Association Between Neuroinflammation and Parkinson's Disease: A Comprehensive Mendelian Randomization Study.

The objective of the study is to determine the causal relationship and potential mechanisms between Parkinson's disease (PD) and neuroinflammatory and neurotoxic mediators. We conducted two-sample Mendelian randomization (2SMR) study and multivariable Mendelian randomization (MVMR) analysis to investigate the causality between PD and neuroinflammatory and neurotoxic mediators. The mediation analysis with MR was also conducted to determine the potential mediating effect of neuroinflammatory and neurotoxic mediators between asthma and PD. Genetically predicted levels of nine neuroinflammation were associated with changes in PD risk. The associations of PD with CCL24, galectin-3 levels, haptoglobin, and Holo-Transcobalamin-2 remained significant in multivariable analyses. The mediation analysis with MR revealed that asthma affects PD through CCL24 and galectin-3. The results showed neuroinflammation could affect the pathogenesis of PD. In the combined analysis of these nine variables, CCL24, galectin-3 levels, HP, and Holo-Transcobalamin-2 alone were found to be significant. Asthma plays an intermediary role through CCL24 and galectin-3 levels.

Analysis of the Relationship Between Parkinson's Disease and Diabetic Retinopathy Based on Bioinformatics Methods.

The objective of the study was to explore the relationship and potential mechanism between Parkinson's disease (PD) and diabetic retinopathy (DR) using bioinformatics methods. We first examined the causal relationship between PD and DR by Mendelian randomization (MR) analysis. The datasets of PD and DR patients from the Gene Expression Omnibus database were used to identify differentially expressed genes (DEGs). Then, we performed the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and immune infiltration analysis. We also constructed a protein-protein interaction network and receiver operating characteristic (ROC) curve. Finally, an online website was used for drug prediction. The MR analysis demonstrated a causal relationship between DR and PD (odds ratio [OR] = 0.86; 95% confidence interval [CI] 0.79-0.93; p = 3.24E - 04), in which DR acted as a protective factor against PD. There were 81 DEGs identified from the PD and DR datasets, of which 29 genes had protein interaction relationships, and enrichment analysis showed that these genes were mainly related to immune pathways. As indicated by immune cell infiltration analysis, the expression of immune cells between PD and the control group was significantly different. ROC curve results showed five genes had diagnostic value, and several potential chemical compounds were predicted to target the genes. Our findings demonstrate a reduced risk of PD in patients with DR. We also found that PD and DR are closely related in terms of inflammation, which provides clues for further exploring the common mechanisms and interaction of these two diseases.

Rapid quantitative 1H-13C two-dimensional NMR with high precision.

Two dimensional (2D) 1H-13C heteronuclear single-quantum correlation (HSQC) spectroscopy has recently been proposed for quantitative determination of typical linear low density polyethylene (LLDPE) with high accuracy. It requires highly precise measurement to achieve further reliable quantification. In this context, this paper aims at determining conditions that allow the achievement of high precision. On the basis of the optimized parameters, two time-saving strategies, nonuniform sampling (NUS) and band-selective HSQC are evaluated on model polyolefins in terms of repeatability. Precision better than 0.3% and 5% for ethylene content (E mol%) and 1-hexene content (H mol%) of the model poly(ethylene-co-1-hexene)s are obtained with 50% NUS or band-selective HSQC. Moreover, dramatic precision enhancements can be achieved with the combination of band-selective HSQC and 50% NUS, in which repeatabilities better than 0.15% and 2.5% for E mol% and H mol% are observed. The experiment times are reduced to about 0.5 h. These methods open important perspectives for rapid, precise and accurate quantitative analysis of complex polymers.

Protective effects of endotoxin tolerance on peripheral lipopolysaccharide-induced neuroinflammation and dopaminergic neuronal injury.

