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.

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.

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.

Fish oil supplementation attenuates neuroinflammation and alleviates depressive-like behavior in rats submitted to repeated lipopolysaccharide.

PURPOSE: Depression is frequently associated with inflammation, whereas omega-3 polyunsaturated fatty acids (PUFAs) primarily found in fish oil possess anti-inflammatory properties. Although converging studies suggest an antidepressant effect of PUFAs, there is limited evidence directly linking the neuro-immune modulating features of PUFAs to the antidepressant actions. METHODS: Therefore, we assessed the effects of fish oil (FO) supplementation on behavioral changes, inflammatory cytokine expression and oxidative reactions in frontal cortex and hippocampus of rats following repeated peripheral immune challenge by lipopolysaccharide (LPS) for 2 weeks (500 µg/kg every other day). RESULTS: Repeated LPS administration induced the rats to a depressive-like state and increased mRNA expression of pro-inflammatory cytokines, including 1L-1ß, 1L-6 and TNF-α, in frontal cortex and hippocampus. FO supplementation attenuated the LPS-induced abnormal behavior and brain inflammatory response. Concurrent with the antidepressant action, FO also reduced LPS-induced oxidative reactions and neural apoptosis in the rat brain, as evidenced by decreased malondialdehyde (MDA) production, increased catalase activities and inhibited pro-apoptotic protein Bax mRNA expression. In addition, FO inhibited activation of NF-κB and iNOS induced by LPS. Interestingly, we found FO suppressed the activation of the inflammasome NLRP3 and ionotropic purinergic receptor P2X7R evoked by LPS, suggesting a potential anti-inflammatory mechanism for PUFAs. Besides, FO also restored the LPS-induced neurochemical disturbance, especially the balance between serotonin and kynurenine branches of tryptophan metabolism, which is tightly associated with depression. CONCLUSIONS: These findings provide novel insights into the antidepressant action of PUFAs and further strengthen the link between inflammation and depression.

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.

Salvianolic acid B protects against lipopolysaccharide-induced behavioral deficits and neuroinflammatory response: involvement of autophagy and NLRP3 inflammasome.

BACKGROUND: The NLRP3 inflammasome activation and neuroinflammation are known to be involved in the pathology of depression, whereas autophagy has multiple effects on immunity, which is partly mediated by the regulation of inflammasome and clearance of proinflammatory cytokines. Given the emerging evidence that autophagy dysfunction plays an essential role in depression, it is very likely that autophagy may interact with the inflammatory process in the development and treatment of depression. Salvianolic acid B (SalB), a naturally occurring compound extracted from Salvia miltiorrhiza, contains anti-inflammatory and antidepression properties and has recently been proven to modulate autophagy. In this study, we sought to investigate whether autophagy is involved in the inflammation-induced depression and the antidepressant effects of SalB. METHODS: The effects of prolonged lipopolysaccharide (LPS) treatment and SalB administration on behavioral changes, neuroinflammation, autophagic markers and NLRP3 activation in rat hippocampus were determined by using behavioral tests, real-time PCR analysis, western blot, and immunostaining. RESULTS: Our data showed that periphery immune challenge by LPS for 2 weeks successfully induced the rats to a depression-like state, accompanied with enhanced expression of pro-inflammatory cytokines and NLRP3 inflammasome activation. Interestingly, autophagic markers, including Beclin-1, and the ratio of LC3II to LC3I were suppressed following prolonged LPS exposure. Meanwhile, co-treatment with SalB showed robust antidepressant effects and ameliorated the LPS-induced neuroinflammation. Additionally, SalB restored the compromised autophagy and overactivated NLRP3 inflammasome in LPS-treated rats. CONCLUSIONS: Collectively, these data suggest that autophagy may interact with NLRP3 activation to contribute to the development of depression, whereas SalB can promote autophagy and induce the clearance of NLRP3, thereby resulting in neuroprotective and antidepressant actions.

Maternal diet of polyunsaturated fatty acid altered the cell proliferation in the dentate gyrus of hippocampus and influenced glutamatergic and serotoninergic systems of neonatal female rats.

BACKGROUND: Long-chain polyunsaturated fatty acids (PUFAs) are major components of the phospholipids that forming the cell membrane. Insufficient availability of PUFAs during prenatal period decreases accretion of docosahexaenoic acid (DHA) in the developing brain. DHA deficiency is associated with impaired attention and cognition, and would precipitate psychiatric symptoms. However, clinical studies on the potential benefits of dietary DHA supplementation to neural development have yielded conflicting results. METHODS: To further investigate the neurochemical influence of maternal PUFAs levels, we assessed the functioning of various neurotransmitter systems including glutamatergic, dopaminergic, norepinephrinergic and serotoninergic systems in the brain of neonatal female rats by HPLC-MS/MS. Meanwhile, the cell proliferation of neonatal rats was investigated using immunefluorescence. RESULTS: Different maternal n-3 PUFAs dietary influenced the FA composition, cell proliferation in the dentate gyrus of hippocampus and the contents of γ-aminobutyric acid (GABA), glutamine (GLN), dopamine (DA) and its metabolites [3,4- dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA)], norepinephrine (NE), vanilmandelic acid (VMA) and 5-HT turnover in the brain of neonatal rats. However, the mRNA expression of key synthase of neurotransmitters remains stable. CONCLUSIONS: Our study showed that maternal deficiency of n-3 PUFAs might play an important role in central nervous system of neonatal female rats mainly through impairing the normal neurogenesis and influencing glutamatergic system and 5-HT turnover.

