Journals
Authors:
Abdel Sater, F.; Younes, M.; Nassar, H.; et al.
Journal:
MOLECULAR BIOLOGY REPORTS
ISSN 0301-4851
Vol. 49
N° 4
Year 2022
pp.3365
Authors:
Rashidi, S.; Vieira, C.; Tuteja, R.; et al.
Journal:
BIOMOLECULES
ISSN 2218-273X
Vol. 12
N° 2
Year 2022
pp.257
Human Leukocyte Antigen-G (HLA-G), a polymorphic non-classical HLA (HLA-Ib) with immune-regulatory properties in cancers and infectious diseases, presents both membrane-bound and soluble (sHLA-G) isoforms. Polymorphism has implications in host responses to pathogen infections and in pathogenesis. Differential expression patterns of HLA-G/sHLA-G or its polymorphism seem to be related to different pathological conditions, potentially acting as a disease progression biomarker. Pathogen antigens might be involved in the regulation of both membrane-bound and sHLA-G levels and impact immune responses during co-infections. The upregulation of HLA-G in viral and bacterial infections induce tolerance to infection. Recently, sHLA-G was found useful to identify the prognosis of Coronavirus disease 2019 (COVID-19) among patients and it was observed that the high levels of sHLA-G are associated with worse prognosis. The use of pathogens, such as Plasmodium falciparum, as immune modulators for other infections could be extended for the modulation of membrane-bound HLA-G in COVID-19-infected tissues. Overall, such information might open new avenues concerning the effect of some pathogens such as parasites in decreasing the expression level of HLA-G to restrict pathogenesis in some infections or to influence the immune responses after vaccination among others.
Authors:
Sater, F. A.; Younes, M.; Nassar, H.; et al.
Journal:
MOLECULAR BIOLOGY REPORTS
ISSN 0301-4851
Vol. 48
N° 11
Year 2021
pp.7243 - 7249
Background The new SARS-CoV-2 variant VOC (202012/01), identified recently in the United Kingdom (UK), exhibits a higher transmissibility rate compared to other variants, and a reproductive number 0.4 higher. In the UK, scientists were able to identify the increase of this new variant through the rise of false negative results for the spike (S) target using a three-target RT-PCR assay (TaqPath kit). Methods To control and study the current coronavirus pandemic, it is important to develop a rapid and low-cost molecular test to identify the aforementioned variant. In this work, we designed primer sets specific to the VOC (202012/01) to be used by SYBR Green-based RT-PCR. These primers were specifically designed to confirm the deletion mutations Delta 69/Delta 70 in the spike and the Delta 106/Delta 107/Delta 108 in the NSP6 gene. We studied 20 samples from positive patients, detected by using the Applied Biosystems TaqPath RT-PCR COVID-19 kit (Thermo Fisher Scientific, Waltham, USA) that included the ORF1ab, S, and N gene targets. 16 samples displayed an S-negative profile (negative for S target and positive for N and ORF1ab targets) and four samples with S, N and ORF1ab positive profile. Results Our results emphasized that all S-negative samples harbored the mutations Delta 69/Delta 70 and Delta 106/Delta 107/Delta 108. This protocol could be used as a second test to confirm the diagnosis in patients who were already positive to COVID-19 but showed false negative results for S-gene. Conclusions This technique may allow to identify patients carrying the VOC (202012/01) or a closely related variant, in case of shortage in sequencing.
Journal:
BIOMOLECULES
ISSN 2218-273X
Vol. 11
N° 7
Year 2021
pp.984
Anti-microbial peptides (AMPs), small biologically active molecules, produced by different organisms through their innate immune system, have become a considerable subject of interest in the request of novel therapeutics. Most of these peptides are cationic-amphipathic, exhibiting two main mechanisms of action, direct lysis and by modulating the immunity. The most commonly reported activity of AMPs is their anti-bacterial effects, although other effects, such as anti-fungal, anti-viral, and anti-parasitic, as well as anti-tumor mechanisms of action have also been described. Their anti-parasitic effect against leishmaniasis has been studied. Leishmaniasis is a neglected tropical disease. Currently among parasitic diseases, it is the second most threating illness after malaria. Clinical treatments, mainly antimonial derivatives, are related to drug resistance and some undesirable effects. Therefore, the development of new therapeutic agents has become a priority, and AMPs constitute a promising alternative. In this work, we describe the principal families of AMPs (melittin, cecropin, cathelicidin, defensin, magainin, temporin, dermaseptin, eumenitin, and histatin) exhibiting a potential anti-leishmanial activity, as well as their effectiveness against other microorganisms.
Journal:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN 1422-0067
Vol. 22
N° 19
Year 2021
pp.10493
Since many of the currently available antileishmanial treatments exhibit toxicity, low effectiveness, and resistance, search and validation of new therapeutic targets allowing the development of innovative drugs have become a worldwide priority. This work presents a structure-based drug discovery strategy to validate the Lmj_04_BRCT domain as a novel therapeutic target in Leishmania spp. The structure of this domain was explored using homology modeling, virtual screening, and molecular dynamics studies. Candidate compounds were validated in vitro using promastigotes of Leishmania major, L. amazonensis, and L. infantum, as well as primary mouse macrophages infected with L. major. The novel inhibitor CPE2 emerged as the most active of a group of compounds against Leishmania, being able to significantly reduce the viability of promastigotes. CPE2 was also active against the intracellular forms of the parasites and significantly reduced parasite burden in murine macrophages without exhibiting toxicity in host cells. Furthermore, L. major promastigotes treated with CPE2 showed significant lower expression levels of several genes (alpha-tubulin, Cyclin CYCA, and Yip1) related to proliferation and treatment resistance. Our in silico and in vitro studies suggest that the Lmj_04_BRCT domain and its here disclosed inhibitors are new potential therapeutic options against leishmaniasis.</p>
Authors:
Rashidi, S.; Mansouri, R.; Ali-Hassanzadeh, M.; et al.
Journal:
PARASITOLOGY
ISSN 0031-1820
Vol. 148
N° 12
Year 2021
pp.1434 - 1446
Leishmania parasites, the causative agents of leishmaniasis, are protozoan parasites with the ability to modify the signalling pathway and cell responses of their infected host cells. These parasite strategies alter the host cell environment and conditions favouring their replication, survival and pathogenesis. Since microRNAs (miRNAs) are able to post-transcriptionally regulate gene expression processes, these biomolecules can exert critical roles in controlling Leishmania-host cell interplay. Therefore, the identification of relevant miRNAs differentially expressed in Leishmania parasites as well as in infected cells, which affect the host fitness, could be critical to understand the infection biology, pathogenicity and immune response against these parasites. Accordingly, the current review aims to address the differentially expressed miRNAs in both, the parasite and infected host cells and how these biomolecules change cell signalling and host immune responses during infection. A deep understanding of these processes could provide novel guidelines and therapeutic strategies for managing and treating leishmaniasis.
