FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury.

BACKGROUND: Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood. METHODS: Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice. RESULTS: We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1high neutrophils. In the chronic stage, the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1high neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI. CONCLUSIONS: FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.

Inhibitory Effects of Sulfated Polysaccharides from the Sea Cucumber Cucumaria Frondosa against Aß40 Aggregation and Cytotoxicity.

Abnormal aggregation and deposition of Aß is one of the causative agents for Alzheimer's disease. The development of inhibitors for Aß aggregation has been considered a possible method to prevent and treat Alzheimer's disease. Edible sea cucumbers contain many bioactive molecules, including saponins, phospholipids, peptides, and polysaccharides. Herein, we report that polysaccharides extracted from sea cucumber Cucumaria frondosa could reduce the aggregation and cytotoxicity of Aß40. By utilizing multiple biochemical and biophysical instruments, we found that the polysaccharides could inhibit the aggregation of Aß40. A chemical kinetics analysis further suggested that the major inhibitory effects of the polysaccharides were achieved by disassembling mature fibrils, which in turn reduced the cytotoxicity of Aß. These results suggested that the polysaccharides extracted from sea cucumber could be used as an effective inhibitor for Aß.

Rational Design of a Cocktail of Inhibitors against Aß Aggregation.

It has been reported that many molecules could inhibit the aggregation of Aß (amyloid-ß) through suppressing either primary nucleation, secondary nucleation, or elongation processes. In order to suppress multiple pathways of Aß aggregation, we screened 23 small molecules and found two types of inhibitors with different inhibiting mechanisms based on chemical kinetics analysis. Trp-glucose conjugates (AS2) could bind with fibril ends while natural products (D3 and D4) could associate with monomers. A cocktail of these two kinds of molecules achieved co-inhibition of various fibrillar species and avoid unwanted interference.

A study on the neurodevelopment outcomes of late preterm infants.

BACKGROUND: The study is intended to fill the knowledge gap about the neuropsychology and neuromotor developmental outcomes, and identify the perinatal risk factors for late preterm infants (LPIs 34~36 weeks GA) born with uncomplicated vaginal birth at the age of 24 to 30 months. METHODS: The parents/guardians of 102 late preterm infants and 153 term infants, from 14 community health centers participated in this study. The Modified Checklist for Autism in Toddlers (M-CHAT) questionnaire, the Chinese version of Gesell Development Diagnosis Scale (GDDS), and the Sensory Integration Schedule (SIS), a neurological examination for motor disorders (MD) were carried out. Infants screening positive to the M-CHAT were referred to specialist autism clinics. RESULTS: Forty-six LPIs (45.1%) scored low in GDDS. Nine LPIs (8.8%) scored positive on M-Chat. 8.8% of LPIs (9 out of 102) were diagnosed MD (p <  0.05). Compared with their full-term peers, LPIs had statistically lower scores in GDDS and the Child Sensory Integration Checklist. LPIs who had positive results on M-CHAT showed unbalanced abilities in every part of GDDS. Risk factors of twin pregnancies, pregnancy induced hypertension and premature rupture of membranes had negative correlation with GDDS (all p <  0.05). Birth weight and gestational age were positively correlated with GDDS. CONCLUSIONS: LPIs shall be given special attention as compared to normal deliveries, as they are at increased risk of neurodevelopment impairment, despite being born with no major problems. Some perinatal factors such as twin pregnancies, and pregnancy induced hypertension etc. have negative effects on their neurodevelopment. Regular neurodevelopmental follow- up and early intervention can benefit their long term outcomes.

Differential Modulation of the Aggregation of N-Terminal Truncated Aß using Cucurbiturils.

Modulating the aggregation of Aß has long been considered to be one of the potential methods to treat Alzheimer's disease (AD). It has been found that different Aß species, including N-terminal truncated or/and modified Aß, co-exist in the brain of AD patients. Yet, there is currently little detailed work about the specific modulation of these Aß species which hinders us to understand their roles in patients' brain. Using thioflavin T (ThT) kinetics and transmission electron microscope, here we showed that cucurbit[7]uril and cucurbit[8]uril could inhibit the aggregation of both Aß4-40 and Aß1-40 through host-guest interactions. Chemical kinetics analysis suggested that this happened through inhibiting the elongation process by binding with fibril ends. In addition, cucurbiturils showed greater capability on the inhibition of Aß4-40 than Aß1-40 , which was possibly due to the N-terminal phenylalanine residue of Aß4-40 . Our work provided new insights for the development of host-guest chemistry based inhibitors for the aggregation of different Aß species.