Cellular and Molecular Life Sciences, Journal Year: 2022, Volume and Issue: 79(3)
Published: Feb. 21, 2022
Language: Английский
Molecular Therapy, Journal Year: 2021, Volume and Issue: 29(5), P. 1683 - 1702
Published: Jan. 21, 2021
Circular RNAs (circRNAs) are with a unique circular structure that is generated from back-splicing processes. These molecules were discovered more than 40 years ago but failed to raise scientific interest until lately. Increasing studies have found these might not just be byproducts of the splicing process possess important regulatory functions through different cellular events. Most currently being studied in field cancer, and many them been confirmed involved tumorigenesis. However, implicated developmental stages diseases other cancer. In this review, we focus on discussing role non-cancer diseases, especially cardiovascular diseases. Following summary life cycle circRNAs, provide input studying circRNA-protein interactions based our experience, which modulate protein translocation. Furthermore, outline potential circRNAs potent biomarkers, effective therapeutic targets, treatments as well fields. Viroids first pathogens. Sanger et al.1Sanger H.L. Klotz G. Riesner D. Gross H.J. Kleinschmidt A.K. single-stranded covalently closed RNA existing highly base-paired rod-like structures.Proc. Natl. Acad. Sci. USA. 1976; 73: 3852-3856Crossref PubMed Scopus (1057) Google Scholar described viroids 1976 "single-stranded molecules." this, another study conducted by Hsu Coca-Prados2Hsu M.T. Coca-Prados M. Electron microscopic evidence for form cytoplasm eukaryotic cells.Nature. 1979; 280: 339-340Crossref (463) 1979 some no free flanking ends. They raised possibility circularity dependent any interactions. During period time, follow up unexpected findings due an explosion linear RNA, after polymerase chain reaction was invented 1985. There late 1990s transcript products non-canonical splicing. reported deletion colon cancer gene3Nigro J.M. Cho K.R. Fearon E.R. Kern S.E. Ruppert Oliner J.D. Kinzler K.W. Vogelstein B. Scrambled exons.Cell. 1991; 64: 607-613Abstract Full Text PDF (616) human EST-1 gene,4Cocquerelle C. Daubersies P. Majérus M.A. Kerckaert J.P. Bailleul Splicing inverted order exons occurs proximal large introns.EMBO J. 1992; 11: 1095-1098Crossref their isoforms. Later, few proposed biogenesis mechanisms molecules. A well-known hypothesis Dubin al.5Dubin R.A. Kazmi Ostrer H. Inverted repeats necessary circularization mouse testis Sry transcript.Gene. 1995; 167: 245-248Crossref (99) circRNA sry complementary intronic sequences drive circularization. Another Pasman al.6Pasman Z. Been M.D. Garcia-Blanco Exon mammalian nuclear extracts.RNA. 1996; 2: 603-610PubMed could produced extracts. mostly located expressed stage tissue-specific manner. Up beginning 21st century, number increased, they still sporadic. People classified non-linear mRNAs,7Dixon R.J. Eperon I.C. Hall L. Samani N.J. genome-wide survey demonstrates widespread mRNA multiple species.Nucleic Acids Res. 2005; 33: 5904-5913Crossref (30) scrambled exons, or exon shuffling.8Al-Balool H.H. Weber Liu Y. Wade Guleria K. Nam P.L. Clayton Rowe W. Coxhead Irving al.Post-transcriptional shuffling events humans can evolutionarily conserved abundant.Genome 2011; 21: 1788-1799Crossref (34) generally regarded errors rare held little significance. Although presence documented decades ago, very about understood past decade. Starting 2010, advancements RNA-sequencing technologies along buildup bioinformatics computational pipelines allowed research explode. Several hundreds thousands conserved.9Salzman Gawad Wang Lacayo N. Brown P.O. predominant isoform genes diverse cell types.PLoS ONE. 2012; 7: e30733Crossref (1377) Scholar,10Hansen T.B. Jensen T.I. Clausen B.H. Bramsen J.B. Finsen Damgaard C.K. Kjems Natural circles function efficient microRNA sponges.Nature. 