scholarly journals Retinal Redox Stress and Remodeling in Cardiometabolic Syndrome and Diabetes

2010 ◽  
Vol 3 (6) ◽  
pp. 392-403 ◽  
Author(s):  
Ying Yang ◽  
Melvin R. Hayden ◽  
Susan Sowers ◽  
Sarika V. Bagree ◽  
James R. Sowers
Keyword(s):  
Metabolic Pathways ◽  
Tissue Injury ◽  
Disease Process ◽  
Polyol Pathway ◽  
The United States ◽  
Redox Stress ◽  
Blood Retinal Barrier ◽  
Cardiometabolic Syndrome ◽  
Hexosamine Pathway ◽  
Pathway Flux

Diabetic retinopathy (DR) is a significant cause of global blindness; a major cause of blindness in the United States in people aged between 20–74. There is emerging evidence that retinopathy is initiated and propagated by multiple metabolic toxicities associated with excess production of reactive oxygen species (ROS). The four traditional metabolic pathways involved in the development of DR include: increased polyol pathway flux, advanced glycation end-product formation, activation of protein kinase Cisoforms and hexosamine pathway flux. These pathways individually and synergisticallycontribute to redox stress with excess ROS resulting in retinal tissue injury resulting in significant microvascular blood retinal barrier remodeling. The toxicity of hyperinsulinemia, hyperglycemia, hypertension, dyslipidemia, increased cytokines and growth factors, in conjunction with redox stress, contribute to the development and progression of DR. Redox stress contributes to the development and progression of abnormalities of endothelial cells and pericytes in DR. This review focuses on the ultrastructural observations of the blood retinal barrier including the relationship between the endothelial cell and pericyte remodeling in young nine week old Zucker obese (fa/ fa) rat model of obesity; cardiometabolic syndrome, and the 20 week old alloxan induced diabetic porcine model. Preventing or delaying the blindness associated with these intersecting abnormal metabolic pathways may be approached through strategies targeted to reduction of tissue inflammation and oxidative—redox stress. Understanding these abnormal metabolic pathways and the accompanying redox stress and remodeling mayprovide both the clinician and researcher a new concept of approaching this complicated disease process

scholarly journals Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets

2014 ◽  
Vol 2014 ◽  
pp. 1-18 ◽  
Author(s):  
Sher Zaman Safi ◽  
Rajes Qvist ◽  
Selva Kumar ◽  
Kalaivani Batumalaie ◽  
Ikram Shah Bin Ismail
Keyword(s):  
Diabetic Retinopathy ◽  
Structural Damage ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Therapeutic Targets ◽  
Polyol Pathway ◽  
Preventive Strategies ◽  
Retinal Cells ◽  
Hexosamine Pathway ◽  
Pathway Flux

The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors.

Deciphering the Neuroprotective Role of Glucagon-like peptide-1 Agonists in Diabetic Neuropathy: Current Perspective and Future Directions

2020 ◽  
Vol 21 ◽  
Author(s):  
Keshav Mehta ◽  
Tapan Behl ◽  
Arun Kumar ◽  
Md Sahab Uddin ◽  
Gokhan Zengin ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Neuropathy ◽  
Metabolic Pathways ◽  
Polyol Pathway ◽  
Dipeptidyl Peptidase 4 ◽  
Hexosamine Pathway ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Incretin Therapy ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract:: Diabetic neuropathy is referred as subsequential and debilitating complication belonging to type 1 and type 2 diabetes mellitus. It is a heterogeneous group of disorder with particularly complex pathophysiology and also includes multiple forms, ranging from normal discomfort to death. The evaluation of diabetic neuropathy is associated with hyperglycemic responses, resulting in alteration in various metabolic pathways including protein kinase C pathway, polyol pathway and hexosamine pathway in sachwann and glial cells of neurons. The essential source of neuronal destruction is analogous to these respective metabolic pathways, thus identified as potential therapeutic targets. These pathways regulating therapeutic medications may be used for diabetic neuropathy, however, only target specific drugs could have partial therapeutic activity. Various antidiabetic medications have been approved and marketed, which possess therapeutic ability to control hyperglycemia and ameliorate the prevalence of diabetic neuropathy. Among all antidiabetic medications, incretin therapy, including Glucagon- like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, are the most favorable medications for the management of diabetes mellitus and associated peripheral neuropathic complications. Besides enhancing glucose-evoked insulin release from pancreatic β–cells, these therapeutic agents also play a vital role to facilitate neurite outgrowth and nerve conduction velocity in dorsal root ganglion. Furthermore, incretin therapy also activates cAMP and ERK signalling pathways, resulting in nerve regeneration and repairing. These effects are evidently supported by a series of preclinical data and investigations associated with these medications. However, the literature lacks an adequate clinical trials outcome related to these novel antidiabetic medications. The manuscript emphasizes on the pathogenesis, current pharmacological approaches and vivid description of preclinical and clinical data for the effective management of diabetic neuropathy.

