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1.
J Cogn Neurosci ; 36(2): 340-361, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38010320

RESUMO

To estimate the size of an indoor space, we must analyze the visual boundaries that limit the spatial extent and acoustic cues from reflected interior surfaces. We used fMRI to examine how the brain processes the geometric size of indoor scenes when various types of sensory cues are presented individually or together. Specifically, we asked whether the size of space is represented in a modality-specific way or in an integrative way that combines multimodal cues. In a block-design study, images or sounds that depict small- and large-sized indoor spaces were presented. Visual stimuli were real-world pictures of empty spaces that were small or large. Auditory stimuli were sounds convolved with different reverberations. By using a multivoxel pattern classifier, we asked whether the two sizes of space can be classified in visual, auditory, and visual-auditory combined conditions. We identified both sensory-specific and multimodal representations of the size of space. To further investigate the nature of the multimodal region, we specifically examined whether it contained multimodal information in a coexistent or integrated form. We found that angular gyrus and the right medial frontal gyrus had modality-integrated representation, displaying sensitivity to the match in the spatial size information conveyed through image and sound. Background functional connectivity analysis further demonstrated that the connection between sensory-specific regions and modality-integrated regions increases in the multimodal condition compared with single modality conditions. Our results suggest that spatial size perception relies on both sensory-specific and multimodal representations, as well as their interplay during multimodal perception.


Assuntos
Mapeamento Encefálico , Encéfalo , Humanos , Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Percepção Espacial , Lobo Parietal , Córtex Pré-Frontal , Estimulação Acústica/métodos , Percepção Auditiva , Imageamento por Ressonância Magnética/métodos
2.
J Am Chem Soc ; 145(40): 21991-22008, 2023 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-37664981

RESUMO

Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin αvß3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvß3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.


Assuntos
Senescência Celular , Senoterapia , Camundongos , Animais , Espécies Reativas de Oxigênio , Peptídeos/farmacologia , Integrinas
3.
Mar Drugs ; 21(6)2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37367665

RESUMO

Agarobiose (AB; d-galactose-ß-1,4-AHG), produced by one-step acid hydrolysis of agarose of red seaweed, is considered a promising cosmetic ingredient due to its skin-moisturizing activity. In this study, the use of AB as a cosmetic ingredient was found to be hampered due to its instability at high temperature and alkaline pH. Therefore, to increase the chemical stability of AB, we devised a novel process to synthesize ethyl-agarobioside (ethyl-AB) from the acid-catalyzed alcoholysis of agarose. This process mimics the generation of ethyl α-glucoside and glyceryl α-glucoside by alcoholysis in the presence of ethanol and glycerol during the traditional Japanese sake-brewing process. Ethyl-AB also showed in vitro skin-moisturizing activity similar to that of AB, but showed higher thermal and pH stability than AB. This is the first report of ethyl-AB, a novel compound produced from red seaweed, as a functional cosmetic ingredient with high chemical stability.


Assuntos
Bebidas Alcoólicas , Alga Marinha , Sefarose/química , Fermentação , Alga Marinha/química , Glucosídeos
4.
Medicina (Kaunas) ; 59(10)2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37893557

RESUMO

Background and Objectives: Schmorl's nodes (SNs), formed by the herniation of intervertebral discs into adjacent vertebral bodies, are generally asymptomatic and do not require treatment. However, certain types of SNs can cause intractable back pain. Case Presentation: A 63-year-old man presented to our hospital with back pain after a fall 1 month prior. Physical examination revealed back pain that worsened with movement and paraspinal tenderness. Magnetic resonance imaging (MRI) performed immediately after presentation revealed subacute to chronic compression fractures with SNs at the upper endplates of the 11th and 12th thoracic and 1st lumbar vertebrae. Pain (numeric rating scale (NRS), 7-8/10) persisted despite 6 months of conservative treatment and MRI revealed increased signal intensity in T2-weighted images in the regions around the SNs. Based on these findings, an epidural nerve block was performed, and then repeated; however, no significant improvement was observed. Percutaneous vertebroplasty (PVP) was performed at the 11th and 12th thoracic and 1st lumbar vertebrae. Pain levels decreased substantially 1 week after PVP (NRS, 3-4/10). Subsequent treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and steroids for two weeks further reduced pain levels (NRS, 1-2/10), following which steroid use was discontinued and NSAID use became intermittent. At the six-month follow-up, pain levels remained low and the patient reported an improvement in activity levels of 90% or more. Conclusions: This case report demonstrates that PVP safely and effectively improved symptoms in a patient with multiple SNs and intractable back pain. Nevertheless, further research, particularly large-scale randomized prospective studies, is necessary to validate the long-term efficacy and safety of this intervention.


