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1.
PLoS Pathog ; 20(8): e1012444, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39173055

RESUMO

The Ebola virus (EBOV) has emerged as a significant global health concern, notably during the 2013-2016 outbreak in West Africa. Despite the clinical approval of two EBOV antibody drugs, there is an urgent need for more diverse and effective antiviral drugs, along with comprehensive understanding of viral-host interactions. In this study, we harnessed a biologically contained EBOVΔVP30-EGFP cell culture model which could recapitulate the entire viral life cycle, to conduct a genome-wide CRISPR/Cas9 screen. Through this, we identified PIK3C3 (phosphatidylinositide 3-kinase) and SLC39A9 (zinc transporter) as crucial host factors for EBOV infection. Genetic depletion of SLC39A9 and PIK3C3 lead to reduction of EBOV entry, but not impact viral genome replication, suggesting that SLC39A9 and PIK3C3 act as entry factors, facilitating viral entry into host cells. Moreover, PIK3C3 kinase activity is indispensable for the internalization of EBOV virions, presumably through the regulation of endocytic and autophagic membrane traffic, which has been previously recognized as essential for EBOV internalization. Notably, our study demonstrated that PIK3C3 kinase inhibitor could effectively block EBOV infection, underscoring PIK3C3 as a promising drug target. Furthermore, biochemical analysis showed that recombinant SLC39A9 protein could directly bind viral GP protein, which further promotes the interaction of viral GP protein with cellular receptor NPC1. These findings suggests that SLC39A9 plays dual roles in EBOV entry. Initially, it serves as an attachment factor during the early entry phase by engaging with the viral GP protein. Subsequently, SLC39A9 functions an adaptor protein, facilitating the interaction between virions and the NPC1 receptor during the late entry phase, prior to cathepsin cleavage on the viral GP. In summary, this study offers novel insights into virus-host interactions, contributing valuable information for the development of new therapies against EBOV infection.


Assuntos
Sistemas CRISPR-Cas , Ebolavirus , Doença pelo Vírus Ebola , Internalização do Vírus , Animais , Humanos , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/genética , Ebolavirus/genética , Ebolavirus/fisiologia , Ebolavirus/metabolismo , Células HEK293 , Doença pelo Vírus Ebola/virologia , Doença pelo Vírus Ebola/metabolismo , Doença pelo Vírus Ebola/genética , Replicação Viral
2.
Circulation ; 149(19): 1501-1515, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38223978

RESUMO

BACKGROUND: During the neonatal stage, the cardiomyocyte undergoes a constellation of molecular, cytoarchitectural, and functional changes known collectively as cardiomyocyte maturation to increase myocardial contractility and cardiac output. Despite the importance of cardiomyocyte maturation, the molecular mechanisms governing this critical process remain largely unexplored. METHODS: We leveraged an in vivo mosaic knockout system to characterize the role of Carm1, the founding member of protein arginine methyltransferase, in cardiomyocyte maturation. Using a battery of assays, including immunohistochemistry, immuno-electron microscopy imaging, and action potential recording, we assessed the effect of loss of Carm1 function on cardiomyocyte cell growth, myofibril expansion, T-tubule formation, and electrophysiological maturation. Genome-wide transcriptome profiling, H3R17me2a chromatin immunoprecipitation followed by sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing were used to investigate the mechanisms by which CARM1 (coactivator-associated arginine methyltransferase 1) regulates cardiomyocyte maturation. Finally, we interrogated the human syntenic region to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks for single-nucleotide polymorphisms associated with human heart diseases. RESULTS: We report that mosaic ablation of Carm1 disrupts multiple aspects of cardiomyocyte maturation cell autonomously, leading to reduced cardiomyocyte size and sarcomere thickness, severe loss and disorganization of T tubules, and compromised electrophysiological maturation. Genomics study demonstrates that CARM1 directly activates genes that underlie cardiomyocyte cytoarchitectural and electrophysiological maturation. Moreover, our study reveals significant enrichment of human heart disease-associated single-nucleotide polymorphisms in the human genomic region syntenic to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks. CONCLUSIONS: This study establishes a critical and multifaceted role for CARM1 in regulating cardiomyocyte maturation and demonstrates that deregulation of CARM1-dependent cardiomyocyte maturation gene expression may contribute to human heart diseases.


