DrugBank 6.0: the DrugBank Knowledgebase for 2024.

First released in 2006, DrugBank (https://go.drugbank.com) has grown to become the 'gold standard' knowledge resource for drug, drug-target and related pharmaceutical information. DrugBank is widely used across many diverse biomedical research and clinical applications, and averages more than 30 million views/year. Since its last update in 2018, we have been actively enhancing the quantity and quality of the drug data in this knowledgebase. In this latest release (DrugBank 6.0), the number of FDA approved drugs has grown from 2646 to 4563 (a 72% increase), the number of investigational drugs has grown from 3394 to 6231 (a 38% increase), the number of drug-drug interactions increased from 365 984 to 1 413 413 (a 300% increase), and the number of drug-food interactions expanded from 1195 to 2475 (a 200% increase). In addition to this notable expansion in database size, we have added thousands of new, colorful, richly annotated pathways depicting drug mechanisms and drug metabolism. Likewise, existing datasets have been significantly improved and expanded, by adding more information on drug indications, drug-drug interactions, drug-food interactions and many other relevant data types for 11 891 drugs. We have also added experimental and predicted MS/MS spectra, 1D/2D-NMR spectra, CCS (collision cross section), RT (retention time) and RI (retention index) data for 9464 of DrugBank's 11 710 small molecule drugs. These and other improvements should make DrugBank 6.0 even more useful to a much wider research audience ranging from medicinal chemists to metabolomics specialists to pharmacologists.

Detailed pharmacokinetic characterization of advanced topical acyclovir formulations with IVPT and in vivo Open Flow Microperfusion.

Successful treatment of herpes simplex viruses is currently limited by a lack of effective topical drugs. Commonly used topical acyclovir products only reduce the duration of lesions by a few days. Optimizing topical formulations to achieve an enhanced acyclovir solubility and penetration could increase the efficacy of topically applied acyclovir, but new formulations need to show reliable acyclovir delivery into at least the epidermis/dermis and need to provide sustained acyclovir release for extended time periods. The aim of this study was to compare pharmacokinetic data from in vitro permeation testing (IVPT) and preclinical dermal open flow microperfusion (dOFM) experiments regarding the penetration behavior of different acyclovir formulations relative to the reference product Zovirax® 5% cream. Four test formulations that delivered the best penetration data in IVPT were further tested using continuous dOFM in vivo dermal sampling. The use of dOFM identified one of the four tested formulations to perform significantly better than the other three tested formulations and the reference product. In vivo dOFM data showed differences in the dermal acyclovir concentration that had not been detected by using IVPT. Improved acyclovir delivery to the dermis was likely achieved by the new formulation that uses a much lower drug load compared to the reference product. This optimized formulation was able to achieve a dermal concentration similar to oral application and can thus provide the opportunity of more efficacious topical HSV-1 treatment with less side effects than oral systemic treatment.

Targeting lysyl-oxidase (LOX) may facilitate intramural periarterial drainage for the treatment of Alzheimer's disease.

Alzheimer's disease is the commonest form of dementia. It is likely that a lack of clearance of amyloid beta (Aß) results in its accumulation in the parenchyma as Aß oligomers and insoluble plaques, and within the walls of blood vessels as cerebral amyloid angiopathy (CAA). The drainage of Aß along the basement membranes of blood vessels as intramural periarterial drainage (IPAD), could be improved if the driving force behind IPAD could be augmented, therefore reducing Aß accumulation. There are alterations in the composition of the vascular basement membrane in Alzheimer's disease. Lysyl oxidase (LOX) is an enzyme involved in the remodelling of the extracellular matrix and its expression and function is altered in various disease states. The expression of LOX is increased in Alzheimer's disease, but it is unclear whether this is a contributory factor in the impairment of IPAD in Alzheimer's disease. The pharmacological inhibition of LOX may be a strategy to improve IPAD and reduce the accumulation of Aß in the parenchyma and within the walls of blood vessels.

