• Title/Summary/Keyword: JAK3

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Study on the effect of Sagunjatang(SGJT) and Samultang(SMT) extract on the Wave of Human body and Active Oxygen (사군자탕(四君子湯) 및 사물탕(四物湯)이 인체파동(人體波動)과 활성산소(活性酸素)에 미치는 영향(影響)에 관(關)한 실험적(實驗的) 연구(硏究))

  • Cho, Ki-Yong;Yoo, Dong-Youl
    • Journal of Haehwa Medicine
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    • v.9 no.1
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    • pp.305-317
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    • 2000
  • To prove the effect of Sagunjatang(SGJT) and Samultang(SMT) extract on the wave of Human Body and Active Oxygen experimentally, QRS & Free Radical of extract and precipitate of SGJT and SMT was measured. The results were summarized as follows ; 1. SGJT extract and precipitate, as a result of measuring QRS and Free Radical, had a considerable effect on the function of immunity & pituitary gland. 2. BaekBokRung of SGJT, as a result of measuring QRS and Free Radical, had a considerable effect on the function of heart & spleen. 3. BaekChul and Gamcho of SGJT, as a result of measuring QRS and Free Radical, had a considerable effect on the function of stomach & duodenum. 4. YinSam of SGJT, as a result of measuring QRS and Free Radical, had a considerable effect on the function of immunity & spleen. 5. SMT extract and precipitate, as a result of measuring QRS and Free Radical, had a considerable effect on the function of immunity & uterus. 6. SukJiHwang of SMT, as a result of measuring QRS and Free Radical, had a considerable effect on the function of immunity & liver. 7. DangGui of SMT, as a result of measuring QRS and Free Radical, had a considerable effect on the function of heart & spleen. 8. ChunGung of SMT, as a result of measuring QRS and Free Radical, had a considerable effect on the function of spleen & pituitary gland. 9. BaekJakYak of SMT, as a result of measuring QRS and Free Radical, had a considerable effect on the function of stomach & duodenum. 10. SMT extract had an effect on the function of female Urogenital system, SGJT extract had an effect on the function of male Urogenital system. These results suggested that SGJT and SMT extract might be usefully applied for suppresing of Active Oxygen formation, preventing the aging, curing all the disease resulted from Active Oxygen.

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Network pharmacology-based prediction of efficacy and mechanism of Myrrha acting on Allergic Rhinitis (네트워크 약리학을 활용한 알레르기 비염에서의 몰약의 치료 효능 및 기전 예측)

  • Yebin Lim;Bitna Kweon;Dong-Uk Kim;Gi-Sang Bae
    • The Journal of Korean Medicine
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    • v.45 no.1
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    • pp.114-125
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    • 2024
  • Objectives: Network pharmacology is an analysis method that explores drug-centered efficacy and mechanism by constructing a compound-target-disease network based on system biology, and is attracting attention as a methodology for studying herbal medicine that has the characteristics for multi-compound therapeutics. Thus, we investigated the potential functions and pathways of Myrrha on Allergic Rhinitis (AR) via network pharmacology analysis and molecular docking. Methods: Using public databases and PubChem database, compounds of Myrrha and their target genes were collected. The putative target genes of Myrrha and known target genes of AR were compared and found the correlation. Then, the network was constructed using STRING database, and functional enrichment analysis was conducted based on the Gene Ontology (GO) Biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathways. Binding-Docking stimulation was performed using CB-Dock. Results: The result showed that total 3 compounds and 55 related genes were gathered from Myrrha. 33 genes were interacted with AR gene set, suggesting that the effects of Myrrha are closely related to AR. Target genes of Myrrha are considerably associated with various pathways including 'Fc epsilon RI signaling pathway' and 'JAK-STAT signaling pathway'. As a result of blinding docking, AKT1, which is involved in both mechanisms, had high binding energies for abietic acid and dehydroabietic acid, which are components of Myrrha. Conclusion: Through a network pharmacological method, Myrrha was predicted to have high relevance with AR by regulating AKT1. This study could be used as a basis for studying therapeutic effects of Myrrha on AR.

