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1.
Mol Divers ; 2023 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-37733244

RESUMO

Solving the worldwide problem of growing bacterial drug resistance will require a short-run and medium-term strategy. Structure-activity relationship (SAR) and quantitative SAR (QSAR) analyses have recently been utilized to reveal the molecular basis of the antibacterial activity and antibacterial spectrum of penicillins, the use of which is no longer solely empirical. Likewise, a more rational drug design can be achieved with cephalosporins, the largest group of ß-lactam antibiotics. The current contribution aimed to establish the molecular and physicochemical basis of the antibacterial activity of five generations of cephalosporins on methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). With SAR and QSAR analyses, the molecular portions that provide essential and additional antibacterial activity were identified. The substitutions with greater volume and polarity on the R2 side chain of the cephem nucleus increase potency on MSSA. The best effect is produced by substitutions with polar nitrogen atoms at the alpha-carbon (Cα). Substitutions with greater volume and polarity on the R1 side chain further enhance antibacterial activity. In contrast, the effect against MRSA seems to be independent of any substitution on R2 or at the Cα, while depending on the accessory portions with greater volume and polarity on R1.

2.
Ren Fail ; 40(1): 92-98, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29299955

RESUMO

A worldwide public health problem is chronic kidney disease (CKD) presenting alarming epidemiological data. It currently affects about 10% of the adult population worldwide and has a high mortality rate. It is now known that oxidative stress represents one of the most important mechanisms in its pathophysiology, from the early stages to the terminal phase. Oxidation increases inflammation and reduces the capacity of NO• to relax vascular smooth muscle, in part by decreasing bioavailability of tetrahydrobiopterin (BH4), leading to endothelial dysfunction and high blood pressure, and due to the limited effectiveness of existing treatments, new drugs are needed to prevent and/or treat these mechanisms. The aim of this study was to test apocynin in a 5/6 nephrectomy mouse model of CKD to investigate whether its known antioxidant effect can improve the disease outcome. This effect results from the inhibition of NADPH oxidase and consequently a reduced production of the superoxide anion ([Formula: see text]). Animals were divided into five groups: sham, 5/6 nephrectomy only, and 5/6 nephrectomy followed by treatment with captopril, losartan or apocynin. The parameters evaluated were blood pressure and markers of oxidative stress ([Formula: see text]) and endothelial function (BH4). There were significantly lower levels of [Formula: see text] and a greater availability of serum BH4 in the apocynin-treated animals versus the control group and the two other drug treatments. The present findings suggest that apocynin in conjunction with a coadjuvant for modulating blood pressure may be useful for controlling the progression of CRF.


Assuntos
Acetofenonas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Antioxidantes/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Acetofenonas/farmacologia , Adjuvantes Farmacêuticos/farmacologia , Adjuvantes Farmacêuticos/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Captopril/farmacologia , Captopril/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Losartan/farmacologia , Losartan/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/etiologia , Resultado do Tratamento
3.
Elife ; 132024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38597390

RESUMO

Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.


Assuntos
Processamento Alternativo , Éxons , Neurônios , Proteína de Ligação a Regiões Ricas em Polipirimidinas , Proteínas Serina-Treonina Quinases , Animais , Humanos , Camundongos , Éxons/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Fosforilação , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
4.
Rev Biol Trop ; 61(4): 1747-58, 2013 Dec.
Artigo em Espanhol | MEDLINE | ID: mdl-24432531