Assuntos
Epigênese Genética , Miócitos Cardíacos , Proteína-Arginina N-Metiltransferases , Animais , Humanos , Camundongos , Diferenciação Celular/genética , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo
3.
Int Immunol ; 36(10): 541-552, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-38778574

RESUMO

Lymphocyte trafficking via chemokine receptors such as C-C chemokine receptor 5 (CCR5) and CXCR3 plays a critical role in the pathogenesis of acute graft-versus-host disease (aGVHD). Our previous studies showed that the addition of CCR5 or CXCR3 antagonists could only slightly alleviate the development of aGVHD. Given the specificity of T lymphocytes bearing CXCR3 and CCR5, we investigated whether combined CCR5 and CXCR3 blockade could further attenuate murine aGVHD. A mouse model of aGVHD was established to assess the efficacy of CCR5 and/or CXCR3 blockade on the development of aGVHD. The distribution of lymphocytes was calculated by quantification of immunostaining cells. The immunomodulatory effect on T cells was assessed by evaluating T-cell proliferation, viability, and differentiation. Using the murine allogeneic hematopoietic stem cell transplantation model, we demonstrated that blockade of both CCR5 and CXCR3 could efficiently alleviate the development of aGVHD. Further investigation on the immune mechanisms for this prophylactic effect showed that more T cells were detained into secondary lymphoid organs (SLOs), which may lead to reduced infiltration of T cells into GVHD target organs. Our study also showed that T cells detained in SLOs dampened the activation, suppressed the polarization toward T helper type 1 (Th1) and T cytotoxic type 1 (Tc1) cells, and induced the production of Treg cells. These data suggest that concurrent blockade of CCR5 and CXCR3 attenuates murine aGVHD through modulating donor-derived T-cell distribution and function, and this might be applicable for aGVHD prophylaxis in clinical settings.


Assuntos
Doença Enxerto-Hospedeiro , Camundongos Endogâmicos C57BL , Receptores CCR5 , Receptores CXCR3 , Animais , Doença Enxerto-Hospedeiro/imunologia , Receptores CXCR3/metabolismo , Receptores CXCR3/imunologia , Receptores CXCR3/antagonistas & inibidores , Receptores CCR5/metabolismo , Receptores CCR5/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas dos Receptores CCR5/farmacologia , Transplante de Células-Tronco Hematopoéticas , Doença Aguda , Modelos Animais de Doenças , Linfócitos T/imunologia , Feminino
4.
FASEB J ; 38(5): e23530, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38466314

RESUMO

Brevibacillus laterosporus is a strain of probiotic bacteria that has been widely used in pest control, cash crop, and other production areas. However, few studies have been conducted on its use as a feed additive in animals. Therefore, the probiotic potential of B. laterosporus PBC01 was evaluated by characterizing hydrophobicity, auto-aggregation activity, bile salt and simulated gastrointestinal fluid tolerance, bienzymatic, and antibacterial activity. Antibiotic susceptibility, hemolysis assays, and supplemental feeding of mice were also performed to evaluate safety features. Our results showed that B. laterosporus PBC01 had moderate hydrophobicity, high auto-agglutination ability. Meanwhile, B. laterosporus PBC01 had good tolerance to bile salt and simulated gastrointestinal fluid. It had the ability to secrete protease, cellulase, and to inhibit various pathogens. In addition, B. laterosporus PBC01 was sensitive to many antibiotics, and did not produce hemolysin. In the safety assessment of mice, it did not cause any deaths, nor did it affect the cell components of blood, antioxidant capacity, and reproductive health. The study indicated the great probiotic characteristics and safety of B. laterosporus PBC01. This may provide a theoretical basis for the clinical application and development of probiotic-based feed additives.


