Objectives: This study aimed to (a) evaluate the effects of Acceptance and Commitment Therapy (ACT) and Behavioral Activation Therapy for Depression (BATD) on immune-inflammatory biomarkers in patients with chronic low back pain and comorbid depression, and (b) explore whether these biomarkers and genetic polymorphisms in BDNF and FKBP5 predict treatment response. Methods: A total of 114 female participants (mean age=57.5 y) were randomized to a group-based therapy delivered via videoconference (ACT or BATD, both added to treatment-as-usual [TAU]) or TAU alone. Serum IL-6, CXCL-8, TNF-α, IL-1β, IL-10, high-sensitivity CRP, cortisol, vitamin D, and hair cortisol and cortisone were assessed at baseline and post-treatment, whereas BDNF and FKBP5 genotypes were assessed at baseline only. Clinical outcomes included pain interference, pain intensity, depressive symptoms, anxiety, stress, and pain catastrophizing. Results: Psychological interventions did not significantly change biomarker levels compared to TAU. However, ACT and BATD led to significant improvements in different clinical variables (e.g., pain interference, depressive symptomatology, anxiety, pain catastrophizing). Baseline biomarkers and FKBP5 genotype predicted treatment response, with some effects specific to ACT or BATD (e.g., cortisol, vitamin D) and others general across groups (e.g., hair cortisol, cortisone, CXCL-8); TNF-α and hs-CRP showed exploratory, descriptive associations with responder status. Discussion: While ACT and BATD improved clinical outcomes, their effects on immune-inflammatory biomarkers were not significant. Nevertheless, specific baseline biomarkers and genetic factors may serve as predictors of treatment response. These findings underscore the need to further explore the interaction between psychological therapies, biological processes, and individual variability in treatment outcomes.

OBJECTIVES:This study aimed to (a) evaluate the effects of Acceptance and Commitment Therapy (ACT) and Behavioral Activation Therapy for Depression (BATD) on immune-inflammatory biomarkers in patients with chronic low back pain and comorbid depression, and (b) explore whether these biomarkers and genetic polymorphisms in BDNF and FKBP5 predict treatment response. METHODS:A total of 114 female participants (mean age=57.5 y) were randomized to a group-based therapy delivered via videoconference (ACT or BATD, both added to treatment-as-usual [TAU]) or TAU alone. Serum IL-6, CXCL-8, TNF-α, IL-1β, IL-10, high-sensitivity CRP, cortisol, vitamin D, and hair cortisol and cortisone were assessed at baseline and post-treatment, whereas BDNF and FKBP5 genotypes were assessed at baseline only. Clinical outcomes included pain interference, pain intensity, depressive symptoms, anxiety, stress, and pain catastrophizing. RESULTS:Psychological interventions did not significantly change biomarker levels compared to TAU. However, ACT and BATD led to significant improvements in different clinical variables (e.g., pain interference, depressive symptomatology, anxiety, pain catastrophizing). Baseline biomarkers and FKBP5 genotype predicted treatment response, with some effects specific to ACT or BATD (e.g., cortisol, vitamin D) and others general across groups (e.g., hair cortisol, cortisone, CXCL-8); TNF-α and hs-CRP showed exploratory, descriptive associations with responder status. DISCUSSION:While ACT and BATD improved clinical outcomes, their effects on immune-inflammatory biomarkers were not significant. Nevertheless, specific baseline biomarkers and genetic factors may serve as predictors of treatment response. These findings underscore the need to further explore the interaction between psychological therapies, biological processes, and individual variability in treatment outcomes.

Objective Fibromyalgia (FM) is a prevalent pain syndrome with significant healthcare and societal costs. The aim of the SMART-FM-SP study is to determine the effectiveness, cost-utility, and physiological effects in patients with FM of a digital intervention (STANZA®) currently marketed in the United States, which delivers smartphone-based, fully self-guided Acceptance and Commitment Therapy (Digital ACT) for treating FM-related symptoms. Methods A single-site, parallel-group, superiority, randomized controlled trial (RCT) will be conducted, including a total of 360 adults diagnosed with FM. Individuals will be randomly allocated (1:1:1) to treatment as usual (TAU), to TAU plus 12 weeks of treatment with Digital ACT, or to TAU plus 12 weeks of treatment with digital symptom tracking (i.e. FibroST). Participants will be assessed at baseline, post-treatment, and 6-month follow-up. An intention-to-treat analysis using linear mixed models will be computed to analyze the effects of Digital ACT on functional impairment (primary outcome), as measured by the Fibromyalgia Impact Questionnaire Revised at 6 months from the inception of the treatment. Secondary outcomes include impression of change, symptoms of distress, pain catastrophising, quality of life, cost-utility, and selected biomarkers (cortisol and cortisone, immune-inflammatory markers, and FKBP5 gene polymorphisms). The role of ACT-related processes of change will be tested with path analyses. Conclusions This study is the first RCT that tests Digital ACT for Spanish patients with FM. Results will be important not only for patients and clinicians, but also for policy makers by examining the cost-utility of the app in a public healthcare context.

