Hark Kyun Kim

ABSTRACT Osteoarthritis (OA) is a chronic degenerative disease of articular cartilage that is the most common joint disease worldwide. Mesenchymal stem cells (MSCs) have been the most extensively explored for the treatment of OA. Recently, it has been demonstrated that MSC‐derived extracellular vesicles (EVs) may contribute to the potential mechanisms of MSC‐based therapies. In this study, we investigated the therapeutic potential of human adipose‐derived stem cells EVs (hASC‐EVs) in alleviating OA, along with the mechanism. EVs were isolated from the culture supernatants of hASCs by a multi‐filtration system based on the tangential flow filtration (TFF) system. The isolated EVs were characterised using dynamic light scattering (DLS), transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and flow cytometry analysis. The hASC‐EVs not only promoted the proliferation and migration of human OA chondrocytes, but also maintained the chondrocyte matrix by increasing type Ⅱ collagen synthesis and decreasing MMP‐1, MMP‐3, MMP‐13 and ADAMTS‐5 expression in the presence of IL‐1β in vitro . Intra‐articular injection of hASC‐EVs significantly attenuated OA progression and protected cartilage from degeneration in both the monosodium iodoacetate (MIA) rat and the surgical destabilisation of the medial meniscus (DMM) mouse models. In addition, administration of hASC‐EVs inhibited the infiltration of M1 macrophages into the synovium. Overall results suggest that the hASC‐EVs should be considered as a potential therapeutic approach in the treatment of OA.

Significance Considering that Alzheimer’s disease (AD) is a chronic disease progressing over a long period of time, even a slight increase of BACE1 expression may have a profound effect on Aβ accumulation. We describe a previously unknown mechanism that negatively regulates BACE1 and BACE1-AS expression and demonstrate its pivotal role in the progression of Aβ and Tau pathologies and cognitive impairment in two mouse models of AD. Given the recent failures of the clinical trials using enzymatic inhibitors of BACE1, it is critical to explore alternative approaches such as down-regulating BACE1 and BACE1-AS transcription. Our finding that NRF2 negatively regulates BACE1 and BACE1-AS therefore suggests a potential for disease modification by NRF2-activating phytochemicals or synthetic small molecules in AD.

PURPOSE: A major obstacle in chemotherapy is treatment failure due to anticancer drug resistance. The emergence of acquired resistance results from host factors and genetic or epigenetic changes in the cancer cells. The purpose of this study was to identify differentially expressed genes associated with acquisition of resistance in human gastric cancer cells. EXPERIMENTAL DESIGN: We performed global gene expression analysis in the acquired drug-resistant gastric cancer cell lines to the commonly used drugs 5-fluorouracil, doxorubicin, and cisplatin using Affymetrix HG-U133A microarray. The gene expression patterns of 10 chemoresistant gastric cancer cell lines were compared with those of four parent cell lines using fold-change and Wilcoxon's test for data analysis. RESULTS: We identified over 250 genes differentially expressed in 5-fluorouracil-, cisplatin-, or doxorubicin-resistant gastric cancer cell lines. Our expression analysis also identified eight multidrug resistance candidate genes that were associated with resistance to two or more of the tested chemotherapeutic agents. Among these, midkine (MDK), a heparin-binding growth factor, was overexpressed in all drug-resistant cell lines, strongly suggesting that MDK might contribute to multidrug resistance in gastric cancer cells. CONCLUSIONS: Our investigation provides comprehensive gene information associated with acquired resistance to anticancer drugs in gastric cancer cells and a basis for additional functional studies.

Osteoporosis is one of the most common skeletal disorders caused by the imbalance between bone formation and resorption, resulting in quantitative loss of bone tissue. Since stem cell-derived extracellular vesicles (EVs) are growing attention as novel cell-free therapeutics that have advantages over parental stem cells, the therapeutic effects of EVs from adipose tissue-derived stem cells (ASC-EVs) on osteoporosis pathogenesis were investigated. ASC-EVs were isolated by a multi-filtration system based on the tangential flow filtration (TFF) system and characterized using transmission electron microscopy, dynamic light scattering, zeta potential, flow cytometry, cytokine arrays, and enzyme-linked immunosorbent assay. EVs are rich in growth factors and cytokines related to bone metabolism and mesenchymal stem cell (MSC) migration. In particular, osteoprotegerin (OPG), a natural inhibitor of receptor activator of nuclear factor-κB ligand (RANKL), was highly enriched in ASC-EVs. We found that the intravenous administration of ASC-EVs attenuated bone loss in osteoporosis mice. Also, ASC-EVs significantly inhibited osteoclast differentiation of macrophages and promoted the migration of bone marrow-derived MSCs (BM-MSCs). However, OPG-depleted ASC-EVs did not show anti-osteoclastogenesis effects, demonstrating that OPG is critical for the therapeutic effects of ASC-EVs. Additionally, small RNA sequencing data were analysed to identify miRNA candidates related to anti-osteoporosis effects. miR-21-5p in ASC-EVs inhibited osteoclast differentiation through Acvr2a down-regulation. Also, let-7b-5p in ASC-EVs significantly reduced the expression of genes related to osteoclastogenesis. Finally, ASC-EVs reached the bone tissue after they were injected intravenously, and they remained longer. OPG, miR-21-5p, and let-7b-5p in ASC-EVs inhibit osteoclast differentiation and reduce gene expression related to bone resorption, suggesting that ASC-EVs are highly promising as cell-free therapeutic agents for osteoporosis treatment.

Increased O -GlcNAcylation can confer neuroprotective effects against necroptosis in the context of Alzheimer’s disease.