RESUMO

The spatial and temporal distribution of gastrointestinal nematodes of cattle has been little studied in Mexico. Previous studies have described periods of higher larval presence, vertical and horizontal migration in grasslands, and the frequency of adult nematodes; as well as the effect of pasture trichomes on the migration and survival of Haemonchus larvae. The aim of this study was to determine the time-space layout and spread of gastrointestinal nematode larvae on pasture, and to estimate the effect of ivermectin applied to cattle on the time-dependent abundance of their eggs in a ranch in Veracruz. To determine the spatio-temporal arrangement, monthly morning grass samples were obtained from 30 sampling points from July 2008 to June 2009. Third stage larvae (L3) from each point were counted, and aggregation patterns were estimated through variance/mean and negative binomial K indices. Additionally, the number of eggs per gram in cattle feces was determined, from samples with (CI) and without ivermectin (SI), using standard techniques. A total of 20 276 L(3) larvae were recovered in the pasture, of which an 80% corresponded to Haemonchus contortus. The highest nematode density with more than 5 000L(3)/kgDM was detected in October 2008, and the lowest in February and March 2009. The L3 showed an aggregated spatial pattern of varying intensity throughout the year. The number of eggs in the stool was not reduced with the ivermectin application to cattle, which suggested a failure of control. However, the highest parasite loads were observed from July to November 2008. We concluded that the application of ivermectin was not effective to control nematodes eggs, and that L3 populations fluctuated on pasture for ten months, providing an infection source to grazing animals afterwards.


Assuntos
Doenças dos Bovinos/parasitologia , Hemoncose/veterinária , Haemonchus/isolamento & purificação , Enteropatias Parasitárias/veterinária , Animais , Antiparasitários/administração & dosagem , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Fezes/parasitologia , Hemoncose/tratamento farmacológico , Hemoncose/parasitologia , Enteropatias Parasitárias/parasitologia , Ivermectina/administração & dosagem , Larva , México , Contagem de Ovos de Parasitas/veterinária , Poaceae/parasitologia , Conglomerados Espaço-Temporais
5.
Rev Biol Trop ; 60(1): 333-45, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22458228

RESUMO

The State of Veracruz in Mexico is one of the main cattle producers, and uses several veterinary products for disease and parasite control. For parasite control, ivermectin is one of the most frequently used substances. Nevertheless, even though previous research conducted in other countries has found that this product has negative effects on beneficial coprophagous fauna, no studies have described its effects on coprophagous insects at a local scale in Veracruz, Mexico. This study evaluated Euoniticellus intermedius survival, fecundity, fertility and preimaginal development under laboratory conditions when ivermectin was added to cattle dung at three different concentrations. The design included two controls (spiked dung), and the following product concentrations: 0.01, 1.0 and 100ppm, which were homogenized with wet cattle dung. 20 female-male E. intermedius couples between five and 15 days old were used and kept at 27 degrees C, 70% RH, and 12h light for 10 days. The survival of all specimens, the fertility of 20 females and the gonadal maturity of 17 males were verified. The larval development in 162 pieces of brood-mass was examined, and a total of 974 larvae developed and reached adulthood. The highest ivermectin concentration was toxic at 1.0ppm dose, the survival of adults was reduced to almost the half, and at 100ppm, total mortality was observed. The effects on specimen reproductive systems showed that the ovary was not affected, that the testicle size increased, and that the fecundity and weight of brood-masses were reduced. Pre-imaginal development increased 0.5 times at 0.01ppm concentration, and the width of the cephalic capsule in third instar larvae diminished. The prolonging of development time may cause a phase lag in the field activity cycle, this lag may reduce the number of E. intermedius individuals and the efficiency of the environmental services that they provide.


Assuntos
Antiparasitários/farmacologia , Besouros/efeitos dos fármacos , Ivermectina/farmacologia , Animais , Bovinos , Besouros/crescimento & desenvolvimento , Coprofagia , Resíduos de Drogas , Fezes/parasitologia , Feminino , Fertilidade/efeitos dos fármacos , Masculino , México , Fatores Sexuais
6.
Biology (Basel) ; 11(3)2022 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-35336827

