Hypertension is one of the major predisposing factors for neurodegenerative disease characterized with activated renin-angiotensin system (RAS) in both periphery and brain. Vitamin D (VitD) is recently recognized as a pleiotropic hormone with strong neuroprotective properties. While multiple lines of evidence suggest that VitD can act on RAS, the evidence concerning the crosstalk between VitD and RAS in the brain is limited. Therefore, this study aims to evaluate whether VitD can modulate brain RAS to trigger neuroprotective actions in the brain of spontaneously hypertensive rats (SHR). Our data showed that calcitriol treatment induced VDR expression and inhibited neural death in the prefrontal cortex of SHR. Sustained calcitriol administration also inhibited microglia M1 polarization, but enhanced M2 polarization, accompanied with decreased expression of proinflammatory cytokines. We then further explored the potential mechanisms and showed that SHR exhibited overactivated classical RAS with increased expression of angiotensin II (Ang II) receptor type 1 (AT1), angiotensin converting enzyme (ACE) and Ang II production, whereas the counteracting arm of traditional RAS, ACE2/Ang(1–7)/MasR, was impaired in the SHR brain. Calcitriol nonsignificantly suppressed AT1 and ACE but markedly reduced Ang II formation. Intriguingly, calcitriol exerted pronouncedly impact on ACE2/Ang(1–7)/MasR axis with enhanced expression of ACE2, MasR and Ang(1–7) generation. Meanwhile, calcitriol ameliorated the overactivation of NADPH-oxidase (Nox), the downstream of RAS, in SHR, and also mitigated oxidative stress. In microglial (BV2) cells, we further found that calcitriol induced ACE2 and MasR with no significant impact on ACE and AT1. In accordance, calcitriol also attenuated Ang II-induced Nox activation and ROS production, and shifted the microglia polarization from M1 to M2 phenotype. However, co-treatment with A779, a specific MasR antagonist, abrogated the antioxidant and neuroimmune modulating actions of VitD. These findings strongly indicate the involvement of ACE2/Ang(1–7)/MasR pathway in the neuroprotective mechanisms of VitD in the hypertensive brain.

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Exposure of on-duty vehicle inspection workers to heavy metals in Beijing was investigated from April 18 to May 17, 2011. Particulate samples were collected by personal environmental monitors during vehicle inspectors' work time, and were analyzed by inductively coupled plasma-mass spectroscopy (ICP-MS) for V, Cr, Mn, Co, Ni, Cu, Zn, As, Cd and Pb. The results showed that in three vehicle inspection lines, Zn was the most abundant element, accounting for over 45% of the total metal concentration. Cr and Pb were the next most abundant compositions. The geoaccumulation index and enrichment factor analysis showed that Cr, Zn, As, Cd and Pb exhibited heavy or extreme contamination and significant enrichment, indicating the influence of anthropogenic sources. Mn and Co were mostly non-enriched and were mainly influenced by crustal sources. Ni and V presented moderate or heavy contamination, and were influenced by both crustal materials and anthropogenic sources. Principle component analysis revealed that the major sources were vehicle emissions, re-suspended dust and industrial processes. Cr and Mn could trigger adverse non-cancer health effects. The median values of incremental lifetime cancer risk (ILCR) of inhalation exposure route were estimated to be 2.59 × 10 , respectively for gasoline, bus, and diesel inspection workers, respectively. The ILCR was higher than the acceptable risk level of 10 -6 , indicating an unacceptable potential cancer risk.

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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.

Doxorubicin (DOX) is widely used to treat solid tumors, but its use is limited by its severe cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity. Metabolomic studies on DOX-induced toxicity are mainly focused on alterations in the heart and kidney, but systematic research on multiple matrices (serum, heart, liver, brain, and kidney) is rare. Thus, in our study, gas chromatography–mass spectrometry analysis of main targeted tissues (serum, heart, liver, brain, and kidney) was used to systemically evaluate the toxicity of DOX. Multivariate analyses, including orthogonal projections to the latent structure and t-test, revealed 21 metabolites in the serum, including cholesterol, d-glucose, d-lactic acid, glycine, l-alanine, l-glutamic acid, l-isoleucine, l-leucine, l-proline, l-serine, l-tryptophan, l-tyrosine, l-valine, MG (0:0/18:0/0:0), MG (16:0/0:0/0:0), N-methylphenylethanolamine, oleamide, palmitic acid, pyroglutamic acid, stearic acid, and urea. In the heart, perturbed metabolites included 3-methyl-1-pentanol, cholesterol, d-glucose, d-lactic acid, glycerol, glycine, l-alanine, l-valine, MG (16:0/0:0/0:0), palmitic acid, phenol, propanoic acid, and stearic acid. For the liver, DOX exposure caused alterations of acetamide, acetic acid, d-glucose, glycerol, l-threonine, palmitic acid, palmitoleic acid, stearic acid, and urea. In the brain, metabolic changes involved 2-butanol, carbamic acid, cholesterol, desmosterol, d-lactic acid, l-valine, MG (16:0/0:0/0:0), palmitic acid, and stearic acid. In the kidney, disturbed metabolites were involved in cholesterol, glycerol, glycine, l-alanine, MG (0:0/18:0/0:0), MG (16:0/0:0/0:0), and squalene. Complementary evidence by multiple matrices revealed disturbed pathways concerning amino acid metabolism, energy metabolism, and lipid metabolism. Our results may help to systematically elucidate the metabolic changes of DOX-induced toxicity and clarify the underlying mechanisms.

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Background: Depression is a well-known co-morbidity of coronary heart disease (CHD) and these two diseases share common risk mechanisms. Here, the aim of this study was to investigate the possible link between energy homeostasis regulation and CHD patients comorbid with depression.Methods: Two hundred and nine CHD patients and 101 matched healthy individuals were included. Demographic, clinical data were collected, serum irisin, adropin, preptin and brain-derived neurotrophic factor (BDNF) levels were determined by a double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA), and the depression was scored by Patient Health Questionnaire-9 (PHQ-9). Correlation analysis as well as multiple linear regression was used to assess the relationship between the three peptides, BDNF serum levels and PHQ-9 scores.Results: Irisin serum level was significantly lower in CHD patients without depression as compared with healthy controls (P=0.002), as well as adropin (P=0.000), preptin (P=0.000) and BDNF (P=0.000). Furthermore, similar trends were observed in CHD patients with depression in terms of irisin, adropin and BDNF as compared with CHD patients without depression (P=0.006; P=0.003; P=0.002; respectively).Multiple logistic regression results confirmed the contribution of irisin and BDNF to the occurrence of depression in CHD. Interestingly, correlations analysis revealed significant negative correlations between PHQ-9 scores and irisin, adropin, BDNF level (r=−0.43, P<0.01; r=−0.29, P<0.05; r=−0.45, P<0.001 respectively), and irisin serum level was positively correlated with BDNF (r=0.38, P<0.01). Conclusions:Our study firstly identified the role of energy homeostasis in the susceptibility to depression in CHD patients, and the interaction between irisin and BDNF could trigger the imbalance of energy homeostasis that occurs in depression of CHD patients.