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Azetidine Derivative

The Experts below are selected from a list of 87 Experts worldwide ranked by ideXlab platform

Soo Young Choi – 1st expert on this subject based on the ideXlab platform

  • 3-(Naphthalen-2-yl(propoxy)methyl)Azetidine hydrochloride attenuates MPP+-induced cytotoxicity by regulating oxidative stress and mitochondrial dysfunction in SH-SY5Y cells.
    Journal of Biochemistry and Molecular Biology, 2018
    Co-Authors: Seung-ju Yang, Ji Woong Yang, Jung-min Na, Ji Sun Ha, Soo Young Choi

    Abstract:

    : Parkinson’s disease (PD) is a common chronic neurodegenerative disease mainly caused by the death of dopaminergic neurons. However, no complete pharmacotherapeutic approaches are currently available for PD therapies. 1-methyl-4- phenylpyridinium (MPP+)-induced SH-SY5Y neurotoxicity has been broadly utilized to create cellular models and study the mechanisms and critical aspects of PD. In the present study, we examined the role of a novel Azetidine Derivative, 3-(naphthalen-2-yl(propoxy)methyl)Azetidine hydrochloride (KHG26792), against MPP+-induced neurotoxicity in SH-SY5Y cells. Treatment of KHG26792 significantly attenuated MPP+-induced changes in the protein levels of Bcl-2 and Bax together with efficient suppression of MPP+-induced activation of caspase-3 activity. KHG26792 also attenuated mitochondrial potential and levels of ROS, Ca2+, and ATP in MPP+-treated SH-SY5Y cells. Additionally, KHG26792 inhibited the induced production of nitric oxide and malondialdehyde. Moreover, the protective effect of KHG26792 is mediated through regulation of glutathione peroxidase and GDNF levels. Our results suggest a possibility that KHG26792 treatment significantly protects against MPP+-induced neurotoxicity in SH-SY5Y cells and KHG26792 may be a valuable therapeutic agent for the treatment of PD induced by an environmental toxin. [BMB Reports 2018; 51(11): 590-595].

  • Anti-inflammatory and anti-oxidative effects of 3-(naphthalen-2-yl(propoxy)methyl)Azetidine hydrochloride on β-amyloid-induced microglial activation.
    Journal of Biochemistry and Molecular Biology, 2017
    Co-Authors: Seung-ju Yang, Soo Young Choi

    Abstract:

    : We aimed to assess the anti-inflammatory and antioxidative properties of KHG26792, a novel Azetidine Derivative, in amyloid β (Aβ)-treated primary microglial cells. KHG26792 attenuated the Aβ-induced production of inflammatory mediators such as IL-6, IL-1β, TNF-α, and nitric oxide. The levels of protein oxidation, lipid peroxidation, ROS, and NADHP oxidase enhanced by Aβ were also downregulated by KHG26792 treatment. The effects of KHG26792 against the Aβ-induced increases in inflammatory cytokine levels and oxidative stress were achieved by increasing the phosphorylation of Akt/ GSK-3β signaling and by decreasing the Aβ-induced translocation of NF-κB. Our results provide novel insights into the use of KHG26792 as a potential agent against Aβ toxicity, including its role in the reduction of inflammation and oxidative stress. Nevertheless, further investigations of cellular signaling are required to clarify the in vivo effects of KHG26792 against Aβ-induced toxicity. [BMB Reports 2017; 50(12): 634-639].

  • Neuroprotective Effect of 3-(Naphthalen-2-Yl(Propoxy)Methyl)Azetidine Hydrochloride on Brain Ischaemia/Reperfusion Injury
    Journal of Neuroimmune Pharmacology, 2017
    Co-Authors: Jung-min Na, Soo Young Choi

    Abstract:

