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Brown Adipose Crosstalk in Tissue Plasticity and Human Metabolism.
Scheele, C, Wolfrum, C
Endocrine reviews. 2020;41(1)
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Brown adipose tissue (BAT) is an important contributor to the regulation of metabolism via cellular communication with organs such as liver, muscle, gut and central nervous system. BAT is important for heat generation and is at high levels in human infants. Levels of activation of BAT decline as we age and it has been shown that the amount of BAT is smaller and its activity reduced in those with obesity and type 2 diabetes. To date, there is no answer to efficiently restore functional BAT in aging and obese subjects. This review looks at experiments done on the factors secreted from active BAT (batokines). The review aims to provide a structure for the processes and cell types involved in BAT and the recent findings of BAT whole-body communication are discussed. Altogether, these findings demonstrate that BAT has an adaptive capacity. Studying batokines, offers an alternative approach to identify novel drug targets for metabolic regulation.
Abstract
Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central nervous system and acute activation increases metabolic rate. Brown adipose tissue (BAT) recruitment occurs during cold acclimation and includes secretion of factors, known as batokines, which target several different cell types within BAT, and promote adipogenesis, angiogenesis, immune cell interactions, and neurite outgrowth. All these processes seem to act in concert to promote an adapted BAT. Recent studies have also provided exciting data on whole body metabolic regulation with a broad spectrum of mechanisms involving BAT crosstalk with liver, skeletal muscle, and gut as well as the central nervous system. These widespread interactions might reflect the property of BAT of switching between an active thermogenic state where energy is highly consumed and drained from the circulation, and the passive thermoneutral state, where energy consumption is turned off. (Endocrine Reviews 41: XXX - XXX, 2020).
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Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target.
Sorgdrager, FJH, Naudé, PJW, Kema, IP, Nollen, EA, Deyn, PP
Frontiers in immunology. 2019;10:2565
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Inflammation is a normal physiological process activated by the immune system in response to injury or infection. As we age, the immune system changes and the balance between pro- and anti-inflammatory agents can shift. This causes a chronic inflammatory state referred to as inflammaging. The rate of inflammaging is strongly associated with age-related disability, disease and mortality. The way in which the essential amino acid tryptophan (Trp) is broken down affects inflammation. If it is converted to kynurenine (Kyn) and its metabolites, inflammation is modulated. Studies have shown that the Kyn/Trp ratio, measured in blood, is strongly associated with ageing in humans. It could therefore be a useful marker to predict the onset of age-related diseases. This review discusses the metabolism of Trp and the links to inflammation. The authors hypothesize how intervening in these pathways could impact health- and lifespan. Future studies are needed to confirm the value of Trp metabolism as a biomarker for (un)healthy ageing and as drug target for inflammaging-related disease.
Abstract
Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD+). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.
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Cannabidiol in Anxiety and Sleep: A Large Case Series.
Shannon, S, Lewis, N, Lee, H, Hughes, S
The Permanente journal. 2019;23:18-041
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After the psychoactive tetrahydrocannabinol (THC), cannabidiol (CBD) is the second most abundant, and non-psychoactive, cannabinoid of the cannabis plant. CBD appears to have a calming effect on the central nervous system, however, clinical evidence for its use is limited. The purpose of the present study is to describe the effects of CBD on anxiety and sleep. A retrospective chart review of 72 adult patients with primary concerns of anxiety (47 patients) or poor sleep (25 patients) and treated with CBD for at least 1 month as an adjunct to usual treatment, was conducted at a large integrative psychiatric outpatient clinic. Nearly all patients were given CBD 25 mg/d in capsule form. If anxiety complaints predominated, the dosing was every morning, after breakfast. If sleep complaints predominated, the dosing was every evening, after dinner. Monthly visits included clinical evaluation and documentation of patients’ anxiety and sleep status. Whilst anxiety scores showed a rapid and sustained decrease over the three months study period, no sustained improvements in sleep was seen. The treatment with CBD was generally well accepted and tolerated. The authors conclude that these results support the existing scientific evidence, and that more clinical research is needed to provide better clinical guidance on the use of CBD.