Assuntos
Bacillus , Brevibacillus , Animais , Camundongos , Antibacterianos/farmacologia , Ácidos e Sais Biliares
5.
Gut ; 73(2): 268-281, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37734910

RESUMO

BACKGROUND AND AIMS: Deregulation of RNA N6-methyladenosine (m6A) modification in intestinal epithelial cells (IECs) influences intestinal immune cells and leads to intestinal inflammation. We studied the function of fat mass-and obesity-associated protein (FTO), one of the m6A demethylases, in patients with ulcerative colitis (UC). METHODS: We analysed colon tissues of Ftoflox/flox; Villin-cre mice and their Ftoflox/flox littermates with dextran sulfate sodium (DSS) using real-time PCR and 16s rRNA sequencing. RNA and methylated RNA immunoprecipitation sequencing were used to analyse immunocytes and IECs. Macrophages were treated with conditioned medium of FTO-knockdown MODE-K cells or sphingosine-1-phosphate (S1P) and analysed for gene expression. Liquid chromatograph mass spectrometry identified C16-ceramide. RESULTS: FTO downregulation was identified in our in-house cohort and external cohorts of UC patients. Dysbiosis of gut microbiota, increased infiltration of proinflammatory macrophages, and enhanced differentiation of Th17 cells were observed in Ftoflox/flox;Villin-cre mice under DSS treatment. FTO deficiency resulted in an increase in m6A modification and a decrease in mRNA stability of CerS6, the gene encoding ceramide synthetase, leading to the downregulation of CerS6 and the accumulation of S1P in IECs. Subsequentially, the secretion of S1P by IECs triggered proinflammatory macrophages to secrete serum amyloid A protein 1/3, ultimately inducing Th17 cell differentiation. In addition, through bioinformatic analysis and experimental validation, we identified UC patients with lower FTO expression might respond better to vedolizumab treatment. CONCLUSIONS: FTO downregulation promoted UC by decreasing CerS6 expression, leading to increased S1P accumulation in IECs and aggravating colitis via m6A-dependent mechanisms. Lower FTO expression in UC patients may enhance their response to vedolizumab treatment.


Assuntos
Colite Ulcerativa , Colite , Humanos , Animais , Camundongos , Colite Ulcerativa/metabolismo , RNA Ribossômico 16S/metabolismo , Mucosa Intestinal/metabolismo , Colite/induzido quimicamente , Colite/genética , Colo/metabolismo , Esfingolipídeos/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo
6.
Mol Microbiol ; 119(1): 126-142, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36537557

RESUMO

In dimorphic fungi, the yeast-to-filament transition critical for cell survival under nutrient starvation is controlled by both activators and repressors. However, very few filamentation repressors are known. Here we report that, in the dimorphic yeast Yarrowia lipolytica, the conserved transcription factor YlNrg1 plays a minor role whereas Fts1, a newly identified Zn(II)2 Cys6 zinc cluster transcription factor, plays a key role in filamentation repression. FTS1 deletion caused hyperfilamentation whereas Fts1 overexpression drastically reduced filamentation. The expression of FTS1 is downregulated substantially during the yeast-to-filament transition. Transcriptome sequencing revealed that Fts1 represses 401 genes, including the filamentation-activating transcription factor genes MHY1, YlAZF1, and YlWOR4 and key cell wall protein genes. Tup1-Ssn6, a general transcriptional corepressor, is involved in the repression of many cellular functions in fungi. We show that both YlTup1 and YlSsn6 strongly repress filamentation in Y. lipolytica. YlTup1 and YlSsn6 together repress 1383 genes, including a large number of transcription factor and cell wall protein genes, which overlap substantially with Fts1-repressed genes. Fts1 interacts with both YlTup1 and YlSsn6, and LexA-Fts1 fusion represses a lexAop-promoter-lacZ reporter in a Tup1-Ssn6-dependent manner. Our findings suggest that Fts1 functions as a transcriptional repressor, directing the repression of target genes through the Tup1-Ssn6 corepressor.


