Chronic Low-Grade Inflammation and Brain Structure in the Middle-Aged and Elderly Adults.

Low-grade inflammation (LGI) mainly acted as the mediator of the association of obesity and inflammatory diet with numerous chronic diseases, including neuropsychiatric diseases. However, the evidence about the effect of LGI on brain structure is limited but important, especially in the context of accelerating aging. This study was then designed to close the gap, and we leveraged a total of 37,699 participants from the UK Biobank and utilized inflammation score (INFLA-score) to measure LGI. We built the longitudinal relationships of INFLA-score with brain imaging phenotypes using multiple linear regression models. We further analyzed the interactive effects of specific covariates. The results showed high level inflammation reduced the volumes of the subcortex and cortex, especially the globus pallidus (ß [95% confidence interval] = -0.062 [-0.083, -0.041]), thalamus (-0.053 [-0.073, -0.033]), insula (-0.052 [-0.072, -0.032]), superior temporal gyrus (-0.049 [-0.069, -0.028]), lateral orbitofrontal cortex (-0.047 [-0.068, -0.027]), and others. Most significant effects were observed among urban residents. Furthermore, males and individuals with physical frailty were susceptive to the associations. The study provided potential insights into pathological changes during disease progression and might aid in the development of preventive and control targets in an age-friendly city to promote great health and well-being for sustainable development goals.

Associations of long-term exposure to low-level PM2.5 and brain disorders in 260,922 middle-aged and older adults.

Long-term exposure to high-level ambient PM2.5 was associated with increased risks of brain disorders, while the associations remain uncertain when the exposure is lower than current air quality standards in numerous countries. This study aimed to assess the effects of PM2.5 exposure on the brain system in the population with annual mean concentrations ≤15 µg/m3. We analyzed data from 260,922 participants without preexisting brain diseases at baseline in the UK Biobank. The geographical distribution of PM2.5 in 2010 was estimated by a land use regression model and linked with individual residential address. We investigated associations of ambient PM2.5 with incident neurological (dementia, Parkinson's diseases [PD], epilepsy, and migraine) and psychiatric (major depressive disorder [MDD] and anxiety disorder) diseases through Cox proportional hazard models. We further estimated the links with brain imaging phenotypes by neuroimaging analysis. Results showed that in the population with PM2.5 concentrations ≤15 µg/m3, each interquartile range (IQR, 1.28 µg/m3) increment in PM2.5 was related to incidence risks of dementia, epilepsy, migraine, MDD, and anxiety disorder with hazard ratios of 1.08 (95% confidence interval [CI]: 1.03, 1.13), 1.12 (1.05, 1.20), 1.07 (1.00, 1.13), 1.06 (1.03, 1.09), and 1.05 (1.02, 1.08), respectively. We did not observe a significant association with PD. The association with dementia was stronger among the population with poor cardiovascular health (measured by Life's Essential 8) than the counterpart (P for interaction = 0.037). Likewise, per IQR increase was associated with specific brain imaging phenotypes, including volumes of total brain (ß = -0.036; 95% CI: -0.050, -0.022), white matter (-0.030; -0.046, -0.014), grey matter (-0.030; -0.042, -0.017), respectively. The findings suggest long-term exposure to ambient PM2.5 at low-level still has an adverse impact on the neuro-psychiatric systems. The brain-relevant epidemiological assessment suggests that each country should update the standard for ambient PM2.5 following the World Health Organization Air Quality Guidelines 2021.

Associations of Triglycerides and Atherogenic Index of Plasma with Brain Structure in the Middle-Aged and Elderly Adults.

