The emerging role of exosomes in communication between the periphery and the central nervous system.

Exosomes, membrane-enclosed vesicles, are secreted by all types of cells. Exosomes can transport various molecules, including proteins, lipids, functional mRNAs, and microRNAs, and can be circulated to various recipient cells, leading to the production of local paracrine or distal systemic effects. Numerous studies have proved that exosomes can pass through the blood-brain barrier, thus, enabling the transfer of peripheral substances into the central nervous system (CNS). Consequently, exosomes may be a vital factor in the exchange of information between the periphery and CNS. This review will discuss the structure, biogenesis, and functional characterization of exosomes and summarize the role of peripheral exosomes deriving from tissues like the lung, gut, skeletal muscle, and various stem cell types in communicating with the CNS and influencing the brain's function. Then, we further discuss the potential therapeutic effects of exosomes in brain diseases and the clinical opportunities and challenges. Gaining a clearer insight into the communication between the CNS and the external areas of the body will help us to ascertain the role of the peripheral elements in the maintenance of brain health and illness and will facilitate the design of minimally invasive techniques for diagnosing and treating brain diseases.

Nutrition and schizophrenia: associations worthy of continued revaluation.

BACKGROUND: Accumulating evidence have shown that diet and nutrition play significant roles in mental illness, such as depression, anxiety and bipolar disorder. However, comprehensive evaluation of the relationship between nutrition and schizophrenia is lacking. OBJECTIVE: The present review aims to synthetic elaborate the associations between nutrition and schizophrenia. Relevant studies on dietary patterns, macronutrients, micronutrients were performed through a literature search to synthesize the extracted data. SUMMARY: Dietary interventions may help prevent the occurrence of schizophrenia, or delay symptoms: Healthy diets like nutritious plant-based foods and high-quality protein, have been linked to reducing the risk or symptoms of schizophrenia. Moreover, diet high in saturated fat and sugar is linked to more serious outcomes of schizophrenia. Additionally, when N-acetylcysteine acts as an adjuvant therapy, the overall symptoms of schizophrenia are significantly reduced. Also nascent evidence showed mental disorders may be related to intestinal microbiota dysfunction. Our study offered important insights into the dietary habits of patients with schizophrenia and the potential impact of nutritional factors on the disease. We also emphasized the need for further research, particularly in the form of large randomized double-blind controlled trials, to better understand the effects of nutrients on schizophrenia symptoms in different populations and disease types.

Vitamin D Receptor Activation Attenuates Olanzapine-Induced Dyslipidemia in Mice Through Alleviating Hepatic Endoplasmic Reticulum Stress.

The involvement of vitamin D (VD) signaling in atypical antipsychotics (AAPs)-induced metabolic disturbances has been previously established. This study aims to elucidate the role of VD in maintaining endoplasmic reticulum (ER) homeostasis and its impact on AAPs-induced metabolic adverse effects. Female C57BL/6 mice receive either calcitriol or vehicle one week prior to co-treatment with olanzapine (OLZ) for an additional four weeks. Metabolic parameters, hepatic ER homeostasis, and the SREBPs pathway are assessed through biochemical assays and protein expression profiling. HepG2 cells are transfected with vitamin D receptor (VDR) siRNA for VDR knockdown. OLZ-treated HepG2 cells are exposed to calcitriol to examine its effects on SREBPs and the unfolded protein response (UPR) pathways. VDR activation by calcitriol reduces OLZ-induced hepatic ER stress, leading to decreased SREBPs activity and lipid accumulation. Conversely, the knockdown of VDR in HepG2 cells diminishes the protective effects of calcitriol against OLZ-induced ER stress and SREBPs activation. This resulted in sustained UPR activation, elevated cleaved SREBPs levels, and increased lipid accumulation. These findings highlight an essential role of VDR signaling in the beneficial effects of VD on OLZ-induced metabolic side effects. Targeting VDR to resolve ER stress is likely an applicable therapeutic strategy for AAPs-induced metabolic disturbances.

