RESUMO
Reactive oxygen species (ROS) are produced during oxidative metabolism in aerobic organisms. Under normal conditions, ROS production and elimination are in a relatively balanced state. However, under internal or external environmental stress, such as high glucose levels or UV radiation, ROS production can increase significantly, leading to oxidative stress. Excess ROS production not only damages biomolecules but is also closely associated with the pathogenesis of many diseases, such as skin photoaging, diabetes, and cancer. Antioxidant peptides (AOPs) are naturally occurring or artificially designed peptides that can reduce the levels of ROS and other pro-oxidants, thus showing great potential in the treatment of oxidative stress-related diseases. In this review, we discussed ROS production and its role in inducing oxidative stress-related diseases in humans. Additionally, we discussed the sources, mechanism of action, and evaluation methods of AOPs and provided directions for future studies on AOPs.
Assuntos
Antioxidantes , Estresse Oxidativo , Humanos , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico , OxirreduçãoRESUMO
BACKGROUND: In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism. METHODS: We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1. RESULTS: HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions. CONCLUSIONS: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.
Assuntos
Morte Celular Imunogênica , Proteínas de Membrana , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Animais , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Feminino , Camundongos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismoRESUMO
OBJECTIVES: Depression is a widely prevalent mental disorder, and nutritional interventions play an increasingly important role in its treatment. In this paper, effects of linoleic acid (LA) on depressive behavior in mice induced by gut microbiome disorders were investigated. METHODS: Fifty C57BL/6J male mice were randomly separated into five groups, control group (CK), ceftriaxone sodium group (CRO), low-dose linoleic acid group (LLA, 1 g/kg), medium-dose linoleic acid group (MLA, 2 g/kg), and high-dose linoleic acid group (HLA, 5 g/kg). In the LLA, MLA, and HLA groups, mice were treated with ceftriaxone sodium (CRO) to induce depressive behaviors, followed by LA administration. Behavioral tests were used to evaluate depressive behavior. High-throughput sequencing and Hematoxylin-eosin (H&E) staining in gut microenvironment were carried out. ELISA kits were used to measure brain inflammatory factors, and 5-hydroxy-tryptamine (5-HT). Gas chromatography and western blot were used to determine fatty acids compositions and the enzymes expression involved in lipid metabolism in brain respectively. RESULTS: The results showed that 10 weeks CRO treatment contribute to depressive behavior, gut microbiome disturbance, and serotonin system disturbance. LLA and MLA improved the depressive-like behavior, and significantly increased the levels of 5-HT1A, 5-HTT and 5-HT in the hippocampus. LLA was found to improve the diversity of gut microbiome and alleviate colon tissue damage. Meantime, LLA increased the content of linoleic acid, improved the expression of FADS2 and COX-2, increased IL-10 levels, and decreased IL-6 levels in the brain. DISCUSSION: LA alleviated depressive behavior in mice by improving the gut microenvironment, regulate fatty acid metabolism, and modulate inflammation.
RESUMO
Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), are important effector immune defense molecules in multicellular organisms. AMPs exert their antimicrobial activities through several mechanisms; thus far, induction of drug resistance through AMPs has been regarded as unlikely. Therefore, they have great potential as new generation antimicrobial agents. To date, more than 30 AMP-related drugs are in the clinical trial phase. In recent years, studies show that some AMPs and conventional antibiotics have synergistic effects. The combined use of AMPs and antibiotics can kill drug-resistant pathogens, prevent drug resistance, and significantly improve the therapeutic effects of antibiotics. In this review, we discuss the progress in synergistic studies on AMPs and conventional antibiotics. An overview of the current understanding of the functional scope of AMPs, ongoing clinical trials, and challenges in the development processes are also presented.
