RESUMO
Nasopharyngeal carcinoma (NPC) is a highly recurrent and metastatic malignant tumor affecting a large number of individuals in southern China. Traditional Chinese herbal medicine has been found to be a rich source of natural compounds with mild therapeutic effects and minimal side effects, making them increasingly popular for treating various diseases. Trifolirhizin, a natural flavonoid derived from leguminous plants, has gained significant attention for its therapeutic potential. In this study, we confirmed that trifolirhizin could effectively inhibit the proliferation, migration and invasion of nasopharyngeal carcinoma 6-10B and HK1 cells. Furthermore, our findings demonstrated that trifolirhizin achieves this by suppressing the PI3K/Akt signaling pathway. The findings of the present study provides a valuable perspective on the potential therapeutic applications of trifolirhizin for the treatment of nasopharyngeal carcinoma.
Assuntos
Neoplasias Nasofaríngeas , Proteínas Proto-Oncogênicas c-akt , Humanos , Carcinoma Nasofaríngeo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transdução de Sinais , Proliferação de Células , Regulação Neoplásica da Expressão GênicaRESUMO
Dilated cardiomyopathy (DCM) is a heart disease that injured greatly to the people wordwide. Systemic co-expression analysis for this cancer is still limited, although massive clinic experiments and gene profiling analyses had been well performed previously. Here, using the public RNA-Seq data "GSE116250" and gene annotation of Ensembl database, we built the co-expression modules for DCM by Weighted Gene Co-Expression Network Analysis, and investigated the function enrichment and protein-protein interaction (PPI) network of co-expression genes of each module by Database for Annotation, Visualization, and Integrated Discovery and Search Tool for the Retrieval of Interacting Genes/Proteins database, respectively. First, 5,000 genes in the 37 samples were screened and 11 co-expression modules were conducted. The number of genes for each module ranged from 77 to 936, with a mean of 455. Second, interaction relationships of hub-genes between pairwise modules showed great differences, suggesting relatively high-scale independence of the modules. Third, functional enrichments of the co-expression modules exhibited great differences. We found that genes in module 3 were significantly enriched in the pathways of focal adhesion and ubiquitin-mediated proteolysis. This module was inferred as the key module involved in DCM. In addition, PPI analysis revealed that the genes HSP90AA1, CTNNB1, MAPK1, GART, and PPP2CA owned the largest number of adjacency genes, unveiling that they may function importantly during the occurrence of DCM. Focal adhesion and ubiquitin-mediated proteolysis play important roles in human DCM.
Assuntos
Cardiomiopatia Dilatada/genética , Adesões Focais/genética , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Mapas de Interação de Proteínas/genética , Biomarcadores , Carbono-Nitrogênio Ligases/genética , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/patologia , Biologia Computacional , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Proteínas de Choque Térmico HSP90/genética , Humanos , Proteína Quinase 1 Ativada por Mitógeno/genética , Miocárdio/patologia , Fosforribosilglicinamido Formiltransferase/genética , Prognóstico , Proteína Fosfatase 2/genética , beta Catenina/genéticaRESUMO
BACKGROUND: Utilization of primary health care is an important aspect of elderly internal migrants' access to screening and preventive services in China. It has been evident that social contacts, such as community engagement, social mobilization, and the ability to communicate were related to health service delivery, but little has been done to explore the relationship between social contacts and utilization of primary health care for this group. This study aimed to explore the factors influencing utilization of primary health care from the perspective of social contacts among elderly internal migrants in China. METHODS: This was a cross-sectional study including 1544 elderly internal migrants in eight cities. Whether these indivdiuals had chosen to participate in the free health checkup organized in the previous year was adopted as an indicator of the utilization of primary health care. The number of local friends and amount of exercise time per day were measured as a proxy for social contacts. Multivariate binary logistic regression was used to investigate the association of social contacts with the likelihood of using primary health care. RESULTS: 55.6% of the respondents were men, and the mean age was 66.34 years (SD, 5.94). 88.6% had received an education of high school or below. 12.9% had no local friends. 5.2% did not exercise. Just 33.1% had participated in a free medical check-up. Social contacts, age, and medical insurance were associated with more use of primary health care among elderly internal migrants in China. CONCLUSION: The role of the community in promoting the use of primary health care should be expanded, such as creating community-based campaigns specifically targeting elderly internal migrants or designing social or sports activities tailored to increase the opportunity for contact between local elders and their internal migrant peers.
