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1.
Oxid Med Cell Longev ; 2022: 5401760, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35528521

RESUMO

Background: Artemisinin and its derivatives have potential antidiabetic effects. There is no evaluation of reported studies in the literature on the treatment of diabetic nephropathy (DN), one of the commonest diabetic microangiopathies, with artemisinins. Here, we aimed to evaluate preclinical evidence for the efficacy and possible mechanisms of artemisinins in reducing diabetic renal injury. Methods: We conducted an electronic literature search in fourteen databases from their inception to November 2021. All animal studies assessing the efficacy and safety of artemisinins in DN were included, regardless of publication or language. Overall, 178 articles were screened according to predefined inclusion and exclusion criteria. Finally, 18 eligible articles were included in this systematic review. The SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool was used to assess the risk of bias in the included studies. The primary outcomes were kidney function, proteinuria, and renal pathology. Secondary endpoints included changes in fasting plasma glucose (FPG) levels, body weight, and relevant mechanisms. Results: Of the 18 included articles involving 418 animal models of DN, 1, 2, 6, and 9 used dihydroartemisinin, artemether, artesunate, and artemisinin, respectively. Overall, artemisinins reduced indicators of renal function, including blood urea nitrogen (P < 0.00001), serum creatinine (P < 0.00001), and kidney index (P = 0.0001) compared with control group treatment. Measurements of proteinuria (P < 0.00001), microalbuminuria (P < 0.05), and protein excretion (P = 0.0002) suggested that treatment with artemisinins reduced protein loss in animals with DN. Artemisinins may lower blood glucose levels (P = 0.01), but there is a risk of weight gain (P < 0.00001). Possible mechanisms of action of artemisinins include delaying renal fibrosis, reducing oxidative stress, and exerting antiapoptotic and anti-inflammatory effects. Conclusion: Available evidence suggests that artemisinins may be protective against renal injury secondary to diabetes in preclinical studies; however, high-quality and long-term trials are needed to reliably determine the balance of benefits and harms.


Assuntos
Artemisininas , Diabetes Mellitus , Nefropatias Diabéticas , Animais , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Feminino , Humanos , Masculino , Modelos Animais , Proteinúria
2.
ChemistryOpen ; 11(5): e202200064, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35543215

RESUMO

The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin-based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin-resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8-amino- or 8-hydroxyquinoline entity covalently bound to a 1,4-naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC50 =622 nm on an artemisinin-resistant P. falciparum strain) and no cytotoxicity at 50 µm indicating a specific antiplasmodial mode of action.


Assuntos
Antimaláricos , Artemisininas , Antagonistas do Ácido Fólico , Plasmodium , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/farmacologia , Atovaquona/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Plasmodium falciparum
3.
PLoS One ; 17(5): e0268095, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35511795

