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Ovarian cancer (OC) is among the most common and deadly solid malignancies in women. Despite many advances in OC research, the incidence of OC continues to rise, and its pathogenesis remains largely unknown. Herein, we elucidated the function of hsa_circ_0061179 in OC. The levels of hsa_circ_0061179, miR-143-3p, TIMELESS, and DNA damage repair-related proteins in OC or normal ovarian tissues and cells were measured using real-time quantitative polymerase chain reaction and immunoblotting. The biological effects of hsa_circ_0061179 and miR-143-3p on proliferation, clone formation, DNA damage, and apoptosis of OC cells were detected by the cell counting kit-8 assay, 5-methylethyl-2'-deoxyuridine, flow cytometry, the comet assay, and immunofluorescence staining combined with the confocal microscopy. The interaction among hsa_circ_0061179, miR-143-3p, and TIMELESS was validated by the luciferase reporter assay. Mice tumor xenograft models were used to evaluate the influence of hsa_circ_0061179 on OC growth in vivo. We found that human OC biospecimens expressed higher levels of hsa_circ_0061179 and lower levels of miR-143-3p. Hsa_circ_0061179 was found to bind with miR-143-3p, which directly targets TIMELESS. Hsa_circ_0061179 knockdown or miR-143-3p overexpression suppressed the proliferation and clone formation of OC cells and increased DNA damage and apoptosis of OC cells via the miR-143-3p/TIMELESS axis. Furthermore, we demonstrated that METTL3 could direct the formation of has_circ_0061179 through a specific m6A modification site. YTHDC1 facilitated the cytoplasmic transfer of has_circ_0061179 by directly binding to the modified m6A site. Our findings suggest that hsa_circ_0061179 acts as the sponge of miR-143-3p to activate TIMELESS signaling and inhibits DNA damage and apoptosis in OC cells.
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Apoptose , Proliferação de Células , Dano ao DNA , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias Ovarianas , RNA Circular , Animais , Feminino , Humanos , Camundongos , Adenosina/análogos & derivados , Linhagem Celular Tumoral , Metiltransferases , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , RNA Circular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND AND AIMS: Lipid accumulation induced by alcohol consumption is not only an early pathophysiological response but also a prerequisite for the progression of alcohol-associated liver disease (ALD). Alternative splicing regulates gene expression and protein diversity; dysregulation of this process is implicated in human liver diseases. However, how the alternative splicing regulation of lipid metabolism contributes to the pathogenesis of ALD remains undefined. APPROACH AND RESULTS: Serine-arginine-rich protein kinase 2 (SRPK2), a key kinase controlling alternative splicing, is activated in hepatocytes in response to alcohol, in mice with chronic-plus-binge alcohol feeding, and in patients with ALD. Such induction activates sterol regulatory element-binding protein 1 and promotes lipogenesis in ALD. Overexpression of FGF21 in transgenic mice abolishes alcohol-mediated induction of SRPK2 and its associated steatosis, lipotoxicity, and inflammation; these alcohol-induced pathologies are exacerbated in FGF21 knockout mice. Mechanistically, SRPK2 is required for alcohol-mediated impairment of serine-arginine splicing factor 10, which generates exon 7 inclusion in lipin 1 and triggers concurrent induction of lipogenic regulators-lipin 1ß and sterol regulatory element-binding protein 1. FGF21 suppresses alcohol-induced SRPK2 accumulation through mammalian target of rapamycin complex 1 inhibition-dependent degradation of SRPK2. Silencing SRPK2 rescues alcohol-induced splicing dysregulation and liver injury in FGF21 knockout mice. CONCLUSIONS: These studies reveal that (1) the regulation of alternative splicing by SRPK2 is implicated in lipogenesis in humans with ALD; (2) FGF21 is a key hepatokine that ameliorates ALD pathologies largely by inhibiting SRPK2; and (3) targeting SRPK2 signaling by FGF21 may offer potential therapeutic approaches to combat ALD.
