HMGB1 in depression: An overview of microglial HMBG1 in the pathogenesis of depression.

Depression is a prevalent psychiatric disorder with elusive pathogenesis. Studies have proposed that enhancement and persistence of aseptic inflammation in the central nervous system (CNS) may be closely associated with the development of depressive disorder. High mobility group box 1 (HMGB1) has obtained significant attention as an evoking and regulating factor in various inflammation-related diseases. It is a non-histone DNA-binding protein that can be released as a pro-inflammatory cytokine by glial cells and neurons in the CNS. Microglia, as the immune cell of the brain, interacts with HMGB1 and induces neuroinflammation and neurodegeneration in the CNS. Therefore, in the current review, we aim to investigate the role of microglial HMGB1 in the pathogenetic process of depression.

COVID-19 pandemic-related depression and anxiety under lockdown: The chain mediating effect of self-efficacy and perceived stress.

Objective: In early March 2022, the highly contagious Omicron variant rapidly emerged in Shanghai. This study aimed to explore the prevalence and associated factors of depression and anxiety in isolated or quarantined populations under lockdown. Methods: A cross-sectional study was conducted between May 12 and 25, 2022. The depressive and anxiety symptoms, perceived stress, self-efficacy and perceived social support in the 167 participants under isolated or quarantined were examined using the Patient Health Questionnaires-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7), the Perceived Stress Scale-10 (PSS-10), the General Self-Efficacy Scale (GSES) and the Perceived Social Support Scale (PSSS). Data on demographic information were also collected. Findings: The prevalence of depression and anxiety in isolated or quarantined populations was estimated to be 12 and 10.8%, respectively. Higher education level, being healthcare workers, being infected, longer duration of segregation and higher perceived stress level were identified as risk factors for depression and anxiety. Furthermore, the relationship between perceived social support and depression (anxiety) was mediated not only by perceived stress but also the chain of self-efficacy and perceived stress. Conclusion: Being infected, higher education level, longer duration of segregation and higher perceived stress were associated with higher levels of depression and anxiety among isolated or quarantined populations under lockdown. The formulation of psychological strategies that promote one's perceived social support and self-efficacy as well as reduce perceived stress is supposed to be drawn.

Higher inflammation and cerebral white matter injury associated with cognitive deficit in asthmatic patients with depression.

OBJECTIVE: Depression is a common co-morbidity in asthma, worsening asthma control and impairing quality of life. Previous studies have reported a higher risk of cognitive deficit in depression, yet little research has focused on the level of cognition in asthmatic patients with depression. Evidence shows that inflammation may play an important role in both asthma and depression. Cerebral white matter injury, possibly induced by inflammation, has been associated with depression. This study assesses cognitive function in patients with asthma and a depression comorbidity, compared to patients with asthma only or depression only. METHODS: Four groups were studied: Asthma comorbid Depression group (A + D, n = 26), Depression group (D, n = 25), Asthma group (A, n = 33) and Normal controls (N, n = 28). Cognitive function was evaluated using Montreal Cognitive Assessment (MoCA). Inflammatory cytokines were measured, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-mobility group box 1(HMGB1) and Netrin-1. Cerebral white matter injury was assessed by serum myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG), and their correlations with cognitive performance were calculated. RESULTS: A + D group showed the highest incidence of cognitive deficit, with the cognitive domain particularly affected. Compared to N group, serum levels of IL-6, HMGB1, Netrin-1, MBP and MOG were significantly elevated in A + D group. MOG level negatively correlated with the MoCA score. CONCLUSION: Patients with comorbidities presented with more severe cognitive deficits and higher levels of inflammatory cytokines. Cerebral white matter injury may account for the cognitive deficit in patients and MOG could be a potential biomarker for this process.

Anti-mouse CX3CR1 Antibody Alleviates Cognitive Impairment, Neuronal Loss and Myelin Deficits in an Animal Model of Brain Ischemia.

