger from children under 15 years of age suffering from uncomplicated falciparum malaria, six years after the introduction of artemisinin-based combinations and the withdrawal of CQ. The wild-type Pfcrt haplotype CVMNK was found in 22 of the 26 isolates, with CVIET sequences observed in only three of the samples. We also describe for the first time a new CVINT haplotype. The ex vivo responses were better for CVMNK than for CVIET parasites. Pfcrt sequence data were compared with those obtained for 26 additional parasitized blood samples collected in Gabon, from an area of CQ resistance used as a control. Our findings suggest that there has been a significant decline in CQ-resistant genotypes since the previous estimates for Niger were obtained. No such decline in molecular resistance to CQ was observed in the subset of samples collected in similar conditions from Gabon. These results have important implications for public health and support the policy implemented in Niger since 2005, which aims to increase the efficacy and availability of antimalarial drugs whilst controlling the spread of resistance.

  15. [Mutant alleles associated to chloroquine and sulfadoxine-pyrimethanime resistance in Plasmodium falciparum of the Ecuador-Peru and Ecuador-Colombia borders].

    Science.gov (United States)

    Arróspide, Nancy; Hijar-Guerra, Gisely; de Mora, Doménica; Diaz-Cortéz, César Eduardo; Veloz-Perez, Raúl; Gutierrez, Sonia; Cabezas-Sánchez, César

    2014-04-01

    The frequency of mutations in pfCRT and DHFR/DHPS genes of Plasmodium falciparum associated with resistance to chloroquine and sulfadoxine-pyrimethamine was evaluated in 83 strains from the districts of Esmeralda and Machala, located on the borders of Ecuador-Peru and Ecuador-Colombia in 2002. Polymerase chain reaction (PCR), conventional and its variants, was used. Mutations in the pfCRT gene were found in more than 90% of the samples from Esmeralda and Machala. For the DHFR gene, 90% of the strains were mutant samples from Esmeralda, 3 were double mutations and 1 was a triple mutation. In Machala, 25% were simple mutant forms and 75% mixed mutant forms (wild forms/mutant). In conclusion, resistance to chloroquine has been fixed in strains carrying K76T pfCRT mutation, whereas genetic imprinting for resistance to pyrimethamine is evolving, particularly in the district of Esmeralda.

  16. In vivo and in vitro Plasmodium falciparum Resistance to Chloroquine, Amodiaquine and Quinine in the Brazilian Amazon

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    Aluisio Augusto Cotrim SEGURADO

    1997-03-01

    Full Text Available In order to study the chemoresistance of Plasmodium falciparum to commonly used antimalarial drugs in Brazil the authors have studied ten patients with falciparum malaria, acquired in the Brazilian Amazon region. Patients were submitted to in vivo study of drug sensitivity, after chemotherapy with either 4-aminoquinolines (chloroquine or amodiaquine or quinine. Adequate drug absorption was confirmed by standard urine excretion tests for antimalarials. Eight patients could be followed up to 28 days. Among these in vivo resistance (R I and R II responses was seen in all patients who received 4-amino-quinolines. One patient treated with quinine exhibited a R III response. Peripheral blood samples of the same patients were submitted to in vitro microtests for sensitivity to antimalarials. Out of nine successful tests, resistance to chloroquine and amodiaquine was found in 100% and resistance to quinine in 11.11% of isolates. Probit analysis of log dose-response was used to determine effective concentrations EC50, EC90 and EC99 to the studied drugs. Good correlation between in vivo and in vitro results was seen in six patients. The results emphasize high levels of P. falciparum resistance to 4- aminoquinolines and suggest an increase in resistance to quinine in the Brazilian Amazon region, reinforcing the need for continuous monitoring of drug sensitivity to adequate chemotherapy according to the most efficacious drug regimensResistência in vivo e in vitro do Plasmodium falciparum à cloroquina, amodiaquina e quinino na Amazônia Brasileira. Com o propósito de avaliar a resistência do Plasmodium falciparum às drogas antimaláricas, rotineiramente empregadas no Brasil, os autores acompanharam dez pacientes com malária falciparum adquirida na Amazônia brasileira. Os pacientes foram submetidos a estudo in vivo de sensibilidade a drogas, após tratamento com derivados 4-aminoquinoleínicos (cloroquina e amodiaquina ou quinino. A absorção das

  17. pfmdr1 Amplification and Fixation of pfcrt Chloroquine Resistance Alleles in Plasmodium falciparum in Venezuela ▿ †

    Science.gov (United States)

    Griffing, Sean; Syphard, Luke; Sridaran, Sankar; McCollum, Andrea M.; Mixson-Hayden, Tonya; Vinayak, Sumiti; Villegas, Leopoldo; Barnwell, John W.; Escalante, Ananias A.; Udhayakumar, Venkatachalam

    2010-01-01

    Molecular tools are valuable for determining evolutionary history and the prevalence of drug-resistant malaria parasites. These tools have helped to predict decreased sensitivity to antimalarials and fixation of multidrug resistance genotypes in some regions. In order to assess how historical drug policies impacted Plasmodium falciparum in Venezuela, we examined molecular changes in genes associated with drug resistance. We examined pfmdr1 and pfcrt in samples from Sifontes, Venezuela, and integrated our findings with earlier work describing dhfr and dhps in these samples. We characterized pfmdr1 genotypes and copy number variation, pfcrt genotypes, and proximal microsatellites in 93 samples originating from surveillance from 2003 to 2004. Multicopy pfmdr1 was found in 12% of the samples. Two pfmdr1 alleles, Y184F/N1042D/D1246Y (37%) and Y184F/S1034C/N1042D/D1246Y (63%), were found. These alleles share ancestry, and no evidence of strong selective pressure on mutations was found. pfcrt chloroquine resistance alleles are fixed with two alleles: StctVMNT (91%) and SagtVMNT (9%). These alleles are associated with strong selection. There was also an association between pfcrt, pfmdr1, dhfr, and dhps genotypes/haplotypes. Duplication of pfmdr1 suggests a potential shift in mefloquine sensitivity in this region, which warrants further study. A bottleneck occurred in P. falciparum in Sifontes, Venezuela, and multidrug resistance genotypes are present. This population could be targeted for malaria elimination programs to prevent the possible spread of multidrug-resistant parasites. PMID:20145087

  18. Chloroquine clinical failures in P. falciparum malaria are associated with mutant Pfmdr-1, not Pfcrt in Madagascar.

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    Valérie Andriantsoanirina

    2010-10-01

    Full Text Available Molecular studies have demonstrated that mutations in the Plasmodium falciparum chloroquine resistance transporter gene (Pfcrt play a major role in chloroquine resistance, while mutations in P. falciparum multidrug resistance gene (Pfmdr-1 act as modulator. In Madagascar, the high rate of chloroquine treatment failure (44% appears disconnected from the overall level of in vitro CQ susceptibility (prevalence of CQ-resistant parasites 60% of isolates, but did not explore their association with P. falciparum chloroquine resistance. To document the association of Pfmdr-1 alleles with chloroquine resistance in Madagascar, 249 P. falciparum samples collected from patients enrolled in a chloroquine in vivo efficacy study were genotyped in Pfcrt/Pfmdr-1 genes as well as the estimation of the Pfmdr-1 copy number. Except 2 isolates, all samples displayed a wild-type Pfcrt allele without Pfmdr-1 amplification. Chloroquine treatment failures were significantly associated with Pfmdr-1 86Y mutant codon (OR = 4.6. The cumulative incidence of recurrence of patients carrying the Pfmdr-1 86Y mutation at day 0 (21 days was shorter than patients carrying Pfmdr-1 86N wild type codon (28 days. In an independent set of 90 selected isolates, in vitro susceptibility to chloroquine was not associated with Pfmdr-1 polymorphisms. Analysis of two microsatellites flanking Pfmdr-1 allele showed that mutations occurred on multiple genetic backgrounds. In Madagascar, Pfmdr-1 polymorphism is associated with late chloroquine clinical failures and unrelated with in vitro susceptibility or Pfcrt genotype. These results highlight the limits of the current in vitro tests routinely used to monitor CQ drug resistance in this unique context. Gaining insight about the mechanisms that regulate polymorphism in Pfmdr1 remains important, particularly regarding the evolution and spread of Pfmdr-1 alleles in P. falciparum populations under changing drug pressure which may have important

  19. A 3D QSAR pharmacophore model and quantum chemical structure--activity analysis of chloroquine(CQ)-resistance reversal.

    Science.gov (United States)

    Bhattacharjee, Apurba K; Kyle, Dennis E; Vennerstrom, Jonathan L; Milhous, Wilbur K

    2002-01-01

    Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.

  20. Multiple Origins of Mutations in the mdr1 Gene--A Putative Marker of Chloroquine Resistance in P. vivax.

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    Mette L Schousboe

    2015-11-01

    Full Text Available Chloroquine combined with primaquine has been the recommended antimalarial treatment of Plasmodium vivax malaria infections for six decades but the efficacy of this treatment regimen is threatened by chloroquine resistance (CQR. Single nucleotide polymorphisms (SNPs in the multidrug resistance gene, Pvmdr1 are putative determinants of CQR but the extent of their emergence at population level remains to be explored.In this study we describe the prevalence of SNPs in the Pvmdr1 among samples collected in seven P. vivax endemic countries and we looked for molecular evidence of drug selection by characterising polymorphism at microsatellite (MS loci flanking the Pvmdr1 gene.We examined the prevalence of SNPs in the Pvmdr1 gene among 267 samples collected from Pakistan, Afghanistan, Sri Lanka, Nepal, Sudan, São Tomé and Ecuador. We measured and diversity in four microsatellite (MS markers flanking the Pvmdr1 gene to look evidence of selection on mutant alleles.SNP polymorphism in the Pvmdr1 gene was largely confined to codons T958M, Y976F and F1076L. Only 2.4% of samples were wildtype at all three codons (TYF, n = 5, 13.3% (n = 28 of the samples were single mutant MYF, 63.0% of samples (n = 133 were double mutant MYL, and 21.3% (n = 45 were triple mutant MFL. Clear geographic differences in the prevalence of these Pvmdr mutation combinations were observed. Significant linkage disequilibrium (LD between Pvmdr1 and MS alleles was found in populations sampled in Ecuador, Nepal and Sri Lanka, while significant LD between Pvmdr1 and the combined 4 MS locus haplotype was only seen in Ecuador and Sri Lanka. When combining the 5 loci, high level diversity, measured as expected heterozygosity (He, was seen in the complete sample set (He = 0.99, while He estimates for individual loci ranged from 0.00-0.93. Although Pvmdr1 haplotypes were not consistently associated with specific flanking MS alleles, there was significant differentiation between geographic

  1. Microsatellite polymorphism within pfcrt provides evidence of continuing evolution of chloroquine-resistant alleles in Papua New Guinea

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    Sharma Yagya D

    2007-03-01

    Full Text Available Abstract Background Polymorphism in the pfcrt gene underlies Plasmodium falciparum chloroquine resistance (CQR, as sensitive strains consistently carry lysine (K, while CQR strains carry threonine (T at the codon 76. Previous studies have shown that microsatellite (MS haplotype variation can be used to study the evolution of CQR polymorphism and to characterize intra- and inter-population dispersal of CQR in Papua New Guinea (PNG. Methods Here, following identification of new polymorphic MS in introns 2 and 3 within the pfcrt gene (msint2 and msint3, respectively, locus-by-locus and haplotype heterozygosity (H analyses were performed to determine the distribution of this intronic polymorphism among pfcrt chloroquine-sensitive and CQR alleles. Results For MS flanking the pfcrt CQR allele, H ranged from 0.07 (B5M77, -18 kb to 0.094 (9B12, +2 kb suggesting that CQ selection pressure was responsible for strong homogenisation of this gene locus. In a survey of 206 pfcrt-SVMNT allele-containing field samples from malaria-endemic regions of PNG, H for msint2 was 0.201. This observation suggests that pfcrt msint2 exhibits a higher level of diversity than what is expected from the analyses of pfcrt flanking MS. Further analyses showed that one of the three haplotypes present in the early 1980's samples has become the predominant haplotype (frequency = 0.901 in CQR parasite populations collected after 1995 from three PNG sites, when CQR had spread throughout malaria-endemic regions of PNG. Apparent localized diversification of pfcrt haplotypes at each site was also observed among samples collected after 1995, where minor CQR-associated haplotypes were found to be unique to each site. Conclusion In this study, a higher level of diversity at MS loci within the pfcrt gene was observed when compared with the level of diversity at pfcrt flanking MS. While pfcrt (K76T and its immediate flanking region indicate homogenisation in PNG CQR parasite populations

  2. Detection of K76T Mutation in pfcrt Gene as an Applicable Ge-netic Marker for Prediction of Chloroquine Resistant falciparum Malaria in Isolates from an Endemic District of Iran

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    A Raeisi

    2008-04-01

    Full Text Available Background: This study investigated the association between pfcrt, T76 allele and chloroquine resistance in patients with falciparum malaria. Molecular assays for point mutations on drugs resistance-related genes are applied tools for monitoring emerging resistance and surveillance malaria control strategies in endemic areas. The mutant genotype at codon 76 of Plasmodium falciparum chloroquine resistance transporter gene (pfcrt has been proposed as a molecular marker for the faster detection of chloroquine resistance in field. Methods: In 64 samples from patients with uncomplicated falciparum malaria from Sarbaz district in southeast of Iran,  the clinical response to chloroquine and the prevalence of K76T  mutations in pfcrt gene were investigated by in vivo and nested-PCR  followed restriction enzyme digestion methods. Results:  The occurrence of the K76T mutation was very high (60 of 64, i.e. 93.75% among these filed isolates. Only 4 of 64 isolates harbored wild type K76 codon and no case was a mixed of K76 and 76T codons. All of the 22 (100% chloroquine-resistant and 16.7% of sensitive isolates were found to harbor the 76T mutation and none was found to contain the wild type (K76 allele. Conclusions: The frequency of chloroquine resistance associated point mutation K76T, in pfcrt gene in this region suggest that detection of this mutation can be applied for predicting chloroquine resistance in epidemiologic settings with sufficiently high sensitivity to make it an attractive alternative to time and labor-consuming in vivo trials.

  3. Clinical trial of extended-dose chloroquine for treatment of resistant falciparum malaria among Afghan refugees in Pakistan.

    Science.gov (United States)

    Howard, Natasha; Durrani, Naeem; Sanda, Sanda; Beshir, Khalid; Hallett, Rachel; Rowland, Mark

    2011-06-23

    Falciparum malaria is a significant problem for Afghan refugees in Pakistan. Refugee treatment guidelines recommended standard three-day chloroquine treatment (25 mg/kg) for first episodes and extended five-day treatment (40 mg/kg) for recrudescent infections, based on the assumption that a five-day course would more likely achieve a cure. An in-vivo randomized controlled trial was conducted among refugees with uncomplicated falciparum malaria to determine whether five-day treatment (CQ40) was more effective than standard treatment (CQ25). 142 falciparum patients were recruited into CQ25 or CQ40 treatment arms and followed up to 60 days with regular blood smears. The primary outcome was parasitological cure without recrudescence. Treatment failures were retreated with CQ40. PCR genotyping of 270 samples, from the same and nearby sites, was used to support interpretation of outcomes. 84% of CQ25 versus 51% of CQ40 patients experienced parasite recrudescence during follow-up (adjusted odds ratio 0.17, 95%CI 0.08-0.38). Cure rates were significantly improved with CQ40, particularly among adults. Fever clearance time, parasite clearance time, and proportions gametocytaemic post-treatment were similar between treatment groups. Second-line CQ40 treatment resulted in higher failure rates than first-line CQ40 treatment. CQ-resistance marker pfcrt 76T was found in all isolates analysed, while pfmdr1 86Y and 184Y were found in 18% and 37% of isolates respectively. CQ is not suitable for first-line falciparum treatment in Afghan refugee communities. The extended-dose CQ regimen can overcome 39% of resistant infections that would recrudesce under the standard regimen, but the high failure rate after directly observed treatment demonstrates its use is inappropriate.

  4. Occurrence of the Southeast Asian/South American SVMNT haplotype of the chloroquine-resistance transporter gene in Plasmodium falciparum in Tanzania

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Dalgaard, Michael B; Lusingu, John P

    2006-01-01

    Two main haplotypes, CVIET and SVMNT, of the Plasmodium falciparum chloroquine-resistance transporter gene (Pfcrt) are linked to 4-aminoquinoline resistance. The CVIET haplotype has been reported in most malaria-endemic regions, whereas the SVMNT haplotype has only been found outside Africa. We...... investigated Pfcrt haplotype frequencies in Korogwe District, Tanzania, in 2003 and 2004. The SVMNT haplotype was not detected in 2003 but was found in 19% of infected individuals in 2004. Amodiaquine use has increased in the region. The introduction and high prevalence of the SVMNT haplotype may reflect...... this and may raise concern regarding the use of amodiaquine in artemisinin-based combination therapies in Africa....

  5. Magnetic nanoparticles are highly toxic to chloroquine-resistant Plasmodium falciparum, dengue virus (DEN-2), and their mosquito vectors.

    Science.gov (United States)

    Murugan, Kadarkarai; Wei, Jiang; Alsalhi, Mohamad Saleh; Nicoletti, Marcello; Paulpandi, Manickam; Samidoss, Christina Mary; Dinesh, Devakumar; Chandramohan, Balamurugan; Paneerselvam, Chellasamy; Subramaniam, Jayapal; Vadivalagan, Chithravel; Wei, Hui; Amuthavalli, Pandiyan; Jaganathan, Anitha; Devanesan, Sandhanasamy; Higuchi, Akon; Kumar, Suresh; Aziz, Al Thabiani; Nataraj, Devaraj; Vaseeharan, Baskaralingam; Canale, Angelo; Benelli, Giovanni

    2017-02-01

    A main challenge in parasitology is the development of reliable tools to prevent or treat mosquito-borne diseases. We investigated the toxicity of magnetic nanoparticles (MNP) produced by Magnetospirillum gryphiswaldense (strain MSR-1) on chloroquine-resistant (CQ-r) and sensitive (CQ-s) Plasmodium falciparum, dengue virus (DEN-2), and two of their main vectors, Anopheles stephensi and Aedes aegypti, respectively. MNP were studied by Fourier-transform infrared spectroscopy and transmission electron microscopy. They were toxic to larvae and pupae of An. stephensi, LC 50 ranged from 2.563 ppm (1st instar larva) to 6.430 ppm (pupa), and Ae. aegypti, LC 50 ranged from 3.231 ppm (1st instar larva) to 7.545 ppm (pupa). MNP IC 50 on P. falciparum were 83.32 μg ml -1 (CQ-s) and 87.47 μg ml -1 (CQ-r). However, the in vivo efficacy of MNP on Plasmodium berghei was low if compared to CQ-based treatments. Moderate cytotoxicity was detected on Vero cells post-treatment with MNP doses lower than 4 μg ml -1 . MNP evaluated at 2-8 μg ml -1 inhibited DEN-2 replication inhibiting the expression of the envelope (E) protein. In conclusion, our findings represent the first report about the use of MNP in medical and veterinary entomology, proposing them as suitable materials to develop reliable tools to combat mosquito-borne diseases.

  6. Synthesis and study of effects of new 4-chloro – amodiaquine analogues against two resistant and sensitive forms to chloroquine Plasmodium Falciparum, in vitro

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    afra Khosravi

    2009-03-01

    Full Text Available Background: Resistance to chloroquine (CQ in Plasmodium falciparum malaria has become a major health concern of the developing countries.This resistance has prompted a re-examination of the pharmacology of alternative antimalarials that may be effective against resistant strains. Amodiaquine (AQ is a 4-aminoquinoline antimalarial which is effective against many chloroquine-resistant strains of P. falciparum. However, clinical use of AQ has been severely restricted because of associations with hepatotoxicity and agranulocytosis. The aim of this study was to examine the effects of replacing the 4’OH function of amodiaquine with either chlorine or fluorine. Materials and Methods: A successful four-step synthesis of a new series of 4-chloro analogues has been designed and applied to the synthesis of an array of 10 analogues. Malaria parasites were maintained in continuous culture using the method of Jensen and Trager. Cultures were grown in flasks containing human erythrocytes (2-5% with parasitemia in the range of 1% to 10% suspended in RPMI 1640 medium supplemented with 25 mM HEPES and 32 mM NaHCO3, and 10% human serum (complete medium. Cultures were gassed with a mixture of 3% O2, 6% CO2 and 91% N2 and were kept in a 30 degree temperature. Results: It is apparent that several analogues had very potent antimalarial activity against both strains of the parasite. In particular 5b, 5c and 5i were not only active in the single nanomolar range, but they also displayed little cross-resistance. Against the sensitive HB3 strain, these analogues were superior to chloroquine and slightly more potent than amodiaquine. Activity was reduced when the side-chain was large (eg. dibutyl analogue and pyridine analogues, 5g and 5j respectively. Discussion: In a four - step Process, 10 different chloro - amodiaquine were synthesized which showed (in vitro Promising effects against chloroquine resistant strains of Plasmodium falciparum. It is clear that the 4

  7. Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria

    Science.gov (United States)

    Salinas, Jorge L.; Monteiro, Wuelton M.; Val, Fernando; Cordy, Regina J.; Liu, Ken; Melo, Gisely C.; Siqueira, Andre M.; Magalhaes, Belisa; Galinski, Mary R.; Lacerda, Marcus V. G.; Jones, Dean P.

    2017-01-01

    Background Chloroquine (CQ) is the main anti-schizontocidal drug used in the treatment of uncomplicated malaria caused by Plasmodium vivax. Chloroquine resistant P. vivax (PvCR) malaria in the Western Pacific region, Asia and in the Americas indicates a need for biomarkers of resistance to improve therapy and enhance understanding of the mechanisms associated with PvCR. In this study, we compared plasma metabolic profiles of P. vivax malaria patients with PvCR and chloroquine sensitive parasites before treatment to identify potential molecular markers of chloroquine resistance. Methods An untargeted high-resolution metabolomics analysis was performed on plasma samples collected in a malaria clinic in Manaus, Brazil. Male and female patients with Plasmodium vivax were included (n = 46); samples were collected before CQ treatment and followed for 28 days to determine PvCR, defined as the recurrence of parasitemia with detectable plasma concentrations of CQ ≥100 ng/dL. Differentially expressed metabolic features between CQ-Resistant (CQ-R) and CQ-Sensitive (CQ-S) patients were identified using partial least squares discriminant analysis and linear regression after adjusting for covariates and multiple testing correction. Pathway enrichment analysis was performed using Mummichog. Results Linear regression and PLS-DA methods yielded 69 discriminatory features between CQ-R and CQ-S groups, with 10-fold cross-validation classification accuracy of 89.6% using a SVM classifier. Pathway enrichment analysis showed significant enrichment (p<0.05) of glycerophospholipid metabolism, glycosphingolipid metabolism, aspartate and asparagine metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Glycerophosphocholines levels were significantly lower in the CQ-R group as compared to CQ-S patients and also to independent control samples. Conclusions The results show differences in lipid, amino acids, and nucleotide metabolism pathways in the plasma of CQ-R versus

  8. A simple, high-throughput method to detect Plasmodium falciparum single nucleotide polymorphisms in the dihydrofolate reductase, dihydropteroate synthase, and P. falciparum chloroquine resistance transporter genes using polymerase chain reaction- and enzyme-linked immunosorbent

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Enosse, Sonia; Pearce, Richard

    2005-01-01

    Single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum dihydrofolate reductase (dhfr), and dihydropteroate synthetase (dhps), and chloroquine resistance transporter (Pfcrt) genes are used as molecular markers of P. falciparum resistance to sulfadoxine/pyrimethamine and chloroquine....... However, to be a practical tool in the surveillance of drug resistance, simpler methods for high-throughput haplotyping are warranted. Here we describe a quick and simple technique that detects dhfr, dhps, and Pfcrt SNPs using polymerase chain reaction (PCR)- and enzyme-linked immunosorbent assay (ELISA...

  9. Nutritional Modulation of Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Martin O. Weickert

    2012-01-01

    Full Text Available Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM. Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts.

  10. Falciparum malaria in the north of Laos: the occurrence and implications of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT

    DEFF Research Database (Denmark)

    Dittrich, Sabine; Alifrangis, Michael; Stohrer, Jörg M

    2005-01-01

    the SVMNT haplotype. METHOD: Eighty-eight samples from an area with reported in vivo Chloroquine and in vitro Amodiaquine-resistance were screened for the K76T mutation and their Pfcrt-haplotype (c72-76) using a new SSOP-ELISA. RESULTS: Hundred percent of the analysed samples showed the K76T mutation which......OBJECTIVE: The Pfcrt-gene encodes a transmembrane protein located in the Plasmodium falciparum digestive vacuole. Chloroquine resistant (CQR) strains of African and Southeast Asian origin carry the Pfcrt-haplotype (c72-76) CVIET, whereas most South American and Papua New Guinean CQR stains carry...... is highly associated with in vivo drug failure. This very high rate of a CQR-marker is alarming in an area were CQ is still used as first line drug. The distribution of the three main Pfcrt-haplotypes was as follows: 68% CVIET, 31% SVMNT, 0% CVMNT. CONCLUSIONS: These data show, for the first time, the South...

  11. The antimalarial activity of Ru-chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces.

    Science.gov (United States)

    Martínez, Alberto; Rajapakse, Chandima S K; Jalloh, Dalanda; Dautriche, Cula; Sánchez-Delgado, Roberto A

    2009-08-01

    We have measured water/n-octanol partition coefficients, pK(a) values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium-pi-arene-chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied.

  12. The antimalarial activity of Ru–chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces

    Science.gov (United States)

    Martínez, Alberto; Rajapakse, Chandima S. K.; Jalloh, Dalanda; Dautriche, Cula

    2012-01-01

    We have measured water/n-octanol partition coefficients, pKa values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium–πarene–chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied. PMID:19343380

  13. Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain

    OpenAIRE

    Iwaniuk, Daniel P.; Whetmore, Eric D.; Rosa, Nicholas; Ekoue-Kovi, Kekeli; Alumasa, John; de Dios, Angel C.; Roepe, Paul D.; Wolf, Christian

    2009-01-01

    We report the synthesis and in vitro antimalarial activity of several new 4-amino-and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of P. falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11–15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain st...

  14. Real-time polymerase chain reaction assay for the rapid detection and characterization of chloroquine-resistant Plasmodium falciparum malaria in returned travelers.

    Science.gov (United States)

    Farcas, Gabriella A; Soeller, Rainer; Zhong, Kathleen; Zahirieh, Alireza; Kain, Kevin C

    2006-03-01

    Imported drug-resistant malaria is a growing problem in industrialized countries. Rapid and accurate diagnosis is essential to prevent malaria-associated mortality in returned travelers. However, outside of a limited number of specialized centers, the microscopic diagnosis of malaria is slow, unreliable, and provides little information about drug resistance. Molecular diagnostics have the potential to overcome these limitations. We developed and evaluated a rapid, real-time polymerase chain reaction (PCR) assay to detect Plasmodium falciparum malaria and chloroquine (CQ)-resistance determinants in returned travelers who are febrile. A real-time PCR assay based on detection of the K76T mutation in PfCRT (K76T) of P. falciparum was developed on a LightCycler platform (Roche). The performance characteristics of the real-time assay were compared with those of the nested PCR-restriction fragment-length polymorphism (RFLP) and the sequence analyses of samples obtained from 200 febrile returned travelers, who included 125 infected with P. falciparum (48 of whom were infected CQ-susceptible [K76] and 77 of whom were CQ-resistant [T76] P. falciparum), 22 infected with Plasmodium vivax, 10 infected with Plasmodium ovale, 3 infected with Plasmodium malariae malaria, and 40 infected with other febrile syndromes. All patient samples were coded, and all analyses were performed blindly. The real-time PCR assay detected multiple pfcrt haplotypes associated with CQ resistance in geographically diverse malaria isolates acquired by travelers. Compared with nested-PCR RFLP (the reference standard), the real-time assay was 100% sensitive and 96.2% specific for detection of the P. falciparum K76T mutation. This assay is rapid, sensitive, and specific for the detection and characterization of CQ-resistant P. falciparum malaria in returned travelers. This assay is automated, standardized, and suitable for routine use in clinical diagnostic laboratories.

  15. Cell shunt resistance and photovoltaic module performance

    Energy Technology Data Exchange (ETDEWEB)

    McMahon, T.J.; Basso, T.S.; Rummel, S.R. [National Renewable Energy Lab., Golden, CO (United States)

    1996-05-01

    Shunt resistance of cells in photovoltaic modules can affect module power output and could indicate flawed manufacturing processes and reliability problems. The authors describe a two-terminal diagnostic method to directly measure the shunt resistance of individual cells in a series-connected module non-intrusively, without deencapsulation. Peak power efficiency vs. light intensity was measured on a 12-cell, series-connected, single crystalline module having relatively high cell shunt resistances. The module was remeasured with 0.5-, 1-, and 2-ohm resistors attached across each cell to simulate shunt resistances of several emerging technologies. Peak power efficiencies decreased dramatically at lower light levels. Using the PSpice circuit simulator, the authors verified that cell shunt and series resistances can indeed be responsible for the observed peak power efficiency vs. intensity behavior. The authors discuss the effect of basic cell diode parameters, i.e., shunt resistance, series resistance, and recombination losses, on PV module performance as a function of light intensity.

  16. [Therapeutic response of Plasmodium vivax to chloroquine in Bolivia].

    Science.gov (United States)

    Añez, Arletta; Navarro-Costa, Dennis; Yucra, Omar; Garnica, Cecilia; Melgar, Viviana; Moscoso, Manuel; Arteaga, Ricardo; Nakao, Gladys

    2012-01-01

    Knowledge of the therapeutic efficacy of chloroquine for Plasmodium vivax infections improves the capacity for surveillance of anti-malarial drug resistance. The therapeutic efficacy of chloroquine as treatment was evaluated for uncomplicated Plasmodium vivax malaria in Bolivia. An in vivo efficacy study of chloroquine was undertaken in three regions of Bolivia--Riberalta, Guayaramerín and Yacuiba. Two hundred and twenty-three patients (84, 80, and 59 in the three regions, respectively) aged over 5 years old were administered with chloroquine (25 mg/kg/three days) and followed for 28 days. Blood levels of chloroquine and desethylchloroquine were measured on day 2 and on the day of reappearance of parasitemia. The cumulative incidence of treatment failure was calculated using the Kaplan and Meier survival analysis. The mean parasitemias (asexual) on day 0 were 6,147 parasites/μl of blood in the Riberalta population, 4,251 in Guayaramerín and 5,214 in Yacuiba. The average blood concentrations of chloroquine-desethylchloroquine during day 2 were 783, 817, and 815 ng/ml, respectively. No treatment failures were observed in Yacuiba, whereas in Riberalta and Guayaramerín, the frequencies of treatment failures were 6.2% and 10%. Blood levels of chloroquine and desethylchloroquine in patients with treatment failure showed values below 70 ng/ml on the day of reappearance of parasitemia. Resistance of Plasmodium vivax to chloroquine was not demonstrated in three regions of Bolivia.

  17. PUMA: a puzzle piece in chloroquine?s antimelanoma activity

    OpenAIRE

    Amaravadi, Ravi K.

    2013-01-01

    Chloroquine can induce cell death in a subset of cancer cell lines, and some melanoma cell lines are quite susceptible. While it is well known that chloroquine impairs lysosomal function and can serve as an autophagy inhibitor, the molecular target of chloroquine and the subsequent cascade of events that leads to cell death are not fully understood. Recent evidence indicates that in melanoma cell lines, chloroquine induces apoptosis by preventing degradation of the pro-apoptotic BH3-only prot...

  18. Chloroquine induced parkinsonism.

    Directory of Open Access Journals (Sweden)

    Parmar R

    2000-01-01

    Full Text Available A case of parkinsonism is reported in a 5-years-old male child following prolonged use of chloroquine. The patient presented with reduced spontaneous movements and speech with an expressionless face and a parkinsonian gait but no tremors. His investigations including CT scan brain, CSF study and serum ceruloplasmin were normal. Chloroquine was discontinued and the patient was started on oral trihexyphenidyl. The patient showed gradual recovery and the drug was successfully withdrawn. The toxic manifestations were only transient and reversible.

  19. Cinnamoylated chloroquine analogues: A new structural class of antimalarial agents.

    Science.gov (United States)

    Gayam, Venkatareddy; Ravi, Subban

    2017-07-28

    A novel series of cinnamoylated chloroquine hybrid analogues were synthesized and evaluated as antimalarial agents. The trans cinnamic acid derivatives (3-8) were synthesized by utilizing substituted aldehydes and malanoic acid in DMF catalysed by DABCO. The final cinnamoylated chloroquine analogues (9-14) were synthesized by utilizing DCC coupling reagent. The amido chloroquine (17) was prepared from acid (16) and compound 2 in benzene using SOCl 2 as chlorinating agent. The corresponding ester (15) was prepared from 2-hydroxy acetophenone and 2-bromoacetates in actonitrile in presence of K 2 CO 3  as base followed by basic hydrolysis. The preparation of amide based chloroquine-chalcone analogues (18-22), were obtained by the combination of amido chloroquine (17) and aldehydes in 10% aq. KOH in methanol at room temperature. Further we prepared epichlorohydrin based chloroquine-chalcone analogues (25-28), by reacting the epoxide (24a, 24b and 24c) with 2 and methelenedioxy aniline. In vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant strain K1 of P. falciparum and in vitro cytotoxicity of compounds using VERO cell line was carried out. The synthesized molecules showed significant in vitro antimalarial activity especially against CQ resistant strain (K1). Among tested compounds, 13, 9 and 10 were found to be the most potent compounds of the series with IC 50 value of 44.06, 48.04 and 59.37 nM against chloroquine resistant K1 strain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  20. 4-Aminoquinoline derivatives: Synthesis, in vitro and in vivo antiplasmodial activity against chloroquine-resistant parasites.

    Science.gov (United States)

    Singh, Shailja; Agarwal, Drishti; Sharma, Kumkum; Sharma, Manish; Nielsen, Morten A; Alifrangis, Michael; Singh, Ashok K; Gupta, Rinkoo D; Awasthi, Satish K

    2016-10-21

    Synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against CQ-resistant strains of malaria even after the widespread emergence of resistance to CQ. In this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against Plasmodium falciparum under in vitro conditions. Further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial potential against Plasmodium berghei in vivo. These 4-aminoquinolines cured BALB/c mice infected with P. berghei. The ED50 values were calculated to be 2.062, 2.231, 1.431, 1.623 and 1.18 mg/kg of body weight for each of the compounds 1m, 1o, 2c, 2j and amodiaquine, respectively. Total doses of 500 mg/kg of body weight were well received. The study suggests that these new 4-aminoquinolines should be used for structure activity relationship to find lead molecules for treating multidrug-resistant Plasmodium falciparum and Plasmodium vivax. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Chloroquine is a zinc ionophore.

    Directory of Open Access Journals (Sweden)

    Jing Xue

    Full Text Available Chloroquine is an established antimalarial agent that has been recently tested in clinical trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780. Chloroquine enhanced zinc uptake by A2780 cells in a concentration-dependent manner, as assayed using a fluorescent zinc probe. This enhancement was attenuated by TPEN, a high affinity metal-binding compound, indicating the specificity of the zinc uptake. Furthermore, addition of copper or iron ions had no effect on chloroquine-induced zinc uptake. Fluorescent microscopic examination of intracellular zinc distribution demonstrated that free zinc ions are more concentrated in the lysosomes after addition of chloroquine, which is consistent with previous reports showing that chloroquine inhibits lysosome function. The combination of chloroquine with zinc enhanced chloroquine's cytotoxicity and induced apoptosis in A2780 cells. Thus chloroquine is a zinc ionophore, a property that may contribute to chloroquine's anticancer activity.

  2. Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine

    OpenAIRE

    Fogh, S; Schapira, A; Bygbjerg, I C; Jepsen, S; Mordhorst, C H; Kuijlen, K; Ravn, P; Rønn, A; Gøtzsche, P C

    1988-01-01

    As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared with the efficacy of chloroquine 500 mg weekly with sulfadoxine 500 mg-pyrimethamine 25 mg weekly in a randomised study of Scandinavian travellers to Kenya and Tanzania during 1984-5. A total of 767 subjects (416 ...

  3. High frequency of Plasmodium falciparum chloroquine resistance marker (pfcrt T76 mutation) in Yemen: an urgent need to re-examine malaria drug policy.

    Science.gov (United States)

    Al-Mekhlafi, Abdulsalam M; Mahdy, Mohammed A K; Al-Mekhlafi, Hesham M; Azazy, Ahmed A; Fong, Mun Yik

    2011-05-27

    Malaria remains a significant health problem in Yemen with Plasmodium falciparum being the predominant species which is responsible for 90% of the malaria cases. Despite serious concerns regarding increasing drug resistance, chloroquine is still used for the prevention and treatment of malaria in Yemen. This study was carried out to determine the prevalence of choloroquine resistance (CQR) of P. falciparum isolated from Yemen based on the pfcrt T76 mutation. A cross-sectional study was carried out among 511 participants from four governorates in Yemen. Blood samples were screened using microscopic and species-specific nested PCR based on the 18S rRNA gene to detect and identify Plasmodium species. Blood samples positive for P. falciparum were used for detecting the pfcrt T76 mutation using nested-PCR. The prevalence of pfcrt T76 mutation was 81.5% (66 of 81 isolates). Coastal areas/foothills had higher prevalence of pfcrt T76 mutation compared to highland areas (90.5% vs 71.8%) (p = 0.031). The pfcrt T76 mutation had a significant association with parasitaemia (p = 0.045). Univariate analysis shows a significant association of pfcrt T76 mutation with people aged > 10 years (OR = 9, 95% CI = 2.3 - 36.2, p = 0.001), low household income (OR = 5, 95% CI = 1.3 - 19.5, p = 0.027), no insecticide spray (OR = 3.7, 95% CI = 1.16 - 11.86, p = 0.025) and not sleeping under insecticide treated nets (ITNs) (OR = 4.8, 95% CI = 1.38 - 16.78, p = 0.01). Logistic regression model confirmed age > 10 years and low household income as predictors of pfcrt T76 mutation in Yemen P. falciparum isolates. The high prevalence of pfcrt T76 mutation in Yemen could be a predictive marker for the prevalence of P. falciparum CQR. This finding shows the necessity for an in-vivo therapeutic efficacy test for CQ. P. falciparum CQR should be addressed in the national strategy to control malaria.

  4. The efficacy of sulfadoxine-pyrimethamine alone and in combination with chloroquine for malaria treatment in rural Eastern Sudan: the interrelation between resistance, age and gametocytogenesis

    DEFF Research Database (Denmark)

    A-Elbasit, Ishraga E; Elbashir, Mustafa I; Khalil, Insaf F

    2006-01-01

    OBJECTIVE: To compare the efficacy of sulfadoxine-pyremethamine (SP)+chloroquine (CQ) combination treatment against falciparum malaria with SP treatment alone. METHOD: In-vivo study of 254 patients with uncomplicated Plasmodium falciparum malaria in rural eastern Sudan, where the population is semi...

  5. MITF Modulates Therapeutic Resistance through EGFR Signaling.

    Science.gov (United States)

    Ji, Zhenyu; Erin Chen, Yiyin; Kumar, Raj; Taylor, Michael; Jenny Njauw, Ching-Ni; Miao, Benchun; Frederick, Dennie T; Wargo, Jennifer A; Flaherty, Keith T; Jönsson, Göran; Tsao, Hensin

    2015-07-01

    Response to targeted therapies varies significantly despite shared oncogenic mutations. Nowhere is this more apparent than in BRAF (V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace. Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs), although the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR-induced vemurafenib resistance is ligand dependent. We employed whole-genome expression analysis and discovered that vemurafenib resistance correlated with the loss of microphthalmia-associated transcription factor (MITF), along with its melanocyte lineage program, and with the activation of EGFR signaling. An inverse relationship between MITF, vemurafenib resistance, and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients' tumor specimens. Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype. In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors. These findings indicate that an "autocrine drug resistance loop" is suppressed by melanocyte lineage signal(s), such as MITF. This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition.

  6. Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain.

    Science.gov (United States)

    Iwaniuk, Daniel P; Whetmore, Eric D; Rosa, Nicholas; Ekoue-Kovi, Kekeli; Alumasa, John; de Dios, Angel C; Roepe, Paul D; Wolf, Christian

    2009-09-15

    We report the synthesis and in vitro antimalarial activity of several new 4-amino- and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of Plasmodium falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11-15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain structure proved detrimental to the activity against the CQR strain.

  7. Efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria: revisiting molecular markers in an area of emerging AQ and SP resistance in Mali

    Directory of Open Access Journals (Sweden)

    Wele Mamadou

    2009-02-01

    Full Text Available Abstract Background To update the National Malaria Control Programme of Mali on the efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria. Methods During the malaria transmission seasons of 2002 and 2003, 455 children – between six and 59 months of age, with uncomplicated malaria in Kolle, Mali, were randomly assigned to one of three treatment arms. In vivo outcomes were assessed using WHO standard protocols. Genotyping of msp1, msp2 and CA1 polymorphisms were used to distinguish reinfection from recrudescent parasites (molecular correction. Results Day 28 adequate clinical and parasitological responses (ACPR were 14.1%, 62.3% and 88.9% in 2002 and 18.2%, 60% and 85.2% in 2003 for chloroquine, amodiaquine and sulphadoxine-pyrimethamine, respectively. After molecular correction, ACPRs (cACPR were 63.2%, 88.5% and 98.0% in 2002 and 75.5%, 85.2% and 96.6% in 2003 for CQ, AQ and SP, respectively. Amodiaquine was the most effective on fever. Amodiaquine therapy selected molecular markers for chloroquine resistance, while in the sulphadoxine-pyrimethamine arm the level of dhfr triple mutant and dhfr/dhps quadruple mutant increased from 31.5% and 3.8% in 2002 to 42.9% and 8.9% in 2003, respectively. No infection with dhps 540E was found. Conclusion In this study, treatment with sulphadoxine-pyrimethamine emerged as the most efficacious on uncomplicated falciparum malaria followed by amodiaquine. The study demonstrated that sulphadoxine-pyrimethamine and amodiaquine were appropriate partner drugs that could be associated with artemisinin derivatives in an artemisinin-based combination therapy.

  8. Similar efficacy and tolerability of double-dose chloroquine and artemether-lumefantrine for treatment of Plasmodium falciparum infection in Guinea-Bissau: a randomized trial

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia

    2011-01-01

    In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele,......, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine.......In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele...

  9. Chloroquine is grossly overdosed and overused but well tolerated in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia

    2009-01-01

    High chloroquine doses are commonly prescribed in Guinea-Bissau. Double dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed and it is not known if the high doses prescribed in Guinea-Bissau are t...... prescribed to children without parasitaemia. Use of high dose CQ is concurrent with an exceptionally low prevalence of chloroquine resistant P. falciparum.......High chloroquine doses are commonly prescribed in Guinea-Bissau. Double dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed and it is not known if the high doses prescribed in Guinea......-Bissau are taken or whether they cause adverse effects. We aimed to determine the dosage of chloroquine commonly prescribed, the doses commonly taken and if there were concentration dependent adverse events in routine practice. Chloroquine prescriptions by 8 physicians and chloroquine intake by 102 children were...

  10. High-Affinity Accumulation of Chloroquine by Mouse Erythrocytes Infected with Plasmodium berghei

    Science.gov (United States)

    Fitch, Coy D.; Yunis, Norman G.; Chevli, Rekha; Gonzalez, Yolanda

    1974-01-01

    Washed erythrocytes infected with chloroquine-susceptible (CS) or with chloroquine-resistant (CR) P. berghei were used in model systems in vitro to study the accumulation of chloroquine with high affinity. The CS model could achieve distribution ratios (chloroquine in cells: chloroquine in medium) of 100 in the absence of substrate. 200—300 in the presence of 10 mM pyruvate or lactate, and over 600 in the presence of 1 mM glucose or glycerol. In comparable studies of the CR model, the distribution ratios were 100 in the absence of substrate and 300 or less in the presence of glucose or glycerol. The presence of lactate stimulated chloroquine accumulation in the CR model, whereas the presence of pyruvate did not. Lactate production from glucose and glycerol was undiminished in the CR model, and ATP concentrations were higher than in the CS model. Cold, iodoacetate, 2,4-dinitrophenol, or decreasing pH inhibited chloroquine accumulation in both models. These findings demonstrate substrate involvement in the accumulation of chloroquine with high affinity. In studies of the CS model, certain compounds competitively inhibited chloroquine accumulation, while others did not. This finding is attributable to a specific receptor that imposes structural constraints on the process of accumulation. For chloroquine analogues, the position and length of the side chain, the terminal nitrogen atom of the side chain, and the nitrogen atom in the quinoline ring are important determinants of binding to this receptor. PMID:4600044

  11. Enhanced lysosomal acidification leads to increased chloroquine accumulation in CHO cells expressing the pfmdr1 gene

    NARCIS (Netherlands)

    van Es, H. H.; Renkema, H.; Aerts, H.; Schurr, E.

    1994-01-01

    Expression of the pfmdr1-encoded Pgh1 protein of Plasmodium falciparum in CHO cells confers a phenotype of increased sensitivity to chloroquine due to an increased Pgh1-mediated accumulation of this antimalarial. Pgh1 carrying amino acid substitutions associated with chloroquine resistance in P.

  12. A series of structurally simple chloroquine chemosensitizing dibemethin derivatives that inhibit chloroquine transport by PfCRT.

    Science.gov (United States)

    Zishiri, Vincent K; Hunter, Roger; Smith, Peter J; Taylor, Dale; Summers, Robert; Kirk, Kiaran; Martin, Rowena E; Egan, Timothy J

    2011-05-01

    A series of 12 new dibemethin (N-benzyl-N-methyl-1-phenylmethanamine) derivatives bearing an N-aminomethyl group attached to the one phenyl ring and an H, Cl, OCH3 or N(CH3)2 group on the other have been synthesized. These compounds all showed strong chloroquine chemosensitizing activity, comparable to verapamil, when present at 1 μM in an in vitro culture of the chloroquine-resistant W2 strain of the human malaria parasite, Plasmodium falciparum. Their N-formylated derivatives also exhibited resistance-reversing activity, but only at substantially higher IC10 concentrations. A number of the dibemethin derivatives were shown to inhibit chloroquine transport via the parasite's 'chloroquine resistance transporter' (PfCRT) in a Xenopus laevis oocyte expression system. The reduced resistance-reversing activity of the formylated compounds relative to their free amine counterparts can probably be ascribed to two factors: decreased accumulation of the formylated dibemethins within the parasite's internal digestive vacuole (believed to be the site of action of chloroquine), and a reduced ability to inhibit PfCRT. The resistance-reversing activity of the compounds described here demonstrates that the amino group need not be attached to the two aromatic rings via a three or four carbon chain as has been suggested by previous QSAR studies. These compounds may be useful as potential side chains for attaching to a 4,7-dichloroquinoline group in order to generate new resistance-reversing chloroquine analogues with inherent antimalarial activity. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  13. Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine

    DEFF Research Database (Denmark)

    Fogh, S; Schapira, A; Bygbjerg, Ib Christian

    1988-01-01

    As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared...... with the efficacy of chloroquine 500 mg weekly with sulfadoxine 500 mg-pyrimethamine 25 mg weekly in a randomised study of Scandinavian travellers to Kenya and Tanzania during 1984-5. A total of 767 subjects (416 male and 351 female; 384 taking chloroquine phosphate with proguanil hydrochloride and 383 taking...... chloroquine with sulfadoxine-pyrimethamine) completed a diary on the breakthrough of malaria and the side effects of treatment while taking the drugs. They were also asked to make thick blood films when symptoms like those of malaria occurred, which were sent to and analysed in Denmark. Four subjects taking...

  14. Chloroquine: novel uses & manifestations.

    Science.gov (United States)

    Cooper, R G; Magwere, T

    2008-04-01

    Chloroquine (CHQ) is a cheap, relatively well tolerated drug initially developed for the treatment of malaria in the 1930s. CHQ has, however, since accrued a plethora of uses in the treatment and amelioration of several other diseases and conditions because of its lysosomotropic properties. It also has characteristic physiological and systemic effects. This review gives an overview of the history and pharmacology of CHQ, and progresses to consider some of the mechanisms that may underlie its biochemical and physiological effects. Additionally, an overview of some of the novel uses of CHQ in the treatment of viral infections and cancer are presented. The antimalarial mechanisms of CHQ were not discussed in this review. The message is that CHQ, despite its welldocumented toxicity and adverse side effects may have important future uses that are associated with its lysosomotropic and immunomodulatory mechanisms. The possibility exists therefore that CHQ might be re-introduced into regular malaria treatment.

  15. A study of the uptake of chloroquine in malaria-infected erythrocytes. High and low affinity uptake and the influence of glucose and its analogues.

    Science.gov (United States)

    Diribe, C O; Warhurst, D C

    1985-09-01

    A study of concentration- and substrate-dependence of chloroquine uptake has been carried out on mouse erythrocytes infected with the chloroquine-sensitive NK65 and the chloroquine-resistant RC strains of Plasmodium berghei. The presence of drug binding sites of high and low affinity in such strains of P. berghei was confirmed. High affinity uptake sites in cells parasitized with chloroquine-sensitive and chloroquine-resistant parasites have similar characteristics, but in the sensitive strain the major component of chloroquine-uptake is at high affinity and dependent on the availability of ATP whilst in the resistant strain the major component of uptake is at low affinity and independent of energy. An absolute increase in the quantity of the low affinity site in erythrocytes parasitized with chloroquine-resistant P. berghei was noted, which may be related to an increase in quantity of parasite membrane.

  16. Synthesis of chiral chloroquine and its analogues as antimalarial agents.

    Science.gov (United States)

    Sinha, Manish; Dola, Vasanth R; Soni, Awakash; Agarwal, Pooja; Srivastava, Kumkum; Haq, Wahajul; Puri, Sunil K; Katti, Seturam B

    2014-11-01

    In this investigation, we describe a new approach to chiral synthesis of chloroquine and its analogues. All tested compounds displayed potent activity against chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum in vitro and Plasmodium yoelii in vivo. Compounds S-13 b, S-13c, S-13 d and S-13 i displayed excellent in vitro antimalarial activity with an IC50 value of 56.82, 60.41, 21.82 and 7.94 nM, respectively, in the case of resistant strain. Furthermore, compounds S-13a, S-13c and S-13 d showed in vivo suppression of 100% parasitaemia on day 4 in the mouse model against Plasmodium yoelii when administered orally. These results underscore the application of synthetic methodology and need for further lead optimization. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Metallocene-based antimalarials: an exploration into the influence of the ferrocenyl moiety on in vitro antimalarial activity in chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum.

    Science.gov (United States)

    Blackie, Margaret A L; Beagley, Paul; Croft, Simon L; Kendrick, Howard; Moss, John R; Chibale, Kelly

    2007-10-15

    To establish the role of the ferrocenyl moiety in the antiplasmodial activity of ferroquine, compounds in which this moiety is replaced by the corresponding ruthenium-based moieties were synthesized and evaluated. In both the sensitive (D10) and resistant (K1) strains of Plasmodium falciparum, ruthenoquine analogues showed comparable potency to ferroquine. This suggests that a probable role of the ferrocenyl fragment is to serve simply as a hydrophobic spacer group. In addition, ferroquine analogues with different aromatic substituents were synthesized and evaluated. Unexpectedly high activity for quinoline compounds lacking the 7-chloro substituent suggests the ferrocenyl moiety may have an additive and/or synergistic effect.

  18. A longitudinal trial comparing chloroquine as monotherapy or in combination with artesunate, azithromycin or atovaquone-proguanil to treat malaria.

    Directory of Open Access Journals (Sweden)

    Miriam K Laufer

    Full Text Available The predominance of chloroquine-susceptible falciparum malaria in Malawi more than a decade after chloroquine's withdrawal permits contemplation of re-introducing chloroquine for targeted uses. We aimed to compare the ability of different partner drugs to preserve chloroquine efficacy and prevent the re-emergence of resistance.Children with uncomplicated malaria were enrolled at a government health center in Blantyre, Malawi. Participants were randomized to receive chloroquine alone or combined with artesunate, azithromycin or atovaquone-proguanil for all episodes of uncomplicated malaria for one year. The primary outcome was incidence of clinical malaria. Secondary endpoints included treatment efficacy, and incidence of the chloroquine resistance marker pfcrt T76 and of anemia. Of the 640 children enrolled, 628 were included in the intention-to-treat analysis. Malaria incidence (95% confidence interval was 0.59 (.46-.74, .61 (.49-.76, .63 (.50-.79 and .68 (.54-.86 episodes/person-year for group randomized to receive chloroquine alone or in combination with artesunate, azithromycin or atovaquone-proguanil respectively and the differences were not statistically significant. Treatment efficacy for first episodes was 100% for chloroquine monotherapy and 97.9% for subsequent episodes of malaria. Similar results were seen in each of the chloroquine combination groups. The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in two out of 911 infections. Young children treated with chloroquine-azithromycin had higher hemoglobin concentrations at the study's end than did those in the chloroquine monotherapy group.Sustained chloroquine efficacy with repeated treatment supports the eventual re-introduction of chloroquine combinations for targeted uses such as intermittent preventive treatment.ClinicalTrials.gov NCT00379821.

  19. A longitudinal trial comparing chloroquine as monotherapy or in combination with artesunate, azithromycin or atovaquone-proguanil to treat malaria.

    Science.gov (United States)

    Laufer, Miriam K; Thesing, Phillip C; Dzinjalamala, Fraction K; Nyirenda, Osward M; Masonga, Rhoda; Laurens, Matthew B; Stokes-Riner, Abbie; Taylor, Terrie E; Plowe, Christopher V

    2012-01-01

    The predominance of chloroquine-susceptible falciparum malaria in Malawi more than a decade after chloroquine's withdrawal permits contemplation of re-introducing chloroquine for targeted uses. We aimed to compare the ability of different partner drugs to preserve chloroquine efficacy and prevent the re-emergence of resistance. Children with uncomplicated malaria were enrolled at a government health center in Blantyre, Malawi. Participants were randomized to receive chloroquine alone or combined with artesunate, azithromycin or atovaquone-proguanil for all episodes of uncomplicated malaria for one year. The primary outcome was incidence of clinical malaria. Secondary endpoints included treatment efficacy, and incidence of the chloroquine resistance marker pfcrt T76 and of anemia. Of the 640 children enrolled, 628 were included in the intention-to-treat analysis. Malaria incidence (95% confidence interval) was 0.59 (.46-.74), .61 (.49-.76), .63 (.50-.79) and .68 (.54-.86) episodes/person-year for group randomized to receive chloroquine alone or in combination with artesunate, azithromycin or atovaquone-proguanil respectively and the differences were not statistically significant. Treatment efficacy for first episodes was 100% for chloroquine monotherapy and 97.9% for subsequent episodes of malaria. Similar results were seen in each of the chloroquine combination groups. The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in two out of 911 infections. Young children treated with chloroquine-azithromycin had higher hemoglobin concentrations at the study's end than did those in the chloroquine monotherapy group. Sustained chloroquine efficacy with repeated treatment supports the eventual re-introduction of chloroquine combinations for targeted uses such as intermittent preventive treatment. ClinicalTrials.gov NCT00379821.

  20. Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine.

    Science.gov (United States)

    Fogh, S; Schapira, A; Bygbjerg, I C; Jepsen, S; Mordhorst, C H; Kuijlen, K; Ravn, P; Rønn, A; Gøtzsche, P C

    1988-03-19

    As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared with the efficacy of chloroquine 500 mg weekly with sulfadoxine 500 mg-pyrimethamine 25 mg weekly in a randomised study of Scandinavian travellers to Kenya and Tanzania during 1984-5. A total of 767 subjects (416 male and 351 female; 384 taking chloroquine phosphate with proguanil hydrochloride and 383 taking chloroquine with sulfadoxine-pyrimethamine) completed a diary on the breakthrough of malaria and the side effects of treatment while taking the drugs. They were also asked to make thick blood films when symptoms like those of malaria occurred, which were sent to and analysed in Denmark. Four subjects taking chloroquine with proguanil hydrochloride and three taking chloroquine with sulfadoxine-pyrimethamine developed falciparum malaria, which was verified microscopically. Side effects were reported by 36 subjects taking chloroquine phosphate with proguanil hydrochloride and 55 taking the other regimen (p = 0.043). The side effects of both regimens were generally mild, but the combination of chloroquine phosphate with proguanil hydrochloride is recommended because it results in fewer side effects. As breakthroughs of malaria occurred at the earliest after seven weeks self treatment should not be recommended for travellers staying only a short time. Thick blood films are useful for diagnosis of suspected cases of malaria, can be prepared by non-specialists in Africa, and can be analysed successfully after long delays.

  1. Options for modulation of drug resistance in ovarian cancer

    NARCIS (Netherlands)

    Arts, HJG; Van der Zee, AGJ; De Jong, S; De Vries, EGE

    2000-01-01

    The objective of this paper is to present an update of mechanisms responsible for drug resistance in ovarian cancer and the possible therapeutic options to modulate this resistance using literature review with emphasis on data acquired in studies comprising ovarian tumor samples. The classic

  2. COMBINED INVITRO MODULATION OF ADRIAMYCIN RESISTANCE

    NARCIS (Netherlands)

    MEIJER, C; MULDER, NH; TIMMERBOSSCHA, H; PETERS, WHM; DEVRIES, EGE

    1991-01-01

    In a P-glycoprotein-negative cell line, GLC4-Adr90, a 75-fold acquired Adriamycin (Adr) resistance coincided with a reduced cellular Adr level, an increased detoxifying capacity (glutathione (GSH) and glutathione S-transferase (GST) elevated), and a reduced topoisomerase-II (topo-II) activity

  3. Modulation of leptin resistance by food compounds.

    Science.gov (United States)

    Aragonès, Gerard; Ardid-Ruiz, Andrea; Ibars, Maria; Suárez, Manuel; Bladé, Cinta

    2016-08-01

    Leptin is mainly secreted by white adipose tissue and regulates energy homeostasis by inhibiting food intake and stimulating energy expenditure through its action in neuronal circuits in the brain, particularly in the hypothalamus. However, hyperleptinemia coexists with the loss of responsiveness to leptin in common obese conditions. This phenomenon has been defined as leptin resistance and the restoration of leptin sensitivity is considered to be a useful strategy to treat obesity. This review summarizes the existing literature on potentially valuable nutrients and food components to reverse leptin resistance. Notably, several food compounds, such as teasaponins, resveratrol, celastrol, caffeine, and taurine among others, are able to restore the leptin signaling in neurons by overexpressing anorexigenic peptides (proopiomelanocortin) and/or repressing orexigenic peptides (neuropeptide Y/agouti-related peptide), thus decreasing food intake. Additionally, some nutrients, such as vitamins A and D, can improve leptin transport through the blood-brain barrier. Therefore, food components can improve leptin resistance by acting at different levels of the leptin pathway; moreover, some compounds are able to target more than one feature of leptin resistance. However, systematic studies are necessary to define the actual effectiveness of each compound. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. NMSBA - Twist Resist - Rotational Exercise Module

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Aaron [Twist Resist, Albuquerque, NM (United States); Reece, Blake D. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Berger, Jason E. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Guido, Steven Frank [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Linker, Taylor [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2016-08-01

    This report contains a summary of the work completed to develop a modular, rotational exercise device. In the report are images, diagrams, and explanations of the efforts contributed to the project since its inception. The purpose of this document is to provide a walk-through of the progress on this project, from the initial design concepts to the final design and work done, so that the customer (Twist Resist), or individuals/firms who work on this project in the future will have a springboard of ideas/concepts to work from.

