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1.
Structure ; 32(4): 377-379, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38579678

RESUMO

Eiler et al. used cryo-electron microscopy to determine a 2.49 Å resolution structure of Giardia lamblia 80S ribosome bound to tRNA, mRNA, and the anti-protozoal drug emetine. The structure reveals some critical aspects of translation in G. lamblia, including the lack of ribosomal protein RACK1, and how emetine blocks translation by interacting with both the ribosome and mRNA.


Assuntos
Giardia lamblia , Giardia lamblia/química , Giardia lamblia/genética , Giardia lamblia/metabolismo , Microscopia Crioeletrônica , Emetina/metabolismo , Ribossomos/metabolismo , RNA Mensageiro/metabolismo
2.
Proc Natl Acad Sci U S A ; 121(7): e2306993121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38315848

RESUMO

Puromycin is covalently added to the nascent chain of proteins by the peptidyl transferase activity of the ribosome and the dissociation of the puromycylated peptide typically follows this event. It was postulated that blocking the translocation of the ribosome with emetine could retain the puromycylated peptide on the ribosome, but evidence against this has recently been published [Hobson et al., Elife 9, e60048 (2020); and Enam et al., Elife 9, e60303 (2020)]. In neurons, puromycylated nascent chains remain in the ribosome even in the absence of emetine, yet direct evidence for this has been lacking. Using biochemistry and cryoelectron microscopy, we show that the puromycylated peptides remain in the ribosome exit channel in the large subunit in a subset of neuronal ribosomes stalled in the hybrid state. These results validate previous experiments to localize stalled polysomes in neurons and provide insight into how neuronal ribosomes are stalled. Moreover, in these hybrid-state neuronal ribosomes, anisomycin, which usually blocks puromycylation, competes poorly with puromycin in the puromycylation reaction, allowing a simple assay to determine the proportion of nascent chains that are stalled in this state. In early hippocampal neuronal cultures, over 50% of all nascent peptides are found in these stalled polysomes. These results provide insights into the stalling mechanisms of neuronal ribosomes and suggest that puromycylated peptides can be used to reveal subcellular sites of hybrid-state stalled ribosomes in neurons.


Assuntos
Emetina , Ribossomos , Puromicina/farmacologia , Microscopia Crioeletrônica , Emetina/análise , Emetina/metabolismo , Ribossomos/metabolismo , Biossíntese de Proteínas , Peptídeos/metabolismo , Neurônios/metabolismo
3.
Pharm Biol ; 62(1): 195-206, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38339810

RESUMO

CONTEXT: Cephaeline is a natural product isolated from ipecac (Cephaelis ipecacuanha [Brot.] A. Rich. [Rubiaceae]). It exhibits promising anti-lung cancer activity and ferroptosis induction may be a key mechanism for its anti-lung cancer effect. OBJECTIVES: This study investigates the anti-lung cancer activity and mechanisms of cephaeline both in vitro and in vivo. MATERIALS AND METHODS: H460 and A549 lung cancer cells were used. The cephaeline inhibition rate on lung cancer cells was detected via a Cell Counting Kit-8 assay after treatment with cephaeline for 24 h. Subsequently, the concentrations of 25, 50 and 100 nM were used for in vitro experiments. In addition, the antitumour effects of cephaeline (5, 10 mg/kg) in vivo were evaluated after 12 d of cephaeline treatment. RESULTS: Cephaeline showed significant inhibitory effects on lung cancer cells, and the IC50 of cephaeline on H460 and A549 at 24, 48 and 72 h were 88, 58 and 35 nM, respectively, for H460 cells and 89, 65 and 43 nM, respectively, for A549 cells. Meanwhile, we demonstrated that ferroptosis is the key mechanism of cephaeline against lung cancer. Finally, we found that cephaeline induced ferroptosis in lung cancer cells by targeting NRF2. DISCUSSION AND CONCLUSION: We demonstrated for the first time that cephaeline inhibits NRF2, leading to ferroptosis in lung cancer cells. These findings may contribute to the development of innovative therapeutics for lung cancer.


