Circulating serotonin and dopamine concentrations in osteoarthritis patients: a pilot study on the effect of pelotherapy.

Balneotherapy has demonstrated clinical efficacy in the management of pathologies involving low-grade inflammation and stress. In rheumatic conditions such as osteoarthritis (OA), this therapy presents anti-inflammatory properties and potential to improve psychological well-being. Although the neurohormones serotonin and dopamine are known to be involved in these processes, surprisingly they have not been studied in this context. The objective was to evaluate the effect of a cycle of balneotherapy with peloids (pelotherapy) on circulating serotonin and dopamine concentrations in a group of aged individuals with OA, after comparing their basal state to that of an age-matched control group. In our pilot study, a pelotherapy program (10 days) was carried out in a group of 16 elderly patients with OA, evaluating its effects on circulating serotonin and dopamine concentrations (measured by ELISA). Individuals with OA showed higher levels of serotonin and lower dopamine levels, in line with the inflammatory roles of these mediators. After pelotherapy, serotonin concentrations significantly decreased, potentially contributing to the previously reported anti-inflammatory effects of balneotherapy.

Subjective Sleep Quality Versus Objective Accelerometric Measures of Sleep and Systemic Concentrations of Sleep-Related Hormones as Objective Biomarkers in Fibromyalgia Patients.

Poor quality of sleep leads to an increase in severity of the symptoms associated with fibromyalgia (FM) syndrome and vice versa. The aim of this study was to determine if the poor perceived sleep quality in FM patients could be corroborated by objective physiological determinations. Perceived sleep quality was evaluated (through the Pittsburgh Sleep Quality Index) in 68 FM patients compared to an age-matched reference group of 68 women without FM. Objective sleep quality (measured using accelerometry), and systemic concentrations of sleep-related hormones (catecholamines, oxytocin, serotonin, and melatonin) were evaluated in two representative groups from the reference control group (n = 11) and FM patients (n = 11). FM patients reported poorer subjective sleep quality compared to the reference group. However, no significant differences were found in accelerometry parameters, except for a delay in getting in and out of bed. In addition, FM patients showed no significant differences in oxytocin concentration and adrenaline/noradrenaline ratio, as well as a lower serotonin/melatonin ratio. Poor perception of sleep quality in FM patients does not correspond to objective determinations. A dysregulation of the stress response could be associated with the delay in their resting circadian rhythm and difficulty falling asleep. This would be the cause that justifies the perceived lack of rest and the fatigue they feel when waking up.

The anti-inflammatory and bioregulatory effects of habitual exercise in high-fat diet-induced obesity involve crown-like structures and MCP-1 in white adipose tissue.

Macrophage accumulation in the adipose tissue and changes in their inflammatory phenotype is a hallmark of obesity-induced inflammation, notably forming inflammatory structures known as "crown-like structures (CLS)". Exercise can be a key strategy to improve inflammation-related complications, but it is crucial to consider that, although exercise generally exerts systemic and local anti-inflammatory effects, this depends on the basal inflammatory status and exercise modality. In this context, the "bioregulatory effect of exercise" implies to achieve the reduction or prevention of an excessive inflammatory response and also the preservation or stimulation of the innate response. In the present work, our aim was to evaluate the effect of regular exercise on adipose tissue inflammation in high-fat diet-induced obesity in mice, as reflected by macrophage infiltration and phenotype, and CLS formation, together with a potential role for the chemokine MCP-1 in this process. Results showed that obesity is associated with greater MCP-1 expression (p<0.05), macrophage accumulation (p<0.05), and CLS presence (p<0.001). Regular exercise reduced macrophage accumulation (p<0.05), MCP-1 expression (p<0.01), and CLS presence (p<0.05) in obese mice; while it increased macrophage and CLS presence (p<0.01), MCP-1 expression (p<0.05), and M2 polarization (p<0.05) in lean mice. MCP-1 was associated with the proliferation of CLS, showing the first image demonstrating a potential role of this chemokine in the development of these structures. Altogether, these results confirm, for the first time, the "bioregulatory effect of exercise" in the adipose tissue: reducing inflammation in individuals with an elevated inflammatory setpoint, but stimulating this response of the immune system in healthy individuals.