Assuntos
Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Apoio Social , Migrantes/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , China , Comunicação , Estudos Transversais , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , População UrbanaRESUMO
Thymoquinone (TQ), as the active constituents of black cumin (Nigella sativa) seed oil, has been reported to have potential protective effects on the cardiovascular system. This study aimed to investigate the effects and the underlying mechanisms of TQ on myocardial ischemia-reperfusion (I/R) injury in Langendorff-perfused rat hearts. Wister rat hearts were subjected to I/R and the experimental group were pretreated with TQ prior to I/R. Hemodynamic parameters, myocardial infarct size, cardiac marker enzymes, superoxide dismutase (SOD), malondialdehyde (MDA) content, and cardiomyocyte apoptosis were assayed. Compared with the untreated group, TQ preconditioning significantly improved cardiac function, reduced infarct size, decreased cardiac lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) levels, suppressed enedoxidative stress, and apoptosis. In addition, TQ treatment promoted autophagy, which was partially reversed by chloroquine (CQ), a kind of autophagy blocker. Our study suggests that TQ can protect heart against I/R injury, which is associated with anti-oxidative and anti-apoptotic effects through activation of autophagy.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzoquinonas/uso terapêutico , Cardiotônicos/uso terapêutico , Coração/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Análise de Variância , Animais , Creatina Quinase Forma MB/antagonistas & inibidores , Frequência Cardíaca/efeitos dos fármacos , Preparação de Coração Isolado/métodos , L-Lactato Desidrogenase/antagonistas & inibidores , Masculino , Infarto do Miocárdio/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Óleos de Plantas/química , Ratos , Ratos Wistar , Pressão Ventricular/efeitos dos fármacosRESUMO
The mammalian paraoxonases (PONs 1, 2 and 3) are a family of esterases that are highly conserved within and between species. They exhibit antioxidant and anti-inflammatory activities. However, their physiological function(s) and native substrates are uncertain. Previous structure-activity relationship studies demonstrate that PONs have a high specificity for lipophilic lactones, suggesting that such compounds may be representative of native substrates. This report describes the ability of PONs to hydrolyze two bioactive δ-lactones derived from arachidonic acid, 5,6-dihydroxy-eicosatrienoic acid lactone (5,6-DHTL) and cyclo-epoxycyclopentenone (cyclo-EC). Both lactones were very efficiently hydrolyzed by purified PON3. PON1 efficiently hydrolyzed 5,6-DHTL, but with a specific activity about 15-fold lower than PON3. 5,6-DHTL was a poor substrate for PON2. Cyclo-EC was a poor substrate for PON1 and not hydrolyzed by PON2. Studies with the PON inhibitor EDTA and a serine esterase inhibitor indicated that the PONs are the main contributors to hydrolysis of the lactones in human and mouse liver homogenates. Studies with homogenates from PON3 knockout mouse livers indicated that >80% of the 5,6-DHTL and cyclo-EC lactonase activities were attributed to PON3. The findings provide further insight into the structural requirements for PONs substrates and support the hypothesis that PONs, particularly PON1 and PON3, evolved to hydrolyze and regulate a class of lactone lipid mediators derived from polyunsaturated fatty acids.