  5. Effect of chloroquine on human lymphocyte proliferation

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Flachs, H

    1986-01-01

    The effect of chloroquine on human blood mononuclear cells was studied. High concentrations of chloroquine in vitro profoundly suppressed the proliferation of mitogen- and antigen-stimulated cells, as indicated by decreased 14C-thymidine incorporation. Lower concentrations of chloroquine increase...... to large particulate antigens; the response to small antigens was not affected. The mode of action of chloroquine and the possible consequences of the findings for dosage of chloroquine when used for malaria prophylaxis is discussed.......The effect of chloroquine on human blood mononuclear cells was studied. High concentrations of chloroquine in vitro profoundly suppressed the proliferation of mitogen- and antigen-stimulated cells, as indicated by decreased 14C-thymidine incorporation. Lower concentrations of chloroquine increased...... the response to pokeweed mitogen. The response to concanavalin A and to various antigens was suppressed, especially the response to large particulate antigens. Oral intake of 300 mg of chloroquine base/week did not affect the lymphocyte proliferative responses. 600 mg of base/week decreased the response...

  6. Antiplasmodial activity of novel keto-enamine chalcone-chloroquine based hybrid pharmacophores.

    Science.gov (United States)

    Sashidhara, Koneni V; Kumar, Manoj; Modukuri, Ram K; Srivastava, Rajeev Kumar; Soni, Awakash; Srivastava, Kumkum; Singh, Shiv Vardan; Saxena, J K; Gauniyal, Harsh M; Puri, Sunil K

    2012-05-01

    A series of novel keto-enamine chalcone-chloroquine based hybrids were synthesized following new methodology developed in our laboratory. The synthesized compounds were screened against chloroquine sensitive strain (3D7) of Plasmodium falciparum in an in vitro model. Some of the compounds were showing comparable antimalarial activity at par with chloroquine. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii (chloroquine resistant N-67 strain), wherein compounds 25 and 27 each showed an in vivo suppression of 99.9% parasitaemia on day 4. Biochemical studies reveal that inhibition of hemozoin formation is the primary mechanism of action of these analogues. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Antimalarial activity of 4-(5-trifluoromethyl-1H-pyrazol-1-yl)-chloroquine analogues.

    Science.gov (United States)

    Cunico, Wilson; Cechinel, Cleber A; Bonacorso, Helio G; Martins, Marcos A P; Zanatta, Nilo; de Souza, Marcus V N; Freitas, Isabela O; Soares, Rodrigo P P; Krettli, Antoniana U

    2006-02-01

    The antimalarial activity of chloroquine-pyrazole analogues, synthesized from the reaction of 1,1,1-trifluoro-4-methoxy-3-alken-2-ones with 4-hydrazino-7-chloroquinoline, has been evaluated in vitro against a chloroquine resistant Plasmodium falciparum clone. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]hypoxanthine in comparison to controls with no drugs. All but one of the eight (4,5-dihydropyrazol-1-yl) chloroquine 2 derivatives tested showed a significant activity in vitro, thus, are a promising new class of antimalarials. The three most active ones were also tested in vivo against Plasmodium berghei in mice. However, the (pyrazol-1-yl) chloroquine 3 derivatives were mostly inactive, suggesting that the aromatic functionality of the pyrazole ring was critical.

  8. A new class of potential chloroquine-resistance reversal agents for Plasmodia: syntheses and biological evaluation of 1-(3'-diethylaminopropyl)-3-(substituted phenylmethylene)pyrrolidines.

    Science.gov (United States)

    Batra, S; Srivastava, P; Roy, K; Pandey, V C; Bhaduri, A P

    2000-09-07

    1-(3'-Diethylaminopropyl)-3-(substituted phenylmethylene)pyrrolidines were synthesized and evaluated for CQ-resistant reversal activity. In general the compounds of the series elicit better biological response than their phenylmethyl analogues. The most active compound 4b has been evaluated in vivo in detail, and the results are presented. The possible mode of action of the compounds of this series is by inhibition of the enzyme heme oxygenase, thereby increasing the levels of heme and hemozoin, which are lethal to the parasite.

  9. Serum testosterone concentration in chloroquine- treated rats ...

    African Journals Online (AJOL)

    ONOS

    2010-07-05

    Jul 5, 2010 ... The effects of ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) were studied on serum testosterone ... chloroquine are probably mediated via the generation of free radicals. ... Effects of ascorbic acid and alpha-tocopherol on serum testosterone concentration in chloroquine-treated rats. Groups.

  10. Chloroquine induced pruritus - questionnaire based epidemiological ...

    African Journals Online (AJOL)

    Chloroquine (CQ) is a very useful drug with a broad spectrum of uses (as anti malarial, anti amoebiasis and for connective tissue diseases). A major side effect preventing or limiting its utilization in blacks is chloroquine induced pruritus (CP). A descriptive cross sectional questionnaire based epidemiological study of ...

  11. Radiation resistance of electro-optic polymer-based modulators

    International Nuclear Information System (INIS)

    Taylor, Edward W.; Nichter, James E.; Nash, Fazio D.; Haas, Franz; Szep, Attila A.; Michalak, Richard J.; Flusche, Brian M.; Cook, Paul R.; McEwen, Tom A.; McKeon, Brian F.; Payson, Paul M.; Brost, George A.; Pirich, Andrew R.; Castaneda, Carlos; Tsap, Boris; Fetterman, Harold R.

    2005-01-01

    Mach-Zehnder interferometric electro-optic polymer modulators composed of highly nonlinear phenyltetraene bridge-type chromophores within an amorphous polycarbonate host matrix were investigated for their resistance to gamma rays and 25.6 MeV protons. No device failures were observed and the majority of irradiated modulators exhibited decreases in half-wave voltage and optical insertion losses compared to nonirradiated control samples undergoing aging processes. Irradiated device responses were attributed to scission, cross-linking, and free volume processes. The data suggests that strongly poled devices are less likely to de-pole under the influence of ionizing radiation

  12. Module Five: Relationships of Current, Voltage, and Resistance; Basic Electricity and Electronics Individualized Learning System.

    Science.gov (United States)

    Bureau of Naval Personnel, Washington, DC.

    This module covers the relationships between current and voltage; resistance in a series circuit; how to determine the values of current, voltage, resistance, and power in resistive series circuits; the effects of source internal resistance; and an introduction to the troubleshooting of series circuits. This module is divided into five lessons:…

  13. Psychiatric adverse effects of chloroquine

    OpenAIRE

    Anna Bogaczewicz; Tomasz Sobów

    2017-01-01

    Chloroquine is a prototype antimalarial drug, widely used in several branches of medicine. Antimalarial drugs are used in the treatment of various dermatological, immunological, rheumatological and infectious diseases. Examples of off-labelled indications for chloroquine analogues use include dermatomyositis, sarcoidosis, polymorphous light eruption, disseminated granuloma annulare and porfiria cutanea tarda. There is a relatively small number of adverse effects related to chloroquine anal...

  14. PUMA: a puzzle piece in chloroquine's antimelanoma activity.

    Science.gov (United States)

    Amaravadi, Ravi K

    2013-09-01

    Chloroquine (CQ) can induce cell death in a subset of cancer cell lines, and some melanoma cell lines are quite susceptible. Although it is well known that CQ impairs lysosomal function and can serve as an autophagy inhibitor, the molecular target of CQ and the subsequent cascade of events that lead to cell death are not fully understood. Recent evidence indicates that in melanoma cell lines, CQ induces apoptosis by preventing degradation of the pro-apoptotic BH3-only protein p53-upregulated modulator of apoptosis. This finding adds to the unfolding story of CQ's mechanism of action as a cancer therapeutic agent.

  15. Chloroquine use improves dengue-related symptoms

    Directory of Open Access Journals (Sweden)

    Marcos Carvalho Borges

    2013-08-01

    Full Text Available Dengue is the most important arboviral disease in the world. As chloroquine, an antimalarial agent, has shown some antiviral effects, this study evaluated its effect in patients with dengue. A randomised, double-blind study was performed by administering chloroquine or placebo for three days to 129 patients with dengue-related symptoms. Of these patients, 37 were confirmed as having dengue and completed the study; in total, 19 dengue patients received chloroquine and 18 received placebo. There was no significant difference in the duration of the disease or the degree and days of fever. However, 12 patients (63% with confirmed dengue reported a substantial decrease in pain intensity and a great improvement in their ability to perform daily activities (p = 0.0004 while on the medication and the symptoms returned immediately after these patients stopped taking the medication. The same effect was not observed in patients with diseases other than dengue. Therefore, this study shows that patients with dengue treated with chloroquine had an improvement in their quality of life and were able to resume their daily activities. However, as chloroquine did not alter the duration of the disease or the intensity and days of fever, further studies are necessary to confirm the clinical effects and to assess the side effects of chloroquine in dengue patients.

  16. Vanillin selectively modulates the action of antibiotics against resistant bacteria.

    Science.gov (United States)

    Bezerra, Camila Fonseca; Camilo, Cicera Janaine; do Nascimento Silva, Maria Karollyna; de Freitas, Thiago Sampaio; Ribeiro-Filho, Jaime; Coutinho, Henrique Douglas Melo

    2017-12-01

    The treatment of infections caused by microorganisms that are resistant to antibiotics represent one of the main challenges of medicine today, especially due to the inefficacy of long-term drug therapy. In the search for new alternatives to treat these infections, many researchers have been looking for new substances derived from natural products to replace, or be used in combination with conventional antibiotics. Vanillin is a phenolic compound whose antimicrobial activity has been used in the elimination of pathogens present in fruits and vegetables. However, its antibacterial and modulating properties remain to be characterized. Therefore, this work aimed to evaluate the antibacterial activity and analyze the modulator activity of vanillin in association with conventional antibiotics. The antimicrobial activity of vanillin was evaluated using the microdilution method to determine the Minimum Inhibitory Concentration (MIC) Standard strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and multi-resistant strains of Escherichia coli 06, Staphylococcus aureus 10, Pseudomonas aeruginosa 24 were used in this study. The antibiotic modulating effect was analyzed by combining vanillin with Norfloxacin, Imipenem, Gentamicin, Erythromycin and Tetracycline against the following multiresistant bacteria strains: Escherichia coli 06, Staphylococcus aureus 10 and Pseudomonas aeruginosa 24. Data were analyzed using the ANOVA test of two tracks followed by the post hoc Bonferroni test. Vanillin presented CIMs ≥1024μg/mL against all tested strains demonstrating that it did not present significant antibacterial activity. However, modulated the activity of gentamicin and imipenem against S. aureus and E. coli, causing a synergistic effect, but did not affect the activity of norfloxacin, tetracycline and erythromycin against these same microorganisms. A synergistic effect was also obtained from the association of vanillin with norfloxacin against P

  17. Arterial Stiffness and Autonomic Modulation After Free-Weight Resistance Exercises in Resistance Trained Individuals.

    Science.gov (United States)

    Kingsley, J Derek; Mayo, Xián; Tai, Yu Lun; Fennell, Curtis

    2016-12-01

    Kingsley, JD, Mayo, X, Tai, YL, and Fennell, C. Arterial stiffness and autonomic modulation after free-weight resistance exercises in resistance trained individuals. J Strength Cond Res 30(12): 3373-3380, 2016-We investigated the effects of an acute bout of free-weight, whole-body resistance exercise consisting of the squat, bench press, and deadlift on arterial stiffness and cardiac autonomic modulation in 16 (aged 23 ± 3 years; mean ± SD) resistance-trained individuals. Arterial stiffness, autonomic modulation, and baroreflex sensitivity (BRS) were assessed at rest and after 3 sets of 10 repetitions at 75% 1-repetition maximum on each exercise with 2 minutes of rest between sets and exercises. Arterial stiffness was analyzed using carotid-femoral pulse wave velocity (cf-PWV). Linear heart rate variability (log transformed [ln] absolute and normalized units [nu] of low-frequency [LF] and high-frequency [HF] power) and nonlinear heart rate complexity (Sample Entropy [SampEn], Lempel-Ziv Entropy [LZEn]) were measured to determine autonomic modulation. BRS was measured by the sequence method. A 2 × 2 repeated measures analysis of variance (ANOVA) was used to analyze time (rest, recovery) across condition (acute resistance exercise, control). There were significant increases in cf-PWV (p = 0.05), heart rate (p = 0.0001), normalized LF (LFnu; p = 0.001), and the LF/HF ratio (p = 0.0001). Interactions were also noted for ln HF (p = 0.006), HFnu (p = 0.0001), SampEn (p = 0.001), LZEn (p = 0.005), and BRS (p = 0.0001) such that they significantly decreased during recovery from the resistance exercise compared with rest and the control. There was no effect on ln total power, or ln LF. These data suggest that a bout of resistance exercise using free-weights increases arterial stiffness and reduces vagal activity and BRS in comparison with a control session. Vagal tone may not be fully recovered up to 30 minutes after a resistance exercise bout.

  18. Psychiatric adverse effects of chloroquine

    Directory of Open Access Journals (Sweden)

    Anna Bogaczewicz

    2017-06-01

    Full Text Available Chloroquine is a prototype antimalarial drug, widely used in several branches of medicine. Antimalarial drugs are used in the treatment of various dermatological, immunological, rheumatological and infectious diseases. Examples of off-labelled indications for chloroquine analogues use include dermatomyositis, sarcoidosis, polymorphous light eruption, disseminated granuloma annulare and porfiria cutanea tarda. There is a relatively small number of adverse effects related to chloroquine analogues used in standard doses, such as gastrointestinal disturbances, headaches, skin reactions, hypotension, convulsions, extrapyramidal symptoms and visual disturbances. Psychiatric side effects of chloroquine seem to be rare, but may manifest in a wide range of symptoms, such as confusion, disorientation, ideas of persecution, agitation, outbursts of violence, loss of interest, feeling sad, suicidal ideas and impaired insight. There is also a report of a manic episode with psychotic features in the course of bipolar disorder, and another case report of persecutory delusions, anxiety, derealisation and visual illusions triggered by chloroquine. The duration of psychiatric symptoms usually ranges from one to two weeks, and symptoms usually disappear within several days following cessation of chloroquine usage and starting psychiatric treatment where indicated. This article reviews the case studies of patients diagnosed with mental disorders resulting from the use of chloroquine, and discusses the management in such cases.

  19. Using a genome-scale metabolic network model to elucidate the mechanism of chloroquine action in Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Shivendra G. Tewari

    2017-08-01

    Full Text Available Chloroquine, long the default first-line treatment against malaria, is now abandoned in large parts of the world because of widespread drug-resistance in Plasmodium falciparum. In spite of its importance as a cost-effective and efficient drug, a coherent understanding of the cellular mechanisms affected by chloroquine and how they influence the fitness and survival of the parasite remains elusive. Here, we used a systems biology approach to integrate genome-scale transcriptomics to map out the effects of chloroquine, identify targeted metabolic pathways, and translate these findings into mechanistic insights. Specifically, we first developed a method that integrates transcriptomic and metabolomic data, which we independently validated against a recently published set of such data for Krebs-cycle mutants of P. falciparum. We then used the method to calculate the effect of chloroquine treatment on the metabolic flux profiles of P. falciparum during the intraerythrocytic developmental cycle. The model predicted dose-dependent inhibition of DNA replication, in agreement with earlier experimental results for both drug-sensitive and drug-resistant P. falciparum strains. Our simulations also corroborated experimental findings that suggest differences in chloroquine sensitivity between ring- and schizont-stage P. falciparum. Our analysis also suggests that metabolic fluxes that govern reduced thioredoxin and phosphoenolpyruvate synthesis are significantly decreased and are pivotal to chloroquine-based inhibition of P. falciparum DNA replication. The consequences of impaired phosphoenolpyruvate synthesis and redox metabolism are reduced carbon fixation and increased oxidative stress, respectively, both of which eventually facilitate killing of the parasite. Our analysis suggests that a combination of chloroquine (or an analogue and another drug, which inhibits carbon fixation and/or increases oxidative stress, should increase the clearance of P

  20. Chloroquine increases phosphorylation of AMPK and Akt in myotubes

    Directory of Open Access Journals (Sweden)

    Larry D. Spears

    2016-03-01

    Significance: These ATM-independent effects of chloroquine on AMPK and Akt and the additional effect to decrease intracellular calcium are likely to partially underlie the positive metabolic effects of chloroquine that have been reported in the literature.

  1. Quantitative analysis of some brands of chloroquine tablets ...

    African Journals Online (AJOL)

    Quantitative analysis of some brands of chloroquine tablets marketed in Maiduguri using spectrophotometric ... and compared with that of the standard, wavelength of maximum absorbance at 331nm for chloroquine. ... HOW TO USE AJOL.

  2. Evaluation of disintegration and dissolution of chloroquine tablets in ...

    African Journals Online (AJOL)

    Evaluation of disintegration and dissolution of chloroquine tablets in some States in Northern Nigeria. ... This study seeks to assess the quality of chloroquine tablets in some States in Northern Nigeria by determining ... HOW TO USE AJOL.

  3. In vivo seasonal assessment of Plasmodium falciparum sensitivity to chloroquine in two different malaria endemic communities in Southern Ghana.

    Science.gov (United States)

    Afari, Edwin A.; Dunyo, Samuel; Appawu, Maxwell; Nkrumah, Francis K.

    1994-08-01

    A two year (1992 to 1993) in vivo assessment of Plasmodium falciparum sensitivity to chloroquine was conducted in two communities at Dodowa (hyperendemic) and Prampram (mesoendemic) in Southern Ghana. A slightly modified World Helath Organization standard field test (7 day test) for response of Plasmodium falciparum asexual parasites to chloroquine was used for the survey. In 1992, 16.2% (12/74) responses were classified as exhibiting chloroquine resistance at RI (14.8% ) and RII (1.4%) in the dry season and 8.2% (10/122) responses at RI in the wet season in the hyperendemic community. Only a single response (1/144; 0.7%) at RI showed resistance in the mesoendemic community. The rest of the responses in both communities were classified as sensitive to chloroquine. In the hyperendemic community, 8.4% (13/154) of responses in the dry season showed resistance at RI and 1.3% (82/150) at RI (0.7%) and RII (0.7%) in the wet season in 1993. In the mesoendemic community 1 (1.0%) response was resistant at RI in the wet season. The rest of the responses were classified as sensitive responses to chloroquine. No RIII response was encountered in any of the communities. The pattern of RI and RII responses did not show any seasonal variations in the mesoendemic community. However, they were generally higher in the dry season than in the wet season in the hyperendemic community.

  4. Chloroquine Interference with Hemoglobin Endocytic Trafficking Suppresses Adaptive Heme and Iron Homeostasis in Macrophages: The Paradox of an Antimalarial Agent

    Directory of Open Access Journals (Sweden)

    Christian A. Schaer

    2013-01-01

    Full Text Available The CD163 scavenger receptor pathway for Hb:Hp complexes is an essential mechanism of protection against the toxicity of extracellular hemoglobin (Hb, which can accumulate in the vasculature and within tissues during hemolysis. Chloroquine is a lysosomotropic agent, which has been extensively used as an antimalarial drug in the past, before parasite resistance started to limit its efficacy in most parts of the world. More recent use of chloroquine is related to its immunomodulatory activity in patients with autoimmune diseases, which may also involve hemolytic disease components. In this study we examined the effects of chloroquine on the human Hb clearance pathway. For this purpose we developed a new mass-spectrometry-based method to specifically quantify intracellular Hb peptides within the endosomal-lysosomal compartment by single reaction monitoring (SRM. We found that chloroquine exposure impairs trafficking of Hb:Hp complexes through the endosomal-lysosomal compartment after internalization by CD163. Relative quantification of intracellular Hb peptides by SRM confirmed that chloroquine blocked cellular Hb:Hp catabolism. This effect suppressed the cellular heme-oxygenase-1 (HO-1 response and shifted macrophage iron homeostasis towards inappropriately high expression of the transferrin receptor with concurrent inhibition of ferroportin expression. A functional deficiency of Hb detoxification and heme-iron recycling may therefore be an adverse consequence of chloroquine treatment during hemolysis.

  5. Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review

    OpenAIRE

    Arezoo Rafiee Parhizgar; Azar Tahghighi

    2017-01-01

    Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the othe...

  6. Authenticating a tamper-resistant module in a base station router

    NARCIS (Netherlands)

    Bosch, H.G.P.; Kraml, M.; Mullender, Sape J.; Polakos, P.; Samuel, L.G.

    2007-01-01

    The present invention provides a method involving a tamper-resistant module and an authentication server. The method includes receiving, at the tamper-resistant module, information encrypted using a first secret key stored in the authentication server. The method also includes authenticating the

  7. Antimuscarinic effects of chloroquine in rat pancreatic acini

    International Nuclear Information System (INIS)

    Habara, Y.; Williams, J.A.; Hootman, S.R.

    1986-01-01

    Chloroquine inhibited carbachol-induced amylase release in a dose-dependent fashion in rat pancreatic acini; cholecystokinin- and bombesin-induced secretory responses were almost unchanged by the antimalarial drug. The inhibition of carbachol-induced amylase release by chloroquine was competitive in nature with a K/sub i/ of 11.7 μM. Chloroquine also inhibited [ 3 H]N-methylscopolamine binding to acinar muscarinic receptors. The IC 50 for chloroquine inhibition of [ 3 H]N-methylscopolamine binding was lower than that for carbachol or the other antimalarial drugs, quinine and quinidine. These results demonstrate that chloroquine is a muscarinic receptor antagonist in the exocrine pancreas

  8. Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum.

    Science.gov (United States)

    Pradines, B; Fusai, T; Daries, W; Laloge, V; Rogier, C; Millet, P; Panconi, E; Kombila, M; Parzy, D

    2001-08-01

    The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 microM, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine, halofantrine, primaquine, atovaquone or artesunate. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

  9. Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border.

    Science.gov (United States)

    Höglund, Richard; Moussavi, Younis; Ruengweerayut, Ronnatrai; Cheomung, Anurak; Äbelö, Angela; Na-Bangchang, Kesara

    2016-02-29

    A three-day course of chloroquine remains a standard treatment of Plasmodium vivax infection in Thailand with satisfactory clinical efficacy and tolerability although a continuous decline in in vitro parasite sensitivity has been reported. Information on the pharmacokinetics of chloroquine and its active metabolite desethylchloroquine are required for optimization of treatment to attain therapeutic exposure and thus prevent drug resistance development. The study was conducted at Mae Tao Clinic for migrant worker, Tak province, Thailand. Blood samples were collected from a total of 75 (8 Thais and 67 Burmeses; 36 males and 39 females; aged 17-52 years) patients with mono-infection with P. vivax malaria [median (95 % CI) admission parasitaemia 4898 (1206-29,480)/µL] following treatment with a three-day course of chloroquine (25 mg/kg body weight chloroquine phosphate over 3 days). Whole blood concentrations of chloroquine and desethylchloroquine were measured using high performance liquid chromatography with UV detection. Concentration-time profiles of both compounds were analysed using a population-based pharmacokinetic approach. All patients showed satisfactory response to standard treatment with a three-day course of chloroquine with 100 % cure rate within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred. A total of 1045 observations from 75 participants were included in the pharmacokinetic analysis. Chloroquine disposition was most adequately described by the two-compartment model with one transit compartment absorption model into the central compartment and a first-order transformation of chloroquine into desethylchloroquine with an additional peripheral compartment added to desethylchloroquine. First-order elimination from the central compartment of chloroquine and desethylchloroquine was assumed. The model exhibited a strong predictive ability and the pharmacokinetic parameters were

  10. Presumed Chloroquine Retinopathy in Ibadan | Ajayi | Nigerian ...

    African Journals Online (AJOL)

    Objective: To review patients with clinical features of chloroquine retinopathy seen during the study period with the view of identifying the trend and creating public awareness for behavioural change. Methods: A retrospective review of case notes of patients seen between 1996 and 2002. Results: 19 patients with features of ...

  11. Use of chloroquine in uncomplicated falciparum malaria ...

    African Journals Online (AJOL)

    Use of chloroquine in uncomplicated falciparum malaria chemotherapy: The past, the present and the future. ... regions. It was initially highly effective against the four Plasmodium species (P. falciparum, P. malaria, P. ovale and P. vivax) infecting human. It is also effective against gametocytes except those of P. falciparum.

  12. Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons

    Directory of Open Access Journals (Sweden)

    Matthew Redmann

    2017-04-01

    Full Text Available Autophagy is an important cell recycling program responsible for the clearance of damaged or long-lived proteins and organelles. Pharmacological modulators of this pathway have been extensively utilized in a wide range of basic research and pre-clinical studies. Bafilomycin A1 and chloroquine are commonly used compounds that inhibit autophagy by targeting the lysosomes but through distinct mechanisms. Since it is now clear that mitochondrial quality control, particularly in neurons, is dependent on autophagy, it is important to determine whether these compounds modify cellular bioenergetics. To address this, we cultured primary rat cortical neurons from E18 embryos and used the Seahorse XF96 analyzer and a targeted metabolomics approach to measure the effects of bafilomycin A1 and chloroquine on bioenergetics and metabolism. We found that both bafilomycin and chloroquine could significantly increase the autophagosome marker LC3-II and inhibit key parameters of mitochondrial function, and increase mtDNA damage. Furthermore, we observed significant alterations in TCA cycle intermediates, particularly those downstream of citrate synthase and those linked to glutaminolysis. Taken together, these data demonstrate a significant impact of bafilomycin and chloroquine on cellular bioenergetics and metabolism consistent with decreased mitochondrial quality associated with inhibition of autophagy.

  13. Chloroquine transport in Plasmodium falciparum. 1. Influx and efflux kinetics for live trophozoite parasites using a novel fluorescent chloroquine probe.

    Science.gov (United States)

    Cabrera, Mynthia; Natarajan, Jayakumar; Paguio, Michelle F; Wolf, Christian; Urbach, Jeffrey S; Roepe, Paul D

    2009-10-13

    Several models for how amino acid substitutions in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to chloroquine (CQ) and other antimalarial drugs have been proposed. Distinguishing between these models requires detailed analysis of high-resolution CQ transport data that is unfortunately impossible to obtain with traditional radio-tracer methods. Thus, we have designed and synthesized fluorescent CQ analogues for drug transport studies. One probe places a NBD (6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid) group at the tertiary aliphatic N of CQ, via a flexible 6 C amide linker. This probe localizes to the malarial parasite digestive vacuole (DV) during initial perfusion under physiologic conditions and exhibits similar pharmacology relative to CQ, vs both CQ-sensitive (CQS) and CQ-resistant (CQR) parasites. Using live, synchronized intraerythrocytic parasites under continuous perfusion, we define NBD-CQ influx and efflux kinetics for CQS vs CQR parasites. Since this fluorescence approach provides data at much higher kinetic resolution relative to fast-filtration methods using (3)H-CQ, rate constants vs linear initial rates for CQ probe flux can be analyzed in detail. Importantly, we find that CQR parasites have a decreased rate constant for CQ influx into the DV and that this is due to mutation of PfCRT. Analysis of zero trans efflux for CQS and CQR parasites suggests that distinguishing between bound vs free pools of intra-DV drug probe is essential for proper kinetic analysis of efflux. The accompanying paper (DOI 10.1021/bi901035j ) further probes efflux kinetics for proteoliposomes containing purified, reconstituted PfCRT.

  14. Chloroquine Increases Glucose Uptake via Enhancing GLUT4 Translocation and Fusion with the Plasma Membrane in L6 Cells

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    Qi Zhou

    2016-05-01

    Full Text Available Background/Aims: Chloroquine can induce an increase in the cellular uptake of glucose; however, the underlying mechanism is unclear. Methods: In this study, translocation of GLUT4 and intracellular Ca2+ changes were simultaneously observed by confocal microscope in L6 cells stably over-expressing IRAP-mOrange. The GLUT4 fusion with the plasma membrane (PM was traced using HA-GLUT4-GFP. Glucose uptake was measured using a cell-based glucose uptake assay. GLUT4 protein was detected by Western blotting and mRNA level was detected by RT-PCR. Results: We found that chloroquine induced significant increases in glucose uptake, glucose transporter GLUT4 translocation to the plasma membrane (GTPM, GLUT4 fusion with the PM, and intracellular Ca2+ in L6 muscle cells. Chloroquine-induced increases of GTPM and intracellular Ca2+ were inhibited by Gallein (Gβγ inhibitor and U73122 (PLC inhibitor. However, 2-APB (IP3R blocker only blocked the increase in intracellular Ca2+ but did not inhibit GTPM increase. These results indicate that chloroquine, via the Gβγ-PLC-IP3-IP3R pathway, induces elevation of Ca2+, and this Ca2+ increase does not play a role in chloroqui-ne-evoked GTPM increase. However, GLUT4 fusion with the PM and glucose uptake were significantly inhibited with BAPTA-AM. This suggests that Ca2+ enhances GLUT4 fusion with the PM resulting in glucose uptake increase. Conclusion: Our data indicate that chloroquine via Gβγ-PLC-IP3-IP3R induces Ca2+ elevation, which in turn promotes GLUT4 fusion with the PM. Moreover, chloroquine can enhance GLUT4 trafficking to the PM. These mechanisms eventually result in glucose uptake increase in control and insulin-resistant L6 cells. These findings suggest that chloroquine might be a potential drug for improving insulin tolerance in diabetic patients.

  15. Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

    Energy Technology Data Exchange (ETDEWEB)

    Kaini, Ramesh R. [Department of Biochemistry and Molecular Biology and UNM Cancer and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM (United States); Hu, Chien-An A., E-mail: AHu@salud.unm.edu [Department of Biochemistry and Molecular Biology and UNM Cancer and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM (United States)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. Black-Right-Pointing-Pointer Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. Black-Right-Pointing-Pointer Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. Black-Right-Pointing-Pointer Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

  16. Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

    International Nuclear Information System (INIS)

    Kaini, Ramesh R.; Hu, Chien-An A.

    2012-01-01

    Highlights: ► Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. ► Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. ► Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. ► Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

  17. Effect of chloroquine on intestinal lipid metabolism

    International Nuclear Information System (INIS)

    Mansbach, C.M. II; Arnold, A.; Garrett, M.

    1987-01-01

    Most studies that have quantitated recovery of infused lipid in the intestinal mucosa and mesenteric lymph have only been able to recapture 50-75%. One possibility is that the missing lipid enters a triacylglycerol (TG) storage pool in the enterocyte and is hydrolyzed by lysosomal lipase, and the free fatty acid released is transported by the portal vein. This postulate was tested by comparing glyceryl trioleate (TO)-infused rats pretreated with the lysosomotropic drug, chloroquine (6.3 mg.kg-1.h-1) with saline controls. Chloroquine increased mucosal TG from 94 +/- 6 to 128 +/- 8 mumol. Additionally, the specific activity of the mucosal TG relative to the infused [ 3 H]TO was reduced in the treated rats. The mucosal TG increase was not due to impaired TG output, which remained the same as controls. We conclude that the TG in the acid lipase-sensitive pool derives most of its glyceride-glycerol from endogenous sources. Furthermore, the increment in mucosal TG caused by chloroquine is not enough to explain the majority of the acyl groups unaccounted for in the mucosa and lymph after a TG infusion. For these a direct passage of acyl groups through the enterocyte is postulated

  18. Insulin resistance and circadian rhythm of cardiac autonomic modulation

    Directory of Open Access Journals (Sweden)

    Cai Jianwen

    2010-12-01

    Full Text Available Abstract Background Insulin resistance (IR has been associated with cardiovascular diseases (CVD. Heart rate variability (HRV, an index of cardiac autonomic modulation (CAM, is also associated with CVD mortality and CVD morbidity. Currently, there are limited data about the impairment of IR on the circadian pattern of CAM. Therefore, we conducted this investigation to exam the association between IR and the circadian oscillations of CAM in a community-dwelling middle-aged sample. Method Homeostasis models of IR (HOMA-IR, insulin, and glucose were used to assess IR. CAM was measured by HRV analysis from a 24-hour electrocardiogram. Two stage modeling was used in the analysis. In stage one, for each individual we fit a cosine periodic model based on the 48 segments of HRV data. We obtained three individual-level cosine parameters that quantity the circadian pattern: mean (M, measures the overall average of a HRV index; amplitude (Â, measures the amplitude of the oscillation of a HRV index; and acrophase time (θ, measures the timing of the highest oscillation. At the second stage, we used a random-effects-meta-analysis to summarize the effects of IR variables on the three circadian parameters of HRV indices obtained in stage one of the analysis. Results In persons without type diabetes, the multivariate adjusted β (SE of log HOMA-IR and M variable for HRV were -0.251 (0.093, -0.245 (0.078, -0.19 (0.06, -4.89 (1.76, -3.35 (1.31, and 2.14 (0.995, for log HF, log LF, log VLF, SDNN, RMSSD and HR, respectively (all P Conclusion Elevated IR, among non-diabetics significantly impairs the overall mean levels of CAM. However, the  or θ of CAM were not significantly affected by IR, suggesting that the circadian mechanisms of CAM are not impaired. However, among persons with type 2 diabetes, a group clinically has more severe form of IR, the adverse effects of increased IR on all three HRV circadian parameters are much larger.

  19. Atovaquone and proguanil hydrochloride compared with chloroquine or pyrimethamine/sulfadoxine for treatment of acute Plasmodium falciparum malaria in Peru

    Directory of Open Access Journals (Sweden)

    A. Llanos-Cuentas

    Full Text Available The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (MalaroneTM were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15 or 1,500 mg chloroquine (base over a 3 day period (n=14 (phase 1. The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9 or atovaquone/proguanil as before (n=5 (phase 2. In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] versus 8% [1/13], P<0.0001. In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]. There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

  20. Atovaquone and proguanil hydrochloride compared with chloroquine or pyrimethamine/sulfadoxine for treatment of acute Plasmodium falciparum malaria in Peru

    Directory of Open Access Journals (Sweden)

    Llanos-Cuentas A.

    2001-01-01

    Full Text Available The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (MalaroneTM were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15 or 1,500 mg chloroquine (base over a 3 day period (n=14 (phase 1. The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9 or atovaquone/proguanil as before (n=5 (phase 2. In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] versus 8% [1/13], P<0.0001. In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]. There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

  1. Atovaquone and proguani hydrochloride compared with chloroquine or pyrimethamine/sulfodaxine for treatment of acute Plasmodium falciparum malaria in Peru.

    Science.gov (United States)

    Llanos-Cuentas, A; Campos, P; Clendenes, M; Canfield, C J; Hutchinson, D B

    2001-04-01

    The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (Malarone) were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14) (phase 1). The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9) or atovaquone/proguanil as before (n=5) (phase 2). In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] vs. 8% [1/13], Pproguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]). There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

  2. Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy

    Directory of Open Access Journals (Sweden)

    Greenwood Brian

    2008-12-01

    Full Text Available Abstract In the high malaria-transmission settings of sub-Saharan Africa, malaria in pregnancy is an important cause of maternal, perinatal and neonatal morbidity. Intermittent preventive treatment of malaria in pregnancy (IPTp with sulphadoxine-pyrimethamine (SP reduces the incidence of low birth-weight, pre-term delivery, intrauterine growth-retardation and maternal anaemia. However, the public health benefits of IPTp are declining due to SP resistance. The combination of azithromycin and chloroquine is a potential alternative to SP for IPTp. This review summarizes key in vitro and in vivo evidence of azithromycin and chloroquine activity against Plasmodium falciparum and Plasmodium vivax, as well as the anticipated secondary benefits that may result from their combined use in IPTp, including the cure and prevention of many sexually transmitted diseases. Drug costs and the necessity for external financing are discussed along with a range of issues related to drug resistance and surveillance. Several scientific and programmatic questions of interest to policymakers and programme managers are also presented that would need to be addressed before azithromycin-chloroquine could be adopted for use in IPTp.

  3. Effect of ciprofloxacin on single dose chloroquine salivary and ...

    African Journals Online (AJOL)

    The effects of ciprofloxacin on the salivary and urinary concentrations of chloroquine (CQ) were investigated in six healthy volunteers, 20 to 30 years of age. Ciprofloxacin reduced the absorption, excretion rate and t1/2 of chloroquine in urine, Cmax and AUC in saliva but increased the Tmax in saliva. Thus, concurrent ...

  4. Effects of three classes of alcoholic beverages on chloroquine ...

    African Journals Online (AJOL)

    The effects of three different types of alcoholic beverages (beer, wine and gin) on the absorption of chloroquine in the stomach and intestine of rats were determined. The in situ loop method and in situ re-circulation technique were used to determine the absorption of chloroquine [CQ] in the stomach and intestine ...

  5. Visual function and long-term chloroquine treatment | Bartel | South ...

    African Journals Online (AJOL)

    A small group of patients with relatively poor scores on one or more tests had normal visual fields and ophthalmic findings. There were no significant partial correlations between test results and the cumulative dose of chloroquine. These results support the opinion that currently recommended doses of chloroquine pose a ...

  6. Circumvention of inherent or acquired cytotoxic drug resistance in vitro using combinations of modulating agents.

    Science.gov (United States)

    Cadagan, David; Merry, Stephen

    2013-10-01

    Modulating agents are used to circumvent drug resistance in the clinical setting. However achievable serum concentrations are often lower than those which are optimal in vitro. Combination of modulating agents with non-overlapping toxicities may overcome this obstacle. We have investigated combinations of three modulating agents (quinine, verapamil, and cinnarizine) to circumvent inherent or acquired resistance to the cytotoxic drugs doxorubicin, vincristine and paclitaxel. Dose-response curves to cytotoxic drugs in the presence/absence of modulating agents were determined using colony formation and cell proliferation assays. Doxorubicin accumulation into cell monolayers was measured by fluorescence spectrophotometry. Greater (1.9-fold) sensitisation to particular cytotoxic drugs was observed for certain combinations of modulating agents compared to individual effects. The most effective combination was quinine-plus-verapamil with the cytotoxic drug doxorubicin. This increase in sensitivity was associated with increased doxorubicin accumulation. Such enhanced activity was, however, not observed for all combinations of modulating agents or for all studied cytotoxic drugs. The findings of the present study suggest certain combinations of modulating agents to have a clinical role in circumventing drug resistance. Particular combinations of modulating agents must be carefully chosen to suit particular cytotoxic drug treatments.

  7. Mitochondrial modulation of phosphine toxicity and resistance in Caenorhabditis elegans.

    Science.gov (United States)

    Zuryn, Steven; Kuang, Jujiao; Ebert, Paul

    2008-03-01

    Phosphine is a fumigant used to protect stored commodities from infestation by pest insects, though high-level phosphine resistance in many insect species threatens the continued use of the fumigant. The mechanisms of toxicity and resistance are not clearly understood. In this study, the model organism, Caenorhabditis elegans, was employed to investigate the effects of phosphine on its proposed in vivo target, the mitochondrion. We found that phosphine rapidly perturbs mitochondrial morphology, inhibits oxidative respiration by 70%, and causes a severe drop in mitochondrial membrane potential (DeltaPsim) within 5 h of exposure. We then examined the phosphine-resistant strain of nematode, pre-33, to determine whether resistance was associated with any changes to mitochondrial physiology. Oxygen consumption was reduced by 70% in these mutant animals, which also had more mitochondrial genome copies than wild-type animals, a common response to reduced metabolic capacity. The mutant also had an unexpected increase in the basal DeltaPsim, which protected individuals from collapse of the membrane potential following phosphine treatment. We tested whether directly manipulating mitochondrial function could influence sensitivity toward phosphine and found that suppression of mitochondrial respiratory chain genes caused up to 10-fold increase in phosphine resistance. The current study confirms that phosphine targets the mitochondria and also indicates that direct alteration of mitochondrial function may be related to phosphine resistance.

  8. Chloroquine treatment enhances regulatory T cells and reduces the severity of experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Rodolfo Thomé

    Full Text Available BACKGROUND: The modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg cells and suppressive Dendritic Cells (DCs, to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ, an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE, an experimental model for human Multiple Sclerosis, was investigated as well. METHODOLOGY/PRINCIPAL FINDINGS: EAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35-55 peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS and increased frequency of Treg cells. Also, proliferation of MOG35-55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset. CONCLUSION: We show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of

  9. Dietary modulation of the resistance to intestinal infections

    NARCIS (Netherlands)

    Bovee-Oudenhoven, I.M.J.

    1998-01-01

    Gastrointestinal infections are still a major health problem, not only in developing countries. Even in Europe and the United States about 10-15 % of the population contracts an intestinal infection each year, mostly of foodborne origin. The growing resistance of pathogens to antibiotics

  10. Distribution pattern of Plasmodium falciparum chloroquine transporter (pfcrt) gene haplotypes in Sri Lanka 1996-2006

    DEFF Research Database (Denmark)

    Zhang, Jenny J; Senaratne, Tharanga N; Daniels, Rachel

    2011-01-01

    Abstract. Widespread antimalarial resistance has been a barrier to malaria elimination efforts in Sri Lanka. Analysis of genetic markers in historic parasites may uncover trends in the spread of resistance. We examined the frequency of Plasmodium falciparum chloroquine transporter (pfcrt; codons 72......-76) haplotypes in Sri Lanka in 1996-1998 and 2004-2006 using a high-resolution melting assay. Among 59 samples from 1996 to 1998, we detected the SVMNT (86%), CVMNK (10%), and CVIET (2%) haplotypes, with a positive trend in SVMNT and a negative trend in CVMNK frequency (P = 0.004) over time. Among 24 samples...

  11. Cardiac Insulin Resistance and MicroRNA Modulators

    Directory of Open Access Journals (Sweden)

    Lakshmi Pulakat

    2012-01-01

    Full Text Available Cardiac insulin resistance is a metabolic and functional disorder that is often associated with obesity and/or the cardiorenal metabolic syndrome (CRS, and this disorder may be accentuated by chronic alcohol consumption. In conditions of over-nutrition, increased insulin (INS and angiotensin II (Ang II activate mammalian target for rapamycin (mTOR/p70 S6 kinase (S6K1 signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2, it also renders cardioprotection via increased Ang II receptor 2 (AT2R upregulation and adaptive hypertrophy. In the INS-resistant and hyperinsulinemic Zucker obese (ZO rat, a rodent model for CRS, activation of mTOR/S6K1signaling in cardiac tissue is regulated by protective feed-back mechanisms involving mTOR↔AT2R signaling loop and profile changes of microRNA that target S6K1. Such regulation may play a role in attenuating progressive heart failure. Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy.

  12. Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial

    Directory of Open Access Journals (Sweden)

    Woodrow Charles J

    2010-04-01

    Full Text Available Abstract Background Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail. Methods Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3 and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Δ = 5% difference in proportion of failures. Results Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1% than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%, a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%. The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003. Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported. Conclusions Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical

  13. Interaction of chloroquine and its analogues with heme: An isothermal titration calorimetric study.

    Science.gov (United States)

    Bachhawat, K; Thomas, C J; Surolia, N; Surolia, A

    2000-10-05

    Quinoline-containing drugs such as chloroquine and quinine have had a long and successful history in antimalarial chemotherapy. Identification of ferriprotoporphyrin IX ([Fe(III)PPIX], haematin) as the drug receptors for these antimalarials called for investigations of the binding affinity, mode of interaction, and the conditions affecting the interaction. The parameters obtained are significant in recent times with the emergence of chloroquine resistant strains of the malaria parasites. This has underlined the need to unravel the molecular mechanism of their action so as to meet the requirement of an alternative to the existing antimalarial drugs. The isothermal titration calorimetric studies on the interaction of chloroquine with haematin lead us to propose an altered mode of binding. The initial recognition is ionic in nature mediated by the propionyl group of haematin with the quaternary nitrogen on CQ. This ionic interaction induces a conformational change, such as to favour binding of subsequent CQ molecules. On the contrary, conditions emulating the cytosolic environment (pH 7.4 and 150 mM salt) reveal the hydrophobic force to be the sole contributor driving the interaction. Interaction of a carefully selected panel of quinoline antimalarial drugs with monomeric ferriprotoporphyrin IX has also been investigated at pH 5.6 mimicking the acidic environment prevalent in the food vacuoles of parasite, the center of drug activity, which are consistent with their antimalarial activity. Copyright 2000 Academic Press.

  14. Effects of PV Module Soiling on Glass Surface Resistance and Potential-Induced Degradation: Preprint

    Energy Technology Data Exchange (ETDEWEB)

    Hacke, Peter; Burton, Patrick; Hendrickson, Alex; Spartaru, Sergiu; Glick, Stephen; Terwilliger, Kent

    2015-12-03

    The sheet resistance of three soil types (Arizona road dust, soot, and sea salt) on glass were measured by the transmission line method as a function of relative humidity (RH) between 39% and 95% at 60 degrees C. Sea salt yielded a 3.5 order of magnitude decrease in resistance on the glass surface when the RH was increased over this RH range. Arizona road dust showed reduced sheet resistance at lower RH, but with less humidity sensitivity over the range tested. The soot sample did not show significant resistivity change compared to the unsoiled control. Photovoltaic modules with sea salt on their faces were step-stressed between 25% and 95% RH at 60 degrees C applying -1000 V bias to the active cell circuit. Leakage current from the cell circuit to ground ranged between two and ten times higher than that of the unsoiled controls. Degradation rate of modules with salt on the surface increased with increasing RH and time.

  15. Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds.

    Science.gov (United States)

    Macfarlane, D E; Manzel, L

    1998-02-01

    Phosphorothioate oligodeoxynucleotides containing CpG (CpG-ODN) activate immune responses. We report that quinacrine, chloroquine, and structurally related compounds completely inhibit the antiapoptotic effect of CpG-ODN on WEHI 231 murine B lymphoma cells and inhibit CpG-ODN-induced secretion of IL-6 by WEHI 231. They also inhibit IL-6 synthesis and thymidine uptake by human unfractionated PBMC induced by CpG-ODN. The compounds did not inhibit LPS-induced responses. Half-maximal inhibition required 10 nM quinacrine or 100 nM chloroquine. Inhibition was noncompetitive with respect to CpG-ODN. Quinine, quinidine, and primaquine were much less powerful. Quinacrine was effective even when added after the CpG-ODN. Near-toxic concentrations of ammonia plus bafilomycin A1 (used to inhibit vesicular acidification) did not reduce the efficacy of the quinacrine, but the effects of both quinacrine and chloroquine were enhanced by inhibition of the multidrug resistance efflux pump by verapamil. Agents that bind to DNA, including propidium iodide, Hoechst dye 33258, and coralyne chloride did not inhibit CpG-ODN effect, nor did 4-bromophenacyl bromide, an inhibitor of phospholipase A2. Examination of the structure-activity relationship of seventy 4-aminoquinoline and 9-aminoacridine analogues reveals that increased activity was conferred by bulky hydrophobic substituents on positions 2 and 6 of the quinoline nucleus. No correlation was found between published antimalarial activity and ability to block CpG-ODN-induced effects. These results are discussed in the light of the ability of quinacrine and chloroquine to induce remission of rheumatoid arthritis and lupus erythematosus.

  16. Large resistivity modulation in mixed-phase metallic systems.

    Science.gov (United States)

    Lee, Yeonbae; Liu, Z Q; Heron, J T; Clarkson, J D; Hong, J; Ko, C; Biegalski, M D; Aschauer, U; Hsu, S L; Nowakowski, M E; Wu, J; Christen, H M; Salahuddin, S; Bokor, J B; Spaldin, N A; Schlom, D G; Ramesh, R

    2015-01-07

    In numerous systems, giant physical responses have been discovered when two phases coexist; for example, near a phase transition. An intermetallic FeRh system undergoes a first-order antiferromagnetic to ferromagnetic transition above room temperature and shows two-phase coexistence near the transition. Here we have investigated the effect of an electric field to FeRh/PMN-PT heterostructures and report 8% change in the electrical resistivity of FeRh films. Such a 'giant' electroresistance (GER) response is striking in metallic systems, in which external electric fields are screened, and thus only weakly influence the carrier concentrations and mobilities. We show that our FeRh films comprise coexisting ferromagnetic and antiferromagnetic phases with different resistivities and the origin of the GER effect is the strain-mediated change in their relative proportions. The observed behaviour is reminiscent of colossal magnetoresistance in perovskite manganites and illustrates the role of mixed-phase coexistence in achieving large changes in physical properties with low-energy external perturbation.

  17. Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: Synthesis, characterization and in vitro antimalarial activity†

    Science.gov (United States)

    Glans, Lotta; Ehnbom, Andreas; de Kock, Carmen; Martínez, Alberto; Estrada, Jesús; Smith, Peter J.; Haukka, Matti; Sánchez-Delgado, Roberto A.; Nordlander, Ebbe

    2012-01-01

    Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η6-cym)(L1)Cl]Cl (1, cym = p-cymene, L1 = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η6-cym)(L2)Cl]Cl (2, L2 = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η6-cym)(L3)Cl] (3, L3 = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1–3 and ligands L1, L2 and L3, as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L4), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L2 also shows good activity against both the choloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR50) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR50 properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L3 to ruthenium, to give a metal complex (3) with promising antimalarial activity. PMID:22249579

  18. Series Resistance Monitoring for Photovoltaic Modules in the Vicinity of MPP

    DEFF Research Database (Denmark)

    Sera, Dezso

    2010-01-01

    Faults and performance deterioration issues related to increases of the series resistance in PV modules or arrays are one of the most common causes to decrease the energy yield of photovoltaic installations. Therefore, the early detection of such failure types is very important in order to minimize...

  19. A study of the pharmaceutical quality of chloroquine and ...

    African Journals Online (AJOL)

    kemrilib

    products obtained from a major Nigerian drug “market” using a less elaborate sampling procedure. Results have ... chloroquine and paracetamol tablets (10 brands each) and syrups (6 brands ..... strategy aimed at attaining the United Nations'.

  20. Combination cyclosporine and (hydroxy)chloroquine in rheumatoid arthritis

    NARCIS (Netherlands)

    Dijkmans, B. A.; Landewé, R. B.; van den Borne, B. E.; Breedveld, F. C.

    1999-01-01

    Antimalarials are attractive candidates for combination therapy. In vitro experiments have revealed a synergistic mode of action of cyclosporine and chloroquine which could not, however, be confirmed in a clinical trial

  1. Malaria Parasite Infection and Chloroquine-Induced Pruritus: The ...

    African Journals Online (AJOL)

    induced body scratching, whereas, the histaminergic system was implicated in CQ-induced itching. Keywords: Rats, parasitaemia, chloroquine, opioids, antihistamine, naltrexone. West African Journal of Pharmacology and Drug Research Vol.

  2. Dynamics of pfcrt alleles CVMNK and CVIET in chloroquine-treated Sudanese patients infected with Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Warhurst David C

    2010-03-01

    Full Text Available Abstract Background Parasite resistance to the anti-malarial drug chloroquine is common in eastern Sudan. Dynamic within-host changes in the relative abundance of both sensitive and resistant Plasmodium falciparum parasites were examined in a cohort of chloroquine-treated patients presenting with uncomplicated falciparum malaria, using a novel allele-specific quantitative approach. Methods Treatment outcomes were determined for 93 patients of all ages in a per protocol cohort using a modified 14-day WHO protocol. Parasite DNA samples at days 0, 1, 2, 3, 7 and 14 following treatment were analysed using real-time quantitative PCR methods that distinguished resistant and sensitive genotypes at amino acids 72 - 76 of the pfcrt locus. Results Chloroquine treatment was not efficacious, and of 93 assessable patients, only 10 individuals (10.7%; 95% C.I. 4.34 - 17.2% enjoyed an adequate clinical and parasitological response. Resistant parasites with the haplotype CVIET at codons 72-76 of the pfcrt locus were dominant in the starting population. Chloroquine sensitive parasites with the haplotype CVMNK were detected in 19 individuals prior to treatment (20.43%; 95% C.I. 5.14 - 18.5%. In these patients, CQ treatment rapidly selected CVIET parasites, and this haplotype overwhelmingly dominated the parasite population in each individual by day 2 after treatment. Conclusions Such rapid intra-host selection of particular genotypes after the introduction of drug will cause frequent misidentification of parasite genotypes present in the starting population. This will have a potentially serious confounding effect on clinical trials which employ PCR-corrected estimates of treatment failure, as resistant parasites below the detection threshold in the pre-treatment sample can be erroneously classified as "new" infections during follow-up, over-estimating drug efficacy.

  3. Study of radiosensitization of chloroquine on esophageal cancer cell line

    International Nuclear Information System (INIS)

    Yuan Xiaoli; Li Tao; Huang Jianming; Zha Xiao; Deng Bifang; Lang Jinyi

    2014-01-01

    Objective: To investigate the possibility of chloroquine radiosensitization of esophageal cancer cell line TE-1 and its further mechanism. Methods: Effect of chloroquine on cell viability of TE-1 cells was determined by MTT method. Expression of LC3, Beclin-1 and formation of acidic vesicular organelles (AVOs) were determined by Western blot, and fluorescence staining with Lyso-Tracker Red DND-99, respectively. Clonogenic survival of TE-1 cells was examined by clonogenic forming assay. Results: Chloroquine showed dose-dependent inhibition of TE-1 cell growth, and its values of IC_5_0 and IC_1_0 were (72.33±5.28) and (15.42±3.33) μmol/L, respectively. The expression of Beclin-1 and LC3-II/I markedly increased in irradiated TE-1 cells. The addition of chloroquine with IC_1_0 concentration significantly reduced the fluorescence and intensity of AVOs accumulation in the cytoplasm of TE-1 cells. Clonogenic survival fraction decreased obviously in TE-1 cells with addition of chloroquine after radiation and the value of SERD0 was 1.439. Conclusions: Chloroquine could radiosensitize esophageal cancer cells by blocking autophagy-lysosomal pathway and be used as a potential radiosensitizing strategy. (authors)

  4. Drug resistance and genetic diversity of Plasmodium falciparum parasites from Suriname

    NARCIS (Netherlands)

    Peek, Ron; van Gool, Tom; Panchoe, Daynand; Greve, Sophie; Bus, Ellen; Resida, Lesley

    2005-01-01

    Plasmodium falciparum in Suriname was studied for the presence of drug resistance and genetic variation in blood samples of 86 patients with symptomatic malaria. Drug resistance was predicted by determining point mutations in the chloroquine resistance marker of the P. falciparum chloroquine

  5. [Chloroquine analogues from benzofuro- and benzothieno[3,2-b]-4-pyridone-2-carboxylic acid esters].

    Science.gov (United States)

    Gölitzer, K; Meyer, H; Jomaa, H; Wiesner, J

    2004-08-01

    The amides 7 were synthesized from the annulated methyl 4-pyridone-2-carboxylates 4 via the carboxylic acids 5 and their acid chlorides by reacting with the novaldiamine base 6. The alcohol 8b, obtained from DIBAH reduction of the ester 4b, was transformed to the chloromethyl derivative 9 which reacted with 6 and 18-crown-6 leading to the 2-novaldiaminomethyl-4-pyridone 10. Compound 10 was obtained with higher yield from DIBAH reduction of the amide 7b. The substances 7 and 10 were inactive when tested against the chloroquine resistant Plasmodium falciparum strain Dd2.

  6. Reported side effects to chloroquine, chloroquine plus proguanil, and mefloquine as chemoprophylaxis against malaria in Danish travelers

    DEFF Research Database (Denmark)

    Petersen, E; Ronne, T; Ronn, A

    2000-01-01

    BACKGROUND: The aim of the study was to provide data on the relative frequency of reported symptoms in travelers using chloroquine, chloroquine plus proguanil, and mefloquine. METHOD: The study was an open, nonrandomized study recording self-reported events in travelers recruited consecutively from...... included and 4,158 questionnaires (76.3%) returned. Compliance was significantly better in mefloquine users with 83.3% of short term travelers compared to 76.3% in chloroquine plus proguanil users. Also, 84.8%, 59.3% and 69.5% using chloroquine, chloroquine plus proguanil, and mefloquine respectively...... reported no symptoms and 0.6%, 1.1% and 2.8% reported "unacceptable" symptoms. Compared to chloroquine, mefloquine users had a significantly higher risk of reporting depression, RR 5.06 (95% CI 2.71 - 9.45), "strange thoughts," RR 6.36 (95% CI 2.52 - 16.05) and altered spatial perception, RR 3.00 (95% CI 1...

  7. Resistive Switching and Voltage Induced Modulation of Tunneling Magnetoresistance in Nanosized Perpendicular Organic Spin Valves

    Science.gov (United States)

    Schmidt, Georg; Goeckeritz, Robert; Homonnay, Nico; Mueller, Alexander; Fuhrmann, Bodo

    Resistive switching has already been reported in organic spin valves (OSV), however, its origin is still unclear. We have fabricated nanosized OSV based on La0.7Sr0.3MnO3/Alq3/Co. These devices show fully reversible resistive switching of up to five orders of magnitude. The magnetoresistance (MR) is modulated during the switching process from negative (-70%) to positive values (+23%). The results are reminiscent of experiments claiming magnetoelectric coupling in LSMO based tunneling structures using ferroelectric barriers. By analyzing the I/V characteristics of the devices we can show that transport is dominated by tunneling through pinholes. The resistive switching is caused by voltage induced creation and motion of oxygen vacancies at the LSMO surface, however, the resulting tunnel barrier is complemented by a second adjacent barrier in the organic semiconductor. Our model shows that the barrier in the organic material is constant, causing the initial MR while the barrier in the LMSO can be modulated by the voltage resulting in the resistive switching and the modulation of the MR as the coupling to the states in the LSMO changes. A switching caused by LSMO only is also supported by the fact that replacing ALQ3 by H2PC yields almost identical results. Supported by the DFG in the SFB762.

  8. Is chloroquine still effective for the treatment of vivax malaria in children in northern punjab of pakistan?

    International Nuclear Information System (INIS)

    Subhani, F.A.; Shaheen, S.; Nawaz, M.A.

