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Macular Degeneration: HELP
Articles from Lousiana
Based on 19 articles published since 2008
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These are the 19 published articles about Macular Degeneration that originated from Lousiana during 2008-2019.
 
+ Citations + Abstracts
1 Review A Pathogenic Mechanism Potentially Operative in Multiple Progressive Diseases and Its Therapeutic Implications. 2017

Re, Richard N. ·Division of Academics-Research, Ochsner Clinic Foundation, New Orleans, LA, USA. ·J Clin Pharmacol · Pubmed #28884862.

ABSTRACT: A variety of peptide signaling moieties that we have termed intracrines can act in the interiors of their cells of synthesis or of target cells after internalization. These intracrine factors are known to be upregulated in such disorders as diabetic nephropathy, systolic heart failure, and age-related macular degeneration. Indeed, a similar set of intracrines is upregulated in each of these disorders, suggesting a commonality of mechanism. In addition, several chronic neurodegenerative disorders such as Alzheimer disease and Parkinson disease involve intercellular trafficking of intracellular disease-causing proteins. These disorders can be considered intracrine-like. Here the mechanistic and therapeutic implications of these observations, and of the relevant modes of intracrine action, are discussed, including the possibility that similar therapeutic approaches could be effective in multiple progressive disorders and the implications of these observations for intracrine pharmacology in general.

2 Review Current therapeutic developments in atrophic age-related macular degeneration. 2016

Hanus, Jakub / Zhao, Fangkun / Wang, Shusheng. ·Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA. · Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, P. R. China. · Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA Department of Ophthalmology, Tulane University, New Orleans, Louisiana, USA. ·Br J Ophthalmol · Pubmed #26553922.

ABSTRACT: Age-related macular degeneration (AMD), a degenerative disorder of the central retina, is the leading cause of irreversible blindness in the elderly. The underlying mechanism of the advanced form of dry AMD, also named geographic atrophy (GA) or atrophic AMD, remains unclear. Consequently, no cure is available for dry AMD or GA. The only prevention option currently available is the Age-Related Eye Disease Study (AREDS) formulation, which has been demonstrated to slow down the progression of dry AMD. This review summarises recent advances in therapy for dry AMD and GA. Building on the new understanding of the disease and recent technological breakthroughs, numerous ongoing clinical trials have the goal of meeting the need to cure AMD. Therapeutic agents are being developed to target the key features of the disease, including inhibiting the complement pathway and other inflammatory pathways, reducing oxidative stress and protecting retinal pigment epithelial (RPE) cells, inhibiting lipofuscin and visual cycle, regenerating RPE cells from stem cells and restoring choroidal blood flow. Some of these therapeutic options, especially the stem cell-based therapy, hold great promise, which brings great hope for this devastating blinding disease.

3 Review RPE necroptosis in response to oxidative stress and in AMD. 2015

Hanus, Jakub / Anderson, Chastain / Wang, Shusheng. ·Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA. · Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; Department of Ophthalmology, Tulane University, New Orleans, LA 70118, USA. Electronic address: swang1@tulane.edu. ·Ageing Res Rev · Pubmed #26369358.

ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly. The underlying mechanism of non-neovascular AMD (dry AMD), also named geographic atrophy (GA) remains unclear and the mechanism of retinal pigment epithelial (RPE) cell death in AMD is controversial. We review the history and recent progress in understanding the mechanism of RPE cell death induced by oxidative stress, in AMD mouse models, and in AMD patients. Due to the limitation of toolsets to distinguish between apoptosis and necroptosis (or necrosis), most previous research concludes that apoptosis is a major mechanism for RPE cell death in response to oxidative stress and in AMD. Recent studies suggest necroptosis as a major mechanism of RPE cell death in response to oxidative stress. Moreover, ultrastructural and histopathological studies support necrosis as major mechanism of RPE cells death in AMD. In this review, we discuss the mechanism of RPE cell death in response to oxidative stress, in AMD mouse models, and in human AMD patients. Based on the literature, we hypothesize that necroptosis is a major mechanism for RPE cell death in response to oxidative stress and in AMD.

