Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
J Biomol Struct Dyn ; : 1-21, 2024 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-38433423

RESUMEN

In the current study, metronidazole derivatives containing 1H-1,2,3-triazole and carboxylate moieties were evaluated in vitro and by computational methods for their anti-diabetic potential to insight into their medicinal use for the management of type II diabetes mellitus. Interestingly all 14 compounds displayed high to significant inhibitory capability against the key carbohydrate's digestive enzyme α-glucosidase with IC50 values in range of 9.73-56.39 µM, as compared to marketed drug acarbose (IC50 = 873.34 ± 1.67 µM). Compounds 5i and 7c exhibited the highest inhibition, therefore, these two compounds were further evaluated for their mechanistic studies to explore its type of inhibition. Compounds 5i and 7c both displayed a concentration-dependent (competitive type of inhibition) with Ki values 7.14 ± 0.01, 6.15 ± 0.02 µM, respectively, which conclude their favourable interactions with the active site residues of the α-glucosidase. Interestingly all compounds are non-cytotoxic against BJ cell line. To further validate our findings, in-silico approaches like molecular docking, and molecular dynamic simulations were applied to investigate the mode of bindings of compounds with the enzyme and identifies their inhibition mechanism, which strongly complements our experimental findings.Communicated by Ramaswamy H. Sarma.

2.
J Health Care Poor Underserved ; 34(2): 535-548, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37464516

RESUMEN

OBJECTIVE: To determine whether the introduction of telemedicine at a rural pediatric clinic was associated with reduced disparities in visit attendance. METHODS: A retrospective cohort study was conducted of all clinic visits from 1 January 2019 to 31 December 2021. Visit types were divided into telemedicine visits, in-person urgent, and in-person non-urgent visits. Visits were stratified into periods based on the statewide pandemic response. RESULTS: A total of 8,412 patients with 54,746 scheduled visits were analyzed. Visits were less likely to be completed for older patients, Black patients, and patients with Medicaid insurance than their counterparts. Despite a pandemic-era increase in telemedicine utilization, disparities in visit completion that were present in the pre-pandemic era persisted after stay-at-home orders were lifted. DISCUSSION: The adoption of telemedicine did not reduce pre-existing disparities in visit attendance. Further work is needed to identify the reasons for the disparities and improve visit attendance of historically disadvantaged patient populations.


Asunto(s)
COVID-19 , Telemedicina , Humanos , Niño , COVID-19/epidemiología , Pandemias , Estudios Retrospectivos , Atención Primaria de Salud
3.
Cureus ; 15(6): e40985, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37503488

RESUMEN

Paraganglioma (PGL) is a rare neuroendocrine tumor arising from chromaffin cells outside the adrenal medulla. The most common sites are the abdomen and head and neck. Seventy percent (70%) of PGLs are sporadic, and 30% are hereditary; the latter are more often aggressive and malignant and occur in young adults. We report a case of a 36-year-old woman with a history of hypertension and abdominal pheochromocytoma resected at the age of 10 years who presented with back pain. Magnetic resonance imaging of the spine showed vertebral metastasis at L2-L5. Computed tomography of the abdomen showed a mass in the body of the pancreas and a laparoscopic biopsy was performed. The tumor cells had granular eosinophilic/basophilic cytoplasm and showed a nested pattern (Zellballen) with a prominent vascular network and infiltration of dense fibrous connective tissue. Strong and diffuse expression of synaptophysin in tumor cells, S100 expression in sustentacular cells at the periphery of nests, and lack of pancytokeratin expression supported the diagnosis of PGL. Due to limited tissue, it was difficult to determine metastatic vs primary neoplasm of the pancreas. The earlier age of onset and history of abdominal pheochromocytoma suggested the possibility of hereditary PGL associated with succinate dehydrogenase (SDH) deficiency. The tumor cells lacked SDHB expression. Germline mutation testing for SDH was recommended. The patient underwent palliative radiotherapy and systemic chemotherapy. Most PGLs are benign and asymptomatic, but there is an increased risk of cardiovascular mortality secondary to catecholamine secretion, and surgical excision is curative. Malignant PGLs are rare (10-40%), have poor prognosis, and are incurable. Increased size of the tumor, deep tissue infiltration, and high proliferative index increase the risk of malignancy, but metastasis is required for the diagnosis of malignant PGL. The advanced disease is treated with surgical removal of the tumor and combined radiotherapy and chemotherapy.

