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Background: Atherosclerosis (AS) is a chronic arterial pathology and a leading cause of vascular disease-related mortality. Fatty streaks in the arterial wall develop into atherosclerosis and characteristic plaques. Clinical interventions typically involve lipid-lowering medications and drugs for stabilizing vulnerable plaques, but no direct therapeutic agent specifically targets atherosclerosis. Garlic, also locally known as DASUAN, is recognized as a widely sold herbal dietary supplement esteemed for its cardiovascular benefits. However, the specific mechanisms of garlic's anti-atherosclerotic effects remain unclear. Aims: This study aims to elucidate the pharmacological mechanisms through which garlic ameliorates atherosclerosis. Methods: The study identified the major active components and targets of garlic by screening the TCMSP, TCM-ID, and, ETCM databases. Atherosclerosis-associated targets were obtained from the DisGeNET, GeneCards, and DiGSeE databases, and garlic intervention targets were determined through intersection. Utilizing the intersected genes, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using R software. A garlic component-disease target network was constructed using Cytoscape. RNA-seq datasets from the GEO database were utilized to identify differentially expressed genes (DEGs) associated with atherosclerosis. The target genes were intersected with DEGs and the FerrDb (ferroptosis database). Molecular docking predicted the binding interactions between active components and the core targets. In vitro and in vivo experiments validated the identified core targets. Results: The integration of garlic drug targets with atherosclerotic disease targets identified 230 target genes. Intersection with RNA-seq DEGs revealed 15 upregulated genes, including 8 target genes related to ferroptosis. Molecular docking indicated favorable affinities between garlic active components [Sobrol A, (+)-L-Alliin, Benzaldoxime, Allicin] and target genes (DPP4, ALOX5, GPX4). Experimental validation showed that GARLIC reduces the expression of ferroptosis-related genes in AS, suggesting its therapeutic potential through the regulation of ferroptosis. Conclusion: Garlic ameliorates atherosclerosis by targeting intra-plaque ferroptosis and reducing lipid peroxidation. These findings provide novel insights into the pharmacological mechanisms underlying the efficacy of garlic in treating AS.
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Total astragalus saponins (TAS) are the main active components of astragali radix, and have potent anti-hepatic fibrosis effect. However, the therapeutic efficacy of TAS and their potential mechanisms in the treatment of primary sclerosing cholangitis (PSC) remain unclear. In this study, two mouse models of PSC, including 3,5-Diethoxycarbonyl-1,4-Dihydro-2,4,6-Collidine (DDC)-induced PSC and Mdr2-/- spontaneous PSC, and the Tgr5-/- mice were used to investigate the therapeutic effect and mechanisms of TAS. Treatment with TAS, particularly with a dose of 56 mg/kg, significantly ameliorated the PSC-related liver injury, cholestasis, collagen deposition, ductular reaction (DR), and fibrosis in the DDC-induced and Mdr2-/-spontaneous PSC mice. Furthermore, treatment with TAS significantly mitigated the PSC-related inflammatory responses in vivo and HIBEpiC cells by inhibiting the expression of TNF-α, IL-6, and IL-1ß. Mechanistically, treatment with TAS rescued the PSC-decreased hepatic TGR5 expression to attenuate the NF-κB p65 phosphorylation. Notably, the therapeutic efficacy of TAS on PSC in DDC-induced mice was abrogated in Tgr5-/- mice, suggesting the anti-PSC effect of TAS may depend on enhancing TGR5 expression. In conclusion, TAS ameliorated DR, inflammation and liver fibrosis in both models of PSC mice by rescuing TGR5 expression. Our findings may aid in the design of new therapeutic strategies for the treatment of PSC.