Assuntos
Yarrowia , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica/genética , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Yarrowia/genética , Yarrowia/metabolismo
7.
Small ; : e2406518, 2024 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-39183518

RESUMO

The ability to manufacture 3D metallic architectures with microscale resolution is greatly pursued because of their diverse applications in microelectromechanical systems (MEMS) including microelectronics, mechanical metamaterials, and biomedical devices. However, the well-developed photolithography and emerging metal additive manufacturing technologies have limited abilities in manufacturing micro-scaled metallic structures with freeform 3D geometries. Here, for the first time, the high-fidelity fabrication of arbitrary metallic motifs with sub-10 µm resolution is achieved by employing an embedded-writing embedded-sintering (EWES) process. A paraffin wax-based supporting matrix with high thermal stability is developed, which permits the printed silver nanoparticle ink to be pre-sintered at 175 °C to form metallic green bodies. Via carefully regulating the matrix components, the printing resolution is tuned down to ≈7 µm. The green bodies are then embedded in a supporting salt bath and further sintered to realize freeform 3D silver motifs with great structure fidelity. 3D printing of various micro-scaled silver architectures is demonstrated such as micro-spring arrays, BCC lattices, horn antenna, and rotatable windmills. This method can be extended to the high-fidelity 3D printing of other metals and metal oxides which require high-temperature sintering, providing the pathways toward the design and fabrication of 3D MEMS with complex geometries and functions.

8.
Mol Carcinog ; 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39291848

RESUMO

Thyroid carcinoma (TC) is the most common malignant tumor of the endocrine system with increasing incidence. In this study, we found that BCL9 is markedly upregulated in human TC tumors and its expression is positively corrected with the process of TC. Functionally, we found that overexpression of BCL9 promoted the proliferation and migration of TC cells, while reduced the sensitivity of TC cells to ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation and implicated as a novel cancer therapeutic strategy. Mechanistically, the co-immunoprecipitation assay determined that BCL9 could bind to Nrf2 which has been confirmed to play an important role in ferroptosis. Furthermore, we demonstrated that silence of BCL9 could decrease Nrf2 expression, and then affect the expression of the downstream genes of Nrf2, ultimately induce ferroptosis. Importantly, we confirmed the effects of BCL9 on TC tumors in vivo. Overall, this study unveils the functional role and clinical significance of BCL9 in TC progression, and highlights the potential of targeting BCL9/Nrf2 ferroptosis axis as a novel therapeutic strategy for TC treatment.

9.
New Phytol ; 243(2): 567-579, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38812270

RESUMO

Aerosols could significantly influence ecosystem carbon and water fluxes, potentially altering their interconnected dynamics, typically characterized by water-use efficiency (WUE). However, our understanding of the underlying ecophysiological mechanisms remains limited due to insufficient field observations. We conducted 4-yr measurements of leaf photosynthesis and transpiration, as well as 3-yr measurements of stem growth (SG) and sap flow of poplar trees exposed to natural aerosol fluctuation, to elucidate aerosol's impact on plant WUE. We found that aerosol improved sun leaf WUE mainly because a sharp decline in photosynthetically active radiation (PAR) inhibited its transpiration, while photosynthesis was less affected, as the negative effect induced by declined PAR was offset by the positive effect induced by low leaf vapor pressure deficit (VPDleaf). Conversely, diffuse radiation fertilization (DRF) effect stimulated shade leaf photosynthesis with minimal impact on transpiration, leading to an improved WUE. The responses were further verified by a strong DRF on SG and a decrease in sap flow due to the suppresses in total radiation and VPD. Our field observations indicate that, contrary to the commonly assumed coupling response, carbon uptake and water use exhibited dissimilar reactions to aerosol pollution, ultimately enhancing WUE at the leaf and canopy level.


Assuntos
Aerossóis , Carbono , Fotossíntese , Folhas de Planta , Transpiração Vegetal , Populus , Água , Água/metabolismo , Fotossíntese/efeitos da radiação , Fotossíntese/efeitos dos fármacos , Carbono/metabolismo , Folhas de Planta/fisiologia , Folhas de Planta/efeitos da radiação , Folhas de Planta/efeitos dos fármacos , Transpiração Vegetal/fisiologia , Transpiração Vegetal/efeitos da radiação , Populus/fisiologia , Populus/efeitos da radiação , Populus/efeitos dos fármacos , Caules de Planta/efeitos da radiação , Caules de Planta/efeitos dos fármacos , Caules de Planta/fisiologia
10.
Plant Cell Environ ; 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39101480

