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Realizing room-temperature, efficient, and reversible fluoride-ion redox is critical to commercializing the fluoride-ion battery, a promising post-lithium-ion battery technology. However, this is challenging due to the absence of usable electrolytes, which usually suffer from insufficient ionic conductivity and poor (electro)chemical stability. Herein we report a water-in-salt (WIS) electrolyte based on the tetramethylammonium fluoride salt, an organic salt consisting of hydrophobic cations and hydrophilic anions. The new WIS electrolyte exhibits an electrochemical stability window of 2.47 V (2.08-4.55 V vs Li+/Li) with a room-temperature ionic conductivity of 30.6 mS/cm and a fluoride-ion transference number of 0.479, enabling reversible (de)fluoridation redox of lead and copper fluoride electrodes. The relationship between the salt property, the solvation structure, and the ionic transport behavior is jointly revealed by computational simulations and spectroscopic analysis.
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Solid polymer electrolytes based on plastic crystals are promising for solid-state sodium metal (Na0) batteries, yet their practicality has been hindered by the notorious Na0-electrolyte interface instability issue, the underlying cause of which remains poorly understood. Here, by leveraging a model plasticized polymer electrolyte based on conventional succinonitrile plastic crystals, we uncover its failure origin in Na0 batteries is associated with the formation of a thick and non-uniform solid electrolyte interphase (SEI) and whiskery Na0 nucleation/growth. Furthermore, we design a new additive-embedded plasticized polymer electrolyte to manipulate the Na0 deposition and SEI formulation. For the first time, we demonstrate that introducing fluoroethylene carbonate (FEC) additive into the succinonitrile-plasticized polymer electrolyte can effectively protect Na0 against interfacial corrosion by facilitating the growth of dome-like Na0 with thin, amorphous, and fluorine-rich SEIs, thus enabling significantly improved performances of Na//Na symmetric cells (1,800â h at 0.5â mA cm-2) and Na//Na3V2(PO4)3 full cells (93.0 % capacity retention after 1,200 cycles at 1â C rate in coin cells and 93.1 % capacity retention after 250 cycles at C/3 in pouch cells at room temperature). Our work provides valuable insights into the interfacial failure of plasticized polymer electrolytes and offers a promising solution to resolving the interfacial instability issue.
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The rechargeability of aqueous zinc metal batteries is plagued by parasitic reactions of the zinc metal anode and detrimental morphologies such as dendritic or dead zinc. To improve the zinc metal reversibility, hereby we report a new solution structure of aqueous electrolyte with hydroxyl-ion scavengers and hydrophobicity localized in solvent clusters. We show that although hydrophobicity sounds counterintuitive for an aqueous system, hydrophilic pockets may be encapsulated inside a hydrophobic outer layer, and a hydrophobic anode-electrolyte interface can be generated through the addition of a cation-philic, strongly anion-phobic, and OH--reactive diluent. The localized hydrophobicity enables less active water and less absorbed water on the Zn anode surface, which suppresses the parasitic water reduction; while the hydroxyl-ion-scavenging functionality further minimizes undesired passivation layer formation, thus leading to superior reversibility (an average Zn plating/stripping efficiency of 99.72% for 1000 cycles) and lifetime (80.6% capacity retention after 5000 cycles) of zinc batteries.
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Eletrólitos , Zinco , Ânions , Cátions , Interações Hidrofóbicas e Hidrofílicas , Solventes , ÁguaRESUMO
Single Li+ ion conducting polyelectrolytes (SICs), which feature covalently tethered counter-anions along their backbone, have the potential to mitigate dendrite formation by reducing concentration polarization and preventing salt depletion. However, due to their low ionic conductivity and complicated synthetic procedure, the successful validation of these claimed advantages in lithium metal (Li0 ) anode batteries remains limited. In this study, we fabricated a SIC electrolyte using a single-step UV polymerization approach. The resulting electrolyte exhibited a high Li+ transference number (t+ ) of 0.85 and demonstrated good Li+ conductivity (6.3×10-5 â S/cm at room temperature), which is comparable to that of a benchmark dual ion conductor (DIC, 9.1×10-5 â S/cm). Benefitting from the high transference number of SIC, it displayed a three-fold higher critical current density (2.4â mA/cm2 ) compared to DIC (0.8â mA/cm2 ) by successfully suppressing concentration polarization-induced short-circuiting. Additionally, the t+ significantly influenced the deposition behavior of Li0 , with SIC yielding a uniform, compact, and mosaic-like morphology, while the low t+ DIC resulted in a porous morphology with Li0 whiskers. Using the SIC electrolyte, Li0 ||LiFePO4 cells exhibited stable operation for 4500 cycles with 70.5 % capacity retention at 22 °C.
