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1.
Molecules ; 28(16)2023 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-37630391

RESUMEN

Kelussia odoratissima Mozaff. is a species of Apiaceae endemic to the Zagros Mountains in Iran. In the present investigation, for the first time, the polyphenolic compounds and flavonoids of its leaves were determined by liquid chromatography-mass spectrometry (LC-MS). As a result, p-coumaric acid, ferulic acid, caffeic acid, chlorogenic acid, acetyl phloroglucinol, vanillic acid, m-coumaric acid, and 4-methylsiringol were determined as the main phenolic compounds, while 3-hydroxyflavone, flavone, quercetin, rutin, neohesperidin, polydatin, and diosmin were the main flavonoid components, of which chlorogenic acid (303.08 µL/gDW), neohesperidin (38.37 µL/gDw), and diosmin (28.62 µL/gDW) were the most abundant. Solid-phase microextraction (SPME) was also used to determine the chemical compounds. Based on SPME, (Z)-undec-6-en-2-one (17.48%) and (Z)-butylidenephthalide (4.348%) were the major components. Based on GC-MS analyses, (Z)-ligustilide was the main compound; however, some new compounds were also determined, including 3-ethylisobenzofuran-1 (3H)-one, (E)-ligugustilide, and E-n-butylidene phthalide. Also, for the first time, we have identified EOs ethyl and isobutyl phthalides on the basis of the obtained EI-MS spectra. Finally, the fragmentation of phthalides is also discussed in this research.


Asunto(s)
Apiaceae , Diosmina , Cromatografía de Gases y Espectrometría de Masas , Cromatografía Liquida , Microextracción en Fase Sólida , Espectrometría de Masas en Tándem , Hojas de la Planta , Flavonoides
2.
Chem Biodivers ; 15(8): e1800075, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29779268

RESUMEN

A comparative study was carried out on the methanolic extracts from six Achillea species and the examined polyphenols from these plants on the formation of advanced glycation end-products (AGE) in vitro. A. pachycephala which was richer in flavonoids (15 mg quercetin/g W) and phenolics (111.10 mg tannic acid/g DW) with substantial antioxidant activity (IC50  = 365.5 µg/ml) presented strong anti-AGE properties. Chlorogenic acid, luteolin, quercetin and caffeic acid were identified as the major polyphenols in the extracts by HPLC. In general, polyphenolic content follows the order of A. pachycephalla > A. nobilis > A. filipendulina > A. santolina > A. aucheri > A. millefolium. Most extracts exhibited marked anti-AGE ability in the bovine serum albumin (BSA)/methylglyoxal (MG) system, though A. pachycephala showed the highest potential. The formation of AGEs was assessed by monitoring the production of fluorescent products and circular dichroism (CD) spectroscopy. Diminution in free radical production (assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays) is discussed as potential mechanism for delay or reduced AGE. The results demonstrate the antiglycative, antioxidant and antimicrobial potential of Achillea species which can be attributed to polyphenols content and the effectiveness on generation of AGEs, thus Achillea species can be considered as natural sources for slowing down glycation related diseases.


Asunto(s)
Achillea/química , Antiinfecciosos/farmacología , Antioxidantes/farmacología , Productos Biológicos/farmacología , Polifenoles/farmacología , Antiinfecciosos/química , Antiinfecciosos/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Bacillus subtilis/efectos de los fármacos , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Polifenoles/química , Polifenoles/aislamiento & purificación , Salmonella typhimurium/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Streptococcus/efectos de los fármacos , Relación Estructura-Actividad
3.
Artículo en Inglés | MEDLINE | ID: mdl-38351429

