• BMB Reports
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• 제55권1호
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• pp.48-56
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• 2022

Small extracellular vesicles (sEVs) secreted by most cells carry bioactive macromolecules including proteins, lipids, and nucleic acids for intercellular communication. Given that some immune cell-derived sEVs exhibit anti-cancer properties, these sEVs have received scientific attention for the development of novel anti-cancer immunotherapeutic agents. In this paper, we reviewed the latest advances concerning the biological roles of immune cell-derived sEVs for cancer therapy. sEVs derived from immune cells including dendritic cells (DCs), T cells, natural-killer (NK) cells, and macrophages are good candidates for sEV-based cancer therapy. Besides their role of cancer vaccines, DC-shed sEVs activated cytotoxic lymphocytes and killed tumor cells. sEVs isolated from NK cells and chimeric antigen receptor (CAR) T cells exhibited cytotoxicity against cancer cells. sEVs derived from CD8⁺ T and CD4⁺ T cells inhibited cancer-associated cells in tumor microenvironment (TME) and activated B cells, respectively. M1-macrophage-derived sEVs induced M2 to M1 repolarization and also created a pro-inflammatory environment. Hence, these sEVs, via mono or combination therapy, could be considered in the treatment of cancer patients in the future. In addition, sEVs derived from cytokine-stimulated immune cells or sEV engineering could improve their anti-tumor potency.

• Asian Pacific Journal of Cancer Prevention
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• 제15권8호
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• pp.3471-3476
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• 2014

Background: Aberrant expression of the microRNA-29 family is associated with tumorigenesis and cancer progression. As transport carriers, tumor-derived exosomes are released into the extracellular space and regulate multiple functions of target cells. Thus, we assessed the possibility that exosomes could transport microRNA-29c as a carrier and correlations between microRNA-29c and apoptosis of bladder cancer cells. Materials and Methods: A total of 28 cancer and adjacent tissues were examined by immunohistochemistry to detect BCL-2 and MCL-1 expression. Disease was Ta-T1 in 12 patients, T2-T4 in 16, grade 1 in 8, 2 in 8 and 3 in 12. The expression of microRNA-29c in cancer tissues was detected by quantitative reverse transcriptase PCR (QRT-PCR). An adenovirus containing microRNA-29c was used to infect the BIU-87 human bladder cancer cell line. MicroRNA-29c in exosomes was measured by QRT-PCR. After BIU-87 cells were induced by exosomes-derived microRNA-29c, QRT-PCR was used to detect the level of microRNA-29c. Apoptosis was examined by flow cytometry and BCL-2 and MCL-1 mRNA expressions were assessed by reverse transcription-polymerase chain reaction. Western blotting was used to determine the protein expression of BCL-2 and MCL-1. Results: The expressions of BCL-2 and MCL-1 protein were remarkably increased in bladder carcinoma (p<0.05), but was found mainly in the basal and suprabasal layers in adjacent tissues. The expression of microRNA-29c in cancer tissues was negatively correlated with the BCL-2 and MCL-1. The expression level of microRNA-29c in exosomes and BIU-87 cells from the experiment group was higher than that in control groups (p<0.05). Exosome-derived microRNA-29c induced apoptosis (p<0.01). Although only BCL-2 was reduced at the mRNA level, both BCL-2 and MCL-1 were reduced at the protein level. Conclusions: Human bladder cancer cells infected by microRNA-29c adenovirus can transport microRNA-29c via exosomes. Moreover, exosome-derived microRNA29c induces apoptosis in bladder cancer cells by down-regulating BCL-2 and MCL-1.

• The Korean Journal of Physiology and Pharmacology
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• 제22권2호
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• pp.113-125
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• 2018

Exosomes are membranous vesicles of 30-150 nm in diameter that are derived from the exocytosis of the intraluminal vesicles of many cell types including immune cells, stem cells, cardiovascular cells and tumor cells. Exosomes participate in intercellular communication by delivering their contents to recipient cells, with or without direct contact between cells, and thereby influence physiological and pathological processes. They are present in various body fluids and contain proteins, nucleic acids, lipids, and microRNAs that can be transported to surrounding cells. Theragnosis is a concept in next-generation medicine that simultaneously combines accurate diagnostics with therapeutic effects. Molecular components in exosomes have been found to be related to certain diseases and treatment responses, indicating that they may have applications in diagnosis via molecular imaging and biomarker detection. In addition, recent studies have reported that exosomes have immunotherapeutic applications or can act as a drug delivery system for targeted therapies with drugs and biomolecules. In this review, we describe the formation, structure, and physiological roles of exosomes. We also discuss their roles in the pathogenesis and progression of diseases including neurodegenerative diseases, cardiovascular diseases, and cancer. The potential applications of exosomes for theragnostic purposes in various diseases are also discussed. This review summarizes the current knowledge about the physiological and pathological roles of exosomes as well as their diagnostic and therapeutic uses, including emerging exosome-based therapies that could not be applied until now.

