• YAKHAK HOEJI
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• v.54 no.5
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• pp.410-415
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• 2010

We explored the role of phosphodiesterase 4 (PDE4) on parathyroid (PTH)-induced signaling in osteoblasts. PTH was shown to increase the activity of PDE, mainly PDE4, in osteoblasts, which is partly attributable to elevated PDE4B and PDE4D mRNA expression. The use of PDE4 inhibitor strengthened the PTH-induced extracellular signal-regulated kinase (ERK) and p38 MAP kinase (MAPK) activation. Furthermore, the PDE4 inhibitor stimulated PTH-induced receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL) expression in osteoblasts, which in turn increased osteoclast formation. Taken together, these data suggest the negative role of PDE4 on PTH-induced signaling in osteoblasts.

• YAKHAK HOEJI
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• v.51 no.4
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• pp.235-238
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• 2007

To determine the regulatory roles of phosphodiesterase (PDE) inhibitors on $PGE_2$-induced osteoclastogenesis, we investigated the effect of PDE inhibitors on osteoclast formation in the presence of $PGE_2$. Among PDE isozyme specific inhibitors, milrinone, a selective PDE3 inhibitor, and rolipram, a specific PDE4 inhibitor, increased $PGE_2$-induced osteoclast formation in cocultures of mouse bone marrow cells and osteoblasts. To verify that whether the PDE3 and PDE4 inhibitors act indirectly on osteoblasts, we measured the concentration of intracellular cAMP in osteoblasts. Treatment of milrinone or rolipram increased $PGE_2$-stimulated cAMP levels in osteoblasts. Furthermore, northern blot analysis revealed that the PDE3 and PDE4 inhibitors works synergistically with $PGE_2$ to increase the expression of TRANCE mRNA in osteoblasts. On the contrary, the PDE3 and PDE4 inhibitors did not augment the number of osteoclasts differentiated from bone marrow cells by $PGE_2$. In conclusion, the stimulation of $PGE_2$-induced osteoclast formation by the PDE3 and PDE4 inhibitors are attributable to their indirect effect on osteoblasts, not to their direct effect on bone marrow-derived osteoclast precursors.

• Analytical Science and Technology
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• v.26 no.1
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• pp.106-112
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• 2013

PDE plays an important role in cAMP-mediated cellular signaling within the cells. The proper targeting of each PDE is mediated by unique N-terminal of each PDE isoform. It has been recently reported that supershort-, short- and long-forms of PDE4 in Aplysia were cloned in Aplysia. Long-form of ApPDE4 was localized at plasma membrane and presynaptic terminal in Aplysia sensory neurons. However, it remains elusive which part of ApPDE4 is minimal region for the proper targeting and what are the effects on the cell functions. Here, we identified that N-terminal 13 amino acids of ApPDE4 long-form is minimal regions for the plasma membrane targeting. In addition, overexpression of ApPDE4(N20)-mRFP could induce morphological changes in HEK293T cells. Interestingly, mRFP-$PLC{\delta}1$(PH), which selectively binds to PI4,$5P_2$, could induce morphological changes in similar with that by ApPDE4(N20)-mRFP. These results suggested that binding of ApPDE4(N20) to lipids including PI4,$5P_2$ might be responsible for targeting of ApPDE4 to plasma membrane and morphological changes in HEK293T cells.

• Oncology Letters
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• v.17 no.3
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• pp.3589-3598
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• 2019