4 Review Recurrent hematuria in a patient with a previously undiagnosed transitional cell carcinoma of the right ureter after intravitreal bevacizumab (Avastin) injection: a case report. 2015

Lemor, Daniel / Lazar, David / Mazzulla, D Anthony. ·*Department of Ophthalmology, Ochsner Clinic Foundation, New Orleans, Louisiana; and †Department of Ophthalmology, Louisiana State University, Health Sciences Center, New Orleans, Louisiana. ·Retin Cases Brief Rep · Pubmed #25383854.

ABSTRACT: PURPOSE: To report a case of gross hematuria in a patient with previously undiagnosed urothelial carcinoma of the right ureter after intravitreal bevacizumab (Avastin) injections. METHODS: In this case report and review of the literature, an 81-year-old woman presented with neovascular age-related macular degeneration in the left eye. She was treated with repeated intravitreal bevacizumab (Avastin) injections. After injection, she reported two episodes of gross hematuria. After disclosing this information to her ophthalmologist, bevacizumab treatment was suspended and the hematuria resolved. Urological evaluation revealed no abnormalities. Approximately 1 year later, treatment with intravitreal bevacizumab was resumed. After three injections, she again reported gross hematuria. Urological evaluation at that time revealed a high-grade urothelial carcinoma of the right ureter. A right nephroureterectomy was performed, and bevacizumab treatment was resumed. She did not report any subsequent episodes of hematuria. CONCLUSION: Hematuria has previously been reported with systemic administration of bevacizumab. However, hematuria after intravitreal injections of bevacizumab has not been reported and is most likely occurring as a result of the systemic absorption of the drug. Further investigation of the systemic effects of intravitreal bevacizumab may be warranted.

5 Review Beta-Amyloid Precursor Protein (βAPP) Processing in Alzheimer's Disease (AD) and Age-Related Macular Degeneration (AMD). 2015

Zhao, Yuhai / Bhattacharjee, Surjyadipta / Jones, Brandon M / Hill, James M / Clement, Christian / Sambamurti, Kumar / Dua, Prerna / Lukiw, Walter J. ·LSU Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112, USA. ·Mol Neurobiol · Pubmed #25204496.

ABSTRACT: Amyloid is a generic term for insoluble, often intensely hydrophobic, fibrous protein aggregates that arise from inappropriately folded versions of naturally-occurring polypeptides. The abnormal generation and accumulation of amyloid, often referred to as amyloidogenesis, has been associated with the immune and pro-inflammatory pathology of several progressive age-related diseases of the human central nervous system (CNS) including Alzheimer's disease (AD) and age-related macular degeneration (AMD). This 'research perspective' paper reviews some of the research history, biophysics, molecular-genetics and environmental factors concerning the contribution of amyloid beta (Aβ) peptides, derived from beta-amyloid precursor protein (βAPP), to AD and AMD that suggests an extensive similarity in immune and inflammatory degenerative mechanisms between these two CNS diseases.

6 Article Up-regulated Pro-inflammatory MicroRNAs (miRNAs) in Alzheimer's disease (AD) and Age-Related Macular Degeneration (AMD). 2018

Pogue, Aileen I / Lukiw, Walter J. ·Alchem Biotech Research, Toronto, ON, Canada. · Alchem Biotech Research, Toronto, ON, Canada. wlukiw@lsuhsc.edu. · Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112-2272, USA. wlukiw@lsuhsc.edu. · Department of Neurology, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112-2272, USA. wlukiw@lsuhsc.edu. · Department of Ophthalmology, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112-2272, USA. wlukiw@lsuhsc.edu. · LSU Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112-2272, USA. wlukiw@lsuhsc.edu. ·Cell Mol Neurobiol · Pubmed #29302837.