Journal:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN 1422-0067
Vol. 22
N° 22
Year 2021
pp.12592
Leishmaniasis is a neglected tropical disease caused by Leishmania spp. The improvement of existing treatments and the discovery of new drugs remain ones of the major goals in control and eradication of this disease. From the parasite genome, we have identified the homologue of the human oncogene PES1 in Leishmania major (LmjPES). It has been demonstrated that PES1 is involved in several processes such as ribosome biogenesis, cell proliferation and genetic transcription. Our phylogenetic studies showed that LmjPES encodes a highly conserved protein containing three main domains: PES N-terminus (shared with proteins involved in ribosomal biogenesis), BRCT (found in proteins related to DNA repair processes) and MAEBL-type domain (C-terminus, related to erythrocyte invasion in apicomplexan). This gene showed its highest expression level in metacyclic promastigotes, the infective forms; by fluorescence microscopy assay, we demonstrated the nuclear localization of LmjPES protein. After generating mutant parasites overexpressing LmjPES, we observed that these clones displayed a dramatic increase in the ratio of cell infection within macrophages. Furthermore, BALB/c mice infected with these transgenic parasites exhibited higher footpad inflammation compared to those inoculated with non-overexpressing parasites.
Authors:
Kalantar, K.; Manzano-Roman, R.; Ghani, E.; et al.
Journal:
FUTURE MICROBIOLOGY
ISSN 1746-0913
Vol. 16
N° 8
Year 2021
pp.607 - 613
Apolipoprotein A-I (apo A-I) represents the main component of the Trypanosome lytic factor (TLF) which contributes to the host innate immunity against Trypanosoma and Leishmania. These parasites use complex and multiple strategies such as molecular mimicry to evade or subvert the host immune system. Previous studies have highlighted the adaptation mechanisms of TLF-resistant Trypanosoma species. These data might support the hypothesis that Leishmania parasites (amastigote forms in macrophages) might express apo A-I to bypass and escape from TLF action as a component of the host innate immune responses. The anti-inflammatory property of apo A-I is another mechanism that supports our idea that apo A-I may play a role in Leishmania parasites allowing them to bypass the host innate immune system.
Journal:
PARASITOLOGY
ISSN 0031-1820
Vol. 148
N° 6
Year 2021
pp.655 - 671
The association of leishmaniasis and malignancies in human and animal models has been highlighted in recent years. The misdiagnosis of coexistence of leishmaniasis and cancer and the use of common drugs in the treatment of such diseases prompt us to further survey the molecular biology of Leishmania parasites and cancer cells. The information regarding common expressed proteins, as possible therapeutic targets, in Leishmania parasites and cancer cells is scarce. Therefore, the current study reviews proteins, and investigates the regulation and functions of several key proteins in Leishmania parasites and cancer cells. The up- and down-regulations of such proteins were mostly related to survival, development, pathogenicity, metabolic pathways and vital signalling in Leishmania parasites and cancer cells. The presence of common expressed proteins in Leishmania parasites and cancer cells reveals valuable information regarding the possible shared mechanisms of pathogenicity and opportunities for therapeutic targeting in leishmaniasis and cancers in the future.
Authors:
Rashidi, S.; Mansouri, R.; Ali-Hassanzadeh, M.; et al.
Journal:
PARASITOLOGY RESEARCH
ISSN 0932-0113
Vol. 120
N° 4
Year 2021
pp.1151 - 1166
The mechanistic (or mammalian) target of rapamycin (mTOR) is considered as a critical regulatory enzyme involved in essential signaling pathways affecting cell growth, cell proliferation, protein translation, regulation of cellular metabolism, and cytoskeletal structure. Also, mTOR signaling has crucial roles in cell homeostasis via processes such as autophagy. Autophagy prevents many pathogen infections and is involved on immunosurveillance and pathogenesis. Immune responses and autophagy are therefore key host responses and both are linked by complex mTOR regulatory mechanisms. In recent years, the mTOR pathway has been highlighted in different diseases such as diabetes, cancer, and infectious and parasitic diseases including leishmaniasis, toxoplasmosis, and malaria. The current review underlines the implications of mTOR signals and intricate networks on pathogen infections and the modulation of this master regulator by parasites. Parasitic infections are able to induce dynamic metabolic reprogramming leading to mTOR alterations in spite of many other ways impacting this regulatory network. Accordingly, the identification of parasite effects and interactions over such a complex modulation might reveal novel information regarding the biology of the abovementioned parasites and might allow the development of therapeutic strategies against parasitic diseases. In this sense, the effects of inhibiting the mTOR pathways are also considered in this context in the light of their potential for the prevention and treatment of parasitic diseases.
Authors:
Rashidi, S.; Tuteja, R.; Mansouri, R.; et al.
Journal:
JOURNAL OF PROTEOMICS
ISSN 1874-3919
Vol. 245
Year 2021
pp.104279
There are important challenges when investigating individual post-translational modifications (PTMs) or protein interaction network and delineating if PTMs or their changes and cross-talks are involved during infection, disease initiation or as a result of disease progression. Proteomics and in silico approaches now offer the possibility to complement each other to further understand the regulatory involvement of these modifications in parasites and infection biology. Accordingly, the current review highlights key expressed or altered proteins and PTMs are invisible switches that turn on and off the function of most of the proteins. PTMs include phosphorylation, glycosylation, ubiquitylation, palmitoylation, myristoylation, prenylation, acetylation, methylation, and epigenetic PTMs in P. falciparum which have been recently identified. But also other low-abundant or overlooked PTMs that might be important for the parasite's survival, infectivity, antigenicity, immunomodulation and pathogenesis. We here emphasize the PTMs as regulatory pathways playing major roles in the biology, pathogenicity, metabolic pathways, survival, host-parasite interactions and the life cycle of P. falciparum. Further validations and functional characterizations of such proteins might confirm the discovery of therapeutic targets and might most likely provide valuable data for the treatment of P. falciparum, the main cause of severe malaria in human.
Authors:
Penalvo, J. L. (Autor de correspondencia); Mertens, E.; Ademovic, E.; et al.
