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1.
Food Chem ; 349: 129066, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33556728

RESUMEN

The objective of this study was to explore the oxidative modification induced by AAPH (2,2'-azobis (2-amidinopropane) dihydrochloride) on the microbial transglutaminase (MTGase) cross-linking reaction and gelling properties of silver carp myofibril protein (SCMP). Compared to AAPH treatment, MTGase addition resulted further changes of protein properties as evidenced by the decreasing free amino and thiol group content, the decreased secondary and tertiary structure, and the increasing storage modulus (G') and gel strength (P < 0.05). The proper oxidation induced by AAPH (5 mM) promoted the glutamine-lysine and disulfide cross-linking due to MTGase (10 U/g). Therefore, the quality of the SCMP gel was improved with a good water-holding capacity (WHC), gel strength and G'. This results could lay a theoretical foundation for the development of silver carp surimi products with good quality. Chemical compounds: (2,2'-azobis(2-amidinopropane)dihydrochloride (PubChem CID:76344); O-Phthalaldehyde (PubChem CID:4807); 5,5'-Dithiobis(2-Nitrobenzoic Acid) (PubChem CID:6254); 8-Anilino-1-naphthalenesulfonic acid (PubChem CID:1369); Acrylamide (PubChem CID: 6579); ß-Mercaptoethanol (PubChem CID: 1567); Sodium dodecyl sulfate (PubChem CID:3423265).


Asunto(s)
Carpas , Proteínas Musculares/química , Peróxidos/farmacología , Proteínas/metabolismo , Animales , Geles , Oxidación-Reducción/efectos de los fármacos , Alimentos Marinos , Compuestos de Sulfhidrilo/química , Transglutaminasas/metabolismo , Agua/química
2.
Int J Mol Med ; 47(4)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33537813

RESUMEN

The activation of oxidative stress is a primary cause of chondrocyte apoptosis in osteoarthritis (OA). The 78­kDa glucose­regulated protein (GRP78)/mammalian target of rapamycin (mTOR) signaling pathway has been demonstrated to be linked with the endoplasmic reticulum (ER) and autophagy. Hydrogen sulfide (H2S) has been reported to exert antioxidant effects. The present study investigated oxidative stress levels via 2',7'­dichlorofluorescin diacetate and MitoSOX staining, apoptosis rates via flow cytometry and the expression levels of ER stress­related proteins in GYY4137 (donor of H2S)­treated chondrocytes (CHs). CHs were isolated from the bilateral hip joints of male rats to examine mitochondrial permeability transition pore opening­ and mTOR signaling pathway­related proteins. The results demonstrated that tert­Butyl hydroperoxide (TBHP) increased CH apoptosis, and treatment with GYY4137 ameliorated TBHP­mediated the generation of ROS and CH apoptosis. Moreover, TBHP­treated CHs displayed elevated ER stress sensor expression levels and apoptotic rates; however, the TBHP­induced protein expression levels were decreased following GYY4137 treatment. In the present study, treatment with either GYY4137 or transfection with GRP78 siRNA both suppressed the activation of p­P70S6k and p­mTOR. H2S played an important role in regulating ER stress in TBHP­stimulated CHs. GYY4137 promoted autophagy, which was accompanied by the inhibition of ER stress. On the whole, the present study demonstrates that TBHP­induced oxidative stress stimulates ER interactions and CH apoptosis, which are suppressed by exogenous H2S via modulating the GRP78/mTOR signaling pathway.


Asunto(s)
Condrocitos/metabolismo , Condrocitos/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteínas de Choque Térmico/metabolismo , Sulfuro de Hidrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cloroquina/farmacología , Condrocitos/efectos de los fármacos , Citoprotección/efectos de los fármacos , Masculino , Morfolinas/química , Morfolinas/farmacología , Compuestos Organotiofosforados/química , Compuestos Organotiofosforados/farmacología , Peróxidos/farmacología , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
3.
Molecules ; 26(3)2021 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-33525706

