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1.
Endocrinology ; 165(5)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38368624

RESUMO

Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.


Assuntos
Comportamento Alimentar , Hipotálamo , Neurônios , Neuropeptídeo Y , Ratos Sprague-Dawley , Animais , Feminino , Masculino , Ratos , Desoxiglucose/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Glucose/metabolismo , Região Hipotalâmica Lateral/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Melaninas/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , Neuropeptídeo Y/farmacologia , Neuropeptídeos/metabolismo , Orexinas/metabolismo , Hormônios Hipofisários/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/genética , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Saporinas/farmacologia
2.
Mol Pharm ; 17(2): 683-694, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31913047

RESUMO

Plant-based saponins are amphipathic glycosides composed of a hydrophobic aglycone backbone covalently bound to one or more hydrophilic sugar moieties. Recently, the endosomal escape activity of triterpenoid saponins has been investigated as a potentially powerful tool for improved cytosolic penetration of protein drugs internalized by endocytic uptake, thereby greatly enhancing their pharmacological effects. However, only a few saponins have been studied, and the paucity in understanding the structure-activity relationship of saponins imposes significant limitations on their applications. To address this knowledge gap, 12 triterpenoid saponins with diverse structural side chains were screened for their utility as endosomolytic agents. These compounds were used in combination with a toxin (MAP30-HBP) comprising a type I ribosome-inactivating protein fused to a cell-penetrating peptide. Suitability of saponins as endosomolytic agents was assessed on the basis of cytotoxicity, endosomal escape promotion, and synergistic effects on toxins. Five saponins showed strong endosomal escape activity, enhancing MAP30-HBP cytotoxicity by more than 106 to 109 folds. These saponins also enhanced the apoptotic effect of MAP30-HBP in a pH-dependent manner. Additionally, growth inhibition of MAP30-HBP-treated SMMC-7721 cells was greater than that of similarly treated HeLa cells, suggesting that saponin-mediated endosomolytic effect is likely to be cell-specific. Furthermore, the structural features and hydrophobicity of the sugar side chains were analyzed to draw correlations with endosomal escape activity and derive predictive rules, thus providing new insights into structure-activity relationships of saponins. This study revealed new saponins that can potentially be exploited as efficient cytosolic delivery reagents for improved therapeutic drug effects.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Endossomos/efeitos dos fármacos , Saponinas/química , Saponinas/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Glicosilação , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteínas Inativadoras de Ribossomos Tipo 1/química , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Relação Estrutura-Atividade
3.
Antiviral Res ; 164: 123-130, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30817940

RESUMO

Since it was discovered as the first human tumor virus in 1964, Epstein-Barr Virus (EBV) is now implicated in several types of malignancies. Accordingly, certain aspects of EBV pathobiology have shown promise in anti-cancer research in developing virus-targeting methods for EBV-associated cancers. The unique role of EBV nuclear antigen 1 (EBNA1) in triggering episome-dependent functions has made it as the only latent gene to be expressed in most EBV+ neoplasms. Dimeric EBNA1 binds to the replication origin (oriP) to display its biological impact on EBV-driven cell transformation and maintenance. Hence, EBNA1/oriP has been made an ideal drug target site for anti-EBV protocol development. GAP31 protein was originally isolated from the seeds of an ancient medicinal plant Gelonium multiflorum. Although GAP31 has been shown to exhibit both anti-viral and anti-tumor activity, current understanding of the mechanistic picture underlying GAP31 functioning is not clear. Herein, we identify the EBNA1 DNA-binding domain as a core for GAP31 binding by performing affinity pulldown assays. Recombinant GAP31 (rGAP31) was shown to impair EBNA1-induced dimerization; consequently, it abrogated both EBNA1/oriP-mediated binding and transcription. Importantly, the therapeutic effects of GAP31 showed its capability to abrogate EBV-driven cell transformation and proliferation, and EBV-dependent tumorigenesis in xenograft animal models. Notably, the EBNA1 binding-mutant rGAP31R166A/R169A simply exhibits defective phenotypes in the above-mentioned studies. Our data suggest rGAP31 is a potential anti-viral drug which can be applied to the development of therapeutic strategies against EBV-related malignancies.


Assuntos
Antivirais/farmacologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Replicação do DNA , Feminino , Camundongos Endogâmicos NOD , Camundongos SCID , Plantas Medicinais/química , Origem de Replicação , Replicação Viral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Exp Clin Cancer Res ; 36(1): 187, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258566

