• 한국결정성장학회지
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• 제31권5호
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• pp.203-211
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• 2021

옥타칼슘포스페이트(OCP, Ca₈H₂(PO₄)₆·5H₂O)는 골전도성과 생체적합성을 가진 생분해성 인산칼슘계 재료 중 하나이다. 기질세포를 자극하여 조골세포로 분화하는 성질을 가지고 있어 빠른 골형성 및 재흡수되는 장점을 가지고 있다. 그러나 OCP가 체내에 삽입되면 분말 사이의 약한 응집력으로 인해 지지체의 형태를 유지하지 못하고 빠르게 분해된다. 반면, OCP와 유사한 결정구조를 갖는 수산화인회석(HA, Ca₁₀(PO₄)₆(OH)₂)은 골결손이 회복된 이후까지도 분해되지 않고 체내에 남아있다. 이 연구에서는 SBF(simulated body fluid) 용액에 HA 첨가량이 다른 OCP/HA disc을 침적한 후 기간에 따른 Weight loss, pH 변화 및 미세구조 변화의 측면에서 분해거동을 조사하였다. 그 결과 OCP/HA disc는 HA 함량에 관계없이 2주 동안 형태를 유지하였다. 특히, 40HA 시편의 표면이 균일하게 용해되는 양상을 보였고 SBF 용액 침적 후 7일 후부터 disc의 표면에 CDHA(calcium deficient hydroxyapatite)가 형성되었다. 이러한 결과는 40HA 시편이 골결손부의 회복을 위한 지지체로 적합하다는 것을 보여준다.

• Toxicological Research
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• 제31권4호
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• pp.371-392
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• 2015

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of $1000{\mu}g/kg/day$. Rats received TS-DP2 intravenously at doses of 250, 500, and $1000{\mu}g/kg/day$ once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 $500{\mu}g/kg/day$ and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was $250{\mu}g/kg/day$, and no observed adverse effect level (NOAEL) in females was $250{\mu}g/kg/day$ in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures ($AUC_{0-24h}$ and $C_0$) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.

• BMB Reports
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• 제45권12호
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• pp.742-747
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• 2012

Granulocyte colony-stimulating factor (G-CSF) is used for heart failure therapy and promotes myocardial regeneration by inducing mobilization of bone marrow stem cells to the injured heart after myocardial infarction; however, this treatment has one weakness in that its biological effect is transient. In our previous report, we generated 5 mutants harboring N-linked glycosylation to improve its antiapoptotic activities. Among them, one mutant (Phe140Asn) had higher cell viability than wild-type hG-CSF in rat cardiomyocytes, even after treatment with an apoptotic agent ($H_2O_2$). Cells treated with this mutant significantly upregulated the antiapoptotic proteins, and experienced reductions in caspase 3 activity and PARP cleavage. Moreover, the total number of apoptotic cells was dramatically lower in cultures treated with mutant hG-CSF. Taken together, these results suggest that the addition of an N-linked glycosylation was successful in improving the antiapoptotic activity of hG-CSF, and that this mutated product will be a feasible therapy for patients who have experienced heart failure.

• 핵의학기술
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• 제13권3호
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• pp.17-23
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• 2009