RESUMO

In Uganda, Artemether-Lumefantrine and Artesunate are recommended for uncomplicated and severe malaria respectively, but are currently threatened by parasite resistance. Genetic and epigenetic factors play a role in predisposing Plasmodium falciparum parasites to acquiring Pfkelch13 (K13) mutations associated with delayed artemisinin parasite clearance as reported in Southeast Asia. In this study, we report on the prevalence of mutations in the K13, pfmdr-2 (P. falciparum multidrug resistance protein 2), fd (ferredoxin), pfcrt (P. falciparum chloroquine resistance transporter), and arps10 (apicoplast ribosomal protein S10) genes in Plasmodium falciparum parasites prior to (2005) and after (2013) introduction of artemisinin combination therapies for malaria treatment in Uganda. A total of 200 P. falciparum parasite DNA samples were screened. Parasite DNA was extracted using QIAamp DNA mini kit (Qiagen, GmbH, Germany) procedure. The PCR products were sequenced using Sanger dideoxy sequencing method. Of the 200 P. falciparum DNA samples screened, sequencing for mutations in K13, pfmdr-2, fd, pfcrt, arps10 genes was successful in 142, 186, 141, 128 and 74 samples respectively. Overall, we detected six (4.2%, 6/142; 95%CI: 1.4-7.0) K13 single nucleotide polymorphisms (SNPs), of which 3.9% (2/51), 4.4% (4/91) occurred in 2005 and 2013 samples respectively. All four K13 SNPs in 2013 samples were non-synonymous (A578S, E596V, S600C and E643K) while of the two SNPs in 2005 samples, one (Y588N) is non-synonymous and the other (I587I) is synonymous. There was no statistically significant difference in the prevalence of K13 (p = 0.112) SNPs in the samples collected in 2005 and 2013. The overall prevalence of SNPs in pfmdr-2 gene was 39.8% (74/186, 95%CI: 25.1-50.4). Of this, 4.2% (4/95), 76.9% (70/91) occurred in 2005 and 2013 samples respectively. In 2005 samples only one SNP, Y423F (4.2%, 4/95) was found while in 2013, Y423F (38.5%, 35/91) and I492V (38.5%, 35/91) SNPs in the pfmdr-2 gene were found. There was a statistically significant difference in the prevalence of pfmdr-2 SNPs in the samples collected in 2005 and 2013 (p<0.001). The overall prevalence of arps10 mutations was 2.7% (2/72, 95%CI: 0.3-4.2). Two mutations, V127M (4.5%: 1/22) and D128H (4.5%: 1/22) in the arps10 gene were each found in P. falciparum parasite samples collected in 2013. There was no statistically significant difference in the prevalence of arps10 SNPs in the samples collected in 2005 and 2013 (p = 0.238). There were more pfmdr-2 SNPs in P. falciparum parasites collected after introduction of Artemisinin combination therapies in malaria treatment. This is an indicator of the need for continuous surveillance to monitor emergence of molecular markers of artemisinin resistance and its potential drivers in malaria affected regions globally.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Malária , Parasitos , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Resistência a Medicamentos/genética , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/genética , Mutação , Parasitos/metabolismo , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Prevalência , Proteínas de Protozoários/metabolismo , Uganda/epidemiologia
4.
Parasit Vectors ; 15(1): 130, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35413937

RESUMO

BACKGROUND: The fast-declining clinical efficacy of dihydroartemisinin-piperaquine (DHA-PPQ) in Cambodia is a warning of the underlying westward dissemination of piperaquine resistance in the Greater Mekong Subregion (GMS). Mutations in the Plasmodium falciparum Kelch 13-propeller (PfK13) and the P. falciparum chloroquine resistance transporter (PfCRT), as well as plasmepsin 2/3 gene amplification, have been discovered as molecular markers for predicting DHA-PPQ treatment failure. Determining whether these genetic variations of P. falciparum are linked to DHA-PPQ resistance is critical, especially along the China-Myanmar (CM) border, where PPQ has been utilized for decades. METHODS: A total of 173 P. falciparum samples of dried blood spots (DBS) were collected along the CM border between 2007 and 2010, the Thailand-Cambodia (TC) border between 2009 and 2013, and the Thailand-Myanmar (TM) border between 2012 and 2014. PCR and sequencing were used to identified PfCRT mutations, while qPCR was used to determine the copy number of plasmepsin 2/3. The prevalence of DHA-PPQ resistance in three locations was investigated using data paired with K13 mutations. RESULTS: Three fragments of the pfcrt gene were amplified for all 173 samples, and seven SNPs were identified (M74I, N75E/D, K76T, H97L, I218F, A220S, I356L). No new PfCRT mutations conferring resistance to PPQ (T93S, H97Y, F145I, M343L, and G353V) were discovered, except for one mutant I218F identified in the TM border (2.27%, 1/44). Additionally, mutant H97L was found in the TC, TM, and CM borders at 3.57% (1/28), 6.82% (3/44), and 1% (1/101), respectively. A substantial K13 C580Y variant prevalence was found in the TC and TM border, accounting for 64.29% (18/28) and 43.18% (19/44), respectively, while only 1% (1/101) was found in the CM border. The K13 F446I variant was only identified and found to reach a high level (28.71%, 29/101) in the CM border. Furthermore, 10.71% (3/28) of TC isolates and 2.27% (1/44) of TM isolates carried more than one copy of plasmepsin 2/3 and K13 C580Y variant, while no plasmepsin 2/3 amplification was identified in the CM isolates. CONCLUSIONS: Compared with the P. falciparum samples collected from the TC and TM borders, fewer parasites carried plasmepsin 2/3 amplification and novel PfCRT variants, while more parasites carried predominant K13 mutations at position F446I, in the CM border. Clear evidence of DHA-PPQ resistance associated with candidate markers was not found in this border region suggesting a further evaluation of these markers and continuous surveillance is warranted.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Biomarcadores , Camboja , Cloroquina/farmacologia , Resistência a Medicamentos/genética , Humanos , Malária Falciparum/parasitologia , Proteínas de Membrana Transportadoras/genética , Mianmar , Piperazinas , Plasmodium falciparum , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Quinolinas , Tailândia
5.
Mol Brain ; 15(1): 36, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35484595

