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1.
Int Immunopharmacol ; : 108363, 2021 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-34810129

RESUMEN

Rheumatoid arthritis (RA) is an autoimmune disease that causes joint destruction. Although its etiology remains unknown, citrullinated proteins have been considered as an auto-antigen able to trigger an inflammatory response in RA. Herein, we modified the classical antigen-induced arthritis (AIA) model by using citrullinated human plasma fibrinogen (hFIB) as an immunogen to investigate the mechanism of inflammation-driven joint damage by citrullinated hFIB in C57BL/6 mice. We found that hFIB-immunized mice showed high serum levels of anti-citrullinated peptides antibodies (ACPAs). Moreover, hFIB immunized mice showed increased mechanical hyperalgesia, massive leukocyte infiltration, high levels of inflammatory mediators, and progressive joint damage after the intra-articular challenge with citrullinated hFIB. Interestingly, hFIB-induced arthritis was dependent on IL-23/IL-17 immune axis-mediated inflammatory responses since leukocyte infiltration and mechanical hyperalgesia were abrogated in Il17ra-/- and Il23a-/- mice. Thus, we have characterized a novel model of experimental arthritis suitable to investigate the contribution of ACPAs and Th17 cell-mediated immune response in the pathogenesis of RA.

2.
J Pharm Biomed Anal ; 206: 114387, 2021 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-34583125

RESUMEN

Chronic hyperglycemia and hyperlipidemia are associated with excessive formation of reactive oxygen species and advanced glycation end-products. The present study aimed to evaluate the potential in vitro antidiabetic properties of Kielmeyera coriacea inner bark. The main phytochemical compounds were identified by UHPLC-ESI/MSn and the ethanol extract and its fractions were used to evaluate their antioxidant and anti-glycation capacities, as well as their inhibitory potential against glycoside and lipid hydrolases activities. The polar fractions, especially the n-butanol fraction, had free radical scavenging and quenching properties (ORAC and FRAP values>1800 and 1000 µmol trolox eq/g, respectively, and DPPH IC50<4 µg/mL), and inhibited ROS production (p < 0.01), lipid peroxidation (p < 0.001), glycation (IC50 ~ 10 µg/mL in the BSA-fructose assay; IC50 ~ 200 µg/mL in the BSA-methylglyoxal and arginine-methylglyoxal assays), α-amylase (IC50<0.1 µg/mL) and lipase (IC50<5 µg/mL), with no cytotoxicity. Biomolecules well-known as potent antioxidants were identified for the first time in the inner bark of K. coriacea, such as protocatechuic acid, epicatechin and procyanidins A, B and C. Together, our results support the antioxidant, anti-glycation and glycoside and lipid hydrolases inhibitory properties of the inner bark of K. coriacea, a species found in the Brazilian savanna, which makes it especially useful to combat oxidative stress and hyperglycemia and hyperlipidemia.


Asunto(s)
Antioxidantes , alfa-Amilasas , Antioxidantes/farmacología , Productos Finales de Glicación Avanzada , Hipoglucemiantes/farmacología , Lipasa , Extractos Vegetales/farmacología
3.
Biomed Pharmacother ; 142: 112049, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34426250

RESUMEN

Dyslipidemia is a risk factor for the pathogenesis of several diseases, such as obesity, hypertension, atherosclerosis and cardiovascular diseases. In addition to interfering with serum concentrations of cholesterol and triglycerides, hyperlipidemia is involved in oxidative stress increase and reduction of the endogenous antioxidant defenses. The fruit peel of Annona crassiflora crude extract (CEAc) and its polyphenols-rich fraction (PFAc) were investigated against hypertriglyceridemia, hypercholesterolemia and hepatic oxidative stress in Triton WR-1339-induced hyperlipidemic mice. Lipid parameters in serum, feces and liver, as well as hepatic oxidative status, and enzymatic and non-enzymatic antioxidant defense systems were analyzed. Pre-treatment with CEAc for 12 days decreased hepatic triglycerides and total cholesterol, and similar to PFAc, increased the high-density lipoprotein level. There were reductions in lipid peroxidation and protein carbonylation, as well as restoration of the glutathione defense system and total thiol content in the liver of the hyperlipidemic mice treated with PFAc. The fruit peel of A. crassiflora, a promising natural source of bioactive molecules, showed a potential lipid-lowering action and hepatoprotective activities triggered by reduction of oxidative damage and maintenance of the enzymatic and non-enzymatic antioxidant systems impaired by the hyperlipidemic state.