    Because ischaemic stroke is one of the most common brain disorders, diverse effective therapies are urgently required. Recent studies reported a variety of Azetidine-based scaffolds for the development of central nervous system-focused lead-like libraries. However, their mechanisms of action and in vivo functions remain unclear. Here, we investigated the potential mechanism and beneficial effects of 3-(naphthalen-2-yl(propoxy)methyl)Azetidine hydrochloride (KHG26792), a novel Azetidine Derivative, on ischaemia/reperfusion (I/R) brain injury. We adapted a mouse brain ischaemia model induced by 2 h of middle cerebral artery occlusion followed by 24 h of reperfusion. We measured apoptotic cell death, inflammatory mediators, free radical generation, and anti-oxidative enzymes activities. We also measured the mitochondrial ATP level and Na^+, K^+-ATPase and cytochrome c oxidase activities. Using western blotting, we analysed the protein levels of inducible NOS, hypoxia-upregulated protein 1, PTEN-induced putative kinase, uncoupling protein 2, p-Akt, MMP-3, and full-length receptor for advanced glycation end-products (RAGE). KHG26792 significantly improved neurological deficits and brain oedema and suppressed I/R-induced apoptosis. KHG26792 significantly attenuated I/R-induced inflammation and oxidative stress by upregulating SOD and catalase activity, GSH, p-Akt, mitochondrial ATP, Na^+, K^+-ATPase, cytochrome c oxidase, and soluble RAGE and downregulating iNOS, HYOUP1, and MMP-3, suggesting a potential anti-inflammatory and antioxidant role of KHG26792. This is the first study to show that KHG26792 can protect mouse brains against I/R injury by inhibiting apoptotic damage, modulating inflammation, scavenging free radicals, ameliorating oxidative stress, and improving the energy metabolism of the brain, although the clinical relevance of our findings remains unknown.

Maja Di Rocco – 2nd expert on this subject based on the ideXlab platform

  • long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency
    Orphanet Journal of Rare Diseases, 2018
    Co-Authors: Maja Di Rocco, Livia Pisciotta, Angela Madeo, Marta Bertamino, Samuel Bertolini

    Abstract:

    Lysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an Azetidine Derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal acid lipase, are decreased. Furthermore, ezetimibe acts by blocking inflammasome activation which is the cause of liver fibrosis in steatohepatitis and in lysosomal storage diseases. Two patients with Cholesterol Ester Storage Disease were treated with ezetimibe for 9 years and a third patients for 10 years. Treatment was supplemented with low dose of atorvastatin in the first two patients during the last 6 years. All patients showed a significant reduction of alanine aminotransferase, cholesterol and triglyceride. Furthermore, no progression of liver fibrosis was demonstrated. In this observational case series, ezetimibe is effective, safe, and sustainable treatment for lysosomal acid lipase deficiency. Further studies are warranted to demonstrate that ezetimibe is an alternative therapy to enzyme replacement therapy.

  • Long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency
    Orphanet Journal of Rare Diseases, 2018
    Co-Authors: Maja Di Rocco, Livia Pisciotta, Angela Madeo, Marta Bertamino, Stefano Bertolini

    Abstract:

    Background Lysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an Azetidine Derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal acid lipase, are decreased. Furthermore, ezetimibe acts by blocking inflammasome activation which is the cause of liver fibrosis in steatohepatitis and in lysosomal storage diseases. Results Two patients with Cholesterol Ester Storage Disease were treated with ezetimibe for 9 years and a third patients for 10 years. Treatment was supplemented with low dose of atorvastatin in the first two patients during the last 6 years. All patients showed a significant reduction of alanine aminotransferase, cholesterol and triglyceride. Furthermore, no progression of liver fibrosis was demonstrated. Conclusion In this observational case series, ezetimibe is effective, safe, and sustainable treatment for lysosomal acid lipase deficiency. Further studies are warranted to demonstrate that ezetimibe is an alternative therapy to enzyme replacement therapy.

Seung-ju Yang – 3rd expert on this subject based on the ideXlab platform

  • 3-(Naphthalen-2-yl(propoxy)methyl)Azetidine hydrochloride attenuates MPP+-induced cytotoxicity by regulating oxidative stress and mitochondrial dysfunction in SH-SY5Y cells.
    Journal of Biochemistry and Molecular Biology, 2018
    Co-Authors: Seung-ju Yang, Ji Woong Yang, Jung-min Na, Ji Sun Ha, Soo Young Choi

    Abstract:

    : Parkinson’s disease (PD) is a common chronic neurodegenerative disease mainly caused by the death of dopaminergic neurons. However, no complete pharmacotherapeutic approaches are currently available for PD therapies. 1-methyl-4- phenylpyridinium (MPP+)-induced SH-SY5Y neurotoxicity has been broadly utilized to create cellular models and study the mechanisms and critical aspects of PD. In the present study, we examined the role of a novel Azetidine Derivative, 3-(naphthalen-2-yl(propoxy)methyl)Azetidine hydrochloride (KHG26792), against MPP+-induced neurotoxicity in SH-SY5Y cells. Treatment of KHG26792 significantly attenuated MPP+-induced changes in the protein levels of Bcl-2 and Bax together with efficient suppression of MPP+-induced activation of caspase-3 activity. KHG26792 also attenuated mitochondrial potential and levels of ROS, Ca2+, and ATP in MPP+-treated SH-SY5Y cells. Additionally, KHG26792 inhibited the induced production of nitric oxide and malondialdehyde. Moreover, the protective effect of KHG26792 is mediated through regulation of glutathione peroxidase and GDNF levels. Our results suggest a possibility that KHG26792 treatment significantly protects against MPP+-induced neurotoxicity in SH-SY5Y cells and KHG26792 may be a valuable therapeutic agent for the treatment of PD induced by an environmental toxin. [BMB Reports 2018; 51(11): 590-595].

  • Anti-inflammatory and anti-oxidative effects of 3-(naphthalen-2-yl(propoxy)methyl)Azetidine hydrochloride on β-amyloid-induced microglial activation.
    Journal of Biochemistry and Molecular Biology, 2017
    Co-Authors: Seung-ju Yang, Soo Young Choi

    Abstract:

    : We aimed to assess the anti-inflammatory and antioxidative properties of KHG26792, a novel Azetidine Derivative, in amyloid β (Aβ)-treated primary microglial cells. KHG26792 attenuated the Aβ-induced production of inflammatory mediators such as IL-6, IL-1β, TNF-α, and nitric oxide. The levels of protein oxidation, lipid peroxidation, ROS, and NADHP oxidase enhanced by Aβ were also downregulated by KHG26792 treatment. The effects of KHG26792 against the Aβ-induced increases in inflammatory cytokine levels and oxidative stress were achieved by increasing the phosphorylation of Akt/ GSK-3β signaling and by decreasing the Aβ-induced translocation of NF-κB. Our results provide novel insights into the use of KHG26792 as a potential agent against Aβ toxicity, including its role in the reduction of inflammation and oxidative stress. Nevertheless, further investigations of cellular signaling are required to clarify the in vivo effects of KHG26792 against Aβ-induced toxicity. [BMB Reports 2017; 50(12): 634-639].

  • the Azetidine Derivative khg26792 protects against atp induced activation of nfat and mapk pathways through p2x7 receptor in microglia
    Neurotoxicology, 2015
    Co-Authors: Hohgyu Hahn, Soo Young Choi, Seung-ju Yang

    Abstract:

    Azetidine Derivatives are of interest for drug development because they may be useful therapeutic agents. However, their mechanisms of action remain to be completely elucidated. Here, we have investigated the effects of 3-(naphthalen-2-yl(propoxy)methyl)Azetidine hydrochloride (KHG26792) on ATP-induced activation of NFAT and MAPK through P2X7 receptor in the BV-2 mouse microglial cell line. KHG26792 decreased ATP-induced TNF-α release from BV-2 microglia by suppressing, at least partly, P2X7 receptor stimulation. KHG26792 also inhibited the ATP-induced increase in IL-6, PGE2, NO, ROS, CXCL2, and CCL3. ATP induced NFAT activation through P2X7 receptor, with KHG26792 reducing the ATP-induced NFAT activation. KHG26792 inhibited an ATP-induced increase in iNOS protein and ERK phosphorylation. KHG26792 prevented an ATP-induced increase in MMP-9 activity through the P2X7 receptor as a result of degradation of TIMP-1 by cathepsin B. Our data provide mechanistic insights into the role of KHG26792 in the inhibition of TNF-α produced via P2X7 receptor-mediated activation of NFAT and MAPK pathways in ATP-treated BV-2 cells. This study highlights the potential use of KHG26792 as a therapeutic agent for the many diseases of the CNS related to activated microglia.