RESUMO

BACKGROUND: Development of resistance to 5-fluorouracil (5-FU) is a major problem in treatment of various cancers including pancreatic cancer. In this study, we reveal important resistance mechanisms and photochemical strategies to overcome 5-FU resistance in pancreatic adenocarcinoma. METHODS: 5-FU resistant (5-FUR), epithelial-to-mesenchymal-like sub-clones of the wild type pancreatic cancer cell line Panc03.27 were previously generated in our lab. We investigated the cytotoxic effect of the endosomal/lysosomal-localizing photosensitizer TPCS2a (fimaporfin) combined with light (photochemical treatment, PCT) using MTS viability assay, and used fluorescence microscopy to show localization of TPCS2a and to investigate the effect of photodamage of lysosomes. Flow cytometric analysis was performed to investigate uptake of photosensitizer and to assess intracellular ROS levels. Expression and localization of LAMP1 was assessed using RT-qPCR, western blotting, and structured illumination microscopy. MTS viability assay was used to assess the effect of combinations of 5-FU, chloroquine (CQ), and photochemical treatment. Expression of CD105 was investigated using RT-qPCR, western blotting, flow cytometry, and fluorescence microscopy, and co-localization of TPCS2a and anti-CD105-saporin was assessed using microscopy. Lastly, the MTS assay was used to investigate cytotoxic effects of photochemical internalization (PCI) of the anti-CD105-immunotoxin. RESULTS: The 5-FUR cell lines display hypersensitivity to PCT, which was linked to increased uptake of TPCS2a, altered lysosomal distribution, lysosomal photodamage and increased expression of the lysosomal marker LAMP-1 in the 5-FUR cells. We show that inhibition of autophagy induced by either chloroquine or lysosomal photodamage increases the sensitivity to 5-FU in the resistant cells. The three 5-FUR sub-clones overexpress Endoglin (CD105). Treatment with the immunotoxin anti-CD105-saporin alone significantly reduced the viability of the CD105-expressing 5-FUR cells, whereas little effect was seen in the CD105-negative non-resistant parental cancer cell lines. Strikingly, using the intracellular drug delivery method photochemical internalization (PCI) by combining light-controlled activation of the TPCS2a with nanomolar levels of CD105-saporin resulted in strong cytotoxic effects in the 5-FUR cell population. CONCLUSION: Our findings suggested that autophagy is an important resistance mechanism against the chemotherapeutic drug 5-FU in pancreatic cancer cells, and that inhibition of the autophagy process, either by CQ or lysosomal photodamage, can contribute to increased sensitivity to 5-FU. For the first time, we demonstrate the promise of PCI-based targeting of CD105 in site-specific elimination of 5-FU resistant pancreatic cancer cells in vitro. In conclusion, PCI-based targeting of CD105 may represent a potent anticancer strategy and should be further evaluated in pre-clinical models.


Assuntos
Adenocarcinoma/patologia , Imunotoxinas/farmacologia , Neoplasias Pancreáticas/patologia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Antineoplásicos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endoglina/antagonistas & inibidores , Transição Epitelial-Mesenquimal , Fluoruracila , Humanos , Fototerapia/métodos , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Saporinas
5.
Neurosci Lett ; 655: 82-89, 2017 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-28689926

RESUMO

The facet joint is a common source of neck pain, particularly after excessive stretch of its capsular ligament. Peptidergic afferents have been shown to have an important role in the development and maintenance of mechanical hyperalgesia, dysregulated nociceptive signaling, and spinal hyperexcitability that develop after mechanical injury to the facet joint. However, the role of non-peptidergic isolectin-B4 (IB4) cells in mediating joint pain is unknown. Isolectin-B4 saporin (IB4-SAP) was injected into the facet joint to ablate non-peptidergic cells, and the facet joint later underwent a ligament stretch known to induce pain. Behavioral sensitivity, thalamic glutamate transporter expression, and thalamic hyperexcitability were evaluated up to and at day 7. Administering IB4-SAP prior to a painful injury prevented the development of mechanical hyperalgesia that is typically present. Intra-articular IB4-SAP also prevented the upregulation of the glutamate transporters GLT-1 and EAAC1 in the ventral posterolateral nucleus of the thalamus and reduced thalamic neuronal hyperexcitability at day 7. These findings suggest that a painful facet injury induces changes extending to supraspinal structures and that IB4-positive afferents in the facet joint may be critical for the development and maintenance of sensitization in the thalamus after a painful facet joint injury.


Assuntos
Transportador 2 de Aminoácido Excitatório/metabolismo , Lectinas/metabolismo , Neurônios Aferentes/fisiologia , Dor/fisiopatologia , Proteínas Inativadoras de Ribossomos Tipo 1/metabolismo , Tálamo/fisiopatologia , Articulação Zigapofisária/lesões , Animais , Transportador 3 de Aminoácido Excitatório/metabolismo , Hiperalgesia/fisiopatologia , Lectinas/farmacologia , Masculino , Estimulação Física , Ratos , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Saporinas , Tálamo/metabolismo , Núcleos Ventrais do Tálamo/metabolismo , Articulação Zigapofisária/inervação
6.
Biochemistry (Mosc) ; 82(3): 373-379, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28320279