Abstract
CONTEXT Cannabidiol (CBD) is one of many cannabinoid compounds found in cannabis. It does not appear to alter consciousness or trigger a "high." A recent surge in scientific publications has found preclinical and clinical evidence documenting value for CBD in some neuropsychiatric disorders, including epilepsy, anxiety, and schizophrenia. Evidence points toward a calming effect for CBD in the central nervous system. Interest in CBD as a treatment of a wide range of disorders has exploded, yet few clinical studies of CBD exist in the psychiatric literature. OBJECTIVE To determine whether CBD helps improve sleep and/or anxiety in a clinical population. DESIGN A large retrospective case series at a psychiatric clinic involving clinical application of CBD for anxiety and sleep complaints as an adjunct to usual treatment. The retrospective chart review included monthly documentation of anxiety and sleep quality in 103 adult patients. MAIN OUTCOME MEASURES Sleep and anxiety scores, using validated instruments, at baseline and after CBD treatment. RESULTS The final sample consisted of 72 adults presenting with primary concerns of anxiety (n = 47) or poor sleep (n = 25). Anxiety scores decreased within the first month in 57 patients (79.2%) and remained decreased during the study duration. Sleep scores improved within the first month in 48 patients (66.7%) but fluctuated over time. In this chart review, CBD was well tolerated in all but 3 patients. CONCLUSION Cannabidiol may hold benefit for anxiety-related disorders. Controlled clinical studies are needed.
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Effectiveness of Vitamin D Supplementation in the Management of Multiple Sclerosis: A Systematic Review.
Berezowska, M, Coe, S, Dawes, H
International journal of molecular sciences. 2019;20(6)
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Epidemiological research shows that Vitamin D status is associated with reduced activity and progression of disease in multiple sclerosis (MS). This review assessed the evidence from ten double-blind randomised controlled trials, including a total of 627 adults with relapsing remitting MS (RRMS), for the clinical effectiveness of vitamin D supplementation compared to placebo in disease and symptom management. The results from the reviewed studies on disease progression and immunological blood parameters were mixed. Where benefits of vitamin D supplementation were seen this tended to be in those groups where vitamin D levels were low at the start of the study. Those studies evaluating the safety and tolerability of vitamin D reported no serious adverse events. The authors conclude that baseline serum vitamin D levels may be a predictor of improvements in RRMS with vitamin D supplementation, and that further research should include baseline vitamin D as part of the assessment.
Abstract
OBJECTIVE to examine the extent of effect vitamin D in Multiple Sclerosis (MS) on pathology and symptoms. METHODS A literature search was performed in November 2018 (CRD42018103615). Eligibility criteria: randomised control trials in English from 2012 to 2018; a clinical diagnosis of MS; interventions containing vitamin D supplementation (vitamin D3 or calcitriol) in disease activity compared to a control/placebo; improvement in: serum 25(OH)D, relapse rates, disability status by Expanded Disability Status Scale (EDSS) scores, cytokine profile, quality of life, mobility, T2 lesion load and new T2 or T1 Gd enhancing lesions, safety and adverse effects. Risk of bias was evaluated. RESULTS Ten studies were selected. The study size ranged from 40 to 94 people. All studies evaluated the use of vitamin D supplementation (ranging from 10 to 98,000 IU), comparing to a placebo or low dose vitamin D. The duration of the intervention ranged from 12 to 96 weeks. One trial found a significant effect on EDSS score, three demonstrated a significant change in serum cytokines level, one found benefits to current enhancing lesions and three studies evaluating the safety and tolerability of vitamin D reported no serious adverse events. Disease measures improved to a greater extent overall in those with lower baseline serum 25(OH)D levels. CONCLUSIONS As shown in 3 out of 10 studies, improvement in disease measures may be more apparent in those with lower baseline vitamin D levels.