4.
PLoS One ; 16(7): e0250394, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34237060

RESUMEN

Plant species from Annonaceae are commonly used in traditional medicine to treat various cancer types. This study aimed to investigate the antiproliferative potential of an alkaloid and acetogenin-rich fraction from the fruit peel of Annona crassiflora in HepG2 cells. A liquid-liquid fractionation was carried out on the ethanol extract of A. crassiflora fruit peel in order to obtain an alkaloid and acetogenin-rich fraction (AF-Ac). Cytotoxicity, proliferation and migration were evaluated in the HepG2 cells, as well as the proliferating cell nuclear antigen (PCNA), vinculin and epidermal growth factor receptor (EGFR) expression. In addition, intracellular Ca2+ was determined using Fluo4-AM and fluorescence microscopy. First, 9 aporphine alkaloids and 4 acetogenins that had not yet been identified in the fruit peel of A. crassiflora were found in AF-Ac. The treatment with 50 µg/mL AF-Ac reduced HepG2 cell viability, proliferation and migration (p < 0.001), which is in accordance with the reduced expression of PCNA and EGFR levels (p < 0.05). Furthermore, AF-Ac increased intracellular Ca2+ in the HepG2 cells, mobilizing intracellular calcium stores, which might be involved in the anti-migration and anti-proliferation capacities of AF-Ac. Our results support the growth-inhibitory potential of AF-Ac on HepG2 cells and suggest that this effect is triggered, at least in part, by PCNA and EGFR modulation and mobilization of intracellular Ca2+. This study showed biological activities not yet described for A. crassiflora fruit peel, which provide new possibilities for further in vivo studies to assess the antitumoral potential of A. crassiflora, especially its fruit peel.


Asunto(s)
Acetogeninas/análisis , Alcaloides/análisis , Annona/química , Frutas/química , Neoplasias Hepáticas/patología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Humanos
5.
Nano Lett ; 21(14): 6328-6335, 2021 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-33999635

RESUMEN

Recent studies of silicon spin qubits at temperatures above 1 K are encouraging demonstrations that the cooling requirements for solid-state quantum computing can be considerably relaxed. However, qubit readout mechanisms that rely on charge sensing with a single-island single-electron transistor (SISET) quickly lose sensitivity due to thermal broadening of the electron distribution in the reservoirs. Here we exploit the tunneling between two quantized states in a double-island single-electron transistor (SET) to demonstrate a charge sensor with an improvement in the signal-to-noise ratio by an order of magnitude compared to a standard SISET, and a single-shot charge readout fidelity above 99% up to 8 K at a bandwidth greater than 100 kHz. These improvements are consistent with our theoretical modeling of the temperature-dependent current transport for both types of SETs. With minor additional hardware overhead, these sensors can be integrated into existing qubit architectures for a high-fidelity charge readout at few-kelvin temperatures.

6.
Nat Protoc ; 16(6): 2765-2787, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33953393

RESUMEN

Early prediction of patient outcomes is important for targeting preventive care. This protocol describes a practical workflow for developing deep-learning risk models that can predict various clinical and operational outcomes from structured electronic health record (EHR) data. The protocol comprises five main stages: formal problem definition, data pre-processing, architecture selection, calibration and uncertainty, and generalizability evaluation. We have applied the workflow to four endpoints (acute kidney injury, mortality, length of stay and 30-day hospital readmission). The workflow can enable continuous (e.g., triggered every 6 h) and static (e.g., triggered at 24 h after admission) predictions. We also provide an open-source codebase that illustrates some key principles in EHR modeling. This protocol can be used by interdisciplinary teams with programming and clinical expertise to build deep-learning prediction models with alternate data sources and prediction tasks.


