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1.
Front Bioeng Biotechnol ; 12: 1439846, 2024.
Article in English | MEDLINE | ID: mdl-39157447

ABSTRACT

Introduction: Mild stenosis [degree of stenosis (DS) < 50%] is commonly labeled as nonobstructive lesion. Some lesions remain stable for several years, while others precipitate acute coronary syndromes (ACS) rapidly. The causes of ACS and the factors leading to diverse clinical outcomes remain unclear. Method: This study aimed to investigate the hemodynamic influence of mild stenosis morphologies in different coronary arteries. The stenoses were modeled with different morphologies based on a healthy individual data. Computational fluid dynamics analysis was used to obtain hemodynamic characteristics, including flow waveforms, fractional flow reserve (FFR), flow streamlines, time-average wall shear stress (TAWSS), and oscillatory shear index (OSI). Results: Numerical simulation indicated significant hemodynamic differences among different DS and locations. In the 20%-30% range, significant large, low-velocity vortexes resulted in low TAWSS (<4 dyne/cm2) around stenoses. In the 30%-50% range, high flow velocity due to lumen area reduction resulted in high TAWSS (>40 dyne/cm2), rapidly expanding the high TAWSS area (averagely increased by 0.46 cm2) in left main artery and left anterior descending artery (LAD), where high OSI areas remained extensive (>0.19 cm2). Discussion: While mild stenosis does not pose any immediate ischemic risk due to a FFR > 0.95, 20%-50% stenosis requires attention and further subdivision based on location is essential. Rapid progression is a danger for lesions with 20%-30% DS near the stenoses and in the proximal LAD, while lesions with 30%-50% DS can cause plaque injury and rupture. These findings support clinical practice in early assessment, monitoring, and preventive treatment.

2.
Sci Total Environ ; 950: 175200, 2024 Aug 06.
Article in English | MEDLINE | ID: mdl-39117196

ABSTRACT

Comprehensive studies on the freeze-thaw (F-T) damage mechanism in siliceous slates are lacking. In this study, we investigated the evolutionary characteristics of F-T damage in siliceous slates. To this end, scanning electron microscopy, X-ray diffraction, X-ray fluorescence, and uniaxial compression tests were used to analyze the microstructure, phase composition, porosity, and macroscopic mechanical parameters of siliceous slate with varying initial water content during F-T cycles. The results revealed several insights. (1) The microstructure of siliceous slate undergoes significant change with respect to increasing water content and number of F-T cycles. The rock surface changed from smooth to rough, and the arrangement of the mineral particles changed from tight to loose. (2) More than 80 % of the contents of siliceous slate comprise oxygen, aluminum, silicon, potassium, and iron. In particular, siliceous slate comprises muscovite, quartz, clinochlore, and kaolinite. Both the clinochlore and kaolinite are unstable clay minerals. As clay minerals exhibit strong water absorption and expansion characteristics, kaolinite undergoes strong hydration reactions. Compared to rock samples without F-T cycles in the dry state, the clay mineral content of siliceous slate decreased by nearly 50 %, from 28.8 % to 15.5 %, after 30 F-T cycles in the saturated state. (3) The mechanical parameters of siliceous slates with varying water content decreased exponentially with the number of F-T cycles, while their porosity exhibited a positive correlation with the number of F-T cycles. The degree of deterioration in both increased with increasing water content. Both the number of F-T cycles and the initial water content were observed to wield a significant effect on the deterioration of siliceous slates. (4) The evolution curve of F-T load damage in siliceous slate exhibited characteristics of transitioning from gentle to concave and then to a convex stage of growth. Our results are expected to provide theoretical guidance for the evaluation and prevention of F-T disasters in cold regions.

