Going for the Trunk

Although angiogenesis (new blood vessel formation) is an absolute requirement for tumor growth, therapies designed to treat cancer by targeting specific angiogenic factors have had limited success. One theory is that there are many different angiogenic factors that can compensate for the loss of a single factor. Therefore, a more effective strategy may be to move upstream, identify a factor that regulates the expression of many different downstream angiogenic mediators, and then measure the effect of blocking this single common factor on angiogenesis-mediated tumor growth

The Mechanisms by Which the Ketone Body D-β-Hydroxybutyrate May Improve the Multiple Cellular Pathologies of Parkinson's Disease

Parkinson's disease, a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, is strongly associated with the death of dopaminergic neurons in the brain's substantia nigra. Although dopamine replacement therapy temporarily helps patients manage their motor symptoms, this current standard of care fails to address the underlying network of pathologies that contribute to the persistent death of dopaminergic neurons. Thus, new treatment approaches are needed that address the underlying pathologies and, thereby, slow or halt the progression of the actual disease. D-β-hydroxybutyrate – a ketone body produced by the liver to support brain function during periods of starvation – may provide an option. Lifestyle interventions that induce endogenous D-β-hydroxybutyrate production, such as caloric restriction and ketogenic diets, are known to increase healthspan and lifespan in animal models and are used to treat neurological disorders. The efficacy of these ketosis-inducing interventions, along with the recent development of commercially available D-β-hydroxybutyrate-based nutritional supplements, should inspire interest in the possibility that D-β-hydroxybutyrate itself exerts neuroprotective effects. This review provides a molecular model to justify the further exploration of such a possibility. Herein, we explore the cellular mechanisms by which the ketone body, D-β-hydroxybutyrate, acting both as a metabolite and as a signaling molecule, could help to prevent the development, or slow the progression of, Parkinson's disease. Specifically, the metabolism of D-β-hydroxybutyrate may help neurons replenish their depleted ATP stores and protect neurons against oxidative damage. As a G-protein-coupled receptor ligand and histone deacetylase inhibitor, D-β-hydroxybutyrate may further protect neurons against energy deficit and oxidative stress, while also decreasing damaging neuroinflammation and death by apoptosis. Restricted to the available evidence, our model relies largely upon the interpretation of data from the separate literatures on the cellular effects of D-β-hydroxybutyrate and on the pathogenesis of Parkinson's disease. Future studies are needed to reveal whether D-β-hydroxybutyrate actually has the potential to serve as an adjunctive nutritional therapy for Parkinson's disease

LRP5, Bone Density, and Mechanical Stress: A Case Report and Literature Review

The Wnt-β-catenin pathway receptor, low-density lipoprotein receptor-related protein 5 (LRP5), is a known regulator of bone mineral density. It has been hypothesized that specific human polymorphisms in LRP5 impact bone density, in part, by altering the anabolic response of bone to mechanical loading. Although experiments in animal models support this hypothesis, there is limited evidence that LRP5 polymorphisms can alter the anabolic response of bone to mechanical loading in humans. Herein, we report a young male who harbors a rare LRP5 missense mutation (A745V) and who provides potential proof of principle for this mechanotransduction hypothesis for low bone density. The subject had no history of fractures until age 18, a year into a career in competitive distance running. As he continued to run over the following 2 years, his mileage threshold to fracture steadily and rapidly decreased until he was diagnosed with severe osteoporosis (lumbar spine BMD Z-score of −3.2). By contextualizing this case within the existing LRP5 and mechanical stress literature, we speculate that this represents the first documented case of an individual in whom a genetic mutation altered the anabolic response of bone to mechanical stress in a manner sufficient to contribute to osteoporosis

Thyroid markers and body composition predict LDL-cholesterol change in lean healthy women on a ketogenic diet: experimental support for the lipid energy model