RESUMO

Glaucoma is a group of ophthalmologic conditions characterized by progressive retinal ganglion cell death, optic nerve degeneration, and irreversible vision loss. While intraocular pressure is the only clinically modifiable risk factor, glaucoma may continue to progress at controlled intraocular pressure, indicating other major factors in contributing to the disease mechanisms. Recent studies demonstrated the feasibility of advanced diffusion magnetic resonance imaging (dMRI) in visualizing the microstructural integrity of the visual system, opening new possibilities for non-invasive characterization of glaucomatous brain changes for guiding earlier and targeted intervention besides intraocular pressure lowering. In this review, we discuss dMRI methods currently used in visual system investigations, focusing on the eye, optic nerve, optic tract, subcortical visual brain nuclei, optic radiations, and visual cortex. We evaluate how conventional diffusion tensor imaging, higher-order diffusion kurtosis imaging, and other extended dMRI techniques can assess the neuronal and glial integrity of the visual system in both humans and experimental animal models of glaucoma, among other optic neuropathies or neurodegenerative diseases. We also compare the pros and cons of these methods against other imaging modalities. A growing body of dMRI research indicates that this modality holds promise in characterizing early glaucomatous changes in the visual system, determining the disease severity, and identifying potential neurotherapeutic targets, offering more options to slow glaucoma progression and to reduce the prevalence of this world's leading cause of irreversible but preventable blindness.

7.
Neurotox Res ; 40(6): 1690-1706, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36522511

RESUMO

The Endocannabinoid System (ECS, also known as Endocannabinoidome) plays a key role in the function of the Central Nervous System, though the participation of this system on the early development - specifically in neuroprotection and proliferation of nerve cells - has been poorly studied. Here, we collect and describe evidence regarding how cannabinoid receptors CB1R and CB2R regulate several cell markers related to proliferation. While CB1R participates in the modulation of neuronal and glial proliferation, CB2R is involved in the proliferation of glial cells. The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) exert significant effects on nerve cell proliferation. AEA generated during embryogenesis induces major effects on the differentiation of neuronal progenitor cells, whereas 2-AG participates in modulating cell migration events rather than affecting the neural proliferation rate. However, although the ECS has been demonstrated to participate in neuroprotection, more characterization on its role in neuronal and glial proliferation and differentiation is needed, especially in brain areas with recognized high neurogenesis rates. This has encouraged scientists to elucidate and propose specific mechanisms related with these cell proliferation mechanisms to better understand some neurodegenerative disorders such as Parkinson, Huntington and Alzheimer diseases, in which neuronal loss and poor neurogenesis are crucial factors for their onset and progression. In this review, we collect and present recent evidence published pointing to an active role of the ECS in the development and proliferation of nerve cells.


Assuntos
Sistema Nervoso Central , Endocanabinoides , Receptores de Canabinoides/fisiologia , Neurônios , Proliferação de Células
8.
Exp Mol Pathol ; 91(1): 478-83, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21596033

RESUMO

The density of Angiotensin II (Ang) receptors on tissue surfaces is regulated by multiple hormones, cytokines and metabolic factors and is profoundly affected by various pathological conditions, such as age, diet and environmental conditions. The participation of several cardiovascular risk factors in the regulation of Angiotensin II receptor expression has been incompletely studied. We performed an ex-vivo study with human aortic postsurgical specimens to test the hypothesis that Ang AT1 and AT2 receptor expression in human aortic arteries is associated with the presence of cardiovascular risk factors. We included 31 Mexican patients with coronary artery disease. We evaluated Angiotensin II receptor expression by immunostaining and angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphisms by polymerase chain reaction. AT1 and AT2 receptor expression was increased in the aortic segments from the cardiovascular patients compared with control arteries and in patients with the DD genotype. There was a correlation between increased AT1 receptor expression and the number of cardiovascular risk factors present in the patient. Furthermore, reduction of AT1 expression correlated with the number of drug combinations used in the patients. These correlations were not present with respect to AT2 receptor expression. We suggest that increased AT1 receptor expression is associated with the DD genotype. Thus the presence of several cardiovascular risk factors as well as DD genotype, induce AT1 expression increasing the probability to develop coronary occlusive disease.