Decreased FGF19 and FGF21: possible underlying common pathogenic mechanism of metabolic and cognitive dysregulation in depression.

Background: Accumulating studies suggested that major depressive disorder (MDD) was closely related to metabolic syndrome (MetS). Important endogenous regulators fibroblast growth factors (FGFs) 19 and 21 were also reported to participate in psychiatric disorders. This study aimed to investigate the role of FGF19 and FGF21 in MDD and to explore the possible pathogenic mechanism of metabolic and cognitive dysregulation in depression. Methods: A total of 59 MDD patients and 55 healthy control participants were recruited. The serum levels of FGF19 and FGF21 and lipid profiles were measured by means of enzymatic methods. Cognitive function was measured by repeatable battery for the assessment of neuropsychological status (RBANS) scores. The gene expression of PGC-1α and FNDC5 was determined by quantitative polymerase chain reaction (PCR). Results: We found that plasma FGF19 and FGF21 levels were significantly decreased in patients with MDD. Meanwhile, triglyceride (TG) was significantly elevated and PGC-1α was significantly downregulated in MDD patients. Correlation analyses showed negative associations between TG and FGF19 levels. As for cognitive performance, both FGF19 and FGF21 levels were positively correlated with immediate memory. However, FGF19 levels were negatively correlated with language, and FGF21 levels were also negatively correlated with attention and delayed memory. Additionally, negative associations were found between FGF19 levels and PGC-1α. FGF21 levels were positively associated with PGC-1α and negatively associated with FNDC5. Conclusion: This study elucidated the role of FGF19 and FGF21 in MDD. MDD patients were confirmed to have metabolic and cognitive dysregulation, and this abnormality was linked to the decreased concentrations of FGF19 and FGF21 through the PGC-1α/FNDC5 pathway. Our results showed that the alterations of FGF19 and FGF21 levels may be a common pathogenic mechanism of metabolic and cognitive disturbances in patients with MDD.

The effect of tacrolimus-induced toxicity on metabolic profiling in target tissues of mice.

Tacrolimus (Tac) is a common immunosuppressant that used in organ transplantation. However, its therapeutic index is narrow, and it is prone to adverse side effects, along with an increased risk of toxicity, namely, cardio-, nephro-, hepato-, and neurotoxicity. Prior metabolomic investigations involving Tac-driven toxicity primarily focused on changes in individual organs. However, extensive research on multiple matrices is uncommon. Hence, in this research, the authors systemically evaluated Tac-mediated toxicity in major organs, namely, serum, brain, heart, liver, lung, kidney, and intestines, using gas chromatography-mass spectrometry (GC-MS). The authors also employed multivariate analyses, including orthogonal projections to the latent structure (OPLS) and t-test, to screen 8 serum metabolites, namely, D-proline, glycerol, D-fructose, D-glucitol, sulfurous acid, 1-monopalmitin (MG (16:0/0:0/0:0)), glycerol monostearate (MG (0:0/18:0/0:0)), and cholesterol. Metabolic changes within the brain involved alterations in the levels of butanamide, tartronic acid, aminomalonic acid, scyllo-inositol, dihydromorphine, myo-inositol, and 11-octadecenoic acid. Within the heart, the acetone and D-fructose metabolites were altered. In the liver, D-glucitol, L-sorbose, palmitic acid, myo-inositol, and uridine were altered. In the lung, L-lactic acid, L-5-oxoproline, L-threonine, phosphoric acid, phosphorylethanolamine, D-allose, and cholesterol were altered. Lastly, in the kidney, L-valine and D-glucose were altered. Our findings will provide a systematic evaluation of the metabolic alterations in target organs within a Tac-driven toxicity mouse model.

Curcumin Relieves Chronic Unpredictable Mild Stress-Induced Depression-Like Behavior through the PGC-1α/FNDC5/BDNF Pathway.

