Celastrol alleviates comorbid obesity and depression by directly binding amygdala HnRNPA1 in a mouse model.
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ABSTRACT:
SUBMITTER: Zhu C
PROVIDER: S-EPMC8181197 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDepression hinders obesity treatment; elucidating mechanisms may enable treatment enhancements.ObjectivesThe aim was to investigate whether changes in neural targets in the negative affect circuit following psychotherapy mediate subsequent changes in weight and behaviors.MethodsAdults (n = 108) with obesity and depression were randomly assigned to usual care or an intervention that delivered problem-solving therapy (PST) for depression over 2 mo. fMRI for brain imaging was performed at baseline and 2 mo. BMI, physical activity, and diet were measured at baseline and 12 mo. Mediation analysis assessed between-group differences in neural target changes using t test and correlations between neural target changes and outcome changes (simple and interaction effect) using ordinary least-squares regression.ResultsCompared with usual care, PST led to reductions in left amygdala activation (-0.75; 95% CI: -1.49, -0.01) and global scores of the negative affect circuit (-0.43; -0.81, -0.06), engaged by threat stimuli. Increases in amygdala activation and global circuit scores at 2 mo correlated with decreases in physical activity outcomes at 12 mo in the usual-care group; these relations were altered by PST. In relation to change in leisure-time physical activity, standardized β-coefficients were -0.67 in usual care and -0.01 in the intervention (between-group difference: 0.66; 0.02, 1.30) for change in left amygdala activation and -2.02 in usual care and -0.11 in the intervention (difference: 1.92; 0.64, 3.20) for change in global circuit scores. In relation to change in total energy expenditure, standardized β-coefficients were -0.65 in usual care and 0.08 in the intervention (difference: 0.73; 0.29, 1.16) for change in left amygdala activation and -1.65 in usual care and 0.08 in the intervention (difference: 1.74; 0.85, 2.63) for change in global circuit scores. Results were null for BMI and diet.ConclusionsShort-term changes in the negative affect circuit engaged by threat stimuli following PST for depression mediated longer-term changes in physical activity. This trial was registered at www.clinicaltrials.gov as NCT02246413 (https://clinicaltrials.gov/ct2/show/NCT02246413).
| S-EPMC8634561 | biostudies-literature
Project description:While comorbid pain in depression (CP) occurs at a high rate worldwide, the neural connections underlying the core symptoms of CP have yet to be elucidated. Here, we define a pathway whereby GABAergic neurons from the central nucleus of the amygdala (GABACeA) project to glutamatergic neurons in the parafascicular nucleus (GluPF). These GluPF neurons relay directly to neurons in the second somatosensory cortex (S2), a well-known area involved in pain signal processing. Enhanced inhibition of the GABACeA?GluPF?S2 pathway is found in mice exhibiting CP symptoms. Reversing this pathway using chemogenetic or optogenetic approaches alleviates CP symptoms. Together, the current study demonstrates the putative importance of the GABACeA?GluPF?S2 pathway in controlling at least some aspects of CP.
| S-EPMC7020652 | biostudies-literature
Project description:This is a genome-wide differential gene expression survey of cases of comorbid PTSD and depression versus controls
2015-12-01 | GSE67663 | GEO
Project description:BackgroundCelastrol (cel) was one of the earliest isolated and identified chemical constituents of Tripterygium wilfordii Hook. f. Based on a cel probe (cel-p) that maintained the bioactivity of the parent compound, the targets of cel in cerebral ischemia-reperfusion (I/R) injury were comprehensively analyzed by a quantitative chemical proteomics method.MethodsWe constructed an oxygen-glucose deprivation (OGD) model in primary rat cortical neurons and a middle cerebral artery occlusion (MCAO) model in adult rats to detect the direct binding targets of cel in cerebral I/R. By combining various experimental methods, including tandem mass tag (TMT) labeling, mass spectrometry, and cellular thermal shift assay (CETSA), we revealed the targets to which cel directly bound to exert neuroprotective effects.ResultsWe found that cel inhibited the proinflammatory activity of high mobility group protein 1 (HMGB1) by directly binding to it and then blocking the binding of HMGB1 to its inflammatory receptors in the microenvironment of ischemia and hypoxia. In addition, cel rescued neurons from OGD injury in vitro and decreased cerebral infarction in vivo by targeting HSP70 and NF-κB p65.ConclusionCel exhibited neuroprotective and anti-inflammatory effects by targeting HSP70 and NF-κB p65 and directly binding to HMGB1 in cerebral I/R injury.
| S-EPMC8353826 | biostudies-literature
Project description:Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, is a powerful anti-obesity agent. Celastrol suppresses food intake, blocks reduction of energy expenditure, and leads to up to 45% weight loss in hyperleptinemic diet-induced obese (DIO) mice by increasing leptin sensitivity, but it is ineffective in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mouse models. These results indicate that Celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity.