3.
Langmuir ; 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39136319

ABSTRACT

When applied to extra-heavy oil, conventional polymer surfactants exhibit poor efficacy in reducing viscosity and have limited adaptability. In this work, a novel amphiphilic polymer named PAADB was prepared by incorporating 2-acryloylamino-2-methyl-1-propanesulfonic acid (AMPS), benzyldimethyl [2-[(1-oxoallyl) zoxy] propyl] ammonium chloride (DML), and poly(ethylene glycol) methyl ether acrylate (BEM) into the main chain of acrylamide through free radical polymerization. PAADB exhibited outstanding interfacial activity, water-phase thickening ability, and emulsifying performance. The critical micelle concentration of PAADB was approximately 2500 mg/L, with a viscosity of 84.69 mPa·s at 50 °C. Additionally, interfacial tension experienced a notable decrease from 46.53 to 14.56 mN/m. At an optimal concentration of 4000 mg/L, PAADB reduced the viscosity of extra-heavy oil by over 92% across various temperatures and by more than 93% for different types of extra-heavy oil. PAADB demonstrated excellent emulsification ability and emulsion stability, effectively dispersing crude oil to create water-in-oil droplets measuring 35.33 µm in size. Meanwhile, molecular dynamics simulations further unveiled the viscosity reduction mechanism of PAADB. The hydrophilic groups within PAADB molecules are regularly distributed on the water interface, while the hydrophobic groups infiltrate the oil molecules to form a stable interfacial film. PAADB and asphaltene spontaneously form a sandwich structure, reducing intermolecular forces and disrupting the interlayer structure of asphaltene molecules. In general, this novel amphiphilic polymer demonstrates broad applicability and potential in extra-heavy oil recovery, providing valuable insights for the development of new heavy oil viscosity reducers (HOVRs).

5.
Int J Biol Macromol ; 276(Pt 1): 133736, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38992543

ABSTRACT

Pea peptides can lead to degradation through oxidation, deamidation, hydrolysis, or cyclization during production, processing, and storage, which in turn limit their broader application. To stabilize pea peptides, this study employed spray drying technology to create a pea peptide micro-encapsule using maltodextrin, gum tragacanth, and pea peptides. Four key factors, including polysaccharide ratio, glycopeptide ratio, solid-liquid ratio, and inlet temperature, were optimized to enhance the antioxidant properties of the pea peptide micro-encapsule. The results indicated that the utilization of maltodextrin and gum tragacanth significantly improves the storage stability and antioxidant activity of pea peptides. Moreover, optimal storage stability for pea peptides was achieved with a polysaccharide ratio of 9:1, a glycopeptide ratio of 10:1, a solid-liquid ratio of 4:40, and an inlet temperature of 180 °C. After 60 days of storage, the encapsulated pea peptides maintained 70.22 %, 25.19 %, and 40.32 % for scavenging abilities to hydroxyl radical, superoxide anion, and ABTS radical, respectively. In contrast, the unencapsulated pea peptides showed a decline to 47.02 %, 0 %, and 24.46 % in the same antioxidant activities after storage. These findings underscore the potential of spray drying technology to enhance the functional properties of pea peptides for various applications.


Subject(s)
Free Radical Scavengers , Pea Proteins , Polysaccharides , Tragacanth , Free Radical Scavengers/chemistry , Polysaccharides/chemistry , Tragacanth/chemistry , Pea Proteins/chemistry , Peptides/chemistry , Antioxidants/chemistry , Pisum sativum/chemistry , Temperature , Free Radicals/chemistry , Drug Stability
6.
Neurochem Int ; 179: 105811, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39053771

ABSTRACT

Psychological stress induces neuroinflammatory responses, which are associated with the pathogenesis of various psychiatric disorders, such as posttraumatic stress disorder and anxiety. Osthole-a natural coumarin isolated from the seeds of the Chinese herb Cnidium monnieri-exerts anti-inflammatory and antioxidative effects on the central nervous system. However, the therapeutic benefits of osthole against psychiatric disorders remain largely unknown. We previously demonstrated that mice subjected to repeated social defeat stress (RSDS) in the presence of aggressor mice exhibited symptoms of posttraumatic stress disorder, such as social avoidance and anxiety-like behaviors. In this study, we investigated the therapeutic effects of osthole and the underlying molecular mechanisms. Osthole exerted therapeutic effects on cognitive behaviors, mitigating anxiety-like behaviors and social avoidance in a mouse model of RSDS. The anti-inflammatory response induced by the oral administration of osthole was strengthened through the upregulation of heme oxygenase-1 expression. The expression of PPARα was inhibited in mice subjected to RSDS. Nonetheless, osthole treatment reversed the inhibition of PPARα expression. We identified a positive correlation between heme oxygenase-1 expression and PPARα expression in osthole-treated mice. In conclusion, osthole has potential as a Chinese herbal medicine for anxiety disorders. When designing novel drugs for psychiatric disorders, researchers should consider targeting the activation of PPARα.