Recently, intermittent fasting has gained relevance as a strategy to lose weight and improve health as an alternative to continuous caloric restriction. However, the metabolic impact and the sex-related differences are not fully understood. The study aimed to compare the response to a continuous or intermittent caloric restriction in male and female rats following a previous induction of obesity through a cafeteria diet by assessing changes in body weight, energy intake, metabolic parameters, and gene expression in liver hepatic and adipose tissue. The continuous restriction reduced the energy available by 30% and the intermittent restriction consisted of a 75% energy reduction on two non-consecutive days per week. The interventions reduced body weight and body fat in both sexes, but the loss of WAT in females was more marked in both models of caloric restriction, continuous and intermittent. Both caloric restrictions improved insulin sensitivity, but more markedly in females, which showed a more pronounced decrease in HOMA-IR score and an upregulation of hepatic IRS2 and Sirt1 gene expression that was not observed in males. These findings suggest the fact that females are more sensitive than males to reduced caloric content in the diet.

This systematic review aimed to investigate immune-inflammatory and hypothalamic-pituitary-adrenal (HPA) axis biomarkers in individuals with non-specific low back pain (NSLBP) compared to healthy control. The search was performed in five databases until 4 November 2021. Two reviewers independently conducted screenings, data extraction, risk of bias, and methodological quality assessment of 14 unique studies. All studies reported the source of the fluid analyzed: nine studies used serum, two used plasma, one used serum and plasma, and two studies used salivary cortisol. We found preliminary and limited evidence (only one study for each biomarker) of increased levels in growth differentiation factor 15 (GDF-15), interleukin-23 (IL-23), transforming growth factor–beta (TGF-β), and soluble tumor necrosis factor receptor 1 (sTNF-R1) in NSLBP. Inconsistent and limited evidence was identified for interleukin-10 (IL-10). Although C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor–alpha (TNF-α) levels appear to increase in NSLBP, only one study per each biomarker reported statistically significant differences. Interleukin-1 beta (IL-1β), interleukin-17 (IL-17), interferon gamma (IFN-γ), and high-sensitivity CRP (hsCRP) showed no significant differences. Regarding cortisol, one study showed a significant increase and another a significant decrease. More robust evidence between GDF-15, IL-23, TGF-β, and sTNF-R1 with NSLBP is needed. Moreover, contrary to the findings reported in previous studies, when comparing results exclusively with healthy control, insufficient robust evidence for IL-6, TNF-α, and CRP was found in NSLBP. In addition, cortisol response (HPA-related biomarker) showed a dysregulated functioning in NSLBP, with incongruent evidence regarding its directionality. Therefore, our effort is to find adjusted evidence to conclude which immune-inflammatory and HPA axis biomarkers are altered in NSLBP and how much their levels are affected. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020176153 , identifier CRD42020176153.

Corticosteroid-binding globulin (CBG) is the specific carrier of circulating glucocorticoids, but evidence suggests that it also plays an active role in modulating tissue glucocorticoid activity. CBG polymorphisms affecting its expression or affinity for glucocorticoids are associated with chronic pain, chronic fatigue, headaches, depression, hypotension, and obesity with an altered hypothalamic pituitary adrenal axis. CBG has been localized in hippocampus of humans and rodents, a brain area where glucocorticoids have an important regulatory role. However, the specific CBG function in the hippocampus is yet to be established. The aim of this study was to investigate the effect of the absence of CBG on hippocampal glucocorticoid levels and determine whether pathways regulated by glucocorticoids would be altered. We used cbg-/- mice, which display low total-corticosterone and high free-corticosterone blood levels at the nadir of corticosterone secretion (morning) and at rest to evaluate the hippocampus for total- and free-corticosterone levels; 11β-hydroxysteroid dehydrogenase expression and activity; the expression of key proteins involved in glucocorticoid activity and insulin signaling; microtubule-associated protein tau phosphorylation, and neuronal and synaptic function markers. Our results revealed that at the nadir of corticosterone secretion in the resting state the cbg-/- mouse hippocampus exhibited slightly elevated levels of free-corticosterone, diminished FK506 binding protein 5 expression, increased corticosterone downstream effectors and altered MAPK and PI3K pathway with increased pY216-GSK3β and phosphorylated tau. Taken together, these results indicate that CBG deficiency triggers metabolic imbalance which could lead to damage and long-term neurological pathologies.

