The mechanistic role of curcumin on matrix metalloproteinases in osteoarthritis.

A systematic mechanistic review was performed to determine mechanistic evidence for curcumin on pro-inflammatory matrix metalloproteinases and Osteoarthritis to understand the underlying pathophysiology, and to evaluate available human intervention evidence to inform clinical decision making. The systematic literature search was performed in 3 tranches (reviews, mechanistic, intervention studies) using PubMed, with no date limitations and using specific search terms. 65 out of 393 screened papers were accepted based on detailed inclusion and exclusion criteria. The mechanistic search was divided into three searches and the intervention searches were subdivided into four searches. Curcumin demonstrated significant inhibition of matrix metalloproteinases linked to cartilage degradation in Osteoarthritis through reduced activation of the nuclear factor kappa-B signaling pathway via suppressing phosphorylation of Iκßa and p65 nuclear translocation. Mechanistic evidence implicated matrix metalloproteinases in Osteoarthritis by decreasing Type II collagen, leading to cartilage damage. As a potential nutritional intervention for Osteoarthritis, curcumin could reduce inflammatory markers and improve pain and function scores. The evidence indicates most formulations of turmeric extract and curcumin extract, bio-enhanced and non-bio-enhanced, are effective at improving inflammatory markers and pain and function to a greater or lesser extent. Due to the high heterogeneity of the formulations, dosage, and duration of the studies, further research is needed to fully understand curcumin's potential as a promising non-pharmaceutical intervention for Osteoarthritis. This mechanism review identifies a gap in current research for the mechanism by which Type II collagen is mediated.

Microbial Imbalance and Intestinal Permeability in the Pathogenesis of Rheumatoid Arthritis: A Mechanism Review with a Focus on Bacterial Translocation, Citrullination, and Probiotic Intervention.

This review aims to investigate the role of intestinal permeability (IP) in rheumatoid arthritis (RA), following the hypotheses that leakage of intestinal microbes can influence increased citrullination of peptides leading to anti-citrullinated protein antibody (ACPA) production and inflammation in RA; and that leaked microbes can migrate to the peripheral joints, leading to immune responses and synovitis in peripheral joints. This review explored the evidence for the link between microbial dysbiosis and increased IP in the inflammatory state in RA, as well as the role of increased citrullination and bacterial translocation in the link between microbiota and immune responses in RA. Furthermore, this research aims to evaluate the potential effect of probiotics on RA symptoms and pathogenesis via proposed mechanisms, including the support of microbial balance and suppression of inflammatory factors in RA. A systematic literature search was conducted in three tranches (review, mechanism, intervention). 71 peer-reviewed papers met the inclusions criteria and are summarized in a narrative analysis. Primary studies were critically appraised, synthesized and their relevance to clinical practice evaluated. Evidence found in this mechanism review consistently supported intestinal dysbiosis and increased IP in arthritis. An altered intestinal microbiome was demonstrated in RA with specific microbes such as Collinsella and Eggerthella correlating with increased IP, mucosal inflammation, and immune responses. Hypercitrullination and ACPA production correlated with arthritic symptoms and intestinal microbes were shown to influence hypercitrullination. Some in vitro and animal studies demonstrated a link between leakage of microbes and bacterial translocation, but further research is needed to elucidate the link between IP and citrullination. Probiotic intervention studies evidenced reductions in inflammatory markers IL-6 and TNFα, associated with proliferation of synovial tissue and pain perception in RA joint inflammation. Despite some conflict in the literature, probiotics may present a promising nutritional intervention in the suppression of both, disease activity and inflammatory markers.Key teaching pointsThere is evidence for a dysbiotic profile of the RA gut with specific RA-associated microbes.Increased intestinal permeability and leakage of PAD enzyme facilitates citrullination of peptides.Hypercitrullination and ACPA production correlate to arthritic signs.Microbial leakage and translocation plays a role in the pathogenesis of RA.Probiotics (e.g. L. Casei 01) may reduce inflammation and ameliorate RA symptoms.

Circadian misalignment in obesity: The role for time-restricted feeding.