Introduction: There is a large heterogeneity in LDL-cholesterol change among individuals adopting ketogenic diets. Interestingly, lean metabolically healthy individuals seem to be particularly susceptible, with an inverse association between body mass index and LDL-cholesterol change. The lipid energy model proposes that, in lean healthy individuals, carbohydrate restriction upregulates systemic lipid trafficking to meet energy demands. To test if anthropometric and energy metabolism markers predict LDL-cholesterol change during carbohydrate restriction. Methods: Ten lean, healthy, premenopausal women who habitually consumed a ketogenic diet for ≥6 months were engaged in a three-phase crossover study consisting of continued nutritional ketosis, suppression of ketosis with carbohydrate reintroduction, and return to nutritional ketosis. Each phase lasted 21 days. The predictive performance of all available relevant variables was evaluated with the linear mixed-effects models. Results: All body composition metrics, free T3 and total T4, were significantly associated with LDL-cholesterol change. In an interaction model with BMI and free T3, both markers were significant independent and interacting predictors of LDL-cholesterol change. Neither saturated fat, HOMA-IR, leptin, adiponectin, TSH, nor rT3 was associated with LDL-cholesterol changes. Discussion: Among lean, healthy women undergoing carbohydrate restriction, body composition and energy metabolism markers are major drivers of LDL-cholesterol change, not saturated fat, consistent with the lipid energy model

Exogenous ketosis in patients with type 2 diabetes : safety and effect on glycaemic control

Introduction Ketogenic diets have shown to improve glycaemic control in patients with type 2 diabetes. This study investigated the safety, tolerability, and effects on glycaemic control in patients with type 2 diabetes of an exogenous ketone monoester (KE) capable of inducing fasting-like elevations in serum β-hydroxybutyrate (βHB) without the need for caloric or carbohydrate restriction. Methods Twenty one participants (14 men and 7 women, aged 45 ± 11 years) with insulin-independent type 2 diabetes, and unchanged hypoglycaemic medication for the previous 6 months, were recruited for this non-randomised interventional study. Participants wore intermittent scanning glucose monitors (IS-GM) for a total of 6 weeks and were given 25 ml of KE 3 times daily for 4 weeks. Serum electrolytes, acid-base status, and βHB concentrations were measured weekly and cardiovascular risk markers were measured before and after the intervention. The primary endpoints were safety and tolerability, with the secondary endpoint being glycaemic control. Results The 21 participants consumed a total of 1,588 drinks (39.7 litres) of KE over the course of the intervention. Adverse reactions were mild and infrequent, including mild nausea, headache, and gastric discomfort following fewer than 0.5% of the drinks. Serum electrolyte concentrations, acid-base status, and renal function remained normal throughout the study. Compared to baseline, exogenous ketosis induced a significant decrease in all glycaemic control markers, including fructosamine (335 ± 60 μmol/L to 290 ± 49 μmol/L, p < .01), HbA1c (61 ± 10 mmol/mol to 55 ± 9 mmol/mol [7.7 ± 0.9% to 7.2 ± 0.9%], p < .01), mean daily glucose (7.8 ± 1.4 mM to 7.4 ± 1.3 mM [140 ± 23 mg/dl to 133 ± 25 mg/dl], p < .01) and time in range (67 ± 11% to 69 ± 10%, p < .01). Conclusions Constant ketone monoester consumption over 1 month was safe, well tolerated, and improved glycaemic control in patients with type 2 diabetes

Multi-loop model of Alzheimer disease: An integrated perspective on the Wnt/GSK3β, α-synuclein, and type 3 diabetes hypotheses

As the prevalence of Alzheimer disease (AD) continues to rise unabated, new models have been put forth to improve our understanding of this devastating condition. Although individual models may have their merits, integrated models may prove more valuable. Indeed, the reliable failures of monotherapies for AD, and the ensuing surrender of major drug companies, suggests that an integrated perspective may be necessary if we are to invent multifaceted treatments that could ultimately prove more successful. In this review article, we discuss the Wnt/Glycogen Synthase Kinase 3&#x3B2; (GSK3&#x3B2;), &#x3B1;-synuclein, and type 3 diabetes hypotheses of AD, and their deep interconnection, in order to foster the integrative thinking that may be required to reach a solution for the coming neurological epidemic