ABSTRACT: Alzheimer's disease (AD) of the brain neocortex and age-related macular degeneration (AMD) of the retina are two complex neurodegenerative disorders, which (i) involve the progressive dysregulation and deterioration of multiple neurobiological signaling pathways, (ii) exhibit the temporal accumulation of pro-inflammatory lesions including the amyloid beta (Aβ) peptide-containing senile plaques of AD and the drusen of AMD, and (iii) culminate in an insidious inflammatory neurodegeneration ending, respectively, in neural cell atrophy and death and progressive loss of cognition and central visual function. Recent independent research studies have indicated that AD and AMD share common, pathological signaling defects and disease mechanisms at the molecular genetic level. Using high-integrity total RNA samples pooled from AD brain and AMD retina, microfluidic hybridization miRNA arrays, and bioinformatics, the current study was undertaken to quantify microRNA (miRNA) speciation and complexity common to both AD and AMD. These small non-coding (sncRNAs) are known to post-transcriptionally regulate multiple neurobiological pathways and an abundance of research information has already been generated on the roles of these miRNAs in pathological situations involving inflammatory neuropathology and neural cell decline. Here, for the first time, we report the sequence and abundance of a septet of sncRNAs including miRNA-7, miRNA-9-1, miRNA-23a/miRNA-27a, miRNA-34a, miRNA-125b-1, miRNA-146a, and miRNA-155 that are significantly increased in abundance and common to both AD-affected superior temporal lobe neocortex (Brodmann A22) and the AMD-affected macular region of the retina. Bioinformatics, miRNA-mRNA complementarity, next-gen RNA sequencing, and feature alignment analysis further indicate that these 7 up-regulated miRNAs have the potential to interact with and down-regulate ~ 9460 target messenger RNAs (mRNAs; about 3.5% of the genome) involved in the synchronization of amyloid production and clearance, phagocytosis, innate-immune, pro-inflammatory, and neurotrophic signaling and/or synaptogenesis in diseased tissues.

7 Article cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. 2018

Kerur, Nagaraj / Fukuda, Shinichi / Banerjee, Daipayan / Kim, Younghee / Fu, Dongxu / Apicella, Ivana / Varshney, Akhil / Yasuma, Reo / Fowler, Benjamin J / Baghdasaryan, Elmira / Marion, Kenneth M / Huang, Xiwen / Yasuma, Tetsuhiro / Hirano, Yoshio / Serbulea, Vlad / Ambati, Meenakshi / Ambati, Vidya L / Kajiwara, Yuji / Ambati, Kameshwari / Hirahara, Shuichiro / Bastos-Carvalho, Ana / Ogura, Yuichiro / Terasaki, Hiroko / Oshika, Tetsuro / Kim, Kyung Bo / Hinton, David R / Leitinger, Norbert / Cambier, John C / Buxbaum, Joseph D / Kenney, M Cristina / Jazwinski, S Michal / Nagai, Hiroshi / Hara, Isao / West, A Phillip / Fitzgerald, Katherine A / Sadda, SriniVas R / Gelfand, Bradley D / Ambati, Jayakrishna. ·Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA. · Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA. · Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA. · Department of Ophthalmology, University of Tsukuba, Ibaraki, Japan. · Doheny Eye Institute, Los Angeles, Los Angeles, California, USA. · Department of Ophthalmology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA. · Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Department of Ophthalmology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. · Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA. · Center for Digital Image Evaluation, Charlottesville, Virginia, USA. · Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA. · Departments of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA. · Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA. · Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, USA. · Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA. · Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan. · Department of Urology, Wakayama Medical University, Wakayama, Japan. · Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, USA. · Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA. · Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, Virginia, USA. · Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA. · Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA. ·Nat Med · Pubmed #29176737.

ABSTRACT: Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.

8 Article Strand and Cell Type-specific Function of microRNA-126 in Angiogenesis. 2016

Zhou, Qinbo / Anderson, Chastain / Hanus, Jakub / Zhao, Fangkun / Ma, Jing / Yoshimura, Akihiko / Wang, Shusheng. ·Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA. · Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. · Department of Ophthalmology, Tulane University, New Orleans, Louisiana, USA. ·Mol Ther · Pubmed #27203443.

ABSTRACT: microRNAs or miRs have been shown to be pivotal modulators of vascular development. The strand and cell type-specific function of miR-126 in angiogenesis, especially pathological angiogenesis, remains poorly defined. We characterized the retinal vascular phenotype of miR-126

9 Article microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration. 2016

Bhattacharjee, Surjyadipta / Zhao, Yuhai / Dua, Prerna / Rogaev, Evgeny I / Lukiw, Walter J. ·LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America. · Department of Anatomy and Cell Biology, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America. · Louisiana State Technical University, Ruston, LA, 71270, United States of America. · Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, 01604, United States of America. · Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia. · Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119234, Russia. · Department of Ophthalmology, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America. · Department of Neurology, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America. ·PLoS One · Pubmed #26949937.