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Arginina Quinase , Hepatopatias Alcoólicas , Humanos , Camundongos , Animais , Proteínas Serina-Treonina Quinases/metabolismo , Lipogênese/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Arginina Quinase/genética , Arginina Quinase/metabolismo , Processamento Alternativo , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Etanol/toxicidade , Camundongos Knockout , Mamíferos/metabolismoRESUMO
Ursonic acid (UNA) is a natural pentacyclic triterpene found in some medicinal plants and foods. The reproductive protective effect of UNA was evaluated in a mouse model of oligozoospermia induced by busulfan (BUS) at 30 mg/kg b.w.. The mice were initially divided into groups with UNA concentrations of 10, 30, 50, 100 mg/kg. Subsequently, based on sperm parameters, the optimal concentration of 50 mg/kg was identified. As a control, an additional group was supplemented with ursolic acid at a concentration of 50 mg/kg. The results indicated that BUS caused the loss of spermatogenic cells in testis, the decrease of sperm in epididymis, the disorder of testicular cytoskeleton, the decrease of serum sex hormones such as testosterone which induced an increase in feedback of androgen receptor and other testosterone-related proteins, the increase of malondialdehyde and reactive oxygen species levels and the increase of ferroptosis in testis while UNA successfully reversed these injuries. High-throughput sequencing revealed that UNA administration significantly upregulated the expression of genes associated with spermatogenesis, such as Tnp1, Tnp2, Prm1, among others. These proteins are crucial in the histone to protamine transition during sperm chromatin remodeling. Network pharmacology analysis reveals a close association between UNA and proteins related to the transformation of histones to protamine. Molecular docking studies reveal that UNA can interact with the ferroptosis-inhibiting gene SLC7A11, thereby modulating ferroptosis. Taken together, UNA alleviated BUS-induced oligozoospermia by regulating hormone secretion, mitigating oxidative stress and promoting recovery of spermatogenesis by inhibiting the ferroptosis.
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Ferroptose , Oligospermia , Triterpenos , Humanos , Masculino , Camundongos , Animais , Oligospermia/induzido quimicamente , Oligospermia/tratamento farmacológico , Simulação de Acoplamento Molecular , Sêmen/metabolismo , Espermatogênese/fisiologia , Testosterona/farmacologia , Histonas/farmacologia , Protaminas/genética , Protaminas/metabolismo , Protaminas/farmacologiaRESUMO
Oncogenic-driven lipogenic metabolism is a common hallmark of colorectal cancer (CRC) progression. Therefore, there is an urgent need to develop novel therapeutic strategies for metabolic reprogramming. Herein, the metabolic profiles in the plasma between CRC patients and paired healthy controls were compared using metabolomics assays. Matairesinol downregulation was evident in CRC patients, and matairesinol supplementation significantly represses CRC tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS) colitis-associated CRC mice. Matairesinol rewired lipid metabolism to improve the therapeutic efficacy in CRC by inducing mitochondrial damage and oxidative damage and blunting ATP production. Finally, matairesinol-loaded liposomes significantly promoted the enhanced antitumor activity of 5-Fu/leucovorin combined with oxaliplatin (FOLFOX) in CDX and PDX mouse models by restoring chemosensitivity to the FOLFOX regimen. Collectively our findings highlight matairesinol-mediated lipid metabolism reprogramming as a novel druggable strategy to restore CRC chemosensitivity, and this nanoenabled approach for matairesinol will improve the chemotherapeutic efficacy with good biosafety.