Triglyceride (TG) and atherogenic index of plasma (AIP) have been acknowledged to be risk factors for vascular insults, but their impacts on the brain system remain elusive. To fill in some gaps, we investigated associations of TG and AIP with brain structure, leveraging the UK Biobank database. TG and high-density lipoprotein cholesterol (HDL-C) were examined at baseline and AIP was calculated as log (TG/HDL-C). We build several linear regression models to estimate associations of TG and AIP with volumes of brain grey matter phenotypes. Significant inverse associations of TG and AIP with volumes of specific subcortical traits were observed, among which TG and AIP were most significantly associated with caudate nucleus (TG: ß [95% confidence interval CI] = -0.036 [-0.051, -0.022], AIP: -0.038 [-0.053, -0.023]), thalamus (-0.029 [-0.042, -0.017], -0.032 [-0.045, -0.019]). Higher TG and AIP were also considerably related with reduced cortical structure volumes, where two most significant associations of TG and AIP were with insula (TG: -0.035 [-0.048, -0.022], AIP: -0.038 [-0.052, -0.025]), superior temporal gyrus (-0.030 [-0.043, -0.017], -0.033 [-0.047, -0.020]). Modification effects of sex and regular physical activity on the associations were discovered as well. Our findings show adverse associations of TG and AIP with grey matter volumes, which has essential public health implications for early prevention in neurodegenerative diseases.

PM2.5 induced liver lipid metabolic disorders in C57BL/6J mice.

PM2.5 can cause adverse health effects via several pathways, such as inducing pulmonary and systemic inflammation, penetration into circulation, and activation of the autonomic nervous system. In particular, the impact of PM2.5 exposure on the liver, which plays an important role in metabolism and detoxification to maintain internal environment homeostasis, is getting more attention in recent years. In the present study, C57BL/6J mice were randomly assigned and treated with PM2.5 suspension and PBS solution for 8 weeks. Then, hepatic tissue was prepared and identified by metabolomics analysis and transcriptomics analysis. PM2.5 exposure can cause extensive metabolic disturbances, particularly in lipid and amino acids metabolic dysregulation.128 differential expression metabolites (DEMs) and 502 differently expressed genes (DEGs) between the PM2.5 exposure group and control group were detected. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DEGs were significantly enriched in two disease pathways, non-alcoholic fatty liver disease (NAFLD) and type II diabetes mellitus (T2DM), and three signaling pathways, which are TGF-beta signaling, AMPK signaling, and mTOR signaling. Besides, further detection of acylcarnitine levels revealed accumulation in liver tissue, which caused restricted lipid consumption. Furthermore, lipid droplet accumulation in the liver was confirmed by Oil Red O staining, suggesting hepatic steatosis. Moreover, the aberrant expression of three key transcription factors revealed the potential regulatory effects in lipid metabolic disorders, the peroxisomal proliferative agent-activated receptors (PPARs) including PPARα and PPARγ is inhibited, and the activated sterol regulator-binding protein 1 (SREBP1) is overexpressed. Our results provide a novel molecular and genetic basis for a better understanding of the mechanisms of PM2.5 exposure-induced hepatic metabolic diseases, especially in lipid metabolism.

Assessing food security performance from the One Health concept: an evaluation tool based on the Global One Health Index.

BACKGROUND: Food systems instantiate the complex interdependencies across humans, physical environments, and other organisms. Applying One Health approaches for agri-food system transformation, which adopts integrated and unifying approaches to optimize the overall health of humans, animals, plants, and environments, is crucial to enhance the sustainability of food systems. This study develops a potential assessment tool, named the global One Health index-Food Security (GOHI-FS), aiming to evaluate food security performance across countries/territories from One Health perspective and identify relevant gaps that need to be improved for sustainable food systems. METHODS: We comprehensively reviewed existing frameworks and elements of food security. The indicator framework of GOHI-FS was conceptualized following the structure-process-outcome model and confirmed by expert advisory. Publicly available data in 2020 was collected for each indicator. The weighting strategy was determined by the Fuzzy Analytical Hierarchy Process. The data for each indicator was normalized and aggregated by weighted arithmetic mean. Linear regressions were performed to evaluate the associations of GOHI-FS with health and social-economic indicators. RESULTS: The GOHI-FS includes 5 first-level indicators, 19 second-level indicators and 45 third-level indicators. There were 146 countries/territories enrolled for evaluation. The highest average score of first-level indicators was Nutrition (69.8) and the lowest was Government Support and Response (31.3). There was regional heterogeneity of GOHI-FS scores. Higher median scores with interquartile range (IQR) were shown in North America (median: 76.1, IQR: 75.5-76.7), followed by Europe and Central Asia (median: 66.9, IQR: 60.1-74.3), East Asia and the Pacific (median: 60.6, IQR: 55.5-68.7), Latin America and the Caribbean (median: 60.2, IQR: 57.8-65.0), Middle East and North Africa (median: 56.6, IQR: 52.0-62.8), South Asia (median: 51.1, IQR: 46.7-53.8), and sub-Saharan Africa (median: 41.4, IQR: 37.2-46.5). We also found significant associations between GOHI-FS and GDP per capita, socio-demographic index, health expenditure and life expectancy. CONCLUSIONS: GOHI-FS is a potential assessment tool to understand the gaps in food security across countries/territories under the One Health concept. The pilot findings suggest notable gaps for sub-Saharan Africa in numerous aspects. Broad actions are needed globally to promote government support and response for food security.

