RESUMO
Both neuroinflammation and iron accumulation play roles in the pathogenesis of Parkinson's disease (PD). However, whether inflammation induces iron dyshomeostasis in dopaminergic neurons at an early stage of PD, at which no quantifiable dopaminergic neuron loss can be observed, is still unknown. As for the inflammation mediators, although several cytokines have been reported to increase in PD, the functions of these cytokines in the SN are double-edged and controversial. In this study, whether inflammation could induce iron dyshomeostasis in dopaminergic neurons through high mobility group protein B1 (HMGB1) in the early stage of PD is explored. Lipopolysaccharide (LPS), a toxin that primarily activates glia cells, and 6-hydroxydopamine (6-OHDA), the neurotoxin that firstly impacts dopaminergic neurons, were utilized to mimic PD in rats. We found a common and exceedingly early over-production of HMGB1, followed by an increase of divalent metal transporter 1 with iron responsive element (DMT1+) in the dopaminergic neurons before quantifiable neuronal loss. HMGB1 neutralizing antibody suppressed inflammation in the SN, DMT1+ elevation in dopaminergic neurons, and dopaminergic neuronal loss in both LPS and 6-OHDA administration- induced PD models. On the contrary, interleukin-1ß inhibitor diacerein failed to suppress these outcomes induced by 6-OHDA. Our findings not only demonstrate that inflammation could be one of the causes of DMT1+ increase in dopaminergic neurons, but also highlight HMGB1 as a pivotal early mediator of inflammation-induced iron increase and subsequent neurodegeneration, thereby HMGB1 could serve as a potential target for early-stage PD treatment.
Assuntos
Proteína HMGB1 , Doença de Parkinson , Transtornos Parkinsonianos , Animais , Ratos , Citocinas/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Proteína HMGB1/metabolismo , Inflamação/patologia , Ferro/metabolismo , Lipopolissacarídeos , Oxidopamina , Doença de Parkinson/patologia , Transtornos Parkinsonianos/metabolismoRESUMO
BACKGROUND: Long non-coding RNAs (lncRNAs) are closely related to the occurrence and development of cancer. Abnormally expressed lncRNA can be used as a diagnostic marker for cancer. In this study, we aim to investigate the clinical significance of MIR99AHG expression in lung adenocarcinoma (LUAD), and its biological roles in LUAD progression. METHODS: The relative expression of MIR99AHG in LUAD tissues and cell lines was analyzed using public databases and RT-qPCR. The biological functions of MIR99AHG were investigated using a loss-of-function approach. The effect of MIR99AHG on lung fibrosis was assessed by scratch assay, invasion assay and lung fibrosis rat model. FISH, luciferase reporter assay and immunofluorescence were performed to elucidate the underlying molecular mechanisms. RESULTS: LncRNA MIR99AHG expression level was downregulated in LUAD tissues and cell lines. Low MIR99AHG levels were associated with poorer patient overall survival. Functional analysis showed that MIR99AHG is associated with the LUAD malignant phenotype in vitro and in vivo. Further mechanistic studies showed that, MIR99AHG functions as a competitive endogenous RNA (ceRNA) to antagonize miR-136-5p-mediated ubiquitin specific protease 4 (USP4) degradation, thereby unregulated the expression of angiotensin-converting enzyme 2 (ACE2), a downstream target gene of USP4, which in turn affected alveolar type II epithelial cell fibrosis and epithelial-mesenchymal transition (EMT). In summary, the MIR99AHG/miR-136-5p/USP4/ACE2 signalling axis regulates lung fibrosis and EMT, thus inhibiting LUAD progression. CONCLUSION: This study showed that downregulated MIR99AHG leads to the development of pulmonary fibrosis. Therefore, overexpression of MIR99AHG may provide a new approach to preventing LUAD progression.
Assuntos
Adenocarcinoma , Neoplasias Pulmonares , MicroRNAs , Fibrose Pulmonar , RNA Longo não Codificante , Adenocarcinoma/genética , Enzima de Conversão de Angiotensina 2 , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Fibrose Pulmonar/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ratos , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismoRESUMO
Iron accumulation in the substantia nigra is recognized as a hallmark of Parkinson's disease (PD). Therefore, reducing accumulated iron and associated oxidative stress is considered a promising therapeutic strategy for PD. However, current iron chelators have poor membrane permeability and lack cell-type specificity. Here we identified GSK-J4, a histone demethylase inhibitor with the ability to cross blood brain barrier, as a potent iron suppressor. Only a trace amount of GSK-J4 significantly and selectively reduced intracellular labile iron in dopaminergic neurons, and suppressed H2O2 and 6-OHDA-induced cell death in vitro. The iron-suppressive effect was mainly mediated by inducing an increase in the expression of the iron exporter ferroportin-1. In parallel, GSK-J4 rescued dopaminergic neuron loss and motor defects in 6-OHDA-induced PD rats, which was accompanied by reduction of oxidative stress. Importantly, GSK-J4 rescued the abnormal changes of histone methylation, H3K4me3 and H3K27me3 during 6-OHDA treatment although the iron-suppressive and neuroprotective effects were sensitive to H3K4me3 inhibition only. Also, upregulating H3K4me3 increased ferroportin-1 expression and neuroprotection. Taken together, we demonstrate a previously unappreciated action of GSK-J4 on cell-specific iron suppression and neuroprotection via epigenetic mechanism. Compared with conventional iron chelators, this compound has a stronger therapeutic potential for PD.