BACKGROUND AND AIMS: The epidemic of obesity is associated with a substantial, complex and escalating burden of disease. Dietary and lifestyle interventions provide the mainstay of management; however, obesity is multifactorial and challenging to address clinically. Disrupted circadian behaviours, including late eating, are associated with obesity. Time-restricted feeding (TRF), the confinement of calorie intake to a temporal 'eating window', has received growing interest as a weight-loss intervention. Benefits are purported to arise from the fasting period and strengthened circadian metabolism. However, the current evidence-base for TRF is small-scale, limited, and there has been little evaluation of circadian schedule. This research aims to enable evidence-based conclusions regarding circadian-aligned TRF as a weight-loss intervention in obesity. METHODS: A systematic three-tranche search strategy was conducted within PubMed. Included studies were critically evaluated. Search tranches scoped: interventional evidence for TRF; evidence linking meal timing, obesity and metabolic function; and evidence linking circadian function, obesity, and dysmetabolism. Results were summarised in a narrative analysis. RESULTS: A total of 30 studies were included. From small-scale and short-term evidence, TRF was consistently associated with improved weight, glycaemic and anthropometric outcomes versus baseline or control. Good adherence and safety, and consistency of results between studies, were notable. Earlier ('circadian-aligned') eating was associated with greater diet-induced thermogenesis, and improved weight loss and glycaemic outcomes. Limited evidence suggested meaningful correlations between circadian clock function and obesity/metabolic risk. CONCLUSIONS: Circadian-aligned TRF may present a promising intervention for weight loss and metabolic benefits in obese/overweight individuals.

Nutritional entrainment of circadian rhythms under alignment and misalignment: A mechanistic review.

BACKGROUND AND AIMS: The rising prevalence of obesity is a major international concern and is associated with a substantial burden of disease. Disrupted circadian behaviours, including late and extended eating patterns, are identified as risk factors for obesity. The circadian rhythm synchronises metabolic functions between and within tissues, optimising physiology to integrate with environmental and behavioural cycles. Cellular circadian rhythms also separate poorly compatible processes and enable adaptive integration of energy metabolism with autophagy. The timing of nutritional input is a key and easily controllable variable that influences circadian function. Misalignment of nutritional input with the centrally generated circadian rhythm may dampen and disrupt circadian metabolic function. This review seeks to provide a mechanistic overview of nutritional circadian entrainment and its downstream metabolic effects. The aims are: to characterise the key cellular and physiological mechanisms involved in the nutritional entrainment of circadian rhythms; and to explore the perturbation of these pathways by misaligned nutritional inputs, with relevance to obesity-associated dysmetabolism. METHODS: A systematic two-tranche search strategy was employed. Searches were conducted within PubMed between March and December 2020. Included studies were formally evaluated for quality. Evidence was extracted and coded into key themes. RESULTS: 142 records were screened and 50 accepted. The evidence analysed was moderate-to-high quality and enabled the detailed characterisation of cellular pathways involved in nutritional circadian entrainment. Results indicated that diverse nutritional input pathways converge upon key nutrient/redox sensors and nutritionally sensitive core clock genes, which integrate with circadian metabolic pathways, allowing bidirectional communication between circadian clock function and metabolism. Versus alignment, nutritional misalignment was causally associated with dampening and alteration of core clock rhythms, between-tissue rhythmic decoupling, dysmetabolism, and obesity. Signalling through key circadian nodes, such as NAD+/SIRT, was indicated to have importance in these metabolic changes. Misaligned nutritional inputs were associated with altered core circadian temporal dynamics of metabolism and autophagy, and different time division between insulin-sensitive and insulin-resistant metabolic states. Time-restricted feeding protocols aligned with the natural circadian rhythm (light-dark cycle) relatively strengthened circadian oscillatory patterns and protected against diet-induced obesity. CONCLUSIONS: This review suggests potential value in further investigating circadian-normalising nutritional interventions for obesity, such as circadian-aligned time-restricted feeding.

