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1.
J Nutr Sci Vitaminol (Tokyo) ; 67(4): 217-224, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34470996

RESUMO

It is well known that dietary fiber stimulates the release of satiety hormones such as glucagon-like peptide-1 (GLP-1), which in turn suppresses appetite. In order to evaluate appetite regulating role of enzymatically synthesized glycogen (ESG, one of the resistant starch), we examined the effects of dietary supplementation of ESG on food intake and cecal proglucagon gene expression in normal and high fat diet-fed mice. Twenty four male ICR mice were weighed and assigned to four groups: normal diet group; normal diet containing 25% ESG group; high-fat diet (HFD) group; HFD containing 25% ESG group. Each group was fed the relevant diets for 3 wk. All data were analyzed by a two-way ANOVA with the main effects of HFD and ESG. ESG significantly decreased food intake and increased the weight of the cecum and cecal content. Plasma total short chain fatty acids concentration was significantly elevated by ESG. The mRNA levels of proglucagon in the cecum and plasma total GLP-1 concentration were significantly increased by ESG. The mRNA levels of appetite regulating neuropeptides such as neuropeptide Y, agouti-related protein, proopiomelanocortin, and cocain- and amphetamine-regulating transcript in the hypothalamus were not influenced by ESG. There is no significant interaction between diet and ESG in any parameters. These results suggest that ESG-induced upregulation of GLP-1 production in the cecum suppresses food intake in mice and that fecal fermentation may be involved in the anorexigenic effect.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Glicogênio , Animais , Ceco , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos , Masculino , Camundongos , Camundongos Endogâmicos ICR
2.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445470

RESUMO

In regular IVF, a portion of oocytes exhibit abnormal numbers of pronuclei (PN) that is considered as abnormal fertilization, and they are routinely discarded. However, it is known that abnormal ploidy still does not completely abandon embryo development and implantation. To explore the potential of cytoplasm from those abnormally fertilized oocytes, we developed a novel technique for the transfer of large cytoplasm between pronuclear-stage mouse embryos, and assessed its impact. A large volume of cytoplast could be efficiently transferred in the PN stage using a novel two-step method of pronuclear-stage cytoplasmic transfer (PNCT). PNCT revealed the difference in the cytoplasmic function among abnormally fertilized embryos where the cytoplasm of 3PN was developmentally more competent than 1PN, and the supplementing of fresh 3PN cytoplasm restored the impaired developmental potential of postovulatory "aged" oocytes. PNCT-derived embryos harbored significantly higher mitochondrial DNA copies, ATP content, oxygen consumption rate, and total cells. The difference in cytoplasmic function between 3PN and 1PN mouse oocytes probably attributed to the proper activation via sperm and may impact subsequent epigenetic events. These results imply that PNCT may serve as a potential alternative treatment to whole egg donation for patients with age-related recurrent IVF failure.


Assuntos
Núcleo Celular/patologia , Citoplasma/patologia , Embrião de Mamíferos/patologia , Desenvolvimento Embrionário , Fertilização In Vitro/métodos , Zigoto/patologia , Animais , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Embrião de Mamíferos/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos ICR , Zigoto/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445476

RESUMO

4,4'-Dimethylaminorex (4,4'-DMAR) is a new synthetic stimulant, and only a little information has been made available so far regarding its pharmaco-toxicological effects. The aim of this study was to investigate the effects of the systemic administration of both the single (±)cis (0.1-60 mg/kg) and (±)trans (30 and 60 mg/kg) stereoisomers and their co-administration (e.g., (±)cis at 1, 10 or 60 mg/kg + (±)trans at 30 mg/kg) in mice. Moreover, we investigated the effect of 4,4'-DMAR on the expression of markers of oxidative/nitrosative stress (8-OHdG, iNOS, NT and NOX2), apoptosis (Smac/DIABLO and NF-κB), and heat shock proteins (HSP27, HSP70, HSP90) in the cerebral cortex. Our study demonstrated that the (±)cis stereoisomer dose-dependently induced psychomotor agitation, sweating, salivation, hyperthermia, stimulated aggression, convulsions and death. Conversely, the (±)trans stereoisomer was ineffective whilst the stereoisomers' co-administration resulted in a worsening of the toxic (±)cis stereoisomer effects. This trend of responses was confirmed by immunohistochemical analysis on the cortex. Finally, we investigated the potentially toxic effects of stereoisomer co-administration by studying urinary excretion. The excretion study showed that the (±)trans stereoisomer reduced the metabolism of the (±)cis form and increased its amount in the urine, possibly reflecting its increased plasma levels and, therefore, the worsening of its toxicity.


