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Gypenosides (Gyp) are bioactive components of Gynostemma pentaphyllum that have a variety of pharmacological properties. Extracts of G. pentaphyllum have been found to be effective in the reduction of blood sugar and lipids and prevention of atherosclerosis. Here, the functions of Gyp and the mechanisms underlying their effects on atherosclerosis were investigated. Mice were allocated to three groups, namely, the control (C57BL/6), atherosclerosis model (ApoE-/- mice with high-fat diet), and Gyp-treated groups. Differentially expressed mRNAs, miRNAs, circRNA, and differential metabolites among the groups were analyzed. The results showed that "Fatty acid metabolism", "Fatty acid elongation", "Cytokine-cytokine receptor interaction", and "PI3K-Akt signaling pathway", amongst others, were involved in treatment process. Differentially expressed genes, including Fabp1, Apoe, FADS1, ADH1, SYNPO2, and Lmod1were also identified. Mmu-miR-30a and mmu-miR-30e showed reduced expression in atherosclerosis models but were increased following Gyp treatment, suggesting involvement in the effects of Gyp. In addition, chr5:150604177-150608440 were found to interact with mmu-miR-30a and mmu-miR-30e to regulate their abundance. In terms of metabolomics, Gyp may regulate biological processes involving PGD2 and PGJ2, potentially alleviating atherosclerosis. In conclusion, Gyp appeared to have complex effects on atherosclerosis, most of which were positive. These results support the use of Gyp in the treatment of atherosclerosis.
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This study aims to investigate the mechanism of the anti-atherosclerosis effect of Huayu Qutan Recipe (HYQT) on the inhibition of foam cell formation. In vivo, the mice were randomly divided into three groups: CTRL group, MOD group and HYQT group. The HYQT group received HYQT oral administration twice a day (20.54 g/kg/d), and the plaque formation in ApoE-/- mice was observed using haematoxylin-eosin (HE) staining and oil red O (ORO) staining. The co-localization of aortic macrophages and lipid droplets (LDs) was examined using fluorescent labelling of CD11b and BODIPY fluorescence probe. In vitro, RAW 264.7 cells were exposed to 50 µg/mL ox-LDL for 48 h and then treated with HYQT for 24 h. The accumulation of LDs was evaluated using ORO and BODIPY. Cell viability was assessed using the CCK-8 assay. The co-localization of LC3b and BODIPY was detected via immunofluorescence and fluorescence probe. LysoTracker Red and BODIPY 493/503 were used as markers for lysosomes and LDs, respectively. Autophagosome formation were observed via transmission electron microscopy. The levels of LC3A/B II/LC3A/B I, p-mTOR/mTOR, p-4EBP1/4EBP1, p-P70S6K/P70S6K and TFEB protein level were examined via western blotting, while SQSTM1/p62, Beclin1, ABCA1, ABCG1 and SCARB1 were examined via qRT-PCR and western blotting. The nuclear translocation of TFEB was detected using immunofluorescence. The components of HYQT medicated serum were determined using Q-Orbitrap high-resolution MS analysis. Molecular docking was employed to identify the components of HYQT medicated serum responsible for the mTOR signalling pathway. The mechanism of taurine was illustrated. HYQT has a remarkable effect on atherosclerotic plaque formation and blood lipid level in ApoE-/- mice. HYQT decreased the co-localization of CD11b and BODIPY. HYQT (10% medicated serum) reduced the LDs accumulation in RAW 264.7 cells. HYQT and RAPA (rapamycin, a mTOR inhibitor) could promote cholesterol efflux, while chloroquine (CQ, an autophagy inhibitor) weakened the effect of HYQT. Moreover, MHY1485 (a mTOR agonist) also mitigated the effects of HYQT by reduced cholesterol efflux. qRT-PCR and WB results suggested that HYQT improved the expression of the proteins ABCA1, ABCG1 and SCARB1.HYQT regulates ABCA1 and SCARB1 protein depending on the mTORC1/TFEB signalling pathway. However, the activation of ABCG1 does not depend on this pathway. Q-Orbitrap high-resolution MS analysis results demonstrated that seven core compounds have good binding ability to the mTOR protein. Taurine may play an important role in the mechanism regulation. HYQT may reduce cardiovascular risk by promoting cholesterol efflux and degrading macrophage-derived foam cell formation. It has been observed that HYQT and ox-LDL regulate lipophagy through the mTOR/TFEB signalling pathway, rather than the mTOR/4EBP1/P70S6K pathway. Additionally, HYQT is found to regulate cholesterol efflux through the mTORC1/TFEB/ABCA1-SCARB1 signal axis, while taurine plays a significant role in lipophagy.
