Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.578.167
Filtrar
Mais filtros








Intervalo de ano de publicação
1.
Gene ; 806: 145920, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34455026

RESUMO

Depression is deemed a mood disorder characterized by a high rate of relapse. Therefore, overcoming of the recurrent depression is globally expecting. Kososan, a traditional Japanese herbal medicine, has been clinically used for mild depressive mood, and our previous studies have shown some evidence for its antidepressive-like efficacy in experimental animal models of depression. However, it remains unclear whether kososan has beneficial effects on recurrent depression. Here, we examined its effect using a mouse model of modified repeated social defeat stress (SDS) paradigm. Male BALB/c mice were exposed to a 5-min SDS from unfamiliar aggressive CD-1 mice for 5 days. Kososan extract (1.0 kg/kg/day) or an antidepressant milnacipran (60 mg/kg/day) was administered orally for 26 days (days 7-32) to depression-like mice with social avoidant behaviors on day 6. Single 5 min of SDS was subjected to mice recovered from the social avoidance on day 31, and then the recurrence of depression-like behaviors was evaluated on day 32. Hippocampal gene expression patterns were also assayed by DNA microarray analysis. Water- or milnacipran-administered mice resulted in a recurrence of depression-like behaviors by re-exposure of single SDS, whereas kososan-administered mice did not recur depression-like behaviors. Distinct gene expression patterns were also found for treating kososan and milnacipran. Collectively, this finding suggests that kososan exerts a preventive effect on recurrent depression-like behaviors in mice. Pretreatment of kososan is more useful for recurrent depression than that of milnacipran.


Assuntos
Antidepressivos/farmacologia , Depressão/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Proteínas do Tecido Nervoso/genética , Derrota Social , Estresse Psicológico/tratamento farmacológico , Administração Oral , Animais , Depressão/genética , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Japão , Masculino , Medicina Kampo/métodos , Camundongos , Camundongos Endogâmicos BALB C , Milnaciprano/farmacologia , Anotação de Sequência Molecular , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Recidiva , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia
2.
Food Chem ; 366: 130573, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34311232

RESUMO

Based on a murine monoclonal antibody (mAb) against tiamulin (TML), an electrochemical immunosensor was proposed using silver-graphene oxide (Ag-GO) nanocomposites and gold nanocomposites (AuNPs) to detect tiamulin (TML). Due to the synergetic properties of Ag-GO nanocomposites and AuNPs, the conductivity of the immunosensor was significantly enhanced. On account of the specific mAb and conductive nanocomposites, the proposed electrochemical immunosensor exhibited a low LOD of 0.003 ng mL-1 for the detection of TML in a wide linear range of 0.01 to 1000 ng mL-1. In addition, the immunosensor did not involve additional redox species. Furthermore, the efficient and simple electrochemical immunosensor was employed to detect TML in real samples with high accuracy, suggesting a potential detection platform for other veterinary antibiotics in animal derived foods.


Assuntos
Técnicas Biossensoriais , Grafite , Nanopartículas Metálicas , Nanocompostos , Animais , Anticorpos Monoclonais , Diterpenos , Técnicas Eletroquímicas , Ouro , Imunoensaio , Limite de Detecção , Camundongos
3.
Food Chem ; 367: 130735, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34365247

RESUMO

Green and black teas are regarded to possess therapeutic potential for the treatment of obesity, however it is not clear which tea performs better in body weight control. In this study, aiming to eliminate cultivar variation, green tea phenolics (GTP) were oxidized by tyrosinase to obtain oxidized tea phenolics (OTP). Thereafter, their anti-obesity effect on high-fat diet induced obese mice were compared. The results showed that despite their distinctive phenolic profiles, GTP and OTP exerted similar anti-obesity properties after 12 weeks of dietary intervention. Furthermore, cecal microbiota profiling exhibited comparable modulatory effects of GTP and OTP on multiple bacterial taxa, including Parabacteroides distasonis, Bifidobacterium, Prevotella, and Akkermansia muciniphila, which were strongly associated with obesity related indexes. Putative bacterial function profiling implicated that both GTP and OTP might regulate the lipid metabolism similarly. Collectively, the oxidation of GTP did not influence the anti-obesity and gut microbiota modulatory effects to any large extent.


