Biased Homozygous Haplotypes Across the Human Caveolin 1 Upstream Purine Complex in Parkinson’s Disease

The alpha-synuclein–caveolin 1 axis is suggested to be of role in the pathogenesis of Parkinson’s disease in cell line models. The objective of this study was to analyze the homozygous haplotype compartment of the human caveolin 1 gene upstream purine complex in patients afflicted with Parkinson’s disease. This complex was screened in patients with Parkinson’s disease (n?=?141) and compared with a group of controls (n?=?760) using polymerase chain reaction and sequencing. The expression activity of the homozygous haplotypes was then examined using luciferase Dual-Glo system in human neuronal cell line, LAN-5. Six haplotypes were found to be homozygous in the patients, and not in the control pool (Fisher exact p?<?1?×?10^?6). Three of those haplotypes were specific to Parkinson’s disease (Fisher exact p?<?0.002), and the remaining three overlapped with homozygous haplotypes in Alzheimer’s disease and multiple sclerosis (Fisher exact p?<?0.002). The disease haplotypes contained motif lengths that were nonexistent in the control homozygous haplotype pool and significantly increased gene expression (p?<?9?×?10^—6). We conclude that skew in the caveolin 1 purine complex homozygous haplotype compartment and an additive effect of those haplotypes may be linked with Parkinson’s disease.     

Synthesis,characterization, molecular docking,and biological activities of coumarin–1,2,3-triazole-acetamide hybrid derivatives

Coumarins and their derivatives are receiving increasing attention due to numerous biochemical and pharmacological applications. In this study, a series of novel coumarin–1,2,3-triazole-acetamide hybrids was tested against some metabolic enzymes including α-glycosidase (α-Gly), α-amylase (α-Amy), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), human carbonic anhydrase I (hCA I), and hCA II. The new coumarin–1,2,3-triazole-acetamide hybrids showed K_i values in the range of 483.50–1,243.04 nM against hCA I, 508.55–1,284.36 nM against hCA II, 24.85–132.85 nM against AChE, 27.17–1,104.36 nM against BChE, 590.42–1,104.36 nM against α-Gly, and 55.38–128.63 nM against α-Amy. The novel coumarin–1,2,3-triazole-acetamide hybrids had effective inhibition profiles against all tested metabolic enzymes. Also, due to the enzyme inhibitory effects of the new hybrids, they are potential drug candidates to treat diseases such as epilepsy, glaucoma, type-2 diabetes mellitus (T2DM), Alzheimer's disease (AD), and leukemia. Additionally, these inhibition effects were compared with standard enzyme inhibitors like acetazolamide (for hCA I and II), tacrine (for AChE and BChE), and acarbose (for α-Gly and α-Amy). Also, those coumarin–1,2,3-triazole-acetamide hybrids with the best inhibition score were docked into the active site of the indicated metabolic enzymes.     

The prevalence of osteoporosis/osteopenia in patients with multiple sclerosis (MS): a systematic review and meta-analysis

Neurological Sciences - The prevalence of osteoporosis is reported differently. We designed this systematic review and meta-analysis to estimate pooled prevalence of osteoporosis and osteopenia in...     

Therapeutic potential of bevacizumab (Avastin) in herpetic stromal keratitis (HSK)

In the stromal keratitis caused by herpes simplex virus (HSV), the formation of new vessels is the essential step for the pathogenesis of keratitis. Inhibition of angiogenesis diminishes the formation of corneal lesion induced by HSV. Procedures which suppress angiogenesis are proposed as a valuable therapeutic approach to control HSK. The mechanism by which HSV ocular infection results in corneal angiogenesis is not understood. Recent reports identified anti-vascular endothelial growth factor (VEGF) as a molecule that is highly expressed in the HSV infected eye and clearly involved in angiogenesis. The advent of VEGF treatments marks a major advancement in the treatment of angiogenic eye disease. Off-label use of bevacizumab (Avastin), a recombinant humanized monoclonal antibody directed against VEGF, in some neovascular disorders of the eye has been associated with promising short term results. Based on these evidences herein we hypothesize topical application of bevacizumab could inhibit corneal neovascularization and also scarring in HSK. We propose this drug as a novel adjunct to current anti-inflammatory strategies in HSK.     

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma

POLG is the human gene that encodes the catalytic subunit of DNA polymerase gamma (Pol gamma), the replicase for human mitochondrial DNA (mtDNA). A POLG Y955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects. Y955C POLG was targeted transgenically (TG) to the murine heart. Survival was determined in four TG (+/-) lines and wild-type (WT) littermates (-/-). Left ventricle (LV) performance (echocardiography and MRI), heart rate (electrocardiography), mtDNA abundance (real time PCR), oxidation of mtDNA (8-OHdG), histopathology and electron microscopy defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy (CM), mitochondrial oxidative stress, and premature death. Increased LV cavity size and LV mass, bradycardia, decreased mtDNA, increased 8-OHdG, and cardiac histopathological and mitochondrial EM defects supported and defined the phenotype. This study underscores the pathogenetic role of human mutant POLG and its gene product in mtDNA depletion, mitochondrial oxidative stress, and CM as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM.     

Effect of vitamin D supplementation as adjunctive therapy to methylphenidate on ADHD symptoms: A randomized,double blind,placebo-controlled trial

Objectives: Previous studies have shown that serum levels of vitamin D were lower in attention deficit hyperactivity disorder (ADHD) children compared to healthy controls. The aim of the study was to determine the effect of vitamin D supplementation as adjunctive therapy to methylphenidate on symptoms of children with ADHD.

Methods: Sixty-two children aged 5–12 years with a diagnosis of ADHD based on DSM-IV criteria were randomly assigned into two groups to receive either 2000IU vitamin D or placebo in addition to methylphenidate for 8 weeks. Symptoms severity was assessed by Conner's Parent Rating Scale-Revised[S] (CPRS), ADHD rating scale-IV (ADHD-RS), and Weekly Parent Ratings of Evening and Morning Behavior (WPREMB) at weeks 0, 4, and 8. Serum levels of 25(OH)D were measured at baseline and after 8 weeks. Anthropometric variables, dietary intake, physical activity, sun exposure, and side effects were assessed.

Results: Fifty-four participants completed the trial. After 8 weeks of supplementation, serum levels of 25(OH)D significantly increased in the vitamin D group. ADHD symptoms decreased significantly in both groups (P?P?=?0.013, 0.016, respectively), but no differences were found in symptoms by CPRS and ADHD-RS scales.

Discussion: Vitamin D supplementation as adjunctive therapy to methylphenidate improved ADHD evening symptoms. Future research is needed to clarify vitamin D effects as monotherapy in ADHD and its mechanism.

The trial was registered in www.irct.ir is (IRCT201404222394N10).     

Fe3O4@Au core–shell hybrid nanocomposite for MRI-guided magnetic targeted photo-chemotherapy

Lasers in Medical Science - The combination of multiple therapeutic and diagnostic functions is fast becoming a key feature in the area of clinical oncology. The advent of nanotechnology promises...