Drug-drug interactions when treating HIV-related metabolic disorders.

: Drug-drug interactions (DDI) between antiretroviral drugs and drugs for the treatment of metabolic disturbances in people living with human immunodeficiency virus (HIV) (PLWH) have represented a problem of paramount importance in the recent times. The problem has been mainly driven by sharing common metabolizing pathways. This problem has classically been worsened by the frequent use of pharmacokinetic boosters to enhance protease inhibitors and some integrase inhibitors plasma levels.

The role of mitochondrial oxidative stress in the metabolic alterations in diet-induced obesity in rats.

The impact of the mitochondria-targeted antioxidant MitoQ was evaluated in the metabolic alterations and the adipose tissue remodeling associated with obesity. Male Wistar rats were fed either a high-fat diet (HFD; 35% fat) or a standard diet (3.5% fat) for 7 wk and treated with MitoQ (200 µM).

Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure).

Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a complex aetiology that remains to be fully elucidated. Clinical management of AAA is limited to surgical repair, while an effective pharmacotherapy is still awaited. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been involved in the pathogenesis of cardiovascular diseases (CVDs), although their contribution to AAA development is uncertain.

Does choice of antiretroviral drugs matter for inflammation?

The massive implementation of combination antiretroviral therapy (cART) has forever changed the landscape of HIV infection. This unprecedented success has turned HIV infection into a manageable chronic disease. The increased survival of people living with HIV is, however, shadowed by a high burden of aging-related comorbidities.

Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease.

Background: Although the role of Th17 and regulatory T cells in the progression of atherosclerosis has been highlighted in recent years, their molecular mediators remain elusive. We aimed to evaluate the association between the CD69 receptor, a regulator of Th17/regulatory T cell immunity, and atherosclerosis development in animal models and in patients with subclinical disease.

Methods: Low-density lipoprotein receptor-deficient chimeric mice expressing or not expressing CD69 on either myeloid or lymphoid cells were subjected to a high fat diet.

Endothelial NOD1 directs myeloid cell recruitment in atherosclerosis through VCAM-1.

Atherosclerosis is a chronic disease characterized by vascular lipid retention and inflammation, and pattern recognition receptors (PRRs) are important contributors in early stages of the disease. Given the implication of the intracellular PRR nucleotide-binding oligomerization domain 1 (NOD1) in cardiovascular diseases, we investigated its contribution to early atherosclerosis. We evidenced NOD1 induction in atherosclerotic human and mouse tissues, predominantly in vascular endothelial cells.

Tolerability of Current Antiretroviral Single-Tablet Regimens.

The advent of protease inhibitors (PI) in the mid-nineties and its use as part of triple combinations revolutionized the management of HIV infection. Since then, progression to AIDS and AIDS-related deaths can be prevented. However, antiretroviral therapy based on PI has been discouraged for a while given its lower tolerability compared to alternative options; and only recent improvements in pharmacotherapy have renewed the interest for the newest agents within this class.

Lysyl oxidase (LOX) limits VSMC proliferation and neointimal thickening through its extracellular enzymatic activity.

Lysyl oxidase (LOX) plays a critical role in extracellular matrix maturation and limits VSMC proliferation and vascular remodeling. We have investigated whether this anti-proliferative effect relies on the extracellular catalytically active LOX or on its biologically active propeptide (LOX-PP). High expression levels of both LOX and LOX-PP were detected in the vascular wall from transgenic mice over-expressing the full-length human LOX cDNA under the control of SM22α promoter (TgLOX), which targets the transgene to VSMC without affecting the expression of mouse LOX isoenzymes.

The nuclear receptor NOR-1 modulates redox homeostasis in human vascular smooth muscle cells.

The nuclear receptor NOR-1 (Neuron-derived Orphan Receptor-1) has recently been involved in vascular remodeling and coronary artery disease, however, to date, only a few NOR-1 target genes have been described. We aimed to identify genes regulated by NOR-1 in human vascular smooth muscle cells (VSMC). Lentiviral overexpression of NOR-1 increases reactive oxygen species (ROS) in human VSMC.

