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Biomaterials Sep 2024Vascular restenosis following angioplasty continues to pose a significant challenge. The heterocyclic trioxirane compound [1, 3, 5-tris((oxiran-2-yl)methyl)-1, 3,...
Vascular restenosis following angioplasty continues to pose a significant challenge. The heterocyclic trioxirane compound [1, 3, 5-tris((oxiran-2-yl)methyl)-1, 3, 5-triazinane-2, 4, 6-trione (TGIC)], known for its anticancer activity, was utilized as the parent ring to conjugate with a non-steroidal anti-inflammatory drug, resulting in the creation of the spliced conjugated compound BY1. We found that BY1 induced ferroptosis in VSMCs as well as in neointima hyperplasia. Furthermore, ferroptosis inducers amplified BY1-induced cell death, while inhibitors mitigated it, indicating the contribution of ferroptosis to BY1-induced cell death. Additionally, we established that ferritin heavy chain1 (FTH1) played a pivotal role in BY1-induced ferroptosis, as evidenced by the fact that FTH1 overexpression abrogated BY1-induced ferroptosis, while FTH1 knockdown exacerbated it. Further study found that BY1 induced ferroptosis by enhancing the NCOA4-FTH1 interaction and increasing the amount of intracellular ferrous. We compared the effectiveness of various administration routes for BY1, including BY1-coated balloons, hydrogel-based BY1 delivery, and nanoparticles targeting OPN loaded with BY1 (TOP@MPDA@BY1) for targeting proliferated VSMCs, for prevention and treatment of the restenosis. Our results indicated that TOP@MPDA@BY1 was the most effective among the three administration routes, positioning BY1 as a highly promising candidate for the development of drug-eluting stents or treatments for restenosis.
Topics: Ferroptosis; Animals; Muscle, Smooth, Vascular; Humans; Nanoparticles; Myocytes, Smooth Muscle; Male; Mice; Mice, Inbred C57BL; Oxidoreductases; Ferritins
PubMed: 38759485
DOI: 10.1016/j.biomaterials.2024.122613 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Feb 2024Hypoxia is a common pathological phenomenon, usually caused by insufficient oxygen supply or inability to use oxygen effectively. Hydroxylated and methoxylated...
OBJECTIVES
Hypoxia is a common pathological phenomenon, usually caused by insufficient oxygen supply or inability to use oxygen effectively. Hydroxylated and methoxylated flavonoids have significant anti-hypoxia activity. This study aims to explore the synthesis, antioxidant and anti-hypoxia activities of 6-hydroxygenistein (6-OHG) and its methoxylated derivatives.
METHODS
The 6-OHG and its methoxylated derivatives, including 4',6,7-trimethoxy-5-hydroxyisoflavone (compound 3), 4',5,6,7-tetramethoxyisoflavone (compound 4), 4',6-imethoxy-5,7-dihydroxyisoflavone (compound 6), and 4'-methoxy-5,6,7-trihydroxyisoflavone (compound 7), were synthesized by methylation, bromination, methoxylation, and demethylation using biochanin A as raw material. The structure of these products were characterized by hydrogen-nuclear magnetic resonance spectroscopy (H-NMR) and mass spectrometry (MS). The purity of these compounds was detected by high pressure chromatography (HPLC). The antioxidant activity in vitro was investigated by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) free radical scavenging assay. PC12 cells were divided into a normal group, a hypoxia model group, rutin (1×10-1×10 mol/L) groups, and target compounds (1×10-1×10 mol/L) groups under normal and hypoxic conditions. Cell viability was detected by cell counting kit-8 (CCK-8) assay, the target compounds with excellent anti-hypoxia activity and the drug concentration at the maximum anti-hypoxia activity were screened. PC12 cells were treated with the optimal concentration of the target compound or rutin with excellent anti-hypoxia activity, and the cell morphology was observed under light microscope. The apoptotic rate was determined by flow cytometry, and the expressions of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were detected by Western blotting.
