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Nutritional Ketosis in Parkinson's Disease - a Review of Remaining Questions and Insights.
Choi, A, Hallett, M, Ehrlich, D
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2021;(3):1637-1649
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Abstract
Nutritional ketosis has promise for treating Parkinson's disease. Three previous studies explored the use of a ketogenic diet in cohorts with Parkinson's disease, and, while not conclusive, the data suggest non-motor symptom benefit. Before the ketogenic diet can be considered as a therapeutic option, it is important to establish with greater certainty that there is a reliable symptomatic benefit: which symptoms or groups of symptoms are impacted (if non-motor symptoms, which ones, and by which mechanism), what timescale is needed to obtain benefit, and how large an effect size can be achieved? To accomplish this, further investigation into the disease mechanisms based on pre-clinical data and hints from the clinical outcomes to date is useful to understand target engagement and gauge which mechanism could lead to a testable hypothesis. We review research pertaining to ketogenic diet, exogenous ketones, fasting, clinical studies, and theoretical review papers regarding therapeutic mechanisms from direct ketone body signaling and indirect metabolic effects. Through discussion of these findings and consideration of whether the ketogenic diet can be regarded as therapeutically useful for adjunctive therapy for Parkinson's disease, we identify remaining questions for the clinician to consider prior to recommending this diet.
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Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design.
Wu, YJ, Meanwell, NA
Journal of medicinal chemistry. 2021;(14):9786-9874
Abstract
Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.
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Potential of Ethenone (Ketene) to Contribute to Electronic Cigarette, or Vaping, Product Use-associated Lung Injury.
Attfield, KR, Chen, W, Cummings, KJ, Jacob, P, O'Shea, DF, Wagner, J, Wang, P, Fowles, J
American journal of respiratory and critical care medicine. 2020;(8):1187-1189
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Potential Therapeutic Effects of Exogenous Ketone Supplementation for Type 2 Diabetes: A Review.
Walsh, JJ, Myette-Côté, É, Neudorf, H, Little, JP
Current pharmaceutical design. 2020;(9):958-969
Abstract
Type 2 diabetes (T2D) is among the most prevalent non-communicable lifestyle diseases. We propose that overnutrition and low levels of physical activity can contribute to a vicious cycle of hyperglycemia, inflammation and oxidative stress, insulin resistance, and pancreatic β-cell dysfunction. The pathophysiological manifestations of T2D have a particular impact on the vasculature and individuals with T2D are at high risk of cardiovascular disease. Targeting aspects of the vicious cycle represent therapeutic approaches for improving T2D and protecting against cardiovascular complications. The recent advent of exogenous oral ketone supplements represents a novel, non-pharmacological approach to improving T2D pathophysiology and potentially protecting against cardiovascular disease risk. Herein, we review the emerging literature regarding the effects of exogenous ketone supplementation on metabolic control, inflammation, oxidative stress, and cardiovascular function in humans and highlight the potential application for breaking the vicious cycle of T2D pathophysiology.
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Cardiac ketone body metabolism.
Abdul Kadir, A, Clarke, K, Evans, RD
Biochimica et biophysica acta. Molecular basis of disease. 2020;(6):165739
Abstract
The ketone bodies, d-β-hydroxybutyrate and acetoacetate, are soluble 4-carbon compounds derived principally from fatty acids, that can be metabolised by many oxidative tissues, including heart, in carbohydrate-depleted conditions as glucose-sparing energy substrates. They also have important signalling functions, acting through G-protein coupled receptors and histone deacetylases to regulate metabolism and gene expression including that associated with anti-oxidant activity. Their concentration, and hence availability, increases in diabetes mellitus and heart failure. Whilst known to be substrates for ATP production, especially in starvation, their role(s) in the heart, and in heart disease, is uncertain. Recent evidence, reviewed here, indicates that increased ketone body metabolism is a feature of heart failure, and is accompanied by other changes in substrate selection. Whether the change in myocardial ketone body metabolism is adaptive or maladaptive is unknown, but it offers the possibility of using exogenous ketones to treat the failing heart.
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On the Future Design of Bio-Inspired Polyetheretherketone Dental Implants.