Assuntos
Microbioma Gastrointestinal , Chá , Animais , Bacteroidetes , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/etiologia
4.
J Cell Sci ; 135(5)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33771931

RESUMO

The lipid composition of the primary cilia membrane is emerging as a critical regulator of cilia formation, maintenance and function. Here, we show that conditional deletion of the phosphoinositide 5'-phosphatase gene Inpp5e, mutation of which is causative of Joubert syndrome, in terminally developed mouse olfactory sensory neurons (OSNs), leads to a dramatic remodeling of ciliary phospholipids that is accompanied by marked elongation of cilia. Phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2], which is normally restricted to the proximal segment redistributed to the entire length of cilia in Inpp5e knockout mice with a reduction in phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2] and elevation of phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] in the dendritic knob. The redistribution of phosphoinositides impaired odor adaptation, resulting in less efficient recovery and altered inactivation kinetics of the odor-evoked electrical response and the odor-induced elevation of cytoplasmic Ca2+. Gene replacement of Inpp5e through adenoviral expression restored the ciliary localization of PI(4,5)P2 and odor response kinetics in OSNs. Our findings support the role of phosphoinositides as a modulator of the odor response and in ciliary biology of native multi-ciliated OSNs.


Assuntos
Neurônios Receptores Olfatórios , Animais , Cílios , Camundongos , Odorantes , Fosfolipídeos , Monoéster Fosfórico Hidrolases/genética
5.
J Cell Sci ; 135(5)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34080635

RESUMO

Despite the recognized significance of reversible protein lipidation (S-acylation) for T cell receptor signal transduction, the enzymatic control of this post-translational modification in T cells remains poorly understood. Here, we demonstrate that DHHC21 (also known as ZDHHC21), a member of the DHHC family of mammalian protein acyltransferases, mediates T cell receptor-induced S-acylation of proximal T cell signaling proteins. Using Zdhhc21dep mice, which express a functionally deficient version of DHHC21, we show that DHHC21 is a Ca2+/calmodulin-dependent enzyme critical for activation of naïve CD4+ T cells in response to T cell receptor stimulation. We find that disruption of the Ca2+/calmodulin-binding domain of DHHC21 does not affect thymic T cell development but prevents differentiation of peripheral CD4+ T cells into Th1, Th2 and Th17 effector T helper lineages. Our findings identify DHHC21 as an essential component of the T cell receptor signaling machinery and define a new role for protein acyltransferases in regulation of T cell-mediated immunity.


Assuntos
Linfócitos T CD4-Positivos , Cálcio , Acetiltransferases , Aciltransferases/genética , Animais , Diferenciação Celular , Camundongos , Receptores de Antígenos de Linfócitos T/genética
6.
J Ethnopharmacol ; 282: 114574, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34461187

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gekko gecko is used as a traditional medicine for various diseases including respiratory disorders in northeast Asian countries, mainly Korea, Japan, and China. AIM OF THE STUDY: Allergic asthma is a chronic respiratory disease caused by an inappropriate immune response. Due to the recent spread of coronavirus disease 2019, interest in the treatment of pulmonary disorders has rapidly increased. In this study, we investigated the anti-asthmatic effects of G. gecko extract (GGE) using an established mouse model of ovalbumin-induced asthma. MATERIALS AND METHODS: To evaluate the anti-asthmatic effects of GGE, we evaluated histological changes and the responses of inflammatory mediators related to allergic airway inflammation. Furthermore, we investigated the regulatory effects of GGE on type 2 helper T (Th2) cell activation. RESULTS: Administration of GGE attenuated asthmatic phenotypes, including inflammatory cell infiltration, mucus production, and expression of Th2 cytokines. Furthermore, GGE treatment reduced Th2 cell activation and differentiation. CONCLUSIONS: These results indicate that GGE alleviates allergic airway inflammation by regulating Th2 cell activation and differentiation.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Medicina Tradicional do Leste Asiático , Muco/metabolismo , Ovalbumina , Extratos Vegetais/uso terapêutico , Animais , Asma/induzido quimicamente , Asma/patologia , Líquido da Lavagem Broncoalveolar , COVID-19 , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Imunoglobulina E/imunologia , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pandemias , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Triptaminas/farmacologia
7.
Talanta ; 236: 122846, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34635236

