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Mdivi 1 Sale

(Synonyms: 3-(2,4-二氯-5-甲氧基苯基)-2,3-二氢-2-硫代-4(1H)-喹唑啉酮,Mitochondrial division inhibitor 1) 目录号 : GC10200

A mitochondrial division inhibitor

Mdivi 1 Chemical Structure

Cas No.:338967-87-6

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10mM (in 1mL DMSO)
¥378.00
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10mg
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50mg
¥1,386.00
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment [1]:

Cell lines

Primary cortical neuron(PCN)

Preparation Method

PCNs were treated with Mdivi-1 (from 0.001 nM to 1 mM) dissolved in 0.1% DMSO 1 h before scratch cell injury. The release of lactate dehydrogenase(LDH)into the culture media was measured 6 h after scratch cell injury.

Reaction Conditions

0.001 nM to 1 mM for 1hour

Applications

Using LDH assay, exposing PCNs to scratch cell injury with Mdivi-1 (100 µM and 1 mM) resulted in significant dose-dependent inhibition of cell death. Hence the range of the optimum concentration was from 10 µM to 100 µM.

Animal experiment [2]:

Animal models

male ICR mice

Preparation Method

For the mice treated with Mdivi-1 (3 mg/kg), dynamin-related protein 1 (Drp1) inhibitor, was administered by intraperitoneal injection 10 min after TBI. Mdivi-1 was dissolved in 0.01 M PBS. Vehicle animals received an intraperitoneal injection of 0.01 M PBS.

Dosage form

Intraperitoneal injection, 3 mg/kg

Applications

Treatment with Mdivi-1 accelerated the recovery of motor functional outcome on days 3-5 post-TBI. After injury, animals subjected to Mdivi-1 treatment demonstrated a significant decrease in the latencies, relative to vehicle mice on days 15 and 16, thereby Mdivi-1 treatment could result in cognitive functional recovery.

References:

[1]: Q. Wu, C. Gao, H. Wang, X. Zhang, et al. Mdivi-1 alleviates blood-brain barrier disruption and cell death in experimental traumatic brain injury by mitigating autophagy dysfunction and mitophagy activation. Int. J. Biochem. Cell Biol., 94 (2018), pp. 44-55, 10.1016/j.biocel.2017.11.007
[2]: Q. Wu, S.X. Xia, Q.Q. Li, et al. Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury. Brain Res., 1630 (2016), pp. 134-143

产品描述

Mdivi-1 (Mitochondrial division inhibitor 1) inhibits traumatic brain injury (TBI)-induced dynamin-related protein 1(Drp1) up-regulation, autophagy dysfunction and mitophagy activation. Mdivi-1 decreased TBI-induced cell death and lesion volume [1,2].

Mdivi-1 is a selective Drp 1 inhibitor with IC50 value as 10 mμ[3]. Mdivi-1 significantly alleviated the scratch injury-induced cell death, loss of mitochondrial membrane potential, reactive oxygen species (ROS) production and ATP reduction in primary cortical neurons (PCNs). Additionally, the lysosome inhibitor chloroquine (CQ) abrogated the Mdivi-1-induced decrease in autophagosomes accumulation and cell death at 24 h both in the basal state and under the conditions of scratch cell injury [1].

Mdivi-1 could significantly rescue neurons from death induced by seizures in a dose-dependent manner. In addition, the seizures increase Drp1 expression in hippocampus. These suggested that the up-regulation of Drp1 expression could be partially responsible for seizure-induced neuronal death. Moreover, CytC release, AIF translocation and caspase-3 activation may be involved in the protective mechanisms of mdivi-1 against seizure-induced neuronal death [4].

References:
[1]. Q. Wu, C. Gao, H. Wang, X. Zhang, et al. Mdivi-1 alleviates blood-brain barrier disruption and cell death in experimental traumatic brain injury by mitigating autophagy dysfunction and mitophagy activation. Int. J. Biochem. Cell Biol., 94 (2018), pp. 44-55, 10.1016/j.biocel.2017.11.007
[2]. Q. Wu, S.X. Xia, Q.Q. Li, et al. Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury. Brain Res., 1630 (2016), pp. 134-143
[3]. D. Wu, A. Dasgupta, K.H. Chen, M. Neuber-Hess, J. Patel, T.E. Hurst, J.D. Mewburn, P.D.A. Lima, E. Alizadeh, A. Martin, M. Wells, V. Snieckus, S.L. Archer. Identification of novel dynamin-related protein 1 (Drp1) GTPase inhibitors: therapeutic potential of Drpitor1 and Drpitor1a in cancer and cardiac ischemia-reperfusion injury.FASEB J., 34 (2020), pp. 1447-1464
[4]. Xie N, Wang C, Lian Y, Zhang H, Wu C, Zhang Q. A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. (2013b) Neurosci Lett 545: 64 -68.

