keyword
https://read.qxmd.com/read/38383524/structural-optimization-of-sirna-conjugates-for-albumin-binding-achieves-effective-mcl1-directed-cancer-therapy
#1
JOURNAL ARTICLE
Ella N Hoogenboezem, Shrusti S Patel, Justin H Lo, Ashley B Cavnar, Lauren M Babb, Nora Francini, Eva F Gbur, Prarthana Patil, Juan M Colazo, Danielle L Michell, Violeta M Sanchez, Joshua T McCune, Jinqi Ma, Carlisle R DeJulius, Linus H Lee, Jonah C Rosch, Ryan M Allen, Larry D Stokes, Jordan L Hill, Kasey C Vickers, Rebecca S Cook, Craig L Duvall
The high potential of siRNAs to silence oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, divalent lipid-conjugated siRNAs are optimized for in situ binding to albumin to improve pharmacokinetics and tumor delivery. Systematic variation of the siRNA conjugate structure reveals that the location of the linker branching site dictates tendency toward albumin association versus self-assembly, while the lipid hydrophobicity and reversibility of albumin binding also contribute to siRNA intracellular delivery...
February 21, 2024: Nature Communications
https://read.qxmd.com/read/38293013/5-fluorouracil-treatment-represses-pseudouridine-containing-small-rna-export-into-extracellular-vesicles
#2
Sherman Qu, Hannah Nelson, Xiao Liu, Elizabeth Semler, Danielle L Michell, Clark Massick, Jeffrey L Franklin, John Karijolich, Alissa M Weaver, Robert J Coffey, Qi Liu, Kasey C Vickers, James G Patton
5-fluorouracil (5-FU) has been used for chemotherapy for colorectal and other cancers for over 50 years. The prevailing view of its mechanism of action is inhibition of thymidine synthase leading to defects in DNA replication and repair. However, 5-FU is also incorporated into RNA causing toxicity due to defects in RNA metabolism, inhibition of pseudouridine modification, and altered ribosome function. Here, we examine the impact of 5-FU on the expression and export of small RNAs (sRNAs) into small extracellular vesicles (sEVs)...
January 16, 2024: bioRxiv
https://read.qxmd.com/read/38111131/the-anti-inflammatory-effect-of-high-density-lipoprotein-is-blunted-by-delivery-of-altered-microrna-cargo-in-rheumatoid-arthritis-patients
#3
JOURNAL ARTICLE
Qiong Wu, Quanhu Sheng, Danielle Michell, Marisol Ramirez-Solano, Olivia Posey, Anastasiia Phothisane, Shahensha Shaik, Kasey C Vickers, Michelle J Ormseth
OBJECTIVE: High-density lipoprotein (HDL) has well-characterized anti-atherogenic cholesterol efflux and antioxidant functions. Another function of HDL uncharacterized in RA is its ability to transport microRNAs (miRNAs) between cells and thus alter cellular function. The study's purpose was to determine if HDL-miRNA cargo is altered and affects inflammation in RA. METHODS: HDL-miRNAs were characterized in 30 RA and 30 control subjects by next generation sequencing and quantitative PCR...
December 18, 2023: Arthritis & Rheumatology
https://read.qxmd.com/read/37931077/loss-of-p73-expression-contributes-to-chronic-obstructive-pulmonary-disease
#4
JOURNAL ARTICLE
Bradley W Richmond, Clayton B Marshall, Jessica B Blackburn, Tiffany S Tufenkjian, Brian D Lehmann, Wei Han, Dawn Newcomb, Sergey S Gutor, Raphael P Hunt, Danielle L Michell, Kasey C Vickers, Vasiliy V Polosukhin, Timothy S Blackwell, Jennifer A Pietenpol
Rationale: Multiciliated cell (MCC) loss and/or dysfunction is common in the small airways of patients with chronic obstructive pulmonary disease (COPD), but it is unclear if this contributes to COPD lung pathology. Objectives: To determine if loss of p73 causes a COPD-like phenotype in mice and explore whether smoking or COPD impact p73 expression. Methods: p73floxE7-E9 mice were crossed with Shh-Cre mice to generate mice lacking MCCs in the airway epithelium. The resulting p73Δairway mice were analyzed using electron microscopy, flow cytometry, morphometry, forced oscillation technique, and single-cell RNA sequencing...