Assuntos
Emetina/análogos & derivados , Ferroptose , Neoplasias Pulmonares , Humanos , Fator 2 Relacionado a NF-E2 , Emetina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico
4.
Virol J ; 21(1): 5, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38178163

RESUMO

Chikungunya virus (CHIKV) infection causes chikungunya, a viral disease that currently has no specific antiviral treatment. Several repurposed drug candidates have been investigated for the treatment of the disease. In order to improve the efficacy of the known drugs, combining drugs for treatment is a promising approach. The current study was undertaken to explore the antiviral activity of a combination of repurposed drugs that were reported to have anti-CHIKV activity. We explored the effect of different combinations of six effective drugs (2-fluoroadenine, emetine, lomibuvir, enalaprilat, metyrapone and resveratrol) at their non-toxic concentrations against CHIKV under post infection treatment conditions in Vero cells. Focus-forming unit assay, real time RT-PCR, immunofluorescence assay, and western blot were used to determine the virus titre. The results revealed that the combination of 2-fluoroadenine with either metyrapone or emetine or enalaprilat exerted inhibitory activity against CHIKV under post-infection treatment conditions. The effect of these drug combinations was additive in nature compared to the effect of the individual drugs. The results suggest an additive anti-viral effect of these drug combinations against CHIKV. The findings could serve as an outline for the development of an innovative therapeutic approach in the future to treat CHIKV-infected patients.


Assuntos
Febre de Chikungunya , Vírus Chikungunya , Animais , Chlorocebus aethiops , Humanos , Células Vero , Emetina/farmacologia , Emetina/uso terapêutico , Enalaprilato/farmacologia , Enalaprilato/uso terapêutico , Metirapona/farmacologia , Metirapona/uso terapêutico , Replicação Viral , Antivirais/farmacologia , Antivirais/uso terapêutico , Febre de Chikungunya/tratamento farmacológico , Combinação de Medicamentos
5.
PLoS One ; 19(1): e0294769, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38175855

RESUMO

Severe Acute Respiratory Syndrome Corona Virus (SARS-CoV-2) is the causative agent of COVID-19 pandemic, which has resulted in global fatalities since late December 2019. Alkaloids play a significant role in drug design for various antiviral diseases, which makes them viable candidates for treating COVID-19. To identify potential antiviral agents, 102 known alkaloids were subjected to docking studies against the two key targets of SARS-CoV-2, namely the spike glycoprotein and main protease. The spike glycoprotein is vital for mediating viral entry into host cells, and main protease plays a crucial role in viral replication; therefore, they serve as compelling targets for therapeutic intervention in combating the disease. From the selection of alkaloids, the top 6 dual inhibitory compounds, namely liensinine, neferine, isoliensinine, fangchinoline, emetine, and acrimarine F, emerged as lead compounds with favorable docked scores. Interestingly, most of them shared the bisbenzylisoquinoline alkaloid framework and belong to Nelumbo nucifera, commonly known as the lotus plant. Docking analysis was conducted by considering the key active site residues of the selected proteins. The stability of the top three ligands with the receptor proteins was further validated through dynamic simulation analysis. The leads underwent ADMET profiling, bioactivity score analysis, and evaluation of drug-likeness and physicochemical properties. Neferine demonstrated a particularly strong affinity for binding, with a docking score of -7.5025 kcal/mol for main protease and -10.0245 kcal/mol for spike glycoprotein, and therefore a strong interaction with both target proteins. Of the lead alkaloids, emetine and fangchinoline demonstrated the lowest toxicity and high LD50 values. These top alkaloids, may support the body's defense and reduce the symptoms by their numerous biological potentials, even though some properties naturally point to their direct antiviral nature. These findings demonstrate the promising anti-COVID-19 properties of the six selected alkaloids, making them potential candidates for drug design. This study will be beneficial in effective drug discovery and design against COVID-19 with negligible side effects.


Assuntos
Alcaloides , Antivirais , Inibidores de Proteases , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Alcaloides/farmacologia , Antivirais/farmacologia , COVID-19 , Emetina , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores
6.
Structure ; 32(4): 400-410.e4, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38242118

RESUMO

Giardia lamblia is a deeply branching protist and a human pathogen. Its unusual biology presents the opportunity to explore conserved and fundamental molecular mechanisms. We determined the structure of the G. lamblia 80S ribosome bound to tRNA, mRNA, and the antibiotic emetine by cryo-electron microscopy, to an overall resolution of 2.49 Å. The structure reveals rapidly evolving protein and nucleotide regions, differences in the peptide exit tunnel, and likely altered ribosome quality control pathways. Examination of translation initiation factor binding sites suggests these interactions are conserved despite a divergent initiation mechanism. Highlighting the potential of G. lamblia to resolve conserved biological principles; our structure reveals the interactions of the translation inhibitor emetine with the ribosome and mRNA, thus providing insight into the mechanism of action for this widely used antibiotic. Our work defines key questions in G. lamblia and motivates future experiments to explore the diversity of eukaryotic gene regulation.


