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1.
Malar J ; 21(1): 134, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477399

RESUMO

BACKGROUND: Artesunate-amodiaquine (ASAQ) and Artemether-lumefantrine (AL) are the recommended treatment for uncomplicated Plasmodium falciparum malaria in Liberia. Intermittent preventive treatment with sulfadoxine/pyrimethamine is also recommended for pregnant women. The therapeutic efficacy of Artesunate-amodiaquine and Artemether-lumefantrine, and the frequency of molecular markers associated with anti-malarial drug resistance were investigated. METHODS: The therapeutic efficacy of ASAQ and AL was evaluated using the standard World Health Organization protocol (WHO. Methods for Surveillance of Antimalarial Drug Efficacy. Geneva: World Health Organization; 2009. https://www.who.int/malaria/publications/atoz/9789241597531/en/ ). Eligible children were recruited and monitored clinically and parasitologically for 28 days. Polymorphisms in the Pfkelch 13, chloroquine resistance transporter (Pfcrt), multidrug resistance 1 (Pfmdr-1), dihydrofolate reductase (Pfdhfr), and dihydropteroate synthase (Pfdhps) genes and copy number variations in the plasmepsin-2 (Pfpm2) gene were assessed in pretreatment samples. RESULTS: Of the 359 children enrolled, 180 were treated with ASAQ (89 in Saclepea and 91 in Bensonville) and 179 with AL (90 in Sinje and 89 in Kakata). Of the recruited children, 332 (92.5%) reached study endpoints. PCR-corrected per-protocol analysis showed ACPR of 90.2% (95% CI: 78.6-96.7%) in Bensonville and 92.7% (95% CI: 83.4.8-96.5%) in Saclepea for ASAQ, while ACPR of 100% was observed in Kakata and Sinje for AL. In both treatment groups, only two patients had parasites on day 3. No artemisinin resistance associated Pfkelch13 mutations or multiple copies of Pfpm2 were found. Most samples tested had the Pfcrt 76 T mutation (80/91, 87.9%), while the Pfmdr-1 86Y (40/91, 44%) and 184F (47/91, 51.6%) mutations were less frequent. The Pfdhfr triple mutant (51I/59R/108 N) was the predominant allele (49.2%). For the Pfdhps gene, it was the 540E mutant (16.0%), and the 436A mutant (14.3%). The quintuple allele (51I/59R/108 N-437G/540E) was detected in only one isolate (1/357). CONCLUSION: This study reports a decline in the efficacy of ASAQ treatment, while AL remained highly effective, supporting the recent decision by NMCP to replace ASAQ with AL as first-line treatment for uncomplicated falciparum malaria. No association between the presence of the mutations in Pfcrt and Pfmdr-1 and the risk of parasite recrudescence in patients treated with ASAQ was observed. Parasites with signatures known to be associated with artemisinin and piperaquine resistance were not detected. The very low frequency of the quintuple Pfdhfr/Pfdhps mutant haplotype supports the continued use of SP for IPTp. Monitoring of efficacy and resistance markers of routinely used anti-malarials is necessary to inform malaria treatment policy. Trial registration ACTRN12617001064392.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Amodiaquina/farmacologia , Amodiaquina/uso terapêutico , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/farmacologia , Combinação Arteméter e Lumefantrina/uso terapêutico , Artesunato/farmacologia , Artesunato/uso terapêutico , Criança , Cloroquina/farmacologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Libéria , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Malária Falciparum/prevenção & controle , Proteínas de Membrana Transportadoras/genética , Plasmodium falciparum , Gravidez
2.
Cell Death Dis ; 13(4): 379, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35443722

RESUMO

Venetoclax plus cytarabine therapy is approved for elderly acute myeloid leukemia (AML) patients and needs further improvement. We studied the mechanisms of venetoclax plus cytarabine treatment and searched for a third agent to enhance their effects. Cytarabine induces S phase arrest-mediated DNA damage with activation of DNA replication checkpoint kinase 1 (Chk1) through phosphorylation, while venetoclax induces B cell lymphoma 2 (Bcl-2)-interacting mediator of cell death (Bim)-mediated apoptotic DNA damage. Myeloid cell leukemia-1 (Mcl-1) plays negative roles in both events by sequestering Bim and accelerating Chk1 phosphorylation. Venetoclax releases Bim from Bcl-2 with increased Bim binding to Mcl-1. Artesunate, an antimalaria drug, induces Noxa to replace Bim from Mcl-1 and induces synergistic apoptosis with venetoclax accompanied with Mcl-1 reduction. Silencing Mcl-1 or adding venetoclax/artesunate diminishes the cytarabine resistance pathway p-Chk1. The triple combination exhibits S phase arrest with enhanced DNA damage, improves AML colony formation inhibition, and prolongs survival of two mice xenograft models compared to the venetoclax/cytarabine dual combination. Artesunate serves as a bridge for venetoclax and cytarabine combination by Noxa and Bim-mediated apoptosis and Mcl-1 reduction. We provide a new triple combination for AML treatment by targeting the Noxa/Mcl-1/Bim axis to reverse Mcl-1/p-Chk1 resistance of cytarabine therapy.