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BACKGROUND: Acute thoracic aortic dissection (ATAD) is a fatal condition characterized by tear of intima, formation of false lumen and rupture of aorta. However, the subpopulations of normal and dissected aorta remain less studied. METHODS: Single-cell RNA sequencing was performed including 5 patients with ATAD and 4 healthy controls. Immunohistochemistry and immunofluorescence were used to verify the findings. RESULTS: We got 8 cell types from human ascending aorta and identified 50 subpopulations including vascular smooth muscle cells (VSMCs), endothelial cells, fibroblasts, neutrophils, monocytes and macrophages. Six transmembrane epithelial antigen of prostate 4 metalloreductase (STEAP4) was identified as a new marker of synthetic VSMCs. CytoTRACE identified subpopulations with higher differentiation potential in specified cell types including synthetic VSMCs, enolase 1+ fibroblasts and myeloid-derived neutrophils. Synthetic VSMCs-derived C-X-C motif chemokine ligand 12 (CXCL12) might interact with neutrophils and fibroblasts via C-X-C motif chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3), respectively, which might recruit neutrophils and induce transdifferentitation of fibroblasts into synthetic VSMCs. CONCLUSION: We characterized signatures of different cell types in normal and dissected human ascending aorta and identified a new marker for isolation of synthetic VSMCs. Moreover, we proposed a potential mechanism that synthetic VSMCs might interact with neutrophils and fibroblasts via CXCL12-CXCR4/ACKR3 axis whereby deteriorating the progression of ATAD, which might provide new insights to better understand the development and progression of ATAD.
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Aorta Torácica , Dissecção Aórtica , Masculino , Humanos , Células Endoteliais , Transcriptoma , Aorta , FenótipoRESUMO
Although much progress has been made in the diagnosis and treatment of thoracic aortic dissection (TAD), the overall morbidity and mortality rates of TAD are still high. Therefore, the molecular pathogenesis and etiology of TAD need to be elucidated. In this study, we found that histone deacetylase 1 (HDAC1) expression is dramatically higher in the aortic wall of patients with TAD (than that in a normal group) and negatively correlates with the levels of the vascular smooth muscle cell (SMC) contractile-phenotype markers. Knockdown of HDAC1 upregulated both smooth muscle 22 α (SM22α) and α-smooth muscle actin (α-SMA) in platelet-derived growth factor (PDGF)-BB-treated and -untreated SMCs. In addition, the knockdown of HDAC1 markedly decreased SMC viability and migration in contrast to the control group under the conditions of quiescence and PDGF-BB treatment. We also showed that the expression of polycystic kidney disease 1 (PKD1) is decreased in the aortic wall of patients with TAD and negatively correlates with HDAC1 expression. Overexpressed PKD1 obviously increased SM22α and α-SMA expression and reduced the viability and migration of SMCs, but these effects were attenuated by HDAC1. Furthermore, we demonstrated that HDAC1 serves as an important modulator of the migration and phenotypic switch of SMCs by suppressing the PKD1- mammalian target of the rapamycin signaling pathway. HDAC1 downregulation inhibited media degeneration and attenuated the loss of elastic-fiber integrity in a mouse model of TAD. Our results suggest that HDAC1 might be a new target for the treatment of a macrovascular disease such as TAD.
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Aorta Torácica/metabolismo , Histona Desacetilase 1/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Dissecção Aórtica/genética , Dissecção Aórtica/metabolismo , Becaplermina/genética , Células Cultivadas , Humanos , FenótipoRESUMO
Mitophagy, a process that selectively removes damaged organelles by autolysosomal degradation, is an early cellular response to ischemia. Mitophagy is activated in both cardiomyocytes and platelets during ischemia/reperfusion (I/R) and heart disease conditions. We focus on the molecular regulation of mitophagy and highlight the role of mitophagy in cardioprotection.
