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1.
Food Chem ; 366: 130563, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34289441

RESUMO

Herein, a simple, low-cost, environment-friendly strategy was proposed to prepare the composite of three-dimensional hierarchical porous carbon and chitosan, which was applied to modify the glass carbon electrode to fabricate an electrochemical sensor for the determination of niclosamide. The three-dimensional porous carbon with interconnected conductive network, high surface area, and self-generated oxygen-containing functional groups was prepared by salt-templating method with glucose as carbon source and eutectic mixture of LiBr/KBr as both activating and pore-forming agent. During the subsequent ultrasonic process, chitosan with excellent filming property, strong adsorption ability, and good dispersibility was successfully decorated on the obtained porous carbon to further enhance the determination performance of niclosamide. Benefitting from the multi-functional integration of three-dimensional hierarchical porous carbon and chitosan, the fabricated sensor presented a low limit of detection (6.7 nM) in the linear concentration range from 0.01 to 10 µM. Moreover, the fabricated sensor could show good repeatability, reproducibility, stability, and selectivity. Most important, the decent practicability for the detection of niclosamide was obtained in different food samples with low relative standard deviation and satisfactory recoveries. This work provides a very valuable reference for the sensitive determination of niclosamide in food samples.


Assuntos
Quitosana , Carbono , Técnicas Eletroquímicas , Eletrodos , Niclosamida , Porosidade , Reprodutibilidade dos Testes
2.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 33(5): 527-530, 2021 Jun 18.
Artigo em Chinês | MEDLINE | ID: mdl-34791854

RESUMO

OBJECTIVE: To investigate the effectiveness and cost of 50% and 80% wettable powder of niclosamide ethanolamine salt (NESWP) and 26% metaldehyde and niclosamide suspension concentrate (MNSC) in hilly schistosomiasis-endemic regions, so as to provide insights into the selection of chemical molluscicides in hilly regions. METHODS: In September 2020, a wasteland in Guanshanqiao Village, Yanrui Township, Yushan County of Jiangxi Province was selected as the experimental region, which was sectioned into five blocks and defined as four experimental groups (A1, A2, B, C) and a blank control group (D). 80% NESWP were given at doses of 1 g/m2 and 1.5 g/m2 in groups A1 and A2 using the spraying method, 50% NESWP was given at a dose of 2 g/m2 in Group B using the spraying method, and 26% MNSC was at a dose of 4 g/m2 in Group C using the spraying method, while no chemical treatment was given in Group D. Snail survey was performed using a systematic sampling method before chemical treatment and 1, 3, 7 d and 15 d post-treatment to examine the molluscicidal effect, and all molluscicidal costs were estimated to calculate the cost of chemical treatment per 1 m2 and the cost of the reduction in the mean density of living snails per 1%. RESULTS: The highest mortality of snails was 78.95% and the lowest density of living snails was 0.2388 snails/0.1 m2 in the experimental groups within 7 d of chemical treatment, and the highest mortality of snails was 94.74% and the lowest density of living snails was 0.058 0 snails/0.1 m2 7 d post-treatment. There were no significant differences in the snail mortality among the A1, A2, B and C groups 1 (χ2 = 2.250, P > 0.05), 3 (χ2 = 1.779, P > 0.05) or 15 d post-treatment (χ2 = 2.286, P > 0.05), while a significant difference was detected in the snail mortality among the four groups 7 d post-treatment (χ2 = 7.990, P = 0.046). In addition, there were no significant differences in the snail mortality between A1 and A2 groups 1 (χ2 = 0.724, P > 0.05), 3 (χ2 = 0.584, P > 0.05), 7 (χ2 = 0.400, P > 0.05) or 15 d post-treatment (χ2 = 0.251, P > 0.05). The costs of chemical treatment per 1 m2 were 0.58, 0.60, 0.64 Yuan and 0.73 Yuan in groups A1, A2, B and C, and the costs of the mean density of living snail per 1% reduction were 19.29, 20.44, 21.68 Yuan and 23.53 Yuan in groups A1, A2, B and C, respectively. CONCLUSIONS: 80% NESWP shows a high molluscicidal efficacy and low cost in hilly schistosomiasis-endemic regions.