January 15, 2024: American Journal of Respiratory and Critical Care Medicine
https://read.qxmd.com/read/37885043/culture-conditions-greatly-impact-the-levels-of-vesicular-and-extravesicular-ago2-and-rna-in-extracellular-vesicle-preparations
#5
JOURNAL ARTICLE
Lizandra Jimenez, Bahnisikha Barman, Youn Jae Jung, Lauren Cocozza, Evan Krystofiak, Cherie Saffold, Kasey C Vickers, John T Wilson, T Renee Dawson, Alissa M Weaver
Extracellular vesicle (EV)-carried miRNAs can influence gene expression and functional phenotypes in recipient cells. Argonaute 2 (Ago2) is a key miRNA-binding protein that has been identified in EVs and could influence RNA silencing. However, Ago2 is in a non-vesicular form in serum and can be an EV contaminant. In addition, RNA-binding proteins (RBPs), including Ago2, and RNAs are often minor EV components whose sorting into EVs may be regulated by cell signaling state. To determine the conditions that influence detection of RBPs and RNAs in EVs, we evaluated the effect of growth factors, oncogene signaling, serum, and cell density on the vesicular and nonvesicular content of Ago2, other RBPs, and RNA in small EV (SEV) preparations...
November 2023: Journal of Extracellular Vesicles
https://read.qxmd.com/read/37552655/anapole-assisted-low-power-optical-trapping-of-nanoscale-extracellular-vesicles-and-particles
#6
JOURNAL ARTICLE
Ikjun Hong, Chuchuan Hong, Oleg S Tutanov, Clark Massick, Mark Castleberry, Qin Zhang, Dennis K Jeppesen, James N Higginbotham, Jeffrey L Franklin, Kasey Vickers, Robert J Coffey, Justus C Ndukaife
This study addresses the challenge of trapping nanoscale biological particles using optical tweezers without the photothermal heating effect and the limitation presented by the diffraction limit. Optical tweezers are effective for trapping microscopic biological objects but not for nanoscale specimens due to the diffraction limit. To overcome this, we present an approach that uses optical anapole states in all-dielectric nanoantenna systems on distributed Bragg reflector substrates to generate strong optical gradient force and potential on nanoscale biological objects with negligible temperature rise below 1 K...
August 8, 2023: Nano Letters
https://read.qxmd.com/read/37333210/albumin-binding-rnai-conjugate-for-carrier-free-treatment-of-arthritis
#7
Juan M Colazo, Ella N Hoogenboezem, Veeraj Shah, Fang Yu, Justin H Lo, Alexander G Sorets, Nora Francini, Hongsik Cho, Danielle L Michell, Kasey C Vickers, Katherine N Gibson-Corley, Karen A Hasty, Leslie Crofford, Rebecca S Cook, Craig L Duvall
UNLABELLED: Osteoarthritis ( OA ) and rheumatoid arthritis ( RA ) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of OA and RA joints...