Assuntos
Deslocamento do Disco Intervertebral , Fraturas da Coluna Vertebral , Vertebroplastia , Masculino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Dor nas Costas , Vértebras Lombares/cirurgia , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/cirurgia
5.
Gynecol Obstet Invest ; 87(6): 333-343, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36265471

RESUMO

OBJECTIVES: The objective of this study was to evaluate the efficacy of cell therapy using human amniotic epithelial stem cells (hAESCs) for the treatment of premature rupture of membranes (PROM) in vitro. DESIGN: Using the amniotic pore culture technique (APCT), we mimicked the environment of PROM in vitro, thus enabling the observation of the healing process of hAESC-treated amniotic membranes. MATERIALS: Amniotic membrane samples were collected from placentas of pregnant women who underwent elective cesarean sections. APCT model and isolated hAESCs were used in this study. All patients who participated in this study provided their written informed consent prior to the commencement of the study. SETTINGS: To create the APCT model in vitro, isolated amniotic membranes were punched to create 5 mm diameter circles and re-punched to form a 1-mm pore at the center. Membranes were cultured in α-minimal essential medium, and the hAESCs were collected and cultured as well. Subsequently, the APCT models were divided into two groups: hAESC treated and control. METHODS: Within the culture period, pore sizes were calculated to evaluate the degree of tissue regeneration in both groups. We then evaluated the histology, cell density, and epithelial thickness of the regenerated tissues. Statistical analyses were performed using SPSS software ver. 20.0 (IBM, Armonk, NY, USA) with repeated-measures one-way analysis of variance or paired samples t test. The significance level was set at p < 0.05. RESULTS: As per the evaluation of the APCT model in vitro, the pore size in the hAESC-treated group reduced by 62.2% on day 6 (62.2 ± 0.19, n = 24), whereas in the control group, it shrank by only 36.8% (p < 0.05) (36.8 ± 0.19, n = 24). Furthermore, the epithelial thickness in the amniotic epithelial stem cell-treated group (10.08 ± 1.26 µm, n = 8) was significantly higher than that in the control group (5.87 ± 0.94 µm, n = 8). Cell density in the regenerated tissue in the amniotic epithelial stem cell-treated group (57 ± 2.77, n = 8) was significantly higher than that in the control group (49 ± 2.23, n = 8). LIMITATIONS: In this study, we did not explore the molecular mechanisms by which hAESCs participate in membrane healing in the APCT model. Although our results showed a significant difference, this difference was not too obvious. Therefore, further research on the mechanisms of hAESCs is needed, with more amniotic tissues and APCT samples being tested. CONCLUSIONS: We developed an APCT model to investigate the PROM conditions in vitro. By implanting donor hAESCs in the pores of the APCT model, we observed that hAESCs seeding accelerated pore healing in vitro. Thus, hAESCs may be a valuable source of cells for cell therapies in regenerative medicine.


Assuntos
Ruptura Prematura de Membranas Fetais , Nascimento Prematuro , Recém-Nascido , Humanos , Feminino , Gravidez , Âmnio , Transplante de Células-Tronco , Técnicas de Cultura , Ruptura Prematura de Membranas Fetais/terapia , Líquido Amniótico
6.
Int J Mol Sci ; 23(24)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36555112

RESUMO

A moderate amount of reactive oxygen species (ROS) is produced under normal conditions, where they play an important role in cell signaling and are involved in many aspects of the immune response to pathogens. On the other hand, the excessive production of ROS destructs macromolecules, cell membranes, and DNA, and activates pro-inflammatory signaling pathways, which may lead to various pathologic conditions. Gastrointestinal (GI) mucosa is constantly exposed to ROS due to the presence of bacteria and other infectious pathogens in food, as well as alcohol consumption, smoking, and the use of non-steroidal anti-inflammatory drugs (NSAID). Prolonged excessive oxidative stress and inflammation are two major risk factors for GI disorders such as ulcers and cancers. Bioactive food compounds with potent anti-oxidant and anti-inflammatory activity have been tested in experimental GI disease models to evaluate their therapeutic potential. Astaxanthin (AST) is a fat-soluble xanthophyll carotenoid that is naturally present in algae, yeast, salmon, shrimp, and krill. It has been shown that AST exhibits protective effects against GI diseases via multiple mechanisms. Residing at the surface and inside of cell membranes, AST directly neutralizes ROS and lipid peroxyl radicals, enhances the activity of anti-oxidant enzymes, and suppresses pro-inflammatory transcription factors and cytokines. In addition, AST has been shown to inhibit cancer cell growth and metastasis via modulating cell proliferation-related pathways, apoptosis, and autophagy. Considering the potential benefits of AST in GI diseases, this review paper aims to summarize recent advances in AST research, focusing on its anti-oxidant and anti-inflammatory effects against gastric and intestinal ulcers and cancers.