CONTEXT: Parkinson's disease is a common chronic neurodegenerative disease characterized by massive loss of dopaminergic neurons in the substantia nigra. Neuroinflammation has been shown to play an important role in the pathogenesis of neurodegenerative diseases such as Parkinson's disease. The role of immune tolerance in neuroinflammation and neurodegenerative diseases induced by peripheral factors is unclear. OBJECTIVE: This study established a model of endotoxin tolerance to explore the protective effect of endotoxin tolerance on Parkinson-like changes induced by repeated peripheral injections of high-dose LPS, and to explore its inflammatory mechanism. MATERIALS AND METHODS: In this study, mice were injected intraperitoneally with low dose (0.5 mg/kg) LPS for 4 days to induce endotoxin tolerance (ET). Then, high-dose (1 mg/kg) LPS was injected continuously intraperitoneally for 4 days to induce Parkinson-like changes. Cytokines were detected by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Activation of microglial cells was detected by protein expression of CD68 and ionized calcium binding adapter molecule 1(Iba-1) by Western blotting and immunofluorescence. Hematoxylin and eosin staining and expression of tyrosine hydroxylase (TH) and dopamine (DA) were used to assess dopaminergic neuronal injury. The open field test and muscle tension test were used to assess behavioral disorders. RESULTS: As expected, compared with non-ET animals, ET preconditioning significantly reduced the production of inflammatory cytokines in the substantia nigra, inhibited microglial activation, and alleviated the pathological changes of dopaminergic neurons. CONCLUSIONS: ET may be a promising intervention method for neurodegenerative diseases.HighlightsET was successfully induced by continuous low-dose intraperitoneal LPS injection in mice.ET pretreatment inhibited neuroinflammation in the SN induced by continuous peripheral high doses of LPS.ET pretreatment inhibited continuous peripheral high-dose LPS injection-induced microglial activation in the SN.ET pretreatment decreased LPS-induced functional impairment of dopaminergic neurons.ET reversed the morphological changes of dopaminergic neurons induced by peripheral high-dose LPS.ET pretreatment improved continuous peripheral high-dose LPS injection-induced behavioral impairment.

Autonomic behavioral impairment induced by simazine exposure during early life of male mouse is mediated by Lmx1a/Wnt1 pathway.

Simazine is a widely used herbicide and known as an environmental estrogen. Multiple studies have proved simazine can induced the degeneration of dopaminergic neuron resulting in a degenerative disease-like syndrome. Herein, we explored the neurotoxicity of simazine on the dopaminergic nervous system of embryos and weaned offspring during the maternal gestation period or the maternal gestation and lactation periods. We found that simazine disturbed the crucial components expression involved in Lmx1a/Wnt1 pathway of dopaminergic neuron in embryonic and weaned offspring. Furthermore, morphological and behavioral tests performed on weaned male offspring treated by simazine suggested that the grip strength, autonomic exploring, and the space sense ability were weakened, as well as the pathological damage of dopaminergic neuron was clearly observed. But, the same neurotoxicity of simazine is less significantly observed in female offspring. Our findings will provide reliable reference for the determination of environmental limits and new insight into the pathogenesis of nonfamilial neurodegenerative diseases related to environmental risk factors.

Soybean isoflavones protect SH-SY5Y neurons from atrazine-induced toxicity by activating mitophagy through stimulation of the BEX2/BNIP3/NIX pathway.

Atrazine (ATR) is a widely used herbicide that can induce the degeneration of dopaminergic (DAergic) neurons in the substantia nigra, resulting in a Parkinson's disease-like syndrome. Despite the high risk of environmental exposure, few studies have investigated strategies for the prevention of ATR neurotoxicity. Our previous studies demonstrated that ATR can impair mitochondrial function, leading to metabolic failure. Cells maintain mitochondrial quality through selective autophagic elimination, termed mitophagy. Soybean isoflavones (SI) possess multiple beneficial bioactivities, including preservation of mitochondria function, so it was hypothesized that SI can protect neurons against ATR toxicity by promoting mitophagy. Pretreatment of SH-SY5Y neurons with SI prevented ATR-induced metabolic failure and cytotoxicity as assessed by intracellular ATP, Na+-K+-ATPase activity, mitochondrial membrane potential, and cell viability assays. The neuroprotective efficacy of SI was superior to the major individual components genistein, daidzein, and glycitein. Ultrastructural analyses revealed that ATR induced mitochondrial damage, while SI promoted the sequestration of damaged mitochondria into autophagic vesicles. Soybean isoflavones also induced mitophagy as evidenced by upregulated expression of BNIP3/NIX, BEX2, and LC3-II, while co-treatment with the mitophagy inhibitor Mdivi-1 blocked SI-mediated neuroprotection and prevented SI from reversing ATR-induced BEX2 downregulation. Furthermore, BEX2 knockdown inhibited SI-induced activation of the BNIP3/NIX pathway, mitophagy, and neuroprotection. These findings suggest that SI protects against ATR-induced mitochondrial dysfunction and neurotoxicity by activating the BEX2/BNIP3/NIX pathway.