Assuntos
Antibacterianos , Anti-Infecciosos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Peptídeos Antimicrobianos , HumanosRESUMO
OBJECTIVE: Vascular endothelial growth factor B (VEGFB) was regarded to improve lipid metabolism and reduce obesity-related hyperlipidemia. Whether VEGFB participates in lipid metabolism in nonalcoholic fatty liver disease (NAFLD) has not been clear yet. This study investigated the involvement of VEGFB in lipid metabolism and insulin resistance via the AMPK signaling pathway in NAFLD. METHODS: We constructed the animal and cell model of NAFLD after VEGFB gene knockout to detect liver damage and metabolism in NAFLD. Bioinformatics analysis of VEGFB and the AMPK signaling pathway relative genes to verify the differential proteins. And mRNA levels of NAFLD fatty acid metabolism-related genes were detected. RESULTS: After the systemic VEGFB knockout mice were fed with high fat, the body fat, serum lipoprotein, NAFLD score, and insulin resistance were increased. Animal and cell experiments showed that the expression levels of phosphorylated proteins of CaMKK2 and AMPK decreased, the expression of proteins related to AMPK/ACC/CPT1 signaling pathway decreased, and the target genes CPT1α and Lcad decreased accordingly, reducing fatty acid oxidation in hepatocyte mitochondria; The expression of AMPK/SREBP1/Scd1 signaling pathway relative proteins increased, ACC1 and FAS increased correspondingly, which increased lipid synthesis in the endoplasmic reticulum. CONCLUSION: VEGFB can participate in lipid metabolism and insulin resistance of NAFLD through the AMPK signaling pathway.
Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Fator B de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Radiation-induced pneumonitis (RP) is a non-negligible and sometimes life-threatening complication among patients with thoracic radiation. We initially aimed to ascertain the predictive value of acute radiation-induced esophagitis (SARE, grade ≥ 2) to symptomatic RP (SRP, grade ≥ 2) among thoracic cancer patients receiving radiotherapy. Based on that, we established a novel nomogram model to provide individualized risk assessment for SRP. METHODS: Thoracic cancer patients who were treated with thoracic radiation from Jan 2018 to Jan 2019 in Shandong Cancer Hospital and Institute were enrolled prospectively. All patients were followed up during and after radiotherapy (RT) to observe the development of esophagitis as well as pneumonitis. Variables were analyzed by univariate and multivariate analysis using the logistic regression model, and a nomogram model was established to predict SRP by "R" version 3.6.0. RESULTS: A total of 123 patients were enrolled (64 esophageal cancer, 57 lung cancer and 2 mediastinal cancer) in this study prospectively. RP grades of 0, 1, 2, 3, 4 and 5 occurred in 29, 57, 31, 0, 3 and 3 patients, respectively. SRP appeared in 37 patients (30.1%). In univariate analysis, SARE was shown to be a significant predictive factor for SRP (P < 0.001), with the sensitivity 91.9% and the negative predictive value 93.5%. The incidence of SRP in different grades of ARE were as follows: Grade 0-1: 6.5%; Grade 2: 36.9%; Grade 3: 80.0%; Grade 4: 100%. Besides that, the dosimetric factors considering total lung mean dose, total lung V5, V20, ipsilateral lung mean dose, ipsilateral lung V5, and mean esophagus dose were correlated with SRP (all P < 0.05) by univariate analysis. The incidence of SRP was significantly higher in patients whose symptoms of RP appeared early. SARE, mean esophagus dose and ipsilateral mean lung dose were still significant in multivariate analysis, and they were included to build a predictive nomogram model for SRP. CONCLUSIONS: As an early index that can reflect the tissue's radiosensitivity visually, SARE can be used as a predictor for SRP in patients receiving thoracic radiation. And the nomogram containing SARE may be fully applied in future's clinical work.