Asunto(s)
Aprendizaje Profundo , Registros Electrónicos de Salud , Proyectos de Investigación , Medición de Riesgo/métodos , Humanos , Programas Informáticos , Flujo de Trabajo
7.
Nat Commun ; 12(1): 3228, 2021 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-34050152

RESUMEN

An error-corrected quantum processor will require millions of qubits, accentuating the advantage of nanoscale devices with small footprints, such as silicon quantum dots. However, as for every device with nanoscale dimensions, disorder at the atomic level is detrimental to quantum dot uniformity. Here we investigate two spin qubits confined in a silicon double quantum dot artificial molecule. Each quantum dot has a robust shell structure and, when operated at an occupancy of 5 or 13 electrons, has single spin-[Formula: see text] valence electron in its p- or d-orbital, respectively. These higher electron occupancies screen static electric fields arising from atomic-level disorder. The larger multielectron wavefunctions also enable significant overlap between neighbouring qubit electrons, while making space for an interstitial exchange-gate electrode. We implement a universal gate set using the magnetic field gradient of a micromagnet for electrically driven single qubit gates, and a gate-voltage-controlled inter-dot barrier to perform two-qubit gates by pulsed exchange coupling. We use this gate set to demonstrate a Bell state preparation between multielectron qubits with fidelity 90.3%, confirmed by two-qubit state tomography using spin parity measurements.

10.
Nano Lett ; 21(3): 1517-1522, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33481612

RESUMEN

Quantum gates between spin qubits can be implemented leveraging the natural Heisenberg exchange interaction between two electrons in contact with each other. This interaction is controllable by electrically tailoring the overlap between electronic wave functions in quantum dot systems, as long as they occupy neighboring dots. An alternative route is the exploration of superexchange-the coupling between remote spins mediated by a third idle electron that bridges the distance between quantum dots. We experimentally demonstrate direct exchange coupling and provide evidence for second neighbor mediated superexchange in a linear array of three single-electron spin qubits in silicon, inferred from the electron spin resonance frequency spectra. We confirm theoretically, through atomistic modeling, that the device geometry only allows for sizable direct exchange coupling for neighboring dots, while next-nearest neighbor coupling cannot stem from the vanishingly small tail of the electronic wave function of the remote dots, and is only possible if mediated.

11.
J Ethnopharmacol ; 267: 113599, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33220360

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Pfaffia glomerata roots are widely used in Brazil to treat various pathological conditions, particularly psychological disorders. 20-hydroxyecdysone, a phytosteroid present in the plant, can promote greater body resistance against exogenous and endogenous stressors. The objective of this study was to evaluate the possible neuroprotective effect of a 20-hydroxyecdysone-enriched fraction (20E-EF), obtained from P. glomerata roots, in an acute murine stress model. MATERIAL AND METHODS: The 20E-EF was obtained by partitioning the methanol extract from P. glomerata roots with dichloromethane. Mice were treated by gavage with three doses of 20E-EF (3, 10, and 30 mg/kg) and parameters of stress, anxiety, and depression were evaluated. Biomarkers of oxidative stress (enzymes, antioxidant profile, and oxidized molecules) were evaluated in the cortex, striatum (basal ganglia), and hippocampus of animals treated with 30 mg/kg of 20E-EF. RESULTS: Mass spectrometry revealed that 20E was the main compound in the dichloromethane fraction. At a dose of 30 mg/kg, 20E-EF reduced stress, anxiety, and depression, while stimulating antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase), promoting antioxidant activity (antioxidant capacity, sulfhydryl groups, and reduced glutathione), and reducing oxidative markers (lipid peroxidation). In addition, 20E increased the concentration of NO in the striatum, possibly improving memory function and antioxidant activity. CONCLUSION: A 30 mg/kg dose of 20E-EF was able to reduce stress, anxiety, and depression, in addition to maintaining antioxidant defenses of the cortex and striatum. These findings open new perspectives for understanding the therapeutic properties of P. glomerata and the underlying mechanism(s).


