CD8 positive T-cells decrease neurogenesis and induce anxiety-like behaviour following hepatitis B vaccination.

Mounting evidence indicates the involvement of peripheral immunity in the regulation of brain function, influencing aspects such as neuronal development, emotion, and cognitive abilities. Previous studies from our laboratory have revealed that neonatal hepatitis B vaccination can downregulate hippocampal neurogenesis, synaptic plasticity and spatial learning memory. In the current post-epidemic era characterized by universal vaccination, understanding the impact of acquired immunity on neuronal function and neuropsychiatric disorders, along with exploring potential underlying mechanisms, becomes imperative. We employed hepatitis B vaccine-induced CD3 positive T cells in immunodeficient mice to investigate the key mechanisms through which T cell subsets modulate hippocampal neurogenesis and anxiety-like behaviours. Our data revealed that mice receiving hepatitis B vaccine-induced T cells exhibited heightened anxiety and decreased hippocampal cell proliferation compared to those receiving phosphate-buffered saline-T cells or wild-type mice. Importantly, these changes were predominantly mediated by infiltrated CD8+ T cells into the brain, rather than CD4+ T cells. Transcriptome profiling of CD8+ T cells unveiled that C-X-C motif chemokine receptor 6 positive (CXCR6+) CD8+ T cells were recruited into the brain through microglial and astrocyte-derived C-X-C motif chemokine ligand 16 (CXCL16). This recruitment process impaired neurogenesis and induced anxiety-like behaviour via tumour necrosis factor-α-dependent mechanisms. Our findings highlight the role of glial cell derived CXCL16 in mediating the recruitment of CXCR6+CD8+ T cell subsets into the brain. This mechanism represents a potential avenue for modulating hippocampal neurogenesis and emotion-related behaviours after hepatitis B vaccination.

Aagab acts as a novel regulator of NEDD4-1-mediated Pten nuclear translocation to promote neurological recovery following hypoxic-ischemic brain damage.

Hypoxic-ischemic encephalopathy (HIE) is a main cause of mortality and severe neurologic impairment in the perinatal and neonatal period. However, few satisfactory therapeutic strategies are available. Here, we reported that a rapid nuclear translocation of phosphatase and tensin homolog deleted on chromosome TEN (PTEN) is an essential step in hypoxic-ischemic brain damage (HIBD)- and oxygen-glucose deprivation (OGD)-induced neuronal injures both in vivo and in vitro. In addition, we found that OGD-induced nuclear translocation of PTEN is dependent on PTEN mono-ubiquitination at the lysine 13 residue (K13) that is mediated by neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1). Importantly, we for the first time identified α- and γ-adaptin binding protein (Aagab) as a novel NEDD4-1 regulator to regulate the level of NEDD4-1, subsequently mediating Pten nuclear translocation. Finally, we demonstrated that genetic upregulation of Aagab or application of Tat-K13 peptide (a short interference peptide that flanks K13 residue of PTEN) not only reduced Pten nuclear translocation, but also significantly alleviated the deficits of myodynamia, motor and spatial learning and memory in HIBD model rats. These results suggest that Aagab may serve as a regulator of NEDD4-1-mediated Pten nuclear translocation to promote functional recovery following HIBD in neonatal rats, and provide a new potential therapeutic target to guide the clinical treatment for HIE.

Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models.

Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson's disease (PD); however, there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy. This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable α-synuclein knockdown peptide, Tat-ßsyn-degron, that may have therapeutic potential. The peptide effectively reduced the level of α-synuclein via proteasomal degradation both in cell cultures and in animals. Tat-ßsyn-degron decreased α-synuclein aggregates and microglial activation in an α-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T α-synuclein. Moreover, Tat-ßsyn-degron reduced α-synuclein levels and significantly decreased the parkinsonian toxin-induced neuronal damage and motor impairment in a mouse toxicity model of PD. These results show the promising efficacy of Tat-ßsyn-degron in two different animal models of PD and suggest its potential use as an effective PD therapeutic that directly targets the disease-causing process.

7,8-dihydroxyflavone Ameliorates Motor Deficits Via Suppressing α-synuclein Expression and Oxidative Stress in the MPTP-induced Mouse Model of Parkinson's Disease.

