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Calcium/calmodulin dependent protein kinase kinase (CaMKK), a highly conserved protein kinase, is involved in the downstream processes of various biological activities by phosphorylating and activating 5'-AMP-activated protein kinase (AMPK) in response to the increase of cytosolic-free calcium (Ca2+). In the present study, a CaMKKI was identified from Yesso scallop Patinopecten yessoensis. Its mRNA was ubiquitously expressed in haemocytes and all tested tissues with the highest expression level in mantle. The expression level of PyCaMKKI mRNA in adductor muscle was significantly upregulated at 1, 3 and 6 h after high temperature treatment (25 °C), which was 3.43-fold (p < 0.05), 5.25-fold (p < 0.05), and 5.70-fold (p < 0.05) of that in blank group, respectively. At 3 h after high temperature treatment (25 °C), the protein level of PyAMPKα, as well as the phosphorylation level of PyAMPKα at Thr170 in adductor muscle, and the positive co-localized fluorescence signals of PyCaMKKI and PyAMPKα in haemocyte all increased significantly (p < 0.05) compared to blank group (18 °C). The pull-down assay showed that rPyCaMKKI and rPyAMPKα could bind each other in vitro. After PyCaMKKI was silenced by siRNA, the mRNA and protein levels of PyCaMKKI and PyAMPKα, and the phosphorylation level of PyAMPKα at Thr170 in adductor muscle were significantly down-regulated (p < 0.05) compared with the negative control group receiving an injection of siRNA-NC. These results collectively suggested that PyCaMKKI was involved in the activation of PyAMPKα in response to high temperature stress and would be helpful for understanding the function of PyCaMKKI-PyAMPKα pathway in maintaining energy homeostasis under high temperature stress in scallops.
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Proteínas Quinasas Activadas por AMP , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina , Pectinidae , Animales , Pectinidae/inmunología , Pectinidae/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Fosforilación , Respuesta al Choque Térmico , Hemocitos/metabolismo , ARN Interferente Pequeño/genética , Calor , Estrés FisiológicoRESUMEN
Inflammatory responses are associated with the development of vascular dementia (VaD). Circulating cytokines modulate the inflammatory response and are important for the immune system. To further elucidate the role of the immune system in VaD, we used Mendelian randomization (MR) to comprehensively and bi-directionally assess the role of circulating cytokines in VaD. Using state-of-the-art genome-wide association studies, we primarily assessed whether different genetic levels of 41 circulating cytokines affect the risk of developing VaD and, in turn, whether the genetic risk of VaD affects these circulating cytokines. We used inverse variance weighting (IVW) and several other MR methods to assess the bidirectional causality between circulating cytokines and VaD, and performed sensitivity analyses. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was inversely associated with VaD risk [odds ratio (OR): 0.74, 95 % confidence interval (CI): 0.60-0.92, P = 0.007, 0.007]. VaD was associated with seven circulating cytokines: macrophage inflammatory protein 1b (MIP-1 beta) [OR: 1.05, 95 % CI: 1.01-1.08, P = 0.009], Interleukin-12p70 (IL-12) [OR: 1.04, 95 % CI: 1.00-1.08, P = 0.047], Interleukin-17 (IL-17) [OR: 1.04, 95 % CI: 1.00-1.07, P = 0.038], Interleukin-7 (IL-7) [OR: 1.07, 95 % CI: 1.02-1.12, P = 0.009], Interferon gamma (IFN-γ) [OR: 1.03, 95 % CI: 1.00-1.07, P = 0.046], Granulocyte-colony stimulating factor (GCSF) [OR: 1.06, 95 % CI: 1.02-1.09, P = 0.001], Fibroblast growth factor (FGF) [P = 0.001], and Fibroblast growth factor (FGF) [P = 0.001]. Fibroblast growth factor basic (FGF-Basic) [OR: 1.04, 95 % CI: 1.01-1.08, P = 0.02] were positively correlated. Circulating cytokines are associated with VaD, and further studies are needed to determine whether they are effective targets for intervention to prevent or treat VaD.