RESUMO

The morphogenesis of individual organs and the whole organism occurs under the control of intercellular chemical signals mainly during the perinatal period of ontogenesis in rodents. In this study, we tested our hypothesis that the biologically active concentration of noradrenaline (NA) in blood in perinatal ontogenesis of rats is maintained due to humoral interaction between its central and peripheral sources based on their plasticity. As one of the mechanisms of plasticity, we examined changes in the secretory activity (spontaneous and stimulated release of NA) of NA-producing organs under deficiency of its synthesis in the brain. The destruction of NA-ergic neurons was provoked by administration of a hybrid molecular complex - antibodies against dopamine-ß-hydroxylase associated with the cytotoxin saporin - into the lateral cerebral ventricles of neonatal rats. We found that 72 h after the inhibition of NA synthesis in the brain, its spontaneous release from hypothalamus increased, which was most likely due to a compensatory increase of NA secretion from surviving neurons and can be considered as one of the mechanisms of neuroplasticity aimed at the maintenance of its physiological concentration in peripheral blood. Noradrenaline secretion from peripheral sources (adrenal glands and the organ of Zuckerkandl) also showed a compensatory increase in this model. Thus, during the critical period of morphogenesis, the brain is integrated into the system of NA-producing organs and participates in their reciprocal humoral regulation as manifested in compensatory enhancement of NA secretion in each of the studied sources of NA under specific inhibition of NA production in the brain.


Assuntos
Glândulas Suprarrenais , Neurônios Adrenérgicos/metabolismo , Ventrículos Cerebrais , Hipotálamo , Norepinefrina/metabolismo , Glomos Para-Aórticos/metabolismo , Glândulas Suprarrenais/crescimento & desenvolvimento , Glândulas Suprarrenais/metabolismo , Animais , Ventrículos Cerebrais/crescimento & desenvolvimento , Ventrículos Cerebrais/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Masculino , Ratos , Ratos Wistar , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , Saporinas
7.
Planta Med ; 82(18): 1525-1531, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27392242

RESUMO

Triterpenoidal saponins are synthesized in the roots of Saponaria officinalis L. The same plant is also a source for the toxin Saporin, which is a ribosome-inactivating protein. Triterpenoidal saponins are known to increase the cytotoxicity of Saporin by modulating its intracellular trafficking. Here, we investigated if the combinatorial effects elicited by purified saponins and Saporin can be applied to increase the therapeutic efficacy of the immunotoxin Saporin-Rituximab. First, saponins were purified by high-performance liquid chromatography. Thereafter, their intrinsic cytotoxicity was evaluated on Ramos cells with no observed effect up to 5 µg/mL, however, saponins increased the cytotoxicity of Saporin, while no influence was observed on its N-glycosidase activity. Saporin-Rituximab bound to CD20 in Ramos cells and, in the absence of saponins, had a GI50 (concentration inhibiting cell growth to 50 %) of 7 nM. However, in the presence of a nontoxic concentration of saponins, the GI50 of Saporin-Rituximab was 0.01 nM, a nearly 700-fold increase in efficacy. Moreover, two further immunotoxins, namely Saporin-anti-CD22 and Saporin-anti-CD25, were tested in combination with saponins yielding enhancement factors of 170-fold and 25-fold, respectively. All three receptors are present in Ramos cells and the differences in cytotoxicity enhancement may be explained by the differing expression levels of the cellular receptors. The application of purified saponins from S. officinalis L. is therefore a new strategy to potentially improve the cytotoxicity and therapeutic efficacy of Rituximab-immunotoxins for the treatment of B-cell lymphoma.


Assuntos
Imunotoxinas/farmacologia , Linfoma de Células B/patologia , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Rituximab/farmacologia , Saponaria/química , Saponinas/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Sinergismo Farmacológico , Humanos , Imunotoxinas/química , Imunotoxinas/isolamento & purificação , Proteínas Inativadoras de Ribossomos Tipo 1/química , Proteínas Inativadoras de Ribossomos Tipo 1/isolamento & purificação , Saponinas/química , Saponinas/isolamento & purificação , Saporinas
8.
J Neuroendocrinol ; 28(6)2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27144381

RESUMO

Oxytocin (OXT)-containing neurosecretory cells in the parvocellular divisions of the paraventricular nucleus (PVN), which project to the medulla and spinal cord, are involved in various physiological functions, such as sensory modulation and autonomic processes. In the present study, we examined OXT expression in the hypothalamo-spinal pathway, as well as the hypothalamo-neurohypophysial system, which includes the magnocellular neurosecretory cells in the PVN and the supraoptic nucleus (SON), after s.c. injection of saline or formalin into the hindpaws of transgenic rats that express the OXT and monomeric red fluorescent protein 1 (mRFP1) fusion gene. (i) The numbers of OXT-mRFP1 neurones that expressed Fos-like immunoreactivity (-IR) and OXT-mRFP1 intensity were increased significantly in the magnocellular/parvocellular PVN and SON after s.c. injection of formalin. (ii) OXT-mRFP1 neurones in the anterior parvocellular PVN, which may project to the dorsal horn of the spinal cord, were activated by s.c. injection of formalin, as indicated by a significant increases of Fos-IR and mRFP1 intensity intensity. (iii) Formalin injection caused a significant transient increase in plasma OXT. (iv) OXT, mRFP1 and corticotrophin-releasing hormone mRNAs in the PVN were significantly increased after s.c. injection of formalin. (v) An intrathecal injection of OXT-saporin induced hypersensitivity in conscious rats. Taken together, these results suggest that the hypothalamo-neurohypophysial/-spinal OXTergic pathways may be involved in acute nociceptive responses in rats.