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Vitamin D Supplementation in Central Nervous System Demyelinating Disease-Enough Is Enough.
Häusler, D, Weber, MS
International journal of molecular sciences. 2019;20(1)
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Vitamin D is associated with a reduced risk and severity of multiple sclerosis (MS). However, whether supplementing vitamin D level alters disease severity, is a matter of ongoing debate. This review looks at both clinical and pre-clinical evidence for supplementing vitamin D in people with MS. In vitro experiments show that vitamin D and its metabolites can alter function of various immune cells, mostly via interaction with vitamin D receptors (VDR). Results from human clinical trials, however, are mixed. Preclinical evidence suggests that high dose vitamin D supplementation, when leading to hypercalcaemia, a potentially serious side effect of excessive vitamin D intake, may worsen MS. The authors also review research which suggests mechanisms by which sun exposure can improve MS symptoms independent of vitamin D production. The authors conclude that moderate sun exposure, combined with adequate dietary intake of vitamin D, and in conjunction with a regular assessment of vitamin D serum levels (to avoid hypercalcaemia), might be the best strategy for patients with MS.
Abstract
The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS.
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Antidepressant utilisation and incidence of weight gain during 10 years' follow-up: population based cohort study.
Gafoor, R, Booth, HP, Gulliford, MC
BMJ (Clinical research ed.). 2018;361:k1951
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Obesity is an increasing concern worldwide and the USA and UK have some of the highest rates of obesity in the world. Anti-depressant medications are also increasing prescribed, and there is an established association between obesity and depression. These medications may also contribute to weight gain, although the mechanisms for this are not clearly understood. This large UK-population based cohort study aimed to evaluate the long term association between anti-depressant prescriptions and body weight, using data from the UK Clinical Practice Research Datalink from 2004-2014. Weight gain of >=5% was measured. The number of incidences of >=5% weight gain was significantly higher for patients prescribed an anti-depressant than those who were not, after adjusting for confounding factors such as age, smoking status, social status, comorbidity and co-prescribing. This was particularly so during the 2nd and 3rd year of treatment, when there was a 46% higher risk of >=5% weight gain compared to the general population. It was also found that some anti-depressants contributed to higher weight gain than others. Whilst the associations may not be causal, the potential for weight gain should be considered when anti-depressant medications are indicated.
Abstract
OBJECTIVE To evaluate the long term association between antidepressant prescribing and body weight. DESIGN Population based cohort study. SETTING General practices contributing to the UK Clinical Practice Research Datalink, 2004-14. PARTICIPANTS 136 762 men and 157 957 women with three or more records for body mass index (BMI). MAIN OUTCOME MEASURES The main outcomes were antidepressant prescribing, incidence of ≥5% increase in body weight, and transition to overweight or obesity. Adjusted rate ratios were estimated from a Poisson model adjusting for age, sex, depression recording, comorbidity, coprescribing of antiepileptics or antipsychotics, deprivation, smoking, and advice on diet. RESULTS In the year of study entry, 17 803 (13.0%) men and 35 307 (22.4%) women with a mean age of 51.5 years (SD 16.6 years) were prescribed antidepressants. During 1 836 452 person years of follow-up, the incidence of new episodes of ≥5 weight gain in participants not prescribed antidepressants was 8.1 per 100 person years and in participants prescribed antidepressants was 11.2 per 100 person years (adjusted rate ratio 1.21, 95% confidence interval 1.19 to 1.22, P<0.001). The risk of weight gain remained increased during at least six years of follow-up. In the second year of treatment the number of participants treated with antidepressants for one year for one additional episode of ≥5% weight gain was 27 (95% confidence interval 25 to 29). In people who were initially of normal weight, the adjusted rate ratio for transition to overweight or obesity was 1.29 (1.25 to 1.34); in people who were initially overweight, the adjusted rate ratio for transition to obesity was 1.29 (1.25 to 1.33). Associations may not be causal, and residual confounding might contribute to overestimation of associations. CONCLUSION Widespread utilisation of antidepressants may be contributing to long term increased risk of weight gain at population level. The potential for weight gain should be considered when antidepressant treatment is indicated.