Assuntos
Moluscocidas , Esquistossomose , China/epidemiologia , Custos e Análise de Custo , Etanolamina , Humanos , Moluscocidas/farmacologia , Niclosamida/farmacologia , Esquistossomose/tratamento farmacológico , Esquistossomose/epidemiologia , Esquistossomose/prevenção & controle
3.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638761

RESUMO

Niclosamide is an oral anthelmintic drug, approved for use against tapeworm infections. Recent studies suggest however that niclosamide may have broader clinical applications in cancers, spurring increased interest in the functions and mechanisms of niclosamide. Previously, we reported that niclosamide targets a metabolic vulnerability in p53-deficient tumours, providing a basis for patient stratification and personalised treatment strategies. In the present study, we functionally characterised the contribution of the aniline 4'-NO2 group on niclosamide to its cellular activities. We demonstrated that niclosamide induces genome-wide DNA damage that is mechanistically uncoupled from its antitumour effects mediated through mitochondrial uncoupling. Elimination of the nitro group in ND-Nic analogue significantly reduced γH2AX signals and DNA breaks while preserving its antitumour mechanism mediated through a calcium signalling pathway and arachidonic acid metabolism. Lipidomics profiling further revealed that ND-Nic-treated cells retained a metabolite profile characteristic of niclosamide-treated cells. Notably, quantitative scoring of drug sensitivity suggests that elimination of its nitro group enhanced the target selectivity of niclosamide against p53 deficiency. Importantly, the results also raise concern that niclosamide may impose a pleiotropic genotoxic effect, which limits its clinical efficacy and warrants further investigation into alternative drug analogues that may ameliorate any potential unwanted side effects.


Assuntos
Dano ao DNA , Mitocôndrias/metabolismo , Neoplasias , Niclosamida , Células HCT116 , Humanos , Mitocôndrias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Niclosamida/análogos & derivados , Niclosamida/farmacologia
4.
Washington, D.C; PAHO; Sept. 7, 2021. 60 p.
Monografia em Inglês | BIGG - guias GRADE | ID: biblio-1291054

RESUMO

The larval stage of the parasite Taenia solium can encyst in the central nervous system causing neurocysticercosis, which is the main cause of acquired epilepsy in the countries in which the parasite is endemic. Endemic areas are those with the presence (or likely presence) of the full life cycle of Taenia solium. The parasite is most prevalent in poor and vulnerable communities in which pigs roam free, open defecation is practiced, basic sanitation is deficient, and health education is absent or limited. Several tools are available for the control of Taenia solium. Preventive chemotherapy for Taenia solium taeniasis, which is directed at the adult tapeworm, is one of them. Other tools focus on pig management, pig vaccination and treatment, sanitation and hygiene, and community education. Three potential drugs­niclosamide, praziquantel, and albendazole­have been considered for use for preventive chemotherapy in Taenia solium taeniasis control programs through mass drug administration or targeted chemotherapy. In this Guideline, we provide recommendations for preventive chemotherapy in Taenia solium-endemic areas using niclosamide, praziquantel, or albendazole, including at which dose and in which population groups. The development of this Guideline is based on the latest standard World Health Organization methods for guideline development, including the use of systematic search strategies, synthesis, quality assessment of the available evidence to support the recommendations, and participation of experts and stakeholders in the Guideline Development Group and External Review Group. The recommendations are intended for a wide audience, including policymakers and their expert advisers, and technical and program staff at governmental institutions and organizations involved in the planning, implementation, monitoring, and evaluation of preventive chemotherapy programs for the control of Taenia solium.


Assuntos
Humanos , Feminino , Gravidez , Criança , Adolescente , Teníase/tratamento farmacológico , Taenia solium/efeitos dos fármacos , Tratamento Farmacológico , Praziquantel/administração & dosagem , Teníase/complicações , Albendazol/administração & dosagem , Niclosamida/análogos & derivados
5.
Colloids Surf B Biointerfaces ; 208: 112063, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34482191