Assuntos
Comportamento Animal/efeitos dos fármacos , Oxazóis/toxicidade , Transtornos Psicofisiológicos/metabolismo , Transtornos Psicofisiológicos/patologia , Psicotrópicos/toxicidade , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oxazóis/classificação , Oxazóis/urina , Transtornos Psicofisiológicos/induzido quimicamente , Psicotrópicos/classificação , Psicotrópicos/urina , Estereoisomerismo
4.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360821

RESUMO

Dexamethasone (Dexa), frequently used as an anti-inflammatory agent, paradoxically leads to muscle inflammation and muscle atrophy. Receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) lead to nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome formation through nuclear factor-κB (NF-κB) upregulation. NLRP3 inflammasome results in pyroptosis and is associated with the Murf-1 and atrogin-1 upregulation involved in protein degradation and muscle atrophy. The effects of Ecklonia cava extract (ECE) and dieckol (DK) on attenuating Dexa-induced muscle atrophy were evaluated by decreasing NLRP3 inflammasome formation in the muscles of Dexa-treated animals. The binding of AGE or high mobility group protein 1 to RAGE or TLR4 was increased by Dexa but significantly decreased by ECE or DK. The downstream signaling pathways of RAGE (c-Jun N-terminal kinase or p38) were increased by Dexa but decreased by ECE or DK. NF-κB, downstream of RAGE or TLR4, was increased by Dexa but decreased by ECE or DK. The NLRP3 inflammasome component (NLRP3 and apoptosis-associated speck-like), cleaved caspase -1, and cleaved gasdermin D, markers of pyroptosis, were increased by Dexa but decreased by ECE and DK. Interleukin-1ß/Murf-1/atrogin-1 expression was increased by Dexa but restored by ECE or DK. The mean muscle fiber cross-sectional area and grip strength were decreased by Dexa but restored by ECE or DK. In conclusion, ECE or DK attenuated Dexa-induced muscle atrophy by decreasing NLRP3 inflammasome formation and pyroptosis.


Assuntos
Benzofuranos/farmacologia , Dexametasona/efeitos adversos , Glucocorticoides/efeitos adversos , Inflamassomos/efeitos dos fármacos , Atrofia Muscular , Piroptose/efeitos dos fármacos , Animais , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Extratos Vegetais/farmacologia
5.
Plant Foods Hum Nutr ; 76(3): 377-384, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34462872

RESUMO

The two main components from a Nelumbo nucifera leaf extract (NnEx) were investigated for their ability to prevent triglyceride accumulation and promoting lipolysis. Sun-dried Nelumbo nucifera leaves were immersed in hot water to extract the soluble components, and the resulting solution was analyzed by LC-MS and nuclear magnetic resonance. The results showed that quercetin-3-O-ß-glucuronide (Q3GA) and quercetin were the key components of the NnEx. In vitro experiments confirmed that quercetin and Q3GA functioned in lipid metabolism by promoting triglyceride degradation through inhibition of the cAMP pathway. In vivo experiments showed that NnEx ingestion inhibited the accumulation of neutral fats in ICR mice and transitioned the hepatocytes of type II diabetic KK-Ay mice out of glycogenosis. These results highlight the ability of NnEx to control metabolism by modulating fat and sugar absorption and may provide an interesting novel treatment for obesity and related lifestyle diseases such as type II diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Nelumbo , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Folhas de Planta
6.
Ann Palliat Med ; 10(7): 8015-8023, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34353086