Excess Deaths of Gastrointestinal, Liver, and Pancreatic Diseases During the COVID-19 Pandemic in the United States.

Objectives: To evaluate excess deaths of gastrointestinal, liver, and pancreatic diseases in the United States during the COVID-19 pandemic. Methods: We retrieved weekly death counts from National Vital Statistics System and fitted them with a quasi-Poisson regression model. Cause-specific excess deaths were calculated by the difference between observed and expected deaths with adjustment for temporal trend and seasonality. Demographic disparities and temporal-spatial patterns were evaluated for different diseases. Results: From March 2020 to September 2022, the increased mortality (measured by excess risks) for Clostridium difficile colitis, gastrointestinal hemorrhage, and acute pancreatitis were 35.9%; 24.8%; and 20.6% higher than the expected. For alcoholic liver disease, fibrosis/cirrhosis, and hepatic failure, the excess risks were 1.4-2.8 times higher among younger inhabitants than older inhabitants. The excess deaths of selected diseases were persistently observed across multiple epidemic waves with fluctuating trends for gastrointestinal hemorrhage and fibrosis/cirrhosis and an increasing trend for C. difficile colitis. Conclusion: The persistently observed excess deaths of digestive diseases highlights the importance for healthcare authorities to develop sustainable strategies in response to the long-term circulating of SARS-CoV-2 in the community.

Multi-omics analysis reveals neuroinflammation, activated glial signaling, and dysregulated synaptic signaling and metabolism in the hippocampus of aged mice.

Aging is an intricate biological event that occurs in both vertebrates and invertebrates. During the aging process, the brain, a vulnerable organ, undergoes structural and functional alterations, resulting in behavioral changes. The hippocampus has long been known to be critically associated with cognitive impairment, dementia, and Alzheimer's disease during aging; however, the underlying mechanisms remain largely unknown. In this study, we hypothesized that altered metabolic and gene expression profiles promote the aging process in the hippocampus. Behavioral tests showed that exploration, locomotion, learning, and memory activities were reduced in aged mice. Metabolomics analysis identified 69 differentially abundant metabolites and showed that the abundance of amino acids, lipids, and microbiota-derived metabolites (MDMs) was significantly altered in hippocampal tissue of aged animals. Furthermore, transcriptomic analysis identified 376 differentially expressed genes in the aged hippocampus. A total of 35 differentially abundant metabolites and 119 differentially expressed genes, constituting the top 200 correlations, were employed for the co-expression network. The multi-omics analysis showed that pathways related to inflammation, microglial activation, synapse, cell death, cellular/tissue homeostasis, and metabolism were dysregulated in the aging hippocampus. Our data revealed that metabolic perturbations and gene expression alterations in the aged hippocampus were possibly linked to their behavioral changes in aged mice; we also provide evidence that altered MDMs might mediate the interaction between gut and brain during the aging process.

How Transportation Restriction Shapes the Relationship Between Ambient Nitrogen Dioxide and COVID-19 Transmissibility: An Exploratory Analysis.