Colorectal cancer (CRC) is a complex disease involving numerous genetic abnormalities. One of the major characteristics of CRC is enhanced Wnt signaling caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene. Previously, it has been demonstrated that the majority of malignant phenotypes following APC deletion in adult murine small intestines could be rescued when Myc, a downstream target of the Wnt pathway, was deleted. This indicated that Myc is a critical regulator of CRC development following APC loss. Previous studies reported that cyclic adenosine 3',5'-monophosphate (cAMP) can influence the AKT/mammalian target of rapamycin (mTOR) survival pathway in cancer and Myc is a critical downstream molecule of AKT/mTOR signaling. Phosphodiesterase 4D (PDE4D), a member of the cAMP-specific PDE4 family, has been associated with drug resistance in CRC. However, the association between PDE4D and Myc remains unclear. To investigate the potential role of PDE4D in Myc regulation in CRC, the present study evaluated the expression levels of PDE4 subtypes in DLD-1 CRC cells. Additionally, the effects of PDE4 inhibitors on Myc expression and oncogenic properties were analyzed by western blot analysis, reverse transcription-quantitative polymerase chain reaction, colony formation and soft agar assays. It was demonstrated that cAMP/PDE4D signals serve a critical role in regulating Myc expression in DLD-1 CRC cells. Furthermore, PDE4D was identified to be a main hydrolyzer of cAMP and suppression of PDE4D using selective inhibitors of PDE4 increased intracellular cAMP levels, which resulted in a marked decrease in the oncogenic properties of DLD-1 cells, including colony formation, cell proliferation and anchorage-independent growth. Notably, the current data imply that cAMP represses Myc expression via the downregulation of AKT/mTOR signaling, which was abolished by high PDE4D activities in DLD-1 cells. Additionally, a natural polyphenol resveratrol in combination with forskolin elevated the concentration of cAMP and enhanced the expression of Myc and the malignant phenotype of DLD-1 cells, reproducing the effect of known chemical inhibitors of PDE4. In conclusion, the present study identified that cAMP/PDE4D signaling is a critical regulator of Myc expression in DLD-1 and possibly other CRC cells.

• Proceedings of the Ginseng society Conference
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• 1998.06a
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• pp.216-223
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• 1998

Cyclic nucleotide phosphodiesterases (PDEs) represent the unique enzymatic system degrddinf cAMP and cGMP which play a major role in the regulation of cell physiology. To investigate a possible molecular mechanism of ginsenosides, their activities were evaluated on PDEs which are recently described is new therapeutic targets. PDEs are classified into 7 families according to their genes (PDEI to PDE7) and are differently distributed in tissues. The IC50 values of ginsenosides were determined on PDEI to PDE 5 chromatographically isolatetl from bovine aorta. The results show that total ginseng saponin extract preferentially inhibits PDE 1 and PDE4 at concentrations nearby 200 ug/ml. Protopanaxadiol (PPD) fraction acts preferentially on PDE4 with and IC50 value of 100 nlml and inhibits also PDEI and PDE5 at 14 to 2 fold higher concentrations, respectively. Protopanaxatriol (PPT) fraction preferentially inhibits PDE 1 with and IC50 value of 170 ug/ml. Compound Rgl, originated from PPT fraction, and RC3 (5) represent the most active compounds towards PDE 1 with IC50 values around 80 UM. However Rg3 (R), epimer of Rgl (5) has no effect on the various PDEs tested, excepted on PDE3 rich is sligthly sensitive Compound Rbl, originated from PPD, acts on both PDEI and PDE4. It if two fold less active than Rgl and Rg3 (5) on PDEI. Taken together, these results mainly suggest that PDEI and PDE4 inhibitions could be a molecular mechanism which would participate in ginsenoside mechanisms, especially the effect of PPD on blood vessel and on CNS.

• BMB Reports
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• v.41 no.6
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• pp.466-471
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• 2008

Three isoforms of pig PDE4B were cloned and classified as two forms: PDE4B1 and PDE4B3, which contain UCR1 and UCR2; and PDE4B2, which contains only UCR2. The amino acid sequences of each isoform showed good conservation in human and rat. PDE4B2 is expressed in a wide range of tissues, but PDE4B1 and PDE4B3 are not. Using an informative SNP for the Iberian x Landrace intercross detected from intron 12, a linkage map was constructed. The location of PDE4B was estimated at 123.6 cM outside of the QTL-CI (124-128 cM) for IMF. However, the QTL-CI for IMF was reconfirmed with high significance, and its position was narrowed down to an interval of 4 cM (the region defined by markers PDE4B and SW1881). Using radiation hybrid mapping, LEPR, LEPROT, DNAJC6, AK3L1 and AK3L2 were selected as positional and/or functional candidates related to the QTL.

