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1.
ACS Infect Dis ; 6(5): 909-915, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32125140

RESUMO

The recent outbreak of coronavirus disease 2019 (COVID-19) highlights an urgent need for therapeutics. Through a series of drug repurposing screening campaigns, niclosamide, an FDA-approved anthelminthic drug, was found to be effective against various viral infections with nanomolar to micromolar potency such as SARS-CoV, MERS-CoV, ZIKV, HCV, and human adenovirus, indicating its potential as an antiviral agent. In this brief review, we summarize the broad antiviral activity of niclosamide and highlight its potential clinical use in the treatment of COVID-19.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Niclosamida/farmacologia , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pandemias , Vírus da SARS/efeitos dos fármacos
2.
Anticancer Res ; 40(3): 1405-1417, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132037

RESUMO

BACKGROUND/AIM: Niclosamide is an antihe-minthic drug that has shown cytotoxic effects on non-small cell lung carcinoma (NSCLC) cells. However, the exact mechanisms underlying the anti-tumour activity of niclosamide in NSCLC cancer cells remains to be defined. The aim of this study was to evaluate the antitumor activity of niclosamide in human A549 and CL1-5 non-small cell lung cancer cells using in vitro and in vivo. MATERIALS AND METHODS: We investigated the effects of niclosamide on cell viability, apoptosis, the mitochondrial membrane potential (MMP; Δϕm), and autophagy and apoptosis-related protein expression in human A549 and CL1-5 non-small cell lung cancer cells. RESULTS: Niclosamide induced mainly caspase-independent apoptosis through apoptosis-inducible factor (AIF) translocation to the nucleus upon mitochondria damage. Moreover, niclosamide-induced autophagy may act as adaptive response against apoptosis. AMPK/AKT/mTOR pathway were involved in niclosamide-induced cell death and autophagy in response to ATP depletion. Furthermore, niclosamide efficiently suppressed tumor growth and induce autophagy in vivo. CONCLUSION: Niclosamide induced apoptosis by activating the intrinsic and caspase-independent pathway in human A549 and CL1-5 non-small cell lung cancer cells. Therefore, niclosamide is a potential candidate for anti-NSCLC therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Niclosamida/farmacologia , Células A549 , Trifosfato de Adenosina/metabolismo , Adenilato Quinase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Distribuição Aleatória , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
PLoS Negl Trop Dis ; 14(1): e0007873, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31945055

RESUMO

BACKGROUND: Preventive chemotherapy is a useful tool for the control of Taenia solium taeniasis and cysticercosis. The aim of this systematic review is to assess the scientific evidence concerning the effectiveness and safety of different drugs in preventive chemotherapy for T. solium taeniasis in endemic populations. METHODS: A systematic review was conducted of controlled and uncontrolled studies, assessing the efficacy and adverse effects (among other outcomes) of albendazole, niclosamide and/or praziquantel for preventive chemotherapy of T. solium taeniasis. A comprehensive search was conducted for published and unpublished studies. Two reviewers screened articles, completed the data extraction and assessment of risk of bias. A meta-analysis of cure rate and relative reduction in prevalence was performed. The protocol for this review was registered on the International prospective register of systematic reviews (PROSPERO), number CRD42018112533. RESULTS: We identified 3555 records, of which we included 20 primary studies reported across 33 articles. Meta-analyses of drug and dose showed that a single dose of praziquantel 10mg/kg, albendazole 400mg per day for three consecutive days, or niclosamide 2g, resulted in better cure rates for T. solium taeniasis (99.5%, 96.4% and 84.3%, respectively) than praziquantel 5mg/kg or single dose albendazole 400mg (89.0% and 52.0%, respectively). These findings have a low certainty of evidence due to high risk of bias in individual studies and heterogeneity in combined estimates. In relation to side-effects, most studies reported either no or only mild and transient side-effects within the first three days following drug administration for all drugs and doses. CONCLUSION: Evidence indicated that praziquantel 10mg/kg, niclosamide 2g, and triple dose albendazole 400mg were effective as taenicides and could be considered for use in mass drug administration programs for the control of T. solium taeniasis. Evidence was not found that any of these drugs caused severe side effects at the indicated doses, although the extent of the available evidence was limited.


