5′-tiRNA-Cys-GCA regulates VSMC proliferation and phenotypic transition by targeting STAT4 in aortic dissection

Molecular Therapy — Nucleic Acids, Journal Year: 2021, Volume and Issue: 26, P. 295 - 306

Published: July 29, 2021

Accumulating evidence shows that tRNA-derived fragments are a novel class of functional small non-coding RNA; however, their roles in aortic dissection (AD) still unknown. In this study, we found 5′-tiRNA-Cys-GCA was significantly downregulated human and mouse models dissection. The abnormal proliferation, migration, phenotypic transition vascular smooth muscle cells (VSMCs) played crucial role the initiation progression dissection, with as potential switching regulator, because its overexpression inhibited proliferation migration VSMCs increased expression contractile markers. addition, verified signal transducer activator transcription 4 (STAT4) direct downstream target 5′-tiRNA-Cys-GCA. We STAT4 upregulation oxidized low-density lipoprotein (ox-LDL)-treated VSMCs, which promoted cell transformation, reversed by Furthermore, treatment reduced incidence prevented malignant process angiotensin II- β-aminopropionitrile-induced AD mice. conclusion, our findings reveal is regulator pathological via signaling pathway, providing clinical for development future strategies IntroductionThe definition rupture intima due to various reasons, causing blood from orifice enter wall, forming arterial wall separation..1Sun Y. Xiao Sun H. Zhao Z. Zhu J. Zhang L. Dong Han T. Jing Q. Zhou miR-27a regulates remodeling targeting endothelial cells' apoptosis interaction dissection.Theranostics. 2019; 9: 7961-7975Crossref PubMed Scopus (21) Google Scholar,2Cheng M. Yang Xin Li Zong He X. Yu Non-coding RNAs dissection: From biomarkers therapeutic targets.J. Cell. Mol. Med. 2020; 24: 11622-11637Crossref (20) Scholar Eighty percent patients die rupture;3Thompson R.W. Detection management aneurysms.N. Engl. 2002; 346: 1484-1486Crossref (45) hence, once occurs, patient should be immediately hospitalized given surgical intervention. (VSMCs), an important constituent vessels, believed play onset AD.4Liu S. Jiang Tang N. Tian Ponnusamy Tariq M.A. Lian Understanding RNA (ncRNA) stent restenosis.Atherosclerosis. 2018; 272: 153-161Abstract Full Text PDF (36) have prominent feature called flexibility, enables them alternate between (differentiated) synthetic (dedifferentiated) phenotypes.5Li F.J. C.L. Luo X.J. Peng T.L. Involvement MiR-181b-5p/HMGB1 Pathway Ang II-induced Phenotypic Transformation Smooth Muscle Cells Hypertension.Aging Dis. 10: 231-248Crossref (24) Scholar, 6Wang C.Q. G.Y. Huang H.Y. Y.S. Ji Z.C. Shen Z.Y. MicroRNA-134-5p Regulates Media Degeneration through Inhibiting VSMC Switch Migration Thoracic Aortic Dissection.Mol. Ther. Nucleic Acids. 16: 284-294Abstract (28) 7Davis-Dusenbery B.N. Wu C. Hata A. Micromanaging differentiation modulation.Arterioscler. Thromb. Vasc. Biol. 2011; 31: 2370-2377Crossref (180) 8Fu P. Wang Zou et al.Nicotine: Regulatory mechanisms atherosclerosis progression.Food Chem. Toxicol. 