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Background: Bile acids (BAs), products of gut microbiota metabolism, have long been implicated in atherosclerotic disease pathogenesis. Characterizing the serum bile acid profile and exploring its potential role in carotid atherosclerosis (CAS) development are crucial tasks. Methods: In this study, we recruited 73 patients with CAS as the disease group and 77 healthy individuals as the control group. We systematically measured the serum concentrations of 15 bile acids using ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression were applied to analyze the impact of bile acids on the disease and select the key BAs. The possible molecular mechanism was elucidated by network pharmacology. Results: (1) The BA profile of patients with CAS significantly differed. (2) Multifactorial logistic regression analysis identified elevated levels of GCDCA (OR: 1.01, P < 0.001), DCA (OR: 1.01, P = 0.005), and TDCA (OR: 1.05, P = 0.002) as independent risk factors for CAS development. Conversely, GCA (OR: 0.99, P = 0.020), LCA (OR: 0.83, P = 0.002), and GUDCA (OR: 0.99, P = 0.003) were associated with protective effects against the disease. GCA, DCA, LCA, and TDCA were identified as the four key BAs. (3) TNF, FXR, GPBAR1, ESR1 and ACE were predicted to be targets of BAs against AS. These four BAs potentially impact AS progression by triggering signaling pathways, including cAMP, PPAR, and PI3K-AKT pathways, via their targets. Conclusion: This study offers valuable insights into potential therapeutic strategies for atherosclerosis that target bile acids.
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Ácidos e Sais Biliares , Doenças das Artérias Carótidas , Metabolômica , Farmacologia em Rede , Humanos , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/sangue , Masculino , Feminino , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças das Artérias Carótidas/sangue , Pessoa de Meia-Idade , Metabolômica/métodos , Idoso , Estudos de Casos e Controles , Biomarcadores/sangue , Receptores Acoplados a Proteínas G/metabolismo , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: Employing network pharmacology and molecular docking, the study predicts the active compounds in garlic and elucidates their mechanism in inhibiting the development of alcoholic liver disease (ALD). ALD is a global chronic liver disease with potential for hepatocellular carcinoma progression. METHODS: The main active ingredients and targets of garlic were identified through screening the TCMSP, TCM-ID, and ETCM databases. ALD disease targets were sourced from DisGeNET, GeneCards, and DiGSeE databases, and intervention targets for garlic were determined through intersections. Protein interaction networks were constructed using the STRING platform, and GO and KEGG pathway enrichment analyses were performed with R software. The garlic component-disease-target network was established using Cytoscape software. Validation of active ingredients against core targets was conducted through molecular docking simulations using AutoDock Vina software. Expression validation of core targets was carried out using human sequencing data of ALD obtained from the GEO database. RESULTS: Integration of garlic drug targets with ALD disease targets identified 83 target genes. Validation through an alcohol-induced ALD mouse model supported certain network pharmacology findings, suggesting that garlic may impede disease progression by mitigating the inflammatory response and promoting ethanol metabolism. CONCLUSION: This study provides insights into the potential therapeutic mechanisms of garlic in inhibiting ALD development. The identified active ingredients offer promising avenues for further investigation and development of treatments for ALD, emphasizing the importance of botanical remedies in liver disease management.
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Background: Drug therapy for eye diseases has been limited by multiple protective mechanisms of the eye, which can be improved using well-designed drug delivery systems. Mesoporous silica nanoparticles (MSNs) had been used in many studies as carriers of therapeutic agents for ocular diseases treatment. However, no studies have focused on ocular biosafety. Considering that MSNs containing tetrasulfur bonds have unique advantages and have drawn increasing attention in drug delivery systems, it is necessary to explore the ocular biosafety of tetrasulfur bonds before their widespread application as ophthalmic drug carriers. Methods: In this study, hollow mesoporous silica nanoparticles (HMSNs) with different tetrasulfur bond contents were prepared and characterized. The ocular biosafety of HMSN-E was evaluated in vitro on the three selected ocular cell lines, including corneal epithelial cells, lens epithelial cells and retinal endothelial cells (HREC), and in vivo by using topical eye drops and intravitreal injections. Results: In cellular experiments, HMSNs caused obvious S content-dependent cytotoxic effect. HMSNs with the highest tetrasulfur bond content (HMSN-E), showed the highest cytotoxicity among all the HMSNs, and HREC was the most vulnerable cell to HMSN-E. It was shown that HMSN-E could react with intracellular GSH to generate H2S and decrease intracellular GSH concentration. Treatment of HREC with HMSN-E increased intracellular ROS, decreased mitochondrial membrane potential, and induced cell cycle arrest at the G1/S checkpoint, finally caused apoptosis and necrosis of HREC. Topical eye drops of HMSN-E could cause corneal damage. The intravitreal injection of HMSN-E could induce inflammation in the vitreum and ganglion cell layers, resulting in vitreous opacities and retinal abnormalities. Conclusion: The incorporation of tetrasulfur bonds into HMSN can have toxic effects on ocular tissues. Therefore, when mesoporous silica nanocarriers are designed for ophthalmic pharmaceuticals, the ocular toxicity of the tetrasulfur bonds should be considered.