Assuntos
Citarabina , Leucemia Mieloide Aguda , Idoso , Animais , Apoptose , Proteínas Reguladoras de Apoptose , Artesunato/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Citarabina/farmacologia , Citarabina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas
3.
Biomed Res Int ; 2022: 9170053, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35372571

RESUMO

NSCLC (non-small-cell lung cancer) is the deadliest cancer in the world. Artesunate is one of the most potent and rapidly acting antimalarial agents. Recently, emerging evidence has suggested the anticancer function of artesunate. In our work, we aimed to investigate the molecular mechanism of artesunate-induced growth inhibition in human lung adenocarcinoma cells and reported that the anticancer effects of artesunate is related to its ability in downregulating AKT/Survivin signaling in A549 cells. The effect of artesunate on the proliferation of A549 cells was determined by CCK-8 assay and colony formation assay; its effect on A549 cell apoptosis was evaluated by lactate dehydrogenase (LDH) release assay. The role of artesunate on the activation of AKT/Survivin signaling was analyzed by western blot and quantitative QPCR. Finally, we used two mouse tumor models to investigate the function of artesunate on the in vivo growth of lung cancer cells. Artesunate treatment caused significant growth inhibition and apoptosis in A549 cells. Mechanistically, artesunate downregulated the activation of AKT/Survivin signaling. In agreement, hyperactivation of AKT signaling restored artesunate-induced growth inhibition in A549 cells. In mouse lung cancer models, artesunate administration significantly reduced the growth of A549 cells and LLC cells in nude mice and immunocompetent mice, respectively. Our findings suggest that artesunate serves as a potential tumor suppressor in lung cancer and hopefully can provide new insight into the development of therapeutic strategies in the clinical lung cancer treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células A549 , Animais , Apoptose , Artesunato/farmacologia , Artesunato/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Survivina/metabolismo
4.
Bioengineered ; 13(3): 6590-6599, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35361045

RESUMO

We aimed to assess the effects of artesunate (ART) on the proliferation, migration, invasion and apoptosis of the non-small cell lung cancer cells A549 and H1299. The effects of ART and carboplatin (CBP) alone or in combination on the viability of A549 and H1299 cells were evaluated by MTT assay. The effects of 30 µg/ml ART on cell invasion, migration and apoptosis were evaluated by Transwell assay, scratch assay and flow cytometry, respectively. The protein expressions of human antigen R (HuR) and MMP-9 after treatment with 30 µg/ml ART for 48 h were detected by Western blotting. After 48 h of treatment, 9 µg/ml ART in combination with 7 µg/ml CBP exerted a mild synergistic effect on cell viability. The migration rates of cells treated with 30 µg/ml ART and number of invasive cells were significantly lower, and the apoptosis rates were higher than those of the DMSO-treated group. HuR and MMP-9 expressions in cells treated with 30 µg/ml ART for 48 h were significantly lower than those of the DMSO-treated group. ART suppresses the proliferation, migration and invasion of A549 and H1299 cells and induces their apoptosis, probably being associated with decreased expressions of HuR and MMP-9 proteins.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células A549 , Apoptose , Artesunato/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Dimetil Sulfóxido/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Transdução de Sinais
5.
Parasite ; 29: 18, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35348455

RESUMO

Artesunate is the current most potent antimalarial drug widely used for the treatment of malaria. Considering the emergence of artemisinin resistance, several situations may require a simple method for artesunate quantification. We thus developed a quantitative and a semi-quantitative biological method for the determination of artesunate in liquid samples. The tests are based on the measurement of samples' antimalarial activity on Plasmodium falciparum 3D7 using a modified SYBR Green I drug susceptibility test. For the quantitative test, we established a standard curve that resulted from a dose-response curve and evaluated its performances using controls samples. Whereas the linear regression analysis between artesunate concentration and antimalarial activity showed promising results (linearity range 1.5-24.6 ng/mL, r2 = 0.9373), we found that artesunate content of the controls was significantly overestimated (p = 0.0313). For the semi-quantitative test, we compared the antimalarial activities of samples collected during permeation studies of artesunate to that of a reference (artesunate IC50) by statistical analysis. We demonstrated that antimalarial activities of samples from permeation tests using a powder formulation of artesunate were greater than those of samples from tests using a solution formulation. Bioassays can be simple techniques to assess artesunate in liquid samples, particularly in resource-limited settings. Comparison with reference methods is still recommended when accurate drug quantification is required.


