• Radiation Oncology Journal
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• 제13권2호
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• pp.121-128
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• 1995

Purpose: The enhanced cytotoxic effect of combined treatment of hyper-thermia and chemotherapy by increasing intracellular acidity with HMA was investigated. Materials and Methods: FSall tumor cells were injected on the hindlegs of female $C_3H$ mice. When the tumor volume reached about 200mm3, experiments were performed on the groups classified as follows: Group I :Control, Group II : Melphalan alone (2.5mg/kg, 5mg/kg, 10mg/kg, 15mg/kg), Group III : Heat alone $(42.5^{\cdot}C$ for 1 hour) Group IV : Melphalan + Heat $(42.5^{\cdot}C$ for 1 hour), Group V : HMA(10mg/kg) + Melphalan(5.0mg/kg) + Heat$(42.5^{\cdot}C$ for 1hour). Each group included 8-12 mice on each experiment HMA (3-amino-6-chloro-5-(1-homopiperidyl )-N-(diaminomethylene) -c-pyrazinecarboxamide), an analog of amiloride which increases intracellular pH(pHi) was dissolved in dimethyl sulfoxide (DMS) and injected into the tumor-bearing mice through the tail vein. 10mg/kg of HMA and each dose of melphalan were injected into peritoneum of the tumor-bearing mice 30 minutes before heating. Tumor growth delay was calculated when the tumor volme reached at $1500mm^3$ Excision assay was performed on each group and repeated 2-4 times. Results : Tumor growth delay of each experimental groups at $1500mm^3$ were 9, 10, 13 and 19 days respectively. In vivo-in vitro excision assay using FSall tumor cells, the cytotoxicity of each experimental groups was $1.2{\times}10^7,\;1{\times}10^7,\;6{\times}10^6,\;1.7{\times}10^6\;and\;1{\times}10^5$ clonogenic cells/gm respectively When HMA was added to the combined treatment of heat and .chemotherapy, the tumor growth was delayed more than combined treatment without HMA i.e., 6 days tumor growth delay at $1500mm^3$ of tumor volume. Conclusion: The combined effect of cytotoxicity by heat and chemotherapy can be much more enhanced by HMA.

• Journal of the Korean Society for Industrial and Applied Mathematics
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• 제18권4호
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• pp.317-335
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• 2014

In this work, we investigate the global stability analysis of a viral infection model with antibody immune response. The incidence rate is given by a general function of the populations of the uninfected target cells, infected cells and free viruses. The model has been incorporated with two types of intracellular distributed time delays to describe the time required for viral contacting an uninfected cell and releasing new infectious viruses. We have established a set of conditions on the general incidence rate function and determined two threshold parameters $R_0$ (the basic infection reproduction number) and $R_1$ (the antibody immune response activation number) which are sufficient to determine the global dynamics of the model. The global asymptotic stability of the equilibria of the model has been proven by using Lyapunov theory and applying LaSalle's invariance principle.

• 대한수학회지
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• 제49권4호
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• pp.779-794
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• 2012

In this paper, we study the global stability of two mathematical models for human immunodeficiency virus (HIV) infection with intra-cellular delays. The first model is a 5-dimensional nonlinear delay ODEs that describes the interaction of the HIV with two classes of target cells, $CD4^+$ T cells and macrophages taking into account the saturation infection rate. The second model generalizes the first one by assuming that the infection rate is given by Beddington-DeAngelis functional response. Two time delays are used to describe the time periods between viral entry the two classes of target cells and the production of new virus particles. Lyapunov functionals are constructed and LaSalle-type theorem for delay differential equation is used to establish the global asymptotic stability of the uninfected and infected steady states of the HIV infection models. We have proven that if the basic reproduction number $R_0$ is less than unity, then the uninfected steady state is globally asymptotically stable, and if the infected steady state exists, then it is globally asymptotically stable for all time delays.

• Animal cells and systems
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• 제2권1호
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• pp.99-106
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• 1998

In this study, we have examined the role of cAMP in gap junctional communication (GJC) in preimplantation mouse embryos. GJC was monitored by Lucifer Yellow (LY) injected into one blastomere of compacted embryos. The speed of GJC was defined as the time taken for the last blastomere of the embryo to become visibly fluorescent. The median time for 8-cell embrvos (140 sec) was similar to that for 16-cell (135 sec). To determine whether cAMP and cAMP-dependent protein kinase (PKA) are involved in the regulation of GJC, the effects of PKA inhibitor (H8) and cAMP analogues (Rp-cAMP and 8-Br-cAMP) on dye transfer between blastomeres of compacted embryos were examined. Some of the embryos treated with either H8 or Rp-cAMP failed to transfer LY to all blastomeres within 10 min. In contrast, 8-Br-cAMP speeded up fluorescent dye transfer. The median time to fill all blastomeres with LY was 140 sec in untreated controls and 90 sec in siblings treated with 8-Br-cAMP. Inhibition of PKA by H8 or Rp-cAMP induced delay or arrest in embryo development after compaction, but the increase of intracellular cAMP showed no effect. These findings suggest that GJC in preimplantation mouse embryos is regulated by cAMP-PKA pathway and transient interference by PKA inhibitors induces the developmental delay beyond compaction.

