• Biomolecules & Therapeutics
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• 제31권6호
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• pp.629-639
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• 2023

Cardiovascular diseases (CVDs) are the most common cardiovascular system disorders. Cellular senescence is a key mechanism associated with dysfunction of aged vascular endothelium. Hyaluronic acid and proteoglycan link protein 1 (HAPLN1) has been known to non-covalently link hyaluronic acid (HA) and proteoglycans (PGs), and forms and stabilizes HAPLN1-containing aggregates as a major component of extracellular matrix. Our previous study showed that serum levels of HAPLN1 decrease with aging. Here, we found that the HAPLN1 gene expression was reduced in senescent human umbilical vein endothelial cells (HUVECs). Moreover, a recombinant human HAPLN1 (rhHAPLN1) decreased the activity of senescence-associated β-gal and inhibited the production of senescence-associated secretory phenotypes, including IL-1β, CCL2, and IL-6. rhHAPLN1 also downregulated IL-17A levels, which is known to play a key role in vascular endothelial senescence. In addition, rhHAPLN1 protected senescent HUVECs from oxidative stress by reducing cellular reactive oxygen species levels, thus promoting the function and survival of HUVECs and leading to cellular proliferation, migration, and angiogenesis. We also found that rhHAPLN1 not only increases the sirtuin 1 (SIRT1) levels, but also reduces the cellular senescence markers levels, such as p53, p21, and p16. Taken together, our data indicate that rhHAPLN1 delays or inhibits the endothelial senescence induced by various aging factors, such as replicative, IL-17A, and oxidative stress-induced senescence, thus suggesting that rhHAPLN1 may be a promising therapeutic for CVD and atherosclerosis.

• 생명과학회지
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• 제18권3호
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• pp.344-349
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• 2008

이 논문에서는 신생아와 노인 유래의 섬유아세포들의 노화의 특징들을 비교하여 사람의 나이와 세포의 수명 및 세포 형질의 관계에 대해 연구하였다. 본 연구의 결과는 비록 한가지의 노인세포에 대해 얻어진 것이기는 하지만 다음과 같은 세 가지 중요한 가능성을 제시한다. 첫째로, 노인에서 유래한 섬유아세포의 증식속도가 신생아 유래의 세포에 비해서 느릴 가능성이 있다. 이러한 결과는 실제로 노인 신체에 존재하는 세포가 신생아에 존재하는 세포에 비해 낮은 속도로 증식할 가능성을 시사하는 것으로서, 노인에서 관찰되는 조직실질의 감소 원인을 설명하는 자료가 될 수 있겠다. 둘째로, 노인 유래 섬유아세포의 early passage 세포가 신생아 유래의 세포의 early passage 세포와 동일하게 낮은 수준의 SA ${\beta}-Gal$ 활성, autofluorescence, lysosome 함량, 그리고 활성산소 수준을 갖고 있었다. 이 점은, early passage 때의 세포가 보이는 형질이 신체에 존재하는 세포의 상황과 크게 다르지 않다고 가정할 때, 노인 신체의 조직에 존재하는 세포들이 신생아의 세포와 유사한 상태로 존재할 가능성을 시사하는 것이다. 즉, 노인 신체에서는 in vitro 노화세포에서 나타나는 수준의 세포노화가 일어나 있지 않다는 것이다. 셋째, 노인세포가 노화했을 때는 신생아세포의 경우와 거의 동일한 수준의 활성산소, lysosome, SA ${\beta}-Gal$ activity 증가를 보이고 있었는데, 이는 노인 유래의 세포가 in vitro 배양 시 신생아 유래의 세포보다 더 심하거나 또는 빠른 산화적 손상이나 세포학적 변화를 겪지는 않는다는 것을 보여주는 것으로서, 세포가 보유한 항산화적 기능이 노인이 되면서 크게 약화되지는 않음을 시사하고 있다. 결론적으로 노인 유래의 세포는 세포증식 속도를 제외하면 대체로 신생아 때의 상태와 동일한 세포 내 상태를 갖고 있다고 결론 내릴 수 있겠다.

• BMB Reports
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• 제52권1호
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• pp.42-46
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• 2019

Cellular senescence, a process of cell proliferation arrest in response to various stressors, has been considered to be important factor in age-related disease. Identification of senescent cells in tissues is limited and the role of senescent cells is poorly understood. Recently however, several studies showed the characterization of senescent cells in various pathologic conditions and the role of senescent cells in disease progression is becoming important. Senescent cells are growth-arrested cells, however, the senescence associated secretory phenotype (SASP) of senescent cells could modify the tissues' microenvironment. Here, we discuss the progress and understanding of the role of senescent cells in tissues of pathologic conditions and discuss the development of new therapeutic paradigms, such as senescent cells-targeted therapy.