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Nanopartículas , Dióxido de Silício , Humanos , Animais , Nanopartículas/química , Dióxido de Silício/química , Dióxido de Silício/toxicidade , Linhagem Celular , Porosidade , Portadores de Fármacos/química , Apoptose/efeitos dos fármacos , Coelhos , Sobrevivência Celular/efeitos dos fármacos , Olho/efeitos dos fármacos , Soluções Oftálmicas/química , Soluções Oftálmicas/farmacologia , Compostos de Organossilício/química , Compostos de Organossilício/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Injeções IntravítreasRESUMO
Estrogen is thought to have a role in slowing down aging and protecting cardiovascular and cognitive function. However, high doses of estrogen are still positively associated with autoimmune diseases and tumors with systemic inflammation. First, we administered exogenous estrogen to female mice for three consecutive months and found that the aorta of mice on estrogen develops inflammatory manifestations similar to Takayasu arteritis (TAK). Then, in vitro estrogen intervention was performed on mouse aortic vascular smooth muscle cells (MOVAS cells). Stimulated by high concentrations of estradiol, MOVAS cells showed decreased expression of contractile phenotypic markers and increased expression of macrophage-like phenotypic markers. This shift was blocked by tamoxifen and Krüppel-like factor 4 (KLF4) inhibitors and enhanced by Von Hippel-Lindau (VHL)/hypoxia-inducible factor-1α (HIF-1α) interaction inhibitors. It suggests that estrogen-targeted regulation of the VHL/HIF-1α/KLF4 axis induces phenotypic transformation of vascular smooth muscle cells (VSMC). In addition, estrogen-regulated phenotypic conversion of VSMC to macrophages is a key mechanism of estrogen-induced vascular inflammation, which justifies the risk of clinical use of estrogen replacement therapy.
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Estrogênios , Subunidade alfa do Fator 1 Induzível por Hipóxia , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like , Macrófagos , Músculo Liso Vascular , Proteína Supressora de Tumor Von Hippel-Lindau , Animais , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Feminino , Estrogênios/farmacologia , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Fenótipo , Aorta/patologia , Aorta/efeitos dos fármacos , Inflamação/metabolismoRESUMO
The ionic toxicity induced by salinization has adverse effects on the growth and development of crops. However, researches on ionic toxicity and salt tolerance in plants have focused primarily on cations such as sodium ions (Na+), with very limited studies on chloride ions (Cl-). Here, we cloned the homologous genes of Arabidopsis thaliana AtCLCc, GhCLCc-1A/D, from upland cotton (Gossypium hirsutum), which were significantly induced by NaCl or KCl treatments. Subcellular localization showed that GhCLCc-1A/D were both localized to the tonoplast. Complementation of Arabidopsis atclcc mutant with GhCLCc-1 rescued its salt-sensitive phenotype. In addition, the silencing of the GhCLCc-1 gene led to an increased accumulation of Cl- in the roots, stems, and leaves of cotton seedlings under salt treatments, resulting in compromised salt tolerance. And ectopic expression of the GhCLCc-1 gene in Arabidopsis reduced the accumulation of Cl- in transgenic lines under salt treatments, thereby enhancing salt tolerance. These findings elucidate that GhCLCc-1 positively regulates salt tolerance by modulating Cl- accumulation and could be a potential target gene for improving salt tolerance in plants.