scholarly journals A Systems-Level Model Reveals That 1,2-Propanediol Utilization Microcompartments Enhance Pathway Flux Through Intermediate Sequestration

2016 ◽  
Author(s):  
Christopher M. Jakobson ◽  
Marilyn F. Slininger ◽  
Danielle Tullman-Ercek ◽  
Niall M. Mangan
Keyword(s):  
Mathematical Model ◽  
Active Transport ◽  
Substrate Concentration ◽  
Metabolic Pathways ◽  
Salmonella Enterica ◽  
The United States ◽  
Subcellular Organelles ◽  
Bacterial Microcompartments ◽  
Metabolite Concentrations ◽  
Pathway Flux

AbstractThe spatial organization of metabolism is common to all domains of life. Enteric and other bacteria use subcellular organelles known as bacterial microcompartments to spatially organize the metabolism of pathogenicity-relevant carbon sources, such as 1,2-propanediol. The organelles are thought to sequester a private cofactor pool, minimize the effects of toxic intermediates, and enhance flux through the encapsulated metabolic pathways. We develop a mathematical model of the function of the 1,2-propanediol utilization microcompartment of Salmonella enterica and use it to analyze the function of the microcompartment organelles in detail. Our model makes accurate predictions of doubling times based on an optimized compartment shell permeability determined by maximizing metabolic flux in the model. The compartments function primarily to decouple cytosolic intermediate concentrations from the concentrations in the microcompartment, allowing significant enhancement in pathway flux by the generation of large concentration gradients across the microcompartment shell. We find that selective permeability of the microcompartment shell is not absolutely necessary, but is often beneficial in establishing this intermediate-trapping function. Our findings also implicate active transport of the 1,2-propanediol substrate under conditions of low external substrate concentration, and we present a mathematical bound, in terms of external 1,2-proanediol substrate concentration and diffusive rates, on when active transport of the substrate is advantageous. By allowing us to predict experimentally inaccessible aspects of microcompartment function, such as intra-microcompartment metabolite concentrations, our model presents avenues for future research and underscores the importance of carefully considering changes in external metabolite concentrations and other conditions during batch cultures. Our results also suggest that the encapsulation of heterologous pathways in bacterial microcompartments might yield significant benefits for pathway flux, as well as for toxicity mitigation.Author SummaryMany bacterial species, such as Salmonella enterica (responsible for over 1 million illnesses per year in the United States) and Yersinia pestis (the causative agent of bubonic plague), have a suite of unique metabolic capabilities allowing them to proliferate in the hostile environment of the host gut. Bacterial microcompartments are the subcellular organelles that contain the enzymes responsible for these special metabolic pathways. In this study, we use a mathematical model to explore the possible reasons why Salmonella enclose the 1,2-propanediol utilization metabolic pathway within these sophisticated organelle structures. Using our model, we can examine experimentally inaccessible aspects of the system and make predictions to be tested in future experiments. The metabolic benefits that bacteria gain from the microcompartment system may also prove helpful in enhancing bacterial production of fuels, pharmaceuticals, and specialty chemicals.

scholarly journals Metabolic Dysregulation and Neurovascular Dysfunction in Diabetic Retinopathy

