Vitamin D Treatment Prevents Uremia-Induced Reductions in Aortic microRNA-145 Attenuating Osteogenic Differentiation despite Hyperphosphatemia.

In chronic kidney disease, systemic inflammation and high serum phosphate (P) promote the de-differentiation of vascular smooth muscle cells (VSMC) to osteoblast-like cells, increasing the propensity for medial calcification and cardiovascular mortality. Vascular microRNA-145 (miR-145) content is essential to maintain VSMC contractile phenotype. Because vitamin D induces aortic miR-145, uremia and high serum P reduce it and miR-145 directly targets osteogenic osterix in osteoblasts, this study evaluated a potential causal link between vascular miR-145 reductions and osterix-driven osteogenic differentiation and its counter-regulation by vitamin D.

Novel Immune Cell Subsets Exhibit Different Associations With Vascular Outcomes in Chronic Kidney Disease Patients-Identifying Potential Biomarkers.

Alterations in novel immune cell subsets, such as angiogenic T cells (Tang), senescent T cells (CD4CD28), and monocyte subsets are associated with impaired vascular homeostasis in several inflammatory conditions. However, mediators underlying vascular deterioration in chronic kidney disease (CKD) are poorly characterized. This study assessed their role in the vascular deterioration of CKD using a broad spectrum of surrogate markers ranging from altered functionality to overt calcification.

Barley-ß-glucans reduce systemic inflammation, renal injury and aortic calcification through ADAM17 and neutral-sphingomyelinase2 inhibition.

In chronic kidney disease (CKD), hyperphosphatemia-induced inflammation aggravates vascular calcification (VC) by increasing vascular smooth muscle cell (VSMC) osteogenic differentiation, ADAM17-induced renal and vascular injury, and TNFα-induction of neutral-sphingomyelinase2 (nSMase2) to release pro-calcifying exosomes. This study examined anti-inflammatory β-glucans efficacy at attenuating systemic inflammation in health, and renal and vascular injury favoring VC in hyperphosphatemic CKD. In healthy adults, dietary barley β-glucans (Bβglucans) reduced leukocyte superoxide production, inflammatory ADAM17, TNFα, nSMase2, and pro-aging/pro-inflammatory STING (Stimulator of interferon genes) gene expression without decreasing circulating inflammatory cytokines, except for γ-interferon.

Upregulation of the alternative splicing factor NOVA2 in colorectal cancer vasculature.

Background: Tumor-specific isoforms generated by alternative splicing (AS) are demonstrated to contribute to tumor progression and can represent potential biomarkers. NOVA2 is an AS factor that in physiological conditions regulates endothelial cells' (ECs) polarity and vessel lumen maturation, likely by mediating AS of apical-basal polarity regulators. However, NOVA2 expression in tumor ECs and its regulation have never been investigated.

Relationship between low levels of circulating TRAIL and atheromatosis progression in patients with chronic kidney disease.

Background: Chronic kidney disease (CKD) patients experience a high risk of cardiovascular disease (CV); however, the factors involved in CV-related morbidity and mortality in these patients have not been fully defined. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine, which exhibits pleiotropic activities on endothelial, vascular smooth muscle and inflammatory cells, with relevant effects on atheromatous plaque formation. On this basis, the present study aims to investigate the role of TRAIL in atheromatosis progression in CKD patients.

High Levels of Hemoglobin Promote Carotid Adventitial Vasa Vasorum Neoangiogenesis in Chronic Kidney Disease.

Chronic kidney disease (CKD) patients, characterized by traditional and nontraditional risk factors, are prone to develop atheromatosis and thus cardiovascular events and mortality. The angiogenesis of the adventitial vasa vasorum (aVV) surrounding the carotid has been described as the atheromatosis initiator. Therefore, the aim of the study was to (1) evaluate if the carotid aVV in CKD patients increases in comparison to its physiological value of healthy patients; (2) explore which traditional or nontraditional risk factor including inflammation, bone and mineral metabolism, and anemia could be related to the aVV angiogenesis.

Vascular Calcification Induced by Chronic Kidney Disease Is Mediated by an Increase of 1α-Hydroxylase Expression in Vascular Smooth Muscle Cells.