RESUMEN

The pathogenesis of diabetes is related to the amount of advanced glycation end products (AGEs) that are naturally generated from the attachment of glucose with tissue and circular proteins. Human serum albumin (HSA) is more susceptible to AGE occurrence than other circular proteins due to its sensitive sites and high abundance. Considering the location of hydroxyl groups in the structure of flavonoids, which play a major role in suppressing of AGEs generating pathways, the present study was conducted to compare the effect of the chemical peculiarities of five flavonoids: apigenin (AP), naringenin (NA), luteolin (LU), Quercetin (QU), and methylquercetin (MQ), in suppressing AGEs generated in the HSA/glucose system. The results showed that all used flavonoids are capable of quenching the fluorescence intensity of AGEs in vitro. Analytical methods including UV-visible spectroscopy, CD spectro-polarimetry, TNBS, DTNB, DNPH, Congo red assay, ThT, and ANS fluorescence were used to deeper analysis of flavonoid performance. The anti-AGE effects of flavonoids followed the order of LU > QU > MQ > AP > NA. Docking results showed that flavonoids are associated with glycation-prone lysines and arginine residues in the "Sudlow pocket" through non-covalent interactions. Hydroxylation at the C4' and the double bond between C2-C3 increase the antiglycation potential of used flavonoids, while methylation of the OH group at the C3 position decreases this effect. It was also found that hydroxylation at C3 can play a dual role in anti-glycation ability. These findings may introduce a new approach to the structure-inhibition relationship of flavonoids in the design of operative anti-glycemic agents.

4.
Int J Biol Macromol ; 270(Pt 1): 132164, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38729474

RESUMEN

The process of developing novel compounds/drugs is arduous, time-intensive, and financially burdensome, characterized by a notably low success rate and relatively high attrition rates. To alleviate these challenges, compound/drug repositioning strategies are employed to predict potential therapeutic effects for DrugBank-approved compounds across various diseases. In this study, we devised a computational and enzyme inhibitory mechanistic approach to identify promising compounds from the pool of DrugBank-approved substances targeting Diabetes Mellitus (DM). Molecular docking analyses were employed to validate the binding interaction patterns and conformations of the screened compounds within the active site of α-glucosidase. Notably, Asp352 and Glu277 participated in interactions within the α-glucosidase-ligand complexes, mediated by conventional hydrogen bonding and van der Waals forces, respectively. The stability of the docked complexes (α-glucosidase-compounds) was scrutinized through Molecular Dynamics (MD) simulations. Subsequent in vitro analyses assessed the therapeutic potential of the repositioned compounds against α-glucosidase. Kinetic studies revealed that "Forodesine" exhibited a lower IC50 (0.24 ± 0.04 mM) compared to the control, and its inhibitory pattern corresponds to that of competitive inhibitors. In-depth in silico secondary structure content analysis detailed the interactions between Forodesine and α-glucosidase, unveiling significant alterations in enzyme conformation upon binding, impacting its catalytic activity. Overall, our findings underscore the potential of Forodesine as a promising candidate for DM treatment through α-glucosidase inhibition. Further validation through in vitro and in vivo studies is imperative to confirm the therapeutic benefits of Forodesine in conformational diseases such as DM.


Asunto(s)
Diabetes Mellitus , Reposicionamiento de Medicamentos , Inhibidores de Glicósido Hidrolasas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Reposicionamiento de Medicamentos/métodos , alfa-Glucosidasas/química , alfa-Glucosidasas/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Humanos , Simulación por Computador , Cinética , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Dominio Catalítico
5.
Curr Res Struct Biol ; 7: 100146, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38707547

RESUMEN

Nowadays, one of the methods to prevent the progress of Alzheimer's disease (AD) is to prescribe compounds that inhibit the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Researchers are actively pursuing compounds, particularly of natural origin, that exhibit enhanced efficacy and reduced side effects. The inhibition of AChE and BChE using natural flavonoids represents a promising avenue for regulating AD. This study aims to identify alternative flavonoids capable of modulating AD by down-regulating AChE and BChE activity through a molecular docking approach. Molecular docking analysis identified Ginkgetin and Kolaflavanone as potent inhibitors of AChE and BChE, respectively, among the selected flavonoids. Asn87 and Ala127 involved in the interactions of AChE-Ginkgetin complex through conventional hydrogen bonds. While in the BChE-Kolaflavanone complex, Asn83, Ser79, Gln 47, and Ser287 are involved. In vitro analysis further corroborated the inhibitory potential, with Ginkgetin exhibiting an IC50 of 3.2 mM against AChE, and Kolaflavanone displaying an IC50 of 3.6 mM against BChE. These findings underscore the potential of Ginkgetin and Kolaflavanone as candidate inhibitors for the treatment of AD through the inhibition of AChE and BChE enzymes. Nevertheless, additional in vitro and in vivo studies are imperative to validate the efficacy of these compounds.