Background: Several recent studies reported a positive (statistical) association between ambient nitrogen dioxide (NO2) and COVID-19 transmissibility. However, considering the intensive transportation restriction due to lockdown measures that would lead to declines in both ambient NO2 concentration and COVID-19 spread, the crude or insufficiently adjusted associations between NO2 and COVID-19 transmissibility might be confounded. This study aimed to investigate whether transportation restriction confounded, mediated, or modified the association between ambient NO2 and COVID-19 transmissibility. Methods: The time-varying reproduction number (Rt ) was calculated to quantify the instantaneous COVID-19 transmissibility in 31 Chinese cities from January 1, 2020, to February 29, 2020. For each city, we evaluated the relationships between ambient NO2, transportation restriction, and COVID-19 transmission under three scenarios, including simple linear regression, mediation analysis, and adjusting transportation restriction as a confounder. The statistical significance (p-value < 0.05) of the three scenarios in 31 cities was summarized. Results: We repeated the crude correlational analysis, and also found the significantly positive association between NO2 and COVID-19 transmissibility. We found that little evidence supported NO2 as a mediator between transportation restriction and COVID-19 transmissibility. The association between NO2 and COVID-19 transmissibility appears less likely after adjusting the effects of transportation restriction. Conclusions: Our findings suggest that the crude association between NO2 and COVID-19 transmissibility is likely confounded by the transportation restriction in the early COVID-19 outbreak. After adjusting the confounders, the association between NO2 and COVID-19 transmissibility appears unlikely. Further studies are warranted to validate the findings in other regions.

The Impact of Air Pollution on Neurodegenerative Diseases.

BACKGROUND: With the development of industrialization in human society, ambient pollutants are becoming more harmful to human health. Epidemiological and toxicological studies indicate that a close relationship exists between particulate matter with a diameter ≤2.5 µm (PM2.5) and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). To further confirm the relationship, we focus on possible relevant mechanisms of oxidative stress and neuroinflammation underlying the association between PM2.5 and neurodegenerative diseases in the review. METHODS: A literature search was performed on the studies about PM2.5 and neurodegenerative diseases via PubMed. A total of 113 articles published were selected, and 31 studies were included. RESULTS: PM2.5 can enter the central nervous system through 2 main pathways, the blood-brain barrier and olfactory neurons. The inflammatory response and oxidative stress are 2 primary mechanisms via which PM2.5 leads to toxicity in the brain. PM2.5 abnormally activates microglia, inducing the neuroinflammatory process. Inflammatory markers such as IL-1ß play an essential role in neurodegenerative diseases such as AD and PD. Moreover, the association between lipid mechanism disorders related to PM2.5 and neurodegenerative diseases has been gaining momentum. CONCLUSIONS: In conclusion, PM2.5 could significantly increase the risk of neurological disorders, such as AD and PD. Furthermore, any policy aimed at reducing air-polluting emissions and increasing air quality would be protective in human beings.

Phase- and epidemic region-adjusted estimation of the number of coronavirus disease 2019 cases in China.

The outbreak of the coronavirus disease 2019 was first reported in Wuhan in December 2019 and gradually spread to other areas in China. After implementation of prevention and control measures, the estimation of the epidemic trend is needed. A phase- and region-adjusted SEIR model was applied for modeling and predicting the number of cases in Wuhan, Hubei Province and regions outside Hubei Province in China. The estimated number of infections could reach its peak in late February 2020 in Wuhan and Hubei Province, which is 55 303-84 520 and 83 944-129 312, respectively, while the epidemic peaks in regions outside Hubei Province in China could appear on February 13, 2020 with the estimated 13 035-19 108 cases. According to the estimation, the outbreak would abate in March and April all over China. Current estimation provided evidence for planned work resumption under stringent prevention and control in China to further support the fight against the epidemic. Nevertheless, there is still possibility of the second outbreak brought by the work resumption and population migration, especially from Hubei Province and high intensity cities outside Hubei Province. Strict prevention and control measures still need to be considered in the regions with high intensity of epidemic and densely-populated cities.