Assuntos
Antioxidantes , Gastroenteropatias , Humanos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Úlcera , Gastroenteropatias/tratamento farmacológico , Estresse Oxidativo , Xantofilas/farmacologia , Xantofilas/uso terapêutico , Xantofilas/metabolismo , Alimentos Marinhos
7.
Int J Mol Sci ; 23(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35008969

RESUMO

Monoamine serotonin is a major neurotransmitter that acts on a wide range of central nervous system and peripheral nervous system functions and is known to have a role in various processes. Recently, it has been found that 5-HT is involved in cognitive and memory functions through interaction with cholinergic pathways. The natural flavonoid kaempferol (KAE) extracted from Cudrania tricuspidata is a secondary metabolite of the plant. Recently studies have confirmed that KAE possesses a neuroprotective effect because of its strong antioxidant activity. It has been confirmed that KAE is involved in the serotonergic pathway through an in vivo test. However, these results need to be confirmed at the molecular level, because the exact mechanism that is involved in such effects of KAE has not yet been elucidated. Therefore, the objective of this study is to confirm the interaction of KAE with 5-HT3A through electrophysiological studies at the molecular level using KAE extracted from Cudrania tricuspidata. This study confirmed the interaction between 5-HT3A and KAE at the molecular level. KAE inhibited 5-HT3A receptors in a concentration-dependent and voltage-independent manner. Site-directed mutagenesis and molecular-docking studies confirmed that the binding sites D177 and F199 are the major binding sites of human 5-HT3A receptors of KAE.


Assuntos
Quempferóis/farmacologia , Triterpenos Pentacíclicos/farmacologia , Receptores 5-HT3 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Sítios de Ligação , Relação Dose-Resposta a Droga , Humanos , Quempferóis/química , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Triterpenos Pentacíclicos/química , Ligação Proteica , Receptores 5-HT3 de Serotonina/química , Receptores 5-HT3 de Serotonina/genética , Antagonistas do Receptor 5-HT3 de Serotonina/química , Relação Estrutura-Atividade
8.
Sensors (Basel) ; 21(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918278

RESUMO

In this paper, we introduce mapping results in an indoor environment based on our own developed dual-mode radar sensor. Our radar system uses a frequency-modulated continuous wave (FMCW) with a center frequency of 62 GHz and a multiple-input multiple-output antenna system. In addition, the FMCW radar sensor we designed is capable of dual-mode detection, which alternately transmits two waveforms using different bandwidths within one frame. The first waveform is for long-range detection, and the second waveform is for short-range detection. This radar system is mounted on a small robot that moves in indoor environments such as rooms or hallways, and the radar and the robot send and receive necessary information to each other. The radar estimates the distance, velocity, and angle information of targets around the radar-equipped robot. Then, the radar receives information about the robot's motion from the robot, such as its speed and rotation angle. Finally, by combining the motion information and the detection results, the radar-equipped robot maps the indoor environment while finding its own position. Compared to the actual map data, the radar-based mapping is effectively achieved through the radar system we developed.

9.
Sensors (Basel) ; 21(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34372214

RESUMO

This paper proposes a method to embed and extract a watermark on a digital hologram using a deep neural network. The entire algorithm for watermarking digital holograms consists of three sub-networks. For the robustness of watermarking, an attack simulation is inserted inside the deep neural network. By including attack simulation and holographic reconstruction in the network, the deep neural network for watermarking can simultaneously train invisibility and robustness. We propose a network training method using hologram and reconstruction. After training the proposed network, we analyze the robustness of each attack and perform re-training according to this result to propose a method to improve the robustness. We quantitatively evaluate the results of robustness against various attacks and show the reliability of the proposed technique.