Assuntos
Quimiorradioterapia/efeitos adversos , Esofagite/epidemiologia , Nomogramas , Pneumonite por Radiação/epidemiologia , Neoplasias Torácicas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia/métodos , Quimiorradioterapia/estatística & dados numéricos , Esofagite/diagnóstico , Esofagite/etiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Pneumonite por Radiação/diagnóstico , Pneumonite por Radiação/etiologia , Tolerância a Radiação , Dosagem Radioterapêutica , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Recently, the development of distributed renewable energy resources, smart devices, and smart grids empowers the emergence of peer-to-peer energy trading via local energy markets. However, due to security and privacy concerns in energy trading, sensitive information of energy traders could be leaked to an adversary. In addition, malicious users could perform attacks against the energy market, such as collusion, double spending, and repudiation attacks. Moreover, network attacks could be executed by external attackers against energy networks, such as eavesdropping, data spoofing, and tampering attacks. To tackle the abovementioned attacks, we propose a secure and privacy-preserving energy trading system (SPETS). First, a permissioned energy blockchain is presented to perform secure energy transactions between energy sellers and buyers. Second, a discrete-time double auction is proposed for energy allocation and pricing. Third, the concept of reputation scores is adopted to guarantee market reliability and trust. The proposed energy system is implemented using Hyperledger Fabric (HF) where the chaincode is utilized to control the energy market. Theoretical analysis proves that SPETS is resilient to several security attacks. Simulation results demonstrate the increase in sellers' and buyers' welfare by approximately 76.5% and 26%, respectively. The proposed system ensures trustfulness and guarantees efficient energy allocation. The benchmark analysis proves that SPETS consumes few resources in terms of memory and disk usage, CPU, and network utilization.
Assuntos
Blockchain , Privacidade , Fenômenos Físicos , Energia Renovável , Reprodutibilidade dos TestesRESUMO
Antibiotic-resistant bacteria are severe threats to aquaculture industry. Boosting and modulating host immune responses has been proved to be an effective strategy to combat with bacterial infections and there is an urgent need for novel immunomodulators. Cathelicidins is an important family of host defense peptides (HDPs) that possess direct antimicrobial activities and potent immunomodulatory properties. Several cathelicidins have been identified and characterized from diverse fish species. Considering the relatively conserved immune systems between different fish species, it is reasonable to speculate that cathelicidins from different fish species possess immunomodulating functions on the other fish species. In the present study, two fish-derived cathelicidins (CATH_BRALE and codCath1) were selected to investigate their protective effect on zebrafish with bacterial infections. They exhibited potent and broad-spectrum antimicrobial activities against the tested aquatic Gram-positive and Gram-negative pathogenic bacteria, with MIC values ranging 2.34-18.75⯵g/ml for CATH_BRALE and 2.34-37.5⯵g/ml for codCath1. And their antimicrobial effect is so rapid that they killed the bacteria within 60â¯min. Unlike conventional antibiotics, they kill bacteria by inducing bacterial membrane permeabilization and cell disruption. Besides direct antimicrobial activity, CATH_BRALE and codCath1 exhibited potent immunomodulatory functions by both inhibiting bacteria induced zebrafish pro-inflammatory cytokine gene (TNF-α, IL-1ß, and IL-6) expression and stimulating zebrafish chemokine gene IL-8 expression. In vivo challenge test proved that they could significantly decrease the bacterial numbers and enhance the survival rates of zebrafish. All the results above imply the great potential of CATH_BRALE and codCath1 as novel peptide immunomodulators in fish aquaculture industry.
