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1.
Biochem Pharmacol ; 215: 115754, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37597814

RESUMO

Bitter taste receptors (TAS2R) are found in numerous extra-oral tissues, including smooth muscle (SM) cells in both vascular and visceral tissues. Upon activation, TAS2R stimulate the relaxation of the SM. Nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway is involved in penile erection, and type 5 phosphodiesterase (PDE5) inhibitors, a cGMP-specific hydrolase are used as first-line treatments for erectile dysfunction (ED). Nevertheless, PDE5 inhibitors are ineffective in a considerable number of patients, prompting research into alternative pharmacological targets for ED. Since TAS2R agonists regulate SM contractility, this study investigates the role of TAS2Rs in rat corpus cavernosum (CC). We performed immunohistochemistry to detect TAS2R10, isometric force recordings for TAS2R agonists denatonium and chloroquine, the slow-release H2S donor GYY 4137, the NO donor SNAP, the ß-adrenoceptor agonist isoproterenol and electrical field stimulation (EFS), as well as measurement of endogenous hydrogen sulfide (H2S) production. The immunofluorescence staining indicated that TAS2R10 was broadly expressed in the CC SM and to some extent in the nerve fibers. Denatonium, chloroquine, SNAP, and isoproterenol cause potent dose-dependent SM relaxations. H2S production was decreased by NO and H2S synthase inhibitors, while it was enhanced by denatonium. In addition, denatonium increased the relaxations induced by GYY 4137 and SNAP but failed to modify EFS- and isoproterenol-induced responses. These results suggest neuronal and SM TAS2R10 expression in the rat CC, where denatonium induces a strong SM relaxation per se and promotes the H2S- and NO-mediated inhibitory gaseous neurotransmission. Thus, TAS2R10 might represent a valuable therapeutic target in ED.


Assuntos
Cloroquina , Paladar , Masculino , Animais , Ratos , Isoproterenol , GMP Cíclico
2.
Life Sci ; 296: 120432, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35219697

RESUMO

AIMS: Nitric oxide (NO) and hydrogen sulfide (H2S) are involved in nerve-mediated corpus cavernosum (CC) relaxation. Expression of phosphodiesterase type 5 (PDE5) and type 4 (PDE4), cyclic guanosine monophosphate (cGMP)- and cyclic adenosine monophosphate (cAMP)-specific, respectively, has been described and PDE5- and PDE4-inhibitors induce cavernous smooth muscle relaxation. Whereas the NO/cGMP signaling pathway is well established in penile erection, the cAMP-mediated mechanism is not fully elucidated. The aim of this study is to investigate the localization and the functional significance of PDE4 in rat CC tone regulation. MAIN METHODS: We performed immunohistochemistry for the detection of the PDE4A isoenzyme. Isometric tension recordings for roflumilast and tadalafil, PDE4 and PDE5 inhibitors, respectively, electrical field stimulation (EFS) and ß-adrenoceptor agonist isoproterenol and endogenous H2S production measurement. KEY FINDINGS: A marked PDE4A expression was detected mainly localized in the nerve cells of the cavernous smooth muscle. Furthermore, roflumilast and tadalafil exhibited strong corpus cavernous relaxations. Endogenous H2S production was decreased by NO and H2S synthase inhibitors and increased by roflumilast. Isoproterenol- and EFS-induced relaxations were increased by roflumilast. SIGNIFICANCE: These results indicate that PDE4A is mainly expressed within the nerves cells of the rat CC, where roflumilast induces a potent corpus cavernous relaxation per se and potentiates the response induced by ß-adrenoceptor activation. The fact that roflumilast enhances H2S production, as well as EFS-elicited responses suggests that PDE4 inhibitors modulate, in a positive feedback fashion, nerve-mediated relaxation induced by gasotransmitters, thus indicating a key role for neuronal PDE4 in penile erection.


Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Gasotransmissores/metabolismo , Pênis/fisiologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Aminopiridinas/administração & dosagem , Animais , Benzamidas/administração & dosagem , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacologia , Relação Dose-Resposta a Droga , Sulfeto de Hidrogênio/metabolismo , Masculino , Relaxamento Muscular/efeitos dos fármacos , Nitroarginina/farmacologia , Pênis/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiologia , Ratos Wistar , Tadalafila/farmacologia
3.
Eur J Pharmacol ; 895: 173875, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33460612

RESUMO

Given that neuronal degeneration in Alzheimer's disease (AD) is caused by the combination of multiple neurotoxic insults, current directions in the research of novel therapies to treat this disease attempts to design multitarget strategies that could be more effective than the simply use of acetylcholinesterase inhibitors; currently, the most used therapy for AD. One option, explored recently, is the synthesis of new analogues of cannabinoids that could competitively inhibit the acetylcholinesterase (AChE) enzyme and showing the classic neuroprotective profile of cannabinoid compounds. In this work, molecular docking has been used to design some cannabinoid analogues with such multitarget properties, based on the similarities of donepezil and Δ9-tetrahydrocannabinol. The analogues synthesized, compounds 1 and 2, demonstrated to have two interesting characteristics in different in vitro assays: competitive inhibition of AChE and competitive antagonism at the CB1/CB2 receptors. They are highly lipophilic, highlighting that they could easily reach the CNS, and apparently presented a low toxicity. These results open the door to the synthesis of new compounds for a more effective treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Sítios de Ligação , Encéfalo/enzimologia , Encéfalo/patologia , Antagonistas de Receptores de Canabinoides/síntese química , Canabinoides/síntese química , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Desenho Assistido por Computador , Desenho de Fármacos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Humanos , Neurônios/enzimologia , Neurônios/patologia , Fármacos Neuroprotetores/química , Ligação Proteica , Conformação Proteica , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade
4.
Oxid Med Cell Longev ; 2019: 5641645, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531184

RESUMO

PURPOSE: This study investigates whether functionality and/or expression changes of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) channels, oxidative stress, and hydrogen sulfide (H2S) are involved in the bladder dysfunction from an insulin-resistant obese Zucker rat (OZR). MATERIALS AND METHODS: Detrusor smooth muscle (DSM) samples from the OZR and their respective controls, a lean Zucker rat (LZR), were processed for immunohistochemistry for studying the expression of TRPA1 and TRPV1 and the H2S synthase cystathionine beta-synthase (CBS) and cysthathionine-γ-lyase (CSE). Isometric force recordings to assess the effects of TRPA1 agonists and antagonists on DSM contractility and measurement of oxidative stress and H2S production were also performed. RESULTS: Neuronal TRPA1 expression was increased in the OZR bladder. Electrical field stimulation- (EFS-) elicited contraction was reduced in the OZR bladder. In both LZR and OZR, TRPA1 activation failed to modify DSM basal tension but enhanced EFS contraction; this response is inhibited by the TRPA1 blockade. In the OZR bladder, reactive oxygen species, malondialdehyde, and protein carbonyl contents were increased and antioxidant enzyme activities (superoxide dismutase, catalase, GR, and GPx) were diminished. CSE expression and CSE-generated H2S production were also reduced in the OZR. Both TRPV1 and CBS expressions were not changed in the OZR. CONCLUSIONS: These results suggest that an increased expression and functionality of TRPA1, an augmented oxidative stress, and a downregulation of the CSE/H2S pathway are involved in the impairment of nerve-evoked DSM contraction from the OZR.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Resistência à Insulina , Obesidade , Estresse Oxidativo , Canal de Cátion TRPA1/metabolismo , Doenças da Bexiga Urinária , Bexiga Urinária , Animais , Cistationina beta-Sintase , Cistationina gama-Liase , Masculino , Contração Muscular , Músculo Liso , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia , Ratos , Ratos Zucker , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Doenças da Bexiga Urinária/metabolismo , Doenças da Bexiga Urinária/patologia , Doenças da Bexiga Urinária/fisiopatologia
5.
Sci Rep ; 8(1): 4711, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29549279

RESUMO

Nitric oxide (NO) and hydrogen sulfide (H2S) play a pivotal role in nerve-mediated relaxation of the bladder outflow region. In the bladder neck, a marked phosphodiesterase type 4 (PDE4) expression has also been described and PDE4 inhibitors, as rolipram, produce smooth muscle relaxation. This study investigates the role of PDE4 isoenzyme in bladder neck gaseous inhibitory neurotransmission. We used Western blot and double immunohistochemical staining for the detection of NPP4 (PDE4) and PDE4A and organ baths for isometric force recording to roflumilast and tadalafil, PDE4 and PDE5, respectively, inhibitors in pig and human samples. Endogenous H2S production measurement and electrical field stimulation (EFS) were also performed. A rich PDE4 and PDE4A expression was observed mainly limited to nerve fibers of the smooth muscle layer of both species. Moreover, roflumilast produced a much more potent smooth muscle relaxation than that induced by tadalafil. In porcine samples, H2S generation was diminished by H2S and NO synthase inhibition and augmented by roflumilast. Relaxations elicited by EFS were potentiated by roflumilast. These results suggest that PDE4, mainly PDE4A, is mostly located within nerve fibers of the pig and human bladder neck, where roflumilast produces a powerful smooth muscle relaxation. In pig, the fact that roflumilast increases endogenous H2S production and EFS-induced relaxations suggests a modulation of PDE4 on NO- and H2S-mediated inhibitory neurotransmission.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Sulfeto de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Bexiga Urinária/metabolismo , Adulto , Idoso , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Rolipram/farmacologia , Suínos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia
6.
Pulm Pharmacol Ther ; 41: 1-10, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27603231

RESUMO

Hydrogen sulfide (H2S) is a gasotransmitter employed for intra- and inter-cellular communication in almost all organ systems. This study investigates the role of endogenous H2S in nerve-evoked relaxation of pig terminal bronchioles with 260 µm medium internal lumen diameter. High expression of the H2S synthesis enzyme cystathionine γ-lyase (CSE) in the bronchiolar muscle layer and strong CSE-immunoreactivity within nerve fibers distributed along smooth muscle bundles were observed. Further, endogenous H2S generated in bronchiolar membranes was reduced by CSE inhibition. In contrast, cystathionine ß-synthase expression, another H2S synthesis enzyme, however was not consistently detected in the bronchiolar smooth muscle layer. Electrical field stimulation (EFS) and the H2S donor P-(4-methoxyphenyl)-P-4-morpholinylphosphinodithioic acid (GYY4137) evoked smooth muscle relaxation. Inhibition of CSE, nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and of ATP-dependent K+, transient receptor potential A1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) channels reduced the EFS relaxation but failed to modify the GYY4137 response. Raising extracellular K+ concentration inhibited the GYY4137 relaxation. Large conductance Ca2+-activated K+ channel blockade reduced both EFS and GYY4137 responses. GYY4137 inhibited the contractions induced by histamine and reduced to a lesser extent the histamine-induced increases in intracellular [Ca2+]. These results suggest that relaxation induced by EFS in the pig terminal bronchioles partly involves the H2S/CSE pathway. H2S response is produced via NO/sGC-independent mechanisms involving K+ channels and intracellular Ca2+ desensitization-dependent pathways. Thus, based on our current results H2S donors might be useful as bronchodilator agents for the treatment of lung diseases with persistent airflow limitation, such as asthma and chronic obstructive lung disease.


Assuntos
Bronquíolos/metabolismo , Cistationina gama-Liase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Feminino , Histamina/metabolismo , Masculino , Morfolinas/farmacologia , Relaxamento Muscular/fisiologia , Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Compostos Organotiofosforados/farmacologia , Canais de Potássio/metabolismo , Suínos
7.
PLoS One ; 11(6): e0157424, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27285468

RESUMO

Metabolic syndrome (MS) is a known risk factor for lower urinary tract symptoms. This study investigates whether functional and expression changes of cannabinoid CB1 and CB2 receptors are involved in the bladder dysfunction in an obese rat model with insulin resistance. Bladder samples from obese Zucker rat (OZR) and their respective controls lean Zucker rat (LZR) were processed for immunohistochemistry and western blot for studying the cannabinoid receptors expression. Detrusor smooth muscle (DSM) strips from LZR and OZR were also mounted in myographs for isometric force recordings. Neuronal and smooth muscle CB1 and CB2 receptor expression and the nerve fiber density was diminished in the OZR bladder. Electrical field stimulation (EFS) and acetylcholine (ACh) induced frequency- and concentration-dependent contractions of LZR and OZR DSM. ACh contractile responses were similar in LZR and OZR. EFS-elicited contractions, however, were reduced in OZR bladder. Cannabinoid receptor agonists and antagonists failed to modify the DSM basal tension in LZR and OZR In LZR bladder, EFS responses were inhibited by ACEA and SER-601, CB1 and CB2 receptor agonists, respectively, these effects being reversed by ACEA plus the CB1 antagonist, AM-251 or SER-601 plus the CB2 antagonist, AM-630. In OZR bladder, the inhibitory action of ACEA on nerve-evoked contractions was diminished, whereas that SER-601 did not change EFS responses. These results suggest that a diminished function and expression of neuronal cannabinoid CB1 and CB2 receptors, as well as a lower nerve fiber density is involved in the impaired excitatory neurotransmission of the urinary bladder from the OZR.


Assuntos
Obesidade/fisiopatologia , Receptor CB1 de Canabinoide/análise , Receptor CB2 de Canabinoide/análise , Transmissão Sináptica , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Animais , Masculino , Contração Muscular , Músculo Liso/inervação , Músculo Liso/patologia , Músculo Liso/fisiopatologia , Fibras Nervosas/patologia , Obesidade/patologia , Ratos , Ratos Zucker , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Bexiga Urinária/patologia
8.
Curr Neuropharmacol ; 12(1): 2-36, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24533013

RESUMO

The lack of an adequate therapy for Alzheimer's Disease (AD) contributes greatly to the continuous growing amount of papers and reviews, reflecting the important efforts made by scientists in this field. It is well known that AD is the most common cause of dementia, and up-to-date there is no prevention therapy and no cure for the disease, which contrasts with the enormous efforts put on the task. On the other hand many aspects of AD are currently debated or even unknown. This review offers a view of the current state of knowledge about AD which includes more relevant findings and processes that take part in the disease; it also shows more relevant past, present and future research on therapeutic drugs taking into account the new paradigm "Multi-Target-Directed Ligands" (MTDLs). In our opinion, this paradigm will lead from now on the research toward the discovery of better therapeutic solutions, not only in the case of AD but also in other complex diseases. This review highlights the strategies followed by now, and focuses other emerging targets that should be taken into account for the future development of new MTDLs. Thus, the path followed in this review goes from the pathology and the processes involved in AD to the strategies to consider in on-going and future researches.

9.
Br J Nutr ; 110(2): 206-15, 2013 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-23186731

RESUMO

Numerous lines of evidence support a relationship between intestinal inflammation and cancer. Therefore, much attention has recently been focused on the identification of natural compounds with anti-inflammatory activities as a strategy to suppress the early stages of colorectal cancer. Because cocoa is a rich source of bioactive compounds, the present study investigated its anti-inflammatory properties in a rat model of azoxymethane (AOM)-induced colon carcinogenesis and in TNF-α-stimulated Caco-2 cells. A total of forty male rats were fed with control or cocoa-enriched diets (12 %) during 8 weeks and injected with saline or AOM (20 mg/kg body weight) during the third and fourth week (n 10 rats/group). At the end of the experiment, colon samples were evaluated for markers of inflammation. The anti-inflammatory activity of a cocoa polyphenolic extract (10 µg/ml) was examined in TNF-α-stimulated Caco-2 cells, an in vitro model of experimentally induced intestinal inflammation. The signalling pathways involved, including NF-κB and the mitogen-activated protein kinase family such as c-Jun NH2-terminal kinases (JNK), extracellular signal-regulated kinases and p38, were also evaluated. The results show that the cocoa-rich diet decreases the nuclear levels of NF-κB and the expression of pro-inflammatory enzymes such as cyclo-oxygenase-2 and inducible NO synthase induced by AOM in the colon. Additionally, the experiments in Caco-2 cells confirm that cocoa polyphenols effectively down-regulate the levels of inflammatory markers induced by TNF-α by inhibiting NF-κB translocation and JNK phosphorylation. We conclude that cocoa polyphenols suppress inflammation-related colon carcinogenesis and could be promising in the dietary prevention of intestinal inflammation and related cancer development.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cacau/química , Colo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Fitoterapia , Polifenóis/uso terapêutico , Fator de Necrose Tumoral alfa/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Azoximetano , Biomarcadores/metabolismo , Colo/metabolismo , Dieta , Regulação para Baixo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , MAP Quinase Quinase 4/metabolismo , Masculino , NF-kappa B/metabolismo , Neoplasias/prevenção & controle , Fosforilação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polifenóis/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
10.
J Food Sci ; 77(2): H59-62, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22224928

RESUMO

UNLABELLED: The digesta is a highly active biological system where epithelial cells, microbiota, nondigestible dietary components, and a large number of metabolic products interact. The gut microbiota can be modulated by both endogenous and exogenous substrates. Undigested dietary residues are substrates for colonic microbiota and may influence gut microbial ecology. The objective of this work was to study the capacity of grape antioxidant dietary fiber (GADF), which is rich in polyphenols, to modify the bacterial profile in the cecum of rats. Male adult Wistar rats were fed for 4 wk with diets containing either cellulose or GADF as dietary fiber. The effect of GADF on bacterial growth was evaluated in vitro and on the cecal microbiota of rats using quantitative real time polymerase chain reaction (RT-PCR). The results showed that GADF intake stimulates proliferation of Lactobacillus and slightly affects the composition of Bifidobacterium species. GADF was also found to have a stimulative effect on Lactobacillus reuteri and Lactobacillus acidophilus in vitro. These findings suggest that the consumption of a diet rich in plant foods with high dietary fiber and polyphenol content may enhance the gastrointestinal health of the host through microbiota modulation. PRACTICAL APPLICATION: Grape antioxidant fiber combines nutritional and physiological properties of dietary fiber and natural antioxidants from grapes. Grape antioxidant fiber could be used as an ingredient for functional foods and as a dietary supplement to increase the intake of dietary fiber and bioactive compounds.


Assuntos
Antioxidantes/farmacologia , Ceco/microbiologia , Fibras na Dieta/administração & dosagem , Suplementos Nutricionais , Lactobacillus/efeitos dos fármacos , Vitis/química , Animais , Bifidobacterium/crescimento & desenvolvimento , Ceco/efeitos dos fármacos , Dieta , Lactobacillus/crescimento & desenvolvimento , Masculino , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real/métodos
11.
Mol Nutr Food Res ; 55(12): 1895-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21953728

RESUMO

Cocoa is a rich source of bioactive compounds with potential chemopreventive ability but up to date its effectiveness in animal models of colon carcinogenesis has not been addressed. Herein, we investigated the in vivo effect of a cocoa-rich diet in the prevention of azoxymethane (AOM)-induced colon cancer and the mechanisms involved. Our results showed that cocoa feeding significantly reduced AOM-induced colonic aberrant crypt foci formation and crypt multiplicity. Oxidative imbalance in colon tissues seems to be prevented by cocoa as indicated by reduced oxidation markers levels and increased enzymatic and non-enzymatic endogenous defences. Cocoa-rich diet also exhibited antiproliferative effects by decreasing the levels of extracellular regulated kinases, protein kinase B and cyclin D1 together with pro-apoptotic effects evidenced by reduced Bcl-x(L) levels and increased Bax levels and caspase-3 activity. Our findings provide the first in vivo evidence that a cocoa-rich diet may inhibit the early stage of colon carcinogenesis probably by preventing oxidative stress and cell proliferation and by inducing apoptosis.


Assuntos
Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Cacau/química , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Animais , Azoximetano/toxicidade , Caspase 3/genética , Caspase 3/metabolismo , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Ciclina D1/genética , Ciclina D1/metabolismo , Dieta , Regulação da Expressão Gênica , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/prevenção & controle , Ratos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
12.
Br J Nutr ; 103(8): 1110-7, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19930767

RESUMO

Grape antioxidant dietary fibre (GADF) is a grape product rich in dietary fibre and natural antioxidants. We showed previously that the GADF intake induced an epithelial hypoplasia in the rat colonic mucosa. In the present study, we propose that the antioxidant effect of GADF could modulate mucosal apoptosis via modulation of the cellular redox environment. Male Wistar rats (n 20) were fed with diets containing either cellulose (control diet group) or GADF (GADF diet group) as fibre for 4 weeks. The GSH:GSSG ratio, the redox state of the GSSG/2GSH couple (Ehc), the mitochondrial and/or cytosolic antioxidant enzyme activities (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)), lipid peroxidation (LPO) and apoptosis were evaluated. GADF enhanced the cytosolic GSH:GSSG ratio, shifting the redox potential (Ehc) to a more pro-reducing status. Decreased Cu,ZnSOD:CAT, Cu,ZnSOD:GPx and MnSOD:GPx ratios could indicate an enhanced capacity for reducing H2O2, contributing to decreased cytosolic LPO. Reduced apoptosis in GADF-treated mucosa was inversely related to MnSOD activity. Furthermore, apoptosis increased directly as GSSG content increased. These results suggest that the reduction in apoptosis associated with GADF intake may be due to a modulation of the glutathione redox system and endogenous antioxidant enzymes.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Colo/fisiologia , Fibras na Dieta/farmacologia , Glutationa/metabolismo , Mucosa Intestinal/fisiologia , Vitis , Animais , Catalase/metabolismo , Colo/efeitos dos fármacos , Dissulfeto de Glutationa/farmacologia , Glutationa Peroxidase/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Oxirredução , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
13.
Br J Nutr ; 101(4): 518-26, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18590589

RESUMO

The effect of growth hormone (GH) on arylesterase (AE), one of the activities of paraoxonase, has never been studied. The aims of the present study in mice were: (a) to compare the effect of age and sex on serum lipid and lipoprotein levels after consumption of lactalbumin- v. chow-based diets and (b) to study the effect of GH administration, age and sex on serum AE activity, lipid and lipoprotein and body fat levels in mice fed a lactalbumin diet. Seventy-two mice were divided into three age- and sex-matched experimental groups: (1) control chow (CC), (2) non-GH lactalbumin (NGL) and (3) GH-treated lactalbumin (GL) mice. Lactalbumin increased total cholesterol, (LDL+VLDL)-cholesterol and TAG and diminished HDL-cholesterol in all animals (P<0.05). In comparison with their NGL counterparts, old GL males presented lower total cholesterol (15%) and (LDL+VLDL)-cholesterol (17%) levels (P<0.05), whereas values of the same parameters were higher in adult GL males (P<0.05) (22 and 23%, respectively). Adult GL females displayed higher serum HDL-cholesterol concentrations (26%) (P<0.05) than adult NGL females. AE activity was lower in old GL females (78%) and old GL males (20%) (P<0.05), but higher in adult GL males (100%) (P<0.01). GH, that was inversely related to food intake, decreased abdominal and gonadal fat in all mice (P<0.05). To conclude, lactalbumin induced an atherogenic lipoprotein profile in NGL mice that was reverted by GH, preferentially in old males, suggesting that GH therapy will be more effective in aged men. The present results suggest that AE activity was age-, sex- and body fat level-dependent and that it diminished as a consequence of improved antioxidant status.


Assuntos
Aterosclerose/tratamento farmacológico , Hidrolases de Éster Carboxílico/sangue , Hormônio do Crescimento/uso terapêutico , Lipoproteínas/sangue , Adiposidade , Fatores Etários , Animais , Aterosclerose/sangue , Biomarcadores/sangue , Composição Corporal , Colesterol/sangue , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Feminino , Lactalbumina , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Fatores Sexuais , Triglicerídeos/sangue
15.
An. R. Acad. Farm ; 70(3): 695-725, jul. 2004.
Artigo em Es | IBECS | ID: ibc-36133

RESUMO

El eje GH-IGF-I es el regulador fundamental del crecimiento postnatal y el determinante del tamaño corporal. El tratamiento con GH aumenta la masa muscular y disminuye el depósito graso, modificando la redistribución de los depósitos corporales. Por su capacidad de aumentar la síntesis y de disminuir el catabolismo proteico genera un balance nitrogenado positivo, bien actuando directamente a nivel tisular o mediante la acción endocrina, paracrina o autocrina del factor IGF-I. De forma paralela, la hormona somatotropa incrementa la hidrólisis de los triglicéridos y disminuye la lipogénesis. Esta respuesta metabólica a la GH exógena varía con diversos factores, entre los que destacan el nivel nutritivo y la etapa de crecimiento del animal. Se conoce por una parte, que la acción somatotropa requiere de un aporte suficiente de nutrientes en la dieta y por otra, que sus efectos son mínimos entre la segunda y tercera semana de crecimiento postnatal, aumentando su eficacia entre los 31 días de vida y la pubertad. Aunque no se conoce la causa de esta refractoriedad al tratamiento con GH en estas primeras etapas de la vida, podría estar relacionada con la respuesta bifásica a la GH, desarrollada en ratones BALB/c machos rhGH-tratados entre los 21 y 50 días de vida y alimentados con dos concentraciones de proteína en la dieta (12 y 20 por ciento). La hipofagia GH-inducida entre los 21 y 30 días de vida es la causa primordial del estado de subnutrición que aparece en estos animales y que da lugar a la detención del crecimiento por falta de sustratos, eliminando la acción anabólica de la hormona. Posteriormente, el incremento autorregulado de la ingesta favorece la recuperación del crecimiento entre los 35 y 50 días de vida, periodo en el que se desarrolla un crecimiento de carácter compensador, caracterizado por un acúmulo excesivo de la masa grasa, similar al determinado por el crecimiento que sigue a la realimentación después de malnutrición, lo que puede coexistir con un estado de resistencia del tejido adiposo a la GH. Sin embargo el efecto anabólico de la somatotropa parece manifestarse, en los animales bien nutridos, por un mayor depósito de la proteína muscular al incrementar la tasa fraccional de síntesis proteica, que permite la aparición de un fenómeno de hipertrofia compensadora. Por lo tanto, la administración de rhGH en el momento del destete parece interferir con los delicados mecanismos de adaptación a la alimentación sólida característicos de este periodo, e inducir el cese del crecimiento entre los 21 y 30 días, generando más tarde un crecimiento de carácter compensador que se inicia a partir de los 35 días de vida (AU)


Assuntos
Animais , Humanos , Desmame , Estado Nutricional , Receptor IGF Tipo 1 , Hormônio do Crescimento/farmacocinética , Proteínas Alimentares/metabolismo , Crescimento/fisiologia , Transtornos do Crescimento/metabolismo , Músculo Esquelético
16.
Neurosci Lett ; 331(3): 167-70, 2002 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-12383923

RESUMO

Chronic treatment, of SH-SY5Y cells, with KCl (20 mM) for 4 days decreased 100 mM KCl-evoked noradrenaline (NA) release by 50% and nicotine (100 microM)-evoked NA release by 55%. Pretreatment with the L-type calcium channel antagonist, nifedipine, prevented this inhibitory effect of chronic exposure to 20 mM KCl on NA release. In contrast pretreatment with 10 microM nicotine for 4 days had no effect on 100 mM KCl -evoked secretion and decreased nicotinic -evoked NA release by only 25%. Inclusion of nifedipine prevented the inhibition of NA release by chronic nicotine treatment. These data are discussed in relation to effects of chronic moderate, depolarisation by either K(+) or nicotine on influx of Ca(2+) via L-type voltage sensitive calcium channels.


Assuntos
Estimulantes Ganglionares/farmacologia , Nicotina/farmacologia , Norepinefrina/biossíntese , Cloreto de Potássio/farmacologia , Humanos , Potenciais da Membrana/efeitos dos fármacos , Neuroblastoma/metabolismo , Fatores de Tempo , Células Tumorais Cultivadas , Veratridina/farmacologia
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