Journal:
BMJ OPEN
ISSN 2044-6055
Vol. 11
N° 11
Year 2021
pp.e055630
Introduction unCoVer-Unravelling data for rapid evidence-based response to COVID-19-is a Horizon 2020-funded network of 29 partners from 18 countries capable of collecting and using real-world data (RWD) derived from the response and provision of care to patients with COVID-19 by health systems across Europe and elsewhere. unCoVer aims to exploit the full potential of this information to rapidly address clinical and epidemiological research questions arising from the evolving pandemic. Methods and analysis From the onset of the COVID-19 pandemic, partners are gathering RWD from electronic health records currently including information from over 22 000 hospitalised patients with COVID-19, and national surveillance and screening data, and registries with over 1 900 000 COVID-19 cases across Europe, with continuous updates. These heterogeneous datasets will be described, harmonised and integrated into a multi-user data repository operated through Opal-DataSHIELD, an interoperable open-source server application. Federated data analyses, without sharing or disclosing any individual-level data, will be performed with the objective to reveal patients' baseline characteristics, biomarkers, determinants of COVID-19 prognosis, safety and effectiveness of treatments, and potential strategies against COVID-19, as well as epidemiological patterns. These analyses will complement evidence from efficacy/safety clinical trials, where vulnerable, more complex/heterogeneous populations and those most at risk of severe COVID-19 are often excluded. Ethics and dissemination After strict ethical considerations, databases will be available through a federated data analysis platform that allows processing of available COVID-19 RWD without disclosing identification information to analysts and limiting output to data aggregates. Dissemination of unCoVer's activities will be related to the access and use of dissimilar RWD, as well as the results generated by the pooled analyses. Dissemination will include training and educational activities, scientific publications and conference communications.
Journal:
PATHOGENS AND DISEASE
ISSN 2049-632X
Vol. 78
N° 1
Year 2020
pp.ftaa007
Leishmaniasis includes a broad spectrum of pathological outcomes in humans caused by protozoan parasites from the genus Leishmania. In recent years, proteomic techniques have introduced novel proteins with critical functions in Leishmania parasites. Based on our report of a Chitin binding protein (CBP) in our previous immunoproteomic study, this article suggests that CBP might be an RNA binding protein (RBP) in Leishmania parasites. RBPs, as key regulatory factors, have a role in post-transcriptional gene regulation. The presence of RBPs in Leishmania parasites has not been considered so far; however, this study aims to open a new venue regarding RBPs in Leishmania parasites. Confirming CBP as an RBP in Leishmania parasites, exploring other RBPs and their functions might lead to interesting issues in leishmaniasis. In fact, due to the regulatory role of RBPs in different diseases including cancers and their further classification as therapeutic targets, the emerging evaluation of CBP and RBPs from Leishmania parasites may allow the discovery of novel and effective drugs against leishmaniasis.
Journal:
EASTERN MEDITERRANEAN HEALTH JOURNAL
ISSN 1020-3397
Vol. 26
N° 12
Year 2020
pp.1548 - 1555
Background: In the Mediterranean region, Leishmania infantum is the main cause of visceral leishmaniasis. Dogs with canine visceral leishmaniasis are an important reservoir of visceral leishmaniasis. Control of canine visceral leishmaniasis could disrupt transmission of visceral leishmaniasis to humans. The secreted antigens of Leishmania promastigotes are potential stimuli of the host immune system. Proteomic techniques facilitate the identification of new protein markers. Aims: This study aimed to identify immunoreactive proteins in the secretions of L. infantum promastigotes which could be possible targets for the diagnosis and treatment of canine visceral leishmaniasis and the development of vaccines against the disease. Methods: Secretions of L. infantum promastigotes were obtained from the cultivation of 6 x 10(9) promastigotes in serum-free RPMI-1640 medium during a period of 72 h. After deionization and lyophilization, two-dimensional gel electrophoresis was used for protein separation followed by Western blotting. Thirteen common and repeatable immunoreactive spots were analysed by mass spectrometry. Results: Nine proteins were identified by spectrometry. Most of these proteins were involved in metabolism pathways, survival and pathogenicity of Leishmania parasites. Phospholipase C, immune inhibitor A, chitin-binding protein and a single peptide match to chain A crystal structure of selenomethionine were observed in the secretions of L. infantum promastigotes. Conclusions: The proteins identified in metabolism pathways, survival and pathogenicity of Leishmania parasites are possible targets that could be used for the diagnosis and treatment of canine visceral leishmaniasis and the development of vaccines against the disease in the future.
Journal:
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE
ISSN 0035-9203
Vol. 114
N° 7
Year 2020
pp.541 - 544
Optimum Levels of selenoproteins are essential for starting and managing the host immune responses against pathogens. According to the expression of selenoproteins in Leishmania parasites, and since high Levels of selenoproteins Lead to adverse effects on immune cells and their functions, Leishmania parasites might then express selenoproteins such as selenomethionine in their structure and/or secretions able to challenge the host immune system. Finally, this adaptation may Lead to evasion of the parasite from the host immune system. The expression of selenoproteins in Leishmania parasites might then induce the development of infection. We therefore suggest these molecules as new therapeutic candidates for the treatment of leishmaniasis.
Journal:
BIOMEDICINES
ISSN 2227-9059
Vol. 8
N° 11
Year 2020
pp.452
A novel serine/threonine protein kinase, LmjF.22.0810, was recently described in Leishmania major. After generating an L. major cell line overexpressing LmjF.22.0810 (named LmJ3OE), the ability of this novel protein to modulate the Th2-type immune response was analyzed. Our results suggest that the protein kinase LmjF.22.0810 might be involved in leishmaniasis outcomes. Indeed, our study outlined the LmJ3OE parasites infectivity in vitro and in vivo. Transgenic parasites displayed lower phagocytosis rates in vitro, and their promastigote forms exhibited lower expression levels of virulence factors compared to their counterparts in control parasites. In addition, LmJ3OE parasites developed significantly smaller footpad swelling in susceptible BALB/c mice. Hematoxylin-eosin staining allowed the observation of a lower inflammatory infiltrate in the footpad from LmJ3OE-infected mice compared to animals inoculated with control parasites. Gene expression of Th2-associated cytokines and effectors revealed a dramatically lower induction in interleukin (IL)-4, IL-10, and arginase 1 (ARG1) mRNA levels at the beginning of the swelling; no expression change was found in Th1-associated cytokines except for IL-12. Accordingly, such results were validated by immunohistochemistry studies, illustrating a weaker expression of ARG1 and a similar induction for inducible NO synthase (iNOS) in footpads from LmJ3OE-infected mice compared to control L. major infected animals. Furthermore, the parasite burden was lower in footpads from LmJ3OE-infected mice. Our analysis indicated that such significant smaller footpad swellings might be due to an impairment of the Th2 immune response that subsequently benefits Th1 prevalence. Altogether, these studies depict LmjF.22.0810 as a potential modulator of host immune responses to Leishmania. Finally, this promising target might be involved in the modulation of infection outcome.