4.
Artículo en Inglés | MEDLINE | ID: mdl-36315412

RESUMEN

BACKGROUND: Although Coronavirus disease 2019 rapidly increased the use of telemedicine for pediatric primary care, vaccinations, screening tests, lab draws, and other procedures still require follow-up in-person visits. We investigated in-person follow-up rates after telemedicine visits at our primary care clinic, and what patient or visit characteristics were associated with non-completion of in-person follow-up. METHODS: A retrospective cohort study was conducted of telemedicine visits completed between April and May 2020. A manual chart review was performed to determine which encounters required a follow-up in-person visit; and was tracked through August 2020. Bivariate comparisons were performed according to completion of in-person follow-up and multivariable analysis of follow-up visit attendance was performed using Cox proportional hazards regression. RESULTS: Of 500 eligible encounters, 16% did not attend at least one in-person follow-up. The median time for follow-up was 2 days (IQR: 1, 6). Patients older than 1 year of age (32%, p= <0.001) and with Medicaid insurance (83%, p=0.019) were more likely to not complete a follow-up visit. The likelihood of completion was higher for Hispanic as compared to non-Hispanic Black patients (HR: 1.65; 95% CI: 1.28, 2.12; p<0.001) and patients requiring routine screening (HR: 1.40; 95% CI: 1.04, 1.89; p=0.028). CONCLUSIONS: Not all required in-person follow-ups were completed after telemedicine visits, which could have negative impacts on children's health. Improving the transition between telemedicine and inperson follow-up of primary care can help ensure the quality of care provided in a telemedicine-first model.

5.
ACS Omega ; 7(34): 30359-30368, 2022 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-36061660

RESUMEN

Heterocyclic compounds with a five-membered ring as a core, particularly those containing more than one heteroatom, have a wide spectrum of biological functions, especially in enzyme inhibition. In this study, we present the synthesis of five-membered heterocyclic isoxazole derivatives via sonication of ethyl butyrylacetate with aromatic aldehyde in the presence of a SnII-Mont K10 catalyst. The synthesized compounds were characterized using sophisticated spectroscopic methods. In vitro testing of the compounds reveals three derivatives with significant inhibitory action against carbonic anhydrase (CA) enzyme. The compound AC2 revealed the most promising inhibitory activity against CA among the entire series, with an IC50 = 112.3 ± 1.6 µM (%inh = 79.5) followed by AC3 with an IC50 = 228.4 ± 2.3 µM (%inh = 68.7) compared to the standard with 18.6 ± 0.5 µM (%inh = 87.0). Molecular docking (MD) study coupled with extensive MD simulations (400 ns) and MMPBSA study fully supported the in vitro enzyme inhibition results, evident from the computed ΔG bind (AC2 = -13.53 and AC3 = -12.49 kcal/mol). The in vitro and in silico studies are also augmented by a fluorescence-based enzymatic assay in which compounds AC2 and AC3 showed significant fluorescence enhancement. Therefore, on the basis of the present study, it is inferred that AC2 and AC3 may serve as a new framework for designing effective CA inhibitors.

6.
Curr Pharm Des ; 28(36): 3010-3022, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35909284

RESUMEN

BACKGROUND: Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. OBJECTIVE: In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized. METHODS: This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out. RESULTS: In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety plays a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetic studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki). CONCLUSION: Subsequently, (3e, 3f, 3l and 3p) were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 µM, while (3d) as a noncompetitive inhibitor of bCA-II (Ki = 2.5 ± 0.015 µM), however, (3g) demonstrated competitive inhibition of hCA-II with a Ki value of 5.95 ± 0.002 µM. The selectivity index reflects that compound (3g) is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.