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1244
Author(s):  
Thangal Yumnamcha ◽  
Michael Guerra ◽  
Lalit Pukhrambam Singh ◽  
Ahmed S. Ibrahim
Keyword(s):  
Diabetic Retinopathy ◽  
Oxidative Phosphorylation ◽  
Glucose Homeostasis ◽  
Krebs Cycle ◽  
Polyol Pathway ◽  
Developed Countries ◽  
The United States ◽  
Glycolytic Flux ◽  
Obesity And Diabetes ◽  
Hexosamine Pathway

Diabetic retinopathy is a major cause of ocular complications in patients with type 1 and type 2 diabetes in developed countries. Due to the continued increase in the number of people with obesity and diabetes in the United States of America and globally, the incidence of diabetic retinopathy is expected to increase significantly in the coming years. Diabetic retinopathy is widely accepted as a combination of neurodegenerative and microvascular changes; however, which change occurs first is not yet understood. Although the pathogenesis of diabetic retinopathy is very complex, regulated by numerous signaling pathways and cellular processes, maintaining glucose homeostasis is still an essential component for normal physiological functioning of retinal cells. The maintenance of glucose homeostasis is finely regulated by coordinated interplay between glycolysis, Krebs cycle, and oxidative phosphorylation. Glycolysis is the most conserved metabolic pathway in biology and is tightly regulated to maintain a steady-state concentration of glycolytic intermediates; this regulation is called scheduled or regulated glycolysis. However, an abnormal increase in glycolytic flux generates large amounts of intermediate metabolites that can be shunted into different damaging pathways including the polyol pathway, hexosamine pathway, diacylglycerol-dependent activation of the protein kinase C pathway, and Amadori/advanced glycation end products (AGEs) pathway. In addition, disrupting the balance between glycolysis and oxidative phosphorylation leads to other biochemical and molecular changes observed in diabetic retinopathy including endoplasmic reticulum-mitochondria miscommunication and mitophagy dysregulation. This review will focus on how dysregulation of glycolysis contributes to diabetic retinopathy.

Mosquito and Tick-borne Illnesses in the United States. Guidelines for the Recognition and Empiric Treatment of Zoonotic Diseases in the Wilderness.

2019 ◽  
Vol 19 (3) ◽  
pp. 238-257
Author(s):  
Suresh Antony
Keyword(s):  
United States ◽  
Lyme Disease ◽  
Spotted Fever ◽  
Disease Process ◽  
Rocky Mountain ◽  
The United States ◽  
Health Care Facilities ◽  
Diagnostic Tools ◽  
Rocky Mountain Spotted Fever ◽  
Number Of Patients

Background:In the United States, tick-borne illnesses account for a significant number of patients that have been seen and treated by health care facilities. This in turn, has resulted in a significant morbidity and mortality and economic costs to the country.Methods:The distribution of these illnesses is geographically variable and is related to the climate as well. Many of these illnesses can be diagnosed and treated successfully, if recognized and started on appropriate antimicrobial therapy early in the disease process. Patient with illnesses such as Lyme disease, Wet Nile illness can result in chronic debilitating diseases if not recognized early and treated.Conclusion:This paper covers illnesses such as Lyme disease, West Nile illness, Rocky Mountain Spotted fever, Ehrlichia, Tularemia, typhus, mosquito borne illnesses such as enteroviruses, arboviruses as well as arthropod and rodent borne virus infections as well. It covers the epidemiology, clinical features and diagnostic tools needed to make the diagnosis and treat these patients as well.