The Keap1/Nrf2-ARE signaling pathway is involved in atrazine induced dopaminergic neurons degeneration via microglia activation.

OBJECTIVE: To investigate the mechanisms of ATR-induced dopaminergic toxicity by microglia activation and the response of the Keap1/ Nrf2- ARE signaling pathway. METHODS: Wistar rats were treated with 50, 100 and 200 mg/kg ATR and BV-2 microglia cells were treated with 50, 100 µM ATR or 100 ng/mL LPS, respectively. Rats behavioral responses and histopathological changes were monitored. Immunohistochemical and immunofluorescence analysis detected Iba-1 and TH+ cells in rats. Keap1/Nrf2-ARE signaling-related proteins and inflammatory factors from BV-2 cells and rats were detected using ELISA, Western blot and Real-time PCR. RESULTS: After ATR treatment, the grip strength of Wistar rats was significantly decreased, and anxiety were clearly observed. TH+ neurons were reduced, however, the number of microglia cells and Iba-1 levels were increased clearly in SN. The release of ROS, TNF-α and IL-Iß were increased, and levels of SOD and GSH-Px were significantly decreased. Keap1 mRNA expression and protein levels were decreased, while nuclear Nrf2 mRNA expression and protein levels were both increased in vivo and in vitro. CONCLUSION: ATR could significantly activate microglia and exacerbate neurotoxicity and neuroinflammation, leading to accelerate dopaminergic neuron cell death by inhibiting Keap1/Nrf2-ARE signaling pathway.

Fluorinated α-Diimine Nickel Mediated Ethylene (Co)Polymerization.

Fluorine substituents in transition metal catalysts are of great importance in olefin polymerization catalysis; however, the comprehensive effect of fluorine substituents is elusive in seminal late transition metal α-diimine catalytic system. In this contribution, fluorine substituents at various positions (ortho-, meta-, and para-F) and with different numbers (Fn ; n=0, 1, 2, 3, 5) were installed into the well-defined N-terphenyl amine and thus were studied for the first time in the nickel α-diimine promoted ethylene polymerization and copolymerization with polar monomers. The position of the fluorine substituent was particularly crucial in these polymerization reactions in terms of catalytic activity, polymer molecular weight, branching density, and incorporation of polar monomer, and thus a picture on the fluorine effect was given. As a notable result, the ortho-F substituted α-diimine nickel catalyst produced highly linear polyethylenes with an extremely high molecular weight (Mw =8703 kDa) and a significantly low degree of branching of 1.4/1000 C; however, the meta-F and/or para-F substituted α-diimine nickel catalysts generated highly branched (up to 80.2/1000 C) polyethylenes with significantly low molecular weights (Mw =20-50 kDa).

Effect of atrazine on accumulation of iron via the iron transport proteins in the midbrain of SD rats.

Atrazine (ATR), a widely used herbicide that belongs to the triazine class, has detrimental effects on several organ systems. It has also been shown that ATR exposure results in dopaminergic neurotoxicity. However, the mechanism of herbicides causing ferroptosis in neurons is less concerned. So, the present study aimed to investigate the effects of long-term oral exposure to ATR on ferroptosis in adult male rats. In this study, we show that there was a dose-dependent increase in the concentration of iron in the midbrain. Simultaneously, the expression of tyrosine hydroxylase (TH) and Synuclein (α-syn) were altered by the ATR. We carried out miRNA profiling brain tissue in order to identify factors that mediate ferroptosis. We also found that the mRNA and protein expression of the transferrin receptor (TFR), divalent metal transporter 1 (DMT1), hephaestin (HEPH), and ferroportin 1 (Fpn1) in the midbrain were affected by ATR. Based on the current results and previously published data, it is clear that exposure of adult male rats to high doses of ATR leads to iron loading in the midbrain. The long-term adverse effects of ATR on the midbrain have a special relevance after exposure.