Assuntos
Segurança Computacional , Interpretação de Imagem Assistida por Computador , Algoritmos , Redes Neurais de Computação , Reprodutibilidade dos Testes
10.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672594

RESUMO

High alcohol intake results in the accumulation of non-oxidative ethanol metabolites such as fatty acid ethyl esters (FAEEs) in the pancreas. High FAEE concentrations mediate pancreatic acinar cell injury and are associated with alcoholic pancreatitis. Treatment with ethanol and the fatty acid palmitoleic acid (EtOH/POA) increased the levels of palmitoleic acid ethyl ester and induced zymogen activation and cytokine expression in pancreatic acinar cells. EtOH/POA induces nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated reactive oxygen species (ROS) production and pancreatic acinar cell injury. Lycopene, a bright-red carotenoid, is a potent antioxidant due to its high number of conjugated double bands. This study aimed to investigate whether lycopene inhibits the EtOH/POA-induced increase in ROS production, zymogen activation, and expression of the inflammatory cytokine IL-6 in EtOH/POA-stimulated pancreatic acinar AR42J cells. EtOH/POA increased the ROS levels, NADPH oxidase and NF-κB activities, zymogen activation, IL-6 expression, and mitochondrial dysfunction, which were inhibited by lycopene. The antioxidant N-acetylcysteine and NADPH oxidase 1 inhibitor ML171 suppressed the EtOH/POA-induced increases in ROS production, NF-κB activation, zymogen activation, and IL-6 expression. Therefore, lycopene inhibits EtOH/POA-induced mitochondrial dysfunction, zymogen activation, and IL-6 expression by suppressing NADPH oxidase-mediated ROS production in pancreatic acinar cells.


Assuntos
Células Acinares/patologia , Inflamação/patologia , Licopeno/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pâncreas Exócrino/patologia , Acetilcisteína/farmacologia , Células Acinares/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Precursores Enzimáticos/metabolismo , Etanol , Ácidos Graxos Monoinsaturados , Interleucina-6/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
11.
Molecules ; 26(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668306

RESUMO

Irritable bowel syndrome (IBS) is a chronic disease that causes abdominal pain and an imbalance of defecation patterns due to gastrointestinal dysfunction. The cause of IBS remains unclear, but intestinal-brain axis problems and neurotransmitters have been suggested as factors. In this study, chanoclavine, which has a ring structure similar to 5-hydroxytryptamine (5-HT), showed an interaction with the 5-HT3A receptor to regulate IBS. Although its derivatives are known to be involved in neurotransmitter receptors, the molecular physiological mechanism of the interaction between chanoclavine and the 5-HT3A receptor is unknown. Electrophysiological experiments were conducted using a two-electrode voltage-clamp analysis to observe the inhibitory effects of chanoclavine on Xenopus oocytes in which the h5-HT3A receptor was expressed. The co-application of chanoclavine and 5-HT resulted in concentration-dependent, reversible, voltage-independent, and competitive inhibition. The 5-HT3A response induced by 5-HT was blocked by chanoclavine with half-maximal inhibitory response concentration (IC50) values of 107.2 µM. Docking studies suggested that chanoclavine was positioned close F130 and N138 in the 5-HT3A receptor-binding site. The double mutation of F130A and N138A significantly attenuated the interaction of chanoclavine compared to a single mutation or the wild type. These data suggest that F130 and N138 are important sites for ligand binding and activity. Chanoclavine and ergonovine have different effects. Asparagine, the 130th amino acid sequence of the 5-HT3A receptor, and phenylalanine, the 138th, are important in the role of binding chanoclavine, but ergonovine has no interaction with any amino acid sequence of the 5-HT3A receptor. The results of the electrophysiological studies and of in silico simulation showed that chanoclavine has the potential to inhibit the hypergastric stimulation of the gut by inhibiting the stimulation of signal transduction through 5-HT3A receptor stimulation. These findings suggest chanoclavine as a potential antiemetic agent for excessive gut stimulation and offer insight into the mechanisms of 5-HT3A receptor inhibition.