Introduction The IMPACT study focuses on chronic low back pain (CLBP) and depression symptoms, a prevalent and complex problem that represents a challenge for health professionals. Acceptance and Commitment Therapy (ACT) and Brief Behavioural Activation Treatment for Depression (BATD) are effective treatments for patients with persistent pain and depression, respectively. The objectives of this 12 month, multicentre, randomised, controlled trial (RCT) are (i) to examine the efficacy and cost-utility of adding a group-based form of ACT or BATD to treatment-as-usual (TAU) for patients with CLBP and moderate to severe levels of depressive symptoms; (ii) identify pre–post differences in levels of some physiological variables and (iii) analyse the role of polymorphisms in the FKBP5 gene, psychological process measures and physiological variables as mediators or moderators of long-term clinical changes.Methods and analysis Participants will be 225 patients with CLBP and moderate to severe depression symptoms recruited at Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, Spain) and Hospital del Mar (Barcelona, Spain), randomly allocated to one of the three study arms: TAU vs TAU+ACT versus TAU+BATD. A comprehensive assessment to collect clinical variables and costs will be conducted pretreatment, post-treatment and at 12 months follow-up, being pain interference the primary outcome measure. The following physiological variables will be considered at pretreatment and post-treatment assessments in 50% of the sample: immune-inflammatory markers, hair cortisol and cortisone, serum cortisol, corticosteroid-binding globulin and vitamin D. Polymorphisms in the FKBP5 gene (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916) will be analysed at baseline assessment. Moreover, we will include mobile-technology-based ecological momentary assessment, through the Pain Monitor app, to track ongoing clinical status during ACT and BATD treatments. Linear mixed-effects models using restricted maximum likelihood, and a full economic evaluation applying bootstrapping techniques, acceptability curves and sensitivity analyses will be computed.Ethics and dissemination This study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu and Hospital del Mar. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and various community engagement activities.Trial registration number NCT04140838

Corticosteroid-binding globulin (CBG) is synthesized by the liver and secreted into the bloodstream where binds to glucocorticoids. Thus CBG has the role of glucocorticoid transport and free hormone control. In addition, CBG has been detected in some extrahepatic tissues without a known role. CBG-deficient mice show decreased total corticosterone levels with missing of classical sexual dimorphism, increased free corticosterone, higher adrenal gland size and altered HPA axis response to stress. Our aim was to ascertain whether CBG deficiency could affect the endocrine synthetic activity of adrenal gland and if the adrenal gland produces CBG. We determined the expression in adrenal gland of proteins involved in the cholesterol uptake and its transport to mitochondria and the main enzymes involved in the corticosterone, aldosterone and catecholamine synthesis. The results showed that CBG is synthesized in the adrenal gland. CBG-deficiency reduced the expression of ACTH receptor, SRB1 and the main genes involved in the adrenal hormones synthesis, stronger in females resulting in the loss of sexual dimorphism in corticosteroid adrenal synthesis, despite corticosterone content in adrenal glands from CBG-deficient females was similar to wildtype ones. In conclusion, these results point to an unexplored and relevant role of CBG in the adrenal gland functionality related to corticosterone production and release.

Excessive and prolonged glucocorticoid (GC) exposure, resulting from either prescribed or endogenous hypercortisolism, is associated with a high cardiovascular and metabolic burden (Cushing's syndrome). Although previous studies in humans and mice have reported heterogeneous data about the persistence of metabolic syndrome features after remission of hypercortisolism, there is still controversy as to whether this is due to the deleterious changes induced by GCs during active disease or the result of various other factors interfering in the recovery period. In order to study metabolic effects after remission, we used a reversible mouse model of corticosterone (CORT) (100 µg/mL) administration in drinking water for 5 weeks, followed by a 10-week recovery period. We compared CORT-induced effects at these time points with a high-fat diet-treated group (HFD 45%) and a vehicle group (VEH). Plasma CORT, 11β-HSD activity, food intake, glucose levels, interscapular brown adiposity, hepatic triglycerides and muscle mass were found altered during CORT treatment but normalized after recovery. Although hyperinsulinemia and insulin resistance were increased during CORT and HFD treatment, insulin homeostasis remained altered following the recovery period only in CORT-treated mice. Subcutaneous and visceral adipose tissues (SAT and VAT) were enlarged during HFD and CORT treatment as measured by MRI. However, increased muscle lipid content, adiposity and macrophage infiltration in VAT were only present in the CORT group following recovery. Taken together, CORT-induced insulin alterations were more potent than HFD-induced ones during the same period of treatment, and also more persistent long term. Moreover, we demonstrated that CORT treatment induces more long-lasting VAT enlargement than HFD.