RESUMO

COVID-19 is a rapidly evolving emergency, which necessitates scientific community to come up with novel formulations that could find quick relief to the millions affected around the globe. Remdesivir being the only injectable drug by FDA for COVID-19, it initially showed promising results, however, later on failed to retain its claims, hence rejected by the WHO. Therefore, it is important to develop injectable formulation that are effective and affordable. Here in this work, we formulated poly ethylene glycol (PEG) coated bovine serum albumin (BSA) stabilized Niclosamide (NIC) nanoparticles (NPs) (∼BSA-NIC-PEG NPs) as an effective injectable formulation. Here, serum albumin mediated strategy was proposed as an effective strategy to specifically target SARS-CoV-2, the virus that causes COVID-19. The in-vitro results showed that the developed readily water dispersible formulation with a particle size <120 nm size were well stable even after 3 weeks. Even though the in-vitro studies showed promising results, the in-vivo pharmaco-kinetic (PK) study in rats demands the need of conducting further experiments to specifically target the SARS-CoV-2 in the virus infected model. We expect that this present formulation would be highly preferred for targeting hypoalbuminemia conditions, which was often reported in elderly COVID-19 patients. Such studies are on the way to summarize its potential applications in the near future.


Assuntos
COVID-19 , Nanopartículas , Idoso , Animais , Humanos , Niclosamida/farmacologia , Ratos , SARS-CoV-2 , Soroalbumina Bovina
6.
Eur J Pharm Sci ; 167: 105992, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517104

RESUMO

Triple negative breast cancer (TNBC) is the most dangerous subtype of breast cancer accompanying by unfavorable prognosis due to lack of specific therapeutic targets. Paclitaxel (PTX) is the first-line chemotherapeutic drug for TNBC and niclosamide (NLM) was identified as an inhibitor for TNBC and breast cancer stem cells (BCSCs). Intratumoral drug delivery system was a hopeful alternative for chemotherapeutic drug administration due to its targeting efficiency with lower systemic toxicity. Herein, an injectable PTX nanocrystals (PTX-NCs) and NLM nanocrystals (NLM-NCs) co-loaded PLGA-PEG-PLGA thermosensitive hydrogel (PNNCs-Ts Gel) was designed for TNBC intratumoral treatment. The final formulation realized high drug loading and appropriate particle size. PNNCs-Ts Gel displayed sustained drug release for up to 8 days in vitro. In vitro antitumor tests observed synergetic effects of combined therapy in terms of inhibiting cell proliferation and migration, inducing apoptosis. In vivo combined therapy presented a tumor growth inhibition rate about 68.8% and desired safety. Moreover, tumors after PNNCs-Ts Gel intratumoral injection possessed the lowest ratio of BCSCs, exhibiting this formulation had good ability in suppressing BCSCs and therefore could possibly prevent TNBC recurrence and metastasis. These results suggested that PNNCs-Ts Gel could be a promising strategy for TNBC treatment.


Assuntos
Antineoplásicos Fitogênicos , Nanopartículas , Neoplasias de Mama Triplo Negativas , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Hidrogéis/uso terapêutico , Niclosamida/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Washington, D.C.; PAHO; 2021-09-07.
em Inglês | PAHO-IRIS | ID: phr-54800

RESUMO

The larval stage of the parasite Taenia solium can encyst in the central nervous system causing neurocysticercosis, which is the main cause of acquired epilepsy in the countries in which the parasite is endemic. Endemic areas are those with the presence (or likely presence) of the full life cycle of Taenia solium. The parasite is most prevalent in poor and vulnerable communities in which pigs roam free, open defecation is practiced, basic sanitation is deficient, and health education is absent or limited. Several tools are available for the control of Taenia solium. Preventive chemotherapy for Taenia solium taeniasis, which is directed at the adult tapeworm, is one of them. Other tools focus on pig management, pig vaccination and treatment, sanitation and hygiene, and community education. Three potential drugs—niclosamide, praziquantel, and albendazole—have been considered for use for preventive chemotherapy in Taenia solium taeniasis control programs through mass drug administration or targeted chemotherapy. In this Guideline, we provide recommendations for preventive chemotherapy in Taenia solium-endemic areas using niclosamide, praziquantel, or albendazole, including at which dose and in which population groups. The development of this Guideline is based on the latest standard World Health Organization methods for guideline development, including the use of systematic search strategies, synthesis, quality assessment of the available evidence to support the recommendations, and participation of experts and stakeholders in the Guideline Development Group and External Review Group. The recommendations are intended for a wide audience, including policymakers and their expert advisers, and technical and program staff at governmental institutions and organizations involved in the planning, implementation, monitoring, and evaluation of preventive chemotherapy programs for the control of Taenia solium.


