Calcitriol attenuates lipopolysaccharide-induced neuroinflammation and depressive-like behaviors by suppressing the P2X7R/NLRP3/caspase-1 pathway.

RATIONALE: Microglia-mediated neuroinflammation is a vital hallmark in progression of depression, while calcitriol exerts anti-inflammatory effects in the brain. The activation of the P2X7 receptor has an important link to neuroinflammation. However, it is unclear whether calcitriol treatment exerts anti-inflammatory effects in association with P2X7R activation. OBJECTIVE: In this study, we assessed the antidepressive and neuroprotective effects of calcitriol on lipopolysaccharide (LPS)-mediated depressive-like behavior, neuroinflammation, and neuronal damage. METHODS: In in vitro experiments, the BV2 cells were exposed to LPS, and the protective effects of calcitriol were assessed. For in vivo experiment, thirty-two male C57BL/6 mice were divided into four groups of control, calcitriol, LPS and LPS + calcitriol. Calcitriol was administered at 1 µg/kg for 14 days and LPS at 1 mg/kg once every other day for 14 days. The control group mice were given equal volumes of vehicles. All treatments were delivered intraperitoneally. RESULTS: The in vitro experiments showed calcitriol inhibited the release of inflammatory mediators induced by LPS in BV2 cells. The in vivo experiments revealed that calcitriol alleviated LPS-induced behavioral abnormalities and spatial learning impairments. Moreover, calcitriol treatment reduced the mRNA levels of pro-inflammatory cytokines, while increasing anti-inflammatory cytokine levels in the hippocampus. Our results further revealed that calcitriol administration attenuated LPS-induced microglia activation by suppressing P2X7R/NLRP3/caspase-1 signaling. Moreover, calcitriol inhibited apoptosis of neurons in the hippocampus as evidenced by expression of apoptosis-related proteins and TUNEL assay. CONCLUSIONS: Collectively, our findings demonstrated that calcitriol exerts antidepressive and neuroprotective effects through the suppression of the P2X7R/NLRP3/caspase-1 pathway both in LPS-induced inflammation models in vitro and in vivo.

CoO supported NiFe layered double hydroxide sandwich-like nanosheets on hierarchical carbon framework for efficient electrocatalytic oxygen evolution.

Exploration of greatly efficient and steady non-noble oxygen evolution reaction (OER) electrocatalysts is of great significance in improving the overall efficiency of energy density systems such as regenerative fuel cells, water electrolyzes, and metal-air batteries. Herein, inspired by hierarchical 3D porous structures with open microchannels of natural wood, CoO@NiFe LDH sandwich-like nanosheets were anchored on the carbonized wood (CW) via electrodeposition and calcination strategies. The strong interactions between CoO nanosheets and NiFe LDH nanosheets endow CoO@NiFe LDH/CW electrocatalyst with high catalytic properties toward the OER comparable to CoO/CW and NiFe LDH/CW. The optimized CoO@NiFe LDH/CW electrocatalyst demonstrates good OER catalytic performance with an overpotential of 230 mV at 100 mA cm-2. This work presents an innovative approach to utilize renewable resources for constructing advanced free-standing catalysts.

Methylglyoxal accumulation contributes to accelerated brain aging in spontaneously hypertensive rats.

While it is well-acknowledged that neurovascular dysfunction in hypertension is tightly associated with accelerated brain aging, we contend that the deleterious effects of hypertension may extend beyond affecting only the arteries. Methylglyoxal (MG) derived from glycolysis, is involved in the accumulation of advanced glycated end products (AGEs), which are the hallmarks of neurodegenerative disorders. Therefore, the present study aims to firstly investigate the role of MG metabolism in the hypertension-accelerated brain aging process. The results of our study indicate that the levels of MG increase with age in both the plasma and hippocampus of SHRs at 12, 16, and 30 weeks old. AGE methylglyoxal-hydro imidazoline-1 (MG-H1) is primarily localized in astrocytes, while its presence was not observed in neurons and microglia within the hypertensive hippocampus. Our observations also suggest that angiotensin II (Ang II) enhances glucose uptake and glycolysis while reducing the expression of Glo1 in cultured astrocytes. N-acetylcysteine (NAC) was found to counteract the increase in escape latency and inhibit the activation of the AGEs-RAGE axis in 30-week-old SHRs. NAC decreased Iba-1 immunofluorescence intensity, inhibited the levels of pro-inflammatory markers, and enhanced the abundance of anti-inflammatory markers in the hippocampus of SHRs. Moreover, NAC reduced the immunofluorescence signal of 4HNE and increased the content of GSH and SOD in SHRs. Finally, NAC was observed to inhibit apoptosis in the hippocampus of SHRs. Collectively, we firstly showed the enhanced accumulation of MG in the hypertensive brain, whereas the clearance of MG by NAC treatment mitigated the aging process and attenuated AGEs generation, neuroinflammation, and oxidative damage.