Title: Évaluation de méthodes de tests biologiques quantitatives et semi-quantitatives de l'artésunate in vitro. Abstract: L'artésunate est le médicament antipaludique le plus puissant actuellement, largement utilisé pour le traitement du paludisme. Compte tenu de l'émergence de la résistance à l'artémisinine, plusieurs situations peuvent nécessiter une méthode simple de quantification de l'artésunate. Nous avons ainsi développé un test biologique quantitatif et un test semi-quantitatif pour le dosage de l'artésunate dans des échantillons liquides. Les méthodes sont basées sur la mesure de l'activité antipaludique des échantillons sur Plasmodium falciparum 3D7 à l'aide d'un test de sensibilité aux médicaments SYBR Green I modifié. Pour le test quantitatif, nous avons établi une courbe standard issue d'une courbe dose-réponse et évalué ses performances à l'aide d'échantillons témoins. Alors que l'analyse de régression linéaire entre la concentration d'artésunate et l'activité antipaludique a montré des résultats prometteurs (gamme de linéarité de 1,5 à 24,6 ng/mL, r2 = 0,9373), nous avons constaté que la teneur en artésunate des témoins était significativement surestimée (p = 0,0313). Pour le test semi-quantitatif, nous avons comparé les activités antipaludiques d'échantillons collectés lors des études de perméation de l'artésunate à celle d'une référence (artésunate IC50) par analyse statistique. Nous avons démontré que les activités antipaludiques des échantillons provenant de tests de perméation utilisant une formulation en poudre d'artésunate étaient supérieures à celles des échantillons provenant de tests utilisant une formulation en solution. Les dosages biologiques peuvent être des techniques simples pour évaluer l'artésunate dans des échantillons liquides, en particulier dans les milieux à ressources limitées. La comparaison avec des méthodes de référence est toujours recommandée lorsqu'une quantification précise du médicament est requise.


Assuntos
Antimaláricos , Malária Falciparum , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artesunato/farmacologia , Artesunato/uso terapêutico , Humanos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum
6.
Cell Commun Signal ; 20(1): 34, 2022 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-35305671

RESUMO

BACKGROUND: KRAS mutation is one of the dominant gene mutations in colorectal cancer (CRC). Up to present, targeting KRAS for CRC treatment remains a clinical challenge. WNT974 (LGK974) is a porcupine inhibitor that interferes Wnt signaling pathway. Artesunate (ART) is a water-soluble semi-synthetic derivative of artemisinin. METHODS: The synergistic effect of ART and WNT974 combination in reducing CRC cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RT-PCR was utilized for the mRNA levels of KRAS, CUL7, ANAPC2, UBE2M, RNF123, SYVN1, or ß-TrCP. Western blot assay was utilized for the protein levels of NRAS, HRAS, KRAS, ANAPC2, ß-TrCP, GSK-3ß, p-Akt (Ser473), t-Akt, p-PI3K (Tyr458), t-PI3K, p-mTOR (Ser2448), t-mTOR. Xenograft mouse model assay was performed for the anti-CRC effect of combination of ART and WNT974 in vivo. IHC assay was utilized for the levels of KRAS, ß-TrCP, GSK-3ß or ANAPC2 in tumor tissues. RESULTS: Our study shows that the combination of WNT974 and ART exhibits synergistic effect in reducing CRC growth. The combination treatment significantly reduces KRAS protein level and activity in CRC cells. Interestingly, the combination treatment increases E3 ligases ANAPC2 expression. Our data show that overexpression of ANAPC2 significantly reduces KRAS protein levels, which is reversed by MG132. Knockdown of ANAPC2 in CRC abolishes the combination treatment-reduce KRAS expression. Besides, the treatment also increases the expressions of GSK-3ß and E3 ligase ß-TrCP that is known to degrade GSK-3ß-phosphorylated KRAS protein. Knockdown of ß-TrCP- and inhibition of GSK-3ß abolish the combination treatment-induce KRAS ubiquitination and reduction in expression. Last but not least, combination treatment suppresses PI3K/Akt/m-TOR signaling pathway. CONCLUSIONS: Our data clearly show that the combination treatment significantly enhances KRAS protein degradation via the ubiquitination ubiquitin-proteasome pathway, which is also demonstrated in xenograft mouse model. The study provides strong scientific evidence for the development of the combination of WNT974 and ART as KRAS-targeting therapeutics for CRC treatment. Video Abstract.