Silencing of Suppressor of Cytokine Signaling-3 due to Methylation Results in Phosphorylation of STAT3 in Imatinib Resistant BCR-ABL Positive Chronic Myeloid Leukemia Cells

  • Al-Jamal, Hamid AN;Jusoh, Siti Asmaa Mat;Yong, Ang Cheng;Asan, Jamaruddin Mat;Hassan, Rosline;Johan, Muhammad Farid
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.11
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    • pp.4555-4561
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    • 2014
  • Background: Silencing due to methylation of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator gene for the JAK/STAT signaling pathway has been reported to play important roles in leukemogenesis. Imatinib mesylate is a tyrosine kinase inhibitor that specifically targets the BCR-ABL protein and induces hematological remission in patients with chronic myeloid leukemia (CML). Unfortunately, the majority of CML patients treated with imatinib develop resistance under prolonged therapy. We here investigated the methylation profile of SOCS-3 gene and its downstream effects in a BCR-ABL positive CML cells resistant to imatinib. Materials and Methods: BCR-ABL positive CML cells resistant to imatinib (K562-R) were developed by overexposure of K562 cell lines to the drug. Cytotoxicity was determined by MTS assays and $IC_{50}$ values calculated. Apoptosis assays were performed using annexin V-FITC binding assays and analyzed by flow cytometry. Methylation profiles were investigated using methylation specific PCR and sequencing analysis of SOCS-1 and SOCS-3 genes. Gene expression was assessed by quantitative real-time PCR, and protein expression and phosphorylation of STAT1, 2 and 3 were examined by Western blotting. Results: The $IC_{50}$ for imatinib on K562 was 362nM compared to 3,952nM for K562-R (p=0.001). Percentage of apoptotic cells in K562 increased upto 50% by increasing the concentration of imatinib, in contrast to only 20% in K562-R (p<0.001). A change from non-methylation of the SOCS-3 gene in K562 to complete methylation in K562-R was observed. Gene expression revealed down-regulation of both SOCS-1 and SOCS-3 genes in resistant cells. STAT3 was phosphorylated in K562-R but not K562. Conclusions: Development of cells resistant to imatinib is feasible by overexposure of the drug to the cells. Activation of STAT3 protein leads to uncontrolled cell proliferation in imatinib resistant BCR-ABL due to DNA methylation of the SOCS-3 gene. Thus SOCS-3 provides a suitable candidate for mechanisms underlying the development of imatinib resistant in CML patients.

Role of STAT3 as a Molecular Adaptor in Cell Growth Signaling: Interaction with Ras and other STAT Proteins

  • Song, Ji-Hyon;Park, Hyon-Hee;Park, Hee-Jeong;Han, Mi-Young;Kim, Sung-Hoon;Lee, Choong-Eun
    • BMB Reports
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    • v.34 no.5
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    • pp.484-488
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    • 2001
  • STATs are proteins with a dual function: signal transducers in the cytoplasm and transcriptional activators in the nucleus. Among the six known major STATs (STAT1-6), STAT3 has been implicated in the widest range of signaling pathways that regulate cell growth and differentiation. As a part of our on-going investigation on the pleiotropic functions of STAT proteins, we examined the role of STAT3 as a molecular adaptor that links diverse cell growth signaling pathways. We observed that STAT3 can be specifically activated by multiple cytokines, such as IL-3, in transformed fibroblasts and IL-4 or IFN-$\gamma$ in primary immune cells, respectively. The selective activation of STAT3 in H-ras-transformed NIH3T3 cells is associated with an increased expression of phosphoserioe STAT3 in these cells, compared to the parental cells. Notably phosphoresine-STAT3 interacts with oncogenic ras, shown by immunoprecipitation and Western blots. The results suggest the role of STAT3 in rasinduced cellular transformation as a molecular adaptor linking the Jak/STAT and Ras/MAPK pathways. In primary immune cells, IL-4 and IFN-$\gamma$ each induced (in addition to the characteristic STAT6 and STAT1 homodimers) the formation of STAT3-containing complexes that bind to GAS probes, which correspond to the $Fe{\varepsilon}$ Rll and $Fe{\gamma}$ RI promoter sequences, respectively. Since IL-4 and IFN-$\gamma$ are known to counter-regulate the expression of these genes, the ability of STAT3 to form heterodimeric complexes with STAT6 or STAT1 implies its role in the fine-tuned control of genes that are regulated by IL-4 and IFN-$\gamma$.