Mdivi-1(线粒体分裂抑制剂 1)抑制创伤性脑损伤 (TBI) 诱导的动力蛋白相关蛋白 1 (Drp1) 上调、自噬功能障碍和线粒体自噬激活。 Mdivi-1 减少了 TBI 诱导的细胞死亡和损伤体积 [1,2]

Mdivi-1 是一种选择性 Drp 1 抑制剂,IC50 值为 10 mμ[3]。 Mdivi-1 显着减轻了划痕损伤引起的细胞死亡、线粒体膜电位丧失、活性氧 (ROS) 产生和原代皮层神经元 (PCN) 中 ATP 的减少。此外,在基础状态和划痕细胞损伤条件下,溶酶体抑制剂氯喹 (CQ) 在 24 小时内消除了 Mdivi-1 诱导的自噬体积累减少和细胞死亡[1]

Mdivi-1 可以剂量依赖性方式显着挽救神经元免于癫痫发作引起的死亡。此外,癫痫发作会增加海马体中 Drp1 的表达。这些表明 Drp1 表达的上调可能是癫痫发作引起的神经元死亡的部分原因。此外,CytC释放、AIF易位和caspase-3激活可能参与了mdivi-1对癫痫引起的神经元死亡的保护机制[4]

Chemical Properties

Cas No. 338967-87-6 SDF
别名 3-(2,4-二氯-5-甲氧基苯基)-2,3-二氢-2-硫代-4(1H)-喹唑啉酮,Mitochondrial division inhibitor 1
化学名 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanylidene-1H-quinazolin-4-one
Canonical SMILES COC1=C(C=C(C(=C1)N2C(=O)C3=CC=CC=C3NC2=S)Cl)Cl
分子式 C15H10Cl2N2O2S 分子量 353.22
溶解度 ≥ 17.65mg/mL in DMSO 储存条件 Store at -20°C
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1 mM 2.8311 mL 14.1555 mL 28.311 mL
5 mM 0.5662 mL 2.8311 mL 5.6622 mL
10 mM 0.2831 mL 1.4155 mL 2.8311 mL
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Research Update

Mdivi-1 alleviates atopic dermatitis through the inhibition of NLRP3 inflammasome

Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder with few treatment options. Dynamin-related protein 1 (Drp1)-dependent mitochondrial fission contributes to the activation of NLRP3 inflammasome, and inhibiting Drp1 has been become an attractive therapeutic strategy for inflammatory diseases. This study aimed to investigate the effects of Drp1 inhibitor mdivi-1 on experimental AD. We firstly detected the effects of mdivi-1 on primary human keratinocytes in an inflammatory cocktail-induced AD-related inflammation in vitro. Results showed that mdivi-1 inhibited NLRP3 inflammasome activation and pyroptosis which were evidenced by decreased expression of NLRP3, ASC, cleavage of caspase-1, GSDMD-NT, mature interleukin (IL)-1β and IL-18 in keratinocytes under AD-like inflammation. Next, mouse model of AD-like skin lesions was induced by epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) and mdivi-1 (25 mg/kg/day, days 5-33 during construction of AD model) was intraperitoneally injected into DNCB-induced mice. AD mice with mdivi-1 treatment exhibited ameliorated AD symptoms, lower serum IgE level, and reduced epidermal thickening, mast cells infiltration, and production of IL-4, IL-5 and IL-13 in the lesional tissues. Indeed, mdivi-1 significantly inhibited NLRP3 inflammasome activation and pyroptotic injury occurred in DNCB-treated skin tissues. Mechanically, mdivi-1 regulated the expression of mitochondrial dynamic proteins and suppressed the activation of NF-κB signal pathway which is an upstream of NLRP3 inflammasome both in vitro and in vivo. This study demonstrated that mdivi-1 could protect against experimental AD through inhibiting the activation of NLRP3 inflammasome and subsequent inflammatory cytokine release, and mdivi-1 might exert this function by inhibiting mitochondrial fission and subsequently blocking NF-κB pathway.

Mdivi-1: a promising drug and its underlying mechanisms in the treatment of neurodegenerative diseases

Mitochondria are energy-producing organelles, and neurons are high energy consumption cells. Therefore, mitochondrial dysfunction is a critical factor in neurodegenerative processes. Mitochondrial division inhibitor-1 (Mdivi-1) is a small chemical inhibitor of mitochondrial division dynamin, which plays multiple roles in mitochondrial dynamics, mitochondrial autophagy, ATP production, the immune response, and Ca?? homeostasis. Mdivi-1 inhibition of excessive mitochondrial fission exerted cytoprotective effects in neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Mdivi-1 changed the mRNA expression of the electron transport chain (ETC) and reduced Ca?? overload against neuronal injury. Elucidation of the molecular mechanism of Mdivi-1 in neurodegenerative diseases will help evaluate its therapeutic potential and promote its application in clinical studies. The present article focused on the multiple effects of Mdivi-1 on mitochondrial function and its potential therapeutic effects in neurodegenerative diseases.

