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排序方式: 共有4041条查询结果,搜索用时 31 毫秒
31.
Mario Gimona Maria Felice Brizzi Andre Boon Hwa Choo Massimo Dominici Sean M. Davidson Johannes Grillari Dirk M. Hermann Andrew F. Hill Dominique de Kleijn Ruenn Chai Lai Charles P. Lai Rebecca Lim Marta Monguió-Tortajada Maurizio Muraca Takahiro Ochiya Luis A. Ortiz Wei Seong Toh Yong Weon Yi Sai Kiang Lim 《Cytotherapy》2021,23(5):373-380
Mesenchymal stromal/stem cells (MSCs) have been widely tested against many diseases, with more than 1000 registered clinical trials worldwide. Despite many setbacks, MSCs have been approved for the treatment of graft-versus-host disease and Crohn disease. However, it is increasingly clear that MSCs exert their therapeutic functions in a paracrine manner through the secretion of small extracellular vesicles (sEVs) of 50–200 nm in diameter. Unlike living cells that can persist long-term, sEVs are non-living and non-replicative and have a transient presence in the body. Their small size also renders sEV preparations highly amenable to sterilization by filtration. Together, acellular MSC-sEV preparations are potentially safer and easier to translate into the clinic than cellular MSC products. Nevertheless, there are inherent challenges in the development of MSC-sEV drug products. MSC-sEVs are products of living cells, and living cells are sensitive to changes in the external microenvironment. Consequently, quality control metrics to measure key identity and potency features of MSC-sEV preparations have to be specified during development of MSC-sEV therapeutics. The authors have previously described quantifiable assays to define the identity of MSC-sEVs. Here the authors discuss requirements for prospective potency assays to predict the therapeutic effectiveness of the drug substance in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Although potency assays should ideally reflect the mechanism of action (MoA), this is challenging because the MoA for the reported efficacy of MSC-sEV preparations against multiple diseases of diverse underlying pathology is likely to be complex and different for each disease and difficult to fully elucidate. Nevertheless, robust potency assays could be developed by identifying the EV attribute most relevant to the intended biological activity in EV-mediated therapy and quantifying the EV attribute. Specifically, the authors highlight challenges and mitigation measures to enhance the manufacture of consistent and reproducibly potent sEV preparations, to identify and select the appropriate EV attribute for potency assays despite a complex “work-in-progress” MoA and to develop assays likely to be compliant with regulatory guidance for assay validation. 相似文献
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33.
Yulia Zilber Sima Babayeva Jung Hwa Seo Jia Jia Liu Steven Mootin Elena Torban 《Molecular biology of the cell》2013,24(5):555-565
The planar cell polarity (PCP) pathway controls multiple cellular processes during vertebrate development. Recently the PCP pathway was implicated in ciliogenesis and in ciliary function. The primary cilium is an apically projecting solitary organelle that is generated via polarized intracellular trafficking. Because it acts as a signaling nexus, defects in ciliogenesis or cilial function cause multiple congenital anomalies in vertebrates. Loss of the PCP effector Fuzzy affects PCP signaling and formation of primary cilia; however, the mechanisms underlying these processes are largely unknown. Here we report that Fuzzy localizes to the basal body and ciliary axoneme and is essential for ciliogenesis by delivering Rab8 to the basal body and primary cilium. Fuzzy appears to control subcellular localization of the core PCP protein Dishevelled, recruiting it to Rab8-positive vesicles and to the basal body and cilium. We show that loss of Fuzzy results in inhibition of PCP signaling and hyperactivation of the canonical WNT pathway. We propose a mechanism by which Fuzzy participates in ciliogenesis and affects both canonical WNT and PCP signaling. 相似文献
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35.
Min-Young Song Chi-Yeol Kim Muho Han Hak-Seung Ryu Sang-Kyu Lee Li Sun Zuhua He Young-Su Seo Patrick Canal Pamela C. Ronald Jong-Seong Jeon 《Molecules and cells》2013,35(4):327-334
The required for Mla12 resistance (RAR1) protein is essential for the plant immune response. In rice, a model monocot species, the function of Oryza sativa RAR1 (OsRAR1) has been little explored. In our current study, we characterized the response of a rice osrar1 T-DNA insertion mutant to infection by Magnaporthe oryzae, the causal agent of rice blast disease. osrar1 mutants displayed reduced resistance compared with wild type rice when inoculated with the normally virulent M. oryzae isolate PO6-6, indicating that OsRAR1 is required for an immune response to this pathogen. We also investigated the function of OsRAR1 in the resistance mechanism mediated by the immune receptor genes Pib and Pi5 that encode nucleotide binding-leucine rich repeat (NB-LRR) proteins. We inoculated progeny from Pib/osrar1 and Pi5/osrar1 heterozygous plants with the avirulent M. oryzae isolates, race 007 and PO6-6, respectively. We found that only Pib-mediated resistance was compromised by the osrar1 mutation and that the introduction of the OsRAR1 cDNA into Pib/osrar1 rescued Pib-mediated resistance. These results indicate that OsRAR1 is required for Pib-mediated resistance but not Pi5-mediated resistance to M. oryzae. 相似文献
36.
Drug repositioning can identify new therapeutic applications for existing drugs, thus mitigating high R&D costs. The Protein kinase 2 (CK2) inhibitor CX-4945 regulates human cancer cell survival and angiogenesis. Here we found that CX-4945 significantly inhibited the RANKL-induced osteoclast differentiation, but enhanced the BMP2-induced osteoblast differentiation in a cell culture model. CX-4945 inhibited the RANKL-induced activation of TRAP and NFATc1 expression accompanied with suppression of Akt phosphorylation, but, in contrast, it enhanced the BMP2-mediated ALP induction and MAPK ERK1/2 phosphorylation. CX-4945 is thus a novel drug candidate for bone-related disorders such as osteoporosis. 相似文献
37.