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Chicken novel leukocyte immunoglobulin-like receptor subfamilies B1 and B3 are transcriptional regulators of major histocompatibility complex class I genes and signaling pathways

  • Truong, Anh Duc;Hong, Yeojin;Lee, Janggeun;Lee, Kyungbaek;Tran, Ha Thi Thanh;Dang, Hoang Vu;Nguyen, Viet Khong;Lillehoj, Hyun S.;Hong, Yeong Ho
    • Asian-Australasian Journal of Animal Sciences
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    • v.32 no.5
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    • pp.614-628
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    • 2019
  • Objective: The inhibitory leukocyte immunoglobulin-like receptors (LILRBs) play an important role in innate immunity. The present study represents the first description of the cloning and structural and functional analysis of LILRB1 and LILRB3 isolated from two genetically disparate chicken lines. Methods: Chicken LILRB1-3 genes were identified by bioinformatics approach. Expression studies were performed by transfection, quantitative polymerase chain reaction. Signal transduction was analyzed by western blots, immunoprecipitation and flow cytometric. Cytokine levels were determined by enzyme-linked immunosorbent assay. Results: Amino acid homology and phylogenetic analyses showed that the homologies of LILRB1 and LILRB3 in the chicken line 6.3 to those proteins in the chicken line 7.2 ranged between 97%-99%, while homologies between chicken and mammal proteins ranged between 13%-19%, and 13%-69%, respectively. Our findings indicate that LILRB1 and LILRB3 subdivided into two groups based on the immunoreceptor tyrosine-based inhibitory motifs (ITIM) present in the transmembrane domain. Chicken line 6.3 has two ITIM motifs of the sequence LxYxxL and SxYxxV while line 7.2 has two ITIM motifs of the sequences LxYxxL and LxYxxV. These motifs bind to SHP-2 (protein tyrosine phosphatase, non-receptor type 11) that plays a regulatory role in immune functions. Moreover, our data indicate that LILRB1 and LILRB3 associated with and activated major histocompatibility complex (MHC) class I and ${\beta}2-microglobulin$ and induced the expression of transporters associated with antigen processing, which are essential for MHC class I antigen presentation. This suggests that LILRB1 and LILRB3 are transcriptional regulators, modulating the expression of components in the MHC class I pathway and thereby regulating immune responses. Furthermore, LILRB1 and LILRB3 activated Janus kinase2/tyrosine kinase 2 (JAK2/TYK2); signal transducer and activator of transcription1/3 (STAT1/3), and suppressor of cytokine signaling 1 genes expressed in Macrophage (HD11) cells, which induced Th1, Th2, and Th17 cytokines. Conclusion: These data indicate that LILRB1 and LILRB3 are innate immune receptors associated with SHP-2, MHC class I, ${\beta}2-microglobulin$, and they activate the Janus kinase/signal transducer and activator of transcription signaling pathway. Thus, our study provides novel insights into the regulation of immunity and immunopathology.

Opto-mechanical Analysis for Primary Mirror of Earth Observation Camera of the MIRIS (MIRIS EOC 주경의 광기계 해석)