RESUMO

Simultaneous detection of multiple microRNAs (miRNAs) with high sensitivity can give accurate and reliable information for clinical applications. By uniformly anchoring hairpin probes on the surface of DNA nanolantern, a three-dimensional DNA nanostructure contains abundant and adjustable modification sites, highly integrated DNA nanoprobes were designed and developed as catalytic hairpin assembly (CHA)-based signal amplifiers for enzyme-free signal amplification detection of target miRNAs. The nanolantern-based CHA (NLC) amplifiers, which were facilely prepared via a simple "one-pot" annealing method, showed enhanced biostability, improved cell internalization efficiency, accelerated CHA reaction kinetics, and increased signal amplification capability compared to the single-stranded DNA hairpin probes used in traditional CHA reaction. By co-assembling multiple hairpin probes on a DNA nanolantern surface, as-prepared NLC amplifiers were demonstrated to work well for highly sensitive and specific imaging, expression level fluctuation analysis of two miRNAs in living cells, and miRNAs-guided tumor imaging in living mice. The proposed DNA nanolantern-based nanoamplifier strategy might provide a feasible way to promote the cellular and in vivo applications of nucleic acid probes.


Assuntos
Técnicas Biossensoriais , MicroRNAs , Animais , Catálise , DNA/genética , Camundongos , MicroRNAs/genética , Sondas de Ácido Nucleico
8.
J Hazard Mater ; 421: 126707, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34315018

RESUMO

Triclosan (TCS) is an antimicrobial ingredient that has been widely incorporated in consumer products. TCS can cause hepatic damage by disturbing lipid metabolism, which is often accompanied with gut microbiota dysbiosis. However, the effects of gut microbiota on the TCS-induced liver injury are still unknown. Therefore, we constructed a mouse model based on five-week-old male C57BL/6 mice to investigate the effects of dietary TCS exposure (40 ppm) on liver injury. We found that TCS treatment for 4 weeks dramatically disturbed gut microbiota homeostasis, resulting in overproduction of lipopolysaccharides (LPS) and deficiency of secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA). In addition, TCS considerably increased intestinal permeability by reducing mucus excretion and expression of tight junction proteins (ZO-1, occludin and claudin 4), which facilitated translocation of LPS. The LPS accumulation in blood contributed to liver injury by triggering the inflammatory response via TLR4 pathway. In summary, this study provides novel insights into the underlying mechanisms of TCS-associated liver injury induced by gut microbiota via the gut-liver axis, and contributes to better interpretation of the health impact of the environmentally emerging contaminant TCS.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Microbioma Gastrointestinal , Triclosan , Animais , Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Triclosan/toxicidade
9.
J Colloid Interface Sci ; 605: 296-310, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34329981

RESUMO

This paper presents the design of a new type of intelligent and versatile all-in-one therapeutic nanoplatform for the co-delivery of chemotherapeutic drugs and photosensitizers to facilitate multimodal antitumor treatment; the system is based on hyaluronic acid (HA)-modified manganese dioxide (MnO2)-enveloped hollow porous copper sulfide (CuS) nanoparticles (CuS@MnO2/HA NPs). In this system, a CuS inner shell allows for the co-loading of doxorubicin (DOX) and indocyanine green (ICG) and induces photothermal effects, and a biodegradable MnO2 external shell affords on-demand tumor microenvironment (TME)-triggered release and catalase- andFenton-like activities. Moreover, the HA modification endows the system with a CD44 receptor-mediated tumor-targeting property. The formulated DOX and ICG co-loaded CuS@MnO2/HA (DOX/ICG-CuS@MnO2/HA) NPs were found to exhibit excellent photothermal performance both in vitro and in vivo. In addition, DOX/ICG-CuS@MnO2/HA NPs were found to display both TME and near-infrared (NIR)-responsive controlled release properties. The NPs also have a superior reactive oxygen species (ROS) generation capacity due to the combination of enhanced ICG-induced singlet oxygen and CuS@MnO2-mediated hydroxyl radicals. The cellular uptake, fluorescence imaging property, cytotoxicity, and thermal imaging of these NPs were also evaluated. In tumor-bearing mice, the DOX/ICG-CuS@MnO2/HA NPs displayeda superior antitumor efficacy (2.57-fold) as compared with free DOX. Therefore, the developed DOX/ICG-CuS@MnO2/HA NPs have a great potential for use as an all-in-one nanotherapeutic agent for the efficient and precise induction of chemo/photothermal/photodynamic/chemodynamic therapy with superior antitumor efficacy and fewer side effects.