Assuntos
Arildialquilfosfatase/metabolismo , Eicosanoides/metabolismo , Lactonas/metabolismo , Animais , Ácido Araquidônico/química , Ácido Araquidônico/metabolismo , Arildialquilfosfatase/genética , Eicosanoides/química , Células HEK293 , Humanos , Hidrólise , Lactonas/química , Fígado/metabolismo , Camundongos Knockout , Estrutura Molecular , Especificidade por SubstratoRESUMO
Dilated cardiomyopathy (DCM) is a lethal inflammatory heart disease and closely connected with dysfunction of the immune system. Glycoprotein A repetitions predominant (GARP) expressed on activated CD4+ T cells with suppressive activity has been established. This study aimed to investigate the frequency and function of circulating CD4+ CD25+ GARP+ regulatory T (Treg) cells in DCM. Forty-five DCM patients and 46 controls were enrolled in this study. There was a significant increase in peripheral T helper type 1 (Th1) and Th17 number and their related cytokines [interferon-γ (IFN-γ), interleukin (IL-17)], and an obvious decrease in Treg number, transforming growth factor-ß1 (TGF-ß1 ) levels and the expression of forkhead box P3 (FOXP3) and GARP in patients with DCM compared with controls. In addition, the suppressive function of CD4+ CD25+ GARP+ Treg cells was impaired in DCM patients upon T-cell receptor stimulation detected using CFSE dye. Lower level of TGF-ß1 and higher levels of IFN-γ and IL-17 detected using ELISA were found in supernatants of the cultured CD4+ CD25+ GARP+ Treg cells in DCM patients compared with controls. Together, our results indicate that CD4+ CD25+ GARP+ Treg cells are defective in DCM patients and GARP seems to be a better molecular definition of the regulatory phenotype. Therefore, it might be an attractive stategy to pay more attention to GARP in DCM patients.
Assuntos
Imunidade Adaptativa , Cardiomiopatia Dilatada/imunologia , Proliferação de Células , Subunidade alfa de Receptor de Interleucina-2/imunologia , Ativação Linfocitária , Proteínas de Membrana/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Contagem de Linfócito CD4 , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/metabolismo , Estudos de Casos e Controles , Comunicação Celular , Células Cultivadas , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Fenótipo , Transdução de Sinais , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta1/imunologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND/AIMS: Regulatory T cells (Tregs) can suppress immunologic damage in myocardial ischaemia/reperfusion injury (MIRI), however, the isolation and ex vivo expansion of these cells for clinical application remains challenging. Here, we investigated whether the IL-2/anti-IL-2 complex (IL-2C), a mediator of Treg expansion, can attenuate MIRI in mice. METHODS: Myocardial I/R was surgically induced in male C57BL/6 mice, aged 8-10 weeks, that were randomly assigned to 1) sham group (Sham), 2) Phosphate Buffered Saline (PBS), 3) IL-2-anti-IL-2 Ab complex (IL-2C), or 4) sham group, 5) PBS, 6) IL-2C after MIRI, or 7) IL-2C, 8) IL-2C+anti-CD25 mAbs, or 9) IL-2C; 10) IL-2C+anti-TGF-ß1 mAbs, 11) IL-2C+anti-IL-10 mAbs. The following parameters were measured at different time points: infarct area, myocardial apoptosis, splenocytes, the inhibitory function of Tregs, and presence of inflammatory factors. In addition, immunohistochemistry analysis was performed. RESULTS: We observed that Tregs were activated in response to MIRI. IL-2C administered before MIRI induced Treg expansion in both spleen and heart, attenuated Th1 and Th17 cell numbers, improved myocardial function, and attenuated both infiltration of inflammatory cells and apoptosis after MIRI. Furthermore, IL-2C administration reduced expression of inflammatory cytokines in the heart and attenuated proliferation of splenic cells. Depletion of Tregs with anti-CD25 mAb abrogated the beneficial effects of IL-2C. However, IL-2C-mediated myocardial protection was not dependent on either IL-10 or TGF-ß. In addition, IL-2C administration after MIRI did not reduce infarct area, but did improve myocardial function slightly and reduced myocardial fibrosis. CONCLUSION: Our results demonstrate that IL-2C-induced Treg expansion attenuates MIRI and improves myocardial recovery in vivo, suggesting that IL-2C is a promising therapeutic target for myocardial IRI.