Reprogrammed astrocytes display higher neurogenic competence, migration ability and cell death resistance than reprogrammed fibroblasts.

The direct reprogramming of somatic cells into induced neural progenitor cells (iNPCs) has been envisioned as a promising approach to overcome ethical and clinical issues of pluripotent stem cell transplantation. We previously reported that astrocyte-derived induced pluripotent stem cells (iPSCs) have more tendencies for neuronal differentiation than fibroblast-derived iPSCs. However, the differences of neurogenic potential between astrocyte-derived iNPCs (AiNPCs) and iNPCs from non-neural origins, such as fibroblast-derived iNPCs (FiNPCs), and the underlying mechanisms remain unclear. Our results suggested that AiNPCs exhibited higher differentiation efficiency, mobility and survival capacities, compared to FiNPCs. The whole transcriptome analysis revealed higher activities of TGFß signaling in AiNPCs, versus FiNPCs, following a similar trend between astrocytes and fibroblasts. The higher neurogenic competence, migration ability, and cell death resistance of AiNPCs could be abrogated using TGFß signaling inhibitor LY2157299. Hence, our study demonstrates the difference between iNPCs generated from neural and non-neural cells, together with the underlying mechanisms, which, provides valuable information for donor cell selection in the reprogramming approach.

PM2.5, Fine Particulate Matter: A Novel Player in the Epithelial-Mesenchymal Transition?

Epithelial-mesenchymal transition (EMT) refers to the conversion of epithelial cells to mesenchymal phenotype, which endows the epithelial cells with enhanced migration, invasion, and extracellular matrix production abilities. These characteristics link EMT with the pathogenesis of organ fibrosis and cancer progression. Recent studies have preliminarily established that fine particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) is correlated with EMT initiation. In this pathological process, PM2.5 particles, excessive reactive oxygen species (ROS) derived from PM2.5, and certain components in PM2.5, such as ions and polyaromatic hydrocarbons (PAHs), have been implicated as potential EMT mediators that are linked to the activation of transforming growth factor ß (TGF-ß)/SMADs, NF-κB, growth factor (GF)/extracellular signal-regulated protein kinase (ERK), GF/phosphatidylinositol 3-kinase (PI3K)/Akt, wingless/integrated (Wnt)/ß-catenin, Notch, Hedgehog, high mobility group box B1 (HMGB1)-receptor for advanced glycation end-products (RAGE), and aryl hydrocarbon receptor (AHR) signaling cascades and to cytoskeleton rearrangement. These pathways directly and indirectly transduce pro-EMT signals that regulate EMT-related gene expression in epithelial cells, finally inducing the characteristic alterations in morphology and functions of epithelia. In addition, novel associations between autophagy, ATP citrate lyase (ACLY), and exosomes with PM2.5-induced EMT have also been summarized. However, some debates and paradoxes remain to be consolidated. This review discusses the potential molecular mechanisms underlying PM2.5-induced EMT, which might account for the latent role of PM2.5 in cancer progression and fibrogenesis.

Effects of chronic PM2.5 exposure on pulmonary epithelia: Transcriptome analysis of mRNA-exosomal miRNA interactions.

Epidemiological studies have established the correlations between PM2.5 and a wide variety of pulmonary diseases. However, their underlying pathogeneses have not been clearly elucidated yet. In the present study, the epithelial-mesenchymal transition (EMT) phenotype with enhanced proliferation and migration activity of human pulmonary epithelial cell line BEAS-2B was observed after exposure to low dose PM2.5 exposure (50 µg/ml) for 30 passages. Then, epithelial cells derived-exosomal micro-RNA (miRNA) and intracellular total RNA were extracted, and the differentially expressed exosomal miRNAs (DE-Exo-MiRs) as well as differentially expressed protein coding genes (DEGs) were identified by RNA sequencing (RNA-seq) and transcriptome analysis. We found that chronic PM2.5 exposure stimulated the release of pulmonary epithelium derived exosomes. 45 DE-Exo-MiRs including 32 novelly predicted miRNAs and 843 DEGs between PM2.5 exposed group and the normal control were detected. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DEGs were significantly enriched in extracellular matrix organization, focal adhesion and cancer related terms. Besides, the enrichment analyses on 7774 mRNA targets of 27 DE-Exo-MiRs predicted by MiRanda software also revealed the potential regulatory role of exosomal miRNAs in pathways in cancer, Wingless/Integrated (Wnt) signaling pathway, focal adhesion related genes and other multiple pathogenic pathways. Moreover, the interactive exosomal miRNA-mRNA pair networks were constructed using Cytoscape software. Our results provided a novel basis for a better understanding of the mechanisms of chronic PM2.5 exposure induced pulmonary disorders including pulmonary fibrosis and cancer, in which exosomal miRNAs (Exo-MiRs) potentially functions by dynamically regulating gene expressions.