Assuntos
Ergolinas/farmacologia , Receptores 5-HT3 de Serotonina/metabolismo , Relação Dose-Resposta a Droga , Ergolinas/química , Ergonovina/química , Ergonovina/farmacologia , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos
12.
Stat Appl Genet Mol Biol ; 18(4)2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31145697

RESUMO

Modeling the high-throughput next generation sequencing (NGS) data, resulting from experiments with the goal of profiling tumor and control samples for the study of DNA copy number variants (CNVs), remains to be a challenge in various ways. In this application work, we provide an efficient method for detecting multiple CNVs using NGS reads ratio data. This method is based on a multiple statistical change-points model with the penalized regression approach, 1d fused LASSO, that is designed for ordered data in a one-dimensional structure. In addition, since the path algorithm traces the solution as a function of a tuning parameter, the number and locations of potential CNV region boundaries can be estimated simultaneously in an efficient way. For tuning parameter selection, we then propose a new modified Bayesian information criterion, called JMIC, and compare the proposed JMIC with three different Bayes information criteria used in the literature. Simulation results have shown the better performance of JMIC for tuning parameter selection, in comparison with the other three criterion. We applied our approach to the sequencing data of reads ratio between the breast tumor cell lines HCC1954 and its matched normal cell line BL 1954 and the results are in-line with those discovered in the literature.


Assuntos
Variações do Número de Cópias de DNA , Genômica/métodos , Análise de Sequência de DNA/métodos , Algoritmos , Teorema de Bayes , Linhagem Celular Tumoral , Simulação por Computador , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Análise de Regressão , Software
13.
Biochem Genet ; 58(4): 617-630, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32347401

RESUMO

Tobacco smoking, a risk factor for several human diseases, can lead to alterations in DNA methylation. Smoking is a key source of cadmium exposure; however, there are limited studies examining DNA methylation alterations following smoking-related cadmium exposure. To identify such cadmium exposure-related DNA methylation, we performed genome-wide DNA methylation profiling using DNA samples from 50 smokers and 50 non-smokers. We found that a total of 136 CpG sites (including 70 unique genes) were significantly differentially methylated in smokers as compared to that in non-smokers. The CpG site cg05575921 in the AHRR gene was hypomethylated (Δ ß > - 0.2) in smokers, which was in accordance with previous studies. The rs951295 (within RNA gene LOC105370802) and cg00587941 sites were under-methylated by > 15% in smokers, whereas cg11314779 (within CELF6) and cg02126896 were over-methylated by ≥ 15%. We analyzed the association between blood cadmium concentration and DNA methylation level for 50 smokers and 50 non-smokers. DNA methylation rates of 307 CpG sites (including 207 unique genes) were significantly correlated to blood cadmium concentration (linear regression P value < 0.001). The four significant loci (cg05575921 and cg23576855 in AHRR, cg03636183 in F2RL3, and cg21566642) were under-methylated by > 10% in smokers compared to that in non-smokers. In conclusion, our study demonstrated that DNA methylation levels of rs951295, cg00587941, cg11314779, and cg02126896 sites may be new putative indicators of smoking status. Furthermore, we showed that these four loci may be differentially methylated by cadmium exposure due to smoking.


Assuntos
Cádmio/sangue , Metilação de DNA/genética , Fumar Tabaco/sangue , Fumar Tabaco/genética , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cotinina/urina , Ilhas de CpG/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Trombina/genética , Proteínas Repressoras/genética , Fumar Tabaco/urina
14.
Int J Mol Sci ; 21(12)2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32570692

RESUMO

Cardiovascular disease (CVD) occurs globally and has a high mortality rate. The highest risk factor for developing CVD is high blood pressure. Currently, natural products are emerging for the treatment of hypertension to avoid the side effects of drugs. Among existing natural products, lupeol is known to be effective against hypertension in animal experiments. However, there exists no study regarding the molecular physiological evidence against the effects of lupeol. Consequently, we investigated the interaction of lupeol with α3ß4 nicotinic acetylcholine receptors (nAChRs). In this study, we performed a two-electrode voltage-clamp technique to investigate the effect of lupeol on the α3ß4 nicotine acetylcholine receptor using the oocytes of Xenopus laevis. Coapplication of acetylcholine and lupeol inhibited the activity of α3ß4 nAChRs in a concentration-dependent, voltage-independent, and reversible manner. We also conducted a mutational experiment to investigate the influence of residues of the α3 and ß4 subunits on lupeol binding with nAChRs. Double mutants of α3ß4 (I37A/N132A), nAChRs significantly attenuated the inhibitory effects of lupeol compared to wild-type α3ß4 nAChRs. A characteristic of α3ß4 nAChRs is their effect on transmission in the cardiac sympathetic ganglion. Overall, it is hypothesized that lupeol lowers hypertension by mediating its effects on α3ß4 nAChRs. The interaction between lupeol and α3ß4 nAChRs provides evidence against its effect on hypertension at the molecular-cell level. In conclusion, the inhibitory effect of lupeol is proposed as a novel therapeutic approach involving the antihypertensive targeting of α3ß4 nAChRs. Furthermore, it is proposed that the molecular basis of the interaction between lupeol and α3ß4 nAChRs would be helpful in cardiac-pharmacology research and therapeutics.