June 8, 2023: bioRxiv
https://read.qxmd.com/read/36824780/structural-optimization-of-sirna-conjugates-for-albumin-binding-achieves-effective-mcl1-targeted-cancer-therapy
#8
Ella N Hoogenboezem, Shrusti S Patel, Ashley B Cavnar, Justin H Lo, Lauren M Babb, Nora Francini, Prarthana Patil, Juan M Colazo, Danielle L Michell, Violeta M Sanchez, Joshua T McCune, Jinqi Ma, Carlisle R DeJulius, Linus H Lee, Jonah C Rosch, Ryan M Allen, Larry D Stokes, Jordan L Hill, Kasey C Vickers, Rebecca S Cook, Craig L Duvall
The high potential for therapeutic application of siRNAs to silence traditionally undruggable oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, siRNAs were optimized for in situ binding to albumin through C18 lipid modifications to improve pharmacokinetics and tumor delivery. Systematic variation of siRNA conjugates revealed a lead structure with divalent C 18 lipids each linked through three repeats of hexaethylene glycol connected by phosphorothioate bonds. Importantly, we discovered that locating the branch site of the divalent lipid structure proximally (adjacent to the RNA) rather than at a more distal site (after the linker segment) promotes association with albumin, while minimizing self-assembly and lipoprotein association...
February 15, 2023: bioRxiv
https://read.qxmd.com/read/36626966/high-density-lipoproteins-mediate-small-rna-intercellular-communication-between-dendritic-cells-and-macrophages
#9
JOURNAL ARTICLE
Mark Castleberry, Chase A Raby, Anca Ifrim, Yasuhiro Shibata, Sachi Matsushita, Shinya Ugawa, Yutaka Miura, Atsushi Hori, Takashi Miida, MacRae F Linton, Danielle L Michell, Maki Tsujita, Kasey C Vickers
AIMS: HDL are dynamic transporters of diverse molecular cargo and play critical roles in lipid metabolism and inflammation. We have previously reported that HDL transport both host and non-host sRNA-based qPCR and small RNA (sRNA) sequencing approaches; however, these methods require RNA isolation steps which have potential biases and may not isolate certain forms of RNA molecules from samples. HDL have also been reported to accept functional sRNAs from donor macrophages and deliver them to recipient endothelial cells; however, using PCR to trace HDL-sRNA intercellular communication has major limitations...
January 7, 2023: Journal of Lipid Research
https://read.qxmd.com/read/36496485/electrodeposited-magnetic-nanoporous-membrane-for-high-yield-and-high-throughput-immunocapture-of-extracellular-vesicles-and-lipoproteins
#10
JOURNAL ARTICLE
Chenguang Zhang, Xiaoye Huo, Yini Zhu, James N Higginbotham, Zheng Cao, Xin Lu, Jeffrey L Franklin, Kasey C Vickers, Robert J Coffey, Satyajyoti Senapati, Ceming Wang, Hsueh-Chia Chang
Superparamagnetic nanobeads offer several advantages over microbeads for immunocapture of nanocarriers (extracellular vesicles, lipoproteins, and viruses) in a bioassay: high-yield capture, reduction in incubation time, and higher capture capacity. However, nanobeads are difficult to "pull-down" because their superparamagnetic feature requires high nanoscale magnetic field gradients. Here, an electrodeposited track-etched membrane is shown to produce a unique superparamagnetic nano-edge ring with multiple edges around nanopores...
December 10, 2022: Communications Biology
https://read.qxmd.com/read/36474072/ldl-delivery-of-microbial-small-rnas-drives-atherosclerosis-through-macrophage-tlr8
#11
JOURNAL ARTICLE
Ryan M Allen, Danielle L Michell, Ashley B Cavnar, Wanying Zhu, Neil Makhijani, Danielle M Contreras, Chase A Raby, Elizabeth M Semler, Carlisle DeJulius, Mark Castleberry, Youmin Zhang, Marisol Ramirez-Solano, Shilin Zhao, Craig Duvall, Amanda C Doran, Quanhu Sheng, MacRae F Linton, Kasey C Vickers
Macrophages present a spectrum of phenotypes that mediate both the pathogenesis and resolution of atherosclerotic lesions. Inflammatory macrophage phenotypes are pro-atherogenic, but the stimulatory factors that promote these phenotypes remain incompletely defined. Here we demonstrate that microbial small RNAs (msRNA) are enriched on low-density lipoprotein (LDL) and drive pro-inflammatory macrophage polarization and cytokine secretion via activation of the RNA sensor toll-like receptor 8 (TLR8). Removal of msRNA cargo during LDL re-constitution yields particles that readily promote sterol loading but fail to stimulate inflammatory activation...