ERα upregulates the expression of long non-coding RNA LINC00472 which suppresses the phosphorylation of NF-κB in breast cancer.

PURPOSE: Low expression of long intergenic non-coding RNA LINC00472 in breast cancer is associated with aggressive tumors and unfavorable disease outcomes in multiple clinical datasets, but the reasons for these associations were unknown. METHODS: To study the mechanisms underlying the lncRNA's connection to breast cancer, we investigated the molecular targets and regulation of LINC00472 in breast cancer cells, and analyzed relevant molecular features in relation to patient survival. Gene expression profiles of breast cancer cells overexpressing LINC00472 were analyzed for its regulatory pathways and downstream targets. Effects of LINC00472 overexpression on cell behaviors were evaluated in vitro and in vivo. Meta-analysis was performed using online datasets and our own study. RESULTS: Analysis of LINC00472 transcriptome revealed ERα upregulation of LINC00472 expression, and an ERα-binding site in the LINC00472 promoter was identified. Evaluation of LINC00472 overexpression also indicated a possible link between LINC00472 and NF-κB. Cell experiments confirmed that LINC00472 suppressed the phosphorylation of p65 and IκBα through binding to IKKß, inhibiting its phosphorylation. High LINC00472 expression inhibited tumor growth both in vitro and in vivo and suppressed aggressive tumor cell behaviors in vitro. Suppressing LINC00472 expression in ER-positive tumor cells increased cell aggressive behaviors. Tamoxifen treatment of ER-positive cells inhibited ERα and LINC00472 expression and increased p65 and IκBα phosphorylation. Meta-analysis showed that LINC00472 expression were higher in ER-positive than ER-negative tumors and that high expression was associated with better disease outcomes in ER-positive patients. CONCLUSIONS: The study demonstrates that ERα upregulates LINC00472 which suppresses the phosphorylation of NF-κB, and suggests that endocrine treatment may lower LINC00472 and increase NF-κB activities, leading to tumor progression and disease recurrence.

PM2.5 induced pulmonary fibrosis in vivo and in vitro.

Epidemiological studies have revealed positive correlation between particulate matter with an aerodynamic diameter of < 2.5 µm (PM2.5) and pulmonary fibrosis (PF). As etiology and pathogenesis of PF have not been fully elucidated, this study was to investigate the potential mechanism by which PM2.5 exposure adversely induced PF in vivo and in vitro. In the present study, 6-week-old C57/BL6J mice were intranasally administrated with PM2.5 (100 µg/day) for 4 weeks. Micro-CT and hematoxylin-eosin (HE) staining analysis showed that lung inflammation and incipient fibrosis symptoms were induced after PM2.5 exposure. The expression of Transforming growth factor-ß1 (TGF-ß1), α-Smooth muscle actin (α-SMA), and Collagen type I (COL1) in mice lung was increased. Upregulation of TGF-ß1 in mice serum was also detected by ELISA after exposure to PM2.5. Moreover, chronic PM2.5 exposure on human bronchial epithelial cell line BEAS-2B cells led to activation of TGF-ß1/SMAD3 pathway, TGF-ß1 excretion and epithelial-mesenchymal transition (EMT), while PM2.5 also triggered the activation of TGF-ß1/SMAD3 pathway, TGF-ß1 excretion as well as differentiation of human pulmonary fibroblast cell line HFL-1 cells, and TGF-ß1 production in mouse macrophage cell line RAW264.7 cells. Furthermore, cell culture medium of PM2.5-treated BEAS-2B and RAW264.7 cells could both activate TGF-ß1/SMAD3 signaling, α-SMA and COL1 upregulation in HFL-1 cells. Therefore, we concluded that PM2.5 could induce PF by targeting pulmonary epithelium, macrophages and fibroblasts, suggesting that PM2.5 was a potent initiator of PF.