The evolving classifications and epidemiological challenges surrounding chronic migraine and medication overuse headache: a review.

Changes in diagnostic criteria, for example, the various International Classification of Headache Disorders criteria, would lead to changes in the outcomes of epidemiological studies. International Classification of Headache Disorders-1 was based mainly on expert opinion, yet most of the diagnostic criteria were reliable and valid, but it did not include chronic migraine. In its second version, the classification introduced chronic migraine, but this diagnosis resembled more a high-frequency migraine rather than the actual migraine transformation process. It also introduced medication overuse headache, but it necessitated analgesic withdrawal and subsequent headache improvement to be diagnosed as such. Hence patients having medication overuse headache could only be diagnosed in retrospect, which was an awkward situation. Such restrictive criteria for chronic migraine and medication overuse headache omitted a high proportion of patients. International Classification of Headache Disorders-3 allows a diagnosis of medication overuse headache due to combination analgesics if taken for at least 10 days per month for more than three months. Hence the prevalence rate of medication overuse headache and chronic migraine can increase compared to the previous version of the headache classification. Different criteria have been used across studies to identify chronic migraine and medication overuse headache, and therefore the information acquired from previous studies using earlier criteria becomes uncertain. Hence much epidemiological research would need to be interpreted cautiously or repeated with the most updated criteria, since the subjects in studies that apply the latest criteria may be phenotypically different from those in older studies.

Intermittent fasting and cognitive performance - Targeting BDNF as potential strategy to optimise brain health.

Aging is the major risk factor for neurodegenerative diseases, accelerated by excessive calorie consumption and sedentary lifestyles. Bioenergetic challenges such as intermittent fasting (IF) have shown to promote lifespan and healthspan via an adaptive stress response. Activity-dependent brain-derived neurotrophic factor (BDNF) has emerged as key regulator of cognitive performance and brain health. This review aims to investigate the pathophysiological mechanisms linking IF and cognitive function with a focus on the role of BDNF, evaluating evidence from pre-clinical and human studies. A systematic literature search was performed. 82 peer-reviewed papers were accepted, critically appraised and summarised in a narrative analysis. Aging-related loss of BDNF has been associated with reduced synaptic plasticity, memory and learning as well as increased risk of cognitive impairment and Alzheimer's disease. IF was consistently reported to upregulate BDNF and improve cognitive performance in animal models. Further research is required to assess cognitive outcomes of IF in humans.

Transforming personalized nutrition practice.

The strengths and limitations of current approaches to clinical nutrition practice and their underpinning research are explored in this article. It describes how a personalized nutrition practice approach supported by evidence-based pathophysiological reasoning could direct additional research, which could then transform practice and support food industry developments. Current use of the term "personalized nutrition" is reviewed and a definition is provided. Also explored are current approaches to personalized nutrition practice and evidence-based practice in clinical nutrition. Patient-centered practice, which involves individuals in their healthcare decisions, is currently being provided under the name "personalized." An evidence-based personalized practice approach should include the use of robust, standardized, and validated tools that gather a patient's signs and symptoms, health history, family history, genetics, environment, lifestyle, social life, diet, behavior and other factors that have an impact on physiological processes. It should also gather anthropometric measures as well as functional, diagnostic, and prognostic biomarkers for pathophysiological mechanisms. Such tools would pool n = 1 data into a case-by-case evidence base that uses computational network modelling to predict the efficacy of personalized nutrition interventions. Prediction of the efficacy of interventions should also be validated using, when possible, blinded, randomized, controlled, stratified intervention studies. This model would provide practitioners with data that support evidence-based pathophysiological reasoning. It would enable clinicians to prioritize interventions on the basis of the mechanisms of action of interventions and to ameliorate the mechanisms of pathophysiology, which are a priority for the individual. Interventions then may be applied using a patient-centered practice approach. This would transform evidence-based nutrition practice into a P4 medicine approach that is personalized, preventive, predictive, and participatory. Developing pathophysiological mechanistic understanding also provides new opportunities for stakeholders, including the food industry, researchers, healthcare practitioners, and consumers.