• Molecules and Cells
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• 제43권4호
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• pp.397-407
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• 2020

DNAJB9 is known to be a member of the molecular chaperone gene family, whose cellular function has not yet been fully characterized. Here, we investigated the cellular function of DNAJB9 under strong mitogenic signals. We found that DNAJB9 inhibits p53-dependent oncogene-induced senescence (OIS) and induces neoplastic transformation under oncogenic RAS activation in mouse primary fibroblasts. In addition, we observed that DNAJB9 interacts physically with p53 under oncogenic RAS activation and that the p53-interacting region of DNAJB9 is critical for the inhibition of p53-dependent OIS and induction of neoplastic transformation by DNAJB9. These results suggest that DNAJB9 induces cell transformation under strong mitogenic signals, which is attributable to the inhibition of p53-dependent OIS by physical interactions with p53. This study might contribute to our understanding of the cellular function of DNAJB9 and the molecular basis of cell transformation.

• Molecules and Cells
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• 제43권7호
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• pp.645-661
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• 2020

Leaf senescence is a developmental process by which a plant actively remobilizes nutrients from aged and photosynthetically inefficient leaves to young growing ones by disassembling organelles and degrading macromolecules. Senescence is accelerated by age and environmental stresses such as prolonged darkness. Phytochrome B (phyB) inhibits leaf senescence by inhibiting phytochrome-interacting factor 4 (PIF4) and PIF5 in prolonged darkness. However, it remains unknown whether phyB mediates the temperature signal that regulates leaf senescence. We found the light-activated form of phyB (Pfr) remains active at least four days after a transfer to darkness at 20℃ but is inactivated more rapidly at 28℃. This faster inactivation of Pfr further increases PIF4 protein levels at the higher ambient temperature. In addition, PIF4 mRNA levels rise faster after the transfer to darkness at high ambient temperature via a mechanism that depends on ELF3 but not phyB. Increased PIF4 protein then binds to the ORE1 promoter and activates its expression together with ABA and ethylene signaling, accelerating leaf senescence at high ambient temperature. Our results support a role for the phy-PIF signaling module in integrating not only light signaling but also temperature signaling in the regulation of leaf senescence.

• Journal of Ginseng Research
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• 제36권1호
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• pp.78-85
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• 2012

Endothelial progenitor cells (EPC) are a population of cells that circulate in the blood stream. They play a role in angiogenesis and, therefore, can be prognostic markers of vascular repair. Ginsenoside $Rg_3$ prevents endothelial cell apoptosis through the inhibition of the mitochondrial caspase pathway. It also affects estrogen activity, which reduces EPC senescence. Sun ginseng (SG), which is heat-processed ginseng, has a high content of ginsenosides. The purpose of this study was to investigate the protective effects of SG on senescence-associated apoptosis in EPCs. In order to isolate EPCs, mononuclear cells of human blood buffy coats were cultured and characterized by their uptake of acetylated low-density lipoprotein (acLDL) and their binding of Ulex europaeus agglutinin I (ulex-lectin). Flow cytometry with annexin-V staining was performed in order to assess early and late apoptosis. Senescence was determined by ${\beta}$-galactosidase (${\beta}$-gal) staining. Staining with 4'-6-Diamidino-2-phenylindole verified that most adherent cells (93${\pm}$2.7%) were acLDL-positive and ulex-lectin-positive. The percentage of ${\beta}$-gal-positive EPCs was decreased from 93.8${\pm}$2.0% to 62.5${\pm}$3.6% by SG treatment. A fluorescence-activated cell sorter (FACS) analysis showed that 4.9% of EPCs were late apoptotic in controls. Sun ginseng decreased the apoptotic cell population by 39% in the late stage of apoptosis from control baseline levels. In conclusion, these results show antisenescent and antiapoptotic effects of SG in human-derived EPCs, indicating that SG can enhance EPC-mediated repair mechanisms.