    2013-01-01

    Introduction: Every year more than one billion persons in the world suffer from malaria. It kills about 1-3 million people in the world per year. In Pakistan estimated burden of malaria is 1.6 million cases each year. As most of people belong to poor socioeconomic group, it is essential that cost effective remedial measures must be taken. Moreover judicious use of antimalarials is required to avoid development of resistance. Objective: To determine the frequency of types of malaria and frequency of cases responding to chloroquine as first line treatment in vivax malaria in children of Northern Punjab of Pakistan. Study Design: Descriptive study. Place and Duration of Study: From Jun 2011 to Sept 2012 at Combined Military Hospital Gujranwala in children reporting from surrounding areas both rural and urban with clinical suspicion of malaria. Materials and Methods: During the study period, 175 children were admitted with clinical suspicion of malaria. Out of which 102 were smear positive for malarial parasites, 13 cases were excluded from the study as they lost to follow up, leaving a total of 89 children in the study. Patients under study remained admitted till the fever settled and malarial parasites were negative on smear. Chloroquine was used as first line treatment in cases with vivax malaria. On discharge from hospital, parents of children were advised fortnightly follow up for 28 days. Results: Out of 89 children approx 54% were males and 46% were females. Mean age of participants was 5.91 years. The minimum age was 1 year and maximum 11 years (SD +- 3.09) out of the 89 cases, 84 (94.3%) had vivax malaria, 2 (2.24%) had falciparum malaria and 3 (3.37%) had mixed infection. Our study showed that 79 (94%) cases of vivax malaria fully responded to chloroquine, 5 (6%) cases treated with Chloroquine reported with relapse. Conclusion: Chloroquine is still the drug of choice in vivax malaria. (author)

  9. The Role of ABC Proteins in Drug Resistant Breast Cancer Cells

    Science.gov (United States)

    2008-04-01

    called the Plasmodium falciparum Chloroquine Transporter (PfCRT). While PfCRT is known to be the main molecular determinant of chloroquine resistance...proteins (such as human P-glycoprotein) and labeled PfCRT with a photoaffinity drug analogue . A manuscript is currently in preparation detailing my results...directly responsible for drug response, the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT) (Fidock et al 2000). While not a member of

  10. Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains.

    Science.gov (United States)

    Tasso, Bruno; Novelli, Federica; Tonelli, Michele; Barteselli, Anna; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Sparatore, Anna; Sparatore, Fabio

    2015-09-01

    Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Preliminary formulation and characterization of solid lipid nanoparticles containing chloroquine and a P-glycoprotein inhibitor: Influences of lipid-surfactant ratios

    CSIR Research Space (South Africa)

    Nzekwe, IT

    2015-02-01

    Full Text Available . In this work, the inclusion of a P-gp inhibitor, chlorpheniramine, and chloroquine in a lipid-based nanoparticle carrier is proposed, with the aim of ensuring that adequate drug levels are attained, so as to overcome drug resistance. Methods: The nanoparticles...

  12. Monitoring of Plasmodium vivax and Plasmodium falciparum response to chloroquine in Bandar-Abbas district, Hormozgan province, Iran

    Directory of Open Access Journals (Sweden)

    Nateghpour M M

    2009-06-01

    Full Text Available "n Normal 0 false false false EN-GB X-NONE AR-SA MicrosoftInternetExplorer4 st1":*{behavior:url(#ieooui } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Malaria is an important parasitic vector-borne disease with considerable infectivity and world-wide distribution. Since prevalence of chloroquine resistance in Plasmodium falciparum at the malarious areas such as Iran and reliable reports from many countries indicating emergence of chloroquine- resistant strains of P.vivax, this study was conducted to monitor the current response of vivax and falciparum plasmodia to chloroquine in Bandar-Abbas district, a malarious area in Iran."n"nMethods: The study was conducted at the Bandar-Abbas district in Hormozgan province, Iran. 123 patients were enrolled and considered. The patients were treated with a standard 3-day regimen of chloroquine and were followed-up clinically and parasitologically. The results were interpreted as mean parasite clearance time (MPCT in P. vivax and early treatment failure (ETF, late treatment failure (LTF and adequate clinical and parasitological response (ACPR in P. falciparum."n"nResults: The patients with vivax malaria were responded to the regimen of chloroquine within 24-216 hours. Most cases of the parasite clearance time occurred at 48 hours (50.40%, and less of them at 120, 168, 192 and 216 hours

  13. Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS.

    Directory of Open Access Journals (Sweden)

    Xianzhi Qu

    Full Text Available The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy. However, the mechanism of autophagy and metabolism in chemotherapeutic drug resistance is still poorly understood. In this study, we investigated the role and mechanism of autophagy and glucose metabolism in chemotherapeutic drug resistance by using cholangiocarcinoma QBC939 cells with primary cisplatin resistance and hepatocellular carcinoma HepG2 cells. We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells. It is suggested that there are some differences in the metabolism of glucose in hepatocellular carcinoma and cholangiocarcinoma cells, and the activation of PPP pathway may be related to the drug resistance. Through the detection of autophagy substrates p62 and LC3, found that QBC939 cells have a higher flow of autophagy, autophagy inhibitor chloroquine can significantly increase the sensitivity of cisplatin in cholangiocarcinoma cells compared with hepatocellular carcinoma HepG2 cells. The mechanism may be related to the inhibition of QBC939 cells with higher activity of the PPP, the key enzyme G6PDH, which reduces the antioxidant capacity of cells and increases intracellular ROS, especially mitochondrial ROS. Therefore, we hypothesized that autophagy and the oxidative stress resistance mediated by glucose metabolism may be one of the causes of cisplatin resistance in cholangiocarcinoma cells. It is suggested that according to the metabolism characteristics of tumor cells, inhibition of autophagy lysosome pathway with chloroquine may be a new route for therapeutic agents against cholangiocarcinoma.

  14. Ginger Phytochemicals Inhibit Cell Growth and Modulate Drug Resistance Factors in Docetaxel Resistant Prostate Cancer Cell.

    Science.gov (United States)

    Liu, Chi-Ming; Kao, Chiu-Li; Tseng, Yu-Ting; Lo, Yi-Ching; Chen, Chung-Yi

    2017-09-05

    Ginger has many bioactive compounds with pharmacological activities. However, few studies are known about these bioactive compounds activity in chemoresistant cells. The aim of the present study was to investigate the anticancer properties of ginger phytochemicals in docetaxel-resistant human prostate cancer cells in vitro. In this study, we isolated 6-gingerol, 10-gingerol, 4-shogaol, 6-shogaol, 10-shogaol, and 6-dehydrogingerdione from ginger. Further, the antiproliferation activity of these compounds was examined in docetaxel-resistant (PC3R) and sensitive (PC3) human prostate cancer cell lines. 6-gingerol, 10-gingerol, 6-shogaol, and 10-shogaol at the concentration of 100 μM significantly inhibited the proliferation in PC3R but 6-gingerol, 6-shogaol, and 10-shogaol displayed similar activity in PC3. The protein expression of multidrug resistance associated protein 1 (MRP1) and glutathione-S-transferase (GSTπ) is higher in PC3R than in PC3. In summary, we isolated the bioactive compounds from ginger. Our results showed that 6-gingerol, 10-gingerol, 6-shogaol, and 10-shogaol inhibit the proliferation of PC3R cells through the downregulation of MRP1 and GSTπ protein expression.

  15. Synthesis of multidrug resistance modulator LY335979 labeled with deuterium and tritium

    International Nuclear Information System (INIS)

    Czeskis, B.A.

    1997-01-01

    DIDEUTERO AND DITRITIOISOTOPOMERS OF THE MULTIDRUG RESISTANCE MODULATOR LY335979 WERE PREPARED BY INITIAL BROMINATION OF 5-HYDROXYQUINOLINE UNDER ACIDIC CONDITIONS FOLLOWED BY MITSUNOBU COUPLING OF 6,8-DIBROMO-5-HYDROXYQUINOLINE WITH (S)-GLYCIDOL. OPENING OF THE RESULTING EPOXIDE WITH DIBENZOSUBERYLPIPERAZINE LY335995 RESULTED IN DIBROMOANALOG OF LY335979, WHICH WAS FINALLY REDUCTIVELY DEBROMINATED WITH DEUTERIUM OR TRITIUM IN THE PRESENCE OF PALLADIUM ON CARBON. (AUTHOR)

  16. Strain-Modulated Bandgap and Piezo-Resistive Effect in Black Phosphorus Field-Effect Transistors.

    Science.gov (United States)

    Zhang, Zuocheng; Li, Likai; Horng, Jason; Wang, Nai Zhou; Yang, Fangyuan; Yu, Yijun; Zhang, Yu; Chen, Guorui; Watanabe, Kenji; Taniguchi, Takashi; Chen, Xian Hui; Wang, Feng; Zhang, Yuanbo

    2017-10-11

    Energy bandgap largely determines the optical and electronic properties of a semiconductor. Variable bandgap therefore makes versatile functionality possible in a single material. In layered material black phosphorus, the bandgap can be modulated by the number of layers; as a result, few-layer black phosphorus has discrete bandgap values that are relevant for optoelectronic applications in the spectral range from red, in monolayer, to mid-infrared in the bulk limit. Here, we further demonstrate continuous bandgap modulation by mechanical strain applied through flexible substrates. The strain-modulated bandgap significantly alters the density of thermally activated carriers; we for the first time observe a large piezo-resistive effect in black phosphorus field-effect transistors (FETs) at room temperature. The effect opens up opportunities for future development of electromechanical transducers based on black phosphorus, and we demonstrate an ultrasensitive strain gauge constructed from black phosphorus thin crystals.

  17. Chloroquine cardiotoxicity mimicking connective tissue disease heart involvement.

    Science.gov (United States)

    Vereckei, András; Fazakas, Adám; Baló, Timea; Fekete, Béla; Molnár, Mária Judit; Karádi, István

    2013-04-01

    The authors report a case of rare chloroquine cardiotoxicity mimicking connective tissue disease heart involvement in a 56-year-old woman with mixed connective tissue disease (MCTD) manifested suddenly as third degree A-V block with QT(c) interval prolongation and short torsade de pointes runs ultimately degenerating into ventricular fibrillation. Immunological tests suggested an MCTD flare, implying that cardiac arrest had resulted from myocardial involvement by MCTD. However, QT(c) prolongation is not a characteristic of cardiomyopathy caused by connective tissue disease, unless anti-Ro/SSA positivity is present, but that was not the case. Therefore, looking for another cause of QT(c) prolongation the possibility of chloroquine cardiotoxicity emerged, which the patient had been receiving for almost two years in supramaximal doses. Biopsy of the deltoid muscle was performed, because in chloroquine toxicity, specific lesions are present both in the skeletal muscle and in the myocardium, and electron microscopy revealed the accumulation of cytoplasmic curvilinear bodies, which are specific to antimalarial-induced myocyte damage and are absent in all other muscle diseases, except neuronal ceroid lipofuscinosis. Thus, the diagnosis of chloroquine cardiotoxicity was established. It might be advisable to supplement the periodic ophthalmological examination, which is currently the only recommendation for patients on long-term chloroquine therapy, with ECG screening.

  18. Multifocal Electroretinography after High Dose Chloroquine Therapy for Malaria

    Directory of Open Access Journals (Sweden)

    Aline Correa de Carvalho

    2013-01-01

    Full Text Available Purpose: To investigate changes in multifocal electroretinography (mfERG parameters associated with high dose chloroquine therapy for treatment of malaria in the Amazonia region of Brazil. Methods: Forty-eight subjects who had received chloroquine treatment for single or multiple malaria infections with a cumulative dose ranging from 1,050 to 27,000mg were included. The control group consisted of 37 healthy aged-matched subjects. Data was collected on amplitude and implicit time of the N1, P1 and N2 waves in the central macular hexagon (R1 and in five concentric rings at different retinal eccentricities (R2-R6. Results: No significant difference was observed in any mfERG parameter between chloroquine treated patients and control subjects. A comparison with previous data obtained from patients with rheumatologic disorders in the same region of Brazil who had received larger cumulative doses of chloroquine and had displayed mfERG changes, indicated that retinal toxicity seems to be dependent on cumulative dose. Conclusion: Lack of mfERG changes in the current study suggests that intensive high dose chloroquine therapy for treatment of malaria is not associated with retinal toxicity.

  19. A Method for testing the integrated thermal resistance of thermoelectric modules

    Science.gov (United States)

    Gao, Junling; Du, Qungui; Chen, Min

    2013-11-01

    The integrated thermal resistance (ITR) of thermoelectric modules (TEMs) is an important parameter that represents the thermal-conduction of ceramic substrates, copper conducting strips, and welding material used in the TEM as well as the thermal contact resistances between different materials. In this study, an accurate and practical test method is proposed for the ITR of TEMs according to thermoelectric heat transfer theory and the equivalent characteristics of heat flux through the cold and hot sides of TEMs in an open-circuit situation. By using such measurements and comparisons, it is verified that the measured ITR value in our mode is accurate and reliable. In particular this method accurately predicts the actual operating conditions of TEMs, in which TEMs are under certain mechanical pressure. It effectively solves the problem of thermal resistance extraction from operating TEMs and is of great significance in their analysis and optimization.

  20. Stability of chloroquine phosphate tablets inoculated with bacterial species

    International Nuclear Information System (INIS)

    Obuekwe, I.F.; Orhe, C.A.; Iwaagu, M.U.

    2003-01-01

    Five popular brands of chloroquine tablets available to the average Nigerian consumers were examined for the effects of Staphylococcus aureus and Bacillus cereus, on the dissolution, disintegration and hardness after six weeks of incubation. The maximum percent dissolution was 98.34% with bacillus subtilis while the minimum was 19.12% with staphylococcus aureus. The disintegration results showed a maximum of 69 min. 19 sec with Staphylococcus aureus while the least was 56 sec with Bacillus subtilis. The maximum hardness obtained was 12.75 kg and the least was 1.25 kg also with Staphylococcus aureus. The dissolution, disintegration and hardness also varied with the control. The metabolic activities of the bacterial species were believed to have caused the variations in the physical properties of the chloroquine phosphate tablets. The results from this investigation strongly advises adequate storage of chloroquine phosphate tablets, especially when it is the drug of choice for the of sub-Saharan Africa. (author)

  1. Noise analysis due to strip resistance in the ATLAS SCT silicon strip module

    International Nuclear Information System (INIS)

    Kipnis, I.

    1996-08-01

    The module is made out of four 6 cm x 6 cm single sided Si microstrip detectors. Two detectors are butt glued to form a 12 cm long mechanical unit and strips of the two detectors are electrically connected to form 12 cm long strips. The butt gluing is followed by a back to back attachment. The module in this note is the Rφ module where the electronics is oriented parallel to the strip direction and bonded directly to the strips. This module concept provides the maximum signal-to-noise ratio, particularly when the front-end electronics is placed near the middle rather than at the end. From the noise analysis, it is concluded that the worst-case ΔENC (far-end injection) between end- and center-tapped modules will be 120 to 210 el. rms (9 to 15%) for a non-irradiated detector and 75 to 130 el. rms (5 to 9%) for an irradiated detector, for a metal strip resistance of 10 to 20 Ω/cm

  2. Lack of protection against ebola virus from chloroquine in mice and hamsters.

    Science.gov (United States)

    Falzarano, Darryl; Safronetz, David; Prescott, Joseph; Marzi, Andrea; Feldmann, Friederike; Feldmann, Heinz

    2015-06-01

    The antimalarial drug chloroquine has been suggested as a treatment for Ebola virus infection. Chloroquine inhibited virus replication in vitro, but only at cytotoxic concentrations. In mouse and hamster models, treatment did not improve survival. Chloroquine is not a promising treatment for Ebola. Efforts should be directed toward other drug classes.

  3. Tritium labelling and characterization of the antimalarial drug (+/-)-chloroquine by several methods

    Energy Technology Data Exchange (ETDEWEB)

    Egan, J.A.Judith A.; Laseter, Anne G; Filer, C.N.Crist N. E-mail: crist.filer@perkinelmer.com

    2002-09-01

    To study its mechanism of antimalarial action, a tritium labelled analogue of (+/-)-chloroquine was required at high specific activity. Two synthetic methods were successfully employed. [3-{sup 3}H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl-{sup 3}H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [{sup 3}H] ethyl iodide.

  4. Tritium labelling and characterization of the antimalarial drug (+/-)-chloroquine by several methods

    International Nuclear Information System (INIS)

    Egan, J.A.Judith A.; Laseter, Anne G.; Filer, C.N.Crist N.

    2002-01-01

    To study its mechanism of antimalarial action, a tritium labelled analogue of (+/-)-chloroquine was required at high specific activity. Two synthetic methods were successfully employed. [3- 3 H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl- 3 H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [ 3 H] ethyl iodide

  5. Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids

    Directory of Open Access Journals (Sweden)

    Buddhasukh Duang

    2004-04-01

    Full Text Available Abstract Background Multidrug resistance (MDR is a phenomenon that is often associated with decreased intracellular drug accumulation in patient's tumor cells resulting from enhanced drug efflux. It is related to the overexpression of a membrane protein, P-glycoprotein (Pgp-170, thereby reducing drug cytotoxicity. A variety of studies have tried to find MDR modulators which increase drug accumulation in cancer cells. Methods In this study, natural curcuminoids, pure curcumin, demethoxycurcumin and bisdemethoxycurcumin, isolated from turmeric (Curcuma longa Linn, were compared for their potential ability to modulate the human MDR-1 gene expression in multidrug resistant human cervical carcinoma cell line, KB-V1 by Western blot analysis and RT-PCR. Results Western blot analysis and RT-PCR showed that all the three curcuminoids inhibited MDR-1 gene expression, and bisdemethoxycurcumin produced maximum effect. In additional studies we found that commercial grade curcuminoid (approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemthoxycurcumin decreased MDR-1 gene expression in a dose dependent manner and had about the same potent inhibitory effect on MDR-1 gene expression as our natural curcuminoid mixtures. Conclusion These results indicate that bisdemethoxycurcumin is the most active of the curcuminoids present in turmeric for modulation of MDR-1 gene. Treatment of drug resistant KB-V1 cells with curcumin increased their sensitivity to vinblastine, which was consistent with a decreased MDR-1 gene product, a P-glycoprotein, on the cell plasma membrane. Although many drugs that prevent the P-glycoprotein function have been reported, this report describes the inhibition of MDR-1 expression by a phytochemical. The modulation of MDR-1 expression may be an attractive target for new chemosensitizing agents.

  6. Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids

    International Nuclear Information System (INIS)

    Limtrakul, Pornngarm; Anuchapreeda, Songyot; Buddhasukh, Duang

    2004-01-01

    Multidrug resistance (MDR) is a phenomenon that is often associated with decreased intracellular drug accumulation in patient's tumor cells resulting from enhanced drug efflux. It is related to the overexpression of a membrane protein, P-glycoprotein (Pgp-170), thereby reducing drug cytotoxicity. A variety of studies have tried to find MDR modulators which increase drug accumulation in cancer cells. In this study, natural curcuminoids, pure curcumin, demethoxycurcumin and bisdemethoxycurcumin, isolated from turmeric (Curcuma longa Linn), were compared for their potential ability to modulate the human MDR-1 gene expression in multidrug resistant human cervical carcinoma cell line, KB-V1 by Western blot analysis and RT-PCR. Western blot analysis and RT-PCR showed that all the three curcuminoids inhibited MDR-1 gene expression, and bisdemethoxycurcumin produced maximum effect. In additional studies we found that commercial grade curcuminoid (approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemthoxycurcumin) decreased MDR-1 gene expression in a dose dependent manner and had about the same potent inhibitory effect on MDR-1 gene expression as our natural curcuminoid mixtures. These results indicate that bisdemethoxycurcumin is the most active of the curcuminoids present in turmeric for modulation of MDR-1 gene. Treatment of drug resistant KB-V1 cells with curcumin increased their sensitivity to vinblastine, which was consistent with a decreased MDR-1 gene product, a P-glycoprotein, on the cell plasma membrane. Although many drugs that prevent the P-glycoprotein function have been reported, this report describes the inhibition of MDR-1 expression by a phytochemical. The modulation of MDR-1 expression may be an attractive target for new chemosensitizing agents

  7. Monitoring of clinical efficacy and in vitro sensitivity of Plasmodium vivax to chloroquine in area along Thai Myanmar border during 2009-2010

    Directory of Open Access Journals (Sweden)

    Rungsihirunrat Kanchana

    2011-02-01

    Full Text Available Abstract Background In Thailand, the proportion of Plasmodium vivax infection has become equal to Plasmodium falciparum. Reports of a trend of gradual decline of in vitro sensitivity of P. vivax to chloroquine in some areas of the country, together with accumulating evidences of chloroquine resistance P. vivax in other parts of the world, emphasize the need for closely and continuously monitoring clinical efficacy in conjunction with in vitro sensitivity of P. vivax isolates. Methods The study was conducted at Mae Tao clinic for migrant workers, Tak Province during March 2008 - August 2009. A total of 130 patients (17 Thais and 113 Burmeses; 64 males and 66 females with mono-infection of P. vivax malaria, aged between 15-60 years and weighing more than 40 kg, were included in the study. Patients received treatment with chloroquine (2,000 mg chloroquine phosphate over three days and the anti-relapse drug primaquine (15 mg for 14 days. In vitro sensitivity of P. vivax isolates was evaluated by schizont maturation inhibition assay. Results All patients showed satisfactory response to treatment. The cure rate was virtually 100% within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred during the investigation period. In vitro data showed a stable sensitivity of chloroquine in this area since 2006. Geometric mean and median (95% CI values of IC50 for chloroquine were 100.1 and 134.7 (1.1-264.9 nM, respectively. Conclusion In vivo results suggest that the standard regimen of chloroquine was still very effective for the treatment of blood infections with P. vivax in the Thai-Myanmar border area. In vitro sensitivity data however, raise the possibility of potential advent of resistance in the future. Regular monitoring of the chloroquine sensitivity of P. vivax is essential to facilitate the early recognition of treatment failures and to expedite the formulation of appropriate changes to

  8. Labeled chloroquine analog in diagnosis of ocular and dermal melanomas

    International Nuclear Information System (INIS)

    Beierwaltes, W.H.

    1974-01-01

    On the basis of the melanin-specific properties of chloroquine, an 125 I-labeled chloroquine analog (NM-113) was synthesized for use in the diagnosis of ocular and dermal melanomas. The limitations and indications for the use of NM-113 in the diagnosis of dermal melanomas are summarized, and its efficiency in the diagnosis of ocular melanomas is discussed. The low probability of side effects (radiation effects) on the retina from a diagnostic dose of 2 m Ci (46 rads) is mentioned. (U.S.)

  9. Chloroquine-resistant Plasmodium falciparum malaria·in the ...

    African Journals Online (AJOL)

    of 4-aminoquinolines. The blood and urine specimens were transported on ice to a fIeld laboratory where they were processed within 12 hours of collection. The laboratory con- sisted of a thatch-roofed hut, with reed walls and ~ement floor. A pair of portable 220 V generators supplied power to a microscope, a centrifuge, an ...

  10. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: a randomised, double-blind study. Malarone International Study Team.

    Science.gov (United States)

    Høgh, B; Clarke, P D; Camus, D; Nothdurft, H D; Overbosch, D; Günther, M; Joubert, I; Kain, K C; Shaw, D; Roskell, N S; Chulay, J D

    2000-12-02

    Chloroquine plus proguanil is widely used for malaria chemoprophylaxis despite low effectiveness in areas where multidrug-resistant malaria occurs. Studies have shown that atovaquone and proguanil hydrochloride is safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but little is known about non-immune travellers. In a double-blind equivalence trial, 1083 participants travelling to a malaria-endemic area were randomly assigned to two treatment groups: atovaquone-proguanil plus placebos for chloroquine and proguanil, or chloroquine, proguanil, and placebo for atovaquone-proguanil. Follow-up was by telephone 7 and 60 days after travel and at a clinic at 28 days. Serum samples were tested for antibodies to a malaria circumsporozoite protein. Blood and serum samples of participants with a potential malaria diagnosis were tested in a reference laboratory. 7 days after travel, at least one adverse event was reported by 311 (61%) of 511 participants who received atovaquone-proguanil and 329 (64%) of 511 who received chloroquine-proguanil. People receiving atovaquone-proguanil had a lower frequency of treatment-related gastrointestinal adverse events (59 [12%] vs 100 [20%], p=0.001), and of treatment-related adverse events of moderate or severe intensity (37 [7%] vs 56 [11%], p=0.05). There were fewer treatment-related adverse events that caused prophylaxis to be discontinued in the atovaquone-proguanil group than in the chloroquine-proguanil group (one [0.2%] vs ten [2%], p=0.015). Overall the two preparations were similarly tolerated. However, significantly fewer adverse gastrointestinal events were observed in the atovaquone-proguanil group in than in the chloroquine-proguanil group.

  11. Role of Nutrients and Phyto-compounds in the Modulation of Antimicrobial Resistance.

    Science.gov (United States)

    Harakeh, Steve; Khan, Imran; Almasaudi, Saad B; Azhar, Esam I; Al-Jaouni, Soad; Niedzweicki, Aleksandra

    2017-01-01

    Antimicrobial resistance is quickly spreading and has become a major public health problem worldwide. If this issue is not resolved, it may cause a shift back to the pre-antibiotics era and infectious disease will again be a serious problem, especially in developing countries. Since the discovery of antibiotics, bacterial resistance has emerged, enabling certain bacteria to withstand antibiotic action. The emergence of antibiotic resistance is fueled by excessive and improper use of antimicrobial agents, especially in developing countries. For this reason, alternatives to or modifications of current treatment methods have been sought. The aim of this review is to highlight the possible synergies of various agents that can augment antibiotic activities. A structured literature search was conducted using only papers that have been published in PubMed with the focus on the agents that are likely to modulate antimicrobial resistance. In this review, data was retrieved from the literature regarding the possible synergies that exist between commercially available antimicrobial drugs with agents of interest. The papers included were summarized and analyzed, critiqued and compared for their contents using a conceptual frame-work. In total, one hundred and twenty six papers were reviewed. The number of papers that dealt with the different topics included are as follows (): emergence of antimicrobial resistance (22), bioactive phyto-compounds (36) (phytobiologics, and phytochemicals), Antioxidants (40) (N-acetylcysteine, Ambroxol, Ascorbic acid, Glutathione and vitamin E), Peptide synergies (14) (Synthetic cationic α-helical AMPs, CopA3, Alafosfalin, PMAP-36, Phosphonopeptide L-norvalyl-L-1-aminoethylphosphonic acid and norcardicin-A), nano-antibiotics (10), drug-compound interactions (4).This review addressed the new strategies using the above compounds in the modulation of antimicrobial resistance to avoid issues related to resistance of bacteria to antibiotics. The

  12. Human Intestinal Cells Modulate Conjugational Transfer of Multidrug Resistance Plasmids between Clinical Escherichia coli Isolates

    DEFF Research Database (Denmark)

    Machado, Ana Manuel; Sommer, Morten

    2014-01-01

    Bacterial conjugation in the human gut microbiota is believed to play a major role in the dissemination of antibiotic resistance genes and virulence plasmids. However, the modulation of bacterial conjugation by the human host remains poorly understood and there is a need for controlled systems...... to study this process. We established an in vitro co-culture system to study the interaction between human intestinal cells and bacteria. We show that the conjugation efficiency of a plasmid encoding an extended spectrum beta-lactamase is reduced when clinical isolates of Escherichia coli are co...... of the intestinal cells exposed to bacteria leading to a two-fold reduction in conjugation efficiency. These results show that human gut epithelial cells can modulate bacterial conjugation and may have relevance to gene exchange in the gut....

  13. Chloroquine is grossly under dosed in young children with malaria

    DEFF Research Database (Denmark)

    Ursing, Johan; Eksborg, Staffan; Rombo, Lars

    2014-01-01

    BACKGROUND: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy...

  14. Visual function and long-term chloroquine treatment

    African Journals Online (AJOL)

    Amsler grids and a further battery offour tests of macular function (visual evoked potentials, criti- cal flicker fusion threshold, Cambridge contrast sensitivity and the macular dazzle test) were administered. No case of retinal pigmentary abnonnalities plus visual loss was found, but 2 patients were advised to cease chloroquine.

  15. Effects Of Chloroquine On Some Visceral Organs In The Rabbit ...

    African Journals Online (AJOL)

    Effects Of Chloroquine On Some Visceral Organs In The Rabbit: Histopathological Perspective. ... Journal of Experimental and Clinical Anatomy ... 60 and 90 days in the albino (n=10) and pigmented (n=22) rabbits, with mean weight value of 1.40 ± 0.44kg and mean age value of 9.0 ± 0.25 months were investigated in the ...

  16. Effects of co-administration of chloroquine with paracetamol or ...

    African Journals Online (AJOL)

    The effects of co-administration of oral chloroquine with paracetamol or with ibuprofen on renal function were studied using 6 groups of New Zealand White rabbits. Group 1, the control group received only feed and water. The other groups (Groups 2-6) either received single therapies of paracetamol (10 mg/kg of body ...

  17. Abscisic acid-cytokinin antagonism modulates resistance against pseudomonas syringae in Tobacco

    DEFF Research Database (Denmark)

    Grosskinsky, Dominik Kilian; van der Graaff, Eric; Roitsch, Thomas Georg

    2014-01-01

    Phytohormones are known as essential regulators of plant defenses, with ethylene, jasmonic acid, and salicylic acid as the central immunity backbone, while other phytohormones have been demonstrated to interact with this. Only recently, a function of the classic phytohormone cytokinin in plant...... immunity has been described in Arabidopsis, rice, and tobacco. Although interactions of cytokinins with salicylic acid and auxin have been indicated, the complete network of cytokinin interactions with other immunity-relevant phytohormones is not yet understood. Therefore, we studied the interaction...... of kinetin and abscisic acid as a negative regulator of plant immunity to modulate resistance in tobacco against Pseudomonas syringae. By analyzing infection symptoms, pathogen proliferation, and accumulation of the phytoalexin scopoletin as a key mediator of kinetin-induced resistance in tobacco...

  18. Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo.

    Science.gov (United States)

    Takano, Tomomi; Katoh, Yasuichiroh; Doki, Tomoyoshi; Hohdatsu, Tsutomu

    2013-08-01

    Feline infectious peritonitis (FIP) is a feline coronavirus-induced fatal disease in domestic and wild cats. Several studies have investigated potential treatments for FIP. However, there have been no reports on agents that have exhibited a therapeutic effect. Recently, chloroquine has been reported to antiviral effect. We investigated whether chloroquine can be used to treat FIP in vitro and in vivo. It was demonstrated that chloroquine has inhibitory effect against the replication of FIPV and anti-inflammatory effect in vitro. In vivo study using cats with experimentally induced FIP, the clinical score of chloroquine-treatment groups were better than in chloroquine-untreated group. However, alanine aminotransferase levels increased in the chloroquine-treated groups. It will be necessary to further investigate the possibility of FIP treatment with a combination of chloroquine and other agents. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Impact of Chloroquine on Viral Load in Breast Milk

    Science.gov (United States)

    Semrau, Katherine; Kuhn, Louise; Kasonde, Prisca; Sinkala, Moses; Kankasa, Chipepo; Shutes, Erin; Vwalika, Cheswa; Ghosh, Mrinal; Aldrovandi, Grace; Thea, Donald M.

    2006-01-01

    Summary The anti-malarial agent chloroquine has activity against HIV. We compared the effect of chloroquine (n = 18) to an anti-malarial agent without known anti-HIV-activity, sulfadoxine-pyrimethamine (n = 12), on breast milk HIV RNA levels among HIV-infected breastfeeding women in Zambia. After adjusting for CD4 count and plasma viral load, chloroquine was associated with a trend towards lower levels of HIV RNA in breast milk compared with sulfadoxine-pyrimethamine (P 0.05). Higher breastmilk viral load was also observed among women receiving presumptive treatment = for symptomatic malaria compared with asymptomatic controls and among controls reporting fever in the prior week. Further research is needed to determine the potential role of chloroquine in prevention of HIV transmission through breastfeeding. Impacte de la chloroquine sur la charge virale dans le lait maternelle La chloroquine, agent antimalarique, a une activité contre le VIH. Nous avons comparé l’effet de la chloroquine à celui d’un autre agent antimalarique, la sulfadoxine-pyrimethamine, dont l’activité sur le VIH n’est pas connue, en mesurant les taux d’ARN de VIH dans le lait maternel de femmes allaitantes infectées par le VIH en Zambie. Après ajustement pour les taux de CD4 et la charge virale dans le plasma, la chloroquine comparée à la sulfadoxine pyrimethamine était associée à une tendance vers des teneurs plus bas en ARN de VIH dans le lait maternel (P = 0,05). Des charges virales plus élevées dans le lait maternel étaient aussi observées chez des femmes recevant un traitement présomptif pour des symptômes de malaria par rapport aux contrôles asymptomatiques et par rapport à des contrôles rapportant de la fièvre durant la première semaine. Des études supplémentaires sont nécessaires pour déterminer le rôle potentiel de la chloroquine dans la prévention de la transmission du VIH par l’allaitement maternel. mots clésVIH, malaria, allaitement maternel

  20. Abscisic Acid-Cytokinin Antagonism Modulates Resistance Against Pseudomonas syringae in Tobacco.

    Science.gov (United States)

    Großkinsky, Dominik K; van der Graaff, Eric; Roitsch, Thomas

    2014-12-01

    Phytohormones are known as essential regulators of plant defenses, with ethylene, jasmonic acid, and salicylic acid as the central immunity backbone, while other phytohormones have been demonstrated to interact with this. Only recently, a function of the classic phytohormone cytokinin in plant immunity has been described in Arabidopsis, rice, and tobacco. Although interactions of cytokinins with salicylic acid and auxin have been indicated, the complete network of cytokinin interactions with other immunity-relevant phytohormones is not yet understood. Therefore, we studied the interaction of kinetin and abscisic acid as a negative regulator of plant immunity to modulate resistance in tobacco against Pseudomonas syringae. By analyzing infection symptoms, pathogen proliferation, and accumulation of the phytoalexin scopoletin as a key mediator of kinetin-induced resistance in tobacco, antagonistic interaction of these phytohormones in plant immunity was identified. Kinetin reduced abscisic acid levels in tobacco, while increased abscisic acid levels by exogenous application or inhibition of abscisic acid catabolism by diniconazole neutralized kinetin-induced resistance. Based on these results, we conclude that reduction of abscisic acid levels by enhanced abscisic acid catabolism strongly contributes to cytokinin-mediated resistance effects. Thus, the identified cytokinin-abscisic acid antagonism is a novel regulatory mechanism in plant immunity.

  1. A vacancy-modulated self-selective resistive switching memory with pronounced nonlinear behavior

    Science.gov (United States)

    Ma, Haili; Feng, Jie; Gao, Tian; Zhu, Xi

    2017-12-01

    In this study, we report a self-selective (nonlinear) resistive switching memory cell, with high on-state half-bias nonlinearity of 650, sub-μA operating current, and high On/Off ratios above 100×. Regarding the cell structure, a thermal oxidized HfO x layer in combination with a sputtered Ta2O5 layer was configured as an active stack, with Pt and Hf as top and bottom electrodes, respectively. The Ta2O5 acts as a selective layer as well as a series resistor, which could make the resistive switching happened in HfO x layer. Through the analysis of the physicochemical properties and electrical conduction mechanisms at each state, a vacancy-modulated resistance switching model was proposed to explain the switching behavior. The conductivity of HfO x layer was changed by polarity-dependent drift of the oxygen vacancy ( V o), resulting in an electron hopping distance change during switching. With the help of Ta2O5 selective layer, high nonlinearity observed in low resistance state. The proposed material stack shows a promising prospect to act as a self-selective cell for 3D vertical RRAM application.

  2. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Hannele Yki-Järvinen

    2015-11-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL to non-alcoholic steatohepatitis (NASH and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD. Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA as compared to monounsaturated (MUFA or polyunsaturated (PUFA fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.

  3. Molecular surveillance of drug resistance through imported isolates of Plasmodium falciparum in Europe

    DEFF Research Database (Denmark)

    Jelinek, Tomas; Peyerl-Hoffmann, Gabriele; Mühlberger, Nikolai

    2002-01-01

    and chloroquine. The screening results were used to map the prevalence of mutations and, thus, levels of potential drug resistance in endemic areas world-wide. RESULTS: 337 isolates have been tested so far. Prevalence of mutations that are associated with resistance to chloroquine on the pfcrt and pfmdr genes...

  4. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice.

    Directory of Open Access Journals (Sweden)

    Andréa M Caricilli

    2011-12-01

    Full Text Available Environmental factors and host genetics interact to control the gut microbiota, which may have a role in the development of obesity and insulin resistance. TLR2-deficient mice, under germ-free conditions, are protected from diet-induced insulin resistance. It is possible that the presence of gut microbiota could reverse the phenotype of an animal, inducing insulin resistance in an animal genetically determined to have increased insulin sensitivity, such as the TLR2 KO mice. In the present study, we investigated the influence of gut microbiota on metabolic parameters, glucose tolerance, insulin sensitivity, and signaling of TLR2-deficient mice. We investigated the gut microbiota (by metagenomics, the metabolic characteristics, and insulin signaling in TLR2 knockout (KO mice in a non-germ free facility. Results showed that the loss of TLR2 in conventionalized mice results in a phenotype reminiscent of metabolic syndrome, characterized by differences in the gut microbiota, with a 3-fold increase in Firmicutes and a slight increase in Bacteroidetes compared with controls. These changes in gut microbiota were accompanied by an increase in LPS absorption, subclinical inflammation, insulin resistance, glucose intolerance, and later, obesity. In addition, this sequence of events was reproduced in WT mice by microbiota transplantation and was also reversed by antibiotics. At the molecular level the mechanism was unique, with activation of TLR4 associated with ER stress and JNK activation, but no activation of the IKKβ-IκB-NFκB pathway. Our data also showed that in TLR2 KO mice there was a reduction in regulatory T cell in visceral fat, suggesting that this modulation may also contribute to the insulin resistance of these animals. Our results emphasize the role of microbiota in the complex network of molecular and cellular interactions that link genotype to phenotype and have potential implications for common human disorders involving obesity, diabetes

  5. Detection of expression and modulation of multidrug-resistance (MDR) and establishment of a new bioassay

    International Nuclear Information System (INIS)

    Berger, W.

    1993-08-01

    The present thesis deals with the resistance of human malignant cells against cellular toxicity of anticancer drugs, a phenomenon representing one of the major obstacles to successful chemotherapy. One mechanism underlying a cross-resistance to different drugs called multidrug resistance (MDR) is characterized by the expression of an active transport protein (P-glycoprotein), causing decreased intracellular drug retention and cytotoxicity. The main subjects of the present work were to establish different detection methods for MDR and its modulation (by substances blocking activity of P-glycoprotein) including immunological methods (immunocytochemistry, radioimmunoassay), molecular biology (slot-blot analysis, in-situ hybridization) and functional assays (drug-accumulation analysis, drug-cytotoxicity analysis). The methods were evaluated and compared using human and mouse MDR control cell lines and human tumor cell lines established in our laboratory. In cell lines derived from human melanoma - a malignancy insensitive to chemotherapy - expression of P-glycoprotein of relatively low transporting activity was detected by different methods in 8 of 33 cases. Furthermore a new sensitive in vitro assay for the functional detection of MDR was established using the biological features of cytochalasins, a microfilament disrupting substance group. These compounds were shown to be substrates for the P-glycoprotein efflux pump and their effects on cell division (blockade of cytokinesis resulting in multinucleate cells) correlated with MDR-activity of the tested cells. With this new assay P-glycoprotein activity can be demonstrated and analysed over a wide range of resistance against different cytotoxic drugs. Therefore it may by a suitable tool for research and diagnosis in the field of drug resistance

  6. Tannic Acid as a Potential Modulator of Norfloxacin Resistance in Staphylococcus Aureus Overexpressing norA.

    Science.gov (United States)

    Diniz-Silva, Helena Taina; Cirino, Isis Caroline da Silva; Falcão-Silva, Vivyanne Dos Santos; Magnani, Marciane; de Souza, Evandro Leite; Siqueira-Júnior, José P

    2016-01-01

    Tannins have shown inhibitory effects against pathogenic bacteria, and these properties make tannins potential modifying agents in bacterial resistance. The minimum inhibitory concentration (MIC) of tannic acid (TA), gallic acid (GA) and norfloxacin (Nor) against Staphylococcus aureus SA-1119 (NorA-effluxing strain) was determined using broth microdilution tests. To assess the modulation of antibiotic resistance, the MIC of Nor was determined in growth media with or without TA or GA at a subinhibitory concentration (1/4 MIC). The checkerboard method was performed to obtain the fractional inhibitory concentration index (FICI) for the combined application of TA and Nor. TA displayed a weak inhibitory effect (MIC 512 μg/ml) against S. aureus SA-1119, while no inhibitory effect was displayed by GA (MIC >512 μg/ml). However, when TA was tested at a subinhibitory concentration in combination with Nor, the MIC of Nor against S. aureus SA-1119 decreased from 128 to 4 μg/ml (32-fold); this effect was not observed for GA. In the checkerboard assay, the MIC of TA and Nor decreased from 512 to 128 μg/ml (4-fold) and from 128 to 8 μg/ml (16-fold), respectively. The combination of TA and Nor presented an FICI as low as 0.31, which indicates a synergistic interaction. TA is a potential agent for increasing the clinical efficacy of Nor to control resistant S. aureus. © 2016 S. Karger AG, Basel.

  7. Alcohol resistance in Drosophila is modulated by the Toll innate immune pathway.

    Science.gov (United States)

    Troutwine, B R; Ghezzi, A; Pietrzykowski, A Z; Atkinson, N S

    2016-04-01

    A growing body of evidence has shown that alcohol alters the activity of the innate immune system and that changes in innate immune system activity can influence alcohol-related behaviors. Here, we show that the Toll innate immune signaling pathway modulates the level of alcohol resistance in Drosophila. In humans, a low level of response to alcohol is correlated with increased risk of developing an alcohol use disorder. The Toll signaling pathway was originally discovered in, and has been extensively studied in Drosophila. The Toll pathway is a major regulator of innate immunity in Drosophila, and mammalian Toll-like receptor signaling has been implicated in alcohol responses. Here, we use Drosophila-specific genetic tools to test eight genes in the Toll signaling pathway for effects on the level of response to ethanol. We show that increasing the activity of the pathway increases ethanol resistance whereas decreasing the pathway activity reduces ethanol resistance. Furthermore, we show that gene products known to be outputs of innate immune signaling are rapidly induced following ethanol exposure. The interaction between the Toll signaling pathway and ethanol is rooted in the natural history of Drosophila melanogaster. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  8. Efficacy of chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in Honduras.

    Science.gov (United States)

    Mejia Torres, Rosa Elena; Banegas, Engels Ilich; Mendoza, Meisy; Diaz, Cesar; Bucheli, Sandra Tamara Mancero; Fontecha, Gustavo A; Alam, Md Tauqeer; Goldman, Ira; Udhayakumar, Venkatachalam; Zambrano, Jose Orlinder Nicolas

    2013-05-01

    Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization-World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras.

  9. NFκBP65 transcription factor modulates resistance to doxorubicin through ABC transporters in breast cancer.

    Science.gov (United States)

    Velaei, Kobra; Samadi, Nasser; Soltani, Sina; Barazvan, Balal; Soleimani Rad, Jafar

    2017-07-01

    Shedding light on chemoresistance biology of breast cancer could contribute to enhance the clinical outcome. Intrinsic or acquired resistance to chemotherapy is a major problem in breast cancer treatment. The NFκB pathway by siRNAP65 and JSH-23 as a translocational inhibitor of NFκBP65 in the doxorubicin-resistant MCF-7 (MCF-7/Dox) and MCF-7 cells was blocked. Then, the ABC transporter expression and function were assessed by real-time qRT-PCR and flow cytometry, respectively. Induction of apoptosis was evaluated after inhibition of the NFΚB pathway as well. Our study underlined the upregulation of NFκBP65 and anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax in the MCF-7/Dox cells compared with control MCF-7 cells. Here, we showed that interplay between nuclear factor kappa B P65 (NFkBP65) as a transcriptional regulator and ABC transporters in the MCF-7/Dox cancer cells. We found that inhibition of the elevated expression of NFκBP65 in the resistant breast cancer, whether translocational inhibition or silencing by siRNA, decreased the expression and function of MDR1 and MRP1 efflux pumps. Furthermore, the blockade of NFκBP65 promoted apoptosis via modulating Bcl-2 and BAX expression. After inhibition of the NFκBP65 signaling pathway, elevated baseline expression of survival Bcl-2 gene in the resistant breast cells significantly decreased. Suppression of the NFκB pathway has a profound dual impact on promoting the intrinsic apoptotic pathway and reducing ABC transporter function and expression, which are some of the chemoresistance features. It was speculated that the NFκB pathway directly acts on doxorubicin-induced MDR1 and MRP1 expression in MCF-7/Dox cells.

  10. In vitro sensitivity pattern of chloroquine and artemisinin in Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Supriya Sharma

    2016-01-01

    Full Text Available Artemisinin (ART and its derivatives form the mainstay of antimalarial therapy. Emergence of resistance to them poses a potential threat to future malaria control and elimination on a global level. It is important to know the mechanism of action of drug and development of drug resistance. We put forwards probable correlation between the mode of action of chloroquine (CQ and ART. Modified trophozoite maturation inhibition assay, WHO Mark III assay and molecular marker study for CQ resistance at K76T codon in Plasmodium falciparum CQ-resistant transporter gene were carried out on cultured P. falciparum. On comparing trophozoite and schizont growth for both CQ-sensitive (MRC-2 and CQ-resistant (RKL-9 culture isolates, it was observed that the clearance of trophozoites and schizonts was similar with both drugs. The experiment supports that CQ interferes with heme detoxification pathway in food vacuoles of parasite, and this may be correlated as one of the plausible mechanisms of ART.

  11. Sulfadoxine-pyrimethamine monotherapy in Tanzanian children gives rapid parasite clearance but slow fever clearance that is improved by chloroquine in combination therapy

    DEFF Research Database (Denmark)

    Tarimo, D S; Minjas, J N; Bygbjerg, I C

    2002-01-01

    Following widespread chloroquine (CQ) resistance, sulfadoxine plus pyrimethamine (SP) is now the first line antimalarial drug in a number of African countries including Tanzania. Unlike CQ, SP has no antipyretic effects, a feature that might delay fever clearance, and by acting on late stage para...... on possible delayed parasitological and clinical responses to SP that could result from its action on late stage parasites. Despite its diminishing antimalarial activity, CQ has beneficial in vivo antipyretic effects in therapeutic combination with SP.......Following widespread chloroquine (CQ) resistance, sulfadoxine plus pyrimethamine (SP) is now the first line antimalarial drug in a number of African countries including Tanzania. Unlike CQ, SP has no antipyretic effects, a feature that might delay fever clearance, and by acting on late stage...

  12. Synthesis and Anticancer Activity of Gold(I)-Chloroquine Complexes

    OpenAIRE

    Navarro, Maribel; Castro, William; González, Sorenlis; Abad, María Jesús; Taylor, Peter

    2013-01-01

    Two new gold(I) -chloroquine complexes, Au(CQ)(Cl) (1) and Au(CQ)(tgta) (2), were prepared and their most probable structure were established through a combination of different spectroscopic and analytical techniques. Their interaction with two important targets of action, DNA and thioredoxin reductase (TrxR), were investigated. These studies showed that complexes 1 and 2 displayed two types of interaction with DNA, covalent binding through the metal center, and additionally a non-covalent in...

  13. Comparative In - vitro Efficacy of Chloroquine, Fansidar, Cotecxin ...

    African Journals Online (AJOL)

    le test de medicament invitro avec la methode microtest de l'OMS on été utilisés pour comparer l'efficacité de quatre antimalariales: chloroquine, Fansidar, Cotexin and Amalar sur des plasmodium malariae isolés. Une période de trios jous (72hrs) d'incubation pour interaction medicament-parasite était utilisé. Treize (13) ...

  14. Network analysis of S. aureus response to ramoplanin reveals modules for virulence factors and resistance mechanisms and characteristic novel genes.

    Science.gov (United States)

    Subramanian, Devika; Natarajan, Jeyakumar

    2015-12-10

    Staphylococcus aureus is a major human pathogen and ramoplanin is an antimicrobial attributed for effective treatment. The goal of this study was to examine the transcriptomic profiles of ramoplanin sensitive and resistant S. aureus to identify putative modules responsible for virulence and resistance-mechanisms and its characteristic novel genes. The dysregulated genes were used to reconstruct protein functional association networks for virulence-factors and resistance-mechanisms individually. Strong link between metabolic-pathways and development of virulence/resistance is suggested. We identified 15 putative modules of virulence factors. Six hypothetical genes were annotated with novel virulence activity among which SACOL0281 was discovered to be an essential virulence factor EsaD. The roles of MazEF toxin-antitoxin system, SACOL0202/SACOL0201 two-component system and that of amino-sugar and nucleotide-sugar metabolism in virulence are also suggested. In addition, 14 putative modules of resistance mechanisms including modules of ribosomal protein-coding genes and metabolic pathways such as biotin-synthesis, TCA-cycle, riboflavin-biosynthesis, peptidoglycan-biosynthesis etc. are also indicated. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Pulse width and height modulation for multi-level resistance in bi-layer TaOx based RRAM

    Science.gov (United States)

    Alamgir, Zahiruddin; Beckmann, Karsten; Holt, Joshua; Cady, Nathaniel C.

    2017-08-01

    Mutli-level switching in resistive memory devices enables a wide range of computational paradigms, including neuromorphic and cognitive computing. To this end, we have developed a bi-layer tantalum oxide based resistive random access memory device using Hf as the oxygen exchange layer. Multiple, discrete resistance levels were achieved by modulating the RESET pulse width and height, ranging from 2 kΩ to several MΩ. For a fixed pulse height, OFF state resistance was found to increase gradually with the increase in the pulse width, whereas for a fixed pulse width, the increase in the pulse height resulted in drastic changes in resistance. Resistive switching in these devices transitioned from Schottky emission in the OFF state to tunneling based conduction in the ON state, based on I-V curve fitting and temperature dependent current measurements. These devices also demonstrated endurance of more than 108 cycles with a satisfactory Roff/Ron ratio and retention greater than 104 s.

  16. Fallopia japonica, a Natural Modulator, Can Overcome Multidrug Resistance in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Safaa Yehia Eid

    2015-01-01

    Full Text Available Resistance of cancer cells to chemotherapy is controlled by the decrease of intracellular drug accumulation, increase of detoxification, and diminished propensity of cancer cells to undergo apoptosis. ATP-binding cassette (ABC membrane transporters with intracellular metabolic enzymes contribute to the complex and unresolved phenomenon of multidrug resistance (MDR. Natural products as alternative medicine have great potential to discover new MDR inhibitors with diverse modes of action. In this study, we characterized several extracts of traditional Chinese medicine (TCM plants (N = 16 for their interaction with ABC transporters, cytochrome P3A4 (CYP3A4, and glutathione-S-transferase (GST activities and their cytotoxic effect on different cancer cell lines. Fallopia japonica (FJ (Polygonaceae shows potent inhibitory effect on CYP3A4 P-glycoprotein activity about 1.8-fold when compared to verapamil as positive control. FJ shows significant inhibitory effect (39.81% compared with the known inhibitor ketoconazole and 100 μg/mL inhibited GST activity to 14 μmol/min/mL. FJ shows moderate cytotoxicity in human Caco-2, HepG-2, and HeLa cell lines; IC50 values were 630.98, 198.80, and 317.37 µg/mL, respectively. LC-ESI-MS were used to identify and quantify the most abundant compounds, emodin, polydatin, and resveratrol, in the most active extract of FJ. Here, we present the prospect of using Fallopia japonica as natural products to modulate the function of ABC drug transporters. We are conducting future study to evaluate the ability of the major active secondary metabolites of Fallopia japonica to modulate MDR and their impact in case of failure of chemotherapy.

  17. Chloroquine induced pruritus--questionnaire based epidemiological study.

    Science.gov (United States)

    George, Adekunle O

    2004-01-01

    Chloroquine (CQ) is a very useful drug with a broad spectrum of uses (as anti malarial, anti amoebiasis and for connective tissue diseases). A major side effect preventing or limiting its utilization in blacks is chloroquine induced pruritus (CP). A descriptive cross sectional questionnaire based epidemiological study of medical and nursing students, medical doctors and other workers with historic CP in a Nigerian tertiary (teaching) hospital was carried out to determine factors and features related to the development of CP. From the study the intensity of CP was not reduced by taking less CQ. About 92% of the subjects had close relations who suffered from CP. 84.5% of responders itched for 1-3 days. The longest duration for CP was 7 days. The sites of itching in descending order were generalized (49.2%) hands (46%), legs and feet (46%), perineum/genitalia (28.5%). Relieving factor/drug was identified in 66.6% of responders. Itching with oral CQ occurred in 100%. Intramuscular injection of CQ caused 49% of itching. 19% had pre-chloroquine itch. 28.5% had CP with other antimalarials notably Amodiaquine (23.8%). 50.7% took other antimalarials when down with malaria. There is a need for the identification of a cheap and readily available antidote for CP to enable CQ remain useful/relevant in Nigeria and in the West African sub-region.

  18. Synthesis and preliminary pharmacological evaluation of asymmetric chloroquine analogues.

    Science.gov (United States)

    Witiak, D T; Grattan, D A; Heaslip, R J; Rahwan, R G

    1981-06-01

    Asymmetric chloroquine analogues (1-4) were prepared of known absolute configuration in order to assess stereochemical influences on selected biological activities. Since chloroquine has been shown to possess spasmolytic properties, analogues 1-4 were tested for similar pharmacological effects on smooth-muscle contraction. The (S)- and (R)-chlorochloroquine enantiomers (1 and 2, respectively) were more potent antispasmodics than the less lipophilic (S)- and (R)-hydroxychloroquines (3 and 4, respectively) when tested against KCl- or acetylcholine-induced contractions of the isolated mouse ileum. A membrane stabilizing mechanism of action for the chloroquine analogues is proposed since neither cellular toxicity nor calcium antagonism plays a role in the spasmolytic action of these compounds. Although compounds 1-4 also inhibited PGF2 alpha-induced contractions of the ileum, 1 was significantly more potent than 2; the latter in turn was equipotent to 3 and 4. It is tentatively proposed that 1 may possess stereoselective affinity for the PGF2 alpha receptor in the ileum. This observation may be further exploited to obtain more selective profiles of biological activity through molecular manipulation.

  19. Emerging antibiotic resistance in bacteria with special reference to ...

    Indian Academy of Sciences (India)

    Prakash

    utility of antibiotics in the control of infections has been indicated. [Raghunath D 2008 ..... 6.4 Protozoa. Plasmodium falciparum has become resistant to chloroquin ... The partial success of a polysaccharide vaccine against S. aureus in ...

  20. Antimalarial therapy selection for quinolone resistance among Escherichia coli in the absence of quinolone exposure, in tropical South America.

    Science.gov (United States)

    Davidson, Ross J; Davis, Ian; Willey, Barbara M; Rizg, Keyro; Bolotin, Shelly; Porter, Vanessa; Polsky, Jane; Daneman, Nick; McGeer, Allison; Yang, Paul; Scolnik, Dennis; Rowsell, Roy; Imas, Olga; Silverman, Michael S

    2008-07-16

    Bacterial resistance to antibiotics is thought to develop only in the presence of antibiotic pressure. Here we show evidence to suggest that fluoroquinolone resistance in Escherichia coli has developed in the absence of fluoroquinolone use. Over 4 years, outreach clinic attendees in one moderately remote and five very remote villages in rural Guyana were surveyed for the presence of rectal carriage of ciprofloxacin-resistant gram-negative bacilli (GNB). Drinking water was tested for the presence of resistant GNB by culture, and the presence of antibacterial agents and chloroquine by HPLC. The development of ciprofloxacin resistance in E. coli was examined after serial exposure to chloroquine. Patient and laboratory isolates of E. coli resistant to ciprofloxacin were assessed by PCR-sequencing for quinolone-resistance-determining-region (QRDR) mutations. In the very remote villages, 4.8% of patients carried ciprofloxacin-resistant E. coli with QRDR mutations despite no local availability of quinolones. However, there had been extensive local use of chloroquine, with higher prevalence of resistance seen in the villages shortly after a Plasmodium vivax epidemic (pwater, but chloroquine was demonstrated to be present. Chloroquine was found to inhibit the growth of E. coli in vitro. Replica plating demonstrated that 2-step QRDR mutations could be induced in E. coli in response to chloroquine. In these remote communities, the heavy use of chloroquine to treat malaria likely selected for ciprofloxacin resistance in E. coli. This may be an important public health problem in malarious areas.

  1. Fabrication of robot head module using contact resistance force sensor for human robot interaction and its evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Ki; Kim, Jong Ho [Korea Reserch Institute of Standards and Science, Daejeon (Korea, Republic of); Kwon, Hyun Joon [Univ. of Maryland, Maryland (United States); Kwon, Young Ha [Kyung Hee Univ., Gyunggi Do (Korea, Republic of)

    2012-10-15

    This paper presents a design of a robot head module with touch sensing algorithms that can simultaneously detect contact force and location. The module is constructed with a hemisphere and three sensor units that are fabricated using contact resistance force sensors. The surface part is designed with the hemisphere that measures 300 mm in diameter and 150 mm in height. Placed at the bottom of the robot head module are three sensor units fabricated using a simple screen printing technique. The contact force and the location of the model are evaluated through the calibration setup. The experiment showed that the calculated contact positions almost coincided with the applied load points as the contact location changed with a location error of about {+-}8.67 mm. The force responses of the module were evaluated at two points under loading and unloading conditions from 0 N to 5 N. The robot head module showed almost the same force responses at the two points.

  2. Ability of TEP1 in intestinal flora to modulate natural resistance of Anopheles dirus.

    Science.gov (United States)

    Wang, Yanyan; Wang, Ying; Zhang, Jingru; Xu, Wenyue; Zhang, Jian; Huang, Fu Sheng

    2013-08-01

    Blocking transmission of malaria is a reliable way to control and eliminate infection. However, in-depth knowledge of the interaction between Plasmodium and mosquito is needed. Studies suggest that innate immunity is the main mechanism inhibiting development of malaria parasites in the mosquito. Recent studies have found that use of antibiotics that inhibit the mosquito gut flora can reduce the immune response of Anopheles gambiae, thereby contributing to the development of malaria parasites. In our study, we used the non susceptible model of Anopheles dirus-Plasmodium yoelii to explore the effect of Anopheles intestinal flora on the natural resistance of A. dirus to P. yoelii. We found that in mosquitoes infected with Plasmodium, the intestinal flora can regulate expression of thioester-containing protein (TEP1) via an RNAi gene-silencing approach. Our results suggest that in the absence of TEP1, the natural microbiota cannot suppress the development of P. yoelii in A. dirus. This suggests that AdTEP1 plays an important role in the resistance of A. dirus to P. yoelii. The intestinal flora may modulate the development of P. yoelii in A. dirus by regulating TEP1 expression. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Nicotine induces resistance to chemotherapy by modulating mitochondrial signaling in lung cancer.