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Canais de Cloreto , Gossypium , Proteínas de Plantas , Tolerância ao Sal , Arabidopsis/genética , Arabidopsis/metabolismo , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Cloretos/metabolismo , Regulação da Expressão Gênica de Plantas , Gossypium/genética , Gossypium/metabolismo , Gossypium/crescimento & desenvolvimento , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Tolerância ao Sal/genética , Cloreto de Sódio/metabolismoRESUMO
BACKGROUND: Surface-enhanced Raman scattering (SERS) technology have unique advantages of rapid, simple, and highly sensitive in the detection of serum, it can be used for the detection of liver cancer. However, some protein biomarkers in body fluids are often present at ultra-low concentrations and severely interfered with by the high-abundance proteins (HAPs), which will affect the detection of specificity and accuracy in cancer screening based on the SERS immunoassay. Clearly, there is a need for an unlabeled SERS method based on low abundance proteins, which is rapid, noninvasive, and capable of high precision detection and screening of liver cancer. RESULTS: Serum samples were collected from 60 patients with liver cancer (27 patients with stage T1 and T2 liver cancer, 33 patients with stage T3 and T4 liver cancer) and 40 healthy volunteers. Herein, immunoglobulin and albumin were separated by immune sorption and Cohn ethanol fractionation. Then, the low abundance protein (LAPs) was enriched, and high-quality SERS spectral signals were detected and obtained. Finally, combined with the principal component analysis-linear discriminant analysis (PCA-LDA) algorithm, the SERS spectrum of early liver cancer (T1-T2) and advanced liver cancer (T3-T4) could be well distinguished from normal people, and the accuracy rate was 98.5% and 100%, respectively. Moreover, SERS technology based on serum LAPs extraction combined with the partial least square-support vector machine (PLS-SVM) successfully realized the classification and prediction of normal volunteers and liver cancer patients with different tumor (T) stages, and the diagnostic accuracy of PLS-SVM reached 87.5% in the unknown testing set. SIGNIFICANCE: The experimental results show that the serum LAPs SERS detection combined with multivariate statistical algorithms can be used for effectively distinguishing liver cancer patients from healthy volunteers, and even achieved the screening of early liver cancer with high accuracy (T1 and T2 stage). These results showed that serum LAPs SERS detection combined with a multivariate statistical diagnostic algorithm has certain application potential in early cancer screening.
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Proteínas Sanguíneas , Neoplasias Hepáticas , Humanos , Análise Discriminante , Biomarcadores , Neoplasias Hepáticas/diagnóstico , Análise Espectral Raman/métodos , Análise de Componente PrincipalRESUMO
Histone H2B is a member of the core histones, which together with other histones form the nucleosome, the basic structural unit of chromosomes. As scientists delve deeper into histones, researchers gradually realize that histone H2B is not only an important part of nucleosomes, but also plays a momentous role in regulating gene transcription, acting as a receptor and antimicrobial action outside the nucleus. There are a variety of epigenetically modified sites in the H2B tail rich in arginine and lysine, which can occur in ubiquitination, phosphorylation, methylation, acetylation, etc. When stimulated by foreign factors such as bacteria, viruses or parasites, histone H2B can act as a receptor for the recognition of these pathogens, and induce an intrinsic immune response to enhance host defense. In addition, the extrachromosomal histone H2B is also an important anti-microorganism agent, which may be the key to the development of antibiotics in the future. This review aims to summarize the interaction between histone H2B and etiological agents and explore the role of H2B in epigenetic modifications, receptors and antimicrobial activity.
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Epigênese Genética , Histonas , Histonas/metabolismo , Humanos , Animais , Bactérias/metabolismo , Bactérias/genéticaRESUMO
As China's coal mines have transitioned to deep mining, the ground stress within the coal seams has progressively increased, resulting in reduced permeability and poor wetting ability of conventional wetting agents. Consequently, these agents have become inadequate in fulfilling the requirements for preventing washouts during deep mining operations. In response to the aforementioned challenges, a solution was proposed to address the issues by formulating a composite wetting agent. This composite wetting agent combines a conventional surfactant with a chelating agent called tetrasodium iminodisuccinate (IDS). By conducting a meticulous screening of surfactant monomer solutions, the ideal formulation for the composite wetting agent was determined by combining the monomer surfactant with IDS. Extensive testing, encompassing evaluations of the composite solution's apparent strain, contact angle measurements, and alterations in the oxygenated functional groups on the coal surface, led to the identification of the optimal composition. This composition consisted of IDS serving as the chelating agent and fatty alcohol polyoxyethylene ether (JFCS).Subsequent assessment of the physical and mechanical performance of the coal briquettes treated with the composite wetting agent revealed notable enhancements. These findings signify significant advancements in the field and hold promising implications. Following the application of the composite wetting agent, notable reductions were observed in the dry basis ash and dry basis full sulfur of coal. Additionally, the water content within the coal mass increased significantly, leading to a substantial enhancement in the wetting effect of the coal body. This enhanced wetting effect effectively mitigated the coal body's inclination towards impact, thereby offering technical support for optimizing water injection into coal seams and preventing as well as treating impact ground pressure.