ABSTRACT: The aggregation of Aβ42-peptides and the formation of drusen in age-related macular degeneration (AMD) are due in part to the inability of homeostatic phagocytic mechanisms to clear self-aggregating Aβ42-peptides from the extracellular space. The triggering receptor expressed in myeloid/microglial cells-2 (TREM2), a trans-membrane-spanning, sensor-receptor of the immune-globulin/lectin-like gene superfamily is a critical component of Aβ42-peptide clearance. Here we report a significant deficit in TREM2 in AMD retina and in cytokine- or oxidatively-stressed microglial (MG) cells. RT-PCR, miRNA-array, LED-Northern and Western blot studies indicated up-regulation of a microglial-enriched NF-кB-sensitive miRNA-34a coupled to a down-regulation of TREM2 in the same samples. Bioinformatics/transfection-luciferase reporter assays indicated that miRNA-34a targets the 299 nucleotide TREM2-mRNA-3'UTR, resulting in TREM2 down-regulation. C8B4-microglial cells challenged with Aβ42 were able to phagocytose these peptides, while miRNA-34a down-regulated both TREM2 and the ability of microglial-cells to phagocytose. Treatment of TNFα-stressed MG cells with phenyl-butyl nitrone (PBN), caffeic-acid phenethyl ester (CAPE), the NF-kB - [corrected] inhibitor/resveratrol analog CAY10512 or curcumin abrogated these responses. Incubation of anti-miRNA-34a (AM-34a) normalized miRNA-34a abundance and restored TREM2 back to homeostatic levels. These data support five novel observations: (i) that a ROS- and NF-kB - [corrected] sensitive, miRNA-34a-mediated modulation of TREM2 may in part regulate the phagocytic response; (ii) that gene products encoded on two different chromosomes (miRNA-34a at chr1q36.22 and TREM2 at chr6p21.1) orchestrate a phagocytic-Aβ42-peptide clearance-system; (iii) that this NF-kB-mediated-miRNA-34a-TREM2 mechanism is inducible from outside of the cell; (iv) that when operating normally, this pathway can clear Aβ42 peptide monomers from the extracellular medium; and (v) that anti-NF-kB and/or anti-miRNA (AM)-based therapeutic strategies may be useful against deficits in TREM-2 receptor-based-sensing and -phagocytic signaling that promote pathogenic amyloidogenesis.

10 Article NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration. 2016

Wang, Yujuan / Hanus, Jakub W / Abu-Asab, Mones S / Shen, Defen / Ogilvy, Alexander / Ou, Jingxing / Chu, Xi K / Shi, Guangpu / Li, Wei / Wang, Shusheng / Chan, Chi-Chao. ·Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. yujuanwang2013@gmail.com. · State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. yujuanwang2013@gmail.com. · Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA. jhanus@tulane.edu. · Histopathology Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. mones@nei.nih.gov. · Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. defen.shen@gmail.com. · Histopathology Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. ogilvy.alexander@gmail.com. · Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. ouj@nei.nih.gov. · Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. xi.kathy.chu@gmail.com. · Experimental Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. shig@nei.nih.gov. · Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. liwei2@nei.nih.gov. · Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA. swang1@tulane.edu. · Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. chanc@nei.nih.gov. · Histopathology Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. chanc@nei.nih.gov. ·Int J Mol Sci · Pubmed #26760997.

ABSTRACT: Inflammation and oxidative stress are involved in age-related macular degeneration (AMD) and possibly associated with an activation of neuronal apoptosis inhibitor protein/class II transcription activator of the Major Histocompatibility Complex (MHC)/heterokaryon incompatibility/telomerase-associated protein 1, leucine-rich repeat or nucleotide-binding domain, leucine-rich repeat-containing family, and pyrin domain-containing 3 (NLRP3) inflammasome. In the present study, we used a translational approach to address this hypothesis. In patients with AMD, we observed increased mRNA levels of NLRP3, pro-interleukin-1 beta (IL-1β) and pro-IL-18 in AMD lesions of the retinal pigment epithelium (RPE) and photoreceptor. In vitro, a similar increase was evoked by oxidative stress or lipopolysaccharide (LPS) stimulation in the adult retinal pigment epithelium (ARPE-19) cell line, and the increase was reduced in siRNA transfected cells to knockdown NLRP3. Ultrastructural studies of ARPE-19 cells showed a swelling of the cytoplasm, mitochondrial damage, and occurrence of autophagosome-like structures. NLRP3 positive dots were detected within autophagosome-like structures or in the extracellular space. Next, we used a mouse model of AMD, Ccl2/Cx3cr1 double knockout on rd8 background (DKO rd8) to ascertain the in vivo relevance. Ultrastructural studies of the RPE of these mice showed damaged mitochondria, autophagosome-like structures, and cytoplasmic vacuoles, which are reminiscent of the pathology seen in stressed ARPE-19 cells. The data suggest that the NLRP3 inflammasome may contribute in AMD pathogenesis.