Assuntos
Estenose Coronária/genética , Predisposição Genética para Doença , Receptor Tipo 1 de Angiotensina/genética , Adulto , Antagonistas de Receptores de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Aorta/metabolismo , Aorta/patologia , Estenose Coronária/metabolismo , Estenose Coronária/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Fatores de Risco
9.
Ren Fail ; 33(1): 47-53, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21219205

RESUMO

We evaluated the effects of vitamins with antioxidant properties (a combination of vitamins C and E) and L-arginine treatment on renal failure in mice by measuring survival rate. The molecular changes were elucidated by determining endothelial tetrahydrobiopterin (BH4) levels and nitric oxide synthase (eNOS) mRNA expression in mice with renal ablation. Previous studies have shown that endothelial dysfunction in 5/6 nephrectomized mice is associated with decreased nitric oxide (NO) bioavailability and increased vascular superoxide production. WTC57 mice were divided into three groups: Group 1 was the sham-operated group (C); Group 2 was the 5/6 nephrectomized group (Nfx); and Group 3 was a group of 5/6 nephrectomized mice, treated with L-arginine and vitamins with antioxidant properties (NfxTx; 200 mg/kg L-arginine, 83 mg/kg vitamin C, and 46.6 mg/kg vitamin E). After 20 weeks of treatment, urinary protein excretion, blood pressure, BH4 and dihydrobiopterin (BH2) levels, eNOS mRNA, oxidative stress, and survival rate were determined. An increase in urinary protein excretion, blood pressure, and oxidative stress was prevented in the NfxTx group, but not in the Nfx group. BH4 and eNOS mRNA expression was increased by 32% and 78%, respectively, in the NfxTx group. Furthermore, the treatment increased the survival rate by 33%. Our results indicate that under normal conditions, NO appears to protect renal function. However, this NO-dependent protection is lost during kidney failure, probably due to increased reactive oxygen species synthesis. The treatment restores the viability of NO and prevents the BH4 oxidation. Therefore, this treatment may represent a therapeutic approach for the management of kidney disease.


Assuntos
Antioxidantes/uso terapêutico , Arginina/uso terapêutico , Ácido Ascórbico/uso terapêutico , Insuficiência Renal/prevenção & controle , Vitamina E/uso terapêutico , Vitaminas/uso terapêutico , Animais , Endotélio/fisiopatologia , Masculino , Camundongos
10.
Sci Rep ; 11(1): 15513, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330952

RESUMO

This study employed in vivo 7-T magnetic resonance imaging (MRI) to evaluate the postnatal ocular growth patterns under normal development or neonatal impairments in Sprague-Dawley rats. Using T2-weighted imaging on healthy rats from postnatal day (P) 1 (newborn) to P60 (adult), the volumes of the anterior chamber and posterior chamber (ACPC), lens, and vitreous humor increased logistically with ACPC expanding by 33-fold and the others by fivefold. Intravitreal potassium dichromate injection at P1, P7, and P14 led to T1-weighted signal enhancement in the developing retina by 188-289%. Upon unilateral hypoxic-ischemic encephalopathy at P7, monocular deprivation at P15, and monocular enucleation at P1, T2-weighted imaging of the adult rats showed decreased ocular volumes to different extents. In summary, in vivo high-field MRI allows for non-invasive evaluation of early postnatal development in the normal and impaired rat eyes. Chromium-enhanced MRI appeared effective in examining the developing retina before natural eyelid opening at P14 with relevance to lipid metabolism. The reduced ocular volumes upon neonatal visual impairments provided evidence to the emerging problems of why some impaired visual outcomes cannot be solely predicted by neurological assessments and suggested the need to look into both the eye and the brain under such conditions.


Assuntos
Encéfalo/diagnóstico por imagem , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Animais , Animais Recém-Nascidos , Câmara Anterior/fisiologia , Encéfalo/metabolismo , Ratos , Ratos Sprague-Dawley , Retina/diagnóstico por imagem , Retina/metabolismo , Visão Ocular/fisiologia , Corpo Vítreo/diagnóstico por imagem , Corpo Vítreo/metabolismo
11.
J Cell Biol ; 220(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33480968

RESUMO

Stress granules (SGs) are conserved biomolecular condensates that originate in response to many stress conditions. These membraneless organelles contain nontranslating mRNAs and a diverse subproteome, but our knowledge of their regulation and functional relevance is still incipient. Here, we describe a mutual-inhibition interplay between SGs and Cdc28, the budding yeast Cdk. Among Cdc28 interactors acting as negative modulators of Start, we have identified Whi8, an RNA-binding protein that localizes to SGs and recruits the mRNA of CLN3, the most upstream G1 cyclin, for efficient translation inhibition and Cdk inactivation under stress. However, Whi8 also contributes to recruiting Cdc28 to SGs, where it acts to promote their dissolution. As predicted by a mutual-inhibition framework, the SG constitutes a bistable system that is modulated by Cdk. Since mammalian cells display a homologous mechanism, we propose that the opposing functions of specific mRNA-binding proteins and Cdk's subjugate SG dynamics to a conserved hysteretic switch.


