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ML385

Katalog-Nr.GC19254

ML385 ist ein spezifischer nuklearer Erythroid-2-bezogener Faktor 2 (NRF2)-Inhibitor mit einem IC50-Wert von 1,9 μM.

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ML385 Chemische Struktur

Cas No.: 846557-71-9

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10mM (in 1mL DMSO)
59,00 $
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5mg
42,00 $
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10mg
63,00 $
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25mg
133,00 $
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50mg
217,00 $
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100mg
343,00 $
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Sample solution is provided at 25 µL, 10mM.

Product has been cited by 10 publications

Product Documents

Quality Control & SDS

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Protocol

Cell experiment [1]:

Cell lines

A549 cells

Preparation Method

A549 cells were transfected with a firefly luciferase reporter (Fluc) construct driven by a minimal TATA promoter with upstream NRF2-specific antioxidant response element (ARE) enhancer sequence from human NQO1 promoter ARE and clones stably expressing ARE-FLuc7 were screened and validated.

Reaction Conditions

Cells were cultured in the presence of ML385 (5 μM) for 48h and 72 h and measured the changes in the expression levels of NRF2 and its target genes.

Applications

ML385 treatment to A549 cells demonstrated a reduction in glutathione synthesis and recycling enzymes, members of the thioredoxin family, and glucose metabolism-related genes with a time-dependent manner. ML385 treatment significantly attenuated NQO1 enzyme activity and reduced GSH levels along with cellular antioxidant capacity.

Animal experiment [2]:

Animal models

1-8-week-old C57B/6 male mice

Preparation Method

Mice received a daily intraperitoneal injection of ML385 (30 mg/kg) dissolved in PBS with 5% Dimethyl Sulfoxide (DMSO) for 7 d.

Dosage form

30 mg/kg

Applications

ML385 could inhibit Nrf2 and used to explore the mechanism of Nrf2-NF-κB signaling pathway involved in the inhibition of astrocyte activation. Mice treated with ML385 had a significant decrease in Keap1, HO-1, Nrf2, and p-P65/P-65 (P < 0.05) expression compared to Sham or Vehicle control groups.

References:

[1]. Singh A, et al. Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors. ACS Chem Biol. 2016 Nov 18;11(11):3214-3225.

[2]. Xian P, et al. Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice. Theranostics. 2019 Aug 14;9(20):5956-5975.

Background

ML385 ist ein spezifischer Inhibitor des nukleären Faktors erythroid 2-bezogenen Faktor 2 (NRF2). ML385 bindet an NRF2 und hemmt die Expression seiner Zielgene als Sondenmolekül. Speziell bindet ML385 an Neh1, das Cap 'N' Collar Basic Leucine Zipper (CNC-bZIP)-Domäne von NRF2, und stört die Bindung des V-Maf Avian Musculoaponeurotic Fibrosarkom-Onkogen-Homolog G (MAFG)-NRF2-Protein-Komplexes an regulatorische DNA-Bindungssequenzen. ML385 zeigt Spezifität und Selektivität für NSCLC-Zellen mit KEAP1-Mutation, was zu einer Gewinnung der NRF2-Funktion führt.[1][2]

Eine In-vitro-Studie zeigte, dass ML385 potenziell NRF2 durch direkte Interaktion hemmt. Das NRF2-Signal wurde zeitabhängig verringert und der maximale Rückgang trat nach 72 Stunden auf. Es wurde auch eine Reduktion der NRF2-mRNA-Levels beobachtet. Darüber hinaus führte die Behandlung mit ML385 zu einer globalen Hemmung des NRF2-Signals in Lungenkrebszellen mit KEAP1-Mutationen sowie anderen Zielgenen. Die Behandlung mit ML385 reduzierte auch signifikant die NQO1-Enzymaktivität und senkte den GSH-Spiegel zusammen mit der zellulären antioxidativen Kapazität. [2]

Die In-vivo-Studie von ML385 zeigte, dass es NRF2 hemmt und vielversprechende antitumorale Aktivität aufweist. Die Kombination von ML385 mit Carboplatin führte zu einer signifikanten Reduktion des Tumorwachstums im Vergleich zum Fahrzeug. Obwohl die Behandlung mit einem einzelnen Wirkstoff (entweder ML385 oder Carboplatin) zu einer Reduktion des Tumorwachstums führte, war das Ausmaß dieser Effekte zwischen den Zelllinien variabel und erreichte keine statistische Signifikanz. Darüber hinaus zeigten Tumormuster, die mit ML385 behandelt wurden, eine signifikante Reduktion des NRF2-Proteinlevels und seiner downstreamen Zielgene. Zusätzlich verringerte die Zugabe von ML385 dosisabhängig Anisotropie mit einem IC50-Wert von 1,9 μM, was darauf hinweist, dass der NRF2-MAFG-Protein-Komplex vom fluoreszenzmarkierten ARE-DNA dissoziiert wurde. [2]

References:
[1]. Xian P, et al. Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice. Theranostics. 2019 Aug 14;9(20):5956-5975.
[2]. Singh A, et al. Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors. ACS Chem Biol. 2016 Nov 18;11(11):3214-3225.

