KMUP-1 attenuates serum deprivation-induced neurotoxicity in SH-SY5Y cells: Roles of PKG, PI3K/Akt and Bcl-2/Bax pathways

Hsu, Ya-Yun; Liu, Chi-Ming; Tsai, Hsin-Hung; Jong, Yuh‐Jyh; Chen, Ing‐Jun; Lo, Yi-Ching

doi:10.1016/j.tox.2009.11.021

Cited by 29 publications

(22 citation statements)

References 53 publications

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“…PI3K/AKT-regulated apoptotic signaling pathway was involved in ROS production [26]. And Bcl-2/Caspase-3 signaling pathway activation is closely related with PI3K/AKT [27]. As shown in Fig.…”

Section: Genesmentioning

confidence: 89%

Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway

Zhao

Yao

et al. 2017

Biomedicine & Pharmacotherapy

103

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Section: Genesmentioning

confidence: 89%

Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway

Zhao

Yao

et al. 2017

Biomedicine & Pharmacotherapy

103

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“…In addition, KMUP-1 has been shown to possess multifunctional properties, including anti-inflammatory [17], anti-proliferation [18], [19], cardioprotective [20] and neuroprotective properties [21]. However, the effects of KMUP-1 on osteoclast differentiation and bone resorption have not been reported.…”

Section: Introductionmentioning

confidence: 99%

KMUP-1 Suppresses RANKL-Induced Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss: Roles of MAPKs, Akt, NF-κB and Calcium/Calcineurin/NFATc1 Pathways

et al. 2013

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BackgroundKMUP-1 is a xanthine derivative with inhibitory activities on the phosphodiesterase (PDE) 3,4 and 5 isoenzymes to suppress the degradation of cyclic AMP and cyclic GMP. However, the effects of KMUP-1 on osteoclast differentiation are still unclear. In this study, we investigated whether KMUP-1 inhibits osteoclastogenesis induced by RANKL in RAW 264.7 cells and bone loss induced by ovariectomy in mice, and the underlying mechanisms.Principal Findings In vitro, KMUP-1 inhibited RANKL-induced TRAP activity, the formation of multinucleated osteoclasts and resorption-pit formation. It also inhibited key mediators of osteoclastogenesis including IL-1β, IL-6, TNF-α and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-κB), mRNA expression of osteoclastogensis-associated genes (TRAP, MMP-9, Fra-1, and cathepsin K) and transcription factors (c-Fos and NFATc1). Furthermore, most inhibitory effects of KMUP-1 on RANKL-mediated signal activations were reversed by a protein kinase A inhibitor (H89) and a protein kinase G inhibitor (KT5823). In vivo, KMUP-1 prevented loss of bone mineral content, preserved serum alkaline phosphate and reduced serum osteocalcin in ovariectomized mice.ConclusionsKMUP-1 inhibits RANKL-induced osteoclastogenesis in vitro and protects against ovariectomy-induced bone loss in vivo. These effects are mediated, at least in part, by cAMP and cGMP pathways. Therefore, KMUP-1 may have a role in pharmacologic therapy of osteoporosis.

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“…KMUP‐1 (7‐[2‐[4‐(2‐chlorophenyl)piperazinyl]ethyl]‐1,3‐dimethylxanthine), a chemical synthetic xanthine‐based derivative, has been demonstrated to inhibit the enzyme activity of PDE3, 4 and 5, suggesting that they are able to inhibit the metabolism of cAMP and cGMP, resulting in the relaxation of smooth muscle in the aorta (Wu et al, ), corporeal cavernosa (Lin et al, ), and trachea (Wu et al, ). Moreover, KMUP‐1 has been suggested to possess pleotropic effects including anti‐inflammatory (Wu et al, ), anti‐proliferation (Liu et al, , ), cardioprotective (Yeh et al, ), and neuroprotective properties (Hsu et al, ). A recent study has demonstrated that KMUP‐1 effectively suppressed RANKL‐induced osteoclast differentiation in vitro and prevented bone loss in vivo (Liou et al, ).…”

mentioning

confidence: 99%

KMUP‐1 Promotes Osteoblast Differentiation Through cAMP and cGMP Pathways and Signaling of BMP‐2/Smad1/5/8 and Wnt/β‐Catenin

Liou

Hsu

Chu

et al. 2015

Journal Cellular Physiology

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Phosphodiesterase (PDE) inhibitors have been suggested as a possible candidate for the treatment of osteopenia, including osteoporosis. KMUP-1 is a novel xanthine derivative with inhibitory activities on the PDE 3, 4, and 5 iso-enzymes to suppress the degradation of cAMP and cGMP. This study aimed to investigate the effect of KMUP-1 on osteoblast differentiation and the underlying cellular and molecular mechanisms. Primary osteoblasts and osteoblastic MC3T3-E1 cells were examined. KMUP-1 enhanced alkaline phosphatase (ALP) activity and mineralization compared to untreated controls in primary osteoblasts and MC3T3-E1 cells. KMUP-1 also increased the mRNA expression of the osteoblastic differentiation markers, including collagen type 1a, ALP, osteocalcin, osteoprotegerin, BMP-2, and Runx2, a key transcription regulator for osteoblastic differentiation. The osteogenic effect of KMUP-1 was abolished by BMP signaling inhibitor, noggin. Furthermore, we found that KMUP-1 upregulated Smad1/5/8 phosphorylations with subsequent BRE-Luc activation confirmed by transient transfection assay. In addition, KMUP-1 inactivated glycogen synthase kinase-3β (GSK-3β), with associated nuclear translocation of β-catenin. Co-treatment with H89 and KT5823, cAMP and cGMP pathway inhibitors, respectively, reversed the KMUP-1-induced activations of Smad1/5/8, β-catenin, and Runx2. The findings demonstrate for the first time that KMUP-1 can promote osteoblast maturation and differentiation in vitro via BMP-2/Smad1/5/8 and Wnt/β-catenin pathways. These effects are mediated, in part, by the cAMP and cGMP signaling. Thus, KMUP-1 may be a novel osteoblast activator and a potential new therapy for osteoporosis.

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KMUP-1 attenuates serum deprivation-induced neurotoxicity in SH-SY5Y cells: Roles of PKG, PI3K/Akt and Bcl-2/Bax pathways

Cited by 29 publications

References 53 publications

Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway

Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway

KMUP-1 Suppresses RANKL-Induced Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss: Roles of MAPKs, Akt, NF-κB and Calcium/Calcineurin/NFATc1 Pathways

KMUP‐1 Promotes Osteoblast Differentiation Through cAMP and cGMP Pathways and Signaling of BMP‐2/Smad1/5/8 and Wnt/β‐Catenin

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