Assuntos
Ubiquitina-Proteína Ligases , Proteínas Contendo Repetições de beta-Transducina , Animais , Subunidade Apc2 do Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Artesunato/farmacologia , Linhagem Celular Tumoral , Proteínas Culina , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Pirazinas , Piridinas , Serina-Treonina Quinases TOR/metabolismo , Enzimas de Conjugação de Ubiquitina , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas/metabolismo , Via de Sinalização Wnt , Proteínas Contendo Repetições de beta-Transducina/genética , Proteínas Contendo Repetições de beta-Transducina/metabolismo
7.
J Pharmacol Sci ; 148(3): 300-306, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35177209

RESUMO

Ferroptosis is implicated in various tumors, including glioblastoma. Artesunate (ART), an anti-malarial drug, exerted antitumor properties in several cancer types. However, the role of ferroptosis in the inhibiting effect of artesunate on glioblastoma remains unclear. The purpose of this study was to investigate the effects of ART on the ferroptosis of glioblastoma and to elucidate the underlying mechanisms. We found that ART inhibited the proliferation of glioblastoma cells in vitro and glioblastoma tumorigenesis in vivo. Characteristic changes of ferroptosis were observed in ART group, including GSH depletion, lipid peroxidation and iron overload. Meanwhile, the protein level of GPX4 were lower in ART group than that in control group. Ferrostatin-1, a ferroptosis inhibitor, could rescue the cell death induced by ART in U251 cells. Further examination of the mechanism revealed that the effect of ART on ferroptosis was partially governed by regulating iron homeostasis and p38 and ERK signaling pathway. These findings support that ART triggers ferroptosis in glioblastoma and might be a potential therapeutic agent for glioblastoma treatment.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos , Artesunato/farmacologia , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Glioblastoma/genética , Glioblastoma/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Glioblastoma/tratamento farmacológico , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Ferro/metabolismo , Terapia de Alvo Molecular , Espécies Reativas de Oxigênio/metabolismo
8.
Int J Mol Sci ; 23(3)2022 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-35163507

RESUMO

Normal activation of platelets and their aggregation are crucial for proper hemostasis. It appears that excessive or abnormal aggregation of platelets may bring about cardiovascular diseases such as stroke, atherosclerosis, and thrombosis. For this reason, finding a substance that can regulate platelet aggregation or suppress aggregation will aid in the prevention and treatment of cardiovascular diseases. Artesunate is a compound extracted from the plant roots of Artemisia or Scopolia, and its effects have shown to be promising in areas of anticancer and Alzheimer's disease. However, the role and mechanisms by which artesunate affects the aggregation of platelets and the formation of a thrombus are currently not understood. This study examines the ways artesunate affects the aggregation of platelets and the formation of a thrombus on platelets induced by U46619. As a result, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) production were increased significantly by artesunate relative to the doses, as well as phosphorylated vasodilator-stimulated phosphoprotein (VASP) and inositol 1,4,5-trisphosphate receptor (IP3R), substrates to cAMP-dependent kinase and cGMP-dependent kinase, in a significant manner. The Ca2+, normally mobilized from the dense tubular system, was inhibited due to IP3R phosphorylation from artesunate, and phosphorylated VASP aided in inhibiting platelet activity via αIIb/ß3 platelet membrane inactivation and inhibiting fibrinogen binding. In addition, MAPK and PI3K/Akt phosphorylation was inhibited via artesunate in a significant manner, causing the production of TXA2 and intracellular granular secretion (serotonin and ATP release) to be reduced. Therefore, we suggest that artesunate has value as a substance that inhibits platelet aggregation and thrombus formation through an antiplatelet mechanism.


Assuntos
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/efeitos adversos , Artesunato/farmacologia , AMP Cíclico/metabolismo , Fibrinolíticos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Cálcio/metabolismo , GMP Cíclico/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Tromboxano A2/metabolismo
9.
J Cell Biochem ; 123(2): 155-160, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34668225

RESUMO

Drug repurposing is an attractive option for identifying new treatment strategies, in particular in extraordinary situations of urgent need such as the current coronavirus disease 2019 (Covid-19) pandemic. Recently, the World Health Organization announced testing of three drugs as potential Covid-19 therapeutics that are known for their dampening effect on the immune system. Thus, the underlying concept of selecting these drugs is to temper the potentially life-threatening overshooting of the immune system reacting to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This viewpoint discusses the possibility that the impact of these and other drugs on autophagy contributes to their therapeutic effect by hampering the SARS-CoV-2 life cycle.