RESUMEN

Polycyclic endoperoxides are rare natural metabolites found and isolated in plants, fungi, and marine invertebrates. The purpose of this review is a comparative analysis of the pharmacological potential of these natural products. According to PASS (Prediction of Activity Spectra for Substances) estimates, they are more likely to exhibit antiprotozoal and antitumor properties. Some of them are now widely used in clinical medicine. All polycyclic endoperoxides presented in this article demonstrate antiprotozoal activity and can be divided into three groups. The third group includes endoperoxides, which show weak antiprotozoal activity with a reliability of up to 70%, and this group includes only 1.1% of metabolites. The second group includes the largest number of endoperoxides, which are 65% and show average antiprotozoal activity with a confidence level of 70 to 90%. Lastly, the third group includes endoperoxides, which are 33.9% and show strong antiprotozoal activity with a confidence level of 90 to 99.6%. Interestingly, artemisinin and its analogs show strong antiprotozoal activity with 79 to 99.6% confidence against obligate intracellular parasites which belong to the genera Plasmodium, Toxoplasma, Leishmania, and Coccidia. In addition to antiprotozoal activities, polycyclic endoperoxides show antitumor activity in the proportion: 4.6% show weak activity with a reliability of up to 70%, 65.6% show an average activity with a reliability of 70 to 90%, and 29.8% show strong activity with a reliability of 90 to 98.3%. It should also be noted that some polycyclic endoperoxides, in addition to antiprotozoal and antitumor properties, show other strong activities with a confidence level of 90 to 97%. These include antifungal activity against the genera Aspergillus, Candida, and Cryptococcus, as well as anti-inflammatory activity. This review provides insights on further utilization of polycyclic endoperoxides by medicinal chemists, pharmacologists, and the pharmaceutical industry.


Asunto(s)
Antineoplásicos/farmacología , Antiprotozoarios/farmacología , Productos Biológicos/farmacología , Peróxidos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Antineoplásicos/química , Antiprotozoarios/química , Productos Biológicos/química , Humanos , Peróxidos/química
4.
Eur J Med Chem ; 213: 113193, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33508479

RESUMEN

Malaria is a life-threatening infectious disease caused by protozoal parasites belonging to the genus Plasmodium. It caused an estimated 405,000 deaths and 228 million malaria cases globally in 2018 as per the World Malaria Report released by World Health Organization (WHO) in 2019. Artemisinin (ART), a "Nobel medicine" and its derivatives have proven potential application in antimalarial drug discovery programs. In this review, antimalarial activity of the most active artemisinin derivatives modified at C-10/C-11/C-16/C-6 positions and synthetic peroxides (endoperoxides, 1,2,4-trioxolanes, 1,2,4-trioxanes, and 1,2,4,5-tetraoxanes) are systematically summarized. The developmental trend of ART derivatives, and cyclic peroxides along with their antimalarial activity and how the activity is affected by structural variations on different sites of the compounds are discussed. This compilation would be very useful towards scaffold hopping aimed at avoiding the unnecessary complexity in cyclic peroxides, and ultimately act as a handy resource for the development of potential chemotherapeutics against Plasmodium species.


Asunto(s)
Antimaláricos/farmacología , Artemisininas/farmacología , Descubrimiento de Drogas , Malaria/tratamiento farmacológico , Peróxidos/farmacología , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Artemisininas/síntesis química , Artemisininas/química , Humanos , Peróxidos/síntesis química , Peróxidos/química
5.
PLoS Pathog ; 16(6): e1008485, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32589689

RESUMEN

Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a "multi-omics" workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. Ozonide-induced depletion of short Hb-derived peptides was less extensive in a drug-treated K13-mutant artemisinin resistant parasite line (Cam3.IIR539T) than in the drug-treated isogenic sensitive strain (Cam3.IIrev), further confirming the association between ozonide activity and Hb catabolism. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage ozonide-induced damage.


Asunto(s)
Adamantano/análogos & derivados , Antimaláricos/farmacología , Eritrocitos , Hemoglobinas/metabolismo , Compuestos Heterocíclicos con 1 Anillo/farmacología , Peróxidos/farmacología , Plasmodium falciparum/metabolismo , Compuestos de Espiro/farmacología , Adamantano/farmacología , Eritrocitos/metabolismo , Eritrocitos/parasitología , Hemoglobinas/genética , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Plasmodium falciparum/genética , Proteómica
6.
Food Chem Toxicol ; 138: 111184, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32061727