Asunto(s)
Amaranthaceae , Ansiolíticos/farmacología , Antidepresivos/farmacología , Ansiedad/prevención & control , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Depresión/prevención & control , Ecdisterona/farmacología , Extractos Vegetales/farmacología , Raíces de Plantas , Estrés Psicológico/prevención & control , Amaranthaceae/química , Animales , Ansiolíticos/aislamiento & purificación , Antidepresivos/aislamiento & purificación , Antioxidantes/farmacología , Ansiedad/metabolismo , Ansiedad/fisiopatología , Ansiedad/psicología , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Depresión/metabolismo , Depresión/fisiopatología , Depresión/psicología , Modelos Animales de Enfermedad , Ecdisterona/aislamiento & purificación , Conducta Exploratoria/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas/química , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología
12.
J Ethnopharmacol ; 268: 113667, 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33301920

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The substantial increase in diabetes cases worldwide has been a major public health problem, and the use of medicinal plants can be considered an interesting alternative to control the disease and its complications. Anacardium humile St. Hill. (Anacardiaceae) is a typical plant from the Brazilian savanna, popularly known for its antidiarrheal, expectorant, antidiabetic and anti-inflammatory properties, however, few studies have fully described its biological properties. This study aimed to investigate in vitro and ex vivo the antioxidant and antiglycation potential of A. humile ethanolic extract, its organic fractions and three isolated molecules (quercetin, catechin and gallic acid), their capacity to inhibit the glycolytic enzyme α-amylase, as well as their cytotoxic effects against RAW264.7 macrophages. MATERIAL AND METHODS: The ethanolic extract of A. humile, its organic fractions and three isolated molecules (catechin, quercetin and gallic acid) were tested for their antioxidant (ORAC, FRAP and DPPH) and antiglycation (BSA/Fructose, BSA/Methylglyoxal, Arginine/Methylglyoxal and Lysine/Methylglyoxal) capacities, and also for its potential to inhibit the enzyme α-amylase. Additionally, bioactive compounds present in the A. humile leaves fractions were elucidated by an HPLC-ESIMS/MS analysis. RESULTS: The analysis showed relevant antioxidant activity of DCM (1264.85 ± 76.90 µM Trolox eq/g ORAC; 216.71 ± 1.04 µM Trolox eq/g FRAP and 3.03 ± 0.08 IC50 µg/mL IC50 DPPH) and EtOAc (1300.11 ± 33.04 ORAC, 236.21 ± 23.86 FRAP and 3.03 ± 0.14 µg/mL IC50 DPPH) fractions and also of the isolated molecules, mainly gallic acid (1291.19 ± 8.41 µM Trolox eq/g ORAC, 1103.52 ± 31.48 µM Trolox eq/g FRAP and 0.78 ± 0.11 µg/mL IC50 DPPH). Concerning the antiglycation activity, all samples inhibited over 88% in the BSA-FRU method. In the BSA-MGO and ARG-MGO methods, the Hex, DCM, EtOAc fractions and the isolated molecule catechin stood out. However, in the LYS-MGO model, only the isolated molecules showed significant results. In α-amylase assay, all fractions, for exception Hex, presented notable inhibition capacity with low IC50 values, especially DCM, EtOAc, ButOH and H2O (IC50 0.56 ± 0.10, 0.84 ± 0.01, 0.74 ± 0.03 and 0.79 ± 0.06 µg/mL, respectively). Tests using hepatic tissue showed a notorious capacity of the DCM, AcOEt and ButOH fractions, as well as of the isolated molecules to inhibit lipid peroxidation and ROS production, and also to preserve thiol groups. Molecules of great antioxidant potential were found in our samples, such as kaempferol, quercetin, catechin, gallic acid and luteolin. CONCLUSION: A. humile extract and its organic fractions showed promising antioxidant and antiglycation potential and a prominent capacity to inhibit the α-amylase enzyme. Hence, this study presents new results and stimulates further research to elucidate the biological properties of A. humile and its capacity to manage DM and its complications.


