Identification of RP11-770J1.4 as immune-related lncRNA regulating the CTXN1-cGAS-STING axis in histologically lower-grade glioma.

Human gliomas are lethal brain cancers. Emerging evidence revealed the regulatory role of long noncoding RNAs (lncRNAs) in tumors. Here, we performed a comprehensive analysis of the expression profiles of RNAs in histologically lower-grade glioma (LGG). Enrichment analysis revealed that glioma is influenced by immune-related signatures. Survival analysis further established the close correlation between network features and glioma prognosis. Subsequent experiments showed lncRNA RP11-770J1.4 regulates CTXN1 expression through hsa-miR-124-3p. Correlation analysis identified lncRNA RP11-770J1.4 was immune related, specifically involved in the cytosolic DNA sensing pathway. Downregulated lncRNA RP11-770J1.4 resulted in increased spontaneous gene expression of the cGAS-STING pathway. Single-cell RNA sequencing analysis, along with investigations in a glioblastoma stem cell model and patient sample analysis, demonstrated the predominant localization of CTXN1 within tumor cores rather than peripheral regions. Immunohistochemistry staining established a negative correlation between CTXN1 expression and infiltration of CD8+ T cells. In vivo, Ctxn1 knockdown in GL261 cells led to decreased tumor burden and improved survival while increasing infiltration of CD8+ T cells. These findings unveil novel insights into the lncRNA RP11-770J1.4-CTXN1 as a potential immune regulatory axis, highlighting its therapeutic implications for histologically LGGs.

Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway.

Glutamate is excitotoxic to neurons. The entry of glutamine or glutamate from the blood into the brain is limited. To overcome this, branched-chain amino acids (BCAAs) catabolism replenishes the glutamate in brain cells. Branched-chain amino acid transaminase 1 (BCAT1) activity is silenced by epigenetic methylation in IDH mutant gliomas. However, glioblastomas (GBMs) express wild type IDH. Here, we investigated how oxidative stress promotes BCAAs' metabolism to maintain intracellular redox balance and, consequently, the rapid progression of GBMs. We found that reactive oxygen species (ROS) accumulation promoted the nuclear translocation of lactate dehydrogenase A (LDHA), which triggered DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation and enhanced BCAA catabolism in GBM cells. Glutamate derived from BCAAs catabolism participates in antioxidant thioredoxin (TxN) production. The inhibition of BCAT1 decreased the tumorigenicity of GBM cells in orthotopically transplanted nude mice, and prolonged their survival time. In GBM samples, BCAT1 expression was negatively correlated with the overall survival time (OS) of patients. These findings highlight the role of the non-canonical enzyme activity of LDHA on BCAT1 expression, which links the two major metabolic pathways in GBMs. Glutamate produced by the catabolism of BCAAs was involved in complementary antioxidant TxN synthesis to balance the redox state in tumor cells and promote the progression of GBMs.

Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses.

As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.

Metabolic regulation on the immune environment of glioma through gut microbiota.

The gut-brain axis has paved our way in understanding varieties of disease. The gut microbiota especially the bacterial population plays critical roles in immune system development and function. Glioma comprises 80 percent of malignant brain cancer and glioblastoma (GBM) is the most malignant kind. GBM has a reputation for its suppressive immune environment and poor patient prognosis. Moreover, altered metabolites from gut microbiota affect both systemic immune and central nervous system (CNS) immunity. Here we will focus on the crosstalk between gut microbiota and GBM, and further explore how this communication contributes to glioma initiation and development. Finally, we highlight the latest insights on the metabolic regulation of immunity through gut microbiota, which provides a promising therapeutic strategy for GBM.

[Effects of mitophagy on aerobic exercise intervention for depression in rats].