많은 암 환자들 중 특히 미만성 거대 B 세포 림프종 환자의 추적 검사에서 PET/CT 검사는 기타 다른 검사들과 견주어 볼 때 매우 중요하다는 것은 이미 알려져 있다. 이들 환자의 치료는 대부분 환자의 장기 한 곳에 국한된 경우가 없으므로, 방사선 치료나 항암 화학 요법 치료로 시행한다. 이러한 항암 화학 요법 치료는 골수의 활동을 억제하는 치료이기 때문에 환자에게서 호중구감소증과 같은 백혈구의 감소가 나타날 수 있다. 이러한 증상을 개선하기 위하여 과립구 자극요소(Granulocyte colony-stimulating factor)인 Filgrastim 성분의 골수촉진제를 사용하는 경우가 일반적이며, 이 약제가 투여된 환자에게서 단기간에 PET/CT 검사를 진행하게 되면, 검사에 사용되는 $^{18}F$-FDG의 섭취가 조혈 세포가 모여 있는 골수의 활성화로 그 곳에 섭취가 가중되어 정확한 영상의 정보를 얻는데 한계가 있다. 이 연구의 목적은 Filgrastim의 약제 투여 1일 후의 영상과 어느 정도 시간이 지난 후 영상의 SUV를 각각 비교하여 수치화하고, 대략 어느 정도 시간이 지난후에 정확한 영상의 정보를 줄 수 있는 $^{18}F$-FDG의 섭취가 일어나는지를 유추해 보고자 한다. 환자대상은 2007년 1월~2009년 1월까지 미만성 거대 B 세포 림프종을 진단받고 추적 검사 중인 환자 10명을 대상으로 하였다. 남자 4명, 여자 6명이고, 평균나이는 53.8세 평균 체중은 57.3 kg이다. PET/CT (Discovery STe; GE Healthcare, Milwaukee, WI, USA) 검사를 위해 환자에게 $^{18}F$-FDG 정맥주사 후 1시간 가량 안정시키고, PET/CT 영상을 획득하였다. 영상 분석은 ROI ($12\;mm^2$)를 $C_6$ (6 번 경추), $L_4$ (4 번 요추), 간, 비장, 폐에 각각 그린 후 표준화 섭취 계수(SUV)를 측정하였다. 같은 환자를 골수촉진제 주사 1일 후 영상과 5~7일 후 영상을 각각 분석하였으며, 통계 프로그램으로는 SPSS version 12. Wilcoxon signed rank test를 사용하여 두 집단 간의 유의성을 확인하였다. 검사를 시행한 10명의 환자의 SUV를 분석한 결과, 골수촉진제를 투여하고 1일 후의 SUV가 5~7일 후에 비해 $C_6$ (6 번경추), L4 (4 번 요추), 비장에서 현저하게 높게 나타났고, 간과 폐에서는 비슷하게 나타났다. SUV의 차이와 더불어, 5~7일 후의 영상에서는 뼈의 섭취가 거의 없어진 정상 섭취 영상을 얻을 수 있었다. 위의 연구에서도 보여진 것과 같이 과립구 자극요소 약제투여 후 1일째 환자의 영상과 5~7일 후의 영상에서 SUV의 현저한 차이가 있었으며, 약제를 투여한 환자의 영상에 뼈의 $^{18}F$-FDG 섭취가 집중되었으며, 평균 5~7일 후에 검사에서는 뼈의 섭취가 현저하게 줄어든 정상적이 영상을 얻을 수 있었다. 본 연구를 통하여 SUV를 측정하고, 통계분석 함으로서 기존의 사실을 수치화 하였으며, 정상 섭취가 가능한 기간을 유추 할 수 있었다. 추후에 과립구 자극요소인 Filgrastim 이 외에 Pegfilgrastim, Lenograstim등 기타약제와의 유사성과 차이점에 대한 유사 연구에도 기여할 수 있으리라 사료된다.

• 한국임상수의학회지
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• 제31권2호
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• pp.77-84
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• 2014