Authors:
Pires, V. C. ; Magalhaes, C. P. ; Ferrante, M.; et al.
Journal:
ACTA TROPICA
ISSN 0001-706X
Vol. 211
Year 2020
17-N-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) is an inhibitor of heat shock protein 90 (Hsp90), which has been studied in the treatment of cancer such as leukemia or solid tumors. Alternatively, 17-AAG may represent a promising therapeutic agent against leishmaniasis. However, the delivery of 17-AAG is difficult due to its poor aqueous solubility. For exploring the therapeutic value of 17-AAG, we developed solid lipid nanoparticles (SLN) by double emulsion method. SLN exhibited similar to 100 nm, PDI < 0.2 and zeta potential similar to 20 mV. In addition, SLN were morphologically spherical with negligible aggregation. The entrapment efficiency of 17-AAG into the lipid matrix reached at nearly 80%. In a separate set of experiments, fluorescent SLN (FITC-labeled) showed a remarkable macrophage uptake, peaking within 2 h of incubation by confocal microscopy. Regarding the drug internalization as critical step for elimination of intracellular Leishmania, this finding demonstrates an important feature of the developed SLN. Collectively, these data indicate the feasibility of developing SLN as potential delivery systems for 17-AAG in leishmaniasis chemotherapy.
Authors:
Mansouri, R.; Ali-Hassanzadeh, M.; Shafiei, R.; et al.
Journal:
PARASITOLOGY
ISSN 0031-1820
Vol. 147
N° 12
Year 2020
pp.1255 - 1262
Plasmodium falciparumis the main cause of severe malaria in humans that can lead to death. There is growing evidence of drug-resistance inP. falciparumtreatment, and the design of effective vaccines remains an ongoing strategy to control the disease. On the other hand, the recognition of specific diagnostic markers forP. falciparumcan accelerate the diagnosis of this parasite in the early stages of infection. Therefore, the identification of novel antigenic proteins especially by proteomic tools is urgent for vaccination and diagnosis ofP. falciparum. The proteome diversity of the life cycle stages ofP. falciparum, the altered proteome ofP. falciparum-infected human sera and altered proteins inP. falciparum-infected erythrocytes could be proposed as appropriate proteins for the aforementioned aims. Accordingly, this review highlights and proposes different proteins identified using proteomic approaches as promising markers in the diagnosis and vaccination ofP. falciparum.It seems that most of the candidates identified in this study were able to elicit immune responses in theP. falciparum-infected hosts and they also played major roles in the life cycle, pathogenicity and key pathways of this parasite.
Journal:
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE
ISSN 0002-9637
Vol. 101
N° Supl. 5
Year 2019
pp.361 - 361
Journal:
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN 0066-4804
Vol. 63
N° 2
Year 2019
pp.e00904-18
Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects against Leishmania In this study, the in vitro leishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested against Leishmania major and Leishmania amazonensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated in L. amazonensis and L. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 than L. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels of Leishmania genes involved in the cell cycle, such as topoisomerase-2 (TOP-2), PCNA, and MCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G1 phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.
Journal:
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE
ISSN 0002-9637
Vol. 101
N° Supl. 5
Year 2019
pp.171
Authors:
Ojo, O. E.; Adebayo, A. S.; Awobode, H. O.; et al.
Journal:
SCIENTIFIC AFRICAN
ISSN 2468-2276
Vol. 6
Year 2019
pp.e00186
Malaria and schistosomiasis continue to contribute a big burden to infectious disease prevalence in the tropical areas, mainly in sub Saharan African countries. We previously reported high levels of schistosome specific antibody IgG3 in children coinfected with malaria and schistosomiasis. The aim of the current study was to examine the current co-infection rates of these diseases in Nigeria. Published and unpublished studies on co-infection of human urogenital schistosomiasis and malaria carried out in Nigeria between 2001 and August 2018 were retrieved through literature searches in PubMed, Google Scholar, AJOL, and university theses repositories. The filtered and relevant articles were reviewed and combined in a meta-analysis. Studies involving children reported higher rates of coinfection. The fourteen research articles involving 6,559 individuals were combined in a meta-analysis. Our analyses revealed an estimated 15% co-infection for the country, though with wide variability depending on location. In addition, there are few and well-designed research publications in Nigeria on prevalence and mechanism of malaria and schistosomiasis coinfection.
Journal:
BIOMOLECULES
ISSN 2218-273X
Vol. 9
N° 11
Year 2019
The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania.
Journal:
JOURNAL OF DERMATOLOGICAL SCIENCE
ISSN 0923-1811
Vol. 92
N° 1
Year 2018
pp.78 - 88
Background: Cutaneous leishmaniasis (CL) skin lesions are the result of a deregulated immune response, which is unable to eliminate Leishmania parasites. The control of both, parasites and host immune response, is critical to prevent tissue destruction. The skin ulceration has been correlated with high TNF-alpha level. Objective: Because human anti-TNF-alpha antibodies (Ab) have been successfully assayed in several mice inflammatory diseases, we hypothesized that their anti-inflammatory effect could optimize the healing of CL lesions achieved after topical application of paromomycin (PM), the current chemotherapy against CL. Methods and results: We first compared the in vitro efficacy of PM and Ab alone and the drug given in combination with Ab to assess if the Ab could interfere with PM leishmanicidal activity in L. major-infected bone marrow-derived macrophages. The combination therapy had similar antileishmanial activity to the drug alone and showed no influence on NO production, which allows macrophage-mediated parasite killing. Next, we demonstrated in an in vivo model of Imiquimod (R)-induced inflammation that topical Ab and PM inhibit the infiltration of inflammatory cells in the skin. In the efficacy studies in L. major-infected BALB/c mice, PM combined with Ab led to a sharp infection reduction and showed a stronger anti-inflammatory activity than PM alone. This was confirmed by the down-regulation of TNE-alpha, IL-1 beta, iNOS, IL 17, and CCL3 as well as by a decrease of the neutrophilic infiltrate during infection upon treatment with the Ab. Conclusions: In terms of parasite elimination and inflammation reduction, topical application of Ab in combination with PM was more effective than the drug alone. (C) 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
Journal:
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE
ISSN 0002-9637
Vol. 99
N° 4
Year 2018
pp.176 - 177
Authors:
Vacas, A. ; Sugden, C. ; Velasco-Rodríguez, Ó.; et al.