2021; 151: 112154Crossref (18) Contractile characterized high α-smooth actin (α-SMA) capabilities. contrast, contain low levels markers exhibit migration.9Owens G.K. Kumar M.S. Wamhoff B.R. Molecular regulation disease.Physiol. Rev. 2004; 84: 767-801Crossref (2536) accelerate occurrence alternations caused stimulants, such (ox-LDL) platelet-derived growth factor BB (PDGF-BB).10Inamoto Kwartler C.S. Lafont A.L. Liang Y.Y. Fadulu V.T. Duraisamy Willing Estrera Safi Hannibal M.C. al.TGFBR2 mutations alter phenotype predispose thoracic aneurysms dissections.Cardiovasc. Res. 2010; 88: 520-529Crossref (100) 11Jones J.A. Beck Barbour J.R. Zavadzkas Mukherjee R. Spinale F.G. Ikonomidis J.S. Alterations cellular constituents during aneurysm development: myofibroblast-mediated remodeling.Am. Pathol. 2009; 175: 1746-1756Abstract (54) 12Wang Liu Yuan Suppression miR-4463 promotes treated Ox-LDL.Cell Tissue 383: 1155-1165Crossref (7) Vascular involves subsequently damaging state balance.13McMurtry Bonnet Dyck Haromy Hashimoto K. Michelakis E.D. Dichloroacetate prevents reverses pulmonary hypertension inducing artery apoptosis.Circ. 95: 830-840Crossref (371) Scholar,14Yang Guo Meng Aung L.H.H. Targeting epigenome in-stent restenosis: therapy.Mol. 23: 1136-1160Abstract addition also link progression.15Liao W.L. Tan M.W. Xu Brahma-related gene 1 inhibits directly up-regulating Ras-related associated diabetes pathophysiologic processes dissection.J. Thorac. Cardiovasc. Surg. 2015; 150 (1292–301.e2)Abstract (16) Scholar,16Wang Fu W. D. Association phenotypes extracellular matrix disorders dissection.J Vasc 2012; 56: 1698-1709Abstract (72) Recent studies confirmed compared control group, samples more common.17Xiao Ma G. al.MicroRNA-22 Inhibits Apoptosis Cell p38MAPKα Remodeling 22: 1051-1062Abstract (13) Scholar,18Shi B. MST1 down-regulation decreasing apoptosis.Eur. Pharmacol. Sci. 2044-2051PubMed Therefore, elucidation involved conversion under conditions essential new diagnosis AD.The stress-induced (tiRNAs) kind newly discovered produced mature tRNAs.14Yang Scholar,19Li Sheng tRNA-Derived Small RNA: A Novel Non-Coding RNA.Genes (Basel). 246Crossref (148) 20Li J.X. Piwi-interacting (piRNAs) targets cardiovascular diseases.Angiogenesis. 19-34Crossref (26) 21Yang P.F. miRNAs diagnostic disease particular focus on WO2010091204.Expert Opin. Pat. 2017; 27: 1021-1029Crossref (32) Under specific conditions, tRNAs cleaved angiogenin (ANG), position anticodon loop will produce two kinds tiRNAs. These tiRNAs 5′-tiRNAs 3′-tiRNAs, length approximately 28–36 nts.16Wang Scholar,22Saikia Krokowski Guan B.J. Ivanov Parisien Hu G.F. Anderson Pan Hatzoglou Genome-wide identification quantitative analysis tRNA induced stress.J. 287: 42708-42725Abstract (147) 23Yamasaki Angiogenin cleaves translational repression.J. 185: 35-42Crossref (572) 24He Expression profiles transfer RNA-derived atherosclerosis.J. 25: 7052-7065Crossref (9) 25Zhang R.C. function molecular mechanism formaldehyde heart development.J. 5358-5371Crossref (15) 26Yang Zhan Shan Ding al.Blood TfR+ exosomes separated pH-responsive method deliver chemotherapeutics tumor therapy.Theranostics. 