JOURNAL/nrgr/04.03/01300535-202506000-00028/figure1/v/2024-08-08T040853Z/r/image-tiff The pathophysiology of Huntington’s disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington’s disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington’s disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS (a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2 inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington’s disease by activating nuclear factor erythroid 2-related factor 2, suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington’s disease.

2025-03-01·EXPERIMENTAL NEUROLOGY

Acteoside alleviates salsolinol-induced Parkinson's disease by inhibiting ferroptosis via activating Nrf2/SLC7A11/GPX4 pathway

Article

作者: Sun, Huiyan ; Li, Wenjing ; Jiang, Xiaodong ; Wang, Yumin ; Wang, Hongquan ; Wu, Shuang ; Li, Qiang

Salsolinol (SAL), i.e.1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroiso-quinoline, is a dopamine metabolite and endogenous neurotoxin that is toxic to dopaminergic neurons, and is involved in the genesis of Parkinson's disease (PD). However, the machinery underlying SAL induces neurotoxicity in PD are still being elucidated. In the present study, we first used RNA sequencing (RNAseq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to detect differentially expressed genes in SAL-treated SH-SY5Y cells. We found that ferroptosis-related pathway was enriched by SAL, which was validated by in vitro and in vivo SAL models. SAL inducing ferroptosis through downregulating SLC7A11/GPX4 in SH-SY5Y cells, which neurotoxic effect was reversed by ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (Fer-1). Acteoside, a phenylethanoid glycoside of plant origin with neuroprotective effect, attenuates SAL-induced neurotoxicity by inhibiting ferroptosis in in vitro and in vivo PD models through upregulating SLC7A11/GPX4. Mechanistically, acteoside activates Nrf2. Nrf2 inhibitor ML385 abolished acteoside-mediated increased SLC7A11/GPX4 and neuroprotection against SAL in SH-SY5Y cells. Meanwhile, the PI3K inhibitor LY294002 suppressed the acteoside-induced Nrf2 expression and ensued decreased expression of SLC7A11/GPX4 in SAL-treated SH-SY5Y cells. Taken together, these results demonstrate that salsolinol-induced PD through inducing ferroptosis via downregulating SLC7A11/GPX4. Acteoside attenuates SAL-induced PD through inhibiting ferroptosis via activating PI3K/Akt-dependant Nrf2. The present study revealed a novel molecular mechanisms underlining SAL-induced neurotoxicity via induction of ferroptosis in PD, and uncovered a new pharmacological effect against PD through inhibiting ferroptosis. This study highlights SAL-induced ferroptosis -dependent neurotoxicity as a potential therapeutic target in PD.

2025-03-01·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

Nrf2 protects against oxidative damage induced by hemoglobin in the liver of grass carp (Ctenopharyngodon idella)

Article

作者: Huang, Xiaoman ; Chen, Bing ; Qin, Zhendong ; Li, Ningjing ; Yang, Yan ; Lin, Li ; Song, Jialing ; Tian, Ye

Hemoglobin (Hb) releases during hemorrhaging and causes oxidative damage, further exacerbates the development of multiple diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates cellular defenses against toxic and oxidative challenges. However, the regulation mechanism of Nrf2 in Hb-induced oxidative stress remains unclear in teleost. To accomplish this goal, a hemolysis model was established by injecting grass carp with phenylalanine (PHZ), and the immunofluorescence analysis (IFA) and hematoxylin and eosin (H&E) staining revealed that PHZ-induced hemolysis caused Hb accumulation and hepatic vacuolization, resulted in tissue damage. Prussian blue, Sirius red, and Masson staining results revealed significant iron deposition and extensive collagen fiber accumulation in the liver. IFA and immunohistochemical analyses demonstrated that PHZ-induced hemolysis markedly increased the production of reactive oxygen species (ROS), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE). The quantitative real-time PCR (qRT-PCR) analysis data revealed that the PHZ-induced hemolysis also significantly upregulated the expression of antioxidant-related genes through activation of the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/Nrf2 signaling pathway. To further explore the molecule regulation mechanism of PHZ-induced hemolysis, the RNA-seq analysis was performed, and the data revealed that the AMPK/Nrf2 and multiple programmed cell death pathways, including ferroptosis, autophagy, apoptosis, and necroptosis in PHZ injection groups were significant upregulated. In vitro, the hemin supplementation activated the expression of target genes in the AMPK/Nrf2 pathway detected by qRT-PCR. To further verify the regulation function of Nrf2, an Nrf2 activator (4OI) was supplemented, and the flow cytometer analysis results suggested that the Hb-induced cell damage was significantly attenuated. However, the supplementary of ML385 down-regulated the AMPK/Nrf2 pathway and aggravated the hemin induced cell death. In conclusion, these findings highlight the critical regulatory role of the AMPK/Nrf2 signaling pathway in protecting against Hb-induced oxidative damage in the liver of grass carp.