Vascular calcification (VC) is a complication of chronic kidney disease that predicts morbidity and mortality. Uremic serum promotes VC, but the mechanism involved is unknown. A role for 1,25(OH) D in VC has been proposed, but the mechanism is unclear because both low and high levels have been shown to increase it.

Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia.

Objective: The aim of this study was to investigate the anti-leukemic activity of the Bruton tyrosine kinase inhibitor Ibrutinib in combination with the small molecule MDM-2 inhibitor Nutlin-3 in preclinical models.

Methods: The potential efficacy of the Ibrutinib/Nutlin-3 combination was evaluated in vitro in a panel of B leukemic cell lines (EHEB, JVM-2, JVM-3, MEC-1, MEC-2) and in primary B-chronic lymphocytic leukemia (B-CLL) patient samples, by assessing cell viability, cell cycle profile, apoptosis and intracellular pathway modulations. Validation of the combination therapy was assessed in a B leukemic xenograft mouse model.

Increased Burden of Cerebral Small Vessel Disease in Patients With Type 2 Diabetes and Retinopathy.

Objective: We sought to examine the presence and severity of brain small vessel disease (SVD) in patients with type 2 diabetes and diabetic retinopathy (DR) compared with those without DR.

Research Design And Methods: We evaluated 312 patients with type 2 diabetes without previous cardiovascular disease (men 51%; mean age 57 years; age range 40-75 years); 153 patients (49%) had DR. MRI was performed to evaluate the presence and severity (age-related white matter changes scale) of white matter lesions (WMLs) and lacunes, and transcranial Doppler ultrasound was used to measure the Gosling pulsatility index (PI) of the middle cerebral artery (MCA).

Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function.

Background: Warfarin, a widely used anticoagulant, is a vitamin K antagonist impairing the activity of vitamin K-dependent Bone Gla Protein (BGP or Osteocalcin) and Matrix Gla Protein (MGP). Because dabigatran, a new anticoagulant, has no effect on vitamin K metabolism, the aim of this study was to compare the impact of warfarin and dabigatran administration on bone structure and vascular calcification.

Methods: Rats with normal renal function received for 6 weeks warfarin, dabigatran or placebo.

Microangiopathy of common carotid vasa vasorum in type 1 diabetes mellitus.

Objective: We hypothesize that in type 1 diabetes vasa vasorum (VV) are affected by microangiopathic changes. For this purpose, we assessed the status of the VV signal in patients with type 1 diabetes.

Methods: The VV signal at the arterial adventitia of the common carotid artery was evaluated by contrast-enhanced ultrasound imaging.

Left carotid adventitial vasa vasorum signal correlates directly with age and with left carotid intima-media thickness in individuals without atheromatous risk factors.

Objective: The early identification of the onset of subclinical atheromatosis is essential in reducing the high mortality risk from cardiovascular disease (CVD) worldwide. Although carotid intima-media thickness (cIMT) is the most commonly used early predictor of ongoing atherosclerosis, an experimental model of atherosclerosis, demonstrated that increases in adventitial microvessels (vasa vasorum (VV)) precede endothelial dysfunction. Using the reported accuracy of contrast-enhanced ultrasound (CEU) to measure carotid adventitial VV, this study assessed whether measurements of carotid adventitial VV serve as a marker of subclinical atherosclerotic lesions in a control population with none of the classical risk factors for CVD.

A novel rat model of vitamin D deficiency: safe and rapid induction of vitamin D and calcitriol deficiency without hyperparathyroidism.

Vitamin D deficiency is associated with a range of clinical disorders. To study the mechanisms involved and improve treatments, animal models are tremendously useful. Current vitamin D deficient rat models have important practical limitations, including time requirements when using, exclusively, a vitamin D deficient diet.

Parathyroid-specific epidermal growth factor-receptor inactivation prevents uremia-induced parathyroid hyperplasia in mice.

Background: In chronic kidney disease (CKD), parathyroid hyperplasia contributes to high serum parathyroid hormone (PTH) and also to an impaired suppression of secondary hyperparathyroidism by calcium, vitamin D and fibroblast growth factor 23 (FGF23). In rats, systemic inhibition of epidermal growth factor receptor (EGFR) activation markedly attenuated uremia-induced parathyroid hyperplasia and vitamin D receptor (VDR) loss, hence restoring the response to vitamin D. Therefore, we propose that parathyroid-specific EGFR inactivation should prevent CKD-induced parathyroid hyperplasia.