Assuntos
Giardia lamblia , Humanos , Giardia lamblia/genética , Giardia lamblia/química , Giardia lamblia/metabolismo , Emetina/farmacologia , Emetina/análise , Emetina/metabolismo , Microscopia Crioeletrônica , Ribossomos/química , RNA Mensageiro/metabolismo , Antibacterianos
7.
Virus Res ; 341: 199322, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38228190

RESUMO

The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC50 ∼ 50-100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC50 ∼ 40-60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.


Assuntos
Alcaloides , Emetina , Emetina/análogos & derivados , Humanos , Emetina/farmacologia , Ipeca/farmacologia , Cardiotoxicidade , Antivirais/toxicidade
8.
J Cell Physiol ; 239(2): e31164, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38149816

RESUMO

Tumor resistance remains an obstacle to successfully treating oral squamous cell carcinoma (OSCC). Cisplatin is widely used as a cytotoxic drug to treat solid tumors, including advanced OSCC, but with low efficacy due to chemoresistance. Therefore, identifying the pathways that contribute to chemoresistance may show new possibilities for improving the treatment. This work explored the role of the tumor necrosis factor-alpha (TNF-alpha)/NFkB signaling in driving the cisplatin resistance of OSCC and its potential as a pharmacological target to overcome chemoresistance. Differential accessibility analysis demonstrated the enrichment of opened chromatin regions in members of the TNF-alpha/NFkB signaling pathway, and RNA-Seq confirmed the upregulation of TNF-alpha/NFkB signaling in cisplatin-resistant cell lines. NFkB was accumulated in cisplatin-resistant cell lines and in cancer stem cells (CSC), and the administration of TNF-alpha increased the CSC, suggesting that TNF-alpha/NFkB signaling is involved in the accumulation of CSC. TNF-alpha stimulation also increased the histone deacetylases HDAC1 and SIRT1. Cisplatin-resistant cell lines were sensitive to the pharmacological inhibition of NFkB, and low doses of the NFkB inhibitors, CBL0137, and emetine, efficiently reduced the CSC and the levels of SIRT1, increasing histone acetylation. The NFkB inhibitors decreased stemness potential, clonogenicity, migration, and invasion of cisplatin-resistant cell lines. The administration of the emetine significantly reduced the tumor growth of cisplatin-resistant xenograft models, decreasing NFkB and SIRT1, increasing histone acetylation, and decreasing CSC. TNF-alpha/NFkB/SIRT1 signaling regulates the epigenetic machinery by modulating histone acetylation, CSC, and aggressiveness of cisplatin-resistant OSCC and the NFkB inhibition is a potential strategy to treat chemoresistant OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Emetina/metabolismo , Emetina/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Histonas/metabolismo , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Células-Tronco Neoplásicas/patologia , Sirtuína 1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
9.
J Cell Mol Med ; 27(23): 3839-3850, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37723905

RESUMO

Radiation-induced lung injury (RILI), divided into early radiation pneumonia (RP) and late radiation-induced pulmonary fibrosis (RIPF), is a common serious disease after clinical chest radiotherapy or nuclear accident, which seriously threatens the life safety of patients. There has been no effective prevention or treatment strategy till now. Epithelial-mesenchymal transition (EMT) is a key step in the occurrence and development of RILI. In this study, we demonstrated that emetine dihydrochloride (EDD) alleviated RILI through inhibiting EMT. We found that EDD significantly attenuated EMT-related markers, reduced Smad3 phosphorylation expression after radiation. Then, for the first time, we observed EDD alleviated lung hyperaemia and reduced collagen deposit induced by irradiation, providing protection against RILI. Finally, it was found that EDD inhibited radiation-induced EMT in lung tissues. Our study suggested that EDD alleviated RILI through inhibiting EMT by blocking Smad3 signalling pathways. In summary, our results indicated that EDD is a novel potential radioprotector for RILI.