| S-EPMC4768733 | biostudies-literature
Project description:Purpose of reviewTo synthesize evidence from randomized controlled trials on the effects of integrated behavioral interventions for comorbid obesity and depression in adults.Recent findingsSeven trials (n = 33 to 409) were included. The quality of evidence was mixed. In 2 trials, integrated interventions led to greater improvements in both obesity and depression over 12 months, compared with usual care. Of 4 trials comparing integrated interventions with a standalone obesity intervention, 2 showed incremental effects on depression only, and 2 did not detect a significant effect for either outcome. One 3-arm trial compared an integrated intervention with standalone obesity and depression interventions and only detected incremental effects on obesity when compared with a standalone depression intervention. The effects of integrated interventions for comorbid obesity and depression are varied but promising. Implications for future research to guide intervention optimization and implement integrated interventions in clinical practice are provided.
| S-EPMC8930483 | biostudies-literature
Project description:BACKGROUND:Depression and obesity are significant global health concerns that commonly occur together. An integrated group cognitive behavioural therapy program was therefore developed to simultaneously address comorbid depression and obesity. METHODS:Twenty-four participants (63% women, mean age 46?years) who screened positively for depression with a body mass index ?25 were recruited from a self-referred general population sample. The group therapy program (10 two-hour weekly sessions) was examined in a single-arm, before-after pilot trial, conducted in a behavioural health clinic in Adelaide, Australia. Primary outcomes included survey and assessment-based analyses of depression, anxiety, body image, self-esteem, and weight (kg), assessed at four time-points: baseline, post-intervention, three-months and 12-months post program. Eighteen participants (75%) completed the program and all assessments. RESULTS:Significant improvements in depression, anxiety, self-esteem and body shape concern scores, several quality of life domains, eating behaviours and total physical activity (among others) - but not weight - were observed over the course of the trial. CONCLUSIONS:Results from this pilot trial suggest that combining interventions for depression and obesity may be useful. Further development of the program, particularly regarding the potential for physical health benefits, and a randomised controlled trial, are warranted. TRIAL REGISTRATION:Trial registration: ANZCTR, ACTRN12617001079336, 13 July 2017. Retrospectively registered after date of the first consent (6 July 2017), but before the date of the first intervention session (20 July 2017).
| S-EPMC7164235 | biostudies-literature
Project description:Renal fibrosis is the final manifestation of various chronic kidney diseases, and no effective therapy is available to prevent or reverse it. Celastrol, a triterpene that derived from traditional Chinese medicine, is a known potent anti-fibrotic agent. However, the underlying mechanisms of action of celastrol on renal fibrosis remain unknown. In this study, we found that celastrol treatment remarkably attenuated unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis. This was evidenced by the significant reduction in tubular injury; collagen deposition; accumulation of fibronectin, collagen I, and α-smooth muscle actin; and the expression levels of pro-fibrotic factors Vim, Cola1, and TGF-β1 mRNA, as well as inflammatory responses. Celastrol showed similar effects in a folic acid-induced mouse renal fibrosis model. Furthermore, celastrol potentiated the expression of the anti-fibrotic factor cannabinoid receptor 2 (CB2R) in established mouse fibrotic kidney tissues and transforming growth factor β1 (TGF-β1)-stimulated human kidney 2 (HK-2) cells. In addition, the CB2R antagonist (SR144528) abolished celastrol-mediated beneficial effects on renal fibrosis. Moreover, UUO- or TGF-β1-induced activation of the pro-fibrotic factor SMAD family member 3 (Smad3) was markedly inhibited by celastrol. Inhibition of Smad3 activation by an inhibitor (SIS3) markedly reduced TGF-β1-induced downregulation of CB2R expression. In conclusion, our study provides the first direct evidence that celastrol significantly alleviated renal fibrosis, by contributing to the upregulation of CB2R expression through inhibiting Smad3 signaling pathway activation. Therefore, celastrol could be a potential drug for treating patients with renal fibrosis.
| S-EPMC5964092 | biostudies-literature
Project description:Objective:This review aimed at searching for scientific literature on mobile apps for the management of comorbid overweight/obesity and depression/anxiety and providing a brief and comprehensive summary of their main features, targeted groups, and relevant results. Methods:A bibliographical search was performed in Pubmed, PsycNet, Web of Science, ResearchGate, and Lilacs databases. The terms "obesity" and "overweight" were introduced in combination with "anxiety" and "depression" and "mobile app (application)," "smartphone app (application)," "android app (applicattion)," "iOS app (application)," "mobile health app (application)," and "mHealth app (application)." Results:The initial search eliciting 204 citations was reduced to 7 relevant papers (4 original articles, 1 brief communication, and 2 study protocols). All publications were from the last five years, most were produced by research teams from the United States. All had adult samples, and interventions mostly followed a cognitive behavioral framework. Regarding mobile apps, five studies only used one to monitor weight and physical activity, one study to provide therapy to improve psychological wellness, and one study to monitor cognitions and emotions. No mobile app was found for the simultaneous management of overweight/obesity and depression/anxiety. Conclusions:The prevalence and costs related to overweight/obesity and depression/anxiety are significant and likely to increase. Very often these conditions overlap; thus, it would be recommendable to treat their comorbidity simultaneously. Nevertheless, no mobile app has been designed for this purpose, which would help to reduce service provision costs and make treatment more easily accessible for patients.
| S-EPMC7003257 | biostudies-literature
Project description:We aimed to examine genome-wide differential expression profiles of miRNA in PTSD&Dep cases versus controls
2015-12-01 | GSE74162 | GEO