Pipoxolan Ameliorates Cerebral Ischemia via Inhibition of Neuronal Apoptosis and Intimal Hyperplasia through Attenuation of VSMC Migration and Modulation of Matrix Metalloproteinase-2/9 and Ras/MEK/ERK Signaling Pathways

Chen, Yuh Fung; Tsai, Huei Yann; Wu, Kuo Jen; Siao, Lian Ru; Wood, W. G.

doi:10.1371/journal.pone.0075654

Cited by 15 publications

(10 citation statements)

References 38 publications

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“…Pipoxolan has also been shown to have anticancer activity, including against human leukemia HL-60 (19,20) and non-small lung cancer cells (21). Pipoxolan has also been shown to protect from ischemia/reperfusion-induced cerebral infarction, carotid artery ligation-induced intimal hyperplasia and affects vascular smooth muscle cell migration both in vivo and in vitro (22). In this study, we aimed to investigate the impact of pipoxolan on cytotoxicity toward OSCC cells and explored possible molecular mechanisms of action.…”

mentioning

confidence: 99%

Pipoxolan Exhibits Antitumor Activity Toward Oral Squamous Cell Carcinoma Through Reactive Oxygen Species-mediated Apoptosis

Chou

Lee

Lin

et al. 2017

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Pipoxolan is frequently prescribed as a smooth muscle relaxant. Pipoxolan has also been shown to have anticancer activity. Our study investigated whether pipoxolan induced apoptosis in oral squamous cell carcinoma (OSCC). Cell cytotoxicity was evaluated by the MTT assay. Cell apoptosis and cell-cycle distribution were measured by annexin V/propidium iodide (PI) double staining and flow cytometry, respectively. Apoptotic-related proteins were assessed by western blotting. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Following exposure of TW206 OSCC cells to pipoxolan, a time-dependently decrease in MMP and an increase in ROS were observed. However, these effects were significantly abrogated by the free radical scavenger N-acetyl-L-cysteine. Since high levels of ROS were produced early in the treatment, intracellular ROS seemed to play a key role in pipoxolan-induced apoptosis. In HSC-3 OSCC cells, our results demonstrated that pipoxolan treatment caused a time-dependent increase of protein expression of active caspase-3 and -9, cytosolic cytochrome c, cleavage of poly (ADP-ribose) polymerase, and B-cell lymphoma 2 (BCL2)-like protein 4 (BAX). However, expression of BCL2 itself was reduced. Clearly, such an increase in BAX/BCL2 ratio would be associated with apoptosis. In addition, pipoxolan markedly suppressed the protein expression of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and phosphorylation of protein kinase B (AKT). These data suggest that pipoxolan acts against HSC-3 in vitro via intrinsic apoptotic signaling pathways, and inhibition of PI3K/AKT signaling.

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mentioning

confidence: 99%

Pipoxolan Exhibits Antitumor Activity Toward Oral Squamous Cell Carcinoma Through Reactive Oxygen Species-mediated Apoptosis

Chou

Lee

Lin

et al. 2017

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“…PCNA is only expressed and synthesized in the cell proliferation period, increasing at the beginning of the G1 phase and then reaching a peak in S phase. Its expression level is proportional to the degree of cell proliferation (Chen et al , ; Dilme et al , ). Therefore, we also performed immunocytochemical staining of PCNA to verify effects on proliferation.…”

Section: Discussionmentioning

confidence: 99%

Effects of Tilianin on Proliferation, Migration and TGF-β/Smad Signaling in Rat Vascular Smooth Muscle Cells Induced with Angiotensin II

Cao

Yang

et al. 2017

Phytother. Res.

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Flavonoid Tilianin was isolated from Dracocephalum moldavica, and its pharmacological mechanism on proliferation, migration and the TGF-β/Smad signaling pathway in rat vascular smooth muscle cells (VSMCs) induced with Angiotensin II (Ang II) was systematically evaluated. Primary rat VSMCs were stimulated with Ang II to induce proliferation. The cells were then treated with Tilianin for 24 or 48 h. MTT assay and Transwell assays were used to evaluate the effects of Tilianin on proliferation and migration. The expression of intracellular proliferating cell nuclear antigen (PCNA), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured by immunohistochemistry as verification of effects on proliferation and migration. The expression of TGF-β1, Smad2 and Smad3 mRNA was measured by qRT-PCR, and the expression of TGF-β1 and P-Smad2/3 protein was measured by Western blotting. The results show that Tilianin can inhibit proliferation and expression of intracellular PCNA in VSMCs induced with Ang II, in a dose-dependent manner. Tilianin also mediates a dose-dependent inhibition of migration and the expression of intracellular ICAM-1, VCAM-1, MMP-2 and MMP-9. Furthermore, TGF-β1, Smad2, Smad3, Smad2/3 and P-Smad2/3 in Ang II-induced VSMCs are suppressed by Tilianin. The inhibitory effects of Tilianin support its use in the suppression and treatment of atherosclerosis. Copyright © 2017 John Wiley & Sons, Ltd.