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Citocinas , Demencia Vascular , Humanos , Demencia Vascular/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Factores de Crecimiento de FibroblastosRESUMEN
Liver kinase B1 (LKB1) is a classical serine/threonine protein kinase and plays an important role in maintaining energy homeostasis through phosphorylate AMP-activated protein kinase α subunit (AMPKα). In this study, a homologous molecule of LKB1 with a typical serine/threonine kinase domain and two nuclear localization sequences (NLSs) was identified in Yesso Scallop Patinopecten yessoensis (PyLKB1). The mRNA transcripts of PyLKB1 were found to be expressed in haemocytes and all the examined tissues, including gill, mantle, gonad, adductor muscle and hepatopancreas, with the highest expression level in hepatopancreas. PyLKB1 was mainly located in cytoplasm and nucleus of scallop haemocytes. At 3 h after high temperature stress treatment (25 °C), the mRNA transcripts of PyLKB1, PyAMPKα, and PyGLUT1 in hepatopancreas, the phosphorylation level of PyAMPKα at Thr170 in hepatopancreas, the positive fluorescence signals of PyLKB1 in haemocytes, glucose analogue 2-NBDG content in haemocytes, and glucose content in hepatopancreas, haemocytes and serum all increased significantly (p < 0.05) compared to blank group (15 °C). However, there was no significant difference at the protein level of PyLKB1 and PyAMPKα. After PyLKB1 was knockdown by siRNA, the mRNA expression level of PyGLUT1, and the glucose content in hepatopancreas and serum were significantly down-regulated (p < 0.05) compared with the negative control group receiving an injection of siRNA-NC. However, there were no significant difference in PyGLUT1 expression, glucose content and glucose analogue 2-NBDG content in haemocytes. These results collectively suggested that PyLKB1-PyAMPKα pathway was activated to promote glucose transport by regulating PyGLUT1 in response to high temperature stress. These results would be helpful for understanding the function of PyLKB1-PyAMPKα pathway in regulating glucose metabolism and maintaining energy homeostasis under high temperature stress in scallops.
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Pectinidae , Animales , Temperatura , Pectinidae/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Serina/metabolismoRESUMEN
AMP-activated protein kinase α subunit (AMPKα), the central regulatory molecule of energy metabolism, plays an important role in maintaining energy homeostasis and helping cells to resist the influence of various adverse factors. In the present study, an AMPKα was identified from Yesso scallop Patinopecten yessoensis (PyAMPKα). The open reading frame (ORF) of PyAMPKα was of 1599 bp encoding a putative polypeptide of 533 amino acid residues with a typical KD domain, a α-AID domain and a α-CTD domain. The deduced amino acid sequence of PyAMPKα shared 59.89-74.78% identities with AMPKαs from other species. The mRNA transcripts of PyAMPKα were found to be expressed in haemocytes and all the examined tissues, including gill, mantle, gonad, adductor muscle and hepatopancreas, with the highest expression level in adductor muscle. PyAMPKα was mainly located in cytoplasm of scallop haemocytes. At 3 h after high temperature stress treatment (25 °C), the mRNA transcripts of PyAMPKα, the phosphorylation level of PyAMPKα at Thr170 and the lactic acid (LD) content in adductor muscle all increased significantly, while the glycogen content decreased significantly. The activity of pyruvate kinase (PyPK) and the relative mRNA expression level of phosphofructokinase (PyPFK) were significantly up-regulated at 3 h after high temperature stress treatment (25 °C). Furthermore, the PyAMPKα activator AICAR could effectively upregulate the phosphorylation level of PyAMPKα, and increase activities of PyPFK and pyruvate kinase (PyPK). Meanwhile the glycogen content also declined under AICAR treatment. These results collectively suggested that PyAMPKα was involved in the high temperature stress response of scallops by enhancing glycolysis pathway of glycogen. These results would be helpful for understanding the functions of PyAMPKα in maintaining energy homeostasis under high temperature stress in scallops.