Assuntos
Nanopartículas , Preparações Farmacêuticas , Animais , Cobre , Doxorrubicina/farmacologia , Ácido Hialurônico , Compostos de Manganês , Camundongos , Óxidos , Fármacos Fotossensibilizantes , Fototerapia , Sulfetos
10.
Med Gas Res ; 12(1): 18-23, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34472498

RESUMO

Cytoreg is an ionic therapeutic agent comprising a mixture of hydrochloric, sulfuric, phosphoric, hydrofluoric, oxalic, and citric acids. In diluted form, it has demonstrated efficacy against human cancers in vitro and in vivo. Although Cytoreg is well tolerated in mice, rats, rabbits, and dogs by oral and intravenous administration, its mechanism of action is not documented. The acidic nature of Cytoreg could potentially disrupt the pH and levels of ions and dissolved gases in the blood. Here, we report the effects of the intravenous administration of Cytoreg on the arterial pH, oxygen and carbon dioxide pressures, and bicarbonate, sodium, potassium, and chloride concentrations. Our results demonstrate that Cytoreg does not disturb the normal blood pH, ion levels, or carbon dioxide content, but increases oxygen levels in rats. These data are consistent with the excellent tolerability of intravenous Cytoreg observed in rabbits, and dogs. The study was approved by the Bioethics Committee of the University of the Andes, Venezuela (CEBIOULA) (approval No. 125) on November 3, 2019.


Assuntos
Equilíbrio Ácido-Base , Antineoplásicos , Animais , Antineoplásicos/farmacologia , Bicarbonatos/farmacologia , Cães , Concentração de Íons de Hidrogênio , Camundongos , Coelhos , Ratos , Ratos Wistar
11.
Handb Exp Pharmacol ; 271: 197-220, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34463847

RESUMO

Ligands for kappa opioid receptors (KOR) have potential uses as non-addictive analgesics and for the treatment of pruritus, mood disorders, and substance abuse. These areas continue to have major unmet medical needs. Significant advances have been made in recent years in the preclinical development of novel opioid peptides, notably ones with structural features that inherently impart stability to proteases. Following a brief discussion of the potential therapeutic applications of KOR agonists and antagonists, this review focuses on two series of novel opioid peptides, all-D-amino acid tetrapeptides as peripherally selective KOR agonists for the treatment of pain and pruritus without centrally mediated side effects, and macrocyclic tetrapeptides based on CJ-15,208 that can exhibit different opioid profiles with potential applications such as analgesics and treatments for substance abuse.


Assuntos
Antagonistas de Entorpecentes , Receptores Opioides kappa , Animais , Desenvolvimento de Medicamentos , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL
12.
Chemosphere ; 287(Pt 2): 132160, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34509005

RESUMO

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes long-term inflammation and ulcers in the colon and rectum. Approximately 3 million adults were diagnosed with IBD in the US in 2015, and its incidence rate is estimated to increase by 4-6 times in 2030. Industrial pollutants are largely responsible for this significant increase in UC cases. Several epidemiological and animal studies have demonstrated the correlation between pollutants and gastrointestinal diseases, but detailed molecular mechanisms responsible for adverse effects of environmental pollutants on UC are still unknown. In the present study, we used a dextran sulfate sodium (DSS)-induced colitis mouse model, comparative metabolomics analysis, and systematic bioinformatics analysis to delineate the synergistic adverse effects of bisphenol A (BPA) and its substitute fluorene-9-bisphenol (BHPF) on UC. Subsequently, a significant alteration in gut metabolites was observed by the BPA and BHPF treatments. Furthermore, the bioinformatics analysis indicated deregulation of sugar and fatty acid metabolisms in the DSS-induced colitis model by the BPA and BHPF treatments, respectively. Additionally, both the treatments induced an inflammatory response in the model. Particularly, some DSS-deregulated metabolites, which play important roles in gut inflammation, were synergistically induced or reduced by the BPA and BHPF treatments. To the best knowledge of the authors, the synergistic adverse effects of the BPA and BHPF treatments on UC were demonstrated for the first time through gut metabolism alterations. Therefore, the present study provides novel insights in the role of environmental pollutants, such as BPA and BHPF, in UC development.


