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1.
J Nanosci Nanotechnol ; 21(2): 1054-1060, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33183443

RESUMO

This article explores the role of lysin nanocarriers in inducing apoptosis of human hepatocellular carcinoma cells and the possible molecular mechanisms. Cytotoxicity tests were performed in human fibroblast cell line MRC-5. Anti-cancer activity was tested in liver cancer cell lines HepG2 and HCCLM3. The results show that nanocarriers have a targeting effect on cancer cells, have high safety, and are good delivery vehicles for drugs. In this paper, the stability of lycopene and its degradation in aqueous solutions at different temperatures were studied, and the structure and mechanism of degradation products were determined. A new type of mesoporous silica nanocarrier was synthesized as a delivery carrier of lysin and its derivatives, which has a targeting effect on cancer cells and has a slow-release effect. Surface modification can improve circulation time and stability for future resistance in vivo. The cancer experiment laid the foundation. The results showed that the lysin nanocarriers inhibited the proliferation of HepG2 and HCCLM3 human liver cancer cells in a dependent manner. After the lysin nanocarriers acted on HepG2 human hepatocellular carcinoma cells for 48 h, the cell apoptosis rate was significantly increased by flow cytometry analysis. The carrier can significantly increase the levels of reactive oxygen species and malondialdehyde, and reduce the content of reduced glutathione and superoxide dismutase. At the same time, the lysin nanocarrier can down-regulate the expression of Nrf2 and HO-1 proteins, and inhibit the occurrence of Nrf2 Nuclear displacement. The lycopene nanocarrier inhibits the proliferation of HepG2, HCCLM3 human liver cancer cells, induces apoptosis, regulates the oxidative stress response in the cell, and regulates the Nrf2/AREE antioxidant signaling pathway, thereby promoting tumor cell apoptosis.

2.
Nano Lett ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33263394

RESUMO

Using first-principles calculations, we investigate the electronic and topological properties of an antiferromagnetic (AFM) superatomic graphene lattice superimposed on a bipartite honeycomb lattice governed by Lieb's theorem of itinerant magnetism. It affords a concrete material realization of the AFM honeycomb model with a Dirac Mott insulating state, characterized by a gap opening at the Dirac point due to inversion symmetry breaking by long-range AFM order. The opposite Berry curvatures of the K and K' valleys induces a circular dichroism (CD) Hall effect. Different from the valley Hall effect that activates only one valley, the CD Hall effect activates carriers from both K and K' valleys, generating the opposite directions of transversal Hall currents for the left- and right-handed circularly polarized light, respectively.

3.
Phys Chem Chem Phys ; 22(44): 25827-25832, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33150895

RESUMO

π-Orbital bonding plays an important role not only in traditional molecular science and solid-state chemistry but also in modern quantum physics and materials, such as the relativistic Dirac states formed by bonding and antibonding π-bands in graphene. Here, we disclose an interesting manifestation of π-orbitals in forming the Yin-Yang Kagome bands, which host potentially a range of exotic quantum phenomena. Based on first-principles calculations and tight-binding orbital analyses, we show that the frontier π2- and π3-orbitals in anilato-based metal-organic frameworks form concurrently a conduction and valence set of Kagome bands, respectively, but with opposite signs of lattice hopping to constitute a pair of enantiomorphic Yin and Yang Kagome bands, as recently proposed in a diatomic Kagome lattice. The twisted configuration of neighboring benzene-derived organic ligands bridged by an octahedrally O-coordinated metal ion is found to play a critical role in creating the opposite sign of lattice hopping for the π2- versus π3-orbitals. Our finding affords a new material platform to study π-orbital originated quantum chemistry and physics.