RESUMO

BACKGROUND: Safflower extract (SE) improves depression in mice by inhibiting the TLR4-NLRP3 inflammatory signaling pathway. METHODS: Chronic unpredictable mild stress (CUMS) was used to establish a mouse model of depression. A total of 60 adult male ICR mice were randomly divided into 6 groups: control group, depression group (CUMS only), SE (10 mg/kg) + depression group (CUMS+SE, 10 mg/kg), SE (30 mg/kg) + depression group (CUMS+SE, 30 mg/kg), Cli-095 + depression group (CUMS+Cli-95), and fluoxetine hydrochloride (FLU) + depression group (CUMS+FLU). We assessed the depressive behaviors of these mice using the sucrose preference test (SPT), the open field test (OFT), the forced swim test (FST), and the tail suspension test (TST). We measured the expression levels of SOD, MDA, GSH-Px, 5-HT, NE, TNF-α, IL-1ß, and IL-6 using ELISA kits. Western blot was used to determine the relative expression levels of TLR4, p38, NF-κB, NLRP3, and caspase-1. RESULTS: SE significantly improved the results of the SPT, OFT, FST, and TST. SE also increased the expression levels of 5-HT and NE in the prefrontal cortex while decreased the expression levels of TNF-α, IL-1ß, and IL-6 compared with CUMS. SE (10 or 30 mg/kg) or FLU (10 mg/kg) significantly inhibited the expression of TLR4 and p-p38 induced by CUMS. SE significantly inhibited the expression of p-NF-κB in the prefrontal cortex and hippocampus induced by CUMS. The decrease of NLRP3 and caspase-1 were obviously reversed after administration of SE (10 or 30 mg/kg) or FLU (10 mg/kg). CONCLUSIONS: The results showed that SE has potential antidepressant effects in CUMS mice, and its underlying mechanism may be related to its effects on inflammation and the TLR4-NF-κB-NLRP3 signaling pathway in the brain.


Assuntos
Carthamus tinctorius , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Depressão/tratamento farmacológico , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Transdução de Sinais , Estresse Psicológico/tratamento farmacológico , Receptor 4 Toll-Like
7.
Neuroscience ; 472: 128-137, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34400248

RESUMO

Ketamine, an N-methyl-d-aspartate receptor (NMDAR) blocker, is gaining ground as a treatment option for depression. The occurrence of persistent psychosis and cognitive impairment after repeated use of ketamine remains a concern. N, N-dimethylglycine (DMG) is a nutrient supplement and acts as an NMDAR glycine site partial agonist. The objective of this study was to assess whether DMG could potentially prevent the behavioral and synaptic deficits in mice after repeated ketamine exposure. Male ICR mice received ketamine (20 mg/kg) from postnatal day (PN) 33-46, twice daily, for 14 days. The locomotor activity, novel location recognition test (NLRT), novel object recognition test (NORT), social interaction test, head twitch response induced by serotonergic hallucinogen, and the basal synaptic transmission and long-term potentiation (LTP) in the hippocampal slices were monitored after repeated ketamine treatment. Furthermore, the protective effects of repeated combined administration of DMG (30 and 100 mg/kg) with ketamine on behavioral abnormalities and synaptic dysfunction were assessed. The results showed that mice exhibited memory impairments, social withdrawal, increased head twitch response, reduced excitatory synaptic transmission, and lower LTP after repeated ketamine exposure. The ketamine-induced behavioral and synaptic deficits were prevented by co-treatment with DMG. In conclusion, these findings may pave a new path forward to developing a combination formula with ketamine and DMG for the treatment of depression and other mood disorders.


Assuntos
Ketamina , Animais , Ketamina/toxicidade , Potenciação de Longa Duração , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptores de N-Metil-D-Aspartato , Sarcosina/análogos & derivados
8.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202590

RESUMO

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone's antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone's action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.