6.
J Spinal Cord Med ; 36(3): 231-6, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23809594

RESUMEN

BACKGROUND: Induction of p75 neurotrophin receptor (p75NTR) could be one of the first steps that initiate apoptotic cascade after injury, or it may indicate regeneration responses undertaken by the injured system, possibly in collaboration with resident tropomyosin-receptor-kinase (Trk). OBJECTIVE: To measure quantitative changes in messenger RNA (mRNA) expression levels of p75NTR, Trk A, and caspase-9 in rat's injured spinal cord (SCI). The reciprocal interaction between Trk and p75NTR signaling pathways can dictate cellular responses to neurotrophins. p75NTR can regulate Trk-dependent responses, but the role of Trk in regulating p75NTR-dependent signaling is not well documented. DESIGN: Using real-time polymerase chain reaction, this study analyzed changes in the mRNA abundance of the mentioned genes at 6, 24, and 72 hours and 7 and 10 days after SCI in adult male rats. SCI was induced at T9 level by transsection. RESULTS: Results show a complicated temporal and spatial pattern of alteration with different degrees and direction (up- or down-regulation) in p75NTR, Trk A, and caspase-9 mRNA expression levels after SCI. The greatest variation was seen in center regions following SCI. This study shows that alteration in p75NTR, Trk A, and caspase-9 expression starts as early as 6 hours after SCI. Alterations in p75NTR, Trk A, and caspase-9 expression within the spinal cord may play a key role in the apoptotic cell death. CONCLUSION: Results suggest that the role of p75NTR is to eliminate damaged cells by activating the apoptotic machinery, especially at the center of damage and during first week after injury.


Asunto(s)
Receptor de Factor de Crecimiento Nervioso/biosíntesis , Receptor trkA/biosíntesis , Traumatismos de la Médula Espinal/metabolismo , Animales , Caspasa 9/análisis , Caspasa 9/biosíntesis , Caspasa 9/genética , Modelos Animales de Enfermedad , Masculino , ARN Mensajero/análisis , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor de Factor de Crecimiento Nervioso/análisis , Receptor de Factor de Crecimiento Nervioso/genética , Receptor trkA/análisis , Receptor trkA/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Traumatismos de la Médula Espinal/genética , Transcriptoma
7.
J Oleo Sci ; 72(8): 787-797, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37532567

RESUMEN

Inhibition of α-amylase, α-glucosidase, and advanced glycation end products (AGEs) is considered a prospective method for the prevention of type II diabetes. As two flavonoids obtained from fruits, swertisin (SW) and apigenin (AP) have similar structures and display various pharmacological properties. To examine the effects of flavonoid structure on inhibition of AGEs adducts and carbohydrate hydrolyzing enzymes activity, molecular docking and molecular dynamic simulations (MDs) were used. The molecular docking method was performed by the Autodock program, and the ligand that showed the most negative binding energy was selected for further investigation. SW showed the potential ability to inhibit the AGEs formation and carbohydrate hydrolyzing enzymes activity. The stability of the receptor/SW complex was evaluated by MDs. Based on the findings of the present study, it was found that SW has the potential to reduce glycation and delay the activity of α-amylase and α-glucosidase enzymes.


Asunto(s)
Diabetes Mellitus Tipo 2 , Flavonoides , Humanos , alfa-Amilasas , alfa-Glucosidasas/metabolismo , Carbohidratos , Diabetes Mellitus Tipo 2/prevención & control , Flavonoides/farmacología , Productos Finales de Glicación Avanzada/metabolismo , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Glicósidos , Simulación del Acoplamiento Molecular , Almidón
8.
Int J Biol Macromol ; 253(Pt 7): 127380, 2023 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-37838108