2013; 495: 384-388Crossref (3970) addition discovering new products, revised techniques specific detection without overlapping products. methods include RNase R treatment samples before sequencing, digests affecting resulting enrichment compared RNAs. Since 2017, databases annotation quantification established developed over time. On top powerful techniques, novel verification validation also developed.11Jeck W.R. Sharpless N.E. Detecting characterizing RNAs.Nat. Biotechnol. 2014; 32: 453-461Crossref (1368) adapted techniques. quantitative reverse transcriptase PCR, northern blot, and, later on, PCRs such digital PCR developed. made it possible wet laboratory scientists validate data dry laboratories. identification including vector expression plasmids siRNA silencing used overexpress knock down respectively, functions. situ hybridization pull-down assays underlying molecular circRNAs. With advent all able expand. More contributed conclusion simply actually hold critical physiological pathological during biological brief update We discuss localization translocation then bring insights into circRNA-based diagnostic strategies extensively conserved, stable, tissue-specific, subcellular location- stage-specific. direct where 3′ terminal directly joined 5′ precursor thereby proceed structure. This driven sequence (Figure 1A) RNA-binding (RBP) 1B). lariat-mediated model cut off forms lariat structure, further spliced 1C).12Kristensen L.S. Andersen M.S. Stagsted L.V.W. Ebbesen K.K. Hansen The biogenesis, biology characterization Rev. Genet. 2019; 20: 675-691Crossref (841) DDX39A DDX39B proteins export formed nucleus 1D). While usually transports short assists forming longer ones.13Huang Liang Tatomer D.C. Wilusz J.E. length-dependent pathway controls RNAs.Genes Dev. 2018; 639-644Crossref (116) Formed ordinarily stable owing exclusive defends cleavage exonuclease. undergo degradation. (A) (ICS)-driven model, intron regions both sides contain sequences, paired tightly connected promote (B) (RBP)-driven under bridging action RBP, sites at ends (C) lariat-driven back-splicing. (D) transport mature cytoplasm. (E–H) degradation (E) YTHDF2 recognizes m6A modification site circRNA. At same HRSP12 bridge P/MRP complex, initiating via P/MRP. (F) MicroRNA miR-671 mediates binding CDR1as AGO2 triggers regulated PKR activation. (G) Pathological exogenous double-stranded activate L cells degrade (H) complex UPF1 G3BP1 mediate (I) gene transcription, block genomic DNA, (J) serve miRNA decoy, inhibiting miRNAs. (K) inhibit activity functional domain. (L) combine complexes change activity. (M) translated polypeptides proteins. (N) Exosomes extracellular vesicles wrap secrete out cell. (O) Under certain conditions, take exosomes vesicles, intake recipient cells. Due cannot eliminated conventional pathways, half-life RNA. degraded, although fully understood. Theoretically, even though protects exonuclease cleavage, decay initiated endonucleases completed cascade exonucleases endonucleases. recent indicated N6-methylation adenosine (m6A) recognized HRSP12, reader protein, interact endonuclease trigger degradation14Park O.H. Ha Lee Boo S.H. Kwon D.H. Song H.K. Kim Y.K. Endoribonucleolytic m6A-containing complex.Mol. Cell. 74: 494-507.e8Abstract (143) 1E). mediated synthetic hairpin (shRNAs)/small interfering (siRNAs) conventionalmethod only example naturally occurring small RNA-mediated involves miR-671, has high complementarity induces AGO2-mediated degradation15Hansen Wiklund E.D. Villadsen S.B. Statham A.L. Clark S.J. miRNA-dependent involving Ago2-mediated antisense RNA.EMBO 30: 4414-4422Crossref (602) 1F). poly(I:C) stimulation encephalomyocarditis virus (EMCV) infection introduces (dsRNA) HeLa activates endoribonuclease L16Liu C.X. Li X. Nan F. Jiang S. Gao Guo S.K. Xue Cui Dong Ding al.Structure regulate activation innate immunity.Cell. 177: 865-880.e21Abstract (213) 1G). addition, there spontaneous peripheral blood mononuclear (PBMCs) derived patients systemic lupus erythematosus (SLE).16Liu Such L-mediated requires kinase (PKR) formation intra-dsRNA duplexes, activated cause global For secondary structures, structured ATP-dependent helicase upstream frameshift 1 (UPF1) G3BP1, subsequently induce degradation17Fischer J.W. Busa V.F. Shao Leung A.K.L. Structure-mediated G3BP1.Mol. 2020; 78: 70-84.e6Abstract (43) 1H). inside cells, exocytosis endocytosis occur discharge exosomes18Li Zheng Q. Bao Zhao Chen Gu He Huang enriched exosomes: promising biomarker diagnosis.Cell 2015; 25: 981-984Crossref (1107) Scholar,19Wang Ma Sun T. Zhou Wu al.Exosomal circRNAs: effect application diseases.Mol. Cancer. 