Assuntos
Neuralgia , PPAR alfa/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Sesquiterpenos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia , PPAR alfa/metabolismo , PPAR gama/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo
9.
Int J Nanomedicine ; 16: 4239-4250, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194227

RESUMO

Purpose: Pore-forming toxins (PFTs) perform important functions during bacterial infections. Among various virulence-targeting therapies, nanosponges (NSs) have excellent neutralization effects on multiple PFTs. To enhance treatment efficacy, NSs tend to be incorporated into other biomaterials, such as hydrogels. Methods: In the present work, red blood cell (RBC) vesicles were harvested to wrap polymer nanoparticles, leading to the formation of NSs, and the optimal Pluronic F127 hydrogel concentration was determined for gelation. Then, a novel detoxification system was constructed by incorporating NSs into an optimized Pluronic F127 hydrogel (NS-pGel). Next, the system was characterized by rheological and sustained release behavior as well as micromorphology. Then, the in vitro neutralization effect of NS-pGel on various PFTs was examined by a hemolysis protocol. Finally, therapeutic and prophylactic detoxification efficiency was evaluated in a mouse subcutaneous infection model in vivo. Results: A thermosensitive, injectable detoxification system was successfully constructed by loading NSs into a 30% Pluronic F127 hydrogel. Characterization results demonstrated that the NS-pGel hybrid system sustained an ideal fluidity and viscosity at lower temperatures but exhibited a quick sol-gel transition capacity near body temperature. In addition, this hybrid system had a sustained release behavior accompanied by good biocompatibility and biodegradability. Finally, the NS-pGel system showed neutralization effects similar to those of NSs both in vitro and in vivo, indicating a good preservation of NS functionality. Conclusion: In conclusion, we constructed a novel temperature-sensitive detoxification system with good biocompatibility and biodegradability, which may be applied to the clinical treatment of PFT-induced local lesions and infections.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/química , Hidrogéis/administração & dosagem , Hidrogéis/química , Poloxâmero/química , Animais , Proteínas de Bactérias , Materiais Biocompatíveis , Eritrócitos/química , Proteínas Hemolisinas , Hemólise/efeitos dos fármacos , Masculino , Teste de Materiais , Camundongos Endogâmicos ICR , Nanopartículas/química , Testes de Neutralização , Reologia , Staphylococcus aureus/patogenicidade , Temperatura , Vibrio vulnificus/patogenicidade , Viscosidade
10.
Int J Mol Sci ; 22(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299276

RESUMO

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.


Assuntos
Analgésicos Opioides/toxicidade , Anisóis/toxicidade , Derivados de Benzeno/toxicidade , Alucinógenos/toxicidade , Fenciclidina/toxicidade , Psicotrópicos/toxicidade , Receptores Opioides/metabolismo , Tramadol/toxicidade , Analgésicos Opioides/química , Animais , Anisóis/química , Derivados de Benzeno/química , Células Cultivadas , Cricetinae , Alucinógenos/química , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Fenciclidina/química , Psicotrópicos/química , Tramadol/química
11.
Emerg Microbes Infect ; 10(1): 1555-1573, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34304724

RESUMO

To curb the pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), multiple platforms have been employed toward a safe and highly effective vaccine. Here, we develop a novel cell-based vaccine candidate, namely K562-S, by utilizing human cell K562 as a cellular carrier to display Spike (S) protein of SARS-CoV-2 on the membrane. Analogous to the traditional inactivated vaccine, K562-S cells can be propagated to a large scale by culturing and completely lose their viability after exposure to X-ray irradiation or formalin. We in turn demonstrated high immunogenicity of formalin-inactivated K562-S vaccine in both mouse and non-human primates and its protective efficacy in mice. In mice, immunization with inactivated K562-S vaccines can elicit potent neutralizing antibody (nAb) responses persisting longer than 5 months. We consequently showed in a hACE2 mouse model of SARS-CoV-2 infection that a two-shot vaccination with adjuvanted K562-S rendered greater than 3 log reduction in viral lung load and concomitant ameliorated lung pathology. Of importance, the administration of the same regimen in non-human primates was able to induce a neutralizing antibody titer averaging three-fold higher relative to human convalescent serum. These results together support the promise of K562-based, S-protein-expressing vaccines as a novel vaccination approach against SARS-CoV-2. Importantly, with a powerful capacity to carry external genes for cell-based vectors, this platform could rapidly generate two- and multiple-valent vaccines by incorporating SARS-CoV-2 mutants, SARS-CoV, or MERS-CoV.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunogenicidade da Vacina , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Animais Geneticamente Modificados , Vacinas contra COVID-19/administração & dosagem , Feminino , Células HEK293 , Humanos , Células K562 , Macaca mulatta , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Primatas , Organismos Livres de Patógenos Específicos , Glicoproteína da Espícula de Coronavírus/administração & dosagem , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodos , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia
12.
Methods Mol Biol ; 2312: 309-320, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228299