4.
Zhongguo Zhong Yao Za Zhi ; 44(7): 1464-1474, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090306

RESUMO

To predict the targets of active ingredients of Kuihua Hugan Tablets by network pharmacology, and explore the "multi-component-multi-target-multi-pathway" hepatoprotective mechanism of action. First, through traditional Chinese medicine systems pharmacology(TCMSP) and TCM Database@Taiwan Database, main active ingredients of Kuihua Hugan Tablets were screened out based on oral bioavailability(OB), drug-likeness(DL) and effective half-lives(HL). The targets of active ingredients of Kuihua Hugan Tablets were predicted based on the PharmMapper method. Then, the prediction was conducted by screening the target genes associated with chronic hepatitis and early cirrhosis through CooLGeN and GeneCards databases. Target gene functions and signal pathways were analyzed by bioinformatics annotation database Metascape. Cytoscape software was used to construct the Kuihua Hugan Tablets ingredient-target and ingredient-target-pathway network. String database combined with Cytoscape software was used to construct the networks of component-target and component-target-pathway. STRING database was combined with Cytoscape software to draw protein-protein interaction(PPI) network and conduct network topology analysis. Finally, Systems Dock Web Site software was applied in verifying the molecular docking between active ingredients and potential protein targets. A total of 26 compounds and 509 potential targets were screened out from Kuihua Hugan Tablets in the experiment. The results of PPI network analysis indicated that albumin(ALB), insulin-like growth factor 1(IGF1), matrix metalloproteinase-9(MMP9), matrix metalloproteinase-2(MMP2), non-receptor tyrosine kinase proto-oncogene(SRC), estrogen receptor 1(ESR1) and cancer-signal transduction-inflammation-drugs metabolism-related biological processes and metabolic pathways were closely associated with the active ingredients in Kuihua Hugan Tablets. The effects of Kuihua Hugan Tablets in alleviating chronic hepatitis and early cirrhosis indicated the multi-component, multi-target, and multi-pathway characteristics of traditional Chinese medicines, providing new ideas for further research and development of Kuihua Hugan Tablets.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Redes e Vias Metabólicas , Mapeamento de Interação de Proteínas , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Comprimidos
5.
Nanoscale ; 10(35): 16759-16764, 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30156239

RESUMO

A thickness dependent band gap is commonly found in layered two-dimensional (2D) materials. Here, using a C3N bilayer as a prototypical model, we systematically investigated the evolution of a band gap from a single layer to a bilayer using first principles calculations and tight binding modeling. We show that in addition to the widely known effect of interlayer hopping, de-charge transfer also plays an important role in tuning the band gap. The de-charge transfer is defined with reference to the charge states of atoms in the single layer without stacking, which shifts the energy level and modifies the band gap. Together with band edge splitting induced by the interlayer hopping, the energy level shifting caused by the de-charge transfer determines the size of the band gap in bilayer C3N. Our finding, applicable to other 2D semiconductors, provides an alternative approach for realizing band gap engineering in 2D materials.

6.
Phys Rev Lett ; 121(6): 066401, 2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30141639

RESUMO

We theoretically demonstrate that screw dislocation (SD), a 1D topological defect widely present in semiconductors, exhibits ubiquitously a new form of spin-orbit coupling (SOC) effect. Differing from the widely known conventional 2D Rashba-Dresselhaus (RD) SOC effect that typically exists at surfaces or interfaces, the deep-level nature of SD-SOC states in semiconductors readily makes it an ideal SOC. Remarkably, the spin texture of 1D SD-SOC, pertaining to the inherent symmetry of SD, exhibits a significantly higher degree of spin coherency than the 2D RD-SOC. Moreover, the 1D SD-SOC can be tuned by ionicity in compound semiconductors to ideally suppress spin relaxation, as demonstrated by comparative first-principles calculations of SDs in Si/Ge, GaAs, and SiC. Our findings therefore open a new door to manipulating spin transport in semiconductors by taking advantage of an otherwise detrimental topological defect.