RESUMO

Increased atmospheric nitrogen (N) deposition significantly disturbs ecosystem N cycle. Although foliar interception and uptake of N deposition can provide an important alternative N supply to forest ecosystems, the mechanisms regulating foliar N uptake from wet deposition are not fully understood. Here, we selected 19 woody species with a wide range of plant traits from different functional groups and conducted a 15N isotope labelling experiment through brushing 15NH4 + and 15NO3 - solution on canopy leaves. Our findings demonstrate that leaves can directly absorb N from wet deposition within a few hours. The average leaf 15N recoveries were 10% and 28% under 15NH4 + and 15NO3 - treatments across species, respectively, while twig N recoveries were only 1%-7% of leaf N recoveries. Differences in foliar N uptake efficiency among species were closely associated with leaf traits but were little influenced by meteorological conditions or soil nutrient status. Specifically, plants with higher leaf N concentration, larger specific leaf area and lower wax concentration exhibited higher leaf N recovery. Our results indicated that tree canopies could directly absorb N from atmospheric deposition. We highlight the critical role of leaf traits in determining canopy foliar N uptake, which may consequently influence plant competition under elevated N deposition.

11.
Cancer Cell Int ; 24(1): 92, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38431620

RESUMO

BACKGROUND: Cholangiocarcinoma represents a malignant neoplasm originating from the hepatobiliary tree, with a subset of tumors developing inside the liver. Intrahepatic cholangiocarcinomas (ICC) commonly exhibit an asymptomatic presentation, rendering both diagnosis and treatment challenging. Cuproptosis, an emerging regulated cell death pathway induced by copper ions, has garnered attention recently. As cancer cells show altered copper metabolism and comparatively higher copper needs, cuproptosis may play a role in the development of ICC. However, studies investigating this possibility are currently lacking. METHODS: Single-cell and bulk RNA sequence data were analyzed, and correlations were established between the expression of cuproptosis-related molecules and ICC patient survival. Genes with predicting survival were used to create a CUPT score using Cox and LASSO regression and tumor mutation burden (TMB) analysis. The CIBERSORT software was employed to characterize immune cell infiltration within the tumors. Furthermore, immune infiltration prediction, biological function enrichment, and drug sensitivity analyses were conducted to explore the potential implications of the cuproptosis-related signature. The effects of silencing solute carrier family 39 member 4 gene (SLC39A4) expression using siRNA were investigated using assays measuring cell proliferation, colony formation, and cell migration. Key genes of cuproptosis were detected by western blotting. RESULTS: The developed CUPT score divided patients into high and low CUPT score groups. Those with a low score had significantly better prognosis and longer survival. In contrast, high CUPT scores were associated with worse clinical outcomes and significantly higher TMB. Comparisons of the two groups also indicated differences in the immune infiltrate present in the tumors. Finally, we were able to identify 95 drugs potentially affecting the cuproptosis pathway. Some of these might be effective in the treatment of ICC. The in vitro experiments revealed that suppressing the expression of SLC39A4 in ICC cell lines resulted in reduced cell proliferation, colony formation, and cell migration. It also led to an increase in cell death and the upregulation of key genes associated with cuproptosis, namely ferredoxin 1 (FDX1) and dihydrolipoyl transacetylase (DLAT). These findings strongly suggest that this cuproptosis-associated molecule may play a pivotal role in the development and metastasis of ICC. CONCLUSIONS: Changes in the expression of a cuproptosis-related gene signature can predict the clinical prognosis of ICC with considerable accuracy. This supports the notion that cuproptosis influences the diversity and complexity of the immune microenvironment, mutational landscape, and biological behavior of ICC. Understanding this pathway better may hold promise for the development of innovative strategies in the management of this disease.

12.
J Org Chem ; 89(12): 8363-8375, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38848119

RESUMO

Palladium-catalyzed decarboxylation of 5-methylene-1,3-oxazinan-2-ones and 5-methylene-1,3-dioxan-2-ones to generate aza-π-allylpalladium and oxa-π-allylpalladium 1,4-dipoles for [4 + 2] cycloaddition reaction with 1,3,5-triazinanes was developed, affording a wide range of hexahydropyrimidine and 1,3-oxazinane derivatives in good to excellent yields (up to 99%). The acyclic sulfonamido-substituted allylic carbonates as aza-π-allylpalladium 1,4-dipole precursors also apply to the developed synthesized strategy, achieving the synthesis of hexahydropyrimidines. Moreover, the in situ-generated aza-π-allylpalladium 1,4-dipoles undergoing dimeric [4 + 4] cycloaddition were also demonstrated by the construction of 1,5-diazocane derivatives.