Assuntos
Catelicidinas/farmacologia , Doenças dos Peixes/prevenção & controle , Proteínas de Peixes/farmacologia , Substâncias Protetoras/farmacologia , Peixe-Zebra , Animais , Doenças dos Peixes/microbiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/prevenção & controle , Infecções por Bactérias Gram-Negativas/veterinária , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/prevenção & controle , Infecções por Bactérias Gram-Positivas/veterinária , Distribuição AleatóriaRESUMO
The cathelicidins represent an important family of host defense peptides (HDPs) found exclusively in vertebrates, which serve as a critical effector in host immune response against microbial infections. To date, a large number of cathelicidins has been identified from diverse vertebrates, such as mammals, birds, reptiles, amphibians and fishes. Sixteen cathelicidins have been identified from snakes in the Elapidae, Viperidae, and Biodae families. However, no cathelicidin has been discovered from a snake of the Colubrinae family. In the present study, we report the identification and characterization of a novel cathelicidin, SA-CATH, from the Colubrinae family snake, Sinonatrix annularis. The cDNA sequence encoding SA-CATH precursor is 735 bp in length, and the mature peptide (SA-CATH) is composed of 30 amino acid residues. Sequence alignment result indicated that SA-CATH precursor possesses relatively high sequence similarity with the cathelicidins from Elapidae and Viperidae family snakes. Similar as the cathelicidins from Elapidae, Viperidae, and Biodae family snakes, SA-CATH mainly assumes an amphipathic alpha-helical conformation, and possesses potent antimicrobial, biofilm inhibitory and anti-inflammatory activities. The results in the present study imply that cathelicidins serve as a kind of conserved effectors with similar structures in the immune systems of Colubrinae, Boidae, Elapidae and Viperidae family snakes. The identification of SA-CATH provides novel clues for the understanding of function and evolution of snake immune systems. The potent antimicrobial, biofilm inhibitory, anti-inflammatory, and slight cytotoxic activities of SA-CATH imply that it is a potential drug candidate in novel antimicrobial agent development.
Assuntos
Catelicidinas/isolamento & purificação , Colubridae , Sequência de Aminoácidos , Animais , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Catelicidinas/química , Catelicidinas/farmacologia , Feminino , Fungos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Camundongos Endogâmicos C57BL , Filogenia , Análise de Sequência de DNARESUMO
Crocodilians are regarded as possessing a powerful immune system. However, the composition and action of the crocodilian immune system have remained unclear until now. Cathelicidins, the principal family of host defense peptides, play pivotal roles in vertebrate immune defense against microbial invasions. However, cathelicidins from crocodilians have not been extensively studied to date. In the present study, six novel cathelicidins (As-CATH1-6) were identified and characterized from the endangered Chinese alligator (Alligator sinensis). As-CATH1-6 exhibit no sequence similarity with any of the known cathelicidins. Structure analysis indicated that As-CATH1-3 adopt a random coil secondary conformation, whereas As-CATH4-6 were predicted to mainly adopt an amphipathic α-helix conformation. Among them, As-CATH4-6 exhibited potent, broad-spectrum and rapid antimicrobial activity by inducing the disruption of cell membrane integrity. They also exhibited strong ability to prevent the formation of bacterial biofilms and eradicate preformed biofilms. Furthermore, As-CATH4-6 exhibited potent anti-inflammatory activity by inhibiting the lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and pro-inflammatory cytokines in mouse peritoneal macrophages. They directly neutralized LPS toxicity and therefore inhibited the binding of LPS to the TLR4 receptor and the subsequent activation of inflammatory response pathways. In a peritonitis mice model, As-CATH2-6 provided effective protection against bacterial infection through enhanced immune cell recruitment. In the host Chinese alligator, As-CATH1-6 are mainly expressed in immune organs and epithelial tissues. Bacterial infection significantly enhances their expression, which implies an important role in host anti-infective response. Taken together, the diversity and multiple functions of As-CATH1-6 partially reveal the powerful immune system of the Chinese alligator.
Assuntos
Jacarés e Crocodilos/imunologia , Anti-Infecciosos/imunologia , Anti-Inflamatórios não Esteroides/imunologia , Peptídeos Catiônicos Antimicrobianos/imunologia , Peritonite/tratamento farmacológico , Isoformas de Proteínas/imunologia , Sequência de Aminoácidos , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Sequência de Bases , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Expressão Gênica , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Sistema Imunitário , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Peritonite/microbiologia , Peritonite/patologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Domínios Proteicos , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/química , Isoformas de Proteínas/farmacologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologiaRESUMO
BACKGROUND: Binary functional monomers, allyl-ß-cyclodextrin (allyl-ß-CD) and methacrylic acid (MAA) or allyl-ß-CD and acrylonitrile (AN), were exploited in a fabrication of molecularly imprinted polymers (MIPs) for selective recognition and large enrichment of pirimicarb from aqueous media. RESULTS: Special attention was paid to the computational simulation of the imprinting molecular and functional monomers. The morphological characteristics of MIPs made of allyl-ß-CD and MAA (M-MAA) were characterised by scanning electron microscopy. The effect of binding capacity of MAA-linked allyl-ß-CD MIPs (M-MAA) demonstrated higher efficiency than that of AN-linked allyl-ß-CD MIPs (M-AN) when tested in binding specificity. Finally, M-MAA was chosen to run through molecularly imprinted solid-phase extraction (MISPE) to analyse the spiked fresh leafy vegetables of pirimicarb. CONCLUSION: The present proposed technique is a promising tool for the preparation of the receptors which could recognise pirimicarb pesticide in aqueous media. © 2017 Society of Chemical Industry.
