The role of the aryl hydrocarbon receptor (AhR) in modulating intestinal ILC3s to optimise gut pathogen resistance in lupus and benefits of nutritional AhR ligands.

BACKGROUND AND AIMS: Dysbiosis is emerging as a potential trigger of systemic lupus erythematosus (SLE). Group 3 innate lymphoid cells (ILC3s) are recognised as key regulators of intestinal homeostasis. The aryl hydrocarbon receptor (AhR) is critical to intestinal ILC3 development and function. This mechanistic review aimed to investigate whether AhR activation of gut ILC3s facilitates IL-22-mediated antimicrobial peptide (AMP) production to enhance colonisation resistance and ameliorate SLE pathology associated with intestinal dysbiosis. Furthermore, nutritional AhR ligand potential to enhance pathogen resistance was explored. METHODOLOGY: This mechanistic review involved a three-tranche systematic literature search (review, mechanism, intervention) using PubMed with critical appraisal. Data was synthesised into themes and summarised in a narrative analysis. RESULTS: Preclinical mechanistic data indicate that AhR modulation of intestinal ILC3s optimises pathogen resistance via IL-22-derived AMPs. Pre-clinical research is required to validate this mechanism in SLE. Data on systemic immune consequences of AhR modulation in lupus suggest UVB-activated ligands induce aberrant AhR signalling while many dietary ligands exert beneficial effects. Data on xenobiotic-origin ligands is varied, although considerable evidence has demonstrated negative effects on Th17 to Treg balance. Limited human evidence supports the role of nutritional AhR ligands in modulating SLE pathology. Preclinical and clinical data support anti-inflammatory effects of dietary AhR ligands. CONCLUSION: Current evidence is insufficient to fully validate the hypothesis that AhR modulation of intestinal ILC3s can enhance pathogen resistance to ameliorate lupus pathology driven by dysbiosis. However, anti-inflammatory effects of dietary AhR ligands suggest a promising role as a therapeutic intervention for SLE.

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.

Investigating the Role of 17ß-Estradiol on the Serotonergic System, Targeting Soy Isoflavones as a Strategy to Reduce Menopausal Depression: A Mechanistic Review.

Low serotonin is one factor implicated in the development of depression. 17ß-estradiol (E2) has been shown to modulate gene expression regulating the neurotransmission of serotonin. Sex hormone levels fluctuate dramatically during the menopausal transition, coinciding with a 14-fold increased risk of depression. This review aimed to examine the effect of soy isoflavones to support decreased and variable E2 levels before and after menopause, linked to an investigation of the pathophysiological mechanisms underlying the protective influence of E2 on the serotonin pathway. The overall aim of this review is to assess the potential of soy isoflavones to reduce depression in middle-aged women. A systematic literature search was performed in three stages. 1,421 papers were screened for relevance to the research aims and objectives. 63 papers were selected based on pre-defined inclusion/exclusion criteria (13 reviews, 24 mechanistic and 26 intervention studies) and critically appraised. Available research supported the hypotheses that E2 increases serotonin synthesis and availability through stimulation of tryptophan hydroxylase-2 (TPH-2) and decreased degradation by monoamine oxidase-A (MAO-A). There was less scientific agreement on the effects of E2 on serotonin transporter (SERT) and serotonin receptors 1 A and 2 A. Studies varied widely on the effectiveness of soy isoflavones in reducing depressive symptoms in (peri)menopausal women. Animal and human studies acknowledge women's increased risk of depression linked to fluctuating E2 rather than absolute levels. However, mechanisms linking E2 variability with depression remain an underrepresented area of research. Study limitations and heterogeneity may contribute to varying results for soy isoflavones and some effects of E2 on the serotonin pathway.

17ß-estradiol increases serotonin synthesis and availability through its effects on tryptophan hydroxylase-2, monoamine oxidase-A, serotonin transporter and serotonin receptors 1A and 2A.Soy isoflavones may ameliorate depressive symptoms around the menopausal transition by replicating the effect of 17ß-estradiol on serotonin.Combining research on the mechanistic pathway of soy isoflavones with the effectiveness of outcomes can enhance clinical decision-making.

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.

Vitamin D deficiency and female infertility: A mechanism review examining the role of vitamin D in ovulatory dysfunction as a symptom of polycystic ovary syndrome.