White matter lesions are common when global cerebral ischemia (GCI) occurs in the elderly, and cause damage to neurological and psychological functions. Remyelination often fails because of the limited recruitment of oligodendrocyte progenitor cells (OPCs) to the demyelinated site or the inefficient differentiation of OPCs to mature oligodendrocytes (OLs). The activation of microglia, the most important immune cells in the central nervous system, and subsequent inflammation have been implicated in myelination repair disorder. Little is known about the role of the Fractalkine/CX3CR1 signaling pathway, the key regulator of microglia activation, on myelin in microglia. In this study, a GCI animal model was generated through bilateral common carotid artery occlusion to induce ischemic inflammation and white matter damage; then, we downregulated CX3CR1 by intracerebroventricular administration of neutralizing antibody anti-FKR. Downregulation of CX3CR1 significantly reversed the depression-like behavior and cognitive impairment in GCI mice. Activation of microglia was inhibited, and the peripheral inflammatory responses were also ameliorated as revealed by decreased serum levels of IL-1ß, IL-6 and TNF-α. CX3CR1 block substantially reversed demyelination in striatum, cortex and hippocampus and promoted differentiation and maturation of OPCs into mature OLs in the hippocampus. No effect was found on myelin in the corpus callosum. Besides, hippocampal neurons were protected by anti-FKR treatment after GCI. Collectively, our data demonstrated that downregulating of the Fractalkine/CX3CR1 signaling pathway had an anti-depressant and cognition-improvement effect by inhibiting microglia activation, promoting OPCs maturation and remyelination.

Minocycline Ameliorates Depressive-Like Behavior and Demyelination Induced by Transient Global Cerebral Ischemia by Inhibiting Microglial Activation.

Global cerebral ischemia (GCI) commonly occurs in the elderly. Subcortical white matter lesions and oligodendrocyte (OLG) loss caused by cerebral ischemia have been implicated in the development of post-ischemic depression and cognitive impairment. OLGs are necessary for axonal myelination; the disrupted differentiation of OLG progenitor cells (OPCs) is associated with impaired remyelination. Evidence has indicated that increased levels of inflammatory cytokines released from activated microglia induce depression-like behaviors by affecting neurotransmitter pathways, but the mechanisms remain elusive. We explored the potential mechanisms that link microglia activation with GCI-induced depression and cognitive dysfunction by studying effects of minocycline on white matter damage, cytokine levels, and the monoaminergic neurotransmitters. An acute GCI animal model was generated through bilateral common carotid artery occlusion to induce ischemic inflammation and subcortical white matter damage. Minocycline, an inhibitor of microglia activation, was intraperitoneally administrated immediately after surgery and continued daily for additional six days. Minocycline shortened the immobile duration in tail suspension test and forced swimming test, while no improvement was found in Morris water maze test. The plasma levels of IL-1ß, IL-6, TNF-α, HMGB1, and netrin-1 were significantly reduced with the treatment of minocycline. Minocycline treatment substantially reversed demyelination in corpus callosum and hippocampus, alleviated hippocampal microglia activation, and promoted OPCs maturation, while no effect was found on hippocampal neurodegeneration. Besides, the content of dopamine (DA) in the hippocampus was upregulated by minocycline treatment after GCI. Collectively, our data demonstrated that minocycline exerts an anti-depressant effect by inhibiting microglia activation, promoting OPCs maturation and remyelination. Increased DA in hippocampus may also play a role in ameliorating depressive behavior with minocycline treatment.

Strong Association of Serum GSK-3ß/BDNF Ratio with Mild Cognitive Impairment in Elderly Type 2 Diabetic Patients.