Assuntos
Anticestoides/uso terapêutico , Quimioprevenção/métodos , Taenia solium/efeitos dos fármacos , Teníase/tratamento farmacológico , Albendazol/uso terapêutico , Animais , Cisticercose/tratamento farmacológico , Cisticercose/prevenção & controle , Humanos , Niclosamida/uso terapêutico , Praziquantel/uso terapêutico , Teníase/prevenção & controle
4.
PLoS Negl Trop Dis ; 13(12): e0006927, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31841501

RESUMO

BACKGROUND: Schistosomiasis is one of the world's most common NTDs. Successful control operations often target snail vectors with the molluscicide niclosamide. Little is known about how niclosamide affects snails, including for Biomphalaria pfeifferi, the most important vector for Schistosoma mansoni in Africa. We used Illumina technology to explore how field-derived B. pfeifferi, either uninfected or harboring cercariae-producing S. mansoni sporocysts, respond to a sublethal treatment of niclosamide. This study afforded the opportunity to determine if snails respond differently to biotic or abiotic stressors, and if they reserve unique responses for when presented with both stressors in combination. We also examined how sporocysts respond when their snail host is treated with niclosamide. PRINCIPAL FINDINGS: Cercariae-producing sporocysts within snails treated with niclosamide express ~68% of the genes in the S. mansoni genome, as compared to 66% expressed by intramolluscan stages of S. mansoni in snails not treated with niclosamide. Niclosamide does not disable sporocysts nor does it seem to provoke from them distinctive responses associated with detoxifying a xenobiotic. For uninfected B. pfeifferi, niclosamide treatment alone increases expression of several features not up-regulated in infected snails including particular cytochrome p450s and heat shock proteins, glutathione-S-transferases, antimicrobial factors like LBP/BPI and protease inhibitors, and also provokes strong down regulation of proteases. Exposure of infected snails to niclosamide resulted in numerous up-regulated responses associated with apoptosis along with down-regulated ribosomal and defense functions, indicative of a distinctive, compromised state not achieved with either stimulus alone. CONCLUSIONS/SIGNIFICANCE: This study helps define the transcriptomic responses of an important and under-studied schistosome vector to S. mansoni sporocysts, to niclosamide, and to both in combination. It suggests the response of S. mansoni sporocysts to niclosamide is minimal and not reflective of a distinct repertoire of genes to handle xenobiotics while in the snail host. It also offers new insights for how niclosamide affects snails.


Assuntos
Antinematódeos/farmacologia , Biomphalaria/efeitos dos fármacos , Moluscocidas/farmacologia , Niclosamida/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Biomphalaria/genética , Perfilação da Expressão Gênica , Schistosoma mansoni/genética
5.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 31(5): 535-537, 2019 Oct 16.
Artigo em Chinês | MEDLINE | ID: mdl-31713388

RESUMO

OBJECTIVE: To compare the effectiveness of snail control between immersion of molluscicides through tide diversion and mollusciciding by spraying in marshland areas. METHODS: Immersion of 26% suspension concentrate of metaldehyde and niclosamide through tide diversion and spraying 26% suspension concentrate of metaldehyde and niclosamide alone were employed for snail control in two neighboring snail-breeding marshlands, and snails were surveyed before and after mollusciciding. The mortality of snails and the density of living snails were estimated. RESULTS: The density of living snails reduced by 72.19% and 100.00% 1 and 2 years after immersion of 26% suspension concentrate of metaldehyde and niclosamide through tide diversion, and 5.93% and 18.15% 1 and 2 years after spraying 26% suspension concentrate of metaldehyde and niclosamide alone. CONCLUSIONS: Immersion of 26% suspension concentrate of metaldehyde and niclosamide through tide diversion is significantly superior to spraying 26% suspension concentrate of metaldehyde and niclosamide along for snail control, and implementation of immersion of 26% suspension concentrate of metaldehyde and niclosamide through tide diversion for more than 2 successive years may achieve a higher snail control efficiency.