Assuntos
Complexo Antígeno-Anticorpo/farmacologia , Interleucina-2/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Complexo Antígeno-Anticorpo/uso terapêutico , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/citologia , Miocárdio/imunologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Baço/citologia , Baço/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th17/citologia , Células Th17/imunologia , Fator de Crescimento Transformador beta1/imunologiaRESUMO
Pseudomonas aeruginosa produces N-(3-oxo-dodecanoyl)-L-homoserine lactone (3OC12), a crucial signaling molecule that elicits diverse biological responses in host cells thought to subvert immune defenses. The mechanism mediating many of these responses remains unknown. The intracellular lactonase paraoxonase 2 (PON2) hydrolyzes and inactivates 3OC12 and is therefore considered a component of host cells that attenuates 3OC12-mediated responses. Here, we demonstrate in cell lines and in primary human bronchial epithelial cells that 3OC12 is rapidly hydrolyzed intracellularly by PON2 to 3OC12 acid, which becomes trapped and accumulates within the cells. Subcellularly, 3OC12 acid accumulated within the mitochondria, a compartment where PON2 is localized. Treatment with 3OC12 caused a rapid PON2-dependent cytosolic and mitochondrial pH decrease, calcium release, and phosphorylation of stress signaling kinases. The results indicate a novel, PON2-dependent intracellular acidification mechanism by which 3OC12 can mediate its biological effects. Thus, PON2 is a central regulator of host cell responses to 3OC12, acting to decrease the availability of 3OC12 for receptor-mediated effects and acting to promote effects, such as calcium release and stress signaling, via intracellular acidification.
Assuntos
Arildialquilfosfatase/metabolismo , Homosserina/análogos & derivados , Interações Hospedeiro-Parasita/fisiologia , Lactonas/metabolismo , Infecções por Pseudomonas/metabolismo , Western Blotting , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Homosserina/metabolismo , Humanos , Imunoprecipitação , Microscopia Confocal , Pseudomonas aeruginosa , Percepção de Quorum/fisiologia , Interferência de RNARESUMO
BACKGROUND: Oxidative stress is closely associated with cardiac fibrosis. However, the effect of copper, zinc-superoxide dismutase (SOD1) as a therapeutic agent is limited due to the insufficient transduction. This study was aimed to investigate the effect of PEP-1-SOD1 fusion protein on angiotensin II (ANG II)-induced collagen metabolism in rat cardiac myofibroblasts (MCFs). METHODS: MCFs were pretreated with SOD1 or PEP-1-SOD1 fusion protein for 2 h followed by incubation with ANG II for 24 h. Cell proliferation was measured by Cell Counting Kit-8. Superoxide anion productions were detected by both fluorescent microscopy and Flow Cytometry. MMP-1 and TIMP-1 were determined by ELISA. Intracellular MDA content and SOD activity were examined by commercial assay kits. Protein expression was analyzed by western blotting. RESULTS: PEP-1-SOD1 fusion protein efficiently transduced into MCF, scavenged intracellular O2 (-), decreased intracellular MDA content, increased SOD activity, suppressed ANG II-induced proliferation, reduced expression of TGF-ß1, α-SMA, collagen type I and III, restored MMP-1 secretion, and attenuated TIMP-1 secretion. CONCLUSION: PEP-1-SOD1 suppressed MCF proliferation and differentiation and reduced production of collagen type I and III. Therefore, PEP-1-SOD1 fusion protein may be a potential novel therapeutic agent for cardiac fibrosis.
Assuntos
Colágeno Tipo III/metabolismo , Colágeno Tipo I/metabolismo , Cisteamina/análogos & derivados , Miofibroblastos/metabolismo , Peptídeos/farmacologia , Superóxido Dismutase/farmacologia , Angiotensina II , Animais , Proliferação de Células/efeitos dos fármacos , Cisteamina/farmacologia , Masculino , Malondialdeído/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Superóxido Dismutase-1 , Superóxidos/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
BACKGROUND: Osteoarthritis (OA) is a global public health problem, and limited information is available on the effects of Cd on OA. The purpose of this study is to explore the relationship between Cd and OA. METHOD: Weighted multivariable logistic regression model, trend test, restricted cubic spline, and stratified analysis were used to study the association between BCd and OA. RESULTS: In the two regression models of weighted multivariable logistic regression analysis, the correlation between BCd and OA was positive. Compared with the lowest quartile of BCd exposure, the highest quartile had a 2.03-fold (95% confidence interval, 1.67 to 2.47), displaying a dose-response relationship (P for trend <0.00001). The restrictive cubic spline shows a positive linear relationship between BCd and OA. CONCLUSION: There was a positive linear relationship between BCd and OA and a dose-response relationship.