Assuntos
Doenças Transmissíveis , Taenia solium , Parasitos , Niclosamida , Praziquantel , Terapia com Helmintos , Neurocisticercose
8.
J Biosci Bioeng ; 132(6): 640-650, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34429248

RESUMO

Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron loss in the brain and spinal cord; however, its etiology is unknown, and no curative treatment exists. TAR DNA-binding protein 43 (TDP-43), encoded by TARDBP, is a genetic mutation observed in 2-5% of familial ALS, and TDP is known to be mislocalized in the cytoplasm. This study aimed to identify compounds that inhibited the nuclear to cytoplasmic localization of TDP-43 in human induced pluripotent stem (iPS) cells-derived neurons. TDP-43 transgenic human iPS cells were constructed, differentiated into motor neurons, and then treated with MG-132 and sodium arsenite (stressors) to induce nuclear to cytoplasmic localization of TDP-43. STAT3 inhibitors, such as niclosamide, prevented TDP-43 mislocalization and degraded TDP-43 aggregates, and attenuated morphological changes under stress. Furthermore, niclosamide activated mitophagy via the PINK1-parkin-ubiquitin pathway. These findings suggest niclosamide may be a therapeutic candidate for ALS.


Assuntos
Esclerose Amiotrófica Lateral , Niclosamida , Esclerose Amiotrófica Lateral/tratamento farmacológico , Proteínas de Ligação a DNA/genética , Humanos , Mitofagia , Neurônios Motores , Niclosamida/farmacologia
9.
Molecules ; 26(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209118

RESUMO

Redox-active drugs are the mainstay of parasite chemotherapy. To assess their repurposing potential for eumycetoma, we have tested a set of nitroheterocycles and peroxides in vitro against two isolates of Madurella mycetomatis, the main causative agent of eumycetoma in Sudan. All the tested compounds were inactive except for niclosamide, which had minimal inhibitory concentrations of around 1 µg/mL. Further tests with niclosamide and niclosamide ethanolamine demonstrated in vitro activity not only against M. mycetomatis but also against Actinomadura spp., causative agents of actinomycetoma, with minimal inhibitory concentrations below 1 µg/mL. The experimental compound MMV665807, a related salicylanilide without a nitro group, was as active as niclosamide, indicating that the antimycetomal action of niclosamide is independent of its redox chemistry (which is in agreement with the complete lack of activity in all other nitroheterocyclic drugs tested). Based on these results, we propose to further evaluate the salicylanilides, niclosamidein particular, as drug repurposing candidates for mycetoma.


Assuntos
Actinomadura/crescimento & desenvolvimento , Madurella/crescimento & desenvolvimento , Micetoma , Niclosamida/farmacologia , Animais , Humanos , Micetoma/tratamento farmacológico , Micetoma/microbiologia
10.
PLoS Pathog ; 17(7): e1009706, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34252168

RESUMO

Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/virologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Internalização do Vírus/efeitos dos fármacos , Cloreto de Amônio/farmacologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/fisiologia , Animais , Antivirais/administração & dosagem , Antivirais/farmacologia , Linhagem Celular , Chlorocebus aethiops , Cloroquina/farmacologia , Clatrina/metabolismo , Sinergismo Farmacológico , Endocitose/efeitos dos fármacos , Endocitose/fisiologia , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Hidroxicloroquina/administração & dosagem , Macrolídeos/farmacologia , Niclosamida/administração & dosagem , Niclosamida/farmacologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/fisiologia , Células Vero
11.
Artigo em Inglês | MEDLINE | ID: mdl-34332199