Assuntos
Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Hipotálamo/metabolismo , Ocitocina/fisiologia , Neuro-Hipófise/metabolismo , Animais , Hormônio Liberador da Corticotropina/biossíntese , Formaldeído , Injeções Espinhais , Proteínas Luminescentes/genética , Masculino , Neurônios/metabolismo , Ocitocina/administração & dosagem , Ocitocina/análogos & derivados , Ocitocina/biossíntese , Ocitocina/sangue , Ocitocina/farmacologia , Medição da Dor , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Transgênicos , Proteínas Inativadoras de Ribossomos Tipo 1/administração & dosagem , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Saporinas , Núcleo Supraóptico/metabolismo , Núcleo Supraóptico/fisiologia , Proteína Vermelha Fluorescente
9.
Planta Med ; 80(11): 896-901, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25029173

RESUMO

Pachyrhizus erosus seeds have a high protein content and are used in China due to their cytotoxic effect. Here we report the biological and pharmacological activity of the protein extracts from P. erosus seeds. A novel ribosome-inactivating protein, pachyerosin, from P. erosus seeds was successively purified to homogeneity using ammonium sulfate precipitation, DEAE-sepharose FF, and Sephacryl S-200. Pachyerosin showed to be a type I ribosome-inactivating protein with a molecular mass of 29 kDa and an isoelectric point of 9.19. It strongly inhibited protein synthesis of rabbit reticulocyte lysate with an IC50 of 0.37 ng/mL and showed N-glycosidase activity on rat liver ribosomes with an EC50 of 85.9 pM. The N-terminal 27 amino acids of pachyerosin revealed a 60.71% sequence identity with abrin A from the seeds of Abrus precatorius. With the aim of targeting the delivery of pachyerosin, immunotoxin was prepared by conjugating pachyerosin with anti-human AFP monoclonal antibodies SM0736. The immunotoxin pachyerosin-SM0736 efficiently inhibited the growth of the human hepatoma cell line HuH-7 with an IC50 of 0.050 ± 0.004 nM, 2360 times lower than that of pachyerosin and 430 times lower than that of the immunotoxin against human gastric cancer cell line SGC7901. These results imply that pachyerosin may be used as a new promising anticancer agent.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pachyrhizus/química , Extratos Vegetais/farmacologia , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Humanos , Imunotoxinas/isolamento & purificação , Imunotoxinas/farmacologia , Dados de Sequência Molecular , Peso Molecular , Extratos Vegetais/isolamento & purificação , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/farmacologia , Plantas Medicinais , Biossíntese de Proteínas/efeitos dos fármacos , Coelhos , Proteínas Inativadoras de Ribossomos Tipo 1/isolamento & purificação , Sementes/química , Alinhamento de Sequência
10.
Antiviral Res ; 108: 173-80, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24929084

RESUMO

Chikungunya virus (CHIKV) outbreaks have led to a serious economic burden, as the available treatment strategies can only alleviate disease symptoms, and no effective therapeutics or vaccines are currently available for human use. Here, we report the use of a new cost-effective approach involving production of a recombinant antiviral peptide-fusion protein that is scalable for the treatment of CHIKV infection. A peptide-fusion recombinant protein LATA-PAP1-THAN that was generated by joining Latarcin (LATA) peptide with the N-terminus of the PAP1 antiviral protein, and the Thanatin (THAN) peptide to the C-terminus, was produced in Escherichia coli as inclusion bodies. The antiviral LATA-PAP1-THAN protein showed 89.0% reduction of viral plaque formation compared with PAP1 (46.0%), LATA (67.0%) or THAN (79.3%) peptides alone. The LATA-PAP1-THAN protein reduced the viral RNA load that was 0.89-fold compared with the untreated control cells. We also showed that PAP1 resulted in 0.44-fold reduction, and THAN and LATA resulting in 0.78-fold and 0.73-fold reductions, respectively. The LATA-PAP1-THAN protein inhibited CHIKV replication in the Vero cells at an EC50 of 11.2µg/ml, which is approximately half of the EC50 of PAP1 (23.7µg/ml) and protected the CHIKV-infected mice at the dose of 0.75mg/ml. We concluded that production of antiviral peptide-fusion protein in E. coli as inclusion bodies could accentuate antiviral activities, enhance cellular internalisation, and could reduce product toxicity to host cells and is scalable to epidemic response quantities.