Assuntos
Cádmio , Inquéritos Nutricionais , Osteoartrite , Humanos , Masculino , Feminino , Osteoartrite/sangue , Osteoartrite/epidemiologia , Cádmio/sangue , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Adulto , Idoso , Modelos Logísticos , Estudos Transversais , Exposição Ambiental/efeitos adversosRESUMO
In this study, a scandium concentrate with Sc2O3 content of 66.24 g/t was obtained from V-Ti magnetite tailings by physical concentration, and the main Sc-bearing minerals were augite and hornblende. A novel process of roasting and leaching was proposed to extract scandium from scandium concentrate with titanium dioxide wastewater. Scandium concentrate was pretreated by roasting, and titanium dioxide wastewater was used to directly leach scandium from the roasted ore. The effects of roasting and leaching parameters such as roasting temperature, roasting time, roasting agents, leaching temperature, leaching time, liquid-to-solid ratio, and leaching agents on scandium separation were thoroughly researched in the experimental procedure. The results show that a scandium leaching efficiency of 85.89% was obtained, and the scandium content of leaching residue decreased to 9.31 g/t under the optimal conditions: a roasting temperature of 1123 K, a roasting time of 120 min, a leaching temperature of 343 K, a leaching time of 120 min, and a m (titanium dioxide wastewater)â¶m (roasted ore)â¶m (ammonium fluoride) ratio of 8â¶1â¶0.09. The main findings of the scandium separation mechanism show that Sc-bearing minerals can effectively decompose and release scandium element after roasting, and created favorable conditions for scandium leaching with titanium dioxide wastewater to achieve the purpose of scandium recovery.
Assuntos
Escândio , Águas Residuárias , Minerais , Titânio/químicaRESUMO
In this study, a core-shell structural nano-composite material, namely CdTeS@SiO2, is synthesized by a simple silanization of Te-doped CdS quantum dots (CdTeS QDs). Through SiO2 capping, CdTeS QDs not only improve the fluorescence performance effectively, but also greatly enhance the anti-interference ability in the environment. Based on its excellent optical properties, a novel fluorescence sensor is constructed for the ultramicro detection of Ag+. The fluorescence of CdTeS@SiO2 is strongly quenched in the presence of Ag+ and shows good linearity in the range of 0.005-5.0 µmol L-1 with a detection limit as low as 1.6 nmol L-1. This is mainly due to its unique quenching mechanism: Ag+ destroys the spherical structure of SiO2 and promotes the formation of non-radiative electron-hole pairs through electron transfer, leading to fluorescence quenching. At the same time, it competes with Cd for Te, S and MPA on the CdTeS surface, forming Ag-Te, Ag-S and Ag-MPA complexes attached to the CdTeS surface leading to wavelength red-shift. The feasibility of the proposed sensor is demonstrated through spiking experiments, which confirmed the potential value of the constructed fluorescence probe for real-world applications in detecting Ag+ in environmental water.
RESUMO
In this study, a nanocomposite consisting of graphitic carbon nitride nanosheets loaded with graphitic carbon nitride quantum dots (CNQDs/CNNNs) was synthesized via a one-step pyrolysis method. This nanocomposite exhibited excellent thermal stability, photobleaching and salt resistance. Then a new fluorescence sensing platform based on CNQDs/CNNNs was constructed, which showed high sensitivity and selectivity towards trace mercury ions (Hg2+). By using X-ray photoelectron spectroscopy, UV-vis diffuse reflectance spectra and density functional theory, the fluorescence response mechanism was elucidated where Hg2+ could interact with CNQDs/CNNNs, causing a structural change in the nanocomposite, further affecting its bandgap structure, and finally leading to fluorescence quenching. The linear range for detecting Hg2+ was found to be 0.025-4.0 µmol L-1, with a detection limit of 7.82 nmol L-1. This strategy provided the advantages of a rapid response and a broad detection range, making it suitable for quantitative detection of Hg2+ in environmental water.