RESUMO

Developments in genome-editing technology, especially CRISPR-Cas9, have revolutionized the way in which genetically engineered animals are generated. However, the process of generation includes microinjection to the one-cell stage embryo and the transfer of the microinjected embryo to the surrogate animals, which requires trained personnel. We recently reported the method includes introduction of CRISPR-Cas9 systems to the developing cerebral cortex via in utero electroporation thus generating gene-targeted neural stem cells in vivo. This technique is widely applicable for gene knockout, monitoring gene expression, and lineage analysis in developmental biology. In this chapter, the detailed protocol of EGFP (enhanced green fluorescent protein) knock-in method via in utero electroporation is described.


Assuntos
Encéfalo/metabolismo , Eletroporação , Regulação da Expressão Gênica no Desenvolvimento , Marcação de Genes , Técnicas de Transferência de Genes , Animais , Encéfalo/embriologia , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Feminino , Técnicas de Introdução de Genes , Genes Reporter , Idade Gestacional , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Gravidez , RNA Guia/genética , RNA Guia/metabolismo
13.
Toxicology ; 459: 152853, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34252480

RESUMO

Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo. Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1-100 µM) reduced OXA (40 µM) induced cytotoxicity in MDCK-hOCT2 (Madin-Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5-20 mg/kg for mice, 10-40 mg/kg for rats; twice a week, iv or ig) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1-100 µM for cells; 10-20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 µM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Alcaloides de Berberina/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Gânglios Espinais/metabolismo , Mitocôndrias/metabolismo , Oxaliplatina/farmacocinética , Oxaliplatina/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Cães , Gânglios Espinais/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Ratos , Membro 5 da Família 22 de Carreadores de Soluto/antagonistas & inibidores , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo
14.
Molecules ; 26(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34279442

RESUMO

Partially purified ginsenoside extract (PGE) and compound K enriched extract (CKE) were prepared from ginseng sprouts, and their antioxidant, anti-inflammatory and antithrombotic effects were investigated. Compared to the 6-year-old ginseng roots, ginseng sprouts were found to have a higher content of phenolic compounds, saponin and protopanaxadiol-type ginsenoside by about 56%, 36% and 43%, respectively. PGE was prepared using a macroporous adsorption resin, and compound K(CK) was converted and enriched from the PGE by enzymatic hydrolysis with a conversion rate of 75%. PGE showed higher effects than CKE on radical scavenging activity in antioxidant assays. On the other hand, CKE reduced nitric oxide levels more effectively than PGE in RAW 264.7 cells. CKE also reduced pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 than PGE. Tail bleeding time and volume were investigated after administration of CKE at 70-150 mg/kg/day to mice. CKE administered group showed a significant increase or increased tendency in bleeding time than the control group. Bleeding volume in the CKE group increased than the control group, but not as much as in the aspirin group. In conclusion, ginseng sprouts could be an efficient source of ginsenoside, and CKE converted from the ginsenosides showed antioxidant, anti-inflammatory and antithrombotic effects. However, it was estimated that the CKE might play an essential role in anti-inflammatory effects rather than antioxidant effects.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Fibrinolíticos/farmacologia , Ginsenosídeos/farmacologia , Panax/química , Extratos Vegetais/farmacologia , Animais , Citocinas/metabolismo , Hemorragia/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/metabolismo , Células RAW 264.7
15.
Zool Res ; 42(4): 514-524, 2021 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-34254745

