Psychological responses of medical staff during COVID-19 and the adjustment effect of brief mindfulness meditation.

BACKGROUND: COVID-19 has posed an unprecedented threat to public health and remains a critical challenge for medical staff, especially those who have been fighting against the virus in Wuhan, China. Limited data have been reported regarding the psychological status of these medical staff members. Therefore, we conducted this study to explore the mental health status of medical staff and the efficacy of brief mindfulness meditation (BMM) in improving their mental health. METHODS: A survey was conducted between April 18 and May 3, 2020. Upon completing the pre-test, participants in the treatment group received a 15-min BMM intervention every day at 8 p.m. Post-test questionnaires were completed after 16 days of therapy. The questionnaire comprised demographic data and psychological measurement scales. The levels of pre and post-test depression, anxiety, stress, and insomnia were assessed using the 9-item Patient Health Questionnaire, 7-item Generalized Anxiety Disorder Scale, Perceived Stress Scale, and Athens Insomnia Scale, respectively. RESULTS: A total of 134 completed questionnaires were received. Of the medical staff, 6.7%, 1.5%, and 26.7% reported symptoms of depression, anxiety, and insomnia, respectively. Public officials from military hospitals reported experiencing greater pressure than private officials (t = 2.39, p = 0.018, d = 0.50). Additionally, BMM treatment appeared to effectively alleviate insomnia (t = 2.27, p = 0.027, d = 0.28). CONCLUSIONS: The medical staff suffered negative psychological effects during the COVID-19 pandemic. BMM interventions are advantageous in supporting the mental health of medical staff.

Pyruvate Kinase M2 Mediates Glycolysis Contributes to Psoriasis by Promoting Keratinocyte Proliferation.

Psoriasis is characterized by keratinocyte proliferation and immune cell infiltration. M2 isoform of pyruvate kinase (PKM2) was reported to have an important role in cell proliferation, which is a rate-limiting enzyme that regulates the final step of glycolysis. However, how PKM2 regulates cell metabolism and proliferation in psoriatic keratinocytes is still poorly understood. Interestingly, we found that PKM2 was highly expressed in psoriatic epidermis from patients and mouse models. PKM2 overexpression promoted keratinocyte glycolytic metabolism while knockdown inhibited keratinocyte proliferation and glycolysis. Mice lacking PKM2 specifically in keratinocytes, pharmacological inhibition of PKM2 or glycolysis inhibited keratinocyte proliferation and showed obvious remission in an imiquimod-induced psoriatic mouse model. Moreover, the inhibitor of the EGF-receptor blocked EGF-stimulated PKM2 expression and glycolysis in keratinocytes. We identify PKM2 as an upregulated gene in psoriasis. PKM2 is essential in keratinocyte over-proliferation and may represent a therapeutic target for psoriasis.

Chronic stress induces fur color change from dark to brown by decreasing follicle melanocytes and tyrosinase activity in female C57BL/6 mice.

Increasing evidence suggests that stress may induce changes in hair color, with the underlying mechanism incompletely understood. In this study, female C57BL/6 mice subjected to electric foot shock combined with restraint stress were used to build chronic stress mouse model. The melanin contents and tyrosinase activity were measured in mouse skin and B16F10 melanoma cells. The enzyme-linked immunosorbent assay (ELISA) was used to determine the content of tumor necrosis factor α (TNF-α), interleukin- 1ß (IL-1ß) and interleukin-6 (IL-6) in the mouse skin. The content of nuclear factor κB (NFκB)/p65 subunit in mouse skins was valued by immunofluorescence staining. The results demonstrated that under chronic stress, the fur color turned from dark to brown in C57BL/6 mice due to the decrease of follicle melanocytes and tyrosinase activity in C57BL/6 mouse skin. Simultaneously, inflammatory responses in skins were detected as shown by increased NFκB activity and TNF-α expression in stressed mouse skin. In cultured B16F10 melanoma cells, TNF-α reduced the melanogenesis and tyrosinase activity in a dose-dependent manner. These findings indicate that chronic stress induces fur color change by decreasing follicle melanocytes and tyrosinase activity in female C57BL/6 mice, and TNF-α may play an important role in stress-induced hair color change.