7.
Nano Lett ; 17(10): 6166-6170, 2017 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-28898086

RESUMO

Superconductivity is a fascinating quantum phenomenon characterized by zero electrical resistance and the Meissner effect. To date, several distinct families of superconductors (SCs) have been discovered. These include three-dimensional (3D) bulk SCs in both inorganic and organic materials as well as two-dimensional (2D) thin film SCs but only in inorganic materials. Here we predict superconductivity in 2D and 3D organic metal-organic frameworks by using first-principles calculations. We show that the highly conductive and recently synthesized Cu-benzenehexathial (BHT) is a Bardeen-Cooper-Schrieffer SC. Remarkably, the monolayer Cu-BHT has a critical temperature (Tc) of 4.43 K, while Tc of bulk Cu-BHT is 1.58 K. Different from the enhanced Tc in 2D inorganic SCs which is induced by interfacial effects, the Tc enhancement in this 2D organic SC is revealed to be the out-of-plane soft-mode vibrations, analogous to surface mode enhancement originally proposed by Ginzburg. Our findings not only shed new light on better understanding 2D superconductivity but also open a new direction to search for SCs by interface engineering with organic materials.

8.
Nano Lett ; 16(10): 6058-6063, 2016 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-27588556

RESUMO

In the hydrogen evolution reaction (HER), the reactivity as a function of the hydrogen adsorption energy on different metal substrates follows a well-known volcano curve, peaked at the precious metal Pt. The goal of turning nonprecious metals into efficient catalysts for HER and other important chemical reactions is a fundamental challenge; it is also of technological significance. Here, we present results toward achieving this goal by exploiting the synergistic power of marginal catalysis and confined catalysis. Using density functional theory calculations, we first show that the volcano curve stays qualitatively intact when van der Waals attractions between a hydrogen adatom and different metal (111) surfaces are included. We further show that the hydrogen adsorption energy on the metal surfaces is weakened by 0.12-0.23 eV when hydrogen is confined between graphene and the metal surfaces, with Ni exhibiting the largest change. In particular, we find that the graphene-modified volcano curve peaks around Ni, whose bare surface already possesses moderate (or marginal) reactivity, and the corresponding HER rate of graphene-covered Ni is comparable to that of bare Pt. A hydrogen adatom has high mobility within the confined geometry. These findings demonstrate that graphene-covered Ni is an appealing effective, stable, and economical catalytic platform for HER.

9.
Clin Pediatr (Phila) ; 52(7): 599-607, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23610239

RESUMO

OBJECTIVE: To assess the pharmacokinetics (PK) and safety profile of aliskiren in pediatric patients (6-17 years old) with hypertension. METHODS: Patients were randomized to a single weight-based dose of either 2 mg/kg (n = 19) or 6 mg/kg (n = 20) of aliskiren daily for 8 days. The PK, pharmacodynamics, safety profile, and efficacy of aliskiren were assessed. RESULTS: Of the 39 randomized patients, 37 (94.9%) completed the study. Aliskiren plasma concentration (maximum plasma concentration and area under the plasma concentration-time curve) increased dose dependently, achieving peak concentrations in 1 to 2 hours, and t(max) was comparable across the dose and age groups. Treatment-emergent adverse events (AEs) were reported in 18 (46.2%) patients, with headache, abdominal pain, and nausea being the most frequent. CONCLUSIONS: Aliskiren 2 mg/kg and 6 mg/kg daily showed dose-dependent increases in the plasma concentration. The drug was well tolerated in hypertensive children aged 6 to 17 years. AEs were generally mild and not related to either the drug or the dose.


Assuntos
Amidas/farmacocinética , Amidas/uso terapêutico , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/uso terapêutico , Fumaratos/farmacocinética , Fumaratos/uso terapêutico , Hipertensão/tratamento farmacológico , Administração Oral , Adolescente , Fatores Etários , Amidas/efeitos adversos , Amidas/sangue , Análise de Variância , Anti-Hipertensivos/efeitos adversos , Criança , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fumaratos/efeitos adversos , Fumaratos/sangue , Humanos , Masculino , Análise de Regressão , Comprimidos , Resultado do Tratamento
10.
Mutat Res ; 677(1-2): 53-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19465145