RESUMO

Niclosamide, which is an anti-tapeworm drug, was developed in 1958. However, recent studies have demonstrated the antiviral effects of niclosamide against the SARS-CoV-2 virus, which causes COVID-19. In this study, we developed and validated a quantitative analysis method for the determination of niclosamide in rat and dog plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and used this method for pharmacokinetic studies. Biological samples were prepared using the protein precipitation method with acetonitrile. Ibuprofen was used as an internal standard. The mobile phase used to quantify niclosamide in rat or dog plasma consisted of 10 mM ammonium formate in distilled water-acetonitrile (30:70, v/v) or 5 mM ammonium acetate-methanol (30:70, v/v). An XDB-phenyl column (5 µm, 2.1 × 50 mm) and a Kinetex® C18 column (5 µm, 2.1 × 500 mm) were used as reverse-phase liquid chromatography columns for rat and dog plasma analyses, respectively. Niclosamide and ibuprofen were detected under multiple reaction monitoring conditions using the electrospray ionization interface running in the negative ionization mode. Niclosamide presented linearity in the concentration ranges of 1-3000 ng/mL (r = 0.9967) and 1-1000 ng/mL (r = 0.9941) in rat and dog plasma, respectively. The intra- and inter-day precision values were < 7.40% and < 6.35%, respectively, for rat plasma, and < 3.95% and < 4.01%, respectively, for dog plasma. The intra- and inter-day accuracy values were < 4.59% and < 6.63%, respectively, for rat plasma, and < 12.1% and < 10.9%, respectively, for dog plasma. In addition, the recoveries of niclosamide ranged between 87.8 and 99.6% and 102-104% for rat and dog plasma, respectively. Niclosamide was stable during storage under various conditions (three freeze-thaw cycles, 6 h at room temperature, long-term, and processed samples). A reliable LC-MS/MS method for niclosamide detection was successfully used to perform pharmacokinetic studies in rats and dogs. Niclosamide presented dose-independent pharmacokinetics in the dose range of 0.3-3 mg/kg after intravenous administration, and drug exposure in rats and dogs after oral administration was very low. Additionally, niclosamide presented high plasma protein binding (>99.8%) and low metabolic stability. These results can be helpful for further developing and understanding the pharmacokinetic characteristics of niclosamide to expand its clinical use.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Niclosamida/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Cães , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
12.
Nat Commun ; 12(1): 3818, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155207

RESUMO

Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC50 values of 136.7, 7.67, 0.11, and 0.13 µM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19.


Assuntos
COVID-19/metabolismo , COVID-19/virologia , SARS-CoV-2/metabolismo , Animais , Antinematódeos/farmacologia , Autofagossomos/metabolismo , Autofagia , Proteínas Relacionadas à Autofagia/metabolismo , COVID-19/tratamento farmacológico , COVID-19/patologia , Células Cultivadas , Chlorocebus aethiops , Cricetinae , Modelos Animais de Doenças , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Metaboloma , Niclosamida/farmacologia , Organoides , SARS-CoV-2/isolamento & purificação , Espermidina/farmacologia , Espermina/farmacologia
13.
Int J Pharm ; 605: 120819, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34166727

RESUMO

Targeted delivery of chemotherapeutic agents is considered a prominent strategy for the treatment of cancer due to its site-specific delivery, augmented penetration, bioavailability, and improved therapeutic efficiency. In the present study, we employed UniPR126 as a carrier in a mixed nanomicellar delivery system to target and deliver anticancer drug NIC specifically to cancer cells via EphA2 receptors as these receptors are overexpressed in cancer cells but not in normal cells. The specificity of the carrier was confirmed from the significant enhancement in the uptake of coumarin-6 loaded mixed nanomicelle by EphA2 highly expressed PC-3 cells compared to EphA2 low expressed H4 cells. Further, niclosamide-loaded lithocholic acid tryptophan conjugate-based mixed nanomicelle has shown significant synergistic cytotoxicity in PC-3 but not in H4 cells. In vivo anticancer efficacy data in PC-3 xenograft revealed a significant reduction in the tumor volume (66.87%) with niclosamide-loaded lithocholic acid tryptophan conjugate nanomicelle, where pure niclosamide showed just half of the activity. Molecular signaling data by western blotting also indicated that niclosamide-loaded lithocholic acid tryptophan conjugate nanomicelle interfered with the EphA2 receptor signaling and inhibition of the Wnt/beta-catenin pathway and resulted in the synergistic anticancer activity compared to niclosamide pure drug.