Assuntos
Lesão Pulmonar , Fibrose Pulmonar , Lesões por Radiação , Humanos , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Emetina/farmacologia , Pulmão/patologia , Lesões por Radiação/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Transição Epitelial-Mesenquimal
10.
Acta Trop ; 245: 106980, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37419379

RESUMO

Trypanosoma evansi, a hemoflagellate poses huge economic threat to the livestock industry of several countries of Asia, Africa, South America and Europe continents of the world. Limited number of available chemical drugs, incidents of growing drug resistance, and related side effects encouraged the use of herbal substitutes. In the present investigation, the impact of six alkaloids of quinoline and isoquinoline group was evaluated on the growth and multiplication of Trypanosoma evansi and their cytotoxic effect was examined on horse peripheral blood mononuclear cells in an in vitro system. Quinine, quinindine, cinchonine, cinchonidine, berbamine and emetine showed potent trypanocidal activities with IC50/24 h values 6.631 ± 0.244, 8.718 ± 0.081, 16.96 ± 0.816, 33.38 ± 0.653, 2.85 ± 0.065, and 3.12 ± 0.367 µM, respectively, which was comparable to the standard anti-trypanosomal drug, quinapyramine sulfate (20 µM). However, in the cytotoxicity assay, all the drugs showed dose dependent cytotoxic effect and quinine, berbamine and emetine showed selectivity index more than 5, based of ration of CC50 to IC50. Among the selected alkaloids, quinidine, berbamine and emetine exhibited higher apoptotic effects in T. evansi. Likewise, drug treated parasites showed a dose-dependent and time-dependent increase in reactive oxygen species (ROS) production. Therefore, increased apoptosis in combination with ROS generation could be responsible for the observed trypanocidal effect which could be further evaluated in T. evansi-infected mice model.


Assuntos
Alcaloides , Tripanossomicidas , Trypanosoma , Tripanossomíase , Camundongos , Animais , Cavalos , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Espécies Reativas de Oxigênio , Emetina/farmacologia , Emetina/uso terapêutico , Quinina/farmacologia , Quinina/uso terapêutico , Leucócitos Mononucleares , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Isoquinolinas/farmacologia , Tripanossomíase/tratamento farmacológico
11.
Physiol Behav ; 269: 114278, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37352906

RESUMO

No prior studies have shown that gaping reactions are produced with the avoidance of conditioned taste caused by cisplatin and emetine. Therefore, we tried to demonstrate it using a taste reactivity test in rats and found the gaping reactions induced when saccharin is readministered after gustatory conditioning that paired saccharin with cisplatin or emetine. Since conditioned gaping reactions indicate the aversion to saccharin taste and conditioned nausea, the present study suggest that the taste aversion is induced by cisplatin and emetine. It was also found that with intraperitoneal injections of emetine alone, gaping almost never occurs.


Assuntos
Cisplatino , Emetina , Ratos , Animais , Emetina/efeitos adversos , Cisplatino/toxicidade , Sacarina/farmacologia , Paladar , Cloreto de Lítio/farmacologia , Náusea/induzido quimicamente , Aprendizagem da Esquiva
12.
Cancer Chemother Pharmacol ; 91(4): 303-315, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36941385

RESUMO

BACKGROUND: Gastric cancer (GC) is a life-threatening malignant tumor with high incidence rate. Despite great progress, there are still many GC sufferers that cannot benefit from the existing anti-GC treatments. Therefore, it is still necessary to develop novel medicines against GC. Emetine, a natural small molecule isolated from Psychotria ipecacuanha, has been broadly used for medicinal purposes including cancer treatment. Here, we conducted a comprehensive study on the anti-GC effects of emetine and the related mechanisms of action. METHODS: The cell viability was evaluated by MTT and colony formation assay. Cellular proliferation and apoptosis were analyzed by edu incorporation assay and Annexin V-PI staining, respectively. Moreover, wound healing assay and transwell invasion assay were conducted to detect cell migration and invasion after treatment with emetine. To elucidate the molecular mechanism involved in the anti-GC effects of emetine, RNA sequencing and functional enrichment analysis were carried out on MGC803 cells. Then, the western blot analysis was performed to further verify the anti-GC mechanism of emetine. In vivo anti-tumor efficacy of emetine was evaluated in the MGC803 xenograft model. RESULTS: MTT and colony formation assay exhibited a strong potency of emetine against GC cell growth, with IC50 values of 0.0497 µM and 0.0244 µM on MGC803 and HGC-27 cells, respectively. Further pharmacodynamic studies revealed that emetine restrained the growth of GC cells mainly via proliferation inhibition and apoptosis induction. Meanwhile, emetine also had the ability to block GC cell migration and invasion. The results of RNA sequencing and western blot showed that emetine acted through regulating multiple signaling pathways, including not only MAPKs and Wnt/ß-catenin signaling axes, but also PI3K/AKT and Hippo/YAP signaling cascades that were not found in other tumor types. Notably, the antitumor efficacy of emetine could also be observed in MGC803 xenograft models. CONCLUSION: Our data demonstrate that emetine is a promising lead compound and even a potential drug candidate for GC treatment, deserving further structural optimization and development.