Assuntos
Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Antivirais/uso terapêutico , Febre de Chikungunya/prevenção & controle , Vírus Chikungunya/efeitos dos fármacos , Proteínas Inativadoras de Ribossomos Tipo 1/uso terapêutico , Venenos de Aranha/uso terapêutico , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/farmacologia , Antivirais/farmacologia , Febre de Chikungunya/tratamento farmacológico , Vírus Chikungunya/fisiologia , Chlorocebus aethiops , Modelos Animais de Doenças , Escherichia coli/genética , Expressão Gênica , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Proteínas Associadas a Pancreatite , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Inativadoras de Ribossomos Tipo 1/genética , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Venenos de Aranha/genética , Venenos de Aranha/farmacologia , Resultado do Tratamento , Células Vero , Carga Viral , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacos
11.
Eur J Neurosci ; 40(2): 2359-77, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24750426

RESUMO

Orexin (hypocretin) and melanin-concentrating hormone (MCH) neurons are unique to the lateral hypothalamic (LH) region, but project throughout the brain. These cell groups have been implicated in a variety of functions, including reward learning, responses to stimulants, and the modulation of attention, arousal and the sleep/wakefulness cycle. Here, we examined roles for LH in two aspects of attention in associative learning shown previously to depend on intact function in major targets of orexin and MCH neurons. In experiments 1 and 2, unilateral orexin-saporin lesions of LH impaired the acquisition of conditioned orienting responses (ORs) and bilaterally suppressed FOS expression in the amygdala central nucleus (CeA) normally observed in response to food cues that provoke conditioned ORs. Those cues also induced greater FOS expression than control cues in LH orexin neurons, but not in MCH neurons. In experiment 3, unilateral orexin-saporin lesions of LH eliminated the cue associability enhancements normally produced by the surprising omission of an expected event. The magnitude of that impairment was positively correlated with the amount of LH damage and with the loss of orexin neurons in particular, but not with the loss of MCH neurons. We suggest that the effects of the LH orexin-saporin lesions were mediated by their effect on information processing in the CeA, known to be critical to both behavioral phenomena examined here. The results imply close relations between LH motivational amplification functions and attention, and may inform our understanding of disorders in which motivational and attentional impairments co-occur.


Assuntos
Aprendizagem por Associação , Atenção , Hipotálamo/fisiologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Animais , Sinais (Psicologia) , Hormônios Hipotalâmicos/genética , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/citologia , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Melaninas/genética , Melaninas/metabolismo , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Proteínas Oncogênicas v-fos/genética , Proteínas Oncogênicas v-fos/metabolismo , Orexinas , Especificidade de Órgãos , Orientação , Hormônios Hipofisários/genética , Hormônios Hipofisários/metabolismo , Ratos , Ratos Long-Evans , Proteínas Inativadoras de Ribossomos Tipo 1/genética , Proteínas Inativadoras de Ribossomos Tipo 1/metabolismo , Saporinas
12.
Brain Struct Funct ; 219(4): 1213-29, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23625147

RESUMO

Methamphetamine (METH) induces stereotypy, which is characterized as inflexible, repetitive behavior. Enhanced activation of the patch compartment of the striatum has been correlated with stereotypy, suggesting that stereotypy may be related to preferential activation of this region. However, the specific contribution of the patch compartment to METH-induced stereotypy is not clear. To elucidate the involvement of the patch compartment to the development of METH-induced stereotypy, we determined if destruction of this sub-region altered METH-induced behaviors. Animals were bilaterally infused in the striatum with the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/µl) to specifically ablate the neurons of the patch compartment. Eight days later, animals were treated with METH (7.5 mg/kg), placed in activity chambers, observed for 2 h and killed. DERM-SAP pretreatment significantly reduced the number and total area of mu-labeled patches in the striatum. DERM-SAP pretreatment significantly reduced the intensity of METH-induced stereotypy and the spatial immobility typically observed with METH-induced stereotypy. In support of this observation, DERM-SAP pretreatment also significantly increased locomotor activity in METH-treated animals. In the striatum, DERM-SAP pretreatment attenuated METH-induced c-Fos expression in the patch compartment, while enhancing METH-induced c-Fos expression in the matrix compartment. DERM-SAP pretreatment followed by METH administration augmented c-Fos expression in the SNpc and reduced METH-induced c-Fos expression in the SNpr. In the medial prefrontal, but not sensorimotor cortex, c-Fos and zif/268 expression was increased following METH treatment in animals pre-treated with DERM-SAP. These data indicate that the patch compartment is necessary for the expression of repetitive behaviors and suggests that alterations in activity in the basal ganglia may contribute to this phenomenon.