Assuntos
Acetilcolina/farmacologia , Sistema Cardiovascular/metabolismo , Triterpenos Pentacíclicos/farmacologia , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Animais , Sistema Cardiovascular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Modelos Moleculares , Simulação de Acoplamento Molecular , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp , Triterpenos Pentacíclicos/química , Mutação Puntual , Receptores Nicotínicos/química , Xenopus laevis
15.
J Cell Biochem ; 120(10): 18193-18208, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31172579

RESUMO

DDX3 is a host viral factor that can inhibit the hepatitis B virus-induced innate immune responses. In this study, the 20 bioactive compounds have screened the effects on DDX3 and we found that 5-HT upregulated DDX3 promoter activity via the 5-HT7 receptor on liver hepatocellular cells (HepG2 cells) by using a luciferase assay, reverse transcription-polymerase chain reaction analysis, and Western blot analysis. Furthermore, we are trying to elucidate the pathways involved in the stimulating effect of 5-HT on DDX3 expression to induce innate immune responses against hepatitis B virus infection. A knockdown of the 5-HT7 receptor by transfection si-5-HT7 receptors or si-control into HepG2 cells treated by 5-HT (or 5-HT plus agonist) confirmed the role of the 5-HT7 receptor in DDX3 expression. The IFN-ß-Luc expression and level of hepatitis B virus surface Antigen (HBsAg) showed that DDX3 mediated by the 5-HT7 agonist (AS-19) increased IFN-ß expression and inhibited HBV replication. Luciferase assays showed the involvement of 5-HT7 receptors in DDX3 expression via cAMP/AC/PKA pathways by using protein kinase A (PKA) and adenylyl cyclase inhibitor (MDL 12330A). AS-19 mediated DDX3 promoter activated PKA extracellular signal-regulated kinase ERK signaling the p53 phosphorylation (-1080/-1070) resulted in upregulation of DDX3 promoter transactivation via the 5-HT7 receptors agonist. Overall, 5-HT7 was found to be a new potential target to inhibit hepatitis B infection by activating AC/PKA/ERK pathways by phosphorylating p53 via the 5-HT7 agonist response by mediating DDX3 expression.


Assuntos
RNA Helicases DEAD-box/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas/metabolismo , Receptores de Serotonina/genética , Serotonina/farmacologia , Adenilil Ciclases/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , RNA Helicases DEAD-box/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Hep G2 , Vírus da Hepatite B/fisiologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virologia , Fosforilação/efeitos dos fármacos , Interferência de RNA , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Replicação Viral/efeitos dos fármacos
16.
PLoS Med ; 16(6): e1002830, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31199792

