The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling.

The E3 ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase (DUB)-mediated deubiquitination processes are closely associated with the occurrence and development of colonic inflammation. Ovarian tumor deubiquitinase 1 (OTUD1) is involved in immunoregulatory functions linked to infectious diseases. However, the effect of OTUD1 on intestinal immune responses during colonic inflammatory disorders such as inflammatory bowel disease (IBD) remains unclear. Here, we show that loss of OTUD1 in mice contributes to the pathogenesis of dextran sulfate sodium (DSS)-induced colitis via excessive release of proinflammatory cytokines. In addition, bone marrow transplantation experiments revealed that OTUD1 in hematopoietic cells plays a dominant role in protection against colitis. Mechanistically, OTUD1 physically interacts with receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and selectively cleaves K63-linked polyubiquitin chains from RIPK1 to inhibit the recruitment of NF-κB essential modulator (NEMO). Moreover, the expression of OTUD1 in mucosa samples from ulcerative colitis (UC) patients was lower than that in mucosa samples from healthy controls. Furthermore, we demonstrate that the UC-associated OTUD1 G430V mutation abolishes the ability of OTUD1 to inhibit RIPK1-mediated NF-κB activation and intestinal inflammation. Taken together, our study unveils a previously unexplored role of OTUD1 in moderating intestinal inflammation by inhibiting RIPK1-mediated NF-κB activation, suggesting that the OTUD1-RIPK1 axis could be a potential target for the treatment of IBD.

Applying dimensional psychopathology: transdiagnostic associations among regional homogeneity, leptin and depressive symptoms.

Dimensional psychopathology and its neurobiological underpinnings could provide important insights into major psychiatric disorders, including major depressive disorder, bipolar disorder and schizophrenia. In a dimensional transdiagnostic approach, we examined depressive symptoms and their relationships with regional homogeneity and leptin across major psychiatric disorders. A total of 728 participants (including 403 patients with major psychiatric disorders and 325 age-gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging at a single site. We obtained plasma leptin levels and depressive symptom measures (Hamilton Depression Rating Scale (HAMD)) within 24 h of scanning and compared the regional homogeneity (ReHo), plasma leptin levels and HAMD total score and factor scores between patients and healthy controls. To reveal the potential relationships, we performed correlational and mediational analyses. Patients with major psychiatric disorders had significant lower ReHo in primary sensory and visual association cortices and higher ReHo in the frontal cortex and angular gyrus; plasma leptin levels were also elevated. Furthermore, ReHo alterations, leptin and HAMD factor scores had significant correlations. We also found that leptin mediated the transdiagnostic relationships among ReHo alterations in primary somatosensory and visual association cortices, core depressive symptoms and body mass index. The transdiagnostic associations we demonstrated support the common neuroanatomical substrates and neurobiological mechanisms. Moreover, leptin could be an important association among ReHo, core depressive symptoms and body mass index, suggesting a potential therapeutic target for dimensional depressive symptoms across major psychiatric disorders.

Cholesterol and triglyceride levels in first-episode patients with major depressive disorder: A meta-analysis of case-control studies.

BACKGROUND: Lipid profile disturbances are frequently observed in major depressive disorder (MDD) and constitute to high mortality rates. However, less is known about whether this risk is present in patients with first-episode MDD. Therefore, this meta-analysis was conducted to examine if lipid parameters differed between healthy controls and first-episode MDD patients. METHODS: Cochrane Library, PubMed, PsycINFO, EMBASE, Chinese Journal Net, and WanFang databases were searched from inception to October 23, 2018. The primary outcomes were triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total cholesterol levels. RESULTS: A total of 11 case-control studies compared 690 subjects with first-episode MDD and 614 healthy controls were included and analyzed. Compared to healthy controls, patients with first-episode MDD were significantly associated with higher triglyceride (SMD = 0.29, 95% CI: 0.09, 0.48, P = 0.004) and lower HDL cholesterol levels (SMD = -0.54, 95% CI: -0.86, -0.22, P = 0.001). Subgroup analyses revealed that first-episode MDD patients with higher triglyceride and lower HDL levels were found only in Chinese and plasma group when compared to healthy controls (P < 0.05). Meta-regression analysis showed that the significant heterogeneity for triglyceride and HDL cholesterol was partly explained by the quality of study. No significant difference was found in LDL cholesterol and total cholesterol levels between the two groups. LIMITATIONS: Heterogeneity was relatively high among the included studies. CONCLUSIONS: Elevated triglyceride and decreased HDL cholesterol levels may be associated with first-episode MDD. Findings support early lipid monitoring and interventions targeting healthy lifestyle.