The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease.

Background: In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGFα, the most potent EGFR-activating ligand.

Methods: Computer analysis of the ADAM17 promoter identified TGFα and C/EBPβ as potential regulators of the ADAM17 gene.

Prevalence of subclinical atheromatosis and associated risk factors in chronic kidney disease: the NEFRONA study.

Background: The causes of the high cardiovascular mortality observed in chronic kidney disease (CKD) are unknown. Here, we report data on prevalence of subclinical atherosclerosis in the NEFRONA population and a stratified multivariate logistic analysis of factors associated with the presence of plaque.

Methods: We analysed 2445 patients with an estimated glomerular filtration rate (eGFR) <60 mL/min (CKD 3: 937; CKD 4-5: 820; CKD 5D: 688) and 559 non-CKD subjects (eGFR >60 mL/min), 18-75 years old, without previous cardiovascular events.

Microangiopathy of large artery wall: a neglected complication of diabetes mellitus.

Objective: To test the concept that diabetic patients with microangiopathy of the retinal microcirculation would also show an involvement of the carotid adventitial microcirculation, we aimed to assess the status of the vasa vasorum (VV) signal, measured by contrast-enhanced carotid ultrasound imaging, in type 2 diabetic patients with and without retinopathy.

Methods And Results: Using contrast-enhanced ultrasound imaging, we quantified the signal of the VV of the common carotid artery. We investigated two subgroups of type 2 diabetic patients who did not have previous cardiovascular disease: 51 with retinopathy and 56 without retinopathy.

Large artery calcification on dialysis patients is located in the intima and related to atherosclerosis.

Background And Objectives: Vascular calcification (VC) has a significant effect in cardiovascular diseases on dialysis patients. However, VC is assessed with x-ray-based techniques, which do not inform about calcium localization (intima, media, atherosclerosis-related). The aim of this work is to study VC and its related factors using arterial ultrasound to report the exact location of calcium.

Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality.

In the course of kidney disease, the progressive loss of renal capacity to maintain normal serum levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) is a main contributor to parathyroid hyperplasia and high serum PTH. High PTH causes mineral and skeletal abnormalities predisposing to ectopic calcifications and increased mortality. Intriguingly, replacement therapy with 1,25(OH)2D or its less calcemic analogs was recently shown to improve survival in kidney disease patients through renal and cardiovascular protective actions that are independent of PTH suppression.

Activator protein 2alpha mediates parathyroid TGF-alpha self-induction in secondary hyperparathyroidism.

In secondary hyperparathyroidism, enhanced expression of TGF-alpha in the parathyroid leads to its own upregulation, generating a feed-forward loop for TGF-alpha activation of its receptor, EGFR receptor (EGFR), which promotes parathyroid hyperplasia. These studies examined the role of activator protein 2alpha (AP2), an inducer of TGF-alpha gene transcription, in the upregulation of parathyroid TGF-alpha in secondary hyperparathyroidism. In rat and human secondary hyperparathyroidism, parathyroid AP2 expression strongly correlated with TGF-alpha levels and with the rate of parathyroid growth, as expected.

EGFR activation increases parathyroid hyperplasia and calcitriol resistance in kidney disease.

Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-alpha is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown.

A role for enhanced integrin and FAK expression in uremia-induced parathyroid hyperplasia.

Parathyroid (PT) hyperplasia is a major feature of secondary hyperparathyroidism (SH) in uremia. The transforming growth factor-alpha (TGFalpha) / epidermal growth factor receptor (EGFR)Ethgrowth loop is the main contributor to uremia-induced PT hyperplasia. Since integrin beta1 and focal adhesion kinase (FAK) are known to directly activate cell growth and enhance EGFR-driven growth, these studies examined their contribution to PT hyperplasia in uremia.

Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils.

The potential activity of cannabidiol, a non-psychoactive constituent of marijuana, in preventing damage caused by cerebral ischemia was studied. Cannabidiol (1.25-20 mg/kg) was given 5 min after 10 min bilateral carotid occlusion in freely-moving awake gerbils.