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BACKGROUND: Heart failure (HF) is characterized by a disorder of cardiomyocyte energy metabolism. Xinbao Pill (XBW), a traditional Chinese medicine formulation integrating "Liushen Pill" and "Shenfu Decoction," has been approved by China Food and Drug Administration for the treatment of HF for many years. The present study reveals a novel mechanism of XBW in HF through modulation of cardiac energy metabolism. METHODS: In vivo, XBW (60, 90, 120 mg/kg/d) and fenofibrate (100 mg/kg/d) were treated for six weeks in Sprague-Dawley rats that were stimulated by isoproterenol to induce HF. Cardiac function parameters were measured by echocardiography, and cardiac pathological changes were assessed using H&E, Masson, and WGA staining. In vitro, primary cultured neonatal rat cardiomyocytes (NRCMs) were induced by isoproterenol to investigate the effects of XBW on myocardial cell damage, mitochondrial function and fatty acid energy metabolism. The involvement of the SGLT1/AMPK/PPARα signalling axis was investigated. RESULTS: In both in vitro and in vivo models of ISO-induced HF, XBW significantly ameliorated cardiac hypertrophy cardiac fibrosis, and improved cardiac function. Significantly, XBW improved cardiac fatty acid metabolism and mitigated mitochondrial damage. Mechanistically, XBW effectively suppressed the expression of SGLT1 protein while upregulating the phosphorylation level of AMPK, ultimately facilitating the nuclear translocation of PPARα and enhancing its transcriptional activity. Knockdown of SGLT1 further enhanced cardiac energy metabolism by XBW, while overexpression of SGLT1 reversed the cardio-protective effect of XBW, highlighting that SGLT1 is probably a critical target of XBW in the regulation of cardiac fatty acid metabolism. CONCLUSIONS: XBW improves cardiac fatty acid energy metabolism to alleviate HF via SGLT1/AMPK/PPARα signalling axis.
RESUMO
BACKGROUND: According to recent research, treating heart failure (HF) by inhibiting G protein-coupled receptor kinase 2 (GRK2) to improve myocardial energy metabolism has been identified as a potential approach. Cinnamaldehyde (CIN), a phenylpropyl aldehyde compound, has been demonstrated to exhibit beneficial effects in cardiovascular diseases. However, whether CIN inhibits GRK2 to ameliorate myocardial energy metabolism in HF is still unclear. PURPOSE: This study examines the effects of CIN on GRK2 and myocardial energy metabolism to elucidate its underlying mechanism to treat HF. METHODS: The isoproterenol (ISO) induced HF model in vivo and in vitro were constructed using Sprague-Dawley (SD) rats and primary neonatal rat cardiomyocytes (NRCMs). Based on this, the effects of CIN on myocardial energy metabolism and GRK2 were investigated. Additionally, validation experiments were conducted after interfering and over-expressing GRK2 in ISO-induced NRCMs to verify the regulatory effect of CIN on GRK2. Furthermore, binding capacity between GRK2 and CIN was explored by Cellular Thermal Shift Assay (CETSA) and Microscale Thermophoresis (MST). RESULTS: In vivo and in vitro, CIN significantly improved HF as demonstrated by reversing abnormal changes in myocardial injury markers, inhibiting myocardial hypertrophy and decreasing myocardial fibrosis. Additionally, CIN promoted myocardial fatty acid metabolism to ameliorate myocardial energy metabolism disorder by activating AMPK/PGC-1α signaling pathway. Moreover, CIN reversed the inhibition of myocardial fatty acid metabolism and AMPK/PGC-1α signaling pathway by GRK2 over-expression in ISO-induced NRCMs. Meanwhile, CIN had no better impact on the stimulation of cardiac fatty acid metabolism and the AMPK/PGC-1α signaling pathway in ISO-induced NRCMs when GRK2 was disrupted. Noticeably, CETSA and MST confirmed that CIN binds to GRK2 directly. The binding of CIN and GRK2 promoted the ubiquitination degradation of GRK2 mediated by murine double mimute 2. CONCLUSION: This study demonstrates that CIN exerts a protective intervention in HF by targeting GRK2 and promoting its ubiquitination degradation to activate AMPK/PGC-1α signaling pathway, ultimately improving myocardial fatty acid metabolism.