Asunto(s)
Anhidrasa Carbónica II , Tiosemicarbazonas , Humanos , Bovinos , Animales , Anhidrasa Carbónica II/metabolismo , Tiosemicarbazonas/farmacología , Simulación del Acoplamiento Molecular , Cinética , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Relación Estructura-Actividad , Estructura Molecular
7.
Int J Biol Macromol ; 220: 788-801, 2022 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-35995179

RESUMEN

Chitosan (CS)/metal oxide (MO) nano-carriers have recently attracted attention due to their great integration into several biomedical applications. Herein, CS and dysprosium oxide based bio-nanocomposites (Dy2O3/CuFe3O4/CS) were prepared using a citrate sol-gel route for biomedical settings at large and drug delivery, in particular. The chemical structure, average crystallite size, and surface morphology of Dy2O3/CuFe3O4/CS bio-nanocomposites were characterized using spectroscopic techniques, including FT-IR, PXRD, and SEM. The prepared nano composite's drug loading or release kinetics were investigated by FT-IR, zeta potential (ZP), and ultraviolet-visible spectroscopy (UV-Vis). In the FT-IR spectrum, the peaks in the range of 800-400 cm-1 confirmed the formation of meta-oxides, while amide bands at 1661 and 1638 cm-1 revealed the existence of CS in the bio-nanocomposite. The peaks at 2θ = 35.46 and 28.5, 39.4 indicated the presence and chemical interaction of Dy2O3 and CuFe3O4, respectively. The crystallite size was <20 nm. The model drug used in the loading and in vitro release assays was ciprofloxacin hydrochloride. Ciprofloxacin's CF stretch caused a modest peak to be seen at 1082 cm-1 and changed in zeta potential value from 7.90 mV to 8.88 mV endorsing that the drug had been loaded onto the nanomaterial. The loading efficiency (%) of CIP onto the composite was from 25 to 30 %, calculated from optical density measurements. Different kinetic models, such as zero-order, first-order, Higuchi, Hixon-Crowell, and Korsmeyer-Peppas, were determined to confirm the drug release mechanism. The percent (%) of drug release from the surface of Dy2O3/CuFe3O4/CS in PBS (pH 7.4), acidic (pH 2.2) and basic (pH 9.4) dissolution media were found to be 70, 28 and 20 %, respectively. Drug kinetics showed that mainly the release is fickian type followed "Fick's law of diffusion", slightly deviated from fickian release (dissolution-dependent system). Korsmeyer-Peppas (R2 0.9773, n < 0.4) and Higuchi's (R2 0.9846) models were the best for fitting controlled drug release data. The results revealed that the Dy2O3/CuFe3O4/CS bio-nanocomposite has good potential for a controlled drug delivery system.


Asunto(s)
Quitosano , Nanocompuestos , Amidas , Quitosano/química , Ciprofloxacina/química , Citratos , Portadores de Fármacos/química , Liberación de Fármacos , Cinética , Nanocompuestos/química , Óxidos , Espectroscopía Infrarroja por Transformada de Fourier
8.
Brain ; 145(10): 3666-3680, 2022 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-35552612

RESUMEN

While several studies have attributed the development of tumour-associated seizures to an excitatory-inhibitory imbalance, we have yet to resolve the spatiotemporal interplay between different types of neuron in glioma-infiltrated cortex. Herein, we combined methods for single unit analysis of microelectrode array recordings with wide-field optical mapping of Thy1-GCaMP pyramidal cells in an ex vivo acute slice model of diffusely infiltrating glioma. This enabled simultaneous tracking of individual neurons from both excitatory and inhibitory populations throughout seizure-like events. Moreover, our approach allowed for observation of how the crosstalk between these neurons varied spatially, as we recorded across an extended region of glioma-infiltrated cortex. In tumour-bearing slices, we observed marked alterations in single units classified as putative fast-spiking interneurons, including reduced firing, activity concentrated within excitatory bursts and deficits in local inhibition. These results were correlated with increases in overall excitability. Mechanistic perturbation of this system with the mTOR inhibitor AZD8055 revealed increased firing of putative fast-spiking interneurons and restoration of local inhibition, with concomitant decreases in overall excitability. Altogether, our findings suggest that diffusely infiltrating glioma affect the interplay between excitatory and inhibitory neuronal populations in a reversible manner, highlighting a prominent role for functional mechanisms linked to mTOR activation.