Mechanisms of vascular aging: What can we learn from Hutchinson-Gilford progeria syndrome?

Aging is the main risk factor for cardiovascular disease (CVD). The increased prevalence of CVD is partly due to the global increase in life expectancy. In this context, it is essential to identify the mechanisms by which aging induces CVD, with the ultimate aim of reducing its incidence.

Inhibition of enzymes involved in collagen cross-linking reduces vascular smooth muscle cell calcification.

Vascular smooth muscle cells (VSMCs) transdifferentiate into osteoblast-like cells during vascular calcification, inducing active remodeling and calcification of the extracellular matrix (ECM). Intracellular and extracellular enzymes, such as lysyl hydroxylase 1 (PLOD1) and lysyl oxidase (LOX), contribute to ECM maturation and stabilization. We assessed the contribution of these enzymes to hyperphosphatemia-induced calcification.

MT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis.

Matrix metalloproteinases are involved in vascular remodeling. Little is known about their immune regulatory role in atherosclerosis. Here we show that mice deficient for MT4-MMP have increased adherence of macrophages to inflamed peritonea, and larger lipid deposits and macrophage burden in atherosclerotic plaques.

m-RESIST, a complete m-Health solution for patients with treatmentresistant schizophrenia: a qualitative study of user needs and acceptability in the Barcelona metropolitan area.

Background: Despite the theoretical potential of m-health solutions in the treatment of patients with schizophrenia, there remains a lack of technological solutions in daily practice. The aim of this study was to measure the receptivity of patients, informal carers, and clinicians to an integral intervention model focused on patients with persistent positive symptoms: Mobile Therapeutic Attention for Patients with Treatment Resistant Schizophrenia (m-RESIST).

Methods: A qualitative study of the needs and acceptability of outpatients with treatment-resistant schizophrenia was carried out in Parc Sanitari Sant Joan de Déu (Barcelona).

McArdle disease does not affect skeletal muscle fibre type profiles in humans.

Patients suffering from glycogen storage disease V (McArdle disease) were shown to have higher surface electrical activity in their skeletal muscles when exercising at the same intensity as their healthy counterparts, indicating more muscle fibre recruitment. To explain this phenomenon, this study investigated whether muscle fibre type is shifted towards a predominance in type I fibres as a consequence of the disease. Muscle biopsies from the Biceps brachii (BB) (n = 9) or Vastus lateralis (VL) (n = 8) were collected over a 13-year period from male and female patients diagnosed with McArdle disease, analysed for myosin heavy chain (MHC) isoform content using SDS-PAGE, and compared to healthy controls (BB: n = 3; VL: n = 10).

Clinical and scientific aspects of acetylcholine receptor myasthenia gravis.

Purpose Of Review: Myasthenia gravis is a rare disease that causes impairment of the neuromuscular junction. In this review we will focus on the literature published in the last 18 months regarding autoimmune myasthenia gravis caused by antibodies against the nicotinic acetylcholine receptor myasthenia gravis. Acetylcholine receptor is the most common target of this autoimmune disease.

The pathogenomics of McArdle disease--genes, enzymes, models, and therapeutic implications.

Numerous biomedical advances have been made since Carl and Gerty Cori discovered the enzyme phosphorylase in the 1940s and the Scottish physician Brian McArdle reported in 1951 a previously 'undescribed disorder characterized by a gross failure of the breakdown in muscle of glycogen'. Today we know that this disorder, commonly known as 'McArdle disease', is caused by inherited deficiency of the muscle isoform of glycogen phosphorylase (GP). Here we review the main aspects of the 'pathogenomics' of this disease including, among others: the spectrum of mutations in the gene (PYGM) encoding muscle GP; the interplay between the different tissue GP isoforms in cellular cultures and in patients; what can we learn from naturally occurring and recently laboratory-generated animal models of the disease; and potential therapies.