Assuntos
Proteínas Quinases Ativadas por AMP , Acroleína , Quinase 2 de Receptor Acoplado a Proteína G , Insuficiência Cardíaca , Miócitos Cardíacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ratos Sprague-Dawley , Animais , Acroleína/farmacologia , Acroleína/análogos & derivados , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Masculino , Ratos , Proteínas Quinases Ativadas por AMP/metabolismo , Transdução de Sinais/efeitos dos fármacos , Isoproterenol , Metabolismo Energético/efeitos dos fármacos , Modelos Animais de Doenças , Miocárdio/metabolismoRESUMO
Existing studies often focus on the impact of the neighbourhood environment on the subjective wellbeing (SWB) of the residents. Very few studies explore the impacts of the neighbourhood environment on migrant older adults. This study was conducted to investigate the correlations between perceived neighbourhood environment (PNE) and SWB among migrant older adults. A cross-sectional design was adopted. Data were collected from 470 migrant older adults in Dongguan, China. General characteristics, levels of SWB, and PNE were collected via a self-reported questionnaire. Canonical correlation analysis was performed to evaluate the relationship between PNE and SWB. These variables accounted for 44.1% and 53.0% of the variance, respectively. Neighbourhood relations, neighbourhood trust, and similar values in social cohesion made the most important contributions correlated with positive emotion and positive experience. A link between SWB and walkable neighbourhoods characterized by opportunities and facilities for physical activities with other people walking or exercising in their community, is positively associated with positive emotions. Our findings suggest that migrant older adults have a good walkable environment and social cohesion in neighbourhoods positively correlated with their subjective wellbeing. Therefore, the government should provide a more robust activity space for neighbourhoods and build an inclusive community for older adults.
Assuntos
Análise de Correlação Canônica , Características de Residência , Humanos , Idoso , Estudos Transversais , Exercício Físico , Caminhada , Características da Vizinhança , Planejamento AmbientalRESUMO
Near-infrared II fluorescent probes targeting tumors for diagnostic purposes have received much attention in recent years. In this study, a fluorescent probe for the NIR-II was constructed by using IRDye800CW-NHS fluorescent dye with Trastuzumab, which was investigated for its ability to target HER-2-positive breast cancer in xenograft mice models. This probe was compared with Trastuzumab-ICG which was synthesized using a similar structure, ICG-NHS. The results demonstrated that the IRDye800CW-NHS had significantly stronger fluorescence in the NIR-I and NIR-II than ICG-NHS in the aqueous phase. And the different metabolic modes of IRDye800CW-NHS and ICG-NHS were revealed in bioimaging experiments. IRDye800CW-NHS was mainly metabolised by the kidneys, while ICG-NHS was mainly metabolised by the liver. After coupling with Trastuzumab, Trastuzumab-800CW (TMR = 5.35 ± 0.39) not only had a stronger tumor targeting ability than Trastuzumab-ICG (TMR = 4.42 ± 0.10) based on the calculated maximum tumor muscle ratio (TMR), but also had a comparatively lower hepatic uptake and faster metabolism. Histopathology analysis proved that both fluorescent probes were non-toxic to various organ tissues. These results reveal the excellent optical properties of IRDye800CW-NHS, and the great potential of coupling with antibodies to develop fluorescent probes that will hopefully be applied to intraoperative breast cancer navigation in humans.
Assuntos
Neoplasias da Mama , Humanos , Animais , Camundongos , Feminino , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Trastuzumab , Xenoenxertos , Corantes Fluorescentes/química , Medicina Estatal , Linhagem Celular Tumoral , Imagem Óptica/métodosRESUMO
Rose Bengal (RB) is used as a sensitizer in ambient water due to its property of catalyzing the production of singlet oxygen (1O2). However, this property also brings phototoxicity and carcinogenicity. The NaYF4:3%Er@NaYF4 core-shell upconversion nanoparticles (UCNPs) with higher upconversion efficiency was synthesized to detect RB in ambient water. Due to fluorescence resonance energy transfer (FRET) between RB and UCNPs, the upconversion fluorescence at 538 nm emitted by UCNPs was quenched by the RB, while the emission at 566 nm of RB raised. In the best conditions, the ratiometric emission intensity F566/F538 was positively proportional to RB concentration and the linear range was 0.04-15.0 µg·mL-1 (R2 = 0.996). The detection limit (S/N = 3) of RB was 2.46 ng·mL-1. The recoveries ranged from 99.0% to 105.6% (relative standard deviation 0.97-3.24%, n = 3) in tap water and 100.3%-104.9% (relative standard deviation 0.66-1.94%, n = 3) in lake water. This proposed method exhibits lower detection limit and larger linear, which possesses practical application value to the detection of RB in water.