RESUMO

Normal spermatogenic processes require the scrotal temperature to be lower than that of the body as excessive heat affects spermatogenesis in the testes, reduces sperm quality and quantity, and even causes infertility. Endoplasmic reticulum stress (ERS) is a crucial factor in many pathologies. Although several studies have linked ERS to heat stress, researchers have not yet determined which ERS signaling pathways contribute to heat-induced testicular damage. Melatonin activates antioxidant enzymes, scavenges free radicals, and protects the testes from inflammation; however, few studies have reported on the influence of melatonin on heat-induced testicular damage. Using a murine model of testicular hyperthermia, we observed that heat stress causes both ERS and apoptosis in the testes, especially in the spermatocytes. These observations were confirmed using the mouse spermatocyte cell line GC2, where the Atf6 and Perk signaling pathways were activated during heat stress. Knockout of the above genes effectively reduced spermatocyte damage caused by heat stress. Pretreatment with melatonin alleviated heat-induced apoptosis by inhibiting the Atf6 and Perk signaling pathways. This mitigation was dependent on the melatonin receptors. In vivo experiments verified that melatonin treatment relieved heat-induced testicular damage. In conclusion, our results demonstrated that ATF6 and PERK are important mediators for heat-induced apoptosis, which can be prevented by melatonin treatment. Thus, our study highlights melatonin as a potential therapeutic agent in mammals for subfertility/infertility induced by testicular hyperthermia.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Temperatura Alta/efeitos adversos , Melatonina/farmacologia , Espermatócitos/efeitos dos fármacos , Testículo/fisiologia , eIF-2 Quinase/metabolismo , Fator 6 Ativador da Transcrição/genética , Animais , Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Transdução de Sinais/efeitos dos fármacos , eIF-2 Quinase/genética
16.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299127

RESUMO

Reelin is a secretory protein involved in a variety of processes in forebrain development and function, including neuronal migration, dendrite growth, spine formation, and synaptic plasticity. Most of the function of Reelin is focused on excitatory neurons; however, little is known about its effects on inhibitory neurons and inhibitory synapses. In this study, we investigated the phosphatidylinositol 3-kinase/Akt pathway of Reelin in primary cortical and hippocampal neurons. Individual neurons were visualized using immunofluorescence to distinguish inhibitory neurons from excitatory neurons. Reelin-rich protein supplementation significantly induced the phosphorylation of Akt and ribosomal S6 protein in excitatory neurons, but not in most inhibitory neurons. In somatostatin-expressing inhibitory neurons, one of major subtypes of inhibitory neurons, Reelin-rich protein supplementation induced the phosphorylation of S6. Subsequently, we investigated whether or not Reelin-rich protein supplementation affected dendrite development in cultured inhibitory neurons. Reelin-rich protein supplementation did not change the total length of dendrites in inhibitory neurons in vitro. Finally, we examined the development of inhibitory synapses in primary hippocampal neurons and found that Reelin-rich protein supplementation significantly reduced the density of gephyrin-VGAT-positive clusters in the dendritic regions without changing the expression levels of several inhibitory synapse-related proteins. These findings indicate a new role for Reelin in specific groups of inhibitory neurons and the development of inhibitory synapses, which may contribute to the underlying cellular mechanisms of RELN-associated neurological disorders.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Dendritos/fisiologia , Proteínas da Matriz Extracelular/metabolismo , Potenciais Pós-Sinápticos Inibidores , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural , Plasticidade Neuronal , Neurônios/fisiologia , Serina Endopeptidases/metabolismo , Sinapses/fisiologia , Animais , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Hipocampo/citologia , Hipocampo/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Proteínas do Tecido Nervoso/genética , Neurogênese , Neurônios/citologia , Serina Endopeptidases/genética , Transdução de Sinais
17.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(4): 605-611, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34323038