Influence of Codiagnosis of Chronic Fatigue Syndrome and Habitual Physical Exercise on the Psychological Status and Quality of Life of Patients with Fibromyalgia.

Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) are two diseases that are frequently codiagnosed and present many similarities, such as poor tolerance to physical exercise. Although exercise is recommended in their daily routine to improve quality of life, little is known about how CFS codiagnosis affects that. Using scientifically validated questionnaires, we evaluated the psychological state and quality of life of patients with FM (n = 70) and how habitual physical exercise (HPE) reported by patients with only FM (FM-only n = 38) or codiagnosed with CFS (FM + CFS, n = 32) influences those aspects. An age-matched reference group of "healthy" women without FM (RG, n = 70) was used. The FM-only group presented a worse psychological state and quality of life compared to RG, with no influence of CFS codiagnosis. The patients of the FM-only and FM + CFS groups who perform HPE presented better levels of stress and state anxiety, but with no differences between them. Depression and trait anxiety improved only in women with just FM. CFS codiagnosis does not worsen the psychological and quality of life impairment of FM patients and does not have a great influence on the positive effect of HPE.

The Influence of Obesity and Weight Loss on the Bioregulation of Innate/Inflammatory Responses: Macrophages and Immunometabolism.

Obesity is characterized by low-grade inflammation and more susceptibility to infection, particularly viral infections, as clearly demonstrated in COVID-19. In this context, immunometabolism and metabolic flexibility of macrophages play an important role. Since inflammation is an inherent part of the innate response, strategies for decreasing the inflammatory response must avoid immunocompromise the innate defenses against pathogen challenges. The concept "bioregulation of inflammatory/innate responses" was coined in the context of the effects of exercise on these responses, implying a reduction in excessive inflammatory response, together with the preservation or stimulation of the innate response, with good transitions between pro- and anti-inflammatory macrophages adapted to each individual's inflammatory set-point in inflammatory diseases, particularly in obesity. The question now is whether these responses can be obtained in the context of weight loss by dietary interventions (low-fat diet or abandonment of the high-fat diet) in the absence of exercise, which can be especially relevant for obese individuals with difficulties exercising such as those suffering from persistent COVID-19. Results from recent studies are controversial and do not point to a clear anti-inflammatory effect of these dietary interventions, particularly in the adipose tissue. Further research focusing on the innate response is also necessary.

Influence of Obesity and Exercise on ß2-Adrenergic-Mediated Anti-Inflammatory Effects in Peritoneal Murine Macrophages.

Obesity is a chronic low-grade inflammatory condition, and ß2-adrenergic agonists as well as exercise have been proposed as anti-inflammatory strategies in obesity, so it is critical to accurately determine the effects of ß2-adrenergic stimulation, especially when combined with other non-pharmacological therapies. The aim of this investigation was to determine the effect of ß2-adrenergic activation on the inflammatory profile and phenotype of macrophages, and whether these effects could be affected by obesity and exercise in this condition. High-fat diet-induced obese and lean C57BL/6J mice were allocated to sedentary or exercised groups. The inflammatory profiles and phenotypes of their peritoneal macrophages were assessed by flow cytometry in the presence or absence of the selective ß2-adrenergic receptor agonist terbutaline. ß2-adrenergic activation caused global phenotypic anti-inflammatory effects in lean and obese sedentary mice, which were more drastic (also including anti-inflammatory effects on the cytokine profile) in obese animals. In exercised lean and obese animals, this anti-inflammatory effect is weaker and only evident by decreased iNOS and IL-8 expression, without changes in the anti-inflammatory markers. Therefore, ß2-adrenergic activation leads to anti-inflammatory effects, but these effects are modulated by obesity in sedentary conditions, as well as by regular exercise; but not by obesity in trained conditions.

ß2 Adrenergic Regulation of the Phagocytic and Microbicide Capacity of Circulating Monocytes: Influence of Obesity and Exercise.