Asunto(s)
Glioma , Células Piramidales , Humanos , Potenciales de Acción/fisiología , Células Piramidales/fisiología , Neuronas/fisiología , Convulsiones , Serina-Treonina Quinasas TOR
9.
ACS Omega ; 6(47): 32334-32341, 2021 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-34870053

RESUMEN

Benzanthrone dyes are organic luminophores with excellent optoelectronic properties. This computational investigation is based on density functional theory and aims to explore the photophysical behavior of some of the reported aminobenzanthrones in addition to many unreported dyes containing different electron-donating substituents. Significant changes in the dipole moment and the overall structure of the dyes upon solvation in ethanol have been observed. We find that intramolecular charge transfer is more pronounced in the solvent medium, which facilitates the emission to shift bathochromically. Intersystem crossing is predicted to be absent, which makes relaxation of the molecule to ground state more efficient by emitting in the visible region.

10.
Eur J Med Chem ; 210: 112986, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33187806

RESUMEN

To tackle leishmaniasis, search for efficient therapeutic drug targets should be pursued. Dihydrofolate reductase (DHFR) is considered as a key target for the treatment of leishmaniasis. In current study, we are interested in the design and synthesis of selective antifolates targeting DHFR from L. major. We focused on the development of new antifolates based on 3,4-dihydropyrimidine-2-one and 5-(3,5-dimethoxybenzyl)pyrimidine-2,4-diamine motif. Structure activity relationship (SAR) studies were performed on 4-phenyl ring of dihydropyrimidine (26-30) template. While for 5-(3,5-dimethoxybenzyl)pyrimidine-2,4-diamine, the impact of different amino acids (valine, tryptophan, phenylalanine, and glutamic acid) and two carbon linkers were explored (52-59). The synthesized compounds were assayed against LmDHFR. Compound 59 with the IC50 value of 0.10 µM appeared as potent inhibitors of L. major. Selectivity for parasite DHFR over human DHFR was also determined. Derivatives 55-59 demonstrated excellent selectivity for LmDHFR. Highest selectivity for LmDHFR was shown by compounds 56 (SI = 84.5) and 58 (SI = 87.5). Compounds Antileishmanial activity against L. major and L. donovani promastigotes was also performed. To explore the interaction pattern of the synthesized compounds with biological macromolecules, the docking studies were carried out against homology modelled LmDHFR and hDHFR targets.


Asunto(s)
Antiprotozoarios/farmacología , Antagonistas del Ácido Fólico/farmacología , Leishmania/efectos de los fármacos , Pirimidinas/farmacología , Tetrahidrofolato Deshidrogenasa/metabolismo , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Antagonistas del Ácido Fólico/síntesis química , Antagonistas del Ácido Fólico/química , Leishmania/enzimología , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad
11.
Neurobiol Dis ; 134: 104676, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31731042

RESUMEN

The purpose of this study is to develop a platform in which the cellular and molecular underpinnings of chronic focal neocortical lesional epilepsy can be explored and use it to characterize seizure-like events (SLEs) in an ex vivo model of infiltrating high-grade glioma. Microelectrode arrays were used to study electrophysiologic changes in ex vivo acute brain slices from a PTEN/p53 deleted, PDGF-B driven mouse model of high-grade glioma. Electrode locations were co-registered to the underlying histology to ascertain the influence of the varying histologic landscape on the observed electrophysiologic changes. Peritumoral, infiltrated, and tumor sites were sampled in tumor-bearing slices. Following the addition of zero Mg2+ solution, all three histologic regions in tumor-bearing slices showed significantly greater increases in firing rates when compared to the control sites. Tumor-bearing slices demonstrated increased proclivity for SLEs, with 40 events in tumor-bearing slices and 5 events in control slices (p-value = .0105). Observed SLEs were characterized by either low voltage fast (LVF) onset patterns or short bursts of repetitive widespread, high amplitude low frequency discharges. Seizure foci comprised areas from all three histologic regions. The onset electrode was found to be at the infiltrated margin in 50% of cases and in the peritumoral region in 36.9% of cases. These findings reveal a landscape of histopathologic and electrophysiologic alterations associated with ictogenesis and spread of tumor-associated seizures.