Assuntos
Emetina , Neoplasias Gástricas , Humanos , Emetina/farmacologia , Emetina/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Gástricas/metabolismo , Proliferação de Células , Via de Sinalização Wnt , Linhagem Celular Tumoral , Movimento Celular , Apoptose
13.
J Infect Public Health ; 16(5): 754-770, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36958171

RESUMO

Nature has given us yet another wild card in the form of Zika virus (ZIKV). It was found in 1947, but has only recently become an important public health risk, predominantly to pregnant women and their unborn offspring. Currently, no specific therapeutic agent exists for ZIKV and treatment is mainly supportive. Natural products (NPs) can serve as a major source of potent antiviral drugs. To create this review, a comprehensive search was conducted from different databases (PubMed, ScienceDirect, Google scholar). A statistical analysis on the number of publications related to NPs and ZIKV was conducted to analyse the trend in research covering the period 1980-2020. From the data collated in this review, a number of NPs have been found to be inhibitive towards different stages of the ZIKV lifecycle in in vitro studies. For instance, baicalin, (-)-epigallocatechin gallate, curcumin, nanchangmycin, gossypol, cephaeline, emetine, resveratrol, berberine, amongst others, can prevent viral entry by attacking ZIKV E protein. Compounds luteolin, myricetin, astragalin, rutin, (-)-epigallocatechin gallate, carnosine, pedalitin, amongst others, inhibited NS2B-NS3 protease activity which consequently hamper replication. Interestingly, a few NPs had the ability to arrest both viral entry and replication, namely baicalin, (-)-epigallocatechin gallate, curcumin, cephaeline, emetine, and resveratrol. To the best of our knowledge, we obtained only one in vivo study conducted on emetine and results showed that it decreased the levels of circulating ZIKV by approximately 10-fold. Our understanding on NPs exhibiting anti-ZIKV effects in in vivo testing as well as clinical trials is limited. Our trend analysis showed that interest in searching for a cure or prevention against Zika in NPs is negligible and there are no publications yet covering the clinical evaluation. NPs with anti-ZIKV property can a winning strategy in controlling the bio-burden of an epidemic or pandemic. We therefore opine that in the future, more research should be devoted to ZIKV. This review attempts to provide baseline data and roadmap to pursuit detailed investigations for developing potent and novel therapeutic agents to prevent and cure ZIKV infection.


Assuntos
Curcumina , Infecção por Zika virus , Zika virus , Humanos , Feminino , Gravidez , Emetina/farmacologia , Emetina/uso terapêutico , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Curcumina/farmacologia , Curcumina/uso terapêutico , Infecção por Zika virus/prevenção & controle , Antivirais/farmacologia , Antivirais/uso terapêutico
14.
Biosci Biotechnol Biochem ; 87(5): 501-510, 2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-36809780

RESUMO

TEAD is a transcription factor responsible for the output of the tumor suppressor Hippo pathway. The transcriptional activity of TEAD requires molecular interaction with its transcriptional coactivator, YAP. Aberrant activation of TEAD is deeply involved in tumorigenesis and is associated with poor prognosis, suggesting that inhibitors targeting the YAP-TEAD system are promising as antitumor agents. In this study, we identified NPD689, an analog of the natural product alkaloid emetine, as an inhibitor of the YAP-TEAD interaction. NPD689 suppressed the transcriptional activity of TEAD and reduced the viability of human malignant pleural mesothelioma and non-small cell lung cancer cells but not the viability of normal human mesothelial cells. Our results suggest that NPD689 is not only a new useful chemical tool for elucidating the biological role of the YAP-TEAD system but also has potential as a starting compound for developing a cancer therapeutic agent that targets the YAP-TEAD interaction.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/farmacologia , Emetina , Neoplasias Pulmonares/patologia , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP , Fatores de Transcrição de Domínio TEA/metabolismo
15.
Commun Biol ; 6(1): 37, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639418