RESULTS
The structure of 6-OHG and its 4 methylated derivatives were correct, and the purity was all more than 97%. When the concentration was 4 mmol/L, the DPPH free radical removal rates of chemical compounds 7 and 6-OHG were 81.16% and 86.94%, respectively, which were higher than those of rutin, the positive control. The removal rates of chemical compounds 3, 4, and 6 were all lower than 20%. Compared with the normal group, the cell viability of the hypoxia model group was significantly decreased (<0.01). Compared with the hypoxia model group, compounds 3, 4, and 6 had no significant effect on cell viability under hypoxic conditions. At all experimental concentrations, the cell viability of the 6-OHG group was significantly higher than that of the hypoxia model group (all <0.05). The cell viability of compound 7 group at 1×10 and 1×10 mol/L was significantly higher than that of the hypoxia model group (both <0.05). The anti-hypoxia activity of 6-OHG and compound 7 was excellent, and the optimal drug concentration was 1×10 and 1×10 mol/L. After PC12 cells was treated with 6-OHG (1×10 mol/L) and compound 7 (1×10 mol/L), the cell damage was reduced, the apoptotic rate was significantly decreased (<0.01), and the protein expression levels of HIF-1α and VEGF were significantly decreased in comparison with the hypoxia model group (both <0.01).
CONCLUSIONS
The optimized synthesis route can increase the yield of 6-OHG and obtain 4 derivatives by methylation and selective demethylation. 6-OHG and compound 7 have excellent antioxidant and anti-hypoxia activities, which are related to the structure of the A-ring ortho-triphenol hydroxyl group in the molecule.
Topics: Antioxidants; Rats; Animals; PC12 Cells; Methylation; Cell Hypoxia; Vascular Endothelial Growth Factor A; Isoflavones; Flavones
PubMed: 38755719
DOI: 10.11817/j.issn.1672-7347.2024.230228 -
Ophthalmology Science 2024To localize early capillary perfusion deficits in patients with diabetes mellitus (DM) without clinical diabetic retinopathy (DR) using averaged OCT angiography (OCTA).
PURPOSE
To localize early capillary perfusion deficits in patients with diabetes mellitus (DM) without clinical diabetic retinopathy (DR) using averaged OCT angiography (OCTA).
DESIGN
Retrospective cross-sectional study.
PARTICIPANTS
Patients with DM without DR and healthy controls.
METHODS
We measured perfusion deficits in the full retina, superficial capillary plexus (SCP), and deep capillary plexus (DCP) on averaged 3 × 3-mm OCTA images. Perfusion deficits were defined as the percentage of retinal tissue located >30 μm from blood vessels, excluding the foveal avascular zone (FAZ). One eye from each patient was selected based on image quality. We measured deficits in the parafoveal region, the 300 μm surrounding the FAZ, and 300 to 1000 μm surrounding the FAZ. If a capillary layer within one of these regions was significantly different in DM without DR compared with controls, we further characterized the location of perfusion deficit as periarteriolar, perivenular, or the capillaries between these 2 zones.
MAIN OUTCOME MEASURES
Location of increased perfusion deficits in patients with DM without DR compared with controls.
RESULTS
Sixteen eyes from 16 healthy controls were compared with 16 eyes from 16 patients with DM without DR (age 45.1 ± 10.7 and 47.4 ± 15.2 years respectively, = 0.64). Foveal avascular zone area and perfusion deficits in the entire parafovea and the 300 to 1000-μm ring around the FAZ were not significantly different between groups ( > 0.05 for all). Perfusion deficits in 300 μm around the FAZ were significantly increased in patients with DM without DR in full retinal thickness, SCP, and DCP ( < 0.05 for all). When analyzing the perivenular, periarteriolar, and capillary zones, only the perivenular DCP perfusion deficits were significantly increased (5.03 ± 2.92% in DM without DR and 2.73 ± 1.97% in controls, = 0.014).
CONCLUSIONS
Macular perfusion deficits in patients with DM without DR were significantly increased in the region nearest the FAZ, mainly at the perivenular deep capillaries. Further research on these early changes may improve our understanding of the capillaries most susceptible to vascular injury and disruption during diabetes.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38751454
DOI: 10.1016/j.xops.2024.100482 -
JACC. Cardiovascular Interventions May 2024Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve (BAV) stenosis is technically challenging and is burdened by an increased risk of...
BACKGROUND
Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve (BAV) stenosis is technically challenging and is burdened by an increased risk of paravalvular regurgitation (PVR).
OBJECTIVES
To identify the incidence, predictors, and clinical outcomes of PVR following TAVR in Sievers type 1 BAV stenosis.
METHODS
Consecutive patients with severe Sievers type 1 BAV stenosis undergoing TAVR with current generation transcatheter heart valves (THVs) in 24 international centres were enrolled. PVR was graded as none/trace, mild, moderate, and severe according to echocardiographic criteria. The endpoint of major adverse events (MAE), defined as a composite of all-cause death, stroke, or hospitalization for heart failure, was assessed at the last available follow-up.