Obese individuals present anomalous immune/inflammatory responses with dysregulations in neuroendocrine responses and immune/stress feedback mechanisms. In this context, exercise and ß2 adrenergic activation present monocyte-mediated anti-inflammatory effects that are modulated by obesity. However, these anti-inflammatory effects could immunocompromise the monocyte-mediated innate response against a pathogen challenge. Thus, the objective of this work was to evaluate the effect of obesity, and exercise in this condition, on the ß2 adrenergic regulation of the phagocytic and microbicide capacity of circulating monocytes. C57BL/6J mice were allocated to different sedentary or exercised, lean or obese groups. Obese mice showed a lower monocyte-mediated innate response than that of lean mice. Globally, selective ß2 adrenergic receptor agonist terbutaline decreased the innate response of monocytes from lean and obese sedentary animals, whereas exercise stimulated it. Exercise modulates ß2 adrenergic regulation of the innate response in lean and obese animals, with a global stimulatory or neutral effect, thus abolishing the inhibitory effect of terbutaline occurring in sedentary animals. These effects cannot be explained only by changes in the surface expression of toll-like receptors. Therefore, in general, terbutaline does not hinder the effects of regular exercise, but regular exercise does abolish the effects of terbutaline in sedentary individuals.

Obesity Affects ß2 Adrenergic Regulation of the Inflammatory Profile and Phenotype of Circulating Monocytes from Exercised Animals.

Anomalous immune/inflammatory responses in obesity take place along with alterations in the neuroendocrine responses and dysregulation in the immune/stress feedback mechanisms. Exercise is a potential anti-inflammatory strategy in this context, but the influence of exercise on the ß2 adrenergic regulation of the monocyte-mediated inflammatory response in obesity remains completely unknown. The first objective of this study was to analyze the effect of exercise on the inflammatory profile and phenotype of monocytes from obese and lean animals, and the second aim was to determine whether obesity could affect monocytes' inflammatory response to ß2 adrenergic activation in exercised animals. C57BL/6J mice were allocated to different lean or obese groups: sedentary, with acute exercise, or with regular exercise. The inflammatory profile and phenotype of their circulating monocytes were evaluated by flow cytometry in the presence or absence of the selective ß2 adrenergic receptor agonist terbutaline. Exercise caused an anti-inflammatory effect in obese individuals and a pro-inflammatory effect in lean individuals. ß2 adrenergic receptor stimulation exerted a global pro-inflammatory effect in monocytes from exercised obese animals and an anti-inflammatory effect in monocytes from exercised lean animals. Thus, ß2 adrenergic regulation of inflammation in monocytes from exercised animals seems to depend on the inflammatory basal set-point.

ß2 Adrenergic Regulation of the Phagocytic and Microbicide Capacity of Macrophages from Obese and Lean Mice: Effects of Exercise.

Macrophages are crucial in the inflammation associated with obesity. Exercise is the main non-pharmacological strategy against obesity, not only for improving metabolic impairment, but also because of its anti-inflammatory effects, particularly those mediated by ß2 adrenergic receptors (ß2-AR). Nevertheless, these anti-inflammatory effects could immunocompromise the innate response against pathogen challenge. Thus, the objective of this work was to evaluate the effect of obesity, and of exercise in this condition, on the ß2 adrenergic regulation of the innate function of macrophages. High fat diet-induced obese C57BL/6J mice were used to evaluate the effects of acute and regular exercise on the phagocytic and microbicide capacities of peritoneal macrophages. Selective ß2-AR agonist terbutaline (1 µM) decreased the phagocytic and microbicide activities of macrophages from control lean and obese sedentary animals. While acute exercise did not modify the inhibitory capacity of terbutaline, regular exercise abolished this inhibitory effect. These effects cannot be explained only by changes in the surface expression of ß2-AR. In conclusion, (1) obesity does not alter the ß2-AR-mediated decrease of the innate response of macrophages and (2) regular exercise can revert the inhibitory effect of terbutaline on the phagocytic activity of macrophages, although obesity seems to hinder this immunophysiological adaptation.