RESUMEN

Marsh rosemary (Ledum palustre, Ericaceae) has been widely used in the traditional medicine of various regions worldwide, and as insect repellent. Little is known on its essential oil insecticidal potential. This study explored the insecticidal effects of the essential oil obtained from L. palustre growing in Poland on selected insect pests and vectors. GC-MS analysis evidenced an uncommon chemotype characterized by ascaridole (35.3% as sum of cis-ascaridole and isoascaridole) and p-cymene (25.5%). The essential oil was effective against Culex quinquefasciatus, Spodoptera littoralis and Musca domestica, showing LC50/LD50 of 66.6 mg L-1, 117.2 µg larva-1 and 61.4 µg adult-1, respectively. It was not toxic to non-target Eisenia fetida earthworms and moderately toxic to Daphnia magna microcrustaceans, over the positive control α-cypermethrin. The essential oil cytotoxicity on human keratinocytes and fibroblasts showed high IC50 values (71.3 and 84.4 µg mL-1, respectively). Comet assay data highlighted no DNA damages. Based on our findings, this essential oil, characterized by the ascaridole/p-cymene chemotype, could be a candidate for the formulation of botanical insecticides; large-scale production of green insecticides by this rare species may be assured by ex situ cultivation and biotechnological techniques.


Asunto(s)
Monoterpenos Ciclohexánicos/farmacología , Insecticidas/farmacología , Aceites Volátiles/farmacología , Peróxidos/farmacología , Rosmarinus/química , Animales , Línea Celular , Ensayo Cometa , Culex/efectos de los fármacos , Culicidae/efectos de los fármacos , Monoterpenos Ciclohexánicos/análisis , Cimenos/análisis , Cimenos/farmacología , Daphnia/efectos de los fármacos , Moscas Domésticas/efectos de los fármacos , Humanos , Repelentes de Insectos/análisis , Repelentes de Insectos/farmacología , Insecticidas/análisis , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Larva/efectos de los fármacos , Mosquitos Vectores/efectos de los fármacos , Mariposas Nocturnas/efectos de los fármacos , Aceites Volátiles/análisis , Oligoquetos/efectos de los fármacos , Peróxidos/análisis , Polonia , Piretrinas/análisis , Piretrinas/farmacología , Spodoptera/efectos de los fármacos
7.
J Vet Med Sci ; 82(3): 320-324, 2020 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-31932534

RESUMEN

Four concentrations of potassium peroxymonosulfate (PPMS) were evaluated for bactericidal activities and indicated that the concentration is less than the manufacturing-recommended concentrations, must extend the exposure time for bacterial inactivation. However, even with and without of organic material contamination, did not show marked inactivation difference. In addition, all concentrations were inactivated on all carrier surfaces within 30 sec, except on rubber where inactivation occurred within 1 min. However, quaternary ammonium compounds were inactivated on stainless steel and plastic within 1 min and 30 sec, respectively, but not inactivated within 5 min on rubber surfaces. Conclusion, PPMS inactivated bacteria under optimal concentration, organic material conditions, exposure timing and on carrier surfaces which can useful as an alternative disinfectant for biosecurity enhancement.


Asunto(s)
Desinfectantes/farmacología , Escherichia coli/efectos de los fármacos , Peróxidos/farmacología , Salmonella/efectos de los fármacos , Crianza de Animales Domésticos/métodos , Desinfección/métodos , Plásticos , Compuestos de Amonio Cuaternario/farmacología , Goma , Acero Inoxidable
9.
Biochem Pharmacol ; 173: 113737, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31786259