    Science.gov (United States)

    Zhang, Jingmei; Kamdar, Opal; Le, Wei; Rosen, Glenn D; Upadhyay, Daya

    2009-02-01

    Continued smoking causes tumor progression and resistance to therapy in lung cancer. Carcinogens possess the ability to block apoptosis, and thus may induce development of cancers and resistance to therapy. Tobacco carcinogens have been studied widely; however, little is known about the agents that inhibit apoptosis, such as nicotine. We determine whether mitochondrial signaling mediates antiapoptotic effects of nicotine in lung cancer. A549 cells were exposed to nicotine (1 muM) followed by cisplatin (35 muM) plus etoposide (20 muM) for 24 hours. We found that nicotine prevented chemotherapy-induced apoptosis, improved cell survival, and caused modest increases in DNA synthesis. Inhibition of mitogen-activated protein kinase (MAPK) and Akt prevented the antiapoptotic effects of nicotine and decreased chemotherapy-induced apoptosis. Small interfering RNA MAPK kinase-1 blocked antiapoptotic effects of nicotine, whereas small interfering RNA MAPK kinase-2 blocked chemotherapy-induced apoptosis. Nicotine prevented chemotherapy-induced reduction in mitochondrial membrane potential and caspase-9 activation. Antiapoptotic effects of nicotine were blocked by mitochondrial anion channel inhibitor, 4,4'diisothiocyanatostilbene-2,2'disulfonic acid. Chemotherapy enhanced translocation of proapoptotic Bax to the mitochondria, whereas nicotine blocked these effects. Nicotine up-regulated Akt-mediated antiapoptotic X-linked inhibitor of apoptosis protein and phosphorylated proapoptotic Bcl2-antagonist of cell death. The A549-rho0 cells, which lack mitochondrial DNA, demonstrated partial resistance to chemotherapy-induced apoptosis, but blocked the antiapoptotic effects of nicotine. Accordingly, we provide evidence that nicotine modulates mitochondrial signaling and inhibits chemotherapy-induced apoptosis in lung cancer. The mitochondrial regulation of nicotine imposes an important mechanism that can critically impair the treatment of lung cancer, because many cancer

  4. Cortisol Modulation by Ayahuasca in Patients With Treatment Resistant Depression and Healthy Controls

    Directory of Open Access Journals (Sweden)

    Ana C. de Menezes Galvão

    2018-05-01

    Full Text Available Major depression is a highly prevalent mood disorder, affecting about 350 million people, and around 30% of the patients are resistant to currently available antidepressant medications. Recent evidence from a randomized controlled trial (RCT supports the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression. The aim of this study was to explore the effect of ayahuasca on plasma cortisol and awakening salivary cortisol response, in the same group of treatment-resistant patients (MD and in healthy volunteers (C. Subjects received a single dose of ayahuasca or placebo (dosing session, and both plasma and awakening salivary cortisol response were measured at baseline (before dosing session and 48 h after the dosing session. Baseline assessment (D0 showed blunted awakening salivary cortisol response and hypocortisolemia in patients, with respect to healthy controls. Salivary cortisol was also measured during dosing session, and we observed higher increases for both C and MD that ingested ayahuasca than placebo. After 48 h from the dosing session with ayahuasca, patients' awakening salivary cortisol response is similar to the ones detected in controls. No significant changes in plasma cortisol levels were observed 48 h after the sessions. Therefore, these findings point to new evidence on the modulation of salivary cortisol levels as a result of an ayahuasca session, both in healthy and depressive volunteers. Considering that cortisol acts in regulation of distinct physiological pathways, emotional and cognitive processes, it is assumed to be critically involved to the etiology of depression and its regulation seems to be important for the treatment and remission of major depression, ayahuasca use as antidepressant should be further investigated. Moreover, this study highlights the importance of psychedelics in the treatment of human mental disorders.

  5. Resilience versus Resistance: Affectively Modulating Contemporary Diagrams of Social Resilience, Social Sustainability, and Social Innovation

    Directory of Open Access Journals (Sweden)

    Petra Hroch

    2013-11-01

    Full Text Available This article critically interrogates the twin notions of social sustainability and activities grouped under the term social innovation in order to argue that sustainability and innovation are schizoid modes of representing what Deleuze calls “the cliché” (the authority of the same as “the new” (difference that short-circuit any real possibility of social transformation. I argue that the kinds of solutions presented by social innovation to the problems of social sustainability in the context of a neoliberal governmentality are sustainable only in the sense that they are a model for a more collective mode of existence in an individualized realm that reciprocally supports a realm in which collective responsibility is individualized. In other words, this neo-liberal diagram catches and captures creative energies in service to the status quo. To illustrate these ideas I turn to Dutch filmmaker Bregtje van der Haak’s 2010 documentary, California Dreaming, in which she compares the popular response to the 2008 financial crisis by focusing on several families across the transatlantic transcontinental divide. She interviews Europeans who blame the state as the source of the economic problem, and thus expect the state to fix it. And she interviews Americans who, reflecting on the “American dream,” reveal their faith in meritocracy, blame themselves, and thus look to their own families and communities for solutions. Their respective stories tell us how different neo-liberal diagrams structure and modulate subjectivity and its relation to the social, as well as the emerging ways in which this relation is being framed. If, as Deleuze writes, “there is no diagram that does not also include, besides the points which it connects up, certain relatively free points, points of creativity, change and resistance,” how can analysis of these shifty subjective-social structures point us to points of resistance" (Foucault? And why is it crucial that

  6. Cell Wall Remodeling Enzymes Modulate Fungal Cell Wall Elasticity and Osmotic Stress Resistance.

    Science.gov (United States)

    Ene, Iuliana V; Walker, Louise A; Schiavone, Marion; Lee, Keunsook K; Martin-Yken, Hélène; Dague, Etienne; Gow, Neil A R; Munro, Carol A; Brown, Alistair J P

    2015-07-28

    The fungal cell wall confers cell morphology and protection against environmental insults. For fungal pathogens, the cell wall is a key immunological modulator and an ideal therapeutic target. Yeast cell walls possess an inner matrix of interlinked β-glucan and chitin that is thought to provide tensile strength and rigidity. Yeast cells remodel their walls over time in response to environmental change, a process controlled by evolutionarily conserved stress (Hog1) and cell integrity (Mkc1, Cek1) signaling pathways. These mitogen-activated protein kinase (MAPK) pathways modulate cell wall gene expression, leading to the construction of a new, modified cell wall. We show that the cell wall is not rigid but elastic, displaying rapid structural realignments that impact survival following osmotic shock. Lactate-grown Candida albicans cells are more resistant to hyperosmotic shock than glucose-grown cells. We show that this elevated resistance is not dependent on Hog1 or Mkc1 signaling and that most cell death occurs within 10 min of osmotic shock. Sudden decreases in cell volume drive rapid increases in cell wall thickness. The elevated stress resistance of lactate-grown cells correlates with reduced cell wall elasticity, reflected in slower changes in cell volume following hyperosmotic shock. The cell wall elasticity of lactate-grown cells is increased by a triple mutation that inactivates the Crh family of cell wall cross-linking enzymes, leading to increased sensitivity to hyperosmotic shock. Overexpressing Crh family members in glucose-grown cells reduces cell wall elasticity, providing partial protection against hyperosmotic shock. These changes correlate with structural realignment of the cell wall and with the ability of cells to withstand osmotic shock. The C. albicans cell wall is the first line of defense against external insults, the site of immune recognition by the host, and an attractive target for antifungal therapy. Its tensile strength is conferred by

  7. Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review

    Directory of Open Access Journals (Sweden)

    Arezoo Rafiee Parhizgar

    2017-03-01

    Full Text Available Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ and amodiaquine (AQ, have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

  8. Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review.

    Science.gov (United States)

    Parhizgar, Arezoo Rafiee; Tahghighi, Azar

    2017-03-01

    Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

  9. Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics

    Energy Technology Data Exchange (ETDEWEB)

    Tocchetti, Guillermo Nicolás [Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario (Argentina); Rigalli, Juan Pablo [Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario (Argentina); Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg (Germany); Arana, Maite Rocío; Villanueva, Silvina Stella Maris [Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario (Argentina); Mottino, Aldo Domingo, E-mail: amottino@unr.edu.ar [Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 570, 2000 Rosario (Argentina)

    2016-07-15

    The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a group of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs. - Highlights: • Intestinal MRP2 (ABCC2) expression and activity can be regulated by xenobiotics. • PXR and CAR are major MRP2 modulators through a transcriptional mechanism. • Rifampicin

  10. High short-term effectiveness of modulated dry bed training in adolescents and young adults with treatment-resistant enuresis

    NARCIS (Netherlands)

    Hofmeester, I.; Cobussen-Boekhorst, J.G.L.; Kortmann, B.B.M.; Mulder, Z.; Steffens, M.G.; Feitz, W.F.J.; Van Capelle, J.W.; Blanker, M.H.

    2015-01-01

    Hypothesis/aims of study Two percent of adolescents and adults suffers from enuresis. In this age group, social problems can arise. We evaluated the effect of a Modulated Dry Bed Training (MDBT) in a previously therapy-resistant group of adolescents and adults with enuresis, provided by a

  11. High short-term effectiveness of modulated dry bed training in adolescents and young adults with treatment-resistant enuresis

    NARCIS (Netherlands)

    Hofmeester, I.; Cobussen-Boekhorst, J.G.L.; Kortmann, B.B.M.; Mulder, Z.; Steffens, M.G.; Feitz, W.F.J.; Van Capelle, J.W.; Blanker, M.H.

    2015-01-01

    INTRODUCTION & OBJECTIVES: Two percent of adolescents and young adults suffer from therapy-resistant enuresis, with considerable negative impact on self-esteem and relationships. We evaluated the effect of a Modulated Dry Bed Training (MDBT) in a previously therapyresistant group of adolescents with

  12. Implications of Glutathione Levels in the Plasmodium berghei Response to Chloroquine and Artemisinin.

    Directory of Open Access Journals (Sweden)

    Joel Vega-Rodríguez

    Full Text Available Malaria is one of the most devastating parasitic diseases worldwide. Plasmodium drug resistance remains a major challenge to malaria control and has led to the re-emergence of the disease. Chloroquine (CQ and artemisinin (ART are thought to exert their anti-malarial activity inducing cytotoxicity in the parasite by blocking heme degradation (for CQ and increasing oxidative stress. Besides the contribution of the CQ resistance transporter (PfCRT and the multidrug resistant gene (pfmdr, CQ resistance has also been associated with increased parasite glutathione (GSH levels. ART resistance was recently shown to be associated with mutations in the K13-propeller protein. To analyze the role of GSH levels in CQ and ART resistance, we generated transgenic Plasmodium berghei parasites either deficient in or overexpressing the gamma-glutamylcysteine synthetase gene (pbggcs encoding the rate-limiting enzyme in GSH biosynthesis. These lines produce either lower (pbggcs-ko or higher (pbggcs-oe levels of GSH than wild type parasites. In addition, GSH levels were determined in P. berghei parasites resistant to CQ and mefloquine (MQ. Increased GSH levels were detected in both, CQ and MQ resistant parasites, when compared to the parental sensitive clone. Sensitivity to CQ and ART remained unaltered in both pgggcs-ko and pbggcs-oe parasites when tested in a 4 days drug suppressive assay. However, recrudescence assays after the parasites have been exposed to a sub-lethal dose of ART showed that parasites with low levels of GSH are more sensitive to ART treatment. These results suggest that GSH levels influence Plasmodium berghei response to ART treatment.

  13. Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus

    DEFF Research Database (Denmark)

    de Evgrafov, Mari Cristina Rodriguez; Gumpert, Heidi; Munck, Christian

    2015-01-01

    As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations......, to reflect drug concentrations more likely to be encountered during treatment. We performed a series of adaptive evolution experiments using Staphylococcus aureus. Interestingly, no relationship between drug interaction type and resistance evolution was found as resistance increased significantly beyond wild......-type levels. All drug combinations, irrespective of interaction types, effectively limited resistance evolution compared with monotreatment. Cross-resistance and collateral sensitivity were found to be important factors in the extent of resistance evolution toward a combination. Comparative genomic analyses...

  14. Modulation of TRAIL resistance in colon carcinoma cells: Different contributions of DR4 and DR5

    International Nuclear Information System (INIS)

    Geelen, Caroline MM van; Pennarun, Bodvael; Le, Phuong TK; Vries, Elisabeth GE de; Jong, Steven de

    2011-01-01

    rhTRAIL is a therapeutic agent, derived from the TRAIL cytokine, which induces apoptosis in cancer cells by activating the membrane death receptors 4 and 5 (DR4 and DR5). Here, we investigated each receptor's contribution to rhTRAIL sensitivity and rhTRAIL resistance. We assessed whether agonistic DR4 or DR5 antibodies could be used to circumvent rhTRAIL resistance, alone or in combination with various chemotherapies. Our study was performed in an isogenic model comprised of the SW948 human colon carcinoma cell line and its rhTRAIL resistant sub-line SW948-TR. Effects of rhTRAIL and agonistic DR4/DR5 antibodies on cell viability were measured using MTT assays and identification of morphological changes characteristic of apoptosis, after acridine orange staining. Sensitivity to the different death receptor ligands was stimulated using pretreatment with the cytokine IFN-gamma and the proteasome inhibitor MG-132. To investigate the mechanisms underlying the changes in rhTRAIL sensitivity, alterations in expression levels of targets of interest were measured by Western blot analysis. Co-immunoprecipitation was used to determine the composition of the death-inducing signalling complex at the cell membrane. SW948 cells were sensitive to all three of the DR-targeting agents tested, although the agonistic DR5 antibody induced only weak caspase 8 cleavage and limited apoptosis. Surprisingly, agonistic DR4 and DR5 antibodies induced equivalent DISC formation and caspase 8 cleavage at the level of their individual receptors, suggesting impairment of further caspase 8 processing upon DR5 stimulation. SW948-TR cells were cross-resistant to all DR-targeting agents as a result of decreased caspase 8 expression levels. Caspase 8 protein expression was restored by MG-132 and IFN-gamma pretreatment, which also re-established sensitivity to rhTRAIL and agonistic DR4 antibody in SW948-TR. Surprisingly, MG-132 but not IFN-gamma could also increase DR5-mediated apoptosis in SW948

  15. Modulation of TRAIL resistance in colon carcinoma cells: Different contributions of DR4 and DR5

    Directory of Open Access Journals (Sweden)

    de Vries Elisabeth GE

    2011-01-01

    Full Text Available Abstract Background rhTRAIL is a therapeutic agent, derived from the TRAIL cytokine, which induces apoptosis in cancer cells by activating the membrane death receptors 4 and 5 (DR4 and DR5. Here, we investigated each receptor's contribution to rhTRAIL sensitivity and rhTRAIL resistance. We assessed whether agonistic DR4 or DR5 antibodies could be used to circumvent rhTRAIL resistance, alone or in combination with various chemotherapies. Methods Our study was performed in an isogenic model comprised of the SW948 human colon carcinoma cell line and its rhTRAIL resistant sub-line SW948-TR. Effects of rhTRAIL and agonistic DR4/DR5 antibodies on cell viability were measured using MTT assays and identification of morphological changes characteristic of apoptosis, after acridine orange staining. Sensitivity to the different death receptor ligands was stimulated using pretreatment with the cytokine IFN-gamma and the proteasome inhibitor MG-132. To investigate the mechanisms underlying the changes in rhTRAIL sensitivity, alterations in expression levels of targets of interest were measured by Western blot analysis. Co-immunoprecipitation was used to determine the composition of the death-inducing signalling complex at the cell membrane. Results SW948 cells were sensitive to all three of the DR-targeting agents tested, although the agonistic DR5 antibody induced only weak caspase 8 cleavage and limited apoptosis. Surprisingly, agonistic DR4 and DR5 antibodies induced equivalent DISC formation and caspase 8 cleavage at the level of their individual receptors, suggesting impairment of further caspase 8 processing upon DR5 stimulation. SW948-TR cells were cross-resistant to all DR-targeting agents as a result of decreased caspase 8 expression levels. Caspase 8 protein expression was restored by MG-132 and IFN-gamma pretreatment, which also re-established sensitivity to rhTRAIL and agonistic DR4 antibody in SW948-TR. Surprisingly, MG-132 but not IFN

  16. In vitro and in vivo antitumor effects of chloroquine on oral squamous cell carcinoma

    Science.gov (United States)

    Jia, Lihua; Wang, Juan; Wu, Tong; Wu, Jinan; Ling, Junqi; Cheng, Bin

    2017-01-01

    Chloroquine, which is a widely used antimalarial drug, has been reported to exert anticancer activity in some tumor types; however, its potential effects on oral squamous cell carcinoma (OSCC) remain unclear. The present study aimed to explore the effects and possible underlying mechanisms of chloroquine against OSCC. MTT and clonogenic assays were conducted to evaluate the effects of chloroquine on the human OSCC cell lines SCC25 and CAL27. Cell cycle progression and apoptosis were detected using flow cytometry. Autophagy was monitored using microtubule-associated protein 1A/1B-light chain 3 as an autophagosomal marker. In order to determine the in vivo antitumor effects of chloroquine on OSCC, a CAL27 xenograft model was used. The results demonstrated that chloroquine markedly inhibited the proliferation and the colony-forming ability of both OSCC cell lines in a dose- and time-dependent manner in vitro. Chloroquine also disrupted the cell cycle, resulting in the cell cycle arrest of CAL27 and SCC25 cells at G0/G1 phase, via downregulation of cyclin D1. In addition, chloroquine inhibited autophagy, and induced autophagosome and autolysosome accumulation in the cytoplasm, thus interfering with degradation; however, OSCC apoptosis was barely affected by chloroquine. The results of the in vivo study demonstrated that chloroquine effectively inhibited OSCC tumor growth in the CAL27 xenograft model. In conclusion, the present study reported the in vitro and in vivo antitumor effects of chloroquine on OSCC, and the results indicated that chloroquine may be considered a potent therapeutic agent against human OSCC. PMID:28849182

  17. Syzygium jambos Displayed Antibacterial and Antibiotic-Modulating Activities against Resistant Phenotypes

    Directory of Open Access Journals (Sweden)

    Brice E. N. Wamba

    2018-01-01

    Full Text Available The present study was designed to evaluate the antibacterial activities of methanol extracts of bark and leaves of Syzygium jambos, as well as their synergistic effects with selected antibiotics against drug-resistant Gram-positive and Gram-negative bacteria. The crude extracts were subjected to qualitative phytochemical screening; broth microdilution method was used for antibacterial assays. Phytochemical studies indicate that leaves and bark extracts contained polyphenols, anthraquinones, tannins, and steroids. Extract of the leaves was active against all the 26 strains of Staphylococcus aureus and all the 21 strains of Gram-negative bacteria tested, within the minimum inhibitory concentration (MIC range of 32–512 μg/mL. The lowest MIC value of 32 μg/mL was obtained with extract of the leaves against Staphylococcus aureus MRSA9 strain. In Gram-negative bacteria, the lowest MIC value of 64 μg/mL was also obtained against Enterobacter aerogenes EA294 and Klebsiella pneumoniae K24 strains. Against S. aureus strains, antibiotic-modulating activity of extracts at MIC/2 towards more than 70% of the tested strains was obtained when leaves and bark extracts were tested in association with chloramphenicol (CHL. This was also the case when leaves extract was combined with CHL, kanamycin (KAN, tetracycline (TET, and erythromycin (ERY and when bark extract was combined with ciprofloxacin (CIP, TET, and ERY against Gram-negative bacteria. In conclusion, this study demonstrated that Syzygium jambos has antibacterial and antibiotic-modulating activities.

  18. Study on the Thermal Resistance of Multi-chip Module High Power LED Packaging Heat Dissipation System

    Directory of Open Access Journals (Sweden)

    Kailin Pan

    2014-10-01

    Full Text Available Thermal resistance is a key technical index which indicates the thermal management of multi-chip module high power LED (MCM-LED packaging heat dissipation system. In this paper, the prototype structure of MCM-LED packaging heat dissipation system is proposed to study the reliable thermal resistance calculation method. In order to analyze the total thermal resistance of the MCM-LED packaging heat dissipation system, three kinds of thermal resistance calculation method including theoretical calculation, experimental testing and finite element simulation are developed respectively. Firstly, based on the thermal resistance network model and the principle of steady state heat transfer, the theoretical value of total thermal resistance is 6.111 K/W through sum of the thermal resistance of every material layer in the major direction of heat flow. Secondly, the thermal resistance experiment is carried out by T3Ster to obtain the experimental result of total thermal resistance, and the value is 6.729 K/W. Thirdly, a three-dimensional finite element model of MCM-LED packaging heat dissipation system is established, and the junction temperature experiment is also performed to calculated the finite element simulated result of total thermal resistance, the value is 6.99 K/W. Finally, by comparing the error of all the three kinds of result, the error of total thermal resistance between the theoretical value and experimental result is 9.2 %, and the error of total thermal resistance between the experimental result and finite element simulation is only about -3.9 %, meanwhile, the main reason of each error is discussed respectively.

  19. Evaluation of chloroquine as a potent anti-malarial drug: issues of public health policy and healthcare delivery in post-war Liberia.

    Science.gov (United States)

    Massaquoi, Moses B F; Kennedy, Stephen B

    2003-02-01

    Chloroquine-resistant plasmodium falciparum malaria is a serious public health threat that is spreading rapidly across Sub-Saharan Africa. It affects over three quarters (80%) of malarial endemic countries. Of the estimated 300-500 million cases of malaria reported annually, the vast majority of malarial-related morbidities occur among young children in Africa, especially those concentrated in the remote rural areas with inadequate access to appropriate health care services. In Liberia, in vivo studies conducted between 1993 and 2000 observed varying degrees of plasmodium falciparum malaria infections that were resistant to chloroquine, including sulfadiazine-pyrimethamine. As the country emerges from a prolonged civil war, the health care delivery system may not be adequately prepared to implement an effective nation-wide malarial control strategy. As a result, the management of uncomplicated malaria in Liberia poses a significant public health challenge for the government-financed health care delivery system. Therefore, based on extensive literature review, we report the failure of chloroquine as an effective first-line drug for the treatment of uncomplicated plasmodium falciparum malaria in Liberia and recommend that national health efforts be directed at identifying alternative drug(s) to replace it.

  20. Comparison of chloroquine with artesunate in the treatment of cerebral malaria in Ghanaian children

    DEFF Research Database (Denmark)

    Goka, B Q; Adabayeri, V; Ofori-Adjei, E

    2001-01-01

    and neurological deficits were documented. There was no difference in mortality rates (chloroquine, 16.7 per cent; artesunate, 21.7 per cent; p = 0.6), neurological deficit at day 14 (chloroquine, 0 per cent; artesunate, 4.3 per cent; p = 0.3), resolution of fever (p = 0.55), and coma recovery time (p = 0...

  1. In situ localization of chloroquine and immunohistological studies in UVB-irradiated skin of photosensitive patients

    NARCIS (Netherlands)

    Sjölin-Forsberg, G.; Berne, B.; Eggelte, T. A.; Karlsson-Parra, A.

    1995-01-01

    Chloroquine can prevent photosensitivity reactions, but its mechanism of action is poorly understood. To investigate if the drug may interfere with inflammatory or immunological mechanisms of the UV-induced erythema of photosensitive patients, we studied the localization of chloroquine in the skin

  2. Selenocysteine modulates resistance to environmental stress and confers anti-aging effects in C. elegans.

    Science.gov (United States)

    Kim, Jun-Sung; Kim, So-Hyeon; Park, Sang-Kyu

    2017-08-01

    The free radical theory of aging suggests that cellular oxidative damage caused by free radicals is a leading cause of aging. In the present study, we examined the effects of a well-known anti-oxidant amino acid derivative, selenocysteine, in response to environmental stress and aging using Caenorhabditis elegans as a model system. The response to oxidative stress induced by H2O2 or ultraviolet irradiation was compared between the untreated control and selenocysteine-treated groups. The effect of selenocysteine on lifespan and fertility was then determined. To examine the effect of selenocysteine on muscle aging, we monitored the change in motility with aging in both the untreated control and selenocysteine-treated groups. Dietary supplementation with selenocysteine significantly increased resistance to oxidative stress. Survival after ultraviolet irradiation was also increased by supplementation with selenocysteine. Treatment with selenocysteine confers a longevity phenotype without an accompanying reduction in fertility, which is frequently observed in lifespan-extending interventions as a trade-off in C. elegans. In addition, the age-related decline in motility was significantly delayed by supplementation of selenocysteine. These findings suggest that dietary supplementation of selenocysteine can modulate response to stressors and lead to lifespan extension, thus supporting the free radical theory of aging.

  3. Endogenous cytokinin overproduction modulates ROS homeostasis and decreases salt stress resistance in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Yanping eWang

    2015-11-01

    Full Text Available Cytokinins in plants are crucial for numerous biological processes, including seed germination, cell division and differentiation, floral initiation and adaptation to abiotic stresses. The salt stress can promote reactive oxygen species (ROS production in plants which are highly toxic and ultimately results in oxidative stress. However, the correlation between endogenous cytokinin production and ROS homeostasis in responding to salt stress is poorly understood. In this study, we analyzed the correlation of overexpressing the cytokinin biosynthetic gene AtIPT8 (adenosine phosphate-isopentenyl transferase 8 and the response of salt stress in Arabidopsis. Overproduction of cytokinins, which was resulted by the inducible overexpression of AtIPT8, significantly inhibited the primary root growth and true leaf emergence, especially under the conditions of exogenous salt, glucose and mannitol treatments. Upon cytokinin overproduction, the salt stress resistance was declined, and resulted in less survival rates and chlorophyll content. Interestingly, ROS production was obviously increased with the salt treatment, accompanied by endogenously overproduced cytokinins. The activities of CAT and SOD, which are responsible for scavenging ROS, were also affected. Transcription profiling revealed that the differential expressions of ROS-producing and scavenging related genes, the photosynthesis-related genes and stress responsive genes were existed in transgenic plants of overproducing cytokinins. Our results suggested that broken in the homeostasis of cytokinins in plant cells could modulate the salt stress responses through a ROS-mediated regulation in Arabidopsis.

  4. Melatonin Modulates Neuronal Cell Death Induced by Endoplasmic Reticulum Stress under Insulin Resistance Condition.

    Science.gov (United States)

    Song, Juhyun; Kim, Oh Yoen

    2017-06-10

    Insulin resistance (IR) is an important stress factor in the central nervous system, thereby aggravating neuropathogenesis and triggering cognitive decline. Melatonin, which is an antioxidant phytochemical and synthesized by the pineal gland, has multiple functions in cellular responses such as apoptosis and survival against stress. This study investigated whether melatonin modulates the signaling of neuronal cell death induced by endoplasmic reticulum (ER) stress under IR condition using SH-SY5Y neuroblastoma cells. Apoptosis cell death signaling markers (cleaved Poly [ADP-ribose] polymerase 1 (PARP), p53, and Bax) and ER stress markers (phosphorylated eIF2α (p-eIF2α), ATF4, CHOP, p-IRE1 , and spliced XBP1 (sXBP1)) were measured using reverse transcription-PCR, quantitative PCR, and western blottings. Immunofluorescence staining was also performed for p-ASK1 and p-IRE1 . The mRNA or protein expressions of cell death signaling markers and ER stress markers were increased under IR condition, but significantly attenuated by melatonin treatment. Insulin-induced activation of ASK1 ( p-ASK1 ) was also dose dependently attenuated by melatonin treatment. The regulatory effect of melatonin on neuronal cells under IR condition was associated with ASK1 signaling. In conclusion, the result suggested that melatonin may alleviate ER stress under IR condition, thereby regulating neuronal cell death signaling.

  5. Chloroquine inhibits accessory cell presentation of soluble natural and synthetic protein antigens

    DEFF Research Database (Denmark)

    Buus, S; Werdelin, O

    1984-01-01

    We have studied the in vitro effect of the lysosomotrophic agent, chloroquine, on the presentation of soluble protein antigens by guinea pig accessory cells. Chloroquine inhibited the capacity of antigen-pulsed accessory cells to stimulate proliferation in appropriately primed T cells. The effect...... was time- and dose-dependent. A brief treatment solely of the accessory cells with the drug compromised their ability to stimulate primed T cells in a subsequent culture provided the accessory cells were treated with chloroquine before their exposure to the antigen. These results suggest that chloroquine...... acts on an early event in the antigen handling by accessory cells. Chloroquine is a well known inhibitor of lysosomal proteolysis, and it is likely that its effect on antigen presentation is caused by an inhibition of antigen degradation....

  6. Optical coherence tomography in a patient with chloroquine-induced maculopathy

    Directory of Open Access Journals (Sweden)

    Korah Sanita

    2008-01-01

    Full Text Available We herein report the optical coherence tomography (OCT findings in a case of chloroquine-induced macular toxicity, which to our knowledge, has so far not been reported. A 53-year-old lady on chloroquine for treatment of rheumatoid arthritis developed decrease in vision 36 months after initiation of the treatment. Clinical examination revealed evidence of retinal pigment epithelial (RPE disturbances. Humphrey field analyzer (HFA, fundus fluorescein angiography (FFA and OCT for retinal thickness and volume measurements at the parafoveal region were done. The HFA revealed bilateral superior paracentral scotomas, FFA demonstrated RPE loss and OCT revealed anatomical evidence of loss of ganglion cell layers, causing marked thinning of the macula and parafoveal region. Parafoveal retinal thickness and volume measurements may be early evidence of chloroquine toxicity, and OCT measurements as a part of chloroquine toxicity screening may be useful in early detection of chloroquine maculopathy.

  7. Use of pre-packaged chloroquine for the home management of presumed malaria in Malagasy children

    Directory of Open Access Journals (Sweden)

    Malvy Denis

    2006-09-01

    Full Text Available Abstract Objective The main objective of this study was to assess the quality of home malaria management with pre-packaged chloroquine in two areas in the Moramanga district of Madagascar. The knowledge, attitude and practices of care providers in terms of home treatment options were evaluated and compared. The availability of treatment options by studying retailers and community-based service providers was also investigated. Methods A cross-sectional investigation in two communities, in the hamlets and villages located close to carers, retailers, community-based service providers and primary health centres was carried out. Results Carers in the two districts were equally well aware of the use of pre-packaged chloroquine. Their first response to the onset of fever was to treat children with this antimalarial drug at home. The dose administered and treatment compliance were entirely satisfactory (100% with pre-packaged chloroquine and rarely satisfactory (1.6% to 4.5% with non pre-packaged chloroquine. In cases of treatment failure, the carers took patients to health centres. Chloroquine was supplied principally by private pharmacies and travelling salesmen selling unpackaged chloroquine tablets. Non pre-packaged chloroquine was the most common drug used at health centres. The frequency of positive rapid malaria tests (P = 0.01 was significantly higher in children treated with non pre-packaged chloroquine (38% than in children treated with pre-packaged chloroquine (1.3%. Conclusion Home malaria management should be improved in Madagascar. Efforts should focus on communication, the training of community-based service providers, access to pre-packaged drugs and the gradual withdrawal of pre-packaged chloroquine and its replacement by pre-packaged artemisinin-based combination therapies.

  8. Modulation of P-glycoprotein-mediated multidrug resistance in K562 leukemic cells by indole-3-carbinol

    International Nuclear Information System (INIS)

    Arora, Annu; Seth, Kavita; Kalra, Neetu; Shukla, Yogeshwer

    2005-01-01

    Resistance to chemotherapeutic drugs is one of the major problems in the treatment of cancer. P-glycoprotein (P-gp) encoded by the mdr gene is a highly conserved protein, acts as a multidrug transporter, and has a major role in multiple drug resistance (MDR). Targeting of P-gp by naturally occurring compounds is an effective strategy to overcome MDR. Indole-3-carbinol (I3C), a glucosinolates present in cruciferous vegetables, is a promising chemopreventive agent as it is reported to possess antimutagenic, antitumorigenic, and antiestrogenic properties in experimental studies. In the present investigation, the potential of I3C to modulate P-gp expression was evaluated in vinblastine (VBL)-resistant K562 human leukemic cells. The resistant K562 cells (K562/R10) were found to be cross-resistant to vincristine (VCR), doxorubicin (DXR), and other antineoplastic agents. I3C at a nontoxic dose (10 x 10 -3 M) enhanced the cytotoxic effects of VBL time dependently in VBL-resistant human leukemia (K562/R10) cells but had no effect on parent-sensitive cells (K562/S). The Western blot analysis of K 562/R 10 cells showed that I3C downregulates the induced levels of P-gp in resistant cells near to normal levels. The quantitation of immunocytochemically stained K562/R10 cells showed 24%, 48%, and 80% decrease in the levels of P-gp by I3C for 24, 48, and 72 h of incubation. The above features thus indicate that I3C could be used as a novel modulator of P-gp-mediated multidrug resistance in vitro and may be effective as a dietary adjuvant in the treatment of MDR cancers

  9. miR-193b Modulates Resistance to Doxorubicin in Human Breast Cancer Cells by Downregulating MCL-1

    Directory of Open Access Journals (Sweden)

    Jingpei Long

    2015-01-01

    Full Text Available MicroRNAs (miRNAs family, which is involved in cancer development, proliferation, apoptosis, and drug resistance, is a group of noncoding RNAs that modulate the expression of oncogenes and antioncogenes. Doxorubicin is an active cytotoxic agent for breast cancer treatment, but the acquisition of doxorubicin resistance is a common and critical limitation to cancer therapy. The aim of this study was to investigate whether miR-193b mediated the resistance of breast cancer cells to doxorubicin by targeting myeloid cell leukemia-1 (MCL-1. In this study, we found that miR-193b levels were significantly lower in doxorubicin-resistant MCF-7 (MCF-7/DOXR cells than in the parental MCF-7 cells. We observed that exogenous miR-193b significantly suppressed the ability of MCF-7/DOXR cells to resist doxorubicin. It demonstrated that miR-193b directly targeted MCL-1 3′-UTR (3′-Untranslated Regions. Further studies indicated that miR-193b sensitized MCF-7/DOXR cells to doxorubicin through a mechanism involving the downregulation of MCL-1. Together, our findings provide evidence that the modulation of miR-193b may represent a novel therapeutic target for the treatment of breast cancer.

  10. The Effects of Chloroquine-Resistant and Chloroquine-Sensitive Strains of Berghei on Rodent Hepatic Drug-Metabolizing Enzymes

    Science.gov (United States)

    1993-10-14

    fascioliasis and visceral leishmaniasis (Tekwani et al., 1988; Cha and Edwards, 1976: Hosts showed reduction of reductase. Facino et al...in bovine fascioliasis . Toxicology Letters 159 20,231-236. Feyereisen , R., J. F. Koener, D. E. Farnsworth, and D. W. Nebert. 1989. Isolation and...More, and M. France . 1983 . Impairment of drug metabolism by the liver in experimental fascioliasis in the rat . Journal of Pharmacy and

  11. Selective estrogen receptor modulators (SERMs): Mechanisms of anticarcinogenesis and drug resistance

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, Joan S. [Fox Chase Cancer Center, Alfred G. Knudson Chair of Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111 (United States); Jordan, V. Craig [Fox Chase Cancer Center, Alfred G. Knudson Chair of Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111 (United States)]. E-mail: v.craig.jordan@fccc.edu

    2005-12-11

    Despite the beneficial effects of estrogens in women's health, there is a plethora of evidence that suggest an important role for these hormones, particularly 17{beta}-estradiol (E{sub 2}), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ER{alpha} or ER{beta}, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues (i.e. bone and cardiovascular system) act like estrogens but block estrogen action in others. Tamoxifen is the first SERM that has been successfully tested for the prevention of breast cancer in high-risk women and is currently approved for the endocrine treatment of all stages of ER-positive breast cancer. Raloxifene, a newer SERM originally developed for osteoporosis, also appears to have preventive effect on breast cancer incidence. Numerous studies have examined the molecular mechanisms for the tissue selective action of SERMs, and collectively they indicate that different ER ligands induce distinct conformational changes in the receptor that influence its ability to interact with coregulatory proteins (i.e. coactivators and corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and its target gene promoter also affect SERM biocharacter. This review summarizes the therapeutic application of SERMs in medicine; particularly breast cancer, and highlights the emerging understanding of the mechanism of action of SERMs in select target tissues, and the inevitable development of resistance.

  12. Chemical composition and modulation of bacterial drug resistance of the essential oil from leaves of Croton grewioides.

    Science.gov (United States)

    de Medeiros, Vivianne Marcelino; do Nascimento, Yuri Mangueira; Souto, Augusto Lopes; Madeiro, Sara Alves Lucena; Costa, Vicente Carlos de Oliveira; Silva, Suellen Maria P M; Falcão Silva, Vivyanne Dos Santos; Agra, Maria de Fátima; de Siqueira-Júnior, José Pinto; Tavares, Josean Fechine

    2017-10-01

    The essential oil from leaves of Croton grewioides Baill was obtained by hydrodistillation using Clevenger apparatus, and its chemical composition was analyzed by GC-MS, where 18 compounds were identified, mostly as monoterpenes (55.56%) and sesquiterpenes (44.44%), in which the major constituent was the α-pinene (47.43%). The essential oil of Croton grewioides (EOCg) and its major compound (α-pinene) were evaluated as modulators of antibiotic resistance in strain SA-1199B and IS-58 of Staphylococcus aureus that overexpresses efflux protein. The minimum inhibitory concentrations (MICs) of the antibiotics were determined by the microdilution assay in the absence and in the presence of sub-inhibitory concentration of EOCg and α-pinene. Although the EOCg and α-pinene did not indicate relevant antibacterial activity in vitro, they acted as antibiotic resistance modulators, i.e., EOCg in combination with norfloxacin, reducted its MIC, by 64× whereas in combination with tetracycline it was observed a reduction of 4×. Additionally, it was observed a MIC reduction of tetracycline by 32×, when combined with α-pinene. The results suggest that EOCg and α-pinene modulate or even reverse bacterial resistance as a putative efflux pump inhibitor. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells

    NARCIS (Netherlands)

    Hulleman, Esther; Kazemier, Karin M.; Holleman, Amy; VanderWeele, David J.; Rudin, Charles M.; Broekhuis, Mathilde J. C.; Evans, William E.; Pieters, Rob; Den Boer, Monique L.

    2009-01-01

    Treatment failure in pediatric acute lymphoblastic leukemia (ALL) is related to cellular resistance to glucocorticoids (eg, prednisolone). Recently, we demonstrated that genes associated with glucose metabolism are differentially expressed between prednisolone-sensitive and prednisolone-resistant

  14. Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda.

    Science.gov (United States)

    Stölzel, Ulrich; Köstler, Erich; Schuppan, Detlef; Richter, Matthias; Wollina, Uwe; Doss, Manfred O; Wittekind, Christian; Tannapfel, Andrea

    2003-03-01

    To examine the role of hemochromatosis (HFE) gene mutations, which are associated with porphyria cutanea tarda (PCT), in the therapeutic response to chloroquine. We retrospectively analyzed a database (Excel version 2001 [Microsoft Excel, Redmond, Wash]; date range of search, 1985-1999) of chloroquine-treated patients with PCT on whether HFE mutations (C282Y and H63D) might have influenced the clinical response, urinary porphyrin excretion, liver enzyme activities, and serum iron markers. Serum samples and corresponding complete sets of data before and after therapy were available in 62 of 207 patients with PCT who were treated exclusively with chloroquine. Academic teaching hospital. For treatment, low-dose chloroquine diphosphate, 125 to 250 mg twice weekly, was used during a median time of 16 months (range, 12-26 months). Of the 62 German patients with PCT, 37 (60%) carries HFE mutations. Chloroquine therapy was accompanied by clinical remission and reduced urinary porphyrin excretion (P<.001) in the 24 patients (39%) with HFE wild type as well as in 35 HFE heterozygous patients with PCT (56%). Decreases of serum iron markers following chloroquine therapy were limited to patients with PCT and HFE wild type. All patients homozygous for the C282Y mutation (3 [5%] of 62) had high serum iron, ferritin, and transferrin saturation and failed to respond to chloroquine treatment. The therapeutic response to chloroquine was not compromised by C282Y heterozygosity and compound heterozygosity of HFE mutations. Because HFE C282Y homozygotes (+/+) did not respond to chloroquine and a decrease in serum iron concentration was limited to patients with PCT and HFE wild type, phlebotomy should be first-line therapy in patients with PCT and HFE mutations.

  15. Color vision loss in patients treated with chloroquine

    Directory of Open Access Journals (Sweden)

    Ventura Dora F.

    2003-01-01

    Full Text Available Patients that make use of chloroquine or hydroxychloroquine, drugs which are frequently administered for treatment of rheumatoid arthritis, lupus erithromatosus or malaria, may suffer alterations in color vision and in contrast sensitivity. The present work evaluates the visual function of these patients in a joint study of the University of São Paulo (USP, in São Paulo, and of the Federal University of Pará (UFPA, in Belém. Thirty two chloroquine user patients without alterations in the eye fundus exam were evaluated in São Paulo (n=10; aged 38 to 71 years; mean=55,8 years and in Belém (n=22; aged 20 to 67; mean=40 years. The prescribed accumulated chloroquine dose was 45 to 430 g (mean=213 g; sd = 152 g for the São Paulo group, and 36 to 540 g (mean=174 g; sd=183 g for the Belém group. Tests were performed monocularly with corrected eye refractive state. Color discrimination was evaluated using the Cambridge Colour Test (CCT: the color discrimination threshold was measured first in the protan, deutan and tritan axes and, in succession, three MacAdam's ellipses were determined. The patient's color vision was also evaluated with color arrangement tests: the Farnsworth-Munsell 100 Hue (FM100, the Farnsworth-Munsell D15, and the Lanthony Desaturated (D15d tests. We also measured the contrast sensitivity for black-and-white sine wave grating of twenty two patients. The results were compared with controls without ophthalmologic or neuro-ophthalmologic pathologies. Twenty four patients presented acquired dyschromatopsia. There were cases of selective loss (11 patients and of diffuse loss (13 patients. Although losses were present in the FM100 there was no correlation between the FM100 error score and the ellipse area measured by the CCT. Moreover, three patients that scored normal in the FM100, failed to reach normal threshold in the CCT. The Lanthony test was less sensitive than the other two tests, since it failed to indicate loss in about

  16. Malaria epidemic and drug resistance, Djibouti.

    Science.gov (United States)

    Rogier, Christophe; Pradines, Bruno; Bogreau, H; Koeck, Jean-Louis; Kamil, Mohamed-Ali; Mercereau-Puijalon, Odile

    2005-02-01

    Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations.

  17. Pentamethylcyclopentadienyl-rhodium and iridium complexes containing (N^N and N^O) bound chloroquine analogue ligands: synthesis, characterization and antimalarial properties.

    Science.gov (United States)

    Ekengard, Erik; Kumar, Kamlesh; Fogeron, Thibault; de Kock, Carmen; Smith, Peter J; Haukka, Matti; Monari, Magda; Nordlander, Ebbe

    2016-03-07

    The synthesis and characterization of twenty new pentamethylcyclopentadienyl-rhodium and iridium complexes containing N^N and N^O-chelating chloroquine analogue ligands are described. The in vitro antimalarial activity of the new ligands as well as the complexes was evaluated against the chloroquine sensitive (CQS) NF54 and the chloroquine resistant (CQR) Dd2 strains of Plasmodium falciparum. The antimalarial activity was found to be good to moderate; although all complexes are less active than artesunate, some of the ligands and complexes showed better activity than chloroquine (CQ). In particular, rhodium complexes were found to be considerably more active than iridium complexes against the CQS NF54 strain. Salicylaldimine Schiff base ligands having electron-withdrawing groups (F, Cl, Br, I and NO2) in para position of the salicyl moiety and their rhodium complexes showed good antiplasmodial activity against both the CQS-NF54 and the CQR-Dd2 strains. The crystal structures of (η(5)-pentamethylcyclopentadienyl){N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)} chlororhodium(III) chloride and (η(5)-pentamethylcyclopentadienyl){(4-chloro-2-(((2-((7-chloroquinolin-4-yl)amino)ethyl)imino)methyl)phenolate)}chlororhodium(III) chloride are reported. The crystallization of the amino-pyridyl complex (η(5)-pentamethylcyclopentadienyl){(N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)}chloroiridium(III) chloride in acetone resulted in the formation of the imino-pyridyl derivative (η(5)-pentamethylcyclopentadienyl){(N1-(7-chloroquinolin-4-yl)-N2-(pyridin-2-ylmethylene)ethane-1,2-diamine)}chloroiridium(III) chloride, the crystal structure of which is also reported.

  18. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling

    DEFF Research Database (Denmark)

    Balic, Anamaria; Sørensen, Morten Dræby; Trabulo, Sara Maria

    2014-01-01

    effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent...... is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer...

  19. Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues.

    Science.gov (United States)

    Pérez, Bianca C; Fernandes, Iva; Mateus, Nuno; Teixeira, Cátia; Gomes, Paula

    2013-12-15

    Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cell lines: MKN-28, Caco-2, and MCF-7. All compounds display anti-proliferative activity in the micromolar range against the three cell lines tested, and most of them were more active than their parent drug, chloroquine, against all cell lines tested. Hence, N-cinnamoyl-chloroquine analogues are a good start towards development of affordable antitumor leads. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. A review of mechanisms of circumvention and modulation of chemotherapeutic drug resistance.

    Science.gov (United States)

    O'Connor, R

    2009-05-01

    Drug resistance is a serious limitation to the effective treatment of a number of common malignancies. Thirty years of laboratory and clinical research have greatly defined the molecular alterations underlying many drug resistance processes in cancer. Based on this knowledge, strategies to overcome the impact of resistance and increase the efficacy of cancer treatment have been translated from laboratory models to clinical trials. This article reviews laboratory and, in particular, clinical attempts at drug resistance circumvention from early forays in the inhibition of cellular efflux pump-mediated drug resistance through to more selective circumvention agent strategies and into inhibition of the other important mechanisms which can allow cancer cells to survive therapy, such as apoptosis resistance. Despite some promising results to date, resistance inhibition strategies have largely failed due to poor understanding of the pharmacology, dynamics and complexity of the resistance phenotype. With the realisation that new molecularly-targeted agents can also be rendered ineffectual by the actions of resistance mechanisms, a major focus is once again emerging on identifying new strategies/pharmaceuticals which can augment the activity of the arsenal of more conventional cytotoxics and newer targeted anti-cancer drugs. Future tactical directions where old and new resistance strategies may merge to overcome this challenge are discussed.

  1. Military Curricula for Vocational & Technical Education. Basic Electricity and Electronics Individualized Learning System. CANTRAC A-100-0010. Module Five: Relationships of Current, Voltage, and Resistance. Study Booklet.

    Science.gov (United States)

    Chief of Naval Education and Training Support, Pensacola, FL.

    This individualized learning module on the relationships of current, voltage, and resistance is one in a series of modules for a course in basic electricity and electronics. The course is one of a number of military-developed curriculum packages selected for adaptaticn to vocational instructional and curriculum development in a civilian setting.…

  2. Military Curricula for Vocational & Technical Education. Basic Electricity and Electronics Individualized Learning System. CANTRAC A-100-0010. Module Fourteen: Parallel AC Resistive-Reactive Circuits. Study Booklet.

    Science.gov (United States)

    Chief of Naval Education and Training Support, Pensacola, FL.

    This individualized learning module on parallel alternating current resistive-reaction circuits is one in a series of modules for a course in basic electricity and electronics. The course is one of a number of military-developed curriculum packages selected for adaptation to vocational instructional and curriculum development in a civilian…

  3. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models

    Directory of Open Access Journals (Sweden)

    Rodrigo Delvecchio

    2016-11-01

    Full Text Available Zika virus (ZIKV infection in utero might lead to microcephaly and other congenital defects. Since no specific therapy is available thus far, there is an urgent need for the discovery of agents capable of inhibiting its viral replication and deleterious effects. Chloroquine is widely used as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in Vero cells, human brain microvascular endothelial cells, human neural stem cells, and mouse neurospheres. We demonstrate that chloroquine reduces the number of ZIKV-infected cells in vitro, and inhibits virus production and cell death promoted by ZIKV infection without cytotoxic effects. In addition, chloroquine treatment partially reveres morphological changes induced by ZIKV infection in mouse neurospheres.

  4. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models.

    Science.gov (United States)

    Delvecchio, Rodrigo; Higa, Luiza M; Pezzuto, Paula; Valadão, Ana Luiza; Garcez, Patrícia P; Monteiro, Fábio L; Loiola, Erick C; Dias, André A; Silva, Fábio J M; Aliota, Matthew T; Caine, Elizabeth A; Osorio, Jorge E; Bellio, Maria; O'Connor, David H; Rehen, Stevens; de Aguiar, Renato Santana; Savarino, Andrea; Campanati, Loraine; Tanuri, Amilcar

    2016-11-29

    Zika virus (ZIKV) infection in utero might lead to microcephaly and other congenital defects. Since no specific therapy is available thus far, there is an urgent need for the discovery of agents capable of inhibiting its viral replication and deleterious effects. Chloroquine is widely used as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in Vero cells, human brain microvascular endothelial cells, human neural stem cells, and mouse neurospheres. We demonstrate that chloroquine reduces the number of ZIKV-infected cells in vitro, and inhibits virus production and cell death promoted by ZIKV infection without cytotoxic effects. In addition, chloroquine treatment partially reveres morphological changes induced by ZIKV infection in mouse neurospheres.

  5. Effects of ethanol and/or chloroquine with low protein dietary intake

    African Journals Online (AJOL)

    filtration rate, aldosterone synthesis and alteration of kidney structure [8]. ... faeces and urine to pass into a lower compartment filled with sawdust preventing any .... Figure 3: Serum levels of urea in ethanol and/or chloroquine-treated rats, fed.

  6. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models

    Science.gov (United States)

    Delvecchio, Rodrigo; Higa, Luiza M.; Pezzuto, Paula; Valadão, Ana Luiza; Garcez, Patrícia P.; Monteiro, Fábio L.; Loiola, Erick C.; Dias, André A.; Silva, Fábio J. M.; Aliota, Matthew T.; Caine, Elizabeth A.; Osorio, Jorge E.; Bellio, Maria; O’Connor, David H.; Rehen, Stevens; de Aguiar, Renato Santana; Savarino, Andrea; Campanati, Loraine; Tanuri, Amilcar

    2016-01-01

    Zika virus (ZIKV) infection in utero might lead to microcephaly and other congenital defects. Since no specific therapy is available thus far, there is an urgent need for the discovery of agents capable of inhibiting its viral replication and deleterious effects. Chloroquine is widely used as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in Vero cells, human brain microvascular endothelial cells, human neural stem cells, and mouse neurospheres. We demonstrate that chloroquine reduces the number of ZIKV-infected cells in vitro, and inhibits virus production and cell death promoted by ZIKV infection without cytotoxic effects. In addition, chloroquine treatment partially reveres morphological changes induced by ZIKV infection in mouse neurospheres. PMID:27916837

  7. Trade-offs with stability modulate innate and mutationally acquired drug-resistance in bacterial dihydrofolate reductase enzymes.

    Science.gov (United States)

    Matange, Nishad; Bodkhe, Swapnil; Patel, Maitri; Shah, Pooja

    2018-06-05

    Structural stability is a major constraint on the evolution of protein sequences. However, under strong directional selection, mutations that confer novel phenotypes but compromise structural stability of proteins may be permissible. During the evolution of antibiotic resistance, mutations that confer drug resistance often have pleiotropic effects on the structure and function of antibiotic-target proteins, usually essential metabolic enzymes. In this study, we show that trimethoprim-resistant alleles of dihydrofolate reductase from Escherichia coli (EcDHFR) harbouring the Trp30Gly, Trp30Arg or Trp30Cys mutations are significantly less stable than the wild type making them prone to aggregation and proteolysis. This destabilization is associated with lower expression level resulting in a fitness cost and negative epistasis with other TMP-resistant mutations in EcDHFR. Using structure-based mutational analysis we show that perturbation of critical stabilizing hydrophobic interactions in wild type EcDHFR enzyme explains the phenotypes of Trp30 mutants. Surprisingly, though crucial for the stability of EcDHFR, significant sequence variation is found at this site among bacterial DHFRs. Mutational and computational analyses in EcDHFR as well as in DHFR enzymes from Staphylococcus aureus and Mycobacterium tuberculosis demonstrate that natural variation at this site and its interacting hydrophobic residues, modulates TMP-resistance in other bacterial DHFRs as well, and may explain the different susceptibilities of bacterial pathogens to trimethoprim. Our study demonstrates that trade-offs between structural stability and function can influence innate drug resistance as well as the potential for mutationally acquired drug resistance of an enzyme. ©2018 The Author(s).

  8. Chloroquine-Primaquine versus Chloroquine Alone to Treat Vivax Malaria in Afghanistan: An Open Randomized Superiority Trial.

    Science.gov (United States)

    Awab, Ghulam Rahim; Imwong, Mallika; Bancone, Germana; Jeeyapant, Atthanee; Day, Nicholas P J; White, Nicholas J; Woodrow, Charles J

    2017-12-01

    Afghanistan's national guidelines recommend primaquine (PQ) for radical treatment of Plasmodium vivax malaria, but this is rarely implemented because of concerns over potential hemolysis in patients who have G6PD deficiency. Between August 2009 and February 2014, we conducted an open-label, randomized controlled trial of chloroquine (CQ) alone versus chloroquine plus primaquine (0.25 mg base/kg/day for 14 days) (CQ+PQ) in patients aged 6 months and older with microscopy confirmed P. vivax infection. In the CQ+PQ group, G6PD deficiency was excluded by fluorescent spot testing. The primary outcome was P. vivax recurrence assessed by survival analysis over one year follow-up. Of 593 patients enrolled, 570 attended at or after 14 days of follow-up. Plasmodium vivax recurrences occurred in 37 (13.1%) of 282 patients in the CQ+PQ arm versus 86 (29.9%) of 288 in the CQ arm (Cox proportional hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.25-0.54) (intention-to-treat analysis). Protection against recurrence was greater in the first 6 months of follow-up (HR 0.082; 95% CI 0.029-0.23) than later (HR 0.65, 95% CI 0.41-1.03). Five of seven patients requiring hospital admission were considered possible cases of PQ-related hemolysis, and PQ was stopped in a further six; however, in none of these cases did hemoglobin fall by ≥ 2 g/dL or to below 7 g/dL, and genotyping did not detect any cases of Mediterranean variant G6PD deficiency. PQ 0.25 mg/kg/day for 14 days prevents relapse of P. vivax in Afghanistan. Patient visits during the first week may improve adherence. Implementation will require deployment of point-of-care phenotypic tests for G6PD deficiency.

  9. Binding of chloroquine to ionic micelles: Effect of pH and micellar surface charge

    Energy Technology Data Exchange (ETDEWEB)

    Souza Santos, Marcela de, E-mail: marcelafarmausp77@gmail.com [Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, São Paulo 14040-903 (Brazil); Perpétua Freire de Morais Del Lama, Maria, E-mail: mpemdel@fcfrp.usp.br [Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, São Paulo 14040-903 (Brazil); Instituto Nacional de Ciência e Tecnologia de Bioanalítica, Departamento de Química Analítica, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, s/n, Campinas, São Paulo 13083-970 (Brazil); Siuiti Ito, Amando, E-mail: amandosi@ffclrp.usp.br [Departamento de Física, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo 14040-901 (Brazil); and others

    2014-03-15

    The pharmacological action of chloroquine relies on its ability to cross biological membranes in order to accumulate inside lysosomes. The present work aimed at understanding the basis for the interaction between different chloroquine species and ionic micelles of opposite charges, the latter used as a simple membrane model. The sensitivity of absorbance and fluorescence of chloroquine to changes in its local environment was used to probe its interaction with cetyltrimethylammonium micelles presenting bromide (CTAB) and sulfate (CTAS) as counterions, in addition to dodecyl sulfate micelles bearing sodium (SDS) and tetramethylammonium (TMADS) counterions. Counterion exchange was shown to have little effect on drug–micelle interaction. Chloroquine first dissociation constant (pKa{sub 1}) shifted to opposite directions when anionic and cationic micelles were compared. Chloroquine binding constants (K{sub b}) revealed that electrostatic forces mediate charged drug–micelle association, whereas hydrophobic interactions allowed neutral chloroquine to associate with anionic and cationic micelles. Fluorescence quenching studies indicated that monoprotonated chloroquine is inserted deeper into the micelle surface of anionic micelles than its neutral form, the latter being less exposed to the aqueous phase when associated with cationic over anionic assemblies. The findings provide further evidence that chloroquine–micelle interaction is driven by a tight interplay between the drug form and the micellar surface charge, which can have a major effect on the drug biological activity. -- Highlights: • Chloroquine (CQ) pKa{sub 1} increased for SDS micelles and decreased for CTAB micelles. • CQ is solubilized to the surface of both CTAB and SDS micelles. • Monoprotonated CQ is buried deeper into SDS micelles than neutral CQ. • Neutral CQ is less exposed to aqueous phase in CTAB over SDS micelles. • Local pH and micellar surface charge mediate interaction of CQ with

  10. Fundus auto fluorescence and spectral domain ocular coherence tomography in the early detection of chloroquine retinopathy

    OpenAIRE

    Megan B. Goodman; Ari Ziskind

    2015-01-01

    Purpose: To determine the sensitivity of spectral domain ocular coherence tomography (SD-OCT) and fundus auto fluorescence (FAF) images as a screening test to detect early changes in the retina prior to the onset of chloroquine retinopathy. Method: The study was conducted using patients taking chloroquine (CQ), referred by the Rheumatology Department to the Ophthalmology Department at Tygerberg Academic Hospital. Group A consisted of 59 patients on CQ for less than 5 years, and Group B co...

  11. Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues

    OpenAIRE

    Bianca C Perez; Iva Fernandes; Nuno Mateus; Catia Teixeira; Paula Gomes

    2013-01-01

    Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cell lines: MKN-28, Caco-2, and MCF-7. All compounds display anti-proliferative activity in the micromolar range against the three cell lines tested, and most of them were more active than their parent drug, chloroquine, against all cell lines t...

  12. Effects of photovoltaic module soiling on glass surface resistance and potential-induced degradation

    DEFF Research Database (Denmark)

    Hacke, Peter; Burton, Patrick; Hendrickson, Alexander

    2015-01-01

    The sheet resistance of three soil types (Arizona road dust, soot, and sea salt) on glass were measured by the transmission line method as a function of relative humidity (RH) between 39% and 95% at 60°C. Sea salt yielded a 3.5 orders of magnitude decrease in resistance on the glass surface when ...

  13. Evaluation on the effectiveness chemoprophylaxis of chloroquine to irradiated plasmodium berghei by in vivo

    International Nuclear Information System (INIS)

    Darlina; Teja Kisnanto; Citra Ayu Prapmaningtyas

    2016-01-01

    Chloroquine is a compound commonly used as chemoprophylaxis in malaria research. In the malaria vaccine research used chemoprophylaxis that combined with vaccine material was studied to prevent volunteers from malaria. The purpose of the study was to evaluate the efficacy of chloroquine in inhibiting the growth of malaria parasites after radiation. The effectiveness of chloroquine was shown to inhibit the growth P. berghei growth in experimental animals. The study was conducted in vivo with chloroquine administered orally as 0, 5, 10, and 15 mg/kg of body weight daily for 4 days in mice that had been injected with infectious and radiation P. berghei 175 Gy. Density of parasites in the blood, and percent survival was observed every 2 days for 43 days. The results show until the 20"t"h day is not found parasites in the blood of mice immunized and treated Chloroquine. The chloroquine 10 mg/kg is more effective than 5 and 15 mg/kg as observed in percentage of inhibition and survival of mice. (author)

  14. The effect of the series resistance in dye-sensitized solar cells explored by electron transport and back reaction using electrical and optical modulation techniques

    International Nuclear Information System (INIS)

    Liu Weiqing; Hu Linhua; Dai Songyuan; Guo Lei; Jiang Nianquan; Kou Dongxing

    2010-01-01

    The influence of the series resistance on the electron transport and recombination processes in dye-sensitized solar cells (DSC) has been investigated. The series resistances induced by some parts of DSC, such as the transparent conductive oxide (TCO), the electrolyte layer and the counter electrode, influence the performance of DSC. By combining three frequency-domain techniques, specifically electrochemical impedance spectroscopy (EIS), intensity modulated photocurrent spectroscopy (IMPS) and intensity modulated photovoltage spectroscopy (IMVS), we studied the relationship between the series resistance and the dynamic response of DSC. The results show that the series resistance induced by the TCO or counter electrode predominantly affects the electron transport under short circuit conditions and has no significant influence on the recombination under open circuit conditions. However, the resistance related to the electrolyte layer not only limits the carrier transport but also influences the recombination. Possible reasons for the influence of the series resistance on the electron transport and recombination processes in DSC are also discussed.