Assuntos
Corpo Estriado/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Lobo Frontal/efeitos dos fármacos , Metanfetamina/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Corpo Estriado/metabolismo , Lobo Frontal/metabolismo , Masculino , Peptídeos Opioides/toxicidade , Ratos , Ratos Sprague-Dawley , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , Saporinas , Comportamento Estereotipado/fisiologia , Substância Negra/metabolismo
13.
J Med Food ; 16(4): 288-95, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23566055

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than five million Americans and is characterized by a progressive loss of memory, loss of cholinergic neurons in the basal forebrain, formation of amyloid plaques and neurofibrillary tangles, and an increase in oxidative stress. Recent studies indicate that dietary supplements of antioxidants and omega-3 and omega-6 fatty acids may reduce the cognitive deficits in AD patients. The current study tested a combinatorial treatment of antioxidants from tart cherry extract and essential fatty acids from Nordic fish and emu oils for reducing cognitive deficits in the mu-p75 saporin (SAP)-induced mouse model of AD. Mice were given daily gavage treatments of Cerise(®) Total-Body-Rhythm™ (TBR; containing tart cherry extract, Nordic fish oil, and refined emu oil) or vehicle (methylcellulose) for 2 weeks before intracerebroventricular injections of the cholinergic toxin, mu-p75 SAP, or phosphate-buffered saline. The TBR treatments continued for an additional 17 days, when the mice were tested on a battery of cognitive and motor tasks. Results indicate that TBR decreased the SAP-induced cognitive deficits assessed by the object-recognition, place-recognition, and Morris-water-maze tasks. Histological examination of the brain tissue indicated that TBR protected against SAP-induced inflammatory response and loss of cholinergic neurons in the area around the medial septum. These findings indicate that TBR has the potential to serve as an adjunctive treatment which may help reduce the severity of cognitive deficits in disorders involving cholinergic deficits, such as AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Suplementos Nutricionais , Ácidos Graxos Essenciais/uso terapêutico , Inflamação/tratamento farmacológico , Prunus/química , Doença de Alzheimer/patologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Encéfalo/patologia , Cognição/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/patologia , Gorduras na Dieta/farmacologia , Gorduras na Dieta/uso terapêutico , Modelos Animais de Doenças , Dromaiidae , Combinação de Medicamentos , Ácidos Graxos Essenciais/farmacologia , Feminino , Óleos de Peixe/farmacologia , Óleos de Peixe/uso terapêutico , Inflamação/induzido quimicamente , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Reconhecimento Psicológico/efeitos dos fármacos , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas
14.
Behav Brain Res ; 240: 146-52, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23178660

RESUMO

Cholinergic dysfunction and deposition of plaques containing amyloid ß-peptides (Aß) are two of the characteristics of Alzheimer's disease. Here, we combine APPswe/PS1dE9 (APP/PS1) mice with the cholinergic immunotoxin mu p75-saporin (SAP) to integrate partial basal forebrain cholinergic degeneration and the neuropathology of APP/PS1 mice. By 6 months of age, APP/PS1 mice and wild type littermates (Wt) received intracerebroventricular injection of 0.6 µg SAP (lesion) or PBS (sham). Two months following surgery, APP/PS1 mice treated with SAP were significantly impaired compared to sham treated APP/PS1 mice in a behavioural paradigm addressing working memory. Conversely, the performance of Wt mice was unaffected by SAP treatment. Choline acetyltransferase activity was reduced in the hippocampus and frontal cortex following SAP treatment. The selective effect of a mild SAP lesion in APP/PS1 mice was not due to a more extensive cholinergic degeneration since the reduction in choline acetyltransferase activity was similar following SAP treatment in APP/PS1 mice and Wt. Interestingly, plaque load was significantly increased in SAP treated APP/PS1 mice relative to sham lesioned APP/PS1 mice. Additionally, APP/PS1 mice treated with SAP showed a tendency towards an increased level of soluble and insoluble Aß1-40 and Aß1-42 measured in brain tissue homogenate. Our results suggest that the combination of cholinergic degeneration and Aß overexpression in the APP/PS1 mouse model results in cognitive decline and accelerated plaque burden. SAP treated APP/PS1 mice might thus constitute an improved model of Alzheimer's disease-like neuropathology and cognitive deficits compared to the conventional APP/PS1 model without selective removal of basal forebrain cholinergic neurons.


Assuntos
Doença de Alzheimer/etiologia , Neurônios Colinérgicos/efeitos dos fármacos , Modelos Animais de Doenças , Imunotoxinas/farmacologia , Placa Amiloide/patologia , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Colina O-Acetiltransferase/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/patologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Injeções Intraventriculares , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Placa Amiloide/fisiopatologia , Presenilina-1/genética , Saporinas
15.
Fitoterapia ; 83(5): 849-52, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22445551

RESUMO

Curcin is a ribosome-inactivating protein expressed in the endosperm of Jatropha curcas. Curcin can inhibit growth of mouse sarcoma-180 cells. At a curcin concentration of 100 µg/ml, mouse sarcoma-180 cell growth was inhibited by over 40% after seven days of incubation. Acridine orange staining and flow cytometry analysis also showed that the curcin could induce apoptosis of mouse sarcoma-180 cells. These observations provide a possible explanation for the anti-tumor properties of curcin.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Jatropha/química , Fitoterapia , Extratos Vegetais/uso terapêutico , Proteínas Inativadoras de Ribossomos Tipo 1/uso terapêutico , Sarcoma/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Citometria de Fluxo , Camundongos , Extratos Vegetais/farmacologia , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia
16.
J Sci Food Agric ; 92(3): 511-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21993892