Injury to dopaminergic neurons development via the Lmx1a/Wnt1 autoregulatory loop induced by simazine.

Simazine is a kind of persistent organic pollutant that is detected in both ground and water and has several routes of exposure. Here, we explored the mechanisms underlying simazine-related effects on dopaminergic neurons via development-related factors using mouse embryos and embryonic mesencephalic hybrid cell line (MN9D cells). We treated pregnant mice with 50 µg/kg bw, 200 µg/kg bw simazine from the 0.5 day to the 10.5 day of embryonic phase and MN9D cells with 600 µM simazine for 24 h to research the mechanism of dopaminergic neurons acute respond to simazine through preliminary experiments. Protein expressions of LIM homeobox transcription factor 1-alpha (Lmx1a) and LIM homeobox transcription factor 1-beta (Lmx1b) displayed a dose- and time-dependent increase after the exposure to simazine. In the 200 µg/kg bw of embryos and the 24h-600 µM of MN9D cells, protein levels of dopaminergic developmental factors were significantly upregulated, and dopaminergic function was significantly damaged for the abnormal expression of Dyt5b. We demonstrated simazine induced the injury to dopaminergic neurons via the Lmx1a/wingless-related integration site 1 (Wnt1) and Lmx1b pathways. In the transfection experiments, we knocked down Lmx1a and Lmx1b of cells to verify the potential target of simazine-induced injury to dopaminergic neurons, respectively. We detected the protein and mRNA levels of development-related genes of dopaminergic neurons and intracellular dopamine levels in different treatment groups. Based on our experiments' results, we demonstrated an acute response to 24 h-600 µM simazine treatment, the simazine-induced injury to dopaminergic neuronal which leads to abnormal dopamine levels and dopaminergic impairment is via the activation of the Lmx1a/Wnt1 autoregulatory loop. Lmx1a is a promising target in the search for the mechanisms underlying simazine-induced dopaminergic injury.

Kinetics and metabolism of mercury in rats fed with mercury contaminated rice using mass balance and mercury isotope approach.

Consumption of mercury (Hg) contaminated rice can be a major environmental health issue but the toxicokinetics is not well known. Hg isotopes have been shown to be good tracers in studying Hg exposure and metabolic processes. We established a Hg mass balance and Hg isotope model in rats fed with Hg contaminated rice (THg 51.3 ng/g; MeHg 25 ng/g) for 90 days to investigate Hg toxicokinetics. Overall 80% of feeding THg was recovered in rat body and excrement, while the excrement accounted for 55% of total observed THg in rats. Feces were the main route of Hg elimination in rats, while urinary excretion was negligible. However, only 32% of utilized MeHg was recovered in rats, indicating significant demethylation of MeHg in rat body. Positive net fractionations of δ202Hg (relative to the feeding rice) were observed in hair and blood samples (1.21‰ and 1.25‰, respectively), which have similar trend with the results obtained in human hair study, exhibiting higher δ202Hg values (2‰- 3‰) than consumed fish and rice. Most importantly, we observed negative net fractionations in feces (-0.44‰), which confirmed the missed Hg with negative δ202Hg signal. We concluded that mass balance and Hg isotope are useful tools for quantifying toxicokinetics of Hg. Demethylation of MeHg in the intestine were the important detoxification process in rat body characterizing with negative net Hg fractionations in feces.

Soybean isoflavones prevent atrazine-induced neurodegenerative damage by inducing autophagy.