Asunto(s)
Anacardium , Antioxidantes/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/uso terapéutico , alfa-Amilasas/antagonistas & inhibidores , Animales , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Diabetes Mellitus/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/fisiología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , alfa-Amilasas/metabolismo
13.
Nano Lett ; 20(11): 7882-7888, 2020 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-33108202

RESUMEN

The advanced nanoscale integration available in CMOS technology provides a key motivation for its use in spin-based quantum computing applications. Initial demonstrations of quantum dot formation and spin blockade in CMOS foundry-compatible devices are encouraging, but results are yet to match the control of individual electrons demonstrated in university-fabricated multigate designs. We show that quantum dots formed in a CMOS nanowire device can be measured with a remote single electron transistor (SET) formed in an adjacent nanowire, via floating coupling gates. By biasing the SET nanowire with respect to the nanowire hosting the quantum dots, we controllably form ancillary quantum dots under the floating gates, thus enabling control of all quantum dots in a 2 × 2 array, and charge sensing down to the last electron in each dot. We use effective mass theory to investigate the ideal geometrical parameters in order to achieve interdot tunnel rates required for spin-based quantum computation.

14.
J Leukoc Biol ; 108(4): 1215-1223, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32745297

RESUMEN

Macrophages are highly plastic cells, responding to diverse environmental stimuli to acquire different functional phenotypes. Signaling through MAPKs has been reported to regulate the differentiation of macrophages, but the role of ERK5 in IL-4-mediated M2 macrophage differentiation is still unclear. Here, we showed that the ERK5 signaling pathway plays a critical role in IL-4-induced M2 macrophage differentiation. Pharmacologic inhibition of MEK5, an upstream activator of ERK5, markedly reduced the expression of classical M2 markers, such as Arg-1, Ym-1, and Fizz-1, as well as the production of M2-related chemokines and cytokines, CCL22, CCL17, and IGF-1 in IL-4-stimulated macrophages. Moreover, pharmacologic inhibition of ERK5 also decreased the expression of several M2 markers induced by IL-4. In accordance, myeloid cell-specific Erk5 depletion (Erk5∆mye ), using LysMcre /Erk5f/f mice, confirmed the involvement of ERK5 in IL-4-induced M2 polarization. Mechanistically, the inhibition of ERK5 did not affect STAT3 or STAT6 phosphorylation, suggesting that ERK5 signaling regulates M2 differentiation in a STAT3 and STAT6-independent manner. However, genetic deficiency or pharmacologic inhibition of the MEK5/ERK5 pathway reduced the expression of c-Myc in IL-4-activated macrophages, which is a critical transcription factor involved in M2 differentiation. Our study thus suggests that the MEK5/ERK5 signaling pathway is crucial in IL-4-induced M2 macrophage differentiation through the induction of c-Myc expression.


Asunto(s)
Diferenciación Celular/inmunología , Interleucina-4/inmunología , MAP Quinasa Quinasa 5/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Macrófagos/inmunología , Proteína Quinasa 7 Activada por Mitógenos/inmunología , Proteínas Proto-Oncogénicas c-myc/inmunología , Animales , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/inmunología , Diferenciación Celular/genética , Regulación de la Expresión Génica/inmunología , Interleucina-4/genética , MAP Quinasa Quinasa 5/genética , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Proteína Quinasa 7 Activada por Mitógenos/genética , Proteínas Proto-Oncogénicas c-myc/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/inmunología , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/inmunología
15.
J Ethnopharmacol ; 261: 113132, 2020 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-32673709