项与 ML385 相关的新闻（医药）

2024-11-06

·转化医学网

【Nature子刊】成都医学院陈虎团队：食管鳞癌有前景的靶向治疗方法

11月5日，成都医学院陈虎研究团队在期刊《Cell Death&Disease》上发表了研究论文，题为“ΔNp63α promotes radioresistance in esophageal squamous cell carcinoma through the PLEC-KEAP1-NRF2 feedback loop”，在本研究中，研究人员发现ΔNP63α在ESCC中高度表达，并与放射耐药相关。此外，ΔNP63α在放射耐药中发挥关键作用，可直接激活PLEC的表达。PLEC与KEAP1竞争性相互作用，导致NRF2从KEAP1中释放并从细胞质转移到核内，在那里激活基因表达以促进ROS消除。此外，放射治疗诱导的ROS还可通过NRF2激活ΔNP63α的表达。通过抑制NRF2，可有效改善裸鼠的放射敏感性。综合研究结果，强烈表明ΔNp63α/PLEC/NRF2轴在ESCC的放射耐药中起着关键作用，这表明靶向NRF2是治疗ESCC的一种有前途的治疗方法。 https://www.nature.com/articles/s41419-024-07194-4 背景信息 01 食管癌是全球第六大癌症相关死亡原因。根据组织病理学特征，食管癌可分为鳞状细胞癌（ESCC）和腺癌（ESCA）两种类型。全球近70%的食管癌病例发生在中国，其中90%为ESCC病例。在过去的十年中，靶向ESCC的早期诊断和治疗的临床方法已经发生了演变，在所有阶段都出现了新的范式取代传统方法。然而，超过50%的ESCC患者对目前的治疗方法反应不佳，大多数患者死于复发性癌症。ESCC被认为对抗癌疗法具有耐药性。越来越多的证据表明，ESCC容易产生放射性耐药，导致放疗失败。因此，了解放射性耐药的机制对于开发ESCC的新型治疗策略至关重要。 p63蛋白是由TP63基因编码的，是p53/p63/p73家族的成员，是表皮分化过程中的关键调节因子。p63也是鳞状细胞癌（SCC）中依赖于谱系的癌基因。TP63基因通过不同的启动子产生两种主要的异构体，TAp63和N-端截短的ΔNp63。ΔNp63α是TP63在表皮细胞和SCC（包括ESCC）中表达的主要异构体。ΔNp63α通过激活β-连环蛋白/c-Myc信号通路来促进ESCC细胞的侵袭和转移。ΔNp63α还通过Akt信号通路或DKK3/CKAP4促进ESCC细胞的生长。据报道，ΔNp63α在ESCC患者中的表达与生存率相关。然而，ΔNp63α是否参与ESCC的治疗耐药目前尚不清楚。 ΔNp63α通过降低放疗诱导的ROS来促进食管鳞癌的辐射耐药 02 为了评估ΔNp63α在放疗中的关键作用，研究人员首先筛选了一组ESCC细胞系，并选择了表达低水平（KYSE30和KYSE150）和高水平（KYSE180和KYSE450）ΔNp63α的两个细胞系。接下来，研究人员对细胞进行照射并测量细胞存活率。如图1B所示，ΔNp63α表达水平较高的KYSE450细胞在照射后表现出较高的存活率，而ΔNp63α表达水平较低的KYSE150细胞则没有。10 Gy的照射导致KYSE150细胞中ΔNp63α蛋白轻微升高，但未影响KYSE450细胞中的ΔNp63α表达。相反，ΔNp63α敲低显著降低了细胞在放疗后的存活率。另外，野生型ΔNp63α的过表达，但不是转录激活缺陷型突变体（R304W），在放疗时显著提高了细胞存活率。