  • Park, Kwi-Jong;Moon, Bong-Kon;Park, Sung-Jun;Park, Young-Sik;Lee, Dae-Hee;Ree, Chang-Hee;Nah, Jak-Young;Jeong, Woog-Seob;Pyo, Jeong-Hyun;Lee, Duk-Hang;Nam, Uk-Won;Rhee, Seung-Wu;Yang, Sun-Choel;Han, Won-Yong
    • Korean Journal of Optics and Photonics
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    • v.22 no.6
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    • pp.262-268
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    • 2011
  • MIRIS(Multi-purpose Infra-Red Imaging System) is the main payload of the STSAT-3(Korea Science and Technology Satellite. 3), which is being developed by KASI(Korea Astronomy & Space Institute). EOC(Earth Observation Camera), which is one of two infrared cameras in MIRIS, is the camera for observing infrared rays from the Earth in the range of $3{\sim}5{\mu}m$. The optical system of the EOC is a Cassegrain prescription with aspheric primary and secondary mirrors, and its aperture is 100mm. A ring type flexure supports the EOC primary mirror with pre-loading in order to withstand expected load due to the shock and vibration from the launcher. Here we attempt to use the same mechanism by which a retainer supports the lens. Through opto-mechanical analysis it was confirmed that the EOC primary mirror is effectively supported.

A Study of Mac(脈)-Theory and Change of Mac(脈)-Diagnosis in Whang Di Nei Qing(黃帝內經) (황제내경(黃帝內經)의 맥(脈) 이론(理論)과 진맥법(診脈法)의 변화(變化)에 관(關)한 연구(硏究))