Cerebral endothelial cell-derived extracellular vesicles regulate microglial polarization and promote autophagy via delivery of miR-672-5p.

The interaction between cerebral endothelial cells (CEC) and brain parenchymal cells is critical to maintain neurovascular homeostasis, whereas extracellular vesicles (EVs) are essential to mediate the cell-cell communication. Previous researches demonstrated that CEC-derived EVs (CEC-EVs) confer neuroprotective actions. However, the molecular mechanisms remain unknown. In this study, we isolated EVs from CEC and assessed their immune-regulatory actions in microglial cells and mice following lipopolysaccharide (LPS) exposure. We found that CEC-EVs treatment significantly ameliorated LPS-induced inflammatory activation, shifting microglial polarization from pro-inflammatory phenotype to anti-inflammatory phenotype. Meanwhile, microglial cells can effectively internalize CEC-EVs and this process was further enhanced by immune activation. Next, the miRNA microarray analysis revealed that CEC-EVs increased expression of miR-672-5p, which was demonstrated to be the cargo of CEC-EVs. TGFß-activated kinase 1 (TAK1)-binding proteins 2 (TAB2) was identified to be the target of miR-672-5p. Through inhibiting TAB2, miR-672-5p derived from CEC-EVs suppressed TAK1-TAB signaling and thereby mitigating the downstream NF-κB activation. Furthermore, we found that by delivering miR-672-5p, CEC-EVs promoted autophagy and hence stimulating autophagic degradation of NLRP3 inflammasome. Our work firstly revealed the neuroimmune-modulating actions of CEC-EVs and further demonstrated that miR-672-5p secreted from CEC-EVs inhibits microglial pro-inflammatory polarization and facilitates autophagic process via targeting TAB2.

Targeting PDK2 rescues stress-induced impaired brain energy metabolism.

Depression is a mental illness frequently accompanied by disordered energy metabolism. A dysregulated hypothalamus pituitary adrenal axis response with aberrant glucocorticoids (GCs) release is often observed in patients with depression. However, the associated etiology between GCs and brain energy metabolism remains poorly understood. Here, using metabolomic analysis, we showed that the tricarboxylic acid (TCA) cycle was inhibited in chronic social defeat stress (CSDS)-exposed mice and patients with first-episode depression. Decreased mitochondrial oxidative phosphorylation was concomitant with the impairment of the TCA cycle. In parallel, the activity of pyruvate dehydrogenase (PDH), the gatekeeper of mitochondrial TCA flux, was suppressed, which is associated with the CSDS-induced neuronal pyruvate dehydrogenase kinase 2 (PDK2) expression and consequently enhanced PDH phosphorylation. Considering the well-acknowledged role of GCs in energy metabolism, we further demonstrated that glucocorticoid receptors (GR) stimulated PDK2 expression by directly binding to its promoter region. Meanwhile, silencing PDK2 abrogated glucocorticoid-induced PDH inhibition, restored the neuronal oxidative phosphorylation, and improved the flux of isotope-labeled carbon (U-13C] glucose) into the TCA cycle. Additionally, in vivo, pharmacological inhibition and neuron-specific silencing of GR or PDK2 restored CSDS-induced PDH phosphorylation and exerted antidepressant activities against chronic stress exposure. Taken together, our findings reveal a novel mechanism of depression manifestation, whereby elevated GCs levels regulate PDK2 transcription via GR, thereby impairing brain energy metabolism and contributing to the onset of this condition.