Glycyrrhizic acid as an adjunctive treatment for depression through anti-inflammation: A randomized placebo-controlled clinical trial.

BACKGROUND: Recently, abundant evidence indicated proinflammatory cytokines might play a crucial role in pathophysiology and treatment of depression. According to our preclinical research, we propose glycyrrhizic acid (GZA) for an adjunctive treatment owing to its safety, economical and anti-inflammatory profile. METHODS: Eligible participants were recruited and randomly allocated into independent treatment groups of SSRI+GZA (n = 30) and SSRI+PBO (placebo, n = 26). Depressive symptoms and specific serum biomarkers were detected during the 4-week treatment course. Afterward, the relationships between biomarkers and clinical effects were explored. RESULTS: Depressive symptoms relieved more in SSRI+GZA than SSRI+PBO, both at week 2 (P = 0.003) and week 4 (P = 0.016). Meanwhile, at week 4, both response rate (P = 0.035) and remission rate (P = 0.031) acutely became higher in SSRI+GZA compared with SSRI+PBO. Mediation analysis further demonstrated that TNF-α reduction mediated the association between GZA treatment and clinical improvement, the indirect effect lay between 0.124 and 3.514 (95% CI). The exploratory analysis also suggested that the symptomatic improvement existed in patients with high-inflammation (baseline CRP > 3 mg/L) rather than those with low-inflammation (baseline CRP ≤ 3 mg/L). LIMITATIONS: The sample size in this study was not large enough and the follow-up duration was relatively short. CONCLUSIONS: This study offers a novel strategy for the diagnosis, categorization, individualization and prognosis regarding upgrading traditional antidepressant therapy, which is from biomarkers to diagnostic indicator and therapeutic target. Patients are necessary to be classified according to the inflammatory state, those with high levels of baseline inflammation should receive combined treatment with anti-inflammatory agents like GZA.

FoxO1 is a critical regulator of hepatocyte lipid deposition in chronic stress mice.

Forkhead box O1 (FoxO1) is involved in lipid metabolisms. However, its role in chronic stress-related nonalcoholic fatty liver disease (NAFLD) is unclear. The scientific premise of our study was based on the finding that FoxO1 expression is increased in the liver of mice after chronic stress. It is important to understand the mechanisms involved in the activation of FoxO1 and how its function affects the liver lipid deposition. We employed a murine chronic stress model, in which mice were treated by plantar electrical stimulation and restraint for 6 weeks, and a cellular model, in which Hepa1-6 cells were treated with corticosterone. We also used a pharmacologic approach as1842856, a highly specific FoxO1 inhibitor. Lipid metabolism related genes levels were measured by qRT-PCR and the lipid levels by biochemical detection. We show that the level of FoxO1 is significantly elevated in the liver of chronic stress mice. Transcription factor FoxO1 regulates a lipid synthesis phenotype of hepatocyte that is involved in the development and progression of NAFLD. We have shown that inhibition of FoxO1 induced phenotypic conversion of hepatocytes and down-regulates lipid synthesis genes expression by hepatocytes, which contribute to lipid deposition in NAFLD. At the cellular level, the inhibitor of FoxO1 as1842856 can also attenuate the lipid deposition of Hepa1-6 cells induced by corticosterone. Targeting FoxO1 is a novel therapeutic target for chronic stress-related NAFLD.

Endoplasmic reticulum stress and proteasome pathway involvement in human podocyte injury with a truncated COL4A3 mutation.