7680-7696Crossref (50) report tiRNAs, may biological functions, abnormally expressed or participate certain diseases, cancer, neurological, metabolic, viral infectious diseases.26Yang 27Shen Yan Transfer halves: biogenesis, functions diseases.J. (Berl.). 96: 1167-1176Crossref (104) 28Zhang Shi Cao Gao Ren Ning al.Identification characterization ancient enriched serum associating active infection.J. 2014; 6: 172-174Crossref 29Qi Selective arginine deprivation single injection non-uptake deiminase nanocapsules sustained inhibition.Nanoscale. 12: 24030-24043Crossref 30Qi Xue Stability Maintenance Protein Drugs Organic Coatings Based Nanogels.Pharmaceutics. 115Crossref (11) Notably, recent 5′-tiRNA regulating cancer cells31Mo Mao Wei F. fragment, 5′-tiRNAVal, suppresses Wnt/β-catenin pathway FZD3 breast cancer.Cancer Lett. 457: 60-73Crossref (66) biomarker ischemia-reperfusion damage death.32Elkordy Rashad Shehabeldeen Mishima E. Niizuma Abe Tominaga assessment vitro model rat neuronal PC12 cells.Brain 1714: 8-17Crossref However, relationship diseases whether altering unknown.Signal member STAT family.33Verhoeven Tilborghs Jacobs De Waele Quatannens Deben Prenen Pauwels Trinh X.B. Wouters al.The controversy family members cancer.Semin. Cancer 60: 41-56Crossref (113) protein located surfaces.34Lv Ye deficiency protects against neointima formation following injury mice.J. Cardiol. 74: After phosphorylation JAK proteins, proteins nucleus, combine transcripts, regulate genes related differentiation.35Guo Zarella Wagner W.D. atherosclerosis.Exp. 2006; 81: 15-22Crossref highly organs, including testis, spleen, heart, brain, thymus.36Yamamoto Kobayashi Arai Miura O. Hirosawa Miyasaka cDNA cloning, chromosome mapping gene: both STAT1 mapped 2q32.2-->q32.3.Cytogenet. Genet. 1997; 77: 207-210Crossref several can detected main apoptosis.34Lv Scholar,35Guo hypothesized cells.Our study explores AD. Our shed light identify regulatory pathways VSMCs. Future research focused present interventional AD.ResultsDifferential localization vivo vitroWe first level aorta. normal aorta, co-localized α-SMA, suggesting most likely (Figure 1A). Moreover, tissue lower than aorta (Figures 1A 1B). Consistent these data, mice 2.5× 1C). suggest serve protective To further investigate function, mimicked treating ox-LDL (100 μg/mL), plays vital VSMCs.37Xue Cho J.Y. Functional ginsenosides Panax ginseng Ginseng 45: 22-31Crossref (46) 38Tang Noncoding mellitus.Cardiovasc. 36: e12436Crossref 39Bai Chu X.M. NLRP3 inflammasome dysfunction.Cell Death 11: 776Crossref (116) 40He Long PEBP1P2 Suppresses Proliferative Switching Proliferation Atherosclerosis.Mol. 84-98Abstract (34) 41Wang noncoding XXYLT1-AS2 adhesion binding FUS HUVEC.Atherosclerosis. 298: 58-69Abstract 42Liu al.Insights into circRNA angiogenesis implications.Atherosclerosis. 14-26Abstract (55) 43Yu Jie Kim kinase inhibitor BX795 inflammatory response multiple kinases.Biochem. 