• Archives of Pharmacal Research
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• v.12 no.4
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• pp.276-281
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• 1989

Selective inhibition of seven new PDE inhibitors on cyclic nucleotide PDE isozymes was investigated. Three PDE isozymes (PDE I, II and III) of guinea pig left ventricular muscles were used. All tested agents inhibited cyclic AMP hydrolysis by PDE III IN A concentration-dependent manner. Some agents represented more potent and selective inhibitory effect on PDE III than that of imazodan.

• Journal of Life Science
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• v.27 no.2
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• pp.149-154
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• 2017

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-hodgkin lymphoma. Advances in the chemotherapeutic treatment of this disease have improved the outcomes of DLBCL; nonetheless, many patients still die of DLBCL, and therefore, a better understanding of this disease and identification of novel therapeutic targets are urgently required. In a recent gene expression profiling study, PDE (phosphodiesterase) 4B was found to be overexpressed in chemotherapy-resistant tumors. The major function of PDE4B is to inactivate the second messenger cyclic 3',5' monophosphate (cAMP) by catalyzing the hydrolysis of cAMP to 5'AMP. It is known that cAMP induces cell cycle arrest and/or apoptosis in B cells, and PDE4B abolishes cAMP's effect on B cells. However, the mechanism by which PDE4B is overexpressed remains unclear. Here, we show that the aberrant expression of miRNA may be associated with the overexpression of this gene. The PDE4B 3' untranslated region (UTR) has three functional binding sites of miR-23b, as confirmed by luciferase reporter assays. Interestingly, miR-23b-binding sites were evolutionarily conserved from humans to lizards, implying the critical role of PDE4B-miR-23b interaction in cellular physiology. The ectopic expression of miR-2 3b repressed PDE4B mRNA levels and enhanced intracellular cAMP concentrations. Additionally, miR-23b expression inhibited cell proliferation and survival of DLBCL cells only in the presence of forskolin, an activator of adenylyl cyclase, suggesting that miR-23b's effect is via the downregulation of PDE4B. These results together suggest that miR-23b could be a therapeutic target for overcoming drug resistance by repressing PDE4B in DLBCL.

• YAKHAK HOEJI
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• v.52 no.1
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• pp.43-47
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• 2008

To determine the regulatory roles of PDE4 inhibitor on LPS-induced osteoclastogenesis, we investigated the effect of a PDE4 inhibitor on osteoclast formation in the presence of LPS. A specific PDE4 inhibitor, rolipram, increased LPS-induced osteoclast formation in cocultures. To verify that whether rolipram acts indirectly on osteoblasts, we investigated the TRANCE and COX-2 mRNA expression levels in osteoblasts. Treatment of rolipram increased the expression of TRANCE and COX-2 mRNA in osteoblasts stimulated by LPS. On the contrary, rolipram did not augment the number of osteoclasts differentiated from bone marrow cells by LPS. In conclusion, the stimulation of LPS-induced osteoclast formation by the PDE4 inhibitor are attributable to its indirect effect on osteoblasts, not to their direct effect on bone marrow-derived osteoclast precursors.

• Journal of the Korean earth science society
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• v.43 no.4
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• pp.490-497
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• 2022

The practice turn in the science education community emphasizes students' engagement in the activities that scientists and engineers actually do when they see, explain, and critique a phenomenon, or solve a problem. This turn highlights the importance of science learning environments for students. Consequently, the purpose of this study was the examination of relevant literature with the aim of proposing theoretically and empirically derived teaching strategies for students' productive disciplinary engagement (PDE) through model-based learning (MBL) in science classrooms. To this end, collected literature focusing on PDE and MBL was analyzed to better understand 1) how teachers can foster students' PDE in science classrooms, 2) how PDE can be connected to MBL, and 3) what supports are required for students' PDE through MBL. As a result of our analysis, a close relationship between PDE and MBL was identified. Importantly, this research reveals the promise of MBL for supporting students' PDE through the problematizing, authority, accountability, and resources. Further, our literature examination provided a better understanding of what supports are required for students' engagement in PDE through MBL and why this matters in the context of the practice turn in science education.