A Company Is Only as Healthy as Its Workers: A 6-Month Metabolic Health Management Pilot Program Improves Employee Health and Contributes to Cost Savings

Chronic diet-related metabolic diseases, including diabetes and obesity, impose enormous burdens on patient wellness, healthcare costs, and worker productivity. Given the interdependent nature of the human and economic costs of metabolic disease, companies should be incentivized to invest in the health of their workforce. We report data from an ongoing pilot program in which employees of a manufacturing company with obesity, prediabetes, or diabetes are being treated by a metabolic health clinic using a carbohydrate restriction, community-orientated telemedicine approach. 10 patients completed the first 6 months of the program, and all lost weight, with a mean weight reduction of 38.4 lbs (17.4 kg). Improvements in HbA1c, fasting glucose, HOMA-IR, triglycerides, C-reactive protein, and systolic blood pressure were also observed across the group. Furthermore, the 10-year risk of having a major cardiovascular event, as calculated by the American Heart Association risk calculator, decreased from a mean of 9.22 to 5.18%, representing a 44% relative risk reduction. As a result of improvements in their metabolic health, patients were able to discontinue medications, leading to an estimated annualized cost savings of USD 45,171.70. These preliminary data provide proof-of-principle that when companies invest in the metabolic health of their workers, both parties stand to gain

Dynamics of Base Excision Repair at the Maternal-Fetal Interface in Pregnancies Complicated by Preeclampsia

Preeclampsia (PE) (gestational proteinuric hypertension) is the leading cause of maternal and perinatal mortality worldwide. Although placental endothelial dysfunction and oxidative stress are known to contribute to PE, the exact pathological basis for this disorder remains unclear. Previously, we demonstrated that DNA damage at the maternal-fetal interface is more common in the placentas of women with PE than normotensive controls. In this study, we utilized an in vivo comparative study, including 20 preeclamptic women and 8 healthy control subjects, and an in vitro hypoxia/reperfusion model to mimic the effects of oxidative stress at the maternal-fetal interface. We tracked the spatial pattern of expression of 2 base excision repair proteins, 8-oxoguanine glycosylase (OGG1) and apurinic/apyrimidinic endonuclease-1 (APE1), at the maternal-fetal interface in response to oxidative stress. In vivo, we found a significant increase in OGG1 and APE1 concentrations in PE placental tissues as compared to normotensive controls (P < .0001). Further, our in vitro study revealed that OGG1 and APE1 expression is much greater in maternal cells (decidua) than in fetal cells (cytotrophoblasts) of placental tissue subjected to oxidative stress (P < .0001). Our results suggest that OGG1 and APE1 likely protect decidual cells from oxidative base damage

In vivo and in vitro evidence for placental DNA damage in preeclampsia.

Preeclampsia (PE) is an idiopathic multisystem disease affecting 5-7% of pregnant women. Placental oxidative stress is a characteristic feature of PE and occurs when the production of reactive oxygen species (ROS) within the placenta overwhelms the intrinsic anti-oxidant defenses. We hypothesize that excessive oxidative DNA damage at the fetal-maternal interface coupled with a defective DNA damage/repair response is causally related to PE. Here we demonstrate that γH2AX (a sensitive marker of DNA damage) is expressed in the maternal decidua but not trophoblast of normal placentas, and that expression is significantly higher in PE placental tissues in vivo. Using primary in vitro cultures of maternal decidual stromal cells (DSCs) and fetal cytotrophoblast cells (CTs), we show an increase in γH2AX foci in DSCs cultured with vs without H2O2 (70.6% vs 11.6%; P<0.0001) or under hypoxia-reperfusion vs normoxia (20- vs 3-fold; P = 0.01); no foci were seen in CTs. We further demonstrate that Base Excision Repair (BER) intermediates are significantly increased in DSCs (not CTs) under these same conditions. Our data show that DNA damage is significantly more common in PE placentas, and that this DNA damage is localized to the maternal and not fetal side of the placenta. CTs may be selectively resistant to DNA damage in an effort to protect the fetus