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Aterosclerose , Compostos de Boro , Proteínas Quinases S6 Ribossômicas 70-kDa , Animais , Camundongos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Colesterol/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Simulação de Acoplamento Molecular , Células Espumosas/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Taurina/metabolismoRESUMO
Arrhythmias are a prevalent cardiovascular condition, frequently seen in athletes and fitness enthusiasts due to their high-intensity physical activities, which can complicate or be secondary to heart failure, myocardial hypoxia, ischemia, and in severe cases, lead to sudden death. In the context of athletic and fitness-oriented lifestyles, myocardial hypoxiaoften a result of intense physical exertioncan significantly impact endoplasmic reticulum stress and mitochondrial autophagy. The endoplasmic reticulum (ER) plays a crucial role in cellular protein synthesis. Disruptions in ER homeostasis, due to various factors including strenuous physical activity, can lead to an accumulation of misfolded proteins in the ER, triggering ER stress. This stress has been identified in various diseases and is of particular interest in the athletic population, where the body's systems, including the heart, are often pushed to their limits. Furthermore, mitochondrial autophagy, a process vital for maintaining cellular health by degrading and recycling mitochondrial components, has been linked to arrhythmia. This connection is especially pertinent in athletes, as their hearts undergo considerable physiological stress and adaptation in response to ongoing physical demands. This study aims to explore the mechanisms by which myocardial hypoxia induces ER stress and mitochondrial autophagy, and how these processes contribute to the development of cardiac arrhythmias in athletes and fitness enthusiasts. By focusing on this specific group, the research seeks to provide a deeper understanding of the cardiac risks associated with high levels of physical activity and to inform preventative and therapeutic strategies tailored to this population (AU)
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Humanos , Hipóxia/fisiopatologia , Estresse do Retículo Endoplasmático/fisiologia , Mitocôndrias Cardíacas/fisiologia , Arritmias Cardíacas/fisiopatologia , AtletasRESUMO
With the population aging, age-related sinoatrial node dysfunction (SND) has been on the rise. Sinoatrial node (SAN) degeneration is an important factor for the age-related SND development. However, there is no suitable animal modeling method in this field. Here, we investigated whether D-galactose could induce SAN degeneration and explored the associated mechanism. In vivo, twelve C57BL/6 mice were divided into Control and D-galactose group to receive corresponding treatments. Senescence was confirmed by analyzing the hair and weight; cardiac function was evaluated through echocardiography, cerebral blood flux and serum-BNP; the SAN function was evaluated by electrocardiogram; fibrotic change was evaluated by Masson's trichrome staining and oxidative stress was assessed through DHE staining and serum indicators. Mechanism was verified through immunofluorescence-staining and Western blotting. In vitro, mouse-atrial-myocytes were treated with D-galactose, and edaravone was utilized as the ROS scavenger. Senescence, oxidative stress, proliferation ability and mechanism were verified through various methods, and intuitive evidence was obtained through electrophysiological assay. Finally, we concluded that D-galactose can be used to induce age-related SND, in which oxidative stress plays a key role, causing PITX2 ectopic expression and downregulates SHOX2 expression, then through the downstream GATA4/NKX2-5 axis, results in pacing-related ion channels dysfunction, and hence SND development.
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Galactose , Nó Sinoatrial , Camundongos , Animais , Nó Sinoatrial/metabolismo , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , FenótipoRESUMO
Cardiac microvascular dysfunction contributes to cardiac hypertrophy (CH) and can progress to heart failure. Lutein is a carotenoid with various pharmacological properties, such as anti-apoptotic, anti-inflammatory, and antioxidant effects. Limited research has been conducted on the effects of lutein on pressure overload-induced CH. Studies have shown that CH is accompanied by ferroptosis in the cardiac microvascular endothelial cells (CMECs). This study aimed to investigate the effect of lutein on ferroptosis of CMECs in CH. The transcription factor interferon regulatory factor (IRF) is associated with immune system function, tumor suppression, and apoptosis. The results of this study suggested that pressure overload primarily inhibits IRF expression, resulting in endothelial ferroptosis. Administration of lutein increased the expression of IRF, providing protection to endothelial cells during pressure overload. IRF silencing downregulated solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, leading to the induction of ferroptosis in CMECs. Lutein supplementation suppressed endothelial ferroptosis by upregulating IRF. These data suggest that IRF may function as a transcription factor for SLC7A11 and that lutein represses ferroptosis in CMECs by upregulating IRF expression. Therefore, targeting IRF may be a promising therapeutic strategy for effective cardioprotection in patients with CH and heart failure.