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Proteínas Quinasas Activadas por AMP , Pectinidae , Animales , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Temperatura , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismo , Pectinidae/genética , Pectinidae/metabolismo , Glucólisis , ARN Mensajero/metabolismo , FilogeniaRESUMEN
Glycogen is the main energy storage material in mollusc, and the regulation of its metabolism is essential for the response against high temperature stress. In the present study, the alternation of lactic acid (LD) content, glycogen reserves, mRNA expression level of genes encoding glycogen metabolism enzymes and activities of glycogen metabolism enzymes in gills of Yesso scallop Patinopecten yessoensis after an acute high temperature treatment at 25 °C were examined to understand the effect of high temperature on glycogen metabolism. The activity of T-ATPase in gills of scallops presented a gradual increase trend especially at 6 h after the acute high temperature treatment (p < 0.05). The glycogen reserves did not change significantly even there was a downward trend at 24 h after the acute high temperature treatment (p > 0.05). The mRNA transcripts of glycogen synthase (PyGCS) in gills of scallops decreased significantly at 1, 3, 6 and 12 h (p < 0.05), and recovered to normal level at 24 h (p > 0.05) after the acute high temperature treatment, while that of glycogen phosphorylase a (PyGPa) and phosphoenol pyruvate carboxy kinase (PyPEPCK) were both significantly down-regulated from 1 h to 24 h (p < 0.05) after the acute high temperature treatment. The activity of PyGPa at 1, 12 and 24 h and the content of LD at 3 and 24 h in gills of scallops after the acute high temperature treatment both increased significantly (p < 0.05). Furthermore, the mRNA transcripts of hexokinase (PyHK) and pyruvate kinase (PyPK) in gills of scallops increased significantly (p < 0.05) after the acute high temperature treatment, and the response of PyHK was stronger. However, there was no significant difference on the activity of PyPK in gills of scallops between the experimental samples and the blank samples (p > 0.05). In addition, the mRNA transcripts of citrate synthase (PyCS) in gills of scallops were significantly down-regulated at 6 h and 12 h (p < 0.05), and finally returned to normal level at 24 h (p > 0.05) after the acute high temperature treatment. These results collectively indicated acute high temperature stress leaded the alternation of glycogen metabolism in the gills of Yesso scallop, glycogenesis, gluconeogenesis and TCA cycle were inhibited, and the glycolysis pathway of glycogen was enhanced to produce more energy for coping with environmental pressure.
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Branquias , Pectinidae , Animales , Temperatura , Pectinidae/genética , Pectinidae/metabolismo , ARN Mensajero/metabolismoRESUMEN
Transient receptor potential vanilloid 4 (TRPV4) is one of the major non-selective cation channel proteins, which plays a crucial role in sensing biotic and abiotic stresses, such as pathogen infection, temperature, mechanical pressure and osmotic pressure changes by regulating Ca2+ homeostasis. In the present study, a TRPV4 homologue was identified in Pacific oyster Crassostrea gigas, designated as CgTRPV4. The open reading frame (ORF) of CgTRPV4 was of 2298 bp encoding a putative polypeptide of 765 amino acid residues with three typical ankyrin domains and six conserved transmembrane domains of TRPV4 subfamily proteins, as well as multiple N-glycosylation sites, cAMP- and cGMP-dependent protein kinase phosphorylation sites, protein kinase C phosphorylation sites, casein kinase II phosphorylation sites, and prokaryotic membrane lipoprotein lipid attachment site. The deduced amino acid sequence of CgTRPV4 shared 20.5%-26.2% similarity with TRPV4s from other species. During the early ontogenesis stages of oyster, the mRNA transcripts of CgTRPV4 were detectable in all the stages with the highest expression level in fertilized eggs and the lowest in D-hinged larvae. In adult oyster, the CgTRPV4 mRNA could be detected in all the examined tissues, including gill, hepatopancreas, adductor muscle, labial palp, mantle and haemocyte, with the highest expression level in gill (45.08-fold of that in hepatopancreas, p < 0.05). In immunocytochemical assay, the CgTRPV4 positive signals were distributed in both endoplasmic reticulum and cytoplasmic membrane of oyster haemocytes. The mRNA expression of CgTRPV4 in gill was significantly up-regulated after high temperature stress at 30°C (p < 0.05) and after Vibrio splendidus stimulation (p < 0.05). These results indicated that CgTRPV4 was a classical member of TRPV4 family in oyster, which was induced by either biotic or abiotic stimulations and involved in mediating the stress response of oysters.
