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1.
Biomolecules ; 11(7)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34356672

RESUMO

In the search for new therapeutic strategies to contrast SARS-CoV-2, we here studied the interaction of polydatin (PD) and resveratrol (RESV)-two natural stilbene polyphenols with manifold, well known biological activities-with Spike, the viral protein essential for virus entry into host cells, and ACE2, the angiotensin-converting enzyme present on the surface of multiple cell types (including respiratory epithelial cells) which is the main host receptor for Spike binding. Molecular Docking simulations evidenced that both compounds can bind Spike, ACE2 and the ACE2:Spike complex with good affinity, although the interaction of PD appears stronger than that of RESV on all the investigated targets. Preliminary biochemical assays revealed a significant inhibitory activity of the ACE2:Spike recognition with a dose-response effect only in the case of PD.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/tratamento farmacológico , Glucosídeos/farmacologia , Resveratrol/farmacologia , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Estilbenos/farmacologia , COVID-19/metabolismo , Descoberta de Drogas , Medicamentos de Ervas Chinesas/farmacologia , Inibidores Enzimáticos/farmacologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , SARS-CoV-2/metabolismo
2.
Chem Sci ; 12(23): 8058-8072, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-34194695

RESUMO

We present electronic structure methods to unveil the non-radiative pathways of photoinduced charge transfer (CT) reactions that play a main role in photophysics and light harvesting technologies. A prototypical π-stacked molecular complex consisting of an electron donor (1-chloronaphthalene, 1ClN) and an electron acceptor (tetracyanoethylene, TCNE) was investigated in dichloromethane solution for this purpose. The characterization of TCNE:π:1ClN in both its equilibrium ground and photoinduced low-lying CT electronic states was performed by using a reliable and accurate theoretical-computational methodology exploiting ab initio molecular dynamics simulations. The structural and vibrational time evolution of key vibrational modes is found to be in excellent agreement with femtosecond stimulated Raman spectroscopy experiments [R. A. Mathies et al., J. Phys. Chem. A, 2018, 122, 14, 3594], unveiling a correlation between vibrational fingerprints and electronic properties. The evaluation of nonadiabatic coupling matrix elements along generalized normal modes has made possible the interpretation on the molecular scale of the activation of nonradiative relaxation pathways towards the ground electronic state. In particular, two low frequency vibrational modes such as the out of plane bending and dimer breathing and the TCNE central C[double bond, length as m-dash]C stretching play a prominent role in relaxation phenomena from the electronic CT state to the ground state one.

3.
Front Mol Biosci ; 7: 569990, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195416

RESUMO

The Green Fluorescent Protein (GFP) is a widely studied chemical system both for its large amount of applications and the complexity of the excited state proton transfer responsible of the change in the protonation state of the chromophore. A detailed investigation on the structure of the chromophore environment and the influence of chromophore form (either neutral or anionic) on it is of crucial importance to understand how these factors could potentially influence the protein function. In this study, we perform a detailed computational investigation based on the analysis of ab-initio molecular dynamics simulations, to disentangle the main structural quantities determining the fine balance in the chromophore environment. We found that specific hydrogen bonds interactions directly involving the chromophore (or not), are correlated to quantities, such as the volume of the cavity in which the chromophore is embedded and that it is importantly affected by the chromophore protonation state. The cross-correlation analysis performed on some of these hydrogen bonds and the cavity volume, demonstrates a direct correlation among them and we also identified the ones specifically involved in this correlation. We also found that specific interactions among residues far in the space are correlated, demonstrating the complexity of the chromophore environment and that many structural quantities have to be taken into account to properly describe and understand the main factors tuning the active site of the protein. From an overall evaluation of the results obtained in this work, it is shown that the residues which a priori are perceived to be spectators play instead an important role in both influencing the chromophore environment (cavity volume) and its dynamics (cross-correlations among spatially distant residues).

4.
J Comput Chem ; 41(20): 1835-1841, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32500950

RESUMO

Electrons and protons are the main actors in play in proton coupled electron transfer (PCET) reactions, which are fundamental in many biological (i.e., photosynthesis and enzymatic reactions) and electrochemical processes. The mechanism, energetics and kinetics of PCET reactions are strongly controlled by the coupling between the transferred electrons and protons. Concerted PCET reactions are classified according to the electronical adiabaticity degree of the process. To discriminate among different mechanisms, we propose a new analysis based on the use of electron density based indexes. We choose, as test case, the 3-Methylphenoxyl/phenol system in two different conformations to show how the proposed analysis is a suitable tool to discriminate between the different degree of adiabaticity of PCET processes. The very low computational cost of this procedure is extremely promising to analyze and provide evidences of PCET mechanisms ruling the reactivity of many biological and catalytic systems.