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Colite , Neoplasias Colorretais , Camundongos , Animais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Metabolismo dos Lipídeos , Furanos/uso terapêutico , Modelos Animais de DoençasRESUMO
BACKGROUND: Post-stroke cognitive impairment (PSCI) is a serious complication of stroke that warrants prompt detection and management. Consequently, the development of a diagnostic prediction model holds clinical significance. OBJECTIVE: Machine learning algorithms were employed to identify crucial variables and forecast PSCI occurrence within 3-6 months following acute ischemic stroke (AIS). METHODS: A prospective study was conducted on a developed cohort (331 patients) utilizing data from the Affiliated Zhongda Hospital of Southeast University between January 2022 and August 2022, as well as an external validation cohort (66 patients) from December 2022 to January 2023. The optimal model was determined by integrating nine machine learning classification models, and personalized risk assessment was facilitated by a Shapley Additive exPlanations (SHAP) interpretation. RESULTS: Age, education, baseline National Institutes of Health Scale (NIHSS), Cerebral white matter degeneration (CWMD), Homocysteine (Hcy), and C-reactive protein (CRP) were identified as predictors of PSCI occurrence. Gaussian Naïve Bayes (GNB) model was determined to be the optimal model, surpassing other classifier models in the validation set (area under the curve [AUC]: 0.925, 95 % confidence interval [CI]: 0.861 - 0.988) and achieving the lowest Brier score. The GNB model performed well in the test sets (AUC: 0.919, accuracy: 0.864, sensitivity: 0.818, and specificity: 0.932). CONCLUSIONS: The present study involved the development of a GNB model and its elucidation through employment of the SHAP method. These findings provide compelling evidence for preventing PSCI, which could serve as a guide for high-risk patients to undertake appropriate preventive measures.
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Iron is an essential element for cell proliferation and homeostasis by engaging in cell metabolism including DNA synthesis, cell cycle, and redox cycling; however, iron overload could contribute to tumor initiation, proliferation, metastasis, and angiogenesis. Therefore, manipulating iron metabolisms, such as using iron chelators, transferrin receptor 1 (TFR1) Abs, and cytotoxic ligands conjugated to transferrin, has become a considerable strategy for cancer therapy. However, there remain major limitations for potential translation to the clinic based on the regulation of iron metabolism in cancer treatment. Nanotechnology has made great advances for cancer treatment by improving the therapeutic potential and lowering the side-effects of the proved drugs and those under various stages of development. Early studies that combined nanotechnology with therapeutic means for the regulation of iron metabolism have shown certain promise for developing specific treatment options based on the intervention of cancer iron acquisition, transportation, and utilization. In this review, we summarize the current understanding of iron metabolism involved in cancer and review the recent advances in iron-regulatory nanotherapeutics for improved cancer therapy. We also envision the future development of nanotherapeutics for improved treatment for certain types of cancers.
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Ferro/metabolismo , Nanomedicina , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Terapia Combinada , Sistemas de Liberação de Medicamentos , Ferroptose/efeitos dos fármacos , Humanos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Neoplasias/patologiaRESUMO
Hypertension is considered a risk factor for a series of systematic diseases. Known factors including genetic predisposition, age, and diet habits are strongly associated with the initiation of hypertension. The current study aimed to investigate the role of miR-22-3p in hypertension. In this study, we discovered that the miR-22-3p level was significantly decreased in the thoracic aortic vascular tissues and aortic smooth muscle cells (ASMCs) of spontaneously hypertensive rats. Functionally, the overexpression of miR-22-3p facilitated the switch of ASMCs from the synthetic to contractile phenotype. To investigate the underlying mechanism, we predicted 11 potential target mRNAs for miR-22-3p. After screening, chromodomain helicase DNA-binding 9 (CHD9) was validated to bind with miR-22-3p. Rescue assays showed that the co-overexpression of miR-22-3p and CHD9 reversed the inhibitory effect of miR-22-3p mimics on cell proliferation, migration, and oxidative stress in ASMCs. Finally, miR-22-3p suppressed vascular remodeling and oxidative stress in vivo. Overall, miR-22-3p regulated ASMC phenotype switch by targeting CHD9. This new discovery provides a potential insight into hypertension treatment.
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Caderinas/metabolismo , Hipertensão/metabolismo , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo , Remodelação Vascular , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Caderinas/genética , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , MicroRNAs/genética , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/patologia , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
The quest for interesting properties and phenomena in liquid crystals toward their employment in nondisplay application is an intense and vibrant endeavor. Remarkable progress has recently been achieved with regard to liquid crystals in curved confined geometries, typically represented as enclosed spherical geometries and cylindrical geometries with an infinitely extended axial-symmetrical space. Liquid-crystal emulsion droplets and fibers are intriguing examples from these fields and have attracted considerable attention. It is especially noteworthy that the rapid development of microfluidics brings about new capabilities to generate complex soft microstructures composed of both thermotropic and lyotropic liquid crystals. This review attempts to outline the recent developments related to the liquid crystals in curved confined geometries by focusing on microfluidics-mediated approaches. We highlight a wealth of novel photonic applications and beyond and also offer perspectives on the challenges, opportunities, and new directions for future development in this emerging research area.
