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A ferroptosis-associated prognostic model correlated with immune landscape and radiotherapy response in low-grade gliomas (LGGs)

Despite receiving comprehensive treatment, the prognosis for low-grade gliomas (LGGs) patients varies considerably. Recent studies have focused extensively on ferroptosis, across a range of tumor types. Nevertheless, methodologies to evaluate the efficacy of radiotherapy for LGGs, from the perspective of ferroptosis-related genes (FRGs), remain strikingly rare. In this study, we conducted a retrospective study on the transcriptional profiles of LGG patients from the public databases and a local cohort. An FRG model was developed and validated, exhibits heightened robustness when contrasted with the traditional ssGSEA model. Patients demonstrating higher FRG scores were identified as a high-risk group, displaying a worse prognosis. By incorporating the FRG score alongside other prognosis-associated clinical indicators, we formulated an enhanced nomogram to achieve a higher level of prediction performance. Additionally, among LGG patients receiving radiotherapy, a poorer prognosis was observed in the high-risk group. Further investigation revealed that samples from the high-risk group generally exhibit a TME in an immuno-suppressive state. Collectively, we developed an FRG model and a robust nomogram for LGG prognostication. This study suggests that a high FRG score, indicative of an immunosuppressive TME, could potentially lead to a less favorable prognosis for certain LGG patients receiving radiotherapy.

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Effectiveness of double-filtration plasmapheresis in reducing immunoglobulin and culprit antibody levels in neuroimmune disorders: A single-center retrospective analysis from China

ObjectiveThis study aims to evaluate the effectiveness of double-filtration plasmapheresis (DFPP) in reducing immunoglobulins and culprit antibodies in neuroimmune disorders. MethodsA retrospective analysis was conducted on 51 patients with neuroimmune diseases treated with DFPP, immunotherapy, and symptomatic treatment. Immunoglobulin and antibody levels were measured pre- and post-treatment, along with neurological function assessments using scales like the modified Rankin Scale (mRS), Expanded Disability Status Scale (EDSS), Clinical Assessment Scale for Autoimmune Encephalitis (CASE), and Myasthenia Gravis-specific scales. ResultsThe cohort included patients with neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalitis (AIE), myasthenia gravis (MG), anti-myelin oligodendrocyte glycoprotein associated disease (MOGAD), and paraneoplastic neurological syndromes (PNS). DFPP significantly reduced immunoglobulin levels (IgG, IgA, IgM) by ∼70 %. Most patients showed decreased antibody titers and significant neurological improvement. The median mRS score improved from 2 (IQR 2–3) to 1 (IQR 1–2) post-treatment, with further improvement at 90 days. Notable improvements were observed across various scales specific to NMOSD, MOGAD, AIE, and MG. Minor adverse events were reported, with no serious adverse events. ConclusionsDFPP is effective in reducing immunoglobulin and antibody levels, leading to improved neurological function in neuroimmune disorders. Further large-scale studies are warranted to confirm these findings.

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Nicotine is an Immunosuppressant: Implications for Women's Health and Disease

A plethora of evidence supports that nicotine, the primary alkaloid in tobacco products that is generally accepted for maintaining use, is immunoregulatory and may function as an immunosuppressant. Women have unique experiences with use of nicotine-containing products and also undergo significant reproductive transitions throughout their lifespan which may be impacted by nicotine use. Within the extant literature, there is conflicting evidence that nicotine may confer beneficial health effects in specific disease states (e.g., in ulcerative colitis). Use prevalence of nicotine-containing products is exceptionally high in individuals presenting with some comorbid disease states that impact immune system health and can be a risk factor for the development of diseases which disproportionately impact women; however, the mechanisms underlying these relationships are largely unclear. Further, little is known regarding the impacts of nicotine's immunosuppressive effects on women's health during the menopausal transition, which is arguably an inflammatory event characterized by a pro-inflammatory peri-menopause period. Given that post-menopausal women are at a higher risk than men for the development of neurodegenerative diseases such as Alzheimer's disease and are also more vulnerable to negative health effects associated with diseases such as HIV-1 infection, it is important to understand how use of nicotine-containing products may impact the immune milieu in women. In this review, we define instances in which nicotine use confers immunosuppressive, anti-inflammatory, or pro-inflammatory effects in the context of comorbid disease states, and focus on how nicotine impacts neuroimmune signaling to maintain use. We posit that regardless of potential health benefits, nicotine use cessation should be a priority in the clinical care of women. The synthesis of this review demonstrates the importance of systematically defining the relationships between volitional nicotine use, immune system function, and comorbid disease states in women to better understand how nicotine impacts women's health and disease.