BACKGROUND: Collagen type IV (COL4)-related nephropathy includes a variety of kidney diseases that occur with or without extra-renal manifestations caused by COL4A3-5 mutations. Previous studies revealed several novel mutations, including three COL4A3 missense mutations (G619R, G801R, and C1616Y) and the COL4A3 chr:228172489delA c.4317delA p.Thr1440ProfsX87 frameshift mutation that resulted in a truncated NC1 domain (hereafter named COL4A3 c.4317delA); however, the mutation mechanisms that lead to podocyte injury remain unclear. This study aimed to further explore the mutation mechanisms that lead to podocyte injury. METHODS: Wild-type (WT) and four mutant COL4A3 segments were constructed into a lentiviral plasmid, then stably transfected into human podocytes. Real-time polymerase chain reaction and Western blotting were applied to detect endoplasmic reticulum stress (ERS)- and apoptosis-related mRNA and protein levels. Then, human podocytes were treated with MG132 (a proteasome inhibitor) and brefeldin A (a transport protein inhibitor). The human podocyte findings were verified by the establishment of a mus-Col4a3 knockout mouse monoclonal podocyte using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) technology. RESULTS: Our data showed that COL4A3 mRNA was significantly overexpressed in the lentivirus stably transfected podocytes. Moreover, the COL4A3 protein level was significantly increased in all groups except the COL4A3 c.4317delA group. Compared to the other test groups, the COL4A3 c.4317delA group showed excessive ERS and apoptosis. Podocytes treated with MG132 showed remarkably increased intra-cellular expression of the COL4A3 c.4317delA mutation. MG132 intervention improved higher ERS and apoptosis levels in the COL4A3 c.4317delA group. Mouse monoclonal podocytes with COL4A3 chr:82717932insA c.4852insA p.Arg1618ThrfsX4 were successfully acquired; this NC1-truncated mutation suggested a higher level of ERS and relatively remarkable level of apoptosis compared to that of the WT group. CONCLUSIONS: We demonstrated that excessive ERS and ERS-induced apoptosis were involved in the podocyte injury caused by the NC1-truncated COL4A3 mutation. Furthermore, proteasome pathway intervention might become a potential treatment for collagen type IV-related nephropathy caused by a severely truncated COL4A3 mutation.

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.

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.

Inflammation: The Common Pathway of Stress-Related Diseases.

While modernization has dramatically increased lifespan, it has also witnessed that the nature of stress has changed dramatically. Chronic stress result failures of homeostasis thus lead to various diseases such as atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. However, while 75%-90% of human diseases is related to the activation of stress system, the common pathways between stress exposure and pathophysiological processes underlying disease is still debatable. Chronic inflammation is an essential component of chronic diseases. Additionally, accumulating evidence suggested that excessive inflammation plays critical roles in the pathophysiology of the stress-related diseases, yet the basis for this connection is not fully understood. Here we discuss the role of inflammation in stress-induced diseases and suggest a common pathway for stress-related diseases that is based on chronic mild inflammation. This framework highlights the fundamental impact of inflammation mechanisms and provides a new perspective on the prevention and treatment of stress-related diseases.

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.

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.

Effect of Hypertriglyceridemia on Beta Cell Mass and Function in ApoC3 Transgenic Mice.

Hypertriglyceridemia results from increased production and decreased clearance of triglyceride-rich very low-density lipoproteins, a pathological condition that accounts for heightened risk of ischemic vascular diseases in obesity and type 2 diabetes. Despite its intimate association with insulin resistance, whether hypertriglyceridemia constitutes an independent risk for beta cell dysfunction in diabetes is unknown. Answering this fundamental question is stymied by the fact that hypertriglyceridemia is intertwined with hyperglycemia and insulin resistance in obese and diabetic subjects. To circumvent this limitation, we took advantage of apolipoprotein C3 (ApoC3)-transgenic mice, a model with genetic predisposition to hypertriglyceridemia. We showed that ApoC3-transgenic mice, as opposed to age/sex-matched wild-type littermates, develop hypertriglyceridemia with concomitant elevations in plasma cholesterol and non-esterified fatty acid levels. Anti-insulin and anti-glucagon dual immunohistochemistry in combination with morphometric analysis revealed that ApoC3-transgenic and wild-type littermates had similar beta cell and alpha cell masses as well as islet size and architecture. These effects correlated with similar amplitudes of glucose-stimulated insulin secretion and similar degrees of postprandial glucose excursion in ApoC3-transgenic versus wild-type littermates. Oil Red O histology did not visualize lipid infiltration into islets, correlating with the lack of ectopic triglyceride and cholesterol depositions in the pancreata of ApoC3-transgenic versus wild-type littermates. ApoC3-transgenic mice, despite persistent hypertriglyceridemia, maintained euglycemia under both fed and fasting conditions without manifestation of insulin resistance and fasting hyperinsulinemia. Thus, hypertriglyceridemia per se is not an independent risk factor for beta cell dysfunction in ApoC3 transgenic mice.