METHODS: All rats were randomly divided into four groups, namely, control, CUMS, CUMS + CUR, and CUMS + CUR + SR18292 (PGC-1α inhibitor). Behavioral tests were conducted to assess the antidepressant-like effects of CUR. The expressions of PGC-1α, estrogen-related receptor alpha (ERRα), FNDC5, and BDNF were determined to investigate the regulatory effects of CUR on the PGC-1α/FNDC5/BDNF pathway. The PGC-1α inhibitor SR18292 was used to explore the role of PGC-1α in the induction of BDNF by CUR. RESULTS: Daily gavage of 100 mg/kg CUR successfully attenuated the abnormal behaviors induced by CUMS and effectively prevented CUMS-induced reduction of PGC-1α, ERRα, FNDC5, and BDNF expressions. CUR also enhanced PGC-1α and ERRα translocation from cytoplasm to nucleus. Furthermore, we found that CUR supplementation effectively promoted neurocyte proliferation and suppressed neuronal apoptosis induced by CUMS. Of note, the PGC-1α inhibitor SR18292 remarkably reversed the beneficial effects of CUR on depressed rats, indicating an important role of PGC-1α in the antidepressant-like effects of CUR. CONCLUSION: Collectively, our data evaluating the neuroprotective action of CUR in the CUMS rats highlights the involvement of the PGC-1α/FNDC5/BDNF pathway in the antidepressant-like effects of CUR.

Activation of angiotensin-converting enzyme 2/angiotensin (1-7)/mas receptor axis triggers autophagy and suppresses microglia proinflammatory polarization via forkhead box class O1 signaling.

Brain renin-angiotensin (Ang) system (RAS) is implicated in neuroinflammation, a major characteristic of aging process. Angiotensin (Ang) II, produced by angiotensin-converting enzyme (ACE), activates immune system via angiotensin type 1 receptor (AT1), whereas Ang(1-7), generated by ACE2, binds with Mas receptor (MasR) to restrain excessive inflammatory response. Therefore, the present study aims to explore the relationship between RAS and neuroinflammation. We found that repeated lipopolysaccharide (LPS) treatment shifted the balance between ACE/Ang II/AT1 and ACE2/Ang(1-7)/MasR axis to the deleterious side and treatment with either MasR agonist, AVE0991 (AVE) or ACE2 activator, diminazene aceturate, exhibited strong neuroprotective actions. Mechanically, activation of ACE2/Ang(1-7)/MasR axis triggered the Forkhead box class O1 (FOXO1)-autophagy pathway and induced superoxide dismutase (SOD) and catalase (CAT), the FOXO1-targeted antioxidant enzymes. Meanwhile, knockdown of MasR or FOXO1 in BV2 cells, or using the selective FOXO1 inhibitor, AS1842856, in animals, suppressed FOXO1 translocation and compromised the autophagic process induced by MasR activation. We further used chloroquine (CQ) to block autophagy and showed that suppressing either FOXO1 or autophagy abrogated the anti-inflammatory action of AVE. Likewise, Ang(1-7) also induced FOXO1 signaling and autophagic flux following LPS treatment in BV2 cells. Cotreatment with AS1842856 or CQ all led to autophagic inhibition and thereby abolished Ang(1-7)-induced remission on NLRP3 inflammasome activation caused by LPS exposure, shifting the microglial polarization from M1 to M2 phenotype. Collectively, these results firstly illustrated the mechanism of ACE2/Ang(1-7)/MasR axis in neuroinflammation, strongly indicating the involvement of FOXO1-mediated autophagy in the neuroimmune-modulating effects triggered by MasR activation.

Comprehensive analysis of metabolic changes in rats exposed to acrylamide.