RESUMEN

Biflavonoids (BFs) are a group of polyphenols that have a unique biochemical structure. One of the key biomedical mechanisms that BFs can have high potential in managing Diabetes mellitus (DM) is α-glucosidase inhibition. Normally, elevated blood glucose levels are caused by high absorption of glucose in the epithelium of the small intestine. Since α-glucosidase helps increase the absorption of glucose in the small intestine in the final stage of glycan catabolism, inhibition of this essential biochemical process in diabetic patients can be considered a suitable approach in the treatment of this disease. The interaction between the BFs and α-glucosidase are still not clear, and need to be deeply investigated. Herein, the aim is to identify BFs with strong α-glucosidase inhibitory activity. Using docking-based virtual screening approach, the potential binding affinity of 18 selected BFs to α-glucosidase was evaluated. The dynamic activity and stability of α-glucosidase-BFs complexes were then measured by molecular dynamics simulation (MDs). "Strychnobiflavone" showed the best score in α-glucosidase inhibition. Arg315 and Phe303 involved in the interactions of α-glucosidase-strychnobiflavone complex through cation-π and π-π stacking, respectively. Based on in vitro kinetic studies, it was determined that the type of inhibition of "strychnobiflavone" corresponds to the pattern of mixed inhibitors. Furthermore, details of the interactions between strychnobiflavone and α-glucosidase were performed by in silico secondary structure content analysis. The findings showed when "strychnobifone" binds to the enzyme, significant alterations occur in the enzyme conformation affecting its catalytic activity. In general, the findings highlighted the potential of "strychnobiflavone" as a promising candidate for the treatment of diabetes mellitus through α-glucosidase inhibition. Further in vitro and in vivo studies have to confirm the therapeutic benefits of "strychnobiflavone" in conformational diseases such as diabetes mellitus.


Asunto(s)
Biflavonoides , Diabetes Mellitus , Humanos , alfa-Glucosidasas/metabolismo , Inhibidores de Glicósido Hidrolasas/química , Simulación del Acoplamiento Molecular , Cinética , Biflavonoides/farmacología , Glucosa
9.
In Silico Pharmacol ; 10(1): 5, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35310017

RESUMEN

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global threat. Despite the production of various vaccines and different treatments, finding natural compounds to control COVID-19 is still a challenging task. Isoquinoline alkaloids are naturally occurring compounds known to have some potential antiviral activity. In this study, ten abundant isoquinoline alkaloids with antiviral activity were selected to analyze the preventive effect on COVID-19. A scrutinized evaluation based on Lipinski's rule showed that one out of ten compounds was toxic. Based on molecular docking analysis using Autodock software one of the best molecules with maximum negative binding energy was selected for further analysis. The Gromacs simulation analysis revealed that Coptisine has more action against active site Mpro of COVID-19. Overall, to make a rational design of various preventive analogues that inhibit the COVID-19, associated in vitro and in vivo analyses are needed to confirm this claim.

10.
J Mol Model ; 28(5): 113, 2022 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-35381900

RESUMEN

There is a growing interest in designing a nanocarrier containing an EGFR targeting affibody to direct toward cancer cells. Here, cytolysin A was cloned at the N-terminus of ZEGFR:1907 affibody to guarantee its surface presentation on the OMVs while targeting the epidermal growth factor receptors (EGFRs). A separate construct including a fusogenic peptide (GALA) was also designed for the endosomal escape of the nanocarrier. Binding of the two constructs ClyA-affiEGFR and ClyA-affiEGFR-GALA to domain III of EGFR was investigated using molecular docking and molecular dynamic simulations. The higher stability of the ClyA-affiEGFR-GALA/EGFR as compared to the ClyA-affiEGFR/EGFR complex was evident. The ClyA-affiEGFR-GALA structure showed a higher RMSD during the first half of the simulation time implying a much less stable behavior. Plateau state of the radius of gyration plot of ClyA-affiEGFR-GALA confirmed a well-folded structure in the presence of the GALA sequence. Solvent accessible surface area for both proteins was in the same range. The data obtained from hydrogen bond analysis revealed a more equilibrated and stable form of the ClyA-affiEGFR-GALA structure upon interaction with EGFR. The data provided here was a requisite for our biological evaluation of the synthesized constructs as a component of a novel drug delivery system.


Asunto(s)
Receptores ErbB , Péptidos , Receptores ErbB/metabolismo , Simulación del Acoplamiento Molecular , Péptidos/química
11.
Food Funct ; 13(19): 10055-10068, 2022 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-36093798