Atrazine (ATR) is a widely used herbicide with documented dopaminergic (DAergic) neurotoxicity that can lead to a Parkinson's disease (PD)-like motor syndrome. However, there have been few studies on preventative interventions. The aim of the present study was to investigate the neuroprotective efficacy of soybean isoflavones (SI) and associated molecular mechanisms in a rat model of ATR-induced DAergic toxicity. Male Sprague-Dawley rats (6 weeks old) received daily intraperitoneal injection of SI (10, 50, or 100 mg/kg) or vehicle followed 1 h later by oral gavage of ATR (50 mg/kg) for 45 consecutive days. Open field and grip-strength tests indicated no differences in motor function among treatment groups. Alternatively, histopathology revealed neuronal damage in the striatum of rats receiving vehicle plus ATR that was ameliorated by SI pretreatment. SI attenuate ATR-induced oxidative stress (indicated by MDA accumulation and GSH depletion) and inflammatory damage (as evidenced by TNF-α and IL-6 elevation) in the substantia nigra. ATR increased expression of the pro-apoptotic factor Bax and reduced expression levels of the DA synthesis enzyme tyrosine hydroxylase (TH) and the anti-apoptotic factor Bcl-2 in the substantia nigra and striatum. All of these effects were reversed by SI pretreatment, suggesting that SI can inhibit ATR-induced apoptosis of DAergic neurons. ATR also inhibited autophagy in the substantial nigra as evidenced by LC3-II and Beclin-1 downregulation and increased expression of p62, whereas SI pretreatment reversed these effects, indicating autophagy induction. Furthermore, ATR increased the expression of mTOR and reduced the expression of phosphorylated S6 (p-S6) and BEX2 in the substantia nigra. Collectively, these findings suggest that SI can prevent ATR-mediated degeneration of DAergic neurons by inducing autophagy through an mTOR-dependent signaling pathway.

Wnt1 silencing enhances neurotoxicity induced by paraquat and maneb in SH-SY5Y cells.

Wingless (Wnt) signaling regulates the proliferation and differentiation of midbrain dopamine (DA) neurons. Paraquat (PQ) and maneb (MB) are environmental pollutants that can be used to model Parkinson's disease (PD) in rodents. A previous study demonstrated that developmental exposure to PQ and MB affects the expression of Wnt1, Wnt5a, nuclear receptor-related factor 1 (NURR1) and tyrosine hydroxylase (TH). However, how Wnt signaling regulates these developmental factors in vitro is yet to be determined. To explore this, SH-SY5Y cells were exposed to PQ and MB. The results of the current study indicated that exposure to PQ and MB decreased Wnt1, ß-catenin, NURR1 and TH levels and increased Wnt5a levels. Furthermore, Wnt1 silencing has the same effect as exposure to PQ and MB. Additionally, the neurotoxicity induced by PQ and MB is more severe in siWnt1-SH-SY5Y cells compared with normal SH-SY5Y cells. Therefore, Wnt1 may serve an important role in regulating developmental DA factors, and may be a candidate gene for PD diagnosis or gene therapy.

Identification of miRNA-7 as a regulator of brain-derived neurotrophic factor/α-synuclein axis in atrazine-induced Parkinson's disease by peripheral blood and brain microRNA profiling.

Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine; ATR) is widely used as an herbicide, and its accumulation in the environment is a health risk to humans; for instance, it has been shown to cause dopaminergic neurotoxicity. MicroRNAs (miRNAs) are endogenous small RNAs that regulate gene expression in diverse physiological contexts; however, the extent of their involvement in the development of Parkinson's disease (PD) is not known. In this study, we carried out miRNA profiling of peripheral blood and brain tissue in a rat model of PD in order to identify factors that mediate PD pathogenesis. The miRNAmiR-7 is known to cause the downregulation of α-synuclein (α-syn), which is linked to the neuropathology of PD. Here we found that miR-7 was upregulated in brain tissue but downregulated in peripheral blood of rats with ATR-induced PD. We also found that miR-7 regulates the expression of brain-derived neurotrophic factor (BDNF) through an auto regulatory mechanism. These findings indicate that miRNA-7 regulates the BDNF/α-syn axis in the early stages of PD and can serve as a biomarker or therapeutic target for disease treatment.

The Effects of Maternal Atrazine Exposure and Swimming Training on Spatial Learning Memory and Hippocampal Morphology in Offspring Male Rats via PSD95/NR2B Signaling Pathway.