RESULTS
A total of 946 patients were enrolled. PVR occurred in 423 patients (44.7%): mild, moderate, and severe in 387 (40.9%), 32 (3.4%), and 4 (0.4%) patients, respectively. Independent predictors of moderate or severe PVR were larger virtual raphe ring (VRR) perimeter (OR 1.07, 95% CI 1.02-1.13), severe annular or left ventricular outflow tract (LVOT) calcification (OR 5.21, 95% CI 1.45-18.77), self-expanding valve (OR 9.01, 95% CI 2.09-38.86), and intentional supra-annular THV positioning (OR 3.31, 95% CI 1.04-10.54). At a median follow-up of 1.3 [IQR 0.5-2.4] years, moderate or severe PVR was associated with an increased risk of MAE (HR 2.52, 95% CI 1.24-5.09).
CONCLUSIONS
After TAVR with current-generation THVs in Sievers type 1 BAV stenosis, moderate or severe PVR occurred in about 4% of cases and was associated with an increased risk of MAE during follow-up.
PubMed: 38749449
DOI: 10.1016/j.jcin.2024.05.002 -
The Plant Journal : For Cell and... May 2024Proline metabolism plays a crucial role in both environmental stress responses and plant growth. However, the specific mechanism by which proline contributes to abiotic...
Rhamnogalacturonan lyase 1 (RGL1), as a suppressor of E3 ubiquitin ligase Arabidopsis thaliana ring zinc finger 1 (AtRZF1), is involved in dehydration response to mediate proline synthesis and pectin rhamnogalacturonan-I composition.
Proline metabolism plays a crucial role in both environmental stress responses and plant growth. However, the specific mechanism by which proline contributes to abiotic stress processes remains to be elucidated. In this study, we utilized atrzf1 (Arabidopsis thaliana ring zinc finger 1) as a parental line for T-DNA tagging mutagenesis and identified a suppressor mutant of atrzf1, designated proline content alterative 31 (pca31). The pca31 mutant suppressed the insensitivity of atrzf1 to dehydration stress during early seedling growth. Using Thermal Asymmetric Interlaced-PCR, we found that the T-DNA of pca31 was inserted into the promoter region of the At2g22620 gene, which encodes the cell wall enzyme rhamnogalacturonan lyase 1 (RGL1). Enzymatic assays indicated that RGL1 exhibited rhamnogalacturonan lyase activity, influencing cell wall pectin composition. The decrease in RGL1 gene expression suppressed the transcriptomic perturbation of the atrzf1 mutant. Silencing of the RGL1 gene in atrzf1 resulted in a sensitive phenotype similar to pca31 under osmotic stress conditions. Treatment with mannitol, salt, hydrogen peroxide, and abscisic acid induced RGL1 expression. Furthermore, we uncovered that RGL1 plays a role in modulating root growth and vascular tissue development. Molecular, physiological, and genetic experiments revealed that the positive modulation of RGL1 during abiotic stress was linked to the AtRZF1 pathway. Taken together, these findings establish that pca31 acts as a suppressor of atrzf1 in abiotic stress responses through proline and cell wall metabolisms.
PubMed: 38743860
DOI: 10.1111/tpj.16808 -
Computed Tomography Angiography Characteristics of Thin-Cap Fibroatheroma in Patients With Diabetes.Journal of the American Heart... May 2024It was recently reported that thin-cap fibroatheroma (TCFA) detected by optical coherence tomography was an independent predictor of future cardiac events in patients...
BACKGROUND
It was recently reported that thin-cap fibroatheroma (TCFA) detected by optical coherence tomography was an independent predictor of future cardiac events in patients with diabetes. However, the clinical usefulness of this finding is limited by the invasive nature of optical coherence tomography. Computed tomography angiography (CTA) characteristics of TCFA have not been systematically studied. The aim of this study was to investigate CTA characteristics of TCFA in patients with diabetes.
METHODS AND RESULTS
Patients with diabetes who underwent preintervention CTA and optical coherence tomography were included. Qualitative and quantitative analyses were performed for plaques on CTA. TCFA was assessed by optical coherence tomography. Among 366 plaques in 145 patients with diabetes, 111 plaques had TCFA. The prevalence of positive remodeling (74.8% versus 50.6%, <0.001), low attenuation plaque (63.1% versus 33.7%, <0.001), napkin-ring sign (32.4% versus 11.0%, <0.001), and spotty calcification (55.0% versus 34.9%, <0.001) was significantly higher in TCFA than in non-TCFA. Low-density noncalcified plaque volume (25.4 versus 15.7 mm, <0.001) and remodeling index (1.30 versus 1.20, =0.002) were higher in TCFA than in non-TCFA. The presence of napkin-ring sign, spotty calcification, high low-density noncalcified plaque volume, and high remodeling index were independent predictors of TCFA. When all 4 predictors were present, the probability of TCFA increased to 82.4%.