Assessment of the Efficacy of a Low-Dose Iron Supplement in Restoring Iron Levels to Normal Range among Healthy Premenopausal Women with Iron Deficiency without Anemia.

(1) Background: Iron deficiency without anemia (IDWA) is a prevalent health concern in premenopausal women. Oral supplementation of iron may be a viable solution to improve blood-iron status in women; however, the effects of a high-dose iron-supplement regimen have been associated with gastrointestinal side effects. Therefore, the purpose of the present study was to evaluate the effectiveness of a low-dose liquid fermented iron-bisglycinate supplement (LIS) on improving blood-iron status in premenopausal women with IDWA without increasing constipation or gastrointestinal distress. (2) Methods: 85 premenopausal women with IDWA (ferritin < 70 ng/dL and hemoglobin > 11.0 g/dL) took a LIS (27 mg) or a placebo (PLA) for 8 weeks. Blood draws were taken at Wk0 and Wk8 of the study to measure serum-iron markers. In addition, surveys of gastrointestinal distress were administered at Wk0, Wk4, and Wk8 while the profile of mood states (POMS) was surveyed at Wk0 and Wk8. (3) Results: Compared to the placebo, the LIS was able to increase serum ferritin (p = 0.03), total serum iron (p = 0.03), and mean corpuscular volume (p = 0.02), while exhibiting no significant interaction in subjective gastrointestinal distress (p > 0.05). No significant effects were detected for POMS (p > 0.05). (4) Conclusions: Supplementing with LIS appears to improve blood-iron status without causing significant gastrointestinal distress in premenopausal women with IDWA.

A randomized, crossover study to evaluate α-tocopherol bioavailability via a microemulsion gel or dry tablet delivery in healthy adults.

BACKGROUND: Vitamin E (α-tocopherol) is an essential micronutrient for human health and optimal physiological function. Inadequacy may be common due to a lack of bioavailability. The use of dietary lipids alongside other emulsification agents may elicit more robust serum concentrations of α-tocopherol via improved bioavailability. Therefore, the aim of the study was to examine oral bioavailability of two delivery methods of α-tocopherol, (1) a microemulsion gel formula composed of dietary lipids and other emulsification agents and (2) a dry solid tablet over 12 hours. METHODS: Twelve participants (age = 37.3 ± 9.6 years; height = 173.4 ± 11.8 cm; body mass = 71.2 ± 10.0 kg) participated in a double-blind, randomized, crossover trial comparing two delivery methods both dosed at 288 mg of α-tocopherol. Serum α-tocopherol concentrations were assessed from blood donated by participants at pre-consumption, 2-, 4-, 8-, and 12-hour post-consumption. Study conditions were separated by a 7-day washout. RESULTS: The microemulsion gel formula delivery demonstrated significantly greater area under the curve (p < 0.001) and serum concentration maximums (p = 0.003) for serum α-tocopherol compared to the tablet delivery. No significant differences were detected between conditions for the time to reach concentration maximums (p = 0.375). CONCLUSION: We conclude that a mixture of dietary lipids and emulsification agents in the form of a microemulsion gel formula was able to significantly improve bioavailability of serum α-tocopherol compared to a tablet by yielding higher serum α-tocopherol maximum concentrations and area under the curve over a 12-hour study period despite dosage being matched.

α-Dystrobrevin knockout mice have increased motivation for appetitive reward and altered brain cannabinoid receptor 1 expression.