Insu Jeon Ji-Yong Bae Jin-Hong Park Taek-Rim Yoon Mitsugu Todo Masaaki Mawatari 《Computer methods in biomechanics and biomedical engineering》2013,16(1):103-112
To investigate the biomechanical effect of collars, finite element analyses are carried out through two hip joints that are implanted using collared and collarless stems, respectively, and an intact hip joint model. For the analyses, the sacrum, coxal bone, and the cancellous and cortical bones of a femur are modelled using finite elements based on X-ray computed tomographic images taken from a 27-year-old woman. From the results, it is found that a collar with perfect calcar contact prevents stem subsidence and decreases the proximal–lateral gap and the lateral stem tilting. Therefore, it can impart reasonable biomechanical stability for total hip arthroplasty. However, its low load transmission ability and increased stem tilting effect due to the imperfect contact between the collar and the calcar are found to be serious problems that need to be solved. Results of clinical follow-up are presented for supporting the computational results. 相似文献
38.
Jin Sil Chung Seung Baek Lee Seon Ho Park Sung Tae Kang Ah Ram Na Tong-Shin Chang 《Free radical research》2013,47(8):729-737
Reactive oxygen species (ROS) steady-state levels are required for entry into the S phase of the cell cycle in normal cells, as well as in tumour cells. However, the contribution of mitochondrial ROS to normal cell proliferation has not been well investigated thus far. A previous report showed that Romo1 was responsible for the high ROS levels in tumour cells. Here, we show that endogenous ROS generated by Romo1 are indispensable for cell cycle transition from G1 to S phase in normal WI-38 human lung fibroblasts. The ROS level in these cells was down-regulated by Romo1 knockdown, resulting in cell cycle arrest in the G1 phase. This arrest was associated with an increase in the level of p27Kip1. These results demonstrate that mitochondrial ROS generated by Romo1 expression is required for normal cell proliferation and it is suggested that Romo1 plays an important role in redox signalling during normal cell proliferation. 相似文献
39.
Jae-Jin Lee Hyun Ji Lee Gi Seon Jang Ja Myoung Yu Ji Yoon Cha Su Jeong Kim Eun Bit Lee Myung Kyum Kim 《Journal of microbiology (Seoul, Korea)》2013,51(3):305-311
Strain DY59T, a Gram-positive non-motile bacterium, was isolated from soil in South Korea, and was characterized to determine its taxonomic position. Phylogenetic analysis based on the 16S rRNA gene sequence of strain DY59T revealed that the strain DY59T belonged to the family Deinococcaceae in the class Deinococci. The highest degree of sequence similarities of strain DY59T were found with Deinococcus radiopugnans KACC 11999T (99.0%), Deinococcus marmoris KACC 12218T (97.9%), Deinococcus saxicola KACC 12240T (97.0%), Deinococcus aerolatus KACC 12745T (96.2%), and Deinococcus frigens KACC 12220T (96.1%). Chemotaxonomic data revealed that the predominant fatty acids were iso-C15:0 (19.0%), C16:1 ω7c (17.7%), C15:1 ω6c (12.6%), iso-C17:0 (10.3%), and iso-C17:1 ω9c (10.3%). A complex polar lipid profile consisted of a major unknown phosphoglycolipid. The predominant respiratory quinone is MK-8. The cell wall peptidoglycan contained D-alanine, L-glutamic acid, glycine, and L-ornithine (di-amino acid). The novel strain showed resistance to gamma radiation, with a D10 value (i.e. the dose required to reduce the bacterial population by 10-fold) in excess of 5 kGy. Based on the phylogenetic, chemotaxonomic, and phenotypic data, strain DY59T (=KCTC 33033T =JCM 18581T) should be classified as a type strain of a novel species, for which the name Deinococcus swuensis sp. nov. is proposed. 相似文献
40.
Muhammad Yasir Haji Khan Syed Sikander Azam Amar Telke Seon Won Kim Young Ryun Chung 《Journal of microbiology (Seoul, Korea)》2013,51(3):329-335
In the vermicomposting of paper mill sludge, the activity of earthworms is very dependent on dietetic polysaccharides including cellulose as energy sources. Most of these polymers are degraded by the host microbiota and considered potentially important source for cellulolytic enzymes. In the present study, a metagenomic library was constructed from vermicompost (VC) prepared with paper mill sludge and dairy sludge (fresh sludge, FS) and functionally screened for cellulolytic activities. Eighteen cellulase expressing clones were isolated from about 89,000 fosmid clones libraries. A short fragment library was constructed from the most active positive clone (cMGL504) and one open reading frame (ORF) of 1,092 bp encoding an endo-β-1,4-glucanase was indentified which showed 88% similarity with Cellvibrio mixtus cellulase A gene. The endo-β-1,4-glucanase cmgl504 gene was overexpressed in Escherichia coli. The purified recombinant cmgl504 cellulase displayed activities at a broad range of temperature (25–55°C) and pH (5.5–8.5). The enzyme degraded carboxymethyl cellulose (CMC) with 15.4 U, while having low activity against avicel. No detectable activity was found for xylan and laminarin. The enzyme activity was stimulated by potassium chloride. The deduced protein and three-dimensional structure of metagenome-derived cellulase cmgl504 possessed all features, including general architecture, signature motifs, and N-terminal signal peptide, followed by the catalytic domain of cellulase belonging to glycosyl hydrolase family 5 (GHF5). The cellulases cloned in this work may play important roles in the degradation of celluloses in vermicomposting process and could be exploited for industrial application in future. 相似文献