Telemedicine for Patients with Inflammatory Bowel Disease (TELE-IBD) Clinical Trial: Qualitative Assessment of Participants’ Perceptions of the TELE-IBD Intervention (Preprint)

2019 ◽  
Author(s):  
Charlene C Quinn ◽  
Sarah Chard ◽  
Erin G Roth ◽  
J. Kevin Eckert ◽  
Katharine M Russman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Disease Activity ◽  
Remote Monitoring ◽  
Standard Care ◽  
Disease Process ◽  
The United States ◽  
Qualitative Assessment ◽  
Structured Interviews ◽  
Treatment Groups ◽  
Inflammatory Bowel

BACKGROUND Inflammatory bowel diseases (IBD), comprising Crohn’s disease and ulcerative colitis, affects 1 to 3 million people in the United States. Telemedicine has shown promise in IBD. The objective of the parent study, TELE-IBD, was to compare disease activity and quality of life (QoL) in a one-year randomized clinical trial of IBD patients receiving telemedicine versus standard care. Treatment groups experienced improvements in disease activity and QoL but there was not significant differences between groups. Study adherence to the text-based intervention was less than the 80% of the targeted goal. OBJECTIVE To understand adherence to remote monitoring, the goal of this qualitative assessment was to obtain TELE-IBD trial participants’ perceptions of the TELE-IBD system, including their recommendations for future TELE-IBD monitoring. METHODS In the parent study, patients attending three tertiary referral centers with worsening IBD symptoms in the previous two years were eligible for randomization to remote monitoring via texts every other week (EOW), weekly (W) or standard care. Participants (n=348) were evenly enrolled in the treatment groups and 259 (74.4%) completed the study. For this study, a purposive sample of adherent (N=15) and non-adherent (N=14) patients was drawn from the TELE-IBD trial population. Adherence was defined as the completion of 80% or more of the W or EOW self-assessments. Semi-structured interviews conducted by phone surveyed 1) the strengths and benefits of TELE-IBD; 2) challenges associated with using TELE-IBD; and 3) how to improve the TELE-IBD intervention. Interviews were recorded, professionally transcribed, and coded based on a priori concepts and emergent themes with the aid of ATLAS.ti qualitative data analysis software. RESULTS Participants' discussions centered on three elements of the intervention: 1) self-assessment questions, 2) action plans, and 3) educational messages. Participants also commented on: text-based platform, depression and adherence, TELE-IBD system in place of office visit, and their recommendations for future TELE-IBD systems. Adherent and non-adherent participants prefer a flexible system that is personalized, including targeted education messages, and they perceive TELE-IBD as effective in facilitating IBD self-management. CONCLUSIONS Participants identified clear benefits to the TELE-IBD system, including obtaining a better understanding of the disease process, monitoring their symptoms, and feeling connected to their health care provider. Participants' perceptions obtained in this qualitative study will assist in improving the TELE-IBD system to be more responsive to patients with IBD. CLINICALTRIAL NCT01692743

Vascular Fluid Mechanics, the Arterial Wall, and Atherosclerosis

1992 ◽  
Vol 114 (3) ◽  
pp. 274-282 ◽  
Author(s):  
R. M. Nerem
Keyword(s):  
Cell Culture ◽  
Blood Flow ◽  
Fluid Mechanics ◽  
Arterial Wall ◽  
Disease Process ◽  
The United States ◽  
Structure And Function ◽  
Medium Size ◽  
Important Relationship ◽  
And Function

Atherosclerosis, a disease of large- and medium-size arteries, is the chief cause of death in the United States and in most of the western world. Severe atherosclerosis interferes with blood flow; however, even in the early stages of the disease, i.e. during atherogenesis, there is believed to be an important relationship between the disease processes and the characteristics of the blood flow in the arteries. Atherogenesis involves complex cascades of interactions among many factors. Included in this are fluid mechanical factors which are believed to be a cause of the highly focal nature of the disease. From in vivo studies, there is evidence of hemodynamic influences on the endothelium, on intimal thickening, and on monocyte recruitment. In addition, cell culture studies have demonstrated the important effect of a cell’s mechanical environment on structure and function. Most of this evidence is for the endothelial cell, which is believed to be a key mediator of any hemodynamic effect, and it is now well documented that cultured endothelial monolayers, in response to a fluid flow-imposed laminar shear stress, undergo a variety of changes in structure and function. In spite of the progress in recent years, there are many areas in which further work will provide important new information. One of these is in the engineering of the cell culture environment so as to make it more physiologic. Animal studies also are essential in our efforts to understand atherogenesis, and it is clear that we need better information on the pattern of the disease and its temporal development in humans and animal models, as well as the specific underlying biologic events. Complementary to this will be in vitro model studies of arterial fluid mechanics. In addition, one can foresee an increasing role for computer modelling in our efforts to understand the pathophysiology of the atherogenic process. This includes not only computational fluid mechanics, but also modelling the pathobiologic processes taking place within the arterial wall. A key to the atherogenic process may reside in understanding how hemodynamics influences not only intimal smooth muscle cell proliferation, but also the recruitment of the monocyte/macrophage and the formation of foam cells. Finally, it will be necessary to begin to integrate our knowledge of cellular phenomena into a description of the biologic processes within the arterial wall and then to integrate this into a picture of the disease process itself.