Anti-inflammatory effect of ß2 adrenergic stimulation on circulating monocytes with a pro-inflammatory state in high-fat diet-induced obesity.

Obesity is a chronic condition associated with low-grade inflammation, and it also involves alterations of the function of the hypothalamic-pituitaryadrenal axis and the sympathetic nervous system. Adrenergic agonists such as catecholamines are important immunoregulatory molecules that are involved in modulating both metabolism and most of the mechanisms of the immune response. The first objective of this study was to determine whether the systemic inflammatory state associated with obesity is also manifested in the inflammatory profile and phenotype of circulating monocytes; and the second objective was to evaluate the effects of ß2 adrenergic stimulation on the inflammatory profile and phenotype of monocytes in obesity, and whether this response could be different from that in lean individuals. C57BL/6J mice were randomly allocated to one of two diets for 18 weeks: high-fat diet in order to obtain an experimental model of obesity, and standard diet in the control lean group. Circulating monocyte expression of inflammatory cytokines (MCP-1, TNF-α, IL-8, IL-6, IL-10, and TGF-ß), surface membrane marker Ly6C, inducible nitric oxide synthase and arginase-1, and Toll-like receptor 4 were evaluated through flow cytometry in the presence or absence of selective ß2 adrenergic receptor agonist terbutaline. Monocytes from high-fat diet-induced obese animals presented higher expression levels of all pro-inflammatory cytokines and a higher percentage of monocytes with a pro-inflammatory phenotype than those from lean animals. ß2 adrenergic stimulation induced a shift towards an anti-inflammatory activity profile and phenotype in obese mice, whereas it induced a shift towards a pro-inflammatory activity profile and phenotype in lean mice. In conclusion, ß2 adrenergic stimulation in monocytes was anti-inflammatory only in obese animals, which presented a pro-inflammatory state at baseline.

Adrenergic Regulation of Macrophage-Mediated Innate/Inflammatory Responses in Obesity and Exercise in this Condition: Role of ß2 Adrenergic Receptors.

BACKGROUND: The effects of exercise on the innate/inflammatory immune responses are crucially mediated by catecholamines and adrenoreceptors; and mediations in both stimulatory and anti-inflammatory responses have been attributed to them. Obesity and metabolic syndrome are included among low-grade chronic inflammatory pathologies; particularly because patients have a dysregulation of the inflammatory and stress responses, which can lead to high levels of inflammatory cytokines that induce insulin resistance, contributing to the onset or exacerbation of type 2 diabetes. Macrophages play a crucial role in this obesity-induced inflammation. Although most of the antiinflammatory effects of catecholamines are mediated by ß adrenergic receptors (particularly ß2), it is not known whether in altered homeostatic conditions, such as obesity and during exercise, innate/ inflammatory responses of macrophages to ß2 adrenergic stimulation are similar to those in cells of healthy organisms at baseline. OBJECTIVE: This review aims to emphasize that there could be possible different responses to ß2 adrenergic stimulation in obesity, and exercise in this condition. METHODS: A revision of the literature based on the hypothesis that obesity affects ß2 adrenergic regulation of macrophage-mediated innate/inflammatory responses, as well as the effect of exercise in this context. CONCLUSION: The inflammatory responses mediated by ß2 adrenoreceptors are different in obese individuals with altered inflammatory states at baseline compared to healthy individuals, and exercise can also interfere with these responses. Nevertheless, it is clearly necessary to develop more studies that contribute to widening the knowledge of the neuroimmune regulation process in obesity, particularly in this context.

Immune-Neuroendocrine Dysregulation in Patients with Osteoarthritis: A Revision and a Pilot Study.