Assuntos
Proteína Quinase CDC28 de Saccharomyces cerevisiae/metabolismo , Grânulos Citoplasmáticos/metabolismo , Saccharomyces cerevisiae/metabolismo , Estresse Fisiológico , Ciclo Celular , Ciclinas/metabolismo , Células HeLa , Humanos , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/metabolismo , Modelos Biológicos , Ligação Proteica , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
12.
Sci Signal ; 14(691)2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257105

RESUMO

Synaptic plasticity involves structural modifications in dendritic spines that are modulated by local protein synthesis and actin remodeling. Here, we investigated the molecular mechanisms that connect synaptic stimulation to these processes. We found that the phosphorylation of isoform-specific sites in eEF1A2-an essential translation elongation factor in neurons-is a key modulator of structural plasticity in dendritic spines. Expression of a nonphosphorylatable eEF1A2 mutant stimulated mRNA translation but reduced actin dynamics and spine density. By contrast, a phosphomimetic eEF1A2 mutant exhibited decreased association with F-actin and was inactive as a translation elongation factor. Activation of metabotropic glutamate receptor signaling triggered transient dissociation of eEF1A2 from its regulatory guanine exchange factor (GEF) protein in dendritic spines in a phosphorylation-dependent manner. We propose that eEF1A2 establishes a cross-talk mechanism that coordinates translation and actin dynamics during spine remodeling.


Assuntos
Actinas , Espinhas Dendríticas , Fator 1 de Elongação de Peptídeos/metabolismo , Biossíntese de Proteínas , Citoesqueleto de Actina , Actinas/genética , Plasticidade Neuronal , Neurônios
13.
Can J Diabetes ; 45(6): 504-511, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33341391

RESUMO

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by impaired glucose homeostasis, insulin resistance and hyperglycemia. Among its serious multisystemic complications is diabetic retinopathy (DR), which develops slowly and often insidiously. This disorder-the most common cause of vision loss in working-age adults-is characterized by functional and morphological changes in the retina. It results from the exacerbation of ischemic and inflammatory conditions prompted by alterations in the blood vessels, such as the development of leukostasis, thickening of the basement membrane, retinal neovascularization and fibrovascular tissue formation at the vitreoretinal interface. The pathogenic alterations are usually triggered at the biochemical level, involving a greater activity in 4 pathways: the polyol pathway, the hexosamine pathway, the formation of advanced glycation end-products and the activation of protein kinase C isoforms. When acting together, these pathways give rise to increased levels of reactive oxygen species and decreased levels of endogenous antioxidant agents, thus generating oxidative stress. All current therapies are aimed at the later stages of DR, and their application implies side effects. One possible strategy for preventing the complications of DM is to counteract the elevated superoxide production stemming from a high level of blood glucose. Accordingly, some treatments are under study for their capacity to reduce vascular leakage and avoid retinal ischemia, retinal neovascularization and macular edema. The present review summarizes the biochemical aspects of DR and the main approaches for treating it.


Assuntos
Retinopatia Diabética/metabolismo , Retinopatia Diabética/terapia , Fenômenos Bioquímicos , Humanos
14.
Med Chem ; 17(9): 1023-1045, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32998678

