일산화탄소에 의한 면역 관련 이상 반응 억제 기전 및 필버톤의 아밀로이드 생성 완화 작용

Abstract

Combined immune checkpoint blockade (ICB) targeting CTLA-4 and PD-1 has improved the prognosis of malignancies but has also led to a high rate of immune-related adverse events (irAEs). The manifestation of these toxicities is an important limiting factor for the successful implementation of ICB, restraining its antitumor efficacy. Carbon monoxide (CO) is a pivotal endogenous signaling molecule that can maintain cell and tissue homeostasis and may have therapeutic uses. In our previous reports, CO regulates inflammatory diseases by increasing tristetraprolin (TTP) levels, which binds to the AU-rich elements in a target mRNA. In this study, we observed that CO-induced TTP activation ameliorated colitis and hepatitis and improved antitumor efficacy in ICB treatment. We found that the colitis and hepatitis in TTP deficient mice were further exacerbated by ICB treatment. CO enhances ICB efficacy by disrupting tumor associated macrophages (TAM) metabolic adaptation in the tumor microenvironment (TME). TTP destabilizes CD36 mRNA, causing metabolic maladaptation in TAMs within the TME. Thus, we suggest that CO may efficiently decouple antitumor effectiveness and toxicity of ICB by enhancing TTP. |The molecular mechanisms underlying the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease 54, and Huntington’s disease remain enigmatic, resulting in an unmet need for therapeutics development. Here, we suggest that filbertone, a key flavor compound found in the fruits of hazel trees of the genus Corylus, can ameliorate PD via lowering the abundance of aggregated α-synuclein. We previously reported that inhibition of hypothalamic inflammation by filbertone is mediated by suppression of nuclear factor kappa-B (NF- κB). Here, we report that filbertone activates PERK through mitochondrial ROS (mtROS) production, resulting in the increased nuclear translocation of transcription factor-EB (TFEB) in SH-SY5Y human neuroblastoma cells. TFEB activation by filbertone promotes the autophagy-lysosomal pathway (ALP), which in turn alleviates the accumulation of α-synuclein. We also demonstrate that filbertone prevented the loss of dopaminergic neurons in the substantia nigra and striatum of mice on high-fat diet (HFD). Filbertone treatment also reduced HFD-induced α-synuclein accumulation through upregulation of the ALP pathway. In addition, filbertone improved behavioral abnormalities (i.e., latency time to fall and decrease of running distance) in the MPTP-induced PD murine model. In conclusion, filbertone may show promise as a potential therapeutic for neurodegenerative disease. |Parkinson's disease (PD) as a prevalent neurodegenerative disorder is characterized by the loss of dopaminergic neurons in the substantia nigra compacta (SNc), which is considered the primary cause of PD. Ferroptosis is a recently discovered form of cell death that is characterized by iron accumulation, reduction of GPX4, and lipid peroxidation. Several studies have implicated the ferroptotic cell death as a contributing factor of PD. We previously reported that protection of neurodegeneration by filbertone is mediated by enhancing the PERK-ALP pathway. However, the anti-ferroptotic effects of filbertone on PD pathology have not been fully comprehended. Here, we show that filbertone induces the activation of Nrf2 via PERK activation, leading to the upregulation of antioxidant gene transcription, including GPX4 and SLC7A11. In addition, The Nrf2 activation by filbertone mitigate the accumulation of α-synuclein as well as dopaminergic neuron loss in the midbrain region of a mouse model of PD. Our study has shown that filbertone can prevent the reduction of GPX4 induced by specific ferroptosis inducers such as RSL3 or neurotoxins like MPP+/MPTP, which is achieved through the activation of Nrf2. In conclusion, the findings suggest that filbertone has the potential to act as a ferroptosis inhibitor and could serve as a promising therapeutic approach for PD.