Assuntos
Moluscocidas , Niclosamida , Controle de Pragas , Caramujos , Animais , Imersão , Controle de Pragas/métodos , Inquéritos e Questionários , Suspensões , Ondas de Maré , Áreas Alagadas
6.
World Neurosurg ; 131: 252-263.e2, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31376551

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common and deadly form of brain tumor. After standard treatment of resection, radiotherapy, and chemotherapy, the 5-year survival is <5%. In recent years, research has uncovered several potential targets within the Notch signaling pathway, which may lead to improved patient outcomes. METHODS: A literature search was performed for articles containing the terms "Glioblastoma" and "Receptors, Notch" between 2003 and July 2015. Of the 62 articles retrieved, 46 met our criteria and were included in our review. Nine articles were identified from other sources and were subsequently included, leaving 55 articles reviewed. RESULTS: Of the 55 articles reviewed, 47 used established human GBM cell lines. Seventeen articles used human GBM surgical samples. Forty-five of 48 articles that assessed Notch activity showed increased expression in GBM cell lines. Targeting the Notch pathway was carried out through Notch knockdown and overexpression and targeting δ-like ligand, Jagged, γ-secretase, ADAM10, ADAM17, and Mastermindlike protein 1. Arsenic trioxide, microRNAs, and several other compounds were shown to have an effect on the Notch pathway in GBM. Notch activity in GBM was also shown to be associated with hypoxia and certain cancer-related molecular pathways such as PI3K/AKT/mTOR and ERK/MAPK. Most articles concluded that Notch activity amplifies malignant characteristics in GBM and targeting this pathway can bring about amelioration of these effects. CONCLUSIONS: Recent literature suggests targeting the Notch pathway has great potential for future therapies for GBM.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Proteínas de Neoplasias/antagonistas & inibidores , Receptores Notch/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteínas ADAM/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Antineoplásicos/farmacologia , Trióxido de Arsênio/farmacologia , Neoplasias Encefálicas/irrigação sanguínea , Hipóxia Celular , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Glioblastoma/irrigação sanguínea , Humanos , Proteínas Inibidoras de Diferenciação/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , MicroRNAs/farmacologia , Microvasos , Terapia de Alvo Molecular/métodos , Netrina-1/antagonistas & inibidores , Niclosamida/farmacologia , Receptores Notch/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Resveratrol/farmacologia , Transdução de Sinais/genética , Tretinoína/farmacologia
7.
Med Hypotheses ; 129: 109241, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31371076

RESUMO

Oral Squamous Cell Carcinoma (OSCC) is one of the major causes of cancer related deaths worldwide. Presence of chemoresistant cancer stem cells is the major reason behind metastasis, tumor relapse and treatment resistance in OSCC. STAT 3 signalling plays a key role in survival of cancer stem cells (CSC's), Epithelial Mesenchymal Transition (EMT) mediated metastasis in OSCC. CD 133 is the surface marker for identification of cancer stem cells. In the present study we hypothesise the selective targeting of CSC's using CD 133 mediated delivery of STAT 3 inhibitor, Niclosamide to specifically target CSC's and Non CSC's.


Assuntos
Antígeno AC133/química , Carcinoma de Células Escamosas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Neoplasias Bucais/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Niclosamida/administração & dosagem , Fator de Transcrição STAT3/antagonistas & inibidores , Apoptose , Portadores de Fármacos , Transição Epitelial-Mesenquimal , Humanos , Modelos Teóricos , Recidiva Local de Neoplasia , Transdução de Sinais
8.
Trans R Soc Trop Med Hyg ; 113(1): 1-3, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31222345

RESUMO

A paper published in 1990 by Webbe and El Hag described the progress being made in the control of schistosomiasis with the introduction of a new medicine 'Praziquantel' to treat infected individuals, and the use of a molluscicide 'niclosamide', with which to kill the intermediate host snails. Almost 30 years from the date of publication, the situation in Egypt and indeed globally has changed out of all recognition. Almost every country in Africa has a school health programme to deworm children, each country has a national plan which includes school health, and praziquantel is now donated through the World Health Organization for countries to treat school aged children to protect them from the serious consequences of chronic schistosomiasis. As the socio-economic status in Africa improves the chances seem good for elimination of schistosomiasis as a public health problem in most areas in Africa.