Assuntos
Antivirais/farmacologia , Artesunato/farmacologia , Autofagia/efeitos dos fármacos , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Mesilato de Imatinib/farmacologia , Infliximab/farmacologia , Pandemias , SARS-CoV-2/efeitos dos fármacos , Antidepressivos/farmacologia , Antivirais/uso terapêutico , Artesunato/uso terapêutico , Cloroquina/farmacologia , Desenvolvimento de Medicamentos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/virologia , Endossomos/efeitos dos fármacos , Endossomos/virologia , Humanos , Hidroxicloroquina/farmacologia , Mesilato de Imatinib/uso terapêutico , Infliximab/uso terapêutico , Membranas Intracelulares/efeitos dos fármacos , Membranas Intracelulares/fisiologia , Membranas Intracelulares/virologia , Ivermectina/farmacologia , Macrolídeos/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Niclosamida/farmacologia , Niclosamida/uso terapêutico , RNA Viral/metabolismo , SARS-CoV-2/fisiologia , Replicação Viral
10.
J Virol ; 96(3): e0148721, 2022 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-34787456

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the pork industry worldwide. Currently, vaccine strategies provide limited protection against PRRSV transmission, and no effective drug is commercially available. Therefore, there is an urgent need to develop novel antiviral strategies to prevent PRRSV pandemics. This study showed that artesunate (AS), one of the antimalarial drugs, potently suppressed PRRSV replication in Marc-145 cells and ex vivo primary porcine alveolar macrophages (PAMs) at micromolar concentrations. Furthermore, we demonstrated that this suppression was closely associated with AS-activated AMPK (energy homeostasis) and Nrf2/HO-1 (inflammation) signaling pathways. AS treatment promoted p-AMPK, Nrf2, and HO-1 expression and, thus, inhibited PRRSV replication in Marc-145 and PAM cells in a time- and dose-dependent manner. These effects of AS were reversed when the AMPK or HO-1 gene was silenced by short interfering RNA. In addition, we demonstrated that AMPK works upstream of Nrf2/HO-1, as its activation by AS is AMPK dependent. Adenosine phosphate analysis showed that AS activates AMPK via improving the AMP/ADP-to-ATP ratio rather than direct interaction with AMPK. Altogether, our findings indicate that AS is a promising novel therapeutic for controlling PRRSV and that its anti-PRRSV mechanism, which involves the functional link between energy homeostasis and inflammation suppression pathways, may provide opportunities for developing novel antiviral agents. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) infections have continuously threatened the pork industry worldwide. Vaccination strategies provide very limited protection against PRRSV infection, and no effective drug is commercially available. We show that artesunate (AS), one of the antimalarial drugs, is a potent inhibitor against PRRSV replication in Marc-145 cells and ex vivo primary porcine alveolar macrophages (PAMs). Furthermore, we demonstrate that AS inhibits PRRSV replication via activation of AMPK-dependent Nrf2/HO-1 signaling pathways, revealing a novel link between energy homeostasis (AMPK) and inflammation suppression (Nrf2/HO-1) during viral infection. Therefore, we believe that AS may be a promising novel therapeutics for controlling PRRSV, and its anti-PRRSV mechanism may provide a strategy to develop novel antiviral agents.


Assuntos
Antimaláricos/farmacologia , Artesunato/farmacologia , Síndrome Respiratória e Reprodutiva Suína/metabolismo , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/efeitos dos fármacos , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antimaláricos/química , Artesunato/química , Linhagem Celular , Suscetibilidade a Doenças , Heme Oxigenase-1/metabolismo , Interações Hospedeiro-Patógeno , Modelos Biológicos , Fator 2 Relacionado a NF-E2/metabolismo , Suínos
11.
Ann Parasitol ; 68(1): 111-120, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35491857

RESUMO

This study investigates the effects of Ficus platyphylla and artesunate combination on the prognosis of malaria in parasitized mice. Five groups (n=6) of mice were used. Groups one and two were normal control (NC) and parasitemia control (PC) respectively. Groups 3-5 were all parasitized and administered 300 mg/kg of the extract (FPE300), 5 mg/kg artesunate (ART5), and a combination of both (ART5+FPE300) respectively. Within the five days of oral treatments, daily packed cell volume (PCV) and parasitemia load were measured. The experiment was terminated by cervical dislocation. Blood samples were immediately taken by cardiac puncture and separated into plasma and serum. Plasma samples were used to determine erythrocytes, haemoglobin and leukocytes while some cytokines (TNF- α, IL-10), antioxidant profile (malondialdehyde, reduced gluthathione, catalase, superoxide dismutase), renal (urea, creatinine, uric acid), and hepatic markers (alanine transferase, aspartate transferase, alkaline phosphatase) were assessed from serum. Administration of ART5+FPE300 significantly (P<0.01) reduced daily parasitemia load and PCV compared to PC, with erythrocytes, haemoglobin and leukocytes values being comparable to NC. In addition, this drug- herb combination significantly (P<0.05) mitigated inflammatory response, oxidative stress and hepato-renal toxicities respectively compared to PC. Co-administration of Ficus platyphylla and artesunate improves the prognosis of malaria and the resulting pathological consequences by inhibiting inflammatory response and oxidative stress in parasitized mice.