7.
Int J Biol Macromol ; 278(Pt 2): 134243, 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-39084422

ABSTRACT

The progress of modern medical technology has made artificial heart valve replacement an effective means to treat valvular disease, but the impact of cardiac function on patients after surgery is still a key issue. The purpose of this study was to construct the cirRNA-miRNA-mRNA network after artificial heart valve replacement in valvular disease patients, and to explore the regulatory mechanism related to MAPK1 protein, so as to reveal its potential role in affecting cardiac function. We downloaded cyclic cRNA expression profiles from the GEO database. Use the limma package to identify dec. WGCNA is used to identify key modules of circular rna. The target miRNAs of circular rna and the corresponding target genes of miRNAs were screened by ring intertome and target scan database. GO and KEGG analysis using the DAVID database. The genes associated with iron sag disease were derived from FerrDb database. The overlapping genes were obtained by Wien analysis. Next, the CircrNa-mirNa-mrna network was constructed based on the circRNA-miRNA pair and miRNA-mRNA pair and their cyclic landscape software. This study revealed the changes in the structure and expression of MAPK1 protein in the cirRNA-miRNA-mRNA network after artificial heart valve replacement in valvular disease patients, suggesting the potential role of MAPK1 protein in regulating cardiac function, and laying a foundation for further revealing its mechanism and clinical application.

8.
Angew Chem Int Ed Engl ; : e202410392, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39078407

ABSTRACT

The poor electrochemical stability window and low ionic conductivity in solid-state electrolytes hinder the development of safe, high-voltage, and energy-dense lithium metal batteries. Herein, taking advantage of the unique electronic effect of nitrile groups, we designed a novel azanide-based single-ion covalent organic framework (CN-iCOF) structure that possesses effective Li+ transport and high-voltage stability in lithium metal batteries. Density functional theory (DFT) calculations and molecular dynamics (MD) revealed that electron-withdrawing nitrile groups not only resulted in an ultralow HOMO energy orbital but also enhanced Li+ dissociation through charge delocalization, leading to a high tLi+ of 0.93 and remarkable oxidative stability up to 5.6 V (vs. Li+/Li) simultaneously. Moreover, cyanation leveraging Strecker reaction transformed reversible imine-linkage to a stable sp3-carbon-containing azanide anion, which facilitated contorted alignment of transport "ladders" along the one-dimensional anionic channels and the ionic conductivity could reach 1.33 × 10-5 S cm-1 at ambient temperature without any additives. As a result, CN-iCOF allowed operation of solid-state lithium metal batteries with high-voltage cathodes such as LiNi0.8Mn0.1Co0.1O2 (NCM811), demonstrating stable lithium deposition up to 1,100 h and reversible battery cycling at ambient temperature up to 4.5 V, shedding light on the importance of discovering new functionality for forthcoming high-performance batteries.

9.
Plant Physiol Biochem ; 214: 108940, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39024781

ABSTRACT

Plant growth is severely harmed by cadmium (Cd) contamination, while the addition of zinc (Zn) can reduce the toxic effects of Cd. However, the interaction between Cd and Zn on the molecular mechanism and cell wall of Cosmosbipinnatus is unclear. In this study, a transcriptome was constructed using RNA-sequencing. In C. bipinnatus root transcriptome data, the expression of 996, 2765, and 3023 unigenes were significantly affected by Cd, Zn, and Cd + Zn treatments, respectively, indicating different expression patterns of some metal transporters among the Cd, Zn, and Cd + Zn treatments. With the addition of Zn, the damage to the cell wall was reduced, both the proportion and content of polysaccharides in the cell wall were changed, and Cd accumulation was decreased by 32.34%. In addition, we found that Cd and Zn mainly accumulated in pectins, the content of which increased by 30.79% and 61.4% compared to the CK treatment. Thus, Zn could alleviate the toxicity of Cd to C. bipinnatus. This study revealed the interaction between Cd and Zn at the physiological and molecular levels, broadening our understanding of the mechanisms of tolerance to Cd and Zn stress in cosmos.