scholarly journals Diabetic Cataract—Pathogenesis, Epidemiology and Treatment

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Andreas Pollreisz ◽  
Ursula Schmidt-Erfurth
Keyword(s):  
Experimental Studies ◽  
Disease Process ◽  
Basic Research ◽  
Polyol Pathway ◽  
Population Based ◽  
Diabetic Patients ◽  
Diabetic Cataract ◽  
Cataract Development

Cataract in diabetic patients is a major cause of blindness in developed and developing countries. The pathogenesis of diabetic cataract development is still not fully understood. Recent basic research studies have emphasized the role of the polyol pathway in the initiation of the disease process. Population-based studies have greatly increased our knowledge concerning the association between diabetes and cataract formation and have defined risk factors for the development of cataract. Diabetic patients also have a higher risk of complications after phacoemulsification cataract surgery compared to nondiabetics. Aldose-reductase inhibitors and antioxidants have been proven beneficial in the prevention or treatment of this sightthreatening condition in in vitro and in vivo experimental studies. This paper provides an overview of the pathogenesis of diabetic cataract, clinical studies investigating the association between diabetes and cataract development, and current treatment of cataract in diabetics.

Role of Image-Guided Percutaneous Drainage in Pancreatic Collections

2018 ◽  
Vol 02 (02) ◽  
pp. 125-130
Author(s):  
Katayoun Samadi ◽  
Ronald Arellano
Keyword(s):  
United States ◽  
Acute Pancreatitis ◽  
Percutaneous Drainage ◽  
Hospital Admissions ◽  
Disease Process ◽  
The United States ◽  
Morbidity And Mortality ◽  
Image Guided ◽  
Gastrointestinal Conditions

AbstractAcute pancreatitis is one of the major gastrointestinal conditions that lead to around 300,000 hospital admissions per year in the United States. While mild inflammation of the pancreas is often managed conservatively, progression of the disease process to necrosis significantly increases the overall morbidity and mortality and often requires surgical or other interventional techniques for management. The purpose of this review is to describe the role of percutaneous drainage for the management of complicated pancreatitis.

Metabolic Disorders: Inborn Errors of Carbohydrate Metabolism

2019 ◽  
Author(s):  
Sameer S Chopra ◽  
Gerald T Berry
Keyword(s):  
Genetic Diseases ◽  
Disease Process ◽  
Signs And Symptoms ◽  
The United States ◽  
Glycogen Storage ◽  
Inborn Errors ◽  
Life Threatening Illness ◽  
Glycogen Storage Diseases ◽  
Life Threatening ◽  
Biochemical Genetic

The small molecule diseases include the inborn errors of carbohydrate, ammonia, amino acid, organic acid, and fatty acid metabolism. They are central to the cohort of biochemical genetic diseases that are often associated with catastrophic presentations and life-threatening illness during infancy and childhood. Many of these entities are now routinely detected through newborn screening in the majority, if not all, of the states in the United States. Several of these diseases have effective therapies that largely eliminate the signs and symptoms of disease. In many, however, the disease process is without an effective treatment or may be brought under control but not corrected. This review contains 1 figure, 6 tables, and 11 references. Keywords: glycogen storage diseases, galactosemia, hyperbilirubinemia, hyperchloremic metabolic acidosis, hypofibrinogenemia, and thrombocytopenia, hypophosphatemia, fructose-1,6-bisphosphatase deficiency

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