G protein-coupled receptors: A target for microbial metabolites and a mechanistic link to microbiome-immune-brain interactions

Human-microorganism interactions play a key role in human health. However, the underlying molecular mechanisms remain poorly understood. Small-molecules that offer a functional readout of microbe-microbe-human relationship are of great interest for deeper understanding of the inter-kingdom crosstalk at the molecular level. Recent studies have demonstrated that small-molecules from gut microbiota act as ligands for specific human G protein-coupled receptors (GPCRs) and modulate a range of human physiological functions, offering a mechanistic insight into the microbe-human interaction. To this end, we focused on analysis of bacterial metabolites that are currently recognized to bind to GPCRs and are found to activate the known downstream signaling pathways. We further mapped the distribution of these molecules across the public mass spectrometry-based metabolomics data, to identify the presence of these molecules across body sites and their association with health status. By combining this with RNA-Seq expression and spatial localization of GPCRs from a public human protein atlas database, we inferred the most predominant GPCR-mediated microbial metabolite-human cell interactions regulating gut-immune-brain axis. Furthermore, by evaluating the intestinal absorption properties and blood-brain barrier permeability of the small-molecules we elucidated their molecular interactions with specific human cell receptors, particularly expressed on human intestinal epithelial cells, immune cells and the nervous system that are shown to hold much promise for clinical translational potential. Furthermore, we provide an overview of an open-source resource for simultaneous interrogation of bioactive molecules across the druggable human GPCRome, a useful framework for integration of microbiome and metabolite cataloging with mechanistic studies for an improved understanding of gut microbiota-immune-brain molecular interactions and their potential therapeutic use

Sex-specific roles of cellular inflammation and cardiometabolism in obesity-associated depressive symptomatology.

BackgroundObesity and depression are complex conditions with stronger comorbid relationships among women than men. Inflammation and cardiometabolic dysfunction are likely mechanistic candidates for increased depression risk, and their prevalence differs by sex. Whether these relationships extend to depressive symptoms is poorly understood. Therefore, we analyzed sex in associations between inflammation and metabolic syndrome (MetS) criteria on depressive symptomatology. Specifically, we examined whether sex positively moderates the relationship between depressive symptoms and inflammation among women, and whether MetS has parallel effects among men.MethodsDepressive symptoms, MetS, and inflammation were assessed in 129 otherwise healthy adults. Depressive symptoms were assessed using Beck Depression Inventory (BDI-Ia). Monocyte inflammation regulation (BARIC) was quantified using flow cytometry measurement of TNF-α suppression by β-agonist. Moderation effects of sex on associations between BARIC, MetS criteria, and BDI were estimated using two-way ANOVA and linear regression, adjusting for BMI, and by sex subgroup analyses.ResultsObese individuals reported more depressive symptoms. Sex did not formally moderate this relationship, though BDI scores tended to differ by BMI among women, but not men, in subgroup analysis. Poorer inflammation control and higher MetS criteria were correlated with somatic depressive symptoms. Sex moderated associations between MetS criteria and somatic symptoms; among men, MetS criteria predicted somatic symptoms, not among women. Subgroup analysis further indicated that poorer inflammation control tended to be associated with higher somatic symptoms in women.ConclusionsThese results indicate that obesity-related inflammation and MetS factors have sex-specific effects on depressive symptoms in a non-clinical population. Although pathophysiological mechanisms underlying sex differences remain to be elucidated, our findings suggest that distinct vulnerabilities to depressive symptoms exist between women and men, and highlight the need to consider sex as a key biological variable in obesity-depression relationships. Future clinical studies on comorbid obesity and depression should account for sex, which may optimize therapeutic strategies

Association of Blood Pressure and Fitness With Levels of Atherosclerotic Risk Markers Pre-Exercise and Post-exercise

Background: Physical fitness may attenuate the increased atherosclerotic risk in patients with systemic hypertension. We investigated the association of screening blood pressure (BP) and cardiorespiratory fitness with baseline levels and exercise-induced changes in levels of soluble atherosclerotic risk markers. Methods: Twenty-six otherwise healthy and unmedicated subjects with elevated BP (systolic BP and/or diastolic BP ≥130/85 mm Hg) and 40 subjects with normal BP underwent 20-min treadmill exercise at 65% to 70% of predetermined peak oxygen consumption (VO2peak). Interleukin (IL)-6, soluble intercellular adhesion molecule (sICAM)-1, von Willebrand factor (VWF) antigen, and plasminogen activator inhibitor (PAI)-1 antigen were measured at baseline (ie, pre-exercise), early postexercise, and late postexercise (ie, 25 min after exercise). Results: At baseline, higher screening mean arterial BP (MAP) independently predicted higher sICAM-1 levels (P = .031), and lower VO2peak independently predicted higher IL-6 (P = .016) and PAI-1 (P < .001) levels. Early and late postexercise lower VO2peak was associated with higher mean PAI-1 (P ≤ .072) and IL-6 (P ≤ .026) levels, and higher screening MAP was associated with higher mean sICAM-1 levels (P ≤ .035). Higher VO2peak was associated with a greater PAI-1 increase from baseline to early postexercise in subjects with elevated BP (P = .045) but not in those with normal BP. Conclusions: Circulating levels of some atherosclerotic risk markers at baseline and with exercise were higher with elevated BP and lower with better fitness. Greater fitness did not particularly protect subjects with elevated BP from potentially harmful responses of atherosclerotic risk markers to acute physical exercise. Am J Hypertens 2007;20: 670-675 © 2007 American Journal of Hypertension, Lt

Brief report: Characteristics of antidepressant use in patients with heart failure