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Ferroptose , Insuficiência Cardíaca , Humanos , Células Endoteliais , Luteína/farmacologia , Fatores Reguladores de Interferon/metabolismo , Fatores Reguladores de Interferon/farmacologia , Células Cultivadas , Cardiomegalia/metabolismo , Insuficiência Cardíaca/patologiaRESUMO
Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis. In particular, the mitochondria-endoplasmic reticulum (ER) membrane contact site (MAM) is known to regulate ion and lipid transfer, as well as signaling and organelle dynamics. However, the regulatory mechanisms of MAM formation and their function are still elusive. Here, we identify mitochondrial Lon protease (LonP1), a highly conserved mitochondrial matrix protease, as a new MAM tethering protein. The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation. Furthermore, deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER (UPRER). Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling. These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity, mitochondrial dynamics, and UPRER, offering exciting new insights into the potential therapeutic strategy for heart failure.
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Cesium copper halide perovskite is one of the promising materials for solar-blind light detection. However, most of the cesium copper halide perovskite-based photodetectors (PDs) are focused on ultraviolet A detection and realized on the rigid substrate in the single device configuration. Here, a flexible solar-blind PDs array (10 × 10 pixels) based on the CsCu2 I3 film patterns for ultraweak light sensing and light distribution imaging is reported. Large-scale CsCu2 I3 film arrays are synthesized with various shapes and uniform dimensions through a simple vacuum-heating-assisted solution method. Benefiting from excellent air stability and superior resistance to the photodegrading of the CsCu2 I3 film, the array device exhibits long-term stable photoswitching behavior for 8 h and ultralow light detection capability to resolve the light intensity of 6.1 nW cm-2 with a high responsivity of 62 A W-1 , and the array device can acquire clear images of "G", "X", and "U" showing the input light distribution. Moreover, the flame detection and warning system based on a curved solar-blind PDs array is demonstrated, which can be used for multi-flame monitoring and locating. These results can encourage potential applications of the CsCu2 I3 film-based PDs array in the field of optical communication and environment monitoring.
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Two new natural products, belonging to alkaloids, identified as ((2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl acetate (1) and (5-hydroxypyridin-2-yl)methyl acetate (2), were isolated from Portulaca oleracea L. The structures were identified by spectroscopic methods, including 1D, 2D NMR, and UHPLC-ESI-QTOF/MS methods. Meanwhile, the anti-inflammatory and anticholinesterase bioactivities were found in these two compounds.
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Alcaloides , Portulaca , Portulaca/química , Estrutura Molecular , Alcaloides/farmacologia , Alcaloides/química , Extratos Vegetais/farmacologia , Extratos Vegetais/químicaRESUMO
A rapid and highly selective and sensitive ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QQQ-MS/MS) method was applied to simultaneously determine ephedrine, gastrodin, and liquiritin in rat plasma. The three analytes and vitexin-2â³-O-rhamnoside (I.S.) were analyzed on a Waters Acquity UPLC C18 column (1.7 µm, 2.1 mm × 100 mm) at 30°C with gradient mobile phase consisting of 0.1% formic acid aqueous solution (A) and acetonitrile (B) after one-step direct protein precipitation with acetonitrile. The detection was performed by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source in positive and negative ion modes. The product ions m/z 166.1â¶148.1, 285.1â¶123.1, 417.1â¶255.1, and 579.0â¶433.1 were used for determination of ephedrine, gastrodin, liquiritin, and I.S., respectively. The calibration curves of the three analytes were linear with r 2 greater than 0.994. The intra and interday precision RSD% was less than 11.5 and 13.4. The intra and interday precision RE% was between -10.4% and 9.33%. The average extraction recoveries of the three analytes were no less than 86.88 ± 1.08%. The developed and validated method was for the first time applied to the pharmacokinetics of three compounds in rat plasma after intragastric administration of Banxia Baizhu Tianma Tang.