RESUMO

BACKGROUND: Anticonvulsants are drugs used in the treatment of seizures; their pharmacology includes promoters of brain inhibition and inhibitors of brain activity. Of the latter, voltagedependent sodium channel blockers (VGSCB) are the most widely used in therapeutics. OBJECTIVE: The study aimed at proposing the structural requirements of VGSC blockers through a quantitative structure-activity relationship analysis of drugs with proven activity. METHODS: IC50 values of anticonvulsant drugs on VGSCs were considered under similar experimental conditions; some physicochemical properties of the molecules that were correlated with their biological activity were determined in silico. RESULTS: Relationships were observed between the dipole moment, pKa, EHOMO, and MR with the biological activity, which infers that between greater polarity and basicity of the drugs, their activity as blockers will increase. Subsequently, the structural subclassification of the drugs was carried out, based on the urea derivation, the groups of which were: Group 1 (direct and bioisostere derivatives) and Group 2 (homologue and vinylogue derivatives of urea). CONCLUSION: The biological activity depends on the polarity, basicity, and electronic density of the drugs. The derivation of urea is essential, which is present in its original substituted form or a bioisosteric form. Urea can be in the form of a homologue or a vinylogue at the ends of the molecule. Aromatic substitution to the urea portion is necessary.


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Relação Quantitativa Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Epilepsia/metabolismo , Humanos , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismo
15.
Hum Exp Toxicol ; 40(12_suppl): S826-S850, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34610256

RESUMO

Inorganic arsenic (iAs) exposure is a serious health problem that affects more than 140 million individuals worldwide, mainly, through contaminated drinking water. Acute iAs poisoning produces several symptoms such as nausea, vomiting, abdominal pain, and severe diarrhea, whereas prolonged iAs exposure increased the risk of several malignant disorders such as lung, urinary tract, and skin tumors. Another sensitive endpoint less described of chronic iAs exposure are the non-malignant health effects in hepatic, endocrine, renal, neurological, hematological, immune, and cardiovascular systems. The present review outlines epidemiology evidence and possible molecular mechanisms associated with iAs-toxicity in several non-carcinogenic disorders.


Assuntos
Intoxicação por Arsênico/patologia , Arsênio/toxicidade , Água Potável/química , Poluentes Químicos da Água/toxicidade , Arsênio/química , Exposição Ambiental , Humanos , Poluentes Químicos da Água/química
16.
Plant J ; 59(3): 359-74, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19392689

RESUMO

The transcription factor ABA INSENSITIVE 4 (ABI4), discovered nearly 10 years ago, plays a central role in a variety of functions in plants, including sugar responses. However, not until very recently has its mechanism of action begun to be elucidated. Modulating gene expression is one of the primary mechanisms of sugar regulation in plants. Nevertheless, the transcription factors involved in regulating sugar responses and their role(s) during the signal transduction cascade remain poorly defined. In this paper we analyzed the participation of ABI4, as it is one of the main transcription factors implicated in glucose signaling during early seedling development. Our studies show that ABI4 is an essential activator of its own expression during development, in ABA signaling and in sugar responses. It is also important for the glucose-mediated expression of the genes ABI5 and SBE2.2. We demonstrate that ABI4 binds directly to the promoter region of all three genes and activates their expression in vivo through at CE1-like element. Previous studies found that ABI4 also functions as a transcriptional repressor of sugar-regulated genes, therefore this transcription factor is a versatile protein with dual functions for modulating gene expression.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores de Transcrição/metabolismo , Ácido Abscísico/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Sequência de Bases , Regulação da Expressão Gênica de Plantas , Glucose/metabolismo , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Ligação Proteica , RNA de Plantas/genética , Plântula/crescimento & desenvolvimento , Transdução de Sinais , Fatores de Transcrição/genética , Sítio de Iniciação de Transcrição
17.
J Ren Nutr ; 20(3): 158-68, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20097580