Acrylamide (ACR) is a widely used environmentally hazardous compound that is known to be neurotoxic, genotoxic, carcinogenic, and reproductive toxicity. It is widely present in soil, water, agents used in chemical industries, and food. It can be distributed to all organs and tissues, and can cause damage to various human systems and those of other animals. Previous metabolomics studies have mainly focused on metabolites in serum and urine, but have lacked comprehensive analysis of major organs and tissues. In the current study, a gas chromatography-massspectrometry method was used to investigate mechanisms underlying organ toxicity, in an effort to identify potentially sensitive biomarkers in the main target tissues of rats after ACR exposure. Male Sprague-Dawley rats were assigned to two groups; a control group and a group treated with 20 mg kg-1 ACR intragastrically for 6 weeks. Metabolite changes in the two groups were statistically analyzed. The respective numbers of altered metabolites in the hippocampus, cortex, kidney, serum, heart, liver, and kidney fat were 21, 21, 17, 5, 15, 14, and 6. There were 14 metabolic pathways related to amino acid, fatty acid, purine, and energy metabolism, revealing that the toxic mechanism of ACR may involve oxidative stress, inflammation, and amino acid metabolism and energy disorders.

The interaction between autophagy and neuroinflammation in major depressive disorder: From pathophysiology to therapeutic implications.

The past decade has revealed neuroinflammation as an important mechanism of major depressive disorder (MDD). Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome is the key regulator interleukin-1ß (IL-1ß) maturation, whose activation has been reported in MDD patients and various animal models. Function as a dominant driver of neuroinflammation, NLRP3 bridges the gap between immune activation with stress exposure, and further leads to subsequent occurrence of neuropsychiatric disorders such as MDD. Of note, autophagy is a tightly regulated cellular degradation pathway that removes damaged organelles and intracellular pathogens, and maintains cellular homeostasis from varying insults. Serving as a critical cellular monitoring system, normal functioned autophagy signaling prevents excessive NLRP3 inflammasome activation and subsequent release of IL-1 family cytokines. This review will describe the current understanding of how autophagy regulates NLRP3 inflammasome activity and discuss the implications of this regulation on the pathogenesis of MDD. The extensive crosstalk between autophagy pathway and NLRP3 inflammasome is further discussed, as it is critical for developing new therapeutic strategies for MDD aimed at modulating the neuroinflammatory responses.

Effects of maternal deprivation stress and maternal dietary of n-3 polyunsaturated fatty acids on the neurobehavioral development of male offspring.

Objectives: Early-life stress and polyunsaturated fatty acids (PUFAs) have profound effects on brain development. Polyunsaturated fatty acids (PUFAs) are essential nutrients and normal components for development. The aims of this study are to investigate the effects of maternal deprivation (MD) stress and maternal dietary of n-3 PUFAs on the physical and neurobiological developments of offspring.Methods: According to the content of n-3 PUFAs in diets, female dams were divided into three groups (n = 6-7): deficiency, control and supplementary. MD paradigm was performed 6 h a day from postnatal days (PND) 1 to PND 14. The physical parameters and neurobehavioral tests were measured.Results: Different effects of MD stress, maternal diet and time on physical and neurobehavioral developments were observed. There was an interaction among stress, diet and time on body weight. MD stress markedly decreased weight among different diet groups, while deficiency diet significantly increased weight on PND 21 in N-MD pups and on PND 14 in MD pups. Moreover, MD stress delayed fur appearance and eye opening, whereas deficiency diet accelerated eye opening. On cliff avoidance and rearing frequency, MD pups performed worse; however a subtle delay on the surface righting was observed in supplementary group. Additionally, MD pups performed worse on PND 14 in forelimb grip. Unfortunately, there were no significant effects on incisor eruption, locomotion frequency and negative geotaxis.Discussion: This study suggests that early MD and inadequate intake of n-3 PUFAs are harmful to optimal growth and neurobehavioral development.

Angiotensin-â ¡ and angiotensin-(1-7) imbalance affects comorbidity of depression and coronary heart disease.