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Background: Myocardial infarction is a well-established severe consequence of coronary artery disease. However, the lack of effective early biomarkers accounts for the lag time before clinical diagnosis of myocardial infarction. The present study aimed to predict critical genes for the diagnosis of MI by immune infiltration analysis and establish a nomogram. Methods: Gene microarray data were downloaded from Gene Expression Omnibus (GEO). Differential expression analysis, single-cell sequencing, and disease ontology (DO) enrichment analysis were performed to determine the distribution of Differentially Expressed Genes (DEGs) in cell subpopulations and their correlation with MI. Next, the level of infiltration of 16 immune cells and immune functions and their hub genes were analyzed using a Single-sample Gene Set Enrichment Analysis (ssGSEA). In addition, the accuracy of critical markers for the diagnosis of MI was subsequently assessed using receiver operating characteristic curves (ROC). One datasets were used to test the accuracy of the model. Finally, the genes with the most diagnostic value for MI were screened and experimentally validated. Results: 335 DEGs were identified in GSE66360, including 280 upregulated and 55 downregulated genes. Single-cell sequencing results demonstrated that DEGs were mainly distributed in endothelial cells. DO enrichment analysis suggested that DEGs were highly correlated with MI. In the MI population, macrophages, neutrophils, CCR, and Parainflammation were significantly upregulated compared to the average population. NR4A2 was identified as the gene with the most significant diagnostic value in the immune scoring and diagnostic model. 191 possible drugs for the treatment of myocardial infarction were identified by drug prediction analysis. Finally, our results were validated by Real-time Quantitativepolymerase chain reaction and Western Blot of animal samples. Conclusion: Our comprehensive in silico analysis revealed that NR4A2 has huge prospects for application in diagnosing patients with MI.
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Doença da Artéria Coronariana , Infarto do Miocárdio , Animais , Células Endoteliais , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Western Blotting , Biologia ComputacionalRESUMO
Three novel alkaloids, identified as (E)-N-((2R)-3-(2,5-dihydroxy-4-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-hydroxypropanoyl)-3-(4-hydroxyphenyl)acrylamide (1), named oleracrylimide A, (E)-N-((2R)-3-(2,5-dihydroxy-4-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-hydroxypropanoyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide (2), named oleracrylimide B, and (E)-N-((2R)-3-(2,5-dihydroxy-4-((3,4,5-trihydroxy-6-(((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-hydroxypropanoyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide (3), named oleracrylimide C were isolated from Portulaca oleracea L. and the structures of the three novel compounds were determined by 1D and 2D NMR, circular dichroism, and UHPLC-ESI-QTOF/MS spectroscopic methods. Moreover, the bioactivities of anti-inflammation of the three compounds were investigated via testing RAW 264.7 macrophage cell stimulated by Lipopolysaccharide.
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Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Portulaca/química , Alcaloides/química , Animais , Anti-Inflamatórios/química , Sobrevivência Celular , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Células RAW 264.7RESUMO
Two new compounds, identified as 3-(2-hydroxybenzyl)-6,8-dimethoxy-4H-chromen-4-one (1), named oleracone J and 3-(2-hydroxybenzyl)-6,8-dimethoxychroman-4-one (2), named oleracone K, were isolated from Portulaca oleracea L., and the structures of them were determined by spectroscopy, including one-dimensional and two-dimensional nuclear magnetic resonance, high-resolution electrospray ionisation time-of-flight mass spectrometry. The two compounds have scavenging activities in 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical quenching assay, with IC50 values of 18.34, 23.92 µM, and anticholinesterase activities with IC50 values of 59.08, 67.89 µM, respectively.
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Isoflavonas , Portulaca , Isoflavonas/farmacologia , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Portulaca/química , Espectrometria de Massas por Ionização por Electrospray/métodosRESUMO
Humans are extensively exposed to polycyclic aromatic hydrocarbons (PAHs) daily via multiple pathways. Epidemiological studies have demonstrated that occupational exposure to PAHs increases the risk of lung cancer, but related studies in the general population are limited. Hence, we conducted a case-control study among the Chinese general population to investigate the associations between PAHs exposure and lung cancer risk and analyze the modifications of genetic polymorphisms in DNA repair genes. In this study, we enrolled 122 lung cancer cases and 244 healthy controls in Wuhan, China. Urinary PAHs metabolites were determined by gas chromatography-mass spectrometry, and rs25487 in X-ray repair cross-complementation 1 (XRCC1) gene was genotyped by the Agena Bioscience MassARRAY System. Then, multivariable logistic regression models were performed to estimate the potential associations. We found that urinary hydroxynaphthalene (OH-Nap), hydroxyphenanthrene (OH-Phe) and the sum of hydroxy PAHs (∑OH-PAHs) levels were significantly higher in lung cancer cases than those in controls. After adjusting for gender, age, BMI, smoking status, smoking pack-years, drinking status and family history, urinary ∑OH-Nap and ∑OH-Phe levels were positively associated with lung cancer risk, with dose-response relationships. Compared with those in the lowest tertiles, individuals in the highest tertiles of ∑OH-Nap and ∑OH-Phe had a 2.13-fold (95% CI: 1.10, 4.09) and 2.45-fold (95% CI: 1.23, 4.87) increased risk of lung cancer, respectively. Effects of gender, age, smoking status and smoking pack-years on the associations of PAHs exposure with lung cancer risk were shown in the subgroup analysis. Furthermore, associations of urinary ∑OH-Nap and ∑OH-PAHs levels with lung cancer risk were modified by XRCC1 rs25487 (Pinteraction ≤ 0.025), and were more pronounced in wild-types of rs25487. These findings suggest that environmental exposure to naphthalene and phenanthrene is associated with increased lung cancer risk, and polymorphism of XRCC1 rs25487 might modify the naphthalene exposure-related lung cancer effect.