这些结果表明，ΔNp63α在ESCC的放疗耐药中起着关键作用。图1：ΔNp63α通过抑制放疗诱导的ROS来促进辐射耐药性放射疗法主要通过离子辐射和活性氧分子（ROS）引起的DNA损伤来发挥治疗作用，通过自由基破坏DNA的化学键。因此，DNA损伤检查点响应在细胞辐射敏感性中起着关键作用。在ΔNp63α过表达的KYSE150细胞中，由辐射引起的检查点蛋白ATM和CHK2的激活磷酸化显著增加，而在ΔNp63α敲除的KYSE450细胞中则降低，这表明ΔNp63α促进对DNA损伤的检查点激活。此外，在ΔNp63α敲除的KYSE450细胞中，由辐射引起的活性氧分子显著升高。通过N-乙酰半胱氨酸（NAC）清除活性氧分子可显著提高细胞存活率，并抑制由辐射引起的p-AMT和p-CHK2的表达。据报道，ΔNp63α激活RAD51（一种重组酶）以维持基因组完整性。研究人员在ΔNp63α敲除的KYSE450细胞中恢复了RAD51的表达，发现RAD51在一定程度上，但并非完全逆转了辐射治疗后的细胞存活率。然而，RAD51的恢复结合ROS清除完全恢复了辐射引起的细胞生存抑制，这表明RAD51在不解决ROS诱导的损伤的情况下并不足以发挥作用。总之，这些数据表明ΔNp63α通过减少放疗诱导的ROS来促进放射耐药性。靶向NRF2抑制ΔNp63α介导的辐射耐药 03 为了研究激活或抑制NRF2对ROS水平和细胞存活率的影响，研究人员分别用SFN或ML385处理KYSE150或KYSE450细胞。研究显示，SFN激活NRF2明显降低了ROS水平，尽管这并未显著改善细胞存活率。相反，ML385抑制NRF2导致ROS水平显著升高，细胞存活率显著降低。这些结果表明，较低的内源性ROS水平可能不会显著影响细胞存活率。然而，在KYSE150细胞接受辐射治疗后，随着ROS水平的升高，细胞存活率明显降低。使用SFN或NAC可有效中和辐射诱导的ROS并显著改善细胞存活率。相反，ML385抑制NRF2进一步升高了辐射诱导的ROS。尤其是，NAC治疗几乎完全恢复了辐射后的细胞存活率。这些发现强调了NRF2在维持ROS水平和支持细胞存活方面的关键作用。为了研究ΔNp63α和NRF2对食管鳞状细胞癌（ESCC）进展的影响，研究人员通过向裸鼠皮下注射转染的ESCC细胞来建立异种移植模型，并通过照射和NRF2抑制剂ML385进行治疗。研究显示，ΔNp63α的过表达可促进肿瘤生长和体重增加。照射显著降低了肿瘤生长和体重，而过表达ΔNp63α则在照射后促进肿瘤生长。照射结合NRF2抑制可显著抑制ΔNp63α介导的肿瘤生长，表明NRF2抑制可对抗ΔNp63α介导的辐射耐药。此外，免疫组织化学检测显示，照射后，ΔNp63α增加了Ki67+细胞并减少了Cleaved Caspase-3+（CC3）凋亡细胞，而NRF2抑制剂与照射结合则显著减少了Ki67+细胞并增加了CC3+凋亡细胞。这些结果表明，NRF2抑制可对抗ΔNp63α介导的ESCC辐射耐药。结论 04 本研究结果表明，ΔNp63α/PLEC/NRF2信号通路和抗氧化防御机制可能是癌症治疗的有前景的治疗策略。（转化医学网360zhyx.com）【参考资料】 https://www.nature.com/articles/s41419-024-07194-4 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。