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A double-blind, randomized, comparative study of the use of a combination of uridine triphosphate trisodium, cytidine monophosphate disodium, and hydroxocobalamin, versus isolated treatment with hydroxocobalamin, in patients presenting with compressive neuralgias.
Goldberg, H, Mibielli, MA, Nunes, CP, Goldberg, SW, Buchman, L, Mezitis, SG, Rzetelna, H, Oliveira, L, Geller, M, Wajnsztajn, F
Journal of pain research. 2017;10:397-404
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Uridine and cytidine are nucleotides, which play several fundamental roles in cellular metabolism, including being components of DNA, energy transfer, intracellular signalling and neurotransmission. Vitamin B12 is essential for growth and maintenance of a variety of processes, including synthesis of myelin (an important structure of the nervous system) and nerve metabolism. The objectives of this randomised, double-blind, comparative, controlled clinical trial were to assess the safety and efficacy of the combination of nucleotides (uridine triphosphate, UTP and cytidine monophosphate, CMP) and vitamin B12 in patients presenting with pain due to neural compression, compared with vitamin B12 on its own. Patients received 15mg CMP, 9mg UTP and 6mg vitamin B12 or 6mg vitamin B12 only, for 30 days and were assessed before start and at 15 and 30 days of treatment. Outcome measures included a visual analog pain scale (VAS), and the Patient Functionality Questionnaire (PFQ), as well as adverse effects, including changes in blood parameters. 191 patients in each group completed the trial. Both groups showed statistically significant improvements at the end of the study in relation to pre-treatment PFQ and VAS scores, but improvements were statistically better in the combination therapy compared to vitamin B12 alone. Adverse events were reported in both treatment groups, but these were transient and no severe adverse event occurred during the study period. The authors conclude that the combination of uridine, cytidine, and vitamin B12 was effective in the treatment of neuropathic pain and that further, larger studies are warranted.
Abstract
CONTEXT This paper reports on the results of treatment of compressive neuralgia using a combination of nucleotides (uridine triphosphate trisodium [UTP] and cytidine monophosphate disodium [CMP]) and vitamin B12. OBJECTIVES To assess the safety and efficacy of the combination of nucleotides (UTP and CMP) and vitamin B12 in patients presenting with neuralgia arising from neural compression associated with degenerative orthopedic alterations and trauma, and to compare these effects with isolated administration of vitamin B12. METHODS A randomized, double-blind, controlled trial, consisting of a 30-day oral treatment period: Group A (n=200) receiving nucleotides + vitamin B12, and Group B (n=200) receiving vitamin B12 alone. The primary study endpoint was the percentage of subjects presenting pain visual analog scale (VAS) scores ≤20 at end of study treatment period. Secondary study endpoints included the percentage of subjects presenting improvement ≥5 points on the patient functionality questionnaire (PFQ); percentage of subjects presenting pain reduction (reduction in VAS scores at study end in relation to pretreatment); and number of subjects presenting adverse events. RESULTS The results of this study showed a more expressive improvement in efficacy evaluations among subjects treated with the combination of nucleotides + vitamin B12, with a statistically significant superiority of the combination in pain reduction (evidenced by VAS scores). There were adverse events in both treatment groups, but these were transitory and no severe adverse event was recorded during the study period. Safety parameters were maintained throughout the study in both treatment groups. CONCLUSION The combination of uridine, cytidine, and vitamin B12 was safe and effective in the treatment of neuralgias arising from neural compression associated with degenerative orthopedic alterations and trauma.