Assuntos
Carbamatos/química , Praguicidas/química , Pirimidinas/química , Extração em Fase Sólida/métodos , Poluentes Químicos da Água/química , beta-Ciclodextrinas/química , Adsorção , Carbamatos/isolamento & purificação , Metacrilatos/química , Impressão Molecular , Praguicidas/isolamento & purificação , Polímeros/síntese química , Polímeros/química , Pirimidinas/isolamento & purificação , Extração em Fase Sólida/instrumentação , Poluentes Químicos da Água/isolamento & purificação , beta-Ciclodextrinas/síntese químicaRESUMO
Host defense peptides (HDPs), a class of conserved components of animal innate immune system, possess direct antimicrobial activities against invading pathogens and broadly participate in boosting and modulating host immune responses. Cathelicidins is an important family of HDPs that has been identified exclusively in vertebrates. Considering the relatively conserved innate immune system between invertebrates and vertebrates, it is speculated that HDPs from vertebrates may also possess modulating functions on invertebrate innate immune system. In the present study, two novel cathelicidins (As-CATH4 and 5), which had been identified from the Chinese alligator in our previous study, were employed to investigate their functions as novel peptide immunostimulants in Chinese mitten crab. As-CATH4 and 5 exhibited potent, broad-spectrum, and rapid antimicrobial activities against all the tested aquatic pathogenic bacteria. Unlike traditional antibiotics, they target on bacterial cell membrane, induce membrane permeabilization and cell disruption, and ultimately result in cell death. The antimicrobial effect is far more rapid than traditional antibiotics. Therefore they are unlikely to induce bacteria resistance. After the crabs were administered with As-CATH4 and 5, the activities of lysozyme, acid phosphatase and alkaline phosphatase were significantly enhanced, which indicated that the immune system of crabs could be activated by As-CATH4 and 5. In bacteria challenge test, As-CATH4 and 5 could significantly decrease the bacterial numbers in crabs, and increase the survival rates of crabs in both pre-stimulation and co-stimulation groups. All of the results above indicated the great potential of As-CATH4 and 5 as novel peptide immunostimulants in the crab aquaculture.