  15. Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility.

    Science.gov (United States)

    Pava, Zuleima; Handayuni, Irene; Wirjanata, Grennady; To, Sheren; Trianty, Leily; Noviyanti, Rintis; Poespoprodjo, Jeanne Rini; Auburn, Sarah; Price, Ric N; Marfurt, Jutta

    2016-01-01

    Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance. Copyright © 2015 Pava et al.

  16. The roles of the pfcrt 76T and pfmdr1 86Y mutations, immunity and the initial level of parasitaemia, in predicting the outcome of chloroquine treatment in two areas with different transmission intensities

    DEFF Research Database (Denmark)

    Khalil, I F; Alifrangis, M; Tarimo, D S

    2005-01-01

    The resistance of Plasmodium falciparum to chloroquine (CQ) is probably mediated by point mutations in two genes: pfcrt and pfmdr1. The aim of the present study was to investigate, in patients treated with CQ, the association between host factors, such as immunity and initial level of parasitaemia......, and the ability to clear P. falciparum parasites carrying the key chloroquine-resistance (CQR) mutations, pfcrt 76T and pfmdr1 86Y. Identical CQ-efficacy trials were performed in 51 young children (aged ..., such as level of parasitaemia when treated and age, are also important. The 76T and 86Y alleles could still be used as predictive markers for CQR, in non-immune individuals and low-transmission areas....

  17. Mediator Tail Module Is Required for Tac1-Activated CDR1 Expression and Azole Resistance in Candida albicans.

    Science.gov (United States)

    Liu, Zhongle; Myers, Lawrence C

    2017-11-01

    The human fungal pathogen Candida albicans develops drug resistance after long-term exposure to azole drugs in the treatment of chronic candidiasis. Gain-of-function (GOF) mutations in the transcription factor Tac1 and the consequent expression of its targets, drug efflux pumps Cdr1 and Cdr2, are a common mechanism by which C. albicans acquires fluconazole resistance. The mechanism by which GOF mutations hyperactivate Tac1 is currently unknown. Here, we define a transcriptional activation domain (TAD) at the C terminus of Tac1. GOF mutations within the Tac1 TAD, outside the context of full-length Tac1, generally do not enhance its absolute potential as a transcriptional activator. Negative regulation of the Tac1 TAD by the Tac1 middle region is necessary for the activating effect of GOF mutations or fluphenazine to be realized. We have found that full-length Tac1, when hyperactivated by xenobiotics or GOF mutations, facilitates the recruitment of the Mediator coactivator complex to the CDR1 promoter. Azole resistance and the activation of Tac1 target genes, such as CDR1 , are dependent on the Tac1 TAD and subunits of the Mediator tail module. The dependence of different Tac1 target promoters on the Mediator tail module, however, varies widely. Lastly, we show that hyperactivation of Tac1 is correlated with its Mediator-dependent phosphorylation, a potentially useful biomarker for Tac1 hyperactivation. The role of Mediator in events downstream of Tac1 hyperactivation in fluconazole-resistant clinical isolates is complex and provides opportunities and challenges for therapeutic intervention. Copyright © 2017 American Society for Microbiology.

  18. Shunt and series resistance of photovoltaic module evaluated from the I-V curve; I-V tokusei kara hyokashita taiyo denchi no shunt teiko to chokuretsu teiko

    Energy Technology Data Exchange (ETDEWEB)

    Asano, K; Kawamura, H; Yamanaka, S; Kawamura, H; Ono, H [Meijo University, Nagoya (Japan)

    1997-11-25

    With an objective of discussing I-V characteristics when a shadow has appeared on part of a photovoltaic module, evaluations were given as a first stage of the study on saturation current, shunt resistance and series resistance for the solar cell module. As a result of measuring change in amount of power generated in a sunny day with a shadow appearing over the solar cell module, reduction in power generation capability of about 23% was verified. In other words, the I-V characteristics of the solar cell module change largely because of existence of the shadow caused on the module. The I-V characteristics curve may be expressed and calculated as a function of the shunt resistance and series resistance. By curve-fitting measurement data for a case of changing insolation without existence of partial shadow, values of the shunt resistance and series resistance were derived. As a result, it was found that the calculations agree well with measurements. It was made also clear that each parameter shows temperature dependence. 6 refs., 10 figs., 1 tab.

  19. Modulation of resistive switching characteristics for individual BaTiO3 microfiber by surface oxygen vacancies

    Science.gov (United States)

    Miao, Zhilei; Chen, Lei; Zhou, Fang; Wang, Qiang

    2018-01-01

    Different from traditional thin-film BaTiO3 (BTO) RRAM device with planar structure, individual microfiber-shaped RRAM device, showing promising application potentials in the micro-sized non-volatile memory system, has not been investigated so far to demonstrate resistive switching behavior. In this work, individual sol-gel BTO microfiber has been formed using the draw-bench method, followed by annealing in different atmospheres of air and argon, respectively. The resistive switching characteristics of the individual BTO microfiber have been investigated by employing double-probe SEM measurement system, which shows great convenience to test local electrical properties by modulating the contact sites between the W probes and the BTO microfiber. For the sample annealed in air, the average resistive ON/OFF ratio is as high as 108, enhanced about four orders in comparison with the counterpart that annealed in Argon. For the sample annealed in argon ambience, the weakened resistive ON/OFF ratio can be attributed to the increased presence of oxygen vacancies in the surface of BTO fibers, and the underlying electrical conduction mechanisms are also discussed.

  20. Atomic Scale Modulation of Self-Rectifying Resistive Switching by Interfacial Defects

    KAUST Repository

    Wu, Xing; Yu, Kaihao; Cha, Dong Kyu; Bosman, Michel; Raghavan, Nagarajan; Zhang, Xixiang; Li, Kun; Liu, Qi; Sun, Litao; Pey, Kinleong

    2018-01-01

    Higher memory density and faster computational performance of resistive switching cells require reliable array‐accessible architecture. However, selecting a designated cell within a crossbar array without interference from sneak path currents through neighboring cells is a general problem. Here, a highly doped n++ Si as the bottom electrode with Ni‐electrode/HfOx/SiO2 asymmetric self‐rectifying resistive switching device is fabricated. The interfacial defects in the HfOx/SiO2 junction and n++ Si substrate result in the reproducible rectifying behavior. In situ transmission electron microscopy is used to quantitatively study the properties of the morphology, chemistry, and dynamic nucleation–dissolution evolution of the chains of defects at the atomic scale. The spatial and temporal correlation between the concentration of oxygen vacancies and Ni‐rich conductive filament modifies the resistive switching effect. This study has important implications at the array‐level performance of high density resistive switching memories.

  1. Atomic Scale Modulation of Self-Rectifying Resistive Switching by Interfacial Defects

    KAUST Repository

    Wu, Xing

    2018-04-14

    Higher memory density and faster computational performance of resistive switching cells require reliable array‐accessible architecture. However, selecting a designated cell within a crossbar array without interference from sneak path currents through neighboring cells is a general problem. Here, a highly doped n++ Si as the bottom electrode with Ni‐electrode/HfOx/SiO2 asymmetric self‐rectifying resistive switching device is fabricated. The interfacial defects in the HfOx/SiO2 junction and n++ Si substrate result in the reproducible rectifying behavior. In situ transmission electron microscopy is used to quantitatively study the properties of the morphology, chemistry, and dynamic nucleation–dissolution evolution of the chains of defects at the atomic scale. The spatial and temporal correlation between the concentration of oxygen vacancies and Ni‐rich conductive filament modifies the resistive switching effect. This study has important implications at the array‐level performance of high density resistive switching memories.

  2. Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation

    International Nuclear Information System (INIS)

    Lim Yiting; Hedayati, Mohammad; Merchant, Akil A.; Zhang Yonggang; Yu, Hsiang-Hsuan M.; Kastan, Michael B.; Matsui, William; DeWeese, Theodore L.

    2012-01-01

    Purpose: We have previously shown that the antimalarial agent chloroquine can abrogate the lethal cellular effects of low-dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo. Methods and Materials: C57BL/6 mice were irradiated with a total of 12.8 Gy delivered at 9.4 cGy/hour. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 μg per 17 g of body weight, 24 hours and 4 hours before irradiation. Bone marrow cells isolated from tibia, fibula, and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retroorbital injection. Chimerism was assessed by flow cytometry. In vitro methylcellulose colony-forming assay of whole bone marrow cells and fluorescence activated cell sorting analysis of lineage depleted cells were used to assess the effect of chloroquine on progenitor cells. Results: Mice pretreated with chloroquine before radiation exhibited a significantly higher survival rate than did mice treated with radiation alone (80% vs. 31%, p = 0.0026). Chloroquine administration before radiation did not affect the survival of ATM null mice (p = 0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after transplantation (4.2% vs. 0.4%, p = 0.015). Conclusion: Chloroquine administration before radiation had a significant effect on the survival of normal but not ATM null mice, strongly suggesting that the in vivo effect, like the in vitro effect, is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR-irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection

  3. Partial ablation of adult Drosophila insulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance.

    Science.gov (United States)

    Haselton, Aaron; Sharmin, Effat; Schrader, Janel; Sah, Megha; Poon, Peter; Fridell, Yih-Woei C

    2010-08-01

    In Drosophila melanogaster (D. melanogaster), neurosecretory insulin-like peptide-producing cells (IPCs), analogous to mammalian pancreatic beta cells are involved in glucose homeostasis. Extending those findings, we have developed in the adult fly an oral glucose tolerance test and demonstrated that IPCs indeed are responsible for executing an acute glucose clearance response. To further develop D. melanogaster as a relevant system for studying age-associated metabolic disorders, we set out to determine the impact of adult-specific partial ablation of IPCs (IPC knockdown) on insulin-like peptide (ILP) action, metabolic outcomes and longevity. Interestingly, while IPC knockdown flies are hyperglycemic and glucose intolerant, these flies remain insulin sensitive as measured by peripheral glucose disposal upon insulin injection and serine phosphorylation of a key insulin-signaling molecule, Akt. Significant increases in stored glycogen and triglyceride levels as well as an elevated level of circulating lipid measured in adult IPC knockdown flies suggest profound modulation in energy metabolism. Additional physiological outcomes measured in those flies include increased resistance to starvation and impaired female fecundity. Finally, increased life span and decreased mortality rates measured in IPC knockdown flies demonstrate that it is possible to modulate ILP action in adult flies to achieve life span extension without insulin resistance. Taken together, we have established and validated an invertebrate genetic system to further investigate insulin action, metabolic homeostasis and regulation of aging regulated by adult IPCs.

  4. Collusion-resistant audio fingerprinting system in the modulated complex lapped transform domain.

    Directory of Open Access Journals (Sweden)

    Jose Juan Garcia-Hernandez

    Full Text Available Collusion-resistant fingerprinting paradigm seems to be a practical solution to the piracy problem as it allows media owners to detect any unauthorized copy and trace it back to the dishonest users. Despite the billionaire losses in the music industry, most of the collusion-resistant fingerprinting systems are devoted to digital images and very few to audio signals. In this paper, state-of-the-art collusion-resistant fingerprinting ideas are extended to audio signals and the corresponding parameters and operation conditions are proposed. Moreover, in order to carry out fingerprint detection using just a fraction of the pirate audio clip, block-based embedding and its corresponding detector is proposed. Extensive simulations show the robustness of the proposed system against average collusion attack. Moreover, by using an efficient Fast Fourier Transform core and standard computer machines it is shown that the proposed system is suitable for real-world scenarios.

  5. Vorinostat-induced autophagy switches from a death-promoting to a cytoprotective signal to drive acquired resistance.

    Science.gov (United States)

    Dupéré-Richer, D; Kinal, M; Ménasché, V; Nielsen, T H; Del Rincon, S; Pettersson, F; Miller, W H

    2013-02-07

    Histone deacetylase inhibitors (HDACi) have shown promising activity against hematological malignancies in clinical trials and have led to the approval of vorinostat for the treatment of cutaneous T-cell lymphoma. However, de novo or acquired resistance to HDACi therapy is inevitable, and their molecular mechanisms are still unclear. To gain insight into HDACi resistance, we developed vorinostat-resistant clones from the hematological cell lines U937 and SUDHL6. Although cross-resistant to some but not all HDACi, the resistant cell lines exhibit dramatically increased sensitivity toward chloroquine, an inhibitor of autophagy. Consistent with this, resistant cells growing in vorinostat show increased autophagy. Inhibition of autophagy in vorinostat-resistant U937 cells by knockdown of Beclin-1 or Lamp-2 (lysosome-associated membrane protein 2) restores sensitivity to vorinostat. Interestingly, autophagy is also activated in parental U937 cells by de novo treatment with vorinostat. However, in contrast to the resistant cells, inhibition of autophagy decreases sensitivity to vorinostat. These results indicate that autophagy can switch from a proapoptotic signal to a prosurvival function driving acquired resistance. Moreover, inducers of autophagy (such as mammalian target of rapamycin inhibitors) synergize with vorinostat to induce cell death in parental cells, whereas the resistant cells remain insensitive. These data highlight the complexity of the design of combination strategies using modulators of autophagy and HDACi for the treatment of hematological malignancies.

  6. Baicalein modulates stress-resistance and life span in C. elegans via SKN-1 but not DAF-16.

    Science.gov (United States)

    Havermann, Susannah; Humpf, Hans-Ulrich; Wätjen, Wim

    2016-09-01

    The flavonoid baicalein has been demonstrated to be an activator of the transcription factor Nrf2 in mammalian cell lines. We show that it further modulates the Nrf2 homolog SKN-1 in Caenorhabditis elegans and by this pathway mediates beneficial effects in the nematode: baicalein enhances the resistance of C. elegans against lethal thermal and sodium arsenite stress and dose-dependently prolongs the life span of the nematode. Using RNA interference against SKN-1 we were able to show that the induction of longevity and the enhanced stress-resistance were dependent on this transcription factor. DAF-16 (homolog to mammalian FOXO) is another pivotal aging-related transcription factor in the nematode. We demonstrate that DAF-16 does not participate in the beneficial effects of baicalein: since baicalein causes no increase in the nuclear translocation of DAF-16 (DAF-16::GFP expressing strain, incubation time: 1h) and it still induces longevity even in a DAF-16 loss-of-function strain, we conclude, that baicalein increases stress-resistance and life span in C. elegans via SKN-1 but not DAF-16. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Photovoltaic module diagnostics by series resistance monitoring and temperature and rated power estimation

    DEFF Research Database (Denmark)

    Sera, Dezso; Teodorescu, Remus; Rodriguez, Pedro

    2008-01-01

    One of the most important parameters, which characterize a photovoltaic panel health state, is its series resistance. An increase of this normally indicates bad contacts between cells or panels. Another important property, which characterizes the aging of the panel is the reduction of its MPP power...

  8. Review: Potential biotechnological assets related to plant immunity modulation applicable in engineering disease-resistant crops.

    Science.gov (United States)

    Silva, Marilia Santos; Arraes, Fabrício Barbosa Monteiro; Campos, Magnólia de Araújo; Grossi-de-Sa, Maira; Fernandez, Diana; Cândido, Elizabete de Souza; Cardoso, Marlon Henrique; Franco, Octávio Luiz; Grossi-de-Sa, Maria Fátima

    2018-05-01

    This review emphasizes the biotechnological potential of molecules implicated in the different layers of plant immunity, including, pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI), effector-triggered susceptibility (ETS), and effector-triggered immunity (ETI) that can be applied in the development of disease-resistant genetically modified (GM) plants. These biomolecules are produced by pathogens (viruses, bacteria, fungi, oomycetes) or plants during their mutual interactions. Biomolecules involved in the first layers of plant immunity, PTI and ETS, include inhibitors of pathogen cell-wall-degrading enzymes (CWDEs), plant pattern recognition receptors (PRRs) and susceptibility (S) proteins, while the ETI-related biomolecules include plant resistance (R) proteins. The biomolecules involved in plant defense PTI/ETI responses described herein also include antimicrobial peptides (AMPs), pathogenesis-related (PR) proteins and ribosome-inhibiting proteins (RIPs), as well as enzymes involved in plant defensive secondary metabolite biosynthesis (phytoanticipins and phytoalexins). Moreover, the regulation of immunity by RNA interference (RNAi) in GM disease-resistant plants is also considered. Therefore, the present review does not cover all the classes of biomolecules involved in plant innate immunity that may be applied in the development of disease-resistant GM crops but instead highlights the most common strategies in the literature, as well as their advantages and disadvantages. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Modulation of TRAIL resistance in colon carcinoma cells : Different contributions of DR4 and DR5

    NARCIS (Netherlands)

    van Geelen, Caroline M. M.; Pennarun, Bodvael; Le, Phuong T. K.; de Vries, Elisabeth G. E.; de Jong, Steven

    2011-01-01

    Background: rhTRAIL is a therapeutic agent, derived from the TRAIL cytokine, which induces apoptosis in cancer cells by activating the membrane death receptors 4 and 5 (DR4 and DR5). Here, we investigated each receptor's contribution to rhTRAIL sensitivity and rhTRAIL resistance. We assessed whether

  10. Migration of interfacial oxygen ions modulated resistive switching in oxide-based memory devices

    Science.gov (United States)

    Chen, C.; Gao, S.; Zeng, F.; Tang, G. S.; Li, S. Z.; Song, C.; Fu, H. D.; Pan, F.

    2013-07-01

    Oxides-based resistive switching memory induced by oxygen ions migration is attractive for future nonvolatile memories. Numerous works had focused their attentions on the sandwiched oxide materials for depressing the characteristic variations, but the comprehensive studies of the dependence of electrodes on the migration behavior of oxygen ions are overshadowed. Here, we investigated the interaction of various metals (Ni, Co, Al, Ti, Zr, and Hf) with oxygen atoms at the metal/Ta2O5 interface under electric stress and explored the effect of top electrode on the characteristic variations of Ta2O5-based memory device. It is demonstrated that chemically inert electrodes (Ni and Co) lead to the scattering switching characteristics and destructive gas bubbles, while the highly chemically active metals (Hf and Zr) formed a thick and dense interfacial intermediate oxide layer at the metal/Ta2O5 interface, which also degraded the resistive switching behavior. The relatively chemically active metals (Al and Ti) can absorb oxygen ions from the Ta2O5 film and avoid forming the problematic interfacial layer, which is benefit to the formation of oxygen vacancies composed conduction filaments in Ta2O5 film thus exhibit the minimum variations of switching characteristics. The clarification of oxygen ions migration behavior at the interface can lead further optimization of resistive switching performance in Ta2O5-based memory device and guide the rule of electrode selection for other oxide-based resistive switching memories.

  11. Pulse-modulated multilevel data storage in an organic ferroelectric resistive memory diode

    NARCIS (Netherlands)

    Lee, J.; Breemen, A.J.J.M. van; Khikhlovskyi, V.; Kemerink, M.; Janssen, R.A.J.; Gelinck, G.H.

    2016-01-01

    We demonstrate multilevel data storage in organic ferroelectric resistive memory diodes consisting of a phase-separated blend of P(VDF-TrFE) and a semiconducting polymer. The dynamic behaviour of the organic ferroelectric memory diode can be described in terms of the inhomogeneous field mechanism

  12. MicroRNA‑663b mediates TAM resistance in breast cancer by modulating TP73 expression.

    Science.gov (United States)

    Jiang, Hua; Cheng, Lin; Hu, Pan; Liu, Renbin

    2018-05-23

    Breast cancer is the second leading cause of cancer‑associated mortalities in women. Tamoxifen (TAM) is an endocrine therapy commonly used in the treatment of patients with breast cancer expressing estrogen receptor α. However, treatment often ends in failure due to the emergence of drug resistance. MicroRNAs (miRNAs), a family of small non‑coding RNAs, serve critical roles in the regulation of gene expression and cell events. To date, whether miRNA‑663b could mediate TAM resistance in breast cancer remains unknown. Therefore, the aim of the present study was to investigate the role of miRNA‑663b in TAM resistance in breast cancer. The results demonstrated that miRNA‑663b was upregulated in breast cancer with TAM resistance. Tumor protein 73 (TP73) was a direct target of miRNA‑663b, and was negatively regulated by miRNA‑663b in MCF‑7 cells. Furthermore, it was identified that downregulation of miRNA‑663b inhibited cell proliferation ability and promoted cell apoptosis, resulting in enhanced TAM sensitivity. In addition, these findings suggested that TP73 silencing may have eliminated the effects of miRNA‑663b inhibitor on breast cancer cells. In conclusion, the present study verified a novel molecular link between miRNA‑663b and TP73, and indicated that miRNA‑663b may be a critical therapeutic target in breast cancer.

  13. A Pseudo-tRNA Modulates Antibiotic Resistance in Bacillus cereus

    DEFF Research Database (Denmark)

    Rogers, Theresa E; Ataide, Sandro F; Dare, Kiley

    2012-01-01

    . Deletion of tRNA(Other) led to significant changes in cell wall morphology and antibiotic resistance and was accompanied by changes in the expression of numerous genes involved in oxidative stress responses, several of which contain significant complementarities to sequences surrounding t...

  14. Regular examinations for toxic maculopathy in long-term chloroquine or hydroxychloroquine users.

    Science.gov (United States)

    Nika, Melisa; Blachley, Taylor S; Edwards, Paul; Lee, Paul P; Stein, Joshua D

    2014-10-01

    According to evidence-based, expert recommendations, long-term users of chloroquine or hydroxychloroquine sulfate should undergo regular visits to eye care providers and diagnostic testing to check for maculopathy. To determine whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) taking chloroquine or hydroxychloroquine are regularly visiting eye care providers and being screened for maculopathy. Patients with RA or SLE who were continuously enrolled in a particular managed care network for at least 5 years between January 1, 2001, and December 31, 2011, were studied. Patients' amount of chloroquine or hydroxychloroquine use in the 5 years since the initial RA or SLE diagnosis was calculated, along with their number of eye care visits and diagnostic tests for maculopathy. Those at high risk for maculopathy were identified. Logistic regression was performed to assess potential factors associated with regular eye care visits (annual visits in ≥3 of 5 years) among chloroquine or hydroxychloroquine users, including those at highest risk for maculopathy. Among chloroquine or hydroxychloroquine users and those at high risk for toxic maculopathy, the proportions with regular eye care visits and diagnostic testing, as well as the likelihood of regular eye care visits. Among 18 051 beneficiaries with RA or SLE, 6339 (35.1%) had at least 1 record of chloroquine or hydroxychloroquine use, and 1409 (7.8%) had used chloroquine or hydroxychloroquine for at least 4 years. Among those at high risk for maculopathy, 27.9% lacked regular eye care visits, 6.1% had no visits to eye care providers, and 34.5% had no diagnostic testing for maculopathy during the 5-year period. Among high-risk patients, each additional month of chloroquine or hydroxychloroquine use was associated with a 2.0% increased likelihood of regular eye care (adjusted odds ratio, 1.02; 95% CI, 1.01-1.03). High-risk patients whose SLE or RA was managed by rheumatologists had a 77

  15. A Case Report of Suicide with Chloroquine Overdose and Review of Literature

    Directory of Open Access Journals (Sweden)

    Maryam Hosseini

    2016-09-01

    Full Text Available Background & Objective: Suicide is considered as the tenth cause of death worldwide. There are several suicide reports consist in the use of certain unusual drugs, such as chloroquine. Case report: The cadaver of a 25-year-old single woman was found dead in her home and with suspect to using toxins or drugs was brought to Fars Province Forensic administration. She had history of psychiatric problems for which had referred to psychologist several times. Results: After the autopsy, there was no observation of pathologic lesions in her samples of liver, kidney, or heart. In bile samples, using Thin Layer Chromatography (TLC and High Performance Liquid Chromatography (HPLC methods, chloroquine was detected. In visceral and gut samples, chloroquine was found using TLC as +4 reactions and it was confirmed by HPLC and Gas Chromatography Mass Spectrometry (GC-MS. After examining all the aspects, eventually chloroquine overdose and its complications was determined as the cause of the death. Conclusion: Due to the high incidence of suicide in depressed patients and according to family and previous positive experience, preventive strategies based on the recognition and the treatment of depressed patients and also teaching the families to diagnose the illness in addition to the limitation of the free access to chloroquine and similar drugs is suggested to reduce overdose complications or suicide.

  16. Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

    International Nuclear Information System (INIS)

    Ratikan, Josephine Anna; Sayre, James William; Schaue, Dörthe

    2013-01-01

    Purpose: This study used chloroquine to direct radiation-induced tumor cell death pathways to harness the antitumor activity of the immune system. Methods and Materials: Chloroquine given immediately after tumor irradiation increased the cure rate of MCaK breast cancer in C3H mice. Chloroquine blocked radiation-induced autophagy and drove MCaK cells into a more rapid apoptotic and more immunogenic form of cell death. Results: Chloroquine treatment made irradiated tumor vaccines superior at inducing strong interferon gamma-associated immune responses in vivo and protecting mice from further tumor challenge. In vitro, chloroquine slowed antigen uptake and degradation by dendritic cells, although T-cell stimulation was unaffected. Conclusions: This study illustrates a novel approach to improve the efficacy of breast cancer radiation therapy by blocking endosomal pathways, which enhances radiation-induced cell death within the field and drives antitumor immunity to assist therapeutic cure. The study illuminates and merges seemingly disparate concepts regarding the importance of autophagy in cancer therapy

  17. Resistive switching and voltage induced modulation of tunneling magnetoresistance in nanosized perpendicular organic spin valves

    Directory of Open Access Journals (Sweden)

    Robert Göckeritz

    2016-04-01

    Full Text Available Nanoscale multifunctional perpendicular organic spin valves have been fabricated. The devices based on an La0.7Sr0.3MnO3/Alq3/Co trilayer show resistive switching of up to 4-5 orders of magnitude and magnetoresistance as high as -70% the latter even changing sign when voltage pulses are applied. This combination of phenomena is typically observed in multiferroic tunnel junctions where it is attributed to magnetoelectric coupling between a ferromagnet and a ferroelectric material. Modeling indicates that here the switching originates from a modification of the La0.7Sr0.3MnO3 surface. This modification influences the tunneling of charge carriers and thus both the electrical resistance and the tunneling magnetoresistance which occurs at pinholes in the organic layer.

  18. Modulation of the norfloxacin resistance in Staphylococcus aureus by Cordia verbenaceae DC

    OpenAIRE

    Edinardo F.F Matias; Karla K. A Santos; Vivyanne S Falcão-Silva; José P Siqueira-Júnior; José G. M Costa; Henrique D.M Coutinho

    2013-01-01

    Background & objectives: Several chemical compounds isolated from natural sources have antibacterial activity and some enhance the antibacterial activity of antibiotics reversing the natural resistance of bacteria to certain antibiotics. In this study, the hexane and methanol extract of Cordia verbenaceae were assessed for antibacterial activity alone and combinated with norfloxacin against the Staphylococcus aureus strain SA1199B. Methods: The minimum inhibitory concentration (MIC) of ex...

  19. Modulating affect, cognition and behavior – prospects of deep brain stimulation for treatment resistant psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Thomas E. Schlaepfer

    2011-06-01

    Full Text Available Most patients suffering from psychiatric disorders respond to combina-tions of psycho- and psychopharmacotherapy, however there are patients who profit little if anything even after many years of treatment. Since about a decade different modalities of targeted neuromodulation – among them most prominently – Deep Brain Stimulation (DBS - are being actively researched as putative approaches to very treatment resistant forms of those disorders. Recently, promising pilot data have been re-ported both for Major Depression (MD and Obsessive-Compulsive Disor-der (OCD. Given the fact that patients studied had been treated unsuc-cessfully for many years renders these findings remarkable. Remarkable is the fact, that in case of the long-term studies underway for MD, patients show a stable response. This gives hope to a substantial percentage of therapy-resistant psychiatric patients requiring new therapy approaches. There are no fundamental ethic objections to its use in psychiatric disor-ders, but until substantial clinical data is available, mandatory standards are needed. DBS is a unique and very promising method for the treat-ment of therapy-resistant psychiatric patients. The method allows ma-nipulating pathological neuronal networks in a very precise way.

  20. Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells.

    Directory of Open Access Journals (Sweden)

    Cristiano Farace

    Full Text Available The presence of cancer stem cells (CSCs or tumor-initiating cells can lead to cancer recurrence in a permissive cell-microenvironment interplay, promoting invasion in glioblastoma (GBM and neuroblastoma (NB. Extracellular matrix (ECM small leucine-rich proteoglycans (SLRPs play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs, SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN and lumican (LUM are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+ CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge

  1. Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells.

    Science.gov (United States)

    Farace, Cristiano; Oliver, Jaime Antonio; Melguizo, Consolacion; Alvarez, Pablo; Bandiera, Pasquale; Rama, Ana Rosa; Malaguarnera, Giulia; Ortiz, Raul; Madeddu, Roberto; Prados, Jose

    2015-01-01

    The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell-microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities

  2. Radiation resistance of γ-detector modules at the labelling station of labelled neutrino complex

    International Nuclear Information System (INIS)

    Pishchal'nikov, Yu.M.

    1986-01-01

    The data on efficiency and transparency decrease of various types of lightpipe-spectrum (LSS) and scintillation plates on the basis of PMMA and polystyrene under the dose irradiation ranging from 10 4 to 3x10 6 rad have been obtained. Sample irradiation was carried out in a wide muon beam and with the intensive radioactie source 60 Co. The deterioration in the γ-detector (TNF) energy resolution due to the radiation damage of scintillators and (LSS) is discussed. Radiation damage of the lead glass detectors (the GAMS detector) and ''sandwich'' type modules have been compared

  3. Derivation of optimal design of cockpit module considering vibration and heat-resistance characteristics

    International Nuclear Information System (INIS)

    Kim, Hyun Jun; Cho, Hoon; Son, Young Tak; Suh, Myung Won; Kim, Hye Kyung; Kim, Hae Ryong

    2010-01-01

    Elimination of noise caused by the permanent deformation of interior plastic parts has been one of the major factors driving the design of automotive interior assemblies. Noise, indeed, is one of the main criteria affecting the perception of vehicle quality. Traditionally, noise issues have been identified and rectified through extensive hardware testing. However, to shorten the product development cycle and minimize the amount of costly hardware manufactured, hardware testing must rely on engineering analysis and upfront simulation in the design cycle. In this paper, an analytical study conducted to reduce permanent deformation in a cockpit module is discussed. The analytical investigation utilized a novel and practical methodology, implemented through the software tools ABAQUS and iSight, for the identification and minimization of permanent deformation. Here, the emphasis was placed on evaluating the software for issues relating to the prediction of permanent deformation. The analytical results were compared with the experimental findings for two types of deformation location, and the qualitative correlation was found to be very good. We also developed a methodology for the determination of the optimal guide and mount locations of the cockpit module that minimizes permanent deformation. To this end, the methodology implements and integrates nonlinear finite element analysis with sensitivity-analysis techniques

  4. Antimalarial therapy selection for quinolone resistance among Escherichia coli in the absence of quinolone exposure, in tropical South America.

    Directory of Open Access Journals (Sweden)

    Ross J Davidson

    Full Text Available BACKGROUND: Bacterial resistance to antibiotics is thought to develop only in the presence of antibiotic pressure. Here we show evidence to suggest that fluoroquinolone resistance in Escherichia coli has developed in the absence of fluoroquinolone use. METHODS: Over 4 years, outreach clinic attendees in one moderately remote and five very remote villages in rural Guyana were surveyed for the presence of rectal carriage of ciprofloxacin-resistant gram-negative bacilli (GNB. Drinking water was tested for the presence of resistant GNB by culture, and the presence of antibacterial agents and chloroquine by HPLC. The development of ciprofloxacin resistance in E. coli was examined after serial exposure to chloroquine. Patient and laboratory isolates of E. coli resistant to ciprofloxacin were assessed by PCR-sequencing for quinolone-resistance-determining-region (QRDR mutations. RESULTS: In the very remote villages, 4.8% of patients carried ciprofloxacin-resistant E. coli with QRDR mutations despite no local availability of quinolones. However, there had been extensive local use of chloroquine, with higher prevalence of resistance seen in the villages shortly after a Plasmodium vivax epidemic (p<0.01. Antibacterial agents were not found in the drinking water, but chloroquine was demonstrated to be present. Chloroquine was found to inhibit the growth of E. coli in vitro. Replica plating demonstrated that 2-step QRDR mutations could be induced in E. coli in response to chloroquine. CONCLUSIONS: In these remote communities, the heavy use of chloroquine to treat malaria likely selected for ciprofloxacin resistance in E. coli. This may be an important public health problem in malarious areas.

  5. Selective elution of HLA antigens and beta 2-microglobulin from human platelets by chloroquine diphosphate

    International Nuclear Information System (INIS)

    Kao, K.J.

    1988-01-01

    To determine whether chloroquine can specifically elute HLA antigens and beta 2-microglobulin (beta 2-M) from the platelet surface, quantitative immunofluorescence flow cytometry and monoclonal antibodies were used to show that HLA antigens and beta 2-M were proportionally eluted from the platelet surface without affecting the membrane glycoproteins IIb and IIIa. Second, an autoradiogram of electrophoresed I-125-labeled platelets showed that only beta 2-M but not other I-125-labeled membrane proteins could be eluted. Although HLA antigens were poorly labeled by I-125 and could not be detected on the autoradiogram, the eluted HLA antigens could be detected by anti-HLA monoclonal antibody and immunoblotting techniques. No loss of plasma membrane integrity was observed by transmission electron microscopy after chloroquine treatment of platelets. The results indicate that chloroquine selectively elutes HLA antigens and their noncovalently associated beta 2-M without affecting other integral platelet membrane proteins

  6. Standard Test Method for Determining Resistance of Photovoltaic Modules to Hail by Impact with Propelled Ice Balls

    CERN Document Server

    American Society for Testing and Materials. Philadelphia

    2010-01-01

    1.1 This test method provides a procedure for determining the ability of photovoltaic modules to withstand impact forces of falling hail. Propelled ice balls are used to simulate falling hailstones. 1.2 This test method defines test specimens and methods for mounting specimens, specifies impact locations on each test specimen, provides an equation for determining the velocity of any size ice ball, provides a method for impacting the test specimens with ice balls, provides a method for determining changes in electrical performance, and specifies parameters that must be recorded and reported. 1.3 This test method does not establish pass or fail levels. The determination of acceptable or unacceptable levels of ice ball impact resistance is beyond the scope of this test method. 1.4 The size of the ice ball to be used in conducting this test is not specified. This test method can be used with various sizes of ice balls. 1.5 This test method may be applied to concentrator and nonconcentrator modules. 1.6 The v...

  7. miR-297 modulates multidrug resistance in human colorectal carcinoma by down-regulating MRP-2.

    Science.gov (United States)

    Xu, Ke; Liang, Xin; Shen, Ke; Cui, Daling; Zheng, Yuanhong; Xu, Jianhua; Fan, Zhongze; Qiu, Yanyan; Li, Qi; Ni, Lei; Liu, Jianwen

    2012-09-01

    Colorectal carcinoma is a frequent cause of cancer-related death in men and women. miRNAs (microRNAs) are endogenous small non-coding RNAs that regulate gene expression negatively at the post-transcriptional level. In the present study we investigated the possible role of microRNAs in the development of MDR (multidrug resistance) in colorectal carcinoma cells. We analysed miRNA expression levels between MDR colorectal carcinoma cell line HCT116/L-OHP cells and their parent cell line HCT116 using a miRNA microarray. miR-297 showed lower expression in HCT116/L-OHP cells compared with its parental cells. MRP-2 (MDR-associated protein 2) is an important MDR protein in platinum-drug-resistance cells and is a predicted target of miR-297. Additionally miR-297 was down-regulated in a panel of human colorectal carcinoma tissues and negatively correlated with expression levels of MRP-2. Furthermore, we found that ectopic expression of miR-297 in MDR colorectal carcinoma cells reduced MRP-2 protein level and sensitized these cells to anti-cancer drugs in vitro and in vivo. Taken together, our findings suggest that miR-297 could play a role in the development of MDR in colorectal carcinoma cells, at least in part by modulation of MRP-2.

  8. Chloroquine, quinine, procaine, quinidine, tricyclic antidepressants, and methylxanthines as prostaglandin agonists and antagonists.

    Science.gov (United States)

    Manku, M S; Horrobin, D F

    1976-11-20

    Chloroquine, quanine, procaine, quinidine, clomipramine, theophylline, and caffeine have been shown to be strong prostaglandin antagonists and weak agonists. The antagonist effect is clearly demonstrable at concentrations reached in human plasma when the drugs are used therapeutically. This suggests that prostaglandins are important in several situations in which their role has hitherto been unsuspected. New approaches to the development of prostaglandin antagonists and new uses for established drugs are indicated. In a preliminary study chloroquine has been successfully used to close patent ductus arteriosus in three infants.

  9. CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia

    Science.gov (United States)

    Díaz-Chico, Juan Carlos; McNaughton-Smith, Grant; Jiménez-Alonso, Sandra; Hueso-Falcón, Idaira; Montero, Juan Carlos; Blanco, Raquel; León, Javier; Rodríguez-González, Germán; Estévez-Braun, Ana; Pandiella, Atanasio; Díaz-Chico, Bonifacio Nicolás; Fernández-Pérez, Leandro

    2017-01-01

    Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 ± 0.5 μM) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker γH2AX. CM363 caused a time-dependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl-Stat5 related malignancies. PMID:27557509

  10. Modulation of the norfloxacin resistance in Staphylococcus aureus by Cordia verbenaceae DC.

    Science.gov (United States)

    Matias, Edinardo F F; Santos, Karla K A; Falcão-Silva, Vivyanne S; Siqueira-Junior, Jose P; Costa, Jose G M; Coutinho, Henrique D M

    2013-01-01

    Several chemical compounds isolated from natural sources have antibacterial activity and some enhance the antibacterial activity of antibiotics reversing the natural resistance of bacteria to certain antibiotics. In this study, the hexane and methanol extract of Cordia verbenaceae were assessed for antibacterial activity alone and combinated with norfloxacin against the Staphylococcus aureus strain SA1199B. The minimum inhibitory concentration (MIC) of extracts was assayed using microdilution assay and the modulatory activity was evaluated using plate diffusion assay. The MIC observed varied between 256 to >1024 μg/ml. However, the antibiotic activity of norfloxacin was enhanced in the presence of subinhibitory concentrations of hexane extract of C. verbenaceae (HECV). INTERPRETATIONS & CONCLUSIONS: Our results indicate that Cordia verbenaceae DC. can be a source of plant derived products with antibiotic modifying activity.

  11. Acute resistance exercise modulates microRNA expression profiles: Combined tissue and circulatory targeted analyses.

    Directory of Open Access Journals (Sweden)

    Randall F D'Souza

    Full Text Available A subset of short non-coding RNAs, microRNAs (miRs, have been identified in the regulation of skeletal muscle hypertrophy and atrophy. Expressed within cells, miRs are also present in circulation (c-miR and have a putative role in cross-tissue signalling. The aim of this study was to examine the impact of a single bout of high intensity resistance exercise (RE on skeletal muscle and circulatory miRs harvested simultaneously. Resistance trained males (n = 9, 24.6 ± 4.9 years undertook a single bout of high volume RE with venous blood and muscle biopsies collected before, 2 and 4hr post-exercise. Real time polymerase chain reaction (Rt-PCR analyses was performed on 30 miRs that have previously been shown to be required for skeletal muscle function. Of these, 6 miRs were significantly altered within muscle following exercise; miR-23a, -133a, -146a, -206, -378b and 486. Analysis of these same miRs in circulation demonstrated minimal alterations with exercise, although c-miR-133a (~4 fold, p = 0.049 and c-miR-149 (~2.4 fold; p = 0.006 were increased 4hr post-exercise. Thus a single bout of RE results in the increased abundance of a subset of miRs within the skeletal muscle, which was not evident in plasma. The lack a qualitative agreement in the response pattern of intramuscular and circulating miR expression suggests the analysis of circulatory miRs is not reflective of the miR responses within skeletal muscle after exercise.

  12. Uptake of 14C-labelled chloroquine and an 125I-labelled chloroquine analogue in some polypeptide hormone producing cell systems

    International Nuclear Information System (INIS)

    Dencker, L.; Lindquist, N.G.; Tjaelve, H.

    1976-01-01

    After the injection of 14 C-labelled chloroquine and the 125 I-labelled chloroquine analogue 4-(3 1 -dimethylaminopropylamino)-7-iodoquinoline [ 125 I]DAPQ into mice, rats and a monkey the distribution of the radioactivity was studied by autoradiographical methods. A high and persistent uptake occurred in some endocrine cell systems, such as the pancreatic islets, the hypophysis, the adrenal medulla and the thyroid (in cells that were probably identical with the parafollicular cells). The melanin-containing tissues were the only ones which showed a higher uptake and retention of radioactivity. The above mentioned endocrine cells and the melanocytes have a common embryological origin and common morphological and cytochemical characteristics. They have been called the APUD (Amine Precursor Uptake and Decarboxylation)-cell series. It is proposed that the polypeptide hormone producing cells and the melanocytes may use a similar mechanism for accumulating chloroquine and (as shown earlier) also some other drugs such as nicotine, alprenolol, local anesthetics and atropine. These drugs however, accumulate stronger within the melanocytes and become bound to the melanin for a long time. The ability to accumulate these drugs may be considered another characteristic of the APUD-cell series. (author)

  13. Natural lignans from Arctium lappa modulate P-glycoprotein efflux function in multidrug resistant cancer cells.

    Science.gov (United States)

    Su, Shan; Cheng, Xinlai; Wink, Michael

    2015-02-15

    Arctium lappa is a well-known traditional medicinal plant in China (TCM) and Europe that has been used for thousands of years to treat arthritis, baldness or cancer. The plant produces lignans as secondary metabolites which have a wide range of bioactivities. Yet, their ability to reverse multidrug resistance (MDR) in cancer cells has not been explored. In this study, we isolated six lignans from A. lappa seeds, namely arctigenin, matairesinol, arctiin, (iso)lappaol A, lappaol C, and lappaol F. The MDR reversal potential of the isolated lignans and the underlying mechanism of action were studied using two MDR cancer cell lines, CaCo2 and CEM/ADR 5000 which overexpress P-gp and other ABC transporters. In two-drug combinations of lignans with the cytotoxic doxorubicin, all lignans exhibited synergistic effects in CaCo2 cells and matairesinol, arctiin, lappaol C and lappaol F display synergistic activity in CEM/ADR 5000 cells. Additionally, in three-drug combinations of lignans with the saponin digitonin and doxorubicin MDR reversal activity was even stronger enhanced. The lignans can increase the retention of the P-gp substrate rhodamine 123 in CEM/ADR 5000 cells, indicating that lignans can inhibit the activity of P-gp. Our study provides a first insight into the potential chemosensitizing activity of a series of natural lignans, which might be candidates for developing novel adjuvant anticancer agents. Copyright © 2015 Elsevier GmbH. All rights reserved.

  14. Burkholderia sp. KCTC 11096BP modulates pepper growth and resistance against Phytophthora capsici

    International Nuclear Information System (INIS)

    Kang, S.M.; Hamayun, M.; Shinwari, Z.K.

    2016-01-01

    Biological control of crop diseases is desirable for sustainable agriculture as it minimizes chemical inputs in the agricultural system and promotes eco-friendly environment. We analyzed the favorable role of Burkholderia sp. KCTC 11096BP against the pathogen Phytophthora capsici in pepper. We screen thirty rhizobateria for their anti-pathogen activity, and found that Burkholderia sp. KCTC 11096BP exhibits maximum growth inhibition of the pathogen P. capsici. The bacterium inoculation to pepper plants significantly enhanced growth attributes of pepper in infected and control treatments. The total proteins (10.9%), and the amino acids viz. glycine (4.08 ug/g), leucine (3.3 ug/g), and alanine (3.26 ug/g) were preset in considerably higher quantities in Burkholderia sp. applied treatments as compare to control. The systemic acquired resistance (SAR) of the host plant was up-regulated by Burkholderia sp. KCTC, as endogenous salicylic acid (235.5 ng/g) and jasmonic acid (22.8 ng/g) levels were found higher in such treatments. It was concluded that Burkholderia sp. KCTC 11096BP mitigates the adverse effects of P. capsici on pepper crop and can improve crop productivity at the field level. (author)

  15. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells

    International Nuclear Information System (INIS)

    Sasaki, Kazuhito; Hiyoshi, Masaya; Kaneko, Manabu; Kitayama, Joji; Takahashi, Koki; Nagawa, Hirokazu; Tsuno, Nelson H; Sunami, Eiji; Tsurita, Giichiro; Kawai, Kazushige; Okaji, Yurai; Nishikawa, Takeshi; Shuno, Yasutaka; Hongo, Kumiko

    2010-01-01

    Chloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but in most cases, resistance to 5-FU develops through various mechanisms. Here, we focused on the combination of CQ as a mechanism to potentiate the inhibitory effect of 5-FU on human colon cancer cells. HT-29 cells were treated with CQ and/or 5-FU, and their proliferative ability, apoptosis and autophagy induction effects, and the affection of the cell cycle were evaluated. The proliferative ability of HT-29 was analyzed by the MTS assay. Apoptosis was quantified by flow-cytometry after double-staining of the cells with AnnexinV/PI. The cell cycle was evaluated by flow-cytometry after staining of cells with PI. Autophagy was quantified by flow-cytometry and Western blot analysis. Finally, to evaluate the fate of the cells treated with CQ and/or 5-FU, the colony formation assay was performed. 5-FU inhibited the proliferative activity of HT-29 cells, which was mostly dependent on the arrest of the cells to the G0/G1-phase but also partially on apoptosis induction, and the effect was potentiated by CQ pre-treatment. The potentiation of the inhibitory effect of 5-FU by CQ was dependent on the increase of p21 Cip1 and p27 Kip1 and the decrease of CDK2. Since CQ is reported to inhibit autophagy, the catabolic process necessary for cell survival under conditions of cell starvation or stress, which is induced by cancer cells as a protective mechanism against chemotherapeutic agents, we also analyzed the induction of autophagy in HT-29. HT-29 induced autophagy in response to 5-FU, and CQ inhibited this induction, a possible mechanism of the potentiation of the anti-cancer effect of 5-FU. Our

  16. In vitro antiplasmodial activity of marine sponge Clathria vulpina extract against chloroquine sensitive Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Sundaram Prasanna Kumar

    2014-02-01

    Full Text Available Objective: To explore the antiplasmodial potential of marine sponge Clathria vulpina (C. vulpina against chloroquine sensitive Plasmodium falciparum (P. falciparum. Methods: The marine sponge C. vulpina was collected from Thondi coast, authenticated and subjected for extraction by soaking in ethanol:water mixture (3:1 ratio. The percentage of extract was calculated. Filter sterilized extracts (100, 50, 25, 12.5, 6.25, 3.125 μg/mL were screened for antiplasmodial activity against chloroquine sensitive P. falciparum. The extract was also tested for its hemolytic activity. Results: The percentage yield of extract of C. vulpina was found to be 4.8%. The crude extract of C. vulpina showed excellent antiplasmodial activity (IC 50=14.75 μg/mL which was highly comparable to the positive control chloroquine (IC50=7 μg/mL. Statistical analysis reveals that the significant antiplasmodial activity (P<0.05 was observed between the concentrations and the time of exposure. The chemical injury to erythrocytes was also carried out, which showed that there were no morphological changes in erythrocytes by the ethanolic extracts of sponges after 48 h of incubation. The extract showed slight hemolytic activity which almost equal to chloroquine at 100 μg/mL concentration (1.023%. Conclusions: The marine sponge C. vulpina can be used as a putative antiplasmodial drug after completing successful clinical trials.

  17. Screening for chloroquine maculopathy in populations with uncertain reliability in outcomes of automatic visual field testing

    NARCIS (Netherlands)

    P. Kunavisarut (Paradee); Chavengsaksongkram, P. (Pimploy); A. Rothová (Aniki); K. Pathanapitoon (Kessara)

    2016-01-01

    textabstractPurpose: The purpose of this study was to compare screening methods for the early detection of maculopathy in patients treated with chloroquine (CQ) or hydroxychloroquine (HCQ) and to identify the risk factors for the development of toxic maculopathy. Methods: We performed a prospective

  18. Chloroquine allows the secretion of internalized 125I-epidermal growth factor from fibroblasts

    International Nuclear Information System (INIS)

    Wakshull, E.; Cooper, J.L.; Wharton, W.

    1985-01-01

    Incubation of cells with labelled hormone in the presence of the lysosomotropic agent chloroquine produces an enhanced intracellular accumulation of hormone and receptor. Using a pulse-chase paradigm in which cell surface receptors were labelled with 125 I-EGF at 4 degrees C, it was found that when 100 microM chloroquine was present in the 37 degrees C chase medium intact hormone was accumulated in the medium. Without chloroquine, low molecular weight (mw) degradation products were found in the medium. The processes of receptor-mediated endocytosis and subcellular distribution of 125 I-EGF-receptor complexes were unchanged by chloroquine. The source of the intact hormone accumulating in the medium was therefore an intracellular compartment(s). The 125 I-EGF released from the cells could rebind to surface receptors and be re-internalized; rebinding was inhibited by unlabelled EGF or Concanavalin A in the incubation medium. The concentration of unlabelled EGF required to inhibit rebinding was more than three orders of magnitude greater than the amount of 125 I-EGF whose rebinding was inhibited. Thus, the 125 I-EGF released from intracellular sites was rebound preferentially over exogenous EGF. The possible pathways for secretion of intact 125 I-EGF and mechanisms of its preferential rebinding are discussed

  19. The effect of chloroquine on the male worms of Onchocerca volvulus ...

    African Journals Online (AJOL)

    Chloroqunie is a well-known anti-malaria drug commonly used in the tropics. Chloroquine was in this study, tested on adult male worms of Onchocerca volvulus to assess its possible effect. Male worms were mechanically isolated from nodules of untreated onchocerciasis patients. After 24hours incubation in a drug-free ...

  20. Atovaquone and proguanil hydrochloride compared with chloroquine or pyrimethamine/sulfadoxine for treatment of acute Plasmodium falciparum malaria in Peru

    OpenAIRE

    Llanos-Cuentas, A.; Campos, P.; Clendenes, M.; Canfield, C. J.; Hutchinson, D. B. A.

    2001-01-01

    The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (MalaroneTM) were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14) (phase 1). The cure rate with chloroquine was lower than expected and patients were sub...

  1. Antibiotic stress-induced modulation of the endoribonucleolytic activity of RNase III and RNase G confers resistance to aminoglycoside antibiotics in Escherichia coli.

    Science.gov (United States)

    Song, Wooseok; Kim, Yong-Hak; Sim, Se-Hoon; Hwang, Soonhye; Lee, Jung-Hyun; Lee, Younghoon; Bae, Jeehyeon; Hwang, Jihwan; Lee, Kangseok

    2014-04-01

    Here, we report a resistance mechanism that is induced through the modulation of 16S ribosomal RNA (rRNA) processing on the exposure of Escherichia coli cells to aminoglycoside antibiotics. We observed decreased expression levels of RNase G associated with increased RNase III activity on rng mRNA in a subgroup of E. coli isolates that transiently acquired resistance to low levels of kanamycin or streptomycin. Analyses of 16S rRNA from the aminoglycoside-resistant E. coli cells, in addition to mutagenesis studies, demonstrated that the accumulation of 16S rRNA precursors containing 3-8 extra nucleotides at the 5' terminus, which results from incomplete processing by RNase G, is responsible for the observed aminoglycoside resistance. Chemical protection, mass spectrometry analysis and cell-free translation assays revealed that the ribosomes from rng-deleted E. coli have decreased binding capacity for, and diminished sensitivity to, streptomycin and neomycin, compared with wild-type cells. It was observed that the deletion of rng had similar effects in Salmonella enterica serovar Typhimurium strain SL1344. Our findings suggest that modulation of the endoribonucleolytic activity of RNase III and RNase G constitutes a previously uncharacterized regulatory pathway for adaptive resistance in E. coli and related gram-negative bacteria to aminoglycoside antibiotics.

  2. Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth.

    Science.gov (United States)

    Vippagunta, S R; Dorn, A; Matile, H; Bhattacharjee, A K; Karle, J M; Ellis, W Y; Ridley, R G; Vennerstrom, J L

    1999-11-04

    Considerable data now support the hypothesis that chloroquine (CQ)-hematin binding in the parasite food vacuole leads to inhibition of hematin polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin mu-oxo dimers in a cofacial pi-pi sandwich-type complex. Association constants (K(a)'s) ranged from 0.46 to 2.9 x 10(5) M(-1) compared to 4.0 x 10(5) M(-1) for CQ. Remarkably, we were not able to measure any significant interaction between hematin mu-oxo dimer and 11, the 6-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin mu-oxo dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable pi-pi interaction observed in the CQ-hematin mu-oxo dimer complex derives from a favorable alignment of the out-of-plane pi-electron density in CQ and hematin mu-oxo dimer at the points of intermolecular contact. For 4-aminoquinolines related to CQ, our data suggest that electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom, is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K(a) and hematin polymerization IC(50) values suggests that other properties of the CQ-hematin mu-oxo dimer complex, rather than its association

  3. Presurgical language localization with visual naming associated ECoG high- gamma modulation in pediatric drug-resistant epilepsy.

    Science.gov (United States)

    Arya, Ravindra; Wilson, J Adam; Fujiwara, Hisako; Rozhkov, Leonid; Leach, James L; Byars, Anna W; Greiner, Hansel M; Vannest, Jennifer; Buroker, Jason; Milsap, Griffin; Ervin, Brian; Minai, Ali; Horn, Paul S; Holland, Katherine D; Mangano, Francesco T; Crone, Nathan E; Rose, Douglas F

    2017-04-01

    This prospective study compared presurgical language localization with visual naming-associated high-γ modulation (HGM) and conventional electrical cortical stimulation (ECS) in children with intracranial electrodes. Patients with drug-resistant epilepsy who were undergoing intracranial monitoring were included if able to name pictures. Electrocorticography (ECoG) signals were recorded during picture naming (overt and covert) and quiet baseline. For each electrode the likelihood of high-γ (70-116 Hz) power modulation during naming task relative to the baseline was estimated. Electrodes with significant HGM were plotted on a three-dimensional (3D) cortical surface model. Sensitivity, specificity, and accuracy were calculated compared to clinical ECS. Seventeen patients with mean age of 11.3 years (range 4-19) were included. In patients with left hemisphere electrodes (n = 10), HGM during overt naming showed high specificity (0.81, 95% confidence interval [CI] 0.78-0.85), and accuracy (0.71, 95% CI 0.66-0.75, p oral motor function was regarded as the gold standard. Similar results were reproduced by comparing covert naming-associated HGM with ECS naming sites. With right hemisphere electrodes (n = 7), no ECS-naming deficits were seen without interference with oral-motor function. HGM mapping showed a high specificity (0.81, 95% CI 0.78-0.84), and accuracy (0.76, 95% CI 0.71-0.81, p = 0.006), but modest sensitivity (0.44) compared to ECS interference with oral-motor function. Naming-associated ECoG HGM was consistently observed over Broca's area (left posterior inferior-frontal gyrus), bilateral oral/facial motor cortex, and sometimes over the temporal pole. This study supports the use of ECoG HGM mapping in children in whom adverse events preclude ECS, or as a screening method to prioritize electrodes for ECS testing. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  4. Cost implication of irrational prescribing of chloroquine in Lagos State general hospitals.

    Science.gov (United States)

    Aina, Bolajoko A; Tayo, Fola; Taylor, Ogori

    2008-02-01

    A major share of the hospital budget is spent on drugs. Irrational use of these drugs is a waste of financial and human resources that could have been deployed for another use within the hospital setting especially in cases where such drugs are provided free to patients. Also there is increased morbidity and progression of severity with irrational use. The objective of this study was to determine the irrational use of chloroquine and the subsequent cost implications in Lagos State general hospitals. A retrospective study period of one year (January to December, 2000) was selected. A total of 18,781 prescription forms of "Free Eko Malaria" were sampled for children and adults from all the Lagos State general hospitals. Drug costs in each prescription form were identified. Cost effectiveness analysis of chloroquine tablet and intramuscular injection was undertaken. The average cost of medicine per prescription was 132.071 ($1.03) which should have been 94.22 ($0.73) if prescribed rationally. The total cost of prescriptions for malaria under study was 2,480,425.00 ($19,348.09). About 68% {(1,679,444.00) ($13,100.19)} of the total cost was lost to irrational prescribing. This is a waste of scarce resources. When the prescriptions were differentiated into the different dosage forms prescribed, the prescriptions containing intramuscular injections only had over 90% of the cost lost to irrational prescribing. Cost effectiveness analysis showed that chloroquine tablet was 17 times more cost effective than chloroquine injection (intramuscular) from a health care system perspective while it was 14 times more cost effective from a patient perspective. There is waste of scarce resources with irrational dispensing of drugs and these resources could have been deployed to other uses or areas within the hospitals. The tablet chloroquine was more cost effective than injection chloroquine (intramuscular). Increasing the cost of tablets, decreasing effectiveness of tablets

  5. Property-based design and synthesis of new chloroquine hybrids via simple incorporation of 2-imino-thiazolidine-4-one or 1h-pyrrol-2, 5-dione fragments on the 4-amino-7-chloroquinoline side chain

    International Nuclear Information System (INIS)

    Rojas, Fernando A.; Kouznetsov, Vladimir V.

    2011-01-01

    In the present work, the syntheses of new 4-amino-7-chloroquinoline N-derivatives were performed by selective modification of the side chain amino group of N-(7-chloroquinoline-4-yl) alkyldiamines, basis framework of chloroquine (CQ) drug through the incorporation of heterocyclic 2-imino-thiazolidine-4-one and 1 H-pyrrol-2,5-dione systems. These potential activity modulators were selected thanks to their characteristic properties, and evaluated by virtual screening employing the OSIRIS and Molinspirations platforms. Designed and synthesized quinolinic derivatives could increase the antimalarial activity of CQ analogues without affecting the lipophilicity as described in literature, suggesting them as candidates for further biological assessments. (author)

  6. Property-based design and synthesis of new chloroquine hybrids via simple incorporation of 2-imino-thiazolidine-4-one or 1h-pyrrol-2, 5-dione fragments on the 4-amino-7-chloroquinoline side chain

    Energy Technology Data Exchange (ETDEWEB)

    Rojas, Fernando A; Kouznetsov, Vladimir V., E-mail: kouznet@uis.edu.co [Laboratorio de Quimica Organica y Biomolecular, Escuela de Quimica, Universidad Industrial de Santander, Bucaramanga (Colombia)

    2011-09-15

    In the present work, the syntheses of new 4-amino-7-chloroquinoline N-derivatives were performed by selective modification of the side chain amino group of N-(7-chloroquinoline-4-yl) alkyldiamines, basis framework of chloroquine (CQ) drug through the incorporation of heterocyclic 2-imino-thiazolidine-4-one and {sup 1}H-pyrrol-2,5-dione systems. These potential activity modulators were selected thanks to their characteristic properties, and evaluated by virtual screening employing the OSIRIS and Molinspirations platforms. Designed and synthesized quinolinic derivatives could increase the antimalarial activity of CQ analogues without affecting the lipophilicity as described in literature, suggesting them as candidates for further biological assessments. (author)

  7. Adaptations of the Saker-Solomons test: simple, reliable colorimetric field assays for chloroquine and its metabolites in urine.