A large body of evidence suggests a relationship between depression and coronary heart disease (CHD). Angiotensin-Ⅱ (Ang-Ⅱ) and angiotensin-(1-7) [Ang-(1-7)] are considered to exert biological effects in both conditions. Here, we aimed to determine the role of Ang-Ⅱ and Ang-(1-7) in the occurrence of comorbid depression in patients with CHD. Our study included 214 CHD patients and 100 matched healthy controls. Serum Ang-Ⅱ and Ang-(1-7) levels were assessed by ELISA, and the depression symptoms were evaluated by the nine-item Patient Health Questionnaire (PHQ-9). Linear regression and correlation analyses were used to estimate the associations between PHQ-9 scores and Ang-Ⅱ and Ang-(1-7) serum levels. Six single-nucleotide polymorphisms (SNPs) spanning the angiotensin converting enzyme 2 (ACE2) and MAS1 genes were genotyped. The associations between SNPs and depression risk in CHD patients were examined using logistic regression analysis with adjustment for age and gender. Decreased Ang-(1-7) (P < 0.05) and an elevated Ang-Ⅱ/Ang-(1-7) ratio (P < 0.01) were observed in CHD patients with depression compared to CHD patients without depression. PHQ-9 scores were negatively correlated with Ang-(1-7) level (r=-0.44, P < 0.01) and positively correlated with the Ang-Ⅱ/Ang-(1-7) ratio (r = 0.33, P < 0.05). Furthermore, carriers of risk allele T for CHD with depression had significantly higher PHQ-9 scores (P < 0.05), lower Ang-(1-7) level (P < 0.01), and higher Ang-Ⅱ/Ang-(1-7) ratio (P < 0.05) than those CC carriers. Collectively, our results firstly showed that Ang-(1-7) serum level in CHD patients may protect against comorbid depression. Moreover, the imbalance between Ang-Ⅱ and Ang-(1-7) may contribute to depression in CHD patients.

The Association Between Sortilin and Inflammation in Patients with Coronary Heart Disease.

PURPOSE: Inflammation is a key contributor to coronary heart disease (CHD). Sortilin is a sorting receptor and has been identified as a critical regulator of inflammatory response. Therefore, our study aimed to determine the link between circulating sortilin levels, proinflammatory cytokine levels, and the occurrence of CHD. PATIENTS AND METHODS: Our study included 227 CHD patients and 101 matched healthy individuals. Circulating serum levels of sortilin and proinflammatory cytokines, including IL-1ß, IL-6 and TNF-α, were assessed by a double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA). Linear regression and correlation analyses were used to estimate the associations between sortilin and proinflammatory cytokines. Moreover, six single-nucleotide polymorphisms (SNPs) spanning the sortilin and SORL1 genes were genotyped. RESULTS: Elevated levels of sortilin (P=0.027) and proinflammatory cytokines IL-1ß (P=0.013), IL-6 (P=0.000) and TNF-α (P=0.010) were observed in CHD patients compared to those in healthy controls. Furthermore, sortilin levels were significantly positively correlated with IL-1ß (r=0.252, P=0.0001), IL-6 (r=0.250, P=0.0001) and TNF-α (r=0.180, P=0.0064) levels. Notably, sortilin polymorphisms were revealed to be associated with the occurrence of CHD and varying sortilin levels. Subjects with the rs599839 AA risk genotype for CHD had significantly higher sortilin levels than those with the GG and GA genotypes (P=0.000); the same tendency was also observed in the levels of the proinflammatory cytokines IL-1ß (P=0.003) and TNF-α (P=0.000). Similarly, GG carriers of rs464218 with increased sortilin levels were found to be at increased risk for CHD (P=0.014). The levels of IL-1ß (P=0.025) and IL-6 (P=0.015) were also increased in these patients. CONCLUSION: Our findings reveal that high sortilin levels may interact with inflammatory response to contribute to the occurrence of CHD. Considering that our clinical evidence suggests for the first time that sortilin involves in inflammatory response in CHD, the mechanistic role of sortilin in the progression of CHD deserves detailed investigation.

Molecular engineering of a high quantum yield NIR-II molecular fluorophore with aggregation-induced emission (AIE) characteristics for in vivo imaging.