RESUMO

Methylphenidate (MPH, Ritalin), has been prescribed to treat attention deficit/hyperactivity disorder (ADHD) since its approval by the FDA over 50 years ago. Diagnoses of pediatric patients with ADHD and the administration of MPH to treat the symptoms have increased in prevalence in recent years. A 2005 study by El-Zein et al. reported statistically significant increases in cytogenetic anomalies including chromosomal aberrations (CA), micronuclei (MN) and sister chromatid exchanges (SCEs) in peripheral blood lymphocytes cultured from pediatric patients treated for 3 months with MPH. These findings led to wide-spread concern regarding the potential for genotoxic risks associated with prolonged administration of MPH. The study described in the present paper was designed to repeat the El-Zein effort with a much larger sample size. The subjects (N = 109) were randomized into two groups: one treated with MPH as well as behavior therapy, the other was a control group that received behavior therapy only. We evaluated CAs, MN, and SCEs in peripheral blood lymphocytes in samples obtained prior to therapy and after 3 months of treatment with MPH. The data were analyzed using a Poisson regression model with a generalized estimating equation method adjusted for several covariates including time, treatment-by-time interaction, sex, and age group. The log(e) rate ratios of the MPH plus behavior therapy and behavior therapy groups were compared. The frequencies of CAs, MN, and SCEs were not increased in the MPH plus behavior therapy group when compared to the behavior therapy group only (p = 0.53, 0.28, 0.81, respectively). These results provide evidence in a large cohort that MPH does not induce cytogenetic anomalies in children, in contrast to the findings of the El-Zein study.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Dano ao DNA , Metilfenidato/efeitos adversos , Mutagênicos , Terapia Comportamental , Criança , Aberrações Cromossômicas , Feminino , Humanos , Masculino , Testes para Micronúcleos , Troca de Cromátide Irmã
11.
Zhongguo Wei Zhong Bing Ji Jiu Yi Xue ; 21(2): 99-102, 2009 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-19220961

RESUMO

OBJECTIVE: To explore interleukin-1 beta (IL-1 beta) and IL-6 gene polymorphism, and investigate the relationship between their gene polymorphism and the morbid state of patients with acute pancreatitis (AP). METHODS: The polymorphism of IL-1 beta gene 511C/T and IL-6 gene 634C/G site was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in patients (74 patients) with AP, including mild acute pancreatitis (MAP, 36 patients) and severe acute pancreatitis (SAP, 38 patients), and also a group of normal control (78 patients). The plasma concentrations of IL-1 beta and IL-6 were measured by enzyme linked immunosorbent assay (ELISA). The patients with SAP were divided into groups on the basis of different genotypes, and the clinical data were compared among different groups. RESULTS: The plasma levels of IL-1 beta and IL-6 in patients with AP were significantly higher than normal control group [IL-1 beta: (13.16+/-2.82) ng/L vs. (6.21+/-1.57) ng/L; IL-6: (84.86+/-32.92) ng/L vs. (9.95+/-2.49) ng/L, both P<0.05]. There was no statistical significance between IL-1 beta gene 511 site and IL-6 gene 634 site genotype or allele frequency between the patients with AP and the normal control. In patients with SAP, IL-1 beta gene 511 site T/T genotype and T allele frequency were significantly higher than that of MAP group (both P<0.05). There was no statistically significant difference in plasma levels of IL-1 beta between C/C group and C/T+T/T group, and the plasma levels of IL-6 in patients with IL-6 gene 634 site C/G were significantly higher than C/C group [(97.23+/-35.49) ng/L vs. (72.14+/-24.55) ng/L, P<0.05]. In patients with SAP, the scores of clinical evaluation in IL-1 beta gene 511 site C/T+T/T group and IL-6 gene 634 site C/G group were significantly higher than that in IL-1 beta gene 511 site C/C group and IL-6 gene 634 site C/C group (all P<0.05). CONCLUSION: IL-1 beta gene 511 site C/T and IL-6 gene 634 site C/G polymorphism may be genetic susceptibility factors for exacerbation of AP.


