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Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

Moos, Walter H; Faller, Douglas V; Glavas, Ioannis P; Harpp, David N; Kanara, Iphigenia; Mavrakis, Anastasios N; Pernokas, Julie; Pernokas, Mark; Pinkert, Carl A; Powers, Whitney R; Sampani, Konstantina; Steliou, Kosta; Vavvas, Demetrios G; Zamboni, Robert J; Kodukula, Krishna; Chen, Xiaohong
In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.
PMCID:7133426
PMID: 32257625
ISSN: 2164-7844
CID: 4378852

Epigenetic treatment of dermatologic disorders

Moos, Walter H.; Faller, Douglas V.; Glavas, Ioannis P.; Harpp, David N.; Kanara, Iphigenia; Pinkert, Carl A.; Powers, Whitney R.; Sampani, Konstantina; Steliou, Kosta; Vavvas, Demetrios G.; Kodukula, Krishna; Zamboni, Robert J.
ISI:000488178700002
ISSN: 0272-4391
CID: 4135812

A New Approach to Treating Neurodegenerative Otologic Disorders

Moos, Walter H; Faller, Douglas V; Glavas, Ioannis P; Harpp, David N; Irwin, Michael H; Kanara, Iphigenia; Pinkert, Carl A; Powers, Whitney R; Steliou, Kosta; Vavvas, Demetrios G; Kodukula, Krishna
Hearing loss, the most common neurological disorder and the fourth leading cause of years lived with disability, can have profound effects on quality of life. The impact of this "invisible disability," with significant consequences, economic and personal, is most substantial in low- and middle-income countries, where >80% of affected people live. Given the importance of hearing for communication, enjoyment, and safety, with up to 500 million affected globally at a cost of nearly $800 billion/year, research on new approaches toward prevention and treatment is attracting increased attention. The consequences of noise pollution are largely preventable, but irreversible hearing loss can result from aging, disease, or drug side effects. Once damage occurs, treatment relies on hearing aids and cochlear implants. Preventing, delaying, or reducing some degree of hearing loss may be possible by avoiding excessive noise and addressing major contributory factors such as cardiovascular risk. However, given the magnitude of the problem, these interventions alone are unlikely to be sufficient. Recent advances in understanding principal mechanisms that govern hearing function, together with new drug discovery paradigms designed to identify efficacious therapies, bode well for pharmaceutical intervention. This review surveys various causes of loss of auditory function and discusses potential neurological underpinnings, including mitochondrial dysfunction. Mitochondria mitigate cell protection, survival, and function and may succumb to cumulative degradation of energy production and performance; the end result is cell death. Energy-demanding neurons and vestibulocochlear hair cells are vulnerable to mitochondrial dysfunction, and hearing impairment and deafness are characteristic of neurodegenerative mitochondrial disease phenotypes. Beyond acting as cellular powerhouses, mitochondria regulate immune responses to infections, and studies of this phenomenon have aided in identifying nuclear factor kappa B and nuclear factor erythroid 2-related factor 2/antioxidant response element signaling as targets for discovery of otologic drugs, respectively, suppressing or upregulating these pathways. Treatment with free radical scavenging antioxidants is one therapeutic approach, with lipoic acid and corresponding carnitine esters exhibiting improved biodistribution and other features showing promise. These compounds are also histone deacetylase (HDAC) inhibitors, adding epigenetic modulation to the mechanistic milieu through which they act. These data suggest that new drugs targeting mitochondrial dysfunction and modulating epigenetic pathways via HDAC inhibition or other mechanisms hold great promise.
PMCID:6069589
PMID: 30069423
ISSN: 2164-7844
CID: 3217142

Epigenetic Treatment of Persistent Viral Infections

Moos, Walter H; Pinkert, Carl A; Irwin, Michael H; Faller, Douglas V; Kodukula, Krishna; Glavas, Ioannis P; Steliou, Kosta
Preclinical Research Approximately 2,500 years ago, Hippocrates used the word herpes as a medical term to describe lesions that appeared to creep or crawl on the skin, advocating heat as a possible treatment. During the last 50 years, pharmaceutical research has made great strides, and therapeutic options have expanded to include small molecule antiviral agents, protease inhibitors, preventive vaccines for a handful of the papillomaviruses, and even cures for hepatitis C virus infections. However, effective treatments for persistent and recurrent viral infections, particularly the highly prevalent herpesviruses, continue to represent a significant unmet medical need, affecting the majority of the world's population. Exploring the population diversity of the human microbiome and the effects its compositional variances have on the immune system, health, and disease are the subjects of intense investigational research and study. Among the collection of viruses, bacteria, fungi, and single-cell eukaryotes that comprise the human microbiome, the virome has been grossly understudied relative to the influence it exerts on human pathophysiology, much as mitochondria have until recently failed to receive the attention they deserve, given their critical biomedical importance. Fortunately, cellular epigenetic machinery offers a wealth of druggable targets for therapeutic intervention in numerous disease indications, including those outlined above. With advances in synthetic biology, engineering our body's commensal microorganisms to seek out and destroy pathogenic species is clearly on the horizon. This is especially the case given recent breakthroughs in genetic manipulation with tools such as the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated) gene-editing platforms. Tying these concepts together with our previous work on the microbiome and neurodegenerative and neuropsychiatric diseases, we suggest that, because mammalian cells respond to a viral infection by triggering a cascade of antiviral innate immune responses governed substantially by the cell's mitochondria, small molecule carnitinoids represent a new class of therapeutics with potential widespread utility against many infectious insults. Drug Dev Res, 2016. (c) 2016 Wiley Periodicals, Inc.
PMID: 27761936
ISSN: 0272-4391
CID: 2280062