    OpenAIRE

    Mount, D. L.; Nahlen, B. L.; Patchen, L. C.; Churchill, F. C.

    1989-01-01

    Two field-adapted colorimetric methods for measuring the antimalarial drug chloroquine in urine are described. Both are modifications of the method of Saker and Solomons for screening urine for phencyclidine and other drugs of abuse, using the colour reagent tetrabromophenolphthalein ethyl ester. One method is semiquantitative, detecting the presence of chloroquine (Cq) and its metabolites in urine with a 1 microgram/ml detection limit; it is more sensitive and reliable than the commonly used...

  8. Alteração da camada de fibras nervosas da retina em usuários crônicos de cloroquina Retinal nerve fiber layer alteration in chronic users of chloroquine

    Directory of Open Access Journals (Sweden)

    Daniela de Almeida Lyra Antunes

    2005-04-01

    Full Text Available OBJETIVOS: Avaliar a camada de fibras nervosas da retina (CFN por meio da polarimetria a laser, em pacientes em uso crônico de cloroquina. MÉTODOS: Foram estudados 44 olhos de 22 pacientes em uso de cloroquina por doenças reumatológicas, por pelo menos um ano. Como controle, foram incluídos vinte indivíduos sem uso de cloroquina com idade, gênero e raça similares. Foram excluídos os pacientes que apresentavam história familiar de hipertensão ocular ou glaucoma. Ambos os olhos foram submetidos à análise da camada de fibras nervosas da retina, com o aparelho GDx® Nerve Fiber Analyser, pelo mesmo examinador. RESULTADOS: Nos usuários crônicos de cloroquina, verificou-se alteração em mais de dois parâmetros do GDx em 28 olhos (63,6%. Ocorreu também alteração no gráfico "Deviation from normal" com perda de fibras nervosas em 11 olhos (25%. Quando comparado com o grupo controle, os parâmetros que demonstraram diferença estatisticamente significante foram: Superior Ratio, Inferior Ratio, Superior Nasal, Elipse Modulation, The Number, Superior Average e Superior Integral. Houve também associação estatisticamente significante entre o tempo de uso de cloroquina e perda da CFN. CONCLUSÕES: Comprovou-se a associação entre o uso crônico da cloroquina e a alteração da CFN detectada pelo GDx. Desta forma, esses resultados podem contribuir para o diagnóstico precoce da perda de fibras nervosas na retinopatia por cloroquina.PURPOSES: To evaluate the retina nerve fiber layer by laser polarimetry in patients in chronic use of chloroquine. METHODS: Forty-four eyes of twenty-two patients were studied. These were in use of chloroquine due to rheumatic diseases during at least one year. As a control group, twenty patients without use of chloroquine with similar characteristics (age, gender and race were included. Patients who had a family history of ocular hypertension or glaucoma were not included in this group. Both eyes were

  9. Chloroquine Inhibits Dengue Virus Type 2 Replication in Vero Cells but Not in C6/36 Cells

    Directory of Open Access Journals (Sweden)

    Kleber Juvenal Silva Farias

    2013-01-01

    Full Text Available Dengue viruses are the most important arthropod-borne viruses in terms of morbidity and mortality in the world. Since there is no dengue vaccine available for human use, we have set out to investigate the use of chloroquine as an antiviral drug against dengue. Chloroquine, an amine acidotropic drug known to affect intracellular exocytic pathways by increasing endosomal pH, was used in the in vitro treatment of Vero and C6/36 cells infected with dengue virus type 2 (DENV-2. Real-time RT-PCR and plaque assays were used to quantify the DENV-2 load in infected Vero and C6/36 cells after chloroquine treatment. Our results showed that a dose of 50 μg/ml of chloroquine was not toxic to the cells and induced a statistically significant inhibition of virus production in infected Vero cells when compared to untreated cells. In C6/36 cells, chloroquine does not induce a statistically significant difference in viral replication when compared to untreated cells, showing that this virus uses an unlikely pathway of penetration in these cells, and results were also confirmed by the plaque assay (PFU. These data suggest that the inhibition of virus infection induced by chloroquine is due to interference with acidic vesicles in mammalian cells.

  10. Chloroquine inhibits dengue virus type 2 replication in Vero cells but not in C6/36 cells.

    Science.gov (United States)

    Farias, Kleber Juvenal Silva; Machado, Paula Renata Lima; da Fonseca, Benedito Antônio Lopes

    2013-01-01

    Dengue viruses are the most important arthropod-borne viruses in terms of morbidity and mortality in the world. Since there is no dengue vaccine available for human use, we have set out to investigate the use of chloroquine as an antiviral drug against dengue. Chloroquine, an amine acidotropic drug known to affect intracellular exocytic pathways by increasing endosomal pH, was used in the in vitro treatment of Vero and C6/36 cells infected with dengue virus type 2 (DENV-2). Real-time RT-PCR and plaque assays were used to quantify the DENV-2 load in infected Vero and C6/36 cells after chloroquine treatment. Our results showed that a dose of 50 μg/ml of chloroquine was not toxic to the cells and induced a statistically significant inhibition of virus production in infected Vero cells when compared to untreated cells. In C6/36 cells, chloroquine does not induce a statistically significant difference in viral replication when compared to untreated cells, showing that this virus uses an unlikely pathway of penetration in these cells, and results were also confirmed by the plaque assay (PFU). These data suggest that the inhibition of virus infection induced by chloroquine is due to interference with acidic vesicles in mammalian cells.

  11. Chloroquine, quinine, procaine, quinidine and clomipramine are prostaglandin agonists and antagonists.

    Science.gov (United States)

    Manku, M S; Horrobin, D F

    1976-11-01

    Chloroquine, quinine, procaine, quinidine and clomipramine behave as prostaglandin (PG) antagonists in a rat mesenteric vascular bed preparation. The ID50 concentrations were within the range of therapeutically effective human plasma levels in each case. Antagonism to PGE2 was studied in detail and seemed to be at least in part competitive. The drugs also antagonized the effects of PGs A1, A2, F2alpha and E1. Each drug also had weak prostaglandin agonist activity but only over a very narrow range of concentrations. It is possible that some of the clinical actions of these drugs may depend on blockade or imitation of natural PG effects. The findings suggest new approaches to the search for PG antagonists, a new screening technique for anti-inflammatory drugs and possible new uses for these established drugs. A preliminary study suggests that chloroquine may be successful in closing a patent ductus arteriosus in infants.

  12. Interaction of primaquine and chloroquine with ionic micelles: 1 H NMR and electronic absorption spectroscopy

    International Nuclear Information System (INIS)

    Perussi, Janice R.; Monte, Shirley C.; Imasato, Hidetake; Tabak, Marcel; Yushmanov, Victor E.

    1995-01-01

    The characteristic of binding of primaquine (PQ) and chloroquine (CQ) to micelles of surfactants with different charge of headgroups were studied by 1 H-NMR and optical absorption spectroscopy. Cetyltrimethylammonium (CTAC) was used as a cationic surfactant, sodium dodecylsulfate (SDS) as an anionic surfactant and N-hexadecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate (HPS) as zwitterionic. The pK values and binding constants were estimated. (author)

  13. Novel lipophilic chloroquine analogues for a highly efficient gene transfer into gynecological tumors.

    Science.gov (United States)

    Keil, O; Bojar, H; Prisack, H B; Dall, P

    2001-10-08

    Liposomal vectors based on cationic lipids have been proven to be an attractive alternative to viral vectors in gene therapy protocols with regard to safety and manufacturing concerns. In order to improve the transfection efficiency we have synthesized two novel carboxycholesteryl-modified chloroquine analogues. Due to their potential endosomal buffering capacity these compounds enable the efficient transfection of various gynecological tumors and therefore are promising reagents in gene therapy applications.

  14. A spot laser modulated resistance switching effect observed on n-type Mn-doped ZnO/SiO2/Si structure.

    Science.gov (United States)

    Lu, Jing; Tu, Xinglong; Yin, Guilin; Wang, Hui; He, Dannong

    2017-11-09

    In this work, a spot laser modulated resistance switching (RS) effect is firstly observed on n-type Mn-doped ZnO/SiO 2 /Si structure by growing n-type Mn-doped ZnO film on Si wafer covered with a 1.2 nm native SiO 2 , which has a resistivity in the range of 50-80 Ω∙cm. The I-V curve obtained in dark condition evidences the structure a rectifying junction, which is further confirmed by placing external bias. Compared to the resistance state modulated by electric field only in dark (without illumination), the switching voltage driving the resistance state of the structure from one state to the other, shows clear shift under a spot laser illumination. Remarkably, the switching voltage shift shows a dual dependence on the illumination position and power of the spot laser. We ascribe this dual dependence to the electric filed produced by the redistribution of photo-generated carriers, which enhance the internal barrier of the hetero-junction. A complete theoretical analysis based on junction current and diffusion equation is presented. The dependence of the switching voltage on spot laser illumination makes the n-type Mn-doped ZnO/SiO 2 /Si structure sensitive to light, which thus allows for the integration of an extra functionality in the ZnO-based photoelectric device.

  15. Fundus auto fluorescence and spectral domain ocular coherence tomography in the early detection of chloroquine retinopathy

    Directory of Open Access Journals (Sweden)

    Megan B. Goodman

    2015-08-01

    Full Text Available Purpose: To determine the sensitivity of spectral domain ocular coherence tomography (SD-OCT and fundus auto fluorescence (FAF images as a screening test to detect early changes in the retina prior to the onset of chloroquine retinopathy. Method: The study was conducted using patients taking chloroquine (CQ, referred by the Rheumatology Department to the Ophthalmology Department at Tygerberg Academic Hospital. Group A consisted of 59 patients on CQ for less than 5 years, and Group B consisted of 53 patients on CQ for more than 5 years. A 200 × 200 macula thickness map, 5-line raster SD-OCT on a Carl Zeiss Meditec Cirrus HD-OCT and FAF images on a Carl Zeiss Meditec Visucam 500 were recorded for 223 eyes. Images were reviewed independently, and then those of Groups A and B compared. Results: There were no statistically significant differences between Groups A and B. The criteria included the internal limiting membrane and the retinal pigment epithelium (ILM-RPE thickness, interdigitation zone integrity (p = 0.891, df = 1, χ² = 0.1876, ellipsoid zone integrity (p = 0.095, df = 2, χ² = 4.699 and FAF image irregularities (p = 0.479, df = 1, χ²= 4995978. Conclusion: The inclusion of SD-OCT and FAF as objective tests into the prescribed screening guidelines does not appear to simplify the detection of subclinical injury in patients on chloroquine treatment.

  16. In utero exposure to chloroquine alters sexual development in the male fetal rat

    International Nuclear Information System (INIS)

    Clewell, Rebecca A.; Pluta, Linda; Thomas, Russell S.; Andersen, Melvin E.

    2009-01-01

    Chloroquine (CQ), a drug that has been used extensively for the prevention and treatment of malaria, is currently considered safe for use during pregnancy. However, CQ has been shown to disrupt steroid homeostasis in adult rats and similar compounds, such as quinacrine, inhibit steroid production in the Leydig cell in vitro. To explore the effect of in utero CQ exposure on fetal male sexual development, pregnant Sprague-Dawley rats were given a daily dose of either water or chloroquine diphosphate from GD 16-18 by oral gavage. Chloroquine was administered as 200 mg/kg CQ base on GD 16, followed by two maintenance doses of 100 mg/kg CQ base on GD 16 and 18. Three days of CQ treatment resulted in reduced maternal and fetal weight on GD 19 and increased necrosis and steatosis in the maternal liver. Fetal livers also displayed mild lipid accumulation. Maternal serum progesterone was increased after CQ administration. Fetal testes testosterone, however, was significantly decreased. Examination of the fetal testes revealed significant alterations in vascularization and seminiferous tubule development after short-term CQ treatment. Anogenital distance was not altered. Microarray and RT-PCR showed down-regulation of several genes associated with cholesterol transport and steroid synthesis in the fetal testes. This study indicates that CQ inhibits testosterone synthesis and normal testis development in the rat fetus at human relevant doses.

  17. Five-year surveillance of molecular markers of Plasmodium falciparum antimalarial drug resistance in Korogwe District, Tanzania: accumulation of the 581G mutation in the P. falciparum dihydropteroate synthase gene

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Lusingu, John P; Mmbando, Bruno

    2009-01-01

    .001). In contrast, the chloroquine-sensitive P. falciparum chloroquine resistance transporter (Pfcrt) CVMNK haplotype increased from 6% to 30% (P use of SP for intermittent presumptive treatment of pregnant women......In January 2007, Tanzania replaced sulfadoxine-pyrimethamine (SP) with artemether-lumefantrine for treatment of uncomplicated malaria. This study examined the impact of widespread SP use on molecular markers of Plasmodium falciparum drug resistance in blood samples from persons living in two...

  18. Prevalence and risk factors associated to pruritus in Plasmodium vivax patients using chloroquine in the Brazilian Amazon.

    Science.gov (United States)

    Ballut, Priscilla C; Siqueira, Andre M; Orlando, Aline C B; Alexandre, Marcia A A; Alecrim, Maria Graças C; Lacerda, Marcus V G

    2013-12-01

    Chloroquine-induced pruritus has been described as a common adverse event in African patients being treated for Plasmodium falciparum malaria, and has been associated with treatment discontinuation in this setting. In Latin America, where Plasmodium vivax is the most common species causing malaria and chloroquine is still used as the first-line schizonticidal for treating this parasite infection, there are no reports on chloroquine-induced pruritus. This study aimed to estimate the frequency of pruritus and associated risk factors in P. vivax-infected patients treated with chloroquine in a reference centre in the Brazilian Amazon. In this cross-sectional study, patients who were prescribed with chloroquine for the treatment of microscopy-confirmed P. vivax infection in the past five days were actively asked about the occurrence of any level of pruritus and potential risk factors were investigated. Univariable and multivariable logistic regression was performed for the analysis of possible risk factors in two sets of patients: (1) all the patients interviewed and (2) restricted to patients with previous use of chloroquine. Among the 510 patients interviewed, 20.4% (95%CI: 16.9-23.9%) developed any level of pruritus during treatment with chloroquine. Most episodes of pruritus occurred during the first two days of treatment and the most common location was hands and feet. In multivariate analysis performed in the entire population, the only risk factors independently associated to pruritus were allergy history (adjusted odds ratio [AOR]: 1.83; 95%CI 1.02-3.31; p=0.044) and high parasitaemia (AOR: 1.96: 95%CI 1.22-3.13; p=0.005). In the analysis restricted to the 215 patients with previous use of chloroquine, previous chloroquine-induced pruritus was a strong predictor of pruritus occurrence (AOR: 11.84: 95%CI 3.15-44.47; pAmazon. Host-parasite interaction may play a relevant role in the development of pruritus and concurs with the finding of strong association of

  19. Emerging drug -resistance and guidelines for treatment of malaria

    International Nuclear Information System (INIS)

    Khan, M.A.; Smego Jr, R.A.; Razi, S.T.; Beg, M.A.

    2004-01-01

    The increasing prevalence of multi-resistant Plasmodium falciparum malaria worldwide is a serious public health threat to the global control of malaria, especially in poor countries like Pakistan. In many countries chloroquine-resistance is a huge problem, accounting for more than 90% of malaria cases. In Pakistan, resistance to chloroquine is on the rise and reported in up to 16- 62% of Plasmodium falciparum. Four to 25% of Plasmodium falciparum also reported to be resistant to sulfadoxine-pyrimethamine and several cases of delayed parasite clearance have been observed in patients with Plasmodium falciparum malaria treated with quinine. In this article we have introduced the concept of artemisinin- based combination therapy (ACT) and emphasize the use of empiric combination therapy for all patients with Plasmodium falciparum malaria to prevent development of drug resistance and to obtain additive and synergistic killing of parasite. (author)

  20. The influence of resistance exercise with emphasis on specific contractions (concentric vs. eccentric on muscle strength and post-exercise autonomic modulation: a randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Mariana O. Gois

    2014-01-01

    Full Text Available Background: Compared to eccentric contractions, concentric contractions result in higher cardiovascular stress. However, we do not know how these two types of contractions influence cardiac autonomic modulation during the post-exercise recovery period. Objective: to compare the effect of resistance training that is performed with concentric vs. eccentric emphasis on muscle strength and on post-exercise recovery which was assessed by examining heart rate variability (HRV, for the knee extensor muscle group in young healthy adults. Methods: For this study, 105 men between 18 and 30 years of age were randomized into 4 groups: concentric control (CONCC, eccentric control (ECCC, concentric training (CONCT and eccentric training (ECCT. The CONCC and ECCC groups underwent one session of resistance exercise (RE using the knee extensor muscle group (3 sets of 1 repetition at 100% of the maximal repetition [1MR] and the CONCT and ECCT groups performed 10 training sessions. The HRV was analyzed at baseline and across four recovery periods (T1, T2, T3 and T4. Results: The ECCT group exhibited increased muscle strength at the end of the study. Regarding cardiac autonomic modulation, the CONCC and ECCC groups exhibited increases in overall variability (SDNN and SD2 at T1 compared to baseline, and the ECCT group demonstrated increases in variables reflecting vagal modulation and the recovery process (RMSSD, SD1 and HF [ms2] at T1, T2 and T4 compared to baseline. Conclusions: Resistance training with emphasis on eccentric contractions promoted strength gain and an increase in cardiac vagal modulation during recovery compared to baseline.

  1. CASC2/miR-24/miR-221 modulates the TRAIL resistance of hepatocellular carcinoma cell through caspase-8/caspase-3.

    Science.gov (United States)

    Jin, Xiaoxin; Cai, Lifeng; Wang, Changfa; Deng, Xiaofeng; Yi, Shengen; Lei, Zhao; Xiao, Qiangsheng; Xu, Hongbo; Luo, Hongwu; Sun, Jichun

    2018-02-23

    Hepatocellular carcinoma is one of the most common solid tumors in the digestive system. The prognosis of patients with hepatocellular carcinoma is still poor due to the acquisition of multi-drug resistance. TNF Related Apoptosis Inducing Ligand (TRAIL), an attractive anticancer agent, exerts its effect of selectively inducing apoptosis in tumor cells through death receptors and the formation of the downstream death-inducing signaling complex, which activates apical caspases 3/8 and leads to apoptosis. However, hepatocellular carcinoma cells are resistant to TRAIL. Non-coding RNAs, including long non-coding RNAs (lncRNAs) and miRNAs have been regarded as major regulators of normal development and diseases, including cancers. Moreover, lncRNAs and miRNAs have been reported to be associated with multi-drug resistance. In the present study, we investigated the mechanism by which TRAIL resistance of hepatocellular carcinoma is affected from the view of non-coding RNA regulation. We selected and validated candidate miRNAs, miR-24 and miR-221, that regulated caspase 3/8 expression through direct targeting, and thereby affecting TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. In addition, we revealed that CASC2, a well-established tumor suppressive long non-coding RNA, could serve as a "Sponge" of miR-24 and miR-221, thus modulating TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. Taken together, we demonstrated a CASC2/miR-24/miR-221 axis, which can affect the TRAIL resistance of hepatocellular carcinoma through regulating caspase 3/8; through acting as a "Sponge" of miR-24 and miR-221, CASC2 may contribute to improving hepatocellular carcinoma TRAIL resistance, and finally promoting the treatment efficiency of TRAIL-based therapies.

  2. The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation.

    Directory of Open Access Journals (Sweden)

    Kurt Warnhoff

    2014-10-01

    Full Text Available The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance.

  3. The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation.

    Science.gov (United States)

    Warnhoff, Kurt; Murphy, John T; Kumar, Sandeep; Schneider, Daniel L; Peterson, Michelle; Hsu, Simon; Guthrie, James; Robertson, J David; Kornfeld, Kerry

    2014-10-01

    The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance.

  4. Modulation in vitro and in vivo of cytotoxicity but not cellular levels of doxorubicin by the calmodulin inhibitor trifluoperazine is dependent on the level of resistance.

    Science.gov (United States)

    Ganapathi, R.; Schmidt, H.; Grabowski, D.; Melia, M.; Ratliff, N.

    1988-01-01

    The role of the calmodulin inhibitor trifluoperazine (TFP) in modulating the cellular levels and cytotoxicity in vitro and antitumour effects in vivo of doxorubicin (DOX), was evaluated in progressively DOX-resistant (5- to 40-fold) sublines of B16-BL6 mouse melanoma. In parental-sensitive B16-BL6 cells treated for 3 h, the IC50 of DOX was 0.1 microgram ml-1, and a less than 2-fold enhancement in DOX cell kill in the presence of a noncytotoxic concentration of 5 microM TFP was observed. However, in the DOX-resistant sublines, the IC50 was 0.7 to 5.0 micrograms ml-1 DOX in the absence of 5 microM TFP and 0.3 to 0.7 microgram ml-1 DOX in the presence of 5 microM TFP. The 2- to 7.5-fold decrease in the IC50 of DOX in the presence of 5 microM TFP, was dependent on the level of DOX-resistance in the various sublines. Compared to parental-sensitive cells, a 2-fold decrease in DOX-accumulation was evident only in the 40-fold DOX-resistant subline. Further, maximal enhancement (50%) of cellular DOX accumulation in the presence of 5 microM TFP was observed only in the 40-fold resistant cells treated with 5.0 micrograms ml-1 DOX. Retention of DOX in the 40-fold resistant subline was only 20% lower than similarly treated sensitive cells, and the inclusion of TFP increased DOX retention less than 10-15%. Antitumour studies in mice with experimental pulmonary metastases revealed that although DOX and DOX plus TFP had similar antitumour activity with the parental sensitive B16-BL6 cells, the combination of DOX plus TFP was significantly more effective than DOX alone with the DOX-resistant sublines. No overt toxicity was observed in normal mice treated with doses of TFP, DOX or DOX plus TFP used for in vivo chemotherapy studies. Results from this study suggest that gross cellular DOX levels do not appear to correlate with the magnitude of resistance, and the effects of TFP in modulating DOX resistance is possibly due to mechanisms other than mere alterations in cellular drug

  5. Improvement of a predictive model of castration-resistant prostate cancer: functional genetic variants in TGFβ1 signaling pathway modulation.

    Directory of Open Access Journals (Sweden)

    Ana L Teixeira

    Full Text Available Prostate cancer (PC is the most frequently diagnosed cancer in men. The acquisition of castration-resistant (CR phenotype is associated with the activation of signaling pathways mediated by growth factors. The TGFβ1 and its receptors have an important role in tumor progression, being the pro-apoptotic function modulated by the expression of TGFBR2. A single nucleotide polymorphism -875 G > A in TGFBR2 gene has been described, which may influence the expression levels of the receptor. Our purpose was to investigate the potential role of TGFBR2-875G>A in PC risk and in the response to androgen deprivation therapy (ADT. TGFBR2-875G>A polymorphism was studied by allelic discrimination using real-time polymerase chain reaction (PCR in 891 patients with PC and 874 controls. A follow-up study was undertaken to evaluate response to ADT. The TGFBR2 and SMAD7 mRNA expression were analyzed by a quantitative real-time PCR. We found that TGFBR2-875GG homozygous patients present lower expression levels of TGFBR2 mRNA (AA/AG: 2(-ΔΔCT =1.5, P=0.016. GG genotype was also associated with higher Gleason grade (OR=1.51, P=0.019 and increased risk of an early relapse after ADT (HR=1.47, P=0.024. The concordance (c index analysis showed that the definition of profiles that contains information regarding tumor characteristics associated with genetic information present an increased capacity to predict the risk for CR development (c-index model 1: 0.683 vs model 2: 0.736 vs model 3: 0.746 vs model 4: 0.759. The TGFBR2-875G>A contribution to an early relapse in ADT patients, due to changes in mRNA expression, supports the involvement of TGFβ1 pathway in CRPC. Furthermore, according to our results, we hypothesize the potential benefits of the association of genetic information in predictive models of CR development.

  6. Correction to: Polymorphisms in chloroquine resistance-associated genes in Plasmodium vivax in Ethiopia.

    Science.gov (United States)

    Golassa, Lemu; Erko, Berhanu; Baliraine, Frederick N; Aseffa, Abraham; Swedberg, Göte

    2018-05-02

    After publication of the original article [1], it came to the authors' attention that the primers mentioned in Table 1 for the amplification of the pvcrt-o gene of Plasmodium vivax are not the ones actually used for the experiments. The correct primers and PCR product size are as below.

  7. Drug resistance associated genetic polymorphisms in Plasmodium falciparum and Plasmodium vivax collected in Honduras, Central America.

    Science.gov (United States)

    Jovel, Irina T; Mejía, Rosa E; Banegas, Engels; Piedade, Rita; Alger, Jackeline; Fontecha, Gustavo; Ferreira, Pedro E; Veiga, Maria I; Enamorado, Irma G; Bjorkman, Anders; Ursing, Johan

    2011-12-19

    In Honduras, chloroquine and primaquine are recommended and still appear to be effective for treatment of Plasmodium falciparum and Plasmodium vivax malaria. The aim of this study was to determine the proportion of resistance associated genetic polymorphisms in P. falciparum and P. vivax collected in Honduras. Blood samples were collected from patients seeking medical attention at the Hospital Escuela in Tegucigalpa from 2004 to 2006 as well as three regional hospitals, two health centres and one regional laboratory during 2009. Single nucleotide polymorphisms in P. falciparum chloroquine resistance transporter (pfcrt), multidrug resistance 1 (pfmdr1), dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes and in P. vivax multidrug resistance 1 (pvmdr1) and dihydrofolate reductase (pvdhfr) genes were detected using PCR based methods. Thirty seven P. falciparum and 64 P. vivax samples were collected. All P. falciparum infections acquired in Honduras carried pfcrt, pfmdr1, pfdhps and pfdhfr alleles associated with chloroquine, amodiaquine and sulphadoxine-pyrimethamine sensitivity only. One patient with parasites acquired on a Pacific Island had pfcrt 76 T and pfmdr1 86Y alleles. That patient and a patient infected in West Africa had pfdhfr 51I, 59 R and 108 N alleles. Pvmdr1 976 F was found in 7/37 and two copies of pvmdr1 were found in 1/37 samples. Pvdhfr 57 L + 58 R was observed in 2/57 samples. The results indicate that P. falciparum from Honduras remain sensitive to chloroquine and sulphadoxine-pyrimethamine. This suggests that chloroquine and sulphadoxine-pyrimethamine should be efficacious for treatment of uncomplicated P. falciparum malaria, supporting current national treatment guidelines. However, genetic polymorphisms associated with chloroquine and sulphadoxine-pyrimethamine tolerance were detected in local P. vivax and imported P. falciparum infections. Continuous monitoring of the prevalence of drug resistant/tolerant P

  8. Epigenetic Modulation of the Biophysical Properties of Drug-Resistant Cell Lipids to Restore Drug Transport and Endocytic Functions

    OpenAIRE

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-01-01

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g....

  9. Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.

    Science.gov (United States)

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-09-04

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

  10. Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1.

    Science.gov (United States)

    El-Diwany, Ramy; Cohen, Valerie J; Mankowski, Madeleine C; Wasilewski, Lisa N; Brady, Jillian K; Snider, Anna E; Osburn, William O; Murrell, Ben; Ray, Stuart C; Bailey, Justin R

    2017-02-01

    Broadly-neutralizing monoclonal antibodies (bNAbs) may guide vaccine development for highly variable viruses including hepatitis C virus (HCV), since they target conserved viral epitopes that could serve as vaccine antigens. However, HCV resistance to bNAbs could reduce the efficacy of a vaccine. HC33.4 and AR4A are two of the most potent anti-HCV human bNAbs characterized to date, binding to highly conserved epitopes near the amino- and carboxy-terminus of HCV envelope (E2) protein, respectively. Given their distinct epitopes, it was surprising that these bNAbs showed similar neutralization profiles across a panel of natural HCV isolates, suggesting that some viral polymorphisms may confer resistance to both bNAbs. To investigate this resistance, we developed a large, diverse panel of natural HCV envelope variants and a novel computational method to identify bNAb resistance polymorphisms in envelope proteins (E1 and E2). By measuring neutralization of a panel of HCV pseudoparticles by 10 μg/mL of each bNAb, we identified E1E2 variants with resistance to one or both bNAbs, despite 100% conservation of the AR4A binding epitope across the panel. We discovered polymorphisms outside of either binding epitope that modulate resistance to both bNAbs by altering E2 binding to the HCV co-receptor, scavenger receptor B1 (SR-B1). This study is focused on a mode of neutralization escape not addressed by conventional analysis of epitope conservation, highlighting the contribution of extra-epitopic polymorphisms to bNAb resistance and presenting a novel mechanism by which HCV might persist even in the face of an antibody response targeting multiple conserved epitopes.

  11. Oxygen-ion-migration-modulated bipolar resistive switching and complementary resistive switching in tungsten/indium tin oxide/gold memory device

    Science.gov (United States)

    Wu, Xinghui; Zhang, Qiuhui; Cui, Nana; Xu, Weiwei; Wang, Kefu; Jiang, Wei; Xu, Qixing

    2018-06-01

    In this paper, we report our investigation of room-temperature-fabricated tungsten/indium tin oxide/gold (W/ITO/Au) resistive random access memory (RRAM), which exhibits asymmetric bipolar resistive switching (BRS) behavior. The device displays good write/erase endurance and data retention properties. The device shows complementary resistive switching (CRS) characteristics after controlling the compliance current. A WO x layer electrically formed at the W/ITO in the forming process. Mobile oxygen ions within ITO migrate toward the electrode/ITO interface and produce a semiconductor-like layer that acts as a free-carrier barrier. The CRS characteristic here can be elucidated in light of the evolution of an asymmetric free-carrier blocking layer at the electrode/ITO interface.

  12. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases.

    Science.gov (United States)

    Al-Bari, Md Abdul Alim

    2015-01-01

    Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Sensitive radioimmunoassay and enzyme-linked immunosorbent assay for the simultaneous determination of chloroquine and its metabolites in biological fluids

    International Nuclear Information System (INIS)

    Escande, C.; Chevalier, P.; Verdier, F.; Bourdon, R.

    1990-01-01

    Two new methods for the simultaneous determination of chloroquine and its two main metabolites (monodesethylchloroquine and bisdesethylchloroquine) in biological samples, radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA), are described. Antiserum is produced in rabbits immunized with N-(2-carboxyethyl)desethylchloroquine:protein conjugate. Besides chloroquine, this antiserum recognizes with good affinity the two main metabolites, monodesethylchloroquine and bisdesethylchloroquine (70 and 40% of crossreaction, respectively). Amodiaquine cross reacts by 4.5%; cross reactions with monodesethylamodiaquine, bisdesethylamodiaquine, and other antimalarial drugs are less than 1%. No extraction step or sample preparation is required for either system. Sensitivity limits are, respectively, 0.70 nM (3 pg of chloroquine sulfate measured in 10 microL of plasma sample) for RIA, and 10 nM (22 pg of chloroquine sulfate measured in 5 microL of plasma sample) for ELISA. The interassay coefficients of variation are, respectively, less than 10 and less than 16% for RIA and ELISA in the range 14-410 nM (6-180 ng/mL). The results of both methods are well correlated (r = 0.97) and correlate with spectrophotometry (r = 0.98) and HPLC results (r = 0.93). Because of their high sensitivity, both methods can be used in the case of chloroquine poisoning and in the control of malaria prophylaxis and treatment

  14. In vivo testing of the therapeutic efficacy of chloroquine on falciparum malaria infections in Chirundu, Mashonaland West, Zimbabwe.

    Science.gov (United States)

    Barduagni, P; Schwartz, U; Nyamayaro, W; Chauke, T L

    1998-10-01

    To detect the level of the in vivo chloroquine efficacy in falciparum malaria infections, in order to assess the need for change in the management and treatment of uncomplicated malaria. Prospective descriptive study. Chirundu Rural Clinic, Mashonaland West Province. 63 patients confirmed by a positive blood slide for P. falciparum who attended Chirundu clinic, who were eligible for the study and, who also agreed to participate. Frequency of treatment success, early treatment failure and late treatment failure in uncomplicated patients treated with chloroquine. Out of 63 cases enrolled and completely followed up, chloroquine treatment was effective in 54 cases (85.7%) and was not effective in nine cases (14.3%). All treatment failures were successfully treated with sulphadoxine + pyrimethamine (Fansidar) or quinine following the approved guidelines. Chloroquine remains highly effective in the treatment of malaria due to P. falciparum in the Zambezi Valley of Hurungwe district and therefore, has to remain the first line drug. Likewise, guidelines for the use of sulphadoxine + pyrimethamine (Fansidar) or quinine as second line drugs, are adequate to the local situation. Health workers directly supervised the patients when they were swallowing the tablets during the whole course, and this without doubt, indirectly increased the efficacy of chloroquine. It is vital to confirm the malaria diagnosis on the spot appointing microscopists or distributing a limited stock of Parasight-F test.

  15. Celastraceae sesquiterpenes as a new class of modulators that bind specifically to human P-glycoprotein and reverse cellular multidrug resistance.

    Science.gov (United States)

    Muñoz-Martínez, Francisco; Lu, Peihua; Cortés-Selva, Fernando; Pérez-Victoria, José María; Jiménez, Ignacio A; Ravelo, Angel G; Sharom, Frances J; Gamarro, Francisco; Castanys, Santiago

    2004-10-01

    Overexpression of ABCB1 (MDR1) P-glycoprotein, a multidrug efflux pump, is one mechanism by which tumor cells may develop multidrug resistance (MDR), preventing the successful chemotherapeutic treatment of cancer. Sesquiterpenes from Celastraceae family are natural compounds shown previously to reverse MDR in several human cancer cell lines and Leishmania strains. However, their molecular mechanism of reversion has not been characterized. In the present work, we have studied the ability of 28 dihydro-beta-agarofuran sesquiterpenes to reverse the P-glycoprotein-dependent MDR phenotype and elucidated their molecular mechanism of action. Cytotoxicity assays using human MDR1-transfected NIH-3T3 cells allowed us to select the most potent sesquiterpenes reversing the in vitro resistance to daunomycin and vinblastine. Flow cytometry experiments showed that the above active compounds specifically inhibited drug transport activity of P-glycoprotein in a saturable, concentration-dependent manner (K(i) down to 0.24 +/- 0.01 micromol/L) but not that of ABCC1 (multidrug resistance protein 1; MRP1), ABCC2 (MRP2), and ABCG2 (breast cancer resistance protein; BCRP) transporters. Moreover, sesquiterpenes inhibited at submicromolar concentrations the P-glycoprotein-mediated transport of [(3)H]colchicine and tetramethylrosamine in plasma membrane from CH(R)B30 cells and P-glycoprotein-enriched proteoliposomes, supporting that P-glycoprotein is their molecular target. Photoaffinity labeling in plasma membrane and fluorescence spectroscopy experiments with purified protein suggested that sesquiterpenes interact with transmembrane domains of P-glycoprotein. Finally, sesquiterpenes modulated P-glycoprotein ATPase-activity in a biphasic, concentration-dependent manner: they stimulated at very low concentrations but inhibited ATPase activity as noncompetitive inhibitors at higher concentrations. Sesquiterpenes from Celastraceae are promising P-glycoprotein modulators with potential

  16. Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

    DEFF Research Database (Denmark)

    Zub, Kamila Anna; Sousa, Mirta Mittelstedt Leal de; Sarno, Antonio

    2015-01-01

    of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further...... and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels...

  17. Human Management of a Wild Plant Modulates the Evolutionary Dynamics of a Gene Determining Recessive Resistance to Virus Infection.

    Science.gov (United States)

    Poulicard, Nils; Pacios, Luis Fernández; Gallois, Jean-Luc; Piñero, Daniel; García-Arenal, Fernando

    2016-08-01

    This work analyses the genetic variation and evolutionary patterns of recessive resistance loci involved in matching-allele (MA) host-pathogen interactions, focusing on the pvr2 resistance gene to potyviruses of the wild pepper Capsicum annuum glabriusculum (chiltepin). Chiltepin grows in a variety of wild habitats in Mexico, and its cultivation in home gardens started about 25 years ago. Potyvirus infection of Capsicum plants requires the physical interaction of the viral VPg with the pvr2 product, the translation initiation factor eIF4E1. Mutations impairing this interaction result in resistance, according to the MA model. The diversity of pvr2/eIF4E1 in wild and cultivated chiltepin populations from six biogeographical provinces in Mexico was analysed in 109 full-length coding sequences from 97 plants. Eleven alleles were found, and their interaction with potyvirus VPg in yeast-two-hybrid assays, plus infection assays of plants, identified six resistance alleles. Mapping resistance mutations on a pvr2/eIF4E1 model structure showed that most were around the cap-binding pocket and strongly altered its surface electrostatic potential, suggesting resistance-associated costs due to functional constraints. The pvr2/eIF4E1 phylogeny established that susceptibility was ancestral and resistance was derived. The spatial structure of pvr2/eIF4E1 diversity differed from that of neutral markers, but no evidence of selection for resistance was found in wild populations. In contrast, the resistance alleles were much more frequent, and positive selection stronger, in cultivated chiltepin populations, where diversification of pvr2/eIF4E1 was higher. This analysis of the genetic variation of a recessive resistance gene involved in MA host-pathogen interactions in populations of a wild plant show that evolutionary patterns differ according to the plant habitat, wild or cultivated. It also demonstrates that human management of the plant population has profound effects on the

  18. Human Management of a Wild Plant Modulates the Evolutionary Dynamics of a Gene Determining Recessive Resistance to Virus Infection.

    Directory of Open Access Journals (Sweden)

    Nils Poulicard

    2016-08-01

    Full Text Available This work analyses the genetic variation and evolutionary patterns of recessive resistance loci involved in matching-allele (MA host-pathogen interactions, focusing on the pvr2 resistance gene to potyviruses of the wild pepper Capsicum annuum glabriusculum (chiltepin. Chiltepin grows in a variety of wild habitats in Mexico, and its cultivation in home gardens started about 25 years ago. Potyvirus infection of Capsicum plants requires the physical interaction of the viral VPg with the pvr2 product, the translation initiation factor eIF4E1. Mutations impairing this interaction result in resistance, according to the MA model. The diversity of pvr2/eIF4E1 in wild and cultivated chiltepin populations from six biogeographical provinces in Mexico was analysed in 109 full-length coding sequences from 97 plants. Eleven alleles were found, and their interaction with potyvirus VPg in yeast-two-hybrid assays, plus infection assays of plants, identified six resistance alleles. Mapping resistance mutations on a pvr2/eIF4E1 model structure showed that most were around the cap-binding pocket and strongly altered its surface electrostatic potential, suggesting resistance-associated costs due to functional constraints. The pvr2/eIF4E1 phylogeny established that susceptibility was ancestral and resistance was derived. The spatial structure of pvr2/eIF4E1 diversity differed from that of neutral markers, but no evidence of selection for resistance was found in wild populations. In contrast, the resistance alleles were much more frequent, and positive selection stronger, in cultivated chiltepin populations, where diversification of pvr2/eIF4E1 was higher. This analysis of the genetic variation of a recessive resistance gene involved in MA host-pathogen interactions in populations of a wild plant show that evolutionary patterns differ according to the plant habitat, wild or cultivated. It also demonstrates that human management of the plant population has profound

  19. Phytochemical Prospection and Modulation of Antibiotic Activity In Vitro by Lippia origanoides H.B.K. in Methicillin Resistant Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Humberto Medeiros Barreto

    2014-01-01

    Full Text Available The Lippia origanoides H.B.K. ethanol extract (LOEE and hexane (LOHEX, dichloromethane (LODCM, and ethyl acetate (LOEA fractions were tested for their antimicrobial activity alone or in combination with antibiotics against a methicillin resistant Staphylococcus aureus (MRSA strain. The natural products did not show antimicrobial activity against multidrug resistant strain at the clinically significant concentrations tested. However, a modulatory effect in the antibacterial activity of the neomycin and amikacin was verified when LOEE, LOHEX and LODCM were added to the growth medium at subinhibitory concentrations. A similar modulation was found when the natural products were changed for chlorpromazine, an inhibitor of bacterial efflux pumps, suggesting the involvement of resistance mediated by efflux system in the MRSA tested. The fractions LOHEX and LODCM showed a modulatory activity bigger than their majority compounds (carvacrol, thymol, and naringenin, indicating that this activity is not due to their majority compounds only, but it is probably due to a synergism between their chemical components. These results indicate that L. origanoides H.B.K. can be a source of phytochemicals able to modify the phenotype of resistance to aminoglycosides in MRSA.

  20. The prevalence and degree of resistance of Plasmodium falciparum to first-line antimalarial drugs: an in vitro study from a malaria endemic region in Yemen

    International Nuclear Information System (INIS)

    Al-Shamahy, H.; Al-Harazy, Abdulilah Hussein; Harmal, Nabil S.; Al-Kabsi, Abdulgudos N.

    2007-01-01

    Unpublished studies on antimalarial drug efficacy have found low levels of chloroquine resistance in Yemen. This study was carried out to determine the current prevalence of drug resistance in Plasmodium falciparum in Yemen to the main anti-malarial drugs and to determine the effective concentration (EC) values. The WHO standard protocol was used for the selection of subjects, collection of blood samples, culture techniques, examination of post-culture blood slides and interpretation of results. The in vitro micro-test Mark III was used for assessing susceptibility of P. falciparum isolates. The criteria for blood parasite density was met by 219 P. falciparum malaria patients. Chloroquine resistance was found in 47% of isolated P. falciparum schizonts. Mefloquine resistance was found in 5.2%. In addition, the EC50 and EC95 values in blood that inhibited schizont maturation in resistant isolates were higher than the normal therapeutic level for mefloquine. No resistance occurred against quinine or artemisinin, with no growth at the cut off level for quinine and inhibition at low concentrations of artemisinin. Our study confirmed the occurrence of chloroquine-resistant P. falciparum and a slow increase in the rate of this resistance will increase further and spread over all the foci of malaria in Yemen. The low rate of chloroquine-resistant P. falciparum was lower than that reported in Africa or Southeast Asia, but is the first report of the mefloquine resistance in Yemen. Finally, the isolates were sensitive to low concentrations of quinine and artemisinin. (author)

  1. Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells.

    Science.gov (United States)

    Kronhardt, Angelika; Beitzinger, Christoph; Barth, Holger; Benz, Roland

    2016-08-10

    C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells' receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa.

  2. Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow.

    Science.gov (United States)

    Htun, Myo Win; Mon, Nan Cho Nwe; Aye, Khin Myo; Hlaing, Chan Myae; Kyaw, Myat Phone; Handayuni, Irene; Trimarsanto, Hidayat; Bustos, Dorina; Ringwald, Pascal; Price, Ric N; Auburn, Sarah; Thriemer, Kamala

    2017-07-10

    Plasmodium vivax malaria remains a major public health burden in Myanmar. Resistance to chloroquine (CQ), the first-line treatment for P. vivax, has been reported in the country and has potential to undermine local control efforts. Patients over 6 years of age with uncomplicated P. vivax mono-infection were enrolled into clinical efficacy studies in Myawaddy in 2014 and Kawthoung in 2012. Study participants received a standard dose of CQ (25 mg/kg over 3 days) followed by weekly review until day 28. Pvmdr1 copy number (CN) and microsatellite diversity were assessed on samples from the patients enrolled in the clinical study and additional cross-sectional surveys undertaken in Myawaddy and Shwegyin in 2012. A total of 85 patients were enrolled in the CQ clinical studies, 25 in Myawaddy and 60 in Kawthoung. One patient in Myawaddy (1.2%) had an early treatment failure and two patients (2.3%) in Kawthoung presented with late treatment failures on day 28. The day 28 efficacy was 92.0% (95% CI 71.6-97.9) in Myawaddy and 98.3% (95% CI 88.7-99.8) in Kawthoung. By day 2, 92.2% (23/25) in Myawaddy and 85.0% (51/60) in Kawthoung were aparasitaemic. Genotyping and pvmdr1 CN assessment was undertaken on 43, 52 and 46 clinical isolates from Myawaddy, Kawthoung and Shwegyin respectively. Pvmdr1 amplification was observed in 3.2% (1/31) of isolates in Myawaddy, 0% (0/49) in Kawthoung and 2.5% (1/40) in Shwegyin. Diversity was high in all sites (H E 0.855-0.876), with low inter-population differentiation (F ST 0.016-0.026, P Myanmar, particularly given the potential connectivity between parasite population at different sites.

  3. PKC-alpha modulation by miR-483-3p in platinum-resistant ovarian carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Arrighetti, Noemi, E-mail: Noemi.Arrighetti@istitutotumori.mi.it [Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy); Cossa, Giacomo, E-mail: Gia.Cossa@gmail.com [Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy); De Cecco, Loris, E-mail: Loris.Dececco@istitutotumori.mi.it [Functional Genomics and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy); Stucchi, Simone, E-mail: Simone.Stucchi@istitutotumori.mi.it [Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy); Carenini, Nives, E-mail: Nives.Carenini@istitutotumori.mi.it [Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy); Corna, Elisabetta, E-mail: Elisabetta.Corna@istitutotumori.mi.it [Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy); Gandellini, Paolo, E-mail: Paolo.Gandellini@istitutotumori.mi.it [Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy); Zaffaroni, Nadia, E-mail: Nadia.Zaffaroni@istitutotumori.mi.it [Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy); Perego, Paola, E-mail: paola.perego@istitutotumori.mi.it [Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy); Gatti, Laura, E-mail: Laura.Gatti@istitutotumori.mi.it [Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133 (Italy)

    2016-11-01

    The occurrence of drug resistance limits the efficacy of platinum compounds in the cure of ovarian carcinoma. Since microRNAs (miRNAs) may contribute to this phenomenon by regulating different aspects of tumor cell response, the aim of this study was to exploit the analysis of expression of miRNAs in platinum sensitive/resistant cells in an attempt to identify potential regulators of drug response. MiR-483-3p, which may participate in apoptosis and cell proliferation regulation, was found up-regulated in 4 platinum resistant variants, particularly in the IGROV-1/Pt1 subline, versus parental cells. Transfection of a synthetic precursor of miR-483-3p in IGROV-1 parental cells elicited a marked up-regulation of the miRNA levels. Growth-inhibition and colony-forming assays indicated that miR-483-3p over-expression reduced cell growth and conferred mild levels of cisplatin resistance in IGROV-1 cells, by interference with their proliferative potential. Predicted targets of miR-483-3p included PRKCA (encoding PKC-alpha), previously reported to be associated to platinum-resistance in ovarian carcinoma. We found that miR-483-3p directly targeted PRKCA in IGROV-1 cells. In keeping with this finding, cisplatin sensitivity of IGROV-1 cells decreased upon molecular/pharmacological inhibition of PKC-alpha. Overall, our results suggest that overexpression of miR-483-3p by ovarian carcinoma platinum-resistant cells may interfere with their proliferation, thus protecting them from DNA damage induced by platinum compounds and ultimately representing a drug-resistance mechanism. The impairment of cell growth may account for low levels of drug resistance that could be relevant in the clinical setting. - Highlights: • miR-483-3p is up-regulated in ovarian carcinoma cells resistant to platinum drugs. • Ectopic expression of miR-483-3p in IGROV-1 confers mild levels of Pt-resistance. • Overexpression of miR-483-3p down-regulates PRKCA levels in ovarian carcinoma cells. • miR 483

  4. ERECTA, salicylic acid, abscisic acid, and jasmonic acid modulate quantitative disease resistance of Arabidopsis thaliana to Verticillium longisporum.

    Science.gov (United States)

    Häffner, Eva; Karlovsky, Petr; Splivallo, Richard; Traczewska, Anna; Diederichsen, Elke

    2014-04-01

    Verticillium longisporum is a soil-borne vascular pathogen infecting cruciferous hosts such as oilseed rape. Quantitative disease resistance (QDR) is the major control means, but its molecular basis is poorly understood so far. Quantitative trait locus (QTL) mapping was performed using a new (Bur×Ler) recombinant inbred line (RIL) population of Arabidopsis thaliana. Phytohormone measurements and analyses in defined mutants and near-isogenic lines (NILs) were used to identify genes and signalling pathways that underlie different resistance QTL. QTL for resistance to V. longisporum-induced stunting, systemic colonization by the fungus and for V. longisporum-induced chlorosis were identified. Stunting resistance QTL were contributed by both parents. The strongest stunting resistance QTL was shown to be identical with Erecta. A functional Erecta pathway, which was present in Bur, conferred partial resistance to V. longisporum-induced stunting. Bur showed severe stunting susceptibility in winter. Three stunting resistance QTL of Ler origin, two co-localising with wall-associated kinase-like (Wakl)-genes, were detected in winter. Furthermore, Bur showed a much stronger induction of salicylic acid (SA) by V. longisporum than Ler. Systemic colonization was controlled independently of stunting. The vec1 QTL on chromosome 2 had the strongest effect on systemic colonization. The same chromosomal region controlled the level of abscisic acid (ABA) and jasmonic acid (JA) in response to V. longisporum: The level of ABA was higher in colonization-susceptible Ler than in colonization-resistant Bur after V. longisporum infection. JA was down-regulated in Bur after infection, but not in Ler. These differences were also demonstrated in NILs, varying only in the region containing vec1. All phytohormone responses were shown to be independent of Erecta. Signalling systems with a hitherto unknown role in the QDR of A. thaliana against V. longisporum were identified: Erecta mediated

  5. Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity

    Czech Academy of Sciences Publication Activity Database

    Maarseveen van, N. M.; Andersson, Dan; Lepšík, Martin; Fun, A.; Schipper, P. J.; Jong de, D.; Boucher, Ch. A. B.; Nijhuis, M.

    2012-01-01

    Roč. 9, č. 29 (2012), s. 1-7 ISSN 1742-4690 EU Projects: European Commission(XE) 37693 - HIV PI RESISTANCE Grant - others:Dutch AIDS Fund(XE) 2006028; (NWO) VIDI(XE) 91796349 Institutional research plan: CEZ:AV0Z40550506 Keywords : HIV-1 * protease * Gag * resistance * cleavage Subject RIV: CE - Biochemistry Impact factor: 5.657, year: 2012

  6. A Critical Review of the Effects of Hydroxychloroquine and Chloroquine on the Eye.

    Science.gov (United States)

    Costedoat-Chalumeau, Nathalie; Dunogué, Bertrand; Leroux, Gaëlle; Morel, Nathalie; Jallouli, Moez; Le Guern, Véronique; Piette, Jean-Charles; Brézin, Antoine P; Melles, Ronald B; Marmor, Michael F

    2015-12-01

    Hydroxychloroquine (HCQ) and chloroquine have been used for more than 50 years to treat systemic lupus erythematosus (SLE) and other rheumatic diseases. In general, these drugs are well tolerated and rarely need to be discontinued because of an adverse systemic reaction. However, both medications can be irreversibly toxic to the retina. A new study indicates that toxicity is not as rare as once believed, but depends critically on daily dosage and duration of use, as well as other risk factors. With attention to dosage and other factors, and with proper screening for early signs of toxicity, HCQ can be prescribed with relative safety even over long periods of time.

  7. Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease?

    Science.gov (United States)

    Shroyer, N F; Lewis, R A; Lupski, J R

    2001-06-01

    To determine if mutations in ABCR (ABCA4) are associated with chloroquine/hydroxychloroquine retinopathy. DNA from eight patients with chloroquine or hydroxychloroquine retinopathy was studied. Controls were 80 individuals over age 65 years with normal retinal examinations. Ophthalmoscopy, color vision testing, visual fields, retinal photography, and fluorescein angiography were performed on the eight patients. Direct DNA sequencing of the exons and flanking intronic regions of the ABCR gene was completed for all patients. Clinical evaluation confirmed the diagnosis of chloroquine/hydroxychloroquine retinopathy and excluded Stargardt disease in each patient. Two patients had heterozygous ABCR missense mutations previously associated with Stargardt disease. None of the controls had these missense mutations. Three other patients had other missense polymorphisms. Some individuals who have ABCR mutations may be predisposed to develop retinal toxicity when exposed to chloroquine/hydroxychloroquine. We urge further study of a larger cohort of patients with chloroquine/hydroxychloroquine retinopathy.

  8. Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model.

    Science.gov (United States)

    Dowall, Stuart D; Bosworth, Andrew; Watson, Robert; Bewley, Kevin; Taylor, Irene; Rayner, Emma; Hunter, Laura; Pearson, Geoff; Easterbrook, Linda; Pitman, James; Hewson, Roger; Carroll, Miles W

    2015-12-01

    Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. Owing to the lack of approved therapies, screening programmes of potentially efficacious drugs have been undertaken. One of these studies has demonstrated the possible utility of chloroquine against EBOV using pseudotyped assays. In mouse models of EBOV disease there are conflicting reports of the therapeutic effects of chloroquine. There are currently no reports of its efficacy using the larger and more stringent guinea pig model of infection. In this study we have shown that replication of live EBOV is impaired by chloroquine in vitro. However, no protective effects were observed in vivo when EBOV-infected guinea pigs were treated with chloroquine. These results advocate that chloroquine should not be considered as a treatment strategy for EBOV.

  9. Clostridium botulinum C2 toxin. Identification of the binding site for chloroquine and related compounds and influence of the binding site on properties of the C2II channel.

    Science.gov (United States)

    Neumeyer, Tobias; Schiffler, Bettina; Maier, Elke; Lang, Alexander E; Aktories, Klaus; Benz, Roland

    2008-02-15

    Clostridium botulinum C2 toxin belongs to the family of binary AB type toxins that are structurally organized into distinct enzyme (A, C2I) and binding (B, C2II) components. The proteolytically activated 60-kDa C2II binding component is essential for C2I transport into target cells. It oligomerizes into heptamers and forms channels in lipid bilayer membranes. The C2II channel is cation-selective and can be blocked by chloroquine and related compounds. Residues 303-330 of C2II contain a conserved pattern of alternating hydrophobic and hydrophilic residues, which has been implicated in the formation of two amphipathic beta-strands involved in membrane insertion and channel formation. In the present study, C2II mutants created by substitution of different negatively charged amino acids by alanine-scanning mutagenesis were analyzed in artificial lipid bilayer membranes. The results suggested that most of the C2II mutants formed SDS-resistant oligomers (heptamers) similar to wild type. The mutated negatively charged amino acids did not influence channel properties with the exception of Glu(399) and Asp(426), which are probably localized in the vestibule near the channel entrance. These mutants show a dramatic decrease in their affinity for binding of chloroquine and its analogues. Similarly, F428A, which represents the Phi-clamp in anthrax protective antigen, was mutated in C2II in several other amino acids. The C2II mutants F428A, F428D, F428Y, and F428W not only showed altered chloroquine binding but also had drastically changed single channel properties. The results suggest that amino acids Glu(399), Asp(426), and Phe(428) have a major impact on the function of C2II as a binding protein for C2I delivery into target cells.

  10. Chloroquine Inhibits Dengue Virus Type 2 Replication in Vero Cells but Not in C6/36 Cells

    OpenAIRE

    Farias, Kleber Juvenal Silva; Machado, Paula Renata Lima; da Fonseca, Benedito Antônio Lopes

    2013-01-01

    Dengue viruses are the most important arthropod-borne viruses in terms of morbidity and mortality in the world. Since there is no dengue vaccine available for human use, we have set out to investigate the use of chloroquine as an antiviral drug against dengue. Chloroquine, an amine acidotropic drug known to affect intracellular exocytic pathways by increasing endosomal pH, was used in the in vitro treatment of Vero and C6/36 cells infected with dengue virus type 2 (DENV-2). Real-time RT-PCR a...

  11. Salivary gland proteome analysis reveals modulation of anopheline unique proteins in insensitive acetylcholinesterase resistant Anopheles gambiae mosquitoes.

    Directory of Open Access Journals (Sweden)

    Sylvie Cornelie

    Full Text Available Insensitive acetylcholinesterase resistance due to a mutation in the acetylcholinesterase (ace encoding ace-1 gene confers cross-resistance to organophosphate and carbamate insecticides in Anopheles gambiae populations from Central and West Africa. This mutation is associated with a strong genetic cost revealed through alterations of some life history traits but little is known about the physiological and behavioural changes in insects bearing the ace-1(R allele. Comparative analysis of the salivary gland contents between An. gambiae susceptible and ace-1(R resistant strains was carried out to charaterize factors that could be involved in modifications of blood meal process, trophic behaviour or pathogen interaction in the insecticide-resistant mosquitoes. Differential analysis of the salivary gland protein profiles revealed differences in abundance for several proteins, two of them showing major differences between the two strains. These two proteins identified as saglin and TRIO are salivary gland-1 related proteins, a family unique to anopheline mosquitoes, one of them playing a crucial role in salivary gland invasion by Plasmodium falciparum sporozoites. Differential expression of two other proteins previously identified in the Anopheles sialome was also observed. The differentially regulated proteins are involved in pathogen invasion, blood feeding process, and protection against oxidation, relevant steps in the outcome of malaria infection. Further functional studies and insect behaviour experiments would confirm the impact of the modification of the sialome composition on blood feeding and pathogen transmission abilities of the resistant mosquitoes. The data supports the hypothesis of alterations linked to insecticide resistance in the biology of the primary vector of human malaria in Africa.

  12. AsrR is an oxidative stress sensing regulator modulating Enterococcus faecium opportunistic traits, antimicrobial resistance, and pathogenicity.

    Directory of Open Access Journals (Sweden)

    François Lebreton

    Full Text Available Oxidative stress serves as an important host/environmental signal that triggers a wide range of responses in microorganisms. Here, we identified an oxidative stress sensor and response regulator in the important multidrug-resistant nosocomial pathogen Enterococcus faecium belonging to the MarR family and called AsrR (antibiotic and stress response regulator. The AsrR regulator used cysteine oxidation to sense the hydrogen peroxide which results in its dissociation to promoter DNA. Transcriptome analysis showed that the AsrR regulon was composed of 181 genes, including representing functionally diverse groups involved in pathogenesis, antibiotic and antimicrobial peptide resistance, oxidative stress, and adaptive responses. Consistent with the upregulated expression of the pbp5 gene, encoding a low-affinity penicillin-binding protein, the asrR null mutant was found to be more resistant to β-lactam antibiotics. Deletion of asrR markedly decreased the bactericidal activity of ampicillin and vancomycin, which are both commonly used to treat infections due to enterococci, and also led to over-expression of two major adhesins, acm and ecbA, which resulted in enhanced in vitro adhesion to human intestinal cells. Additional pathogenic traits were also reinforced in the asrR null mutant including greater capacity than the parental strain to form biofilm in vitro and greater persistance in Galleria mellonella colonization and mouse systemic infection models. Despite overexpression of oxidative stress-response genes, deletion of asrR was associated with a decreased oxidative stress resistance in vitro, which correlated with a reduced resistance to phagocytic killing by murine macrophages. Interestingly, both strains showed similar amounts of intracellular reactive oxygen species. Finally, we observed a mutator phenotype and enhanced DNA transfer frequencies in the asrR deleted strain. These data indicate that AsrR plays a major role in antimicrobial

  13. Caffeic acid phenethylester increases stress resistance and enhances lifespan in Caenorhabditis elegans by modulation of the insulin-like DAF-16 signalling pathway.