Assuntos
Neoplasias da Próstata , Receptor EphA2 , Linhagem Celular Tumoral , Humanos , Ácido Litocólico , Masculino , Micelas , Niclosamida , Neoplasias da Próstata/tratamento farmacológico , Receptor EphA2/metabolismo , Triptofano , Via de Sinalização Wnt
14.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073713

RESUMO

Metastatic prostate cancer is the most common cancer in males and the fifth cause of cancer mortality worldwide. Despite the major progress in this field, leading to the approval of novel anti-androgens, the prognosis is still poor. A significant number of patients acquire an androgen receptor splice variant 7 (AR-V7), which is constitutively activated and lacks the ligand-binding domain (LBD) while maintaining the nuclear localization signal and DNA-binding domain (DBD). This conformational change, even in the absence of the ligand, allows its retention within the nucleus, where it acts as a transcription factor repressing crucial tumor suppressor genes. AR-V7 is an important oncogenic driver and plays a role as an early diagnostic and prognostic marker, as well as a therapeutic target for antagonists such as niclosamide and TAS3681. Anti-AR-V7 drugs have shown promise in recent clinical investigations on this subset of patients. This mini-review focuses on the relevance of AR-V7 in the clinical manifestations of castration-resistant prostate cancer (CRPC) and summarizes redemptive therapeutic strategies.


Assuntos
Mutação , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genética , Processamento Alternativo , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Humanos , Masculino , Niclosamida/farmacologia , Niclosamida/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/genética , Isoformas de Proteínas
15.
Toxicology ; 457: 152805, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33961950

RESUMO

Niclosamide (NIC), a helminthic drug used widely for controlling schistosomiasis, can reportedly disrupt the endocrine system. However, its underlying mechanisms are still unclear. In this study, we revealed the potential endocrine disruption mechanism of NIC by activating estrogen receptors (ERs) and estrogen-related receptors (ERRs). The binding potency of NIC with ERα, ERß and ERRγ were determined by fluorescence competitive binding assays, which shows an IC50 (the concentration of NIC needed to displace 50 % of the probe from the receptor) of 90 ± 4.1, 10 ± 1.7 nM and 0.59 ± 0.07 nM respectively. The IC50 for ERRγ is the lowest one among the three detected receptors, which is three orders of magnitude lower than the known agonist GSK4716.The transcriptional activities of NIC on ERs and ERRs were detected by MVLN cells (stably transfected with ERs reporter gene) and HeLa cells (transiently transfected with ERRs reporter gene)-based luciferase reporter gene assay. The lowest observable effective concentration (LOEC) ranked as follows: ERRγ (0.5 nM) < ERRα (10 nM) < ERs (100 nM). The maximum observed induction rate for ERRγ (294 %) was higher than that for ERRα (191 %). The maximum observed induction rate of NIC for ERs was 30 % relative to 17ß-estradiol. In addition, we simulated the interactions of NIC with ERs and ERRs by molecular docking. NIC could dock into the ligand binding pockets of ERs and ERRs and form hydrogen bonds with different amino acids. The binding energy ranked as follows: ERRγ (-8.90 kcal/mol) < ERß (-7.57 kcal/mol) < ERRα (-7.15 kcal/mol) < ERα (-6.53 kcal/mol), which implied that NIC bound to ERRγ with higher binding affinity than the other receptors. Overall, we clarify that ERRγ might be the dominant target for NIC in cells rather than ERRα and ERs. We reveal potential novel mechanisms for the endocrine disruption effects of NIC by activating both ERRs and ERs at environmentally-related nanomolar levels.


Assuntos
Disruptores Endócrinos/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Niclosamida/metabolismo , Receptores de Estrogênio/metabolismo , Anticestoides/metabolismo , Anticestoides/toxicidade , Relação Dose-Resposta a Droga , Disruptores Endócrinos/toxicidade , Células HeLa , Humanos , Células MCF-7 , Niclosamida/toxicidade , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína
16.
PLoS One ; 16(5): e0252135, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34038481