RESUMO
In this study, we investigated a coarse phosphogypsum containing 49.63% SO3, 41.41% CaO, 10.68%, 4.47% SiO2, 1.28% P2O5, 0.11% F, CaSO4·2H2O purity of 80.65%, and whiteness of 27.68. Phosphogypsum contains calcium sulfate dehydrate as the main mineral, with small amounts of brushite, quartz, muscovite, and zoisite. Harmful elements, such as silicon, phosphorus, and fluorine, are mainly concentrated in the +0.15 mm and -0.025 mm fraction, which can be pre-selected and removed by the grading method to further increase the CaSO4·2H2O content. Gypsum was recovered using a direct flotation method, which included one roughing, one scavenging, and two cleaning operations, from -0.15 mm to +0.025 mm. The test results show that a gypsum concentrate with a CaSO4·2H2O purity of 98.94%, CaSO4·2H2O recovery of 80.02%, and whiteness of 37.05 was achieved. The main mineral in the gypsum concentrate was gypsum, and limited amounts of muscovite and zoisite entered the gypsum concentrate because of the mechanical entrainment of the flotation process.
RESUMO
BACKGROUND: Consensus on the etiology of 1991 Gulf War illness (GWI) has been limited by lack of objective individual-level environmental exposure information and assumed recall bias. OBJECTIVES: We investigated a prestated hypothesis of the association of GWI with a gene-environment (GxE) interaction of the paraoxonase-1 (PON1) Q192R polymorphism and low-level nerve agent exposure. METHODS: A prevalence sample of 508 GWI cases and 508 nonpaired controls was drawn from the 8,020 participants in the U.S. Military Health Survey, a representative sample survey of military veterans who served during the Gulf War. The PON1 Q192R genotype was measured by real-time polymerase chain reaction (RT-PCR), and the serum Q and R isoenzyme activity levels were measured with PON1-specific substrates. Low-level nerve agent exposure was estimated by survey questions on having heard nerve agent alarms during deployment. RESULTS: The GxE interaction of the Q192R genotype and hearing alarms was strongly associated with GWI on both the multiplicative [prevalence odds ratio (POR) of the interaction=3.41; 95% confidence interval (CI): 1.20, 9.72] and additive (synergy index=4.71; 95% CI: 1.82, 12.19) scales, adjusted for measured confounders. The Q192R genotype and the alarms variable were independent (adjusted POR in the controls=1.18; 95% CI: 0.81, 1.73; p=0.35), and the associations of GWI with the number of R alleles and quartiles of Q isoenzyme were monotonic. The adjusted relative excess risk due to interaction (aRERI) was 7.69 (95% CI: 2.71, 19.13). Substituting Q isoenzyme activity for the genotype in the analyses corroborated the findings. Sensitivity analyses suggested that recall bias had forced the estimate of the GxE interaction toward the null and that unmeasured confounding is unlikely to account for the findings. We found a GxE interaction involving the Q-correlated PON1 diazoxonase activity and a weak possible GxE involving the Khamisiyah plume model, but none involving the PON1 R isoenzyme activity, arylesterase activity, paraoxonase activity, butyrylcholinesterase genotypes or enzyme activity, or pyridostigmine. DISCUSSION: Given gene-environment independence and monotonicity, the unconfounded aRERI>0 supports a mechanistic interaction. Together with the direct evidence of exposure to fallout from bombing of chemical weapon storage facilities and the extensive toxicologic evidence of biochemical protection from organophosphates by the Q isoenzyme, the findings provide strong evidence for an etiologic role of low-level nerve agent in GWI. https://doi.org/10.1289/EHP9009.