Gait-Guard: Turn-aware Freezing of Gait Detection for Non-intrusive Intervention Systems.

Freezing of gait significantly reduces the quality of life for Parkinson's disease patients by increasing the risk of injurious falls and reducing mobility. Real-time intervention mechanisms promise relief from these symptoms, but require accurate real-time, portable freezing of gait detection systems to be effective. Current real-time detection systems have unacceptable false positive freezing of gait identification rates to be adopted by the patients for real-world use.

ToPick: Time-of-Pickup Measurement for the Elderly using Wearables.

The ability to pick up objects off the floor can degrade over time with elderly individuals, leading to a reduced quality of life and an increase in the risk of falling. Healthcare professionals have expressed an interest in monitoring the decline in pickup ability of a subject over extended periods of time and intervening when it becomes hazardous to the subject's health. The current means of evaluating pickup ability involving in-clinic patient visits is both time and financially expensive.

Effects of Salvia officinalis L. and Chamaemelum nobile (L.) extracts on inflammatory responses in two models of human cells: Primary subcutaneous adipocytes and neuroblastoma cell line (SK-N-SH).

Ethnopharmacological Relevance: Salvia officinalis L. (sage), and Chamaemelum nobile (L.) (chamomile) have been used traditionally to treat various inflammatory conditions.

Sixty Years of Drug Discovery for Type 2 Diabetes: Where Are We Now?

Today, excluding insulin, there are eight classes of anti-diabetic medicines that have been added to the pharmacy since the introduction of metformin in the mid-1950s; the sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, meglitinides, incretins, and sodium glucose transport 2 inhibitors. Does the fact that metformin is still first-line treatment suggest that our drug discovery efforts over the past 60 years have not been good enough? Or does it suggest that diabetes is such a complex disorder that no single treatment, other than gastric bypass surgery, can affect true normalization of not only blood sugar but also the underlying pathologies? Our understanding of the disease has most definitely improved which may bring hope for the future in terms of science, but for it to be beneficial, this science has to be translated into better drug treatments for the disease. In this review, I have examined the eight classes of anti-diabetes drugs from a drug discovery perspective.

Effects of a specific MCHR1 antagonist (GW803430) on energy budget and glucose metabolism in diet-induced obese mice.

Objective: The melanin-concentrating hormone (MCH) is a centrally acting peptide implicated in the regulation of energy homeostasis and body weight, although its role in glucose homeostasis is uncertain. Our objective was to determine effects of MCHR1 antagonism on energy budgets and glucose homeostasis in mice.

Methods: Effects of chronic oral administration of a specific MCHR1 antagonist (GW803430) on energy budgets and glucose homeostasis in diet-induced obese (DIO) C57BL/6J mice were examined.

NFκB as a potent regulator of inflammation in human adipose tissue, influenced by depot, adiposity, T2DM status, and TNFα.

Objective: Central obesity and sub-clinical inflammation increase metabolic risk, this study examined the intracellular inflammatory pathways in adipose tissue (AT) that contribute to this risk.

Design And Methods: This study therefore addressed the influence of NFκB and JNK activation in human abdominal subcutaneous (AbdSc) and omental (Om) AT, the effect of adiposity, T2DM status and the role of TNFα in vitro, using molecular biology techniques.

Results: Our data showed NFκB activity is increased in Om AT versus AbdSc AT (P<0.

Effects of chronic oral rimonabant administration on energy budgets of diet-induced obese C57BL/6 mice.

The endocannabinoids have been recognized as an important system involved in the regulation of energy balance. Rimonabant (SR141716), a selective inverse agonist of cannabinoid receptor 1 (CB1), has been shown to cause weight loss. However, its suppressive impact on food intake is transient, indicating a likely additional effect on energy expenditure.

Set points, settling points and some alternative models: theoretical options to understand how genes and environments combine to regulate body adiposity.

The close correspondence between energy intake and expenditure over prolonged time periods, coupled with an apparent protection of the level of body adiposity in the face of perturbations of energy balance, has led to the idea that body fatness is regulated via mechanisms that control intake and energy expenditure. Two models have dominated the discussion of how this regulation might take place. The set point model is rooted in physiology, genetics and molecular biology, and suggests that there is an active feedback mechanism linking adipose tissue (stored energy) to intake and expenditure via a set point, presumably encoded in the brain.

Central control of thermogenesis.