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Plaquetas/metabolismo , Mitocôndrias/metabolismo , Mitofagia , Miócitos Cardíacos/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Humanos , Hipóxia/metabolismo , Espécies Reativas de OxigênioRESUMO
Artificial counterparts of conical-shaped transmembrane protein channels are of interest in biomedical sciences for biomolecule detection and selective ion permeation based on ionic size and/or charge differences. However, industrial-scale applications such as seawater desalination, separation of mono- from divalent cations, and treatment of highly-saline industrial waste effluents are still big challenges for such biomimetic channels. A simple monomer seeding experimental approach is used to grow ionically conductive biomimetic charged nanocone pores at the surface of an acid-functionalized membrane. These readily scalable nanocone membranes enable ultra-fast cation permeation (Na+ =8.4× vs. Mg2+ =1.4×) and high ion charge selectivity (Na+ /Mg2+ =6×) compared to the commercial state-of-the-art permselective membrane (CSO, Selemion, Japan) owing to negligible surface resistance and positively charged conical pore walls.
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Materiais Biomiméticos/química , Cátions Bivalentes/metabolismo , Permeabilidade da Membrana Celular , Canais Iônicos/metabolismo , Nanoporos , Canais Iônicos/química , PorosidadeRESUMO
High density lipoprotein (HDL) as well as annexin A1 have been reported to be associated with cardiovascular protection. However, the correlation between HDL and annexin A1 was still unknown. In this study, HDL increased endothelial annexin A1 and prevented the decrease of annexin A1 in TNF-α-activated endothelial cells in vitro and in vivo, and above effects were attenuated after knockdown of annexin A1. Annexin A1 modulation affected HDL-mediated inhibition of monocyte adhesion to TNF-α-activated endothelium (45.2±13.7% decrease for annexin A1 RNA interference; 78.7±16.3% decrease for anti-Annexin A1 antibody blocking; 11.2±6.9% increase for Ad-ANXA1 transfection). Additionally, HDL up-regulated annexin A1 through scavenger receptor class B type I, involving ERK, p38MAPK, Akt and PKC signaling pathways, and respective inhibitors of these pathways attenuated HDL-induced annexin A1 expression as well as impaired HDL-mediated inhibition of monocyte-endothelial cell adhesion. Apolipoprotein AI also increased annexin A1 and activated similar signaling pathways. Endothelial annexin A1 from apolipoprotein AI knockout mice was decreased in comparison to that from wild type mice. Finally, HDL-induced annexin A1 inhibited cell surface VCAM-1, ICAM-1 and E-selectin, and secretion of MCP-1, IL-8, VCAM-1 and E-selectin, thereby inhibiting monocyte adhesion.
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Anexina A1/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipoproteínas HDL/farmacologia , Animais , Anexina A1/genética , Apolipoproteína A-I/farmacologia , Western Blotting , Antígenos CD36/genética , Antígenos CD36/metabolismo , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Adhesion of disseminating tumor cells to vascular endothelium is a pivotal starting point in the metastasis cascade. We have shown previously that diabetic high-density lipoprotein (HDL) has the capability of promoting breast cancer metastasis, and this report summarizes our more recent work studying the role of abnormal HDL in facilitating the adhesion of the circulating tumor cells to the endothelium. This is an initiating step in breast cancer metastasis, and this work assesses the role of ICAM-1 and VCAM-1 in this process. MDA-MB-231, MCF 7, and human umbilical vein endothelial cells (HUVECs) were treated with normal HDL from healthy controls (N-HDL), HDL from breast cancer patients (B-HDL), or HDL from breast cancer patients complicated with type 2 diabetes mellitus (BD-HDL), and the cell adhesion abilities were determined. ICAM-1 and VCAM-1 expression as well as the protein kinase C (PKC) activity were evaluated. The effect of PKC inhibitor and PKC siRNA on adhesion was also studied. The immunohistochemical staining of ICAM-1, VCAM-1, and E-selectin from breast cancer patients and breast cancer patients complicated with type 2 diabetes mellitus (T2DM) were examined. Our results indicate that BD-HDL promoted an increase in breast cancer cell adhesion to HUVECs and stimulated higher ICAM-1 and VCAM-1 expression on the cells surface of both breast cancer and HUVEC cells, along with the activation of PKC. Increased tumor cell (TC)-HUVEC adhesion, as well as ICAM-1 and VCAM-1 expression induced by BD-HDL, could be inhibited by staurosporine and PKC siRNA. In addition, a Db/db type 2 diabetes mouse model has more TC-Vascular Endothelium adhesion compared to a normal model. However, BD patients have a lower expression of ICAM-1, VCAM-1, and E-selectin in their tumor tissues. BD-HDL facilitates the adhesion of tumor cells to vascular endothelium by upregulating the expression of ICAM-1 and VCAM-1, thereby promoting the initial progression of breast cancer metastasis. This work indicates a prospective utilization of HDL-based strategies in the treatment of breast cancer patients with type 2 diabetes.