• International Journal of Oral Biology
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• 제45권3호
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• pp.134-142
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• 2020

Colon cancer is one of the most common malignant tumors, but there are still a few validated biomarkers of colon cancer. Exosome-mediated microRNAs (miRNAs) have been recognized as potential biomarkers in cancers, and miRNAs can regulate a variety of genes. Recently, Fusobacterium nucleatum was discovered in the tissues of human colon cancer patients. Its role in colon cancer was highlighted. F. nucleatum may contribute to the progression of colon cancer through the mechanism of exosome-mediated miRNAs transfer. However, the exosomal miRNAs regulation mechanism by F. nucleatum in colon cancer is not well known. Thus, we performed next-generation sequencing to investigate the overall pattern of exosomal miRNAs expression in the colon cancer cell culture supernatant. We have confirmed the alterations of various exosomal miRNAs. In addition, to investigate the function of exosomal miRNAs, a Kyoto Encyclopedia of Genes and Genomes analysis was performed on the target genes of changed miRNAs. Potential target genes were associated with a variety of signaling pathways, and one of these pathways was related to colorectal cancer. These findings suggested that F. nucleatum can alter exosomal miRNAs released from colorectal cancer cells. Furthermore, exosomal miRNAs altered by F. nucleatum could be potential biomarkers for the diagnosis and therapy of colon cancer.

• The Korean Journal of Physiology and Pharmacology
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• 제27권2호
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• pp.157-165
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• 2023

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and current therapeutic strategies are limited in their effectiveness. The expressions of Rab5 and the M2 tumor-associated macrophage marker CD163 in tissues were detected by Western blot. The migration and invasion of cells were determined using a Transwell assay. The expressions of the exosome markers were evaluated by Western blot. The polarization of human macrophages (THP-1) was determined by incubation of THP-1 cells with conditioned medium or exosomes collected from MDA-MB-231 cells with indicated transfections or by a coculture system of THP-1 and MDA-MB-231 cells. The M1 and M2 macrophage markers were evaluated by qRT-PCR. The expression of Rab5 in TNBC was significantly higher than that in normal breast tissue. Rab5 expressions in triple-negative and luminal A breast cancer were higher than those in other molecular subtypes. Higher CD163 expression was observed in triple-negative breast cancer and in triple-negative and luminal B subtypes. Rab5 knockdown suppressed but Rab5 overexpression promoted the migration and invasion capacity of MDA-MB-231 cells. The levels of CD63 and CD9 in the medium of Rab5 knockdown cells were lower than those in control cells, whereas higher levels of CD63 and CD9 were observed in Rab5 overexpression cells. Rab5 knockdown decreased the excretion but did not alter the diameter of the exosomes. Knockdown of Rab5 facilitated the anti-tumor polarization of macrophages, which was partially reversed by Rab5 overexpression. Therefore, Rab5 is expected to be a potential therapeutic target for triple-negative breast cancer.

• IMMUNE NETWORK
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• 제5권2호
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• pp.105-109
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• 2005

Background: Dendritic cells (DCs) are the most potent APCs (antigen-presenting cells) and playa critical role in immune responses. Galectin-3 is a biological lectin with a beta-galactoside binding affinity. Recently, proteomic analysis revealed the presence of galectin-3 in the exosome of mature DCs. However, the expression and function of galectin-3 in DCs remains unclear yet. Methods: We used bone marrow-derived DCs of mouse and showed the expression of galectin-3 in DCs by using flow cytometry analysis and Western blot analysis. Results: Galectin-3 was determined as single band of 35 kDa in Western blot analysis. Flow cytometry analysis showed the major growth factor for DCs, granulocyte-macrophage colony stimulating factor (GM-CSF) and maturing agents, anti-CD40 monoclonal antibody (mAb) and lipopolysaccharide (LPS) consistently increased the intracellular expression of galectin-3 in DCs compared to medium alone. In addition, DCs treated with maturing agents did marginally express galectin-3 on their surface. Conclusion: This study suggests that galectin-3 in DCs may be regulated by critical factors for DC function.