Epigenetic Treatment of Neurodegenerative Ophthalmic Disorders: An Eye Toward the Future

Moos, Walter H; Faller, Douglas V; Glavas, Ioannis P; Harpp, David N; Irwin, Michael H; Kanara, Iphigenia; Pinkert, Carl A; Powers, Whitney R; Steliou, Kosta; Vavvas, Demetrios G; Kodukula, Krishna
Eye disease is one of the primary medical conditions that requires attention and therapeutic intervention in ageing populations worldwide. Further, the global burden of diabetes and obesity, along with heart disease, all lead to secondary manifestations of ophthalmic distress. Therefore, there is increased interest in developing innovative new approaches that target various mechanisms and sequelae driving conditions that result in adverse vision. The research challenge is even greater given that the terrain of eye diseases is difficult to landscape into a single therapeutic theme. This report addresses the burden of eye disease due to mitochondrial dysfunction, including antioxidant, autophagic, epigenetic, mitophagic, and other cellular processes that modulate the biomedical end result. In this light, we single out lipoic acid as a potent known natural activator of these pathways, along with alternative and potentially more effective conjugates, which together harness the necessary potency, specificity, and biodistribution parameters required for improved therapeutic outcomes.
PMCID:5747116
PMID: 29291141
ISSN: 2164-7844
CID: 2898572

Orbital fractures: a review

Joseph, Jeffrey M; Glavas, Ioannis P
THIS REVIEW OF ORBITAL FRACTURES HAS THREE GOALS: 1) to understand the clinically relevant orbital anatomy with regard to periorbital trauma and orbital fractures, 2) to explain how to assess and examine a patient after periorbital trauma, and 3) to understand the medical and surgical management of orbital fractures. The article aims to summarize the evaluation and management of commonly encountered orbital fractures from the ophthalmologic perspective and to provide an overview for all practicing ophthalmologists and ophthalmologists in training.
PMCID:3037036
PMID: 21339801
ISSN: 1177-5467
CID: 162767

Anatomic properties of the upper eyelid in Asian Americans

Cho, Minhee; Glavas, Ioannis P
BACKGROUND: With increasing demand for 'double eyelid' surgery within the United States, it becomes prudent for U.S. surgeons to become familiar with Asian eyelid anatomy. OBJECTIVE: To identify and describe anatomic characteristics of the Asian upper eyelid. METHODS: A cross-sectional descriptive series of 9 Korean-American and 10 Chinese-American subjects. Standardized photographs of the eyes were analyzed. Three types of eyelid anatomy were described: single eyelid, low eyelid crease, and double eyelid. RESULTS: The incidence rate for the three types of eyelid anatomies varied between Chinese and Korean Americans. The mean palpebral fissure height, width, and inclination were not statistically different between the two populations. A few subjects had asymmetric eyelid configurations. Chinese American and Korean American double eyelids tended to flare up laterally when the eye was open. The mean double eyelid crease height at the medial limbus was 3.7 +/- 1.1 mm, and the mean height at the lateral limbus 4.6 +/- 1.0 mm. This difference was statistically significant (p<.04). CONCLUSION: Eyelid anatomies vary in different Asian Americans. Surgeons need to be mindful of different eyelid configurations and measurement patterns to achieve the most natural-looking Asian double eyelids
PMID: 19660027
ISSN: 1524-4725
CID: 105335

The hyaluronic acid push technique for the nasojugal groove

Bosniak, Stephen; Sadick, Neil S; Cantisano-Zilkha, Marian; Glavas, Ioannis P; Roy, Deborshi
PMID: 18053030
ISSN: 1524-4725
CID: 96468

Definition of the tear trough and the tear trough rating scale

Sadick, Neil S; Bosniak, Stephen L; Cantisano-Zilkha, Marian; Glavas, Ioannis P; Roy, Deborshi
BACKGROUND: Nasojugal groove and tear trough are interchangeably used terms by many authors in the literature despite the fact that they describe distinct and different anatomic entities. In the same vein, there are multiple descriptions of treatments and techniques for the cosmetic improvement of these anatomic areas without specifically addressing the anatomic difference between them. OBJECTIVE: This study aims to define the anatomic characteristics of the tear trough and describe a novel classification scale for the evaluation of the tear trough deformity. METHODS: The tear trough rating scale (TTRS) was applied to a representative sample of our patient population. Five of the authors evaluated each patient using the TTRS, and the numeric results were tabulated and compared. Results The TTRS provided an effective, reproducible method for evaluating tear trough deformities, and there was very little interobserver variability. CONCLUSION: The tear trough should be defined as the depression of the medial lower eyelid just lateral to the anterior lacrimal crest and limited in its inferior aspect by the inferior orbital rim. The TTRS is a reliable tool for the classification of the tear trough and evaluation of therapeutic and cosmetic interventions
PMID: 18047604
ISSN: 1473-2165
CID: 96469

Noninvasive techniques in periorbital rejuvenation

Glavas, Ioannis P; Purewal, Baljeet K
The combination of noninvasive treatments in the periorbital area can be used to achieve dramatic and long-lasting results. New technologies and current therapies may supplement or even delay traditional surgical procedures
PMID: 17691063
ISSN: 0736-6825
CID: 74303