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Background: S100 Calcium Binding Protein A8 (S100A8) is beneficial for cancer immunotherapy. However, the processes underlying its therapeutic potential have not been completely studied. Methods: The Cancer Genome Atlas provides raw data on 33 different cancer types. GEO made available GSE67501, GSE78220, and IMvigor210. We investigated S100A8's genetic changes, expression patterns, and survival studies. The linkages between S100A8 and TME, as well as its association with immunological processes/elements and the major histocompatibility complex, were explored to effectively understand the role of S100A8 in cancer immunotherapy. Three distinct immunotherapeutic cohorts were employed to examine the relationship between S100A8 and immunotherapeutic response. Results: S100A8 expression was high in tumor tissue. The overexpression of S100A8 is associated with poor clinical outcome in patients with overall survival. S100A8 is associated with immune cell infiltration, immunological modulators, and immunotherapeutic indicators. S100A8 overexpression is connected to immune-related pathways. However, no statistically significant connection between S100A8 and immunotherapeutic response was identified. Conclusions: S100A8 may be a reliable biomarker for tumor prognosis and a viable prospective therapeutic target for human cancer immunotherapy (e.g., GBM, KIRC, LGG, and LIHC).
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Beclin 1 and LC3 are important autophagy regulation proteins involved in vesicle nucleation and extension stage, respectively. In the present study, a Beclin 1 and a LC3 were identified from Yesso scallop Patinopecten yessoensis (PyBeclin 1 and PyLC3). The open reading frame (ORF) of PyBeclin 1 was of 1335 bp encoding a putative polypeptide of 444 amino acid residues with an N-terminal BCL-2 homology 3 (BH3) domain, a central coiled-coil domain (CCD), and a C-terminal evolutionarily conserved domain (ECD). The ORF of PyLC3 was of 369 bp encoding a putative polypeptide of 122 amino acid residues with an APG12 domain. The deduced amino acid sequences of PyBeclin 1 and PyLC3 shared 31.92-74.09% and 68.38-79.50% identities with Beclin 1s and LC3s from other species, respectively. The mRNA transcripts of PyBeclin 1 and PyLC3 were found to be expressed in all the examined tissues, including adductor muscle, gonad, gill, haemocytes and mantle, with the highest expression level in gill and haemocytes. The mRNA expression level of PyBeclin 1 in haemocytes increased significantly at 1, 3, 6, 12 and 24 h (2.98-4.07 fold of that in the Blank group, p < 0.05), and returned to normal level at 48 h after acute high temperature stress at 25 °C. Unlike PyBeclin 1, the mRNA transcripts of PyLC3 in haemocytes were significantly up-regulated at1, 3, 6 and 12 h (1.80-2.54 fold of that in the Blank group, p < 0.05), then decreased to blank level at 24 h (p > 0.05), and increased significantly again at 48 h (3.70 fold of that in the Blank group, p < 0.05) after high temperature. PyBeclin 1 and PyLC3 were mainly located in the cytoplasm and a small amount in the nucleus with few puncta, and the numbers of PyBeclin 1 and PyLC3 puncta increased at 3 h after acute high temperature stress. The LC3-II levels in gill and haemocytes were significantly up-regulated at 1 h and 3 h after acute high temperature stress. These results collectively suggested that PyBeclin 1 and PyLC3 were conserved members of Beclin 1 and LC3 family in scallops, and involved in regulating the activation of autophagy in scallops after acute high temperature stress.