13.
Future Oncol ; : 1-8, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39268928

RESUMO

Aim: To develop and validate a T2-weighted-fluid attenuated inversion recovery (T2-FLAIR) images-based radiomics model for predicting early postoperative recurrence (within 1 year) in patients with low-grade gliomas (LGGs).Methods: A retrospective analysis was performed by collecting clinical, pathological and magnetic resonance imaging (MRI) data from patients with LGG between 2017 and 2022. Regions of interest were delineated and radiomic features were extracted from T2-FLAIR images using 3D-Slicer software. To minimize redundant features, the Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm was used. Patients were categorized into two groups based on recurrence status: the recurrence group (RG) and the non-recurrence group (NRG). Radiomic features were used to develop models using three machine learning approaches: logistic regression (LR), random forest (RF) and support vector machine (SVM). The performance of the radiomic features was validated using fivefold cross-validation.Results: After rigorous screening, 105 patients met the inclusion criteria, and five radiomic features were identified. After 5-folds cross-validation, the average areas under the curves for LR, RF and SVM were 0.813, 0.741 and 0.772, respectively.Conclusion: T2-FLAIR-based radiomic features effectively predicted early recurrence in postoperative LGGs.


[Box: see text].

14.
BMC Cardiovasc Disord ; 24(1): 357, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39003444

RESUMO

BACKGROUND: The epidemiological distribution of functional mitral regurgitation (FMR) in heart failure (HF) and mildly reduced ejection fraction (HFmrEF) patients and its impact on outcomes remains unclear. We attempt to investigate the prognosis of FMR in patients with HFmrEF. METHODS: The HF center registry study is a prospective, single, observational study conducted at the Second Affiliated Hospital of Shenzhen University, where 2330 patients with acute HF (AHF) were enrolled and 890 HFmrEF patients were included in the analysis. The patients were stratified into three categories based on the severity of FMR: none/mild, moderate, and moderate-to-severe/severe groups. Subsequently, a comparison of the clinical characteristics among these groups was conducted, along with an assessment of the incidence of the primary endpoint (comprising all-cause mortality and readmission for HF) during a one-year follow-up period. RESULTS: The one-year follow-up results indicated that the primary composite endpoint occurrence rates in the three groups were 23.5%, 32.9%, and 36.5%, respectively. The all-cause mortality rates in the three groups were 9.3%, 13.7%, and 16.4% respectively. Survival analysis demonstrated a statistically significant difference in the occurrence rates of the primary composite endpoint and all-cause mortality among the three groups (P < 0.05). Multifactor Cox regression revealed that moderate FMR and moderate-to-severe/severe FMR were independent risk factors for adverse clinical prognosis in HFmrEF patients, with hazard ratios and 95% confidence intervals of 1.382 (1.020-1.872, P = 0.037) and 1.546 (1.092-2.190, P = 0.014) respectively. CONCLUSIONS: Moderate FMR and moderate-to-severe/severe FMR independently predict an unfavorable prognosis in patients with HFmrEF.


Assuntos
Insuficiência Cardíaca , Insuficiência da Valva Mitral , Admissão do Paciente , Readmissão do Paciente , Sistema de Registros , Índice de Gravidade de Doença , Volume Sistólico , Função Ventricular Esquerda , Humanos , Insuficiência da Valva Mitral/fisiopatologia , Insuficiência da Valva Mitral/mortalidade , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Fatores de Tempo , Fatores de Risco , Doença Aguda , Prognóstico , China/epidemiologia , Medição de Risco
15.
J Nanobiotechnology ; 22(1): 80, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418972