BACKGROUND: Although osteoarthritis (OA) has predominantly been considered a noninflammatory degenerative arthropathy, there is growing evidence that various inflammatory and immunological processes might contribute to the onset, progression, and burden of the disease. OBJECTIVE: The purpose of the present investigation was to study the systemic inflammatory and stress responses and the innate response mediated by neutrophils in OA patients. METHOD: A group of patients diagnosed with primary OA according to the American College of Rheumatology criteria and a control group of age-matched healthy volunteers were enrolled in the study. Serum inflammatory cytokine levels (IL-1ß, TNF-α, IL-8, IL-6, IL-10, and TGF-ß) were evaluated using the Bio-Plex Luminex system. Circulating neuroendocrine-stress biomarkers, such as cortisol and extracellular 72 kDa heat shock protein (eHsp72), were measured by ELISA. The phagocytic and microbicide capacities of circulating neutrophils were evaluated by flow cytometry. All parameters were determined in all volunteers. RESULTS: The OA patients showed an inflammatory state accompanied by an altered stress response. This was manifested in high circulating levels of the inflammatory cytokines IL-1ß, TNF-α, IL-8, IL-6, and TGF-ß and the stress protein eHsp72. There were also decreased systemic levels of cortisol, and a reduction in neutrophil phagocytic and microbicidal capacities. CONCLUSION: An immune-neuroendocrine dysregulation affecting both systemic inflammatory and stress mediators and the function of innate immune cells underlies OA. This reflects an altered feedback between the innate/inflammatory and stress responses in this pathology.

Noradrenaline-mediated inhibition of inflammatory cytokines is altered in macrophages from obese Zucker rats: effect of habitual exercise.

The obese Zucker rat (fa/fa) (ObZ) is a good animal model for Metabolic Syndrome (MS)-associated neuroendocrine and inflammatory disorders. The aim of the present investigation was to evaluate the effect of noradrenaline (NA) on the release of IL-1ß, IL-6 and TNFα by macrophages from ObZ, as well as the effect of habitual exercise (running, 5days/week for 35 min at 35cm/s for 14week); all of them using lean Zucker rats (Fa/fa) (LZ) as reference values. Cytokines were determined by ELISA in the supernatants of macrophages cultured for 24h (37°C, 5% CO2 and 100% RH) in presence or absence of 10(-5)M NA. Both the spontaneous and NA-induced release of IL-1ß and IL-6 were higher in sedentary obese (ObSZ) rats than in healthy LZ rats (a significant lower spontaneous production of TNFα was also found in the ObSZ rats). While the NA-induced release of IL-1ß was higher in the exercised obese (ObTZ) rats, the NA-induced production of IL-6 was lower compared with ObSZ rats. In addition, NA has an inhibitory role on the release of IL-1ß and TNFα (with respect to the spontaneous release) in both lean and obese (sedentary and exercised) rats. However, NA inhibits the IL-6 production by macrophages from lean and exercised obese animals, but promotes IL-6 release in the sedentary obese rats. In conclusion, an altered inflammatory response of macrophages mediated by NA is underlying in MS, and this regulation is improved after regular exercise, particularly on IL-6.

The interleukin-6 and noradrenaline mediated inflammation-stress feedback mechanism is dysregulated in metabolic syndrome: effect of exercise.

BACKGROUND: Metabolic syndrome (MS) is a metabolic disorder associated with obesity, type-II diabetes, and "low grade inflammation", with the concomitant increased risk of cardiovascular events. Removal of the inflammatory mediator signals is a promising strategy to protect against insulin resistance, obesity, and other problems associated with MS such as cardiovascular disease. The aim of the present investigation was to determine the "inflammatory and stress status" in an experimental model of MS, and to evaluate the effect of a program of habitual exercise and the resulting training-induced adaptation to the effects of a single bout of acute exercise. METHODS: Obese Zucker rats (fa/fa) were used as the experimental model of MS, and lean Zucker rats (Fa/fa) were used for reference values. The habitual exercise (performed by the obese rats) consisted of treadmill running: 5 days/week for 14 weeks, at 35 cm/s for 35 min in the last month. The acute exercise consisted of a single session of 25-35 min at 35 cm/s. Circulating concentrations of IL-6 (a cytokine that regulates the inflammatory and metabolic responses), CRP (a systemic inflammatory marker), and corticosterone (CTC) (the main glucocorticoid in rats) were determined by ELISA, and that of noradrenaline (NA) was determined by HPLC. Glucose was determined by standard methods. RESULTS: The genetically obese animals showed higher circulating levels of glucose, IL-6, PCR, and NA compared with the control lean animals. The habitual exercise program increased the concentration of IL-6, CRP, NA, and glucose, but decreased that of CTC. Acute exercise increased IL-6, CRP, and NA in the sedentary obese animals, but not in the trained obese animals. CTC was increased after the acute exercise in the trained animals only. CONCLUSION: Animals with MS present a dysregulation in the feedback mechanism between IL-6 and NA which can contribute to the systemic low-grade inflammation and/or hyperglycaemia of MS. An inappropriate exercise intensity can worsen this dysregulation, contributing to the metabolic, inflammatory, and stress disorders associated with MS. Habitual exercise (i.e., training) induces a positive adaptation in the response to acute exercise.