18: 116Crossref (63) (Figures 1N 1O). shown present exosomes.19Wang Scholar,20Preußer Hung L.H. Schneider Schreiner Hardt Moebus A. Santoso Bindereif Selective release platelet-derived vesicles.J. Extracell. Vesicles. 1424473Crossref (98) cases, levels far those cells.18Li Scholar,21Dou Cha D.J. Franklin J.L. Higginbotham J.N. Jeppesen D.K. Weaver A.M. Prasad Levy Coffey Patton J.G. Zhang down-regulated KRAS mutant transferred exosomes.Sci. Rep. 2016; 6: 37982Crossref (198) Exosomal bind become cell-to-cell communication.22Bao Lyu expands its territory.Mol. Oncol. 3: e1084443Crossref (28) sum, lot remains unknown mediation signal communication, awaits addressed future investigations. mechanisms: regulating transcription 1I), acting (miRNA) sponges 1J), activities scaffolding 1K 1L), encoding 1M). Beyond fields, reviewed well.23Lim Lavenniah Foo R.S. Circles heart system.Cardiovasc. 116: 269-278PubMed Scholar, 24Aufiero Reckman Y.J. Pinto Y.M. Creemers E.E. open chapter biology.Nat. Cardiol. 16: 503-514Crossref (125) 25Lu Thum RNA-based disease.Nat. 661-674Crossref (86) 26Gomes C.P.C. Schroen Kuster G.M. Robinson E.L. Ford Squire I.B. Heymans Martelli Emanueli Devaux EU-CardioRNA COST Action (CA17129)Regulatory failure.Circulation. 141: 313-328Crossref (45) classify interesting developments 2). diagram shows relevant system. left column pink specifies dysfunction interest. middle orange indicates lead sponge mechanism. right green protein-binding most abundant cardiomyocytes circSLC8A1, plays myocardial hypertrophy caused pressure overload27Lim Aliwarga E. Luu T.D.A. Y.P. Ng S.L. Annadoray Sian Ackers-Johnson Targeting circSlc8a1 attenuates overload induced hypertrophy.Cardiovasc. 115: 1998-2007Crossref (47) Scholar,28Chen L.L. expanding Mol. Cell Biol. 475-490Crossref (157) damage ischemia-reperfusion29Li Tariq Chang Xu Hou ncx1 ischemic injury targeting miR-133a-3p.Theranostics. 8: 5855-5869Crossref (108) sponging miR-133a. angiotensin II-induced cardiac circRNA_000203 upregulated acts miR-26b-5p miR-140-3p, leading increased Gata4 aggravated hypertrophy.30Li Fang X.H. Zhu Yang Pan R. Yuan Zeng Z.Z. al.Circular aggravates suppressing miR-140-3p Gata4.Cardiovasc. 1323-1334Crossref (12) showed calcific aortic valve disease (CAVD), circRIC3 significantly upregulated, osteogenic trans-differentiation valvular interstitial circRIC3/miR-204-5p/DPP4 pathway, indicator accelerated calcification. It demonstrated melatonin inhibits expression, reducing calcification.31Wang Han Cao Melatonin ameliorates calcification regulation CircRIC3/miR-204-5p/DPP4 signaling cells.J. Pineal 69: e12666Crossref (3) Similarly, vascular smooth muscle overexpression circLRP6 promotes atherosclerosis development miR-145.32Hall I.F. Climent Quintavalle Farina F.M. Schorn Zani Carullo Kunderfranco Civilini Condorelli Elia circ_Lrp6, miRNA-145 function.Circ. 124: 498-510Crossref (72) Scholar,33Heumüller A.W. Dimmeler control functions.Circ. 456-458Crossref (7) muscle, circCHFR migration proliferation miR-370/FOXO1/cyclin D1 pathway;34Yang facilitates pathway.Mol. Ther. Nucleic Acids. 