TGF-ß1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. METHODS: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. RESULTS: A functional assay identified that transforming growth factor-ß1 (TGF-ß1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-ß1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. CONCLUSIONS: These findings provide compelling evidence for the involvement of TGF-ß1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-ß1 may be used alone or combined with hOM-MSCs therapy for treating PD.

Extracellular vesicles deviced from hypoxia-3D-GMSCs rescue the mitochondrial dysfunction of aging-GMSCs.

Mesenchymal stem cells (MSCs) are ubiquitous multipotent cells exhibiting significant therapeutic potential for various diseases. It is generally accepted that clinical application requires massive expansion of MSCs, which is often accompanied by the occurrence of replicative senescence. Additionally, senescent MSCs exhibit significantly reduced proliferation, differentiation, and therapeutic potential. The scale-up of MSCs production and cellular senescence are major challenges for translational applications. This study first collected extracellular vesicles (EVs) from gingival MSCs (GMSCs) under hypoxia preconditioning combined with 3D dynamic culture (obtained EVs designed as H-3D-EVs). Subsequently, we further explored the effects and mechanisms of H-3D-EVs on aging-GMSCs. The results showed that H-3D-EVs improved the proliferation ability and cell activity of aging-GMSCs, and ameliorated their senescence. mRNA sequencing reveals transcriptomic changes in aging-GMSCs. It was found that H-3D-EVs up-regulated genes related to mitochondrial dynamics, cell cycle, and DNA repair, while down-regulated aging-related genes. Furthermore, we verified that H-3D-EVs corrected the mitochondrial dysfunction of aging-GMSCs by improving mitochondrial dynamics. In summary, this study provides a promising strategy for improving the culture methods of GMSCs and avoiding its senescence in large-scale production.

Large-scale genome-wide association studies reveal the genetic causal etiology between air pollutants and autoimmune diseases.

BACKGROUND: Epidemiological evidence links a close correlation between long-term exposure to air pollutants and autoimmune diseases, while the causality remained unknown. METHODS: Two-sample Mendelian randomization (TSMR) was used to investigate the role of PM10, PM2.5, NO2, and NOX (N = 423,796-456,380) in 15 autoimmune diseases (N = 14,890-314,995) using data from large European GWASs including UKB, FINNGEN, IMSGC, and IPSCSG. Multivariable Mendelian randomization (MVMR) was conducted to investigate the direct effect of each air pollutant and the mediating role of common factors, including body mass index (BMI), alcohol consumption, smoking status, and household income. Transcriptome-wide association studies (TWAS), two-step MR, and colocalization analyses were performed to explore underlying mechanisms between air pollution and autoimmune diseases. RESULTS: In TSMR, after correction of multiple testing, hypothyroidism was causally associated with higher exposure to NO2 [odds ratio (OR): 1.37, p = 9.08 × 10-4] and NOX [OR: 1.34, p = 2.86 × 10-3], ulcerative colitis (UC) was causally associated with higher exposure to NOX [OR: 2.24, p = 1.23 × 10-2] and PM2.5 [OR: 2.60, p = 5.96 × 10-3], rheumatoid arthritis was causally associated with higher exposure to NOX [OR: 1.72, p = 1.50 × 10-2], systemic lupus erythematosus was causally associated with higher exposure to NOX [OR: 4.92, p = 6.89 × 10-3], celiac disease was causally associated with lower exposure to NOX [OR: 0.14, p = 6.74 × 10-4] and PM2.5 [OR: 0.17, p = 3.18 × 10-3]. The risky effects of PM2.5 on UC remained significant in MVMR analyses after adjusting for other air pollutants. MVMR revealed several common mediators between air pollutants and autoimmune diseases. Transcriptional analysis identified specific gene transcripts and pathways interconnecting air pollutants and autoimmune diseases. Two-step MR revealed that POR, HSPA1B, and BRD2 might mediate from air pollutants to autoimmune diseases. POR pQTL (rs59882870, PPH4=1.00) strongly colocalized with autoimmune diseases. CONCLUSION: This research underscores the necessity of rigorous air pollutant surveillance within public health studies to curb the prevalence of autoimmune diseases.

Optimization and mechanism of the novel eco-friendly additives for solidification and stabilization of dredged sediment.

Solidification/stabilization technology is commonly used in the rehabilitation of dredged sediment due to its cost-effectiveness. However, traditional solidification/stabilization technology relies on cement, which increases the risk of soil alkalization and leads to increased CO2 emissions during cement production. To address this issue, this study proposed an innovative approach by incorporating bentonite and citrus peel powder as additives in the solidifying agent, with the aim of reducing cement usage in the dredged sediment solidification process. The research results showed that there is a significant interaction among cement, bentonite, and citrus peel powder. After response surface methodology (RSM) optimization, the optimal ratio of the cementitious mixture was determined to be 14.86 g/kg for cement, 5.85 g/kg for bentonite, and 9.31 g/kg for citrus peel powder. The unconfined compressive strength (UCS) of the solidified sediments reached 3144.84 kPa. The reaction products of the solidification materials, when mixed with sediment, facilitated adsorption, gelation, and network structure connection. Simultaneously, the leaching concentration of heavy metals was significantly decreased with five heavy metals (Zn, As, Cd, Hg, and Pb) leaching concentrations decreasing by more than 50%, which met the prescribed thresholds for green planting. This study demonstrated the ecological benefits of employing bentonite and citrus peel powder in the solidification process of dredged sediment, providing an effective solution for sediment solidification.

Greenway interventions effectively enhance physical activity levels-A systematic review with meta-analysis.

Background: Previous studies have examined the impact of greenway interventions on physical activity (PA); however, the results have been inconclusive. In order to address this issue, our study conducted a systematic review with meta-analysis to thoroughly evaluate the evidence and determine the effectiveness of greenway interventions in promoting PA. Methods: We conducted a comprehensive search of literature databases, such as Web of Science, EMBASE, PubMed (via Medline), Cochrane Library, and Scopus, up to June 15, 2023. To synthesize the available evidence, we performed a meta-analysis using a random effects model. The quality of the included studies was assessed using the criteria developed by the Agency for Healthcare Research and Quality and the Newcastle-Ottawa Scale. Results: A total of 9 publications were identified, involving 6, 589 individuals. The overall quality of most included studies was rated as moderate to high. Our study found that the greenway was effective in promoting PA among participants. Specifically, active travel (AT) showed a standard mean difference (SMD) of 0.10 [95% confidence interval (CI): 0.04 to 0.17], moderate-to-vigorous PA had an SMD of 0.11 (95% CI: 0.02 to 0.20), and total PA had an SMD of 0.14 (95% CI: 0.06 to 0.21). We also observed significant differences in AT levels among participants based on greenway characteristics, exposure distance, exposure duration, and male-to-female ratio. Discussion: Newly developed or upgraded greenways have been shown to effectively promote PA. Additionally, research suggests that the longer a greenway has been in existence, the greater the benefits it provides for PA. As a result, the construction of greenways should be recognized as an effective public health intervention.