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Modulating sonic hedgehog (SHH) pathway to create a rapid CNS-TB model: Facilitating drug discovery

Tuberculous meningitis, a severe complication of Mycobacterium tuberculosis (M. tb) infection, involves the dissemination of bacilli in the brain. This study explored the role of the sonic hedgehog (SHH) signaling pathway in regulating blood-brain barrier (BBB) integrity, M. tb invasion into the central nervous system (CNS), and disease progression of Central Nervous System Tuberculosis (CNS-TB) in a Balb/c mouse model. The modulation of the SHH pathway using agonist Purmorphamine (PUR) and antagonist Cyclopamine (CYC) revealed that CYC treatment led to a rapid and extensive invasion of M. tb in the brain, with bacterial loads increasing by 99 % compared to the untreated-infected group. In contrast, PUR reduced M. tb loads by 50 % and delayed disease progression. Histopathological analysis showed that CYC exacerbated inflammation and immune cell infiltration, while PUR mitigated these responses. Immunohistochemistry demonstrated that CYC caused severe BBB breakdown and reactive gliosis, while PUR partially attenuated this response. Further analysis revealed that CYC upregulated Matrix Metalloproteinase-9 (MMP-9) secretion, a key contributor to BBB disruption. These findings highlight the critical role of the SHH pathway in maintaining BBB integrity and regulating the immunopathological response during CNS-TB, opening up future scope for drug discovery. This Cyclopamine-induced model of rapid M. tb invasion and chronic inflammation provides a new tool for studying CNS-TB pathogenesis and evaluating potential therapeutic interventions targeting the SHH signaling axis. Significance statementUnderstanding how tuberculosis (TB) infection can spread to the brain is crucial, as this “central nervous system TB” (CNS-TB) is a serious and potentially life-threatening health complication. However, studying CNS-TB in humans is very difficult. Animal models are needed to better understand how TB gets into the brain and the resulting damage. This study in mice showed that blocking a signaling pathway called Sonic Hedgehog (SHH) allowed TB to rapidly spread to the brain, damaging the blood-brain barrier and causing severe inflammation. In contrast, activating the SHH pathway helped protect the brain from TB invasion. These findings provide important insights that could lead to new ways to prevent or treat this dangerous form of TB.

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NAD+ supplement relieved chronic sleep restriction (CSR)-induced microglial proinflammation in vivo and in vitro

Sleep insufficiency is a significant health problem worldwide and can induce multiple neurodevelopmental disorders in the central nervous system (CNS). Sleep deprivation (SD), especially chronic SD, leads to cognition and memory loss and worsens neurodegenerative disease liability. Microglia are the main inflammation-dominant glia and play a crucial role in SD-induced neurological impairments. Nicotinamide adenine dinucleotide (NAD+) is a redox reaction coenzyme that exerts anti-inflammatory and mitochondria-protective effects in microglia. Whether NAD+ mitigated SD-induced neurological disorders by regulating microglial functions is still unknown. In the current study, we designed an in vivo and in vitro model to evaluate the neuroprotective effect of NAD+ on chronic sleep restriction (CSR) and further investigate the underlying mechanisms. Behavioral tests and immunofluorescence staining were applied to investigate the cognition impairments and microglial activation. Biochemical experiments were tested to analyze the oxidative status and possible mechanism. In vitro data were used to verify the in vivo data. Our results displayed that NAD+ supplement mitigated CSR-induced cognitive decline and microglial activation response by suppressing the expression of pro-inflammatory cytokines in vivo. NAD+ administration also decreased oxidative stress and mitochondrial impairments in microglia. In vitro results showed that NAD+ treatment inhibited ROS production and prompted M1 conversion to M2 phenotype. cGAS-STING/NF-κB pathways were significantly activated but down-regulated by NAD+ administration. H151, a STING antagonist, was applied to validate that NAD+ treatment alleviates neuroinflammation partially by regulating cGAS-STING pathways in microglia. Our findings suggest that NAD+ supplement is a promising therapy for sleep disorders-induced neurological problems, and cGAS-STING pathway may act as a critical regulator in microglial proinflammation.

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