434-441Abstract (0) meanwhile, circNRG-1 apoptosis miR-193b-5p/NRG-1.35Sun Yue Bi Angiotensin II circNRG-1/miR-193b-5p/NRG-1 axis.Cell Death Dis. 10: 362Crossref (15) Not exert miRNA, activities. doxorubicin (Dox)-induced cardiotoxicity, miR-31-5p suppresses Quaking (QKI), RBP known influence production. As result, circPAN3 synthesis suppressed, leads cardiomyocyte apoptosis.36Ji MicroRNA-31-5p doxorubicin-induced cardiotoxicity quaking Pan3.J. 140: 56-67Abstract Besides classic mechanism, play roles modes action. cardiomyocytes, circFoxo3 higher older tissues younger tissues.37Du W.W. Z.K. Foster F.S. B.B. Foxo3 senescence modulating factors associated stress responses.Eur. Heart 2017; 38: 1402-1412Crossref interacts ID-1 E2F1, FAK, HIF-1α, anti-senescence anti-stress proteins, preventing transfer mitochondria, blocks downstream Dox-induced cardiomyopathy, cardiomyopathy.37Du super-enhancer-regulated circNfix adult hearts neonatal hearts. regulates Gsk3β miR-214, binds Y-box (Ybx1) E3 ubiquitin ligase (Nedd4l) interaction between Ybx1 result two action, suppressed. led promotion angiogenesis, reduced dysfunction, protected infarction (MI).38Huang Si Wei Liao al.Loss Nfix regeneration mice.Circulation. 139: 2857-2876Crossref (113) circFndc3b, whose decreased MI, similar function. Upregulation circFndc3b results enhancement reduction infarct size, improvement post-MI fused sarcoma (FUS) endothelial growth factor-A (VEGF-A).39Garikipati V.N.S. Verma Cheng Truongcao M.M. Cimini Benedict modulates repair FUS/VEGF-A axis.Nat. Commun. 4317Crossref (117) Lastly, autophagy-related (ACR) Dnmt3b, methylation Pink1 gene, promoting expression. phosphorylation FAM65B, death autophagy heart, ultimately protecting reperfusion injury.40Zhou L.Y. Zhai An Y.H. R.C. C.Y. al.The ACR ischemia/reperfusion modulation Pink1/FAM65B pathway.Cell Differ. 26: 1299-1315Crossref (89) van Heesch al.'s41van Witte Schneider-Lunitz V. Schulz J.F. Adami Faber A.B. Kirchner Maatz Blachut Sandmann C.L. translational landscape heart.Cell. 178: 242-260.e29Abstract (153) breakthrough discovery 80 translatomes least 39 ability encode newly detected ribosome-associated circCFLAR, circMYBPC3, circRYR2, CDR1as. authors identified bound ribosomes detect potential. Then, nucleic acid ribosome region junction confirm verified polypeptide (or microprotein) encoded six shotgun mass spectrometry. Translations 5 considered m6A-driven, while others likely IRES-driven.42Yang Fan Mao Jin al.Extensive translation N6-methyladenosine.Cell 27: 626-641Crossref (722) may organs besides liver kidney.41van peptides/microproteins uncovered, reveal diversity previously thought non-coding. Elucidating will increase understanding states heart. Even applied loads circRNA-mRNA started serving One consequence Cytoplasm facilitated circFoxo3, instance, aged mice patients, mentioned before, promoted vitro vivo. mainly localized cytoplasm, ID1 E2F1 (the proteins), FAK HIF1α retention affected act
Language: Английский
Citations
119
Nature Reviews Nephrology, Journal Year: 2021, Volume and Issue: 17(12), P. 814 - 826
Published: Aug. 11, 2021
Language: Английский
Citations
100
Free Radical Biology and Medicine, Journal Year: 2021, Volume and Issue: 178, P. 271 - 294
Published: Dec. 6, 2021
Traumatic brain injury (TBI) can lead to disability or devastating consequences with few established treatments. Although ferroptosis has been shown be involved in TBI, the underlying mechanism was rarely known. Melatonin indicated exhibit neuroprotective activities. However, anti-ferroptotic effects of melatonin on TBI have not yet elucidated. We aimed investigate whether induced humans after and inhibition by could protect against blood-brain barrier (BBB) damage vivo vitro. Circular RNAs (circRNAs) are highly expressed brain. For first time, differentially circRNA treatment for were detected RNA sequencing. found that lipid peroxidation while significantly improved function mice alleviated endoplasmic reticulum (ER) stress A total 1826 circRNAs (fold change >2, Q < 0.01), including 921 down-regulated 905 up-regulated injured tissues receiving treatment. Mechanistically, administration reduced level circPtpn14 (mmu_circ_0000130), which functioned acting as a miR-351-5p sponge positively regulate expression ferroptosis-related 5-lipoxygenase (5-LOX). Moreover, overexpression partly abolished inhibitory ferroptosis. Collectively, our findings provide evidence exert anti-ER alleviating via circPtpn14/miR-351-5p/5-LOX signaling.