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Autofagia/inmunología , Beclina-1/metabolismo , Respuesta al Choque Térmico/inmunología , Pectinidae/inmunología , Secuencia de Aminoácidos , Beclina-1/genética , Calor/efectos adversos , Pectinidae/genéticaRESUMEN
This study aimed to establish a stable animal model of intrauterine adhesion (IUA) using a minimally invasive method that recapitulates the clinicopathologic characteristics of IUA. Mice were randomly divided into groups based on the ethanol treatment time (the EtOH-10 s, EtOH-20 s, EtOH-40 s, EtOH-1 min, and sham operation groups), and after the cervix was relaxed with phloroglucinol, the uterine horn was perfused with 95% ethanol through the cervix to induce endometrial injury. Eight days after the procedure, routine biochemical assays were performed to assess liver and kidney function; HE and Masson staining were used to assess uterine morphology and fibrosis; and immunohistochemistry was performed to evaluate the expression of CD31 and F4/80 in the endometrium. Furthermore, the fertility of mice in the EtOH-40 s group and the sham operation group was compared. As expected, the ethanol treatment time was positively correlated with the degree of uterine damage and kidney dysfunction in mice. In particular, the endometria of mice in the EtOH-40 s group were significantly thinner than those of mice in the sham operation group and exhibited severe necrosis, glandular loss, incomplete epithelial and glandular epithelial cell structure, severe tissue fibrosis, an activated inflammatory response, and a significant decrease in the number of fetuses, consistent with the clinical characteristics of severe IUA. In conclusion, this study resulted in successful establishment, by a minimally invasive transcervical ethanol perfusion technique, of a mouse model of endometrial injury, which could support an in-depth study of IUA pathogenesis and further promote the development of IUA therapies.
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Etanol , Enfermedades Uterinas/patología , Útero/patología , Animales , Proteínas de Unión al Calcio/metabolismo , Modelos Animales de Enfermedad , Endometrio/patología , Femenino , Fertilidad , Fibrosis , Ratones Endogámicos BALB C , Perfusión , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Embarazo , Receptores Acoplados a Proteínas G/metabolismo , Factores de Tiempo , Adherencias Tisulares , Enfermedades Uterinas/etiología , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/fisiopatología , Útero/metabolismo , Útero/fisiopatologíaRESUMEN
Calnexin (CNX) is one of the major calcium-binding proteins in endoplasmic reticulum (ER) and plays a crucial role in regulating Ca2+ homeostasis and unfolded protein response (UPR). In the present study, PyCNX was identified in Yesso Scallop Patinopecten yessoensis. The open reading frame (ORF) of PyCNX was of 1794 bp encoding a putative polypeptide of 598 amino acid residues with an N-terminal signal peptide, a typical calreticulin (CRT) domain and a C-terminal transmembrane domain. The deduced amino acid sequence of PyCNX shared 47.91%-70.16% identities with CNXs from other species. The mRNA transcripts of PyCNX were constitutively expressed in all the examined tissues, including gills, gonad, hepatopancreas, mantle and haemocytes, with the highest expression level in gills. The mRNA transcripts of PyCNX in gills were significantly up-regulated at 1 h (p < 0.01), down-regulated to similar level of Blank group at 3 h (p > 0.05) and 6 h (p > 0.05), and decreased significantly from 12 to 48 h (p < 0.05) after acute high temperature stress (25 °C). PyCNX was mainly located in the ER of haemocytes. The expression profiles of PyATF6, PyIRE1 and PyGRP78 in the gills of scallops after acute high temperature stress were investigated using quantitative real-time PCR. The mRNA transcripts of PyATF6 increased significantly at 1 h, 3 h and 6 h after acute high temperature stress (p < 0.01), then down-regulated to similar level of Blank group at 12 h (p > 0.05) and 24 h (p > 0.05), and finally significantly up-regulated again at 48 h (p < 0.05). Similar to PyATF6, the mRNA transcripts of PyIRE1 were significantly up-regulated at 1 h (p < 0.05), 3 h (p < 0.01), 6 h (p < 0.05) and 48 h (p < 0.05) after acute high temperature stress. The mRNA transcripts of PyGRP78 were significantly up-regulated at 3 h (p < 0.05), reached the highest level at 6 h (p < 0.01) after acute high temperature stress, and kept significant higher level at 12-48 h (p < 0.05). These results indicated that PyCNX was involved in the response upon the acute high temperature stress of scallops probably by regulating UPR.