CONCLUSIONS
The combined qualitative and quantitative plaque analysis of CTA may be helpful in identifying TCFA in patients with diabetes.
REGISTRATION INFORMATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194.
Topics: Humans; Male; Plaque, Atherosclerotic; Female; Computed Tomography Angiography; Tomography, Optical Coherence; Aged; Middle Aged; Coronary Artery Disease; Coronary Angiography; Coronary Vessels; Retrospective Studies; Predictive Value of Tests; Diabetes Mellitus; Vascular Calcification; Vascular Remodeling; Fibrosis
PubMed: 38742509
DOI: 10.1161/JAHA.123.033639 -
Materials Today. Bio Jun 2024The mechanical environment of vascular endothelial cells (ECs) encompasses a wide range of curvatures due to variations in blood vessel diameters. Integrins, key...
The mechanical environment of vascular endothelial cells (ECs) encompasses a wide range of curvatures due to variations in blood vessel diameters. Integrins, key mediators of cell-matrix interactions, establish connections between the extracellular matrix and the actin cytoskeleton, influencing diverse cellular behaviors. In this study, we explored the impact of spatial confinement on human umbilical vein ECs (HUVECs) cultured within three-dimensional hydrogel microgrooves of varying curvatures and the underlying role of integrins in mediating cellular responses. Employing maskless lithography, we successfully fabricated precise and wall curvatures-controlled hydrogel microgrooves, conferring spatial constraints on the cells. Our investigations revealed substantial alterations in HUVEC behavior within the hydrogel microgrooves with varying sidewall curvatures, marked by reduced cell size, enhanced orientation, and increased apoptosis. Interestingly, microgroove curvature emerged as a crucial factor influencing cell orientation and apoptosis, with rectangular microgrooves eliciting distinct changes in cell orientation, while ring-form microgrooves exhibited higher apoptosis rates. The side-wall effect in the 20 μm region near the microgroove wall had the greatest influence on cell orientation and apoptosis. HUVECs within the microgrooves exhibited elevated integrin expression, and inhibition of αV-integrin by cilengitide significantly curtailed cell apoptosis without affecting proliferation. Additionally, integrin-mediated cell traction force closely correlated with the spatial confinement effect. Cilengitide not only reduced integrin and focal adhesion expression but also attenuated cell traction force and cytoskeletal actin filament alignment. Overall, our findings elucidate the spatial confinement of ECs in hydrogel microgrooves and underscores the pivotal role of integrins, particularly αV-integrin, in mediating cell traction force and apoptosis within this microenvironment.
PubMed: 38736613
DOI: 10.1016/j.mtbio.2024.101074 -
International Journal of Biological... Jun 2024The reuse and development of natural waste resources is a hotspots and challenges in the research of new fiber materials and the resolution of environmental concern...
The reuse and development of natural waste resources is a hotspots and challenges in the research of new fiber materials and the resolution of environmental concern globally. Herein, this study aimed to develop a simple and direct manual extraction process to extract Musa core fibers (MCFs) for rapid water conduction and evaporation. Through simple processes such as ring cutting and stretching, this green and non-destructive inside-out extraction strategy enabled Musa fibers to be naturally and harmlessly degummed from natural Musa stems, with good maintenance of the fiber structure and highly helical morphology. The extracted fibers are composed of regularly and closely arranged cellulose nanofibrils in the shape of ribbon spirally arranged multi-filaments, and the single filament is about 2.65 μm. The high-purity fibers exhibit ultra-high tensile strength under a non-destructive extraction process, and the ultimate tensile strength in dry state is as high as 742.95 MPa. The tensile strength is affected by the number of fiber bundles, which shows that tensile strength and tensile modulus is higher than those of vascular bundle fibers in dry or wet condition. In addition, the MCFs membrane indicates good water conductivity, with a water absorption height of 50 mm for the sample in only 60 s. Moreover, the water evaporation rate of MCFs reaches 1.37 kg m h in 30 min, which shows that MCFs have excellent water conductivity and evaporation rate compared with ordinary cotton fibers. These results indicate that MCFs have great potential in replacing the use of chemical methods to extract fibers from vascular bundles, providing an effective way to achieve sustainability in quick-drying applications, as well as in the sustainable development of natural waste resources.