Assuntos
Anti-Helmínticos/uso terapêutico , Niclosamida/farmacologia , Praziquantel/uso terapêutico , Saúde Pública , Schistosoma/efeitos dos fármacos , Esquistossomose/prevenção & controle , Caramujos/efeitos dos fármacos , África , Animais , Anti-Helmínticos/farmacologia , Criança , Vetores de Doenças , Egito , Humanos , Cooperação Internacional , Moluscocidas/farmacologia , Praziquantel/farmacologia , Esquistossomose/tratamento farmacológico , Esquistossomose/transmissão , Serviços de Saúde Escolar
9.
BMC Vet Res ; 15(1): 210, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234851

RESUMO

BACKGROUND: Oxyclozanide is an anthelmintic drug that is widely used to treat fasciolosis. However, the pharmacokinetics of oxyclozanide in cattle are not yet clearly understood. The present study was designed to develop a sensitive method to determine oxyclozanide levels in cattle plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and to study its pharmacokinetics for application in cattle. RESULTS: A simple and rapid HPLC-MS/MS analytical method was established and validated to quantify oxyclozanide levels in cattle plasma using niclosamide as the internal standard (IS) in negative ion mode. Chromatographic separation of the analytes was achieved using a C18 analytical column (75 × 4.6 mm, 2.7 µm) at 30 °C. The mobile phase comprised 0.01% v/v acetic acid (HOAc) diluted in water:acetonitrile (MeCN) (90:10% v/v) and 5 mM ammonium formate in methanol (MeOH):MeCN (75:25, v/v) at a 10:90 ratio (v/v) and was delivered at a flow rate of 0.4 mL min- 1. A good linear response across the concentration range of 0.02048-25.600 µg/mL was achieved (r2 = 0.994). The method was validated with respect to linearity, matrix effect, accuracy, precision, recovery and stability. The lower limit of quantification (LLOQ) was 0.020 µg/mL, and the extraction recovery was > 98% for oxyclozanide. The inter- and intra-day accuracy and precision of the method showed the relative standard deviation (RSD) less than 10%. The method was successfully applied to an assessment of the pharmacokinetics of oxyclozanide in cattle plasma. In healthy cattle, a single oral dose of an oxyclozanide suspension followed the one-compartment model, with a half-life (T1/2) of 64.40 ± 30.18 h, a plasma clearance rate (CL/F) of 11.426 ± 2.442 mL/h/kg, and an average area under the curve (AUC) of 965.608 ± 220.097 h*µg/mL. The peak concentration (Cmax) was 15.870 ± 2.855 µg/mL, which occurred at a peak time (Tmax) = 22.032 ± 3.343 h. CONCLUSIONS: A reliable, accurate HPLC-MS/MS analytical method was established in our study and successful applied to study the pharmacokinetics of oxyclozanide in cattle plasma. These results will be useful for further evaluations of the pharmacokinetic properties of oxyclozanide or for monitoring therapeutic drugs in animals.


Assuntos
Antiplatelmínticos/farmacocinética , Bovinos/metabolismo , Cromatografia Líquida de Alta Pressão/veterinária , Oxiclozanida/farmacocinética , Espectrometria de Massas em Tandem/veterinária , Animais , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Masculino , Niclosamida/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos
10.
Prensa méd. argent ; 105(5): 309-316, jun 2019. tab, fig
Artigo em Inglês | LILACS, BINACIS | ID: biblio-1024643

RESUMO

Ulcerative colitis is an idiopathic chronic inflammatory disease of the colon for which a lot of treatment modalities are present. However, significant side effects are associated with them, and there is a need for a search for other tretment options. This study was aimed to assess the contribution of niclosamide in experimentally established colitis in rats. Animals were categorized into 5 groups; the control group undergoes no induction of UC, colitis group in which UC was induced, and animals receive no treatment, the niclosamide group that received niclosamide and sulfasalazine group that received sulfasalazine. Each group was composed of 10 animals. After the completion of a one-month period of the experiment animals were sacrificed and the following meausres were done: the weight of the colon, determination of the area of mucosal damage by mm2, histological scoring after hematoxylin and eosin stain together with MAC score and immunohistochemistry of IL-6, TNF-alpha, MPO, MDA, CD62, and ICAM1. The results of the current study revealed that Nicosamide was able to reduce the area of mucosal damage, colon weight, histological and Mac scores and immunohistochemical scores of inflammatory and oxidative markers, significantly when contrasted to a group of colitis (P< 0.05). It has been concluded that Niclosamide was proved to have a significant effect as an adjuvant mode of therapy for colitis through its, anti-inflamatory and anti-oxidant effects (AU)


Assuntos
Ratos , Sulfassalazina/uso terapêutico , Colite Ulcerativa/terapia , Efeito Secundário , Avaliação de Resultado de Intervenções Terapêuticas , Epidemiologia Experimental , Tempo para o Tratamento , Abate de Animais , Niclosamida/uso terapêutico
11.
Tuberculosis (Edinb) ; 116S: S28-S33, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31080089