α-Dystrobrevin (α-DB) is a major component of the dystrophin-associated protein complex (DAPC). Knockout (KO) of α-DB in the brain is associated with astrocytic abnormalities and loss of neuronal GABA receptor clustering. Mutations in DAPC proteins are associated with altered dopamine signaling and cognitive and psychiatric disorders, including schizophrenia. This study tested the hypothesis that motivation and associated underlying biological pathways are altered in the absence of α-DB expression. Male wildtype and α-DB KO mice were tested for measures of motivation, executive function and extinction in the rodent touchscreen apparatus. Subsequently, brain tissues were evaluated for mRNA and/or protein levels of dysbindin-1, dopamine transporter and receptor 1 and 2, mu opioid receptor 1 (mOR1) and cannabinoid receptor 1 (CB1). α-DB KO mice had significantly increased motivation for the appetitive reward, while measures of executive function and extinction were unaffected. No differences were observed between wildtype and KO animals on mRNA levels of dysbindin-1 or any of the dopamine markers. mRNA levels of mOR1were significantly decreased in the caudate-putamen and nucleus accumbens of α-DB KO compared to WT animals, but protein levels were unaltered. However, CB1 protein levels were significantly increased in the prefrontal cortex and decreased in the nucleus accumbens of α-DB KO mice. Triple-labelling immunohistochemistry confirmed that changes in CB1 were not specific to astrocytes. These results highlight a novel role for α-DB in the regulation of appetitive motivation that may have implications for other behaviours that involve the dopaminergic and endocannabinoid systems.

Effects of an immersive psychosocial training program on depression and well-being: A randomized clinical trial.

Psychiatry stands to benefit from brief non-pharmacological treatments that effectively reduce depressive symptoms. To address this need, we conducted a single-blind randomized clinical trial assessing how a 6-day immersive psychosocial training program, followed by 10-min daily psychosocial exercises for 30 days, improves depressive symptoms. Forty-five adults were block-randomized by depression score to two arms: (a) the immersive psychosocial training program and 10-min daily exercise group (36 days total; total n = 23; depressed at baseline n = 14); or (b) a gratitude journaling control group (36 days total; total n = 22; depressed at baseline n = 13). The self-report PHQ-9 was used to assess depression levels in both groups at three time points: baseline, study week one, and study week six. Depression severity improved over time, with a significantly greater reduction in the psychosocial training program group (-82.7%) vs. the control group (-23%), p = 0.02 for baseline vs. week six. The effect size for this reduction in depression symptoms was large for the intervention group (d = -1.3; 95% CI, -2.07, -0.45; p < 0.001) and small for the control group (d = -0.3; 95% CI, -0.68, 0.03; p = 0.22). Seventy-nine percent (11/14) of depressed participants in the intervention condition were in remission (PHQ-9 ≤ 4) by week one and 100% (14/14) were in remission at week six. Secondary measures of anxiety, stress, loneliness, and well-being also improved by 15-80% in the intervention group (vs. 0-34% in the control group), ps < 0.05. Overall, this brief, immersive psychosocial training program rapidly and substantially improved depression levels and several related secondary outcomes, suggesting that immersive interventions may be useful for reducing depressive symptoms and enhancing well-being.

Erratum: Sharp et al. Phytoplankton Supplementation Lowers Muscle Damage and Sustains Performance across Repeated Exercise Bouts in Humans and Improves Antioxidant Capacity in a Mechanistic Animal. Nutrients 2020, 12, 1990.

Modifications to the Main Text [...].

Functional Characterization of Undenatured Type II Collagen Supplements: Are They Interchangeable?

Undenatured (native) type II collagen is a dietary supplement ingredient reported to support joint health in healthy individuals by providing relief from symptoms of stiffness and discomfort and improving mobility. This benefit is thought to occur through oral tolerance, a mechanism whereby the immune system distinguishes between innocuous material in the gut and potentially harmful foreign invaders. The presence of antigenic epitopes in undenatured type II collagen, but not in denatured (hydrolyzed) collagen, is thought to be the basis for the therapeutic benefits. The purpose of this study was to investigate the physicochemical and analytical characteristics of type II collagen supplements currently available on the market and to explore whether they might be sufficiently similar in their physical properties to yield similar benefits in promoting joint health. Collagen type II supplement powders (raw material) and capsules (products in the market) were examined for color, particle size, quality profiles, fatty acid profiles, electron microscopy, and were analyzed for amino acid content as well as antigenic potential via an ELISA assay. Powders labeled as undenatured type II collagen were found to have markedly different properties, including the size of collagen fibers as per electron microscopy and antigenic configuration as per the ELISA assay. As significant differences were found between products, it allows consumers and practitioners to not assume that products labeled as undenatured (native) type II collagen are interchangeable.