Effect of Antiepileptic Therapy on Serum 25(OH)D3 and 24,25(OH)2D3 Levels in Epileptic Children.

BACKGROUND: Vitamin D deficiency is not only associated with the adverse effects of chronic treatment with antiepileptic drugs (AEDs), but also with epilepsy. Although emerging evidence suggests that AEDs can accelerate the vitamin D catabolism, resulting in suboptimal vitamin D status, there are a limited number of studies examining the vitamin D status in epileptic patients, especially in first-episode or AEDs-naïve children. METHODS: Determined with high-performance liquid chromatography-tandem mass spectrometry, circulating 25(OH)D3 and 24,25(OH)2D3 levels, and 24,25(OH)2D3:25(OH)D3 ratio were compared between AEDs-treated epileptic (n = 363) and control (n = 159) children. To further figure out whether the patients were in a vitamin D deficient prone state even before treatment, epileptic children before their initiation of treatment (n = 51) were enrolled into a follow-up study. RESULTS: A significant decrease of 25(OH)D3 and 24,25(OH)2D3 levels, but a significant increase of 24,25(OH)2D3:25(OH)D3 ratio was observed in epileptic children, compared with controls. Baseline 25(OH)D3, 24,25(OH)2D3 and 24,25(OH)2D3:25(OH)D3 ratio in the follow-up group were similar to those in controls, but significantly changed with 2 months of AED therapy. CONCLUSIONS: Disturbed vitamin D levels were possibly the consequence of AED therapy, rather than the contributing factor of epilepsy. Collectively, circulating vitamin D levels should be monitored and corrected in AEDs-treated epileptic children.

Chronic administration of calcitriol enhanced neuregulin-1/ErbB signaling in rat myocardium.

Although emerging evidence suggests that vitamin D has beneficial effects in the cardiovascular health, the underlying mechanisms are far from fully elucidated. Given the indispensable role of neuregulin-1 (NRG1)/ErbB signaling in the cardiovascular system, the present study investigated the influences of prolonged administration of calcitriol, the active form of vitamin D, on the NRG1/ErbB system. We examined the protein expression of NRG1, ErbB receptors (ErbB2 and ErbB4) and their phosphorylated forms in the myocardium of rats following 6-week administration of calcitriol (50 ng/kg/day or 100 ng/kg/day). We further assessed the myocardial vitamin D receptor (VDR) to confirm the effect of calcitriol treatment. Additionally, serum neuregulin-1 level was also analyzed. Generally, calcitriol enhanced myocardial VDR expression and NRG1/ErbB signaling. Calcitriol increased NRG1 protein level at the higher dose, while both doses promoted ErbB2 and phosphorylated ErbB2 expression. Although calcitriol has no significant influence on ErbB4 expression, phosphorylated ErbB4 receptors were enhanced at the higher dose. Furthermore, the serum neuregulin-1 concentration was increased at both doses. Overall, our data firstly showed that chronic calcitriol administration enhanced NRG1/ErbB signaling in the heart, indicating a novel mechanism underlying the cardiac effects of vitamin D.

Fish oil supplementation alleviates depressant-like behaviors and modulates lipid profiles in rats exposed to chronic unpredictable mild stress.

BACKGROUND: Patients with major depressive disorder have a higher prevalence and incidence of dyslipidemia. However, clinical studies concerning the association between lipid levels and depression are inconsistent. Adipokines (like leptin and adiponectin) and ghrelin are strongly associated with lipid metabolism. Fish oil, which is reported to possess antidepressant effect, also have beneficial effects on lipid metabolism and the cardiovascular system. In the present study, we investigated lipid metabolism in rats exposed to chronic unpredictable mild stress (CUMS) and the effect of fish oil on lipid profiles, aforementioned adipokines and ghrelin. METHODS: Sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST) were used to evaluate the antidepressant-like effects of fish oil. After the behavior tests, peripheral blood were collected. Serum parameters, including fasting triglyceride (TG), total cholesterol (TCH), high density lipoprotein-cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c), free fatty acid (FFA), glucose (GLU), adipokines (leptin, adiponectin) and ghrelin were assayed. RESULTS: After 5 weeks of CUMS procedures, rats were induced to depressive-like state, and exhibited increased serum levels of TCH, HDL-c, FFA and decreased serum levels of leptin and ghrelin, whereas the serum status of adiponectin, GLU, TG and LDL-c remained stable. Fish oil treatment showed robust antidepressant effect and reversed the stress-induced lipid disturbance and decrease in serum concentration of ghrelin. CONCLUSIONS: Our results suggested that CUMS altered the serum levels of lipid profiles, leptin and ghrelin in rats. Fish oil supplementation not only provided antidepressant-like effects, but also reversed the altered lipid profiles and ghrelin level in serum. Our data indicated that fish oil treatment exerts anti-depressant effect and regulates lipid disturbance simultaneously.

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 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.

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.

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.

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.

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.

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.