Induced neural progenitor cells abundantly secrete extracellular vesicles and promote the proliferation of neural progenitors via extracellular signal-regulated kinase pathways.

Neural stem/progenitor cells (NPCs) are known to have potent therapeutic effects in neurological disorders through the secretion of extracellular vesicles (EVs). Despite the therapeutic potentials, the numbers of NPCs are limited in the brain, curbing the further use of EVs in the disease treatment. To overcome the limitation of NPC numbers, we used a three transcription factor (Brn2, Sox2, and Foxg1) somatic reprogramming approach to generate induced NPCs (iNPCs) from mouse fibroblasts and astrocytes. The resulting iNPCs released significantly higher numbers of EVs compared with wild-type NPCs (WT-NPCs). Furthermore, iNPCs-derived EVs (iNPC-EVs) promoted NPC function by increasing the proliferative potentials of WT-NPCs. Characterizations of EV contents through proteomics analysis revealed that iNPC-EVs contained higher levels of growth factor-associated proteins that were predicted to activate the down-stream extracellular signal-regulated kinase (ERK) pathways. As expected, the proliferative effects of iNPC-derived EVs on WT-NPCs can be blocked by an ERK pathway inhibitor. Our data suggest potent therapeutic effects of iNPC-derived EVs through the promotion of NPC proliferation, release of growth factors, and activation of ERK pathways. These studies will help develop highly efficient cell-free therapeutic strategies for the treatment of neurological diseases.

Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons.

BACKGROUND: Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases. Due to the ethical concerns of ESCs-derived neural progenitor cells (NPCs) and tumorigenic potential of iPSCs, reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation. METHODS: Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors (TFs) Foxg1, Sox2, and Brn2. The generation of subtypes of neurons was directed by the force expression of cell-type specific TFs Lhx8 or Foxa2/Lmx1a. RESULTS: Astrocyte-derived induced NPCs (AiNPCs) share high similarities, including the expression of NPC-specific genes, DNA methylation patterns, the ability to proliferate and differentiate, with the wild type NPCs. The AiNPCs are committed to the forebrain identity and predominantly differentiated into glutamatergic and GABAergic neuronal subtypes. Interestingly, additional overexpression of TFs Lhx8 and Foxa2/Lmx1a in AiNPCs promoted cholinergic and dopaminergic neuronal differentiation, respectively. CONCLUSIONS: Our studies suggest that astrocytes can be converted into AiNPCs and lineage-committed AiNPCs can acquire differentiation potential of other lineages through forced expression of specific TFs. Understanding the impact of the TF sets on the reprogramming and differentiation into specific lineages of neurons will provide valuable strategies for astrocyte-based cell therapy in neurodegenerative diseases.

Knockdown of long non-coding RNA LCPAT1 inhibits autophagy in lung cancer.