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Neoplasias da Mama/genética , Adesão Celular/genética , Diabetes Mellitus Tipo 2/genética , Selectina E/biossíntese , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão de Célula Vascular/biossíntese , Animais , Neoplasias da Mama/sangue , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Selectina E/genética , Endotélio Vascular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/genética , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Metástase Neoplásica/genética , Células Neoplásicas Circulantes , Proteína Quinase C/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
OBJECTIVE: To evaluate the efficacy and safety of using Jiangzhi Tongluo Soft Capsule (JTSC) combined with Atorvastatin Calcium Tablet (ACT) or ACT alone in treatment of combined hyperlipidemia. METHODS: A randomized, double blinded, parallel control, and multi-center clinical research design was adopted. Totally 138 combined hyperlipidemia patients were randomly assigned to the combined treatment group (A) and the atorvastatin treatment group (B) by random digit table, 69 in each group. All patients took ACT 20 mg per day. Patients in the A group took JTSC 100 mg each time, 3 times per day. Those in the B group took JTSC simulated agent, 100 mg each time, 3 times per day. The treatment period for all was 8 weeks. Serum levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were observed before treatment, at week 4 and 8 after treatment; and safety was assessed as well. RESULTS: At week 4 and 8 after treatment serum TG decreased by 26.69% and 33.29% respectively in the A group (both P < 0.01), while it was decreased by 25.7% and 22.98% respectively in the B group (both P < 0.01). At week 8 decreased serum TG was obviously higher in the A group than in the B group (P < 0.05). Compared with before treatment, serum levels of LDL-C and TC levels decreased significantly in the two groups (all P < 0.01). There was no statistical difference in the drop-out value and the drop-out rate of serum LDL-C and TC levels (P > 0.05). At week 8 the serum HDL-C level showed an increasing tendency in the two groups. No obvious increase in peptase or creatase occurred in the two groups after treatment. CONCLUSION: JTSC combined with ACT could lower the serum TG level of combined hyperlipidemia patients with safety.
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Medicamentos de Ervas Chinesas/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Pirróis/uso terapêutico , Adulto , Atorvastatina , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
BACKGROUND: Myocarditis is increasingly recognized as a critical health issue, particularly among youth and middle-aged populations. This study aims to analyze the global burden and trends of myocarditis in these age groups to emphasize the need for region-specific prevention and treatment strategies. METHODS: Using data from the Global Burden of Disease (GBD) study (1990-2019), we evaluated the age-standardized rates (ASR) of myocarditis in individuals aged 10 to 54 years. We calculated average annual percentage changes (AAPC) and estimated annual percentage changes (EAPC). Additionally, we examined the correlation between myocarditis incidence and the Human Development Index (HDI) and Socio-demographic Index (SDI). Age and sex trends in myocarditis were analyzed, and Bayesian age-period-cohort (BAPC) models were used to forecast prevalence trends up to 2050. RESULTS: The High-income Asia Pacific region had the highest ASR of myocarditis, while North Africa and the Middle East had the lowest. North Africa and the Middle East also experienced the fastest average annual growth in ASR, whereas High-income North America saw the most significant decline. Correlational analysis showed that countries with a high SDI exhibited higher myocarditis ASR. The burden of myocarditis was greater among males than females, with this disparity increasing with age. Projections indicate a stable trend in the incidence of myocarditis among the youth and middle-aged population up to 2050, although the total number of cases is expected to rise. CONCLUSION: Our study reveals a significant upward trend in myocarditis among youth and middle-aged populations, highlighting the urgency for early monitoring and preventative strategies.