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Nanotheranostic agents capable of simultaneously enabling real-time tracking and precise treatment at tumor sites play an increasingly pivotal role in the field of medicine. In this article, we report a novel near-infrared-II window (NIR-II) emitting downconversion rare-earth nanoparticles (RENPs) to improve image-guided therapy for breast cancer. The developed α-NaErF4@NaYF4 nanoparticles (α-Er NPs) have a diameter of approximately 24.1 nm and exhibit superior biocompatibility and negligible toxicity. RENPs exhibit superior imaging quality and photothermal conversion efficiency in the NIR-II range compared to clinically approved indocyanine green (ICG). Under 808 nm laser irradiation, the α-Er NPs achieve significant tumor imaging performance and photothermal effects in vivo in a mouse model of breast cancer. Simultaneously, it combines X-ray computed tomography (CT) and ultrasound (US) tri-modal imaging to guide therapy for cancer. The integration of NIR-II imaging technology and RENPs establishes a promising foundation for future medical applications.
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BACKGROUND: Atherosclerosis (AS) is a persistent inflammatory condition triggered and exacerbated by several factors including lipid accumulation, endothelial dysfunction and macrophages infiltration. Nobiletin (NOB) has been reported to alleviate atherosclerosis; however, the underlying mechanism remains incompletely understood. METHODS: This study involved comprehensive bioinformatic analysis, including multidatabase target prediction; GO and KEGG enrichment analyses for function and pathway exploration; DeepSite and AutoDock for drug binding site prediction; and CIBERSORT for immune cell involvement. In addition, target intervention was verified via cell scratch assays, oil red O staining, ELISA, flow cytometry, qRTâPCR and Western blotting. In addition, by establishing a mouse model of AS, it was demonstrated that NOB attenuated lipid accumulation and the extent of atherosclerotic lesions. RESULTS: (1) Altogether, 141 potentially targetable genes were identified through which NOB could intervene in atherosclerosis. (2) Lipid and atherosclerosis, fluid shear stress and atherosclerosis may be the dominant pathways and potential mechanisms. (3) ALB, AKT1, CASP3 and 7 other genes were identified as the top 10 target genes. (4) Six genes, including PPARG, MMP9, SRC and 3 other genes, were related to the M0 fraction. (5) CD36 and PPARG were upregulated in atherosclerosis samples compared to the normal control. (6) By inhibiting lipid uptake in RAW264.7 cells, NOB prevents the formation of foam cell. (7) In RAW264.7 cells, the inhibitory effect of oxidized low-density lipoprotein on foam cells formation and lipid accumulation was closely associated with the PPARG signaling pathway. (8) In vivo validation showed that NOB significantly attenuated intra-arterial lipid accumulation and macrophage infiltration and reduced CD36 expression. CONCLUSIONS: Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.