  • Ra, Kyoung-Chan;Park, Hyun Kook
    • The Journal of Dong Guk Oriental Medicine
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    • v.2 no.1
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    • pp.73-105
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    • 1993
  • To say nothing of the orient and the west, the human beings discover the method of Jin Mac(診脈) by the way that observe disease. But oriental medicine devise special method of Jin Mac(診脈) in the study of Kyoung Mac(經脈). Although sip-ei Kyoung Mac Jin(十二經脈診), Sam Bu Gu Who Jin(三部九候診), In Young Mac Gu Jin(人迎脈口診), Chon Kwan Chuck Jin(寸關尺診) namely Yuk Bu Jung Wee Jin Mac (六部定位診脈) that is used today are devised, it has changed naturally by the changing treatment and the introduction of Yuin Yang(陰陽) and five element(五行). Many methods dg Jin Mac(診脈), it had not developped successing alternative, it had developped of declined by it's own way. 1. Results for the birth of Mac(脈) 1) Mac(脈), it means Kyoung Mac(經脈), at first entirelly Mac(脈), is seized a blood vessel that flows in the body. As presumed today, after finding many acupunture point, a general idea of Mac(脈) is not maked by the line that connect point and point, it connect between acupunture point and acupunture point. 2) Like blood flows in Hyul Mac(血脈), Gie(氣) flows in Kyoung Mac(經脈). The two things relate deeply each other. In a general idea or actrally Kyoung Rak(經洛), the two things sometimes accord, sometimes seperate, sometimes mix alternative. 3) Hyul Mac(血脈) and Kyoung Mac(經脈), we call it Mac(脈) entirely Kyoung Mac(經脈), is a way that manifest disease through Kyoung Mac(經脈) or a boundary that disease belongs to it method of Mac Jin(脈診) individual that disease of Kyoung Mac(經脈) is diagnosed by the jumping situation of Hyul Mac(血脈). 4) In method of Moxa, athough the pathology and the diagnostic of Mac(脈) are created by finding Mac(脈). Finding acupunture have opportunitty fot Mac Jin(脈診) and treatment. 2. Results of Kyoung Mac Mac Jin(經脈脈診) 1) In theory of kyoung Rak(經洛), disease are resumed for malfunction of Young Wee(榮衛) that flows in Kyung Rak(經洛). So to speak, in treatment of Kyoung Rak area, the purpose of diagnosis observe the situation of disease and cause. For fitting the purpose of diagnosis, the dead had esatablised four-diagnosis method mangMunMnnJeul(望聞問切), in four-diagnosis(四診法), the core is Mac Jin(脈診). 2) sip-ei Kyoung Mac Mac Jin(十二經脈診) had existed as Kyoung Mac Mac Jin(經脈脈診), it precedes Sam Bu Gu Who Jin(三部九候診). In Young Ki Gu Mac(人迎脈口診). 3) Although Bu Yang Mac(趺陽脈), So Um Mac(少陰脈) is a part of Sip-ei Kyoung Mac(十二經脈診), they developped especially because they located in the point of Won Hyul(原穴) and they are convenient for diagnose. 4) Sip-ei Kyoung Mac Mac Jin(十二經脈診), which belongs to Bu Yang Mac(趺陽脈) and So Urn Mac(少陰脈), is not important for the comming age medical books compared with Mac Kyoung(脈經). 3. Results gor Sam Bu Gu Who Jin(三部九候診) 1) Mac Jin(脈診) of Sam Bu Gu Who(三部九候), which is noted in the theory of Sam Bu Gu Who(三部九候診) of So Mun(素問), belongs to Kyoung Mac Mac Jin's(經脈脈診) geneology, Sip-ei Kyoung Mac Mac Jin(十二經脈診) is arranged, simplicated by the idealogy three talents(三才思想) in the heaven and the earth. 2) What Sam Bu Gu Jin(三部九候診) is regardded as very important in So Mun(素問), the editor of So Mun(素問) recognize the meaning that one discover disease early in this method of diagnosis. 3) After Young chu(靈樞), Nan Kyoung(難經) it is lacked the method of Sam Bu Gu Who Jin(三部九候診) in the books that treatment has changed. Sam Bu Gu Who Jin(三部九候診) based on actually clinic appropriate. 4. results for In Young Mac Gu Jin(人迎脈口診) 1) In Young Mac Gu Jin(人迎脈口診) is the method of comparative Mac Jin(脈診) according to the theory of Yin Yang(陰陽), it is presumed after Sam Bu Gu Who Jin(三部九候診), it had perished in parallel with the development of the theory of five elelment(五行). The development of the acupunture, the perishment of the treatment of negative(刺絡). 2) In Young Mac Gu Jin(人迎脈口診), Wang Suk Wha(王叔和) recreated that the left is In Young(人迎), the right is Kie Gu(氣口). In future generations by Jin Mu Taek(陳無擇) who is the writer of Sam In Bang(三因方). In Young Mac Gu Jin(人迎脈口診) is a measure for disease which classify it's inside and outside cause. 5. Results for Chon Gu Mac Jin(寸口脈診) 1) What we say Mac Jin(脈診) of Chon Gu(寸口) two means are used in commn. First case, we simply say the area of Chon Gu(寸口), second case, we say Chon Kwan Chuk Jin(寸口尺診) reducingly. Chon Gu(寸口) is the area which is the radial artery of wrist joint. What we attemp diagnose by only Chon Gu Mac(寸口脈), it is clearly shoued in the method of Nan Kyoung, five Nan(難經五難). 2) Because Jin Mac(診脈) is made in only Chon Gu(寸口), that is the area in which is concentated Kyoung Kee(經氣). That is the birth of Jin Kee(眞氣) and Jin Kee(眞氣) is related with disease. We can diagnose disease by taking Chon Gu(寸口). 3) Chuk Jin(尺診) in Nae Kyoung(難經) have two things. One is Il Chuk(一尺), the other is Chon Kwan Chu(寸關尺). 4) Chuk Chon Jin(尺寸診) is the method which diagnose the difference of point and the condition of Mac(脈) by dividing a part of Chuk(尺) in the area of Chon Gu(寸口). In Chon Gu Jin(寸口診), by introducing the theory of Yin Yang(陰陽), the method of Chon Gu Jin(寸口診) is developed by chon Gu Jin(寸口診). 5) What Chuk Kwan Chon Jin(寸關尺診) is that area of the Chon Gu(寸口) are divided fot three point, we can diagnose. By consulting Sam Bu Gu Who Jin(三部九候診), developping of the method of acupunture, utilzing the theory of five element(五行) it is devised by concentrating way of thinking of the method mac Jin(脈診) exiting. 6) Chon Kwan Chuk Jin MaC(寸關尺診脈) begin from Nae Kyoung(內徑) exiting. After Nan Kyoung(內徑), spread out widely from Mac Kyoung(脈診) of Wang Suk wha(王叔和), the future medicins followed it. Yang Hyun Jo(楊玄操) and established Chon Kwan Chuk Jin(寸關尺診) which is used widely today. This right and left Chon Kwan Chuk Jin(寸關尺診), we call it method of Yuk Bu Jung Wee Jin Mac(六部定位診脈). 7) We can think the base which presume the arrangement of the viscera for Chon Kwan Chuk(寸關尺) of the right and the left. 8) The origin, which seperate the right and the left of Mac(脈), is showed at the treory of Ji Jin Yo Dae(至眞要大論) in So Mun(素問) which Chon Chuk(寸尺) seperate the right and the left. But the method of diagnosis in Nan Kyoung(難經) have no seperation the fight and the left. Otherwise this. there is clearly writtened the seperation for the right origin of the method of Yuk Bu Jung Wee Jin Mac(六部定位診脈) seek for Cang Gong(倉公). 9) Yang Hyun Jo(楊玄操) notice that the Chuk(尺) is mentioned for Sam Cho(三焦) in the method of Mac Kyuong(脈經), Sim Po Kyung(心包經) which put together with Sam Cho(三焦) allot on this, he had established the method of Yuk Bu Jung Wee Jin Mac(六部定位診脈). 10) On the method of Paen Jak Yin Yang Mac(扁鵲陰陽脈) in Mac Kyoung(脈經), equal article exist with the theory of Pyung In Kee Sang(平人氣象論) in So Mun(素問). When Wang Suk Wha(王叔和) write Mac Kyung(脈經), we can presume that the book of Mac(脈) which Paen Jak(扁鵲) had experienced the origin have exited besides So Mun(素問), Young Chu(靈樞). If so he must be make Chon Kwan Chuk Jin(寸關尺診) very fairly standard. So Nae Kyoung(內經), which must be fllowed the method of Paen Jak Mac(扁鵲脈), do the method diagnosis of Chon Kwan Chuk(寸關尺), diagnise of disease and treat.