RESUMO

The advancement of biomaterials with antimicrobial and wound healing properties continues to present challenges. Macrophages are recognized for their significant role in the repair of infection-related wounds. However, the interaction between biomaterials and macrophages remains complex and requires further investigation. In this research, we propose a new sequential immunomodulation method to enhance and expedite wound healing by leveraging the immune properties of bacteria-related wounds, utilizing a novel mixed hydrogel dressing. The hydrogel matrix is derived from porcine acellular dermal matrix (PADM) and is loaded with a new type of bioactive glass nanoparticles (MBG) doped with magnesium (Mg-MBG) and loaded with Curcumin (Cur). This hybrid hydrogel demonstrates controlled release of Cur, effectively eradicating bacterial infection in the early stage of wound infection, and the subsequent release of Mg ions (Mg2+) synergistically inhibits the activation of inflammation-related pathways (such as MAPK pathway, NF-κB pathway, TNF-α pathway, etc.), suppressing the inflammatory response caused by infection. Therefore, this innovative hydrogel can safely and effectively expedite wound healing during infection. Our design strategy explores novel immunomodulatory biomaterials, offering a fresh approach to tackle current clinical challenges associated with wound infection treatment.


Assuntos
Anti-Infecciosos , Curcumina , Infecção dos Ferimentos , Animais , Suínos , Hidrogéis/farmacologia , Cicatrização , Biomimética , Bandagens , Antibacterianos/uso terapêutico , Materiais Biocompatíveis , Imunoterapia , Infecção dos Ferimentos/tratamento farmacológico
16.
Nano Lett ; 23(14): 6544-6552, 2023 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-37401457

RESUMO

As a ROS scavenger, resveratrol exerts a neuroprotective effect by polarizing the M1 microglia to the anti-inflammatory M2 phenotype for ischemic stroke treatment. However, the obstruction of the blood-brain barrier (BBB) seriously impairs the efficacy of resveratrol. Herein, we develop a stepwise targeting nanoplatform for enhanced ischemic stroke therapy, which is fabricated by pH-responsive poly(ethylene glycol)-acetal-polycaprolactone-poly(ethylene glycol) (PEG-Acetal-PCL-PEG) and modified with cRGD and triphenylphosphine (TPP) on a long PEG chain and a short PEG chain, respectively. The as-designed micelle system features effective BBB penetration through cRGD-mediated transcytosis. Once entering the ischemic brain tissues and endocytosed by microglia, the long PEG shell can be detached from the micelles in the acidic lysosomes, subsequently exposing TPP to target mitochondria. Thus, the micelles can effectively alleviate oxidative stress and inflammation by enhanced delivery of resveratrol to microglia mitochondria, reversing the microglia phenotype through the scavenging of ROS. This work offers a promising strategy to treat ischemia-reperfusion injury.


Assuntos
AVC Isquêmico , Micelas , Humanos , Espécies Reativas de Oxigênio , Acetais , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Polímeros/uso terapêutico , Polietilenoglicóis/uso terapêutico , Estresse Oxidativo , Inflamação/tratamento farmacológico
17.
Nano Lett ; 23(20): 9609-9617, 2023 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-37843362

RESUMO

Lithium (Li) dendrite growth in a routine carbonate electrolyte (RCE) is the main culprit hindering the practical application of Li metal anodes. Herein, we realize the regulation of the LiPF6 decomposition pathway in RCE containing 1.0 M LiPF6 by introducing a "self-polymerizing" additive, ethyl isothiocyanate (EITC), resulting in a robust LiF-rich solid electrolyte interphase (SEI). The effect of 1 vol % EITC on the electrode/electrolyte interfacial chemistry slows the formation of the byproduct LixPOFy. Such a LiF-rich SEI with EITC polymer winding exhibits a high Young's modulus and a uniform Li-ion flux, which suppresses dendrite growth and interface fluctuation. The EITC-based Li metal cell using a Li4Ti5O12 cathode delivers a capacity retention of 81.4% over 1000 cycles at 10 C, outperforming its counterpart. The cycling stability of 1 Ah pouch cells was further evaluated under EITC. We believe that this work provides a new method for tuning the interfacial chemistry of Li metal through electrolyte additives.