Forkhead Box O6 (FoxO6) Depletion Attenuates Hepatic Gluconeogenesis and Protects against Fat-induced Glucose Disorder in Mice.

Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice.

High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior.

Depression disorder is a common mental illness, of which the pathogenesis is not well understood. Studies suggest that immunity imbalance and up-regulation of pro-inflammatory cytokines may be associated with the pathogenesis of depression. High-mobility group box 1 protein (HMGB1) has gained much attention as an important player in innate immune responses and an modulating factor in several inflammatory diseases. Here we sought to explore the role of HMGB1 in the development of depression. Depression model was established with low dose of lipopolysaccharide (LPS) administration. Depressive behavior was reflected with increased immobility time in tail suspension test. Accompanying with depressive-like behavior, translocation of HMGB1 from nuclei to cytoplasm was observed by immunofluorescence assays. Meanwhile, no significant necrosis was observed evaluated by hematoxylin-eosin staining. These data indicated that HMGB1 was released actively in the central nervous system. In addition, treating the mice with human recombinant HMGB1 (rHMGB1) could induce the development of depressive-like behavior. Blockage of HMGB1 with GZA abrogated the depressive-like behavior induced by LPS or rHMGB1. These results implicated that HMGB1 was involved in LPS-induced depressive-like behavior.

NLRP3 Inflammasome Mediates Chronic Mild Stress-Induced Depression in Mice via Neuroinflammation.

BACKGROUND: Evidence from both clinical and experimental research indicates that the immune-brain interaction plays a pivotal role in the pathophysiology of depression. A multi-protein complex of the innate immune system, the NLRP3 inflammasome regulates cleavage and secretion of proinflammatory cytokine interleukin-1ß. The inflammasome detects various pathogen-associated molecule patterns and damage-associated molecule patterns, which then leads to a series of immune-inflammatory reactions. METHODS: To explore the role of inflammasome activation in the underlying biological mechanisms of depression, we established a mouse model of depression with unpredictable chronic mild stress. RESULTS: Mice subjected to chronic mild stress for 4 weeks had significantly higher serum corticosterone levels, serum interleukin-1ß levels, and hippocampal active interleukin-1ß protein levels. They also displayed depressive-like symptoms, including decreased sucrose preference and increased immobility time. Moreover, the hippocampi of chronic mild stress-exposed mice had significantly higher activity of caspase-1, which accompanied by higher protein levels of NLRP3 and the apoptotic speck-containing protein with a card. Pretreatment with the NLRP3 inflammasome inhibitor VX-765 decreased serum and hippocampal levels of interleukin-1ß protein and significantly moderated the depressive-like behaviors induced by chronic mild stress. CONCLUSIONS: These data suggest the NLRP3 inflammasome mediates stress-induced depression via immune activation. Future procedures targeting the NLRP3 inflammasome may have promising effects in the prevention and treatment of depression.

Chronic stress induces steatohepatitis while decreases visceral fat mass in mice.

BACKGROUND: Prolonged stress leads over time to allostatic load on the body and is likely to exacerbate a disease process. Long-term of stress exposure is one of a risk factor for metabolism-related diseases such as obesity and type 2 diabetes. However, the relationship between chronic stress and non-alcoholic fatty liver disease (NAFLD) remain unknown. METHODS: To address the hypothesis that chronic stress associate to NAFLD development, we subjected C57bl/6 mice to electric foot shock and restraint stress for 12 weeks to set up chronic stress model. Then the serum and hepatic triglyceride (TG), total cholesterol (TC) were measured. Hepatic HE and Oil red O staining were used to specify the state of the NAFLD. To investigate whether inflammation takes part in the stress-induced NAFLD process, related visceral fat, serum and hepatic inflammatory factors were measured. RESULTS: We observed that chronic stress led to an overall increase of hepatic triglyceride and cholesterol while decreasing body weight and visceral fat mass. Microvesicular steatosis, lobular inflammation and ballooning degeneration were seen in stress liver section. This effect was correlated with elevated hepatic and serum inflammatory factors. Although the amount of visceral fat was decreased in stress group, various adipocytokines were elevated. CONCLUSIONS: We showed that chronic stress is associated to NAFLD and chronic inflammation in visceral fat, though food intake and visceral fat mass were decreased. These results may contribute to better understanding of the mechanism from steatosis to steatohepatitis, and propose a novel insight into the prevention and treatment of NAFLD.