L-Carnitine Tartrate Supplementation for 5 Weeks Improves Exercise Recovery in Men and Women: A Randomized, Double-Blind, Placebo-Controlled Trial.

L-carnitine tartrate has been shown to improve relatively short-term recovery among athletes. However, there is a lack of research on the longer-term effects in the general population. OBJECTIVE: The primary objectives of this randomized double-blind, placebo-controlled trial were to evaluate the effects of daily L-carnitine tartrate supplementation for 5 weeks on recovery and fatigue. METHOD: In this study, eighty participants, 21- to 65-years-old, were recruited. Participants were split into two groups of forty participants each, a placebo, and a L-carnitine Tartrate group. Seventy-three participants completed a maintenance exercise training program that culminated in a high-volume exercise challenge. RESULTS: Compared to placebo, L-carnitine tartrate supplementation was able to improve perceived recovery and soreness (p = 0.021), and lower serum creatine kinase (p = 0.016). In addition, L-carnitine tartrate supplementation was able to blunt declines in strength and power compared to placebo following an exercise challenge. Two sub-analyses indicated that these results were independent of gender and age. Interestingly, serum superoxide dismutase levels increased significantly among those supplementing with L-carnitine tartrate. CONCLUSIONS: These findings agree with previous observations among healthy adult subjects and demonstrate that L-carnitine tartrate supplementation beyond 35 days is beneficial for improving recovery and reducing fatigue following exercise across gender and age.

The α-dystrobrevins play a key role in maintaining the structure and function of the extracellular matrix-significance for protein elimination failure arteriopathies.

The extracellular matrix (ECM) of the cerebral vasculature provides a pathway for the flow of interstitial fluid (ISF) and solutes out of the brain by intramural periarterial drainage (IPAD). Failure of IPAD leads to protein elimination failure arteriopathies such as cerebral amyloid angiopathy (CAA). The ECM consists of a complex network of glycoproteins and proteoglycans that form distinct basement membranes (BM) around different vascular cell types. Astrocyte endfeet that are localised against the walls of blood vessels are tethered to these BMs by dystrophin associated protein complex (DPC). Alpha-dystrobrevin (α-DB) is a key dystrophin associated protein within perivascular astrocyte endfeet; its deficiency leads to a reduction in other dystrophin associated proteins, loss of AQP4 and altered ECM. In human dementia cohorts there is a positive correlation between dystrobrevin gene expression and CAA. In the present study, we test the hypotheses that (a) the positive correlation between dystrobrevin gene expression and CAA is associated with elevated expression of α-DB at glial-vascular endfeet and (b) a deficiency in α-DB results in changes to the ECM and failure of IPAD. We used human post-mortem brain tissue with different severities of CAA and transgenic α-DB deficient mice. In human post-mortem tissue we observed a significant increase in vascular α-DB with CAA (CAA vrs. Old p < 0.005, CAA vrs. Young p < 0.005). In the mouse model of α-DB deficiency, there was early modifications to vascular ECM (collagen IV and BM thickening) that translated into reduced IPAD efficiency. Our findings highlight the important role of α-DB in maintaining structure and function of ECM, particularly as a pathway for the flow of ISF and solutes out of the brain by IPAD.

Non-traditional immersive seminar enhances learning by promoting greater physiological and psychological engagement compared to a traditional lecture format.

The purpose of this study was to determine the impact of an immersive seminar, which included moderate intensities of physical activity, on learning when compared to traditional lecture format. Twenty-six healthy participants were randomly divided into an immersive seminar or traditional lecture format group and presented material related to positive psychology and human values/beliefs over the course of two days. Physical activity was collected using a bio-harness while salivary cortisol and perceptual measures of well-being were collected over the two days. Performance on an examination related to course material was used to assess learning. Average time spent over 65% of max heart rate, energy expenditure, total bounds, mechanical and physiological load were significantly greater in the immersive seminar group when compared to traditional lecture group. In addition, cortisol levels and perceptual measures of mood, focus, energy, and well-being were significantly greater in the immersive seminar when compared to the traditional lecture format. Participants in the immersive seminar demonstrated significantly greater memory retention of course material 30-days post lecture when compared to the traditional lecture group. These findings support incorporating more physical activity and increasing arousal in order to enhance learning of lecture material.