Integrated Microbiome and Metabolome Analysis Reveals Correlations Between Gut Microbiota Components and Metabolic Profiles in Mice with Methotrexate-Induced Hepatoxicity.

Purpose: We designed this study to investigate the potential correlations between gut microbiota compositions and hepatic metabolomic disorders in mice with methotrexate (MTX)-induced hepatoxicity. Methods: We used MTX to induce hepatoxicity in healthy Kunming mice, and we determined plasma ALT and AST levels and assessed the liver tissue histopathology. We applied an integrated gas chromatography-mass spectrometry (GC-MS) and 16S ribosomal RNA (rRNA) gene sequencing approach to evaluate the effects of MTX on the gut microbiota and hepatic metabolic profiles of mice. We uncovered correlations between the gut microbiota and hepatic metabolomic profiles by calculating the Spearman correlation coefficient. Results: MTX caused ALT and AST level elevations and hepatoxicity in our mouse model. MTX disrupted amino acid metabolic pathways (including biosyntheses of valine, leucine, and isoleucine; and arginine; and, metabolism of alanine, aspartate, and glutamate; histidine; beta-alanine; and glycine, serine, and threonine); biosyntheses of aminoacyl-tRNA; and pantothenate, and CoA; and, metabolic pathways of energy, glutathione, and porphyrin; and chlorophyll. In addition, MTX increased the abundances of Staphylococcus, Enterococcus, Collinsella, Streptococcus, and Aerococcus, but decreased the amounts of Lactobacillus, Ruminococcus, norank_f_Muribaculaceae, unclassified_f_Lachnospiraceae, norank_f_Lachnospiraceae, A2, Eubacterium_xylanophilum_group, Phascolarctobacterium, Bifidobacterium, and Faecalibaculum. Our correlation analyses showed that different flora abundance changes including those of Phascolarctobacterium, Faecalibaculum, norank_f_Muribaculaceae, Streptococcus, Enterococcus, Staphylococcus, and Collinsella were associated with liver injury. Conclusion: We present evidence supporting the notion that MTX causes hepatoxicity by altering the gut microbiota and hepatic metabolite profiles, our findings provide new venues for the management of MTX-induced hepatoxicity.

New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival.

Autophagy is a dynamic process that maintains the normal homeostasis of cells by digesting and degrading aging proteins and damaged organelles. The effect of autophagy on neural tissue is still a matter of debate. Some authors suggest that autophagy has a protective effect on nerve cells, whereas others suggest that autophagy also induces the death of nerve cells and aggravates nerve injury. In mammals, oxidative stress, autophagy and endoplasmic reticulum stress (ERS) constitute important defense mechanisms to help cells adapt to and survive the stress conditions caused by physiological and pathological stimuli. Under many pathophysiological conditions, oxidative stress, autophagy and ERS are integrated and amplified in cells to promote the progress of diseases. Over the past few decades, oxidative stress, autophagy and ERS and their interactions have been a hot topic in biomedical research. In this review, we summarize recent advances in understanding the interactions between oxidative stress, autophagy and ERS in neuronal cell death and survival.

Impact of a long-term high-fructose diet on systemic metabolic profiles of mice.

Evidence is mounting that chronic high-fructose diets (HFrD) can lead to metabolic abnormalities and cause a variety of diseases. However, the underlying mechanism by which long-term high fructose intake influencing systemic metabolism remains unclarified. This study, therefore, attempted to investigate the impact of a high-fructose diet on metabolic profile. Four-week-old male C57BL/6 mice were fed with 15% fructose solution as their only source of water for 8 weeks. Afterward, gas chromatography-mass spectrometry (GC-MS) was employed to investigate the comprehensive metabolic profile of serum, muscle, liver, heart, white adipose, brain, and kidney tissues, and multivariate analyses including principal component analysis (PCA) and orthogonal partial least squared-discriminant analysis (OPLS-DA) were applied to screen for differential metabolite expression between the HFrD and control groups. Furthermore, the MetaboAnalyst 5.0 (http://www.metaboanalyst.ca) and Kyoto Encyclopedia of Genes and Genomes database (KEGG; http://www.kegg.jp) were employed to portray a detailed metabolic network. This study identified 62 metabolites related to HFrD and 10 disturbed metabolic pathways. The results indicated that high fructose intake mainly influenced amino acid metabolism and biosynthesis (glycine, serine, and threonine metabolism; aspartate, and glutamate metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis, and arginine biosynthesis pathways), glutathione metabolism, sphingolipid metabolism, and glyoxylate and dicarboxylate metabolism in serum, whereas these pathways were suppressed in the brain. Starch and sucrose metabolism in muscle was also disrupted. These results elucidate the effects of long-term high fructose consumption on the metabolic profiles of various tissues and provide new insight for the identification of potential metabolic biomarkers and pathways disrupted by high fructose.