18.
Nano Lett ; 23(11): 4908-4915, 2023 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-37216428

RESUMO

The electrocatalytic conversion of polysulfides is crucial to lithium-sulfur batteries and mainly occurs at triple-phase interfaces (TPIs). However, the poor electrical conductivity of conventional transition metal oxides results in limited TPIs and inferior electrocatalytic performance. Herein, a TPI engineering approach comprising superior electrically conductive layered double perovskite PrBaCo2O5+δ (PBCO) is proposed as an electrocatalyst to boost the conversion of polysulfides. PBCO has superior electrical conductivity and enriched oxygen vacancies, effectively expanding the TPI to its entire surface. DFT calculation and in situ Raman spectroscopy manifest the electrocatalytic effect of PBCO, proving the critical role of enhanced electrical conductivity of this electrocatalyst. PBCO-based Li-S batteries exhibit an impressive reversible capacity of 612 mAh g-1 after 500 cycles at 1.0 C with a capacity fading rate of 0.067% per cycle. This work reveals the mechanism of the enriched TPI approach and provides novel insight into designing new catalysts for high-performance Li-S batteries.

19.
J Environ Manage ; 360: 121155, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38761624

RESUMO

The establishment of large hydropower stations in the main stream poses a threat to fish habitats. Selecting suitable tributaries as alternative habitats is a practical measure for ecological environment protection during large hydropower station's construction. The small dams constructed on certain tributaries need to be removed in order to restore river connectivity. The removal of dams will activate hydro-sedimentary dynamics and change the original habitat in terms of topography and hydrodynamics. To explore the evolution of fish habitats following the removal of small dams, a dam-removed reach of a habitat-alternative tributary was selected as the research object, and the model of water-sediment transport and riverbed evolution in strongly disturbed dam-removed reaches and the model of fish habitat suitability evaluation were established. The key parameters calibration and model verification were completed by field monitoring results. The simulation results showed dramatic evolution in the reservoir riverbed in the initial stage after dam removal and during the high discharge period. One year after dam removal, there was a noticeable 4.0 m incision in front of the dam, along with a decrease in channel slope at the dam site from about 4.8% to approximately 1.5%. Downstream of the dam, alterations to the riverbed were mainly concentrated near the dam, and sedimentary bodies with a height of around 2.0 m have formed on the left bank following the high discharge period. The fish habitat in most areas of the dam-removed reach was suitable, except for the downstream high-velocity area. To compare the evolution process of fish habitat under two dam removal periods in wet and dry seasons, two dam removal schemes were implemented in March and June. The results showed that the riverbed evolved more gradually in the March scheme, creating a larger and continuous suitable habitat for fish. Therefore, the March scheme was recommended. By revealing the evolutionary pattern of fish habitat after dam removal, this research provides a reliable model for assessing and restoring habitats in dam-removed reaches, and enjoys significant implications for protecting river ecology in hydropower development reaches.


Assuntos
Ecossistema , Rios , Animais , Peixes , Centrais Elétricas , Conservação dos Recursos Naturais
20.
Molecules ; 29(2)2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38257252

RESUMO

Dianthus superbus L. has been extensively studied for its potential medicinal properties in traditional Chinese medicine and is often consumed as a tea by traditional folk. It has the potential to be exploited in the treatment of inflammation, immunological disorders, and diabetic nephropathy. Based on previous studies, this study continued the separation of another subfraction of Dianthus superbus and established reversed-phase/reversed-phase and reversed-phase/hydrophilic (RPLC) two-dimensional (2D) high-performance liquid chromatography (HPLC) modes, quickly separating two C-glycosylflavones, among which 2″-O-rhamnosyllutonarin was a new compound and isomer with 6‴-O-rhamnosyllutonarin. This is the first study to investigate the effects of 2″-O-rhamnosyllutonarin and 6‴-O-rhamnosyllutonarin on cellular glucose metabolism in vitro. First, molecular docking was used to examine the effects of 2″-O-rhamnosyllutonarin and 6″-O-rhamnosyllutonarin on AKT and AMPK; these two compounds exhibited relatively high activity. Following this, based on the HepG2 cell model of insulin resistance, it was proved that both of the 2″-O-rhamnosyllutonarin and 6‴-O-rhamnosyllutonarin demonstrated substantial efficacy in ameliorating insulin resistance and were found to be non-toxic. Simultaneously, it is expected that the methods developed in this study will provide a basis for future studies concerning the separation and pharmacological effects of C-glycosyl flavonoids.


Assuntos
Dianthus , Resistência à Insulina , Simulação de Acoplamento Molecular , Metabolismo dos Carboidratos , Glucose
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