Topics: Water; Tensile Strength; Musa; Cellulose; Nanofibers
PubMed: 38734352
DOI: 10.1016/j.ijbiomac.2024.132276 -
Diagnostics (Basel, Switzerland) Apr 2024To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in age-related macular degeneration (AMD) when transitioning...
To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in age-related macular degeneration (AMD) when transitioning from various anti-VEGF treatments to faricimab, using optical coherence tomography angiography (OCTA). 25 eyes of 22 individuals who underwent intravitreal faricimab injections for neovascular AMD with type 1 MNV were included. OCTA images were obtained prior to (T0), after one (T1), and after three faricimab injections (T2); Noteworthy changes occurred in the first ring at T2 in comparison to T0. The percentage of CC flow deficit (FD%), FD average area (FDa), and FD number (FDn) in 5 rings (R1-R5) surrounding the dark halo around the MNV were calculated. A reduction in FD% at T2 compared to T0 (50.5 ± 10.2% at T0, 46.4 ± 10.6% at T2; = 0.020) was seen, indicating CC reperfusion. Additionally, we observed a reduction in the average FDa (140.2 ± 172.1% at T0, 93.7 ± 101.8% at T2; = 0.029). Our study highlights an FD% after three consecutive faricimab injections. The most pronounced effect was observed in the first ring, directly adjacent to the dark halo, suggesting a partial CC reperfusion surrounding the MNV, potentially indicating disease regression.
PubMed: 38732315
DOI: 10.3390/diagnostics14090901 -
JACC. Clinical Electrophysiology Jun 2024Desmin (DES) pathogenic variants cause a small proportion of arrhythmogenic cardiomyopathy (ACM). Outcomes data on DES-related ACM are scarce.
BACKGROUND
Desmin (DES) pathogenic variants cause a small proportion of arrhythmogenic cardiomyopathy (ACM). Outcomes data on DES-related ACM are scarce.
OBJECTIVES
This study sought to provide information on the clinical phenotype and outcomes of patients with ACM caused by pathogenic variants of the DES gene in a multicenter cohort.
METHODS
We collected phenotypic and outcomes data from 16 families with DES-related ACM from 10 European centers. We assessed in vitro DES aggregates. Major cardiac events were compared to historical controls with lamin A/C truncating variant (LMNA-tv) and filament C truncating variant (FLNC-tv) ACM.
RESULTS
Of 82 patients (54% males, median age: 36 years), 11 experienced sudden cardiac death (SCD) (n = 7) or heart failure death (HFd)/heart transplantation (HTx) (n = 4) before clinical evaluation. Among 68 survivors, 59 (86%) presented signs of cardiomyopathy, with left ventricular (LV) dominant (50%) or biventricular (34%) disease. Mean LV ejection fraction was 51% ± 13%; 36 of 53 had late gadolinium enhancement (ring-like pattern in 49%). During a median of 6.73 years (Q1-Q3: 3.55-9.52 years), the composite endpoint (sustained ventricular tachycardia, aborted SCD, implantable cardioverter-defibrillator therapy, SCD, HFd, and HTx) was achieved in 15 additional patients with HFd/HTx (n = 5) and SCD/aborted SCD/implantable cardioverter-defibrillator therapy/sustained ventricular tachycardia (n = 10). Male sex (P = 0.004), nonsustained ventricular tachycardia (P = 0.017) and LV ejection fraction ≤50% (P = 0.012) were associated with the composite endpoint. Males with DES variants had similar outcomes to historical FLNC-tv and LMNA-tv controls. However, females showed better outcomes than those with LMNA-tv. In vitro experiments showed the characteristic finding of DES aggregates in 7 of 12 variants.
CONCLUSIONS
DES ACM is associated with poor outcomes which can be predicted with potentially successful treatments, underscoring the importance of familial evaluation and genetic studies to identify at risk individuals.
Topics: Humans; Male; Female; Adult; Phenotype; Middle Aged; Death, Sudden, Cardiac; Desmin; Arrhythmogenic Right Ventricular Dysplasia; Young Adult; Defibrillators, Implantable; Heart Transplantation; Adolescent
PubMed: 38727660
DOI: 10.1016/j.jacep.2024.02.031