RESUMEN

α-Glucosidase is among the intestinal epithelial enzymes that produce absorbable glucose in the final stage of glycan catabolism. It leads to an increase in blood glucose levels as a result of high glucose uptake in diabetic patients. However, inhibition of this essential biochemical process can be a useful therapeutic approach to diabetes mellitus (DM). Eriocitrin (ER) is an abundant "flavanone glycoside" in citrus fruits with rich antioxidant properties whose effects on α-Glu inhibition in the small intestine remain to be determined. Herein, pH-sensitive microgels (MGs) were designed based on cross-linked methacrylate with acrylamide (AM) and acrylic acid (AAc) (molar ratio 70 : 30 of AAc : AM) as a controlled release system for sustained delivery of ER into the small intestine. The presence of amide and acrylate in MGs and the mechanical resistance were determined using FT-IR spectroscopy, rheology, and viscoelastometry. In vitro experiments showed that MGs could protect ER against diffusion in the gastric location and adjust its release in the intestinal milieu. The intestinal α-Glu activity was inhibited by ER (IC50 value of 12.50 ± 0.73 µM) in an uncompetitive dose-dependent manner. The presence of ER altered the structure of α-Glu and reduced the hydrophobic pockets of the enzyme. Molecular docking analysis along with molecular dynamics simulation displayed that ER-α-Glu formation is directed by hydrogen binding with Asp69, Asp215, Glu411, Asp307, and Tyr347 residues. Moreover, in vivo assessment showed that rat blood glucose concentration decreased after ER administration compared with the control group. The results highlight that ER-loaded-MGs can be considered as a useful releasing strategy in treating DM via α-Glu inhibition.


Asunto(s)
Diabetes Mellitus , Flavanonas , Microgeles , Acrilamidas , Acrilatos , Amidas , Animales , Antioxidantes , Glucemia/metabolismo , Preparaciones de Acción Retardada , Gelatina , Glucosa/metabolismo , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Glicósidos , Hidrógeno , Concentración de Iones de Hidrógeno , Metacrilatos , Simulación del Acoplamiento Molecular , Polisacáridos , Ratas , Espectroscopía Infrarroja por Transformada de Fourier , alfa-Glucosidasas/química
12.
Int J Biol Macromol ; 217: 714-730, 2022 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-35843397

RESUMEN

Flavonoid glycosides (FGs) appear to be good candidates for controlling blood glucose levels, so regular consumption of vegetables/fruits rich in FGs may prevent the consequences of type 2 diabetes (DM). Inhibition of digestive enzymes using natural FGs is a suitable dietary tool to regulate the hydrolysis of polysaccharides and overcome hyperglycemia. The aim of the current research is to find FGs that can effectively inhibit the digestive enzymes α-glucosidase (α-Gl) and α-amylase (α-Am). Accordingly, twenty-three FGs were selected and filtered through docking-based virtual screening. Based on the molecular docking and molecular dynamics (MD) simulation, among the 23 selected FGs, nicotiflorin and swertisin significantly inhibited α-Gl and α-Am, respectively. In vitro analysis revealed the inhibitory capacity of nicotiflorin on α-Gl was equal to IC50 at 0.148 mg/ml and the inhibitory activity of swertisin on α-Am was equal to IC50 at 1.894 mg/ml. It was found that nicotiflorin and swertisin act much like as a competitive inhibitor on α-Gl and α-Am, respectively. Furthermore, the fluorescence intensity of both enzymes decreased after interaction with two FGs. FT-IR and scanning electron microscopy (SEM) measurements suggested that the interactions could alter the conformation and microenvironment of the enzymes. Moreover, in vivo evaluation showed that the administration of nicotiflorin and swertisin can alleviate the blood glucose level of rats compared to the starch group (p < 0.05). The findings highlight that nicotiflorin and swertisin can be considered as possible inhibitors in treating diabetes mellitus via digestive enzymes inhibition.


Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores de Glicósido Hidrolasas , Animales , Glucemia , Flavonoides/farmacología , Inhibidores de Glicósido Hidrolasas/farmacología , Glicósidos/farmacología , Simulación del Acoplamiento Molecular , Ratas , Espectroscopía Infrarroja por Transformada de Fourier , alfa-Amilasas , alfa-Glucosidasas
13.
Sci Rep ; 11(1): 20605, 2021 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-34663861

RESUMEN

Non-enzymatic glycation of DNA and the associated effects are among pathogenic factors in diabetes mellitus. Natural polyphenols have anti-diabetic activity. Herein, the protective role of one of the phytochemicals, rosmarinic acid (RA), was evaluated in glycation (with fructose) of human DNA and expression of Akt genes in the hippocampus of diabetic rats. In-vitro studies using fluorescence, agarose gel electrophoresis, fluorescence microscopy, and thermal denaturation analyses revealed that glycation causes DNA damage and that RA inhibits it. In-vivo studies were performed by induction of diabetes in rats using streptozotocin. The diabetic rats were given RA daily through gavage feeding. The expression of Akt genes (inhibitors of apoptosis) in the hippocampus was evaluated using RT-qPCR. In diabetic rats, Akt1 and Akt3 were significantly down-regulated compared to the control group. Treating the diabetic rats with RA returned the expression of Akt1 and Akt3 relatively to the normal condition. Past studies have shown that diabetes induces apoptosis in the hippocampal neurons. Given that glycation changes the genes expression and causes cell death, apoptosis of the hippocampal neurons can be due to the glycation of DNA. The results also suggest that RA has reliable potency against the gross modification of DNA under hyperglycemic conditions.