BACKGROUND: Parkinson disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and diminished dopamine content in the striatum, which is at least partly associated with α-synuclein protein overexpression in these neurons. Recent reports show that 7,8-dihydroxyflavone (DHF), a TrkB agonist, has beneficial effects in animal model of PD. However, it is unclear whether the therapeutic effects of DHF are associated with the expression of α-synuclein. AIMS: In this study, we investigated the protective effects of DHF on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced deficit of motor functions, the loss of dopaminergic neurons and the expression of α-synuclein as well as antioxidative activity in the C57BL/6 mice. RESULTS: Mice were treated with MPTP (30 mg/kg, i.p.) once a day for 5 days to induce dopaminergic neuron death in the SN. DHF (5 mg/kg, i.p.) was administrated once a day from the first day of MPTP injection until 9 days after the last injection of MPTP. Behavioral tests showed that DHF succeeded in ameliorating the impaired motor functions in the MPTP-treated mice. The immunohistochemical assay showed that the amelioration of motor function was accompanied by a reduction in the loss of dopaminergic neurons in the SN and striatum. Western blot analyses showed that DHF prevented the inactivation of TrkB and suppressed α-synuclein overexpression in the SN and striatum following MPTP treatment. Antioxidative activity detection revealed that DHF prevented MPTP-induced reduction in glutathione and total superoxide dismutase activity in the SN and striatum. CONCLUSION: Taken together, these results indicate that DHF treatment may suppress the accumulation of α-synuclein and oxidative stress via activating TrkB and subsequently block the loss of dopaminergic neurons in the SN and striatum, thereby ameliorating MPTP-induced motor deficits in the C57BL/6 mice.

Towards prenatal biomonitoring in Nanjing, China: lead and cadmium levels in the duration of pregnancy.

BACKGROUND: Prenatal lead and cadmium exposure will not only influence the mother' organ systems, but also will provide an environment that may influence the fetus and neonate in a harmful way.In the present study, we detected the blood lead levels (BLLS) and cadmium levels for the duration of pregnancy and 6-12 weeks after delivery and to analyze the influencing factors of BLLs in healthy pregnant women. METHODS: A cohort study survey was carried out. We recruited 174 healthy pregnant women without pregnancy or obstetric complications or abnormal pregnancy outcomes as the gravida group, and 120 healthy non-pregnant women as the control group. RESULTS: The lead concentrations in the three pregnancy trimesters and in the postpartum period were: (5.98 ± 2.43), (5.54 ± 2.01), (5.59 ± 1.97), and (6.76 ± 1.74) µg/dl; and (6.75 ± 2.13) µg/dl in the control group. The cadmium concentrations in the three pregnancy trimesters and postpartum period were 1.61 ± 0.45, 1.63 ± 0.46, 1.64 ± 0.49, and 1.67 ± 0.57. We found that the BLLs in the gravida group were lower than in the control group during all three trimesters. Occupations, supplement nutritional elements (dietary supplements and nutritional (food) elements), and the time of house painting could affect BLLs in pregnant women. Lead-related occupations, using cosmetics, and living in a house painted more recently than one year previously are risk factors of high BLLs among pregnant women, while calcium, iron, zinc, and milk supplements are protective factors. CONCLUSIONS: These findings may help people, especially pregnant women, to reduce lead exposure via supplements of calcium, iron, zinc, and milk or avoiding contacting risk factors.

Breast milk lead and cadmium levels in suburban areas of Nanjing, China.

OBJECTIVE: To evaluate levels of lead (Pb) and cadmium (Cd) in the breast milk in the second postpartum month, to investigate the relationship between Pb/Cd levels in breast milk and some sociodemographic parameters, and to explore whether these levels affect the infants' physical status or the mothers' psychological status (postpartum depression). METHODS: A cross-sectional study was conducted between November 2009 and December 2010. Altogether 170 healthy mothers were enrolled from Nanjing Maternity and Child Health Care Hospital. The inclusion criteria were: voluntary to participate in this study, healthy, with no chronic disease, breastfeeding in the second postpartum month, living in a suburban but not non-industrial area of Nanjing, and not occupationally exposed to toxic metals. All the mothers completed a questionnaire and were evaluated based on the Edinburgh Postpartum Depression Scale (EPDS) to identify the risk of postpartum depression. Pb and Cd levels in breast milk were determined by inductively coupled plasma mass spectroscopy. The infants of these mothers were examined for their z scores of weight for age, length for age, head circumference for age, and body mass index for age. RESULTS: The median breast milk levels of Pb and Cd were 40.6 µg/L and 0.67 µg/L, respectively. In 164 (96.5%) of the 170 samples, Pb levels were higher than the limit reported by the World Health Organization (> 5 µg/L). Breast milk Cd level was > 1 µg/L in 54 (31.8%) mothers. The mothers with a history of anemia had a higher breast milk Pb level than those without a history of anemia (41.1 µg/L vs. 37.9 µg/L, P = 0.050). The median breast milk Cd level in those who were active and passive smokers during pregnancy was significantly higher than that in non-smokers (0.88 µg/L vs. 0.00 µg/L, P = 0.025). The breast milk Cd level in the mothers not taking iron and vitamin supplements for 2 months postpartum was higher than in those taking the supplements (iron supplement: 0.74 µg/L vs. 0.00 µg/L, P = 0.025; vitamin supplement: 0.78 µg/L vs. 0.00 µg/L, P = 0.005). Breast milk Cd level at the second postpartum month was negatively correlated with the z scores of head circumference (r = - 0.248, P = 0.042) and weight for age at birth (r =- 0.241, P = 0.024) in girls. No correlation was found between the breast milk Pb/Cd levels and the EPDS scores. CONCLUSION: Considering the high levels of Pb and Cd in breast milk in this study, breast milk monitoring programs are necessary.