본 연구는 사람 재조합과립구자극인자 (rhG-CSF) 투여 간격에 따른 말초혈액과 골수의 변화를 평가하였다. 사람 재조합과립구자극인자는 개에서 항암치료 후 나타나는 골수억압 등에서 유용한 치료효과가 있는 것으로 알려져 있으나 그 투여간격에 따른 연구는 아직 진행되지 않았다. 따라서 본 연구에서는 다음과 같은 간격으로 실험 기간 동안 각각 2마리씩 3그룹으로 체중당 $5{\mu}g$으로 사람 재조합과립구자극인자를 주사하였다; (1) 하루에 한번 주사; 그룹 1, (2) 2일에 한번 주사; 그룹 2, (3) 3일에 한번 주사; 그룹 3, 말초혈액 분석과 100개의 직접 현미경 세포계수는 매일 실시하였다. 골수천자는 0일차, 3일차 9일차 마지막으로 말초혈액상 총 백혈구수가 정상범위내로 떨어지는 12일차 혹은 13일차에 시행하였다. 사람 재조합과립구자극인자는 모든 실험견에서 잘 투여되었으며 부작용을 보이지 않았다. 이러한 본 연구의 결과에 따르면 체중당 $5{\mu}g$의 사람 재조합과립구자극인자의 투여는 말초혈액과 골수에서 세포특이적이고 투여간격에 대체적으로 비례하는 효과를 보였으며 사람 재조합과립구자극인자 투여가 반복될수록 그 효과는 증가하였으며 사람 재조합과립구자극인자 투여를 중지한 이후에도 골수에 미치는 효과는 3일이상 지속되는 것으로 보여졌다. 따라서 본 연구의 결과를 통해 임상가들은 적절한 치료 간격을 세울 수 있을 것으로 기대된다.

• Natural Product Sciences
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• 제11권3호
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• pp.183-187
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• 2005

The objective of the present study was to determine the possible immune-enhancing effects of a substance extracted from a submerged culture of Lentinus edodes with rice bran (SLRB). According to the results obtained by measuring the in vitro macrophage activity of the exo-biopolymer from SLRB, it appears to exhibit activity similar to that of LPS, and this activity seems to occur in a dose-dependent manner. According to the results obtained by measuring splenocyte proliferation, the exo-biopolymer appears to induce an increase in proliferation of approximately 1.4-fold compared to the control group. We measured the proliferation of bone marrow cells in order to evaluate gut immunity and, according to our results, proliferation was increased to 109% that of the control group, and was similar to that associated with LPS. In order to characterize the enhancement of immunological activity in vivo, we orally administered the exo-biopolymer (25, 50, 250 mg/kg bw) to C3H/He mice, and then measured the macrophage activity, determining that the activity was higher than that of the controls at concentrations of 50 and 250 mg/kg. Therefore, the exo-biopolymer from SLRB can be considered to be a useful a BRM agent, as it clearly allows some protection against immunological diseases.

• International Journal of Oral Biology
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• 제34권4호
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• pp.199-203
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• 2009

This study investigated whether orthodontic force influences the production of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa B ligand (RANKL) in vivo, both of which are affected by cortical activation. Mechanical force was applied to the maxillary premolars of orthodontic patients by fitting the transpalatal arch prior to cortical activation of the gingival tissue. Gingival crevicular fluid (GCF) samples were then collected from each patient using paper strips before and after 1, 3, 7 or 14 days of treatment. The OPG and RANKL levels in the GCF were determined by enzyme-linked immunosorbent assays. The levels of OPG were significantly increased after 1 day of fitting the appliance and decreased to basal levels at 3 days after fitting. In contrast, the RANKL levels were dramatically decreased at 1 day after fitting, but recovered to those of the untreated control at 3 days after the force application. The force-mediated changes in the OPG and RANKL levels of the GCF were unaffected by cortical activation during these experimental periods. Collectively, these results suggest that an acute and severe change between the OPG and RANKL levels plays an important role in stimulating the cellular responses required for alveolar bone remodeling by orthodontic treatment.

• 대한의생명과학회지
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• 제15권2호
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• pp.161-166
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• 2009