Subject(s)
Cadmium , Cell Wall , Zinc , Cadmium/toxicity , Zinc/metabolism , Zinc/toxicity , Zinc/pharmacology , Cell Wall/metabolism , Cell Wall/drug effects , Transcriptome/drug effects , Gene Expression Profiling , Gene Expression Regulation, Plant/drug effects , Plant Roots/drug effects , Plant Roots/metabolism , Plant Roots/genetics
10.
Angew Chem Int Ed Engl ; : e202409744, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39058330

ABSTRACT

Alternating copolymers are crucial for diverse applications. While dispersity (Ɖ, also known as molecular weight distribution, MWD) influences the properties of polymers, achieving low dispersities in alternating copolymers poses a notable challenge via free radical polymerizations (FRPs). In this work, we demonstrated an unexpected discovery that dispersities are affected by the participation of charge transfer complexes (CTCs) formed between monomer pairs during free radical alternating copolymerization, which have inspired the successful synthesis of various alternating copolymers with low dispersities (>30 examples, Ɖ = 1.13-1.39) under visible-light irradiation. The synthetic method is compatible with binary, ternary and quaternary alternating copolymerizations and is expandable for both fluorinated and non-fluorinated monomer pairs. DFT calculations combined with model experiments indicated that CTC-absent reaction exhibits higher propagation rates and affords fewer radical terminations, which could contribute to low dispersities. Based on the integration of Monte Carlo simulation and Bayesian optimization, we established the relationship map between FRP parameter space and dispersity, further suggested the correlation between low dispersities and higher propagation rates. Our research sheds light on dispersity control via FRPs and creates a novel platform to investigate polymer dispersity through machine learning.

11.
JMIR Public Health Surveill ; 10: e54485, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38848124

ABSTRACT

This study demonstrated that fibrinogen is an independent risk factor for 10-year mortality in patients with acute coronary syndrome (ACS), with a U-shaped nonlinear relationship observed between the two. These findings underscore the importance of monitoring fibrinogen levels and the consideration of long-term anti-inflammatory treatment in the clinical management of patients with ACS.


Subject(s)
Acute Coronary Syndrome , Fibrinogen , Humans , Acute Coronary Syndrome/mortality , Acute Coronary Syndrome/blood , Fibrinogen/analysis , Male , Female , Prospective Studies , Middle Aged , Aged , Risk Factors , Biomarkers/blood
12.
Circulation ; 149(25): 2002-2020, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38885303

ABSTRACT

Myocardial infarction is a cardiovascular disease characterized by a high incidence rate and mortality. It leads to various cardiac pathophysiological changes, including ischemia/reperfusion injury, inflammation, fibrosis, and ventricular remodeling, which ultimately result in heart failure and pose a significant threat to global health. Although clinical reperfusion therapies and conventional pharmacological interventions improve emergency survival rates and short-term prognoses, they are still limited in providing long-lasting improvements in cardiac function or reversing pathological progression. Recently, cardiac patches have gained considerable attention as a promising therapy for myocardial infarction. These patches consist of scaffolds or loaded therapeutic agents that provide mechanical reinforcement, synchronous electrical conduction, and localized delivery within the infarct zone to promote cardiac restoration. This review elucidates the pathophysiological progression from myocardial infarction to heart failure, highlighting therapeutic targets and various cardiac patches. The review considers the primary scaffold materials, including synthetic, natural, and conductive materials, and the prevalent fabrication techniques and optimal properties of the patch, as well as advanced delivery strategies. Last, the current limitations and prospects of cardiac patch research are considered, with the goal of shedding light on innovative products poised for clinical application.


Subject(s)
Myocardial Infarction , Humans , Myocardial Infarction/therapy , Myocardial Infarction/physiopathology , Animals , Tissue Scaffolds
13.
Front Biosci (Landmark Ed) ; 29(6): 233, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38940043

ABSTRACT

BACKGROUND: This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated by TIG1 in melanoma cells and its impact on cell growth. METHODS: The effects of TIG1 expression on cell viability and death were assessed using water-soluble tetrazolium 1 (WST-1) mitochondrial staining and lactate dehydrogenase release assays. RNA sequencing and Western blot analysis were employed to investigate the genes regulated by TIG1 in melanoma cells. Additionally, the correlation between TIG1 expression and its downstream genes was analyzed in a melanoma tissue array. RESULTS: TIG1 expression in melanoma cells was associated with decreased cell viability and increased cell death. RNA-sequencing (RNA-seq), quantitative reverse transcription PCR (reverse RT-QPCR), and immunoblots revealed that TIG1 expression induced the expression of Endoplasmic Reticulum (ER) stress response-related genes such as Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (HERPUD1), Binding immunoglobulin protein (BIP), and DNA damage-inducible transcript 3 (DDIT3). Furthermore, analysis of the melanoma tissue array revealed a positive correlation between TIG1 expression and the expression of HERPUD1, BIP, and DDIT3. Additionally, attenuation of the ER stress response in melanoma cells weakened the impact of TIG1 on cell growth. CONCLUSIONS: TIG1 expression effectively hinders the growth of melanoma cells. TIG1 induces the upregulation of ER stress response-related genes, leading to an increase in caspase-3 activity and subsequent cell death. These findings suggest that the ability of retinoic acid to prevent melanoma formation may be associated with the anticancer effect of TIG1.