Enhanced Electrochemiluminescence of A Macrocyclic Tetradentate Chelate Pt(II) Molecule through Its Collisional Interactions with the Electrode.

A macrocyclic tetradentate chelate Pt(II) molecule (Pt1) served as an excellent luminophore in electrochemiluminescence (ECL) processes. The blue ECL of Pt1/S2 O8 2- coreactant system in N,N'-dimethylformamide was found to be 46 times higher than that of the Ru(bpy)2+ /S2 O8 2- system or 30 times higher than that of the 9,10-diphenylanthracene/S2 O8 2- system. The unprecedented high ECL quantum efficiencies were caused by the cyclic generation of monomer excited states through collisional interactions of Pt1 molecules with the electrode at an elevated frequency. The ECL is tunable from bright blue to pure white by simply changing the solvent from N,N'-dimethylformamide to dichloromethane. The white ECL of Pt(II) molecule was reported for the first time and the mechanism was proposed to be the simultaneous emissions from the monomer excited state (blue) and excimer (red).

A GC-MS-based untargeted metabolomics approach for comprehensive metabolic profiling of vancomycin-induced toxicity in mice.

Background: Vancomycin is a glycopeptide antibiotic that is commonly used for severe drug-resistant infections treatment. Application of vancomycin frequently leads to severe ototoxicity, hepatotoxicity, and nephrotoxicity; however, the comprehensive metabolic analysis of vancomycin-induced toxicity is lacking. Purpose: This study attempted to investigate the metabolic changes after vancomycin administration in mice. Methods: Experimental mice (n = 9) received continuous intraperitoneal injection of vancomycin (400 mg/kg) every day for 7 days, and mice in control group (n = 9) were treated with the same amount of normal saline. Pathological changes of the kidney were examined using haematoxylin and eosin (HE) staining. A gas chromatography-mass spectrometry (GC-MS) approach was used to identify discriminant metabolites in serum and various organs including the heart, liver, kidney, spleen, cerebral cortex, hippocampus, inner ear, lung, and intestine. The potential metabolites were identified using orthogonal partial least squares discrimination analysis (OPLS-DA). Subsequently, the MetaboAnalyst 5.0 (http://www.metaboanalyst.ca) and Kyoto Encyclopedia of Genes and Genomes database (KEGG, http://www.kegg.jp) were employed to depict the metabolic pathways. Results: Compared with the control group, the vancomycin induced 13, 17, 27, 22, 16, 10, 17, 11, 10, and 7 differential metabolites in the serum, liver, kidney, heart, cerebral cortex, lung, spleen, intestine, hippocampus, and inner ear, respectively. Further pathway analyses identified that amino acids metabolism, fatty acids biosynthesis, energy metabolism, and lipid metabolism were disrupted after VCM exposure. Conclusion: Vancomycin affects the metabolism in various organs in mice, which provides new insights for identification of vancomycin-induced toxicity, and facilitate to better understanding of the metabolic pathogenesis of vancomycin.

Comprehensive Analysis of Metabolic Changes in Male Mice Exposed to Sodium Valproate Based on GC-MS Analysis.