In mammals and birds, conservation of body heat at around 37 °C is vital to life. Thermogenesis is the production of this heat which can be obligatory, as in basal metabolic rate, or it can be facultative such as the response to cold. A complex regulatory system has evolved which senses environmental or core temperature and integrates this information in hypothalamic regions such as the preoptic area and dorsomedial hypothalamus.

Physiological and behavioral responses to intermittent starvation in C57BL/6J mice.

The dual intervention point model states that body mass is controlled by upper and lower intervention points, above and below which animals (and humans) intervene physiologically to bring their body mass back into the acceptable range. It has been further suggested that the lower intervention point may be defined by the risk of starvation, while the upper intervention point may be defined by the risk of predation. The objective of the present study was to test whether the risk of starvation determines the lower intervention point and to examine the physiological and behavioral mechanisms that underpin the regulation of body mass, when the risk of starvation is increased.

Factors predicting nongenetic variability in body weight gain induced by a high-fat diet in inbred C57BL/6J mice.

Inbred C57BL/6J mice displayed large individual variations in weight gain when fed a high-fat diet (HFD). The objective of this study was to examine whether this predominantly nongenetic variability could be predicted by relevant baseline features and to explore whether variations in these significant features were influenced during pregnancy and/or lactation. Fat mass (FM), fat-free mass (FFM), food intake (FI), resting metabolic rate (RMR), physical activity (PA), and body temperature (T(b)) were all evaluated at baseline in 60 mice (aged 10-12 weeks) before HFD feeding.

Targeting thermogenesis and related pathways in anti-obesity drug discovery.

The health consequences of the obesity epidemic are a huge burden on patients and society. Yet it remains an unmet therapeutic need. Lifestyle or behaviour modification, although desirable, seems to benefit only a few and bariatric surgery is not an option for all and not without risks.

Binding properties of antagonists to cannabinoid receptors in intact cells.

The implication of the cannabinoid receptor 1 (CB(1) receptor) in several pathophysiological states has sparked the development of selective antagonists. Here we compare binding of the antagonists [(3) H]-AZ12491187, [(3) H]-taranabant and [(3) H]-rimonabant to intact human embryonic kidney cells stably expressing recombinant human CB(1) receptors (CB1r cells). Unlabelled ligands decreased the total binding of the three radioligands with closely the same order of potency: i.

Cell based in vitro and ex vivo models in metabolic disease drug discovery: nice to have or critical path?

Background: The use of cellular models as tools in drug discovery is almost universal. However, in disease areas such as metabolic diseases, are they relevant to the process and do they add value?

Objective: In this article, we explore the variety of cellular models now used in drug discovery in metabolic diseases as revealed by publication. We have tried to make some connections between drug phenotypes in these models with clinical parallels.

Inverse agonism or neutral antagonism at G-protein coupled receptors: a medicinal chemistry challenge worth pursuing?

The identification of constitutive, or intrinsic, activity of G-protein coupled receptors has had major impact on receptor theory, the identification of agents that inhibit this ligand-independent receptor activity has led, in turn, to the concept of inverse agonism. It has subsequently emerged that the majority, around 85%, of all known G-protein coupled receptor antagonists are, in fact, inverse agonists. Agents that affect only ligand-dependent receptor activation, i.

The fatty acid oxidation pathway as a therapeutic target for insulin resistance.

It is recognised that obesity is a major driver for insulin resistance and Type 2 diabetes in both adult and young members of diverse societies. Weight loss strategies involving diet, exercise and behaviour modification work only for the minority of highly motivated individuals, but fail completely in the vast majority; yet weight loss is associated with benefits in metabolic health. Why is it so difficult to maintain weight loss in the longer term? Here, the authors explore the possibility that energy partitioning, especially of lipids, plays a key role in both weight recidivism and, by association, insulin resistance.

Liver-directed overexpression of mitochondrial glycerol-3-phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation.

Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first committed step in triacylglycerol (TAG) and phospholipid biosynthesis. GPAT activity has been identified in both ER and mitochondrial subcellular fractions. The ER activity dominates in most tissues except in liver, where the mitochondrial isoform (mtGPAT) can constitute up to 50% of the total activity.

The effect of high-fat feeding on intramuscular lipid and lipid peroxidation levels in UCP3-ablated mice.

Uncoupling protein-3 (UCP3) has been suggested to protect against lipid-induced oxidative damage. Therefore, we studied intramuscular lipid peroxide levels and high-fat diet induced alterations in muscle lipid metabolism of UCP3-ablated mice. UCP3-/- mice showed approximately 3-fold higher levels of intramuscular lipid peroxides upon standard chow feeding, compared to wild-type littermates.