Objective: This experiment was designed to observe the effects of aerobic exercise on depressive behavior in rats induced by chronic unpredictable mild stress (CUMS), and to explore the possible mechanism by detecting the proteins related to mitochondrial autophagy. Methods: SD rats were randomly divided into three groups: blank control group (C, n=12), depression model group (D, n=12) and post-depression exercise group (D+E, n=12). Group D and D+E were modeled with CUMS for 28 days, and group D+E underwent aerobic exercise intervention for 4 weeks after model establishment. Then the behavior of rats was evaluated. The concentrations of whole brain dopamine and norepinephrine were determined by ELISA kits. The morphology and structure of mitochondria in the frontal lobe were observed with the transmission electron microscope (TEM). Mitochondrial autophagy lysosomes were localized by immunofluorescence colocalization. The expressions of LC3 and P62 proteins in the frontal lobe were measured with Western Blotting. The relative content of mitochondrial DNA was detected using Real-time PCR. Results: ①Compared with group C, the sucrose preference ratio in group D was decreased significantly(P＜0.01); Compared with group D, the sucrose preference ratio in group D+E was increased significantly (P＜0.01). ②In the open field experiment, compared with group C, group D had a significant decrease in activity, average speed and total distance (P＜0.05); Compared with group D, the average rate of activity in group D+E was significantly higher (P＜0.05). ③ELISA results showed that the levels of whole brain dopamine and norepinephrine were significantly lower in group D rats than those in group C (P＜0.05). ④Under transmission electron microscopy, compared with group C, group D had different degrees of mitochondrial swelling, decreased crest density, and intermembrane space dilation.; Compared with group D, a significant increase in mitochondrial autophagosomes and autophagic lysosomes was observed in neurons in group D+E. Increased co-localization of mitochondria with lysosomes in the D+E group could be observed under fluorescence microscopy. ⑤Compared with group C, the expression of P62 was increased significantly(P＜0.05), and LC3II/LC3I ratio was decreased significantly (P＜0.05) in group D; Compared with group D, LC3II/LC3I ratio was significantly higher in group D+E than that in group D (P＜0.05). ⑥Compared with group C, the relative number of mitochondrial DNA in the frontal lobe of group D was increased significantly (P＜0.05). Conclusion: Aerobic exercise has a significant improvement effect on depression induced by CUMS in rats, and its mechanism may be related to the upregulation of the level of linear autophagy.

Built Environment and Self-Rated Health: Comparing Young, Middle-Aged, and Older People in Chengdu, China.

OBJECTIVES: This article explores how the building-scale built environment is associated with self-rated health, examining differences in this association among younger, middle-aged, and older age groups. Features examined included building type, building condition, and sidewalk presence in front of dwellings. BACKGROUND: Understanding how the relationships between built environments and health vary across age groups helps to build a healthy environment for all. However, most studies have concentrated on the neighborhood or indoor environment, rather than whole buildings, and few have compared age groups. METHODS: This study analyzed survey data from 1,019 adults living in 40 neighborhoods in Chengdu, China, recruited through a clustered random sampling approach. It used a Bayesian logistic mixed-effects model with interaction terms between age-group indicators and other variables. RESULTS: Significant differences exist in the relationships of self-rated health with some environmental and other indicators among age groups. For older people, living in multi-floor buildings, having a household smoker, and undertaking fewer hours of weekly exercise were associated with lower odds of reporting good, very good, or excellent health. These relationships were not identified among middle-aged and younger people. More education was associated with higher odds of reporting better health among older and middle-aged groups. CONCLUSIONS: Older people experience more health-related challenges compared to middle-aged and younger people. However, among the examined built environment factors, building type was the only significant factor related to self-rated health among older people. To promote health among older people, this study recommends adding elevators in the multi-floor buildings.

[Automated mapping of urban forests' disturbance and recovery in Nanjing, China].

Using Landsat TM/ETM dense time series observations spanning from 1987 to 2011, taking Laoshan forest farm and Purple Mountain as the research objects, the landsat ecosystem disturbance adaptive processing system (Ledaps) algorithm was used to generate surface reflectance datasets, which were fed to the vegetation change tracker model (VCT) model to derive urban forest disturbance and recovery products over Nanjing, followed by an intensive validation of the products. The results showed that there was a relatively high spatial agreement for forest disturbance products mapped by VCT, ranging from 65.4% to 95.0%. There was an apparent fluctuating forest disturbance and recovery rate over time, and the change trend of forest disturbance occurring at the two sites was roughly similar, but forest recovery was obviously different. Forest coverage in Purple Mountain was less than that in Laoshan forest farm, but the forest disturbance and recovery rates in Laoshan forest farm were larger than those in Purple Mountain.

[Distribution of influenza A (H5N1) virus and pathological lesions in major organ tissues of experimentally infected rhesus macaques].

OBJECTIVE: To investigate the pathological changes and viral invasion in the main organs of rhesus macaques after experimental infection with H5N1 virus. METHODS: The rhesus macaques were infected with H5N1 virus (AF148678/ACGoose/Guangdong/11961H5N1) by nasal inoculation under anesthesia. One rhesus macaque was killed respectively at 1, 3, 6, 14 days after infection. The pathologic changes of the main organs were observed using HE staining and the characteristics of the viral invasion in the body were analyzed using viral isolation, RT-PCR andimmunohistochemistry. RESULTS: The influenza virus replicated only in the lung tissues characterized by diffuse alveolar damage in the infected rhesus macaques, mainly involving alveolar epithelial cells and pulmonary macrophages. The pathological changes showed 3 phases including exudative inflammation, hyperplasia and fibrosis. Extra-pulmonary organs also showed different degree of pathological changes such as degeneration and necrosis, but virus was not isolated in the corresponding organs. CONCLUSIONS: Acute diffuse lung injury was a central part of the pathogenesis in H5N1 avian influenza virus infection. The lung was the main target organ in H5N1 viral infection, and H5N1 virus cannot replicate in other organs, which may be one of the obstacles to H5N1 viral transmission from person to person.