The Effect of Exogenous Beta-Hydroxybutyrate Salt Supplementation on Metrics of Safety and Health in Adolescents.

The ketogenic diet is a high-fat, very low-carbohydrate, moderate-protein diet that will induce a state of ketosis, but because of its restrictive nature, it may be difficult to adhere to, especially in adolescents. Supplementing with exogenous beta-hydroxybutyrate salts may induce a state of temporary ketosis without any undesirable side effects, thereby promoting the benefits of ketosis and minimizing adherence requirements to a ketogenic diet. To date, beta-hydroxybutyrate supplementation in healthy adolescents has not been explored. Therefore, the purpose of this study was to examine the safety of exogenous beta-hydroxybutyrate salt supplementation in a healthy adolescent population. In the present study, 22 healthy male and female adolescents consumed 3.75 g of beta-hydroxybutyrate salts or maltodextrin placebo twice daily for 90 days. Comprehensive blood safety analysis, bone densitometry, happiness and emotional intelligence surveys, and blood pressure were assessed at Pre, Day 45, and Day 90. There were no significant differences detected in subjects supplementing with beta-hydroxybutyrate salts, indicating that exogenous beta-hydroxybutyrate salts had no detrimental impact on fasting blood safety metrics, bone density, happiness, emotional intelligence, or blood pressure. We conclude that supplementing with exogenous beta-hydroxybutyrate salts is safe and well-tolerated by healthy adolescents.

Marine phytoplankton improves recovery and sustains immune function in humans and lowers proinflammatory immunoregulatory cytokines in a rat model.

PURPOSE: This study investigated the effects of marine phytoplankton supplementation (Oceanix®, Tetraselmis chuii) on 1) maximal isometric strength and immune function in healthy humans following a oneweek high-intensity resistance-training program and 2) the proinflammatory cytokine response to exercise in a rat model. METHODS: In the human trial, 22 healthy male and female participants were randomly divided into marine phytoplankton and placebo groups. Following baseline testing, participants underwent a 14-day supplement loading phase before completing five consecutive days of intense resistance training. In the rat model, rats were randomly divided into four groups (n=7 per condition): (i) control, (ii) exercise, (iii) exercise + marine phytoplankton (2.55 mg/kg/day), or (iv) exercise + marine phytoplankton (5.1 mg/kg/day). Rats in the exercising groups performed treadmill exercise 5 days per week for 6 weeks. RESULTS: In the human model, marine phytoplankton prevented significant declines in the isometric peak rate of force development compared to placebo. Additionally, salivary immunoglobulin A concentration was significantly lower following the resistance training protocol in the placebo group but not in the marine phytoplankton group. Marine phytoplankton in exercising rats decreased intramuscular levels and serum concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) and intramuscular concentrations of malondialdehyde. CONCLUSION: Marine phytoplankton prevented decrements in indices of functional exercise recovery and immune function. Mechanistically, these outcomes could be prompted by modulating the oxidative stress and proinflammatory cytokine response to exercise.

Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.

OBJECTIVE: Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20ß-dihydrocorticosterone (20ß-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states. METHODS: The actions of 20ß-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding. RESULTS: 20ß-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20ß-DHB and absent in female mice with higher baseline adipose 20ß-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding. CONCLUSIONS: Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.

Marine Phytoplankton Improves Exercise Recovery in Humans and Activates Repair Mechanisms in Rats.