Paul J Mills1, Joel E Dimsdale1, Suzi Hong1, Geoffrey Van Den Brande2, Laura Redwine2, Barry H Greenberg2, Thomas Rutledge11Department of Psychiatry; 2Department of Medicine, University of California San Diego, La Jolla, CA, USABackground: Depression is common in heart failure (HF), but there is little data on the characteristics of antidepressant use in patients with HF.Objective: To survey basic information on antidepressant prescription characteristics, use, effectiveness, and follow-up.Methods: Observational study in two outpatient cardiology clinics of 37 NYHA class I&amp;ndash;IV HF patients taking antidepressant medication.Results: Thirty-one percent of prescriptions for antidepressants were obtained from psychiatrists, 58% from primary care physicians, and 8% from cardiologists. The majority of patients (87%) reported regularly taking their antidepressant medication as prescribed, however 48% reported never having had the dosage of their antidepressant medication adjusted. Only 53% of the patients reported that the medication had helped their mood &amp;ldquo;almost entirely&amp;rdquo; or &amp;ldquo;mostly&amp;rdquo; back to normal since starting their antidepressants, while the remaining patients reported that their mood was only &amp;ldquo;halfway&amp;rdquo; or &amp;ldquo;somewhat&amp;rdquo; back to normal or that the medication had not helped their depression at all. Among a subset of 10 patients who completed the Beck Depression (BDI) inventory, 6 still had depressed mood (BDI&amp;nbsp;&amp;ge; 10).Conclusion: The findings from this survey study provide insight into the characteristics of antidepressant use in patients with HF and argue for better follow up of HF patients who are prescribed antidepressants.Keywords: heart failure, antidepressant medication, adherence, effectivenes

A novel approach to modeling tissue-level activity of cortisol levels according to the theory of Endobiogeny, applied to chronic heart failure

Background: Chronic heart failure (CHF) is an inflammatory disorder in which cortisol plays an important role. Despite this, cortisol is not routinely quantitatively measured for a number of reasons. It is considered non-specific. Accuracy and validity remain in question. It is not considered convenient or cost effective. Finally, tissue level effects of cortisol do not correlate linearly to quantitative levels. If the functional, tissue level effectiveness of cortisol could be modeled, its evaluation in CHF patient may become relevant. Endobiogeny is a global systems theory that claims to be able to model complex physiology through biomarkers, offering context-rich interpretations of data for meaningful clinical applicability. Cortisol is known to alter circulating levels of elements from a complete blood count (CBC). By relating these biomarkers in a qualitative fashion, the theory of Endobiogeny posits that these elements can be contextualized to reflect the tissue level activity of cortisol, referred to as the cortisol index (CI). The algorithm derived from the theory is called the Biology of Functions (BoF). Aim: The aim of this study was to determine if the cortisol index is accurate in reflecting a greater expression of cortisol activity in ambulatory CHF patients versus controls subjects. Methods: A retrospective observational case control study was performed in 93 patients with New York Heart Association class II-III heart failure patients and 104 individuals with no cardiovascular pathology as a control group. Results from a CBC were entered into BOF modeling software, from which the cortisol index is derived. Results: The Cortisol index (3-7) was significantly elevated in CHF vs. control patients (12.8±0.91 vs. 8.48±0.74, p< 001), as were individual CBC elements used to form the index. Conclusions: The cortisol index, derived from the theory of Endobiogeny showed results consistent with CHF pathophysiology. The cortisol index was able to model the effective tissue level activity of cortisol in CHF patients using only a CBC, without measuring serum cortisol. Future studies should compare the cortisol index to standard inflammatory markers in CHF patients to further correlate the validity of the index to other known effects of cortisol

Virtual reality-based monitoring test for MCI: A multicenter feasibility study

ObjectivesAs the significance of the early diagnosis of mild cognitive impairment (MCI) has emerged, it is necessary to develop corresponding screening tools with high ecological validity and feasible biomarkers. Virtual reality (VR)-based cognitive assessment program, which is close to the daily life of the older adults, can be suitable screening tools for MCI with ecological validity and accessibility. Meanwhile, dehydroepiandrosterone (DHEA) has been observed at a low concentration in the older adults with dementia or cognitive decline, indicating its potential as a biomarker of MCI. This study aimed to determine the efficacy and usability of a VR cognitive assessment program and salivary DHEA for screening MCI.MethodsThe VR cognitive assessment program and the traditional Montreal Cognitive Assessment (MOCA) test were performed on 12 patients with MCI and 108 healthy older adults. The VR program operates in a situation of caring for a grandchild, and evaluates the memory, attention, visuospatial, and executive functions. An analysis of covariance (ANCOVA), a partial correlation analysis, and receiving operating characteristic (ROC) curve analysis were conducted for statistical analysis.ResultsAccording to the ANCOVA, no significant difference in MOCA scores was found between the normal and MCI groups (F = 2.36, p = 0.127). However, the VR total score of the MCI group was significantly lower than that of the normal group (F = 8.674, p = 0.004). There was a significant correlation between the MOCA and VR scores in the total and matched subdomain scores. The ROC curve analysis also showed a larger area under the curve (AUC) for the VR test (0.765) than for the MOCA test (0.598), and the sensitivity and specificity of the VR program were 0.833 and 0.722, respectively. Salivary DHEA was correlated with VR total (R2 = 0.082, p = 0.01) and attention scores (R2 = 0.086, p = 0.009).ConclusionThe VR cognitive test was as effective as the traditional MOCA test in the MCI classification and safe enough for older adults to perform, indicating its potential as a diagnostic tool. It has also been shown that salivary DHEA can be used as a biomarker for MCI