RESUMO

Skeletal muscle atrophy is a feature of aging (termed sarcopenia) and various diseases, such as cancer and kidney failure. Effective drug treatment options for muscle atrophy are lacking. The tapeworm medication, niclosamide is being assessed for repurposing to treat numerous diseases, including end-stage cancer metastasis and hepatic steatosis. In this study, we investigated the potential of niclosamide as a repurposing drug for muscle atrophy. In a myotube atrophy model using the glucocorticoid, dexamethasone, niclosamide did not prevent the reduction in myotube diameter or the decreased expression of phosphorylated FOXO3a, which upregulates the ubiquitin-proteasome pathway of muscle catabolism. Treatment of normal myotubes with niclosamide did not activate mTOR, a major regulator of muscle protein synthesis, and increased the expression of atrogin-1, which is induced in catabolic states. Niclosamide treatment also inhibited myogenesis in muscle precursor cells, enhanced the expression of myoblast markers Pax7 and Myf5, and downregulated the expression of differentiation markers MyoD, MyoG and Myh2. In an animal model of muscle atrophy, niclosamide did not improve muscle mass, grip strength or muscle fiber cross-sectional area. Muscle atrophy is also feature of cancer cachexia. IC50 analyses indicated that niclosamide was more cytotoxic for myoblasts than cancer cells. In addition, niclosamide did not suppress the induction of iNOS, a key mediator of atrophy, in an in vitro model of cancer cachexia and did not rescue myotube diameter. Overall, these results suggest that niclosamide may not be a suitable repurposing drug for glucocorticoid-induced skeletal muscle atrophy or cancer cachexia. Nevertheless, niclosamide may be employed as a compound to study mechanisms regulating myogenesis and catabolic pathways in skeletal muscle.


Assuntos
Reposicionamento de Medicamentos/métodos , Atrofia Muscular/tratamento farmacológico , Niclosamida/uso terapêutico , Células A549 , Animais , Caquexia/tratamento farmacológico , Caquexia/metabolismo , Linhagem Celular Tumoral , Células HCT116 , Humanos , Concentração Inibidora 50 , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteína MyoD/metabolismo , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Miogenina/metabolismo , Cadeias Pesadas de Miosina/metabolismo
17.
Int J Pharm ; 603: 120701, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33989748

RESUMO

In this work, we have developed and tested a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters to gather data about its toxicology and pharmacokinetics. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with pharmacological effect against SARS-CoV-2 infection. TFF was used to develop a niclosamide inhalation powder composition that exhibited acceptable aerosol performance with a fine particle fraction (FPF) of 86.0% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 1.11 µm and 2.84, respectively. This formulation not only proved to be safe after an acute three-day, multi-dose tolerability and exposure study in rats as evidenced by histopathology analysis, and also was able to achieve lung concentrations above the required IC90 levels for at least 24 h after a single administration in a Syrian hamster model. To conclude, we successfully developed a niclosamide dry powder inhalation that overcomes niclosamide's limitation of poor oral bioavailability by targeting the drug directly to the primary site of infection, the lungs.


Assuntos
COVID-19 , Niclosamida , Administração por Inalação , Aerossóis , Animais , Cricetinae , Inaladores de Pó Seco , Congelamento , Humanos , Tamanho da Partícula , Pós , Ratos , SARS-CoV-2
18.
Toxicol Lett ; 347: 23-35, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961984

RESUMO

Liver fibrosis is the conjoint consequence of almost all chronic liver diseases. Cholestatic liver injury is a significant stimulus for fibrotic liver. This study was conducted to investigate the hepatoprotective effect of niclosamide as a NOTCH inhibitor and on the Wnt pathway against cholestatic liver fibrosis (CLF) which was experimentally induced by bile duct ligation (BDL). Rats were randomly divided into five main groups (6 per group): sham, BDL, BDL/niclosamide 5, BDL/niclosamide 10 and niclosamide 10 only group. Niclosamide was administered intraperitoneally (i.p.) for 4 weeks starting at the same day of surgery at doses 5 and 10 mg/kg. Liver function, cholestasis, oxidative stress, inflammation, liver fibrosis, NOTCH signaling pathway and Wnt pathway markers were assessed. Niclosamide (5 and 10 mg/kg) significantly reduced liver enzymes levels, oxidative stress, inflammation and phosphorylated signal transducer and activator of transcription3 (p-STAT3). Niclosamide (5 and 10 mg/kg) also significantly reduced NOTCH pathway (Jagged1, NOTCH2, NOTCH3, HES1, SOX9), Wnt pathway (Wnt5B, and Wnt10A), and fibrosis (transforming growth factor-beta1 (TGF-ß1), alpha smooth muscle actin (α-SMA) and collagen deposition with more prominent effect of the higher dose 10 mg/kg. So, this study presents nicloamide as a promising antifibrotic agent in CLF through inhibition of NOTCH and Wnt pathways.