Purpose: Sodium valproate (VPA) is the most widely used broad-spectrum antiepileptic first-line drug in clinical practice and is effective against various types of epilepsy. However, VPA can induce severe cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity, which limits its use. Metabolomic studies of VPA-induced toxicity have focused primarily on changes in serum and urine metabolites but have not evaluated changes in major organs or tissues. Methods: Central target tissues (intestine, lung, liver, hippocampus, cerebral cortex, inner ear, spleen, kidney, heart, and serum) were analyzed using gas chromatography mass spectrometry to comprehensively evaluate VPA toxicity in mouse models. Results: Multivariate analyses, including orthogonal projections of the latent structure and Student's t test, indicated that depending on the matrix used in the study (the intestine, lung, liver, hippocampus, cerebral cortex, inner ear, spleen, kidney, heart or serum) the number of metabolites differed, the lung being the poorest and the kidney the richest in number. Conclusion: These metabolites were closely related and were found to participate in 12 key pathways related to amino acid, fatty acid, and energy metabolism, revealing that the toxic mechanism of VPA may involve oxidative stress, inflammation, amino acid metabolism, lipid metabolism, and energy disorder.

Design, semi-synthesis and bioactivity evaluation of novel podophyllotoxin derivatives as potent anti-tumor agents.

In this study, a series of potential candidate molecules with excellent antitumor activity targeting tubulin and PTEN/PI3K/Akt signaling pathway was synthesized by modifying the molecule structure of podophyllotoxin (PPT) at the C-4 position via a structure-guided drug design approach. MTT assay results indicated that compound 12c had stronger anti-proliferative activities against HGC-27, MCF-7 and H460 cell lines than etoposide (VP-16), especially for HGC-27 (12c: IC50 = 0.89 ± 0.023 µM; PPT: IC50 = 6.54 ± 0.69 µM, VP-16: IC50 = 2.66 ± 0.28 µM) with lower affect in healthy human cells (293 T and GES-1). Further pharmacological analysis exhibited that 12c could bind the tubulin at the colchicine site and disrupt the dynamic equilibrium of microtubules. Moreover, 12c also suppressed the expressions/activities of matrix metalloprotease (MMP)-2, vimentin and up-regulation E-cadherin suggesting that 12c could block the epithelial-mesenchymal transition (EMT). The increased cell survival and invasion/migration were associated with the inactivation of PTEN/PI3K/Akt, 12c could regulate this pathway and cascade influence on the mitochondrial pathway, eventually, leading to the cell apoptosis. Thus, 12c may have the potential to become a candidate molecule in gastric cancer clinical treatment.

Ghrelin ameliorates diabetes-associated behavioral deficits and NLRP3 inflammasome activation via autophagic flux enhancement.

Ghrelin has recently been associated with the development of diabetes comorbid with depression, but its underlying molecular mechanisms remains poorly understood. Here, molecular and histological methods were applied both in vivo and in vitro studies to investigate the mechanisms of ghrelin in diabetes comorbid with depression. Our results demonstrated the anti-depressive, anxiolytic, and neuroprotective effects of ghrelin, as evidenced by the amelioration of anxiety- and depression-like behaviors, reduction in apoptosis, and preservation of neuron integrity in streptozotocin (STZ)-treated rats. STZ treatment induced M1-phenotypic microglial polarization, accompanied by neuroinflammation, which was reversed by ghrelin treatment. Further exploration showed that autophagy was inhibited, the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and nuclear factor (NF)-κB signaling pathway were activated in STZ rats. In line with the in vivo results, ghrelin could suppress the NLRP3 inflammasome and NF-κB signaling pathway activation via the amelioration of impaired autophagic flux in microglial BV2 cells. Importantly, clinical evidence further verified the anti-inflammatory and antidepressant effects of ghrelin. Collectively, these results suggested that ghrelin ameliorates diabetes-associated behavioral deficits and NLRP3 inflammasome activation via autophagic flux enhancement, highlighting the importance of ghrelin as a potential target of immune regulation in diabetes comorbid with depression.

Therapeutic effect of extracellular vesicles from different cell sources in traumatic brain injury.

Extracellular vesicles (EVs) are biologically active membrane vesicles secreted by many cells in the body. A variety of nucleic acids, proteins, and other biologically active substances in EVs can be used to exchange and transmit information between cells, thereby affecting the progression of various diseases. Numerous studies have demonstrated that EVs not only regulate changes in brain physiology but also regulate synaptic plasticity and neuronal regeneration in traumatic brain injury (TBI), which opens a new approach for the treatment of TBI. In view of the fact that most human cells can secrete EVs, and relevant experiments have proved that different doses of EVs have different therapeutic effects on TBI. To this end, this paper reviews the therapeutic effects of EVs from different cell sources and their doses on TBI.

