Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia

Ciona intestinalis NADH dehydrogenase NDX confers stress-resistance and extended lifespan on Drosophila

Peer reviewe

Successful Amelioration of Mitochondrial Optic Neuropathy Using the Yeast NDI1 Gene in a Rat Animal Model

Background: Leber’s hereditary optic neuropathy (LHON) is a maternally inherited disorder with point mutations in mitochondrial DNA which result in loss of vision in young adults. The majority of mutations reported to date are within the genes encoding the subunits of the mitochondrial NADH-quinone oxidoreductase, complex I. Establishment of animal models of LHON should help elucidate mechanism of the disease and could be utilized for possible development of therapeutic strategies. Methodology/Principal Findings: We established a rat model which involves injection of rotenone-loaded microspheres into the optic layer of the rat superior colliculus. The animals exhibited the most common features of LHON. Visual loss was observed within 2 weeks of rotenone administration with no apparent effect on retinal ganglion cells. Death of retinal ganglion cells occurred at a later stage. Using our rat model, we investigated the effect of the yeast alternative NADH dehydrogenase, Ndi1. We were able to achieve efficient expression of the Ndi1 protein in the mitochondria of all regions of retinal ganglion cells and axons by delivering the NDI1 gene into the optical layer of the superior colliculus. Remarkably, even after the vision of the rats was severely impaired, treatment of the animals with the NDI1 gene led to a complete restoration of the vision to the normal level. Control groups that received either empty vector or the GFP gene had no effects

Comparison of Serum Level of Some Trace Elements and Vitamin D Between Patients with Premenstrual Syndrome and Normal Controls: A Cross-sectional Study

Background: Premenstrual syndrome (PMS) is a common problem among women and is identified by reversal emotional, psychological, and physical signs during the luteal phase. These signs, however, lower down in the follicular phase. The cause of PMS isn't very well-known up to now control group and many researchers have suggested that mineral compounds and vitamins can inhibit these symptoms. Objective: The objective of this study is to compare the serum level of some trace elements and vitamin D between normal controls and patients with PMS. Materials and Methods: 300 female students (19–21 yr old) from Falavarjan County were randomly selected and asked to complete a standard questionnaire on PMS during three menstruation cycles. The students were divided into two groups: healthy persons (control) and PMS persons, and PMS was determined on the basis of the answers to the questionnaire. Thereafter, the serum concentrations of zinc, iron, calcium, magnesium, potassium, sodium, and Vitamin D3 were measured and compared between the two groups. Results: Our results showed that the PMS prevalence was about 41.5%. The level of vitamin D decreased in both the control and PMS groups, with a significantly lower range of vitamin D (p 0.05) in the PMS group. Other factors had no significant change between the two groups. Conclusion: Vitamin D deficiency was probably one of the most important causes of unpleasant symptoms of PMS between these students. Key words: Premenstrual syndrome, Trace elements, Vitamin D

The effects of repeated Ozurdex injections on ocular hypertension

Sepehr Bahadorani,1 Chelsey Krambeer,2 Kendall Wannamaker,1 Wayne Tie,1 Michael Jansen,1 Jason Espitia,2 Jeong-Hyeon Sohn,1 Michael A Singer2 1Department of Ophthalmology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; 2Medical Center Ophthalmology Associates, San Antonio, TX, USA Purpose: The purpose of this study was to correlate the degree of ocular hypertension with the number of Ozurdex injections.Methods: Intraocular pressure (IOP) fluctuations for a total of 183 injections were studied over a period of at least 12 months. The main indications for treatment were uveitis, diabetic macular edema, and retinal vein occlusion.Results: Results of the study demonstrate that repeated Ozurdex injections do not increase the frequency of IOP spikes beyond 30 mmHg. For lower IOPs, however, a positive correlation exists. Furthermore, patients with primary open angle glaucoma and uveitis had the highest IOP response to repeated injections. On average, patients with an IOP of ≥28.6 mmHg received pressure lowering medications, after which their IOP reached a stable level (16.7 mmHg) without the need for additional interventions.Conclusion: The data support the conclusion that multiple Ozurdex injections does not increase the frequency of IOP spikes beyond 30 mmHg, but patients still must be closely monitored if they have a history of primary open angle glaucoma. Keywords: Ozurdex, dexamethasone, glaucoma, intraocular pressure, ocular hypertensio

New developments in the clinical use of drug-coated balloon catheters in peripheral arterial disease

Jesse Naghi, Ethan A Yalvac, Ali Pourdjabbar, Lawrence Ang, John Bahadorani, Ryan R Reeves, Ehtisham Mahmud, Mitul Patel Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California, San Diego, CA, USA Abstract: Peripheral arterial disease (PAD) involving the lower extremity is a major source of morbidity and mortality. Clinical manifestations of PAD span the spectrum from lifestyle limiting claudication to ulceration and gangrene leading to amputation. Advancements including balloon angioplasty, self-expanding stents, drug-eluting stents, and atherectomy have resulted in high technical success rates for endovascular therapy in patients with PAD. However, these advances have been limited by somewhat high rates of clinical restenosis and clinically driven target lesion revascularization. The recent introduction of drug-coated balloon technology shows promise in limiting neointimal hyperplasia induced by vascular injury after endovascular therapies. This review summarizes the contemporary clinical data in the emerging area of drug-coated balloons. Keywords: drug-coated balloons, endovascular, percutaneous transluminal angioplasty, paclitaxel, peripheral arterial diseas

Transcriptional Regulation of the Beta-Synuclein 5′-Promoter Metal Response Element by Metal Transcription Factor-1

The progression of many human neurodegenerative disorders is associated with an accumulation of alpha-synuclein. Alpha-synuclein belongs to the homologous synuclein family, which includes beta-synuclein. It has been proposed that beta-synuclein may be a natural regulator of alpha-synuclein. Therefore controlling beta-synuclein expression may control the accumulation of alpha-synuclein and ultimately prevent disease progression. The regulation of synucleins is poorly understood. We investigated the transcriptional regulation of beta-synuclein, with the aim of identifying molecules that differentially control beta-synuclein expression levels. To investigate transcriptional regulation of beta-synuclein, we used reporter gene assays and bioinformatics. We identified a region −1.1/−0.6 kb upstream of the beta-synuclein translational start site to be a key regulatory region of beta-synuclein 5′-promoter activity in human dopaminergic cells (SH-SY5Y). Within this key promoter region we identified a metal response element pertaining to a putative Metal Transcription Factor-1 (MTF-1) binding site. We demonstrated that MTF-1 binds to this 5′-promoter region using EMSA analysis. Moreover, we showed that MTF-1 differentially regulates beta-synuclein promoter binding site, as well as beta-synuclein mRNA and protein expression. This effect of MTF-1 on expression was found to be specific to beta-synuclein when compared to alpha-synuclein. Understanding the regulation of synucleins and how they interact may point to molecular targets that could be manipulated for therapeutic benefit. In this study we showed that MTF-1 differentially controls the expression of beta-synuclein when compared to its homolog alpha-synuclein. This could potentially provide a novel targets or pathways for therapeutic intervention and/or treatment of synucleinopathies