Subject(s)
Cell Survival , Endoplasmic Reticulum Stress , Gene Expression Regulation, Neoplastic , Melanoma , Humans , Endoplasmic Reticulum Stress/genetics , Endoplasmic Reticulum Stress/drug effects , Melanoma/genetics , Melanoma/metabolism , Melanoma/pathology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Cell Death/genetics , Apoptosis/genetics , Apoptosis/drug effects , Cell Proliferation/genetics , Cell Proliferation/drug effects , Membrane Proteins
14.
Angew Chem Int Ed Engl ; : e202408611, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38924225

ABSTRACT

Controlled radical copolymerizations present attractive avenues to obtain polymers with complicated compositions and sequences. In this work, we report the development of a visible-light-driven organocatalyzed controlled copolymerization of fluoroalkenes and acyclic N-vinylamides for the first time. The approach enables the on-demand synthesis of a broad scope of amide-functionalized main-chain fluoropolymers via novel fluorinated thiocarbamates, facilitating regulations over chemical compositions and alternating fractions by rationally selecting comonomer pairs and ratios. This method allows temporally controlled chain-growth by external light, and maintains high chain-end fidelity that promotes facile preparation of block sequences. Notably, the obtained F/N hybrid polymers, upon hydrolysis, afford free amino-substituted fluoropolymers versatile for post modifications toward various functionalities (e.g., amide, sulfonamide, carbamide, thiocarbamide). We further demonstrate the in situ formation of polymer networks with desirable properties as protective layers on lithium metal anodes, presenting a promising avenue for advancing lithium metal batteries.

15.
Angew Chem Int Ed Engl ; : e202407304, 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38898368

ABSTRACT

Controlling the structure and chemistry of solid electrolyte interphase (SEI) underpins the stability of electrolyte-electrode interface, and is crucial for advancing rechargeable lithium metal batteries (LMBs). Here, we utilized photo-controlled copolymerization to achieve the on-demand synthesis of fluorosulfonyl fluoropolymers as unprecedented artificial SEI layers on Li metal anodes. This work not only enables instant formation of a hybrid polymer-inorganic interphase that consists of a polymer-enriched top layer and a LiF-fortified bottom layer, originating from a single polymeric component, but also imparts various desirable physical properties (e.g., good mechanical strength and flexibility, high ion conductivity, low overpotential) to SEI via a single-to-divergent strategy. Model reactions and structural characterizations supported the formation of a divergent fluorinated interphase, which furnished prolonged stabilization of Li deposition, high coulombic efficiency and improved cycling behavior in electrochemical experiments. This work highlights the great potential of exploring reactive polymers as versatile coatings to stabilize Li metal anodes, providing a promising avenue to solve electrode-electrolyte interfacial problems for LMBs.

16.
Eur Heart J Digit Health ; 5(3): 219-228, 2024 May.
Article in English | MEDLINE | ID: mdl-38774374

ABSTRACT

Aims: Permanent pacemaker implantation and left bundle branch block are common complications after transcatheter aortic valve replacement (TAVR) and are associated with impaired prognosis. This study aimed to develop an artificial intelligence (AI) model for predicting conduction disturbances after TAVR using pre-procedural 12-lead electrocardiogram (ECG) images. Methods and results: We collected pre-procedural 12-lead ECGs of patients who underwent TAVR at West China Hospital between March 2016 and March 2022. A hold-out testing set comprising 20% of the sample was randomly selected. We developed an AI model using a convolutional neural network, trained it using five-fold cross-validation and tested it on the hold-out testing cohort. We also developed and validated an enhanced model that included additional clinical features. After applying exclusion criteria, we included 1354 ECGs of 718 patients in the study. The AI model predicted conduction disturbances in the hold-out testing cohort with an area under the curve (AUC) of 0.764, accuracy of 0.743, F1 score of 0.752, sensitivity of 0.876, and specificity of 0.624, based solely on pre-procedural ECG images. The performance was better than the Emory score (AUC = 0.704), as well as the logistic (AUC = 0.574) and XGBoost (AUC = 0.520) models built with previously identified high-risk ECG patterns. After adding clinical features, there was an increase in the overall performance with an AUC of 0.779, accuracy of 0.774, F1 score of 0.776, sensitivity of 0.794, and specificity of 0.752. Conclusion: Artificial intelligence-enhanced ECGs may offer better predictive value than traditionally defined high-risk ECG patterns.