Chemical Properties

Cas No. 846557-71-9 SDF
Canonical SMILES O=C(NC1=NC(C2=CC=C(N(C(C3=C(C)C=CC=C3)=O)CC4)C4=C2)=C(C)S1)CC5=CC(OCO6)=C6C=C5
Formula C29H25N3O4S M.Wt 511.59
Löslichkeit DMSO : ≥ 30 mg/mL (58.64 mM) Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.
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Research Update

Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway

Background: The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in depression remain unclear. The present study aimed to investigate the antidepressant activity of EDA and its underlying mechanisms. Methods: A chronic social defeat stress (CSDS) depression model was performed to explore whether EDA could produce antidepressant effects. Behaviors tests were carried out to examine depressive, anxiety-like and cognitive behaviors including social interaction (SI) test, sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension test (TST) and forced swim test (FST). Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), measurement of MDA, SOD, GSH, GSH-PX, T-AOC and transmission electron microscopy (TEM). Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. EX527, a Sirt1 inhibitor and ML385, a Nrf2 inhibitor were injected intraperitoneally 30 min before EDA injection daily. Knockdown experiments were performed to determine the effects of Gpx4 on CSDS mice with EDA treatment by an adeno-associated virus (AAV) vector containing miRNAi (Gpx4)-EGFP infusion. Results: The administrated of EDA dramatically ameliorated CSDS-induced depressive and anxiety-like behaviors. In addition, EDA notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, oxidative stress damage, energy metabolism and pro-inflammatory cytokines activation in the hippocampus (Hip) and mPFC of CSDS-induced mice. Further examination indicated that the application of EDA after the CSDS model significantly increased the protein expressions of Sirt1, Nrf2, HO-1 and Gpx4 in the Hip. EX527 abolished the antidepressant effect of EDA as well as the protein levels of Nrf2, HO-1 and Gpx4. Similarly, ML385 reversed the antidepressant and anxiolytic effects of EDA via decreased expressions of HO-1 and Gpx4. In addition, Gpx4 knockdown in CSDS mice abolished EDA-generated efficacy on depressive and anxiety-like behaviors. Conclusion: These findings suggest that EDA possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.

Kaempferol Ameliorates Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Ferroptosis by Activating Nrf2/SLC7A11/GPX4 Axis

Kaempferol has been shown to protect cells against cerebral ischemia/reperfusion injury through inhibition of apoptosis. In the present study, we sought to investigate whether ferroptosis is involved in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuronal injury and the effects of kaempferol on ferroptosis in OGD/R-treated neurons. Western blot, immunofluorescence, and transmission electron microscopy were used to analyze ferroptosis, whereas cell death was detected using lactate dehydrogenase (LDH) release. We found that OGD/R attenuated SLC7A11 and glutathione peroxidase 4 (GPX4) levels as well as decreased endogenous antioxidants including nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and superoxide dismutase (SOD) in neurons. Notably, OGD/R enhanced the accumulation of lipid peroxidation, leading to the induction of ferroptosis in neurons. However, kaempferol activated nuclear factor-E2-related factor 2 (Nrf2)/SLC7A11/GPX4 signaling, augmented antioxidant capacity, and suppressed the accumulation of lipid peroxidation in OGD/R-treated neurons. Furthermore, kaempferol significantly reversed OGD/R-induced ferroptosis. Nevertheless, inhibition of Nrf2 by ML385 blocked the protective effects of kaempferol on antioxidant capacity, lipid peroxidation, and ferroptosis in OGD/R-treated neurons. These results suggest that ferroptosis may be a significant cause of cell death associated with OGD/R. Kaempferol provides protection from OGD/R-induced ferroptosis partly by activating Nrf2/SLC7A11/GPX4 signaling pathway.

Dexmedetomidine attenuates myocardial ischemia/reperfusion-induced ferroptosis via AMPK/GSK-3β/Nrf2 axis