174: 113797Crossref (29) Interestingly, after treatment, exhibited downward trend time-dependent manner 1D). Together, results indicate abundantly close association AD; were interested studying AD.Overexpression then synthesized transfected mimics 24 h transfection 2A), indicating successfully incorporated cells. counting kit-8 (CCK-8) experiment performed same showed 2B). 5-ethynyl-2′-deoxyuridine (EdU) assay inhibitory effect 2C). suppressed ability wound healing 2D) Transwell assays 2E). next determined observed 2F), specifically while calponin (CNN1) myosin heavy chain (SMHC) did not show significant changes.9Owens By rates change 2H), detecting apoptosis-related p53 caspase-3 (c-caspase-3; Figure 2G).44Du Qian Chen Zheng Pu Xia Aloin Preconditioning Attenuates Hepatic Ischemia/Reperfusion Injury TLR4/MyD88/NF-κB Signal Vivo Vitro.Oxid. Longev. 2019: 3765898Crossref (30) Scholar,45Su Lv X.W. Y.L. Cai R.P. Dai R.X. X.H. W.K. Kong B.H. Exosomal LINC00174 derived attenuates myocardial I/R p53-mediated autophagy apoptosis.Mol. 1304-1322Abstract summary, mainly regulated affect VSMCs.Figure 2Overexpression vitroShow full caption(A) used overexpress using real-time PCR. (B C) (B) cell-light EdU staining (C) measure at 0, 12, 24, 36 h. (D E) analyzed wound-healing (D) (E) assay. (F) Western blotting analyses conducted (G H) TUNEL (G) western blot (H) detect Data presented mean ± SD. Each repeated least three times. Scale bars, 200 μm. ∗p < 0.05; ∗∗p 0.01; ∗∗∗p 0.001; ∗∗∗∗p 0.0001; ns, significant.View Large Image ViewerDownload Hi-res image Download (PPT)Knockdown vitroThe knockdown 3A), consequently 3B 3C). Simultaneously, accelerated 3D 3E), 3F). any 3G 3H). validating 3Knockdown inhibitors down-express qPCR. CCK-8 down-expression ware (PPT)5′-tiRNA-Cys-GCA binds downregulates STAT4Investigation 5′-tiRNA-Cys-GCA-mediated KEGG ontology (GO) identified total 153 predicted 4A). revealed only 9 migration. targets, namely STAT4, PC nanoparticles (PCNP), cysteine rich secretory LCCL domain containing 2 (CRISPLD2), pulled down 4B). PCR (qPCR) remaining six (JAK3, KCNE3, HBEGF, TLR4, TREM1, TNFAIP8L2) undetermined Ct values, very levels. had highest enrichment, implying it probable Using miRanda TargetScan software, site 4C) structure score, free energy, Context+ values 145, −24.79, −0.303, respectively. Further displayed degree conservation humans, mice, rats 4C). Additional experiments mRNA 4D) 4E), correspondingly expression. Finally, dual luciferase reporter fluorescence intensities overexpressed wild-type plasmid reduced, there no mutant group. Taken together, bind activities.Figure 45′-tiRNA-Cys-GCA STAT4Show Predicted kyoto encyclopaedia genomes (KEGG) enrichment predictions, literature review pull-down selected. Pull-down Theoretically STAT4. qPCR NC STAT4-3′ UTR-WT mut co-transfected NC. Luciferase activity decreased (PPT)STAT4 ox-LDL-induced transformation 5′-tiRNA-Cys-GCAWe designed interfering (siRNA)-mediated validate 5′-tiRNA-Cys-GCA/STAT4 axis First, siRNA knocks