RESUMO

Objective: To construct a nanodelivery system surface-modified with RD2 peptide (polypeptide sequence PTLHTHNRRRRR) for brain tissue penetration and ß-amyloid (Aß) binding. Epigallocatechin-3-gallate (EGCG) was selected for encapsulation in the targeted delivery system and its therapeutic potential for Alzheimer's disease (AD) was investigated. Methods: EGCG-load nanoparticles (NP/EGCG), NP/EGCG with RD2 peptide surface modification (RD2-NP/EGCG), as well as RD2 peptide-modified blank nanoparticles (RD2-NP) were prepared and characterized. Thioflavin T assay was done to assess the ability of RD2-NP to bind with Aß and ex vivo imaging was conducted to evaluate the distribution of RD2-NP in brain lesion sites. The AD mice model was established by injecting oligomeric Aß 42 in the bilateral hippocampi of ICR mice. Then AD mice were administered intravenously through the tail vein with normal saline, EGCG solution, NP/EGCG or RD2-NP/EGCG for 28 d, respectively, and the Morris water maze tests were performed to assess the spatial memory of mice. Subsequently, RT-PCR method was used to determine the mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the hippocampus of the mice, and the morphological changes of hippocampal neurons were observed with Nissl staining. Additionally, the pathological changes of heart, liver, spleen, lung, and kidney were characterized by hematoxylin-eosin (HE) staining. Results: The particle diameter of the prepared RD2-NP/EGCG was (204.83±2.80) nm and the zeta potential was -23.88 mV. The encapsulation efficiency and drug loading capacity were 94.39% and 5.90%, respectively. The RD2 peptide modification has no significant effect on the physiochemical properties of the nanoparticles. RD2-NP had good Aß binding ability, and it could be concentrated in hippocampus and cerebral cortex, the most common Aß deposition sites. The four-week RD2-NP/EGCG treatment significantly decreased the expression of the pro-inflammatory cytokine TNF-α and IL-1ß, restored neuronal losses and hippocampal damage, and ameliorated spatial memory impairment in AD model mice. Moreover, treatment with the RD2-NP/EGCG did not present organ toxicity. Conclusion: Surface modified RD2 peptide nanodelivery system can efficiently deliver drugs to AD lesions and improve the therapeutic effect of EGCG on AD.


Assuntos
Doença de Alzheimer , Nanopartículas , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Catequina/análogos & derivados , Modelos Animais de Doenças , Hipocampo , Camundongos , Camundongos Endogâmicos ICR , Oligopeptídeos
18.
FASEB J ; 35(8): e21794, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34314059

RESUMO

While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high-fat diet (HFD)-induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD-induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway-driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our results suggest BGN as a potential therapeutic target to treat risk factors for metabolic diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Biglicano/administração & dosagem , Glucose/metabolismo , Músculo Esquelético/efeitos dos fármacos , Obesidade/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Linhagem Celular , Comportamento Alimentar , Camundongos , Camundongos Endogâmicos ICR , Ratos
19.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299015

RESUMO

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity.


Assuntos
Alcaloides/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzodioxóis/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pentanonas/farmacologia , Pirrolidinas/farmacologia , Ácido gama-Aminobutírico/metabolismo
20.
Life Sci ; 282: 119821, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34271059

RESUMO

AIMS: C57BL/6J mice are well-known to exhibit resilience to chronic social defeat stress (CSDS) for induction of depressive-like behavior. Establishment of protocols for reproducible induction of depressive-like behavior in C57BL/6J mice would be useful to elucidate the underlying molecular mechanisms using target gene-knock-in and -out mice whose background is generally C57BL/6J. Here, we developed a modified CSDS protocol for reproducible induction of depressive-like behavior in C57BL/6J mice, and compared the profile of their gut microbiota with that with the standard CSDS protocol. MAIN METHODS: To prevent acclimation of defeated C57BL/6J mice to aggressive ICR mice, the sensory contact following a daily 10 min-defeat episode was performed by housing an individual defeated mouse in a cage set next to a cage for the aggressor one. KEY FINDINGS: The number of attacks by ICR mice on C57BL/6J ones was significantly increased with the modified CSDS protocol, and the susceptible mice exhibited greater hippocampal inflammation and an increased immobility time in the forced swim test, compared in the case of the standard CSDS protocol, and the reproducibility was confirmed in another set of experiments. Both the standard and modified CSDS protocols changed the diversity and relative composition of gut microbiota in the susceptible mice, but there was no apparent difference in them between the standard and modified CSDS-susceptible mice. SIGNIFICANCE: We established a CSDS protocol for reproducible induction of depressive-like behavior in C57BL/6J mice, and the features of the gut microbiota were similar in the susceptible mice with and without the depressive-like behavior.


Assuntos
Comportamento Animal , Depressão/microbiologia , Microbioma Gastrointestinal , Derrota Social , Estresse Psicológico/microbiologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos ICR
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