RESUMO

BACKGROUND: Jatropha curcas seed is a rich source of oil; however, it can not be utilised for nutritional purposes due to presence of toxic and anti-nutritive compounds. The main objective of the present study was to quantify the toxic phytochemicals present in Indian J. curcas (oil, cake, bio-diesel and glycerol). RESULTS: The amount of phorbol esters is greater in solvent extracted oil (2.8 g kg⁻¹) than in expeller oil (2.1 g kg⁻¹). Liquid chromatography-mass spectroscopy analysis of the purified compound from an active extract of oil confirmed the presence of phorbol esters. Similarly, the phorbol esters content is greater in solvent extracted cake (1.1 g kg⁻¹) than in cake after being expelled (0.8 g kg⁻¹). The phytate and trypsin inhibitory activity of the cake was found to be 98 g kg⁻¹ and 8347 TIU g⁻¹ of cake, respectively. Identification of curcin was achieved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the concentration of curcin was 0.95 g L⁻¹ of crude concentrate obtained from cake. CONCLUSION: Higher amounts of phorbol esters are present in oil than cake but bio-diesel and glycerol are free of phorbol esters. The other anti-nutritional components such as trypsin inhibitors, phytates and curcin are present in cake, so the cake should be detoxified before being used for animal feed.


Assuntos
Biocombustíveis/análise , Glicerol/química , Resíduos Industriais/análise , Jatropha/química , Compostos Fitoquímicos/análise , Óleos de Plantas/química , Sementes/química , Agricultura/economia , Ração Animal/análise , Ração Animal/economia , Biocombustíveis/economia , Ácidos Graxos/análise , Contaminação de Alimentos , Glicerol/economia , Glicerol/isolamento & purificação , Índia , Resíduos Industriais/economia , Ésteres de Forbol/análise , Ésteres de Forbol/economia , Ésteres de Forbol/isolamento & purificação , Ácido Fítico/análise , Ácido Fítico/economia , Ácido Fítico/isolamento & purificação , Compostos Fitoquímicos/economia , Compostos Fitoquímicos/isolamento & purificação , Óleos de Plantas/economia , Óleos de Plantas/isolamento & purificação , Proteínas Inativadoras de Ribossomos Tipo 1/análise , Proteínas Inativadoras de Ribossomos Tipo 1/economia , Proteínas Inativadoras de Ribossomos Tipo 1/isolamento & purificação , Inibidores da Tripsina/análise , Inibidores da Tripsina/economia , Inibidores da Tripsina/isolamento & purificação
17.
J Psychopharmacol ; 26(6): 871-86, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21926428

RESUMO

It has been suggested that a sub-population of orexinergic neurones whose somata lie in the lateral hypothalamic area (LHA) play an important role in regulating the reinforcing value of both food and drugs. This experiment examined the effect of disruption of orexinergic mechanisms in the LHA on performance on the progressive ratio schedule of reinforcement, in which the response requirement increases progressively for successive reinforcers. The data were analysed using a mathematical model which yields a quantitative index of reinforcer value and dissociates effects of interventions on motor and motivational processes. Rats were trained under a progressive ratio schedule using food-pellet reinforcement. They received bilateral injections of conjugated orexin-B-saporin (OxSap) into the LHA or sham lesions. Training continued for a further 40 sessions after surgery. Equations were fitted to the response rate data from each rat, and the parameters of the model were derived for successive blocks of 10 sessions. The OxSap lesion reduced the number of orexin-containing neurones in the LHA by approximately 50% compared with the sham-lesioned group. The parameter expressing the incentive value of the reinforcer was not significantly altered by the lesion. However, the parameter related to the maximum response rate was significantly affected, suggesting that motor capacity was diminished in the OxSap-lesioned group. The results indicate that OxSap lesions of the LHA disrupted food-reinforced responding on the progressive ratio schedule. It is suggested that this disruption was brought about by a change in non-motivational (motor) processes.


Assuntos
Comportamento Animal/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Neuropeptídeos/farmacologia , Substâncias para Melhoria do Desempenho/farmacologia , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Hipotálamo/efeitos dos fármacos , Motivação/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Orexinas , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Wistar , Esquema de Reforço , Reforço Psicológico , Saporinas
18.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 31(8): 1104-7, 2011 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-21910345

RESUMO

OBJECTIVE: To clone the pokeweed anti-viral protein (PAP) gene, to express it in Pichia pastoris, and to study the inhibitory effect of PAP on U251 in vitro. METHODS: The cDNA sequence encoding PAP was cloned by Real-time PCR from Phytolacca americana. The recombinant PAP was subcloned into the expression vector pPICZaA and expressed in Pichia pastoris GSI15 after methanol induction. SDS-PAGE analysis showed that the expressed PAP existed in the yeast culture supernatant. The drug cytotoxicity to U251 cells was assessed using MTT assay and the obvious apoptotic nuclei of the tumor cells detected using the method of single cell gel electrophoresis. RESULTS: The full-length PAP gene was cloned. The recombinant expression plasmid pPICZaA-PAP was constructed successfully. SDS-PAGE analysis showed that the relative molecular mass (M) of the recombinant protein was about 35 kDa. The degradation of the genome of the apoptotic cells induced by PAP was detected using the method of single cell gel electrophoresis. PAP possessed very high ability to inhibit the growth of U251. The anti-tumor activities (IC50) to U251 cells of PAP was 81.0 microg/mL. CONCLUSION: PAP could be a potent anti-tumor candidate for inhibiting the growth of U251 and inducing its apoptosis.