December 6, 2022: Nature Cell Biology
https://read.qxmd.com/read/36000433/microrna-expression-levels-change-in-neonatal-patients-during-and-after-exposure-to-cardiopulmonary-bypass
#12
JOURNAL ARTICLE
Lance Hsieh, Lan N Tu, Alison Paquette, Quanhu Sheng, Shilin Zhao, Douglas Bittel, James O'Brien, Kasey Vickers, Peter Pastuszko, Vishal Nigam
Background The systemic inflammation that occurs after exposure to cardiopulmonary bypass (CPB), which is especially severe in neonatal patients, is associated with poorer outcomes and is not well understood. In order to gain deeper insight into how exposure to bypass activates inflammatory responses in circulating leukocytes, we studied changes in microRNA (miRNA) expression during and after exposure to bypass. miRNAs are small noncoding RNAs that have important roles in modulating protein levels and function of cells...
September 6, 2022: Journal of the American Heart Association
https://read.qxmd.com/read/35958027/phase-2-of-extracellular-rna-communication-consortium-charts-next-generation-approaches-for-extracellular-rna-research
#13
REVIEW
Bogdan Mateescu, Jennifer C Jones, Roger P Alexander, Eric Alsop, Ji Yeong An, Mohammad Asghari, Alex Boomgarden, Laura Bouchareychas, Alfonso Cayota, Hsueh-Chia Chang, Al Charest, Daniel T Chiu, Robert J Coffey, Saumya Das, Peter De Hoff, Andrew deMello, Crislyn D'Souza-Schorey, David Elashoff, Kiarash R Eliato, Jeffrey L Franklin, David J Galas, Mark B Gerstein, Ionita H Ghiran, David B Go, Stephen Gould, Tristan R Grogan, James N Higginbotham, Florian Hladik, Tony Jun Huang, Xiaoye Huo, Elizabeth Hutchins, Dennis K Jeppesen, Tijana Jovanovic-Talisman, Betty Y S Kim, Sung Kim, Kyoung-Mee Kim, Yong Kim, Robert R Kitchen, Vaughan Knouse, Emily L LaPlante, Carlito B Lebrilla, L James Lee, Kathleen M Lennon, Guoping Li, Feng Li, Tieyi Li, Tao Liu, Zirui Liu, Adam L Maddox, Kyle McCarthy, Bessie Meechoovet, Nalin Maniya, Yingchao Meng, Aleksandar Milosavljevic, Byoung-Hoon Min, Amber Morey, Martin Ng, John Nolan, Getulio P De Oliveira Junior, Michael E Paulaitis, Tuan Anh Phu, Robert L Raffai, Eduardo Reátegui, Matthew E Roth, David A Routenberg, Joel Rozowsky, Joseph Rufo, Satyajyoti Senapati, Sigal Shachar, Himani Sharma, Anil K Sood, Stavros Stavrakis, Alessandra Stürchler, Muneesh Tewari, Juan P Tosar, Alexander K Tucker-Schwartz, Andrey Turchinovich, Nedyalka Valkov, Kendall Van Keuren-Jensen, Kasey C Vickers, Lucia Vojtech, Wyatt N Vreeland, Ceming Wang, Kai Wang, ZeYu Wang, Joshua A Welsh, Kenneth W Witwer, David T W Wong, Jianping Xia, Ya-Hong Xie, Kaichun Yang, Mikołaj P Zaborowski, Chenguang Zhang, Qin Zhang, Angela M Zivkovic, Louise C Laurent
The extracellular RNA communication consortium (ERCC) is an NIH-funded program aiming to promote the development of new technologies, resources, and knowledge about exRNAs and their carriers. After Phase 1 (2013-2018), Phase 2 of the program (ERCC2, 2019-2023) aims to fill critical gaps in knowledge and technology to enable rigorous and reproducible methods for separation and characterization of both bulk populations of exRNA carriers and single EVs. ERCC2 investigators are also developing new bioinformatic pipelines to promote data integration through the exRNA atlas database...