• BMB Reports
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• 제55권1호
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• pp.3-10
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• 2022

Extracellular vesicles (EVs) released from different types of kidney cells under physiologic conditions contribute to homeostasis maintenance, immune-modulation, and cell-to-cell communications. EVs can also negatively affect the progression of renal diseases through their pro-inflammatory, pro-fibrotic, and tumorigenic potential. Inhibiting EVs by blocking their production, release, and uptake has been suggested as a potential therapeutic mechanism based on the significant implication of exosomes in various renal diseases. On the other hand, stem cell-derived EVs can ameliorate tissue injury and mediate tissue repair by ameliorating apoptosis, inflammation, and fibrosis while promoting angiogenesis and tubular cell proliferation. Recent advancement in biomedical engineering technique has made it feasible to modulate the composition of exosomes with diverse biologic functions, making EV one of the most popular drug delivery tools. The objective of this review was to provide updates of recent clinical and experimental findings on the therapeutic potential of EVs in renal diseases and discuss the clinical applicability of EVs in various renal diseases.

• Molecules and Cells
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• 제45권11호
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• pp.771-780
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• 2022

The field of extracellular vesicles (EVs) has expanded tremendously over the last decade. The role of cell-to-cell communication in neighboring or distant cells has been increasingly ascribed to EVs generated by various cells. Initially, EVs were thought to a means of cellular debris or disposal system of unwanted cellular materials that provided an alternative to autolysis in lysosomes. Intercellular exchange of information has been considered to be achieved by well-known systems such as hormones, cytokines, and nervous networks. However, most research in this field has searched for and found evidence to support paracrine or endocrine roles of EV, which inevitably leads to a new concept that EVs are synthesized to achieve their paracrine or endocrine purposes. Here, we attempted to verify the endocrine role of EV production and their contents, such as RNAs and bioactive proteins, from the regulation of biogenesis, secretion, and action mechanisms while discussing the current technical limitations. It will also be important to discuss how blood EV concentrations are regulated as if EVs are humoral endocrine machinery.

• 한국미생물·생명공학회지
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• 제44권3호
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• pp.383-390
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• 2016

본 연구는 대식세포에서 LPS를 이용하여 염증 유사 세포 모델을 만들고 염증 유사 대식세포 모델에서 성체줄기세포의 면역 조절 능력을 평가하였다. LPS 자극에 의해 증가된 IL-1β, TNF-α 및 IL-10의 생성은 성체줄기세포를 공배양한 실험군 뿐만 아니라 성체줄기세포를 배양한 상층 배양액을 처리한 실험군에서도 동일한 효과를 나타내었으며, 또한 성체줄기세포 유래 엑소좀을 염증 유사 대식세포 모델에 처리하여 유사한 결과를 관찰하였다. 이 결과는 성체줄기세포 자체의 염증 억제 기능보다는 성체줄기세포 유래 엑소좀을 포함하여 성체줄기세포가 분비하는 bioactive molecules에 의해 세포 간 신호 전달이 이루어지고 있음을 의미하며, 이러한 엑소좀은 염증 관련 질환 분야에 치료적 적용이 가능하고 또한 새로운 염증 치료제 개발의 툴로 사용될 수 있음을 시사한다.

• 생명과학회지
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• 제33권9호
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• pp.754-765
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• 2023

엑소좀은 단백질, mRNA 및 miRNA를 포함하고 모든 유형의 세포에서 분비되는 세포 외 소포의 일종이다. 방출된 엑소좀은 인접하거나 멀리 있는 다른 세포에 의해 선택적으로 흡수되어 그 내용물을 방출하고 표적 세포를 재프로그래밍한다. 엑소좀은 세포에 의해 생성되는 작은 천연 소포이므로 무독성과 비면역원성의 특징이 있는 것으로 받아들여지고 있다. 최근에는 엑소좀이 중추신경계에 대한 약물 전달체로 과학적 관심을 받고 있다. 중추신경계에는 약물의 침투를 어렵게 하는 혈뇌장벽이 있고 이는 퇴행성신경질환의 치료제 개발에 큰 걸림돌이 되어왔다. 그러나 축적된 연구결과들을 볼 때, 엑소좀이 주로 트랜스사이토시스를 통해 혈뇌장벽을 통과할 수 있음이 제시되었다. 이러한 결과를 종합하면, 엑소좀은 혈뇌장벽을 넘어 뇌 실질조직에 약물을 전달할 수 있는 새로운 전달 수단이 될 것으로 기대된다. 또한 세포의 종류와 질병상태에 따라 분비되는 엑소좀의 종류가 다르기 때문에 엑소좀은 중추신경계 질환의 진단을 위한 바이오마커로도 활용될 수 있다. 본 총설 논문에서는 중추신경계 질환에 대한 바이오마커 및 치료 옵션으로서의 임상시험을 포함한 엑소좀에 대한 최근 연구동향을 정리하였다.