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Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aß and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aß, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aß: ß-amyloid, GABA: gamma-aminobutyric acid.
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Background: The role of soluble interleukin-1 receptor type 2 (sIL-1R2) in acute myocardial infarction (AMI) remains undocumented. In the present study, we aimed to evaluate the possible associations of sIL-1R2 with left ventricular (LV) function, remodeling and future clinical events in the setting of AMI. Methods: Circulating sIL-1R2 levels were quantified after percutaneous coronary intervention (PCI) on day 1 of hospital admission for 204 AMI patients, and upon enrollment of 204 healthy controls. Echocardiography was conducted in the acute phase and at 12-month follow-up. Adverse clinical events were registered after 12 months. Results: Circulating sIL-1R2 levels were significantly higher in AMI patients than in healthy controls (medians respectively 6652.81 pg/mL, 3799.13 pg/mL, p < 0.0001). AMI patients with sIL-1R2 levels less than the median had a larger proportion of worsened LV ejection fraction [a decrease in LV ejection fraction (LVEF) of more than 10% units] and reduced LVEF (a final LVEF < 50%). After multivariate adjustment, sIL-1R2 levels less than the median were associated with an increased risk of worsened LVEF [odds ratio (OR): 3.7, 95% confidence interval (CI): 1.6-8.5, p = 0.002] and reduced LVEF at 12 months (OR: 2.1, 95% CI: 1.1-4.3, p = 0.035). Moreover, low sIL-1R2 levels were associated with an increased risk of having an adverse clinical event during the first 12 months after AMI [hazard ratio (HR): 2.5, 95% CI: 1.0-6.1, p = 0.039]. Conclusions: Low levels of circulating sIL-1R2 were associated with impaired recovery of LV function and adverse clinical outcomes in AMI patients. These findings might contribute to understanding the important role of sIL-1R2 in postinfarction inflammation.
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The structural characteristics of fucoidans exhibit species and regional diversity. Previous studies have demonstrated that Laminaria japonica- and Ascophyllum nodosum-derived fucoidans have type I and type II fucosyl chains, respectively. These chemical differences may contribute to distinct hypolipidemic effects and mechanisms of action. Chemical analysis demonstrated that the percentage contents of sulfate, glucuronic acid, and galactose were higher in L. japonica-derived fucoidans than those of A. nodosum-derived fucoidans. In hyperlipidemic apolipoprotein E-deficient mice, both A. nodosum- and L. japonica-derived fucoidans significantly decreased the plasma and hepatic levels of total cholesterol and triglyceride, leading to the reduction of atherosclerotic plaques. Western blotting experiments demonstrated that these fucoidans significantly enhanced the expression and levels of scavenger receptor B type 1, cholesterol 7 alpha-hydroxylase A1, and peroxisome proliferator-activated receptor (PPAR)-α, contributing to circulating lipoprotein clearance and fatty acid degradation, respectively. Differentially, L. japonica-derived fucoidan significantly increased the LXR/ATP-binding cassette G8 signaling pathway in the small intestine, as revealed by real-time quantitative PCR, which may lead to further cholesterol and other lipid excretion. Collectively, these data are useful for understanding the hypolipidemic mechanisms of action of seaweed-derived fucoidans, and their potential application for the prevention and/or treatment of atherosclerotic cardiovascular diseases.
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Apolipoproteínas E , Ascophyllum , Hipolipemiantes , Laminaria , Polisacáridos , Animales , Laminaria/química , Ascophyllum/química , Ratones , Polisacáridos/farmacología , Polisacáridos/química , Hipolipemiantes/farmacología , Apolipoproteínas E/genética , Masculino , Ratones Endogámicos C57BL , Triglicéridos/sangre , Triglicéridos/metabolismo , Colesterol/sangre , Colesterol/metabolismo , Ratones Noqueados , PPAR alfa/metabolismo , PPAR alfa/genética , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Hígado/metabolismo , Hígado/efectos de los fármacos , Humanos , Algas ComestiblesRESUMEN
BACKGROUND: Ulcerative colitis (UC) and systemic lupus erythematosus (SLE) are both systemic immunoreactive diseases, and their pathogenesis depends on the interaction between genes and environmental factors. There are no reports of UC with SLE in China, but six cases of SLE with UC have been reported in China. The combination of these two diseases has distinct effects on the pathogenesis of both diseases. CASE SUMMARY: A female patient (30 years old) came to our hospital due to dull umbilical pain, diarrhea and mucous bloody stool in August 2018 and was diagnosed with UC. The symptoms were relieved after oral administration of mesalazine (1 g po tid) or folic acid (5 mg po qd), and the patient were fed a control diet. On June 24, 2019, the patient was admitted for treatment due to anemia and tinnitus. During hospitalization, the patient had repeated low-grade fever and a progressively decreased Hb level. Blood tests revealed positive antinuclear antibody test, positive anti-dsDNA antibody, 0.24 g/L C3 (0.9-1.8 g/L), 0.04 g/L C4 (0.1-0.4 g/L), 32.37 g/L immunoglobulin (8-17 g/L), and 31568.1 mg/24 h total 24-h urine protein (0-150 mg/24 h). The patient was diagnosed with SLE involving the joints, kidneys and blood system. Previously reported cases of SLE were retrieved from PubMed to characterize clinicopathological features and identify prognostic factors for SLE. CONCLUSION: The patient was discharged in remission after a series of treatments, such as intravenous methylprednisolone sodium succinate, intravenous human immunoglobulin, cyclophosphamide injection, and plasma exchange. After discharge, the patient took oral prednisone acetate tablets, cyclosporine capsules, hydroxychloroquine sulfate tablets and other treatments for symptoms and was followed up regularly for 1 month, after which the patient's condition continued to improve and stabilize.