BACKGROUND: Glycogen Synthase Kinase (GSK)-3ß and Brain-derived Neurotrophic Factor (BDNF) play vital roles in both Mild Cognitive Impairment (MCI) and Type 2 Diabetes Mellitus (T2DM). The underlying mechanisms may involve inflammation and oxidative stress. OBJECTIVES: To investigate the association of the GSK-3ß/BDNF ratio with MCI in elderly patients with T2DM and whether GSK-3ß/BDNF ratio can serve as a new diagnostic biomarker for MCI in comorbid with T2DM (MD). METHODS: A total of 326 old Chinese T2DM patients were included and stratified according to cognition and GSK-3ß/BDNF ratio quartiles. MCI was diagnosed according to the National Institute on Aging Alzheimer's Association workgroups criteria. In addition to routine hematuria and biochemical examinations, Montreal Cognitive Assessment (MoCA) scale was also used to evaluate the cognitive function, and ELISA method was used to measure GSK-3ß activity and the serum levels of BDNF, interleukin 1ß (IL-1ß), high mobility group box-1 (HMGB1) protein, Malonaldehyde (MDA) and 8-isoprostaglandinF2α (8-iso-PGF2α). RESULTS: We found that GSK-3ß activity was negatively correlated with BDNF (r=-0.270, P=0.008), and patients with higher GSK-3ß/BDNF ratio had lower MoCA scores (P=0.001). When compared with T2DM patients without MCI (nMD), MD patients had higher GSK-3ß activity and GSK-3ß/BDNF ratio, but lower BDNF levels. As for inflammation and oxidative stress, IL-1ß was inversely correlated with GSK-3ß activity, while 8-isoPGF2α was positively correlated with GSK-3ß activity and GSK-3ß/BDNF ratio. The odds ratio for MCI increased gradually when GSK-3ß/BDNF ratio quartile rose from the lowest to the highest (6.90, 95% CI 3.22-14.78). MoCA score was conversely related to GSK-3ß/BDNF ratio, age and fast blood glucose (FBG), with GSK-3ß/BDNF ratio having the most significant influence on cognition (ß=-0.199, P<0.001). CONCLUSION: Our data provide evidence for a strong link between GSK-3ß/BDNF ratio and MCI. GSK- 3ß/BDNF ratio may serve as a better diagnostic biomarker for MD than either GSK-3ß or BDNF alone and increased GSK-3ß/BDNF ratio indicates a worse cognitive function.

Fr­HMGB1 and ds­HMGB1 activate the kynurenine pathway via different mechanisms in association with depressive­like behavior.

Our previous study reported that fully reduced high mobility group box 1 (fr­HMGB1) and disulfide HMGB1 (ds­HMGB1) induce depressive­like behavior; however, the underlying mechanisms remain unclear. In the present study, the induction of depression via the kynurenine pathway by different redox states of HMGB1 was investigated in vivo and in vitro. To evaluate the expression of enzymes of the kynurenine pathway, reverse transcription­quantitative PCR and western blot analyses were conducted. Additionally, cytokine levels were measured by ELISAs. Following intracerebroventricular injection of ds­ and fr­HMGB1, behavioral tests were performed, revealing the presentation of depressive­like behavior, and essential proteins in the kynurenine pathway were demonstrated to be upregulated at the mRNA level, suggesting that ds­ and fr­HMGB1 contributed to the development of this behavior via the kynurenine pathway. ds­HMGB1 directly activated the kynurenine pathway and cytokines such as tumor necrosis factor­α (TNF­α) and interleukin­1ß (IL­1ß) in the hippocampal tissue. Conversely, fr­HMGB1 upregulated the aforementioned factors only following treatment with H2O2. These findings indicated that ds­HMGB1 induced depression in a manner associated with the kynurenine pathway, whereas oxidation of fr­HMGB1 evoked activation of the kynurenine pathway, resulting in depressive behavior.

Corticosterone rapidly improves the endurance of high-intensity exercise (swimming) via nongenomic mechanisms in mice.

BACKGROUND: Glucocorticoids (GCs) take a pivotal role during the stress response. Some clinical studies suggest short-term GCs intake improves exercise endurance. However, whether the rapid nongenomic effects of GCs are involved in acute exercise is still unknown. Here, we aimed to reveal the potential nongenomic effects of GCs in skeletal muscle of mice during exercise. METHODS: Adrenalectomized mice subjected to a weight-loaded forced swim were used for detecting the changes of time to exhaustion. Corticosterone (CORT) and other drugs were injected via the coccygeal vein before swimming. After exhaustion, the injury of skeletal muscle, nitric oxide generation, blood glucose and lactic acid were determined. RESULTS: The results demonstrated that CORT rapidly extended the time to exhaustion within 30 min (~30%), which could not be abolished by glucocorticoid receptor antagonist RU486. Pretreatment with the nitric oxide synthesis inhibitor L-NAME prior to CORT administration further increased exercise tolerance compared to the increase caused by CORT alone. Moreover, CORT contributed to protecting skeletal muscle from injury and maintaining blood glucose. CONCLUSIONS: Considered together, our results suggest that GCs rapidly improve exercise tolerance via its nongenomic mechanism, which is associated with the inhibition of nitric oxide generation. Pretreatment of GCs may be helpful to enhance exercise tolerance during acute exercise.

Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice.

BACKGROUND: Depression is one of the most common mental disorders characterized mainly by low mood and loss of interest or pleasure. About a third of patients with depression do not respond to classic antidepressant treatments. Recent evidence suggests that Mrp8/14 (myeloid-related protein 8/14) plays a crucial role in cognitive dysfunction and neuroinflammatory diseases, yet its role in mood regulation remains largely uninvestigated. In the present work, we explored the potential role of Mrp8/14 in the progression of depression. METHODS: After 4 weeks of chronic unpredictable mild stress (CUMS), depressive-like symptoms and Mrp8/14 were determined. To verify the effects of Mrp8/14 on depressive-like behaviors, the inhibitor TAK-242 and recombinant Mrp8/14 were used. Furthermore, the molecular mechanisms in Mrp8/14-induced behavioral and biological changes were examined in vivo and ex vivo. RESULTS: Four-week CUMS contributed to the development of depressive symptoms. Mrp8 and Mrp14 were upregulated in the hippocampus and serum after exposure to CUMS. Pharmacological inhibition of Mrp14 attenuated CUMS-induced TLR4/NF-κB signaling activation and depressive-like behaviors. Furthermore, central administration of recombinant Mrp8, Mrp14, and Mrp8/14 resulted in neuroinflammation and depressive-like behaviors. Mrp8/14-provoked proinflammatory effects and depressive-like behaviors were improved by pretreatment with a TLR4 inhibitor. Moreover, pharmacological inhibition of TLR4 reduced the release of nitric oxide and reactive oxygen species in Mrp8/14-activated BV2 microglia. CONCLUSIONS: These data suggest that the hippocampal Mrp8/14-TLR4-mediated neuroinflammation contributes to the development of depressive-like behaviors. Targeting the Mrp8/14 may be a novel promising antidepressant approach.

Glycyrrhizic acid ameliorates the kynurenine pathway in association with its antidepressant effect.

Our previous study implied the role of central high mobility group box 1 (HMGB1) in lipopolysaccharide (LPS)-induced depressive-like behaviors that could partially abrogate by glycyrrhizic acid (GZA). Here, we considered the potential mechanism underlying GZA ameliorating chronic stress-induced depression both in vivo and in vitro. Depression model was established with the 4-week chronic unpredictable mild stress (CUMS) mice. Sucrose preference test, tail suspension test and open field test were performed to reflect depressive-like behaviors. Enzyme activity of indoleamine-2,3-dioxygenase (IDO) was recorded with the ratio of kynurenine (KYN) / tryptophan (Trp). Transcription of gene was evaluated by RT-PCR. Along with depressive-like behaviors, IDO, the rate-limiting enzyme of the kynurenine pathway (KP), was upregulated at the level of mRNA expression, and enzyme activity was also elevated in stressed hippocampi and LPS/HMGB1-treated hippocampus slices. Treatment of mice with GZA, the inhibitor of HMGB1, prevented the activated enzymes in KP and the development of depressive-like behaviors. These experiments demonstrate that GZA may restrain HMGB1 thus improving chronic stress-induced depressive behavior through regulating KP.

HMGB1 mediates depressive behavior induced by chronic stress through activating the kynurenine pathway.