Knaus, J, Schaffarczyk, D, Cölfen, H
Macromolecular bioscience. 2020;(1):e1900239
Abstract
Polyetheretherketone (PEEK) is a promising implant material because of its excellent mechanical characteristics. Although this polymer is a standard material in spinal applications, PEEK is not in use in the manufacturing of dental implants, where titanium is still the most-used material. This may be caused by its relative bio-inertness. By the use of various surface modification techniques, efforts have been made to enhance its osseointegrative characteristics to enable the polymer to be used in dentistry. In this feature paper, the state-of-the-art for dental implants is given and different surface modification techniques of PEEK are discussed. The focus will lie on a covalently attached surface layer mimicking natural bone. The usage of such covalently anchored biomimetic composite materials combines many advantageous properties: A biocompatible organic matrix and a mineral component provide the cells with a surrounding close to natural bone. Bone-related cells may not recognize the implant as a foreign body and therefore, may heal and integrate faster and more firmly. Because neither metal-based nor ceramics are ideal material candidates for a dental implant, the combination of PEEK and a covalently anchored mineralized biopolymer layer may be the start of the desired evolution in dental surgery.
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7.
Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization.
Hattori, Y
Heart failure reviews. 2020;(3):403-408
Abstract
Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce the rate of hospitalization for heart failure in individuals with type 2 diabetes, but the underlying mechanisms remain elusive. Modestly elevated circulating β-hydroxybutyrate (βOHB) during treatment with SGLT2 inhibitors causes different beneficial effects on organs and cells, depending on succinyl-CoA:3-ketoacid CoA transferase (SCOT) levels. In the heart, in which SCOT is highly expressed/up-regulated, βOHB may be an alternative energy source apart from fat and glucose oxidation. The type 2 diabetic failing heart may be energy inefficient. In skeletal muscle, in which SCOT is not highly expressed/down-regulated, βOHB may cause antioxidant effects, resulting in amelioration of insulin resistance, which could lead to improvement in cardiac insulin resistance with metabolic, endocrine, and cytokine alterations. Although various mechanisms have been suggested, we postulate that the potential impact of SGLT2 inhibitors on heart failure lies in fuel energetics and amelioration of insulin resistance with ketone utilization depending upon SCOT levels.
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8.
Ketogenesis in arrhythmogenic cardiomyopathy.
Huynh, K
Nature reviews. Cardiology. 2020;(5):266
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9.
The ketogenic diet and dermatology: a primer on current literature.
Fomin, DA, Handfield, K
Cutis. 2020;(1):40-43
Abstract
The ketogenic diet has been therapeutically employed from antiquity and is still utilized today in many disease states. With the boom of the complementary and alternative health movement over the last 2 decades, the lay population has grown more interested in disease prevention and treatment via dietary and lifestyle changes and enhancing health and human performance. The ketogenic diet, whether exclusive or intermittent, has been purported by health care professionals and laypersons alike to meet these demands. In this review article, we look to the current literature for proven and possible mechanisms by which ketones and a ketogenic diet may be utilized in the field of dermatology and direct our readers to pursue further research for this promising potential treatment option.
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10.
The dark side of the spoon - glucose, ketones and COVID-19: a possible role for ketogenic diet?
Paoli, A, Gorini, S, Caprio, M
Journal of translational medicine. 2020;(1):441
Abstract
The novel coronavirus disease (COVID-19) is posing a serious challenge to the health-care systems worldwide, with an enormous impact on health conditions and loss of lives. Notably, obesity and its related comorbidities are strictly related with worse clinical outcomes of COVID-19 disease. Recently, there is a growing interest in the clinical use of ketogenic diets (KDs), particularly in the context of severe obesity with related metabolic complications. KDs have been proven effective for a rapid reduction of fat mass, preserving lean mass and providing an adequate nutritional status. In particular, the physiological increase in plasma levels of ketone bodies exerts important anti-inflammatory and immunomodulating effects, which may reveal as precious tools to prevent infection and potential adverse outcomes of COVID-19 disease. We discuss here the importance of KDs for a rapid reduction of several critical risk factors for COVID-19, such as obesity, type 2 diabetes and hypertension, based on the known effects of ketone bodies on inflammation, immunity, metabolic profile and cardiovascular function. We do believe that a rapid reduction of all modifiable risk factors, especially obesity with its metabolic complications, should be a pillar of public health policies and interventions, in view of future waves of SARS-CoV-2 infection.