• Clinical and Experimental Pediatrics
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• 제63권8호
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• pp.291-300
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• 2020

Advances in autoimmune encephalitis studies in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to the disorder. The disorder or syndrome has been linked to a wide variety of pathologic processes associated with the neuron-specific autoantibodies targeting intracellular and plasma membrane antigens. However, current criteria for autoimmune encephalitis are quite dependent on antibody testing and responses to immunotherapy, which might delay the diagnosis. This form of encephalitis can involve the multifaceted presentation of seizures and unexpected behavioral changes. The spectrum of neuropsychiatric symptoms in children is less definitive than that in adults, and the incorporation of clinical, immunological, electrophysiological, and neuroradiological results is critical to the diagnostic approach. In this review, we document the clinical and immunologic characteristics of autoimmune encephalitis known to date, with the goal of helping clinicians in differential diagnosis and to provide prompt and effective treatment.

• Nutrition Research and Practice
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• 제4권4호
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• pp.259-269
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• 2010

Resistance training (RT) is associated with reduced risk of low grade inflammation related diseases, such as cardiovascular disease and type 2 diabetes. The majority of the data studying cytokines and exercise comes from endurance exercise. In contrast, evidence establishing a relationship between RT and inflammation is more limited. This review focuses on the cytokine responses both following an acute bout, and after chronic RT. In addition, the effect of RT on low grade systemic inflammation such as individuals at risk for type 2 diabetes is reviewed. Cytokines are secreted proteins that influence the survival, proliferation, and differentiation of immune cells and other organ systems. Cytokines function as intracellular signals and almost all cells in the body either secrete them or have cytokine receptors. Thus, understanding cytokine role in a specific physiological situation such as a bout of RT can be exceedingly complex. The overall effect of long term RT appears to ameliorate inflammation, but the specific effects on the inflammatory cytokine, tumor necrosis factor alpha are not clear, requiring further research. Furthermore, it is critical to differentiate between chronically and acute Interleukin-6 levels and its sources. The intensity of the RT and the characteristics of the training protocol may exert singular cytokine responses and as a result different adaptations to exercise. More research is needed in the area of RT in healthy populations, specifically sorting out gender and age RT acute responses. More importantly, studies are needed in obese individuals who are at high risk of developing low grade systemic inflammatory related diseases. Assuring adherence to the RT program is essential to get the benefits after overcoming the first acute RT responses. Hence RT could be an effective way to prevent, and delay low grade systemic inflammatory related diseases.

• The Korean Journal of Physiology and Pharmacology
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• 제24권6호
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• pp.493-502
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• 2020

Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (ΔΨm), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)-histone H2A.X. and caused a transition delay at the G₂/M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio. ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.

• Archives of Plastic Surgery
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• 제50권4호
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• pp.432-442
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• 2023

Background Macrophages play a major role in wound healing and prevent infection from the outside. Polarization conversion of macrophages regulates aspects of inflammation, and two macrophages, M1 (classically activated) and M2 (alternatively activated), exist at both ends of broad-spectrum macrophage polarization. Thus, we aimed to investigate whether macrophage polarization can be artificially regulated. To this end, MgSO4 and small-interfering RNA (siRNA) targeting magnesium transport 1 (MAGT1) were used to investigate the effects of intracellular magnesium (Mg2+) concentrations on the differentiation of macrophages in vitro. Methods THP-1 derived macrophages maintained in a culture medium containing 5 mM MgSO4 and siRNA to inhibit the expression of MAGT1. As comparative groups, THP-1 derived macrophages polarized into M1 and M2 macrophages by treatment with M1, M2 inducer cytokine. The polarization status of each group of cells was confirmed by cell surface antigen expression and cytokine secretion. Results We found that MgSO4 treatment increased CD163 and CD206, similar to the effect noted in the M2 group. The expression of CD80 and HLA-DR was increased in the group treated with MAGT1 siRNA, similar to the effect noted in the M1 group. Functional assays demonstrated that the group treated with MgSO4 secreted higher levels of IL-10, whereas the MAGT1 siRNA-treated group secreted higher levels of IL-6 cytokines. Additionally, the conditional medium of the Mg2+ treated group showed enhanced migration of keratinocytes and fibroblasts. Conclusion Mg2+ can help to end the delay in wound healing caused by persistent inflammation in the early stages.

