Tissue-engineered vascular grafts (TEVGs) poised for regenerative applications are central to effective vascular repair, with their efficacy being significantly influenced by scaffold architecture and the strategic distribution of bioactive molecules either embedded within the scaffold or elicited from responsive tissues. Despite substantial advancements over recent decades, a thorough understanding of the critical cellular dynamics for clinical success remains to be fully elucidated. Graft failure, often ascribed to thrombogenesis, intimal hyperplasia, or calcification, is predominantly linked to improperly modulated inflammatory reactions. The orchestrated behavior of repopulating cells is crucial for both initial endothelialization and the subsequent differentiation of vascular wall stem cells into functional phenotypes. This necessitates the TEVG to provide an optimal milieu wherein immune cells can promote early angiogenesis and cell recruitment, all while averting persistent inflammation. In this study, we present an innovative TEVG designed to enhance cellular responses by integrating a physicochemical gradient through a multilayered structure utilizing synthetic (poly (ester urethane urea), PEUU) and natural polymers (Gelatin B), thereby modulating inflammatory reactions. The luminal surface is functionalized with a four-arm polyethylene glycol (P4A) to mitigate thrombogenesis, while the incorporation of adhesive peptides (RGD/SV) fosters the adhesion and maturation of functional endothelial cells. The resultant multilayered TEVG, with a diameter of 3.0 cm and a length of 11 cm, exhibits differential porosity along its layers and mechanical properties commensurate with those of native porcine carotid arteries. Analyses indicate high biocompatibility and low thrombogenicity while enabling luminal endothelialization and functional phenotypic behavior, thus limiting inflammation in in-vitro models. The vascular wall demonstrated low immunogenicity with an initial acute inflammatory phase, transitioning towards a pro-regenerative M2 macrophage-predominant phase. These findings underscore the potential of the designed TEVG in inducing favorable immunomodulatory and pro-regenerative environments, thus holding promise for future clinical applications in vascular tissue engineering.
Copyright © 2024 Rodríguez-Soto, Riveros-Cortés, Orjuela-Garzón, Fernández-Calderón, Rodríguez, Vargas, Ostos, Camargo, Cruz, Kim, D’Amore, Wagner and Briceño.

Introduction: Thrombogenesis, a major cause of implantable cardiovascular device failure, can be addressed through the use of biodegradable polymers modified with anticoagulating moieties. This study introduces a novel polyester urethane urea (PEUU) functionalized with various anti-platelet deposition molecules for enhanced antiplatelet performance in regenerative cardiovascular devices. Methods: PEUU, synthesized from poly-caprolactone, 1,4-diisocyanatobutane, and putrescine, was chemically oxidized to introduce carboxyl groups, creating PEUU-COOH. This polymer was functionalized in situ with polyethyleneimine, 4-arm polyethylene glycol, seleno-L-cystine, heparin sodium, and fondaparinux. Functionalization was confirmed using Fourier-transformed infrared spectroscopy and X-ray photoelectron spectroscopy. Bio-compatibility and hemocompatibility were validated through metabolic activity and hemolysis assays. The anti-thrombotic activity was assessed using platelet aggregation, lactate dehydrogenase activation assays, and scanning electron microscopy surface imaging. The whole-blood clotting time quantification assay was employed to evaluate anticoagulation properties. Results: Results demonstrated high biocompatibility and hemocompatibility, with the most potent anti-thrombotic activity observed on pegylated surfaces. However, seleno-L-cystine and fondaparinux exhibited no anti-platelet activity. Discussion: The findings highlight the importance of balancing various factors and addressing challenges associated with different approaches when developing innovative surface modifications for cardiovascular devices.
Copyright © 2023 Rodríguez-Soto, Suárez Vargas, Ayala-Velásquez, Aragón-Rivera, Ostos, Cruz, Muñoz Camargo, Kim, D’Amore, Wagner and Briceño.