Assuntos
Antimaláricos , Ficus , Malária , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artesunato/farmacologia , Artesunato/uso terapêutico , Citocinas , Combinação de Medicamentos , Ficus/metabolismo , Interleucina-10/farmacologia , Interleucina-10/uso terapêutico , Malária/tratamento farmacológico , Camundongos , Estresse Oxidativo , Parasitemia/tratamento farmacológico , Plasmodium berghei/metabolismo , Transferases/farmacologia , Transferases/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/uso terapêutico
12.
Cancer Genomics Proteomics ; 19(1): 19-26, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34949656

RESUMO

BACKGROUND/AIM: The aberrant regulation of erythropoietin-producing hepatocellular carcinoma (EPH) receptors and ephrin ligands has been implicated in breast carcinoma, and artesunate has been shown to have anticancer effects. The aim of this study was to characterize the involvement of EPH receptors and ephrin ligands in mediating artesunate (ART)-induced growth suppression of normal breast cells and breast carcinoma cell lines. MATERIALS AND METHODS: The normal breast epithelial cells (MCF10A), non-invasive ductal breast carcinoma cells (MCF7), and invasive triple-negative breast carcinoma cells (MDA-MB-231) were grown in the absence or the presence of different concentrations of artesunate. The cells were counted, and total RNA was isolated. The abundance of transcripts corresponding to EPH receptors and ephrin ligands was determined by quantitative polymerase chain reaction. RESULTS: Cell viability was significantly reduced when cells were treated with artesunate, with MDA-MB-231 cells having the highest sensitivity. Artesunate had no significant effect on transcription of EPH/ephrins in MCF10A cells, but markedly increased EPHA8, EPHA10, EPHB6 and ephrin-A2 expression in MCF7 cells, and significantly increased EPHA3 and EPHA10 expression while reducing that of EPHA7 and ephrin-A3 in MDA-MB-231 cells. CONCLUSION: The relative changes in artesunate-treated MCF7 and MDA-MB-231 cells as compared to similarly treated MCF10A cells allow us to implicate combinatorial expression and receptor interactions for EPH receptor-mediated signal transduction that converges into pathways responsible for cell growth, proliferation, and apoptosis. Specifically, the alterations in EPHA7, EPHA8, EPHA10 and EPHB6 transcripts appear to be important participants in artesunate-mediated cellular effects.


Assuntos
Artesunato/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Efrinas/metabolismo , Receptores da Família Eph/metabolismo , Apoptose/efeitos dos fármacos , Artesunato/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Ligantes , Células MCF-7 , Transdução de Sinais/efeitos dos fármacos
13.
Aging (Albany NY) ; 13(23): 25325-25341, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887359

RESUMO

OBJECTIVE: Artesunate, a semi-synthetic derivative of artemisinin, exerts various pharmacological activities. Nevertheless, the effects of Art on skin photoaging remain unclear. Herein, we investigated whether Art ameliorated ultraviolet-irradiated skin photoaging in HaCaT cells and mice. METHODS: To construct skin photoaging cellular models, HaCaT cells were irradiated by UV (UVB, 20mJ/cm2) for 5 days. HaCaT cells were pretreated with three concentrations of Art (1, 5 and 20 µg/ml) for 2 h each day. After 5 days, cell senescence, ROS production, SOD levels, p16INK4a and ß-catenin expression, proliferation and apoptosis were detected in HaCaT cells. Effects of Art on normal cells were investigated. After sh-ß-catenin transfection or XAV-939 treatment, HaCaT cells were pretreated with 20 µg/ml Art and irradiated by UVB. After 5 days, skin photoaging was then observed. Furthermore, skin photoaging mouse models were established and the effects of Art and ß-catenin silencing on skin photoaging were investigated. RESULTS: Art treatment suppressed cell senescence, intracellular ROS production, p16INK4a expression and apoptosis and promoted proliferation and SOD and ß-catenin expression in UVB irradiated HaCaT cells. But Art had no toxic effects on normal cells. Silencing ß-catenin by sh-ß-catenin or XAV-939 exacerbated UVB irradiation-mediated cell senescence, apoptosis, and ROS production in HaCaT cells, which was ameliorated by Art treatment. The therapeutic effects of Art on skin photoaging were also confirmed in mouse models. CONCLUSIONS: These findings suggested that Art treatment alleviated UVB irradiation-driven skin photoaging through enhancing ß-catenin expression, which offered novel clues for pharmacological activity of Art.