RESUMO

OBJECTIVE: The increase of reactive oxygen species (ROS) in diabetes potentiates the vascular effects of phenylephrine through nitric oxide (NO) impairment, facilitating the development of diabetic nephropathy. We propose that the combination of an antioxidant and L-arginine as diet supplements could prevent the increased vascular response to phenylephrine in diabetic animals. DESIGN: Changes in the adrenergic system play an important role in the development of vascular complications in the prediabetic condition. The vasoconstrictor effects of phenylephrine are regulated by NO, and the impairment of endothelium-dependent vasodilation in diabetes is associated with ROS. SETTING: Diabetes was induced with a low dose (55 mg/kg body weight) of streptozotocin in 7-week-old rats. Diabetic rats were fed with a diet supplement containing a combination of vitamin E, vitamin C, eicosapentaenoic acid, docosahexaenoic acid, and L-arginine, and the effects on phenylephrine-induced renal vascular responses were evaluated. RESULTS: Phenylephrine increased the renal perfusion pressure of isolated perfused kidneys from diabetic rats compared with nondiabetic rats. This effect was associated with reduced nitrite release as well as reduced plasma tetrahydrobiopterin and increased superoxide anions in the renal tissue. Diet supplementation with a combination of L-arginine and vitamins in diabetic rats partially prevented the generation of superoxide associated with recovery of the renal release of NO and decreased phenylephrine-induced vasoconstrictor effects, compared with untreated diabetic rats. However, the administration of L-arginine or vitamins alone did not affect phenylephrine-induced vasoconstriction. Vitamin treatment alone did decrease superoxide generation. CONCLUSION: The protective mechanism of NO on the vasoconstrictor effects of phenylephrine in the kidney is lost during the development of diabetes, probably via the actions of ROS through a decrease in tetrahydrobiopterin, thus contributing to the pathogenesis of diabetic nephropathy. Restoration of this protective NO mechanism can be achieved by simultaneously stimulating NO synthesis and preventing the effects of ROS through the use of L-arginine and a combination of vitamins E and C as diet supplementation.


Assuntos
Antioxidantes/administração & dosagem , Arginina/administração & dosagem , Diabetes Mellitus Experimental/fisiopatologia , Rim/irrigação sanguínea , Óxido Nítrico/fisiologia , Vasoconstritores/farmacologia , Animais , Ácido Ascórbico/administração & dosagem , Biopterinas/análogos & derivados , Biopterinas/sangue , Nefropatias Diabéticas/prevenção & controle , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Inibidores Enzimáticos/farmacologia , Rim/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/antagonistas & inibidores , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Vasoconstrição/efeitos dos fármacos , Vitamina E/administração & dosagem
18.
Food Funct ; 11(11): 10022-10032, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33135035

RESUMO

Consumer characteristics such as age, gender and ethnicity influence food oral processing behavior. The aim of this study was to determine the effect of age, gender and ethnicity on consumption time, bolus properties and dynamic sensory perception of sausages. Consumption time, bolus properties (saliva incorporation, particle size distribution and rheological properties) and dynamic texture perception (Temporal Dominance of Sensations, TDS) of sausages were compared between young Dutch, Caucasians (n = 21; 22 ± 2.8 years), young Chinese, Asians (n = 21; 23 ± 1.6 years), and elderly Dutch, Caucasians (n = 22; 70 ± 4.3 years). Elderly Dutch masticated the sausage 22% longer (25.6 s) than young Dutch consumers (21.0 s). Elderly Dutch produced sausage boli that were softer, more adhesive, less cohesive and contained more particles than those of young Dutch adults. Elderly females produced more adhesive and less cohesive sausage bolus than males. Young Chinese females had 75.6% longer consumption time (29.5 s) than young Dutch females (16.8 s). Young Chinese males masticated the sausages in less time (18.8 s) than young Chinese females (29.5 s). Young Chinese produced softer and less cohesive bolus with slightly smaller and more particles than young Dutch. Saliva incorporation and bolus particle size were not affected by age, gender and ethnicity. Mediation analysis revealed that the effect of consumer characteristics such as age, gender and ethnicity on bolus properties was mediated by consumption time. At the beginning and end of consumption time, dynamic texture perception of sausages was similar for all consumer groups and strongly correlated with bolus properties. Differences in dynamic texture perception between consumer groups were observed only during the middle stages of mastication with low dominance rates. We conclude that consumers differing in age, gender and ethnicity vary in oral processing time to produce bolus with textural properties optimized to their needs. Furthermore, consumption time is the underlying mechanism that explains the differences in bolus properties between the consumer groups. While variations in consumption time of sausages lead to considerable differences in bolus properties, it only leads to small differences in dynamic texture perception.