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Carga Global da Doença , Miocardite , Humanos , Miocardite/epidemiologia , Adolescente , Criança , Feminino , Masculino , Adulto Jovem , Adulto , Incidência , Pessoa de Meia-Idade , Carga Global da Doença/tendências , Previsões , Prevalência , Saúde Global , Distribuição por Idade , Distribuição por SexoRESUMO
BACKGROUND: Inflammation plays a pivotal role in the pathogenesis of heart failure (HF). This study was aimed to the potential association between complete blood cell count (CBC)-derived inflammatory biomarkers and HF. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2009-2018 were utilised. We evaluated the associations between HF and five systemic inflammation markers derived from CBC: systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR). Demographic characteristics, physical examinations, and laboratory data were systematically collected for comparative analysis between HF and non-HF individuals. Fitted smoothing curves and threshold effect analysis delineated the relationship. In addition, Spearman correlation and subgroup analyses were further conducted. RESULTS: A total of 26,021 participants were categorised into HF (n = 858) and non-HF (n = 25,163) groups. After adjusting for confounding variables, SIRI, NLR, and MLR had significant positive correlations with the risk of HF. Participants in the highest quarter groups of SIRI, NLR, and MLR showed a increased risk of developing HF compared to those in the lowest quarter group. Furthermore, subgroup and sensitivity analyses indicated that SIRI, NLR, and MLR had a stronger correlation to HF (all p < 0.05). Smoothing curve fitting highlighted a nonlinear relationship between CBC-derived inflammatory biomarkers and HF. CONCLUSIONS: Our results illustrated a significant association between elevated levels of SIRI, NLR, and MLR and an increased risk of HF. SIRI, NLR, and MLR could potentially serve as systemic inflammation hazard markers for HF.
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Biomarcadores , Insuficiência Cardíaca , Inflamação , Inquéritos Nutricionais , Humanos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/epidemiologia , Masculino , Feminino , Estudos Transversais , Inflamação/sangue , Pessoa de Meia-Idade , Biomarcadores/sangue , Neutrófilos , Estados Unidos/epidemiologia , Idoso , Linfócitos , Adulto , Fatores de Risco , MonócitosRESUMO
AIMS: Heart failure (HF) and non-alcoholic fatty liver disease (NAFLD) are significant global health issues with a complex interrelationship. This study investigates their shared biomarkers and causal relationships using bioinformatics and Mendelian randomization (MR) approaches. METHODS: We analysed NAFLD and HF datasets from the Gene Expression Omnibus (GEO). The GSE126848 dataset included 57 liver biopsy samples [14 healthy individuals, 12 obese subjects, 15 NAFL patients and 16 non-alcoholic steatohepatitis (NASH) patients]. The GSE24807 dataset comprised 12 NASH samples and 5 healthy controls. The GSE57338 dataset included 313 cardiac muscle samples [177 HF patients (95 ischaemic heart disease patients and 82 idiopathic dilated cardiomyopathy patients) and 136 healthy controls]. The GSE84796 dataset consisted of 10 end-stage HF patients and 7 healthy hearts procured from organ donors. We identified differentially expressed genes (DEGs) and constructed a protein-protein interaction (PPI) network. Functional pathways were elucidated through enrichment analyses using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneMANIA annotation. Single nucleotide polymorphism (SNP) data for HF and NAFLD were sourced from genome-wide association studies (GWAS). The HF dataset included 486 160 samples (14 262 experimental and 471 898 control), and the NAFLD dataset comprised 377 988 samples (4761 experimental and 373 227 control). MR analysis investigates the causal interrelations. RESULTS: Our analysis revealed 4032 DEGs from GSE126848 and 286 DEGs from GSE57338. The top 10 hub genes (CD163, VSIG4, CXCL10, FCER1G, FPR1, C1QB, CCR1, C1orf162, MRC1 and CD38) were significantly enriched in immune response, calcium ion concentration regulation and positive regulation of monocyte chemotaxis. CIBERSORT analysis indicated associations between these hub genes and natural killer (NK) cells and macrophages. Transcription factor (TF) target prediction for CD38, CXCL10 and CCR1 highlighted related TFs. A two-sample MR analysis confirmed a bidirectional causal relationship between NAFLD and HF. The main method [inverse variance weighted (IVW)] demonstrated a significant positive causal relationship between NAFLD and HF [P = 0.037; odds ratio (OR) = 1.024; 95% confidence interval (CI): 1.001 to 1.048]. Similarly, HF was associated with an increase in the risk of NAFLD (P < 0.001; OR = 1.117; 95% CI: 1.053 to 1.185). CONCLUSIONS: Our findings reveal novel molecular signatures common to NAFLD and HF and confirm their bidirectional causality, highlighting the potential for targeted therapeutic interventions and prompting further investigation into their intricate relationship.