OBJECTIVE:Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol.DESIGN:Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 ± 7 years) premenopausal women (n = 32) and men (n = 30), with normal weight and obesity (BMI >30 kg/m2).METHODS:SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labeled hormones.RESULTS:Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI >40 kg/m2) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding/SHBG ratios.CONCLUSIONS:The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity.

Corticosteroid-binding globulin (CBG) is the specific plasma transport glycoprotein for glucocorticoids. Circulating CBG is mainly synthesized in liver but, its synthesis has been located also in other organs as placenta, kidney and adipose tissue with unknown role. Using an experimental model of acute pancreatitis in cbg-/- mice we investigated whether changes in CBG affect the progression of the disease as well as the metabolism of glucocorticoids in the lung. Lack of CBG does not modify the progression of inflammation associated to pancreatitis but resulted in the loss of gender differences in corticosterone serum levels. In the lung, CBG expression and protein level were detected, and it is noteworthy that these showed a sexual dimorphism opposite to the liver, i.e. with higher levels in males. Reduced expression of 11β-HSD2, the enzyme involved in the deactivation of corticosterone, was also observed. Our results indicate that, in addition to glucocorticoids transporter, CBG is involved in the gender differences observed in corticosteroids circulating levels and plays a role in the local regulation of corticosteroids availability in organs like lung.

Background and aims: Data about glucocorticoids role in the development of atherosclerosis are controversial showing different effects in human than in experimental animal models. Atherosclerosis is the result of a chronic inflammatory response to an injured endothelium where an uncontrolled uptake of OxLDL by macrophages triggers the development of foam cells, the main component of fatty streaks in atherosclerotic plaque. There are few data about the direct effect of glucocorticoids in macrophages of atherosclerotic plaque. The aim of the study was to elucidate the role of glucocorticoids in the development of foam cells in atherosclerosis initiation.Methods: For this purpose we used THP1 cells differentiated to macrophages with phorbol esters and incubated with OxLDL alone or with cortisol or cortisone. THP1 cells were also incubated with cortisone plus an inhibitor of 11 beta-hydroxysteroid dehydrogenase 1 (11bHSD1) activity to determine the role of this enzyme on glucocorticoid action in this process.Results: Ours results showed that cortisol and cortisone decreased significantly the inflammation promoted by OxLDL, and also diminished the expression of genes involved in influx and efflux of cholesterol resulting in a reduced lipid accumulation. Likewise cortisol and cortisone decreased 11 beta HSD1 expression in THP1 cells. The presence of the inhibitor of 11 beta HSD1 abolished all the effects elicited by cortisone.Conclusion: Our results indicate a direct effect of glucocorticoids on macrophages braking atherosclerosis initiation, reducing pro-inflammatory markers and OxLDL uptake and cholesterol re-esterification, but also inhibiting cholesterol output. These effects appear to be mediated, at least in part, by 11 beta HSD1 activity. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Objective To evaluate how deficiency in corticosteroid‐binding globulin (CBG), the specific carrier of glucocorticoids, affects glucocorticoid availability and adipose tissue in obesity. Methods C57BL/6 (WT) and CBG‐deficient (KO) male mice were fed during 12 weeks with standard or hyperlipidic diet (HL). Glucocorticoid availability and metabolic parameters were assessed. Results Body weight and food intake were increased in KO compared with WT mice fed a standard diet and were similar when fed a HL diet. Expression of CBG was found in white adipose tissue by immunochemistry, real‐time PCR, and Western blot. In obesity, the subcutaneous depot developed less in KO mice compared with WT, which was associated with a minor adipocyte area and peroxisome proliferator‐activated receptor‐γ expression. Conversely, the epididymal depot displayed higher weight and adipocyte area in KO than in WT mice. CBG deficiency caused a fall of hepatic 11β‐hydroxysteroid dehydrogenase type 2 expression and an increase in epidymal adipose tissue, particularly in HL mice. Conclusions Deficiency in CBG drives lipid partitioning from subcutaneous to visceral adipose depot under a context of lipid excess and differentially modulates 11β‐hydroxysteroid dehydrogenase type 2 expression.