RESUMO

The human immunodeficiency virus (HIV) pandemic is driving the re-emergence of tuberculosis (TB) as a global health threat, both by increasing the susceptibility of HIV-infected people to infection with Mycobacterium tuberculosis (Mtb), and increasing the rate of emergence of drug-resistant Mtb. There are several other clinical challenges for treatment of co-infected patients including: expense, pill burden, toxicity, and malabsorption that further necessitate the search for new drugs that may be effective against both pathogens simultaneously. The anti-helminthic niclosamide has been shown to have activity against a laboratory strain of Mtb in liquid culture while bacteriostatic activity against non-replicating M. abscessus was also recently described. Here we extend these findings to further demonstrate that niclosamide inhibits mycobacterial growth in infected human macrophages and mediates potent bacteriostatic activity against the virulent Mtb Beijing strain. Importantly, we provide the first evidence that niclosamide inhibits HIV replication in human macrophages and Jurkat T cells through post-integration effects on pro-virus transcription. The dual antiviral and anti-mycobacterial activity was further observed in an in vitro model of HIV and Mtb co-infection using human primary monocyte-derived macrophages. These results support further investigation of niclosamide and derivatives as anti-retroviral/anti-mycobacterial agents that may reduce clinical challenges associated with multi-drug regimens and drug resistance.


Assuntos
Fármacos Anti-HIV/farmacologia , Antituberculosos/farmacologia , HIV-1/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Niclosamida/farmacologia , Linfócitos T/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Coinfecção , HIV-1/crescimento & desenvolvimento , Humanos , Células Jurkat , Macrófagos/microbiologia , Macrófagos/virologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/patogenicidade , Linfócitos T/virologia , Virulência
12.
Cells ; 8(5)2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035565

RESUMO

Nucleated teleost red blood cells (RBCs) are known to express molecules from the major histocompatibility complex and peptide-generating processes such as autophagy and proteasomes, but the role of RBCs in antigen presentation of viruses have not been studied yet. In this study, RBCs exposed ex vivo to viral hemorrhagic septicemia virus (VHSV) were evaluated by means of transcriptomic and proteomic approaches. Genes and proteins related to antigen presentation molecules, proteasome degradation, and autophagy were up-regulated. VHSV induced accumulation of ubiquitinated proteins in ex vivo VHSV-exposed RBCs and showed at the same time a decrease of proteasome activity. Furthermore, induction of autophagy was detected by evaluating LC3 protein levels. Sequestosome-1/p62 underwent degradation early after VHSV exposure, and it may be a link between ubiquitination and autophagy activation. Inhibition of autophagosome degradation with niclosamide resulted in intracellular detection of N protein of VHSV (NVHSV) and p62 accumulation. In addition, antigen presentation cell markers, such as major histocompatibility complex (MHC) class I & II, CD83, and CD86, increased at the transcriptional and translational level in rainbow trout RBCs exposed to VHSV. In summary, we show that nucleated rainbow trout RBCs can degrade VHSV while displaying an antigen-presenting cell (APC)-like profile.


Assuntos
Apresentação do Antígeno/imunologia , Eritroblastos/imunologia , Eritroblastos/virologia , Septicemia Hemorrágica Viral/imunologia , Septicemia Hemorrágica Viral/virologia , Novirhabdovirus/imunologia , Oncorhynchus mykiss/imunologia , Oncorhynchus mykiss/virologia , Animais , Apresentação do Antígeno/genética , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Antígenos CD/análise , Antígenos CD/imunologia , Autofagossomos/efeitos dos fármacos , Autofagossomos/imunologia , Autofagossomos/virologia , Autofagia/efeitos dos fármacos , Autofagia/imunologia , Antígeno B7-2/análise , Antígeno B7-2/imunologia , Biomarcadores/análise , Septicemia Hemorrágica Viral/genética , Antígenos de Histocompatibilidade Classe I/análise , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/análise , Antígenos de Histocompatibilidade Classe II/imunologia , Imunoglobulinas/análise , Imunoglobulinas/imunologia , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/imunologia , Niclosamida/farmacologia , Proteínas do Nucleocapsídeo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteômica , Proteína Sequestossoma-1/metabolismo
13.
Eur J Pharm Biopharm ; 141: 58-69, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078739