Language: Английский
Citations
86
Inflammopharmacology, Journal Year: 2022, Volume and Issue: 30(5), P. 1569 - 1596
Published: June 5, 2022
Language: Английский
Citations
58
Stem Cell Research & Therapy, Journal Year: 2021, Volume and Issue: 12(1)
Published: Feb. 25, 2021
Abstract Background Little is known about the implications of circRNAs in effects melatonin (MEL) on bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoporosis (OP) progression. The aim our study was to investigate MEL-regulated BMSC OP Methods measured by qRT-PCR, western blot (WB), Alizarin Red, alkaline phosphatase (ALP) staining. Differential circRNA mRNA profiles BMSCs treated MEL were characterized deep sequencing, followed validation using RT-PCR, Sanger qRT-PCR. Silencing overexpression circ_0003865 conducted for functional investigations. sponged microRNAs targeted mRNAs predicted bioinformatics validated RNA pull-down, dual-luciferase reporter assay. function miR-3653-3p circ_0003865/miR-3653-3p/growth arrest-specific gene 1 (GAS1) cascade CCK-8, WB, ALP development tested murine model. Results promoted BMSCs. sequencing revealed significant alterations associated with multiple biological processes signaling pathways. Circ_0003865 expression significantly decreased treatment. had no effect proliferation while Overexpression abrogated promotion induced MEL, but change whether or not. Furthermore, promote GAS1 enhanced not affected. By contrast, silencing mitigated caused silencing, proliferation. Finally, repressed mouse Conclusion promotes inhibits pathogenesis suppressing circ_0003865, which regulates via sponging miR-3653-3p.
Language: Английский
Citations
57
Circulation, Journal Year: 2024, Volume and Issue: 149(20), P. 1578 - 1597
Published: Jan. 23, 2024
Calcification of the aortic valve leads to increased leaflet stiffness and consequently results in development calcific disease (CAVD). However, underlying molecular cellular mechanisms calcification remain unclear. Here, we identified a novel calcification-associated PIWI-interacting RNA (piRNA; AVCAPIR) that increases valvular promotes CAVD progression.
Language: Английский
Citations
13
Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 21, 2025
The presence of a substantial necrotic core in atherosclerotic plaques markedly heightens the risk rupture, consequence elevated iron levels that exacerbate oxidative stress and lipid peroxidation, thereby sustaining detrimental cycle ferroptosis inflammation. Concurrently targeting both inflammation is crucial for effective treatment vulnerable plaques. In this study, we introduce gallium hexacyanoferrate nanoabsorption catalysts (GaHCF NACs) designed to disrupt pathological cycle. GaHCF NACs function as highly efficient chelators with robust antiferroptosis properties. Through situ capture within plaques, these enhance reactive oxygen species scavenging, initiating an amplified therapeutic response. significantly advance plaque regression, stabilization, vascular functional recovery by inhibiting MAPK13 (p38-δ MAPK) signaling, key mediator cell death. Importantly, process generates detectable photoacoustic signal, offering notable diagnostic advantage allows real-time monitoring plague status. This multifunctional nanocatalytic platform transforms toxic into agent, adapting dynamically microenvironment representing promising strategy reducing vulnerability preventing rupture.