Asunto(s)
Neoplasias Encefálicas/fisiopatología , Encéfalo/fisiopatología , Glioma/fisiopatología , Neuronas/fisiología , Convulsiones/fisiopatología , Potenciales de Acción , Animales , Neoplasias Encefálicas/complicaciones , Modelos Animales de Enfermedad , Glioma/complicaciones , Ratones Transgénicos , Microelectrodos , Convulsiones/complicaciones
12.
Bioorg Chem ; 94: 103404, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31699392

RESUMEN

A series of new hydrazonothiazolines (3a-v) was obtained in good to excellent yields (79-96%) via cyclization of the appropriate thiosemicarbazones with phenacyl bromide. The targeted compounds were characterized by advanced spectroscopic techniques, such as FTIR, 1HNMR, 13CNMR and ESI-MS. The structure of compounds 3n and 3v was unambiguously confirmed by single crystal X-ray analysis. All compounds displayed enhanced inhibitory activity against urease enzyme with IC50 values in range of 1.73 ±â€¯1.57-27.3 ±â€¯0.655 µM when compared to standard thiourea (IC50 = 20.8 ±â€¯0.75 µM). The structure-activity relationship studies demonstrated that the activity of this series is due the central thiazole ring that interacts with nickel atoms in the active site of urease enzyme. Moreover, molecular docking studies were carried out to investigate the binding mode of all active compounds and an inactive (3u) with the active site of the urease enzyme. The docking results are in complete agreement with the experimental finding.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Hidrazonas/farmacología , Simulación del Acoplamiento Molecular , Tiazoles/farmacología , Ureasa/antagonistas & inhibidores , Canavalia/enzimología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Hidrazonas/síntesis química , Hidrazonas/química , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Ureasa/metabolismo
13.
Pak J Pharm Sci ; 32(5): 1971-1977, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31813860

RESUMEN

Based on the ethnomedicinal use of Isodon rugosus the current study was designed to evaluate its crude saponins (Ir.Sp), and subsequent fractions for anti-angiogenic and anti-tumor potentials. Chorioallantoic membrane (CAM) assay was used in anti-angiogenic potentials with Dexamethasone as positive control. The antitumor activity was evaluated with potato disk method using Vincristine sulfate as positive control. Moreover, antibacterial activity was also conducted against A. tumefaciens. The highest anti-angiogenic effect was observed with Ir.Sp, i.e., 79.00±0.58% at concentration of 1000 µg/ml which drop drown to 48.67±1.20% at lowest tested concentration of 31.25 µg/ml with IC50 of 41 µg/ml. Similarly, in the anti-tumor activity the Ir. Chf revealed excellent inhibition of tumor with IC50 value of 60 µg/ml. All the samples (excluding Ir. Sp and Ir. Cr) were inactive against A. tumefaciens, which demonstrates that the samples which did not show any antibacterial activity are rich in certain bioactive principles which may be responsible for the anti-tumor and anti-angiogenic potentials. Our results conclude that the Ir.Sp, Ir.Chfmay be good targets for isolation of bioactive compounds responsible for the inhibition of excessive proliferation of cells and angiogenesis.


Asunto(s)
Antineoplásicos/farmacología , Carcinogénesis/efectos de los fármacos , Isodon/química , Neovascularización Patológica/tratamiento farmacológico , Extractos Vegetales/farmacología , Saponinas/farmacología , Solanum tuberosum/efectos de los fármacos , Agrobacterium tumefaciens/efectos de los fármacos , Animales , Antibacterianos/farmacología , Pollos , Medicina Tradicional/métodos , Metanol/química , Óvulo/efectos de los fármacos
14.
Neuropsychiatr Dis Treat ; 15: 1701-1716, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31303757