RESUMO

Drug repositioning may be defined as a process when new biological effects for known drugs are identified, leading to recommendations for new therapeutic applications. Niclosamide, present in the Model List of Essential Medicines, from the World Health Organization, has been used since the 1960s for tapeworm infection. Several preclinical studies have been shown its impressive anticancer effects, which led to clinical trials for colon and prostate cancer. Despite high expectations, proof of efficacy and safety are still required, which are associated with diverse biopharmaceutical challenges, such as the physicochemical properties of the drug and its oral absorption, and their relationship with clinical outcomes. Nanostructured systems are innovative drug delivery strategies, which may provide interesting pharmaceutical advantages for this candidate. The aim of this review is to discuss challenges involving niclosamide repositioning for cancer diseases, and the opportunities of therapeutic benefits from nanosctrutured system formulations containing this compound.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Niclosamida/administração & dosagem , Niclosamida/química , Animais , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Humanos
14.
Eur J Pharmacol ; 853: 229-235, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30935895

RESUMO

Our previous study found that the anthelmintic drug niclosamide relaxed the constricted arteries and inhibited proliferation and migration of vascular smooth muscle cells. Here, we investigated the effect of niclosamide ethanolamine (NEN) on trachea function and the proliferation and migration of trachea smooth muscle cells. Isometric tension of trachea was recorded by multi-channel myograph system. The cell proliferation was detected by using BrdU cell proliferation assay. The cell migration ability was evaluated by using scratch assay. The protein level was measured by using western blot technique. Acute treatment with NEN dose-dependently relaxed acetylcholine chloride (Ach)- and High K+ physiological salt solution (KPSS)-induced constriction of mice trachea. Pre-treatment with NEN inhibited Ach- and KPSS-induced constriction of mice trachea. NEN treatment inhibited proliferation of human bronchial smooth muscle cells (HBSMCs), inhibited migration of HBSMCs and rat primary trachea smooth muscle cells. NEN treatment activated adenosine monophosphate activated protein kinase (AMPK) activity and inhibited signal transducer and activator of transcription 3 (STAT3) activity in HBSMCs. In conclusion, niclosamide ethanolamine induces trachea relaxation and inhibits proliferation and migration of trachea smooth muscle cells, indicating that niclosamide might be a potential drug for chronic asthma treatment.


Assuntos
Movimento Celular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Niclosamida/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Acetilcolina/farmacologia , Animais , Brônquios/citologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Potássio/farmacologia , Ratos , Traqueia/citologia , Vasoconstrição/efeitos dos fármacos
15.
Biochem J ; 476(5): 779-781, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842311

RESUMO

Colorectal cancer is one of the most common forms of cancer in the world, with more than half a million new cases annually. Amongst the most promising new therapies, niclosamide-an FDA-approved drug for treating tapeworm infections-is being assessed in a stage II clinical trial for the treatment of metastatic colorectal cancer. Despite this advanced stage of research, the underlying mechanisms behind its actions remain uncertain. Niclosamide reduces the growth of colorectal cancer cells by targeting several intracellular signalling pathways, including the ß-catenin-dependent WNT signalling pathway. In a recent paper published in the Biochemical Journal [Biochem. J. (2019) 476, 535-546], Wang and colleagues revealed that niclosamide down-regulates ß-catenin-dependent WNT signalling in colorectal cancer cells by degrading components of the pathway via autophagy. Autophagy is a catabolic process in which cellular macromolecules and organelles are recycled to their monomer units. This finding provides a further understanding of the actions of niclosamide upon colorectal cancer cells and may yield improved future treatment models for colorectal cancer patients.


Assuntos
/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Niclosamida/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Metástase Neoplásica
16.
Artigo em Inglês | MEDLINE | ID: mdl-30917988