Language: Английский

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“Medicine food homology” plants promote periodontal health: antimicrobial, anti-inflammatory, and inhibition of bone resorption

Frontiers in Nutrition, Journal Year: 2023, Volume and Issue: 10

Published: June 15, 2023

"Medicine food homology" (MFH) is a term with lengthy history. It refers to the fact that lot of traditional natural products have both culinary and therapeutic benefits. The antibacterial, anti-inflammatory anticancer effects MFH plants their secondary metabolites been confirmed by numerous research. A bacterially generated inflammatory illness complicated pathophysiology, periodontitis causes loss teeth's supporting tissues. Several recently shown ability prevent treat periodontitis, which exhibited blocking disease's pathogens virulence factors go along them, lowering host's reactions halting alveolar bone. To give theoretical foundation for creation functional foods, oral care adjuvant therapies, this review has especially explored potential medicinal benefit in prevention treatment periodontitis.

Language: Английский

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Ginsenosides retard atherogenesis via remodelling host–microbiome metabolic homeostasis

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(12), P. 1768 - 1792

Published: Feb. 14, 2024

Abstract Background and Purpose Panax ginseng is widely applied in the adjuvant treatment of cardiometabolic diseases clinical practice without clear mechanisms. This study aims to clearly define efficacy underlying mechanism P. its active components protecting against atherosclerosis. Experimental Approach The anti‐atherogenic total saponin extract (TGS) was evaluated on Ldlr −/− mice. Gut microbial structure analysed by 16S rRNA sequencing PCR. Bile acid profiles were revealed using targeted metabolomics with LC–MS/MS analysis. contribution gut microbiota atherosclerosis assessed co‐housing experiments. Key Results Ginsenoside Rb1, representing protopanaxadiol (PPD)‐type saponins, increased intestinal Lactobacillus abundance, resulting enhanced bile salt hydrolase (BSH) activity promote conjugated hydrolysis excretion, followed suppression enterohepatic farnesoid X receptor (FXR)–fibroblast growth factor 15 (FGF15) signal, thereby cholesterol 7α‐hydroxylase (CYP7A1) transcriptional expression facilitated metabolic elimination cholesterol. Synergistically, protopanaxatriol (PPT)‐type represented ginsenoside Rg1, protected atherogenesis‐triggered leak endotoxaemia. Rg1 directly induced mucin production nutritionally maintain Akkermansia muciniphila , which reciprocally inhibited permeation. Rb1/Rg1 combination, rather than a single compound, can largely mimic holistic TGS mice from atherogenesis. Conclusion Implications Our provides strong evidence supporting combinations as effective therapies atherogenesis, via targeting different signal nodes may provide some elucidation mode herbal medicines.

Language: Английский

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Ginsenoside Rb1 in cardiovascular and cerebrovascular diseases: A review of therapeutic potentials and molecular mechanisms

Chinese Herbal Medicines, Journal Year: 2024, Volume and Issue: 16(4), P. 489 - 504

Published: Sept. 16, 2024

Language: Английский

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Targeting non-coding RNAs in unstable atherosclerotic plaques: Mechanism, regulation, possibilities, and limitations

International Journal of Biological Sciences, Journal Year: 2021, Volume and Issue: 17(13), P. 3413 - 3427

Published: Jan. 1, 2021

Cardiovascular diseases (CVDs) caused by arteriosclerosis are the leading cause of death and disability worldwide. In late stages atherosclerosis, atherosclerotic plaque gradually expands in blood vessels, resulting vascular stenosis. When unstable ruptures falls off, it blocks vessel causing thrombosis, to strokes, myocardial infarctions, a series other serious that endanger people's lives. Therefore, regulating stability is main means used address high mortality associated with CVDs. The progression complex integration cell apoptosis, lipid metabolism disorders, inflammatory infiltration, smooth muscle migration, neovascular infiltration. More recently, emerging evidence has demonstrated non-coding RNAs (ncRNAs) play significant role pathophysiological process formation affecting biological functions vasculature its cells. purpose this paper comprehensively review regulatory mechanisms involved susceptibility rupture, discuss limitations current approaches treat instability, highlight potential clinical value ncRNAs as novel diagnostic biomarkers therapeutic strategies improve reduce risk major cardiovascular events.

Language: Английский

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Extracellular Vesicles as Natural Delivery Carriers Regulate Oxidative Stress Under Pathological Conditions

Frontiers in Bioengineering and Biotechnology, Journal Year: 2021, Volume and Issue: 9

Published: Sept. 7, 2021

Extracellular vesicles are cellular secretory particles that can be used as natural drug delivery carriers. They have successfully delivered drugs including chemotherapeutics, proteins, and genes to treat various diseases. Oxidative stress is an abnormal physiological phenomenon, it associated with nearly all In this short review, we summarize the regulation of EVs on oxidative stress. There direct effects indirect through EVs. On one hand, they deliver antioxidant substances or oxides recipient cells, directly relieving aggravating other regulate factors stress-related signaling pathways cells by mediation EVs, realizing To best our knowledge, however, only endogenous been till now. And heterogeneity may complicate Therefore, review aims draw more attention EVs-based stress, hope excellent carriers exogenous exploited.