RESUMO

Fanconi anaemia (FA) is a rare chromosomal-instability syndrome caused by mutations of any of the 22 known FA DNA-repair genes. FA individuals have an increased risk of head-and-neck squamous-cell-carcinomas (HNSCC), often fatal. Systemic intolerance to standard cisplatin-based protocols due to somatic-cell hypersensitivity underscores the urgent need to develop novel therapies. Here, we performed unbiased siRNA screens to unveil genetic interactions synthetic-lethal with FA-pathway deficiency in FA-patient HNSCC cell lines. We identified based on differential-lethality scores between FA-deficient and FA-proficient cells, next to common-essential genes such as PSMC1, PSMB2, and LAMTOR2, the otherwise non-essential RBBP9 gene. Accordingly, low dose of the FDA-approved RBBP9-targeting drug Emetine kills FA-HNSCC. Importantly both RBBP9-silencing as well as Emetine spared non-tumour FA cells. This study provides a minable genome-wide analyses of vulnerabilities to address treatment challenges in FA-HNSCC. Our investigation divulges a DNA-cross-link-repair independent lead, RBBP9, for targeted treatment of FA-HNSCCs without systemic toxicity.


Assuntos
Anemia de Fanconi , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Proteínas de Ciclo Celular/genética , DNA , Emetina/uso terapêutico , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Estudo de Associação Genômica Ampla , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Neoplasias/genética , RNA Interferente Pequeno/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
16.
Life Sci Alliance ; 5(12)2022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-36260751

RESUMO

DNA synthesis of the leading and lagging strands works independently and cells tolerate single-stranded DNA generated during strand uncoupling if it is protected by RPA molecules. Natural alkaloid emetine is used as a specific inhibitor of lagging strand synthesis, uncoupling leading and lagging strand replication. Here, by analysis of lagging strand synthesis inhibitors, we show that despite emetine completely inhibiting DNA replication: it does not induce the generation of single-stranded DNA and chromatin-bound RPA32 (CB-RPA32). In line with this, emetine does not activate the replication checkpoint nor DNA damage response. Emetine is also an inhibitor of proteosynthesis and ongoing proteosynthesis is essential for the accurate replication of DNA. Mechanistically, we demonstrate that the acute block of proteosynthesis by emetine temporally precedes its effects on DNA replication. Thus, our results are consistent with the hypothesis that emetine affects DNA replication by proteosynthesis inhibition. Emetine and mild POLA1 inhibition prevent S-phase poly(ADP-ribosyl)ation. Collectively, our study reveals that emetine is not a specific lagging strand synthesis inhibitor with implications for its use in molecular biology.


Assuntos
DNA de Cadeia Simples , Emetina , Emetina/farmacologia , DNA/genética , Replicação do DNA , Cromatina
17.
Front Immunol ; 13: 975848, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119022

RESUMO

Corona Virus Disease 2019 (COVID-19), an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread rapidly worldwide, resulting in a pandemic with a high mortality rate. In clinical practice, we have noted that many critically ill or critically ill patients with COVID-19 present with typical sepsis-related clinical manifestations, including multiple organ dysfunction syndrome, coagulopathy, and septic shock. In addition, it has been demonstrated that severe COVID-19 has some pathological similarities with sepsis, such as cytokine storm, hypercoagulable state after blood balance is disrupted and neutrophil dysfunction. Considering the parallels between COVID-19 and non-SARS-CoV-2 induced sepsis (hereafter referred to as sepsis), the aim of this study was to analyze the underlying molecular mechanisms between these two diseases by bioinformatics and a systems biology approach, providing new insights into the pathogenesis of COVID-19 and the development of new treatments. Specifically, the gene expression profiles of COVID-19 and sepsis patients were obtained from the Gene Expression Omnibus (GEO) database and compared to extract common differentially expressed genes (DEGs). Subsequently, common DEGs were used to investigate the genetic links between COVID-19 and sepsis. Based on enrichment analysis of common DEGs, many pathways closely related to inflammatory response were observed, such as Cytokine-cytokine receptor interaction pathway and NF-kappa B signaling pathway. In addition, protein-protein interaction networks and gene regulatory networks of common DEGs were constructed, and the analysis results showed that ITGAM may be a potential key biomarker base on regulatory analysis. Furthermore, a disease diagnostic model and risk prediction nomogram for COVID-19 were constructed using machine learning methods. Finally, potential therapeutic agents, including progesterone and emetine, were screened through drug-protein interaction networks and molecular docking simulations. We hope to provide new strategies for future research and treatment related to COVID-19 by elucidating the pathogenesis and genetic mechanisms between COVID-19 and sepsis.