RESUMEN

Endoperoxides (EPs) appear to be promising drug candidates against protozoal diseases, including malaria and leishmaniasis. Previous studies have shown that these drugs need an intracellular activation to exert their pharmacological potential. The efficiency of these drugs is linked to the extensive iron demand of these intracellular protozoal parasites. An essential step of the activation mechanism of these drugs is the formation of radicals in Leishmania. Iron is a known trigger for intracellular radical formation. However, the activation of EPs by low molecular iron or by heme iron may strongly depend on the structure of the EPs themselves. In this study, we focused on the activation of artemisinin (Art) in Leishmania tarentolae promastigotes (LtP) in comparison to reference compounds. Viability assays in different media in the presence of different iron sources (hemin/fetal calf serum) showed that IC50 values of Art in LtP were modulated by assay conditions, but overall were within the low micromolar range. Low temperature electron paramagnetic resonance (EPR) spectroscopy of LtP showed that Art shifted the redox state of the labile iron pool less than the EP ascaridole questioning its role as a major activator of Art in LtP. Based on the high reactivity of Art with hemin in previous biomimetic experiments, we focused on putative heme-metabolizing enzymes in Leishmania, which were so far not well described. Inhibitors of mammalian heme oxygenase (HO; tin and chromium mesoporphyrin) acted antagonistically to Art in LtP and boosted its IC50 value for several magnitudes. By inductively coupled plasma methods (ICP-OES, ICP-MS) we showed that these inhibitors do not block iron (heme) accumulation, but are taken up and act within LtP. These inhibitors blocked the conversion of hemin to bilirubin in LtP homogenates, suggesting that an HO-like enzyme activity in LtP exists. NADPH-dependent degradation of Art and hemin was highest in the small granule and microsomal fractions of LtP. Photometric measurements in the model Art/hemin demonstrated that hemin requires reduction to heme and that subsequently an Art/heme complex (λmax 474 nm) is formed. EPR spin-trapping in the system Art/hemin revealed that NADPH, ascorbate and cysteine are suitable reductants and finally activate Art to acyl-carbon centered radicals. These findings suggest that heme is a major activator of Art in LtP either via HO-like enzyme activities and/or chemical interaction of heme with Art.


Asunto(s)
Artemisininas/metabolismo , Hemo/metabolismo , Leishmania/metabolismo , Esporas Protozoarias/metabolismo , Animales , Artemisininas/química , Artemisininas/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Espectroscopía de Resonancia por Spin del Electrón , Radicales Libres/química , Radicales Libres/metabolismo , Hemo/química , Hemo Oxigenasa (Desciclizante)/metabolismo , Hierro/metabolismo , Leishmania/citología , Leishmania/fisiología , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Ratones , Oxidación-Reducción/efectos de los fármacos , Peróxidos/química , Peróxidos/metabolismo , Peróxidos/farmacología , Esporas Protozoarias/citología , Esporas Protozoarias/efectos de los fármacos
10.
Eur J Med Chem ; 185: 111791, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31669852

RESUMEN

Hybrid molecules have the potential to enhance the efficacy against both drug-sensitive and drug-resistant organisms, and Ferroquine, a ferrocene hybrid, has demonstrated great potency in clinical trials against both drug-sensitive and drug-resistant malaria. Accordingly, hybridization of ferrocene with other antimalarial pharmacophores represents a promising strategy to develop novel antimalarial candidates. This work attempts to systematically review the recent study of ferrocene hybrids in the design and development of antimalarial agents, and the structure-activity relationship (SAR) is also discussed to provide an insight for rational design of more effective antibacterial candidates.


Asunto(s)
Antimaláricos/farmacología , Compuestos Ferrosos/farmacología , Malaria/tratamiento farmacológico , Metalocenos/farmacología , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/química , Artemisininas/química , Artemisininas/farmacología , Compuestos Ferrosos/química , Humanos , Metalocenos/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Peróxidos/química , Peróxidos/farmacología , Quinolinas/química , Quinolinas/farmacología
11.
Chemosphere ; 245: 125678, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31875574

RESUMEN

The search for a suitable heterogeneous catalyst in peroxymonosulfate (PMS) activation holds tremendous promise for the degradation of organic pollutants. Two-dimensional (2D) transition metal dichalcogenides such as WS2 exhibit broad applications in heterogeneous catalysis, and we first extended its application in PMS activation in this work. It was found that WS2 could efficiently activate PMS resulting in the degradation of diclofenac (DCF). The results show that the PMS offers direct oxidation, and WS2 could initiate PMS to produce singlet oxygen (1O2) and superoxide radical (·O2-). This resulted in the improved removal of DCF in the WS2/PMS system. Furthermore, the degradation pathway of DCF was proposed according to the detected intermediates/products and density functional theory (DFT) calculation. Degradation intermediates and the evaluation of product toxicity indicated that the developed WS2/PMS system was a safe and detoxifying process while also offering efficient DCF removal. This study offers more insight into the development of suitable materials for the activation of PMS and gives clear direction for the degradation of DCF and its toxic intermediates.