    Science.gov (United States)

    Havermann, Susannah; Chovolou, Yvonni; Humpf, Hans-Ulrich; Wätjen, Wim

    2014-01-01

    CAPE is an active constituent of propolis which is widely used in traditional medicine. This hydroxycinnamic acid derivate is a known activator of the redox-active Nrf2 signalling pathway in mammalian cells. We used C. elegans to investigate the effects of this compound on accumulation of reactive oxygen species and the modulation of the pivotal redox-active pathways SKN-1 and DAF-16 (homologues of Nrf2 and FoxO, respectively) in this model organism; these results were compared to the effects in Hct116 human colon carcinoma cells. CAPE exerts a strong antioxidative effect in C. elegans: The increase of reactive oxygen species induced by thermal stress was diminished by about 50%. CAPE caused a nuclear translocation of DAF-16, but not SKN-1. CAPE increased stress resistance of the nematode against thermal stress and finally a prolongation of the median and maximum lifespan by 9 and 17%, respectively. This increase in stress resistance and lifespan was dependent on DAF-16 as shown in experiments using a DAF-16 loss of function mutant strain. Life prolongation was retained under SKN-1 RNAi conditions showing that the effect is SKN-1 independent. The results of CAPE obtained in C. elegans differed from the results obtained in Hct116 colon carcinoma cells: CAPE also caused strong antioxidative effects in the mammalian cells, but no activation of the FoxO4 signalling pathway was detectable. Instead, an activation of the Nrf2 signalling pathway was shown by luciferase assay and western blots. CAPE activates the insulin-like DAF-16, but not the SKN-1 signalling pathway in C. elegans and therefore enhances the stress resistance and lifespan of this organism. Since modulation of the DAF-16 pathway was found to be a pivotal effect of CAPE in C. elegans, this has to be taken into account for the investigation of the molecular mechanisms of the traditional use of propolis.

  14. In Vivo Susceptibility of Plasmodium Vivax to Chloroquine in Southeastern Iran

    Directory of Open Access Journals (Sweden)

    S Dittrich

    2012-06-01

    Full Text Available Background: Plasmodium vivax is the predominant species causes of malaria with about 90% total annual reported malaria in Iran. This study conducted to determine the susceptibility of Plasmodium vivax isolates to chloroquine in Sistan and Balochistan Province, southeastern Iran.Methods: A total 270 subjects with symptomatic malaria and confirmed P. vivax infection completed the designed 28-day in vivo study. The thick and thin film blood smears were screened for malaria parasites by microscopy. The nested PCR was applied using the Plasmodium 18 subunit ribosomal ribonu­cleic (Ssr RNA genes for detecting mixed infections and diagnosis of parasites in the samples with low parasite on days 0, 5, 6, 7, and 28. Results: P. vivax was cleared in 15%, 50%, 95%, and 100% of patients on days 1, 2, 3, 4 respectively by microscopy assessment. Six patients were exhibited specific P. vivax band in nested PCR on day 5. No recurrence was observed on days 7, 14 and 28. Mean (±standard deviation parasite clearance time was 2.41 (±0.8 days. Conclusion: P. vivax is still susceptible to chloroquine in Southeatern Iran. This finding is compati­ble with results of neighboring countries Pakistan and Afghanistan.

  15. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions.

    Science.gov (United States)

    Vazquez-Martin, Alejandro; López-Bonetc, Eugeni; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Del Barco, Sonia; Martin-Castillo, Begoña; Menendez, Javier A

    2011-01-01

    Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin ("old drugs") to their recently recognized CSC targets ("new uses") within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the "old drugs-new uses" repurposing strategy to open a new CSC-targeted chemoprevention era. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Protein source in a high-protein diet modulates reductions in insulin resistance and hepatic steatosis in fa/fa Zucker rats.

    Science.gov (United States)

    Wojcik, Jennifer L; Devassy, Jessay G; Wu, Yinghong; Zahradka, Peter; Taylor, Carla G; Aukema, Harold M

    2016-01-01

    High-protein diets are being promoted to reduce insulin resistance and hepatic steatosis in metabolic syndrome. Therefore, the effect of protein source in high-protein diets on reducing insulin resistance and hepatic steatosis was examined. Fa/fa Zucker rats were provided normal-protein (15% of energy) casein, high-protein (35% of energy) casein, high-protein soy, or high-protein mixed diets with animal and plant proteins. The high-protein mixed diet reduced area under the curve for insulin during glucose tolerance testing, fasting serum insulin and free fatty acid concentrations, homeostatic model assessment index, insulin to glucose ratio, and pancreatic islet cell area. The high-protein mixed and the high-protein soy diets reduced hepatic lipid concentrations, liver to body weight ratio, and hepatic steatosis rating. These improvements were observed despite no differences in body weight, feed intake, or adiposity among high-protein diet groups. The high-protein casein diet had minimal benefits. A high-protein mixed diet was the most effective for modulating reductions in insulin resistance and hepatic steatosis independent of weight loss, indicating that the source of protein within a high-protein diet is critical for the management of these metabolic syndrome parameters. © 2015 The Obesity Society.

  17. PoxA, yjeK, and elongation factor P coordinately modulate virulence and drug resistance in Salmonella enterica

    DEFF Research Database (Denmark)

    Navarre, William Wiley; Zou, S Betty; Roy, Hervé

    2010-01-01

    We report an interaction between poxA, encoding a paralog of lysyl tRNA-synthetase, and the closely linked yjeK gene, encoding a putative 2,3-beta-lysine aminomutase, that is critical for virulence and stress resistance in Salmonella enterica. Salmonella poxA and yjeK mutants share extensive...

  18. Scrapie susceptibility-linked polymorphisms modulate the in vitro conversion of sheep prion protein to protease-resistant forms

    NARCIS (Netherlands)

    Bossers, A.; Belt, P.B.G.M.; Raymond, G.J.; Caughey, B.; Vries, de R.; Smits, M.

    1997-01-01

    Prion diseases are natural transmissible neurodegenerative disorders in humans and animals. They are characterized by the accumulation of a protease-resistant scrapie-associated prion protein (PrPSc) of the host-encoded cellular prion protein (PrPC) mainly in the central nervous system.

  19. Construction and functional analysis of Trichoderma harzianum mutants that modulate maize resistance to the pathogen Curvularia lunata.

    Science.gov (United States)

    Fan, Lili; Fu, Kehe; Yu, Chuanjin; Ma, Jia; Li, Yaqian; Chen, Jie

    2014-01-01

    Agrobacterium tumefaciens-mediated transformation (ATMT) was used to generate an insertional mutant library of the mycelial fungus Trichoderma harzianum. From a total of 450 mutants, six mutants that showed significant influence on maize resistance to C. lunata were analyzed in detail. Maize coated with these mutants was more susceptible to C. lunata compared with those coated with a wild-type (WT) strain. Similar to other fungal ATMT libraries, all six mutants were single copy integrations, which occurred preferentially in noncoding regions (except two mutants) and were frequently accompanied by the loss of border sequences. Two mutants (T66 and T312) that were linked to resistance were characterized further. Maize seeds coated with T66 and T312 were more susceptible to C. lunata than those treated with WT. Moreover, the mutants affected the resistance of maize to C. lunata by enhancing jasmonate-responsive gene expression. T66 and T312 induced maize resistance to C. lunata infection through a jasmonic acid-dependent pathway.

  20. Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress

    Directory of Open Access Journals (Sweden)

    Kuljit Singh

    2017-08-01

    Full Text Available Leishmania donovani is the causative organism of the neglected human disease known as visceral leishmaniasis which is often fatal, if left untreated. The cysteine biosynthesis pathway of Leishmania may serve as a potential drug target because it is different from human host and regulates downstream components of redox metabolism of the parasites; essential for their survival, pathogenicity and drug resistance. However, despite the apparent dependency of redox metabolism of cysteine biosynthesis pathway, the role of L. donovani cysteine synthase (LdCS in drug resistance and redox homeostasis has been unexplored. Herein, we report that over-expression of LdCS in Amphotericin B (Amp B sensitive strain (S1-OE modulates resistance towards oxidative stress and drug pressure. We observed that antioxidant enzyme activities were up-regulated in S1-OE parasites and these parasites alleviate intracellular reactive oxygen species (ROS efficiently by maintaining the reduced thiol pool. In contrast to S1-OE parasites, Amp B sensitive strain (S1 showed higher levels of ROS which was positively correlated with the protein carbonylation levels and negatively correlated with cell viability. Moreover, further investigations showed that LdCS over-expression also augments the ROS-primed induction of LdCS-GFP as well as endogenous LdCS and thiol pathway proteins (LdTryS, LdTryR and LdcTXN in L. donovani parasites; which probably aids in stress tolerance and drug resistance. In addition, the expression of LdCS was found to be up-regulated in Amp B resistant isolates and during infective stationary stages of growth and consistent with these observations, our ex vivo infectivity studies confirmed that LdCS over-expression enhances the infectivity of L. donovani parasites. Our results reveal a novel crosstalk between LdCS and thiol metabolic pathway proteins and demonstrate the crucial role of LdCS in drug resistance and redox homeostasis of Leishmania. Keywords

  1. High level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine in children in Tanzania

    DEFF Research Database (Denmark)

    Rønn, A M; Msangeni, H A; Mhina, J

    1996-01-01

    In many areas of tropical Africa affected by chloroquine-resistant Plasmodium falciparum, a combination of sulfadoxine and pyrimethamine (S-P) is used for alternative medication, especially in young children. In Magoda village in Muheza District, north-eastern Tanzania, 38 children 1-10 years...

  2. Chloroquine-treatment failure in northern Ghana: roles of pfcrt T76 and pfmdr1 Y86

    NARCIS (Netherlands)

    Mockenhaupt, F. P.; Ehrhardt, S.; Eggelte, T. A.; Agana-Nsiire, P.; Stollberg, K.; Mathieu, A.; Markert, M.; Otchwemah, R. N.; Bienzle, U.

    2005-01-01

    Although chloroquine (CQ) monotherapy is now generally inadequate for the treatment of Plasmodium falciparum malaria in northern Ghana--recently, 58% of 225 children failed treatment by day 14--use of the drug continues because of its low cost and wide availability. The risk factors associated with

  3. Internal filament modulation in low-dielectric gap design for built-in selector-less resistive switching memory application

    Science.gov (United States)

    Chen, Ying-Chen; Lin, Chih-Yang; Huang, Hui-Chun; Kim, Sungjun; Fowler, Burt; Chang, Yao-Feng; Wu, Xiaohan; Xu, Gaobo; Chang, Ting-Chang; Lee, Jack C.

    2018-02-01

    Sneak path current is a severe hindrance for the application of high-density resistive random-access memory (RRAM) array designs. In this work, we demonstrate nonlinear (NL) resistive switching characteristics of a HfO x /SiO x -based stacking structure as a realization for selector-less RRAM devices. The NL characteristic was obtained and designed by optimizing the internal filament location with a low effective dielectric constant in the HfO x /SiO x structure. The stacking HfO x /SiO x -based RRAM device as the one-resistor-only memory cell is applicable without needing an additional selector device to solve the sneak path issue with a switching voltage of ~1 V, which is desirable for low-power operating in built-in nonlinearity crossbar array configurations.

  4. Seed dormancy is modulated in recently evolved chlorsulfuron-resistant Turkish biotypes of wild mustard (Sinapis arvensis

    Directory of Open Access Journals (Sweden)

    Muhamet eTopuz

    2015-07-01

    Full Text Available Biotypes of the broad-leaved wild mustard (Sinapis arvensis L. found in wheat fields of Aegean and Marmara region of Turkey were characterized and shown to have developed resistance to sulfonylurea (chlorsulfuron, an inhibitor of acetolactate synthase (ALS. DNA sequence analysis of the ALS genes from two such resistant (‘R’ biotypes, KNF-R1 and KNF-R2, revealed point mutations, CCT (Pro 197 to TCT (Ser 197 in KNF-R1 and CCT (Pro 197 to ACT (Thr 197 in KNF-R2; these substitutions are consistent with the presence of chlorsulfuron-insensitive ALS enzyme activity in the ‘R’ S. arvensis biotypes. An additional phenotype of chlorsulfuron resistance in the Turkish S. arvensis ‘R’ biotypes was revealed in the form of an altered seed dormancy behavior over 4 to 48 months of dry storage (after-ripening compared to the susceptible (‘S’ biotypes. Seeds of the ‘S’ biotypes dry stored for 4 months had a higher initial germination, which sharply decreased with storage time, while the seeds of the ‘R’ biotypes had lower germination after 4-months storage, rising sharply and peaking thereafter by 24 months’ of dry storage. The ‘R’ biotype seeds continued to maintain a higher germination percentage even after 48 months of after-ripening. The seed weight of ‘R’ and ‘S’ biotypes after-ripened for 4 months was similar but those after-ripened for 48 months differed, ‘R’ seeds were significantly heavier than those of the ‘S’ seeds. Differential seed germinability between ‘S’ and ‘R’ biotypes was found not a case of differential viability, temperature regimen or non-response to pro-germination hormone GA3. These studies are of relevance to ecological fitness of herbicide-resistant biotypes in terms of seed viability and germination.

  5. Seed dormancy is modulated in recently evolved chlorsulfuron-resistant Turkish biotypes of wild mustard (Sinapis arvensis)

    Science.gov (United States)

    Topuz, Muhamet; Nemli, Yildiz; Fatima, Tahira; Mattoo, Autar

    2015-07-01

    Biotypes of the broad-leaved wild mustard (Sinapis arvensis L.) found in wheat fields of Aegean and Marmara region of Turkey were characterized and shown to have developed resistance to sulfonylurea (chlorsulfuron), an inhibitor of acetolactate synthase (ALS). DNA sequence analysis of the ALS genes from two such resistant (‘R’) biotypes, KNF-R1 and KNF-R2, revealed point mutations, CCT (Pro 197) to TCT (Ser 197) in KNF-R1 and CCT (Pro 197) to ACT (Thr 197) in KNF-R2; these substitutions are consistent with the presence of chlorsulfuron-insensitive ALS enzyme activity in the ‘R’ S. arvensis biotypes. An additional phenotype of chlorsulfuron resistance in the Turkish S. arvensis ‘R’ biotypes was revealed in the form of an altered seed dormancy behavior over 4 to 48 months of dry storage (after-ripening) compared to the susceptible (‘S’) biotypes. Seeds of the ‘S’ biotypes dry stored for 4 months had a higher initial germination, which sharply decreased with storage time, while the seeds of the ‘R’ biotypes had lower germination after 4-months storage, rising sharply and peaking thereafter by 24 months’ of dry storage. The ‘R’ biotype seeds continued to maintain a higher germination percentage even after 48 months of after-ripening. The seed weight of ‘R’ and ‘S’ biotypes after-ripened for 4 months was similar but those after-ripened for 48 months differed, ‘R’ seeds were significantly heavier than those of the ‘S’ seeds. Differential seed germinability between ‘S’ and ‘R’ biotypes was found not a case of differential viability, temperature regimen or non-response to pro-germination hormone GA3. These studies are of relevance to ecological fitness of herbicide-resistant biotypes in terms of seed viability and germination.

  6. Modulation of DNA methylation levels sensitizes doxorubicin-resistant breast adenocarcinoma cells to radiation-induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Luzhna, Lidia [Department of Biological Sciences, University of Lethbridge, AB, Canada T1K 3M4 (Canada); Kovalchuk, Olga, E-mail: olga.kovalchuk@uleth.ca [Department of Biological Sciences, University of Lethbridge, AB, Canada T1K 3M4 (Canada)

    2010-02-05

    Chemoresistant tumors often fail to respond to other cytotoxic treatments such as radiation therapy. The mechanisms of chemo- and radiotherapy cross resistance are not fully understood and are believed to be epigenetic in nature. We hypothesize that MCF-7 cells and their doxorubicin-resistant variant MCF-7/DOX cells may exhibit different responses to ionizing radiation due to their dissimilar epigenetic status. Similar to previous studies, we found that MCF-7/DOX cells harbor much lower levels of global DNA methylation than MCF-7 cells. Furthermore, we found that MCF-7/DOX cells had lower background apoptosis levels and were less responsive to radiation than MCF-7 cells. Decreased radiation responsiveness correlated to significant global DNA hypomethylation in MCF-7/DOX cells. Here, for the first time, we show that the radiation resistance of MCF-7/DOX cells can be reversed by an epigenetic treatment - the application of methyl-donor SAM. SAM-mediated reversal of DNA methylation led to elevated radiation sensitivity in MCF-7/DOX cells. Contrarily, application of SAM on the radiation sensitive and higher methylated MCF-7 cells resulted in a decrease in their radiation responsiveness. This data suggests that a fine balance of DNA methylation is needed to insure proper radiation and drug responsiveness.

  7. Modulation of Steroidogenic Pathway in Rat Granulosa Cells with Subclinical Cd Exposure and Insulin Resistance: An Impact on Female Fertility

    Directory of Open Access Journals (Sweden)

    Muskaan Belani

    2014-01-01

    Full Text Available Changes in lifestyle lead to insulin resistance (IR in females ultimately predisposing them towards infertility. In addition, cadmium (Cd, an environmental endocrine disruptor, is reported for detrimental effects on granulosa cells, thus leading to ovarian dysfunction. A combination of these factors, lifestyle and environment, seems to play a role in etiology of idiopathic infertility that accounts for 50% amongst the total infertility cases. To address this issue, we made an attempt to investigate the extent of Cd impact on insulin-resistant (IR granulosa cells. We exposed adult female Charles Foster rats to dexamethasone and confirmed IR condition by fasting insulin resistance index (FIRI. On treatment of IR rats with Cd, the preliminary studies demonstrated prolonged estrous cyclicity, decrease in serum estradiol concentrations, abnormal histology of ovary, and increased granulosa cell death. Further gene and protein expression studies of steroidogenic acute regulatory (StAR protein, 17β-hydroxysteroid dehydrogenase (17β-HSD, and cytochrome P450 aromatase (CYP19A1 were performed. Protein expression studies demonstrated significant decrease in treated groups when compared with control. Study revealed that, in spite of the molecular parameters being affected at varied level, overall ovarian physiology is maximally affected in IR and Cd coexposed group, thus mimicking the condition similar to those prevailing in infertile females.

  8. Chloroquine causes similar electroretinogram modifications, neuronal phospholipidosis and marked impairment of synaptic vesicle transport in Albino and Pigmented Rats

    International Nuclear Information System (INIS)

    Lezmi, Stéphane; Rokh, Najla; Saint-Macary, Gérard; Pino, Michael; Sallez, Valérie; Thevenard, Françoise; Roome, Nigel; Rosolen, Serge

    2013-01-01

    Retinal toxicity of chloroquine has been known for several years, but the mechanism(s) of toxicity remain controversial; some author support the idea that the binding of chloroquine to melanin pigments in the retinal pigmented epithelium (RPE) play a major toxic role by concentrating the drug in the eye. In our study, 12 albinos Sprague-Dawley (SD) and 12 pigmented Brown Norway (BN) rats were treated orally for 3 months with chloroquine to compare functional and pathological findings. On Flash electroretinograms (ERG) performed in scotopic conditions, similar and progressive (time-dependent) delayed onset and decreased amplitudes of oscillatory potentials (from Day 71) and b-waves (on Day 92) were identified in both BN and SD rats. In both strains, identical morphological changes consisted of neuronal phospholipidosis associated with UV auto-fluorescence without evidence of retinal degeneration and gliosis; the RPE did not show any morphological lesions or autofluorescence. IHC analyses demonstrated a decrease in GABA expression in the inner nuclear layer. In addition, a marked accumulation of synaptic vesicles coupled with a marked disruption of neurofilaments in the optic nerve fibers was identified. In conclusion, ERG observations were very similar to those described in humans. Comparable ERG modifications, histopathology and immunohistochemistry findings were observed in the retina of both rat strains suggesting that melanin pigment is unlikely involved. chloroquine-induced impairment of synaptic vesicle transport, likely related to disruption of neurofilaments was identified and non-previously reported. This new mechanism of toxicity may also be responsible for the burry vision described in humans chronically treated with chloroquine

  9. Chloroquine causes similar electroretinogram modifications, neuronal phospholipidosis and marked impairment of synaptic vesicle transport in albino and pigmented rats.

    Science.gov (United States)

    Lezmi, Stéphane; Rokh, Najla; Saint-Macary, Gérard; Pino, Michael; Sallez, Valérie; Thevenard, Françoise; Roome, Nigel; Rosolen, Serge

    2013-06-07

    Retinal toxicity of chloroquine has been known for several years, but the mechanism(s) of toxicity remain controversial; some author support the idea that the binding of chloroquine to melanin pigments in the retinal pigmented epithelium (RPE) play a major toxic role by concentrating the drug in the eye. In our study, 12 albinos Sprague-Dawley (SD) and 12 pigmented Brown Norway (BN) rats were treated orally for 3 months with chloroquine to compare functional and pathological findings. On Flash electroretinograms (ERG) performed in scotopic conditions, similar and progressive (time-dependent) delayed onset and decreased amplitudes of oscillatory potentials (from Day 71) and b-waves (on Day 92) were identified in both BN and SD rats. In both strains, identical morphological changes consisted of neuronal phospholipidosis associated with UV auto-fluorescence without evidence of retinal degeneration and gliosis; the RPE did not show any morphological lesions or autofluorescence. IHC analyses demonstrated a decrease in GABA expression in the inner nuclear layer. In addition, a marked accumulation of synaptic vesicles coupled with a marked disruption of neurofilaments in the optic nerve fibers was identified. In conclusion, ERG observations were very similar to those described in humans. Comparable ERG modifications, histopathology and immunohistochemistry findings were observed in the retina of both rat strains suggesting that melanin pigment is unlikely involved. chloroquine-induced impairment of synaptic vesicle transport, likely related to disruption of neurofilaments was identified and non-previously reported. This new mechanism of toxicity may also be responsible for the burry vision described in humans chronically treated with chloroquine. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  10. Evaluation of the rosemary essential oil (Rosmarinus officinalis L. as modulator of bacterial resistanceAvaliação do óleo essencial de alecrim (Rosmarinus officinalis L. como modulador da resistência bacteriana

    Directory of Open Access Journals (Sweden)

    Eudes Silva Velozo

    2012-05-01

    Full Text Available Microorganisms can be transmitted by food causing diseases in humans. The antibiotics commonly used in treatment of these diseases have shown little or no effect, and in view of the resistance that many microorganisms have acquired. This study evaluated the essential oil leaves of Rosmarinus officinalis L. as a modulator of resistance bacterial drug. The essential oil was obtained by hydrodistillation in a Clevenger apparatus for 3 hours. We tested four strains of E.coli resistant ampicillin (AMP and tetracycline (TET and four strains of Salmonella spp. Resistant to nitrofurantoin (NIT. The strains in 0.5 MacFarland scale suspension were inoculated on Mueller Hinton agar, then soaked antibiotic disks with 10 and 20?L oil pure rosemary were placed on the plates. After 24h/37 º C were measured halos around the discs. All strains tested showed susceptibility to the combined action of essential oil with antibiotics tested. The results indicate that the use of promising rosemary essential oil in combination with antibiotics to combat pathogenic bacteria. Diversos microrganismos podem ser veiculados por alimentos causando doenças nos seres humanos. Os antibióticos comumente utilizados no tratamento dessas doenças têm apresentado baixo ou nenhum efeito, tendo em vista à resistência que muitos microrganismos têm adquirido. Diante deste quadro, o objetivo desta pesquisa foi avaliar o óleo essencial das folhas de Rosmarinus officinalis L. como modulador da resistência bacteriana a drogas. O óleo essencial foi obtido através de hidrodestilação em aparelho de Clevenger por 3h. Foram testadas 4 cepas de E.coli resistentes a Amplicilina (AMP e a Tetraciclina (TET e 4 cepas de Salmonella spp. resistentes a Nitrofurantoína (NIT. As cepas em suspensão escala MacFarland 0,5 foram inoculadas em agar Mueller Hinton, em seguida os discos dos antibióticos embebidos com 10 e 20?L do óleo de alecrim puro foram dispostos sobre as placas. Após 24h/37º

  11. The role of Pfmdr1 and Pfcrt in changing chloroquine, amodiaquine, mefloquine and lumefantrine susceptibility in western-Kenya P. falciparum samples during 2008-2011.

    Directory of Open Access Journals (Sweden)

    Fredrick L Eyase

    Full Text Available Single Nucleotide Polymorphisms (SNPs in the Pfmdr1, and Pfcrt, genes of Plasmodium falciparum may confer resistance to a number of anti-malaria drugs. Pfmdr1 86Y and haplotypes at Pfcrt 72-76 have been linked to chloroquine (CQ as well as amodiaquine (AQ resistance. mefloquine (MQ and lumefantrine (LU sensitivities are linked to Pfmdr1 86Y. Additionally, Pfcrt K76 allele carrying parasites have shown tolerance to LU. We investigated the association between Pfmdr1 86/Pfcrt 72-76 and P. falciparum resistance to CQ, AQ, MQ and LU using field samples collected during 2008-2011 from malaria endemic sites in western Kenya. Genomic DNA from these samples was genotyped to examine SNPs and haplotypes in Pfmdr1 and Pfcrt respectively. Additionally, immediate ex vivo and in vitro drug sensitivity profiles were assessed using the malaria SYBR Green I fluorescence-based assay. We observed a rapid but steady percent increase in wild-type parasites with regard to both Pfmdr1 and Pfcrt between 2008 and 2011 (p<0.0001. Equally, a significant reciprocate decrease in AQ and CQ median IC50 values occurred (p<0.0001 during the same period. Thus, the data in this study point to a significantly rapid change in parasite response to AQ and CQ in the study period. This may be due to releasing of drug pressure on the parasite from reduced use of AQ in the face of increased Artemisinin (ART Combination Therapy (ACT administration following the intervention of the Global Fund in 2008. LU has been shown to select for 76K genotypes, thus the observed increase in 76K genotypes coupled with significant cross resistance between LU and MQ, may herald emergence of tolerance against both drugs in future.

  12. Dual-mode gradient HPLC procedure for the simultaneous determination of chloroquine and proguanil.

    Science.gov (United States)

    Paci, A; Caire-Maurisier, A-M; Rieutord, A; Brion, F; Clair, P

    2002-01-01

    In order to assay the antipaludic capsule of the Service de Santé des Armées (SSA), that contains two antimalarial drugs, i.e. chloroquine sulfate (CQS, cp1) and proguanil hydrochloride (PGH, cp5), a HPLC procedure was developed. A reversed-phase ion-pair high-performance liquid chromatography (HPLC) method with an ultraviolet detection at 254 nm was set up and validated. Elution system includes programming of both organic concentration and flow-rate known as 'dual-mode gradient'. This method allows the simultaneous determination of both active compounds and separation of four process related substances. The method is simple, rapid, selective and accurate, and the precision is good with an inter- and intra-assay of <2%. The sensitivity is particularly suitable for pharmaceutical quality control.

  13. Membrane fusion inducers, chloroquine and spermidine increase lipoplex-mediated gene transfection

    International Nuclear Information System (INIS)

    Wong-Baeza, Carlos; Bustos, Israel; Serna, Manuel; Tescucano, Alonso; Alcantara-Farfan, Veronica; Ibanez, Miguel; Montanez, Cecilia; Wong, Carlos; Baeza, Isabel

    2010-01-01

    Gene transfection into mammalian cells can be achieved with viral and non-viral vectors. Non-viral vectors, such as cationic lipids that form lipoplexes with DNA, are safer and more stable than viral vectors, but their transfection efficiencies are lower. Here we describe that the simultaneous treatment with a membrane fusion inducer (chlorpromazine or procainamide) plus the lysosomotropic agent chloroquine increases lipoplex-mediated gene transfection in human (HEK293 and C-33 A) and rat (PC12) cell lines (up to 9.2-fold), as well as in situ in BALB/c mice spleens and livers (up to 6-fold); and that the polyamine spermidine increases lipoplex-mediated gene transfection and expression in cell cultures. The use of these four drugs provides a novel, safe and relatively inexpensive way to considerably increase lipoplex-mediated gene transfection efficiency.

  14. Chloroquine inhibits hepatocellular carcinoma cell growth in vitro and in vivo

    Science.gov (United States)

    HU, TAO; LI, PEI; LUO, ZHONGGUANG; CHEN, XIAOYU; ZHANG, JINGYANG; WANG, CHUNYAO; CHEN, PING; DONG, ZIMING

    2016-01-01

    Recently, chloroquine (CQ) has been widely used to improve the efficacy of different chemotherapy drugs to treat tumors. However, the effects of single treatment of CQ on liver cancer have not been investigated. In the present study, we examined the effects of CQ on the growth and viability of liver cancer cells in vitro and in vivo, and revealed that CQ treatment triggered G0/G1 cell cycle arrest, induced DNA damage and apoptosis in a dose- and time-dependent manner in liver cancer cells. Moreover, administration of CQ to tumor-bearing mice suppressed the tumor growth in an orthotopic xenograft model of liver cancer. These findings extend our understanding and suggest that CQ could be repositioned as a treatment option for liver cancer as a single treatment or in combination. PMID:26530158

  15. Role of Autophagy in Glycogen Breakdown and Its Relevance to Chloroquine Myopathy

    Science.gov (United States)

    Zirin, Jonathan; Nieuwenhuis, Joppe; Perrimon, Norbert

    2013-01-01

    Several myopathies are associated with defects in autophagic and lysosomal degradation of glycogen, but it remains unclear how glycogen is targeted to the lysosome and what significance this process has for muscle cells. We have established a Drosophila melanogaster model to study glycogen autophagy in skeletal muscles, using chloroquine (CQ) to simulate a vacuolar myopathy that is completely dependent on the core autophagy genes. We show that autophagy is required for the most efficient degradation of glycogen in response to starvation. Furthermore, we show that CQ-induced myopathy can be improved by reduction of either autophagy or glycogen synthesis, the latter possibly due to a direct role of Glycogen Synthase in regulating autophagy through its interaction with Atg8. PMID:24265594

  16. The Transcription Factor OsWRKY45 Negatively Modulates the Resistance of Rice to the Brown Planthopper Nilaparvata lugens

    Science.gov (United States)

    Huangfu, Jiayi; Li, Jiancai; Li, Ran; Ye, Meng; Kuai, Peng; Zhang, Tongfang; Lou, Yonggen

    2016-01-01

    WRKY transcription factors play a central role not only in plant growth and development but also in plant stress responses. However, the role of WRKY transcription factors in herbivore-induced plant defenses and their underlying mechanisms, especially in rice, remains largely unclear. Here, we cloned a rice WRKY gene OsWRKY45, whose expression was induced by mechanical wounding, by infestation of the brown planthopper (BPH, Nilaparvata lugens) and by treatment with jasmonic acid (JA) or salicylic acid (SA). The antisense expression of OsWRKY45 (as-wrky) enhanced BPH-induced levels of H2O2 and ethylene, reduced feeding and oviposition preference as well as the survival rate of BPH, and delayed the development of BPH nymphs. Consistently, lower population densities of BPH on as-wrky lines, compared to those on wild-type (WT) plants, were observed in field experiments. On the other hand, as-wrky lines in the field had lower susceptibility to sheath blight (caused by Rhizoctonia solani) but higher susceptibility to rice blast (caused by Magnaporthe oryzae) than did WT plants. These findings suggest that OsWRKY45 plays important but contrasting roles in regulating the resistance of rice to pathogens and herbivores, and attention should be paid if OsWRKY45 is used to develop disease or herbivore-resistant rice. PMID:27258255

  17. The Transcription Factor OsWRKY45 Negatively Modulates the Resistance of Rice to the Brown Planthopper Nilaparvata lugens

    Directory of Open Access Journals (Sweden)

    Jiayi Huangfu

    2016-05-01

    Full Text Available WRKY transcription factors play a central role not only in plant growth and development but also in plant stress responses. However, the role of WRKY transcription factors in herbivore-induced plant defenses and their underlying mechanisms, especially in rice, remains largely unclear. Here, we cloned a rice WRKY gene OsWRKY45, whose expression was induced by mechanical wounding, by infestation of the brown planthopper (BPH, Nilaparvata lugens and by treatment with jasmonic acid (JA or salicylic acid (SA. The antisense expression of OsWRKY45 (as-wrky enhanced BPH-induced levels of H2O2 and ethylene, reduced feeding and oviposition preference as well as the survival rate of BPH, and delayed the development of BPH nymphs. Consistently, lower population densities of BPH on as-wrky lines, compared to those on wild-type (WT plants, were observed in field experiments. On the other hand, as-wrky lines in the field had lower susceptibility to sheath blight (caused by Rhizoctonia solani but higher susceptibility to rice blast (caused by Magnaporthe oryzae than did WT plants. These findings suggest that OsWRKY45 plays important but contrasting roles in regulating the resistance of rice to pathogens and herbivores, and attention should be paid if OsWRKY45 is used to develop disease or herbivore-resistant rice.

  18. The Transcription Factor OsWRKY45 Negatively Modulates the Resistance of Rice to the Brown Planthopper Nilaparvata lugens.

    Science.gov (United States)

    Huangfu, Jiayi; Li, Jiancai; Li, Ran; Ye, Meng; Kuai, Peng; Zhang, Tongfang; Lou, Yonggen

    2016-05-31

    WRKY transcription factors play a central role not only in plant growth and development but also in plant stress responses. However, the role of WRKY transcription factors in herbivore-induced plant defenses and their underlying mechanisms, especially in rice, remains largely unclear. Here, we cloned a rice WRKY gene OsWRKY45, whose expression was induced by mechanical wounding, by infestation of the brown planthopper (BPH, Nilaparvata lugens) and by treatment with jasmonic acid (JA) or salicylic acid (SA). The antisense expression of OsWRKY45 (as-wrky) enhanced BPH-induced levels of H₂O₂ and ethylene, reduced feeding and oviposition preference as well as the survival rate of BPH, and delayed the development of BPH nymphs. Consistently, lower population densities of BPH on as-wrky lines, compared to those on wild-type (WT) plants, were observed in field experiments. On the other hand, as-wrky lines in the field had lower susceptibility to sheath blight (caused by Rhizoctonia solani) but higher susceptibility to rice blast (caused by Magnaporthe oryzae) than did WT plants. These findings suggest that OsWRKY45 plays important but contrasting roles in regulating the resistance of rice to pathogens and herbivores, and attention should be paid if OsWRKY45 is used to develop disease or herbivore-resistant rice.

  19. INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Min, Joong Won [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Kwang Il [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Hyun-Ah; Kim, Eun-Kyu; Noh, Woo Chul [Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Jeon, Hong Bae [Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul (Korea, Republic of); Cho, Dong-Hyung [Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do (Korea, Republic of); Oh, Jeong Su [Department of Genetic Engineering, Sungkyunkwan University, Suwon (Korea, Republic of); Park, In-Chul; Hwang, Sang-Gu [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Jae-Sung, E-mail: jaesung@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2013-10-11

    Highlights: •HIF-1α-regulated INPP4B enhances glycolysis. •INPP4B regulates aerobic glycolysis by inducing HK2 via Akt-mTOR pathway. •Blockage of INPP4B and HK2 sensitizes radioresistant laryngeal cancer cells to radiation and anticancer drug. •INPP4B is associated with HK2 in human laryngeal cancer tissues. -- Abstract: Inositol polyphosphate 4-phosphatase type II (INPP4B) was recently identified as a tumor resistance factor in laryngeal cancer cells. Herein, we show that INPP4B-mediated resistance is associated with increased glycolytic phenotype. INPP4B expression was induced by hypoxia and irradiation. Intriguingly, overexpression of INPP4B enhanced aerobic glycolysis. Of the glycolysis-regulatory genes, hexokinase 2 (HK2) was mainly regulated by INPP4B and this regulation was mediated through the Akt-mTOR pathway. Notably, codepletion of INPP4B and HK2 markedly sensitized radioresistant laryngeal cancer cells to irradiation or anticancer drug. Moreover, INPP4B was significantly associated with HK2 in human laryngeal cancer tissues. Therefore, these results suggest that INPP4B modulates aerobic glycolysis via HK2 regulation in radioresistant laryngeal cancer cells.

  20. Structure-function correlation of chloroquine and analogues as transgene expression enhancers in nonviral gene delivery.

    Science.gov (United States)

    Cheng, Jianjun; Zeidan, Ryan; Mishra, Swaroop; Liu, Aijie; Pun, Suzie H; Kulkarni, Rajan P; Jensen, Gregory S; Bellocq, Nathalie C; Davis, Mark E

    2006-11-02

    To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral gene delivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in the aromatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQ is essential to provide increased gene expression. Further, the enhancements are more dramatically affected by changes to the aromatic ring and are positively correlated to the strength of intercalation between DNA and the CQ analogues. Quinacrine (QC), a CQ analogue with a fused acridinyl structure that can strongly intercalate DNA, enhances transfection similarly to CQ at a concentration 10 times lower, while N(4)-(4-pyridinyl)-N(1),N(1)-diethyl-1,4-pentanediamine (CP), a CQ analogue that has a weakly intercalating pyridinyl ring, shows no effect on gene expression. Subtle change on the 7-substituent of the chloroquine aromatic structure can also greatly affect the ability of the CQ analogues to enhance transgene expression. Transfection in the presence of N(4)-(7-trifluoromethyl-4-quinolinyl)-N(1),N(1)-diethyl-1,4-pentanediamin e (CQ7a) shows expression efficiency 10 times higher than in the presence of CQ at same concentration, while transfection in the presence of N(4)-(4-quinolinyl)-N(1),N(1)-diethyl-1,4-pentanediamine (CQ7b) does not reveal any enhancing effects on expression. Through a number of comparative studies with CQ and its analogues, we conclude that there are at least three mechanistic features of CQ that lead to the enhancement in gene expression: (i) pH buffering in endocytic vesicles, (ii) displacement of polycations from the nucleic acids in polyplexes, and (iii) alteration of the biophysical properties of the released nucleic acid.

  1. Adrenaline modulates the global transcriptional profile of Salmonella revealing a role in the antimicrobial peptide and oxidative stress resistance responses

    Directory of Open Access Journals (Sweden)

    Williams P

    2008-10-01

    Full Text Available Abstract Background The successful interaction of bacterial pathogens with host tissues requires the sensing of specific chemical and physical cues. The human gut contains a huge number of neurons involved in the secretion and sensing of a class of neuroendocrine hormones called catecholamines. Recently, in Escherichia coli O157:H7, the catecholamines adrenaline and noradrenaline were shown to act synergistically with a bacterial quorum sensing molecule, autoinducer 3 (AI-3, to affect bacterial virulence and motility. We wished to investigate the impact of adrenaline on the biology of Salmonella spp. Results We have determined the effect of adrenaline on the transcriptome of the gut pathogen Salmonella enterica serovar Typhimurium. Addition of adrenaline led to an induction of key metal transport systems within 30 minutes of treatment. The oxidative stress responses employing manganese internalisation were also elicited. Cells lacking the key oxidative stress regulator OxyR showed reduced survival in the presence of adrenaline and complete restoration of growth upon addition of manganese. A significant reduction in the expression of the pmrHFIJKLM antimicrobial peptide resistance operon reduced the ability of Salmonella to survive polymyxin B following addition of adrenaline. Notably, both phenotypes were reversed by the addition of the β-adrenergic blocker propranolol. Our data suggest that the BasSR two component signal transduction system is the likely adrenaline sensor mediating the antimicrobial peptide response. Conclusion Salmonella are able to sense adrenaline and downregulate the antimicrobial peptide resistance pmr locus through the BasSR two component signalling system. Through iron transport, adrenaline may affect the oxidative stress balance of the cell requiring OxyR for normal growth. Both adrenaline effects can be inhibited by the addition of the β-adrenergic blocker propranolol. Adrenaline sensing may provide an environmental

  2. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

    Directory of Open Access Journals (Sweden)

    Ronn Anita

    2011-08-01

    Full Text Available Abstract Background In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1 therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma. Methods A monoclonal antibody (MAb that reacts with the N-side chain of the CQ molecule was prepared by use of a CQ analogue. A specific and reliable ELISA for detection of CQ was developed. The developed assay was validated by measuring CQ in tablets sold in Denmark, India and Sudan. Furthermore, kinetics of CQ concentrations in plasma of four volunteers, who ingested two tablets of Malarex® containing, 250 mg CQ base, were measured before drug intake, three hours later and thereafter at days 1, 3, 7, 14, 21 and 28. The same plasma samples were simultaneously measured by high performance liquid chromatography (HPLC. Results The ELISA proved an easy-to-handle and very sensitive tool for the detection of CQ with a lower limit of detection at 3.9 ng/ml. ELISA levels of CQ in plasma showed high agreement with the levels obtained by HPLC (r = 0.98. The specificity in the negative control group was 100%. Conclusion The developed ELISA can be used for quality screening of CQ in pharmaceutical formulations and for drug monitoring in malaria and in other infectious diseases, such as HIV, where CQ proved to be an effective therapeutic agent. The methodology has been exploited to develop monoclonal

  3. Direct contact thermoelectric generator (DCTEG): A concept for removing the contact resistance between thermoelectric modules and heat source

    International Nuclear Information System (INIS)

    Kim, Tae Young; Negash, Assmelash; Cho, Gyubaek

    2017-01-01

    Highlights: • A design concept of a direct contact thermoelectric generator (DCTEG) is proposed. • Power generation characteristics of the DCTEG on a diesel engine are examined. • Maximum power output of ∼45 W and conversion efficiency of ∼2.0% are obtained. • Effect of clearance on energy conversion of the DCTEG is numerically investigated. • A 132% increase in output power with a flush mounted configuration is obtained. - Abstract: This paper proposes the concept of a direct contact thermoelectric generator (DCTEG) to enhance the practicality and widen the application areas of thermoelectric generators (TEGs). In the DCTEG, one thermoelectric module (TEM) surface is directly exposed to a heat source, and the other surface is in direct contact with a coolant flow. The current direct-contact configuration is beneficial for system fabrication, maintenance, long-term reliability, and maximizing energy usage in cooperation with other energy systems because of its simple configuration and lack of interfaces between the TEMs and heat sources. In order to validate the proposed concept experimentally, a DCTEG was constructed by fabricating customized TEMs and exhaust gas and coolant channels with openings to mount the TEMs. A diesel engine served as a heat source by providing hot exhaust gas into the DCTEG, while the coolant (water–ethylene glycol mixture) was pumped into the coolant channels to remove heat. Based on the experimental results obtained under various engine operating conditions, the power generation of the DCTEG was characterized in the form of current–voltage and power–voltage curves. The maximum output power of 43 W and conversion efficiency of 2.0% were obtained under the highest engine load and rotation speed conditions. A series of numerical simulations was carried out to investigate the effect of the system configuration on the DCTEG power generation performance with the clearance between the TEM surfaces and exhaust gas

  4. Simultaneous determination of chloroquine and its three metabolites in human plasma, whole blood and urine by ion-pair high-performance liquid chromatography.

    Science.gov (United States)

    Houzé, P; de Reynies, A; Baud, F J; Benatar, M F; Pays, M

    1992-02-14

    A method was developed for the separation and measurement of chloroquine and three metabolites (desethylchloroquine, bisdesethylchloroquine and 4-amino-7-chloroquinoline) in biological samples by ion-pair high-performance liquid chromatography with UV detection. The method uses 2,3-diaminoaphthalene as an internal standard and provides a limit of detection between 1 and 2 ng/ml for chloroquine and its metabolites. The assay was linear in the range 12.5-250 ng/ml and the analytical recovery and reproducibility were sufficient. The assay was applied to the analysis of biological samples from a patient undergoing chloroquine chemoprophylaxis and a patient who had ingested chloroquine in a suicide attempt.

  5. Reaction of photochemical resists used in screen printing under the influence of digitally modulated ultra violet light

    Science.gov (United States)

    Gmuender, T.

    2017-02-01

    Different chemical photo-reactive emulsions are used in screen printing for stencil production. Depending on the bandwidth, optical power and depth of field from the optical system, the reaction / exposure speed has a diverse value. In this paper, the emulsions get categorized and validated in a first step. After that a mathematical model gets developed and adapted due to heuristic experience to estimate the exposure speed under the influence of digitally modulated ultra violet (UV) light. The main intention is to use the technical specifications (intended wavelength, exposure time, distance to the stencil, electrical power, stencil configuration) in the emulsion data sheet primary written down with an uncertainty factor for the end user operating with large projector arc lamps and photo films. These five parameters are the inputs for a mathematical formula which gives as an output the exposure speed for the Computer to Screen (CTS) machine calculated for each emulsion / stencil setup. The importance of this work relies in the possibility to rate with just a few boundaries the performance and capacity of an exposure system used in screen printing instead of processing a long test series for each emulsion / stencil configuration.

  6. SOX9/miR-130a/CTR1 axis modulates DDP-resistance of cervical cancer cell.

    Science.gov (United States)

    Feng, Chenzhe; Ma, Fang; Hu, Chunhong; Ma, Jin-An; Wang, Jingjing; Zhang, Yang; Wu, Fang; Hou, Tao; Jiang, Shun; Wang, Yapeng; Feng, Yeqian

    2018-01-01

    Cisplatin (DDP) -based chemotherapy is a standard strategy for cervical cancer, while chemoresistance remains a huge challenge. Copper transporter protein 1 (CTR1), a copper influx transporter required for high affinity copper (probably reduced Cu I) transport into the cell, reportedly promotes a significant fraction of DDP internalization in tumor cells. In the present study, we evaluated the function of CTR1 in the cell proliferation of cervical cancer upon DDP treatment. MicroRNAs (miRNAs) have been regarded as essential regulators of cell proliferation, apoptosis, migration, as well as chemoresistance. By using online tools, we screened for candidate miRNAs potentially regulate CTR1, among which miR-130a has been proved to promote cervical cancer cell proliferation through targeting PTEN in our previous study. In the present study, we investigated the role of miR-130a in cervical cancer chemoresistance to DDP, and confirmed the binding of miR-130a to CTR1. SOX9 also reportedly act on cancer chemoresistance. In the present study, we revealed that SOX9 inversely regulated miR-130a through direct targeting the promoter of miR-130a. Consistent with previous studies, SOX9 could affect cervical cancer chemoresistance to DDP. Taken together, we demonstrated a SOX9/miR-130a/CTR1 axis which modulated the chemoresistance of cervical cancer cell to DDP, and provided promising targets for dealing with the chemoresistance of cervical cancer.

  7. Treatment of erythrocytes with the 2-cys peroxiredoxin inhibitor, Conoidin A, prevents the growth of Plasmodium falciparum and enhances parasite sensitivity to chloroquine.

    Directory of Open Access Journals (Sweden)

    Mariana Brizuela

    Full Text Available The human erythrocyte contains an abundance of the thiol-dependant peroxidase Peroxiredoxin-2 (Prx2, which protects the cell from the pro-oxidant environment it encounters during its 120 days of life in the blood stream. In malarial infections, the Plasmodium parasite invades red cells and imports Prx2 during intraerythrocytic development, presumably to supplement in its own degradation of peroxides generated during cell metabolism, especially hemoglobin (Hb digestion. Here we demonstrate that an irreversible Prx2 inhibitor, Conoidin A (2,3-bis(bromomethyl-1,4-dioxide-quinoxaline; BBMQ, has potent cytocidal activity against cultured P. falciparum. Parasite growth was also inhibited in red cells that were treated with BBMQ and then washed prior to parasite infection. These cells remained susceptible to merozoite invasion, but failed to support normal intraerythrocytic development. In addition the potency of chloroquine (CQ, an antimalarial drug that prevents the detoxification of Hb-derived heme, was significantly enhanced in the presence of BBMQ. CQ IC50 values decreased an order of magnitude when parasites were either co-incubated with BBMQ, or introduced into BBMQ-pretreated cells; these effects were equivalent for both drug-resistant and drug-sensitive parasite lines. Together these results indicate that treatment of red cells with BBMQ renders them incapable of supporting parasite growth and increases parasite sensitivity to CQ. We also propose that molecules such as BBMQ that target host cell proteins may constitute a novel host-directed therapeutic approach for treating malaria.

  8. Natural thioallyl compounds increase oxidative stress resistance and lifespan in Caenorhabditis elegans by modulating SKN-1/Nrf.

    Science.gov (United States)

    Ogawa, Takahiro; Kodera, Yukihiro; Hirata, Dai; Blackwell, T Keith; Mizunuma, Masaki

    2016-02-22

    Identification of biologically active natural compounds that promote health and longevity, and understanding how they act, will provide insights into aging and metabolism, and strategies for developing agents that prevent chronic disease. The garlic-derived thioallyl compounds S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC) have been shown to have multiple biological activities. Here we show that SAC and SAMC increase lifespan and stress resistance in Caenorhabditis elegans and reduce accumulation of reactive oxygen species (ROS). These compounds do not appear to activate DAF-16 (FOXO orthologue) or mimic dietary restriction (DR) effects, but selectively induce SKN-1 (Nrf1/2/3 orthologue) targets involved in oxidative stress defense. Interestingly, their treatments do not facilitate SKN-1 nuclear accumulation, but slightly increased intracellular SKN-1 levels. Our data also indicate that thioallyl structure and the number of sulfur atoms are important for SKN-1 target induction. Our results indicate that SAC and SAMC may serve as potential agents that slow aging.

  9. High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation.

    Science.gov (United States)

    Pauly, Marion; Assense, Allan; Rondon, Aurélie; Thomas, Amandine; Dubouchaud, Hervé; Freyssenet, Damien; Benoit, Henri; Castells, Josiane; Flore, Patrice

    2017-03-03

    Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21-5% FiO 2 , 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy.

  10. miR-21 modulates resistance of HR-HPV positive cervical cancer cells to radiation through targeting LATS1

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shikai; Song, Lili, E-mail: commasll@163.com; Zhang, Liang; Zeng, Saitian; Gao, Fangyuan

    2015-04-17

    Although multiple miRNAs are found involved in radioresistance development in HR-HPV positive (+) cervical cancer, only limited studies explored the regulative mechanism of the miRNAs. miR-21 is one of the miRNAs significantly upregulated in HR-HPV (+) cervical cancer is also significantly associated with radioresistance. However, the detailed regulative network of miR-21 in radioresistance is still not clear. In this study, we confirmed that miR-21 overexpression was associated with higher level of radioresistance in HR-HPV (+) cervical cancer patients and thus decided to further explore its role. Findings of this study found miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells and decrease radiation induced G2/M block and increase S phase accumulation. By using dual luciferase assay, we verified a binding site between miR-21 and 3′-UTR of large tumor suppressor kinase 1 (LATS1). Through direct binding, miR-21 can regulate LATS1 expression in cervical cancer cells. LATS1 overexpression can reverse miR-21 induced higher colony formation rate and also reduced miR-21 induced S phase accumulation and G2/M phase block reduction under radiation treatment. These results suggested that miR-21-LATS1 axis plays an important role in regulating radiosensitivity. - Highlights: • miR-21 is highly expressed in HR-HPV (+) radioresistant cervical cancer patients. • miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells. • miR-21 can decrease radiation induced G2/M block and increase S phase accumulation. • miR-21 modulates radiosensitivity cervical cancer cell by directly targeting LATS1.

  11. miR-21 modulates resistance of HR-HPV positive cervical cancer cells to radiation through targeting LATS1

    International Nuclear Information System (INIS)

    Liu, Shikai; Song, Lili; Zhang, Liang; Zeng, Saitian; Gao, Fangyuan

    2015-01-01

    Although multiple miRNAs are found involved in radioresistance development in HR-HPV positive (+) cervical cancer, only limited studies explored the regulative mechanism of the miRNAs. miR-21 is one of the miRNAs significantly upregulated in HR-HPV (+) cervical cancer is also significantly associated with radioresistance. However, the detailed regulative network of miR-21 in radioresistance is still not clear. In this study, we confirmed that miR-21 overexpression was associated with higher level of radioresistance in HR-HPV (+) cervical cancer patients and thus decided to further explore its role. Findings of this study found miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells and decrease radiation induced G2/M block and increase S phase accumulation. By using dual luciferase assay, we verified a binding site between miR-21 and 3′-UTR of large tumor suppressor kinase 1 (LATS1). Through direct binding, miR-21 can regulate LATS1 expression in cervical cancer cells. LATS1 overexpression can reverse miR-21 induced higher colony formation rate and also reduced miR-21 induced S phase accumulation and G2/M phase block reduction under radiation treatment. These results suggested that miR-21-LATS1 axis plays an important role in regulating radiosensitivity. - Highlights: • miR-21 is highly expressed in HR-HPV (+) radioresistant cervical cancer patients. • miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells. • miR-21 can decrease radiation induced G2/M block and increase S phase accumulation. • miR-21 modulates radiosensitivity cervical cancer cell by directly targeting LATS1

  12. Further studies on the effect of chloroquine on the uptake, metabolism and intracellular translocation of [35S]cystine in cystinotic fibroblasts.

    Science.gov (United States)

    Danpure, C J; Jennings, P R; Fyfe, D A

    1986-03-14

    The present study uses the lysosomotropic drug chloroquine to investigate the mechanisms by which exogenous [35S]cystine is able to label the intracellular (intralysosomal) cystine pool(s) in cystinotic fibroblasts. When cystinotic fibroblasts were labelled for short periods of time (8 h or less), chloroquine (20 microM) inhibited the labelling of the intracellular cystine pool(s). However, when the cells were labelled for longer periods of time (24 h or more) chloroquine stimulated the labelling of the intracellular cystine pool(s). The short-term effect was selectively abolished when the cells were washed free of chloroquine, while the long-term effect was selectively abolished when the medium was depleted of cystine. Two routes of translocation of exogenous cystine to the lysosomes could be defined. One route was fast, had a low capacity, was inhibited by chloroquine and increased with increasing medium pH, while the other route was slow, had a high capacity, was stimulated by chloroquine and was more active at low pH. The former pathway probably consisted of plasma membrane transport of cystine into the cytosol followed by direct or indirect transport into the lysosomes. The latter route possibly consisted of pinocytosis with fusion of the cystine-containing pinosomes with lysosomes.

  13. Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

    International Nuclear Information System (INIS)

    Lee, Jin Kyung; Leslie, Elaine M.; Zamek-Gliszczynski, Maciej J.; Brouwer, Kim L.R.

    2008-01-01

    Trabectedin is a promising anticancer agent, but dose-limiting hepatotoxicity was observed during phase I/II clinical trials. Dexamethasone (DEX) has been shown to significantly reduce trabectedin-mediated hepatotoxicity. The current study was designed to assess the capability of sandwich-cultured primary rat hepatocytes (SCRH) to predict the hepato-protective effect of DEX against trabectedin-mediated cytotoxicity. The role of multidrug resistance-associated protein 2 (Mrp2; Abcc2) in trabectedin hepatic disposition also was examined. In SCRH from wild-type Wistar rats, cytotoxicity was observed after 24-h continuous exposure to trabectedin. SCRH pretreated with additional DEX (1 μM) exhibited a 2- to 3-fold decrease in toxicity at 100 nM and 1000 nM trabectedin. Unexpectedly, toxicity in SCRH from Mrp2-deficient (TR - ) compared to wild-type Wistar rats was markedly reduced. Depletion of glutathione from SCRH using buthionine sulfoximine (BSO) mitigated trabectedin toxicity associated with 100 nM and 1000 nM trabectedin. Western blot analysis demonstrated increased levels of CYP3A1/2 and Mrp2 in SCRH pretreated with DEX; interestingly, Mrp4 expression was increased in SCRH after BSO exposure. Trabectedin biliary recovery in isolated perfused livers from TR - rats was decreased by ∼ 75% compared to wild-type livers. In conclusion, SCRH represent a useful in vitro model to predict the hepatotoxicity of trabectedin observed in vivo. The protection by DEX against trabectedin-mediated cytotoxicity may be attributed, in part, to enhanced Mrp2 biliary excretion and increased metabolism by CYP3A1/2. Decreased trabectedin toxicity in SCRH from TR - rats, and in SCRH pretreated with BSO, may be due to increased basolateral excretion of trabectedin by Mrp3 and/or Mrp4

  14. Red pitaya betacyanins protects from diet-induced obesity, liver steatosis and insulin resistance in association with modulation of gut microbiota in mice.

    Science.gov (United States)

    Song, Haizhao; Chu, Qiang; Yan, Fujie; Yang, Yunyun; Han, Wen; Zheng, Xiaodong

    2016-08-01

    Growing evidence indicates that gut microbiota contributes to obesity and its related metabolic disorders. Betacyanins possess free radical scavenging and antioxidant activities, suggesting its potential beneficial effects on metabolic diseases. The present study aimed to investigate the metabolic effect of red pitaya (Hylocereus polyrhizus) fruit betacyanins (HPBN) on high-fat diet-fed mice and determine whether the beneficial effects of HPBN are associated with the modulation of gut microbiota. Thirty-six male C57BL/6J mice were divided into three groups and fed low-fat diet (LFD), high-fat diet (HFD), or high-fat diet plus HPBN of 200 mg/kg for 14 weeks. Sixteen seconds rRNA sequencing was used to analyze the composition of gut microbiota. Our results indicated that administration of HPBN reduced HFD-induced body weight gain and visceral obesity and improved hepatic steatosis, adipose hypertrophy, and insulin resistance in mice. Sixteen seconds rRNA sequencing performed on the MiSeq Illumina platform (Illumina, Inc., San Diego, CA, USA) showed that HPBN supplement not only decreased the proportion of Firmicutes and increased the proportion of Bacteroidetes at the phylum level but also induced a dramatic increase in the relative abundance of Akkermansia at the genus level. Red pitaya betacyanins protect from diet-induced obesity and its related metabolic disorders, which is associated with improved inflammatory status and modulation of gut microbiota, especially its ability to decrease the ratio of Firmicutes and Bacteroidetes and increase the relative abundance of Akkermansia. The study suggested a clinical implication of HPBN in the management of obesity, non-alcoholic fatty liver disease, and type 2 diabetes. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  15. Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

    Science.gov (United States)

    Smith, G D; Amos, T A; Mahler, R; Peters, T J

    1987-01-01

    Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes mellitus showed a significant improvement in their glucose tolerance, which paralleled the severity of their diabetes. This response seems to reflect decreased degradation of insulin rather than increased pancreatic output. These observations suggest that treatment with chloroquine or suitable analogues may be a new approach to the management of diabetes. PMID:3103729

  16. Development of novel strategies to combat multidrug resistance mediated by efflux transporters and intracellular bacteria

    OpenAIRE

    Kuriakose, Jerrin

    2014-01-01

    Multidrug resistance (MDR) is the condition where cancer cells or microorganisms cease to respond to multiple drugs. MDR conferred by efflux transporters, that deprive the bioavailability of drugs at their site of action, are a threat to cancer and malarial chemotherapy. Specifically, the mammalian ABC transporter Pglycoprotein (P-gp) has undermined many drugs in treatment of cancer and other disease states. Mutations in the parasitic transporter Plasmodium falciparum chloroquine resistance t...