RESUMO

There is an urgent need for new therapies to overcome antimicrobial resistance especially in Gram-negative bacilli (GNB). Repurposing old U.S. Food and Drug Administration-approved drugs as complementary agents to existing antibiotics in a synergistic combination presents an attractive strategy. Here, we demonstrate that the anthelmintic drug niclosamide selectively synergized with the lipopeptide antibiotic colistin against colistin-susceptible but more importantly against colistin-resistant GNB, including clinical isolates that harbor the mcr-1 gene. Breakpoints for colistin susceptibility in resistant Gram-negative bacilli were reached in the presence of 1 µg/ml (3 µM) niclosamide. Reversal of colistin resistance was also observed in combinations of niclosamide and polymyxin B. Enhanced bacterial killing was evident for the combination, in comparison to colistin monotherapy, against resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae Accumulating evidence in the literature, along with our results, strongly suggests the potential for the combination of niclosamide and colistin to treat colistin-resistant Gram-negative bacillary infections. Our finding is significant since colistin is an antibiotic of last resort for multidrug-resistant Gram-negative bacterial infections that are nonresponsive to conventional treatments. With the recent global dissemination of plasmid-encoded colistin resistance, the addition of niclosamide to colistin therapy may hold the key to overcome colistin resistance.


Assuntos
Anti-Helmínticos/farmacologia , Antibacterianos/farmacologia , Colistina/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Niclosamida/farmacologia , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Testes de Sensibilidade Microbiana/métodos
17.
Carbohydr Polym ; 212: 252-259, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30832855

RESUMO

Niclosamide, previously used as an anthelmintic drug is currently being repurposed for its anticancer activity. Niclosamide is a brick like biopharmaceutical classification system (BCS) class II drug with poor aqueous solubility and dissolution consequently leading to low bioavailability. By considering the physicochemical properties and geometry of niclosamide, inclusion complex with cyclodextrin was prepared by freeze drying method and characterized using FT-IR, DSC, PXRD, and 1HNMR. In silico molecular modeling study was performed to study the possible interactions between niclosamide and cyclodextrin. The anticancer activity of niclosamide formulation was evaluated through in vitro cell cytotoxicity study using various cancer cell lines. The potential of niclosamide complex for improvement of the bioavailability was evaluated in male BALB/c mice. In vitro cytotoxicity studies indicated significantly higher cytotoxicity at lower concentrations and the pharmacokinetic studies showed significant improvement in Cmax and Tmax of niclosamide from cyclodextrin complex in comparison to pure niclosamide alone.


Assuntos
Antineoplásicos/síntese química , Ciclodextrinas/síntese química , Composição de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Niclosamida/síntese química , Animais , Anticestoides/síntese química , Anticestoides/metabolismo , Antineoplásicos/metabolismo , Ciclodextrinas/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Niclosamida/metabolismo
18.
Cells ; 8(3)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875964

RESUMO

Autophagy is a highly- evolutionarily-conserved catabolic pathway activated by various cellular stresses. Recently, non-canonical autophagy (NCA), which does not require all of the ATG proteins to form autophagosome or autophagosome-like structures, has been found in various conditions. Moreover, mounting evidence has indicated that non-canonical LC3 lipidation (NCLL) may reflect NCA. We and others have reported that niclosamide (Nic), an anti-helminthic drug approved by the Food and Drug Administration, could induce canonical autophagy via a feedback downregulation of mTOR complex 1. In this study, we found that Nic could also induce NCLL, which is independent of the ULK1 complex and Beclin 1 complex, but dependent on ubiquitin-like conjugation systems. Although bafilomycin A1 and concanamycin A, two known V-ATPase inhibitors, significantly inhibited Nic-induced NCLL, Nic-induced NCLL was demonstrated to be independent of V-ATPase. In addition, the Golgi complex and vimentin were involved in Nic-induced NCLL, which might be a platform or membrane source for Nic-induced LC3-positive structures. These results would be helpful to broaden our understanding of the working mechanisms of Nic and evaluate its pharmacological activities in diseases.


Assuntos
Lipídeos/química , Proteínas Associadas aos Microtúbulos/metabolismo , Niclosamida/farmacologia , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Cálcio/metabolismo , Embrião de Mamíferos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrolídeos/farmacologia , Camundongos , Ubiquitina/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Vimentina/metabolismo
19.
Plant Physiol ; 180(1): 480-496, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30737267