Assuntos
Artesunato/farmacologia , Envelhecimento da Pele/efeitos da radiação , beta Catenina/metabolismo , Animais , Células HaCaT/efeitos dos fármacos , Células HaCaT/efeitos da radiação , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Envelhecimento da Pele/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Raios Ultravioleta/efeitos adversos
14.
Exp Eye Res ; 213: 108859, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34822854

RESUMO

Proliferative vitreoretinopathy (PVR) is the main cause of retinal detachment surgery failure. The epithelial-mesenchymal transition (EMT) induced by transforming growth factor (TGF-ß2) plays an important role in the development of PVR. Artesunate has been widely studied as a treatment for ophthalmic diseases because of its antioxidant, anti-inflammatory, antiapoptotic and antiproliferative properties. The purpose of this study was to investigate the effects of artesunate on the TGF-ß2-induced EMT in ARPE-19 cells and PVR development. We found that artesunate inhibited the proliferation and contraction of ARPE-19 cells after the EMT and the autocrine effects of TGF-ß2 on ARPE-19 cells. Additionally, the levels of Smad3 and p-Smad3 were increased in clinical samples, and artesunate decreased the levels of Smad3 and p-Smad3 in ARPE-19 cells treated with TGF-ß2. Artesunate also inhibited the occurrence and development of PVR in vivo. In summary, artesunate inhibits the occurrence and development of PVR by inhibiting the EMT in ARPE-19 cells.


Assuntos
Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Proteína Smad3/antagonistas & inibidores , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Vitreorretinopatia Proliferativa/tratamento farmacológico , Animais , Antimaláricos/farmacologia , Artesunato/farmacologia , Western Blotting , Ciclo Celular/fisiologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Injeções Intravítreas , Coelhos , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Vitreorretinopatia Proliferativa/metabolismo
15.
Biomed Pharmacother ; 143: 112211, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34649344

RESUMO

Lipopolysaccharide (LPS) is the major component of the outer membrane of Gram-negative bacteria and is usually administrated to establish models of inflammation. Artesunate (ART), a water-soluble artemisinin derivative, displays multiple pharmacological actions against tumors, viral infections, and inflammation, and has been used as a therapeutic weapon against malaria. In this study, our aim was to evaluate whether ART pretreatment is capable of preventing inflammation induced by LPS. BALB/c mice were treated with 100 mg/kg of ART i.p. for 7 days followed by a single dose of LPS. ART pretreatment led to an improvement in clinical score, prevented alterations in biochemical markers, and reestablished the platelet counts. Flow cytometry analysis showed that ART protected the inflammation mainly by reducing the percentage of M1 macrophages while increasing M2 macrophages and a reestablishment of classical monocytes in the BM. In the spleen, ART pretreatment increased N2 neutrophils, myeloid-derived suppressor cells (MDSC), and regulatory T cells, the latter was also increased in peripheral blood. In addition, a marked decrease in inflammatory cytokines and chemokines was observed in the ART treated group. Our data suggest that ART prevents inflammation, reducing tissue damage and restoring homeostasis.


Assuntos
Anti-Inflamatórios/farmacologia , Artesunato/farmacologia , Inflamação/prevenção & controle , Células Mieloides/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fenótipo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
16.
Malar J ; 20(1): 408, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663346

RESUMO

BACKGROUND: Standard treatment for both uncomplicated and severe malaria is artemisinin derivatives. Delayed parasite clearance times preceded the appearance of artemisinin treatment failures in Southeast Asia. Most worldwide malaria cases are in sub-Saharan Africa (SSA), where clinically significant artemisinin resistance or treatment failure has not yet been detected. The recent emergence of a resistance-conferring genetic mutation in the Plasmodium falciparum parasite in Africa warrants continued monitoring throughout the continent. METHODS: An analysis was performed on data from a retrospective cohort study of Malawian children with cerebral malaria admitted between 2010 and 2019 to a public referral hospital, ascertaining parasite clearance times across years. Data were collected from patients treated for severe malaria with quinine or artesunate, an artemisinin derivative. Parasite density was determined at admission and every subsequent 6 h until parasitaemia was below 1000 parasites/µl.The mean parasite clearance time in all children admitted in any one year was compared to the parasite clearance time in 2014, the first year of artesunate use in Malawi. RESULTS: The median population parasite clearance time was slower from 2010 to 2013 (quinine-treated patients) compared to 2014, the first year of artesunate use in Malawi (30 h (95% CI: 30-30) vs 18 h (95% CI: 18-24)). After adjustment for admission parasite count, there was no statistically significant difference in the median population parasite clearance time when comparing 2014 with any subsequent year. CONCLUSION: Malaria parasite clearance times in Malawian children with cerebral malaria remained constant between 2014 and 2019, arguing against evolving artemisinin resistance in parasites in this region.


