We present a microfluidic vascular device. Vascular cells in a 3D-ECM environment support hemodynamic flow and enable monocyte interaction.

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The lymphatic system plays a crucial role in interstitial fluid drainage, lipid absorption, and immunological defense. Lymphatic dysfunction results in lymphedema, fluid accumulation, and swelling of soft tissues, as well as a potentially impaired immune response. Lymphedema significantly reduces quality of life of patients on a physical, mental, social, and economic basis. Current therapeutic approaches in treatment of lymphatic disease are limited. Over the last decades, great progress has been made in the development of therapeutic strategies to enhance vascular regeneration. These solutions to treat vascular disease may also be applicable in the treatment of lymphatic diseases. Comparison of the organogenic process and biological organization of the vascular and lymphatic systems and studies in the regulatory mechanisms involved in lymphangiogenesis and angiogenesis show many common features. In this study, we address the similarities between both transport systems, and focus in depth on the biology of lymphatic development. Based on the current advances in vascular regeneration, we propose different strategies for lymphatic tissue engineering that may be used for treatment of primary and secondary lymphedema.

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Background and objectives: Sodium glucose transporter 2 (SGLT2)-inhibitor-induced uric acid lowering may contribute to kidney protective effects of the drug-class in people with type 2 diabetes. This study investigates mechanisms of plasma uric acid lowering by SGLT2-inhibitors in people with type 2 diabetes with a focus on urate transporter (URAT)1. Methods: We conducted an analysis of two randomized, clinical trials. First, in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED) study, 44 people with type 2 diabetes were randomized to dapagliflozin or gliclazide for 12 weeks. Plasma uric acid, fractional uric acid excretion and hemodynamic kidney function were measured in the fasted state and during clamped eu- or hyperglycemia. Second, in the Uric Acid Excretion study (UREX) study, 10 people with type 2 diabetes received 1-week empagliflozin, benzbromarone and their combination in a cross-over design and effects on plasma uric acid, fractional uric acid excretion and 24-hr uric acid excretion were measured. Results: In the RED study, compared to the fasted state (5.3±1.1mg/dL), acute hyperinsulinemia and hyperglycemia significantly reduced plasma uric acid by 0.2±0.3 and 0.4±0.3 mg/dL (both p<0.001), while increasing fractional uric acid excretion (by 3.2±3.1% and 8.9±4.5% respectively (both p<0.001). Dapagliflozin reduced plasma uric acid by 0.8±0.8mg/dL, 1.0±1.0mg/dL and by 0.8±0.7mg/dL during fasting, hyperinsulinemic-euglycemic and hyperglycemic conditions (p<0.001), whereas fractional uric acid excretion in 24-hr urine increased by 3.0±2.1% (p<0.001) and 2.6±4.5% during hyperinsulinemic-euglycemic conditions (p=0.003). Fractional uric acid excretion strongly correlated to fractional glucose excretion (r= 0.35, p=0.02). In the UREX study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination therapy did not differ from benzbromarone monotherapy. Conclusion: In conclusion, SGLT2-inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion and which is attenuated during concomitant pharmacological blockade of URAT1.

Background: H3K27ac histone acetylome changes contribute to the phenotypic response in heart diseases, particularly in end-stage heart failure. However, such epigenetic alterations have not been systematically investigated in remodeled non-failing human hearts. Therefore, valuable insight into cardiac dysfunction in early remodeling is lacking. This study aimed to reveal the acetylation changes of chromatin regions in response to myocardial remodeling and their correlations to transcriptional changes of neighboring genes.

Protein bound-uremic toxins (PBUTs) are not efficiently removed by hemodialysis in chronic kidney disease (CKD) patients and their accumulation leads to various co-morbidities via cellular dysfunction, inflammation and oxidative stress. Moreover, it has been shown that increased intrarenal expression of the NLRP3 receptor and IL-1β are associated with reduced kidney function, suggesting a critical role for the NLRP3 inflammasome in CKD progression. Here, we evaluated the effect of PBUTs on inflammasome-mediated IL-1β production in vitro and in vivo. Exposure of human conditionally immortalized proximal tubule epithelial cells to indoxyl sulfate (IS) and a mixture of anionic PBUTs (UT mix) increased expression levels of NLRP3, caspase-1 and IL-1β, accompanied by a significant increase in IL-1β secretion and caspase-1 activity. Furthermore, IS and UT mix induced the production of intracellular reactive oxygen species, and caspase-1 activity and IL-1β secretion were reduced in the presence of antioxidant N-acetylcysteine. IS and UT mix also induced NF-κB activation as evidenced by p65 nuclear translocation and IL-1β production, which was counteracted by an IKK inhibitor. In vivo, using subtotal nephrectomy CKD rats, a significant increase in total plasma levels of IS and the PBUTs, kynurenic acid and hippuric acid, was found, as well as enhanced urinary malondialdehyde levels. CKD kidney tissue showed an increasing trend in expression of NLRP3 inflammasome components, and a decreasing trend in superoxide dismutase-1 levels. In conclusion, we showed that PBUTs induce inflammasome-mediated IL-1β production in proximal tubule cells via oxidative stress and NF-κB signaling, suggesting their involvement in disease-associated inflammatory processes.

Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction. To clarify if and how interaction between these comorbidities contributes to development of diastolic dysfunction, lean and obese ZSF1 rats were treated with deoxycorticosterone acetate implants and a high‐salt diet (DS) to induce severe hypertension, or with placebo. In addition to echocardiographic, metabolic and hemodynamic analyses, immunohistochemistry and RNAseq were performed on left ventricular tissue. Obesity negatively affected cardiac output, led to an elevated E/e’ ratio and mildly reduced ejection fraction. DS‐induced hypertension did not affect cardiac output and minimally elevated E/e’ ratio. Diastolic derangements in placebo‐treated obese rats developed in absence of inflammation and fibrosis, yet in presence of oxidative stress and hypertrophic remodelling. In contrast, hypertension triggered apoptosis, inflammation and fibrosis, with limited synergy of the comorbidities observed for inflammation and fibrosis. Transcriptional data suggested that these comorbidities exerted opposite effects on mitochondrial function. In placebo‐treated obese rats, genes involved in fatty acid metabolism were up‐regulated, whereas DS‐induced a down‐regulation of genes involved in oxidative phosphorylation. Overall, limited interaction was observed between these comorbidities in development of diastolic dysfunction. Importantly, differences in obesity‐ and hypertension‐induced cardiac remodelling emphasize the necessity for comorbidity‐specific phenotypical characterization.