Molten salt/liquid metal extraction: Electrochemical behaviors and thermodynamics properties of La, Pr, U and separation factors of La/U and Pr/U couples in liquid gallium cathode.

The electrochemical behavior of lanthanides (La, Pr) and actinide (U) on inert W and liquid Ga electrodes in LiCl-KCl molten salt as well as their related thermodynamic properties were experimentally determined for further Lns/Ans separation. The results indicate that the reductions of La3+ and Pr3+ in LiCl-KCl melts are both one-step process with three electrons exchanged, and the reactions are quasi-reversible processes at low scan rate. Temperature dependencies of apparent standard redox potentials of La(Ga), Pr(Ga) and U(Ga) alloys were determined by open-circuit chronopotentiometry versus Cl-/Cl2 reference electrode. The activity and activity coefficients of lanthanum, praseodymium and uranium on the liquid Ga electrode in the temperature interval 723-813 K were calculated. The separation factors for La/U and Pr/U on the liquid Ga electrode in the molten salt were determined by logθU/La=-10.39+11440.69T±0.0125 and logθU/Pr=-5.84+7763.27T±0.07. The separation factors of La/U and Pr/U on the liquid Ga electrode indicate that lower temperature should be more effective for separating uranium.

Targeted metabolomics analysis of serum amino acid profiles in patients with Moyamoya disease.

Amino acids are one of the main metabolites in the body, and provide energy for the body and brain. The purpose of this study is to provide a profile of amino acid changes in the serum of patients with Moyamoya disease (MMD) and identify potential disease biomarkers. In this paper, we quantitatively determined the serum amino acid metabolic profiles of 43 MMD patients and 42 healthy controls (HCs). T test, multivariate statistical analysis, and receiver operating characteristic (ROC) curve analysis were used to identify candidate markers. Thirty-nine amino acids were quantified, and 12 amino acid levels differed significantly between the MMD patients and HCs. Moreover, based on ROC curve analysis, four amino acid (L-methionine, L-glutamic acid, ß-alanine and o-phosphoserine) biomarkers showed high sensitivity and specificity (AUC > 0.90), and showed the best sensitivity and specificity in MetaboAnalyst 5.0 using binary logistic regression analysis. We have provided serum amino acid metabolic profiles of MMD patients, and identified four potential biomarkers which may both provide clinicians with an objective diagnostic method for early detection of MMD and further our understanding of MMD pathogenesis.

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.

Calcitriol confers neuroprotective effects in traumatic brain injury by activating Nrf2 signaling through an autophagy-mediated mechanism.

BACKGROUND: The present study aimed to further explore the potential interaction between oxidative stress and autophagy in the progression of traumatic brain injury (TBI) and therapeutic mechanism of calcitriol, the active form of vitamin D (VitD). METHODS: Neuroprotective effects of calcitriol were examined following TBI. We further evaluated the impacts of TBI and calcitriol treatment on autophagic process and nuclear factor E2-related factor 2 (Nrf2) signaling. RESULTS: We found that treatment of calcitriol markedly ameliorated the neurological deficits and histopathological changes following TBI. The brain damage impaired autophagic flux and impeded Nrf2 signaling, the major regulator in antioxidant response, consequently leading to uncontrolled and excessive oxidative stress. Meanwhile, calcitriol promoted autophagic process and activated Nrf2 signaling as evidenced by the reduced Keap1 expression and enhanced Nrf2 translocation, thereby mitigating TBI-induced oxidative damage. In support, we further found that chloroquine (CQ) treatment abrogated calcitriol-induced autophagy and compromised Nrf2 activation with increased Keap1 accumulation and reduced expression of Nrf2-targeted genes. Additionally, both CQ treatment and Nrf2 genetic knockout abolished the protective effects of calcitriol against both TBI-induced neurological deficits and neuronal apoptosis. CONCLUSIONS: Therefore, our work demonstrated a neuroprotective role of calcitriol in TBI by triggering Nrf2 activation, which might be mediated by autophagy.