Assuntos
Adjuvantes Imunológicos/farmacologia , Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Braquiúros/imunologia , Catelicidinas/imunologia , Imunidade Inata , Proteínas de Répteis/imunologia , Adjuvantes Imunológicos/administração & dosagem , Jacarés e Crocodilos/genética , Animais , Braquiúros/microbiologia , Catelicidinas/administração & dosagem , Catelicidinas/síntese química , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica , Distribuição Aleatória , Proteínas de Répteis/administração & dosagem , Proteínas de Répteis/síntese químicaRESUMO
BACKGROUND 5-HT6 receptor (5-HT6R) has pluripotent roles regulating secretion of neurotransmitters. However, whether 5-HT6R is involved in the development of vascular dementia (VD) remains unclear. To evaluate the role and mechanism of 5-HT6R in VD, this study established a rat VD model to evaluate the effect of selective 5-HT6R agonist on the expression of 5-HT6R mRNA and neurotransmitter. MATERIAL AND METHODS Eighty healthy male SD rats (7 weeks old) were randomly assigned to sham, model, 5-HT6R agonist, and placebo groups (N=20 each). A rat VD model was generated by permeant bilateral ligation of the common carotid artery. 5-HT6R agonist, placebo, or saline were given intraperitoneally for 4 weeks. The Morris water maze was utilized to test learning and memory function. Brains were extracted to separate the cortex and hippocampal tissues, in which glutamate and g-aminobutyric acid (GABA) levels were analyzed. mRNA and protein levels of 5-HT6R were determined by RT-PCR and immunohistochemistry (IHC), respectively. RESULTS Model rats had longer escape latency and fewer crossing platform times. Contents of DA, Glu, GABA, and Ach were lowered in cortical and hippocampal tissues, and 5-HT6R expression was suppressed (p<0.05). The application of 5-HT6R agonist shortened escape latency and increased the number of passing through the platform. It also improved hippocampal CA1 neuronal damage and elevated DA, Glu, GABA, and Ach contents and expression of 5-HT6R. Expression of 5-HT6R was not different from the placebo group. CONCLUSIONS Selective 5-HT6R agonist can alleviate learning deficit of VD rats, possibly via improving neurotransmitter levels in brain regions.
Assuntos
Demência Vascular/tratamento farmacológico , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Demência Vascular/metabolismo , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Aprendizagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Memória/fisiologia , Neurotransmissores/agonistas , Neurotransmissores/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
Prostate cancer (PCa), the most common malignancy in men, is a major cause of cancer deaths. A better understanding of the mechanisms that drive tumor initiation and progression may identify actionable targets to improve treatment of this patient group. As a dietary carotenoid, astaxanthin has been demonstrated to exert beneficial effects against inflammation, cardiovascular disease, oxidative damage, or different cancer sites. This study used intragastric administration of astaxanthin to detect its role on tumor proliferation, apoptosis, microRNA (miRNA) overexpression, and microbacteria composition change by establishing androgen-independent PCa cell PC-3 xenograft nude mice. Nude mice were inoculated with androgen-independent prostate cancer PC-3 cells subcutaneously. The intervention was started when tumors reached 0.5-0.6 cm in diameter. Mice were intragastrically administered 100 mg/kg astaxanthin (HA), 25 mg/kg astaxanthin (LA), or olive oil (TC). The results showed that 100 mg/kg astaxanthin significantly inhibited tumor growth compared to the TC group, with an inhibitory rate of 41.7%. A decrease of Ki67 and proliferating cell nuclear antigen (PCNA) as well as an increase of cleaved caspase-3 were observed in HA-treated tumors, along with increasing apoptotic cells, obtained by TUNEL assay. The HA significantly elevated the levels of tumor suppressors miR-375 and miR-487b in tumor tissues and the amount of Lactobacillus sp. and Lachnospiraceae in mice stools, while there was no significant difference between LA and TC groups. These results provide a promising regimen to enhance the therapeutic effect in a dietary supplement manner.
Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Androgênios/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/metabolismo , Transplante Heterólogo/métodos , Xantofilas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Leaf spot disease caused by the fungus Fusarium proliferatum (Matsushima) Nirenberg is a destructive disease of tomato plants in China. Typical symptoms of infected tomato plants are softened and wilted stems and leaves, leading to the eventual death of the entire plant. In this study, we resorted to transcriptional profile analysis to gain insight into the repertoire of effectors involved in F. proliferatum-tomato interactions. A total of 61,544,598 clean reads were de novo assembled to provide a F. proliferatum reference transcriptome. From these, 75,044 unigenes were obtained, with 19.46% of the unigenes being assigned to 276 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, with 22.3% having a homology with genes from F. fujikuroi. A total of 18,075 differentially expressed genes (DEGs) were identified, 720 of which were found to code for secreted proteins. Of these, 184 were identified as candidate effectors, while 79.89% had an upregulated expression. Moreover, 17 genes that were differentially expressed in RNA-seq studies were randomly selected for validation by quantitative real-time polymerase chain reaction (qRT-PCR). The study demonstrates that transcriptome analysis could be an effective method for identifying the repertoire of candidate effectors and may provide an invaluable resource for future functional analyses of F. proliferatum pathogenicity in F. proliferatum and tomato plant-host interactions.