Journal:
JOURNAL OF PARASITOLOGY RESEARCH
ISSN 2090-0023
Vol. 2017
N° 2017
Year 2017
pp.1964531
Leishmania is the causative agent of leishmaniasis, a neglected tropical disease that affects more than 12 million people around the world. Current treatments are toxic and poorly effective due to the acquisition of resistance within Leishmania populations. Thus, the pursuit for new antileishmanial drugs is a priority. The available methods for drug screening based on colorimetric assays using vital dyes are time-consuming. Currently, the use of fluorescent reporter proteins is replacing the use of viability indicator dyes. We have constructed two plasmids expressing the red fluorescent protein mCherry with multiple cloning sites (MCS), adequate for N- and C-terminal fusion protein constructs. Our results also show that the improved pXG-mCherry plasmid can be employed for drug screening in vitro. The use of the red fluorescent protein, mCherry, is an easier tool for numerous assays, not only to test pharmacological compounds, but also to determine the subcellular localization of proteins.
Authors:
Yekkour, F.; Aubert, D.; Mercier, A.; et al.
Journal:
VETERINARY PARASITOLOGY
ISSN 0304-4017
Vol. 239
Year 2017
pp.31 - 36
Toxoplasmosis is a parasitic disease with worldwide distribution and a major public health problem. In Algeria, no data are currently available about genotypes of Toxoplasma gondii isolated from animals or humans. The present study assesses for the first time the seroprevalence of toxoplasmosis in stray cats, and provides molecular characterization of T. gondii strains circulating in this feline population in Algiers, the capital city of Algeria. Sera from 96 stray cats were tested for the presence of antibodies against T. gondii using the modified agglutination test. The seroprevalence was 50% (48/96) using 1:6 as the positivity cut-off. Different organs samples from stray cats, including heart samples, were tested for the presence of Toxoplasma DNA using real-time PCR. T. Gondii DNA was detected in 90.6% (87/96) of hearts. Of these parasitic DNAs, 22 were submitted to genotyping through the analysis of 15 microsatellite markers. The identified genotypes (12 of 22) mainly belonged to the type II lineage.
Journal:
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE
ISSN 0002-9637
Vol. 95
N° 5
Year 2017
pp.548 - 548
Journal:
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN 0066-4804
Vol. 60
N° 6
Year 2016
pp.3802 - 3812
A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 ¿M and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3'-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.
Journal:
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN 0066-4804
Vol. 59
N° 9
Year 2015
pp.5705 - 5713
The generation of new antileishmanial drugs has become a priority. Selenium and its derivatives stand out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations, and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug similarity parameters, we observed that two of them, called compounds 2b [methyl-N,N¿-di(thien-2-ylcarbonyl)-imidoselenocarbamate] and 4b [methyl-N,N¿-di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate], exhibit low 50% inhibitory concentrations (IC50s) (<3 ¿M) and good selectivity indexes (SIs) (>5) in Leishmania major promastigotes and lack toxicity on macrophages. In addition, in analysis of their therapeutic potential against L. major in vitro infection, both compounds display a dramatic reduction of amastigote burden (~80%) with sublethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for defense against intracellular pathogens. Compounds 2b and 4b were demonstrated to cause cell cycle arrest in G1 . Interestingly, evaluation of expression of genes related to proliferation (PCNA), treatment resistance (ABC transporter and alpha-tubulin), and virulence (quinonoid dihydropteridine reductase [QDPR]) showed several alterations in gene expression profiling. All these results prompt us to propose both compounds as candidates to treat leishmanial infections.
Journal:
PROSTATE
ISSN 0270-4137
Vol. 75
N° 11
Year 2015
pp.1137 - 1149
INTRODUCTIONThe need for new treatments for advanced prostate cancer has fostered the experimental use of targeted therapies. Sunitinib is a multi-tyrosine kinase inhibitor that mainly targets membrane-bound receptors of cells within the tumor microenvironment, such as endothelial cells and pericytes. However, recent studies suggest a direct effect on tumor cells. In the present study, we have evaluated both direct and indirect effects of Sunitinib in prostate cancer and how this drug regulates hypoxia, using in vitro and in vivo models.
METHODSWe have used both in vitro (PC-3, DU145, and LNCaP cells) and in vivo (PC-3 xenografts) models to study the effect of Sunitinib in prostate cancer. Analysis of hypoxia based on HIF-1 expression and FMISO uptake was conducted. ALDH activity was used to analyze cancer stem cells (CSC).
RESULTSSunitinib strongly reduced proliferation of PC-3 and DU-145 cells in a dose dependent manner, and decreased levels of p-Akt, p-Erk1/2, and Id-1, compared to untreated cells. A 3-fold reduction in tumor growth was also observed (P<0.001 with respect to controls). Depletion of Hif-1 levels in vitro and a decrease in FMISO uptake in vivo showed that Sunitinib inhibits tumor hypoxia. When combined with radiotherapy, this drug enhanced cell death in vitro and in vivo, and significantly decreased CD-31, PDGFR, Hif-1, Id1, and PCNA protein levels (whereas apoptosis was increased) in tumors as compared to controls or single-therapy treated mice. Moreover, Sunitinib reduced the number of ALDH+ cancer stem-like cells and sensitized these cells to radiation-mediated loss of clonogenicity.
DISCUSIONOur results support the use of Sunitinib in prostate cancer and shows that both hypoxia and cancer stem cells are involved in the effect elicited by this drug. Combination of Sunitinib with radiotherapy warrants further consideration to reduce prostate cancer burden.
Journal:
CANCER LETTERS
ISSN 0304-3835
Vol. 356
N° 2 Pt B
Year 2015
pp.899-909
Id1 has been shown to play a critical role in tumorigenesis and angiogenesis. Moreover, recent reports have involved Id1 in the maintenance of cancer stem cell features in some tumor types. The Id1 gene generates two isoforms through alternative splicing: Id1a and Id1b. We have investigated the role of each isoform in cancer development. Using lentiviral systems we modified the endogenous expression of each of these isoforms in cancer cells and analyzed their biological effect both in vitro and in vivo. Overexpression of Id1b in murine CT26 and 3LL cells caused a G0/G1 cell cycle arrest and reduced proliferation, clonogenicity and phospho-ERK1/2 levels, while increasing p27 levels. High levels of Id1a had an opposite effect and the proportion of cells in the S phase increased significantly. In vivo models confirmed the inhibitory role of Id1b in primary tumor growth and metastasis. Through microarray analysis we found that the cancer stem cell (CSC) markers ALDH1A1 and Notch-1 were up-regulated specifically in Id1b-overexpressing cells. By using qPCR we also found overexpression of Sca-1, Tert, Sox-2 and Oct-4 in these cells. Increased levels of Id1b promoted self-renewal and CSC-like properties, as shown by their high capacity for developing secondary tumorspheres and retaining the PKH26 dye. The acquisition of CSC phenotype was confirmed in human PC-3 cells that overexpressed Id1b. Our results show that Id1b maintains cells in a quiescent state and promotes self-renewal and
Journal:
CLINICAL GENITOURINARY CANCER
ISSN 1558-7673
Vol. 12
N° 2
Year 2014
pp.87 - 93
Inhibitor of differentiation-1 (Id1) might constitute a novel prognostic factor able to differentiate indolent from aggressive prostate tumors. In this study, 2 cohorts of 52 and 79 prostate cancer patients were selected for Id1 expression analysis. Higher levels of Id1 protein in advanced poor-prognosis patients and a correlation of higher Id1 mRNA expression levels with a lower survival in stage I to III patients were observed.
Background: In the prostate-specific antigen era, potentially indolent prostate tumors are radically treated, causing overtreatment. Molecular prognostic factors might differentiate indolent from aggressive tumors, allowing avoidance of unnecessary treatment. Patients and Methods: Fifty-two prostate cancer patients (20 organ-confined and 32 metastatic) were selected. All formalin-fixed and paraffin-embedded primary biopsies and matched metastases of 15 of them were evaluated for tumor and endothelial cell Id1 protein expression. Seventy-nine additional patients with organ-confined prostate cancer were selected for Id1 mRNA in silico analysis. Results: Among metastatic cancer subjects, 48% of primary tumors and 38% of metastases showed Id1 tumor cell expression, and 79% of primary tumors and 81% of metastases showed endothelial immunoreactivity. In the organ-confined group none of them showed Id1 protein tumor cell expression and 50% displayed endothelial expression. In the metastatic patients group, lower levels of Id1 protein predicted a nonsignificant longer overall survival (13 months vs. 7 months; P = .79). In the in silico analysis, however, lower levels of Id1 mRNA predicted a longer disease-free survival (61 months vs. not-reached; P = .018) and the hazard ratio for progression was 0.451 (P = .022) in favor of patients showing lower levels. Conclusion: In our cohort, it seems to be a differential epithelial expression of Id1 protein according to the prognostic features (metastatic/poor prognosis vs. organ-confined/good prognosis). In localized tumors treated with radical prostatectomy, higher Id1 mRNA expression levels might predict a higher hazard ratio for progression and a shorter disease-free survival. Further validation of these results in larger prospective series is warranted.
Journal:
CURRENT MOLECULAR MEDICINE
ISSN 1566-5240
Vol. 14
N° 1
Year 2014
pp.151 - 162
Id-1 is a member of the helix-loop-helix family of proteins that regulates the activity of transcription factors to suppress cellular differentiation and to promote cell growth. Overexpression of Id-1 in tumor cells correlates with increased malignancy and resistance to chemotherapy and radiotherapy. Id-1B is an isoform generated by alternative splicing that differs from the classical Id-1 in the 13-C-terminal amino acids, whose function is at present unknown. We have studied the role of Id-1B in cancer and its expression in healthy/malignant lung tissues. Overexpression of Id-1B in A549 lung and PC3 prostate cancer cells reduced anchorage-dependent and independent proliferation and clonogenic potential. Moreover, it increased the proportion of cells in the G0/G1 phase of the cell cycle and p27 levels, while reduced phospho-Erk and cyclin A levels. Through microarray analysis, we identified genes involved in cell growth and proliferation that are specifically deregulated as a consequence of Id-1B overexpression, including IGF2, BMP4, Id2, GATA3, EREG and AREG. Id-1B overexpressing cells that were treated with 4Gy irradiation dose were significantly less resistant to cell death. In vivo assays demonstrated that tumors with high Id-1B levels exhibited less growth (p< 0.01), metabolic activity (glucose uptake) and angiogenesis (p< 0.05) compared to tumors with low Id-1B expression; mice survival was significantly extended (p< 0.05). Quantification by qRT-PCR revealed that expression of Id-1B was significantly lower (p< 0.01) in human lung tumors compared to their matched nonmalignant counterparts. In conclusion, our results demonstrate that Id-1B decreases the malignancy of lung and prostate cancer cells, sensitizes them to radiotherapy-induced cell death, and counteracts the pro-tumorigenic role of the classical form of Id-1.
Journal:
EXPERT OPINION ON DRUG DELIVERY
ISSN 1742-5247
Vol. 11
N° 4
Year 2014
pp.579 - 597
Introduction: Cutaneous and mucocutaneous leishmaniasis are major tropical skin diseases. Topical treatment is currently limited to the least severe forms of cutaneous leishmaniasis (CL) without risk of dissemination. It is also recommended in combination with systemic therapy for more severe forms. Progresses in this modality of treatment are hindered by the heterogeneity of the disease and shortcomings in the clinical trials.
Areas covered: This review overlooks three major modalities of topical therapies in use or under investigation against CL: chemotherapy, photodynamic therapy and immunotherapy; either with older compounds such as paramonnycin or more recent nitric oxide donors, antimicrobial peptides or silver derivatives. The advantages and limitations of their administration with newer formulation strategies such as nanoparticles (NPs) are discussed.
Expert opinion: The efficacy of a topical treatment against CL depends not only on the intrinsic antileishmanial activity of the drug but also on the amount of drug available in the dermis. NPs as sustained release systems and permeation enhancers could favour the creation of a drug reservoir in the dermis. Additionally, certain NPs have immunomodulatory properties or wound healing capabilities of benefit in CL treatment. Pending task is the selective delivery of active compounds to intracellular amastigotes, because even small NPs are unable to penetrate deeply into the skin to encounter infected macrophages (except in ulcerative lesions).
Journal:
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234
Vol. 74
Year 2014
pp.116-123
Diselenide and sulfonamide derivatives have recently attracted considerable interest as leishmanicidal agents in drug discovery. In this study, a novel series of sixteen hybrid selenosulfonamides has been synthesized and screened for their in vitro activity against Leishmania infantum intracellular amastigotes and THP-1 cells. These assays revealed that most of the compounds exhibited antileishmanial activity in the low micromolar range and led us to identify three lead compounds (derivatives 2, 7 and 14) with IC50 values ranging from 0.83 to 1.47 ¿M and selectivity indexes (SI) over 17, much higher than those observed for the reference drugs miltefosine and edelfosine. When evaluated against intracellular amastigotes, hybrid compound 7 emerged as the most active compound (IC50 = 2.8 ¿M), showing higher activity and much less toxicity against THP-1 cells than edelfosine. These compounds could potentially serve as templates for future drug-optimization and drug-development efforts for their use as therapeutic agents in developing countries.
Journal:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN 0378-5173
Vol. 459
N° 1-2
Year 2014
pp.1-9
Journal:
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
ISSN 0928-0987
Vol. 62
Year 2014
pp.309 - 316
Topical therapy is the ideal outpatient treatment of cutaneous leishmaniasis (CL) because of the ease of administration and lower cost. It could be suitable as monotherapy for localized cutaneous leishmaniasis (LCL) or in combination with systemic therapies for more severe forms of the disease. Although paromomycin (PM) ointment can be recommended for the treatment of LCL caused by Leishmaniamajor, a more effective topical treatment should be achieved regarding the physicochemical properties of this aminoglucoside and its rather poor intrinsic antileishmanial activity, that hampers the accumulation of enough amount of drug in the dermis (where the infected macrophages home) to exert its activity. In this work, we determined a 50% effective dose of 5.6 ¿M for a novel compound, bis-4-aminophenyldiselenide, against L. major intracellular amastigotes. This compound and PM were formulated in chitosan hydrogels and ex vivo permeation and retention studies in the different skin layers were performed with pig ear skin in Franz diffusion cells. The results showed that less than 2¿4% of the diselenide drug penetrated and permeated through the skin. In contrast, the percentage of PM penetration was about 25¿60% without important retention in the skin. When topically applied to lesions of L. major infected BALB/c mice, the novel diselenide chitosan formulation was unable to slow lesion progression and reduce parasite burden. Considerations during the process of novel drug development and
Journal:
HISTOLOGY AND HISTOPATHOLOGY
ISSN 0213-3911
Vol. 28
N° 8
Year 2013
pp.1029 - 1040
Inhibitor of differentiation-1 (Id1) plays a role in cell proliferation, acquisition of epithelial to mesenchymal transition (EMT) features and angiogenesis. Id1 was shown to be expressed in some tumor types, mainly in advanced dedifferentiated stages. However, recent studies using a validated and highly specific monoclonal antibody against Id1 have challenged many of the results obtained by immunohistochemistry. The goal of our work was to perform a thorough analysis of Id1 expression in mouse embryos and adult tissues, as well as healthy and malignant mouse and human samples using this validated antibody (Perk et al., 2006). Our results show that Id1 was highly expressed in the oropharyngeal cavity, lung, cartilage and skin of E14 and E15 mouse embryos, but expression was progressively reduced in more developed embryos. Immunostaining only remained in epithelial cells of the gut and uterus of adult mice. Mammary MMTV-Myc and MMTV-Myc/VEGF transgenic mouse tumors, and squamous cell carcinomas of the lung induced by N-nitroso-tris-chloroethylurea (NTCU) were highly positive for Id1, unlike their respective healthy counterparts. Id1 immunostaining in a human tissue microarray (TMA) revealed strong expression in cancers of the oral cavity, bladder and cervix. Some tumor specimens of esophagus, thyroid and breast were also strongly positive. Our results suggest that Id1 is an oncofetal protein highly expressed in particular tumor types that should be reanalyzed in future studies using large cohorts of patients to reassess its diagnostic/prognostic value. Moreover, MMTV-Myc- and NTCU-induced tumors could serve as appropriate mouse models to study Id1 functions in breast and lung cancer, respectively.
Journal:
CURRENT MEDICINAL CHEMISTRY
ISSN 0929-8673
Vol. 19
N° 25
Year 2012
pp.4259 - 4288
The protozoan diseases leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease (CD) are responsible for substantial global morbidity and mortality in tropical and subtropical regions. Environmental changes, drug resistance and immunosuppression are contributing to the emergence and spread of these diseases. In the absence of safe and efficient vaccines, chemotherapy, together with vector control, remains the most important measure to control kinetoplastid diseases. Nevertheless, the current chemotherapeutic treatments are clearly inadequate because of their toxic effects, generation of resistances as well as route and schedules of administration not adapted to the field-conditions. This review overlooks the strategies that can be addressed to meet immediately the patient needs such as the reconsideration of current regimens of administration and the rational combination of drugs in use. In the medium-long term, due to new methodologies of medicinal-chemistry, the screening from natural products and the identification of new therapeutic targets, new lead compounds have great chance to advance through the drug development pipeline to clinic. Modern pharmaceutical formulation strategies and nanomedicines also merit a place in view of the benefits of a single dose of liposomal Amphotericin B ( AmBisome (R)) against visceral leishmaniasis. BBB-targeted nanodevices could be suited for selective delivery of drugs against HAT encephalitic phase. Bioadhesive nanoparticles can be proposed to enhance the bioavailability of drugs after oral administration by reason of improving the drug solubility, and permeability across the intestinal epithelia.
Journal:
METALLOMICS
ISSN 1756-5901
Vol. 4
N° 12
Year 2012
pp.1297 - 1307
The essential micronutrient selenium (Se) exerts its biological effects mainly through selenoproteins thereby affecting a number of physiological pathways including intracellular redox control, stress response and cancer cell proliferation. Besides affecting selenoprotein expression, some selenocompounds have been synthesized and analyzed in order to serve as chemotherapeutic substances preferentially targeting cancer cells. This promising chemotherapeutic potential has recently been verified for a particular imidoselenocarbamate in a mouse tumor model. In the present study we tested the effects of this and a number of related Se-methyl-and Se-benzyl-imidoselenocarbamates on selenoprotein expression in nontransformed and hepatic carcinoma cells in culture. Most of the Se-benzyl-imidoselenocarbamates strongly stimulated selenoprotein P (SePP) secretion while the Se-methyl-imidoselenocarbamates elicited less pronounced effects in hepatocarcinoma HepG2 cells. However, most of the Se-methyl-imidoselenocarbamates increased glutathione peroxidase (GPx) activity and decreased thioredoxin reductase (TXNRD) activity in parallel, while the majority of the Se-benzyl-imidoselenocarbamates were without a respective effect in HepG2 cells. Performing inhibitor assays in vitro, GPx activity was unaffected by the imidoselenocarbamates. In contrast, most of the Se-methyl-imidoselenocarbamates inhibited TXNRD activity in vitro in line with the results in HepG2 cells. Both classes of imidoselenocarbamates strongly induced selenoprotein S (SELS) expression without a respective increase in ER stress or unfolded protein response which are known inducers of SELS biosynthesis. Notably, many of these effects were cancer cell-specific, and not observed in nontransformed AML12 hepatocytes. Our results indicate that these novel selenocompounds affect expression and activity of crucial selenoenzymes in a compound-and cell-specific way in hepatocytes. Especially the Se-methyl-imidoselenocarbamates elicit a unique spectrum of activities by stimulating GPx activity, SELS expression and SePP secretion while inhibiting TXNRD activity in hepatocarcinoma cells. These effects represent a promising finding with respect to the identification of therapeutic selenocompounds, as cancer-cell specificity is combined with desired effects on selenoprotein expression and activity.
Journal:
CURRENT MEDICINAL CHEMISTRY
ISSN 0929-8673
Vol. 19
N° 18
Year 2012
pp.3031 - 3043
Methylimidoselenocarbamates have previously proven to display potent antitumor activities. In the present study we show that these compounds act as multikinase inhibitors. We found that the most effective compound, quinoline imidoselenocarbamate EI201, inhibits the PI3K/AKT/mTOR pathway, which is persistently activated and contributes to malignant progression in various cancers. EI201 blocked the phosphorylation of AKT, mTOR and several of its downstream regulators (p70(S6K) and 4E-BP1) and ERK1/2 in PC-3, HT-29 and MCF-7 cells in vitro, inducing both autophagy and apoptosis. EI201 also contributes to the loss of maintenance of the self-renewal and tumorigenic capacity of cancer stem cells (CSCs). 0.1 mu mol/L EI201 triggered a reduction in size and number of tumorspheres in PC-3, HT-29 and MCF-7 cells and 4 mu mol/L induced the elimination of almost all the tumorspheres in the three studied cell lines. In addition, EI201 suppressed almost 80% prostate tumor growth in vivo (p < 0.01) compared to controls at a relatively low dose (10 mg/kg) in a mouse xenograft model. There was a significant decrease in the subcutaneous primary tumor [18F]-FDG uptake (76.5% reduction, p < 0.05) and in the total tumor burden (76.8% reduction, p < 0.05) after EI201 treatment compared to vehicle control, without causing toxicity in mice. Taken together, our results support further development of EI201 as a novel multi-kinase inhibitor that may be useful against cancers with aberrant upregulation of PI3K/AKT and MAPK signaling pathways.
Journal:
CLINICAL CANCER RESEARCH
ISSN 1078-0432
Vol. 17
N° 12
Year 2011
pp.4155 -4166
Journal:
British Journal of Cancer
ISSN 0007-0920
Vol. 105
N° 10
Year 2011
pp.1608-1614
Journal:
EXPERT OPINION ON INVESTIGATIONAL DRUGS
ISSN 1354-3784
Vol. 20
N° 1
Year 2011
pp.61 - 74
Journal:
BMCCANCER
ISSN 1471-2407
Vol. 10
N° 188
Year 2010
pp.1 - 10
Journal:
PROSTATE
ISSN 0270-4137
Vol. 70
N° 6
Year 2010
pp.630 - 645
BACKGROUND:
Prostate cancer (PrCa) has a high incidence in Western countries and at present, there is no cure for hormone refractory prostate cancer. Transgenic mouse models have proven useful for understanding mechanisms of prostate carcinogenesis. The characterization of genetically modified mouse PrCa models using high-throughput genomic analyses provides important information to guide appropriate experiment applications for such model.
METHODS:
We have analyzed the transcriptome of the hormone refractory and highly metastatic Fetal Globin-SV40/T-antigen (Ggamma-globin-Tag) transgenic mouse model for PrCa compared to normal mouse prostate tissue. Gene expression patterns found in Ggamma-globin-Tag mouse prostate tumors were compared with publicly available human localized and metastatic prostate tumors (GEO accession # GSE3325) through hierarchical cluster analysis, Pearson's rank correlation coefficient, and Self Organizing Feature Maps (SOM) analyses.
RESULTS:
Ggamma-globin-Tag tumors clustered closely with human metastatic tumors and gene expression patterns had a significant correlation (P < 0.01), unlike human localized primary tumors (P > 0.6). Bioinformatic analyses identified deregulated genetic pathways and networks in Ggamma-globin-Tag tumors, which displayed similarities to alterations in human PrCa. Changes in the expression of genes involved in DNA replication and repair (Rb1, p53, Myc, PCNA, DNMT3A) and growth factor signaling pathways (TGFbeta2, ERK1/2, NRas, and Notch1) are deregulated in the Ggamma-globin-Tag tumors, suggesting their key role in the oncogenic process. Identification of an enrichment of putative binding sites for transcription factors revealed eight transcription factors that may be important in Ggamma-globin-Tag carcinogenesis, including SP1, NF-Y, CREB, Elk1, and E2F. Novel genes related to microtubule regulation were also identified in Ggamma-globin-Tag tumors as potentially important candidate targets for PrCa. Overexpression of stathmin-1, whose expression was increased in human metastatic prostate tumors, was validated in Ggamma-globin-Tag tumors by immunohistochemistry. This protein belongs to the SV40/T-antigen cancer signature identified in previous studies in prostate, breast, and lung cancer mouse models.
CONCLUSIONS:
Our results show that the Ggamma-globin-Tag model for hormone refractory PrCa shares important features with aggressive, metastatic human PrCa. Given the role of stathmin-1 in the destabilization of microtubles and taxane resistance, the Ggamma-globin-Tag model and other SV40/T-antigen driven transgenic models may be useful for testing potential therapies directed at stathmin-1 in human prostate tumors.
Journal:
CURRENT MOLECULAR MEDICINE
ISSN 1566-5240
Vol. 10
N° 8
Year 2010
pp.705 - 718
Prostate cancer is a long latency type of tumor that usually develops in men older than 50 years of age. Prostate epithelial neoplasia (PIN), the initial malignant lesion, progresses to invasive carcinoma over the course of years. Because of the particular features of prostate carcinogenesis, this type of tumor may represent a paradigm for cancer prevention. Several clinical trials have evaluated the effect of different compounds on prostate tumor development, including finasteride, selenium, vitamin E, and carotenes. Although some results are promising, no conclusive data have been achieved as to recommend any of these compounds as preventive agents. Results from some trials, such as SELECT, where supplementation of selenium and/or vitamin-E was used, have been rather disappointing. However, many novel chemopreventive agents that target different cancer-related pathways are being developed lately. Appropriate animal models (in particular, genetically modified mice) are being used to assess the efficacy of these novel compounds. The transgenic adenocarcinoma of the mouse prostate (TRAMP) model has been validated as an accurate model to test a variety of preventive agents. Genistein, alpha-difluoromethylornithine, toremifene, R-flurbiprofen, celecoxib, and green tea polyphenols have been shown to prevent prostate cancer development in TRAMP mice. In conclusion, new chemopreventive compounds which are effective in animal models are likely to be tested soon in clinical trials, with the final goal of reducing prostate cancer incidence in men.