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BACKGROUND: Pregnant women experience physical, physiological, and mental changes. Health-related quality of life (HRQoL) is a relevant indicator of psychological and physical behaviours, changing over the course of pregnancy. This study aims to assess HRQoL of pregnant women during different stages of pregnancy. METHODS: This cross-sectional study was performed using the The EuroQoL Group's five-dimension five-level questionnaire (EQ-5D-5L) to assess the HRQoL of pregnant women, and demographic data were collected. This study was conducted in a regional university hospital in Guangzhou, China. RESULTS: A total of 908 pregnant women were included in this study. Pregnant women in the early 2nd trimester had the highest HRQoL. The HRQoL of pregnant women rose from the 1st trimester to the early 2nd trimester, and dropped to the bottom at the late 3rd trimester due to some physical and mental changes. Reports of pain/discomfort problem were the most common (46.0%) while self-care were the least concern. More than 10% of pregnant women in the 1st trimester had health-related problems in at least one dimension of whole five dimensions. In the whole sample, the EuroQoL Group's visual analog scale (EQ-VAS) was 87.86 ± 9.16. Across the gestational stages, the HRQoL remained stable during the pregnancy but the highest value was observed in the 1st trimester (89.65 ± 10.13) while the lowest was in the late 3rd trimester (87.28 ± 9.13). CONCLUSIONS: During pregnancy, HRQoL were associated with gestational trimesters in a certain degree. HRQoL was the highest in the early 2nd trimester and then decreased to the lowest in the late 3rd trimester due to a series of physical and psychological changes. Therefore, obstetric doctors and medical institutions should give more attention and care to pregnant women in the late 3rd trimester.
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Trimestres da Gravidez , Gestantes/psicologia , Qualidade de Vida , Adulto , China , Estudos Transversais , Feminino , Hospitais Universitários , Humanos , Gravidez , Inquéritos e QuestionáriosRESUMO
Objectives: We aim to investigate the joint effect of iron (enhanced neonatal iron intake), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and biochanin A (BA, oral administration) and possible mechanisms for action on behavioral and neurochemical indicators in the mice. Methods: Rotarod test, pole test and swim test were used to evaluate animal behavior. The neurochemical analysis was conducted by HPLC-ECD. Oxidative stress was determined in this study. Further mechanism was investigated through in vitro experiments. Results: Iron and MPTP co-administration significantly induced behavioral deficits and decreased striatal dopamine content in the male and female mice. The co-administration of iron and MPTP also significantly induced redox imbalance in the substantia nigra (SN) of mice. Furthermore, BA significantly improved behavioral deficits and increased striatal dopamine content in the mice co-treated with iron and MPTP. BA also significantly improved redox imbalance in the SN of mice co-administered with iron and MPTP. Finally, we showed that iron and 1-Methyl-4-phenylpyridinium (MPP+) co-treatment significantly increased superoxide production in microglial cultures by inducing p38 mitogen-activated protein kinase (MAPK) activation. BA also significantly decreased superoxide production and p38 MAPK phosphorylation in the cultures co-treated with iron and MPP+. Conclusion: Iron and MPTP co-treatment may result in worsened behavioral and neurochemical deficits and aggravated redox imbalance through inducing microglial p38 MAPK activation. BA may improve behavioral and neurochemical deficits and redox imbalance through repressing microglial p38 MAPK activation.