17.
EuroIntervention ; 20(9): 536-550, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38726720

ABSTRACT

The identification and management of patients at high bleeding risk (HBR) undergoing transcatheter aortic valve implantation (TAVI) are of major importance, but the lack of standardised definitions is challenging for trial design, data interpretation, and clinical decision-making. The Valve Academic Research Consortium for High Bleeding Risk (VARC-HBR) is a collaboration among leading research organisations, regulatory authorities, and physician-scientists from Europe, the USA, and Asia, with a major focus on TAVI-related bleeding. VARC-HBR is an initiative of the CERC (Cardiovascular European Research Center), aiming to develop a consensus definition of TAVI patients at HBR, based on a systematic review of the available evidence, to provide consistency for future clinical trials, clinical decision-making, and regulatory review. This document represents the first pragmatic approach to a consistent definition of HBR evaluating the safety and effectiveness of procedures, devices and drug regimens for patients undergoing TAVI..


Subject(s)
Consensus , Hemorrhage , Transcatheter Aortic Valve Replacement , Humans , Transcatheter Aortic Valve Replacement/adverse effects , Risk Factors , Hemorrhage/etiology , Risk Assessment , Aortic Valve Stenosis/surgery , Aortic Valve/surgery
18.
Article in English | MEDLINE | ID: mdl-38745381

ABSTRACT

Tricuspid regurgitation is a common valve disease with high incidence and poor prognosis. For elderly patients and those with a history of open heart surgery, second thoracotomy and valve replacement carry a high risk. Transcatheter tricuspid valve replacement (TTVR) has become an alternative treatment for patients with high surgical risk. LuX-Valve is a novel self-expandable valve that does not rely on radial force to anchor the valve annulus. The preliminary results have been satisfactory, and this technology is gradually being adopted in China and around the world. Successful implementation of this technique depends on echocardiographic preoperative screening, intraoperative guidance, and postoperative follow-up. The purpose of this article is to provide a state-of-the-art review of the key points and technical considerations for preoperative screening, intraoperative guidance, and postoperative follow-up for TTVR.

19.
World J Stem Cells ; 16(5): 538-550, 2024 May 26.
Article in English | MEDLINE | ID: mdl-38817334

ABSTRACT

BACKGROUND: Thrombocytopenia 2, an autosomal dominant inherited disease characterized by moderate thrombocytopenia, predisposition to myeloid malignancies and normal platelet size and function, can be caused by 5'-untranslated region (UTR) point mutations in ankyrin repeat domain containing 26 (ANKRD26). Runt related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) have been identified as negative regulators of ANKRD26. However, the positive regulators of ANKRD26 are still unknown. AIM: To prove the positive regulatory effect of GATA binding protein 2 (GATA2) on ANKRD26 transcription. METHODS: Human induced pluripotent stem cells derived from bone marrow (hiPSC-BM) and urothelium (hiPSC-U) were used to examine the ANKRD26 expression pattern in the early stage of differentiation. Then, transcriptome sequencing of these iPSCs and three public transcription factor (TF) databases (Cistrome DB, animal TFDB and ENCODE) were used to identify potential TF candidates for ANKRD26. Furthermore, overexpression and dual-luciferase reporter experiments were used to verify the regulatory effect of the candidate TFs on ANKRD26. Moreover, using the GENT2 platform, we analyzed the relationship between ANKRD26 expression and overall survival in cancer patients. RESULTS: In hiPSC-BMs and hiPSC-Us, we found that the transcription levels of ANKRD26 varied in the absence of RUNX1 and FLI1. We sequenced hiPSC-BM and hiPSC-U and identified 68 candidate TFs for ANKRD26. Together with three public TF databases, we found that GATA2 was the only candidate gene that could positively regulate ANKRD26. Using dual-luciferase reporter experiments, we showed that GATA2 directly binds to the 5'-UTR of ANKRD26 and promotes its transcription. There are two identified binding sites of GATA2 that are located 2 kb upstream of the TSS of ANKRD26. In addition, we discovered that high ANKRD26 expression is always related to a more favorable prognosis in breast and lung cancer patients. CONCLUSION: We first discovered that the transcription factor GATA2 plays a positive role in ANKRD26 transcription and identified its precise binding sites at the promoter region, and we revealed the importance of ANKRD26 in many tissue-derived cancers.