NIR-II biological imaging (1000-1700 nm) has shown promise for deep tissue penetration, high spatial resolution, and low background noise. Among all the NIR-II probes, organic probes particularly attract huge attention due to their excellent stability and biocompatibility, which have the most potential for clinical translation. However, most previously reported organic NIR-II fluorescent agents often suffer from low quantum yields in aqueous solution. Herein, we developed a novel D-π-A-π-D-type NIR II chromophore XA1 with AIE characteristics based on a new design strategy for NIR-II AIE fluorophores. Owing to their intrinsic aggregation-induced emission enhancement nature, the formulated XA1 NPs show a high fluorescence quantum yield up to 14.8%, which is higher than those of most previously reported organic NIR-II fluorophores. Based on the XA1 NPs, noninvasive imaging of limb and cerebral vessels is achieved with a high signal-to-background ratio and deep penetration. Furthermore, the XA1 NPs can be used as good contrast agents for high resolution imaging of blood vessels of tumors and precise detection of tumors based on the EPR mechanism. Collectively, our work demonstrated a novel strategy for designing and manufacturing NIR-II fluorophores with AIE characteristics and proved that XA1 NPs are highly promising NIR-II probes for biomedical imaging under physiological and pathological conditions.

Altered fibrinolytic system in rat models of depression and patients with first-episode depression.

Tissue plasminogen activator (tPA) is a serine protease involved in cleavage of neurotrophic factors. In addition, tPA and neuroserpin can also directly bind to low density lipoprotein receptor-related protein 1 (LRP1), promoting neurogenesis and neurite outgrowth. Given both the cleavage and non-cleavage actions of the fibrinolytic system are crucial in neurological functions, the present study, for the first time, systematically detected the changes of fibrinolytic system factors in rats exposed to chronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS) and patients with depression. In general, our data demonstrated that both CUMS and LPS reduced tPA but elevated plasminogen activator inhibitor-1 (PAI-1; SERPINE1) mRNA expression. Intriguingly, decreased expression of neuroserpin and LRP1 was also observed in rats exposed to CUMS or LPS. The down-regulated neuroserpin and LRP1 signaling were confirmed by western blotting and immunoflurence data. Likewise, elevated PAI-1 but a significant reduction of neuroserpin and LRP1 mRNA expression were observed in the peripheral blood mononuclear cells (PBMCs) of patients with first-episode depression, and the mRNA levels of PAI-1, neuroserpin and LRP1 were correlated with the Beck Depression inventory (BDI) scores, further strengthening the clinical significance and involvement of the fibrinolytic system in depression. Collectively, the present study demonstrated the alterations of fibrinolytic system in stressed and inflamed brain and in patients with first-episode depression, firstly showing that not only the cleavage actions, but also the non-cleavage actions of the system may play an essential role in the development of depression.

The status of ω-3 PUFAs influence chronic unpredicted mild stress-induced metabolic side effects in rats through INSIG/SREBP pathway.

Metabolic disturbances, including lipid metabolism, bone metabolism, and glycometabolism, are common in depression. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which are reported to possess antidepressant effect, have also been shown to regulate metabolism. To further clarify the potential link between ω-3 PUFAs and stress-induced metabolic disturbances, metabolic-related parameters including body weight, visceral fat, fatty acid composition and serum parameters, such as serum lipids, free fatty acid (FFA), glucose (GLU), calcium and phosphorus in rats were measured. Moreover, hepatic insulin induced gene (INSIG)/sterol regulatory element binding protein (SREBP) pathway was also investigated. After 5 weeks of chronic unpredicted mild stress (CUMS) administration, rats were induced to a depressive-like state and exhibited decreased serum high-density lipoprotein (HDL-c), body weight and visceral fat, accompanied by altered C18:2n6c and ω-3/ω-6 PUFAs. Supplement of ω-3 PUFAs showed robust antidepressant effects and has beneficial effects on lipid profile. On the contrary, ω-3 PUFAs deficiency induced the visceral fat accumulation and decreased the serum calcium and phosphorus in stressed rats. Additionally, CUMS significantly increased hepatic expressions of SREBP-cleavage activating protein (SCAP)/SREBP-1 and decreased the expression of INSIG-1. This disturbance of SREBPs system is aggravated by ω-3 PUFAs deficiency and alleviated by ω-3 PUFAs supplementation. This study discloses the novel findings that ω-3 PUFAs deficiency will exacerbate the metabolic disturbances in stressed rats. Furthermore, supplementation of ω-3 PUFAs on individuals with a high risk of depression might be an effective way to prevent metabolic disorders accompanied by depression with the involvement of INSIG/SREBP pathway.