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Antioxidantes/administração & dosagem , Genisteína/administração & dosagem , Ferro/toxicidade , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doença de Parkinson/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Intoxicação por MPTP/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacosRESUMO
Recently, with the popularization of camera tools such as mobile phones and the rise of various short video platforms, a lot of videos are being uploaded to the Internet at all times, for which a video retrieval system with fast retrieval speed and high precision is very necessary. Therefore, content-based video retrieval (CBVR) has aroused the interest of many researchers. A typical CBVR system mainly contains the following two essential parts: video feature extraction and similarity comparison. Feature extraction of video is very challenging, previous video retrieval methods are mostly based on extracting features from single video frames, while resulting the loss of temporal information in the videos. Hashing methods are extensively used in multimedia information retrieval due to its retrieval efficiency, but most of them are currently only applied to image retrieval. In order to solve these problems in video retrieval, we build an end-to-end framework called deep supervised video hashing (DSVH), which employs a 3D convolutional neural network (CNN) to obtain spatial-temporal features of videos, then train a set of hash functions by supervised hashing to transfer the video features into binary space and get the compact binary codes of videos. Finally, we use triplet loss for network training. We conduct a lot of experiments on three public video datasets UCF-101, JHMDB and HMDB-51, and the results show that the proposed method has advantages over many state-of-the-art video retrieval methods. Compared with the DVH method, the mAP value of UCF-101 dataset is improved by 9.3%, and the minimum improvement on JHMDB dataset is also increased by 0.3%. At the same time, we also demonstrate the stability of the algorithm in the HMDB-51 dataset.
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Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) is an emerging method for the analysis of metal nanoparticles (NPs) in single cells. However, two main obstacles, low analytical throughput and lack of commercial reference materials, need to be overcome. In this work, we demonstrated the principles of a new approach termed "single-cell isotope dilution analysis" (SCIDA) to remove the two obstacles. For a proof of concept, macrophage cells were chosen as a model to study the uptake of silver NPs (AgNPs) at a single-cell level. Single cells exposed to AgNPs were placed in an array by a microfluidic technique; each cell in the array was precisely dispensed with a known picoliter droplet of an enriched isotope solution with a commercial inkjet printer; accurate quantification of AgNPs in single cells was done by using isotope dilution LA-ICP-MS. The average Ag mass of 1100 single cells, 396 ± 219 fg Ag per cell, was in good accord with the average of the population of cells determined by solution ICP-MS analysis. The detection limit was 0.2 fg Ag per cell. The SCIDA approach is expected to be widely applied for the study of cell-NP interactions and biological effects of NPs at the single-cell level.
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Espectrometria de Massas , Nanopartículas Metálicas , Prata/química , Prata/metabolismo , Análise de Célula Única/métodos , Animais , Transporte Biológico , Isótopos , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Células RAW 264.7RESUMO
Herein, the absorption and oxidation reactions of SO2 on TiO2 nanoparticles (TiO2 NPs) at 296 K under various environmental conditions (humidity, UV irradiation, and ozone copresence) were investigated by using a flow chamber reaction system, synchrotron X-ray absorption near-edge structure (XANES) and high resolution synchrotron X-ray photoelectron spectroscopy (XPS) measurements. The results showed that oxidation of SO2 to sulfate via TiO2 NP catalysis happened at a very rapid rate. The appropriate relative humidity, UV irradiation and co-presence of ozone all markedly promoted SO2 oxidation on TiO2 NPs. High resolution XPS unraveled that the terminal hydroxyl (OHt) and oxygen vacancy (VO)-Ti3+ states on TiO2 NPs were the active sites for SO2 adsorption and oxidation. The data of XPS measurements suggest that SO2 was adsorbed on a OHt next to a Ti3+ VO and reacted to form HSO3-. HSO3- can then transform into SO32-via transfer of a proton. The resulting adsorbed SO32- could bind to a surface bridging O (Ob) atom and transform into SO42-. A H2O molecule could dissociate on VO-Ti3+ into two bridging hydroxyl (OHb) groups, subsequently forming new Ob, which provides an active O site for the adsorbed HSO3-/SO32- and oxidizes them into HSO4-/SO42- on the surface of the TiO2 NPs. The copresence of O3 could promote H2O dissociation into OHb, promoting the formation of Ob. The copresence of O3 may also promote the dissociation of adsorbed H2O into TiO2-O2- and hydroxyl radicals (ËOH) on VOs, facilitating the oxidation of adsorbed HSO3-/SO32-. Under UV irradiation, new VOs were created via oxidation of lattice O by photo-generated holes, resulting in increased Ob and subsequently enhanced oxidation of adsorbed HSO3-/SO32- on TiO2 NPs.