OBJECTIVE: Long non-coding RNAs (lncRNAs) are involved in numerous biological processes in lung cancer cells. In our previous studies, we identified a lncRNA, ENST00000439577, which is highly expressed in lung carcinomas, and termed it lung cancer progression-associated transcript 1 (LCPAT1). To characterize the role of LCPAT1 in lung cancer, we conducted the current study. METHODS: Expression of LCPAT1 and autophagy-associated markers in tumor tissues and lung cancer cell lines was determined by real-time quantitative polymerase chain reaction (qPCR). Hematoxylin and eosin (HE) staining, qPCR, Western blot, and immunohistochemistry were performed to evaluate xenografted tumor tissues. Autophagy induced by rapamycin was detected by Western blot and immunofluorescence in lung cancer cell lines. RESULTS: Expression of LCPAT1 and microtubule-associated protein 1 light chain 3 beta (LC3B) was positively correlated in lung cancer. Knockdown of LCPAT1 inhibited tumor growth and suppressed cell autophagy in vivo. Moreover, LCPAT1 knockdown in lung cancer cell lines resulted in decreased autophagy-associated gene expression and alleviated the cell autophagy induced by rapamycin. CONCLUSIONS: We speculate that LCPAT1 plays a crucial role in regulating autophagy in lung cancer.

LncRNA LCPAT1 Mediates Smoking/ Particulate Matter 2.5-Induced Cell Autophagy and Epithelial-Mesenchymal Transition in Lung Cancer Cells via RCC2.

BACKGROUND/AIMS: Ecological studies have shown that air pollution and prevalence of cigarette smoking are positively correlated. Evidence also suggests a synergistic effect of cigarette smoking and PM2.5 exposure (Environmental Particulate Matter ≤ 2.5 µm in diameter) on lung cancer risk. We aimed to evaluate the interaction between smoking prevalence and PM2.5 pollution in relation to lung cancer mortality and determine its underlying mechanisms in vitro. METHODS: "MOVER" method was used to analyze the interaction between smoking prevalence and PM2.5 pollution in relation to lung cancer mortality. Cell autophagy and malignant behaviors induced by cigarette smoke extract (CSE) and PM2.5 exposure were examined in vitro. Gene expression was examined by qRT-PCR and western blot. RNA and protein interaction was determined using a RNA binding protein immunoprecipitation assay. RESULTS: An increased risk for lung cancer death (RERI (the relative excess risk) =0.28) was observed with a synergistic interaction between cigarette smoking and PM2.5 pollution. Cell migration, invasion, EMT (epithelial-mesenchymal transition) and autophagy were elevated when lung cancer cells were treated with CSE and PM2.5 in combination. A lncRNA, named lung cancer progression-association transcript 1 (LCPAT1), was up-regulated after the treatment of CSE and PM2.5, and knocking down the lncRNA impaired the effect of CSE and PM2.5 on lung cancer cells. In addition, LCPAT1 was shown to bind to RCC2, and RCC2 mediated the effect of LCPAT1 on cell autophagy, migration, invasion and EMT in lung cancer. CONCLUSIONS: Our results suggest that combined exposure to CSE and PM2.5 induces LCPAT1 expression, which up-regulates autophagy, and promotes lung cancer progression via RCC2.

d-limonene exhibits antitumor activity by inducing autophagy and apoptosis in lung cancer.

PURPOSE: d-limonene is a plant extract with widespread application, and it has been recently reported to have antiproliferative and proapoptotic effects on cancer cells. However, the mechanisms by which d-limonene achieves these effects, especially in lung cancer, are not entirely clear. Therefore, the goal of this study was to examine the effects of d-limonene on lung cancer and explore its mechanisms of action. METHODS: We examined the therapeutic effects of d-limonene on lung cancer cells and in a xenograft animal model by characterizing its effects on the pathways of apoptosis and autophagy. Cell proliferation was measured using the Cell Counting Kit-8, and apoptosis was determined by flow cytometric analysis. Levels of LC3 puncta, an autophagy marker, were analyzed by laser scanning confocal microscopy. Autophagy and apoptosis-related gene expression were assessed by real-time quantitative polymerase chain reaction and Western blot. RESULTS: d-limonene inhibited the growth of lung cancer cells and suppressed the growth of transplanted tumors in nude mice. Expression of apoptosis and autophagy-related genes were increased in tumors after treatment with d-limonene. Furthermore, the use of chloroquine, an autophagy inhibitor, and knockdown of the atg5 gene, suppressed the apoptosis induced by d-limonene. CONCLUSION: d-limonene may have a therapeutic effect on lung cancer as it can induce apoptosis of lung cancer cells by promoting autophagy.