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Neoplasias Pulmonares , Hidrocarbonetos Policíclicos Aromáticos , Biomarcadores , Estudos de Casos e Controles , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Polimorfismo Genético , Raios X , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
The contribution of gut-liver signaling to the development of non-alcoholic hepatic steatosis (NHS) in non-diabetic adults remains unclear. We therefore performed comprehensive 16S ribosomal RNA sequencing and fecal metabolomics analyses in 32 controls and 59 non-diabetic adults with NHS and performed fecal microbiota transplantation into germ-free mice using controls and NHS patients as donors. Compared to controls, the abundance of the genera Collinsella and Acinetobacter were higher, while that of Lachnospira was lower, in NHS subjects. Fecal metabolomics analysis showed decreased L-tryptophan levels and increased abundance of the tryptophan metabolite kynurenine in individuals with NHS. Correlation analysis showed that kynurenine levels positively associated with the abundance of Collinsella and Acinetobacter. ROC analysis demonstrated that the combination of tryptophan and kynurenine could discriminate NHS patients from controls with good statistical power [P < 0.05; AUC = 0.833 (95% CI, 0.747 to 0.918)]. Supporting a key role of dysbiotic gut microbiota in NHS development, incipient hepatic steatosis and increased kynurenine levels were observed in GF mice colonized with samples from NHS patients. These results indicate that enhanced kynurenine production resulting from altered gut microbiota composition contributes to NHS in nondiabetic adults and suggest the relevance of tryptophan metabolites as diagnostic biomarkers.
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Microbioma Gastrointestinal , Cinurenina/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Adulto , Estudos de Casos e Controles , Fezes/química , Feminino , Humanos , MasculinoRESUMO
While bisphenol A (BPA) exposure was inconsistently associated with hypertension risk, little is known about whether its alternatives bisphenol S and F (BPS and BPF) have similar hypertensive effects. Furthermore, epidemiologic studies on the genetic susceptibility to the hypertensive effects of bisphenols are scarce. We conducted a case-control study in 439 pairs of hypertension cases and matched controls. Urinary bisphenols concentrations were measured to characterize the internal exposure levels. The genotyping of ESR1/2, CAT, and eNOS was performed by a multiplex fluorescent polymerase chain reaction. BPA exposure was positively associated with hypertension risk. Carriers of rs2234693 C allele in ESR1 were associated with increased hypertension risk. Significant associations of BPA exposure with increased hypertension risk were suggested in individuals with the major allele of rs1256049 in ESR2, rs769214 in CAT, and rs1799983 in eNOS. Besides, rs4755374 in CAT might modify the association of BPA exposure with hypertension risk. Individuals with specific genotypes in ESR1/2, CAT, and eNOS might be more susceptible to the hypertensive effects of BPA.
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Three novel alkaloids, named oleracone L (1), portulacatone B (2), and portulacatal (3), were isolated from P. oleracea L.. The structures were determined using UV, IR, 1D and 2D NMR spectroscopy and UHPLC-ESI-QTOF/MS. The three compounds in a dose-dependent manner significantly reduced the secretion of IL-1ß in the lipopolysaccharide-stimulated macrophages RAW 264.7 cell culture supernatant, moreover, exhibited the anticholinesterase activities.