Assuntos
Interleucina-1beta/genética , Interleucina-6/genética , Pancreatite/genética , Polimorfismo de Fragmento de Restrição , Doença Aguda , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
12.
Hypertension ; 52(1): 130-6, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18490518

RESUMO

The aim of this study was to explore the effects of the renin inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between renin and the (pro)renin receptor and between aliskiren and prorenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-beta and collagen I expression versus vehicle. Aliskiren reduced (pro)renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 micromol/L to 10 micromol/L) did not inhibit binding of (125)I-renin to the (pro)renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)renin receptor. Evidence was obtained that aliskiren binds to the active site of prorenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)renin receptor and that it may block prorenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this renin inhibitor.


Assuntos
Albuminúria/fisiopatologia , Amidas/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Fumaratos/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Renina/antagonistas & inibidores , Albuminúria/etiologia , Albuminúria/metabolismo , Amidas/farmacocinética , Animais , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacocinética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Fumaratos/farmacocinética , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Renina/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
13.
Brain Res ; 999(2): 167-74, 2004 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-14759495

RESUMO

Spreading depression (SD) has been demonstrated following focal ischemia, and the additional workload imposed by SD on a tissue already compromised by a marked reduction in blood flow may contribute to the evolution of irreversible damage in the ischemic penumbra. SD was elicited in one group of rats by injecting KCl directly into a frontal craniectomy and the wave of depolarization was recorded in two craniectomies 3 and 6 mm posterior to the first one. In a second group, the middle cerebral artery was occluded using the monofilament technique and a recording electrode was placed 5 mm lateral to the midline and 0.2 mm posterior to bregma. To determine the metabolic response in the penumbral region of the cortex ipsilateral to the occlusion, brains from both groups were frozen in situ when the deflection of the SD was maximal. The spatial metabolic response of SD in the ischemic cortex was compared to that in the non-ischemic cortex. Coronal sections of the brains were lyophilized, pieces of the dorsolateral cortex were dissected and weighed, and analyzed for ATP, P-creatine, inorganic phosphate (Pi), glucose, glycogen and lactate at varying distances anterior and posterior to the recording electrode. ATP and P-creatine levels were significantly decreased at the wavefront in both groups and the levels recovered after passage of the wavefront in the normal brain, but not in the ischemic brain. Glucose and glycogen levels were significantly decreased and lactate levels significantly increased in the tissue after the passage of the wavefront. While the changes in the glucose-related metabolites persisted during recovery even in anterior portions of the cortex in both groups in the aftermath of the SD, the magnitude of the changes was greater in the penumbra than in the normal cortex. SD appears to impose an equivalent increase in energy demands in control and ischemic brain, but the ability of the penumbra to recover from the insult is compromised. Thus, increasing the energy imbalance in the penumbra after multiple SDs may hasten the deterioration of the energy status of the tissue and eventually contribute to terminal depolarization and cell death, particularly in the penumbra.


Assuntos
Isquemia Encefálica/metabolismo , Córtex Cerebral/metabolismo , Infarto Cerebral/metabolismo , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Metabolismo Energético/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Isquemia Encefálica/fisiopatologia , Córtex Cerebral/fisiopatologia , Infarto Cerebral/fisiopatologia , Glucose/metabolismo , Glicogênio/metabolismo , Ácido Láctico/metabolismo , Masculino , Potenciais da Membrana/fisiologia , Fosfatos/metabolismo , Fosfocreatina/metabolismo , Cloreto de Potássio , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/fisiologia
14.
Metab Brain Dis ; 18(3): 195-206, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14567470