  17. Lessons learnt from 20 years surveillance of malaria drug resistance prior to the policy change in Burkina Faso.

    Science.gov (United States)

    Tinto, Halidou; Valea, Innocent; Ouédraogo, Jean-Bosco; Guiguemdé, Tinga Robert

    2016-01-01

    The history of drug resistance to the previous antimalarial drugs, and the potential for resistance to evolve to Artemisinin-based combination therapies, demonstrates the necessity to set-up a good surveillance system in order to provide early warning of the development of resistance. Here we report a review summarizing the history of the surveillance of drug resistance that led to the policy change in Burkina Faso. The first Plasmodium falciparum Chloroquine-Resistance strain identified in Burkina Faso was detected by an in vitro test carried out in Koudougou in 1983. Nevertheless, no further cases were reported until 1987, suggesting that resistant strains had been circulating at a low prevalence before the beginning of the systematic surveillance system from 1984. We observed a marked increase of Chloroquine-Resistance in 2002-2003 probably due to the length of follow-up as the follow-up duration was 7 or 14 days before 2002 and 28 days from 2002 onwards. Therefore, pre-2002 studies have probably under-estimated the real prevalence of Chloroquine-Resistance by not detecting the late recrudescence. With a rate of 8.2% treatment failure reported in 2003, Sulfadoxine-Pyrimethamine was still efficacious for the treatment of uncomplicated malaria in Burkina Faso but this rate might rapidly increase as the result of its spreading from neighboring countries and due to its current use for both the Intermittent Preventive Treatment in pregnant women and Seasonal Malaria Chemoprophylaxis. The current strategy for the surveillance of the Artemisinin-based combination treatments resistance should build on lessons learnt under the previous period of 20 years surveillance of Chloroquine and Sulfadoxine-Pyrimethamine resistance (1994-2004). The most important aspect being to extend the number of sentinel sites so that data would be less patchy and could help understanding the dynamic of the resistance.

  18. Internalized insulin-receptor complexes are unidirectionally translocated to chloroquine-sensitive degradative sites. Dependence on metabolic energy

    International Nuclear Information System (INIS)

    Berhanu, P.

    1988-01-01

    Insulin receptors on the surface of isolated rat adipocytes were photoaffinity labeled at 12 degrees C with the iodinated photoreactive insulin analogue, 125I-B2 (2-nitro-4-azidophenylacetyl)-des-PheB1-insulin, and the pathways in the intracellular processing of the labeled receptors were studied at 37 degrees C. During 37 degrees C incubations, the labeled 440-kDa insulin receptors were continuously internalized (as assessed by trypsin inaccessibility) and degraded such that up to 50% of the initially labeled receptors were lost by 120 min. Metabolic poisons (0.125-0.75 mM 2,4-dinitrophenol (DNP) and 1-10 mM NaF), which led to dose-dependent depletion of adipocyte ATP pools, inhibited receptor loss, and caused up to 3-fold increase in intracellular receptor accumulation. This effect was due to inhibition of intracellular receptor degradation, and there was no apparent effect of the metabolic poisons on initial internalization of the receptors. Following maximal intracellular accumulation of labeled insulin receptors in the presence of NaF or DNP, removal of these agents resulted in a subsequent, time-dependent degradation of the accumulated receptors. However, when the lysosomotropic agent, chloroquine (0.2 mM), was added immediately following removal of the metabolic poisons, further degradation of the intracellularly accumulated receptors was prevented, suggesting that the chloroquine-sensitive degradation of insulin receptors occurs distal to the site of inhibition by NaF or DNP. To confirm this, maximal intracellular accumulation of labeled receptors was first allowed to occur in the presence of chloroquine and the cells were then washed and reincubated in chloroquine-free media in the absence or presence of NaF or DNP. Under these conditions, degradation of the intracellularly accumulated receptors continued to occur, and NaF or DNP failed to block the degradation

  19. Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

    OpenAIRE

    Smith, G D; Amos, T A; Mahler, R; Peters, T J

    1987-01-01

    Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes melli...

  20. The behavior of chloroquine (a synthesized anti-malaria drug) labeled with 14C in healthy and malarious animals

    International Nuclear Information System (INIS)

    Coulibaly, Kafana

    1972-01-01

    The distribution of 14 C labeled chloroquine is identical in healthy and malarious animals. Fixation (by order of intensity) takes place in the liver, spleen, lungs, lacrimal glands, cerebrospinal fluid, bones, thyroid, and intestinal walls. This was confirmed from quantitative studies and demonstrates the traversing of the blood-brain barrier and the intestinal elimination after biliary excretion. Pharmaco-kinetic studies were undertaken with healthy animals and those afflicted with malaria. After a phase, in which the distribution of chloroquine is identical for both types of animal, a more rapid decrease in the blood level is observed with the malarious animals. The leucocytes contained distinctly more of the tracer than the normal or malarious red corpuscles or the blood plasma. Examination of the urinary elimination revealed a mono-exponential function; nevertheless, the urinary elimination was less regular with the malarious rats. This elimination corresponds to the excretion of unchanged chloroquine accompanied by two metabolites. A third metabolite appeared after a delay period. (author) [fr

  1. Chloroquine enhances the efficacy of cisplatin by suppressing autophagy in human adrenocortical carcinoma treatment

    Directory of Open Access Journals (Sweden)

    Qin L

    2016-03-01

    Full Text Available Liang Qin,1,* Tianyuan Xu,1,* Leilei Xia,1 Xianjin Wang,1 Xiang Zhang,1 Xiaohua Zhang,1 Zhaowei Zhu,1 Shan Zhong,1 Chuandong Wang,2 Zhoujun Shen1 1Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 2Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: It has been demonstrated that chloroquine (CQ enhances the efficacy of chemotherapy. However, little is known about whether CQ could enhance the efficacy of cisplatin (DDP in the treatment of adrenocortical carcinoma (ACC. In this study, we explore the efficacy and mechanism by which CQ affects DDP sensitivity in human ACC in vitro and in vivo.Methods: The autophagic gene Beclin-1 expression was detected by immunohistochemistry, and the protein levels were analyzed using immunoblotting assays of ACC tissues and normal adrenal cortex tissues. The ACC SW13 cells were treated with DDP and/or CQ. The cell viability assay was performed using the MTT method. Qualitative autophagy detection was performed by monodansylcadaverine staining of autophagic vacuoles. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to count cell apoptosis by flow cytometry. The autophagy-related protein (Beclin-1, LC3, and p62 and apoptosis relative protein (Bax and Bcl-2 levels were evaluated with Western blot analysis. Furthermore, a murine model of nude BALB/c mice bearing SW13 cell xenografts was established to evaluate the efficacy of concomitant therapy.Results: The expression of the autophagic gene Beclin-1 was significantly downregulated in ACC tissues compared to normal adrenal cortex tissues. The Beclin-1 protein level in ACC tissues was lower than that in normal adrenal cortex tissues (P<0.05. In vitro concomitant therapy (DDP and CQ was more

  2. Comparing success levels of different neural network structures in extracting discriminative information from the response patterns of a temperature-modulated resistive gas sensor

    Science.gov (United States)

    Hosseini-Golgoo, S. M.; Bozorgi, H.; Saberkari, A.

    2015-06-01

    Performances of three neural networks, consisting of a multi-layer perceptron, a radial basis function, and a neuro-fuzzy network with local linear model tree training algorithm, in modeling and extracting discriminative features from the response patterns of a temperature-modulated resistive gas sensor are quantitatively compared. For response pattern recording, a voltage staircase containing five steps each with a 20 s plateau is applied to the micro-heater of the sensor, when 12 different target gases, each at 11 concentration levels, are present. In each test, the hidden layer neuron weights are taken as the discriminatory feature vector of the target gas. These vectors are then mapped to a 3D feature space using linear discriminant analysis. The discriminative information content of the feature vectors are determined by the calculation of the Fisher’s discriminant ratio, affording quantitative comparison among the success rates achieved by the different neural network structures. The results demonstrate a superior discrimination ratio for features extracted from local linear neuro-fuzzy and radial-basis-function networks with recognition rates of 96.27% and 90.74%, respectively.

  3. Hypoxia imaging with [F-18] FMISO-PET in head and neck cancer: Potential for guiding intensity modulated radiation therapy in overcoming hypoxia-induced treatment resistance

    International Nuclear Information System (INIS)

    Hendrickson, Kristi; Phillips, Mark; Smith, Wade; Peterson, Lanell; Krohn, Kenneth; Rajendran, Joseph

    2011-01-01

    Background and purpose: Positron emission tomography (PET) imaging with [F-18] fluoromisonidazole (FMISO) has been validated as a hypoxic tracer . Head and neck cancer exhibits hypoxia, inducing aggressive biologic traits that impart resistance to treatment. Delivery of modestly higher radiation doses to tumors with stable areas of chronic hypoxia can improve tumor control . Advanced radiation treatment planning (RTP) and delivery techniques such as intensity modulated radiation therapy (IMRT) can deliver higher doses to a small volume without increasing morbidity. We investigated the utility of co-registered FMISO-PET and CT images to develop clinically feasible RTPs with higher tumor control probabilities (TCP). Materials and methods: FMISO-PET images were used to determine hypoxic sub-volumes for boost planning. Example plans were generated for 10 of the patients in the study who exhibited significant hypoxia. We created an IMRT plan for each patient with a simultaneous integrated boost (SIB) to the hypoxic sub-volumes. We also varied the boost for two patients. Result: A significant (mean 17%, median 15%) improvement in TCP is predicted when the modest additional boost dose to the hypoxic sub-volume is included. Conclusion: Combined FMISO-PET imaging and IMRT planning permit delivery of higher doses to hypoxic regions, increasing the predicted TCP (mean 17%) without increasing expected complications.

  4. Comparing success levels of different neural network structures in extracting discriminative information from the response patterns of a temperature-modulated resistive gas sensor

    International Nuclear Information System (INIS)

    Hosseini-Golgoo, S M; Bozorgi, H; Saberkari, A

    2015-01-01

    Performances of three neural networks, consisting of a multi-layer perceptron, a radial basis function, and a neuro-fuzzy network with local linear model tree training algorithm, in modeling and extracting discriminative features from the response patterns of a temperature-modulated resistive gas sensor are quantitatively compared. For response pattern recording, a voltage staircase containing five steps each with a 20 s plateau is applied to the micro-heater of the sensor, when 12 different target gases, each at 11 concentration levels, are present. In each test, the hidden layer neuron weights are taken as the discriminatory feature vector of the target gas. These vectors are then mapped to a 3D feature space using linear discriminant analysis. The discriminative information content of the feature vectors are determined by the calculation of the Fisher’s discriminant ratio, affording quantitative comparison among the success rates achieved by the different neural network structures. The results demonstrate a superior discrimination ratio for features extracted from local linear neuro-fuzzy and radial-basis-function networks with recognition rates of 96.27% and 90.74%, respectively. (paper)

  5. Effects of chronic exposure of hydroxychloroquine/chloroquine on the risk of cancer, metastasis, and death: a population-based cohort study on patients with connective tissue diseases.

    Science.gov (United States)

    Fardet, L; Nazareth, I; Petersen, I

    2017-01-01

    Hydroxychloroquine and chloroquine may reduce the risk of cancer as they inhibit autophagy, in particular, in people with connective tissue diseases. The hazard ratios of cancers, metastases, and death were assessed in adults with connective tissue diseases prescribed hydroxychloroquine/chloroquine for at least 1 year in comparison with unexposed individuals with the same underlying conditions. A competing risk survival regression analysis was performed. Data were extracted from the Health Improvement Network UK primary care database. Eight thousand nine hundred and ninety-nine individuals exposed to hydroxychloroquine (98.6%) or chloroquine (1.4%) and 24,118 unexposed individuals were included in the study (median age: 56 [45-66] years, women: 76.8%). When compared to the unexposed group, individuals exposed to hydroxychloroquine/chloroquine were not at lower risk of non-skin cancers (adjusted sub-distribution hazard ratio [sHR]: 1.04 [0.92-1.18], p =0.54), hematological malignancies (adjusted sHR: 1.00 [0.73-1.38], p =0.99), or skin cancers (adjusted sHR: 0.92 [0.78-1.07], p =0.26). The risk of metastasis was not significantly different between the two groups. However, it was significantly lower during the exposure period when compared with the unexposed (adjusted sHR: 0.64 [0.44-0.95] for the overall population and 0.61 [0.38-1.00] for those diagnosed with incident cancers). The risk of death was also significantly lower in those exposed to hydroxychloroquine/chloroquine (adjusted HR: 0.90 [0.81-1.00] in the overall population and 0.78 [0.64-0.96] in those diagnosed with incident cancer). Individuals on long-term exposure to hydroxychloroquine/chloroquine are not at lower risk of cancer. However, hydroxychloroquine/chloroquine may lower the risk of metastatic cancer and death.

  6. Chloroquine and hydroxychloroquine inhibit bladder cancer cell growth by targeting basal autophagy and enhancing apoptosis

    Directory of Open Access Journals (Sweden)

    Yi-Chia Lin

    2017-05-01

    Full Text Available Chloroquine (CQ and hydroxychloroquine (HCQ, two antimalarial drugs, are suggested to have potential anticancer properties. in the present study, we investigated the effects of CQ and HCQ on cell growth of bladder cancer with emphasis on autophagy inhibition and apoptosis induction in vitro. The results showed that CQ and HCQ inhibited the proliferation of multiple human bladder cell lines (including RT4, 5637, and T24 in a time- and dose-dependent fashion, especially in advanced bladder cancer cell lines (5637 and T24 compared to immortalized uroepithelial cells (SV-Huc-1 or other reference cancer cell lines (PC3 and MCF-7. We found that 24-hour treatment of CQ or HCQ significantly decreased the clonogenic formation in 5637 and T24 cells compared to SV-Huc-1. As human bladder cancer tumor exhibits high basal level of autophagic activities, we detected the autophagic flux in cells treated with CQ and HCQ, showing an alternation in LC3 flux in CQ- or HCQ-treated cells. Moreover, bladder cancer cells treated with CQ and HCQ underwent apoptosis, resulting in increased caspase 3/7 activities, increased level of cleaved poly(ADP-ribose polymerase (PARP, caspase 3, and DNA fragmentation. Given these results, targeting autophagy with CQ and HCQ represents an effective cancer therapeutic strategy against human bladder cancer.

  7. Chloroquine and hydroxychloroquine inhibit bladder cancer cell growth by targeting basal autophagy and enhancing apoptosis.

    Science.gov (United States)

    Lin, Yi-Chia; Lin, Ji-Fan; Wen, Sheng-I; Yang, Shan-Che; Tsai, Te-Fu; Chen, Hung-En; Chou, Kuang-Yu; Hwang, Thomas I-Sheng

    2017-05-01

    Chloroquine (CQ) and hydroxychloroquine (HCQ), two antimalarial drugs, are suggested to have potential anticancer properties. in the present study, we investigated the effects of CQ and HCQ on cell growth of bladder cancer with emphasis on autophagy inhibition and apoptosis induction in vitro. The results showed that CQ and HCQ inhibited the proliferation of multiple human bladder cell lines (including RT4, 5637, and T24) in a time- and dose-dependent fashion, especially in advanced bladder cancer cell lines (5637 and T24) compared to immortalized uroepithelial cells (SV-Huc-1) or other reference cancer cell lines (PC3 and MCF-7). We found that 24-hour treatment of CQ or HCQ significantly decreased the clonogenic formation in 5637 and T24 cells compared to SV-Huc-1. As human bladder cancer tumor exhibits high basal level of autophagic activities, we detected the autophagic flux in cells treated with CQ and HCQ, showing an alternation in LC3 flux in CQ- or HCQ-treated cells. Moreover, bladder cancer cells treated with CQ and HCQ underwent apoptosis, resulting in increased caspase 3/7 activities, increased level of cleaved poly(ADP-ribose) polymerase (PARP), caspase 3, and DNA fragmentation. Given these results, targeting autophagy with CQ and HCQ represents an effective cancer therapeutic strategy against human bladder cancer. Copyright © 2017. Published by Elsevier Taiwan.

  8. Surface and micellar properties of Chloroquine Diphosphate and its interactions with surfactants and Human Serum Albumin

    International Nuclear Information System (INIS)

    Usman, Muhammad; Siddiq, Mohammad

    2013-01-01

    Highlights: ► Free energy of adsorption is more negative than free energy of micellization. ► Shifts in UV/Visible spectra in presence of SDS indicated interaction of CLQ with SDS. ► The decrease in fluorescence intensity of HSA by CLQ shows its binding with HSA. -- Abstract: This manuscript addresses the physicochemical behavior of an antimalarial drug Chloroquine Diphosphate (CLQ) as well as its interaction with anionic surfactants and Human Serum Albumin (HSA). Surface tension and specific conductivity were employed to detect the critical micelle concentration (CMC) and thus its surface and thermodynamic parameters were calculated. Solubilization of this drug within micelles of anionic surfactant sodium dodecyl sulfate (SDS) has also been studied. UV/Visible spectroscopy was used to calculate partition coefficient (K x ), free energy of partition and number of drug molecules per micelle. The complexation of drug with HSA at physiological conditions (pH 7.4) has also been analyzed by using UV/Visible and fluorescence spectroscopy. The values of drug-protein binding constant, number of binding sites and free energy of binding were calculated

  9. Protective role of tetrahydrocurcumin (THC) an active principle of turmeric on chloroquine induced hepatotoxicity in rats.

    Science.gov (United States)

    Pari, Leelavinothan; Amali, D Rosalin

    2005-04-30

    Tetrahydrocurcumin (THC) is an antioxidative substance, which is derived from curcumin, the component of turmeric. In the present investigation, the effect of THC and curcumin against chloroquine (CQ) induced hepatotoxicity were studied in female Wistar rats. On single oral administration of CQ (970 mg/kg body weight) the activities of serum marker enzymes namely aspartate transaminase, alanine transaminase and alkaline phosphatase and the levels of bilirubin were significantly increased with significant alterations of lipids in serum and lipidperoxidation markers such as thiobarbituric acid reactive substances (TBARS) and hydroperoxides in plasma and liver were also elevated in CQ treated rats. The levels of non-enzymic antioxidants (vitamin C, vitamin E and reduced glutathione) and enzymic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) were also decreased in CQ treated rats. Administration of THC (80 mg/kg body weight) and curcumin (80 mg/kg body weight) for 8 days before and 7 days after single administration of CQ significantly decreased the activities of serum markers and lipids in serum. In addition, the level of TBARS and hydroperoxides were significantly decreased with significant increase in non-enzymic and enzymic antioxidants on treatment with THC and curcumin. The biochemical observation was supplemented by histopathological examination of liver section. The results of the study reveal that THC shows more pronounced protective effect than curcumin against CQ induced toxicity.

  10. Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth.

    Science.gov (United States)

    Gorka, Alexander P; Alumasa, John N; Sherlach, Katy S; Jacobs, Lauren M; Nickley, Katherine B; Brower, Jonathan P; de Dios, Angel C; Roepe, Paul D

    2013-01-01

    We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013).

  11. Uncertainty evaluation in the chloroquine phosphate potentiometric titration: application of three different approaches.

    Science.gov (United States)

    Rodomonte, Andrea Luca; Montinaro, Annalisa; Bartolomei, Monica

    2006-09-11

    A measurement result cannot be properly interpreted if not accompanied by its uncertainty. Several methods to estimate uncertainty have been developed. From those methods three in particular were chosen in this work to estimate the uncertainty of the Eu. Ph. chloroquine phosphate assay, a potentiometric titration commonly used in medicinal control laboratories. The famous error-budget approach (also called bottom-up or step-by-step) described by the ISO Guide to the expression of Uncertainty in Measurement (GUM) was the first method chosen. It is based on the combination of uncertainty contributions that have to be directly derived from the measurement process. The second method employed was the Analytical Method Committee top-down which estimates uncertainty through reproducibility obtained during inter-laboratory studies. Data for its application were collected in a proficiency testing study carried out by over 50 laboratories throughout Europe. The last method chosen was the one proposed by Barwick and Ellison. It uses a combination of precision, trueness and ruggedness data to estimate uncertainty. These data were collected from a validation process specifically designed for uncertainty estimation. All the three approaches presented a distinctive set of advantages and drawbacks in their implementation. An expanded uncertainty of about 1% was assessed for the assay investigated.

  12. Distribution of an 125I-labelled chloroquine analogue in a pregnant macaca monkey

    International Nuclear Information System (INIS)

    Dencker, L.; Lindquist, N.G.; Ullberg, S.

    1975-01-01

    Whole body autoradiography of a pregnant monkey (Macaca irus) of late gestation was performed 72 h after an intravenous injection of the 125 I-labelled chloroquine analogue 4-(3-dimethylaminopropylamino)-7-iodoquinoline (DAPQ). The overall distribution pattern in the monkey was similar to that which was earlier observed in rodents. A few species differences, however, were found in the monkey as compared to the rodents: a high accumulation in the inner part of the adrenal cortex, a high level in the central nervous system, and generally a higher retention in the tissues. The accumulation in the cortex may be of significance for the cortisone-like effects of the 4-aminoquinolines in rheumatoid arthritis and allied conditions. The fact that no accumulation was found in the adrenal cortex of mice and rats indicates that these species may not be appropriate in studies on the mechanisms involved in the anti-inflammatory action of the 4-aminoquinolines. As was earlier observed in small rodents the melanin containing structures accumulated the drug. In both the mother and the fetus a high concentration was thus seen in the uveal tract of the eye, in the inner ear (in the stria vascularis of the cochlea and the planum semilunatum of the ampullae) and in the hair follicles. This accumulation can be related to reported disturbances-also transplacentally induced-in vision and hearing

  13. Chloroquine inhibits autophagy and deteriorates the mitochondrial dysfunction and apoptosis in hypoxic rat neurons.

    Science.gov (United States)

    Li, Peng; Hao, Lei; Guo, Yan-Yan; Yang, Guang-Lu; Mei, Hua; Li, Xiao-Hua; Zhai, Qiong-Xiang

    2018-06-01

    Mitochondrial dysfunction (MD) and apoptosis in the neurons are associated with neonatal hypoxic-ischemic (HI) encephalopathy (HIE). The present study was to explore the influence of autophagy on the induction of MD and apoptosis in the neurons in a neonatal HIE rats and in hypoxia-treated neurons in vitro. Ten-day-old HI rat pups were sacrificed for brain pathological examination and immunohistochemical analysis. The induction of autophagy, apoptosis and MD were also determined in the neurons under hypoxia, with or without autophagy inhibitor, chloroquine (CQ) treatment. HI treatment caused atrophy and apoptosis of neurons, with a significantly increased levels of apoptosis- and autophagy-associated proteins, such as cleaved caspase 3 and the B subunit of autophagy-related microtubule-associated protein 1 light chain 3 (LC3-B). in vitro experiments demonstrated that the hypoxia induced autophagy in neurons, as was inhibited by CQ. The hypoxia-induced cytochrome c release, cleaved caspase 3 and cleaved caspase 9 were aggravated by CQ. Moreover, there were higher levels of reactive oxygen species, more mitochondrial superoxide and less mitochondrial membrane potential in the CQ-treated neurons under hypoxia than in the neurons singularly under hypoxia. Apoptosis and autophagy were induced in HI neonatal rat neurons, autophagy inhibition deteriorates the hypoxia-induced neuron MD and apoptosis. It implies a neuroprotection of autophagy in the hypoxic-ischemic encephalopathy. Administration of autophagy inducer agents might be promising in HIE treatment. Copyright © 2018. Published by Elsevier Inc.

  14. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-02-09

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination.

  15. Nicotine and caffeine modulate haloperidol-induced changes in postsynaptic density transcripts expression: Translational insights in psychosis therapy and treatment resistance.

    Science.gov (United States)

    de Bartolomeis, Andrea; Iasevoli, Felice; Marmo, Federica; Buonaguro, Elisabetta Filomena; Avvisati, Livia; Latte, Gianmarco; Tomasetti, Carmine

    2018-04-01

    Caffeine and nicotine are widely used by schizophrenia patients and may worsen psychosis and affect antipsychotic therapies. However, they have also been accounted as augmentation strategies in treatment-resistant schizophrenia. Despite both substances are known to modulate dopamine and glutamate transmission, little is known about the molecular changes induced by these compounds in association to antipsychotics, mostly at the level of the postsynaptic density (PSD), a site of dopamine-glutamate interplay. Here we investigated whether caffeine and nicotine, alone or combined with haloperidol, elicited significant changes in the levels of both transcripts and proteins of the PSD members Homer1 and Arc, which have been implicated in synaptic plasticity, schizophrenia pathophysiology, and antipsychotics molecular action. Homer1a mRNA expression was significantly reduced by caffeine and nicotine, alone or combined with haloperidol, compared to haloperidol. Haloperidol induced significantly higher Arc mRNA levels than both caffeine and caffeine plus haloperidol in the striatum. Arc mRNA expression was significantly higher by nicotine plus haloperidol vs. haloperidol in the cortex, while in striatum gene expression by nicotine was significantly lower than that by both haloperidol and nicotine plus haloperidol. Both Homer1a and Arc protein levels were significantly increased by caffeine, nicotine, and nicotine plus haloperidol. Homer1b mRNA expression was significantly increased by nicotine and nicotine plus haloperidol, while protein levels were unaffected. Locomotor activity was not significantly affected by caffeine, while it was reduced by nicotine. These data indicate that both caffeine and nicotine trigger relevant molecular changes in PSD sites when given in association with haloperidol. Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.

  16. Glucocorticoid regulation of a novel HPV-E6-p53-miR-145 pathway modulates invasion and therapy resistance of cervical cancer cells.

    Science.gov (United States)

    Shi, Ming; Du, Libin; Liu, Dan; Qian, Lu; Hu, Meiru; Yu, Ming; Yang, Zhengyan; Zhao, Mingzhen; Chen, Changguo; Guo, Liang; Wang, Lina; Song, Lun; Ma, Yuanfang; Guo, Ning

    2012-10-01

    Glucocorticoids are stress-responsive neuroendocrine mediators and play an important role in malignant progression, especially in solid tumours. We demonstrate a novel mechanism by which glucocorticoids modulate p53-dependent miR-145 expression in HPV-positive cervical cancer cells through induction of E6 proteins. We found that expression of miR-145 was reduced in cervical cancer tissues. Cortisol induced HPV-E6 expression and suppressed p53 and miR-145 in cervical cancer cells. MiR-145 expression in cervical cancer cells was wild-type p53-dependent, and cortisol-induced down-regulation of miR-145 expression prevented chemotherapy-induced apoptosis, whereas over-expression of miR-145 enhanced sensitivity to mitomycin and reversed the chemoresistance induced by glucocorticoids. We also show that miR-145 augments the effects of p53 by suppressing the inhibitors of p53 in cervical cancer cells, suggesting that miR-145 plays a role in p53 tumour suppression. Finally, we demonstrate that miR-145 inhibits both the motility and invasion of cervical cancer cells. Our findings identify a novel pathway through which the neuroendocrine macroenvironment affects cervical tumour growth, invasion and therapy resistance and show that miR-145 may serve as a target for cervical cancer therapy. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  17. Submicroscopic gametocytes and the transmission of antifolate-resistant Plasmodium falciparum in Western Kenya

    DEFF Research Database (Denmark)

    Oesterholt, Mayke J A M; Alifrangis, Michael; Sutherland, Colin J

    2009-01-01

    BACKGROUND: Single nucleotide polymorphisms (SNPs) in the dhfr and dhps genes are associated with sulphadoxine-pyrimethamine (SP) treatment failure and gametocyte carriage. This may result in enhanced transmission of mutant malaria parasites, as previously shown for chloroquine resistant parasites...... gametocytemia or enhanced malaria transmission. The absence of wild-type infections is likely to have reduced our power to detect differences. Our data further support the use of ACT to reduce the transmission of drug-resistant malaria parasites....

  18. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults.

    Directory of Open Access Journals (Sweden)

    Vianney Tricou

    2010-08-01

    Full Text Available There is currently no licensed antiviral drug for treatment of dengue. Chloroquine (CQ inhibits the replication of dengue virus (DENV in vitro.A double-blind, randomized, placebo-controlled trial of CQ in 307 adults hospitalized for suspected DENV infection was conducted at the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam between May 2007 and July 2008. Patients with illness histories of 72 hours or less were randomized to a 3-day course of CQ (n = 153 or placebo (n = 154. Laboratory-confirmation of DENV infection was made in 257 (84% patients. The primary endpoints were time to resolution of DENV viraemia and time to resolution of DENV NS1 antigenaemia. In patients treated with CQ there was a trend toward a longer duration of DENV viraemia (hazard ratio (HR = 0.80, 95% CI 0.62-1.05, but we did not find any difference for the time to resolution of NS1 antigenaemia (HR = 1.07, 95% CI 0.76-1.51. Interestingly, CQ was associated with a significant reduction in fever clearance time in the intention-to-treat population (HR = 1.37, 95% CI 1.08-1.74 but not in the per-protocol population. There was also a trend towards a lower incidence of dengue hemorrhagic fever (odds ratio = 0.60, PP 95% CI 0.34-1.04 in patients treated with CQ. Differences in levels of T cell activation or pro- or anti-inflammatory plasma cytokine concentrations between CQ- and placebo-treated patients did not explain the trend towards less dengue hemorrhagic fever in the CQ arm. CQ was associated with significantly more adverse events, primarily vomiting.CQ does not reduce the durations of viraemia and NS1 antigenaemia in dengue patients. Further trials, with appropriate endpoints, would be required to determine if CQ treatment has any clinical benefit in dengue.Current Controlled Trials number ISRCTN38002730.

  19. Evaluation of a follow-up protocol for patients on chloroquine and hydroxychloroquine treatment.

    Science.gov (United States)

    Sanabria, M R; Toledo-Lucho, S C

    2016-01-01

    To review the problems found after a new follow-up protocol for patients on chloroquine and hydroxychloroquine treatment. Retrospective study was conducted between May 2012 and January 2013 on the clinical files, retinographies, fundus auto-fluorescence (FAF) images, and central-10 degree visual fields (VF) of patients who were referred to the Ophthalmology Department as they had started treatment with hydroxychloroquine. One hundred twenty-six patients were included; 94.4% were referred from the Rheumatology Department and 5.6% from Dermatology. Mean age was 59.7 years, and 73.8% were women. All of them were on hydroxychloroquine treatment, and 300mg was the most frequent daily dose. Rheumatoid arthritis was the most common diagnosis (40.5%), followed by systemic lupus erythematosus (15.9%). The mean Snellen visual acuity was 0.76, and 26 patients had lens opacities. The VF were normal in 97 patients, 8 had mild to moderate defects with no definite pattern, and in 9 the results were unreliable. Of the 51 patients older than 65years, 16 (31.4%) had altered or unreliable VF. The FAF was normal in 104 patients (82.5%), and abnormal, but consistent with ophthalmoscopic features, in 12 patients (pathological myopia, age related changes, early, middle or late age-related macular degeneration). Visual fields as a reference test for the diagnosis of AP toxicity are not quite reliable for patients over 65. Therefore, the FAF is recommended as primary test, perhaps combined with another objective test, such as SD-OCT instead of VF. Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  20. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults.

    Science.gov (United States)

    Tricou, Vianney; Minh, Nguyet Nguyen; Van, Toi Pham; Lee, Sue J; Farrar, Jeremy; Wills, Bridget; Tran, Hien Tinh; Simmons, Cameron P

    2010-08-10

    There is currently no licensed antiviral drug for treatment of dengue. Chloroquine (CQ) inhibits the replication of dengue virus (DENV) in vitro. A double-blind, randomized, placebo-controlled trial of CQ in 307 adults hospitalized for suspected DENV infection was conducted at the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam) between May 2007 and July 2008. Patients with illness histories of 72 hours or less were randomized to a 3-day course of CQ (n = 153) or placebo (n = 154). Laboratory-confirmation of DENV infection was made in 257 (84%) patients. The primary endpoints were time to resolution of DENV viraemia and time to resolution of DENV NS1 antigenaemia. In patients treated with CQ there was a trend toward a longer duration of DENV viraemia (hazard ratio (HR) = 0.80, 95% CI 0.62-1.05), but we did not find any difference for the time to resolution of NS1 antigenaemia (HR = 1.07, 95% CI 0.76-1.51). Interestingly, CQ was associated with a significant reduction in fever clearance time in the intention-to-treat population (HR = 1.37, 95% CI 1.08-1.74) but not in the per-protocol population. There was also a trend towards a lower incidence of dengue hemorrhagic fever (odds ratio = 0.60, PP 95% CI 0.34-1.04) in patients treated with CQ. Differences in levels of T cell activation or pro- or anti-inflammatory plasma cytokine concentrations between CQ- and placebo-treated patients did not explain the trend towards less dengue hemorrhagic fever in the CQ arm. CQ was associated with significantly more adverse events, primarily vomiting. CQ does not reduce the durations of viraemia and NS1 antigenaemia in dengue patients. Further trials, with appropriate endpoints, would be required to determine if CQ treatment has any clinical benefit in dengue. Current Controlled Trials number ISRCTN38002730.

  1. Chloroquine and its derivatives exacerbate B19V-associated anemia by promoting viral replication.

    Directory of Open Access Journals (Sweden)

    Claudia Bönsch

    Full Text Available BACKGROUND: An unexpectedly high seroprevalence and pathogenic potential of human parvovirus B19 (B19V have been observed in certain malaria-endemic countries in parallel with local use of chloroquine (CQ as first-line treatment for malaria. The aims of this study were to assess the effect of CQ and other common antimalarial drugs on B19V infection in vitro and the possible epidemiological consequences for children from Papua New Guinea (PNG. METHODOLOGY/PRINCIPAL FINDINGS: Viral RNA, DNA and proteins were analyzed in different cell types following infection with B19V in the presence of a range of antimalarial drugs. Relationships between B19V infection status, prior 4-aminoquinoline use and anemia were assessed in 200 PNG children <10 years of age participating in a case-control study of severe infections. In CQ-treated cells, the synthesis of viral RNA, DNA and proteins was significantly higher and occurred earlier than in control cells. CQ facilitates B19V infection by minimizing intracellular degradation of incoming particles. Only amodiaquine amongst other antimalarial drugs had a similar effect. B19V IgM seropositivity was more frequent in 111 children with severe anemia (hemoglobin <50 g/L than in 89 healthy controls (15.3% vs 3.4%; P = 0.008. In children who were either B19V IgM or PCR positive, 4-aminoquinoline use was associated with a significantly lower admission hemoglobin concentration. CONCLUSIONS/SIGNIFICANCE: Our data strongly suggest that 4-aminoquinoline drugs and their metabolites exacerbate B19V-associated anemia by promoting B19V replication. Consideration should be given for choosing a non-4-aminoquinoline drug to partner artemisinin compounds in combination antimalarial therapy.

  2. Intralesional Versus Oral Chloroquine in Cutaneous Leishmaniasis: Comparison of Outcome, Duration of Treatment and Total Dose of Drug

    International Nuclear Information System (INIS)

    Hanif, M. M.; Akram, K.; Mustafa, G.

    2016-01-01

    Objective: To compare intralesional versus oral chloroquine in cutaneous leishmaniasis and determine the cure rate, duration of treatment, and total dose of drug. Study Design: Randomized controlled study. Place and Duration of Study: Department of Dermatology, Sheikh Zayed Medical College/Hospital, Rahim Yar Khan, from November 2013 to June 2014. Methodology: Consecutive 86 patients of cutaneous leishmaniasis, with single to multiple lesions of various sizes were enrolled and divided randomly into group A and B for the purpose of intralesional and oral chloroquine administration, respectively to compare the effect of the two routes on duration of treatment and total dose of the drug. SPSS version 16 was used for data analysis after data entry into it. Quantitative variables like, duration, cost and total dose of treatment were calculated as mean and standard deviation and compared by using T-test. P-value of less than 0.05 was taken as significant. Results: Cure rate was 100% in both groups towards the end of treatment. Mean duration of treatment was 9.17 ± 3 weeks in intralesional (A) group as against 11.37 ± 3 weeks in oral (B) group (p = 0.0028). Mean total dose of the drug given to each patient in group A was 5.8 ± 0.5 gm and in group B, it was 19.2 ± 1.5 gm, which is significantly higher (p=0.001). The total cost of treatment in group A was Rs. 90 ± 8 and in group B it was Rs. 91 ± 1 (p=0.446). Conclusion: Duration of treatment is significantly shorter and total dose is lesser with intralesional compared to oral chloroquine in treatment of cutaneous leishmaniasis. (author)

  3. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

    Directory of Open Access Journals (Sweden)

    Dea Shahinas

    2013-02-01

    Full Text Available Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

  4. Analysis of Chloroquine and Metabolites Directly from Whole-body Animal Tissue Sections by Liquid Extraction Surface Analysis (LESA) and Tandem Mass Spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Parson, Whitney B [ORNL; Koeniger, Stormy L [Abbott Laboratories; Johnson, Robert W [Abbott Laboratories; Erickson, Jamie [Abbott Laboratories; Tian, Yu [Abbott Laboratories; Stedman, Christopher A. [Abbott Laboratories; Schwartz, Annette [Abbott Laboratories; Tarcsa, Edit [Abbott Laboratories; Cole, Roderic [ORNL; Van Berkel, Gary J [ORNL

    2012-01-01

    The rapid and direct analysis of the amount and spatial distribution of exogenous chloroquine and chloroquine metabolites from tissue sections by liquid extraction surface sampling analysis coupled with tandem mass spectrometry (LESA-MS) was demonstrated. LESA-MS results compared well with previously published chloroquine quantification data collected by organ excision, extraction and fluorescent detection. The ability to directly sample and analyze spatially-resolved exogenous molecules from tissue sections with minimal sample preparation and analytical method development has the potential to facilitate the assessment of target tissue penetration of pharmaceutical compounds, to establish pharmacokinetic/pharmacodynamic (PK/PD) relationships, and to complement established pharmacokinetic methods used in the drug discovery process during tissue distribution assessment.

  5. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine in Guinea-Bissau between 2003 and 2012

    DEFF Research Database (Denmark)

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars

    2015-01-01

    BACKGROUND: Guinea-Bissau, West-Africa introduced artemether-lumefantrine in 2008 but quinine has also been commonly prescribed for treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes...... of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine are described. METHODS: Pfcrt K76T, pfmdr1 gene copy numbers, N86Y, Y184F and 1034-1246 sequences were determined using PCR-based methods. Blood samples came from virtually all (n=1806) children aged.......001). CONCLUSIONS: Following the discontinuation of an effective chloroquine regimen highly artemether-lumefantrine susceptible P. falciparum (with pfcrt 76T) accumulated possibly due to suboptimal use of quinine and despite a fitness cost linked to 76T....

  6. Effects of chloroquine, mefloquine and quinine on natural killer cell activity in vitro. An analysis of the inhibitory mechanism

    DEFF Research Database (Denmark)

    Pedersen, B K; Bygbjerg, I C; Theander, T G

    1986-01-01

    ) or interleukin 2 (Il-2); preincubation of mononuclear cells with IF or Il-2 followed by addition of anti-malarial drugs decreased the inhibitory effects of the drugs. The drug-induced inhibition of the NK cell activity was not dependent on the presence of monocytes. Using monocyte depleted Percoll fractionated......Natural killer (NK) cell activity against K 562 target cells was inhibited by pharmacological concentrations of chloroquine, mefloquine and quinine. The most potent were mefloquine and quinine. The drug-induced inhibition of the NK cell activity was abolished by addition of alpha-interferon (IF...

  7. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

    DEFF Research Database (Denmark)

    Khalil, Insaf F; Alifrangis, Michael; Recke, Camilla

    2011-01-01

    In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ) remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1...... therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite...

  8. Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria

    DEFF Research Database (Denmark)

    Abacassamo, F; Enosse, S; Aponte, J J

    2004-01-01

    This paper reports a two-phase study in Manhiça district, Mozambique: first we assessed the clinical efficacy and parasitological response of Plasmodium falciparum to chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ), then we tested the safety and efficacy in the treatment of......% to AQ. Co-administration of AQ + SP, AR + SP and AQ + AR was safe and had 100% clinical efficacy at 14-day follow-up. The combination therapies affected rapid fever clearance time and reduced the incidence of gametocytaemia during follow-up....

  9. Evaluation of four novel isothermal amplification assays towards simple and rapid genotyping of chloroquine resistant Plasmodium falciparum.

    Science.gov (United States)

    Chahar, Madhvi; Anvikar, Anup; Dixit, Rajnikant; Valecha, Neena

    2018-07-01

    Loop mediated isothermal amplification (LAMP) assay is sensitive, prompt, high throughput and field deployable technique for nucleic acid amplification under isothermal conditions. In this study, we have developed and optimized four different visualization methods of loop-mediated isothermal amplification (LAMP) assay to detect Pfcrt K76T mutants of P. falciparum and compared their important features for one-pot in-field applications. Even though all the four tested LAMP methods could successfully detect K76T mutants of P. falciparum, however considering the time, safety, sensitivity, cost and simplicity, the malachite green and HNB based methods were found more efficient. Among four different visual dyes uses to detect LAMP products accurately, hydroxynaphthol blue and malachite green could produce long stable color change and brightness in a close tube-based approach to prevent cross-contamination risk. Our results indicated that the LAMP offers an interesting novel and convenient best method for the rapid, sensitive, cost-effective, and fairly user friendly tool for detection of K76T mutants of P. falciparum and therefore presents an alternative to PCR-based assays. Based on our comparative analysis, better field based LAMP visualization method can be chosen easily for the monitoring of other important drug targets (Kelch13 propeller region). Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Clinical and molecular surveillance of drug resistant vivax malaria in Myanmar (2009-2016).

    Science.gov (United States)

    Nyunt, Myat Htut; Han, Jin-Hee; Wang, Bo; Aye, Khin Myo; Aye, Kyin Hla; Lee, Seong-Kyun; Htut, Ye; Kyaw, Myat Phone; Han, Kay Thwe; Han, Eun-Taek

    2017-03-16

    One of the major challenges for control and elimination of malaria is ongoing spread and emergence of drug resistance. While epidemiology and surveillance of the drug resistance in falciparum malaria is being explored globally, there are few studies on drug resistance vivax malaria. To assess the spread of drug-resistant vivax malaria in Myanmar, a multisite, prospective, longitudinal study with retrospective analysis of previous therapeutic efficacy studies, was conducted. A total of 906 from nine study sites were included in retrospective analysis and 208 from three study sites in prospective study. Uncomplicated vivax mono-infected patients were recruited and monitored with longitudinal follow-up until day 28 after treatment with chloroquine. Amplification and sequence analysis of molecular markers, such as mutations in pvcrt-O, pvmdr1, pvdhps and pvdhfr, were done in day-0 samples in prospective study. Clinical failure cases were found only in Kawthaung, southern Myanmar and western Myanmar sites within 2009-2016. Chloroquine resistance markers, pvcrt-O 'AAG' insertion and pvmdr1 mutation (Y976F) showed higher mutant rate in southern and central Myanmar than western site: 66.7, 72.7 vs 48.3% and 26.7, 17.0 vs 1.7%, respectively. A similar pattern of significantly higher mutant rate of antifolate resistance markers, pvdhps (S382A, K512M, A553G) and pvdhfr (F57L/I, S58R, T61M, S117T/N) were noted. Although clinical failure rate was low, widespread distribution of chloroquine and antifolate resistance molecular makers alert to the emergence and spread of drug resistance vivax malaria in Myanmar. Proper strategy and action plan to eliminate and contain the resistant strain strengthened together with clinical and molecular surveillance on drug resistance vivax is recommended.

  11. The fruit of Acanthopanax senticosus (Rupr. et Maxim.) Harms improves insulin resistance and hepatic lipid accumulation by modulation of liver adenosine monophosphate-activated protein kinase activity and lipogenic gene expression in high-fat diet-fed obese mice.

    Science.gov (United States)

    Saito, Tetsuo; Nishida, Miyako; Saito, Masafumi; Tanabe, Akari; Eitsuka, Takahiro; Yuan, Shi-Hua; Ikekawa, Nobuo; Nishida, Hiroshi

    2016-10-01

    Obesity-associated insulin resistance is a major risk factor for most metabolic diseases, including dyslipidemia and type 2 diabetes. Acanthopanax senticosus (Rupr. et Maxim.) Harms (Goka) root has been used in traditional Chinese medicine for treatment of diabetes and other conditions; however, little is known about the effects of Goka fruit (GF). Goka fruit is rich in anthocyanin, which has beneficial effects on obesity and insulin resistance via activation of adenosine monophosphate-activated protein kinase (AMPK). We hypothesized that GF can improve obesity-associated insulin resistance. The aim of the present study was to investigate whether GF improves insulin resistance in high-fat diet (HFD)-induced obese mice. High-fat diet mice treated with GF (500 and 1000 mg/kg) for 12 weeks showed an improved glucose tolerance and insulin sensitivity, as well as reduced plasma insulin and liver lipid accumulation. Moreover, GF administration to HFD mice resulted in down-regulation of fatty acid synthase expression and up-regulation of cholesterol 7-alpha-hydroxylase expression in the liver. Notably, AMPK phosphorylation in the liver increased after GF administration. In summary, GF supplementation improved obesity-associated insulin resistance and hepatic lipid accumulation through modulation of AMPK activity and lipid metabolism-associated gene expression. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Characterization and evaluation of acid-modified starch of Dioscorea oppositifolia (Chinese yam as a binder in chloroquine phosphate tablets

    Directory of Open Access Journals (Sweden)

    Adenike Okunlola

    2013-12-01

    Full Text Available Chinese yam (Dioscorea oppositifolia starch modified by acid hydrolysis was characterized and compared with native starch as a binder in chloroquine phosphate tablet formulations. The physicochemical and compressional properties (using density measurements and the Heckel and Kawakita equations of modified Chinese yam starch were determined, and its quantitative effects as a binder on the mechanical and release properties of chloroquine phosphate were analyzed using a 2³ full factorial design. The nature (X1, concentration of starch (X2 and packing fraction (X3 were taken as independent variables and the crushing strength-friability ratio (CSFR, disintegration time (DT and dissolution time (t80 as dependent variables. Acid-modified Chinese yam starch showed a marked reduction (p<0.05 in amylose content and viscosity but increased swelling and water-binding properties. The modified starch had a faster onset and greater amount of plastic flow. Changing the binder from native to acid-modified form led to significant increases (p<0.05 in CSFR and DT but a decrease in t80. An increase in binder concentration and packing fraction gave similar results for CSFR and DT only. These results suggest that acid-modified Chinese yam starches may be useful as tablet binders when high bond strength and fast dissolution are required.

  13. Side Effects of Chloroquine and Primaquine and Symptom Reduction in Malaria Endemic Area (Mâncio Lima, Acre, Brazil

    Directory of Open Access Journals (Sweden)

    Cássio Braga e Braga

    2015-01-01

    Full Text Available Side effects of antimalarial drug can overlap with malaria symptoms. We evaluated 50 patients with vivax malaria in Mâncio Lima, Acre, treated with chloroquine and primaquine. Patients were evaluated for the presence of 21 symptoms before and after treatment and for reported side effects of these drugs after treatment was started. The most frequent symptoms before medication were headache, fever, chills, sweating, arthralgia, back pain, and weakness, which were present in between 40% and 76% of respondents. The treatment reduced the occurrence of these symptoms and reduced the lack of appetite, but gastrointestinal symptoms and choluria increased in frequency. There were no reports of pale stools before medication, but 12% reported the occurrence of this symptom after treatment started. Other symptoms such as blurred vision (54%, pruritus (22%, paresthesia (6%, insomnia (46%, and “stings” into the skin (22% were reported after chloroquine was taken. The antimalarial drugs used to treat P. vivax malaria reduce much of the systemic and algic symptoms but cause mainly gastrointestinal side effects that may lead to lack of adherence to drug treatment. It is important to guide the patient for the appearance and the transience of such side effects in order to avoid abandoning treatment.

  14. Adaptations of the Saker-Solomons test: simple, reliable colorimetric field assays for chloroquine and its metabolites in urine.

    Science.gov (United States)

    Mount, D L; Nahlen, B L; Patchen, L C; Churchill, F C

    1989-01-01

    Two field-adapted colorimetric methods for measuring the antimalarial drug chloroquine in urine are described. Both are modifications of the method of Saker and Solomons for screening urine for phencyclidine and other drugs of abuse, using the colour reagent tetrabromophenolphthalein ethyl ester. One method is semiquantitative, detecting the presence of chloroquine (Cq) and its metabolites in urine with a 1 microgram/ml detection limit; it is more sensitive and reliable than the commonly used Dill-Glazko method and is as easy to apply in the field. The second method uses a hand-held, battery-operated filter photometer to quantify Cq and its metabolites with a 2 microgram/ml detection limit and a linear range up to 8 micrograms/ml. The first method was validated in the field using a published quantitative colorimetric method and samples from a malaria study in Nigeria. The second method was validated in the laboratory against high-performance liquid chromatographic results on paired samples from the Nigerian study. Both methods may be used in remote locations where malaria is endemic and no electricity is available.

  15. Are Long-Term Chloroquine or Hydroxychloroquine Users Being Checked Regularly for Toxic Maculopathy?

    Science.gov (United States)

    Nika, Melisa; Blachley, Taylor S.; Edwards, Paul; Lee, Paul P.; Stein, Joshua D.

    2014-01-01

    Importance According to evidence-based, expert recommendations, long-term users of chloroquine (CQ) or hydroxychloroquine (HCQ) should undergo regular visits to eye-care providers and diagnostic testing to check for maculopathy. Objective To determine whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) taking CQ or HCQ are regularly visiting eye-care providers and being screened for maculopathy. Setting, Design and Participants Patients with RA or SLE who were continuously enrolled in a particular managed-care network for ≥5 years during 2001-2011 were studied. Patients' amount of CQ/HCQ use in the 5 years since initial RA/SLE diagnosis was calculated, along with their number of eye-care visits and diagnostic tests for maculopathy. Those at high risk for maculopathy were identified. Visits to eye providers and diagnostic testing for maculopathy were assessed for each enrollee over the study period. Logistic regression was performed to assess potential factors associated with regular eye-care-provider visits (≥3 in 5 years) among CQ/HCQ users, including those at greatest risk for maculopathy. Main Outcome Measures Among CQ/HCQ users and those at high risk for toxic maculopathy, the proportions with regular eye-care visits and diagnostic testing, and the likelihood of regular eye-care visits (odds ratios [ORs] with 95% confidence intervals [CI]). Results Among 18,051 beneficiaries with RA or SLE, 6,339 (35.1%) had ≥1 record of HCQ/CQ use and 1,409 (7.8%) used HCQ/CQ for ≥4 years. Among those at high risk for maculopathy, 27.9% lacked regular eye-provider visits, 6.1% had no visits to eye providers, and 34.5% had no diagnostic testing for maculopathy during the 5-year period. Among high-risk patients, each additional month of HCQ/CQ use was associated with a 2.0%-increased likelihood of regular eye care (adjusted OR=1.02, CI=1.01-1.03). High-risk patients whose SLE/RA were managed by rheumatologists had a 77%-increased

  16. From chloroquine to artemether-lumefantrine: the process of drug policy change in Zambia

    Directory of Open Access Journals (Sweden)

    Snow Robert W

    2008-01-01

    Full Text Available Abstract Background Following the recognition that morbidity and mortality due to malaria had dramatically increased in the last three decades, in 2002 the government of Zambia reviewed its efforts to prevent and treat malaria. Convincing evidence of the failing efficacy of chloroquine resulted in the initiation of a process that eventually led to the development and implementation of a new national drug policy based on artemisinin-based combination therapy (ACT. Methods All published and unpublished documented evidence dealing with the antimalarial drug policy change was reviewed. These data were supplemented by the authors' observations of the policy change process. The information has been structured to capture the timing of events, the challenges encountered, and the resolutions reached in order to achieve implementation of the new treatment policy. Results A decision was made to change national drug policy to artemether-lumefantrine (AL in the first quarter of 2002, with a formal announcement made in October 2002. During this period, efforts were undertaken to identify funding for the procurement of AL and to develop new malaria treatment guidelines, training materials, and plans for implementation of the policy. In order to avoid a delay in implementation, the policy change decision required a formal adoption within existing legislation. Starting with donated drug, a phased deployment of AL began in January 2003 with initial use in seven districts followed by scaling up to 28 districts in the second half of 2003 and then to all 72 districts countrywide in early 2004. Conclusion Drug policy changes are not without difficulties and demand a sustained international financing strategy for them to succeed. The Zambian experience demonstrates the need for a harmonized national consensus among many stakeholders and a political commitment to ensure that new policies are translated into practice quickly. To guarantee effective policies requires

  17. Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells.

    Science.gov (United States)

    Circu, Magdalena; Cardelli, James; Barr, Martin; O'Byrne, Kenneth; Mills, Glenn; El-Osta, Hazem

    2017-01-01

    Lung cancer is the leading cause of cancer-related deaths. Most patients develop resistance to platinum within several months of treatment. We investigated whether triggering lysosomal membrane permeabilization (LMP) or suppressing autophagy can restore cisplatin susceptibility in lung cancer with acquired chemoresistance. Cisplatin IC50 in A549Pt (parental) and A549cisR (cisplatin resistant) cells was 13 μM and 47 μM, respectively. Following cisplatin exposure, A549cisR cells failed to elicit an apoptotic response. This was manifested by diminished Annexin-V staining, caspase 3 and 9, BAX and BAK activation in resistant but not in parental cells. Chloroquine preferentially promoted LMP in A549cisR cells, revealed by leakage of FITC-dextran into the cytosol as detected by immunofluorescence microscopy. This was confirmed by increased cytosolic cathepsin D signal on Immunoblot. Cell viability of cisplatin-treated A549cisR cells was decreased when co-treated with chloroquine, corresponding to a combination index below 0.8, suggesting synergism between the two drugs. Notably, chloroquine activated the mitochondrial cell death pathway as indicated by increase in caspase 9 activity. Interestingly, inhibition of lysosomal proteases using E64 conferred cytoprotection against cisplatin and chloroquine co-treatment, suggesting that chloroquine-induced cell death occurred in a cathepsin-mediated mechanism. Likewise, blockage of caspases partially rescued A549cisR cells against the cytotoxicity of cisplatin and chloroquine combination. Cisplatin promoted a dose-dependent autophagic flux induction preferentially in A549cisR cells, as evidenced by a surge in LC3-II/α-tubulin following pre-treatment with E64 and increase in p62 degradation. Compared to untreated cells, cisplatin induced an increase in cyto-ID-loaded autophagosomes in A549cisR cells that was further amplified by chloroquine, pointing toward autophagic flux activation by cisplatin. Interestingly, this effect

  18. Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Magdalena Circu

    Full Text Available Lung cancer is the leading cause of cancer-related deaths. Most patients develop resistance to platinum within several months of treatment. We investigated whether triggering lysosomal membrane permeabilization (LMP or suppressing autophagy can restore cisplatin susceptibility in lung cancer with acquired chemoresistance. Cisplatin IC50 in A549Pt (parental and A549cisR (cisplatin resistant cells was 13 μM and 47 μM, respectively. Following cisplatin exposure, A549cisR cells failed to elicit an apoptotic response. This was manifested by diminished Annexin-V staining, caspase 3 and 9, BAX and BAK activation in resistant but not in parental cells. Chloroquine preferentially promoted LMP in A549cisR cells, revealed by leakage of FITC-dextran into the cytosol as detected by immunofluorescence microscopy. This was confirmed by increased cytosolic cathepsin D signal on Immunoblot. Cell viability of cisplatin-treated A549cisR cells was decreased when co-treated with chloroquine, corresponding to a combination index below 0.8, suggesting synergism between the two drugs. Notably, chloroquine activated the mitochondrial cell death pathway as indicated by increase in caspase 9 activity. Interestingly, inhibition of lysosomal proteases using E64 conferred cytoprotection against cisplatin and chloroquine co-treatment, suggesting that chloroquine-induced cell death occurred in a cathepsin-mediated mechanism. Likewise, blockage of caspases partially rescued A549cisR cells against the cytotoxicity of cisplatin and chloroquine combination. Cisplatin promoted a dose-dependent autophagic flux induction preferentially in A549cisR cells, as evidenced by a surge in LC3-II/α-tubulin following pre-treatment with E64 and increase in p62 degradation. Compared to untreated cells, cisplatin induced an increase in cyto-ID-loaded autophagosomes in A549cisR cells that was further amplified by chloroquine, pointing toward autophagic flux activation by cisplatin

  19. The effect of pH on the uptake and toxicity of the bivalent weak base chloroquine tested on Salix viminalis and Daphnia magna

    DEFF Research Database (Denmark)

    Rendal, Cecilie; Kusk, Kresten Ole; Trapp, Stefan

    2011-01-01

    , and therefore a higher toxicity can be expected. The current study examines the pHdependent toxicity and bioaccumulation of the bivalent weak base chloroquine (pKa: 10.47 and 6.33, log KOW 4.67) tested on Salix viminalis (basket willow) and Daphnia magna (water flea). The transpiration rates of hydroponically...

  20. Inhibition of FMLP-stimulated neutrophil chemiluminescence by blood platelets increased in the presence of the serotonin-liberating drug chloroquine

    Czech Academy of Sciences Publication Activity Database

    Jančinová, V.; Drábiková, K.; Nosáľ, R.; Petríková, M.; Číž, Milan; Lojek, Antonín; Danihelová, E.

    2003-01-01

    Roč. 109, 5-6 (2003), s. 293-298 ISSN 0049-3848 R&D Projects: GA MŠk ME 198 Grant - others:VEGA MŠ SR(SK) 2/1012/21 Institutional research plan: CEZ:AV0Z5004920 Keywords : blood platelets * neutrophils * chloroquine Subject RIV: BO - Biophysics Impact factor: 1.710, year: 2003

  1. The Effects of Chloroquine and Hydroxychloroquine on Nitric Oxide Production in RAW 264.7 and Bone Marrow-Derived Macrophages

    Czech Academy of Sciences Publication Activity Database

    Perečko, Tomáš; Kassab, R.B.; Vašíček, Ondřej; Pekarová, Michaela; Jančinová, V.; Lojek, Antonín

    2014-01-01

    Roč. 60, č. 1 (2014), s. 39-44 ISSN 0015-5500 R&D Projects: GA MŠk(CZ) EE2.3.30.0030 Institutional support: RVO:68081707 Keywords : chloroquine * cytotoxicity * hydroxychloroquine Subject RIV: BO - Biophysics Impact factor: 1.000, year: 2014

  2. Effects of chronic exposure of hydroxychloroquine/ chloroquine on the risk of cancer, metastasis, and death: a population-based cohort study on patients with connective tissue diseases

    Directory of Open Access Journals (Sweden)

    Fardet L

    2017-11-01

    Full Text Available L Fardet,1–3 I Nazareth,1 I Petersen1 1Department of Pri