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BACKGROUND: To effectively applied nanomaterials (NMs) in medicine, one of the top priorities is to address a better understanding of the possible sub-organ transfer, clearance routes, and potential toxicity of the NMs in the liver and kidney. RESULTS: Here we explored how the surface chemistry of polyethylene glycol (PEG), chitosan (CS), and polyethylenimine (PEI) capped gold nanoparticles (GNPs) governs their sub-organ biodistribution, transfer, and clearance profiles in the liver and kidney after intravenous injection in mice. The PEG-GNPs maintained dispersion properties in vivo, facilitating passage through the liver sinusoidal endothelium and Disse space, and were captured by hepatocytes and eliminated via the hepatobiliary route. While, the agglomeration/aggregation of CS-GNPs and PEI-GNPs in hepatic Kupffer and endothelial cells led to their long-term accumulation, impeding their elimination. The gene microarray analysis shows that the accumulation of CS-GNPs and PEI-GNPs in the liver induced obvious down-regulation of Cyp4a or Cyp2b related genes, suggesting CS-GNP and PEI-GNP treatment impacted metabolic processes, while the PEI-GNP treatment is related with immune responses. CONCLUSIONS: This study demonstrates that manipulation of nanoparticle surface chemistry can help NPs selectively access distinct cell types and elimination pathways, which help to clinical potential of non-biodegradable NPs.
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Ouro/metabolismo , Ouro/toxicidade , Rim/metabolismo , Fígado/metabolismo , Nanopartículas Metálicas/toxicidade , Animais , Quitosana/metabolismo , Citosol , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Ouro/sangue , Rim/patologia , Cinética , Fígado/patologia , Masculino , Nanopartículas Metálicas/química , Camundongos , Camundongos Endogâmicos ICR , Tamanho da Partícula , Polietilenoglicóis/metabolismo , Polietilenoimina/metabolismo , Ratos , Ratos Wistar , Distribuição Tecidual , TranscriptomaRESUMO
Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation, and liver injury. Chronic-plus-binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6 kinase 1 (S6K1) in hepatocytes. Aberrant activation of mTORC1 was likely attributed to the defects of the DEP domain-containing mTOR-interacting protein (DEPTOR) and the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1) in the liver of chronic-plus-binge ethanol-fed mice and in the liver of patients with ALD. Conversely, adenoviral overexpression of hepatic DEPTOR suppressed mTORC1 signaling and ameliorated alcoholic hepatosteatosis, inflammation, and acute-on-chronic liver injury. Mechanistically, the lipid-lowering effect of hepatic DEPTOR was attributable to decreased proteolytic processing, nuclear translocation, and transcriptional activity of the lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1). DEPTOR-dependent inhibition of mTORC1 also attenuated alcohol-induced cytoplasmic accumulation of the lipogenic regulator lipin 1 and prevented alcohol-mediated inhibition of fatty acid oxidation. Pharmacological intervention with rapamycin alleviated the ability of alcohol to up-regulate lipogenesis, to down-regulate fatty acid oxidation, and to induce steatogenic phenotypes. Chronic-plus-binge ethanol feeding led to activation of SREBP-1 and lipin 1 through S6K1-dependent and independent mechanisms. Furthermore, hepatocyte-specific deletion of SIRT1 disrupted DEPTOR function, enhanced mTORC1 activity, and exacerbated alcoholic fatty liver, inflammation, and liver injury in mice. CONCLUSION: The dysregulation of SIRT1-DEPTOR-mTORC1 signaling is a critical determinant of ALD pathology; targeting SIRT1 and DEPTOR and selectively inhibiting mTORC1-S6K1 signaling may have therapeutic potential for treating ALD in humans. (Hepatology 2018).