11 Article Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway. 2015

Hanus, Jakub / Zhang, Hongmei / Chen, David H / Zhou, Qinbo / Jin, Peng / Liu, Qinghua / Wang, Shusheng. ·Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA. · Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. · Department of Human Genetics, School of Medicine, Emory University, Atlanta, Georgia, USA. · Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. · Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA Department of Ophthalmology, Tulane University, New Orleans, Louisiana, USA swang1@tulane.edu. ·Mol Cell Biol · Pubmed #25802279.

ABSTRACT: The late stage of dry age-related macular degeneration (AMD), or geographic atrophy (GA), is characterized by extensive retinal pigment epithelial (RPE) cell death, and a cure is not available currently. We have recently demonstrated that RPE cells die from necrosis in response to oxidative stress, providing a potential novel mechanism for RPE death in AMD. In this study, we screened U.S. Food and Drug Administration-approved natural compounds and identified gossypol acetic acid (GAA) as a potent inhibitor of oxidative stress-induced RPE cell death. GAA induces antioxidative response and inhibits accumulation of excessive reactive oxygen species in cells, through which it prevents the activation of intrinsic necrotic pathway in response to oxidative stress. Sestrin2 (SESN2) is found to mediate GAA function in antioxidative response and RPE survival upon oxidative stress. Moreover, Forkhead box O3 transcription factor (FoxO3) is further found to be required for GAA-mediated SESN2 expression and RPE survival. Mechanistically, GAA promotes FoxO3 nuclear translocation and binding to the SESN2 enhancer, which in turn increases its transcriptional activity. Taken together, we have identified GAA as a potent inhibitor of oxidative stress-induced RPE necrosis by regulating the FoxO3/SESN2 pathway. This study may have significant implications in the therapeutics of age-related diseases, especially GA.

12 Article Human retinal transmitochondrial cybrids with J or H mtDNA haplogroups respond differently to ultraviolet radiation: implications for retinal diseases. 2014

Malik, Deepika / Hsu, Tiffany / Falatoonzadeh, Payam / Cáceres-del-Carpio, Javier / Tarek, Mohamed / Chwa, Marilyn / Atilano, Shari R / Ramirez, Claudio / Nesburn, Anthony B / Boyer, David S / Kuppermann, Baruch D / Jazwinski, S Michal / Miceli, Michael V / Wallace, Douglas C / Udar, Nitin / Kenney, M Cristina. ·Gavin Herbert Eye Institute, University California Irvine, Irvine, California, United States of America. · Gavin Herbert Eye Institute, University California Irvine, Irvine, California, United States of America; Department of Ophthalmology, El-Minya University, El-Minya, Egypt. · Gavin Herbert Eye Institute, University California Irvine, Irvine, California, United States of America; Cedars-Sinai Medical Center, Los Angeles, California, United States of America. · Retina-Vitreous Associates Medical Group; Beverly Hills, California, United States of America. · Tulane Center for Aging, Tulane University, New Orleans, Louisiana, United States of America. · Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. · Gavin Herbert Eye Institute, University California Irvine, Irvine, California, United States of America; Department of Pathology and Laboratory Medicine, University California Irvine, Irvine, California, United States of America. ·PLoS One · Pubmed #24919117.

