Detecting ferroptosis and immune infiltration profiles in multiple system atrophy using postmortem brain tissue

BackgroundThe importance of ferroptosis and the immune system has been mentioned in the pathogenesis of α-synucleinopathy. The α-synuclein-immunoreactive inclusions that primarily affect oligodendrocytes are the hallmark of multiple system atrophy (MSA). Limited evidence implicates that iron and immune responses are involved in the pathogenesis of MSA, which is associated with neurodegeneration and α-synuclein aggregation.MethodsThe RNA sequencing data were collected from the Gene Expression Omnibus database. MSA-C-related module genes were identified through weighted gene co-expression network analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to predict the potential molecular functions. The candidate ferroptosis-related genes associated with MSA-C were obtained using a machine-learning algorithm. CIBERSORT was used to estimate the compositional patterns of the 22 types of immune cells.ResultsThe tissues for sequencing were extracted from postmortem cerebellar white matter tissues of 11 MSA-C patients and 47 healthy controls. The diagnostic ability of the six MSA-C-related ferroptosis-related genes in discriminating MSA-C from the healthy controls demonstrated a favorable diagnostic value, with the AUC ranging from 0.662 to 0.791. The proportion of CD8+ T cells in MSA-C was significantly higher than in the controls (P = 0.02). The proportion of NK cells resting in MSA-C was significantly higher than in the controls (P = 0.011).ConclusionFerroptosis and T-cell infiltration may be important pathways of disease development in MSA-C, and targeting therapies for these pathways may be disease-modifying

Histological Characteristics of the Kidney in Mongolian Gerbils of Different Ages

ObjectiveTo explore the histological characteristics of the kidney in Mongolian gerbils of different ages.MethodsTen Mongolian gerbils of 2, 6, and 12 months old (half male and half female) were selected. After euthanasia, the kidneys were taken and paraffin sections were made. After HE, MASSON and PAS staining, the structural differences of different parts of the kidney tissue in gerbils of different ages were observed by digital scanning, and the relevant data of the kidney tissue were measured by image analysis software.ResultsThe number of proximal convoluted tubules was more than that of distal convoluted tubules in the renal cortex and outer medulla of gerbils. With age, the glomerular density decreased, the glomerular diameter increased, the basement membrane of renal tubules thickened, and the fibrous components between renal tubules increased.ConclusionThe histological structure of Mongolian gerbil's kidney varies with age, which may be related to glomerulosclerosis and parenchymal cell reduction. The specific mechanism needs further study

CysLT2R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils

Post-stroke depression (PSD) is a kind of prevalent emotional disorder following stroke that usually results in slow functional recovery and even increased mortality. We had reported that the cysteinyl leukotriene receptor 2 (CysLT2R) antagonist HAMI3379 (HM3379) contributes to the improvement of neurological injury. The present study was designed to investigate the role of HM3379 in PSD-induced chronic neuroinflammation and related mechanisms in gerbils. The gerbils were subjected to transient global cerebral ischemia (tGCI) and spatial restraint stress to induce the PSD model. They were randomized to receive the vehicle or HM3379 (0.1 mg/kg, i.p.) for a consecutive 14 days. In the PSD-treated gerbils, HM3379 had noteworthy efficacy in improving the modified neurological severity score (mNSS) and depression-like behaviors, including the sucrose preference test and the forced swim test. HM3379 administration significantly mitigated neuron loss, lessened TUNEL-positive neurons, and reduced the activation of microglia in the cerebral cortex. Importantly, HM3379 downregulated protein expressions of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome and pyroptosis including NLRP3, cleaved caspase-1, interleukin-1β (IL-1β), IL-18, cleaved gasdermin-N domain (GSDMD-N), and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). Mechanistically, HM3379 could repress pyroptosis via inhibiting NLRP3 inflammasome activation under oxygen-glucose deprivation (OGD) stimulation. Knockdown of CysLT2R by short hairpin RNA (shRNA) or overexpression of CysLT2R by lentivirus (LV)-CysLT2R could abolish or restore the anti-depression effect of HM3379. Our results demonstrated that the selective CysLT2R antagonist HM3379 has beneficial effects on PSD, partially by suppressing the NLRP3 inflammasome/pyroptosis pathway