RESUMO

BACKGROUND: Although there is mounting evidence demonstrating beneficial effects of community health workers (CHWs), few studies have examined the impact of CHW programs focused on preventing infectious diseases in children through behavior changes. We assessed the preventive effects of community health volunteers (CHVs), who receive no financial incentive, on child diarrhea and fever prevalence in Ghana. METHODS AND FINDINGS: We conducted a cluster-randomized controlled trial in 40 communities in the Volta Region, Ghana. Twenty communities were randomly allocated to the intervention arm, and 20 to the control arm, using a computer-generated block randomization list. In the intervention arm, CHVs were deployed in their own community with the key task of conducting home visits for health education and community mobilization. The primary outcomes of the trial were diarrhea and fever prevalence at 6 and 12 months among under-5 children based on caregivers' recall. Secondary outcomes included oral rehydration treatment and rapid diagnostic testing for malaria among under-5 children, and family planning practices of caregivers. Generalized estimating equations (GEEs) with a log link and exchangeable correlation matrix were used to determine the relative risk (RR) and 95% confidence intervals (CIs) for diarrhea, fever, and secondary outcomes adjusted for clustering and stratification. Between April 18 and May 4, 2015, 1,956 children were recruited and followed up until September 20, 2016. At 6 and 12 months post-randomization, 1,660 (85%) and 1,609 (82%) participants, respectively, had outcomes assessed. CHVs' home visits had no statistically significant effect on diarrhea or fever prevalence at either time point. After a follow-up of 12 months, the prevalence of diarrhea and fever was 7.0% (55/784) and 18.4% (144/784), respectively, in the control communities and 4.5% (37/825) and 14.7% (121/825), respectively, in the intervention communities (12-month RR adjusted for clustering and stratification: diarrhea, RR 0.73, 95% CI 0.37-1.45, p = 0.37; fever, RR 0.76, 95% CI 0.51-1.14, p = 0.20). However, the following were observed: improved hand hygiene practices, increased utilization of insecticide-treated bed nets, and greater participation in community outreach programs (p-values < 0.05) in the intervention group. In a post hoc subgroup analysis, the prevalence of diarrhea and fever at 6 months was 3.2% (2/62) and 17.7% (11/62), respectively, in the intervention communities with ≥70% coverage and a ≥30-minute visit duration, and 14.4% (116/806) and 30.2% (243/806) in the control communities (RR adjusted for clustering, stratification, baseline prevalence, and covariates: diarrhea, RR 0.23, 95% CI 0.09-0.60, p = 0.003; fever, RR 0.69, 95% CI 0.52-0.92, p = 0.01). The main limitations were the following: We were unable to investigate the longer-term effects of CHVs; the trial may have been underpowered to detect small to moderate effects due to the large decline in diarrheal and fever prevalence in both the intervention and control group; and caregivers' practices were based on self-report, and the possibility of caregivers providing socially desirable responses cannot be excluded. CONCLUSIONS: We found no effect of CHVs' home visits on the prevalence of child diarrhea or fever. However, CHV programs with high community coverage and regular household contacts of effective duration may reduce childhood infectious disease prevalence. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Registry, ISRCTN49236178.


Assuntos
Serviços de Saúde Comunitária/normas , Agentes Comunitários de Saúde/normas , Diarreia/epidemiologia , Febre/epidemiologia , Visita Domiciliar , Adulto , Criança , Pré-Escolar , Análise por Conglomerados , Serviços de Saúde Comunitária/métodos , Diarreia/prevenção & controle , Feminino , Febre/prevenção & controle , Seguimentos , Gana/epidemiologia , Humanos , Masculino
17.
BMC Cancer ; 19(1): 347, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975123

RESUMO

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) remains an important therapeutic option for many hematologic malignancies. Bone marrow harvesting from an appropriate donor must be conducted for hematopoietic stem cell transplantation (HSCT). Many previous studies show complications of the recipient after hematopoietic stem cell transplantation (HSCT). However, complications of the donor after bone marrow harvesting are rare. We here report a unique case of a patient who developed sacral nerve root injury after bone marrow harvesting. CASE PRESENTATION: A 26-year-old man was admitted to our medical center complaining of acute onset painful burning and tingling sensation at the left posterior thigh and calf. He was a bone marrow donor for his brother's bone marrow transplantation. He had underwent a bone marrow harvesting procedure two days before admission as a bone marrow donor, using both posterior superior iliac spine (PSIS) as the puncture site. Pelvic magnetic resonance image (MRI) showed enhancement around the left S2 nerve root in T1 and T2-weighted images. Nerve conduction studies (NCS) revealed normal conduction velocity and amplitude on both lower extremities. Electromyography (EMG) presented abnormal spontaneous activity and neurogenic motor unit potentials on the S2-innervated intrinsic foot muscle and gastrocnemius, soleus muscle on the left. The patient was treated with pregabalin for pain control. The patient was followed up after 3, 6, and 12 months. Neuropathic pain improved to Visual Analogue Scale (VAS) 1, and recovery state was confirmed by re-innervation patterns of motor unit potentials in electromyography. CONCLUSION: Bone marrow harvesting is a relatively safe procedure. However, variable complications may occur. Accurate anatomical knowledge and carefulness are required to avoid sacral nerve root injury when performing the bone marrow harvesting procedure.