Atrazine (ATR), a widely used herbicide, has been previously shown to damage spatial memory capability and the hippocampus of male rats during the development. It has also been indicated that physical exercise can improve learning and memory in both humans and animals, as a neuroprotective method. Our aim here was to investigate the effect of maternal ATR exposure during gestation and lactation on spatial learning and memory function and hippocampal morphology in offspring and to further evaluate the neuroprotective effect of swimming training and identify possible related learning and memory signaling pathways. Using Sprague-Dawley rats, we examined behavioral and molecular biology effects associated with maternal ATR exposure, as well as the effects of 8 or 28 days swimming training. Maternal exposure to ATR was found to impair spatial learning and memory by behavioral test, damage the hippocampal morphology, and reduce related genes and proteins expression of learning and memory in the hippocampus. The extended, 28 days, period of swimming training produced a greater amelioration of the adverse effects of ATR exposure than the shorter, 8 days, training period. Our results suggest that maternal ATR exposure may damage the spatial learning and memory of offspring male rats via PSD95/NR2B signaling pathway. The negative effect of ATR could be at least partially reversed by swimming training, pointing to a potential neuroprotective role of physical exercise in nervous system diseases accompanying by learning and memory deficit.

The MEK/ERK/CREB signaling pathway is involved in atrazine induced hippocampal neurotoxicity in Sprague Dawley rats.

Atrazine (ATR) is a commonly used artificial synthetic herbicide world-wide, which has been implicated as a potential threat to human health. Previous studies have demonstrated that exposure to ATR affects hippocampus-dependent learning and memory in rodents, but the exact molecular mechanism remains to be elucidated. In this study, we investigated the effect of ATR on the hippocampus of postnatal day 35 male Sprague Dawley (SD) rats administered doses of either 10 or 100 mg/kg body weight (BW)/day of ATR for a period of 30 days. A Morris water maze (MWM) test revealed that ATR treatment impaired memory performance in the spatial probe test, especially amongst the high-dose group. Moreover, analysis by electron microscopy showed that hippocampal neuron ultrastructure in the dentate gyrus (DG) and cornu ammonis 1 (CA1) sub-regions was impaired in the ATR-treated groups. Finally, a downregulation in the mRNA and protein expression levels of members of the MEK/ERK/CREB pathway and downstream factors brain-derived neurotrophic factor (BDNF) and Zif268 was observed in hippocampal tissue following ATR treatment. Taken together, these results suggest that developmental exposure to ATR is able to induce functional and morphological lesions in the hippocampus of SD rats, and that the MEK/ERK/CREB signaling pathway may be involved in this process.

Developmental Exposure to Atrazine Impairs Spatial Memory and Downregulates the Hippocampal D1 Dopamine Receptor and cAMP-Dependent Signaling Pathway in Rats.

Atrazine (ATR) is a widely used herbicide that has been implicated as a neurotoxicant. Recent experimental evidence has implicated that ATR exposure also appears to have adverse effects on the hippocampus, which is a critical region for learning and memory. The aim of the present study was to investigate the effects of ATR toxicity on the hippocampus of developing rats. Postnatal day (PND) 28 male Sprague⁻Dawley (SD) rats received ATR by oral gavage at 10 or 100 mg/kg bodyweight (BW) for 30 consecutive days and were sacrificed at PND 90. Behavioral test results indicated that spatial learning and memory were affected by ATR treatment. Electron microscopy analysis showed that the ultrastructures of the hippocampus were altered in the ATR-treated groups, as compared to the control group. Additionally, ATR treatment impacted dopamine and D1 dopamine receptor (D1DR) contents through different mechanisms. Reduced mRNA and protein expression levels of factors involved in the cAMP-dependent signaling pathway were also detected. These results indicate that the developmental exposure of rats to ATR can damage the hippocampus and spatial memory, which might be related to the downregulation of expression levels of the D1DR and its downstream signaling pathway.

LC3-II may mediate ATR-induced mitophagy in dopaminergic neurons through SQSTM1/p62 pathway.