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Multiple Cytotoxic Factors Involved in IL-21 Enhanced Antitumor Function of CIK Cells Signaled through STAT-3 and STAT5b Pathways

  • Rajbhandary, S.;Zhao, Ming-Feng;Zhao, Nan;Lu, Wen-Yi;Zhu, Hai-Bo;Xiao, Xia;Deng, Qi;Li, Yu-Ming
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.10
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    • pp.5825-5831
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    • 2013
  • Background/Objectives: Maintenance of cellular function in culture is vital for transfer and development following adoptive immunotherapy. Dual properties of IL-21 in activating T cells and reducing activation induced cell death led us to explore the mechanism of action of IL-21 enhanced proliferation and cytotoxic potential of CIK cells. Method: CIK cells cultured from PBMCs of healthy subjects were stimulated with IL-21 and cellular viability and cytotoxicity to K562 cells were measured. To elucidate the mechanism of action of IL-21, mRNA expression of cytotoxic factors was assessed by RT-PCR and protein expression of significantly important cytotoxic factors and cytokine secretion were determined through flow cytometry and ELISA. Western blotting was performed to check the involvement of the JAK/STAT pathway following stimulation. Results: We found that IL-21 did not enhance in vitro proliferation of CIK cells, but did increase the number of cells expressing the CD3+/CD56+ phenotype. Cytotoxic potential was increased with corresponding increase in perforin ($0.9831{\pm}0.1265$ to $0.7592{\pm}0.1457$), granzyme B ($0.4084{\pm}0.1589$ to $0.7319{\pm}0.1639$) and FasL ($0.4015{\pm}0.2842$ to $0.7381{\pm}0.2568$). Interferon gamma and TNF-alpha were noted to increase ($25.8{\pm}6.1ng/L$ to $56.0{\pm}2.3ng/L$; and $5.64{\pm}0.61{\mu}g/L$ to $15.14{\pm}0.93{\mu}g/L$, respectively) while no significant differences were observed in the expression of granzyme A, TNF-alpha and NKG2D, and NKG2D. We further affirmed that IL-21 signals through the STAT-3 and STAT-5b signaling pathway in the CIK cell pool. Conclusion: IL-21 enhances cytotoxic potential of CIK cells through increasing expression of perforin, granzyme B, IFN-gamma and TNF-alpha. The effect is brought about by the activation of STAT-3 and STAT-5b proteins.