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BACKGROUND: Prior research underscores the significant impact of remnant cholesterol (RC) on stroke occurrence due to its proatherogenic and proinflammatory traits. This study aims to explore diverse risks of new-onset stroke associated with RC, considering distinct inflammation levels in the middle-aged and senior population in China. METHODS: We analyzed 6509 participants from the China Health and Retirement Longitudinal Study (CHARLS) across four waves (2011-2018). We employed a multivariable Cox proportional hazards regression model, incorporated restricted cubic spline techniques, and conducted sensitivity analyses to evaluate the association among RC, high-sensitivity C-reactive protein (hsCRP), and the risk of new-onset stroke. RESULTS: Over 7 years, 540 new-onset strokes occurred. Individuals in the highest quartile of RC levels exhibited a heightened risk of new-onset stroke, with a multivariable-adjusted hazard ratio (HR) peaking at 1.50 (95% confidence interval 1.12-2.00, P for trend = 0.021), showing a non-linear correlation (P nonlinearity = 0.049). High hsCRP alone had an adjusted HR of 1.10 (95% CI 0.87-1.39), compared to 1.40 (95% CI 1.00-1.96) for high RC alone. Additionally, concurrent high RC and hsCRP showed an adjusted HR of 1.43 (95% CI 1.05-1.96). Consistency persisted across various hsCRP thresholds, after adjusting for additional parameters, or excluding chronic diseases in the primary model, reinforcing result robustness. CONCLUSION: Our findings reveal a substantial and non-linear association between higher baseline RC levels and an elevated risk of new-onset stroke. Moreover, elevated levels of both RC and hsCRP jointly pose the highest risk for new-onset stroke, surpassing the risk associated with each factor individually.
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Colesterol , Inflamación , Accidente Cerebrovascular , Humanos , Masculino , Femenino , China/epidemiología , Estudios Longitudinales , Persona de Mediana Edad , Anciano , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/sangre , Inflamación/sangre , Inflamación/epidemiología , Colesterol/sangre , Jubilación , Factores de Riesgo , Biomarcadores/sangre , Estudios de SeguimientoRESUMEN
Rationale: Adult neurogenesis in the subventricular zone (SVZ) is essential for maintaining neural homeostasis, and its dysregulation contributes to anosmia and delayed tissue healing in neurological disorders, such as Parkinson's disease (PD). Despite intricate regulatory networks identified in SVZ neurogenesis, the molecular mechanisms dynamically maintaining neural stem/progenitor cells (NSPCs) in response to physiological and pathological stimuli remain incompletely elucidated. Methods: We generated an RNA binding motif protein 24 (Rbm24) knockout model to investigate its impact on adult neurogenesis in the SVZ, employing immunofluorescence, immunoblot, electrophysiology, RNA-sequencing, and in vitro experiments. Further investigations utilized a PD mouse model, along with genetic and pharmacological manipulations, to elucidate Rbm24 involvement in PD pathology. Results: Rbm24, a multifaceted post-transcriptional regulator of cellular homeostasis, exhibited broad expression in the SVZ from development to aging. Deletion of Rbm24 significantly impaired NSPC proliferation in the adult SVZ, ultimately resulting in collapsed neurogenesis in the olfactory bulb. Notably, Rbm24 played a specific role in maintaining Notch1 mRNA stability in adult NSPCs. The Rbm24/Notch1 signaling axis was significantly downregulated in the SVZ of PD mice. Remarkably, overexpression of Rbm24 rescued disruption of adult neurogenesis and olfactory dysfunction in PD mice, and these effects were hindered by DAPT, a potent inhibitor of Notch1. Conclusions: Our findings highlight the critical role of the Rbm24/Notch1 signaling axis in regulating adult SVZ neurogenesis under physiological and pathological circumstances. This provides valuable insights into the dynamic regulation of NSPC homeostasis and offers a potential targeted intervention for PD and related neurological disorders.