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Plant materials are commonly used in traditional medicine in order to treat various diseases such as Diabetes mellitus. Some plants, such as Syzygium cumini, have the capability to act controlling oxidative stress and protein glycation besides their potential to decrease hyperglycemia and hyperlipidemia by the inhibition of the catalysis of digestive enzymes. The aim of this study was to evaluate the antioxidant and antiglicant activity of S. cumini leaves fractions, their capacity to inhibit hydrolases and lipase enzymes, as well as the cytotoxicity effects against erythrocytes and comparate these results with isolate quercetin flavonoid. MATERIAL AND METHODS: Ethnobotanical researches, carried out by academic studies at the Federal University of Uberlandia, led us to choose S. cumini as a potential plant for treatment of Diabetes mellitus. Fractions from ethanolic extract of S. cumini (hexane/Hex, dichloromethane/DCM, ethyl acetate/EtOAc, n-butanol/ButOH and water/H2O) were used to evaluate their antioxidant (DPPH, ORAC and FRAP) and antiglycant (BSA/fructose, BSA/methylglyoxal and Arginine/Methylglyoxal) activity as well as the inhibitory potential against α-amylase, α-glucosidase and lipase. In addition, identification of the main bioactive compounds of S. cuimini leaves by HPLC-ESIMS/MS analysis was carried out. RESULTS: Our results indicate that all fractions, for exception Hex, present noteworthy antioxidant activity, mainly in EtOAc and ButOH fractions (FRAP 1154.49 ± 67.37 and 1178.27 ± 21.26 µmol trolox eq g-1, respectively; ORAC 1224.63 ± 58.16 and 1313.53 ± 85.23 µmol trolox eq g-1, respectively; DPPH IC50 15.7 ± 2.4 and 23.5 ± 2.7 µg mL-1, respectively). Regarding the antiglycant activity (BSA/fructose and Arginine/Methylglyoxal models), all fraction, for exception Hex, presented inhibition higher than 85%. All fractions were capable to inhibit 100% of α-amylase and the fractions DCM, EtOAc and ButOH inhibited α-glucosidase more than 50%. Regarding the lipase assay, DCM and Hex had the best activity (31.5 ± 14.3 and 44.3 ± 4.5 µg mL-1, respectively). Various biomolecules known as potent antioxidants were identified in these fractions, such as quercetin, kaempferol, luteolin and (Epi)catechin. CONCLUSION: S. cumini fractions and quercetin presented promising antioxidant and antiglycation properties as well as the ability to inhibit digestive enzymes. This study presents new biological activities not yet described for S. cumini which provide new possibilities for further studies in order to assess the antidiabetic potential of S. cumini fractions especially EtOAc and ButOH.


Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Extractos Vegetales/farmacología , Hojas de la Planta , Syzygium , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/toxicidad , Antioxidantes/aislamiento & purificación , Antioxidantes/toxicidad , Cromatografía Líquida de Alta Presión , Digestión/efectos de los fármacos , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/toxicidad , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Productos Finales de Glicación Avanzada/metabolismo , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/toxicidad , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Oxidación-Reducción , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Hojas de la Planta/química , Hojas de la Planta/toxicidad , Ratas Wistar , Espectrometría de Masa por Ionización de Electrospray , Syzygium/química , Syzygium/toxicidad , Espectrometría de Masas en Tándem , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismo
16.
Bioorg Chem ; 96: 103562, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31981911

RESUMEN

Pain relief represents a critical unresolved medical need. Consequently, the search for new analgesic agents is intensively studied. Annona crassiflora, a native species of the Brazilian Savanna, represents a potential source for painful treatment. This study aimed to investigate the antinociceptive potential of A. crassiflora fruit peel, focusing on its major alkaloid, stephalagine, in animal models of pain evoked by the activation of transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) channels. Male C57BL/6/J mice were submitted to formalin-, cinnamaldehyde-, and capsaicin-induced nociception tests to assess nociceptive behavior, and to the open-field and rotarod tests for motor performance analyses. Moreover, the stephalagine's effect was tested on capsaicin- and cinnamaldehyde-induced Ca2+ influx in spinal cord synaptosomes. In silico assessments of the absorption, distribution, metabolism and central nervous system permeability of stephalagine were carried out. The ethanol extract and alkaloidal fraction reduced the nociception induced by formalin. When administered by oral route (1 mg/kg), stephalagine reduced the spontaneous nociception and paw edema induced by TRPV1 agonist, capsaicin, and by TRPA1 agonists, cinnamaldehyde- and formalin, without altering the animals' locomotor activity. The prediction of in silico pharmacokinetic properties of stephalagine suggests its capacity to cross the blood-brain barrier. Furthermore, this alkaloid reduces the capsaicin- and cinnamaldehyde-mediated Ca2+ influx, indicating a possible modulation of TRPV1 and TRPA1 channels, respectively. Together, our results support the antinociceptive and anti-edematogenic effects of the A. crassiflora fruit peel and suggest that these effects are triggered, at least in part, by TRPV1 and TRPA1 modulation by stephalagine.