Language: Английский

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Expression profiles and potential roles of transfer RNA‐derived small RNAs in atherosclerosis

Journal of Cellular and Molecular Medicine, Journal Year: 2021, Volume and Issue: 25(14), P. 7052 - 7065

Published: June 16, 2021

Abstract Knowledge regarding the relationship between molecular mechanisms underlying atherosclerosis (AS) and transfer RNA‐derived small RNAs (tsRNAs) is limited. This study illustrated expression profile of tsRNAs, thus exploring its roles in AS pathogenesis. Small RNA sequencing was performed with four atherosclerotic arterial healthy subject samples. Using bioinformatics, protein‐protein interaction network cellular experiments were constructed to predict enriched signalling pathways regulatory tsRNAs AS. Of total 315 identified be dysregulated group, 131 184 up‐regulated down‐regulated, respectively. Interestingly, pathway differentiated cell adhesion molecules (CAMs) implicated closely associated Particularly, tRF‐Gly‐GCC might participate pathogenesis via regulating adhesion, proliferation, migration phenotypic transformation HUVECs VSMCs. In conclusion, help understand better. may a promising target for suppressing abnormal vessels functions, suggesting novel strategy preventing progression atherosclerosis.

Language: Английский

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The regulatory roles of aminoacyl-tRNA synthetase in cardiovascular disease

Molecular Therapy — Nucleic Acids, Journal Year: 2021, Volume and Issue: 25, P. 372 - 387

Published: June 24, 2021

Aminoacyl-tRNA synthetases (ARSs) are widely found in organisms, which can activate amino acids and make them bind to tRNA through ester bond form the corresponding aminoyl-tRNA. The classic function of ARS is provide raw materials for protein biosynthesis. Recently, emerging evidence demonstrates that ARSs play critical roles controlling inflammation, immune responses, tumorigenesis as well other important physiological pathological processes. With recent development genome exon sequencing technology, discovery new clinical cases, have been reported be closely associated with a variety cardiovascular diseases (CVDs), particularly angiogenesis cardiomyopathy. Intriguingly, aminoacylation was newly identified modify substrate proteins, thereby regulating activity functions. Sensing availability intracellular related regulation cell physiology. In this review, we summarize research progress on mechanism CVDs caused by abnormal introduce phenotypes characteristics dysfunction. We also highlight potential CVDs. Finally, discuss some limitations challenges present research. current findings suggest significant involved CVDs, values novel diagnostic therapeutic targets CVD treatment.

Language: Английский

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Korean Red Ginseng saponin fraction exerts anti-inflammatory effects by targeting the NF-κB and AP-1 pathways

Journal of Ginseng Research, Journal Year: 2022, Volume and Issue: 46(3), P. 489 - 495

Published: Feb. 24, 2022

Although ginsenosides and saponins in Korea red ginseng (KRG) shows various pharmacological roles, their roles the inflammatory response are little known. This study investigated anti-inflammatory role of identified from KRG saponin fraction (RGSF) potential mechanism macrophages.The ginsenoside composition RGSF was by high-performance liquid chromatography (HPLC) analysis. An effect its mechanisms were studied using nitric oxide (NO) prostaglandin E2 (PGE2) production assays, mRNA expression analyses genes cytokines, luciferase reporter gene assays transcription factors, Western blot signaling pathways lipopolysaccharide (LPS)-treated RAW264.7 cells.HPLC analysis types amounts panaxadiol RGSF. reduced generation molecules levels enzymes cytokines LPS-treated cells. Additionally, inhibited NF-κB AP-1 suppressing both transcriptional factors cells.RGSF contains that have action via restraining macrophages during responses.

Language: Английский

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The role of macrophage polarization in vascular calcification

Biochemical and Biophysical Research Communications, Journal Year: 2024, Volume and Issue: 710, P. 149863 - 149863

Published: March 31, 2024

Vascular calcification is an important factor in the high morbidity and mortality of Cardiovascular cerebrovascular diseases. damage caused by intima or media impairs physiological function vascular wall. Inflammation a central development calcification. Macrophages are main inflammatory cells. Dynamic changes macrophages with different phenotypes play role occurrence, progression stability This review focuses on macrophage polarization relationship between environment, as well mechanism interaction, it considered that can promote releasing mediators promoting osteogenic transdifferentiation smooth muscle cells so on. In addition, several therapeutic strategies aimed at for described, which great significance targeted treatment

Language: Английский

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