• 동의생리병리학회지
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• 제19권3호
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• pp.671-676
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• 2005

In this study, we investigated the antioxidant effect of extract from Monascus pillosus, on the human wild-type p53 and p21 expressing A549 lung epithelial cell line and MCF-7 mammary adenocarcinoma cell line stimulated by NO. $P21^{waf/cip1}$ was identified as a gene induced in senescent cells. It is a cyclin-dependent kinase inhibitor and has been shown to cause cell cycle arrest and apoptosis. While p53-regulated stimulation of p21 appears to be central for the permanent growth-arrest, the role of p21 in p53-triggered cell death is unclear. Low dose of sodium nitroprusside (SNP) induced the development of senescence associated with increased expression of p53 and p21 in A549 cells. Inhibition of p21 transactivating activity requires high level correlates with the amount of p53 necessary to cause cell death. Association of p21 and p53 results in inhibition of p21-stimulated transcription. This requires a higher p53 level than is necessary for transcriptional activation of endogenous p53-responsive gene but correlates well with the level of p53 necessary to cause cell death. Exposure to W-1 inhibited oxidative stresses-induced senescence-like arrest, resulting in a significant reduction in p53 and p21 steady state levels. These results suggest that p53 and p21 play a central role in the onset of senescence. Thus, it is important to emphasize control of oxidative balance in tumor prevention and aging.

• Journal of Plant Biology
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• 제33권2호
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• pp.87-96
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• 1990

The role of S-adenosylmethionine (SAM) as an intermediate in interrelation between polyamine and ethylene biosynthesis was studied in suspension cultures of Nicotiana tabacum L. Exogenous SAM stimulated the polyamine and ethylene biosynthesis in 4 day-cultured cells, which were in active cell divisions, and 10 day cultured cells, which went on with active cell elongation and senescence. SAM-induced ethylene production was more effective in 10 day-cultured cells than in 4 day-cultured cells, but SAM-induced polyamine biosynthesis was more effective in 4 day-cultured cells than in 10 day-cultured cells. Polyamine contents were increased by the blockage of ethylene biosynthetic pathway in the conversion of SAM to ethylene via 1-aminocyclopropane-1-carboxylinc acid (ACC) with aminooxyacetic acid (AOA). Also, ethylene production was increased by the inhibitors of polyamine biosynthesis such as methylglyoxal bis-(guanylhydrazone) (MGBG), dicyclohexylamine (DCHA), $\alpha$-difluoromethylarginine (DFMA) and $\alpha$-difluoromethylorinithine (DFMO). These results suggest that there may be interrelations between polyamine and ethylene biosynthesis for the competition of SAM and the inherent mechanism of switch on-off in polyamine and ethylene biosynthetic activity with the progress of cell growth and senescence.

• 한국동물생명공학회지
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• 제35권3호
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• pp.215-222
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• 2020

Mesenchymal stem cells (MSCs) have been widely used as donor cells for somatic cell nuclear transfer (SCNT) to increase the efficiency of embryo cloning. Since replicative senescence reduces the efficiency of embryo cloning in MSCs during in vitro expansion, transfection of telomerase reverse transcriptase (TERT) into MSCs has been used to suppress the replicative senescence. Here, TERT-transfected MSCs in comparison with early passage MSCs (eMSCs) and sham-transfected MSCs (sMSCs) were used to evaluate the effects of embryo cloning with SCNT in a porcine model. Cloned embryos from tMSC, eMSC, and sMSC groups were indistinguishable in their fusion rate, cleavage rate, total cell number, and gene expression levels of OCT4, SOX2 and NANOG during the blastocyst stage. The blastocyst formation rates of tMSC and sMSC groups were comparable but significantly lower than that of the eMSC group (p < 0.05). In contrast, tMSC and eMSC groups demonstrated significantly reduced apoptotic incidence (p < 0.05), and decreased BAX but increased BCL2 expression in the blastocyst stage compared to the sMSC group (p < 0.05). Therefore, MSCs transfected with telomerase reverse transcriptase do not affect the overall development of the cloned embryos in porcine SCNT, but enables to maintain embryo quality, similar to apoptotic events in SCNT embryos typically achieved by an early passage MSC. This finding offers a bioengineering strategy in improving the porcine cloned embryo quality.

• Journal of Microbiology and Biotechnology
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• 제30권7호
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• pp.1044-1050
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• 2020

Abelmoschus manihot (Linn.) is a medicinal herbal plant that is commonly used to treat chronic kidney disease and hepatitis. However, its effect on cell proliferation has not been clearly revealed. In this report, we sought to determine the effect of the flower extract of A. manihot (FA) on cell proliferation. Based on our findings, FA increased the proliferation of human diploid fibroblast (HDF) and HEK293 cells. Through cell cycle analysis, FA was found to increase the number of HDF cells in the S phase and G2/M phase. FA also increased the expression of cyclin D1 and enhanced the migration of HDF cells. By administering FA to HDF cells with ≥30 passages, a decrease in the number of senescence-associated β galactosidase-positive cells was observed, thereby indicating that FA can ameliorate cellular senescence. Collectively, our findings indicate that FA increases cyclin D1 expression and regulates cell proliferation.