Activation of alpha 7 nicotinic acetylcholine receptor protects mice from radiation-induced intestinal injury and mortality.

Radiation-induced gastrointestinal syndrome occurs when the body is exposed to a high dose of radiation. Currently, safe and effective radioprotectants are not available. Apoptosis was reported to play a primary role in radiation-induced injury. Recent evidence suggests that stimulation of α7 nicotinic acetylcholine receptor (α7nAChR) prevents cell death by inhibition of apoptosis. In this study, we demonstrated that a single dose of PNU282987 (100 µg/kg, i.p.), a selective α7nAChR agonist, protected mice from intestinal injury and significantly improved survival when administered prior to lethal 8 Gy total body irradiation. In vitro, PNU282987 protected against 8 Gy radiation-induced cell death in human umbilical venous endothelial cells by inhibiting apoptosis. We conclude that activation of α7nAChR may provide a new therapeutic pathway for the treatment of radiation-induced damage and mortality.

High-salt diet enhances hippocampal oxidative stress and cognitive impairment in mice.

Previous evidence suggests that a high-salt (HS) diet may increase oxidative stress and contribute to the development of hypertension that is already present. Oxidative stress is thought to play a critical role in the development of neurodegenerative diseases. Lower dietary sodium intake putatively contributes to a lower rate of cognitive impairment; however, the specific effects of HS diet on cognitive function remain poorly understood. In this work, C57BL/6J mice were administered a normal-salt (NS) diet (0.4% NaCl) or a HS diet (7.0% NaCl) for 12 weeks, and cognitive ability and oxidative stress in the brain were measured. It was found that the HS diet significantly impaired retention of spatial memory. Additionally, superoxide anion production in the hippocampus was significantly increased in the HS diet mice compared with that in the NS mice. Interestingly, the antioxidant defense capacities for HS diet mice were markedly reduced in the hippocampus, but not in the cerebral cortex, compared with the NS mice. Taken together, these data demonstrate that HS diet directly impairs retention of spatial memory, which may be related to the increased oxidative stress observed in the hippocampus.

Involvement of inflammasome activation in lipopolysaccharide-induced mice depressive-like behaviors.

AIMS: The NLRP3 inflammasome is a cytoplasmic multiprotein complex of the innate immune system that regulates the cleavage of interleukin-1ß and interleukin-18 precursors. It can detect a wide range of danger signals and trigger a series of immune-inflammatory reactions. There were plenty of studies indicating that activation of the immune system played pivotal roles in depression. However, the underlying mechanisms of immune-depression interactions remained elusive and there was no report about the involvement of inflammasome activation in depression. METHODS: We established an acute depression mouse model with lipopolysaccharide to explore the involvement of inflammasome activation in depression. RESULTS: The lipopolysaccharide-treated mice displayed depressive-like behaviors and pro-inflammatory cytokine interleukin-1ß protein and mRNA levels significantly increased. The NLRP3 inflammasome mRNA expression level also significantly elevated in depressed mice brain. Pretreatment with the NLRP3 inflammasome inhibitor Ac-YVAD-CMK significantly abrogated the depressive-like behaviors induced by lipopolysaccharide. CONCLUSION: These data suggest for the first time that the NLRP3 inflammasome is involved in lipopolysaccharide-induced mice depressive-like behaviors. The NLRP3 inflammasome may be a central mediator between immune activation and depression, which raises the possibility that it may be a more specific target for the depression treatments in the near future.