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Fígado Gorduroso Alcoólico/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipogênese/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Animais , Etanol/farmacologia , Fígado Gorduroso Alcoólico/patologia , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Camundongos , Proteínas Nucleares/metabolismo , Fosfatidato Fosfatase/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
The brain renin-angiotensin system plays a vital role in the modulation of the neuroinflammatory responses and the progression of dopaminergic (DA) degeneration. Angiotensin II (Ang II) induces microglia activation via angiotensin II type 1 receptor (AT1R), which in turn affects the function of DA neurons. Endophilin A2 (EPA2) is involved in fast endophilin-mediated endocytosis and quickly endocytoses several G-protein-coupled receptor (GPCR), while AT1R belongs to GPCR family. Therefore, we speculated that EPA2 may modulate microglia activation via endocytosing AT1R. Biochanin A is an O-methylated isoflavone, classified as a kind of phytoestrogen due to its chemical structure that is similar to mammalian estrogens. In this study, we investigated the protective effects of biochanin A on Ang II-induced DA neurons damage in vivo, and molecular mechanisms. The results showed that biochanin A treatment for 7 days attenuated the behavioral dysfunction, inhibited the microglial activation, and prevented DA neuron damage in Ang II-induced rats. Furthermore, biochanin A increased EPA2 expression and decreased the expression of AT1R, gp91phox, p22 phox, NLRP3, ASC, Caspase-1, IL-1ß, IL-6, IL-18, and TNF-α. In summary, these results suggest that biochanin A exerts protective effects in Ang II-induced model rats, and the mechanisms may involve inhibition of inflammatory responses, an increase in EPA2 expression and a decrease in AT1R expression.
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Aciltransferases/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Genisteína/farmacologia , Aciltransferases/genética , Angiotensina II/farmacologia , Animais , Neurônios Dopaminérgicos/fisiologia , Genisteína/metabolismo , Inflamação , Lipopolissacarídeos , Masculino , Microglia/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Óxido Nítrico/metabolismo , Fitoestrógenos/farmacologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas GRESUMO
BACKGROUND: Uterine fibroids (UFs) are the most common benign tumors in women. They are likely to cause numerous clinical symptoms, such as pain, menorrhagia, and other obstetric complications in pregnant women. This study aimed to determine the health-related quality of life (HRQoL) during pregnancy with uterine fibroids (UF), thus providing a utility-based case value in pregnant women with UF and understanding of whether HRQoL is associated with clinical outcomes in pregnant women with UFs. METHOD: This study was conducted in a cross-sectional manner. This study was based on questionnaire surveys completed by sequential out- and in-patients and was conducted in a regional university hospital in Guangzhou, China. The EuroQoL five-dimension-five-level (EQ-5D-5 L) questionnaire was used, and demographic data were collected. An electronic record of the clinical outcomes of pregnant women with UF was retrieved from the hospital's electronic medical record system. The association between UF and HRQoL was evaluated by ordered regression. RESULTS: Seven-hundred-sixty-seven pregnant women with a mean age (SD) of 32.7 (4.8) years completed 707 questionnaires. Overall, when comparing the UF with non-UF groups, we detected statistical differences in age, body mass index (BMI), gravidity and abortion times, partner's smoking and alcoholic habits, advanced maternal age, and uterine scars (p < 0.05). Furthermore, pregnant women without UF scored significantly higher than those with UF on the EQ-5D value system (0.84 versus 0.79; p = 0.017). Moreover, pregnant women with UF suffered more health-related problems, especially with respect to self-care (odds ratio [OR] = 3.69, p < 0.01) and usual activity dimensions (OR = 2.11; p = 0.01). CONCLUSION: We found that UF has a negative impact on the HRQoL of pregnant women with respect to self-care and usual activity dimensions. Also, the EQ-5D score was a better index than the EQ-VAS score for HRQoL when evaluating of the QoL of our population of pregnant women.