This study investigated the effects of marine phytoplankton supplementation on 1) perceived recovery and ground reaction forces in humans following a non-functional overreaching resistance-training program and 2) myogenic molecular markers associated with muscle cell recovery in a rat model. In the human trial, a 5-week resistance-training program with intentional overreaching on weeks 2 and 5 was implemented. Results indicate that marine phytoplankton prompted positive changes in perceived recovery at post-testing and, while both marine phytoplankton and placebo conditions demonstrated decreased peak and mean rate of force development following the overreaching weeks, placebo remained decreased at post-testing while marine phytoplankton returned to baseline levels. In the rat model, rats were divided into four conditions: (i) control, (ii) exercise, (iii) exercise + marine phytoplankton 2.55 mg·d-1, or (iv) exercise+marine phytoplankton 5.1 mg·d-1. Rats in exercising conditions performed treadmill exercise 5 d·wk-1 for 6 weeks. Marine phytoplankton in exercising rats increased positive and decrease negative myogenic factors regulating satellite cell proliferation. Taken together, marine phytoplankton improved perceptual and functional indices of exercise recovery in an overreaching human model and, mechanistically, this could be driven through cell cycle regulation and a potential to improve protein turnover.

Proteins and Amino Acids Treated with Atmospheric Plasma Show Significantly Increased Bioavailability in Humans.

BACKGROUND: Muscle mass is an important determinant of metabolic health and physical function. It has previously been demonstrated that the postprandial rise in circulating essential amino acids acts as the main stimulus for muscle protein synthesis (MPS). The current study investigated the postprandial plasma essential amino acid (EAA) and branched-chain amino acid (BCAA) responses of (1) Hydrolyzed whey protein isolate (HWPI) compared to plasma treated non-hydrolyzed whey protein isolate (PT-NHWPI), (2) standard branch-chain amino acids (S-BCAA) compared to plasma treated branch-chained amino acids (PT-BCAA), (3) standard pea protein (S-PP), compared to plasma treated pea protein (PT-PP), and (4) HWPI compared to PT-PP. METHODS: Ten subjects (24.6 ± 5.3 years; 178.8 ± 8.1 cm; 78.6 ± 10.1 kg) participated in a double-blind, randomized, crossover trial comparing four separate protein conditions (HWPI, PT-NHWPI, S-PP, PT-PP). A separate cohort of ten subjects (26.4 ± 7.4 years; 178.8 ± 5.9 cm; 85 ± 12.3 kg) participated in a double-blind randomized, crossover trial comparing two branch-chain amino acid conditions: S-BCAA and PT-BCAA. All conditions were administered following a 7-day washout. Plasma EAA and BCAA concentrations were assessed from blood donated by subjects at pre-consumption, 30-, 60-, 90-, 120-, and 180 minutes post-consumption. RESULTS: Blood plasma levels of total EAA and BCAA concentration were significantly greater in all treated conditions at 30-, 60-, 90-, and 120 minutes post consumption (P < .05). There were no differences between PT-PP and HWPI. DISCUSSION: All proteins significantly elevated EAAs, and BCAAs from basal levels. However, we conclude that the consumption of the treated proteins significantly raises blood levels of EAAs, and BCAAs to a greater extent across multiple dairy, vegan, and isolated BCAA conditions. Moreover, atmospheric plasma treatment of a vegan protein source makes its amino acid response similar to whey. Thus, protein supplementation with that has undergone Ingredient Optimized® atmospheric plasma treatment technology may be highly beneficial for improving the blood plasma amino acid response.

Peri-arterial pathways for clearance of α-Synuclein and tau from the brain: Implications for the pathogenesis of dementias and for immunotherapy.