Assuntos
Colite Ulcerativa , Animais , Compostos Benzidrílicos/toxicidade , Colite Ulcerativa/induzido quimicamente , Colo , Modelos Animais de Doenças , Metabolômica , Camundongos , Fenóis
13.
Chemosphere ; 287(Pt 3): 132253, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34543901

RESUMO

Nanopesticides are innovative pesticides involving engineered nanomaterials in their formulation to increase the efficiency of plant protection products, while mitigating their environmental impact. Despite the predicted growth of the nanopesticide use, no data is available on their inhalation toxicity and the potential cocktail effects between their components. In particular, the neurodevelopmental toxicity caused by prenatal exposures might have long lasting consequences. In the present study, we repeatedly exposed gestating mice in a whole-body exposure chamber to three aerosols, involving the paraquat herbicide, nanoscaled titanium dioxide particles (nTiO2), or a mixture of both. Particle number concentrations and total mass concentrations were followed to enable a metrological follow-up of the exposure sessions. Based on the aerosols characteristics, the alveolar deposited dose in mice was then estimated. RNA-seq was used to highlight dysregulations in the striatum of pups in response to the in utero exposure. Modifications in gene expression were identified at post-natal day 14, which might reflect neurodevelopmental alterations in this key brain area. The data suggest an alteration in the mitochondrial function following paraquat exposure, which is reminiscent of the pathological process leading to Parkinson disease. Markers of different cell lineages were dysregulated, showing effects, which were not limited to dopaminergic neurons. Exposure to the nTiO2 aerosol modulated the regulation of cytokines and neurotransmitters pathways, perhaps reflecting a minor neuroinflammation. No synergy was found between paraquat and nTiO2. Instead, the neurodevelopmental effects were surprisingly lower than the one measured for each substance separately.


Assuntos
Paraquat , Efeitos Tardios da Exposição Pré-Natal , Aerossóis , Animais , Encéfalo , Feminino , Expressão Gênica , Exposição por Inalação , Camundongos , Paraquat/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Titânio/toxicidade
14.
Environ Pollut ; 292(Pt A): 118297, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34624399

RESUMO

Polybrominated diphenyl ether (PBDE) as the flame retardant is heavily used in daily necessities, causing adverse health effects on humans. This study aimed to evaluate the hepatotoxicity of decabromodiphenyl ether (BDE-209), the most widely used PBDE, in lean and high-fat diet (HFD)-treated obese mice and elucidate the underlying mechanism. Firstly, the increasing levels of TG and proinflammatory factors in the liver and ALT and AST in serum demonstrated the hepatic damage caused by BDE-209 and further exacerbated by HFD. Tunel image revealed that BDE-209 induced more severe hepatocyte apoptosis with the assistant of HFD. Next, the mechanism analysis showed that the pro-apoptotic action of BDE-209 was in an endoplasmic reticulum (ER)/Ca2+ flux/mitochondria-dependent manner, concluded from the impairment of mitochondrial membrane potential, the enhancive protein expression of p-PERK/PERK, p-IRE1/IRE1, ATF6, CHOP, Bax/Bcl-2, cleaved caspase-3/caspase-3, IP3R1 and Sig-1R, and the over-transfer of Ca2+ from ER to mitochondria. Such proposed mechanism was further confirmed by the IP3R1 siRNA transfection cell experiment, where apoptotic rate was reduced in parallel with the reduced mitochondrial Ca2+ level. Finally, the higher expression of PACS-2 protein and the expanded ER contributed to the enriched ER-mitochondria interaction, reflected by the closer distance between ER and mitochondria visually displayed in the TEM image in HFD groups. This change was conducive to the rapid delivery of apoptosis signals via Ca2+, as proven, mechanically explaining the strengthening effect of HFD on BDE-209 hepatotoxicity. These findings detailedly explained the mechanism of BDE-209 hepatotoxicity and clarified the auxiliary effect of HFD, providing a theoretical basis for further studying other analogs.