Our previous study has reported that the proactive secretion and role of central high mobility group box 1 (HMGB1) in lipopolysaccharide-induced depressive behavior. Here, the potential mechanism of HMGB1 mediating chronic-stress-induced depression through the kynurenine pathway (KP) was further explored both in vivo and in vitro. Depression model was established with the 4-week chronic unpredictable mild stress (CUMS). Sucrose preference and Barnes maze test were performed to reflect depressive behaviors. The ratio of kynurenine (KYN)/tryptophan (Trp) represented the enzyme activity of indoleamine-2,3-dioxygenase (IDO). Gene transcription and protein expression were assayed by real-time RT-PCR and western-blot or ELISA kit respectively. Along with depressive behaviors, HMGB1 concentrations in the hippocampus and serum substantially increased post 4-week CUMS exposure. Concurrent with the upregulated HMGB1 protein, the regulator of translocation of HMGB1, sirtuin 1 (SIRT1) concentration in the hippocampus remarkably increased. In addition to HMGB1 and SIRT1, IDO, the rate limiting enzyme of KP, was upregulated at the level of mRNA expression and enzyme activity in stressed hippocampi and LPS/HMGB1-treated hippocampal slices. The gene transcription of kynurenine monooxygenase (KMO) and kynureninase (KYNU) in the downstream of KP also increased both in vivo and in vitro. Mice treated with ethyl pyruvate (EP), the inhibitor of HMGB1 releasing, were observed with lower tendency of developing depressive behaviors and reduced activation of enzymes in KP. All of these experiments demonstrate that the role of HMGB1 on the induction of depressive behavior is mediated by KP activation.

Antidiabetic drug glyburide modulates depressive-like behavior comorbid with insulin resistance.

BACKGROUND: Abundant reports indicated that depression was often comorbid with type 2 diabetes and even metabolic syndrome. Considering they might share common biological origins, it was tentatively attributed to the chronic cytokine-mediated inflammatory response which was induced by dysregulation of HPA axis and overactivation of innate immunity. However, the exact mechanisms remain obscure. Herein, we mainly focused on the function of the NLRP3 inflammasome to investigate this issue. METHODS: Male C57BL/6 mice were subjected to 12 weeks of chronic unpredictable mild stress (CUMS), some of which were injected with glyburide or fluoxetine. After CUMS procedure, behavioral and metabolic tests were carried out. In order to evaluate the systemic inflammation associated with inflammasome activation, IL-1ß and inflammasome components in hippocampi and pancreases, as well as corticosterone and IL-1ß in serum were detected separately. Moreover, immunostaining was performed to assess morphologic characteristics of pancreases. RESULTS: In the present study, we found that 12 weeks' chronic stress resulted in depressive-like behavior comorbid with insulin resistance. Furthermore, antidiabetic drug glyburide, an inhibitor of the NLRP3 inflammasome, was discovered to be effective in preventing the experimental comorbidity. In brief, it improved behavioral performance, ameliorated insulin intolerance as well as insulin signaling in the hippocampus possibly through inhibiting NLRP3 inflammasome activation by suppressing the expression of TXNIP. CONCLUSIONS: All these evidence supported our hypothesis that chronic stress led to comorbidity of depressive-like behavior and insulin resistance via long-term mild inflammation. More importantly, based on the beneficial effects of blocking the activation of the NLRP3 inflammasome, we provided a potential therapeutic target for clinical comorbidity and a new strategy for management of both diabetes and depression.

NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model.

BACKGROUND: Abundant researches indicate that neuroinflammation has important roles in the pathophysiology of depression. Our previous study found that the NLRP3 inflammasome mediated stress-induced depression-like behavior in mice via regulating neuroinflammation. However, it still remains unclear that how the NLRP3 inflammasome influences related inflammatory signaling pathway to contribute to neuroinflammation in depression. METHODS: We used wild-type mice and NLRP3 gene knockout mice to explore the role of NLRP3 inflammasome and related inflammatory signaling pathways in chronic unpredictable mild stress (CUMS) induced depression mouse model. RESULTS: Both wild-type and NLRP3 knockout stress group mice gained less weight than control group mice after 4 weeks CUMS exposure. The wild-type mice subjected to 4 weeks CUMS displayed depression-like behaviors, including decreased sucrose preference and increased immobility time in the tail suspension test. The NLRP3 knockout stress group mice didn't demonstrate depression-like behaviors. The levels of interleukin-1ß protein in serum and hippocampi of CUMS exposed wild-type mice were significantly higher, while the NLRP3 knockout stress group mice didn't show an elevation of interleukin-1ß levels. Similarly to early researches, we found that CUMS led to promoted NLRP3 expression in hippocampi. In addition, the hippocampi in CUMS exposed wild-type mice had higher p-JNK and p-p38 protein expression, which indicated activation of the mitogen-activated protein kinases (MAPK) pathway. The knockout of NLRP3 gene inhibited CUMS-induced activation of the MAPK pathway. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein complex was activated in the hippocampi of wild-type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation. CONCLUSIONS: These data further proved that the NLRP3 inflammasome mediated CUMS-induced depression-like behavior. The NLRP3 inflammasome regulated CUMS-induced MAPK pathway and NF-κB protein complex activation in depression mouse model. Further researches targeting the NLRP3 inflammasome-signaling pathway might be under a promising future in the prevention and treatment of depression.