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BACKGROUND: To evaluate the effectiveness and safety of warm needle acupuncture (WNA) treatment for Scapulohumeral periarthritis. METHODS: Relevant randomized controlled trials will be searched from the databases of Pubmed, the Cochrane Library, Embase, CNKI, Wanfang Database, CBM and VIP Database from their inception to September 2021. The primary outcomes are effective rate, visual analog scale score. The secondary outcomes are Constant-Murley score, Japanese Orthopaedic Association scores, adverse events. Two reviewers will independently select studies, collect data, and assess the methodology quality by the Cochrane risk of bias tool. The Stata 14.0 will be used for meta-analysis. RESULTS: This study is ongoing and will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will provide an assessment of the current state of WNA for the scapulohumeral periarthritis, aiming to show the efficacy and safety of WNA treatment. ETHICS AND DISSEMINATION: There is no requirement of ethical approval and informed consent, and it will be in print or published by electronic copies. REGISTRATION: INPLASY2020100049.
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Terapia por Acupuntura/métodos , Periartritis/terapia , Articulación del Hombro , Humanos , Húmero , Metaanálisis como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Escápula , Revisiones Sistemáticas como AsuntoRESUMEN
BACKGROUND: Myocarditis is one of the important causes of dilated cardiomyopathy, cardiac morbidity, and mortality worldwide. Chitosan oligosaccharides (COS) may have anti-inflammatory and cardioprotective effects on myocarditis. However, the exact molecular mechanism for the effects of functional COS on myocarditis remains unclear. METHODS: Anti-inflammatory activities of COS (chitobiose, chitotriose, chitotetraose, chitopentaose, chitohexaose, chitoheptaose, and chitooctaose) were measured in lipopolysaccharide- (LPS-) stimulated RAW264.7 cells. A rat model with myocarditis was established and treated with chitopentaose, chitohexaose, chitoheptaose, and chitooctaose. Serum COS were measured by using high-performance liquid chromatography (HPLC) in all rats. Myocarditis injury, the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS), inflammatory factors, and apoptotic factors were also measured. Pearson's correlation coefficient test was used to explore the relationship between the levels of ROS/RNS and cardiac parameters. RESULTS: Among all chitosan oligosaccharides, the COS > degrees of polymerization (DP) 4 showed anti-inflammatory activities (the activity order was chitopentaose
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Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Quitosano/uso terapéutico , Corazón/efectos de los fármacos , Miocarditis/tratamiento farmacológico , Animales , Quitosano/farmacología , Modelos Animales de Enfermedad , Humanos , Masculino , RatasRESUMEN
Oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation plays an important role in the development of cardiovascular diseases. G protein-coupled receptors (GPCR) are gaining traction as potential treatment targets due to their roles in mediating a wide range of physiological processes. GPR120 is a recently identified omega-3 fatty acid receptor. We hypothesized that agonism of GPR120 might attenuate ox-LDL-induced endothelial dysfunction. In the present study, we tested the effects of two GPR120 agonists-GW9508 and TUG-891-in mitigating endothelial insult induced by ox-LDL in human aortic endothelial cells (HAECs). Real-time PCR, western blot, and ELISA analyses were used in our experiments. Our findings demonstrate that GPR120 is downregulated by exposure to ox-LDL, suggesting a role for GPR120 in mediating ox-LDL insult. Furthermore, we found that agonism of GPR120 could suppress oxidative stress and inflammation by inhibiting the production of reactive oxygen species and the expression of proinflammatory cytokines. Importantly, we show that agonism of GPR120 prevents the attachment of monocytes to endothelial cells by suppressing the expression of VCAM-1 and E-selectin. Finally, we show that agonism of GPR120 exerts a remarkable atheroprotective effect by elevating the expression level of Krüppel-like factor 2 (KLF2). Together, our results demonstrate a potential role for specific agonism of GPR120 in the prevention of endothelial damages induced by ox-LDL.