Assuntos
Apoptose , Pichia/metabolismo , Proteínas Inativadoras de Ribossomos Tipo 1/biossíntese , Antineoplásicos Fitogênicos/biossíntese , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Humanos , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia
19.
Dement Geriatr Cogn Disord ; 32(1): 70-8, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21876356

RESUMO

BACKGROUND/AIMS: Previous studies used 192 IgG-saporin to study cholinergic function because of its facility for selective lesioning; however, results varied due to differences in the methods of administration and behavioral tests used. We examined an animal model of dementia using 192 IgG-saporin to confirm its features before applying this model to research of therapeutic drugs or electrical stimulation techniques. METHODS: Features were verified by the Morris water maze test, immunochemistry, and Western blotting. Animals were examined after intraventricular injection of 192 IgG-saporin (0.63 µg/µl; 6, 8, and 10 µl) or phosphate-buffered saline. RESULTS: In the acquisition phase of the Morris water maze test, the latencies of the injection groups were significantly delayed, but recovered within 1 week. In the probe test, 2 of 4 indices (time in the platform zone and the number of crossings) were significantly different in the 8-µl injection group. Immunohistochemistry revealed the extent of cholinergic destruction. Activity-regulated cytoskeleton-associated protein and glutamate decarboxylase expression significantly decreased in the frontal cortex (8- and 10-µl groups), but not in the hippocampus. CONCLUSION: Spatial memory impairment was associated with cholinergic basal forebrain injury as well as frontocortical GABAergic hypofunction and synaptic plasticity deceleration.


Assuntos
Anticorpos Monoclonais/farmacologia , Colinérgicos/farmacologia , Proteínas do Citoesqueleto/biossíntese , Lobo Frontal/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Ácido gama-Aminobutírico/fisiologia , Acetilcolinesterase/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Western Blotting , Colina O-Acetiltransferase/metabolismo , Colinérgicos/administração & dosagem , Demência/induzido quimicamente , Demência/psicologia , Modelos Animais de Doenças , Lobo Frontal/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Parvalbuminas/metabolismo , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Inativadoras de Ribossomos Tipo 1/administração & dosagem , Saporinas , Sinapses/efeitos dos fármacos
20.
Physiol Behav ; 103(3-4): 268-78, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21362434

RESUMO

We investigated whether histaminergic tone contributes to the seasonal catabolic state in Siberian hamsters by determining the effect of ablation of histaminergic neurons on food intake, metabolic rate and body weight. A ribosomal toxin (saporin) conjugated to orexin-B was infused into the ventral tuberomammillary region of the hypothalamus, since most histaminergic neurons express orexin receptors. This caused not only 75-80% loss of histaminergic neurons in the posterior hypothalamus, but also some loss of other orexin-receptor expressing cells e.g. MCH neurons. In the long-day anabolic state, lesions produced a transient post-surgical decrease in body weight, but the hamsters recovered and maintained constant body weight, whereas weight gradually increased in sham-lesioned hamsters. VO(2) in the dark phase was significantly higher in the lesioned hamsters compared to shams, and locomotor activity also tended to be higher. In a second study in short days, sham-treated hamsters showed the expected seasonal decrease in body weight, but weight remained constant in the lesioned hamsters, as in the long-day study. Lesioned hamsters consumed more during the early dark phase and less during the light phase due to an increase in the frequency of meals during the dark and decreased meal size during the light, and their cumulative food intake in their home cages was greater than in the control hamsters. In summary, ablation of orexin-responsive cells in the posterior hypothalamus blocks the short-day induced decline in body weight by preventing seasonal hypophagia, evidence consistent with the hypothesis that central histaminergic mechanisms contribute to long-term regulation of body weight.


Assuntos
Peso Corporal/fisiologia , Ritmo Circadiano/fisiologia , Ingestão de Alimentos/fisiologia , Histamina/metabolismo , Estações do Ano , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Cricetinae , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Histidina Descarboxilase/metabolismo , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Imunotoxinas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Melaninas/metabolismo , Neuropeptídeos/farmacologia , Neurotransmissores/farmacologia , Orexinas , Consumo de Oxigênio/efeitos dos fármacos , Phodopus , Hormônios Hipofisários/metabolismo , Troca Gasosa Pulmonar/efeitos dos fármacos , Troca Gasosa Pulmonar/fisiologia , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Saporinas , Fatores de Tempo
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