ABSTRACT: BACKGROUND: It has been recognized that cells do not respond equally to ultraviolet (UV) radiation but it is not clear whether this is due to genetic, biochemical or structural differences of the cells. We have a novel cybrid (cytoplasmic hybrids) model that allows us to analyze the contribution of mitochondrial DNA (mtDNA) to cellular response after exposure to sub-lethal dose of UV. mtDNA can be classified into haplogroups as defined by accumulations of specific single nucleotide polymorphisms (SNPs). Recent studies have shown that J haplogroup is high risk for age-related macular degeneration while the H haplogroup is protective. This study investigates gene expression responses in J cybrids versus H cybrids after exposure to sub-lethal doses of UV-radiation. METHODOLOGY/PRINCIPAL FINDINGS: Cybrids were created by fusing platelets isolated from subjects with either H (n = 3) or J (n = 3) haplogroups with mitochondria-free (Rho0) ARPE-19 cells. The H and J cybrids were cultured for 24 hours, treated with 10 mJ of UV-radiation and cultured for an additional 120 hours. Untreated and treated cybrids were analyzed for growth rates and gene expression profiles. The UV-treated and untreated J cybrids had higher growth rates compared to H cybrids. Before treatment, J cybrids showed lower expression levels for CFH, CD55, IL-33, TGF-A, EFEMP-1, RARA, BCL2L13 and BBC3. At 120 hours after UV-treatment, the J cybrids had decreased CFH, RARA and BBC3 levels but increased CD55, IL-33 and EFEMP-1 compared to UV-treated H cybrids. CONCLUSION/SIGNIFICANCE: In cells with identical nuclei, the cellular response to sub-lethal UV-radiation is mediated in part by the mtDNA haplogroup. This supports the hypothesis that differences in growth rates and expression levels of complement, inflammation and apoptosis genes may result from population-specific, hereditary SNP variations in mtDNA. Therefore, when analyzing UV-induced damage in tissues, the mtDNA haplogroup background may be important to consider.

13 Article Ensemble selection for feature-based classification of diabetic maculopathy images. 2013

Chowriappa, Pradeep / Dua, Sumeet / Rajendra Acharya, U / Muthu Rama Krishnan, M. ·Department of Computer Science, Louisiana Tech University, Ruston, LA 71272, USA. ·Comput Biol Med · Pubmed #24290932.

ABSTRACT: As diabetic maculopathy (DM) is a prevalent cause of blindness in the world, it is increasingly important to use automated techniques for the early detection of the disease. In this paper, we propose a decision system to classify DM fundus images into normal, clinically significant macular edema (CMSE), and non-clinically significant macular edema (non-CMSE) classes. The objective of the proposed decision system is three fold namely, to automatically extract textural features (both region specific and global), to effectively choose subset of discriminatory features, and to classify DM fundus images to their corresponding class of disease severity. The system uses a gamut of textural features and an ensemble classifier derived from four popular classifiers such as the hidden naïve Bayes, naïve Bayes, sequential minimal optimization (SMO), and the tree-based J48 classifiers. We achieved an average classification accuracy of 96.7% using five-fold cross validation.

14 Article Pharmaceutical composition for treating macular degeneration (WO2012079419). 2013

Wang, Shusheng / Cunnusamy, Khrishen. ·Tulane University, Department of Cell and Molecular Biology, LA, USA. swang1@tulane.edu ·Expert Opin Ther Pat · Pubmed #23215532.

ABSTRACT: A pharmaceutical composition composed of several traditional Chinese medicines is claimed to treat age-related macular degeneration (AMD). This represents a novel and alternative therapeutic solution for wet AMD, with the potential advantage of treating both the symptoms and the underlying causes of this devastating degenerative retinal disease.

15 Article Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. 2011

Bazan, Nicolas G / Molina, Miguel F / Gordon, William C. ·Neuroscience Center of Excellence and Department of Ophthalmology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. nbazan@lsuhsc.edu ·Annu Rev Nutr · Pubmed #21756134.