Ds-HMGB1 and fr-HMGB induce depressive behavior through neuroinflammation in contrast to nonoxid-HMGB1.

High mobility group box 1 (HMGB1) has been implicated as a key factor in several neuroinflammatory conditions. Our previous study suggested that the release of central HMGB1 acts as a late-phase mediator in lipopolysaccharide (LPS)-induced depression. Recent findings indicate that the redox state of HMGB1 is a critical determinant of its immunomodulatory properties. Here, we aimed to investigate the potential mechanisms that link the redox states of HMGB1 to depression in mice. Distinct redox forms of recombinant HMGB1 (rHMGB1) were used that included fully reduced HMGB (fr-HMGB1), which acted as a chemokine, and disulfide-HMGB1 (ds-HMGB1), which possessed cytokine activity. Fr-HMGB1 in vivo was partially oxidized into ds-HMGB1; thus, the mutant protein non-oxidizable chemokine-HMGB (nonoxid-HMGB1) was applied. Concurrent with depressive behavior induced by four-week stress exposure, the HMGB1 concentrations in the serum and cerebral cortex substantially increased. Therefore, a single dose of rHMGB1 (200ng/5µl/mice) or vehicle was administered to mice via intracerebroventricular (i.c.v.) injection. The receptor inhibitors of TLR4/RAGE/CXCR4 (TAK-242/FPS-ZM1/AMD3100) (3mg/kg) were intraperitoneally injected 30min prior to rHMGB1 treatment. Depressive-like behavior was measured 20h post i.c.v. injection. Administration of fr-HMGB1 prolonged the immobility duration in the tail suspension test (TST) and decreased sucrose preference. In addition to depressive behavior, the hippocampal TNF-α protein slightly increased. These depressive behaviors and upregulation of hippocampal TNF-α were alleviated or abrogated by pretreatment with the inhibitors AMD3100, FPS-ZM1, and TAK-242. Alternatively, nonoxid-HMGB1 failed to induce TNF-α protein or prolong the immobility duration. As expected, ds-HMGB1 administration substantially upregulated hippocampal TNF-α protein, increased the immobility time in the TST and decreased sucrose preference. Moreover, both glycyrrhizin and TAK-242 improved ds-HMGB1-induced depressive behavior. Furthermore, TAK-242 significantly blocked the upregulation of hippocampal TNF-α protein and protected hippocampal myelin basic protein from ds-HMGB1-induced reduction. These drugs had no effect on the total or central distance in the open field test. Collectively, this initial experiment demonstrates the role and receptor mechanisms of HMGB1 under different redox states on the induction of depressive-like behavior. Both ds-HMGB1 and fr-HMGB1 may induce depressive-like behavior in vivo mainly via neuroinflammatory response activation.

Mindfulness meditation for insomnia: A meta-analysis of randomized controlled trials.