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Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Inibidores da Colinesterase/farmacologia , Portulaca/química , Alcaloides/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , China , Inibidores da Colinesterase/isolamento & purificação , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Células RAW 264.7RESUMO
A new skeleton flavonoid, identified as (5aR)-10-hydroxy-8-methoxy-5aH,11H-chromeno[2,3-b]chromen-11-one (1), named oleracone G, and a new lignan, confirmed as 8-(4-hydroxy-3-methoxyphenyl)-3-methoxynaphthalen-2-ol (2), named oleralignan B, were isolated from Portulaca oleracea L., and the structures of them were determined using spectroscopic methods including UV, IR, 1D NMR, 2D NMR, and UHPLC-ESI-QTOF/MS. In addition, compounds 1-2 were applied to investigate the anti-inflammatory activities on lipopolysaccharide-stimulated macrophages and scavenging effects in 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical. The results showed that the two compounds at 10 µM and 20 µM could dose-dependently decrease the secretion of interleukin 1ß in RAW 264.7 cells by enzyme-linked immunosorbent assay, moreover, presented remarkable antioxidant activities with IC50 values of 27.57, 20.12 µM, respectively.
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Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Flavonoides/farmacologia , Lignanas/farmacologia , Portulaca/química , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , China , Flavonoides/isolamento & purificação , Lignanas/isolamento & purificação , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Células RAW 264.7RESUMO
BACKGROUND: A high-fat diet can affect lipid metabolism and trigger cardiovascular diseases. A growing body of studies has revealed the HDL-bound miRNA profiles in familial hypercholesterolaemia; in sharp contrast, relevant studies on high-fat diet-induced dyslipidaemia are lacking. In the current study, HDL-bound miRNAs altered by a high-fat diet were explored to offer some clues for elucidating their effects on the pathogenesis of dyslipidaemia. METHODS: Six pigs were randomly divided into two groups of three pigs each, namely, the high-fat diet and the balanced diet groups, which were fed a high-fat diet and balanced diet separately for six months. HDL was separated from plasma, which was followed by dissociation of the miRNA bound to HDL. miRNA sequencing of the isolated miRNA was performed to identify the differential expression profiles between the two groups, which was validated by real-time PCR. TargetScan, miRDB, and miRWalk were used for the prediction of genes targeted by the differential miRNAs. RESULTS: Compared with the balanced diet group, the high-fat diet group had significantly higher levels of TG, TC, LDL-C and HDL-C at six months. miRNA sequencing revealed 6 upregulated and 14 downregulated HDL-bound miRNAs in the high-fat diet group compared to the balanced diet group, which was validated by real-time PCR. GO enrichment analysis showed that dysregulated miRNAs in the high-fat diet group were associated with the positive regulation of lipid metabolic processes, positive regulation of lipid biosynthetic processes, and positive regulation of Ras protein signal transduction. Insulin resistance and the Ras signalling pathway were enriched in the KEGG pathway enrichment analysis. CONCLUSIONS: Twenty HDL-bound miRNAs are significantly dysregulated in high-fat diet-induced dyslipidaemia. This study presents an analysis of a new set of HDL-bound miRNAs that are altered by a high-fat diet and offers some valuable clues for novel mechanistic insights into high-fat diet-induced dyslipidaemia. Further functional verification study using a larger sample size will be required.
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Dieta Hiperlipídica , Dislipidemias/sangue , Lipoproteínas HDL/sangue , MicroRNAs/sangue , Animais , Modelos Animais de Doenças , Dislipidemias/etiologia , Dislipidemias/genética , Regulação da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs/genética , Sus scrofa , Fatores de TempoRESUMO
Acute lung injury (ALI), which is induced by renal ischemia-reperfusion (IR), is one of the leading causes of acute renal IR-related death. Obesity raises the frequency and severity of acute kidney injury (AKI) and ALI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) was employed to lessen the lung apoptosis led by renal IR and to evaluate whether TIIA combined with CsA could alleviate lung apoptosis by regulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. Hematoxylin-eosin (HE) staining was used to assess the histology of the lung injury. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was used to assess apoptosis of the lung. Electron microscopy was used to assess mitochondrial morphology in lung cells. Arterial blood gas and pulmonary function were used to assess the external respiratory function. Mitochondrial function was used to assess the internal respiratory function and mitochondrial dynamics and biogenesis. Western blot (WB) was used to examine the PI3K/Akt/Bad pathway-related proteins. TIIA combined with CsA can alleviate lung apoptosis by regulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.
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BACKGROUND: Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. METHODS: Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined. RESULTS: TIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam). CONCLUSION: We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.