ABSTRACT: Essential polyunsaturated fatty acids (PUFAs) are critical nutritional lipids that must be obtained from the diet to sustain homeostasis. Omega-3 and -6 PUFAs are key components of biomembranes and play important roles in cell integrity, development, maintenance, and function. The essential omega-3 fatty acid family member docosahexaenoic acid (DHA) is avidly retained and uniquely concentrated in the nervous system, particularly in photoreceptors and synaptic membranes. DHA plays a key role in vision, neuroprotection, successful aging, memory, and other functions. In addition, DHA displays anti-inflammatory and inflammatory resolving properties in contrast to the proinflammatory actions of several members of the omega-6 PUFAs family. This review discusses DHA signalolipidomics, comprising the cellular/tissue organization of DHA uptake, its distribution among cellular compartments, the organization and function of membrane domains rich in DHA-containing phospholipids, and the cellular and molecular events revealed by the uncovering of signaling pathways regulated by DHA and docosanoids, the DHA-derived bioactive lipids, which include neuroprotectin D1 (NPD1), a novel DHA-derived stereoselective mediator. NPD1 synthesis agonists include neurotrophins and oxidative stress; NPD1 elicits potent anti-inflammatory actions and prohomeostatic bioactivity, is anti-angiogenic, promotes corneal nerve regeneration, and induces cell survival. In the context of DHA signalolipidomics, this review highlights aging and the evolving studies on the significance of DHA in Alzheimer's disease, macular degeneration, Parkinson's disease, and other brain disorders. DHA signalolipidomics in the nervous system offers emerging targets for pharmaceutical intervention and clinical translation.

16 Article Enhanced oxygen saturation in optic nerve head of non-human primate eyes following the intravitreal injection of NCX 434, an innovative nitric oxide-donating glucocorticoid. 2011

Khoobehi, Bahram / Chiroli, Valerio / Ronchetti, Daniela / Miglietta, Daniela / Thompson, Hillary / Ongini, Ennio / Impagnatiello, Francesco. ·Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA, USA. ·J Ocul Pharmacol Ther · Pubmed #21413860.

ABSTRACT: PURPOSE: Hypoxia of the retina and optic nerve head (ONH) is believed to be pivotal in the development of ocular vascular disorders, including diabetic macular edema (DME). Glucocorticoids are among the most effective agents for the treatment of back of the eye diseases. However, this class of compounds is highly liable to increase intraocular pressure (IOP) and does not improve ocular perfusion or tissue oxygenation. Nitric oxide (NO) has vasodilating properties and lowers IOP in experimental models and humans, suggesting that its properties might complement those of glucocorticoids. NCX 434 is an NO-donating triamcinolone acetonide (TA) that is less likely to increase IOP while targeting both the vascular and inflammatory components of DME. METHODS: NCX 434 was studied in vitro with respect to its NO-releasing properties in isolated methoxamine-precontracted rabbit aortic rings and glucocorticoid-like activity in recombinant human glucocorticoid receptors. IOP and oxygen saturation in the ONH and overlaying arteries and veins were studied in the anesthetized cynomolgus monkey. Measurements were taken using, respectively, an applanation tonometer and a hyperspectral imaging system before and 7, 14, 21, 31 and 41 days after the intravitreal injection of NCX 434 (5.8 mg/eye) or TA equimolar doses (4.0 mg/eye). RESULTS: NCX 434 inhibited (3)H-dexamethasone-specific binding (IC(50)=34±5 nM) on human glucocorticoid receptors and elicited NO-dependent aortic ring relaxation (EC(50) of 0.5±0.1 μM, E(max) 98.9%). In monkey eyes, NCX 434 enhanced, whereas TA did not, oxygen saturation in various ONH areas (*P<0.05 vs. basal), decreased it in veins, and did not affect it in the overlaying arteries. Neither NCX 434 nor TA altered IOP significantly at all time points. However, at 31 days post-treatment TA appeared to start increasing IOP (Δ(IOP)=+3.31±0.51 mmHg, 30.8%, over baseline, NS). CONCLUSIONS: NCX 434 enhances ocular tissue oxygenation. This feature appears to depend on its NO-donating properties; thus, the compound deserves to be further investigated for the treatment of DME and other ocular disorders with impaired ocular perfusion.

17 Article Bartonella henselae neuroretinitis in a 15-year-old girl with chronic myelogenous leukemia. 2009

Irshad, Farhan A / Gordon, Robert A. ·Tulane University School of Medicine, Department of Ophthalmology, 1413 Tulane Avenue, New Orleans, LA 70112, USA. firshad@tulane.edu ·J AAPOS · Pubmed #20006827.