Habitual physical exercise improves macrophage IL-6 and TNF-α deregulated release in the obese zucker rat model of the metabolic syndrome.

OBJECTIVES: The first objective was to evaluate whether the metabolic syndrome (MS) involves deregulation of TNF-α and IL-6 release by non-infiltrated peritoneal macrophages, using obese Zucker rats as the experimental model of MS and lean Zucker rats as a reference for healthy control values. The second purpose was to evaluate in the obese rats the effects of habitual exercise and of a bout of acute exercise on the observed MS-associated deregulation in the release of TNF-α and IL-6 by peritoneal macrophages. METHODS: The habitual exercise consisted of treadmill running: 5 days/week for 14 weeks and 35 cm/s for 35 min in the last month. The acute exercise consisted of a single session of 25-35 min at 35 cm/s. The constitutive or lipopolysaccharide (LPS)-induced release of TNF-α and IL-6 by cultured (24 h, 5% CO2, 100% relative humidity) peritoneal macrophages was determined by ELISA. RESULTS: Macrophages from the obese rats released more IL-6 than those from the lean healthy rats, both spontaneously and after LPS stimulation. However, both spontaneous and LPS-induced release of TNF-α was lower in the obese rats. This deregulated balance in the release of IL-6 and TNF-α in the obese rats was clearly improved following adherence to the program of habitual exercise, reflected by a decrease in the spontaneous release of IL-6 together with a better regulation between the spontaneous and LPS-induced release of TNF-α, approaching the behavior of the lean healthy rats. In addition, an acute bout of exercise decreased the spontaneous release of IL-6 and increased the spontaneous release of TNF-α in the sedentary, but not in the exercise-adapted obese rats. CONCLUSION: MS involves a deregulation of TNF-α and IL-6 release by non-infiltrated peritoneal macrophages, which is improved by habitual physical activity.

Exercise-induced extracellular 72 kDa heat shock protein (Hsp72) stimulates neutrophil phagocytic and fungicidal capacities via TLR-2.

This study evaluated the role of toll like receptor 2 (TLR-2) in the interaction of 72 kDa extracellular heat shock protein (Hsp72, a stress-inducible protein) with neutrophils and the participation on TLR-2 in the stimulation of neutrophil phagocytic and fungicidal capacities by post-exercise physiological concentrations of Hsp72. Human peripheral blood neutrophils were incubated with fluorescein isothiocyanate-conjugated Hsp72, and were analyzed by immunofluorescence microscopy and flow cytometry. Both methods revealed an interaction of Hsp72 with neutrophils. In addition, when neutrophils were pre-incubated with an anti-TLR-2 antibody this interaction was clearly decreased. Post-exercise circulating concentration of Hsp72 (8.6 ng/ml) stimulated the phagocytic and fungicidal capacities of neutrophils and this effect could be also blocked using an antibody against TLR-2. Phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated kinase (ERK) and the nuclear transcription factor kappa beta (NF-kappabeta) were found to be involved in the signaling process, confirming the participation of TLR-2 in the stimulation of neutrophil function by Hsp72. In conclusion, TLR-2 is involved at least in part, in the stimulation of neutrophil phagocytic and fungicidal capacities induced by post-exercise physiological concentrations of Hsp72.