Assuntos
Cirrose Hepática Biliar/prevenção & controle , Fígado/efeitos dos fármacos , Niclosamida/farmacologia , Receptores Notch/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Ductos Biliares/cirurgia , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos Wistar , Fatores de Transcrição SOX9/metabolismo , Fator de Transcrição STAT3/metabolismo
19.
FASEB J ; 35(5): e21584, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33860549

RESUMO

Endometriosis, a common gynecological disease, causes chronic pelvic pain and infertility in women of reproductive age. Due to the limited efficacy of current therapies, a critical need exists to develop new treatments for endometriosis. Inflammatory dysfunction, instigated by abnormal macrophage (MΦ) function, contributes to disease development and progression. However, the fundamental role of the heterogeneous population of peritoneal MΦ and their potential druggable functions is uncertain. Here we report that GATA6-expressing large peritoneal MΦ (LPM) were increased in the peritoneal cavity following lesion induction. This was associated with increased cytokine and chemokine secretion in the peritoneal fluid (PF), as well as MΦ infiltration, vascularization and innervation in endometriosis-like lesions (ELL). Niclosamide, an FDA-approved anti-helminthic drug, was effective in reducing LPM number, but not small peritoneal MΦ (SPM), in the PF. Niclosamide also inhibits aberrant inflammation in the PF, ELL, pelvic organs (uterus and vagina) and dorsal root ganglion (DRG), as well as MΦ infiltration, vascularization and innervation in the ELL. PF from ELL mice stimulated DRG outgrowth in vitro, whereas the PF from niclosamide-treated ELL mice lacked the strong stimulatory nerve growth response. These results suggest LPM induce aberrant inflammation in endometriosis promoting lesion progression and establishment of the inflammatory environment that sensitizes peripheral nociceptors in the lesions and other pelvic organs, leading to increased hyperalgesia. Our findings provide the rationale for targeting LPM and their functions with niclosamide and its efficacy in endometriosis as a new non-hormonal therapy to reduce aberrant inflammation which may ultimately diminish associated pain.


Assuntos
Anticestoides/farmacologia , Endometriose/complicações , Fator de Transcrição GATA6/metabolismo , Gânglios Espinais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos Peritoneais/efeitos dos fármacos , Niclosamida/farmacologia , Animais , Feminino , Fator de Transcrição GATA6/genética , Gânglios Espinais/patologia , Inflamação/etiologia , Inflamação/patologia , Macrófagos Peritoneais/patologia , Camundongos , Camundongos Endogâmicos C57BL
20.
Int J Pharm ; 602: 120611, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33872710

RESUMO

The levitation of samples in an acoustic field has been of interest in the preparation and study of amorphous solid dispersions (ASD). Here, niclosamide-polymer solutions were levitated in a multi-emitter single-axis acoustic levitator and analyzed for 10 min at a High-resolution synchrotron X-ray powder diffraction beamline. This assembly enabled high-quality and fast time-resolved measurements with microliter sample size and measurement of solvent evaporation and recrystallization of niclosamide (NCL). Polymers HPMCP-55S, HPMCP-50, HPMCP-55, Klucel®, and poloxamers were not able to form amorphous dispersions with NCL. Plasdone® and Soluplus® demonstrated excellent properties to form NCL amorphous dispersions, with the last showing superior solubility enhancement. Furthermore, this fast levitation polymer screening showed good agreement with results obtained by conventional solvent evaporation screening evaluated for five days in a stability study, carried out at 40 °C/75% RH. The study showed that acoustic levitation and high-resolution synchrotron combination opens up a new horizon with great potential for accelerating ASD formulation screening and analysis.


Assuntos
Niclosamida , Síncrotrons , Acústica , Química Farmacêutica , Pós , Solubilidade , Difração de Raios X , Raios X
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