INTRODUCTION: Accumulation of amyloid beta (Aß), α-synuclein (αSyn), and tau in dementias indicates their age-related failure of elimination from the brain. Aß is eliminated along basement membranes in walls of cerebral arterioles and leptomeningeal arteries (intramural peri-arterial drainage [IPAD]); IPAD is impaired with age. We test the hypothesis that αSyn and tau are also eliminated from the normal brain along IPAD pathways. METHODS: Soluble αSyn or tau was injected into mouse hippocampus. Animals were perfused 5 minutes to 7 days post-injection. Blood vessels were identified by ROX-SE for light-sheet and immunolabeling for confocal microscopy. IPAD was quantified by measuring the proportion of arterioles with αSyn/tau. RESULTS: αSyn and tau are eliminated from the brain by IPAD but with different dynamics. DISCUSSION: Age-related failure of IPAD may play a role in the pathogenesis of synucleinopathies and tauopathies. αSyn persists within IPAD at 24 hours, which may affect immunotherapy for αSyn.

Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia.

White matter hyperintensities (WMH) occur in association with dementia but the aetiology is unclear. Here we test the hypothesis that there is a combination of impaired elimination of interstitial fluid from the white matter together with a degree of hypoxia in WMH. One of the mechanisms for the elimination of amyloid-ß (Aß) from the brain is along the basement membranes in the walls of capillaries and arteries (Intramural Peri-Arterial Drainage - IPAD). We compared the dynamics of IPAD in the grey matter of the hippocampus and in the white matter of the corpus callosum in 10 week old C57/B16 mice by injecting soluble Aß as a tracer. The dynamics of IPAD in the white matter were significantly slower compared with the grey matter and this was associated with a lower density of capillaries in the white matter. Exposing cultures of smooth muscle cells to hypercapnia as a model of cerebral hypoperfusion resulted in a reduction in fibronectin and an increase in laminin in the extracellular matrix. Similar changes were detected in the white matter in human WMH suggesting that hypercapnia/hypoxia may play a role in WMH. Employing therapies to enhance both IPAD and blood flow in the white matter may reduce WMH in patients with dementia.

Phytoplankton Supplementation Lowers Muscle Damage and Sustains Performance across Repeated Exercise Bouts in Humans and Improves Antioxidant Capacity in a Mechanistic Animal.

The purpose of this study was to investigate the impact of antioxidant-rich marine phytoplankton supplementation (Oceanix, OCX) on performance and muscle damage following a cross-training event in endurance-trained subjects. Additionally, an animal model was carried out to assess the effects of varying dosages of OCX, with exercise, on intramuscular antioxidant capacity. METHODS: In the human trial, endurance-trained subjects (average running distance = 29.5 ± 2.6 miles × week-1) were randomly divided into placebo (PLA) and OCX (25 mg) conditions for 14 days. The subjects were pre-tested on a one-mile uphill run, maximal isometric strength, countermovement jump (CMJ) and squat jump (SJ) power, and for muscle damage (creatine kinase (CK)). On Day 12, the subjects underwent a strenuous cross-training event. Measures were reassessed on Day 13 and 14 (24 h and 48 h Post event). In the animal model, Wistar rats were divided into four groups (n = 7): (i) Control (no exercise and placebo (CON)), (ii) Exercise (E), (iii) Exercise + OCX 1 (Oceanix, 2.55 mg/day, (iv) Exercise + OCX 2 (5.1 mg/day). The rats performed treadmill exercise five days a week for 6 weeks. Intramuscular antioxidant capacity (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px)) and muscle damage (CK and myoglobin (MYOB) were collected. The data were analyzed using repeated measures ANOVA and t-test for select variables. The alpha value was set at p < 0.05. RESULTS: For the human trial, SJ power lowered in PLA relative to OCX at 24 h Post (-15%, p < 0.05). Decrements in isometric strength from Pre to 48 h Post were greater in the PLA group (-12%, p < 0.05) than in the OCX. Serum CK levels were greater in the PLA compared to the OCX (+14%, p < 0.05). For the animal trial, the intramuscular antioxidant capacity was increased in a general dose-dependent manner (E + Oc2 > E + Oc1 > E > CON). Additionally, CK and MYOB were lower in supplemented compared to E alone. CONCLUSIONS: Phytoplankton supplementation (Oceanix) sustains performance and lowers muscle damage across repeated exercise bouts. The ingredient appears to operate through an elevating oxidative capacity in skeletal muscle.