Assuntos
Apoptose , Dieta Hiperlipídica , Animais , Dieta Hiperlipídica/efeitos adversos , Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Éteres Difenil Halogenados , Hepatócitos , Camundongos , Mitocôndrias
15.
Handb Exp Pharmacol ; 271: 23-38, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34085120

RESUMO

Antibodies are important tools for protein and peptide research, including for the kappa opioid receptor (KOR) and dynorphins (Dyns). Well-characterized antibodies are essential for rigorous and reproducible research. However, lack of validation of antibody specificity has been thought to contribute significantly to the reproducibility crisis in biomedical research. Since 2003, many scientific journals have required documentation of validation of antibody specificity and use of knockout mouse tissues as a negative control is strongly recommended. Lack of specificity of antibodies against many G protein-coupled receptors (GPCRs) after extensive testing has been well-documented, but antibodies generated against partial sequences of the KOR have not been similarly investigated. For the dynorphins, differential processing has been described in distinct brain areas, resulting in controversial findings in immunohistochemistry (IHC) when different antibodies were used. In this chapter, we summarized accepted approaches for validation of antibody specificity. We discussed two KOR antibodies most commonly used in IHC and described generation and characterization of KOR antibodies and phospho-KOR specific antibodies in western blotting or immunoblotting (IB). In addition, applying antibodies targeting prodynorphin or mature dynorphin A illustrates the diversity of results obtained regarding the distribution of dynorphins in distinct brain areas.


Assuntos
Dinorfinas , Receptores Opioides kappa , Animais , Encéfalo/metabolismo , Camundongos , Camundongos Knockout , Reprodutibilidade dos Testes
16.
Handb Exp Pharmacol ; 271: 419-433, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33580386

RESUMO

The kappa opioid receptor (KOR) is expressed on a number of hematopoietic cell populations, based on both protein binding analysis and the detection of kappa opioid receptor gene (Oprk1) transcripts. There are prominent Oprk1 splice variants that are expressed in the mouse and human brain cells and leukocytes. The activation of KOR results in reduced antibody production, an inhibition of phagocytic cell activity, an inhibition of T cell development, alterations in the production of various pro-inflammatory cytokines, chemokines, and the receptors for these mediators. Finally, the activation of KOR also leads to the regulation of receptor functional activity of chemokine receptors through the process of heterologous desensitization. The functional activity of KOR is important for the regulation of inflammatory responses and may provide opportunities for the development of therapeutics for the treatment of inflammatory disease states.


Assuntos
Citocinas , Receptores Opioides kappa , Animais , Sistema Imunitário , Camundongos , Receptores Opioides kappa/genética
17.
Handb Exp Pharmacol ; 271: 379-400, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33712941

RESUMO

Temporal lobe epilepsy is considered to be one of the most common and severe forms of focal epilepsies. Patients frequently develop cognitive deficits and emotional blunting along progression of the disease. The high incidence of refractoriness to antiepileptic drugs and a frequent lack of admissibility to surgery pose an unmet medical challenge. In the urgent quest for novel treatment strategies, neuropeptides and their receptors are interesting candidates. However, their therapeutic potential has not yet been fully exploited. This chapter focuses on the functional role of the dynorphins (Dyns) and the kappa opioid receptor (KOR) system in temporal lobe epilepsy and the hippocampus.Genetic polymorphisms in the prepro-dynorphin (pDyn) gene causing lower levels of Dyns in humans and pDyn gene knockout in mice increase the risk to develop epilepsy. This suggests a role of Dyns and KOR as modulators of neuronal excitability. Indeed, KOR agonists induce inhibition of presynaptic neurotransmitter release, as well as postsynaptic hyperpolarization in glutamatergic neurons, both producing anticonvulsant effects.The development of new approaches to modulate the complex KOR signalling cascade (e.g. biased agonism and gene therapy) opens up new exciting therapeutic opportunities with regard to seizure control and epilepsy. Potential adverse side effects of KOR agonists may be minimized through functional selectivity or locally restricted treatment. Preclinical data suggest a high potential of such approaches to control seizures.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Animais , Dinorfinas , Epilepsia do Lobo Temporal/tratamento farmacológico , Hipocampo , Humanos , Camundongos , Receptores Opioides kappa
18.
J Pharm Biomed Anal ; 207: 114421, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34710729