RESUMO

Neonatal hypoxic-ischemic encephalopathy (HIE) induced by perinatal asphyxia is a major cause of neurological disability among infants. Dihydroartemisinin (DHA), derived from artemisinin, well known as an anti-malarial medicine, was proved to be able to inhibit oxidative stress and inflammation. However, whether those functions of DHA play roles in hypoxic-ischemic brain damage (HIBD), an animal model of HIE in patient which also been observed to have oxidative stress and inflammation, is unknown. In this study, we demonstrated that the DHA treatment on newborn rats significantly relieved the neuron loss and motor and cognitive impairment caused by HIBD. One of the underlying mechanisms is that DHA enhanced the anti-oxidant capacity of HIBD rats by up-regulating the total antioxidant capacity (T-AOC), gluathione reductase (GR) and catalase (CAT) while down regulating the pro-oxidative substances including hydrogen peroxide (H2O2), total nitric oxide synthase (T-NOS) and inducible nitric oxide synthase (iNOS). Thus, our study illustrated that DHA could alleviate the damage of brains and improve the cognitive and motor function of HIBD rats by inhibiting oxidative stress, provided an opportunity to interrogate potential therapeutics for affected HIE patients.


Assuntos
Artemisininas , Hipóxia-Isquemia Encefálica , Animais , Animais Recém-Nascidos , Antioxidantes , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Encéfalo , Humanos , Peróxido de Hidrogênio , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Inflamação , Estresse Oxidativo , Ratos
8.
Front Med ; 16(1): 1-9, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35290595

RESUMO

Malaria is an ancient infectious disease that threatens millions of lives globally even today. The discovery of artemisinin, inspired by traditional Chinese medicine (TCM), has brought in a paradigm shift and been recognized as the "best hope for the treatment of malaria" by World Health Organization. With its high potency and low toxicity, the wide use of artemisinin effectively treats the otherwise drug-resistant parasites and helps many countries, including China, to eventually eradicate malaria. Here, we will first review the initial discovery of artemisinin, an extraordinary journey that was in stark contrast with many drugs in western medicine. We will then discuss how artemisinin and its derivatives could be repurposed to treat cancer, inflammation, immunoregulation-related diseases, and COVID-19. Finally, we will discuss the implications of the "artemisinin story" and how that can better guide the development of TCM today. We believe that artemisinin is just a starting point and TCM will play an even bigger role in healthcare in the 21st century.


Assuntos
Artemisininas , COVID-19 , Neoplasias , Artemisininas/farmacologia , Artemisininas/uso terapêutico , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Humanos , Medicina Tradicional Chinesa , Neoplasias/tratamento farmacológico
9.
Biomed Pharmacother ; 148: 112742, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35228063

RESUMO

The activation of artemisinin and its derivatives (ARTs) to generate ROS and other free radicals is mainly heme- or ferrous iron-dependent. ARTs induce ferroptosis in tumor cells, although the involvement of ferroptosis in malaria remains unclear. We found that three typical inducers of ferroptosis (erastin, RSL3 and sorafenib) could effectively mimic DHA inhibition on the growth of blood-stage parasites, which exhibited synergistic or nearly additive interactions in vitro with DHA, while the combination of DHA with ferroptosis inhibitors (deferoxamine, liproxstatin-1) had an obvious antagonistic effect. DHA, similar to ferroptosis inducers, can simultaneously induce the accumulation of ferroptosis-associated cellular labile iron and lipid peroxide. However, deferoxamine and liproxstatin-1 reduced the increase in ferrous iron and lipid peroxide caused by DHA. These results suggested that ferroptosis might be an effective way to induce cell death in parasites and could be a primary mechanism by which DHA kills parasites, with almost 50% contribution at low concentrations. These results provide a new strategy for antimalarial drug screening and clinical medication guidance.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Ferroptose/efeitos dos fármacos , Malária/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Feminino , Humanos , Malária/metabolismo , Malária/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Parasitos/efeitos dos fármacos , Piperazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sorafenibe/farmacologia
10.
Gynecol Endocrinol ; 38(5): 416-424, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35348414

RESUMO

BACKGROUND: Maternal high-fat diet (HFD) is a detrimental factor in developing glucose intolerance, obesity, and islet dysfunction. However, the effect of artemisinin on maternal HFD and whether it is related to the alterations of islet function is seldom studied since artemisinin treatments not only attenuate insulin resistance (IR) and restore islet ß cell function in Diabetes mellitus type 2. METHODS: Female rats were randomly fed a HFD (45% kcal from fat), HFD + artemisinin, or a regular chow diet (RCD) before pregnancy and during gestation. Glucose metabolism and the ß cell phenotypes were assessed. RESULTS: Maternal HFD increased islet load in female rats, proliferation of pancreatic ß cells, increased insulinogen, and decreased insulin secretion response to high glucose stimulation with delayed insulin release, increased fasting glucose, and glucose area under the curve compared with the general diet group. HFD inhibited expression of Foxo1 and PAX6 in female rats. Under the effect of both HFD and pregnancy, islet load was further increased, insulinogen was further increased, and fasting insulin level and fasting glucose were higher than RCD fed general-pregnancy group. ALDH1a3 transdifferentiation and PAX6, Foxo1, and PDX1 expression were increased in islets of high-fat pregnant rats. When adding artemisinin in HFD treated pregnant rats, islet function was significantly improved. CONCLUSIONS: Intervention with artemisinin in maternal HFD resulted in reduced islet size, decreased number of ß-cells and improved islet microcirculation, insulin processing shear process, decreased insulinogen/insulin ratio, and restored islet function through increased expression of PC1/3.


Assuntos
Artemisininas , Resistência à Insulina , Células Secretoras de Insulina , Animais , Artemisininas/metabolismo , Artemisininas/farmacologia , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Glucose/farmacologia , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Gravidez , Ratos
11.
Cell Immunol ; 373: 104500, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35276582

RESUMO

Multiple sclerosis (MS) was one of the major conditions causing neurological dysfunction and was an incurable progressive central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) was the most commonly used experimental model of MS. Artemisinin have been shown to exhibit anti-inflammatory effects through unclear mechanisms. In this study, we aimed to evaluate the effect of administration of the artemisinin derivative TPN10466 in EAE. TPN10466 alleviated the severity of disease in EAE. Further studies showed that TPN10466 inhibited lymphocyte migration by downregulating chemokine expression and adhesion molecules. In addition, studies showed that TPN10466 directly inhibited Th1 and Th17 differentiation and reduced Th1 and Th17 infiltration into the central nervous system. In conclusion, our work demonstrated that TPN10466 provided protection against the autoimmune disease EAE by inhibiting the migration of immune cells and suppressing Th1/Th17 differentiation, suggesting that TPN10466 could be a potential for promising potential agent for the treatment of MS/EAE.


Assuntos
Artemisininas , Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Artemisininas/metabolismo , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Diferenciação Celular , Movimento Celular , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Índice de Gravidade de Doença , Células Th1 , Células Th17
12.
Bioorg Med Chem Lett ; 64: 128682, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35304225

RESUMO

In this paper, a series of artemisinin derivatives were synthesized and evaluated. Studies have shown that IFN-γ produced by Th1 CD4+ T cells and IL-17A secreted by Th17 CD4+ T cells played critical roles in the treatment of multiple sclerosis. We used different concentrations of artemisinin derivatives to inhibit Th1 / Th17 differentiation in naive CD4+ T cells and to characterize IFN-γ / IL-17A in in vitro experiments. The preliminary screening results showed that ester compound 5 exhibited obvious inhibitory activities on Th1 and Th17 (IFN-γ decreased from 41% to 3% and IL-17A decreased from 24% to 8% at the concentration of 10 nM to 10 µM), and carbamate compounds also had obvious inhibitory activities against Th17 at high concentration. Moreover, we investigated the effect of compound 5 on myelin oligodendrocyte glycoprotein (MOG)-induced mice experimental autoimmune encephalomyelitis (EAE) model in vivo. 100 mg/kg compound 5 effectively reduced the disease severity of EAE compared with the vehicle group. This research revealed that compound 5 could be a promising avenue as potential MS inhibitor.


Assuntos
Artemisininas , Encefalomielite Autoimune Experimental , Animais , Artemisininas/farmacologia , Citocinas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Células Th1 , Células Th17
13.
Lancet Microbe ; 3(3): e184-e192, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35265869

RESUMO

Background: The increase in artemisinin resistance threatens malaria elimination in Asia by the target date of 2030 and could derail control efforts in other endemic regions. This study aimed to develop up-to-date spatial distribution visualisations of the kelch13 (K13) gene markers of artemisinin resistance in Plasmodium falciparum for policy makers. Methods: In this systematic review and spatiotemporal analysis we used the WorldWide Antimalarial Resistance Network (WWARN) surveyor molecular markers of artemisinin resistance database. We updated the database by searching PubMed and SCOPUS for studies published between Jan 1, 1990, and March 31, 2021. Articles were included if they contained data on K13 markers of artemisinin resistance from patients' samples in Asia and articles already included in the WWARN database were excluded. Data were extracted from the published articles and authors were contacted when information was missing. We used the lowest administrative unit levels for the sampling locations of all the K13 data to describe the spatiotemporal distribution. The numbers of samples tested and those with each molecular marker in each administrative unit level were aggregated by year to calculate the marker prevalence over time. Findings: Data were collated from 72 studies comprising K13 markers from 16 613 blood samples collected from 1991 to 2020 from 18 countries. Most samples were from Myanmar (3842 [23·1%]), Cambodia (3804 [22·9%]), and Vietnam (2663 [16·0%]). The median time between data collection and publication was 3·6 years (range 0·9-25·0, IQR 2·7 [2·5-5·2]). There was a steady increase in the prevalence of WHO-validated K13 markers, with the lowest of 4·3% in 2005 (n=47) and the highest of 62·9% in 2018 (n=264). Overall, the prevalence of Cys580Tyr mutation increased from 48·9% in 2002 to 84·9% in 2018. Interpretation: From 2002 to 2018, there has been a steady increase in geographical locations and the proportion of infected people with validated artemisinin resistance markers. More consistent data collection, over more extended periods in the same areas with the rapid sharing of data are needed to map the spread and evolution of resistance to better inform policy decisions. Data in the literature are reported in a heterogeneous way leading to difficulties in pooling and interpretation. We propose here a tool with a set of minimum criteria for reporting future studies. Funding: This research was funded in part by the Wellcome Trust.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Antimaláricos/farmacologia , Artemisininas/farmacologia , Ásia/epidemiologia , Resistência a Medicamentos/genética , Marcadores Genéticos/genética , Humanos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/genética , Análise Espaço-Temporal
14.
Molecules ; 27(6)2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35335120

RESUMO

The rich source of heme within malarial parasites has been considered to underly the action specificity of artemisinin. We reasoned that increasing intraparasitic free heme levels might further sensitize the parasites to artemisinin. Various means, such as modulating heme synthesis, degradation, polymerization, or hemoglobin digestion, were tried to boost intracellular heme levels, and under several scenarios, free heme levels were significantly augmented. Interestingly, all results arrived at the same conclusion, i.e., elevating heme acted in a strongly negative way, impacting the antimalarial action of artemisinin, but exerted no effect on several other antimalarial drugs. Suppression of the elevated free heme level by introducing heme oxygenase expression effectively restored artemisinin potency. Consistently, zinc protoporphyrin IX/zinc mesoporphyrin, as analogues of heme, drastically increased free heme levels and, concomitantly, the EC50 values of artemisinin. We were unable to effectively mitigate free heme levels, possibly due to an unknown compensating heme uptake pathway, as evidenced by our observation of efficient uptake of a fluorescent heme homologue by the parasite. Our results thus indicate the existence of an effective and mutually compensating heme homeostasis network in the parasites, including an uncharacterized heme uptake pathway, to maintain a certain level of free heme and that augmentation of the free heme level negatively impacts the antimalarial action of artemisinin. Importance: It is commonly believed that heme is critical in activating the antimalarial action of artemisinins. In this work, we show that elevating free heme levels in the malarial parasites surprisingly negatively impacts the action of artemisinin. We tried to boost free heme levels with various means, such as by modulating heme synthesis, heme polymerization, hemoglobin degradation and using heme analogues. Whenever we saw elevation of free heme levels, reduction in artemisinin potency was also observed. The homeostasis of heme appears to be complex, as there exists an unidentified heme uptake pathway in the parasites, nullifying our attempts to effectively reduce intraparasitic free heme levels. Our results thus indicate that too much heme is not good for the antimalarial action of artemisinins. This research can help us better understand the biological properties of this mysterious drug.


Assuntos
Antimaláricos , Artemisininas , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Artemisininas/metabolismo , Artemisininas/farmacologia , Heme/metabolismo , Plasmodium falciparum
15.
Asian Pac J Cancer Prev ; 23(3): 919-927, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35345364

RESUMO

BACKGROUND: Breast cancer is one of the most significant causes of female cancer death worldwide. To explore the possibility of a novel chemo-preventive strategy for improving breast cancer treatment, the anticancer effects of two natural compounds, Artemisinin (Art) and Chrysin (Chr), against T47D breast cancer cells were investigated. METHODS: For this purpose, Art and Chr were co-encapsulated in PEGylated PLGA nanoparticles (NPs) and the synthesized NPs were characterized by FE-SEM, FTIR, and DLS and then, MTT assay was used to assess and compare the cytotoxicity of various concentrations of the chemotheruptic molecules in pure and nanoformulated forms as well as in alone and combination state after 48 h exposure time. Drug release study was performed using the dialysis method. Also, the mRNA levels of hTERT genes expression were studied by quantitative real-time PCR. RESULTS: The results showed that pure and formulations drugs exhibited dose-dependent cytotoxicity against T47D cells and especially, Art/Chr-PLGA/PEG NPs had a more synergistic anti-proliferative effect and significantly arrested the growth of cancer cells than the other groups. Moreover, Real-time PCR results revealed that Art, Chr and combination of Art-Chr in pure and encapsulated forms inhibited hTERT gene expression. CONCLUSIONS: It was found that Art/Chr-PLGA/PEG NPs relative to pure combination could further decline hTERT expression in all concentrations. Our study demonstrated that Art/Chr-PLGA/PEG NPs based combinational therapy holds promising potential for the treatment of breast cancer.


Assuntos
Artemisininas , Neoplasias da Mama , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular , Feminino , Flavonoides , Expressão Gênica , Humanos , Polietilenoglicóis/uso terapêutico
16.
Emerg Infect Dis ; 28(4): 852-855, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35318931

RESUMO

Artemisinin resistance in Plasmodium falciparum is conferred by mutations in the kelch 13 (K13) gene. In Rwanda, K13 mutations have increased over the past decade, including mutations associated with delayed parasite clearance. We document artemisinin resistance in P. falciparum patient isolates from Rwanda carrying K13 R561H, A675V, and C469F mutations.


Assuntos
Antimaláricos , Artemisininas , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Humanos , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Ruanda/epidemiologia
18.
Gene ; 821: 146339, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35183684

RESUMO

BACKGROUND: Monitoring of drug resistance in Plasmodium populations is crucial for malaria control. This has primarily been performed in humans and rarely in mosquitoes where parasites genetic recombination occurs. Here, we characterized the Plasmodium spp populations in wild Anopheles vectors by analyzing the genetic diversity of the P. falciparum kelch13 and mdr1 gene fragments implicated in artemisinin and partner drug resistance across Cameroon in three major malaria vectors. METHODS: Anopheles mosquitoes were collected across nine localities in Cameroon and dissected into the head/thorax (H/T) and abdomen (Abd) after species identification. A TaqMan assay was performed to detect Plasmodium infection. Fragments of the Kelch 13 and mdr1 genes were amplified in P. falciparum positive samples and directly sequenced to assess their drug resistance polymorphisms and genetic diversity profile. RESULTS: The study revealed a high Plasmodium infection rate in the major Anopheles vectors across Cameroon. Notably, An. funestus vector recorded the highest sporozoite (8.0%) and oocyst (14.4%) infection rates. A high P. falciparum sporozoite rate (80.08%) alongside epidemiological signatures of significant P. malariae (15.9%) circulation were recorded in these vectors. Low genetic diversity with six (A578S, R575I, G450R, L663L, G453D, N458D) and eight (H53H, V62L, V77E, N86Y, G102G, L132I, H143H, Y184F) point mutations were observed in the k13 and mdr1 backbones respectively. Remarkably, the R575I (4.4%) k13 and Y184F (64.2%) mdr1 mutations were the predominant variants in the P. falciparum populations. CONCLUSION: The emerging signal of the R575I polymorphism in the Pfk13 propeller backbone entails the regular surveillance of molecular markers to inform evidence-based policy decisions. Moreover, the high frequency of the 86N184F allele highlights concerns on the plausible decline in efficacy of artemisinin-combination therapies (ACTs); further implying that parasite genotyping from mosquitoes can provide a more relevant scale for quantifying resistance epidemiology in the field.


Assuntos
Artemisininas/farmacologia , Resistência a Medicamentos , Malária Falciparum/epidemiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Animais , Anopheles/parasitologia , Camarões/epidemiologia , Feminino , Frequência do Gene , Malária Falciparum/veterinária , Oócitos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Mutação Puntual , Proteínas de Protozoários/genética , Análise de Sequência de DNA , Esporozoítos/efeitos dos fármacos , Esporozoítos/genética , Esporozoítos/isolamento & purificação
19.
ChemMedChem ; 17(9): e202200005, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35187791

RESUMO

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause life-threatening diseases in millions of people worldwide, in particular, in patients with cancer, and there is an urgent need for antiviral agents against this infection. While in vitro activities of artemisinins against SARS-CoV-2 and cancer have recently been demonstrated, no study of artemisinin and/or synthetic peroxide-based hybrid compounds active against both cancer and SARS-CoV-2 has been reported yet. However, the hybrid drug's properties (e. g., activity and/or selectivity) can be improved compared to its parent compounds and effective new agents can be obtained by modification/hybridization of existing drugs or bioactive natural products. In this study, a series of new artesunic acid and synthetic peroxide based new hybrids were synthesized and analyzed in vitro for the first time for their inhibitory activity against SARS-CoV-2 and leukemia cell lines. Several artesunic acid-derived hybrids exerted a similar or stronger potency against K562 leukemia cells (81-83 % inhibition values) than the reference drug doxorubicin (78 % inhibition value) and they were also more efficient than their parent compounds artesunic acid (49.2 % inhibition value) and quinoline derivative (5.5 % inhibition value). Interestingly, the same artesunic acid-quinoline hybrids also show inhibitory activity against SARS-CoV-2 in vitro (EC50 13-19 µm) and no cytotoxic effects on Vero E6 cells (CC50 up to 110 µM). These results provide a valuable basis for design of further artemisinin-derived hybrids to treat both cancer and SARS-CoV-2 infections.


Assuntos
Artemisininas , COVID-19 , Leucemia , Neoplasias , Quinolinas , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Artemisininas/farmacologia , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Humanos , Leucemia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Peróxidos , Quinolinas/uso terapêutico , SARS-CoV-2 , Células Vero
20.
Eur J Pharmacol ; 919: 174797, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35122867

RESUMO

Photodynamic therapy (PDT) is noninvasive, low toxicity, and photo-selective, but may be resisted by malignant cells. A previous study found chlorin e6 (Ce6) mediated PDT showed drug resistance in lung cancer cells (LLC), which may be associated with PDT-induced DNA damage response (DDR). DDR may up-regulate glutathione peroxidase 4 (GPX4), which in turn degrade ROS induced by PDT. However, dihydroartemisinin (DHA) was found to down-regulate GPX4. Accordingly, the DHA was hypothesized to improve the resistance to PDT. The present work explores the mechanism of Ce6 mediated drug resistance and reveals whether DHA can enhance the efficacy of PDT by suppressing GPX4. The in vitro experiments found Ce6 treatment did not inhibit the viability of LLC within 6 h without inducing significant apoptosis, suggesting LLC were resistant to PDT. Further investigation demonstrated PDT could damage DNA and up-regulate GPX4, thus degrading the generated ROS. DHA effectively inhibited the viability of LLC and induced apoptosis. Importantly, DHA displayed a prominent inhibitory effect on the GPX4 expression and thereby triggered ferroptosis. Combining DHA with Ce6 for treatment of LLC resulted in the suppressed GPX4 and elevated ROS. Finally, the findings showed DHA combined with Ce6 exhibited superb anti-lung cancer efficacy. In summary, Ce6 PDT damages DNA, up-regulates GPX4 to degrade ROS, thereby inducing drug resistance. Down-regulation of GPX4 by DHA-triggered ferroptosis significantly enhances the efficacy of PDT. This study provides an outstanding theoretical basis for the regulation of the intratumoral redox system and improving PDT efficacy against lung cancer by herbal monomer DHA.


Assuntos
Artemisininas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Apoptose/efeitos dos fármacos , Artemisininas/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Clorofilídeos/metabolismo , Ferroptose/efeitos dos fármacos , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
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