Atrazine (2-chloro-4-ethylamino-6-isopropylamine-1,3,5-triazine; ATR) has been demonstrated to regulate autophagy- and apoptosis-related proteins in doparminergic neuronal damage. In our study, we investigated the role of LC3-II in ATR-induced degeneration of dopaminergic neurons. In vivo dopaminergic neuron degeneration model was set up with ATR treatment and confirmed by the behavioral responses and pathological analysis. Dopaminergic neuron cells were transfected with LC3-II siRNA and treated with ATR to observe cell survival and reactive oxygen species release. The process of mitochondrial autophagy and the neurotoxic effects of mitochondrial autophagy were detected by immunofluorescence assay, immunohistochemical analysis, real-time PCR, and western blot analysis. Results showed that after ATR treatment, the grip strength of Wistar rats was significantly decreased, and behavioral signs of anxiety were clearly observed. The mRNA and protein levels of tyrosine hydroxylase, LC3-II, PINK1, and Parkin were significantly decreased in ATR-induced rat dopaminergic neurons and PC-12 cells, while the mRNA expression and protein levels of SQSTM1/p62 and Parl were increased. Exposure to ATR also led to accumulation of autophagic lysosomes and autophagic bodies along with significantly decreased levels of dopaminergic neurons and alterations in mitochondrial homeostasis, which was reversed by LC3-II siRNA. Our results suggest that ATR affects the mitochondria-mediated dopaminergic neuronal death, which may be mediated by LC3-II and other autophagy markers in vivo and in vitro through SQSTM1/p62 signaling pathway.

Mercury bioaccumulation and its toxic effects in rats fed with methylmercury polluted rice.

Recent evidence indicated that methylmercury (MeHg) contaminated rice can be a significant source of MeHg human exposure, but the health implications are not known. The objective of this study was to study the kinetics, speciation, and effects of MeHg contaminated rice using a rat model. Five groups of adult Sprague-Dawley rats (n=10 in each group) were fed control rice, low (10ng/g MeHg) and high (25ng/g MeHg) MeHg contaminated rice. Two groups of the positive control were fed control rice spiked with the same levels of MeHgCl. Short-term exposure to low level of spiked MeHgCl stimulated the growth of male rats while long-term exposure to spiked MeHgCl inhibited the growth in female rats. There was no temporal variation of total mercury (THg) concentrations in the rat fecal samples from each group, and the THg concentrations significantly correlated with the inorganic Hg concentrations in the feeding rice. There were significant differences in the accumulation of THg and MeHg among different groups and different organs. THg and MeHg concentrations in the kidney were the highest among the organs examined. The blood and brain had high percentages of THg as MeHg, which indicates that MeHg can easily pass through the blood-brain barrier and has a high affinity for brain tissue. Exposure to rice containing 25ng/g MeHg decreased antioxidant function and damaged the nervous system in rats, but no significant effects were found in the group fed with rice containing 10ng/g MeHg. MeHgCys in rice is less toxic than spiked MeHgCl to rats. The toxicity of MeHg both decided by its concentration and speciation.

TAT-Ngn2 Enhances Cognitive Function Recovery and Regulates Caspase-Dependent and Mitochondrial Apoptotic Pathways After Experimental Stroke.

Neurogenin-2 (Ngn2) is a basic helix-loop-helix (bHLH) transcription factor that contributes to the identification and specification of neuronal fate during neurogenesis. In our previous study, we found that Ngn2 plays an important role in alleviating neuronal apoptosis, which may be viewed as an attractive candidate target for the treatment of cerebral ischemia. However, novel strategies require an understanding of the function and mechanism of Ngn2 in mature hippocampal neurons after global cerebral ischemic injury. Here, we found that the expression of Ngn2 decreased in the hippocampus after global cerebral ischemic injury in mice and in primary hippocampal neurons after oxygen glucose deprivation (OGD) injury. Then, transactivator of transcription (TAT)-Ngn2, which was constructed by fusing a TAT domain to Ngn2, was effectively transported and incorporated into hippocampal neurons after intraperitoneal (i.p.) injection and enhanced cognitive functional recovery in the acute stage after reperfusion. Furthermore, TAT-Ngn2 alleviated hippocampal neuronal damage and apoptosis, and inhibited the cytochrome C (CytC) leak from the mitochondria to the cytoplasm through regulating the expression levels of brain-derived neurotrophic factor (BDNF), phosphorylation tropomyosin-related kinase B (pTrkB), Bcl-2, Bax and cleaved caspase-3 after reperfusion injury in vivo and in vitro. These findings suggest that the downregulation of Ngn2 expression may have an important role in triggering brain injury after ischemic stroke and that the neuroprotection of TAT-Ngn2 against stroke might involve the modulation of BDNF-TrkB signaling that regulates caspase-dependent and mitochondrial apoptotic pathways, which may be an attractive therapeutic strategy for cerebral ischemic injury.