RESUMEN

For patients with drug-resistant epilepsy, surgical intervention may be an effective treatment option if the epileptogenic zone (EZ) can be well localized. Subdural strip and grid electrode (SDE) implantations have long been used as the mainstay of intracranial seizure localization in the United States. Stereoelectroencephalography (SEEG) is an alternative approach in which depth electrodes are placed through percutaneous drill holes to stereotactically defined coordinates in the brain. Long used in certain centers in Europe, SEEG is gaining wider popularity in North America, bolstered by the advent of stereotactic robotic assistance and mounting evidence of safety, without the need for catheter-based angiography. Rates of clinically significant hemorrhage, infection, and other complications appear lower with SEEG than with SDE implants. SEEG also avoids unnecessary craniotomies when seizures are localized to unresectable eloquent cortex, found to be multifocal or nonfocal, or ultimately treated with stereotactic procedures such as laser interstitial thermal therapy (LITT), radiofrequency thermocoagulation (RF-TC), responsive neurostimulation (RNS), or deep brain stimulation (DBS). While SDE allows for excellent localization and functional mapping on the cortical surface, SEEG offers a less invasive option for sampling disparate brain areas, bilateral investigations, and deep or medial targets. SEEG has shown efficacy for seizure localization in the temporal lobe, the insula, lesional and nonlesional extra-temporal epilepsy, hypothalamic hamartomas, periventricular nodular heterotopias, and patients who have had prior craniotomies for resections or grids. SEEG offers a valuable opportunity for cognitive neurophysiology research and may have an important role in the study of dysfunctional networks in psychiatric disease and understanding the effects of neuromodulation.

15.
Bioorg Chem ; 83: 336-347, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30399465

RESUMEN

Due to recently discovered non-classical acetylcholinesterase (AChE) function, dual binding-site AChE inhibitors have acquired a paramount attention of drug designing researchers. The unique structural arrangements of AChE peripheral anionic site (PAS) and catalytic site (CAS) joined by a narrow gorge, prompted us to design the inhibitors that can interact with dual binding sites of AChE. Eighteen homo- and heterodimers of desloratadine and carbazole (already available tricyclic building blocks) were synthesized and tested for their inhibition potential against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBChE). We identified a six-carbon tether heterodimer of desloratadine and indanedione based tricyclic dihydropyrimidine (4c) as potent and selective inhibitor of eeAChE with IC50 value of 0.09 ±â€¯0.003 µM and 1.04 ±â€¯0.08 µM (for eqBChE) with selectivity index of 11.1. Binding pose analysis of potent inhibitors suggest that tricyclic ring is well accommodated into the AChE active site through hydrophobic interactions with Trp84 and Trp279. The indanone ring of most active heterodimer 4b is stabilized into the bottom of the gorge and forms hydrogen bonding interactions with the important catalytic triad residue Ser200.


Asunto(s)
Carbazoles/química , Inhibidores de la Colinesterasa/química , Loratadina/análogos & derivados , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Animales , Carbazoles/síntesis química , Carbazoles/metabolismo , Dominio Catalítico , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Diseño de Fármacos , Electrophorus , Enlace de Hidrógeno , Loratadina/síntesis química , Loratadina/química , Loratadina/metabolismo , Unión Proteica , Electricidad Estática , Torpedo
16.
17.
Neurosurgery ; 83(5): E207-E208, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30321416
18.
Artículo en Inglés | MEDLINE | ID: mdl-28553620