Human erythropoietin(EPO) is a glycoprotein that enhances red blood cell production by stimulating proliferation and differentiation of erythroid progenitor cells in the bone marrow. Patients with chronic kidney disease(CKD) suffer from anemia caused by reduced production of EPO in the kidney. Recombinant human EPO protein has been used successfully for the treatment of anemia associated with CKD. Recently, attention has been paid to the development of side effect of EPO, pure red cell aplasia(PRCA), in some patients with CKD. PRCA is a rare disorder of erythropoiesis that leads to a severe anemia due to an almost complete cessation of red blood cell production. EPO-related PRCA is caused by the production of EPO-neutralizing antibodies(Abs) that eliminate the biological activity of EPO as well as endogenous EPO in patients undergoing therapy. Since 1988, almost 200 cases worldwide have been reported with Ab-positive PRCA after receiving EPO therapeutics. The underlying mechanisms of the breaking of immune tolerance to self-EPO have been investigated. Modification of formulation, organic compounds of container closures, and route of administration has been suggested for the possible mechanism of increased immunogenicity of EPO. A number of assays have been used to detect Abs specific to EPO. These assays are generally grouped into two major categories: binding Ab assays and neutralizing Ab assays(bioassays). There are several types of binding Ab assays, including radioimmunoprecipitation assay, enzyme-linked immunosorbent assay, and the BIAcore biosensor assay. In vitro cell-based bioassays have been utilized for the detection of neutralizing Abs. Finally, the recent experience with anti-EPO Abs may have considerable implications for the future development and approval of EPO preparations. Also, considering that millions of patients are being treated with EPO, clinicians need to be aware of signs and consequences of this rare but severe clinical case.

• Journal of Periodontal and Implant Science
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• 제37권3호
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• pp.553-562
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• 2007

Osteoblasts regulate osteoclastogenesis by production of various cytokines. Aggregatibacter(A) ac-tinomycetemcomitans is one of periodontopathogens which invades gingival tissue. Therefore, clarifying the effect of alive A. actinomycetemcomitans on osteoblasts is important to understand the mechanism of alveolar bone resorption in periodontitis. We investigated induction of osteoclastogenesis-inducing cytokines, adherence, and invasion by A. actinomycetemcomitans in osteoblasts. Osteoblasts were isolated from mouse calvaria and expression of cytokines was determined by RT-PCR. When the ratio of the number of A. actinomycetemcomtians to the number of osteoblasts was 10:1, 50:1 and 100:1, RANKL mRNA expression was increased. A. actinomycetemcomitans also increased expression of macrophage inflammatory protein (MIP) -1${\alpha}$, interleukin (IL)-1${\beta}$, and tumor necrosis factor (TNF)-${\alpha}$. A. actinomycetemcomitans attached to and invaded osteoblasts at ratio of 1000:1. These results suggest that A. actinomycetemcomitans increases osteoclastogenesis-inducing ability of osteoblasts by stimulating the expression of RANKL, MIP-1${\alpha}$,IL-1${\beta}$, and TNF-${\alpha}$ and that invasion of A. actinomycetemcomitans provides a means by which the bacteria escape from immune system and antibiotic therapy.

• IMMUNE NETWORK
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• 제9권1호
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• pp.27-33
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• 2009

Macrophages generated in vitro using macrophage-colony stimulating factor (M-CSF) and interleukin (IL)-6 from bone marrow cells (BM-Mp) are defective in antigen presenting cell (APC) function as shown by their ability to induce the proliferation of anti-CD3 mAb-primed syngeneic T cells. However, they do express major histocompatibility (MHC) class I and II molecules. accessory molecules and intracellular adhesion molecules. Here we demonstrate that the defective APC function of macrophages is mainly due to production of $TGF-{\beta}1$ by BM-Mp. Methods: Microarray analysis showed that $TGF-{\beta}1$ was highly expressed in BM-Mp, compared to a macrophage cell line, B6D. which exerted efficient APC function. Production of $TGF-{\beta}1$ by BM-Mp was confirmed by neutralization experiments of $TGF-{\beta}1$ as well as by real time-polymerase chain reaction (PCR). Results: Addition of $anti-TGF-{\beta}1$ monoclonal antibody to cultures of BM-Mp and anti-CD3 mAb-primed syngeneic T cells efficiently induced the proliferation of syngeneic T cells. Conversely, the APC function of B6D cells was almost completely suppressed by addition of $TGF-{\beta}1$. Quantitative real time-PCR analysis also confirmed the enhanced expression of $TGF-{\beta}1$ in BM-Mp. Conclusion: The defective APC function of macrophages generated in vitro with M-CSF and IL-6 was mainly due to the production of $TGF-{\beta}1$ by macrophages.