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BACKGROUND: Our study aimed to identify inclisiran-related adverse events(AEs) for primary hypercholesterolemia and arteriosclerotic cardiovascular disease(ASCVD) from the US FDA Adverse Event Reporting System (FAERS) database, analyzing its links to AEs in the overall patient population and sex-specific subgroups to improve medication safety. METHODS: We analyzed inclisiran-related AEs signals by using statistical methods like Reporting Odds Ratio (ROR), Proportional Reporting Ratios (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma-Poisson Shrinker (MGPS). RESULTS: Analyzing 2,400 AE reports with inclisiran as the primary suspected drug in the FAERS database, we identified 70 AE signals over 13 organ systems using the above four methods. Notable findings were strong signals for systemic diseases and various reactions at the site of administration (ROR 1.49, 95% CI 1.41-1.57), and various musculoskeletal and connective tissue diseases (ROR 4.07, 95% CI 3.83-4.03) in overall and gender-specific populations. Myalgia, a new ADE signal not in the drug insert, was a top signal by intensity and frequency (ROR 14.76, 95% CI 12.84-16.98). CONCLUSION: Our study revealed the strongest AE signals associated with inclisiran in both the overall population and gender subgroups, highlighting potential risks in clinical medication use and guiding balanced clinical decision-making.
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Acanthus ilicifolius var. xiamenensis is a traditional herbal medicine in China. In this study, the anti-inflammatory activities of active ingredients of A. ilicifolius var. xiamenensis were investigated in RAW 264.7 cells and Freund's complete adjuvant-induced arthritic rats. Results showed that n-butanol extract exerted antiarthritic potential by reducing paw edema, arthritis score, and altered hematological and biochemical parameters in experimental rats. Phytochemical studies on n-butanol extract resulted in the isolation of five alkaloids (1-5) and five phenylethanoids (6-10). The anti-inflammatory assay of compounds 1-10 on lipopolysaccharide (LPS)-treated RAW 264.7 cells indicated that phenylethanoids 9 and 10 exhibited notable inhibitory activities. The result indicated that compounds 9 and 10 attenuated inflammation by decreasing the production of nuclear factor kappa-B (NF-κB) p65, inhibitory subunit of NF kappa B alpha, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and inducible nitric oxide synthase in LPS-mediated RAW 264.7 macrophages. Phenylethanoids 9 and 10 increased the expression of interleukin-10 and endothelial nitric oxide synthase. Therefore, compounds 9 and 10 showed anti-inflammatory activity by regulation of NF-κB and JAK/STAT signaling pathways.
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Lipopolissacarídeos , NF-kappa B , Animais , Camundongos , Ratos , 1-Butanol/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Acanthaceae/químicaRESUMO
Designing stable Li metal and supporting solid structures (SSS) is of fundamental importance in rechargeable Li-metal batteries. Yet, the stripping kinetics of Li metal and its mechanical effect on the supporting solids (including solid electrolyte interface) remain mysterious to date. Here, through nanoscale in situ observations of a solid-state Li-metal battery in an electron microscope, two distinct cavitation-mediated Li stripping modes controlled by the ratio of the SSS thickness (t) to the Li deposit's radius (r) are discovered. A quantitative criterion is established to understand the damage tolerance of SSS on the Li-metal stripping pathways. For mechanically unstable SSS (t/r < 0.21), the stripping proceeds via tension-induced multisite cavitation accompanied by severe SSS buckling and necking, ultimately leading to Li "trapping" or "dead Li" formation; for mechanically stable SSS (t/r > 0.21), the Li metal undergoes nearly planar stripping from the root via single cavitation, showing negligible buckling. This work proves the existence of an electronically conductive precursor film coated on the interior of solid electrolytes that however can be mechanically damaged, and it is of potential importance to the design of delicate Li-metal supporting structures to high-performance solid-state Li-metal batteries.