Predictable chronic mild stress promotes recovery from LPS-induced depression.

Clinical depression is frequently comorbid with chronic inflammatory disease, and neuroinflammation is currently proposed as a key mechanism in major depressive disorders. Different from unpredictable chronic stress, which is a well-established animal model for depression, predictable chronic mild stress (PCMS), a routine stress experienced in day-to-day life, has been demonstrated to improve mood and memory. In the present study, we assess the effects of PCMS (5 min of daily restrain stress for 4 weeks) on depressive-like behavior, neuroinflammation, oxidative stress, and pyrin domain containing three (NLRP3) activation in hippocampus of mice subjected to peripheral immune challenge by lipopolysaccharide (LPS). We found that PCMS facilitated the recovery from LPS-induced depressive- or anxiety-like behavior. Concurrent with the reversal of abnormal behavioral changes, PCMS suppressed LPS-induced proinflammatory cytokine expression, microglia activation, and oxidative stress in hippocampus. Correspondingly, PCMS inhibited LPS-induced overactivation of NLRP3 inflammasome components (NLRP3, ASC, and Caspase-1), and interleukin 1 beta (IL-1ß) maturation. Nrf2 (nuclear factor (erythroid-derived 2)-like 2) signaling was demonstrated to inhibit NLRP3 inflammasome overactivation and oxidative stress. PCMS activated Nrf2 signaling and inhibited thioredoxin (Trx)-interacting protein (TXNIP) expression in LPS-treated mice. Collectively, present data suggest that PCMS, contrary to severe and uncontrolled stress, alleviated impairments of the Nrf2-TXNIP-Trx system and may contribute to inflammatory brain damage and the imbalance of cellular redox homeostasis in depressed mice. This study provides a mechanistic link to the resilience of PCMS to LPS-induced behavioral deficits.

CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice.

Hormone therapy (HT) is reported to be deficient in improving learning and memory in older postmenopausal women according to recent clinical studies; however, the reason for failure is unknown. A "window of opportunity" for estrogen treatment is proposed to explain this deficiency. Here, we found that facilitation of memory extinction and long-term depression by 17ß-estradiol (E2) was normal in mice 1 week after ovariectomy (OVXST), but it was impaired in mice 3 months after ovariectomy (OVXLT). High-throughput sequencing revealed a decrease of miR-221-5p, which promoted cannabinoid receptor 1 (CB1) ubiquitination by upregulation of Neurl1a/b in E2-treated OVXLT mice. Blood samples from postmenopausal women aged 56-65 indicated decreases of miR-221-5p and 2-arachidonoylglycerol compared with samples from perimenopausal women aged 46-55. Replenishing of miR-221-5p or treatment with a CB1 agonist rescued the impairment of fear extinction in E2-treated OVXLT mice. The present study demonstrates that an HT time window in mice can be prolonged by cotreatment with a CB1 agonist, implying a potential strategy for HT in long-term menopausal women.

The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling.