Asunto(s)
Cinamatos/farmacología , Depsidos/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Animales , Apoptosis/efectos de los fármacos , Glucemia/metabolismo , Encéfalo/metabolismo , Cinamatos/metabolismo , ADN/efectos de los fármacos , ADN/metabolismo , Depsidos/metabolismo , Diabetes Mellitus Experimental/metabolismo , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Productos Finales de Glicación Avanzada/metabolismo , Glicosilación , Hipocampo/metabolismo , Masculino , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Estreptozocina/farmacología , Ácido Rosmarínico
14.
J Mol Model ; 28(1): 24, 2021 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-34970708

RESUMEN

Inflammation is a natural protective response toward various simulators, including tissue damage or pathogens. The cyclooxygenase-2 (COX-2) is a very important protein in triggering pain and inflammation. Previous studies have claimed that Allium sativum offers a wide range of anti-inflammatory therapeutics for human consumption. Drug discovery is a complicated process, though in silico methods can make this procedure simpler and more cost-effective. At the current study, we performed the virtual screening of eight Allium sativum-derived compounds via molecular docking with COX-2 enzyme and confirmed the binding energy by docking score estimate followed by ADMET and drug-likeness investigation. The resulting highest-docking scored compound was exposed to molecular dynamics simulation (MDS) for evaluating stability of the docked enzyme-ligand complex and to gauge the oscillation and conformational alterations for the time of enzyme-ligand interaction. The factors of RMSD, RMSF, hydrogen bond interactions, and Rg after 100 ns of MDS proved the stability of alliin in the active site of COX-2 in comparison with celecoxib (CEL) as the control. Moreover, we investigated the binding affinity analysis of all compounds via MM/PBSA method. The results from this study suggest that alliin (a sulfuric compound) exhibits a higher binding affinity for the COX-2 enzyme compared to the other compounds and CEL. Alliin showed to be a possible anti-inflammatory therapeutic candidate for managing the inflammatory conditions.


Asunto(s)
Inhibidores de la Ciclooxigenasa 2/química , Ajo/química , Extractos Vegetales/química , Sitios de Unión , Dominio Catalítico , Inhibidores de la Ciclooxigenasa 2/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Extractos Vegetales/farmacología , Unión Proteica , Relación Estructura-Actividad
15.
Front Pharmacol ; 12: 719289, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34867325

RESUMEN

Bacterial outer membrane vesicles (OMVs) have recently drawn a great deal of attention due to their therapeutic efficiency and ability to target specific cells. In the present study, we sought to probe engineered OMVs as novel and promising carriers to target breast cancer cells. Following the fusion of the affiEGFR-GALA structure to the C-terminal of ClyA as an anchor protein, the ClyA-affiEGFR-GALA construct was successfully expressed on the surface of ∆msbB/∆pagP E. coli W3110-derived OMVs. Morphological features of the engineered and wild-type OMVs were identical. The engineered OMVs induced no endotoxicity, cytotoxicity, or immunogenicity, indicating the safety of their application. These OMVs could specifically bind to EGF receptors of MDA-MB-468 cells expressing high levels of EGFR and not to those with low levels of EGFR (HEK293T cells). Interestingly, despite a lower binding affinity of the engineered OMVs relative to the positive control Cetuximab, it was strong enough to identify these cells. Moreover, confocal microscopy revealed no uptake of the modified OMVs by the EGFR-overexpressing cells in the presence of EGFR competitors. These results suggest that OMVs might internalize into the cells with EGF receptors, as no OMVs entered the cells with any EGFR expression or those pretreated with EGF or Cetuximab. Regarding the EGFR-binding affinity of the engineered OMVs and their cellular uptake, they are presented here as a potential carrier for cell-specific drug delivery to treat a wide variety of cancer cells. Interestingly, the engineered OMVs are capable of reaching the cytoplasm while escaping the endosome due to the incorporation of a fusogenic GALA peptide in the construct.