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Adhesión Celular/efectos de los fármacos , Lipoproteínas LDL/farmacología , Metilaminas/farmacología , Propionatos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Selectina E/genética , Selectina E/metabolismo , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/prevención & control , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Monocitos/citología , Monocitos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
Inhibition of hypoxia/reoxygenation (H/R)-induced insult in cardiac microvascular endothelial cells (CMECs) has been considered as a promising therapeutic strategy for the treatment of ischemic cardiovascular disease. In the present study, we found that H/R significantly increased the expression of dipeptidyl peptidase (DPP)-4 in CMECs. Treatment with the DPP-4 inhibitor sitagliptin, a licensed drug used for the treatment of type 2 diabetes mellitus (T2DM), ameliorated H/R-induced oxidative stress by decreasing the expression of NOX-4 and restoring the intracellular level of GSH in CMECs. Sitagliptin could also improve H/R-induced mitochondrial dysfunction by increasing intracellular MMP and ATP. Additionally, we found that the presence of sitagliptin prevented H/R-induced reduced cell viability and LDH release. Notably, our findings indicate that sitagliptin possesses an anti-inflammatory effect against H/R-induced expression of IL-6, IL-8, and TNF-α as well as secretion of HMGB1. Mechanistically, we found that sitagliptin suppresses activation of p38/NF-κB signaling. These findings suggest that sitagliptin may have potential as a therapeutic agent for the treatment of cardiovascular diseases.
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High glucose- induced endothelial dysregulation has been recognized as an initiation of vascular complications in Type 2 diabetes mellitus (T2DM). Anagliptin is a novel licensed dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of T2DM. The effects of anagliptin in high glucose- induced endothelial dysfunction are less reported. In the current study, we found that treatment with anagliptin prevented high glucose- induced reduction of cell viability and increase in LDH release in human umbilical vein endothelial cells (HUVECs). Our results indicate that anagliptin- reduced high glucose- induced increase in mitochondrial ROS and NOX-4 expression. Additionally, anagliptin treatment inhibited high glucose- induced expressions of TXNIP in HUVECs. Importantly, anagliptin treatment downregulated high glucose- induced NLRP3 inflammasome activation, as evidenced by reducing the expressions of NLRP3, ASC, and cleaved caspase-1 (P10). Also, ELISA results demonstrate that anagliptin treatment significantly abolished high glucose- induced maturation of IL-1ß and IL-18. Mechanistically, we found that anagliptin treatment restored high glucose- induced reduction of SIRT1 expression. Silencing of SIRT1 by transfection with SIRT1 siRNA abolished the inhibitory effects of anagliptin in NLRP3 inflammasome activation. These results display that anagliptin may confer protection against high glucose- induced endothelial injury via SIRT1-dependent inhibition of NLRP3 infammasome activation.
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Endotelio Vascular/fisiopatología , Glucosa/toxicidad , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Pirimidinas/farmacología , Sirtuina 1/metabolismo , Proteínas Portadoras/metabolismo , Supervivencia Celular/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Biológicos , NADPH Oxidasa 4/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Ternary chalcogenide compounds are such promising and have been used for much practical applications. As a sort of these compounds, cubanite (CuFe2S3) possess some unique properties which can be used in different fields. In our study, we developed a facile one pot synthesis of CuFe2S3 nanocrystals (NCs) at a low reaction temperature, and achieved a morphology and phase composition tuning of the NCs through changing a variety of precursors and surfactants, meanwhile improved their magnetism and optical properties. Eventually, well-ordered and 'nano-brick' like CuFe2S3 NCs were obtained and showed best magnetism and near-infrared fluorescence properties. Furthermore, the NCs were proved with good biocompatibility and possibility for cell labeling. This kind of materials with lower toxicity and potential of magnetic is bound to remedy the defects of photoluminescence quantum dots (QDs) and be with higher potential in the field of biological diagnosis and multi-functional system construction.
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Defect-related fluorescent HAp materials, which require no toxic metal ions or photobleaching fluorescent organic dyes, are expected to be excellent fluorescent probes in biological fields. However, the luminescent mechanism is poorly understood, making it difficult to adjust their emission performance for better applications in bioimaging. Herein, a novel luminescent mechanism for defect-related HAp fluorescent materials obtained from a typical hydrothermal process was revealed. N-Rich carbon dots (CDs), rather than the reported CO2Ë-, were confirmed as the luminescence centers responsible for self-activated luminescence. The mode in which the N-rich CDs and HAp host combined might be through CDs (mainly polymer clusters and/or molecular fluorophores constituents) becoming trapped in the HAp crystal structure. This study should inspire the design of fluorescent HAp materials with tunable fluorescence emissions due to the diverse synthetic methods and tunable fluorescence emission of CDs.