• Molecules and Cells
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• 제40권8호
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• pp.567-576
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• 2017

The $Na^+/H^+$ exchanger is responsible for maintaining the acidic tumor microenvironment through its promotion of the reabsorption of extracellular $Na^+$ and the extrusion of intracellular $H^+$. The resultant increase in the extracellular acidity contributes to the chemoresistance of malignant tumors. In this study, the chemosensitizing effects of cariporide, a potent $Na^+/H^+-exchange$ inhibitor, were evaluated in human malignant mesothelioma H-2452 cells preadapted with lactic acid. A higher basal level of phosphorylated (p)-AKT protein was found in the acid-tolerable H-2452AcT cells compared with their parental acid-sensitive H-2452 cells. When introduced in H-2452AcT cells with a concentration that shows only a slight toxicity in H-2452 cells, cariporide exhibited growth-suppressive and apoptosis-promoting activities, as demonstrated by an increase in the cells with pyknotic and fragmented nuclei, annexin V-PE(+) staining, a $sub-G_0/G_1$ peak, and a $G_2/M$ phase-transition delay in the cell cycle. Preceding these changes, a cariporide-induced p-AKT down-regulation, a p53 up-regulation, an ROS accumulation, and the depolarization of the mitochondrial-membrane potential were observed. A pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 markedly augmented the DNA damage caused by the cariporide, as indicated by a much greater extent of comet tails and a tail moment with increased levels of the p-histone H2A.X, $p-ATM^{Ser1981}$, $p-ATR^{Ser428}$, $p-CHK1^{Ser345}$, and $p-CHK2^{Thr68}$, as well as a series of pro-apoptotic events. The data suggest that an inhibition of the PI3K/AKT signaling is necessary to enhance the cytotoxicity toward the acidtolerable H-2452AcT cells, and it underlines the significance of proton-pump targeting as a potential therapeutic strategy to overcome the acidic-microenvironment-associated chemotherapeutic resistance.

• Parasites, Hosts and Diseases
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• 제27권2호
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• pp.87-100
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• 1989

닭의 맹장 상피세포에 기생하여 출혈, 설사 등을 일으키는 구충류(구충류. Coccidia인 Eimerin tenella는 감염 초기에 상피 내 림프구(intraepithelial Lymphocyte; IEL)와 같은 면역계 세포로 먼저 침입하는 것이 잘 알려져 있다. 이 연구는 E. tenella가 면역계 세포 내로 들어가는 것이 추후 충체 생존 및 발육에 도움이 되는 과정인지를 알아보고자 한 것으로, 분리하기 쉬운 닭의 비장 세포를 면역계 세포로 이용하고 MDBK(Madin-Darby bovine kidney) 세포를 시험관 내(in nitre) 숙주세포로 하여 E. tenella의 생존 및 발육 능력을 정량적으로 측정한 것이다. 실험 과정은 3단계로 나누어 첫째 MDBK 세포가 숙주세포로 적합한지 우선 형태학적으로 관찰한 후, 둘째 E. tvnella sporozoites의 발육, 중식 상황을 3H-uracil 동위원내 흡수시험으로 정량화할 수 있는지 알아보고, 셋째 이 방법을 이용하여 sporozoites를 비장세포와 혼합배양한 후에는그 발육, 중식 능력이 어떻게 변화하는지 관찰하였다. MDBK 세포에 탈낭 직후의 정상 sporozoites를 직접 감염시켜 발육상황을 형태학적으로 관찰한 바 감염 3∼4일에 영양형 및 분열체(schizonts)가 완성되고 merosoites가 터져 나와 다른 세포로 침입하는 분열증식(schizogony)이 활발히 영위되고 있는 것이 확인되었다. 또 3H-uracil 흡수는 감염 12시간부터 뚜렷이 나타났고 48∼60시간에 peak에 달한 다음 서서히 감소하였다. 3H-uracil 흡수량은 sporozoites 감염 농도에 따라서도 변화하였으나 탈낭 후 MDBK 세포 감염까지의 시간 경과 에 따라 현저히 감소하였다. 그러나 sporozoites를 비장세포와 함께 4∼12시간 시험관 내에서 먼저 혼합배양한 다음 MDB노 세포에 감염시켰을 때 3H-uracil 흡수량은 sporozoites만을 태양한 대조군 에 비해 항상 높아 비장세포와의 혼합배양 후 발육증식이 더욱 활발해지는 것으로 나타났다. 이상의 결과로 보아 E. tenella의 sporosoites가 생체 내에서 IEL과 같은 면역계 세포에 침입하는 것이 충체 생존이나 발육에 있어서 비록 필수적인 것은 아니지만 자신의 생존이나 발육능력을 보존 또는 항진시키는데에 도움을 주는 과정의 하나로 판단되었다.