August 19, 2022: IScience
https://read.qxmd.com/read/35447119/elucidation-of-physico-chemical-principles-of-high-density-lipoprotein-small-rna-binding-interactions
#14
JOURNAL ARTICLE
Danielle L Michell, Ryan M Allen, Ashley B Cavnar, Danielle M Contreras, Minzhi Yu, Elizabeth M Semler, Clark Massick, Chase A Raby, Mark Castleberry, Marisol A Ramirez, Wanying Zhu, Linda May-Zhang, Anca Ifrim, John Jeffrey Carr, James G Terry, Anna Schwendeman, Sean S Davies, Quanhu Sheng, MacRae F Linton, Kasey C Vickers
Extracellular small RNAs (sRNA) are abundant in many biofluids, but little is known about their mechanisms of transport and stability in RNase-rich environments. We previously reported that high-density lipoproteins (HDL) in mice were enriched with multiple classes of sRNAs derived from the endogenous transcriptome, but also from exogenous organisms. Here, we show that human HDL transports tRNA-derived sRNAs (tDRs) from host and non-host species, the profiles of which were found to be altered in human atherosclerosis...
April 18, 2022: Journal of Biological Chemistry
https://read.qxmd.com/read/35421371/vap-a-and-its-binding-partner-cert-drive-biogenesis-of-rna-containing-extracellular-vesicles-at-er-membrane-contact-sites
#15
JOURNAL ARTICLE
Bahnisikha Barman, Bong Hwan Sung, Evan Krystofiak, Jie Ping, Marisol Ramirez, Bryan Millis, Ryan Allen, Nripesh Prasad, Sergei Chetyrkin, M Wade Calcutt, Kasey Vickers, James G Patton, Qi Liu, Alissa M Weaver
RNA transfer via extracellular vesicles (EVs) influences cell phenotypes; however, lack of information regarding biogenesis of RNA-containing EVs has limited progress in the field. Here, we identify endoplasmic reticulum membrane contact sites (ER MCSs) as platforms for the generation of RNA-containing EVs. We identify a subpopulation of small EVs that is highly enriched in RNA and regulated by the ER MCS linker protein VAP-A. Functionally, VAP-A-regulated EVs are critical for miR-100 transfer between cells and in vivo tumor formation...
April 25, 2022: Developmental Cell
https://read.qxmd.com/read/34934837/depletion-of-mettl3-alters-cellular-and-extracellular-levels-of-mirnas-containing-m-6-a-consensus-sequences
#16
JOURNAL ARTICLE
Jessica J Abner, Jeffrey L Franklin, Margaret A Clement, Scott A Hinger, Ryan M Allen, Xiao Liu, Stefanie Kellner, Junzhou Wu, John Karijolich, Qi Liu, Kasey C Vickers, Peter Dedon, Alissa M Weaver, Robert J Coffey, James G Patton
Extracellular vesicles (EVs) are capable of transferring cargo from donor to recipient cells, but precisely how cargo content is regulated for export is mostly unknown. For miRNA cargo, we previously showed that when compared to isogenic colorectal cancer (CRC) cells expressing wild-type KRAS, a distinct subset of miRNAs are differentially enriched in EVs from KRAS mutant active CRC cells, with miR-100 being one of the most enriched. The mechanisms that could explain how miR-100 and other miRNAs are differentially exported into EVs have not been fully elucidated...