Asunto(s)
Analgésicos/farmacología , Annona/química , Aporfinas/farmacología , Calcio/metabolismo , Formaldehído/toxicidad , Canal Catiónico TRPA1/fisiología , Canales Catiónicos TRPV/fisiología , Acroleína/administración & dosificación , Acroleína/análogos & derivados , Animales , Conducta Animal , Capsaicina/administración & dosificación , Transporte Iónico , Masculino , Ratones , Ratones Endogámicos C57BL , Dolor/inducido químicamente , Canales Catiónicos TRPV/agonistas
17.
Inflammopharmacology ; 28(3): 759-771, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31845053

RESUMEN

Different parts of Annona crassiflora Mart., a native species from Brazilian savanna, were traditionally used for the treatment of a wide variety of ailments including arthritis. Thus, this study aimed to investigate the possible antinociceptive and anti-inflammatory properties of a polyphenol-enriched fraction of the fruit peel of A. crassiflora, named here as EtOAc, in mice. Pro-inflammatory cytokines and nitric oxide (NO) production were evaluated in LPS-activated macrophages. Then, EtOAc fraction was administered by oral route in male C57BL/6/J mice, and the animals were submitted to glutamate-induced nociception and complete Freund's adjuvant (CFA)-induced monoarthritis tests to assess nociception (mechanical, spontaneous and cold pain) and inflammation (edema and neutrophil infiltration), and to the open-field and rotarod tests for motor performance analysis. EtOAc fraction inhibited the production of IL-6 and NO in the LPS-induced macrophages, and reduced spontaneous nociception induced by glutamate, without altering the animals' locomotor activity. In addition, the polyphenol-enriched fraction was able to revert the early and late hyperalgesia induced by CFA, as well as edema at the acute phase. Reduction of myeloperoxidase activity and inflammatory cell infiltration was observed in the paw tissue of mice injected with CFA and treated with EtOAc fraction. Together, our results support the antinociceptive and anti-inflammatory effects of the polyphenol-enriched fraction of A. crassiflora fruit peel and suggest that these effects are triggered, at least in part, by suppressing pro-inflammatory cytokines and neutrophils infiltration.


Asunto(s)
Annona/química , Frutas/química , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Extractos Vegetales/farmacología , Polifenoles/farmacología , Sustancias Protectoras/farmacología , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Edema/tratamiento farmacológico , Adyuvante de Freund/farmacología , Hiperalgesia/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Nocicepción/fisiología
18.
Biomed Pharmacother ; 123: 109798, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31877553

RESUMEN

Bauhinia forficata Link., a cerrado native plant, is used as a complementary treatment for Type 2 Diabetes Mellitus (T2DM). Several studies involving this plant have shown that it has prominent potential to combat hyperglycemia and oxidative stress. Our objective was suggest the phytochemical constitution of fractions of ethanol extract of B. forficata leaves using HPLC-ESI-MS/MS, and evaluates their activities in enzymatic assays to evaluate their inhibitory potential against α-amylase, α-glucosidase and lipase, as well as their antioxidant and anti-glycation capacities. In addition, we evaluated the cytotoxic effects of these fractions using rodents macrophages and erythrocytes. The ETOAC e ButOH fractions showed high polyphenols concentrations, having been determined 11 flavonoids, including the kaempferitrin, the phytomarker of B. forficata Link. In addition, all fractions presented higher antioxidant and antiglycation activities and prominent capacities to digestive enzymes inhibition. On the other hand, in the cellular assays, none fractions showed cytotoxic and hemolytic effects, able to combat the ROS production in macrophages. Thus, this study presented new results on the biological activities of this plant, contributing to the understanding of the action and effectiveness of its use in the management of diabetes mellitus and its complications.