Assuntos
Elétrons , Fenóis/química , Prótons , Transporte de Elétrons , Fenóis/metabolismo
5.
Phys Chem Chem Phys ; 21(7): 3606-3614, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30306981

RESUMO

In this work, excited state ab initio molecular dynamics together with a time resolved vibrational analysis is employed to shed light on the vibrational photoinduced dynamics of a well-known diarylethene molecule experiencing a ring opening reaction upon electronic excitation. The photoreactivity of diarylethenes is recognized to be controlled by a non-adiabatic intersection point between the ground and the first excited state surfaces. The computation of an energy scan, along a suitable reaction coordinate, allows us to identify the region of potential energy surfaces in which the ground (S0) and the first excited (S1) state are well separated. The adiabatic sampling of that region in S1 shows that in the first 3 picoseconds, the central CC bond, which is subject to break, oscillates in an antiphase with respect to the energy gap ΔE(S1 - S0). A multiresolution analysis based on the wavelet transform was then applied to the structural parameters extracted from the excited state dynamics. The wavelet maps show characteristic oscillations of the frequencies, mainly CC stretching and CCC bending localized on the central 4-ring moiety. Moreover, we have identified the main frequency (methyl wagging motion) involved in the modulation of these oscillations. The anharmonic coupling within a group of vibrational modes was therefore highlighted, in good agreement with experimental evidence. For the first time, a quantitative analysis of time resolved signals from a wavelet transform/ab initio molecular dynamics approach was performed.

6.
J Surg Case Rep ; 2018(10): rjy250, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30310640

RESUMO

Spinal Cord Injury Without Radiologic Abnormality (SCIWORA) accounts for up to 19% of spinal cord related lesions in pediatric population, mostly comprising the cervical spine. A 2-year-old patient is presented, who suffered a motor-vehicle accident. After being admitted, neither X-Ray nor spinal TC scan showed any structural abnormalities. Neurological examination showed complete sensory and motor loss under T7 as well as bladder and bowel dysfunction. Magnetic resonance imaging (MRI) showed spinal cord lesion extending from T7 to T10. The patient was treated with external immobilization and physical therapy. Thoracic SCIWORA is an uncommon diagnosis that should be considered in pediatric patients who suffer spinal trauma. Spinal cord MRI has proven to be the most accurate modality for diagnosis.

7.
Surg Neurol Int ; 8(Suppl 2): S37-S42, 2017.
Artigo em Espanhol | MEDLINE | ID: mdl-29142779

RESUMO

Objective: We aimed to demonstrate the differences between grade I and II (OMS classification) of intracranial meningiomas. We evaluate their location, Simpson resection grade, re-operations rate, adjuvant treatment and patient outcomes. Methods: We conduct a retrospective review of Sixty- three clinical records of patients who were diagnosed with meningiomas grade I and II (OMS) between 2009-2015 and received surgical treatment at our Hospital. We evaluated different variables such as age, sex, histological type, Simpson grade resection, location, symptoms, radiotherapy, follow-up, mortality rate and patient outcome. The main aim was to establish the differences between these intracranial tumors. Results: A total of sixty-three patients diagnosed with meningiomas and received surgical treatment; fifty-one were grade I and thirteen with grade II. There were no differences in the rate between man and women. The average age for both types of meningiomas was 57 years old. The typical meningiomas were located in 55% of the cases outside the cranial base vs. 91.6% of the atypical meningiomas (P = 0.03). Typical meningioma had a Simpson resection grade of I, II and III in 74.5% against 58.3% of the atypical (P = 0.2). The atypical meningioma in 33% had more than one-stage surgery vs. 9.8% of the typical (P = 0.03). The patients with a typical meningioma showed a good outcome in 86.2% vs. 53.8 of the grade II (P = 0, 01). The typical meningiomas showed a good outcome in 82.2% of the cases vs. 53.8% of the atypical. The grade II meningiomas received adjuvant treatment in 33.3%, while the grade I only 1.9%. Conclusions: The atypical intracranial meningiomas have a worse outcome compared with the typical kind and a higher incidence of re-operations. These tumors have a preference for a location outside the cranial base. Concluding that the location could be a risk factor.

8.
Am J Clin Oncol ; 29(1): 45-51, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16462502

RESUMO

OBJECTIVES: Irinotecan or oxaliplatin combined with 5-fluorouracil (5-FU) +/- folinic acid (FA) has changed the treatment standards for metastatic colorectal cancer (CRC). The oxaliplatin and irinotecan combination has reported consistent activity. The purpose of this phase II study was to assess the efficacy and safety of the simultaneous administration of a triple chemotherapy combination of oxaliplatin, irinotecan, 5-FU bolus, and FA. MATERIALS AND METHODS: Eligible patients had metastatic CRC with no prior oxaliplatin or irinotecan-based chemotherapy. Treatment consisted of oxaliplatin 85 mg/m2 followed by irinotecan 150 mg/m2, repeated every 15 days, with 5-FU 500 mg/m2 bolus and FA 20 mg/m2 on days 1, 8, and 15. An early amendment suppressed the day 8 5-FU/FA. RESULTS: Twenty-six eligible treated patients receiving 253 doses were assessed for toxicity. Myelosuppression was the most frequent toxicity; grade 3 to 4 neutropenia and febrile neutropenia occurred in 50% and 15% of patients, respectively. The treatment schedule modification, omitting the 5-FU dosing on day 8, considerably improved treatment compliance, reducing the incidence of febrile neutropenia, diarrhea, and asthenia. Among the 25 patients evaluable for efficacy, 10 had objective responses including 1 complete response (CR) (4%) and 9 partial responses (PR) (36%), giving an overall response rate of 40%. Median time to progression was 6.20 months [95% confidence interval (CI), 5.44-6.96]. Median overall survival was 12.95 months. CONCLUSIONS: The administration of a triple combination produced promising objective responses with acceptable toxicity but does not seem to produce an evident benefit in time-related parameters.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Diarreia/induzido quimicamente , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Injeções Intravenosas , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutropenia/induzido quimicamente , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Resultado do Tratamento
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