Quantitation of n-Hexane Extractable Material (HEM) and Estimation of Annual Pollutant Loading Rate by Sewage Sludge Applicated to Land (하수슬러지 중 노말헥산추출물질 (HEM) 함량 분석 및 토양 시용시 연간 오염부하량 추정)

  • Nam, Jae-Jak;Park, Woo-Kyun;Lim, Dong-Kyu;Lee, Sang-Hak
    • Korean Journal of Environmental Agriculture
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    • v.21 no.1
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    • pp.45-49
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    • 2002
  • To estimate annual pollutant loading rate of n-hexane extractable material (HEM) to soil 84 sewage sludge samples were analyzed. The average content of HEM was 27.7$\pm$26.5 g/kg, and ranged from 1.05 to maximum 194 g/kg. According to the number of population of the city the areas were classified as five regions, i.e. big, large, middle, small, and rural area in which the waste water treated plants were grown. The contents of HEM were 22.7$\pm$16.7, 33.3$\pm$25.8, 22.0$\pm$8.7, 31.0$\pm$38.8, 27.7$\pm$25.1 g/kg, in big, large, middle, small, and rural area, respectively. The applicated areas with sewage sludge to land also were divided as 4 sites by US EPA criteria such as agricultural, forest, public contact sites, and reclamation site. The quantitation of annual pollutant loading rate was estimated using a function (99 percentile concentration = $\bar{X}$ + 3$\sigma$) when the application amounts were in dosages of 7,000, 26,000, 18,000, 74,000 kg/ha in 5 regions, respectively. The annual pollutant loading rate of HEM to soil by sewage sludge application was maximum 1,032, 3,832, 2,653, and 10,908 kg/ha in agricultural, forest, public contact sites, and reclamation site, respectively.

Novel Isoquinolinamine and Isoindoloquinazolinone Compounds Exhibit Antiproliferative Activity in Acute Lymphoblastic Leukemia Cells

  • Roolf, Catrin;Saleweski, Jan-Niklas;Stein, Arno;Richter, Anna;Maletzki, Claudia;Sekora, Anett;Escobar, Hugo Murua;Wu, Xiao-Feng;Beller, Matthias;Junghanss, Christian
    • Biomolecules & Therapeutics
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    • v.27 no.5
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    • pp.492-501
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    • 2019
  • Nitrogen-containing heterocycles such as quinoline, quinazolinones and indole are scaffolds of natural products and have broad biological effects. During the last years those structures have been intensively synthesized and modified to yield new synthetic molecules that can specifically inhibit the activity of dysregulated protein kinases in cancer cells. Herein, a series of newly synthesized isoquinolinamine (FX-1 to 8) and isoindoloquinazolinone (FX-9, FX-42, FX-43) compounds were evaluated in regards to their anti-leukemic potential on human B- and T- acute lymphoblastic leukemia (ALL) cells. Several biological effects were observed. B-ALL cells (SEM, RS4;11) were more sensitive against isoquinolinamine compounds than T-ALL cells (Jurkat, CEM). In SEM cells, metabolic activity decreased with $10{\mu}M$ up to 26.7% (FX-3), 25.2% (FX-7) and 14.5% (FX-8). The 3-(p-Tolyl) isoquinolin-1-amine FX-9 was the most effective agent against B- and T-ALL cells with IC50 values ranging from 0.54 to $1.94{\mu}M$. None of the tested compounds displayed hemolysis on erythrocytes or cytotoxicity against healthy leukocytes. Anti-proliferative effect of FX-9 was associated with changes in cell morphology and apoptosis induction. Further, influence of FX-9 on PI3K/AKT, MAPK and JAK/STAT signaling was detected but was heterogeneous. Functional inhibition testing of 58 kinases revealed no specific inhibitory activity among cancer-related kinases. In conclusion, FX-9 displays significant antileukemic activity in B- and T-ALL cells and should be further evaluated in regards to the mechanisms of action. Further compounds of the current series might serve as templates for the design of new compounds and as basic structures for modification approaches.