Asunto(s)
Diclofenaco/aislamiento & purificación , Nanoestructuras/química , Peróxidos/farmacología , Compuestos de Tungsteno/química , Contaminantes Químicos del Agua/aislamiento & purificación , Purificación del Agua/métodos , Catálisis , Diclofenaco/química , Oxidación-Reducción , Peróxidos/química , Oxígeno Singlete/química , Elementos de Transición/química , Elementos de Transición/farmacología , Compuestos de Tungsteno/farmacología , Contaminantes Químicos del Agua/química
12.
Malar J ; 18(1): 427, 2019 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-31849323

RESUMEN

BACKGROUND: Drug efficacy against kelch 13 mutant malaria parasites can be determined in vitro with the ring-stage survival assay (RSA). The conventional assay protocol reflects the exposure profile of dihydroartemisinin. METHODS: Taking into account that other anti-malarial peroxides, such as the synthetic ozonides OZ439 (artefenomel) and OZ609, have different pharmacokinetics, the RSA was adjusted to the concentration-time profile of these ozonides in humans and a novel, semi-automated readout was introduced. RESULTS: When tested at clinically relevant parameters, it was shown that OZ439 and OZ609 are active against the Plasmodium falciparum clinical isolate Cam3.IR539T. CONCLUSION: If the in vitro RSA does indeed predict the potency of compounds against parasites with increased tolerance to artemisinin and its derivatives, then the herein presented data suggest that following drug-pulses of at least 48 h, OZ439 and OZ609 will be highly potent against kelch 13 mutant isolates, such as P. falciparum Cam3.IR539T.


Asunto(s)
Adamantano/análogos & derivados , Antimaláricos/farmacología , Peróxidos/farmacología , Plasmodium falciparum/efectos de los fármacos , Adamantano/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Malaria Falciparum/tratamiento farmacológico
13.
Free Radic Res ; 53(11-12): 1101-1113, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31684775

RESUMEN

The unregulated oxidative modification of biological molecules has been implicated in the pathogenesis of various diseases, and the beneficial effects of antioxidants against detrimental oxidation have received much attention. Among the multiple oxidants, peroxyl radical and peroxynitrite play an important role as chain-carrying species in lipid peroxidation and one of the major oxidants produced in vivo, respectively. This study was performed to elucidate the prominent features of these two oxidants by comparing their reactivity and selectivity and also the effects of antioxidants against plasma lipid oxidation induced by the two oxidants. It was shown that despite peroxyl radical and peroxynitrite gave similar pattern of lipid peroxidation products of plasma, and these two oxidants exert different selectivity and reactivity towards probes and antioxidants. The capacity of antioxidants to scavenge peroxynitrite and peroxyl radical decreased in the order BSA > glutathione > α-tocopherol ∼ bilirubin ∼ α - tocotrienol > γ-tocotrienol ∼ γ - tocopherol > uric acid and α-tocopherol ∼ α - tocotrienol > bilirubin > γ-tocotrienol ∼ γ - tocopherol > BSA > glutathione > uric acid, respectively. α-Tocopherol localised within plasma lipoproteins was six times less effective than trolox in aqueous phase for scavenging peroxynitrite and the derived oxidants, despite the same chemical reactivity of the two chromanols. BSA was relatively more effective as antioxidant against peroxynitrite than peroxyl radical, whereas TEMPO did not act as efficient antioxidant against both oxidants. It was suggested that thiols act as more potent antioxidant against peroxynitrite than phenolic antioxidants, while phenolic antioxidants are potent inhibitor of lipid peroxidation induced by free radicals including those derived from peroxynitrite. Abbreviations: AAPH: 2,2'-azobis(2-amidinopropane) dihydrochloride; C11-BODIPY: 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid; BSA: bovine serum albumin; DPPP: diphenyl-1-pyrenylphosphine; H(p)ODE: hydro(pero)xyoctadecadienoates; PGR: pyrogallol red; PUFA: polyunsaturated fatty acid; SIN-1: 3-morpholinosydnonimine; TEMPO: 2,2-6,6 tetramethylpiperidine-1-oxyl; Trolox: 2-carboxy-2,5,7,8-tetramethyl-6-hydroxychroman.