Assuntos
Mononeuropatias/diagnóstico , Traumatismos dos Nervos Periféricos/diagnóstico , Coleta de Tecidos e Órgãos/efeitos adversos , Sítio Doador de Transplante , Adulto , Transplante de Medula Óssea , Eletromiografia , Neoplasias Hematológicas/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Mononeuropatias/tratamento farmacológico , Mononeuropatias/etiologia , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/etiologia , Pregabalina/uso terapêutico , Doadores de Tecidos , Resultado do Tratamento
18.
Mar Drugs ; 16(11)2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30469402

RESUMO

Marine algae are considered to be an abundant sources of bioactive compounds with cosmeceutical potential. Recently, a great deal of interest has focused on the health-promoting effects of marine bioactive compounds. Carbohydrates are the major and abundant constituent of marine algae and have been utilized in cosmetic formulations, as moisturizing and thickening agents for example. In addition, marine carbohydrates have been suggested as promising bioactive biomaterials for their various properties beneficial to skin, including antioxidant, anti-melanogenic and skin anti-aging properties. Therefore, marine algae carbohydrates have potential skin health benefits for value-added cosmeceutical applications. The present review focuses on the various biological capacities and potential skin health benefits of bioactive marine carbohydrates.


Assuntos
Organismos Aquáticos , Carboidratos/farmacologia , Cosmecêuticos/farmacologia , Microalgas/química , Alga Marinha/química , Pele/efeitos dos fármacos , Animais , Cosmecêuticos/química , Cosmecêuticos/isolamento & purificação , Humanos
19.
BMC Public Health ; 17(1): 95, 2017 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-28103915

RESUMO

BACKGROUND: In many low- and middle-income countries, community health volunteers (CHVs) are employed as a key element of the public health system in rural areas with poor accessibility. However, few studies have assessed the effectiveness of CHVs in improving child health in sub-Saharan Africa through randomized controlled trials. The present study aims to measure the impact of health promotion and case management implemented by CHVs on the health of under-5 children in Ghana. METHODS/DESIGN: This study presents the protocol of a cluster-randomized controlled trial assessing the impacts of CHVs, in which the community was used as the randomization unit. A phase-in design will be adopted, and the intervention arm will be implemented in the intervention arm during the first phase and in the control arm during the second phase. The key intervention is the deployment of CHVs, who provide health education, provide oral rehydration solutions and zinc tablets to children with diarrhea, and diagnose malaria using a thermometer and a rapid diagnostic test kit during home visits. The primary endpoints of the study are the prevalence of diarrhea and fever/malaria in children under 5 years of age, as well as the proportion of affected children receiving case management for diarrhea and malaria. The first and second rounds of household surveys to collect data will be conducted in the first phase, and the final round will be conducted during the second phase. DISCUSSION: With growing attention paid to the roles of CHVs as an essential part of the community health system in low-income countries, this study will contribute valuable information to the body of knowledge on the effects of CHVs. TRIAL REGISTRATION: ISRCTN49236178 . (June 16th, 2015).


Assuntos
Serviços de Saúde da Criança , Doenças Transmissíveis , Serviços de Saúde Comunitária/métodos , Visita Domiciliar , Voluntários , Pré-Escolar , Protocolos Clínicos , Análise por Conglomerados , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/terapia , Diarreia/terapia , Feminino , Gana , Educação em Saúde/métodos , Humanos , Lactente , Malária/diagnóstico , Masculino , Prevalência
20.
J Nat Prod ; 78(11): 2572-9, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26517152

RESUMO

Six new spiroindole alkaloids (1-6) and two new spiroditerpenoids (7 and 8) were isolated from an EtOAc extract of Aspergillus duricaulis culture media together with five known compounds. The structures of the isolated compounds were elucidated by analysis of NMR and MS data, and the absolute configurations of compounds 1-8 were confirmed by CD spectroscopic methods. All isolated compounds were evaluated for their inhibition of beta-amyloid (Aß) aggregate-induced toxicity in PC12 cells and Aß aggregation. Compounds 8-11 efficiently protected PC12 cells against Aß aggregate-induced toxicity, but only compound 9 inhibited Aß aggregation. On the other hand, compounds 4 and 5 exhibited moderate inhibitory effects on Aß aggregation, but did not protect the cells from Aß aggregate-induced toxicity. Preincubating Aß monomers with compounds 4 and 5 rescued PC12 cells against Aß aggregate-induced toxicity by reducing neurotoxic Aß aggregates. Compound 9 inhibited both Aß aggregate-induced toxicity and Aß aggregation.


Assuntos
Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Aspergillus/efeitos dos fármacos , Diterpenos/química , Alcaloides Indólicos/química , Estrutura Molecular , Fármacos Neuroprotetores/química , Ressonância Magnética Nuclear Biomolecular , Células PC12 , Ratos , Compostos de Espiro/química
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