Assuntos
Leiomioma/psicologia , Complicações Neoplásicas na Gravidez/psicologia , Qualidade de Vida , Neoplasias Uterinas/psicologia , Adulto , Estudos de Casos e Controles , China , Estudos Transversais , Feminino , Humanos , Gravidez , Autocuidado/psicologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Gestational diabetes mellitus (GDM) is one of the most common complications during pregnancy, and it has both short- and long-term adverse effects on the health of mothers and fetuses. To investigate the effect of exercise during pregnancy on the occurrence of GDM among normal-weight pregnant women. METHODS: We searched for studies published between January 1994 and June 2017 that appeared in the Web of Science, Scopus, ClinicalTrials.gov or Cochrane library databases. Randomized controlled trials that investigated the preventive effect of exercise on GDM in normal-weight women were included. Interventions including any confounding factors (e.g., dietary) were excluded. We extracted maternal characteristics, the diagnostic criteria of GDM, and basic information for intervention and obstetric outcomes. The primary outcome was the occurrence of GDM, and the secondary outcomes included gestational weight gain, gestational age at birth, birth weight, and the odds of cesarean section. A meta-analysis was conducted based on calculations of pooled estimates using the random-effects model. RESULTS: Eight studies were included in this systematic review and meta-analysis. Exercise during pregnancy was shown to decrease the occurrence of GDM [RR = 0.58, 95% CI (0.37, 0.90), P = 0.01 and RR = 0.60, 95% CI (0.36, 0.98), P = 0.04 based on different diagnosis criteria, respectively] in normal-weight women. Regarding secondary outcomes, exercise during pregnancy can decrease gestational weight gain [MD = - 1.61, 95% CI (- 1.99, - 1.22), P<0.01], and had no significant effects on gestational age at birth [MD = - 0.55, 95% CI (- 1.57, 0.47), P = 0.29], birth weight [MD = - 18.70, 95% CI (- 52.49, 15.08), P = 0.28], and the odds of caesarean section [RR = 0.88, 95% CI (0.72, 1.08), P = 0.21], respectively. CONCLUSIONS: Exercise during pregnancy can ostensibly decrease the occurrence of GDM without reducing gestational age at delivery and increasing the odds of cesarean section in normal-weight women.
Assuntos
Diabetes Gestacional/epidemiologia , Diabetes Gestacional/etiologia , Exercício Físico/fisiologia , Ganho de Peso na Gestação/fisiologia , Peso Corporal Ideal/fisiologia , Peso ao Nascer , Cesárea/estatística & dados numéricos , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Razão de Chances , GravidezRESUMO
Polyethylene glycol (PEG) has been frequently used for surface modification of nanoparticles (NPs) to reduce non-specific binding of proteins on NPs. The investigation of protein absorption on PEGylated nanoparticles is necessary. In the work, the conjugation of transferrin (Tf) to PEGylated AuNPs via adsorption or bonding was studied. The 13 nm AuNPs were coated with various molecular weight (300, 2000, 5000) carboxyl and methoxy PEG thiol. The presence of Tf on PEGylated AuNP was characterized by dynamic light scattering (DLS) and infrared spectroscopy (IR). The data of IR confirmed the presence of Tf on PEGylated AuNPs. The diameter decrease of PEGylated AuNPs after Tf adsorption was observed by DLS measurement, which is attributed to competitive adsorption between Tf and PEG molecules. These phenomena may be important to the preservation of Tf targeting specificity on PEGylated AuNPs.
RESUMO
OBJECTIVE: To identify the vary of obstetric outcomes by the severity of pulmonary hypertension (PH). METHODS: A retrospective study involved pregnancies with PH in one certain academic institution. Total 78 pregnancies with PH were classified into three groups according the mean pulmonary arterial systolic pressure: mean pulmonary arterial systolic pressure 30-49 mm Hg (mild-PH group), mean pulmonary arterial systolic pressure 50-69 mm Hg (moderate-PH group) and mean pulmonary arterial systolic pressure ≥ 70 mm Hg (severe-PH group). The clinical features and obstetric outcomes were described and compared among three groups. RESULTS: The incidence of PH was 0.23%, including 57 cases in mild-PH group, 10 cases in moderate-PH group and 11 cases in severe-PH group. Meanwhile, pregnancies with mild PH present NYHA class I/II (P < 0.001). General anesthesia (P < 0.001) and advanced intensive care (P = 0.011) were supplied for pregnancies with severe PH. There was no significant difference in rate of caesarean delivery. Furthermore, severity of PH increased the risk of neonatal death (P = 0.040). CONCLUSION: The severity of PH seems to be a poor prognosis of neonatal death. Intensive care should be provided for pregnancies with severe PH.