Assuntos
Produtos da Carne/análise , Boca/metabolismo , Percepção Gustatória , Adulto , Fatores Etários , Povo Asiático/psicologia , Comportamento do Consumidor , Feminino , Humanos , Masculino , Mastigação , Fatores Sexuais , População Branca/psicologia , Adulto Jovem
19.
Food Res Int ; 134: 109213, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32517909

RESUMO

Addition of particles to foods, such as fruit pieces to dairy products or vegetable pieces to soup, is a convenient approach to alter nutritional composition, appearance, perception and acceptance. The aim of this study was to investigate the effect of addition of peach gel particles to yogurt on oral behavior, sensory perception and liking of consumers differing in age. One homogeneous yogurt and seven yogurts with peach gel particles were prepared. The added peach gel particles varied in size, fracture stress, or concentration. Oral behavior of n = 62 healthy Dutch, young adults (21 ± 2 years) and n = 62 healthy Dutch elderly (70 ± 5 years) participants was characterized by video recordings. Yogurts' sensory properties and liking were scored on nine-point scales. Elderly consumed yogurts with higher number of chews and longer consumption time leading to lower eating rate than young adults. Addition of particles, regardless of characteristics, increased number of chews, consumption time, and decreased eating rate up to 60% for both consumer groups, with an average decrement of 110 g/min for young and of 63 g/min for elderly consumers. With increasing peach gel hardness and concentration, the number of chews and consumption time increased while eating rate decreased. Peach gel particle size did not affect oral behavior. Sensory perception of yogurts with added peach gel particles was similar for healthy young adult and healthy elderly. Only small differences in sensory perception were observed between the young adults and elderly for flavor attributes, crumbliness, juiciness, and perceived particle size. Similarly, minor differences in liking of a few yogurts with peach pieces were observed between both consumer groups. Thus, healthy ageing seems to affect sensory perception of semi-solid foods to a limited extent only. We conclude that changes in food texture by addition of particles can be used as a strategy to steer eating rate and potentially impact food intake of young adult and elderly consumers while maintaining or enhancing food palatability. Additionally, particle characteristics can be modified to target specific consumer groups that might differ in eating capabilities.


Assuntos
Comportamento do Consumidor , Preferências Alimentares , Géis , Prunus persica , Iogurte , Idoso , Comportamento Alimentar , Feminino , Humanos , Masculino , Sensação , Paladar , Adulto Jovem
20.
Plant J ; 54(4): 608-20, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18476867

RESUMO

Seeds represent the main source of nutrients for animals and humans, and knowledge of their biology provides tools for improving agricultural practices and managing genetic resources. There is also tremendous interest in using seeds as a sustainable alternative to fossil reserves for green chemistry. Seeds accumulate large amounts of storage compounds such as carbohydrates, proteins and oils. It would be useful for agro-industrial purposes to produce seeds that accumulate these storage compounds more specifically and at higher levels. The main metabolic pathways necessary for oil, starch or protein accumulation are well characterized. However, the overall regulation of partitioning between the various pathways remains unclear. Such knowledge could provide new molecular tools for improving the qualities of crop seeds (Focks and Benning, 1998, Plant Physiol. 118, 91). Studies to improve understanding of the genetic controls of seed development and metabolism therefore remain a key area of research. In the model plant Arabidopsis, genetic analyses have demonstrated that LEAFY COTYLEDON genes, namely LEC1, LEC2 and FUSCA3 (FUS3), are key transcriptional regulators of seed maturation, together with ABSCISIC ACID INSENSITIVE 3 (ABI3). Interestingly, LEC2, FUS3 and ABI3 are related proteins that all contain a 'B3' DNA-binding domain. In recent years, genetic and molecular studies have shed new light on the intricate regulatory network involving these regulators and their interactions with other factors such as LEC1, PICKLE, ABI5 or WRI1, as well as with sugar and hormonal signaling. Here, we summarize the most recent advances in our understanding of this complex regulatory network and its role in the control of seed maturation.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Redes Reguladoras de Genes , Sementes/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Modelos Biológicos , Sementes/crescimento & desenvolvimento , Sementes/metabolismo
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