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Epidemiological studies suggested complicated associations between type 2 diabetes mellitus and breast cancer. There is a significant inverse association between high-density lipoprotein (HDL) and the risk and mortality of breast cancer. However, HDL could be modified in various ways in diabetes patients, and this may lead to the altered effects on many different types of cells. In our study, we found that glycation and oxidation levels are significantly higher in HDL from type 2 diabetes mellitus patients compared to that from healthy subjects. Diabetic HDL dramatically had a stronger capability to promote cell proliferation, migration and invasion of breast cancer (as examined both on hormone-independent cells and on hormone-dependent cells). In addition, glycated and oxidized HDL, which were produced in vitro, acted in similar way as diabetic HDL. Diabetic HDL, glycated HDL and oxidized HDL also induced higher synthesis and secretion of VEGF-C, MMP-2 and MMP-9 from malondialdehyde (MDA)-MB-231 cells. It was indicated that diabetic, glycated and oxidized HDL promote MDA-MB-231 cell migration and invasion through ERK and p38 MAPK pathways, and Akt pathway plays an important role as well in MDA-MB-231 cell invasion. The Akt, ERK and p38 MAPK pathways are also involved in VEGF-C and MMP-9 secretion induced by diabetic, glycated and oxidized HDL. Our study demonstrated that glycation and oxidation of HDL in diabetic patients could lead to abnormal actions on MDA-MB-231 cell proliferation, migration and invasion, thereby promoting the progression of breast cancer. This will largely draw the attention of HDL-based treatments in diabetic patients especially those with breast cancer.
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Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/metabolismo , Lipoproteínas HDL/metabolismo , Adulto , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Diabetes Mellitus Tipo 2/sangue , Progressão da Doença , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glicosilação , Humanos , Lipoproteínas HDL/sangue , Sistema de Sinalização das MAP Quinases , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Oxirredução , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Previous studies suggest that oxidative stress plays an important role in the development of breast cancer. There is a significant inverse relationship between HDL and the risk and mortality of breast cancer. However, it is well known that under conditions of oxidative stress, such as breast cancer, HDL can be oxidatively modifiedand these modifications may have an effect on the functions of HDL. The purpose of this study is to determine the different effects of normal and oxidized (caused by hypochlorite-induced oxidative stress) HDL on breast cancer cell metastasis. METHODS: Human breast cancer cell lines were treated with normal and hypochlorite-oxidized HDL, and then cell metastasis potency in vivo and the abilities of migration, invasion, adhesion to HUVEC and ECM in vitro were examined. Integrin expression and PKC activity were evaluated, and PKC inhibitor and PKC siRNA was applied. RESULTS: We found hypochlorite-oxidized HDL dramatically promotes breast cancer cell pulmonary metastasis (133.4% increase at P < 0.0 l for MDA-MB-231 by mammary fat pad injection; 164.3% increase at P < 0.01 for MCF7 by tail vein injection) and hepatic metastasis (420% increase at P < 0.0 l for MDA-MB-231 by mammary fat pad injection; 1840% fold increase at P < 0.001 for MCF7 by tail vein injection) in nude mice, and stimulates higher cell invasion (85.1% increase at P < 0.00 l for MDA-MB-231; 88.8% increase at P < 0.00 l for MCF7;), TC-HUVEC adhesion (43.4% increase at P < 0.00 l for MDA-MB-231; 35.2% increase at P < 0.00 l for MCF7), and TC-ECM attachment (41.0% increase at P < 0.00 l for MDA-MB-231; 26.7% increase at P < 0.05 for MCF7) in vitro compared with normal HDL. The data also shows that the PKC pathway is involved in the abnormal actions of hypochlorite-oxidized HDL. CONCLUSIONS: Our study demonstrated that HDL under hypochlorite-induced oxidative stress stimulates breast cancer cell migration, invasion, adhesion to HUVEC and ECM, thereby promoting metastasis of breast cancer. These results suggest that HDL-based treatments should be considered for treatment of breast cancer patients.