Around one billion people worldwide are understood to have sub-optimal levels of vitamin D. Polycystic ovary syndrome (PCOS) is reportedly a primary reason for female infertility. The main objective of this research was to understand the mechanistic role of vitamin D in the pathogenesis of female infertility in PCOS, specifically in relation to ovarian follicle development. In addition, the impact of vitamin D deficiency on oxidative stress and hormone production central to folliculogenesis was explored. The efficacy of vitamin D supplementation as an intervention to ameliorate ovulatory dysfunction in individuals with PCOS was evaluated. The systematic search strategy included three stages of search with a critical appraisal of the accepted papers: 1) other review papers; 2) primary mechanistic animal, in vitro and human studies; 3) primary intervention studies. In total, 80 papers were examined in detail and results analysed and evaluated. Mechanistic evidence indicated an association between vitamin D deficiency and impaired ovulatory function. Sub-optimal vitamin D levels were implicated in disrupted reproductive hormone balance, including overproduction of anti-mullerian hormone (AMH); accumulation of pro-inflammatory Advanced Glycation End Products (AGEs) and formation of Reactive Oxygen Species (ROS) in ovarian tissue, leading to abnormal folliculogenesis. Human intervention studies demonstrated the capability of vitamin D supplementation for restoring sufficient serum calcidiol (25(OH)D) levels in deficient individuals. Furthermore, the anti-inflammatory benefit of vitamin D was illustrated in studies examining the impact on oxidative stress. Co-supplementation with calcium was shown to benefit follicle growth; oxidative stress reduced with calcium, omega-3 fatty acid or probiotic co-supplementation.

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.

The link between the gut microbiota and Parkinson's Disease: A systematic mechanism review with focus on α-synuclein transport.

INTRODUCTION: Research has suggested a link between the gut microbiota and Parkinson's Disease (PD), and an early involvement of gastrointestinal dysfunction has been reported in patients. A mechanism review was performed to investigate whether the neurodegenerative cascade begins in the gut; mediated by gut dysbiosis and retrograde transport of α-synuclein. This review provides a summary of microbiome composition associated with PD, and evaluates pathophysiological mechanisms from animal and in vitro models of PD. METHOD: A systematic literature search was performed in PubMed; 82 of 299 papers met the inclusion criteria. RESULTS: All twenty-two human case-control studies demonstrated an altered gut microbiota in PD compared to healthy controls, with results suggesting a proinflammatory phenotype present in PD. A germ-free animal study has demonstrated that gut microbiota are required for microglia activation, α-synuclein pathology and motor deficits. Accumulation of phosphorylated α-synuclein has been observed in the enteric nervous system prior to the onset of motor symptoms in animal models of PD, and there is data to support retrograde transport of α-synuclein from the gut to the brain. Different animal models of PD have demonstrated neuroinflammation, microglial activation and loss of dopaminergic neurons in the brain. CONCLUSION: Evidence from this review supports the hypothesis that pathology spreads from the gut to the brain. Future animal studies using oral LPS or microbiota transplants from human PD cases could provide further insight into the entire mechanism. Prospective longitudinal microbiome studies and novel modelling approaches could help to identify functional dysbiosis and early biomarkers for PD.

Link between microbiota and hypertension: Focus on LPS/TLR4 pathway in endothelial dysfunction and vascular inflammation, and therapeutic implication of probiotics.

High blood pressure (BP) presents a significant public health challenge. Recent findings suggest that altered microbiota can exert a hypertensive effect on the host. One of the possible mechanisms involved is the chronic translocation of its components, mainly lipopolysaccharides (LPS) into systemic circulation leading to metabolic endotoxemia. In animal models, LPS has been commonly used to induce endothelial dysfunction and vascular inflammation. In human studies, plasma LPS concentration has been positively correlated with hypertension, however, the mechanistic link has not been fully elucidated. It is hypothesised here that the LPS-induced direct alterations to the vascular endothelium and resulting hypertension are possible targets for probiotic intervention. The methodology of this review involved a systematic search of the literature with critical appraisal of papers. Three tranches of search were performed: 1) existing review papers; 2) primary mechanistic animal, in vitro and human studies; and 3) primary intervention studies. A total of 70 peer-reviewed papers were included across the three tranches and critically appraised using SIGN50 for human studies and the ARRIVE guidelines for animal studies. The extracted information was coded into key themes and summarized in a narrative analysis. Results highlight the role of LPS in the activation of endothelial toll-like receptor 4 (TLR4) initiating a cascade of interrelated signalling pathways including: 1) Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/ Reactive oxygen species (ROS)/ Endothelial nitric oxide synthase (eNOS) pathway leading to endothelial dysfunction; and 2) Mitogen-Activated Protein Kinase (MAPK) and Nuclear factor kappa B (NF-κB) pathways leading to vascular inflammation. Findings from animal intervention studies suggest an improvement in vasorelaxation, vascular inflammation and hypertension following probiotic supplementation, which was mediated by downregulation of LPS-induced pathways. Randomised controlled trials (RCTs) and systematic reviews provided some evidence for the anti-inflammatory effect of probiotics with statistically significant antihypertensive effect in clinical samples and may offer a viable intervention for the management of hypertension.

Biomimetic mineralization: long-term observations in patients with dentin sensitivity.