Asunto(s)
Antioxidantes/farmacología , Colorantes Fluorescentes/química , Peroxidación de Lípido/efectos de los fármacos , Peróxidos/antagonistas & inhibidores , Ácido Peroxinitroso/antagonistas & inhibidores , Animales , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Peróxidos/farmacología , Ácido Peroxinitroso/farmacología
14.
ACS Infect Dis ; 5(12): 2067-2075, 2019 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-31626733

RESUMEN

Antimalarial peroxides such as the phytochemical artemisinin or the synthetic ozonides arterolane and artefenomel undergo reductive cleavage of the pharmacophoric peroxide bond by ferrous heme, released by parasite hemoglobin digestion. The generated carbon-centered radicals alkylate heme in an intramolecular reaction and proteins in an intermolecular reaction. Here, we determine the proteinaceous alkylation signatures of artemisinin and synthetic ozonides in Plasmodium falciparum using alkyne click chemistry probes to identify target proteins by affinity purification and mass spectrometry-based proteomics. Using stringent controls and purification procedures, we identified 25 P. falciparum proteins that were alkylated by the antimalarial peroxides in a peroxide-dependent manner, but the alkylation patterns were more random than we had anticipated. Moreover, there was little overlap in the alkylation signatures identified in this work and those disclosed in previous studies. Our findings suggest that alkylation of parasite proteins by antimalarial peroxides is likely to be a nonspecific, stochastic process.


Asunto(s)
Antimaláricos/farmacología , Peróxidos/farmacología , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/análisis , Alquilación , Antimaláricos/química , Artemisininas/farmacología , Química Clic , Compuestos Heterocíclicos/farmacología , Espectrometría de Masas , Estructura Molecular , Plasmodium falciparum/efectos de los fármacos , Proteómica , Proteínas Protozoarias/química , Procesos Estocásticos
15.
Curr Top Med Chem ; 19(14): 1201-1225, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31509099

RESUMEN

The significant spread of helminth and protozoan infections, the uncontrolled intake of the known drugs by a large population, the emergence of resistant forms of pathogens have prompted people to search for alternative drugs. In this review, we have focused attention on structures and synthesis of peroxides active against parasites causing neglected tropical diseases and toxoplasmosis. To date, promising active natural, semi-synthetic and synthetic peroxides compounds have been found.


Asunto(s)
Productos Biológicos/farmacología , Brugia Malayi/efectos de los fármacos , Helmintos/efectos de los fármacos , Enfermedades Desatendidas/tratamiento farmacológico , Peróxidos/farmacología , Toxoplasmosis/tratamiento farmacológico , Animales , Productos Biológicos/síntesis química , Productos Biológicos/química , Conformación Molecular , Pruebas de Sensibilidad Parasitaria , Peróxidos/síntesis química , Peróxidos/química
16.
Biochem Biophys Res Commun ; 518(3): 519-525, 2019 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-31445701

RESUMEN

Singlet oxygen causes a cytotoxic process in tumor cells in photodynamic therapy (PDT) and skin photoaging. The mechanism responsible for this cytotoxicity is, however, not fully understood. 1-Methylnaphthalene-4-propionate endoperoxide (MNPE) is a cell-permeable endoperoxide that generates pure singlet oxygen. We previously reported that cell death induced by MNPE did not show the typical profile of apoptosis, and the cause of this cell death remains elusive. We report herein on an investigation of the mechanism for MNPE-induced cell death from the view point of ferroptosis. The findings indicate that the MNPE treatment decreased the viabilities of mouse hepatoma Hepa 1-6 cells in vitro, and that this decrease was accompanied by increases in the concentrations of both intracellular ferrous iron and the level of lipid peroxidation, but that the caspase-mediated apoptotic pathway was not activated. The intracellular levels of cysteine and glutathione were not affected by the MNPE treatment. Importantly, an assay of lactate dehydrogenase activity revealed that the cell death caused by MNPE was suppressed by ferrostatin-1, a ferroptosis-specific inhibitor. Collectively, these results strongly indicate that ferroptosis is the main cell death pathway induced by singlet oxygen.