Language: Английский
Citations
1
European Heart Journal, Journal Year: 2021, Volume and Issue: 42(30), P. 2935 - 2951
Published: May 7, 2021
The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited. Here, we evaluated the role therapeutic value dual-specificity phosphatase 26 (DUSP26) in CAVD.Microarray profiling human valves normal controls demonstrated that DUSP26 was significantly up-regulated valves. ApoE-/- mice fed a diet or cholesterol (HCD) were infected with adeno-associated virus serotype 2 carrying short-hairpin RNA to examine effects silencing on calcification. ameliorated calcification HCD-treated mice, as evidenced by reduced thickness calcium deposition leaflets, improved echocardiographic parameters (decreased peak transvalvular jet velocity mean pressure gradient, well increased area), decreased levels osteogenic markers (Runx2, osterix, osteocalcin) These results confirmed medium-induced valvular interstitial cells. Immunoprecipitation, liquid chromatography-tandem mass spectrometry, functional assays revealed dipeptidyl peptidase-4 (DPP4) interacted mediate procalcific DUSP26. High N6-methyladenosine CAVD; turn, activated DPP4 antagonizing mouse double minute 2-mediated ubiquitination degradation DPP4, thereby promoting CAVD progression.DUSP26 promotes inhibiting degradation. Our findings identify previously unrecognized mechanism up-regulation CAVD, suggesting inhibition is viable strategy impede progression.
Language: Английский
Citations
53
Journal of Pineal Research, Journal Year: 2022, Volume and Issue: 73(2)
Published: June 4, 2022
Melatonin is a hormone synthesized in the pineal gland and has widespread physiological pharmacological functions. Moreover, it can activate protective receptor-dependent processes. These processes prevent tissue carcinogenesis inhibit malignant tumor progression metastasis. Therefore, we investigated regulatory effects of melatonin on dysregulated circular RNAs human lung adenocarcinoma (LUAD) cells. In this study, treated LUAD cells with measured expression hsa_circ_0017109, miR-135b-3p, TOX3 by quantitative reverse transcription polymerase chain reaction. Colony formation cell counting kit-8 assays were used to determine proliferation. The wound-healing assay Transwell experiment carried out evaluate migration potential invasive capacity Also, apoptosis was detected using kit, protein production identified Western blot. It suggested that could vivo vitro, role process explored. Additionally, hsa_circ_0017109 found sponge downstream factor circ_0017109, which demonstrated target promote Hippo pathway epithelial-mesenchymal transition pathway. To summarize, decreases circ_0017109 suppresses non-small-cell cancer migration, invasion, proliferation through decreasing via direct activation miR-135b-3p.
Language: Английский
Citations
36
Stem Cell Research & Therapy, Journal Year: 2022, Volume and Issue: 13(1)
Published: Aug. 13, 2022
Abstract Background Periodontal ligament stem cells (PDLSCs) are the ideal seed for periodontal tissue regeneration. It is well established that persistent inflammation significantly impairs osteogenic differentiation capability of PDLSCs. Therefore, maintaining PDLSC potential under inflammatory microenvironment important treating bone loss in periodontitis. The aim our study was to explore role circular RNA BIRC6 (circBIRC6) regulating PDLSCs conditions. Methods Alkaline phosphatase staining, Alizarin Red quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining were used evaluated effects circBIRC6 on pull-down luciferase assays performed interaction between miR-543. Then, downstream signaling pathway affected by circBIRC6/miR-543 axis further investigated. Results expression level higher exposed stimulus periodontitis tissues compared respective controls. Downregulation enhanced conditions, upregulation led opposite findings. Mechanistically, we found modulated through sponging More importantly, have demonstrated regulated mineralization capacity via PTEN/PI3K/AKT/mTOR microenvironment. Conclusions In summary, miR-543 increased following downregulation, leading inhibition PTEN subsequently activation PI3K/AKT/mTOR pathway. targeting might represent a therapeutic strategy improving
Language: Английский
Citations
33