Assuntos
Fusarium/genética , Doenças das Plantas/microbiologia , Solanum lycopersicum/microbiologia , Transcriptoma , Fusarium/patogenicidade , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Genes Fúngicos , Folhas de Planta/microbiologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Cathelicidins are a family of gene-encoded peptide effectors of innate immunity found exclusively in vertebrates. They play pivotal roles in host immune defense against microbial invasions. Dozens of cathelicidins have been identified from several vertebrate species. However, no cathelicidin from marine reptiles has been characterized previously. Here we report the identification and characterization of a novel cathelicidin (Hc-CATH) from the sea snake Hydrophis cyanocinctus. Hc-CATH is composed of 30 amino acids, and the sequence is KFFKRLLKSVRRAVKKFRKKPRLIGLSTLL. Circular dichroism spectroscopy and structure modeling analysis indicated that Hc-CATH mainly assumes an amphipathic α-helical conformation in bacterial membrane-mimetic solutions. It possesses potent broad-spectrum and rapid antimicrobial activity. Meanwhile, it is highly stable and shows low cytotoxicity toward mammalian cells. The microbial killing activity of Hc-CATH is executed through the disruption of cell membrane and lysis of bacterial cells. In addition, Hc-CATH exhibited potent anti-inflammatory activity by inhibiting the LPS-induced production of nitric oxide (NO) and pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-6. Hc-CATH directly binds with LPS to neutralize its toxicity, and it also binds to Toll-like receptor 4 (TLR4/MD2 complex), which therefore inhibits the binding of LPS to TLR4/MD2 complex and the subsequent activation of LPS-induced inflammatory response pathways. Taken together, our study demonstrates that Hc-CATH, the first cathelicidin from sea snake discovered to have both antimicrobial and anti-inflammatory activity, is a potent candidate for the development of peptide antibiotics.
Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Catelicidinas/farmacologia , Elapidae/metabolismo , Sequência de Aminoácidos , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Bactérias/efeitos dos fármacos , Sequência de Bases , Catelicidinas/química , Catelicidinas/genética , Catelicidinas/metabolismo , Elapidae/classificação , Elapidae/genética , Feminino , Fungos/efeitos dos fármacos , Humanos , Dados de Sequência Molecular , Filogenia , Alinhamento de Sequência , Vertebrados/classificação , Vertebrados/genéticaRESUMO
As being a necessary amino acid, taurine plays an important role in the regulation of neuroendocrine functions and nutrition. In this study, effects of taurine on mice gut microbes and metabolism were investigated. BALB/C mice were randomly divided into three experimental groups: The first group was administered saline (CK), the second was administered 165 mg/kg natural taurine (NE) and the third one administered 165 mg/kg synthetic taurine (CS). Gut microbiota composition in mice feces was analyzed by metagenomics technology, and the content of short-chain fatty acids (SCFA) in mice feces was detected by gas chromatography (GC), while the concentrations of lipopolysaccharide (LPS) and superoxide dismutase (SOD) were detected by a LPS ELISA kit and a SOD assay kit, respectively. The results showed that the effect of taurine on gut microbiota could reduce the abundance of Proteobacteria, especially Helicobacter. Moreover, we found that the SCFA content was increased in feces of the NE group while LPS content was decreased in serum of the NE group; the SOD activity in serum and livers of the NE and CS groups were not changed significantly compare to that of the CK group. In conclusion, taurine could regulate the gut micro-ecology, which might be of benefit to health by inhibiting the growth of harmful bacteria, accelerating the production of SCFA and reducing LPS concentration.
Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Helicobacter/crescimento & desenvolvimento , Metagenoma , Taurina/farmacologia , Animais , Helicobacter/genética , Camundongos , Camundongos Endogâmicos BALB CRESUMO
As a versatile tool in separation science, cyclodextrins and their derivatives, known as emerging functional monomers, have been used extensively in molecular imprinting techniques. The attributes of cyclodextrins and their derivatives are widely known to form host-guest inclusion complex processes between the polymer and template. The exploitation of the imprinting technique could produce a product of molecularly imprinted polymers, which are very robust with long-term stability, reliability, cost-efficiency, and selectivity. Hence, molecularly imprinted polymers have gained popularity in chemical separation and analysis. Molecularly imprinted polymers containing either cyclodextrin or its derivatives demonstrate superior binding effects for a target molecule. As noted in the previous studies, the functional monomers of cyclodextrins and their derivatives have been used in molecular imprinting for selective separation with a wide range of chemical compounds, including steroidals, amino acids, polysaccharides, drugs, plant hormones, proteins, pesticides, and plastic additives. Therefore, the main goal of this review is to illustrate the exotic applications of imprinting techniques employing cyclodextrins and their derivatives as single or binary functional monomers in synthesizing molecularly imprinted polymers in areas of separation science by reviewing some of the latest studies reported in the literature.
Assuntos
Ciclodextrinas/química , Impressão Molecular , Polímeros/químicaRESUMO
Trypsins are key proteins important in animal protein digestion by breaking down the peptide bonds on the carboxyl side of lysine and arginine residues, hence it has been used widely in various biotechnological processes. In the current study, a full-length cDNA library with capacity of 5·10(5) CFU/ml from the duck (Anas platyrhynchos) was constructed. Using express sequence tag (EST) sequencing, genes coding two trypsins were identified and two full-length trypsin cDNAs were then obtained by rapid-amplification of cDNA end (RACE)-PCR. Using Blast, they were classified into the trypsin I and II subfamilies, but both encoded a signal peptide, an activation peptide, and a 223-a.a. mature protein located in the C-terminus. The two deduced mature proteins were designated as trypsin-IAP and trypsin-IIAP, and their theoretical isoelectric points (pI) and molecular weights (MW) were 7.99/23466.4 Da and 4.65/24066.0 Da, respectively. Molecular characterizations of genes were further performed by detailed bioinformatics analysis. Phylogenetic analysis revealed that trypsin-IIAP has an evolution pattern distinct from trypsin-IAP, suggesting its evolutionary advantage. Then the duck trypsin-IIAP was expressed in an Escherichia coli system, and its kinetic parameters were measured. The three dimensional structures of trypsin-IAP and trypsin-IIAP were predicted by homology modeling, and the conserved residues required for functionality were identified. Two loops controlling the specificity of the trypsin and the substrate-binding pocket represented in the model are almost identical in primary sequences and backbone tertiary structures of the trypsin families.
Assuntos
Proteínas Aviárias/genética , Patos/genética , Tripsina/genética , Animais , Proteínas Aviárias/química , Proteínas Aviárias/metabolismo , Etiquetas de Sequências Expressas , Biblioteca Gênica , Modelos Moleculares , Filogenia , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de Proteína , Homologia Estrutural de Proteína , Tripsina/química , Tripsina/metabolismoRESUMO
The objective of this study was to simulate and evaluate the burst behavior of coated tablets. Three-dimensional finite element models of tablet-coating were established using software ANSYS. Swelling pressure of cores was measured by a self-made device and applied at the internal surface of the models. Mechanical properties of the polymer film were determined using a texture analyzer and applied as material properties of the models. The resulted finite element models were validated by experimental data. The validated models were used to assess the factors those influenced burst behavior and predict the coating burst behavior. The simulation results of coating burst and failure location were strongly matched with the experimental data. It was found that internal swelling pressure, inside corner radius and corner thickness were three main factors controlling the stress distribution and burst behavior. Based on the linear relationship between the internal pressure and the maximum principle stress on coating, burst pressure of coatings was calculated and used to predict the burst behavior. This study demonstrated that burst behavior of coated tablets could be simulated and evaluated by finite element method.