Asunto(s)
Ferroptosis/efectos de los fármacos , Naftalenos/farmacología , Peróxidos/farmacología , Oxígeno Singlete/metabolismo , Animales , Línea Celular Tumoral , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Ratones , Especies Reactivas de Oxígeno/metabolismo
17.
Am J Dent ; 32(4): 201-207, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31436941

RESUMEN

PURPOSE: To evaluate in vitro the effectiveness of eight different cleansers containing alkaline peroxide against yeast [Candida albicans (Ca) and Candida glabrata (Cg) ], Gram-negative bacteria [Escherichia coli (Ec) and Pseudomonas aeruginosa (Pa) ], and Gram-positive bacteria [ Bacillus subtilis (Bs), Enterococcus faecalis (Ef), Staphylococcus aureus (Sa), and Streptococcus mutans (Sm) ]. METHODS: Denture base acrylic resin specimens (Lucitone 550; 1264 denture base acrylic resin specimens) were obtained from a circular metal matrix (15 x 3 mm) and sterilized with microwave irradiation (650 W, 6 minutes). The specimens were contaminated with 106 CFU/mL suspension of yeasts and 108 CFU/mL suspensions of Gram-positive and -negative bacteria. The contaminated specimens were incubated (37°C/48 hours) and immersed (short cycle) in a stainless steel basket placed in a beaker. The beaker contained one of the following cleanser solutions, which were prepared and used according to the manufacturers' instructions (n=10): PBS (positive control, C), Fixodent (FI), Medical Interporous (MI), Kukident (KU), Efferdent Plus (EF), Equate (EQ), Kroger (KR), Kirari (KI), and Corega Tabs (CT). Reduction in the viability of microorganisms was evaluated through counting of Colony Forming Units (CFU/mL), metabolic activity (XTT), and cell viability by epifluorescence microscopy (EM) analyses. For counting CFU, the specimens (n=10 of each group) were washed and immersed in Letheen medium, from which aliquots were obtained and seeded into selective solid culture media. After incubation (37°C, 24 hours), the colonies were counted (CFU/mL). The metabolic activity of microorganisms was measured using XTT reduction assay (n=5). For EM analysis, the specimens (n= 2 of each group) were stained (Live/Dead BacLight), and the images were analyzed in terms of biofilm areas (total and living cells). Data were processed and analyzed by Wilcoxon, Mann Whitney and Kruskal-Wallis tests followed by Dunn test (α= 0.05). RESULTS: Significant differences were found between the experimental groups and C for the evaluated microorganisms. MI was the most effective for yeasts; this cleanser reduced the metabolic activity, viability, and total counts of both yeasts evaluated. All cleansers reduced the total counts of Gram-negative microorganisms, except CT for Pa. For Gram-negative bacteria, KR, CT, EF, and EQ significantly reduced the metabolic activity of Ec but did not remove all dead cells. FI and MI significantly reduced the metabolic activity of Pa, and the latter also removed the dead cells of Pa. FI and MI showed improved results against all Gram-positive bacteria. Both cleansers significantly decreased the metabolic activity of all bacterial species and reduced the viability of Sa, Ef, and Bs. MI also reduced the biofilm aggregates of Sm. CLINICAL SIGNIFICANCE: This study concluded that under the experimental conditions tested, denture cleansers can be used as coadjutants in denture cleaning. The evaluated cleansers exhibited disinfectant action, thereby preventing the proliferation of microorganisms on the denture surface and reducing the risk of opportunistic infections.


Asunto(s)
Biopelículas , Bases para Dentadura , Limpiadores de Dentadura , Peróxidos , Biopelículas/efectos de los fármacos , Recuento de Colonia Microbiana , Dentaduras , Peróxidos/farmacología
18.
J Am Assoc Lab Anim Sci ; 58(5): 558-568, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31319899