Glucose and fatty acid metabolism in McA-RH7777 hepatoma cells vs. rat primary hepatocytes: responsiveness to nutrient availability.

The overabundance of dietary fats and simple carbohydrates contributes significantly to obesity and metabolic disorders associated with obesity. The liver balances glucose and lipid distribution, and disruption of this balance plays a key role in these metabolic syndromes. We investigated (1) how hepatocytes balance glucose and fatty acid metabolism when one or both nutrients are supplied in abundance and (2) whether rat hepatoma cells (McA-RH7777) reflect nutrient partitioning in a similar manner as compared with primary hepatocytes.

Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3beta on a muscle-specific promoter.

Glycogen synthase kinase-3 (GSK-3) protein levels and activity are elevated in skeletal muscle in type 2 diabetes, and inversely correlated with both glycogen synthase activity and insulin-stimulated glucose disposal. To explore this relationship, we have produced transgenic mice that overexpress human GSK-3beta in skeletal muscle. GSK-3beta transgenic mice were heavier, by up to 20% (P < .

Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis.

Glycerol-3-phosphate acyltransferase (GPAT) catalyses the first committed step in glycerolipid biosynthesis. The mitochondrial isoform (mtGPAT) is mainly expressed in liver, where it is highly regulated, indicating that mtGPAT may have a unique role in hepatic fatty acid metabolism. Because both mtGPAT and carnitine palmitoyl transferase-1 are located on the outer mitochondrial membrane, we hypothesized that mtGPAT directs fatty acyl-CoA away from beta-oxidation and toward glycerolipid synthesis.

Treating obesity: pharmacology of energy expenditure.

The pharmacological treatment options for obesity are currently very limited but the prevalence of the disease is increasing rapidly. Obesity has many serious sequelae, the most common of which is type-2-diabetes. The benefits of weight loss on health are established but the major impediment to weight loss treatments is maintenance of weight lost over the long term.

Fat oxidation in obesity: druggable or risky enterprise?

Two potential approaches for the treatment of obesity are presented, in which modulation of a target increases fatty acid oxidation. These two methods, which are here referred to as 'pull' and 'push' routes, involve creating a demand for fuel by uncoupling oxidation from ATP production ('pulling'), or shuttling fatty acyl CoA into the mitochondria by an afferent mechanism ('pushing'). Proof-of-principle studies in humans are required to assess the use of these approaches in weight loss maintenance.

Oxidative damage and phospholipid fatty acyl composition in skeletal muscle mitochondria from mice underexpressing or overexpressing uncoupling protein 3.

Five markers of different kinds of oxidative damage to proteins [glutamic semialdehyde, aminoadipic semialdehyde, N (epsilon)-(carboxymethyl)lysine, N (epsilon)-(carboxyethyl)lysine and N (epsilon)-(malondialdehyde)lysine] and phospholipid fatty acyl composition were identified and measured in skeletal muscle mitochondria isolated from mice genetically engineered to underexpress or overexpress uncoupling protein 3 (UCP3). Mitochondria from UCP3-underexpressing mice had significantly higher levels of oxidative damage than wild-type controls, suggesting that UCP3 functions in vivo as part of the antioxidant defences of the cell, but mitochondria from UCP3-overexpressing mice had unaltered oxidative damage, suggesting that mild uncoupling in vivo beyond the normal basal uncoupling provides little protection against oxidative stress. Mitochondria from UCP3-underexpressing mice showed little change, but mitochondria from UCP3-overexpressing mice showed marked changes in mitochondrial phospholipid fatty acyl composition.

Enhanced diabetogenic effect of streptozotocin in mice overexpressing UCP-3 in skeletal muscle.

Diabetic patients exhibit varying degrees of increased muscle UCP-3 expression in skeletal muscle and, in rodents, the pancreatoxin streptozotocin (STZ) upregulates UCP-3 mRNA in skeletal and cardiac muscles. We have investigated the development of STZ-induced diabetes in transgenic mice overexpressing UCP-3 in skeletal muscle in order to provide further insight on the functional role of muscle UCP-3. UCP-3 transgenic mice treated with STZ (UCP3-STZ) showed a significant increase in blood glucose concentration 3 days after the last dose of STZ with a progressive induction of diabetes, attaining blood glucose concentrations of 24.