OBJECTIVE: Cervical tooth erosion is increasingly observed among adults and frequently associated with dentin sensitivity (DS). This study evaluated the effectiveness on DS of a biomimetic mineralization system (BIMIN) in comparison to the current standard treatment (Gluma(®) Desensitizer, Gluma). METHODS: In this single-blind, 2-arm study, 40 patients with confirmed cervical DS were randomized to either the test group or the positive control group. A Visual-Analog-Scale (VAS) was used to assess DS following stimulation of the exposed dentin with a 2-s air blast. Assessments were made at baseline (pre-treatment), 2 days, 4, 8 and 12 weeks, and 12 months after treatment. Two-stage replicas were obtained from the treated teeth and gold sputtered at baseline, and 2 days, 3 and 12 months after treatment. Surface topography of the treated cervical lesions and occlusion of dentinal tubules were investigated using scanning electron microscopy (SEM). RESULTS: Both treatments led to a statistically significant reduction (P<0.0001) in DS that persisted over the entire 12-month observation period. Differences in DS between the treatments were not statistically significant. SEM photomicrographs demonstrated that a mineral layer concealed the dentinal tubules in the test group. In contrast, numerous dentinal tubules remained visible in cervical defects that were treated with Gluma. SIGNIFICANCE: A biomimetic mineralization kit was successfully used to treat patients exhibiting DS. The effect was similar to using Gluma, and was likely the result of the deposition of an enamel-like layer on the exposed cervical dentin.

Sensors for bioanalytes by imprinting--polymers mimicking both biological receptors and the corresponding bioparticles.

Structuring of thin polymer layers by soft lithography with template bioparticles results in the formation of selective surface cavities, leading to highly effective sensor systems when combined with mass-sensitive transducers, especially QCM. These sensors allow selective differentiation of various stages of development of yeast cells. In order to achieve a higher degree of standardisation, we fabricated plastic yeast cells and utilised them for the stamp imprinting procedures. These sensitive layers are capable of the differentiation between Saccharomyces cerevisiae and Saccharomyces bayanus. Aside from achieving the same sensitivity compared to the polymers that were structured using native cells, we realised further enhancement of selectivity exceeding a factor of three regarding the two cell strains. These ideas could also be transferred to develop a recognition system for the more flexible erythrocytes and therefore MIP-layers of polyvinylpyrrolidone were combined with QCMs. These devices provide sensor-based ABO blood group typing. Additionally, the differentiation of the subgroups A(1) and A(2) is shown with the generated MIP-layers that are decorated by high selectivity, namely the threefold frequency effect for the imprinted template, and negligible unspecific effects. Application of soft lithographic methods furthermore allows the design of artificial erythrocytes. These "plastic" blood cells possess an increased robustness compared to the native cells, thus opening up multiple novel strategies of surface patterning.

Application of yeast imprinting in biotechnology and process control.

Rapid advancements in biotechnology depend on the development of reliable sensing sytems adaptable to a variety of analytes. Molecularly imprinted polymers combined with mass-sensitive devices (10 MHz QCMs) provide a reliable and robust method to observe cell growth and allow cell specifications in real-time. Such biosensors selectively detect fermenting yeast in a complex matrix and 10(4) cells/microl in solution correspond to an adhesion of approximately 3 x 10(3) cells on the sensor coating. Over a period of up to 40 hours, the growth of the microorganism at 30 degrees C was observed in various nutrient solutions of glucose, peptone and ammonium sulfate, thereby rendering the determination of optimum growth conditions possible. While almost no change, i.e. no cell propagation, occurred in the absence of glucose, the frequency decreases to more than 700 Hz under rich conditions. Increasing the depth of the imprints to more than 1.5 microm the yeast cells are so strongly bound that they are fixed in the material. With such gravimetric sensors, for instance osmotic effects of cells can be followed by a frequency change of 3 kHz by altering the ion strength by 0.1 M.

Biomimetic Yeast Cell Typing-Application of QCMs.

Artificial antibodies represent a key factor in the generation of sensing systems for the selective detection of bioanalytes of variable sizes. With biomimetic surfaces, the important model organism Saccharomyces cerevisiae and several of its growth stages may be detected. Quartz crystal microbalances (QCM) with 10 MHz fundamental frequency and coated with polymers imprinted with synchronized yeast cells are presented, which are able to detect duplex cells with high selectivity. Furthermore, a multichannel quartz crystal microbalance (MQCM) was designed and optimized for the measurement in liquids. This one-chip system based on four-electrode geometry allows the simultaneous detection of four analytes and, thus, provides a monitoring system for biotechnology and process control. For further standardization of the method, synthetic stamps containing plastic yeast cells in different growth stages were produced and utilized for imprinting. Mass-sensitive measurements with such MIPs resulted in the same sensor characteristics as obtained for those imprinted with native yeast cells.