Effective reduction in seizure severity and prevention of a fatty liver by a novel low ratio ketogenic diet composition in the rapid kindling rat model of epileptogenesis.

Drug-resistant epilepsy patients may benefit from non-pharmacological therapies, such as the ketogenic diet (KD). However, its high fat content poses compliance challenges and metabolic risks. To mitigate this, we developed a novel KD composition with less fat and additional nutrients (citrate, nicotinamide riboside, and omega-3 fatty acids) for ketone-independent neuroprotection.

A novel hepatocyte ketone production assay to help the selection of nutrients for the ketogenic diet treatment of epilepsy.

The classic ketogenic diet is an effective treatment option for drug-resistant epilepsy, but its high fat content challenges patient compliance. Optimizing liver ketone production guided by a method comparing substrates for their ketogenic potential may help to reduce the fat content of the diet without loss in ketosis induction. Here, we present a liver cell assay measuring the β-hydroxybutyrate (βHB) yield from fatty acid substrates.

The EAT-Lancet reference diet and cognitive function across the life course.

The EAT-Lancet Commission devised a sustainable reference diet with the aim of reducing the incidence of non-communicable diseases and mortality globally while improving food system sustainability. The extent to which the reference diet supports cognitive function across the life course, however, has not yet been evaluated. This Review assesses the evidence for diet supporting cognitive function from childhood into old age.

Predictive value of selected geriatric parameters for postoperative outcomes in older patients with rectal cancer - A multicenter cohort study.

Introduction: Older patients have a higher risk for complications after rectal cancer surgery. Although screening for geriatric impairments may improve risk prediction in this group, it has not been studied previously.

Methods: We retrospectively investigated patients ≥70 years with elective surgery for non-metastatic rectal cancer between 2014 and 2018 in nine Dutch hospitals.

High-Throughput Analysis of Astrocyte Cultures Shows Prevention of Reactive Astrogliosis by the Multi-Nutrient Combination Fortasyn Connect.

Astrocytes are specialized glial cells that tile the central nervous system (CNS) and perform numerous essential functions. Astrocytes react to various forms of CNS insults by altering their morphology and molecular profile, through a process known as reactive astrogliosis. Accordingly, astrocyte reactivity is apparent in many neurodegenerative diseases, among which one is Alzheimer's disease (AD).

A new ketogenic formulation improves functional outcome and reduces tissue loss following traumatic brain injury in adult mice.

Traumatic brain injury (TBI) leads to neurological impairment, with no satisfactory treatments available. Classical ketogenic diets (KD), which reduce reliance on carbohydrates and provide ketones as fuel, have neuroprotective potential, but their high fat content reduces compliance, and experimental evidence suggests they protect juvenile brain against TBI, but not adult brain, which would strongly limit their applicability in TBI. We designed a new-KD with a fat to carbohydrate plus protein ratio of 2:1, containing medium chain triglycerides (MCT), docosahexaenoic acid (DHA), low glycaemic index carbohydrates, fibres and the ketogenic amino acid leucine, and evaluated its neuroprotective potential in adult TBI.

Cognitive benefits of the ketogenic diet in patients with epilepsy: A systematic overview.

The ketogenic diet (KD) has been found to be effective in reducing seizures in patients with treatment-refractory epilepsy. Less attention has been paid to additional cognitive benefits of KD. The aim of the present paper was to provide a comprehensive overview of the studies reporting effects on cognition after KD treatment in adults and children with epilepsy.

Anti-inflammatory effects of rice bran components.

Neuroinflammation has been implicated in the pathology of various psychiatric and neurodegenerative disorders. Accumulating evidence suggests that food components can modulate inflammatory processes, and therefore it could be hypothesized that such nutrients might exhibit therapeutic efficacy against these brain diseases. Rice bran is often discarded as a waste product, although it contains a wide range of potentially useful substances.

High Content Analysis of Hippocampal Neuron-Astrocyte Co-cultures Shows a Positive Effect of Fortasyn Connect on Neuronal Survival and Postsynaptic Maturation.

Neuronal and synaptic membranes are composed of a phospholipid bilayer. Supplementation with dietary precursors for phospholipid synthesis -docosahexaenoic acid (DHA), uridine and choline- has been shown to increase neurite outgrowth and synaptogenesis both and . A role for multi-nutrient intervention with specific precursors and cofactors has recently emerged in early Alzheimer's disease, which is characterized by decreased synapse numbers in the hippocampus.

The combination of vitamins and omega-3 fatty acids has an enhanced anti-inflammatory effect on microglia.

Neuroinflammation is a common phenomenon in the pathology of many brain diseases. In this paper we explore whether selected vitamins and fatty acids known to modulate inflammation exert an effect on microglia, the key cell type involved in neuroinflammation. Previously these nutrients have been shown to exert anti-inflammatory properties acting on specific inflammatory pathways.

Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation.

Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A.

The development of automated patch clamp assays for canonical transient receptor potential channels TRPC3, 6, and 7.

The canonical transient receptor potential channel subfamily (TRPC3, TRPC6, and TRPC7) contains Ca(2+) permeable non-selective cation channels that are widely expressed in a variety of tissues. There is increasing evidence implicating TRPC channels, particularly TRPC3 and 6, in physiological and pathophysiological processes, eliciting interest in these channels as novel drug targets. Electrophysiology remains a benchmark technique for measuring ion channel function and accurately determining the pharmacological effects of compounds.