BACKGROUND: Insomnia is a widespread and debilitating condition that affects sleep quality and daily productivity. Although mindfulness meditation (MM) has been suggested as a potentially effective supplement to medical treatment for insomnia, no comprehensively quantitative research has been conducted in this field. Therefore, we performed a meta-analysis on the findings of related randomized controlled trials (RCTs) to evaluate the effects of MM on insomnia. METHODS: Related publications in PubMed, EMBASE, the Cochrane Library and PsycINFO were searched up to July 2015. To calculate the standardized mean differences (SMDs) and 95% confidence intervals (CIs), we used a fixed effect model when heterogeneity was negligible and a random effect model when heterogeneity was significant. RESULTS: A total of 330 participants in 6 RCTs that met the selection criteria were included in this meta-analysis. Analysis of overall effect revealed that MM significantly improved total wake time and sleep quality, but had no significant effects on sleep onset latency, total sleep time, wake after sleep onset, sleep efficiency, total wake time, ISI, PSQI and DBAS. Subgroup analyses showed that although there were no significant differences between MM and control groups in terms of total sleep time, significant effects were found in total wake time, sleep onset latency, sleep quality, sleep efficiency, and PSQI global score (absolute value of SMD range: 0.44-1.09, all p<0.05). CONCLUSIONS: The results suggest that MM may mildly improve some sleep parameters in patients with insomnia. MM can serve as an auxiliary treatment to medication for sleep complaints.

Dexamethasone rapidly inhibits glucose uptake via non-genomic mechanisms in contracting myotubes.

Glucocorticoids (GCs) are a class of steroid hormones that regulate multiple aspects of glucose homeostasis. In skeletal muscle, it is well established that prolonged GC excess inhibits glucose uptake and utilization through glucocorticoid receptor (GR)-mediated transcriptional changes. However, it remains obscure that whether the rapid non-genomic effects of GC on glucose uptake are involved in acute exercise stress. Therefore, we used electric pulse stimulation (EPS)-evoked contracting myotubes to determine whether the non-genomic actions of GC were involved and its underlying mechanism(s). Pretreatment with dexamethasone (Dex, 10 µM) significantly prevented contraction-stimulated glucose uptake and glucose transporter 4 (Glut4) translocation within 20 min in C2C12 myotubes. Neither GC nuclear receptor antagonist (RU486) nor protein synthesis inhibitor (cycloheximide, Chx) affected the rapid inhibition effects of Dex. AMPK and CaMKII-dependent signaling pathways were associated with the non-genomic effects of Dex. These results provide evidence that GC rapidly suppresses glucose uptake in contracting myotubes via GR-independent non-genomic mechanisms. AMPK and CaMKII-mediated Glut4 translocation may play a critical role in GC-induced rapid inhibition of glucose uptake.

TNFα mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress.

Depression is often preceded by exposure to stressful life events. Chronic stress causes perturbations in the immune system, and up-regulates production of proinflammatory cytokines, which has been proposed to be associated with the pathogenesis of clinical depression. However, the potential mechanisms by which stress-induced proinflammatory cytokines lead to the development of depression are not well understood. Here, we sought to screen the main proinflammatory cytokines and the potential mechanisms linking inflammation to depression-like behavior during unpredictable, chronic, mild stress (UCMS), in vivo. Mice were allocated into four groups in each separate experiment: saline-control, saline-UCMS, drug-control and drug-UCMS. Development of depression-like behavior was reflected as a reduction in sucrose preference, and increased immobility in both the forced swim and tail suspension tests. The following drugs were administered intraperitoneally: the pan-anti-inflammatory tetracycline derivative, minocycline (30 mg/kg, daily), the tumor necrosis factor (TNF)α monoclonal antibody, infliximab (10 mg/kg, twice weekly), and the indoleamine 2, 3-dioxygenase (IDO) inhibitor, 1-methyltryptophan (1-MT, 10 mg/mouse, daily). Plasma TNFα, IL-1ß and IL-18 increased significantly after the four-week UCMS exposure. Pretreatment of mice with minocycline completely blocked any upregulation. Concurrent with development of depression-like behaviors, the concentration of TNFα in plasma and the cerebral cortex increased remarkably. The tryptophan-degrading enzyme IDO was up-regulated in the cortex following UCMS exposure. Treatment of mice with minocycline, infliximab or 1-MT prevented the development of depression-like behaviors. Furthermore, blockade of TNFα inhibited expression of IDO and protected cortical neurons from UCMS-induced damage. These results suggest that TNFα plays a critical role in mediating UCMS-induced depression through up-regulation of IDO and subsequent damage of cortical neurons.