20.
Zhongguo Zhong Yao Za Zhi ; 49(10): 2585-2596, 2024 May.
Article in Chinese | MEDLINE | ID: mdl-38812159

ABSTRACT

This study investigated the effects and mechanisms of total saponins of Panax japonicus(TSPJ) against liver injury induced by acetaminophen(APAP). Male Kunming mice were randomly divided into a blank control group, TSPJ group(200 mg·kg~(-1), ig), model group, APAP+ TSPJ low-dose group(50 mg·kg~(-1), ig), APAP+ TSPJ medium-dose group(100 mg·kg~(-1), ig), APAP+ TSPJ high-dose group(200 mg·kg~(-1), ig), and APAP+ N-acetyl-L-cysteine group(200 mg·kg~(-1), ip). The administration group received the corresponding medications via ig or ip once a day for 14 consecutive days. After the last administration for one hour, except for the blank control group and TSPJ group, all groups of mice were given 500 mg·kg~(-1) APAP by gavage. After 24 hours, mouse serum and liver tissue were collected for serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), reactive oxygen species(ROS), tumor necrosis factor alpha(TNF-α), interleukin-1 beta(IL-1ß), cyclooxygenase-2(COX-2), IL-6, IL-4, IL-10, as well as lactate dehydrogenase(LDH), glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and myeloperoxidase(MPO) liver tissue. Hematoxylin-eosin staining was used to observe the morphological changes of liver tissue. The mRNA expression levels of lymphocyte antigen 6G(Ly6G), galectin 3(Mac-2), TNF-α, IL-1ß, COX-2, IL-6, IL-4, and IL-10 in liver tissue were determined by quantitative real-time polymerase chain reaction(PCR). Western blot was utilized to detect the protein expression levels of Ly6G, Mac-2, extracellular regulated protein kinases(ERK), phosphorylated extracellular regulated protein kinases(p-ERK), COX-2, inhibitor of nuclear factor κB protein α(IκBα), phosphorylated inhibitor of nuclear factor κB protein α(p-IκBα), and nuclear factor-κB subunit p65(NF-κB p65) in cytosol and nucleus in liver tissue. The results manifested that TSPJ dramatically reduced liver coefficient, serum ALT, AST, ROS, TNF-α, IL-1ß, IL-6, and COX-2 levels, LDH, MPO, and MDA contents in liver tissue, and mRNA expressions of TNF-α, IL-1ß, and IL-6 in APAP-induced liver injury mice. It prominently elevated serum IL-4 and IL-10 levels, GSH, CAT, SOD, and T-AOC contents, and mRNA expressions of IL-4 and IL-10 in liver tissue, improved the degree of liver pathological damage, and suppressed neutrophil infiltration and macrophage recruitment in liver tissue. In addition, TSPJ lessened the mRNA and protein expressions of neutrophil marker Ly6G, macrophage marker Mac-2, and COX-2 in liver tissue, protein expressions of p-ERK, p-IκBα, and NF-κB p65 in nuclear, and p-ERK/ERK and p-IκBα/p-IκBα ratios and hoisted protein expression of NF-κB p65 in cytosol. These results suggest that TSPJ has a significant protective effect on APAP-induced liver injury in mice, and it can alleviate APAP-induced oxidative damage and inflammatory response. Its mechanism may be related to suppressing ERK/NF-κB/COX-2 signaling pathway activation, thus inhibiting inflammatory cell infiltration, cytokine production, and liver cell damage.


Subject(s)
Acetaminophen , Chemical and Drug Induced Liver Injury , Cyclooxygenase 2 , Liver , NF-kappa B , Panax , Saponins , Signal Transduction , Animals , Acetaminophen/adverse effects , Acetaminophen/toxicity , Mice , Panax/chemistry , Male , Saponins/pharmacology , Saponins/administration & dosage , NF-kappa B/genetics , NF-kappa B/metabolism , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/metabolism , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Liver/drug effects , Liver/metabolism , Signal Transduction/drug effects , Humans , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacology
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