Asunto(s)
Antioxidantes/farmacología , Bauhinia/química , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/farmacología , Lipasa/antagonistas & inhibidores , Extractos Vegetales/farmacología , Hojas de la Planta/química , Animales , Antioxidantes/química , Supervivencia Celular/efectos de los fármacos , Glicosilación , Hemólisis/efectos de los fármacos , Cinética , Lipasa/metabolismo , Masculino , Ratones Endogámicos C57BL , Fitoquímicos/farmacología , Extractos Vegetales/química , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismo , alfa-Glucosidasas/metabolismo
19.
Sci Rep ; 9(1): 19183, 2019 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-31844118

RESUMEN

Advanced glycation end-products (AGEs) have been reported as results of increased oxidative stress. Consequently, the search for new antioxidant and anti-glycating agents is under intense investigation. Plant-derived procyanidins have previously demonstrated anti-glycation properties. Thus, this study aimed to isolate procyanidins from Annona crassiflora fruit peel, a species from the Brazilian Savanna, and investigate their antioxidant and anti-glycation effects. Free radical scavenging and quenching properties, formation of reactive oxygen species (ROS), AGEs, protein carbonyl and thiol groups, lipid peroxidation, crosslinked AGEs, as well as glycated catalase activity, were analyzed. In addition, in silico assessment of absorption, distribution, metabolism, excretion and toxicity was carried out. The procyanidins-enriched fraction, named here as F7, showed high antioxidant and anti-glycation capacities, with inhibitory activities against lipid peroxidation, and AGEs and ROS formation. In addition, there were reductions in AGEs-induced crosslinks and protein carbonyls and protective effects against oxidation of thiol groups and glycated-catalase. ADMET predictions of F7 showed favorable absorption and distribution, with no hepatotoxicity or mutagenicity. Together, our results support the anti-glycation activities of the procyanidins-enriched fraction from A. crassiflora, and suggest that these effects are triggered, at least in part, by scavenging free radical and dicarbonyls intermediates.


Asunto(s)
Annona/química , Biflavonoides/farmacología , Catalasa/metabolismo , Catequina/farmacología , Frutas/química , Peroxidación de Lípido/efectos de los fármacos , Fitoquímicos/farmacología , Proantocianidinas/farmacología , Sustancias Protectoras/farmacología , Carbonilación Proteica/efectos de los fármacos , Animales , Antioxidantes/farmacología , Biflavonoides/química , Catequina/química , Bovinos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/química , Fluorescencia , Productos Finales de Glicación Avanzada/metabolismo , Glicosilación , Fenoles/análisis , Proantocianidinas/química , Especies Reactivas de Oxígeno/metabolismo , Albúmina Sérica Bovina/metabolismo , Compuestos de Sulfhidrilo/metabolismo
20.
Nature ; 572(7767): 116-119, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31367026

RESUMEN

The early prediction of deterioration could have an important role in supporting healthcare professionals, as an estimated 11% of deaths in hospital follow a failure to promptly recognize and treat deteriorating patients1. To achieve this goal requires predictions of patient risk that are continuously updated and accurate, and delivered at an individual level with sufficient context and enough time to act. Here we develop a deep learning approach for the continuous risk prediction of future deterioration in patients, building on recent work that models adverse events from electronic health records2-17 and using acute kidney injury-a common and potentially life-threatening condition18-as an exemplar. Our model was developed on a large, longitudinal dataset of electronic health records that cover diverse clinical environments, comprising 703,782 adult patients across 172 inpatient and 1,062 outpatient sites. Our model predicts 55.8% of all inpatient episodes of acute kidney injury, and 90.2% of all acute kidney injuries that required subsequent administration of dialysis, with a lead time of up to 48 h and a ratio of 2 false alerts for every true alert. In addition to predicting future acute kidney injury, our model provides confidence assessments and a list of the clinical features that are most salient to each prediction, alongside predicted future trajectories for clinically relevant blood tests9. Although the recognition and prompt treatment of acute kidney injury is known to be challenging, our approach may offer opportunities for identifying patients at risk within a time window that enables early treatment.


Asunto(s)
Lesión Renal Aguda/diagnóstico , Técnicas de Laboratorio Clínico/métodos , Lesión Renal Aguda/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Simulación por Computador , Conjuntos de Datos como Asunto , Reacciones Falso Positivas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Curva ROC , Medición de Riesgo , Incertidumbre , Adulto Joven
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