RESUMO

The regional energy status and the availability of metabolic substrates during brain development are important, since a variety of fetal metabolic insults have been increasingly implicated in the evolution of neonatal brain disorders. The response of the brain to a metabolic insult is determined, in large part, by the ability to utilize the various substrates for intermediary metabolism in order to maintain energy stores within the tissue. To ascertain if metabolic conditions of the fetal brain make it more or less vulnerable to a stress, the high-energy phosphates and glucose-related compounds were examined in five regions of the embryonic day 18 (E-18) fetal brain. Glucose and glycogen levels in the E-18 fetal brain were generally higher in the cerebellum and its neuroepithelium than in the hippocampus, cerebral cortex, and its neuroepithelium. Regional lactate and high-energy phosphate concentrations were essentially the same in the five regions. Subsequently, the metabolic profile was examined in the cerebral cortex and striatum from E-18, postpartum day 7 (P-7) and adult rats. At the various stages of development, there were only minimal differences in the high-energy phosphate levels in the striatum and cortex. Glucose levels, the primary substrate in the adult brain, were essentially unchanged throughout development. In contrast, lactate was significantly elevated by 6- and 2-fold over those in the adult brain in the E-18 and P-7 striatum and cortex, respectively. Another alternative substrate, beta-hydroxybutyrate, was also significantly elevated at E-18 and increased more than 2-fold at P-7, but was barely detectable in the adult cortex and striatum. Finally, glucose and lactate levels were examined in cerebrospinal fluid, blood, and brain from the E-18 brain to determine if a gradient among the compartments exists. The levels of both lactate and glucose exhibited a concentration gradient in the E-18 fetus: blood > cerebrospinal fluid > brain parenchyma. The results indicate that energy state in the fetal brain is comparable to that in the neonates and the adults, but that the availability of alternative substrates for intermediary metabolism change markedly with development. The age-dependent substrate specificity for intermediary metabolism could affect the response of the fetal brain to a metabolic insult.


Assuntos
Envelhecimento/fisiologia , Animais Recém-Nascidos/metabolismo , Química Encefálica/fisiologia , Encéfalo/crescimento & desenvolvimento , Metabolismo Energético/fisiologia , Feto/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Trifosfato de Adenosina/metabolismo , Envelhecimento/metabolismo , Animais , Glicemia/metabolismo , Feminino , Glucose/metabolismo , Glicogênio/metabolismo , Lactatos/metabolismo , Fosfocreatina/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley
15.
Bioorg Med Chem ; 11(17): 3695-707, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12901915

RESUMO

A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.


Assuntos
Benzimidazóis/síntese química , Benzodiazepinas/síntese química , Benzodiazepinas/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Benzimidazóis/química , Benzodiazepinas/química , Sítios de Ligação , Células CACO-2 , Diabetes Mellitus Experimental/tratamento farmacológico , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Camundongos , Modelos Moleculares , Ratos , Relação Estrutura-Atividade
16.
Metab Brain Dis ; 17(3): 153-67, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12322786

RESUMO

Traumatic brain injury (TBI) results in an acute altered metabolic profile of brain tissue which resolves within hours of initial insult and yet some of the functional deficits and cellular perturbations persist for days. It is hypothesized that a delayed change in energy status does occur and is a factor in the neural tissue's ability to survive and regain function. Regional metabolic profile and glucose consumption were determined at either 1 or 3 days following two different intensities of parasagittal fluid-percussion (F-P). A significant decrease in both 1CMRgluc and levels of ATP and P-creatine was evident in the hemisphere ipsilateral to the trauma at 1 day after the insult. The effect was greater in the cortical than the subcortical regions and was more pronounced at the higher trauma intensity. Normalization of glucose consumption and energy levels was essentially complete by 3 days. It would appear that the delayed metabolic changes at 1 day postinsult cannot be explained by a secondary ischemia since the changes in the metabolite profile do not elicit an increase in the consumption of glucose. These changes in energy metabolites may account for and contribute to the chronic neurological deficits following TBI.


Assuntos
Química Encefálica/fisiologia , Concussão Encefálica/metabolismo , Metabolismo Energético/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Antimetabólitos , Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Temperatura Corporal/fisiologia , Córtex Cerebral/metabolismo , Desoxiglucose , Glucose/metabolismo , Glicogênio/metabolismo , Hematócrito , Cinética , Ácido Láctico/metabolismo , Masculino , Oxigênio/sangue , Fosfocreatina/metabolismo , Ratos , Ratos Sprague-Dawley
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