Proteasome inhibition with bortezomib depletes plasma cells and specific autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients.

Bortezomib is a potent inhibitor of proteasomes currently used to eliminate malignant plasma cells in multiple myeloma patients. It is also effective in depleting both alloreactive plasma cells in acute Ab-mediated transplant rejection and their autoreactive counterparts in animal models of lupus and myasthenia gravis (MG). In this study, we demonstrate that bortezomib at 10 nM or higher concentrations killed long-lived plasma cells in cultured thymus cells from nine early-onset MG patients and consistently halted their spontaneous production not only of autoantibodies against the acetylcholine receptor but also of total IgG.

Effects of switching from stavudine to raltegravir on subcutaneous adipose tissue in HIV-infected patients with HIV/HAART-associated lipodystrophy syndrome (HALS). A clinical and molecular study.

HIV-1/HAART-associated lipodystrophy syndrome (HALS) has been associated with exposure to stavudine (d4T) through mitochondrial dysfunction. We performed a 48-week study to assess the effects of switching from d4T to raltegravir (RAL) on metabolic and fat molecular parameters of patients with HALS. Forty-two patients with HALS and a median exposure to d4T > 7 years were switched to RAL and followed for 48 weeks.

Human coronary smooth muscle cells internalize versican-modified LDL through LDL receptor-related protein and LDL receptors.

Versican-like proteoglycans are the main component of the intimal extracellular matrix interacting with low density lipoprotein (LDL). The aim of this study has been to investigate the receptors involved in versican-modified LDL uptake by human vascular smooth muscle cells (VSMCs). We have found that versican-LDL interaction leads to the following: (1) monomeric LDL particles that are similar in size and electrophoretic mobility to native LDL but that have a higher capacity to induce intracellular cholesteryl ester (CE) accumulation and (2) fused LDL particles similar in size to those obtained by vortexing.

HMG-CoA reductase inhibitors reduce vascular monocyte chemotactic protein-1 expression in early lesions from hypercholesterolemic swine independently of their effect on plasma cholesterol levels.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase are widely used in the treatment of dyslipemias and have shown beneficial effects in primary and secondary prevention of cardiovascular diseases. There is new information that seems to suggest that the beneficial effects observed may not be solely attributable to plasma cholesterol reduction. Our objective has been to evaluate the effect of two statins at similar dose, although unequivalent plasma lipid lowering potential, on vessel wall expression of two proteins involved in atherosclerotic lesion progression.

3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition prevents endothelial NO synthase downregulation by atherogenic levels of native LDLs: balance between transcriptional and posttranscriptional regulation.

Atherogenic levels of native low density lipoproteins (nLDLs) decrease the bioavailability of endothelium-derived NO and downregulate endothelial NO synthase (eNOS) expression in cultured human endothelial cells. Here, we show that simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, within the therapeutic range (0.01 to 1 micromol/L) prevented the downregulation of eNOS mRNA and protein promoted by nLDL (180 mg cholesterol/dL, 48 hours) in human umbilical vein endothelial cells.

Small oxidative changes in atherogenic LDL concentrations irreversibly regulate adhesiveness of human endothelial cells: effect of the lazaroid U74500A.

The adherence of monocytes to the endothelium is an early event in atherogenesis which is modulated by low density lipoproteins (LDL). We analyzed the effect of atherogenic LDL levels (180 mg cholesterol/dl, for 24 h) with minimal oxidative modifications (thiobarbituric-acid-reactive-substances (TBARS) concentration between 1.2+/-0.

Mevalonate deprivation impairs IGF-I/insulin signaling in human vascular smooth muscle cells.

3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (statins) are therapeutically used to lower plasma cholesterol levels. In addition, these drugs can block vascular smooth muscle cell (VSMC) proliferation. The present study addressed the question whether the inhibitory effect of lovastatin on premitotic DNA synthesis correlates with a downregulation of c-fos mRNA levels, a marker of signaling efficiency, in human SMC.