Soot nanoparticles promote ferroptosis in dopaminergic neurons via alteration of m6A RNA methylation in Parkinson's disease.

Soot nanoparticles (SNPs) are black carbon prevalent in atmospheric environment with significant impacts on public health, leading to neurodegenerative diseases including development of Parkinson's disease (PD). This study investigated the effects of SNPs exposure on PD symptoms, employing both in vivo and in vitro PD models. In the in vivo experiments, animal behavior assessments showed that SNPs exposure exacerbated motor and cognitive impairments in PD mice. Molecular biology techniques further unveiled that SNPs aggravated degeneration of dopaminergic neurons. In vitro experiments revealed that SNPs exposure intensified ferroptosis of PD cells by increasing reactive oxygen species and iron ion levels, while reducing glutathione levels and mitochondrial membrane potential. Sequencing tests indicated elevated N6-methyladenosine (m6A) alteration of the ferroptosis-related protein, acyl-CoA synthetase long chain family member 4 (ACSL4). This study demonstrates that SNPs may exacerbate the onset and progression of PD by recruiting YTH domain-containing family protein 1 (YTHDF1) protein, enhancing m6A methylation in the ACSL4 5'UTR, amplifying ACSL4 protein expression, and accelerating the ferroptosis process in dopaminergic neurons. These molecular mechanisms underlying SNPs exacerbation of PD development may provide crucial insights for formulating environmental safety regulations and potential therapeutic strategies addressing PD in populations residing in regions with varied air quality.

TREM2 Deficiency Aggravates NLRP3 Inflammasome Activation and Pyroptosis in MPTP-Induced Parkinson's Disease Mice and LPS-Induced BV2 Cells.

Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects in PD by regulating the phenotype of microglia. Recent studies suggest that TREM2 regulates high glucose-induced microglial inflammation through the NLRP3 signaling pathway. This study aimed to investigate the effect of TREM2 on NLRP3 inflammasome activation and neuroinflammation in PD. Mice were injected with AAV-TREM2-shRNA into both sides of the substantia nigra using a stereotactic injection method, followed by intraperitoneal injection of MPTP to establish chronic PD mouse model. Behavioral assessments including the pole test and rotarod test were conducted to evaluate the effects of TREM2 deficiency on MPTP-induced motor dysfunction. Immunohistochemistry of TREM2 and tyrosine hydroxylase (TH), immunohistochemistry and immunofluorescence Iba1, Western blot of NLRP3 inflammasome and its downstream inflammatory factors IL-1ß and IL-18, and the key pyroptosis factors GSDMD and GSDMD-N were performed to explore the effect of TREM2 on NLRP3 inflammasome and neuroinflammation. In an in vitro experiment, lentivirus was used to interfere with the expression of TREM2 in BV2 microglia, and then lipopolysaccharide (LPS) and adenopterin nucleoside triphosphate (ATP) were used to stimulate inflammation to construct a cellular inflammation model. The expression differences of NLRP3 inflammasome and its components were detected by qPCR and Western blot. In vivo, TREM2 knockdown aggravated the loss of dopaminergic neuron and the decline of motor function. After TREM2 knockdown, the number of activated microglia was significantly increased, and the expression of cleaved caspase-1, NLRP3 inflammasome, IL-1ß, GSDMD, and GSDMD-N was increased. In vitro, TREM2 knockdown aggravated the inflammatory response of BV2 cells stimulated by LPS and promoted the activation of NLRP3 inflammasome through the NF-κB pathway. In addition, TREM2 knockdown also promoted the expression of TLR4/MyD88, an upstream factor of the NF-κB pathway. Our vivo and vitro data showed that TREM2 knockdown promoted NLRP3 inflammasome activation and downstream inflammatory response, promoted pyroptosis, and aggravated dopaminergic neuron loss. TREM2 acts as an anti-inflammatory in PD through the TLR4/MyD88/NF-κB pathway, which extends previous findings and supports the notion that TREM2 ameliorates neuroinflammation in PD.

Factors Associated with Return Visits by Elders within 72 Hours of Discharge from the Emergency Department.

Elders have a higher rate of return visits to the emergency department (ED) than other patients. It is critical to understand the risk factors for return visits to the ED by elders. The aim of this study was to determine the factors associated with return visits to the ED by elders. This study retrospectively reviewed the hospital charts of elders who returned to the ED within 72 h after discharge from ED. The risk factors identified in the Triage Risk Screening Tool were applied in this study. Of the elders discharged from the ED, 8.64% made a return visit to the ED within 72 h. The highest revisit rate occurred within 24 h after discharge. Factors associated with return ED visits within 24 h by elders were difficulty walking and having discharge care needs. The factor associated with ED return visits within 24-48 h was polypharmacy. Difficulty walking, having discharge care needs, and hospitalization within the past 120 days were associated with return visits made within 48-72 h following discharge. Identifying the reasons for return visits to the ED and providing a continuous review of geriatric assessment and discharge planning could reduce unnecessary revisits.

Increasing age- and gender-specific burden and complexity of multimorbidity in Taiwan, 2003-2013: a cross-sectional study based on nationwide claims data.

OBJECTIVE: Although there is accumulating evidence regarding multimorbidity in Western countries, this information is very limited in Asian countries. This study aimed to estimate population-based, age-specific and gender-specific prevalence and trends of multimorbidity in the Taiwanese population. DESIGN: This was a cross-sectional study based on claims data (National Health Insurance Research Database, Taiwan). PARTICIPANTS: The participants included a subset of the National Health Insurance Research Database, which contains claims data for two million randomly selected beneficiaries (~10% of the total population) under Taiwan's mandatory National Health Insurance system. OUTCOME MEASUREMENTS: The prevalence of multimorbidity in different age groups and in both sexes in 2003 and 2013 was reported. We analysed data on the prevalence of 20 common diseases in each age group and for both sexes. To investigate the clustering effect, we used graphical displays to analyse the likelihood of co-occurrence with one, two, three, and four or more other diseases for each selected disease in 2003 and 2013. RESULTS: The prevalence of multimorbidity (two or more diseases) was 20.07% in 2003 and 30.44% in 2013. In 2013, the prevalence varied between 5.21% in patients aged 20-29 years and 80.96% in those aged 80-89 years. In patients aged 50-79 years, the prevalence of multimorbidity was higher in women than in men. In men, the prevalence of chronic pulmonary disease and cardiovascular-related diseases was predominant, while in women the prevalence of osteoporosis, arthritis, cancer and psychosomatic disorders was predominant. Co-occurring diseases varied across different age and gender groups. CONCLUSIONS: The burden of multimorbidity is increasing and becoming more complex in Taiwan, and it was found to vary across different age and gender groups. Fulfilling the needs of individuals with multimorbidity requires collaborative work between healthcare providers and needs to take the age and gender disparities of multimorbidity into account.