RESUMO

Many signal perception mechanisms are connected to Ca2+-based second messenger signaling to modulate specific cellular responses. The well-characterized plant hormone auxin elicits a very rapid Ca2+ signal. However, the cellular targets of auxin-induced Ca2+ are largely unknown. Here, we screened a biologically annotated chemical library for inhibitors of auxin-induced Ca2+ entry in plant cell suspensions to better understand the molecular mechanism of auxin-induced Ca2+ and to explore the physiological relevance of Ca2+ in auxin signal transduction. Using this approach, we defined a set of diverse, small molecules that interfere with auxin-induced Ca2+ entry. Based on annotated biological activities of the hit molecules, we found that auxin-induced Ca2+ signaling is, among others, highly sensitive to disruption of membrane proton gradients and the mammalian Ca2+ channel inhibitor bepridil. Whereas protonophores nonselectively inhibited auxin-induced and osmotic stress-induced Ca2+ signals, bepridil specifically inhibited auxin-induced Ca2+ We found evidence that bepridil severely alters vacuolar morphology and antagonized auxin-induced vacuolar remodeling. Further exploration of this plant-tailored collection of inhibitors will lead to a better understanding of auxin-induced Ca2+ entry and its relevance for auxin responses.


Assuntos
Arabidopsis/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Ácidos Indolacéticos/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Tabaco/efeitos dos fármacos , Ácido 2,4-Diclorofenoxiacético/farmacologia , Arabidopsis/genética , Proteínas de Bactérias/genética , Bepridil/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/fisiologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Fenamatos/farmacologia , Ácidos Indolacéticos/antagonistas & inibidores , Medições Luminescentes , Proteínas Luminescentes/genética , Niclosamida/farmacologia , Células Vegetais/efeitos dos fármacos , Células Vegetais/metabolismo , Reguladores de Crescimento de Planta/metabolismo , Raízes de Plantas/efeitos dos fármacos , Plantas Geneticamente Modificadas , Tabaco/genética , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo
20.
Aquat Toxicol ; 211: 235-252, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30770146

RESUMO

The invasion of the Laurentian Great Lakes of North America by sea lampreys (Petromyzon marinus) in the early 20th century contributed to the depletion of commercial, recreational and culturally important fish populations, devastating the economies of communities that relied on the fishery. Sea lamprey populations were subsequently controlled using an aggressive integrated pest-management program which employed barriers and traps to prevent sea lamprey from migrating to their spawning grounds and the use of the piscicides (lampricides) 3-trifluoromethyl-4-nitrophenol (TFM) and niclosamide to eliminate larval sea lampreys from their nursery streams. Although sea lampreys have not been eradicated from the Great Lakes, populations have been suppressed to less than 10% of their peak numbers in the mid-1900s. The ongoing use of lampricides provides the foundation for sea lamprey control in the Great Lakes, one of the most successful invasive species control programs in the world. Yet, significant gaps remain in our understanding of how lampricides are taken-up and handled by sea lampreys, how lampricides exert their toxic effects, and how they adversely affect non-target invertebrate and vertebrates species. In this review we examine what has been learned about the uptake, handling and elimination, and the mode of TFM and niclosamide toxicity in lampreys and in non-target animals, particularly in the last 10 years. It is now clear that the mode of TFM toxicity is the same in non-target fishes and lampreys, in which TFM interferes with oxidative phosphorylation by the mitochondria leading to decreased ATP production. Vulnerability to TFM is related to abiotic factors such as water pH and alkalinity, which we propose changes the relative amounts of the bioavailable un-ionized form of TFM in the gill microenvironment. Niclosamide, which is also a molluscicide used to control snails in areas prone to schistosomiasis infections of humans, also likely works by uncoupling oxidative phosphorylation, but less is known about other aspects of its toxicology. The effects of TFM include reductions in energy stores, particularly glycogen and high energy phosphagens. However, non-target fishes readily recover from sub-lethal TFM exposure as demonstrated by the rapid restoration of energy stores and clearance of TFM. Although both TFM and niclosamide are non-persistent in the environment and critical for sea lamprey control, increasing public and institutional concerns about pesticides in the environment makes it imperative to explore other means of sea lamprey control. Accordingly, we also address possible "next-generation" strategies of sea lamprey control including genetic tools such as RNA interference and CRISPR-Cas9 to impair critical physiological processes (e.g. reproduction, digestion, metamorphosis) in lamprey, and the use of green chemistry to develop more environmentally benign chemical methods of sea lamprey control.


Assuntos
Espécies Introduzidas , Niclosamida/toxicidade , Nitrofenóis/toxicidade , Praguicidas/toxicidade , Petromyzon/crescimento & desenvolvimento , Poluentes Químicos da Água/toxicidade , Animais , Humanos , Lagos/química , Larva/efeitos dos fármacos , América do Norte , Fosforilação Oxidativa
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