Brain insulin signaling is accounted for the development of a variety of neuropsychiatric disorders, such as anxiety and depression, whereas both inflammation and the activated renin-angiotensin system (RAS) are two major contributors to insulin resistance. Intriguingly, inflammation and RAS can activate each other, forming a positive feedback loop that would result in exacerbated unwanted tissue damage. To further examine the interrelationship among insulin signaling, neuroinflammation and RAS in the brain, the effect of repeated lipopolysaccharide (LPS) exposure and co-treatment with the angiotensin II (Ang II) receptor type 1 (AT1) blocker, candesartan (Cand), on anxiety and depression-like behaviors, RAS, neuroinflammation and insulin signaling was explored. Our results demonstrated that prolonged LPS challenge successfully induced the rats into anxiety and depression-like state, accompanied with significant neural apoptosis and neuroinflammation. LPS also activated RAS as evidenced by the enhanced angiotensin converting enzyme (ACE) expression, Ang II generation and AT1 expression. However, blocking the activated RAS with Cand co-treatment conferred neurobehavioral protective properties. The AT1 blocker markedly ameliorated the microglial activation, the enhanced gene expression of the proinflammatory cytokines and the overactivated NF-κB signaling. In addition, Cand also mitigated the LPS-induced disturbance of insulin signaling with the normalized phosphorylation of serine 307 and tyrosine 896 of insulin receptor substrate-1 (IRS-1). Collectively, the present study, for the first time, provided the direct evidence indicating that the inflammatory condition may interact with RAS to impede brain insulin pathway, resulting in neurobehavioral damage, and inhibiting RAS seems to be a promising strategy to block the cross-talk and cut off the vicious cycle between RAS and immune system.

Role of t-PA and PAI-1 variants in temporal lobe epilepsy in Chinese Han population.

BACKGROUND: Epilepsy is one of the most common chronic disabling neurologic diseases. The purpose of our study was to investigate whether there is an association between t-PA (tissue plasminogen activator, rs2020918 and rs4646972), PAI-1 (plasminogen activator inhibitor 1, rs1799768) polymorphisms and susceptibility to temporal lobe epilepsy (TLE) in Chinese Han population. METHOD: One hundred and twenty-one cases of patients who were diagnosed as TLE and 146 normal controls were enrolled and the genotypes of t-PA and PAI-1 were detected by polymerase chain reaction-ligase detection reaction (PCR-LDR) method after the genomic DNA being extracted from peripheral blood. RESULT: There were significant differences for the genotypic frequencies at the two polymorphic sites in t-PA gene between TLE patients and controls (P = 0.019; P = 0.001). Furthermore, the frequency of rs2020918 (C > T) with T (CT + TT) and rs4646972 (311 bp insertion/-) with 311 bp deletion (311 bp/- + -/-) was significantly higher among TLE patients relative to controls respectively (P = 0.006; P = 0.001). However, no significant difference in genotypic and allelic frequency was found at the polymorphic site in PAI-1 gene between TLE patients and controls (P = 0.735). CONCLUSION: We reported for the first time to our knowledge the significant role of the two SNPs in t-PA gene (rs2020918 and rs4646972) in developing susceptibility to TLE in Chinese Han population.

Ω-3 fatty acids-supplementary in gestation alleviates neuroinflammation and modulates neurochemistry in rats.

BACKGROUND: The mechanisms underlying the association between immune activation and postpartum depression remained elusive. Although Ω-3 fatty acids possess anti-inflammatory properties, there is limited evidence directly linking the modulating effects of Ω-3 fatty acids on neuroimmune and neurochemistry to the antidepressant actions. METHODS: A between-groups design was used to assess the effects of reproductive status (virgin or parous) and Ω-3 fatty acids content (control and supplementary). Serum inflammatory cytokine levels (IL-1a, IL-1ß, IL-2, IL-6, IL-12, TNF-a, IFN-γ) were evaluated using the Bio-Plex Luminex System. Moreover, we also measured the protein levels of Purinergic type 2X7 receptor (P2X7R), NOD-like receptor pyrin domain containing 3 (NLRP3) and Nuclear factor-kappaB (NF-κB). Lastly, we assessed the function of various neurotransmitter systems to link the inflammatory response and neurotransmitter metabolism. RESULTS: Pro-inflammatory cyrokines, including IL-1a, IL-6, TNF-a and IFN-γ were markedly induced in the serum of parous rats, although no significantly depressive-like behavior was found. Meanwhile, NLRP3 and NF-κB were decreased in certain brain areas. Moreover, gestational stress significantly induced neurochemical disturbance, which is partly restored by Ω-3 fatty acids supplementation. CONCLUSIONS: These findings strengthen the link between inflammation, neurochemistry and postpartum depression, and further provide novel insights into the antidepressant effect of Ω-3 fatty acids.