Assuntos
COVID-19 , Sepse , Biomarcadores , Biologia Computacional/métodos , Estado Terminal , Citocinas/genética , Emetina , Perfilação da Expressão Gênica/métodos , Humanos , Simulação de Acoplamento Molecular , NF-kappa B/genética , Progesterona , Receptores de Citocinas/genética , SARS-CoV-2 , Sepse/genética , Sepse/metabolismo
18.
Cells ; 11(18)2022 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-36139404

RESUMO

Chloroquine and Emetine are drugs used to treat human parasitic infections. In addition, it has been shown that these drugs have an antiviral effect. Both drugs were also found to cause a suppressive effect on the growth of cancer cells of different origins. Here, using the replication-deficient HIV-1-based lentiviral vector particles, we evaluated the ability of the combination of these drugs to reduce viral transduction efficiency. We showed that these drugs act synergistically to decrease cancer cell growth when added in combination with medium containing lentiviral particles. We found that the combination of these drugs with lentiviral particles decreases the viability of treated cells. Taken together, we state the oncolytic potential of the medium containing HIV-1-based particles provoked by the combination of Chloroquine and Emetine.


Assuntos
HIV-1 , Antivirais , Cloroquina/farmacologia , Emetina/farmacologia , Humanos
19.
Viruses ; 14(9)2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-36146673

RESUMO

Background: Enterovirus infections affect people around the world, causing a range of illnesses, from mild fevers to severe, potentially fatal conditions. There are no approved treatments for enterovirus infections. Methods: We have tested our library of broad-spectrum antiviral agents (BSAs) against echovirus 1 (EV1) in human adenocarcinoma alveolar basal epithelial A549 cells. We also tested combinations of the most active compounds against EV1 in A549 and human immortalized retinal pigment epithelium RPE cells. Results: We confirmed anti-enteroviral activities of pleconaril, rupintrivir, cycloheximide, vemurafenib, remdesivir, emetine, and anisomycin and identified novel synergistic rupintrivir-vemurafenib, vemurafenib-pleconaril and rupintrivir-pleconaril combinations against EV1 infection. Conclusions: Because rupintrivir, vemurafenib, and pleconaril require lower concentrations to inhibit enterovirus replication in vitro when combined, their cocktails may have fewer side effects in vivo and, therefore, should be further explored in preclinical and clinical trials against EV1 and other enterovirus infections.


Assuntos
Infecções por Enterovirus , Picornaviridae , Anisomicina/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Cicloeximida/uso terapêutico , Combinação de Medicamentos , Emetina , Humanos , Vemurafenib/uso terapêutico
20.
Sci Rep ; 12(1): 15640, 2022 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123369

RESUMO

Insulin stimulates glucose uptake in adipocytes by triggering translocation of glucose transporter 4-containg vesicles to the plasma membrane. Under basal conditions, these vesicles (IRVs for insulin-responsive vesicles) are retained inside the cell via a "static" or "dynamic" mechanism. We have found that inhibitors of RNA and protein synthesis, actinomycin D and emetine, stimulate Glut4 translocation and glucose uptake in adipocytes without engaging conventional signaling proteins, such as Akt, TBC1D4, or TUG. Actinomycin D does not significantly affect endocytosis of Glut4 or recycling of transferrin, suggesting that it specifically increases exocytosis of the IRVs. Thus, the intracellular retention of the IRVs in adipocytes requires continuous RNA and protein biosynthesis de novo. These results point out to the existence of a short-lived inhibitor of IRV translocation thus supporting the "static" model.


Assuntos
Biossíntese de Proteínas , RNA , Adipócitos/metabolismo , Dactinomicina/metabolismo , Emetina , Glucose/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA/metabolismo , Transferrinas/metabolismo
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