Discovery, optimization, and biological evaluation of 5-(2-(trifluoromethyl)phenyl)indazoles as a novel class of transient receptor potential A1 (TRPA1) antagonists.

A high throughput screening campaign identified 5-(2-chlorophenyl)indazole compound 4 as an antagonist of the transient receptor potential A1 (TRPA1) ion channel with IC50 = 1.23 μM. Hit to lead medicinal chemistry optimization established the SAR around the indazole ring system, demonstrating that a trifluoromethyl group at the 2-position of the phenyl ring in combination with various substituents at the 6-position of the indazole ring greatly contributed to improvements in vitro activity.

Targeting TRP channels in airway disorders.

Novel effective therapeutic agents are actively sought for the treatment of a broad spectrum of respiratory diseases which collectively significantly impact on mortality, morbidity and quality of life of hundreds of millions of people world-wide. These include asthma, allergic rhinitis, chronic obstructive pulmonary disease, cough, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis and acute lung injury. TRP channels are broadly distributed throughout the respiratory tract and play an important physiological role in sensing and subsequently responding to a wide variety of stimuli, for example temperature, osmolarity and oxidant stress.

GPR39 is coupled to TMEM16A in intestinal fibroblast-like cells.

GPR39 is a GPCR implicated as a regulator of gastrointestinal motility, although the mechanism remains elusive. Here, we report that GPR39 is expressed by a specific cell population cultured from mouse small intestine muscle layers, which was subsequently identified as fibroblast-like cells (FLCs) that have recently been shown to modulate gut motility. Application of the GPR39 agonist, Zn(2+), induced large currents and membrane depolarization in FLCs cultured from wild-type mice, but not Gpr39(-/-) mice.

TRPA1 agonist activity of probenecid desensitizes channel responses: consequences for screening.

The transient receptor potential channel subtype A member 1 (TRPA1) is a nonselective cation channel widely viewed as having therapeutic potential, particularly for pain-related indications. Realization of this potential will require potent, selective modulators; however, currently the pharmacology of TRPA1 is poorly defined. As TRPA1 is calcium permeable, calcium indicators offer a simple assay format for high-throughput screening.

Time-lapse imaging of dendritic spines in vitro.

Dendritic spines are small protrusions present postsynaptically at approximately 90% of excitatory synapses in the brain. Spines undergo rapid spontaneous changes in shape that are thought to be important for alterations in synaptic connectivity underlying learning and memory. Visualization of these dynamic changes in spine morphology are especially challenging because of the small size of spines (approximately 1 microm).

Reversible, activity-dependent targeting of profilin to neuronal nuclei.

The actin cytoskeleton in pyramidal neurons plays a major role in activity-dependent processes underlying neuronal plasticity. The small actin-binding protein profilin shows NMDA receptor-dependent accumulation in dendritic spines, which is correlated with suppression of actin dynamics and long-term stabilization of synaptic morphology. Here we show that following NMDA receptor activation profilin also accumulates in the nucleus of hippocampal neurons via a process involving rearrangement of the actin cytoskeleton.

GABAergic transmission in the rat paraventricular nucleus of the hypothalamus is suppressed by corticosterone and stress.

Parvocellular neurons in the hypothalamic paraventricular nucleus receive hormonal inputs mediated by corticosterone as well as neuronal inputs, prominent among which is a GABAergic inhibitory projection. In the present study we examined the functional properties of this GABAergic innervation when corticosteroid levels fluctuate. Frequency, amplitude and kinetic properties of miniature inhibitory postsynaptic potentials (mIPSCs), mediated by gamma amino butyric acid (GABA) were studied with whole cell recording in parvocellular neurons.

Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus.

Chronic stress causes disinhibition of the hypothalamus-pituitary-adrenal axis. Consequently, the brain is overexposed to glucocorticoids which in humans may precipitate stress-related disorders, e.g.

Hippocampal and hypothalamic function after chronic stress.

Hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis is often observed in association with and even prior to the onset of major depression. It is presently unclear (1) which molecular and cellular processes contribute to hyperactivity of parvocellular hypothalamic neurons (key regulators of the HPA system) and (2) how HPA axis hyperactivity can lead to attenuation of central serotonergic transmission, a crucial factor in the onset of clinical symptoms. In an attempt to address these issues in an experimental model we used rats exposed to chronic unpredictable stressors, a paradigm causing prolonged HPA-axis hyperactivity.

Acute stress increases calcium current amplitude in rat hippocampus: temporal changes in physiology and gene expression.

Activation of hippocampal glucocorticoid receptors in vitro increases calcium current amplitude through a process requiring DNA binding of receptor homodimers. We here investigated (i). whether similar increased calcium currents also occur following in vivo glucocorticoid receptor activation due to stress and (ii).

Effect of adrenalectomy on miniature inhibitory postsynaptic currents in the paraventricular nucleus of the hypothalamus.

Within the rat paraventricular nucleus of the hypothalamus two types of neurons have been distinguished based on morphological appearance, i.e., parvocellular and magnocellular neurons.