RESUMO

Cintirorgon (LYC-55716) is a promising first-in-class antitumor agent as a RORγ agonist in the treatment against various types of cancer. To support preclinical mouse studies, a bioanalytical method was developed and successfully applied for quantification of cintirorgon in mouse plasma and tissue homogenates using LC-MS/MS. The method was fully validated in mouse plasma and partial validation was performed in eight different homogenates originating from brain, kidney, liver, lung, small intestine, small intestine content, spleen, and testis. Sample preparation was performed using 96-well plates for fast and efficient analysis. Protein precipitation was done by addition of 20 µL acetonitrile containing monensin as internal standard to 10 µL sample. Chromatographic separation was achieved on a Polaris 3 C18-A column using gradient elution with 0.2% (v/v) formic acid and 0.2% (v/v) ammonium hydroxide in water (A) and methanol (B) as eluents. The total run time was 3 min. Detection was carried out with a triple quadrupole mass spectrometer with electrospray ionization operated in the positive ion-mode. Quantification could be accomplished within a linear validated concentration range of 5-4,000 ng/mL (10-4,000 ng/mL in brain homogenates) with an intra- and inter-day precision between 4.6-14.7% and 5.1-15.6% (including the LLOQ), respectively, and accuracies between 89.1%-111.2%. The method was successfully applied to a preclinical study with cintirorgon in mice.


Assuntos
Plasma , Espectrometria de Massas em Tandem , Animais , Benzoxazinas , Cromatografia Líquida , Masculino , Camundongos , Propionatos , Reprodutibilidade dos Testes
19.
J Pharm Biomed Anal ; 207: 114426, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34689062

RESUMO

Alcoholism is a severe threat to public health, and there are no adequate treatments for alcoholic liver disease. The aim of this study was to identify bioactive peptides derived from natural proteins that prevent acute alcohol-induced liver injury. We identified a peptide with the sequence Gly-Leu-hydroxyproline-Gly-Glu-Arg (GLpGER) from the hydrolysate of crucian carp swim bladder using size-exclusion chromatography and reversed-phase chromatography. The in vitro EC50 value of GLpGER to activate alcohol dehydrogenase (ADH) was 137.9 ± 9 µM. Molecular docking experiments indicated that the mechanism by which GLpGER activates ADH may be related to the formation of stable complexes with ADH active pockets through hydrogen bonding, and electrostatic and hydrophobic interactions. Oral administration of GLpGER one hour before acute alcohol ingestion significantly increased alcohol metabolism, manifesting as reduced incidence of the loss of righting reflex, increased alcohol tolerance time, shortened sobering time, and decreased blood alcohol concentration level. GLpGER restored liver ADH activity, maintained the typical morphology of hepatocytes, and reduced serum levels of alanine aminotransferase and aspartate aminotransferase. These findings suggest that GLpGER might reduce acute alcohol-induced liver injury and may have the potential to be developed as an anti-inebriation ingredient.


Assuntos
Carpas , Doença Hepática Crônica Induzida por Substâncias e Drogas , Álcool Desidrogenase , Animais , Concentração Alcoólica no Sangue , Etanol , Fígado , Camundongos , Simulação de Acoplamento Molecular , Peptídeos , Bexiga Urinária
20.
Food Chem ; 370: 131012, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34500293

RESUMO

Peumus boldus is an endemic tree species from Chile whose leaves have been the focus of study for decades given that their infusions are reported to relieve rheumatic symptoms, headache, dyspepsia, urinary tract inflammation, and symptoms of other illnesses. These health properties have been studied mainly using leaves and bark, then it is relevant to know more about these properties in different parts of the plant. Considering the importance of P. boldus fruits in the diet of some rural populations, we analyzed their properties to explore its impact on the Chilean population health. Liquid chromatography and mass spectrometry analysis confirmed the presence of alkaloids such as boldine, although aporphine N-methyl-laurotetanine was the most abundant. In addition, flavonoids catechin, chrysin and quercetin were also found in the extract. Cytotoxicity and anti-inflammatory activities of the fruit extract were invitro tested by using a murine macrophage cell model, observing that a diluted fraction of the extract was not cytotoxic, but showed anti-inflammatory activity, which is likely attributed to antioxidants activities. By means of quantum chemical calculations, we calculated the redox potential of the respective alkaloids and flavonoids found in the extract. Results suggest a synergistic effect between alkaloids and flavonoids, where boldine and N-methyl-laurotetanine showed similar antioxidant properties. Finally, we present a description of the oxidation mechanisms for both groups of molecules which will sustain P. boldus fruit biological properties, in order to give this kind of fruits scientific value focusing on human health.


Assuntos
Peumus , Animais , Antioxidantes/farmacologia , Frutas , Humanos , Camundongos , Extratos Vegetais/farmacologia , Folhas de Planta
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA