Alzheimer's disease (AD), the most common neurodegenerative disease, remains unclear in terms of its underlying causative genes and effective therapeutic approaches. Meanwhile, abnormalities in iron metabolism have been demonstrated in patients and mouse models with AD. Therefore, this study sought to find hub genes based on iron metabolism that can influence the diagnosis and treatment of AD. First, gene expression profiles were downloaded from the GEO database, including non-demented (ND) controls and AD samples. Fourteen iron metabolism-related gene sets were downloaded from the MSigDB database, yielding 520 iron metabolism-related genes. The final nine hub genes associated with iron metabolism and AD were obtained by differential analysis and WGCNA in brain tissue samples from GSE132903. GO analysis revealed that these genes were mainly involved in two major biological processes, autophagy and iron metabolism. Through stepwise regression and logistic regression analyses, we selected four of these genes to construct a diagnostic model of AD. The model was validated in blood samples from GSE63061 and GSE85426, and the AUC values showed that the model had a relatively good diagnostic performance. In addition, the immune cell infiltration of the samples and the correlation of different immune factors with these hub genes were further explored. The results suggested that these genes may also play an important role in immunity to AD. Finally, eight drugs targeting these nine hub genes were retrieved from the DrugBank database, some of which were shown to be useful for the treatment of AD or other concomitant conditions, such as insomnia and agitation. In conclusion, this model is expected to guide the diagnosis of patients with AD by detecting the expression of several genes in the blood. These hub genes may also assist in understanding the development and drug treatment of AD.

/pdf/hub-genes-diagnostic-model-and-predicted-drugs-related-to-pxxsmu8y.pdf

Hub Genes, Diagnostic Model, and Predicted Drugs Related to Iron Metabolism in Alzheimer's Disease

Abstract Microglia, the resident immune cells of the brain, are increasingly implicated in the regulation of brain health and disease. Microglia perform multiple functions in the central nervous system, including surveillance, phagocytosis and release of a variety of soluble factors. Importantly, a majority of their functions are closely related to changes in their metabolism. This natural inter-dependency between core microglial properties and metabolism offers a unique opportunity to modulate microglial activities via nutritional or metabolic interventions. In this review, we examine the existing scientific literature to synthesize the hypothesis that microglial phagocytosis of amyloid beta (Aβ) aggregates in Alzheimer’s disease (AD) can be selectively enhanced via metabolic interventions. We first review the basics of microglial metabolism and the effects of common metabolites, such as glucose, lipids, ketone bodies, glutamine, pyruvate and lactate, on microglial inflammatory and phagocytic properties. Next, we examine the evidence for dysregulation of microglial metabolism in AD. This is followed by a review of in vivo studies on metabolic manipulation of microglial functions to ascertain their therapeutic potential in AD. Finally, we discuss the effects of metabolic factors on microglial phagocytosis of healthy synapses, a pathological process that also contributes to the progression of AD. We conclude by enlisting the current challenges that need to be addressed before strategies to harness microglial phagocytosis to clear pathological protein deposits in AD and other neurodegenerative disorders can be widely adopted. 

Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics

Background: the 18-kDa translocator protein (TSPO) is a mitochondrial outer membrane protein, and its expression tends to increase in response to inflammatory stimulation, rapidly. However, the role of TSPO in inflammation and pyroptosis is not yet clear. Here, we identified TSPO as a novel key regulator of pyroptosis. (2) Methods: TSPO knockout and DSS induced mouse inflammatory bowel disease (IBD) models were employed to assess the roles of TSPO in the pathogenesis of IBD. Primary peritoneal macrophages from TSPO knockout mice were applied to evaluate the mechanism of TSPO in cell pyroptosis. Conclusions: in response to inflammatory injury, TSPO expression is rapidly upregulated and provides a protective function against GSDMD-mediated pyroptosis, which helps us better understand the biological role of TSPO and a novel regulatory mechanism of the pyroptosis process.

/pdf/tspo-deficiency-exacerbates-gsdmd-mediated-macrophage-3d93urin.pdf

TSPO Deficiency Exacerbates GSDMD-Mediated Macrophage Pyroptosis in Inflammatory Bowel Disease

Remimazolam, a novel benzodiazepine, is widely used as an anesthetic in endoscopic procedures; however, its effects on cognitive function remain unclear, limiting its broader application in general anaesthesia. Neuroinflammation is a well-established key factor in the etiology and progression of cognitive dysfunction, including conditions such as Alzheimer's disease, Parkinson's disease, postoperative delirium, and postoperative cognitive dysfunction. Preclinical studies have demonstrated that remimazolam exerts anti-inflammatory and neuroprotective effects, and clinical reports indicate a reduced incidence of postoperative delirium in patients treated with remimazolam. Nevertheless, whether remimazolam improves cognitive function through its anti-inflammatory properties remains uncertain. This study aimed to investigate the neuroprotective effects of remimazolam and its underlying mechanism in a lipopolysaccharide (LPS)-induced model of neuroinflammation, neuronal injury, and cognitive dysfunction METHODS: C57BL/6J male mice were administered LPS intraperitoneally to establish a model of neuroinflammation-induced cognitive impairment. A subset of mice received remimazolam via intraperitoneal injection 30minutes prior to LPS administration. Cognitive performance was evaluated using behavioural tests, including the Morris Water Maze (MWM), Novel Object Recognition (NOR) test, and Open Field Test (OFT). Hippocampal tissues were analyzed by haematoxylin-eosin (HE) staining to assess structural changes. Inflammatory markers, including Interleukin (IL)-6, IL-1β, and tumor necrosis factor-α, were quantified using enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR. Immunofluorescence was used to detect translocator protein (TSPO) and markers of microglia activation (IBA-1, CD16/32, and CD206). 

Remimazolam attenuates lipopolysaccharide-induced neuroinflammation and cognitive dysfunction

Epidemiology of and factors associated with overall survival for patients with head and neck adenoid cystic carcinoma.

Background Carcinosarcoma is a rare biphasic tumor composed of both carcinoma and sarcoma elements, which occurs at various sites. Most studies are case reports or small population-based studies for a single disease site, so comprehensive evaluations of epidemiology and prognostic factors for carcinosarcoma are needed. Methods Surveillance, Epidemiology, and End Results (SEER)-8 (1975–2019) provided data for the epidemiological analysis. SEER-17 (2000–2019) provided data on the primary tumor sites, initial treatment, construction, and validation of the nomogram. Results The age-adjusted incidence per 100,000 persons of carcinosarcoma increased significantly from 0.46 to 0.91 [1975–2019; average annual percent change (AAPC): 1.3%, P = 0.006], with localized stage increasing from 0.14 to 0.26 [2005–2015; annual percent change (APC): 4.2%]. The 20-year limited-duration prevalence per 100,000 increased from 0.47 to 3.36 (1999–2018). The mortality per 100,000 increased significantly from 0.16 to 0.51 (1975–2019; AAPC: 1.9%, P < 0.001). The 5-year relative survival was 32.8%. The greatest number of carcinosarcomas were from the uterus (68.7%), ovary (17.8%), lung and bronchus (2.3%). The main treatment is comprehensive treatment based on surgery; however, surgery alone is preferred in older patients. In multivariate analysis (N = 11,424), age, sex, race, year of diagnosis, disease stage, tumor site, and treatment were associated with survival. A nomogram was established to predict 1-, 3-, and 5-year survival, and the C-indexes were 0.732 and 0.748 for the training and testing sets, respectively. The receiver operating characteristic curve demonstrated that the nomogram provided a comprehensive and accurate prediction [1-year area under the curve (AUC): 0.782 vs. 0.796; 3-year AUC: 0.771 vs. 0.798; 5-year AUC: 0.777 vs. 0.810]. Conclusions In this study, the incidence, prevalence, and mortality of carcinosarcoma have increased over the past decades. There was a rapid rise in the incidence of localized stage in recent years, which reflected improved early detection. The prognosis of carcinosarcoma remains poor, signifying the urgency of exploring targeted cancer control treatments. Explicating distribution and gender disparities of carcinosarcoma may facilitate disease screening and medical surveillance. The nomogram demonstrated good predictive capacity and facilitated clinical decision-making.

Epidemiology and prediction model of patients with carcinosarcoma in the United States

Thorase belongs to the AAA+ ATPase family, which plays a critical role in maintaining cellular homeostasis. Our previous work reported that Thorase was highly expressed in brain tissue, especially in the cerebellum. However, the roles of Thorase in the cerebellum have still not been characterized. In this study, we generated conditional knockout mice (cKO) with Thorase deletion in Purkinje cells. Thorase cKO mice exhibited cerebellar degenerative diseases-like behavior and significant impairment in motor coordination. Thorase deletion resulted in more Purkinje neuron apoptosis, leading to Purkinje cell loss in the cerebellum of Thorase cKO mice. We also found enhanced expression of the inflammatory protein ASC, IL-1β, IL-6 and TNF-α in the Thorase cKO cerebellum, which contributed to the pathogenesis of cerebellar degenerative disease. Our findings provide a better understanding of the role of Thorase in the cerebellum, which is a theoretical basis for Thorase as a therapeutic drug target for neurodegenerative diseases. 

Genetic Deletion of Thorase Causes Purkinje Cell Loss and Impaired Motor Coordination Behavior

TSPO deficiency accelerates amyloid pathology and neuroinflammation by impairing microglial phagocytosis.

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Epidemiology and prediction model of patients with carcinosarcoma in the United States

Genetic Deletion of Thorase Causes Purkinje Cell Loss and Impaired Motor Coordination Behavior

TSPO deficiency accelerates amyloid pathology and neuroinflammation by impairing microglial phagocytosis.