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Aterosclerose , Flavonas , PPAR gama , Animais , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Macrófagos , Células Espumosas , Lipoproteínas LDL/farmacologia , Antígenos CD36/genética , Antígenos CD36/metabolismoRESUMO
Objective: This study aimed to evaluate the SpO2 (transcutaneous oxygen saturation) -mortality link in elderly T2DM (diabetes mellitus type 2) patients with cerebral infarction and identify their optimal SpO2 range. Methods: In this investigation, we employed a comprehensive approach. Initially, we screened the MIMIC-IV database, identifying elderly T2DM patients with cerebral infarction, utilizing specific ICD-9 and ICD-10 codes. We then harnessed the power of restricted cubic splines to craft a visual representation of the correlation between SpO2 and 1-year mortality. To enhance our analysis, we harnessed Cox multivariate regression, allowing us to compute adjusted hazard ratios (HR) accompanied by 95% confidence intervals (CIs). Additionally, we crafted Cumulative Mortality Curve analyses, augmenting our study by engaging in rigorous subgroup analyses, stratifying our observations based on pertinent covariates. Results: In this study, 448 elderly T2DM patients with cerebral infarction were included. Within 1-year post-discharge, 161 patients (35.94%) succumbed. Employing Restricted Cubic Spline analysis, a statistically significant U-shaped non-linear relationship between admission ICU SpO2 levels and 1-year mortality was observed (P-value < 0.05). Further analysis indicated that both low and high SpO2 levels increased the mortality risk. Cox multivariate regression analysis, adjusting for potential confounding factors, confirmed the association of low (≤94.5%) and high SpO2 levels (96.5-98.5%) with elevated 1-year mortality risk, particularly notably high SpO2 levels (>98.5%) [HR = 2.06, 95% CI: 1.29-3.29, P-value = 0.002]. The cumulative mortality curves revealed the following SpO2 subgroups from high to low cumulative mortality at the 365th day: normal levels (94.5% < SpO2 ≤ 96.5%), low levels (SpO2 ≤ 94.5%), high levels (96.5% < SpO2 ≤ 98.5%), and notably high levels (>98.5%). Subgroup analysis demonstrated no significant interaction between SpO2 and grouping variables, including Sex, Age, Congestive heart failure, Temperature, and ICU length of stay (LOS-ICU; P-values for interaction were >0.05). Conclusions: Striking an optimal balance is paramount, as fixating solely on lower SpO2 limits or neglecting high SpO2 levels may contribute to increased mortality rates. To mitigate mortality risk in elderly T2DM patients with cerebral infarction, we recommend maintaining SpO2 levels within the range of 94.5-96.5%.
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In vivo near infrared (NIR) fluorescence imaging and laser speckle contrast imaging (LSCI) are emerging optical bioimaging modalities, which can provide information on blood vessels morphology, volume and the blood flow velocity. Optical tissue clearing (OTC) technique addresses a light scattering problem in optical bioimaging, which is imperative for the transcranial brain imaging. Herein, we report an approach combining NIR fluorescence and LSC microscopy imaging with OTC. A liposomal nanoformulation comprising NIR fluorescent dye ICG and photosensitizer BPD was synthesized and injected intravenously into mouse with OTC treated skull. Transcranial excitation of BPD in nanoliposomes resulted in the localized, irradiation dose dependent photodynamic damage of the brain blood vessels, which was manifested both in NIR fluorescence and LSC transcranial imaging, revealing changes in the vessels morphology, volume and the blood flow rate. The developed approach allows for bimodal imaging guided, localized vascular PDT of cancer and other diseases.
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The significance of water culture in addressing water crises and ensuring water security has garnered considerable attention, emerging as a focal point in global change and water science research. Water culture is a societal adaptation to changes in hydrological systems. However, this needs to be acknowledged within contemporary discourse on water security governance. This study utilized historical policy document data from many sources, including local municipal records from Shaanxi and Gansu, and water conservancy records. It aimed to identify the significant nodes and stages of policy transformation in the Weihe River Basin (WRB) during the last century (1949-2020). This study employed a content analysis method to elucidate the evolutionary patterns of water culture in the study region during the previous century. Drawing on the co-evolution framework, our investigation delved into the reciprocal relationship between changes in water culture and the evolution of water security in the WRB. Our findings indicated that water culture transformation in the WRB has undergone four significant stages: the Disaster-Resistant Hydraulic (1949-1966), Irrigation Hydraulic (1967-1998), Resources Hydraulic (1999-2010), and Ecological Hydraulic (2011-2020) phases. Water security assessment showed that policy attention varied across the different stages. The disaster-resistant hydraulic phase primarily addressed water-related disaster concerns, whereas the irrigation hydraulic phase emphasized the scarcity of water resources. The resource hydraulic phase focused on ensuring the security of the water environment, while the ecological hydraulic phase placed emphasis on safeguarding water sustainability. Moreover, we found that prevailing water policies prioritize resolving isolated issues; however, water security is a multifaceted systemic matter that requires a comprehensive approach. This study has the potential to offer policy makers a more comprehensive and systematic perspective, enabling them to enhance their understanding of the underlying nature of the problems. Additionally, this study can assist in developing future water security policies.
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Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.