ABSTRACT: A 15-year-old girl being treated with imatinib for chronic myelogenous leukemia (CML) presented with acute vision loss in her right eye accompanied by swelling of the right side of her neck. On examination, she was found to have disk and macular edema of the right eye. Fine-needle aspiration and excisional biopsies of an enlarged submandibular lymph node were negative for malignancy. Although initial serologies were equivocal for Bartonella henselae, repeat serologies performed 1 week later upon the appearance of a macular star were positive. This is the first reported case of B. henselae in a patient with CML.

18 Article Reproducible measurement of macular light flash recovery time using a novel device can indicate the presence and worsening of macular diseases. 2009

Newsome, David A / Negreiro, Manny. ·Retinal Institute of Louisiana, New Orleans, Louisiana, USA. doctordave1618@aol.com ·Curr Eye Res · Pubmed #19219688.

ABSTRACT: PURPOSE: To determine the safety, sensitivity, and specificity of a novel flash photorecovery timing instrument with response verification in differentiating normal from abnormal maculae, and in detecting worsening macular disease. METHODS: Right and left eye photorecovery times were determined at baseline and after 5 min using a xenon arc, flash filtered for infrared, ultraviolet, and visible short wavelengths, delivered through an aperture in a hand-held tube. A push-button actuated timer and flash and stopped timer when lighted numbers became visible post-flash. A numeric keypad verified responses. Normal subjects (two eyes tested, n = 144; one eye tested, n = 108) ranged in age from 15 to 84. Photorecovery times were measured in one eye of subjects with small drusen and 20/20 acuity (53-55 correct ETDRS letters; n = 57); in both eyes of subjects with dry age-related macular degeneration (AMD; n = 118); wet AMD with (n = 19) or without (n = 17) macular fluid; and eyes of diabetics with background retinopathy with (n = 19) or without (n = 17) macular retinal thickening. Once-weekly photorecovery measurements for 6 months in each eye of 10 dry AMD subjects and 10 dry diabetic maculopathy subjects provided longitudinal data. RESULTS: Normal subjects' mean right eye recovery time was 9.6 sec (+/- 1.9 SD); left 10.8 sec (+/- 1.0 SD). Photorecovery lengthened after age 55, nearly doubling that of young subjects by age 80. Macular edema, serous macular detachment, or worsened dry AMD were accompanied by prolonged photorecovery (p < .01). When abnormal new vessels or retinal thickening appeared in three serially followed patients, photorecovery at least doubled (p < .01). In all three, photorecovery prolongation occurred without clinical symptoms. None of the 499 tested subjects reported adverse events due to the flash testing. CONCLUSIONS: These findings support the usefulness of a reproducible light flash macular vision recovery measurement as an indicator of macular pathology and worsening disease.

19 Article A randomized, prospective, placebo-controlled clinical trial of a novel zinc-monocysteine compound in age-related macular degeneration. 2008

Newsome, David A. ·Retinal Institute of Louisiana, New Orleans, Louisiana, USA. doctordave1618@aol.com ·Curr Eye Res · Pubmed #18600492.

ABSTRACT: PURPOSE: To test the hypothesis that daily use of zinc-monocysteine (ZMC) supplement will be well tolerated and result in improved macular function in persons with dry age-related macular degeneration (AMD). METHODS: Eligible, consenting subjects were randomized to either ZMC 25 mg or placebo twice daily for 6 months. Both ZMC and placebo groups enrolled 40 participants, with best corrected visual acuity 20/25 to 20/70, macular drusen, and pigment changes. Masked personnel determined baseline, 3- and 6-month best-corrected visual acuity, contrast sensitivity, and light flash recovery time. Differences between ZMC and placebo were analyzed by a one-sided unpaired t-test of the paired differences between baseline and 3- and 6-month timepoints for right and left eyes separately. RESULTS: By 6 months the ZMC group showed improved visual acuity (p < 0.0001) and contrast sensitivity (p < 0.0001). Macular light flash recovery time shortened in the ZMC group at 3 months by 2.1 sec (left eye, p = 0.0001) to 3.6 sec (right eye, p < 0.0001), and at 6 months by 7.2 sec (left eye, p < 0.0001) to 7.4 sec (right eye, p < 0.0001). This variable had no improvement in the placebo group. ZMC had a gastrointestinal irritation rate of under 2%. CONCLUSION: ZMC 25 mg twice daily was well tolerated and was associated with improved macular function in comparison to a placebo in persons with dry AMD.