December 2021: Heliyon
https://read.qxmd.com/read/34360965/high-density-lipoproteins-in-kidney-disease
#17
REVIEW
Valentina Kon, Hai-Chun Yang, Loren E Smith, Kasey C Vickers, MacRae F Linton
Decades of epidemiological studies have established the strong inverse relationship between high-density lipoprotein (HDL)-cholesterol concentration and cardiovascular disease. Recent evidence suggests that HDL particle functions, including anti-inflammatory and antioxidant functions, and cholesterol efflux capacity may be more strongly associated with cardiovascular disease protection than HDL cholesterol concentration. These HDL functions are also relevant in non-cardiovascular diseases, including acute and chronic kidney disease...
July 30, 2021: International Journal of Molecular Sciences
https://read.qxmd.com/read/34331945/myeloperoxidase-induced-modification-of-hdl-by-isolevuglandins-inhibits-paraoxonase-1-activity
#18
JOURNAL ARTICLE
Geetika Aggarwal, Linda S May-Zhang, Valery Yermalitsky, Sergey Dikalov, Maxim A Voynov, Venkataraman Amaranth, Valentina Kon, MacRae F Linton, Kasey C Vickers, Sean S Davies
Reduced activity of paraoxonase 1 (PON1), a high-density lipoprotein (HDL)-associated enzyme, has been implicated in the development of atherosclerosis. Post-translational modifications of PON1 may represent important mechanisms leading to reduced PON1 activity. Under atherosclerotic conditions, myeloperoxidase (MPO) is known to associate with HDL. MPO generates the oxidants hypochlorous acid and nitrogen dioxide, which can lead to post-translational modification of PON1, including tyrosine modifications that inhibit PON1 activity...
July 28, 2021: Journal of Biological Chemistry
https://read.qxmd.com/read/34233930/profile-of-podocyte-translatome-during-development-of-type-2-and-type-1-diabetic-nephropathy-using-podocyte-specific-trap-mrna-rna-seq
#19
JOURNAL ARTICLE
Yinqiu Wang, Aolei Niu, Yu Pan, Shirong Cao, Andrew S Terker, Suwan Wang, Xiaofeng Fan, Cynthia L Toth, Marisol A Ramirez Solano, Danielle L Michell, Danielle Contreras, Ryan M Allen, Wanying Zhu, Quanhu Sheng, Agnes B Fogo, Kasey C Vickers, Ming-Zhi Zhang, Raymond C Harris
Podocyte injury is important in development of diabetic nephropathy (DN). Although several studies have reported single-cell-based RNA sequencing (RNA-seq) of podocytes in type 1 DN (T1DN), the podocyte translating mRNA profile in type 2 DN (T2DN) has not previously been compared with that of T1DN. We analyzed the podocyte translatome in T2DN in podocin-Cre; Rosa26fsTRAP ; eNOS-/- ; db/db mice and compared it with that of streptozotocin-induced T1DN in podocin-Cre; Rosa26fsTRAP ; eNOS-/- mice using translating ribosome affinity purification (TRAP) and RNA-seq...
October 2021: Diabetes
https://read.qxmd.com/read/34102217/kidney-injury-mediated-disruption-of-intestinal-lymphatics-involves-dicarbonyl-modified-lipoproteins
#20
JOURNAL ARTICLE
Jianyong Zhong, Hai-Chun Yang, Valery Yermalitsky, Elaine L Shelton, Tadashi Otsuka, Carrie B Wiese, Linda S May-Zhang, Babak Banan, Naji Abumrad, Jiansheng Huang, Ashley B Cavnar, Annet Kirabo, Patricia G Yancey, Agnes B Fogo, Kasey C Vickers, MacRae F Linton, Sean S Davies, Valentina Kon
Kidney disease affects intestinal structure and function. Although intestinal lymphatics are central in absorption and remodeling of dietary and synthesized lipids/lipoproteins, little is known about how kidney injury impacts the intestinal lymphatic network, or lipoproteins transported therein. To study this, we used puromycin aminoglycoside-treated rats and NEP25 transgenic mice to show that proteinuric injury expanded the intestinal lymphatic network, activated lymphatic endothelial cells and increased mesenteric lymph flow...
September 2021: Kidney International
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