Assuntos
Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Malária Cerebral/parasitologia , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Quinina/uso terapêutico , Adolescente , Antimaláricos/farmacologia , Artesunato/farmacologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Malária Cerebral/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Malaui , Masculino , Quinina/farmacologia , Estudos Retrospectivos , Fatores de Tempo
17.
Cell Signal ; 88: 110167, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34628002

RESUMO

Artesunate (ART), a water-soluble derivative of artemisinin, has been reported to exert antineoplastic effects via diverse mechanisms in various types of cancer. Therefore, understanding the underlying mechanism of action of ART in distinct cancer types is indispensable to optimizing the therapeutic application of ART for different types of cancer. The present study aimed to investigate the cellular and molecular mechanisms responsible for the antineoplastic effects of ART in diffuse large B cell lymphoma (DLBCL) cells. Cell proliferation was measured using Cell Counting Kit-8 and colony formation assays. The levels of apoptosis and cell cycle distribution were investigated using flow cytometry. In addition, western blotting was used to analyze the expression levels of ART-induced apoptosis-, autophagy- and ferroptosis-related proteins. Monodansylcadaverine staining was performed to determine the levels of autophagy. Moreover, malondialdehyde and reactive oxygen species assays were used to determine the levels of ferroptosis. The results of the present study revealed that ART inhibited proliferation, and induced apoptosis, cell cycle arrest, autophagy and ferroptosis in DLBCL cells. Pharmacological inhibition of autophagy and ferroptosis alleviated the increased levels of apoptosis induced by ART. Notably, ART was found to exert its effects via inhibition of STAT3 activation. The genetic knockdown of STAT3 enhanced ART-induced autophagy and ferroptosis, and concomitantly upregulated the expression levels of apoptosis- and cell cycle-related proteins. In conclusion, the findings of the current study suggested that ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in DLBCL cells.


Assuntos
Ferroptose , Linfoma Difuso de Grandes Células B , Apoptose , Artesunato/farmacologia , Artesunato/uso terapêutico , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Fator de Transcrição STAT3 , Transdução de Sinais
18.
Angew Chem Int Ed Engl ; 60(50): 26254-26259, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34591365

RESUMO

Clinical translation of artesunate (ATS) as a potent antitumor drug has been obstructed by its rapid degradation and low bioavailability. Herein, we report the development of an ATS nanomedicine through the self-assembly with Mn[Co(CN)6 ]2/3 □1/3 metal-organic frameworks (MOFs) that have hidden missing linkers. The defects in MOFs originating from the missing linkers play a key role in increasing the biological stability and tumor accumulation of ATS. Chlorin e6 (Ce6) and ATS can be co-loaded into MOFs for a synergistic antitumor efficacy. In the presence of intracellular HCO3 - , Mn2+ acts as an efficient catalyst to promote the bicarbonate-activated H2 O2 system which oxidizes ATS to generate reactive oxygen species and induce oxidative death to cancer cells. The released [CoIII (CN)6 ] linker undergoes a redox reaction with intracellular glutathione to prevent the scavenging ability of reactive oxygen species, contributing to synergistic chemodynamic therapy of ATS and photodynamic therapy of Ce6. Thus, defect-engineered MOFs with hidden missing linkers hold great promise in advancing the practical use of ATS as an antitumor medicine.


Assuntos
Antineoplásicos/farmacologia , Artesunato/farmacologia , Neoplasias da Mama/tratamento farmacológico , Estruturas Metalorgânicas/química , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/química , Artesunato/química , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo
19.
Molecules ; 26(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34577169

RESUMO

Artemisinin (also known as Qinghaosu), an active component of the Qinghao extract, is widely used as antimalarial drug. Previous studies reveal that artemisinin and its derivatives also have effective anti-inflammatory and immunomodulatory properties, but the direct molecular target remains unknown. Recently, several reports mentioned that myeloid differentiation factor 2 (MD-2, also known as lymphocyte antigen 96) may be the endogenous target of artemisinin in the inhibition of lipopolysaccharide signaling. However, the exact interaction between artemisinin and MD-2 is still not fully understood. Here, experimental and computational methods were employed to elucidate the relationship between the artemisinin and its inhibition mechanism. Experimental results showed that artemether exhibit higher anti-inflammatory activity performance than artemisinin and artesunate. Molecular docking results showed that artemisinin, artesunate, and artemether had similar binding poses, and all complexes remained stable throughout the whole molecular dynamics simulations, whereas the binding of artemisinin and its derivatives to MD-2 decreased the TLR4(Toll-Like Receptor 4)/MD-2 stability. Moreover, artemether exhibited lower binding energy as compared to artemisinin and artesunate, which is in good agreement with the experimental results. Leu61, Leu78, and Ile117 are indeed key residues that contribute to the binding free energy. Binding free energy analysis further confirmed that hydrophobic interactions were critical to maintain the binding mode of artemisinin and its derivatives with MD-2.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artemisininas/química , Artemisininas/farmacologia , Antígeno 96 de Linfócito/antagonistas & inibidores , Antígeno 96 de Linfócito/química , Animais , Artemeter/farmacologia , Artesunato/farmacologia , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Imunomodulação/efeitos dos fármacos , Técnicas In Vitro , Lipopolissacarídeos/toxicidade , Camundongos , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Óxido Nítrico/metabolismo , Ligação Proteica , Termodinâmica , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/química , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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