This article supports experimental evidence on the time-dependent effect on gene expression related to inflammation and cholesterol deposition in lipid-loaded cells. The cells employed were human monocytes THP1 line transformed into macrophages by treatment with phorbol esters. Macrophages were treated at different times with oxidized low density lipoprotein (Ox-LDL) and then gene expression was measured. We also include data about the different types of oxidized lipoprotein obtained (low, media or high oxidation) for differential exposure with Cu ions. These data include characterization to lipid and protein peroxidative damage and also quantification of cell viability by exposure to native and modified LDL. The present article complements data published in "Decreased OxLDL uptake and cholesterol efflux in THP1 cells elicited by cortisol and by cortisone through 11β-hydroxysteroid dehydrogenase type 1" Ledda et al. (in press) [1].

ObjectiveCortisolemia and 11βHSD1 in liver and adipose tissue are altered in obesity. However, their participation in the development of obesity remains unclear. This study analyzed these parameters in the transition from morbid to type 1 obesity after bariatric surgery.MethodsA group of 34 patients with morbid obesity and 22 nonobese subjects were recruited. Initial hypothalamus‐pituitary‐adrenal (HPA) basal activity and 11βHSD1 mRNA expression in liver, subcutaneous (SAT), and visceral adipose tissue (VAT) were evaluated. A year after bariatric surgery (weight loss of 48 kg), these parameters were reappraised in plasma, SAT, and liver.ResultsBody weight loss was accompanied by a downshift in basal HPA activity and 11βHSD1 expression in SAT. In patients with morbid obesity, 11βHSD1 expression correlated positively with BMI in VAT and negatively in liver at 6 and 12 months after surgery. In SAT, a correlation was observed with body weight only when patients showed type 1 obesity. Insulin, glucose, and HOMA correlated positively with all the HPA indicators and 11βHSD1 expression in SAT.ConclusionsBody weight loss after bariatric surgery is accompanied by a downshift in basal HPA activity. Hepatic and VAT 11βHSD1 expressions in morbid obesity are predictors of body weight loss.

Introducción Los glucocorticoides son antiinflamatorios que actúan en la resolución de la inflamación mediante la activación de macrófagos por la vía alternativa M2c anti-inflamatorios, entre otras acciones. Se considera que los glucocorticoides están implicados en el desencadenamiento y/o mantenimiento de la obesidad, tal como se ha postulado para la aterosclerosis. A nivel de tejidos periféricos, entre ellos las células del sistema inmune, la señal glucocorticoide puede verse amplificada o inhibida por la actividad de las enzimas 11β-hidroxiesteroide deshidrogenasa de tipo 1 (11βHSDH1) y de tipo 2 (11βHSDH2), respectivamente. La expresión de 11βHSD1 está involucrada en la reducción de cortisona a cortisol (forma activa del glucocorticoide) y la 11βHSDH2 transforma al cortisol en cortisona (glucocorticoide inactivo).

Adipose tissue (AT) is distributed as large differentiated masses, and smaller depots covering vessels, and organs, as well as interspersed within them. The differences between types and size of cells makes AT one of the most disperse and complex organs. Lipid storage is partly shared by other tissues such as muscle and liver. We intended to obtain an approximate estimation of the size of lipid reserves stored outside the main fat depots. Both male and female rats were made overweight by 4-weeks feeding of a cafeteria diet. Total lipid content was analyzed in brain, liver, gastrocnemius muscle, four white AT sites: subcutaneous, perigonadal, retroperitoneal and mesenteric, two brown AT sites (interscapular and perirenal) and in a pool of the rest of organs and tissues (after discarding gut contents). Organ lipid content was estimated and tabulated for each individual rat. Food intake was measured daily. There was a surprisingly high proportion of lipid not accounted for by the main macroscopic AT sites, even when brain, liver and BAT main sites were discounted. Muscle contained about 8% of body lipids, liver 1-1.4%, four white AT sites lipid 28-63% of body lipid, and the rest of the body (including muscle) 38-44%. There was a good correlation between AT lipid and body lipid, but lipid in "other organs" was highly correlated too with body lipid. Brain lipid was not. Irrespective of dietary intake, accumulation of body fat was uniform both for the main lipid storage and handling organs: large masses of AT (but also liver, muscle), as well as in the "rest" of tissues. These storage sites, in specialized (adipose) or not-specialized (liver, muscle) tissues reacted in parallel against a hyperlipidic diet challenge. We postulate that body lipid stores are handled and regulated coordinately, with a more centralized and overall mechanisms than usually assumed.