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Benzofuranos , Depsídeos , Ferroptose , Animais , Camundongos , Transdução de Sinais , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Hepatócitos/metabolismoRESUMO
Avulsion often occurs in the limb due to heavy shearing forces which not only damage skeletal muscle but also main vessels, resulting in life-threatening muscle ischemia and necrosis. Defining muscle activity is vital for surgical repair. Currently, the color, capacity of blood, contractibility, and consistency (4C) are the primary principles for evaluating the activities of torn muscles. Based on clinical experiences, this standard turns out to be delayed diagnosis, which is not defined by specific parameters. Recently, near-infrared (NIR) fluorescence probes emitting within the second near-infrared window (NIR-II, 1000-1700 nm) have been widely used for non-invasive optical imaging because the tissue absorption and autofluorescence in the NIR-II region are negligible, thus allowing deeper penetration depths with micrometer-scale spatial resolution in vivo. As pathogenesis and development of muscle necrosis, necrosis-related protein may participate in this procedure. There is promising future for NIR-II to be used in evaluating muscle activity in avulsion. A new approach is developed based on experiments with mice and large animals (swine). Myoblasts were incubated with indocyanine green (ICG) to identify the necrosis muscles. The model of extremity damaged muscle was established for the real-time visualization and detection of developed necrosis muscle field under new equipment, both in balb/c mice (female) and long-haired swines. A visible NIR-II/I imaging system was first used in a large animal injured skeletal muscle-related model. Our NIR-II/I imaging system is suitable for evaluating the normal and injured skeletal muscle ICG cycle and pointing to the necrotic skeletal muscle tissue. NIR-II imaging is superior to NIR-I imaging in estimating skeletal muscle, best with 1100 nm filter. NIR-II fluorescence with 1100 nm filter is suitable for analyzing the progress of necrosis muscle tissue, leading to a new approach for intraoperative evaluation.
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Corantes Fluorescentes , Verde de Indocianina , Camundongos , Feminino , Animais , Suínos , Imagem Óptica/métodos , Necrose/diagnóstico por imagem , Músculo Esquelético/diagnóstico por imagemRESUMO
Compact Cas9 nucleases hold great promise for therapeutic applications. Although several compact Cas9 nucleases have been developed, many genomic loci still could not be edited due to a lack of protospacer adjacent motifs (PAMs). We previously developed a compact SlugCas9 recognizing an NNGG PAM. Here we demonstrate that SlugCas9 displays comparable activity to SpCas9. We developed a simple phage-assisted evolution to engineer SlugCas9 for unique PAM requirements. Interestingly, we generated a SlugCas9 variant (SlugCas9-NNG) that could recognize an NNG PAM, expanding the targeting scope. We further developed a SlugCas9-NNG-based adenine base editor and demonstrated that it could be delivered by a single adeno-associated virus to disrupt PCSK9 splice donor and splice acceptor. These genome editors greatly enhance our ability for in vivo genome editing.
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Bacteriófagos , Sistemas CRISPR-Cas , Sistemas CRISPR-Cas/genética , Pró-Proteína Convertase 9 , Adenina , Endonucleases/genéticaRESUMO
Background: Contrast-induced acute kidney injury (CI-AKI) is considered to be the third leading cause of hospital-acquired kidney injury. Current studies mostly suggest that contrast agents mainly harm renal tubular epithelial cells, but we hypothesized that the development of CI-AKI should be the result of the interaction of renal vascular and tubular injury. Methods: First we constructed a CI-AKI mouse model and verified the success of the model by pathological injury and serum creatinine level. Immunohistochemistry, protein quantification and qRT-PCR were used to detect the location and level of expression of neutrophil extracellular traps (NETs) in the kidney. Then, we blocked the in vivo accumulation of NETs using GSK484 and DNase I and detected the expression of NETs and the damage of glomerular and peritubular capillaries. Results: We first identified the presence of NETs in CI-AKI mice, and NETs were mainly accumulated in glomeruli and peritubular capillaries. The expression of NETs was positively correlated with the severity of CI-AKI kidney. After inhibition of NETs release or promotion of NETs degradation by drugs, renal vascular endothelial cell injury was reduced and renal pathological changes and creatinine levels were reversed in CI-AKI mice. In addition, inhibition of NETs reduced apoptosis and pyroptosis of renal cells and attenuated inflammation in vivo. Conclusion: These findings suggest that NETs are involved in the development of CI-AKI by damaging glomerular and peritubular capillary endothelial cells. This study will provide a new strategy for clinical prevention and treatment of CI-AKI.