To mdivi-1 or not to mdivi-1: Is that the question?

The fission/division and fusion of mitochondria are fundamental aspects of mitochondrial biology. The balance of fission and fusion sets the length of mitochondria in cells to serve their physiological requirements. The fission of mitochondria is markedly induced in many disease states and in response to cellular injury, resulting in the fragmentation of mitochondria into dysfunctional units. The mechanism that drives fission is dependent on the dynamin related protein 1 (Drp1) GTPase. mdivi-1 is a quinazolinone originally described as a selective inhibitor of Drp1, over other dynamin family members, and reported to inhibit mitochondrial fission. A recent study has challenged the activity of mdivi-1 as an inhibitor of Drp1. This study raises serious issues regarding the interpretation of data addressing the effects of mdivi-1 as reflective of the inhibition of Drp1 and thus fission. This commentary considers the evidence for and against mdivi-1 as an inhibitor of Drp1 and presents the following considerations; (1) the activity of mdivi-1 toward Drp1 GTPase activity requires further biochemical investigation, (2) as there is a large body of literature using mdivi-1 in vitro with effects as predicted for inhibition of Drp1 and mitochondrial fission, reviewed herein, the evidence is in favor of mdivi-1's originally described bioactivity, and (3) until the issue is resolved, experimental interpretations for the effects of mdivi-1 on inhibition of fission in cell and tissue experiments warrants stringent positive controls directly addressing the effects of mdivi-1 on fission. ? 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1260-1268, 2017.

Mdivi-1, a mitochondrial fission inhibitor, reduces angiotensin-II- induced hypertension by mediating VSMC phenotypic switch

Vascular smooth muscle cell (VSMC) phenotypic switch plays an essential role in the pathogenesis of hypertension. Mitochondrial dynamics, such as mitochondrial fission, can also contribute to VSMC phenotypic switch. Whether mitochondrial fission act as a novel target for anti-hypertensive drug development remains unknown. In the present study, we confirmed that angiotensin II (AngII) rapidly and continuously induced mitochondrial fission in VSMCs. We also detected the phosphorylation status of dynamin-related protein-1 (Drp1), a key protein involved in mitochondrial fission, at Ser616 site; and observed Drp1 mitochondrial translocation in VSMCs or arteries of AngII-induced hypertensive mice. The Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) dramatically reversed AngII-induced Drp1 phosphorylation, mitochondrial fission, and reactive oxidative species generation. Treatment with Mdivi-1 (20 mg/kg/every other day) significantly attenuated AngII-induced hypertension (22 mmHg), arterial remodeling, and cardiac hypertrophy, in part by preventing VSMC phenotypic switch. In addition, Mdivi-1 treatment was not associated with liver or renal functional injury. Collectively, these results indicate that Mdivi-1 inhibited mitochondrial fission, recovered mitochondrial activity, and prevented AngII-induced VSMC phenotypic switch, resulting in reduced hypertension.

Mdivi-1 and mitochondrial fission: recent insights from fungal pathogens

Mitochondrial fission shows potential as a therapeutic target in non-infectious human diseases. The compound mdivi-1 was identified as a mitochondrial fission inhibitor that acts against the evolutionarily conserved mitochondrial fission GTPase Dnm1/Drp1, and shows promising data in pre-clinical models of human pathologies. Two recent studies, however, found no evidence that mdivi-1 acts as a mitochondrial fission inhibitor and proposed other mechanisms. In mammalian cells, Bordt et al. showed that mdivi-1 inhibits complex I in mitochondria (Dev Cell 40:583, 2017). In a second study, we have recently demonstrated that mdivi-1 does not trigger a mitochondrial morphology change in the human yeast pathogen Candida albicans, but impacts on endogenous nitric oxide (NO) levels and inhibits the key virulence property of hyphal formation (Koch et al., Cell Rep 25:2244, 2018). Here we discuss recent insights into mdivi-1's action in pathogenic fungi and the potential and challenges for repurposing it as an anti-infective. We also outline recent findings on the roles of mitochondrial fission in human and plant fungal pathogens, with the goal of starting the conversation on whether the research field of fungal pathogenesis can benefit from efforts in other disease areas aimed at developing therapeutic inhibitors of mitochondrial division.