The long-lasting loss of sleep is a generally acknowledged risk factor for the occurrence of major depressive disorder (MDD), whereas sleep abnormalities being a key clinic symptom of the MDD. In our previous work, we demonstrated that the sleep deprivation (SD) stimulates activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasomes as well as the release of IL-1β and IL-18 from astrocytes. However, the underlying mechanism connecting SD and MDD still requires further study. Apart of the secretion of the pro-inflammatory cytokines, SD affects production of brain-derived neurotrophic factor (BDNF) while release of BDNF from astrocytes appears a key contributor to mood disorders. If and how the activation of NLRP3 inflammasome following SD affects the level of BDNF remains unknown. Antidepressant fluoxetine acts through astroglial 5-hydroxytryptamine receptor 2B (5-HT2B); these receptors are also related to the sleep-wake cycle. Contribution of leptin to MDD has been discovered recently, although the mechanistic links between leptin and the depressive-like behaviors has not been revealed. In this study, we discovered: (i) that activation of NLRP3 inflammasome was involved in the depressive-like behaviors induced by SD; (ii) decrease in BDNF following SD required the activation of NLRP3 inflammasomes; (iii) leptin augmented the anti-depressive action of fluoxetine through an increase in expression of astrocytic 5-HT2B receptors. We suggest that decrease in BDNF by the activated NLRP3 inflammasomes in astrocytes is the key pathological event of the depressive-like behaviors induced by SD, while the combined treatment with fluoxetine and leptin improves therapeutic outcome for the depression induced by SD.
Chronic loss of sleep damages health and disturbs quality of life. The long-lasting sleep deprivation (SD) as well as sleep abnormalities is a substantial risk factor for major depressive disorder (MDD), although the underlying mechanisms are not clear. In our previous studies, we report the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome induced by long-term SD is P2X7 receptors (P2X7R) dependent, and antidepressant fluoxetine could alleviate this neuroinflammasome via 5-HT2B receptors (5-HT2BR) in astrocytes. Here, we discovered that the chronic SD activates astroglial P2X7 receptors, which in turn selectively downregulated expression of 5-HT2BR in astrocytes. Stimulation of P2X7R induced by SD suppressed the phosphorylation of AKT and FoxO3a selectively in astrocytes, but not in neurones. The over-expression of FoxO3a in astrocytes inhibited expression of 5-HT2BR. Down-regulation of 5-HT2BR instigated by SD suppressed activation of STAT3 and relieved the inhibition of Ca 2+ -dependent phospholipase A2 (cPLA2). This latter cascade promoted the release of arachidonic acid (AA) and prostaglandin E2 (PGE2). The depressive-like behaviours induced by SD were alleviated in P2X7R-KO mice. Our study reveals the mechanism underlying chronic SD-induced depressive-like behaviors and highlights that blocking P2X7 receptors or activating 5-HT2BR in astrocytes could play a key role for exploring the therapeutic strategies aimed at the depression evoked by sleep disorders.
Background
Glycemic variability (GV) confers a risk of cardiovascular events. In this study, we aimed to investigate whether long-term GV has an impact on coronary atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM).
Methods
A total of 396 patients with T2DM who had coronary computed tomography angiography and laboratory data available at baseline and for follow-up evaluations [median 2.3 (1.8–3.1) years] were included. Fasting plasma glucose (FPG) was measured every 1–3 months, and HbA1c was measured quarterly. The coefficient of variation (CV) of HbA1c and FPG were calculated as measures of GV. Quantitative assessment of coronary plaques was performed by measuring the annual change and progression rate of total plaque volume (TPV). Significant progression was defined as annual TPV progression ≥ 15%. Multivariable regression analyses were used to assess the effects of GV on atherosclerosis progression.
Results
In the 396 patients, the annual change in TPV was 12.35 ± 14.23 mm3, and annual progression rate was 13.36 ± 12.69%. There were 143 (36.11%) patients with significant progression, and they had a significantly higher CV-HbA1c (P < 0.001) and CV-FPG (P < 0.001) than those without significant progression. In multivariable regression analyses, both CV-HbA1c and CV-FPG were independent predictors of annual change in TPV [CV-HbA1c: β = 0.241 (0.019–0.462), P = 0.034; CV-FPG: β = 0.265 (0.060–0.465), P = 0.012], annual TPV progression [CV-HbA1c: β = 0.214 (0.023–0.405), P = 0.029; CV-FPG: β = 0.218 (0.037–0.399), P = 0.019], and significant atherosclerosis progression [CV-HbA1c: odds ratio [OR] = 1.367 (1.149–1.650), P = 0.010; CV-FPG: OR = 1.321 (1.127–1.634), P = 0.013].
Conclusions
Long-term GV is associated with accelerated progression of coronary atherosclerosis independent of conventional risk factors in patients with T2DM.
Trial registration ClinicalTrials.gov (NCT02587741), October 27, 2015; retrospectively registered
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