RESUMEN

Gnotobiotic animal research has expanded markedly over the past decade. Although germ-free animals were first described more than 100 y ago, little evidence-based guidance is available on best operational procedures. A key aspect of gnotobiotic technology is the sterilization of animal enclosures, most commonly flexible vinyl film isolators. The objective of this study was to determine the most effective methods for chemical sterilization of gnotobiotic isolators and associated equipment. As test microbes, we used bacteria from 4 different accidental isolator contaminations that occurred in a gnotobiotic core facility. Identification by 16S ribotyping revealed facultative anaerobic firmicutes, including several Paenibacillus and Bacillus species, and obligate aerobic actinobacteria, namely Micrococcus luteus, among the contaminants. We selected 6 products commonly used for disinfecting hospital rooms, kitchens, and veterinary facilities to represent chlorine-oxide- and peroxide-based disinfectants and tested the hypothesis that these 2 classes are equally effective. However, evaluation of bactericidal and sporicidal activity in liquid cultures revealed that chlorine oxide-based disinfectants were more effective than peroxide-based disinfectants. In both groups, various products effectively sterilized gnotobiotic isolators by fogging in field tests, although bactericidal concentrations were markedly higher than those in suspension cultures, and effectiveness was contact-time-dependent. In addition, in both groups, some disinfectants were excessively corrosive to ferrous metals and acrylic. These results demonstrate that no single disinfectant has all desirable properties and that the different characteristics of disinfectants must be balanced during their selection. However, chlorine oxide-based disinfectants were generally more effective and less corrosive than peroxide-based products.


Asunto(s)
Compuestos de Cloro/farmacología , Desinfección/métodos , Vida Libre de Gérmenes , Vivienda para Animales/normas , Peróxidos/farmacología , Roedores , Animales , Desinfectantes/farmacología , Ciencia de los Animales de Laboratorio , Esterilización
19.
Biofabrication ; 11(4): 045012, 2019 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-31315098

RESUMEN

Supplying oxygen to inner areas of cell constructs to support cell proliferation and metabolism is a major challenge in tissue engineering involving stem cells. Developing devices that incorporate oxygen release materials to increase the availability of the localized oxygen supply is therefore key to addressing this limitation. Herein, we designed and developed a 3D-printed oxygen-releasing device composed of an alginate hydrogel scaffold combined with an oxygen-generating biomaterial (calcium peroxide) to improve the oxygen supply of the microenvironment for culturing adipose tissue-derived stem cells. The results demonstrated that the 3D-printed oxygen-releasing device alleviated hypoxia, maintained oxygen availability, and ensured proliferation of the embedded cells, whilst also reducing hypoxia-induced apoptosis. The introduction of this 3D-printed oxygen-releasing device could enhance the survival of embedded stem cells.


Asunto(s)
Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Oxígeno/metabolismo , Ingeniería de Tejidos/métodos , Tejido Adiposo/citología , Alginatos , Animales , Apoptosis/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Madre Mesenquimatosas/ultraestructura , Consumo de Oxígeno/efectos de los fármacos , Peróxidos/farmacología , Impresión Tridimensional , Ratas Sprague-Dawley , Reología
20.
J Trace Elem Med Biol ; 55: 78-81, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31345370

RESUMEN

SCOPE: Selenoneine (2-selenyl-Nα, Nα, Nα-trimethyl-L-histidine), the selenium (Se) analogue of the ubiquitous thiol compound and putative antioxidant ergothioneine, is the major organic selenium species in several marine fish species. Although its antioxidant efficacy has been proposed, selenoneine has been poorly characterized, preventing conclusions on its possible beneficial health effects. METHODS AND RESULTS: Treatment of Caenorhabditis elegans (C. elegans) with selenoneine for 18 h attenuated the induction of reactive oxygen and nitrogen species (RONS). However, the effect was not immediate, occurring 48 h post-treatment. Total Se and Se speciation analysis revealed that selenoneine was efficiently taken up and present in its original form directly after treatment, with no metabolic transformations observed. 48 h post-treatment, total Se in worms was slightly higher compared to controls and no selenoneine could be detected. CONCLUSION: The protective effect of selenoneine may not be attributed to the presence of the compound itself, but rather to the activation of molecular mechanisms with consequences at more protracted time points.


Asunto(s)
Antioxidantes/farmacología , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/metabolismo , Histidina/análogos & derivados , Compuestos de Organoselenio/farmacología , Estrés Oxidativo/efectos de los fármacos , Peróxidos/antagonistas & inhibidores , Sustancias Protectoras/farmacología , Animales , Antioxidantes/química , Relación Dosis-Respuesta a Droga , Histidina/química , Histidina/farmacología , Estructura Molecular , Compuestos de Organoselenio/química , Peróxidos/farmacología , Sustancias Protectoras/química , Relación Estructura-Actividad
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