16.
Int J Biol Macromol ; 151: 797-805, 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32061846

RESUMEN

Despite most studied activities of natural biophenols rely on antioxidant properties, little clues explored their key structural components with regard to opposing action on glycation-induced aggregation. Herein, human hemoglobin (hHb)/fructose system used to decipher if structural peculiarities of two biophenols "chlorogenic acid (CGA) and curcumin (CUR)" are effective toward AGEs-bridged aggregate formation. Suppression in amyloid cross-ß formation was monitored by CD spectroscopy, fluorescence microscopy, ANS and AGE fluorescence. Reduction in molten globule structure of modified-Hb by CGA was corroborated with helix structure, thiol group and lysine residues content estimation for native, glycated and biophenols treated samples. ThT and Congo red assays showed the cross-ß breaking properties of CGA. Molecular docking outcomes revealed the positioning of CGA/CUR is driven by "aromatic interactions" with Trp ß1180 and Tyr α2540. These interactions are modulated by the structural constraints such as number of hydroxyl groups and their methylation status directing the biophenols to the amyloidogenic core. The results are applicable to formulation of small-molecule nutraceuticals for treatment of conformational diseases.


Asunto(s)
Hemoglobinas/química , Fenoles/química , Fenoles/farmacología , Agregado de Proteínas/efectos de los fármacos , Dicroismo Circular , Rojo Congo/química , Glicosilación , Hemo/química , Hemoglobinas/metabolismo , Humanos , Microscopía Confocal , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Espectrometría de Fluorescencia
17.
Int J Biol Macromol ; 113: 354-360, 2018 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-29486263

RESUMEN

Enzyme immobilized on magnetic nanoparticles (MNPs) can be used as efficient recoverable biocatalysts under strong magnetic responses. In the present work, α-amylase was immobilized onto naringin functionalized MNPs via ionic interactions. For this purpose, the MNPs were functionalized with naringin, as a biocompatible flavonoid. The morphology, structure, and properties of functionalized MNPs and the immobilization of α-amylase on synthesized nanocomposite were characterized through different analytical tools including TGA, VSM, FTIR, SEM-EDX and TEM. Furthermore, the optimum conditions of temperature, pH, reaction time and enzyme concentration for immobilization process were investigated. The results showed that the optimal conditions for immobilization of α-amylase onto synthesized nanocarrier occurred at pH6.5 and 55°C. The reusability experiments revealed high activity maintenance of immobilized α-amylase even after 10 reaction cycles. Moreover, the storage stability of immobilized enzyme improved via immobilization in comparison with free one and it maintained 60% of its initial activity after 6weeks storage at 4°C. The improvements in enzyme catalytic properties via immobilization made this nanobiocatalyst as a good candidate in bio-industrial applications. Furthermore, the synthesized nanocomposite would have the potential for practical applications in other and binary enzyme immobilization.


Asunto(s)
Biocatálisis , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/metabolismo , Flavanonas/química , Nanopartículas de Magnetita/química , alfa-Amilasas/química , alfa-Amilasas/metabolismo , Bacillus subtilis/enzimología , Concentración de Iones de Hidrógeno , Industrias , Cinética , Temperatura
18.
Pharmacogn Mag ; 13(Suppl 3): S676-S683, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29142432