Central blood pressure (BP) and BP variability are associated with cardiovascular disease risk. However, the influence of exercise on these hemodynamic parameters is unknown among patients with resistant hypertension. The EnRicH (The Exercise Training in the Treatment of Resistant Hypertension) was a prospective, single-blinded randomized clinical trial (NCT03090529). Sixty patients were randomized to a 12-week aerobic exercise program or usual care. The outcome measures include central BP, BP variability, heart rate variability, carotid-femoral pulse wave velocity, and circulating cardiovascular disease risk biomarkers including high-sensitivity C-reactive protein, angiotensin II, superoxide dismutase, interferon gamma, nitric oxide, and endothelial progenitor cells. Central systolic BP decreased by 12.22 mm Hg (95% CI, -1.88 to -22.57, P = 0.022) as did BP variability by 2.85 mm Hg (95% CI, -4.91 to -0.78, P = 0.008), in the exercise (n = 26) compared to the control group (n = 27). Interferon gamma -4.3 pg/mL (95%CI, -7.1 to -1.5, P = 0.003), angiotensin II -157.0 pg/mL (95%CI, -288.1 to -25.9, P = 0.020), and superoxide dismutase 0.4 pg/mL (95%CI, 0.1-0.6, P = 0.009) improved in the exercise compared to the control group. Carotid-femoral pulse wave velocity, heart rate variability, high-sensitivity C-reactive protein, nitric oxide, and endothelial progenitor cells were not different between groups (P > 0.05). In conclusion, a 12-week exercise training program improved central BP and BP variability, and cardiovascular disease risk biomarkers in patients with resistant hypertension. These markers are clinically relevant as they are associated with target organ damage and increased cardiovascular disease risk and mortality.
© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.

Understanding the genetic and molecular function of nitrate sensing and acquisition across crop species will accelerate breeding of cultivars with improved nitrogen use efficiency (NUE). Here, we performed a genome-wide scan using wheat and barley accessions characterized under low and high N inputs that uncovered the NPF2.12 gene, encoding a homolog of the Arabidopsis nitrate transceptor NRT1.6 and other low-affinity nitrate transporters that belong to the MAJOR FACILITATOR SUPERFAMILY. Next, it is shown that variations in the NPF2.12 promoter correlated with altered NPF2.12 transcript levels where decreased gene expression was measured under low nitrate availability. Multiple field trials revealed a significantly enhanced N content in leaves and grains and NUE in the presence of the elite allele TaNPF2.12TT grown under low N conditions. Furthermore, the nitrate reductase encoding gene NIA1 was up-regulated in npf2.12 mutant upon low nitrate concentrations, thereby resulting in elevated levels of nitric oxide (NO) production. This increase in NO correlated with the higher root growth, nitrate uptake, and N translocation observed in the mutant when compared to wild-type. The presented data indicate that the elite haplotype alleles of NPF2.12 are convergently selected in wheat and barley that by inactivation indirectly contribute to root growth and NUE by activating NO signaling under low nitrate conditions.
© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.

Hepatic ischemia-reperfusion (IR) injury occurs in liver surgery, resection, and transplantation. Reactive oxygen species (ROS) produced following IR starts the cascade of cell damage, necrosis/apoptosis, and proinflammatory responses by activating intracellular signaling cascade to drive hepatocellular damage. Cerium oxide nanoparticles (CONPs) act as anti-inflammatory and antioxidant agents. Thus, we evaluated the protective effects of oral (o.g.) and intraperitoneal (i.p.) administration of CONPs on hepatic IR injury.
Mice were randomly divided into five groups: control, sham, IR protocol, CONP+IR (i.p.), and CONP+IR (o.g.). Mouse hepatic IR protocol was applied to the animals in the IR group. CONPs (300 μg/kg) were administered 24 hours before IR protocol. Blood and tissue samples were taken after the reperfusion period.
Hepatic IR injury markedly increased enzyme activities, tissue lipid peroxidation, myeloperoxidase (MPO), xanthine oxidase (XO), nitrite oxide (NO), and tissue nuclear factor kappa-B (NF-κB) p65 levels, plasma pro-inflammatory cytokines, chemokines, and adhesion molecules while decreasing antioxidant markers and caused pathological changes in hepatic tissue. The expression of tumor necrosis factor alpha (TNF-α), matrix metalloproteinase 2 (MMP-2), and 9 increased, and tissue inhibitor matrix metalloproteinase 1 (TIMP-1) expression decreased in the IR group. Pretreatment with CONPs o.g. and i.p. 24 hours before hepatic ischemia improved the biochemical parameters above and alleviated the histopathological findings.
Results of the present study demonstrate a significant reduction in liver degeneration by administering CONPs via i.p. and o.g. route in an experimental liver IR model, suggesting that CONPs have the extensive potential to prevent hepatic IR injury.
Copyright © 2022, Turkish Surgical Society.