RESUMEN

Mycoplasma bovis is an important cause of bovine respiratory disease worldwide. To understand its virulence mechanisms, we sequenced three attenuated M. bovis strains, P115, P150, and P180, which were passaged in vitro 115, 150, and 180 times, respectively, and exhibited progressively decreasing virulence. Comparative genomics was performed among the wild-type M. bovis HB0801 (P1) strain and the P115, P150, and P180 strains, and one 14.2-kb deleted region covering 14 genes was detected in the passaged strains. Additionally, 46 non-sense single-nucleotide polymorphisms and indels were detected, which confirmed that more passages result in more mutations. A subsequent collective bioinformatics analysis of paralogs, metabolic pathways, protein-protein interactions, secretory proteins, functionally conserved domains, and virulence-related factors identified 11 genes that likely contributed to the increased attenuation in the passaged strains. These genes encode ascorbate-specific phosphotransferase system enzyme IIB and IIA components, enolase, L-lactate dehydrogenase, pyruvate kinase, glycerol, and multiple sugar ATP-binding cassette transporters, ATP binding proteins, NADH dehydrogenase, phosphate acetyltransferase, transketolase, and a variable surface protein. Fifteen genes were shown to be enriched in 15 metabolic pathways, and they included the aforementioned genes encoding pyruvate kinase, transketolase, enolase, and L-lactate dehydrogenase. Hydrogen peroxide (H2O2) production in M. bovis strains representing seven passages from P1 to P180 decreased progressively with increasing numbers of passages and increased attenuation. However, eight mutants specific to eight individual genes within the 14.2-kb deleted region did not exhibit altered H2O2 production. These results enrich the M. bovis genomics database, and they increase our understanding of the mechanisms underlying M. bovis virulence.


Asunto(s)
Genes Bacterianos/genética , Genoma Bacteriano/genética , Mycoplasma bovis/genética , Factores de Virulencia/genética , Virulencia/genética , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Bovinos , Biología Computacional , Peróxido de Hidrógeno/metabolismo , Redes y Vías Metabólicas/genética , Mycoplasma bovis/enzimología , Mycoplasma bovis/metabolismo , Polimorfismo de Nucleótido Simple , Mapas de Interacción de Proteínas , Análisis de Secuencia de ADN , Eliminación de Secuencia , Virulencia/inmunología
19.
Chin J Nat Med ; 15(11): 865-870, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29329614

RESUMEN

Two new dimeric naphthoquinones, 5',8'-dihydroxy-6,6'-dimethyl-7,3'-binaphthyl-1,4,1',4'-tetraone (1; Di-naphthodiospyrol D) and 5',8'-dihydroxy-5,8-dimethoxy-6,6'-dimethyl-7,3'-binaphthyl-1,4,1',4'-tetraone (2; Di-naphthodiospyrol E), along with known naphthoquinones diospyrin (3) and 8-hydroxy diospyrin (4) were isolated from the chloroform fraction of extract of Diospyros lotus roots. Their structures were elucidated by advanced spectroscopic analyses, including HSQC, HMBC, NOESY, and J-resolved NMR experiments. The fractions and compounds 1-4 were evaluated for urease activity and phosphodiesterase-I, carbonic anhydrase-II and α-chymotrypsin enzyme inhibitory activities. Compounds 1 and 2 and their corresponding fractions showed significant and selective inhibitory effects on urease activities. The IC50 values of 1 and 2 were 260.4 ± 6.37 and 381.4 ± 4.80 µmol·L-1, respectively, using thiourea (IC50 = 21 ± 0.11 µmol·L-1) as the standard inhibitor. This was the first report demonstrating that the naphthoquinones class showed urease inhibition.


Asunto(s)
Diospyros/química , Inhibidores Enzimáticos/farmacología , Naftoquinonas/farmacología , Extractos Vegetales/farmacología , Ureasa/antagonistas & inhibidores , Bioensayo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Estructura Molecular , Naftoquinonas/química , Naftoquinonas/aislamiento & purificación , Extractos Vegetales/química , Raíces de Plantas
20.
Acta Pol Pharm ; 73(4): 851-854, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-29648710

RESUMEN

Chlorogenic acid (CGA; (IS,3R,4R.5R)-3-{[(2Z)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy}-1,4,5-trihydroxycyclohexanecarboxylic acid) is a naturally occurring polyphenol mostly present in vegetables and fruits. CGA is a prominent component of Traditional Chinese Medicines and is known for various pharmacological activities such as antioxidant, antimicrobial, anti-inflammatory and hepatoprotective etc. This mini-review is an attempt to summarize the available literature in the last decade and to point out future perspectives in this area of research.


Asunto(s)
Ácido Clorogénico/farmacología , Animales , Peso Corporal/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Ácido Clorogénico/uso terapéutico , Humanos , Riñón/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...