RESUMEN

BACKGROUND: Protein glycation and glycotoxicity belong to the main oxidative-stress related complications in diabetes. Perovskia species are used in Asian folk medicine as antidiabetic herbs. OBJECTIVE: The aim of this study was to verify the ability of the methanolic extract from Perovskia atriplicifolia Benth. roots to diminish glycation of albumin and to prevent cell damage in vitro. Furthermore, we tested the extract for in vitro antioxidant activity and inhibition of elastase and collagenase. MATERIAL AND METHODS: The aqueous methanol extract was analyzed by UHPLC-MS for the content of polyphenols and terpenoids. The prevention of glycated albumin-induced cell damage was tested in four mammalian cell lines (peripheral blood mononuclear cells, human embryonic kidney cells - HEK293, normal human fibroblasts, and Chinese hamster ovary cells) with the 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazoly)-3-(4-sulfophenyl) tetrazolium assay. RESULTS: Glycated albumin is significantly more toxic than native human serum albumin (LC50 from 35.00 to 48.34 µg/mL vs. 5.47-9.10 µg/mL, respectively). The extract, rich in rosmarinic acid (344.27 mg/g dry mass), mitigated the glycated albumin toxicity, and increased glycated albumin-treated cell survival by more than 50%. The inhibition of advanced glycation endproduct formation was confirmed by monitoring conformational changes. The free radical scavenging activity was higher than Trolox and metal reducing power was one-third to half that of ascorbic acid. The activity of elastase and collagenase was inhibited by 54.75% ± 6.87% and 60.03% ± 7.22%, respectively. CONCLUSIONS: The results confirm antiglycative and antiglycotoxic potential of Perovskia root and its traditional antidiabetic use. The high activity can be attributed to rosmarinic acid abundance. SUMMARY: Perovskia is a small genus of aromatic shrubby plants growing in arid regions of Central and South Asia. Different parts are used in folk medicine as antiparasitic, anti-infectious and antidiabetic remedy. Here, we have studied the extract from roots for inhibition of: glycation-induced cytotoxicity, human serum albumin glycation, inflammation-related enzymes, as well as for antioxidant activity. Result: the extract from P. atriplicifolia roots inhibited protein glycation and AGE-induced toxicity in cell cultures. The mechanism is likely to rely on the antioxidant activity of high content of rosmarinic acid. Abbreviations used: AGE: advanced glycation end-products; DPPH: 2,2-diphenyl-1-picrylhydrazyl; HSA: human serum albumin.

19.
Int J Biol Macromol ; 39(4-5): 192-6, 2006 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-16682074

RESUMEN

Structural properties of modified forms of glucose oxidase made by stepwise specific modification have been investigated. By a single step modification, one of the modified forms resulted in the conversion of native structure of glucose oxidase to molten globule like form [S. Hosseinkhani, B. Ranjbar, H. Naderi-Manesh, M. Nemat-Gorgani, FEBS Lett. 561 (2004) 213-216]. Chemical modification of lysine residues in glucose oxidase was carried out using different concentration of citraconic anhydride. Modification brought about changes in the tertiary structure with some degree of alteration in secondary structure. FTIR, far and near-UV CD spectropolarimetry, intrinsic and extrinsic fluorescence spectroscopy showed structural changes of glucose oxidase in a concentration dependent manner. This was supported by comparative study of secondary and tertiary structure.


Asunto(s)
Anhídridos Citracónicos , Glucosa Oxidasa/química , Lisina/química , Aspergillus niger/enzimología , Dicroismo Circular , Electroforesis en Gel de Poliacrilamida , Espectrometría de Fluorescencia , Espectroscopía Infrarroja por Transformada de Fourier , Triptófano/química
20.
Comput Biol Chem ; 58: 9-18, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26001286

RESUMEN

Development of a protein-based drug delivery system has major impact on the efficacy and bioavailability of unstable and water insoluble drugs. In the present study, the binding modes of a nonspecific lipid transfer protein (nsLTP2) from Oryza sativa with various nucleosides and analogous molecules were identified. The 3-D structure of the protein was designed and validated using modeler 9.13, Molegro virtual docker and procheck tool, respectively. The binding affinity and strength of interactions, key contributing residues and specificity toward the substrates were accomplished by computational docking and model prediction. The protein presented high affinity to acyclovir and vidarabine as purine-analogous drugs. Binding affinity is influenced by the core template and functional groups of the ligands which are structurally different cause the variation of interaction energies with nsLTP2. Nonetheless, all the evaluated analogous drugs occupy the proximity space at the nsLTP active site with high similarity in their binding modes. Our findings hold great promise for the future applications of nsLTPs in various aspects of pharmaceutical science and molecular biology.


Asunto(s)
Antineoplásicos/metabolismo , Antivirales/metabolismo , Proteínas Portadoras/metabolismo , Nucleósidos/metabolismo , Oryza , Proteínas de Plantas/metabolismo , Antineoplásicos/química , Antivirales/química , Sitios de Unión , Proteínas Portadoras/química , Modelos Moleculares , Nucleósidos/química , Oryza/metabolismo , Proteínas de Plantas/química , Unión Proteica , Conformación Proteica
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