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“…12 Pipoxolan (PIPO) ( Figure 1A) is a smooth muscle relaxant that inhibits phosphodiesterase and maintenance cyclic-AMP levels and prevents Ca 2+ entering the cell membrane in smooth muscle. 13,14 According to earlier studies, PIPO can inhibit the phosphorylation of JNK and p38 and inhibit the expression metalloproteinases-2 (MMP-2) and MMP-9. 15 PIPO also inhibited the phosphatidylinositol-4,-5-diphosphate 3-kinase (PI3K) protein expression, and the phosphorylation of protein kinase B (AKT), indicating that PIPO inhibits PI3K/ AKT intrinsic apoptotic signaling pathways.…”

Section: Introductionmentioning

confidence: 98%

“…Pipoxolan (PIPO) (Figure 1A) is a smooth muscle relaxant that inhibits phosphodiesterase and maintenance cyclic‐AMP levels and prevents Ca 2+ entering the cell membrane in smooth muscle 13,14 . According to earlier studies, PIPO can inhibit the phosphorylation of JNK and p38 and inhibit the expression metalloproteinases‐2 (MMP‐2) and MMP‐9 15 .…”

Section: Introductionmentioning

confidence: 99%

“…16 Moreover, PIPO can also inhibit the Ras/MEK/ERK pathway preventing neuronal apoptosis, decreasing the migration and intimal thickening in vascular smooth muscle cells. 13 Therefore, this study evaluated the anti-inflammatory molecular mechanism of PIPO in inflammatory transcription factor and antioxidant transcription factor in LPS-stimulated mouse RAW264.7 cells.…”

Section: Introductionmentioning

confidence: 99%

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Pipoxolan suppresses the inflammatory factors of NF‐κB, AP‐1, and STATs, but activates the antioxidative factor Nrf2 in LPS‐stimulated RAW 264.7 murine macrophage cells

Lin

Chang

et al. 2020

Environmental Toxicology

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Although pipoxolan (PIPO) is a smooth muscle relaxant, its anti‐inflammatory capability has not been studied. Therefore, we investigated the anti‐inflammatory molecular mechanisms of PIPO in lipopolysaccharide (LPS)‐induced RAW 264.7 macrophages. In this study, we used the MTT assay to evaluate the cytotoxicity, applied the enzyme‐linked immunosorbent assay to determine the inflammatory cytokines, and performed Western blotting to assess protein expression. The results showed that PIPO significantly inhibited cytokine production, including nitric oxide, prostaglandin E2, tumor necrosis factor‐α, and interleukin‐6. PIPO also suppressed the pro‐inflammatory mediator expression with inducible nitric oxide synthase and cyclooxygenase‐2. Moreover, PIPO prohibited the multiple inflammatory transcription factor pathways, including inhibitor kappa B/nuclear factor of the κ light chain enhancer of B cells (NF‐κB), mitogen‐activated protein kinase/activator protein‐1 (AP‐1), Janus kinase/signal transducer and activator of transcription (STAT), and toll‐like receptor 4 (TLR4)/serine/threonine kinase (AKT). Besides, PIPO effectively activated the nuclear factor erythroid 2‐related factor 2 (Nrf2)/heme oxygenase‐1 antioxidative pathway. Collectively, PIPO may attenuate the inflammatory effects via influencing the LPS/TLR4 receptor binding; suppress the expression of anti‐inflammatory transcription factors NF‐κB, AP‐1, and STAT; and activating the antioxidative transcription factor Nrf2 in LPS‐stimulated mouse RAW 264.7 cells.

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Pipoxolan Ameliorates Cerebral Ischemia via Inhibition of Neuronal Apoptosis and Intimal Hyperplasia through Attenuation of VSMC Migration and Modulation of Matrix Metalloproteinase-2/9 and Ras/MEK/ERK Signaling Pathways

Cited by 15 publications

References 38 publications

Pipoxolan Exhibits Antitumor Activity Toward Oral Squamous Cell Carcinoma Through Reactive Oxygen Species-mediated Apoptosis

Pipoxolan Exhibits Antitumor Activity Toward Oral Squamous Cell Carcinoma Through Reactive Oxygen Species-mediated Apoptosis

Effects of Tilianin on Proliferation, Migration and TGF-β/Smad Signaling in Rat Vascular Smooth Muscle Cells Induced with Angiotensin II

Pipoxolan suppresses the inflammatory factors of NF‐κB, AP‐1, and STATs, but activates the antioxidative factor Nrf2 in LPS‐stimulated RAW 264.7 murine macrophage cells

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