The present study aimed to investigate whether dexmedetomidine (Dex) exerts cardioprotection effect through inhibiting ferroptosis. Myocardial ischemia/reperfusion injury (MIRI) was induced in Sprague-Dawley rats in Langendorff preparation. The hemodynamic parameters were recorded. Triphenyltetrazolium chloride (TTC) staining was used to determine infarct size. In the in vitro study, the model of hypoxia/reoxygenation (HR) was established in H9c2 cells. Cell viability and apoptosis were detected using cell counting kit 8 (CCK-8), and AV/PI dual staining respectively. Lipid peroxidation as measured by the fluorescence of the fatty acid analog C11-BODIPY581/591 probe and intracellular ferrous iron levels were measured by fluorescence of Phen Green SK (PGSK) probe, whereas immunofluorescence and transmission electron microscopy were also used to examine ferroptosis. Protein levels were investigated by Western blot. The interactions of AMPK/GSK-3β signaling with Nrf2 were also assessed through AMPK inhibition and GSK-3β overexpression. Our findings indicated that Dex significantly alleviated myocardial infarction, improved heart function, and decreased HR-induced accumulation of Fe2+ and lipid peroxidation in cardiomyocytes. Dex significantly increased the expression levels of Nrf2, SLC7A11, and GPX4. However, inhibition of Nrf2 by ML385 blunted the protective effect of Dex in HR-treated H9c2 cells. Inhibition of AMPK with a specific inhibitor or siRNA decreased the expression levels of phosphorylation of GSK-3β and Nrf2 induced by Dex. Overexpression of GSK-3β resulted in lower levels of nuclear Nrf2, whereas depression of GSK-3β enhanced expressions of nuclear Nrf2. In conclusion, Dex protects hearts against MIRI-induced ferroptosis via activation of Nrf2 through AMPK/GSK-3β signaling pathway.

Melatonin improves hypoxic-ischemic brain damage through the Akt/Nrf2/Gpx4 signaling pathway

Melatonin (Mel) has neuroprotective effects; however, its roles in hypoxic-ischemic brain damage (HIBD) and the underlying mechanisms remain unknown. We aimed to explore its roles and mechanisms in a HIBD rat model. We found that exogenous Mel treatment ameliorated HIBD-induced pathological changes, inhibited neuronal ferroptosis, and promoted hippocampal neuronal survival. Moreover, Mel improved the learning and memory abilities of the HIBD rats. Further, we found that glutathione peroxidase 4 (Gpx4) inhibition with RSL3, Akt inhibition with LY29400, and nuclear factor erythroid-2-related factor 2 (Nrf2) inhibition with ML385 abolished the Mel protective effects in HIBD. Our findings indicate that exogenous Mel treatment has a protective effect on HIBD via the Akt/Nrf2/Gpx4 pathway.

Hydrogen sulfide alleviates particulate matter-induced emphysema and airway inflammation by suppressing ferroptosis

Background: Redox imbalance is an vital mechanism for COPD. At present, insufficient researches have been conducted on the protective effect of hydrogen sulfide (H2S) on PM-induced COPD. However, whether H2S exerts the anti-injury role by blocking ferroptosis and restoring redox equilibrium remain to be investigated.
Methods: Human lung tissue samples were collected for IHC staining, and the expressions of Nrf2, ferritinophagy- and ferroptosis-related proteins were observed. The WT C57BL/6 and Nrf2 knockout mice models were established with PM(200 μg per mouse). NaHS(Exogenous H2S) was injected intraperitoneally 30 min in advance. Twenty-nine days later, mice lung tissues were evaluated by HE's and PERLS-DAB's staining. Meanwhile, inflammation and oxidative stress indicators and iron levels were assessed by corresponding ELISA kit. Related protein expressions were detected through Western blot. BEAS-2B cells with or without H2S were exposed to PM2.5 for 36 h. Cell viability, mitochondrial morphology, inflammatory cytokines, antioxidant factors, iron levels, autophagic flux and the levels of ROS, LIP ROS, MitoROS, MMP, as well as related protein expressions were detected by specific methods, respectively. In addition, V5-Nrf2, Nrf2 siRNA, Nrf2 inhibitor ML385, PPAR-γ inhibitor GW9662, autophagy inhibitor CQ, iron chelator DFO and ferroptosis inhibitor Fer-1 were used to verify the target signaling pathways.
Results: We found that the expressions of LIP ROS, ROS, COX2, MDA and other oxidative factors increased, while the antioxidant markers GPX4, GSH and GSH-Px significantly decreased, as well as active iron accumulation in COPD patients, PM-exposured WT and Nrf2-KO mice models and PM2.5-mediated cell models. NaHS pretreatment markedly inhibited PM-induced emphysema and airway inflammation by alleviating ferroptotic changes in vivo and vitro. With the use of V5-Nrf2 overexpression plasmid, Nrf2 siRNA and pathway inhibitors, we found NaHS activates the expressions of Nrf2 and PPAR-γ, and inhibites ferritinophagy makers LC3B, NCOA4 and FTH1 in BEAS-2B cells. Moreover, the anti-ferroptotic effect of NaHS was further verified to be related to the activation of Nrf2 signal in MEF cells.
Conclusion: This research suggested that H2S alleviated PM-induced emphysema and airway inflammation via restoring redox balance and inhibiting ferroptosis through regulating Nrf2-PPAR-ferritinophagy signaling pathway.

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