Applications and developments of gene therapy drug delivery systems for genetic diseases

Asian Journal of Pharmaceutical Sciences, Journal Year: 2021, Volume and Issue: 16(6), P. 687 - 703

Published: June 27, 2021

Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity. Currently, gene therapy drugs such as siRNA, shRNA, antisense oligonucleotide, CRISPR/Cas9 system, plasmid DNA miRNA shown great potential in biomedical applications. To avoid degradation body effectively deliver them to target tissues, cells organelles, development excellent drug delivery vehicles is utmost importance. Viral vectors are most widely used for vivo vitro due their high transfection efficiency stable transgene expression. With nanotechnology, novel nanocarriers gradually replacing viral vectors, emerging superior performance. This review mainly illuminates current drugs, summarizes non-viral that sums up application treat genetic diseases. Additionally, challenges opportunities field discussed from perspective developing an effective nano-delivery system.

Language: Английский

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Adipose mesenchymal stem cell-derived extracellular vesicles containing microRNA-26a-5p target TLR4 and protect against diabetic nephropathy

Journal of Biological Chemistry, Journal Year: 2020, Volume and Issue: 295(37), P. 12868 - 12884

Published: June 24, 2020

Diabetic nephropathy (DN) is a complication of diabetes that increasing in prevalence China. Extracellular vesicles (EVs) carrying microRNAs (miRs) may represent useful tool the development therapies for DN. Here, we report EVs released by adipose-derived mesenchymal stem cells (ADSCs) during DN contain microRNA, miR-26a-5p, suppresses Using bioinformatic analyses, identified differentially expressed miRs from ADSCs and predicted downstream regulatory target genes. We isolated (MSCs) adipose tissues collected ADSCs. exposed mouse glomerular podocytes MP5 to high glucose (HG), ADSC-derived EVs, miR-26a-5p inhibitor/antagomir, Toll-like receptor 4 (TLR4) plasmids, or NF-κB pathway activator (phorbol-12-myristate-13-acetate, PMA). used cell counting kit-8 (CCK-8) assay flow cytometry investigate impact on viability apoptosis validated results these assays with vivo experiments nude mice. found DN, at very low levels, whereas TLR4 highly expressed. Of note, ameliorated pathological symptoms diabetic mice transferred HG-induced cells, improving while suppressing cells. also protects injury targeting TLR4, inactivating pathway, downregulating vascular endothelial growth factor A (VEGFA). Moreover, podocytes, which pathology. These findings suggest against (DN), common microvascular diabetes, one major causes death among patients (1Wang X. Xu Y. Chu C. Li H. Mi J. Wen Z. Zhang S. Wang Q. Quan Effect safflower yellow early type II nephropathy: systematic review meta-analysis randomized controlled trials.J. Pediatr. Endocrinol. Metab. 2019; 32: 653-66510.1515/jpem-2018-0425Crossref PubMed Scopus (6) Google Scholar). It leading cause both chronic kidney end-stage renal diseases worldwide (2De la Cruz-Cano E. Jimenez-Gonzalez C.D.C. Morales-Garcia V. Pineda-Perez Tejas-Juarez J.G. Rendon-Gandarilla F.J. Jimenez-Morales Diaz-Gandarilla J.A. Arg913Gln variation SLC12A3 gene associated 2 Gitelman syndrome: review.BMC Nephrol. 20 (31660880): 39310.1186/s12882-019-1590-9Crossref (9) The incidence developing countries, including China (3Misra A. Shrivastava U. Obstructive sleep apnea nephropathy.Diabetes Technol. Ther. 2016; 18 (27218687): 405-40710.1089/dia.2016.0147Crossref characterized albuminuria progressive loss function (4Ioannou K. it always there? Assumptions, weaknesses pitfalls diagnosis.Hormones. 2017; 16 (29518755): 351-36110.14310/horm.2002.1755PubMed Scholar), risk factors include hyperglycemia genetic polymorphisms (5Moţa Panduru M.N. Popa S.G. Moţa M. Risk intrinsic extrinsic renal?.Rom. Intern. Med. 2009; 47 (21179923): 397-401PubMed dysfunction contributes (6Tung C.W. Hsu Y.C. Shih Y.H. Chang P.J. Lin C.L. Glomerular mesangial podocyte injuries nephropathy.Nephrology. 2018; 23 (30298646): 32-3710.1111/nep.13451Crossref (102) progression can be slowed reducing (7Zhong F. Chen Xie Azeloglu E.U. Wei W. Chuang P.Y. Jim B. Elmastour Riyad J.M. Weber T. et al.Protein S nephropathy.J. Am. Soc. 29 (29511111): 1397-141010.1681/ASN.2017030234Crossref (29) Current treatment methods mainly rely management blood pressure (8Wang Gu H.F. Wu L. Common drugs stabilization their relations hypertension therapy.Curr. Diabetes Rev. 14 (28201968): 149-16110.2174/1573399813666170214112115Crossref (7) Evidence suggests extracellular slow protecting (9Duan Y.R. B.P. Yang S.X. Zhu C.Y. Ma Y.L. Shi Exosomal microRNA-16-5p human urine-derived ameliorates through protection podocyte.J. Cell Mol. 10.1111/jcmm.14558Crossref (45) Elucidating mechanisms regulate therapeutic are nano-sized membrane exosomes microvesicles, they many types, (10Gangadaran P. Ahn B.C. In tracking tumor-derived bioluminescent mice.Methods Biol. 2020; 2081 (31721127): 203-21010.1007/978-1-4939-9940-8_14Crossref (4) Scholar, 11Fiedler Rabe Mundkowski R.G. Oehmcke-Hecht Peters Adipose-derived release microvesicles procoagulant activity.Int. Biochem. 100 (29778527): 49-5310.1016/j.biocel.2018.05.008Crossref (14) MSCs multipotent differentiate into variety lineages exert important functions bone regeneration repair (12Yang Jia Guo R. Huang Zheng Long noncoding RNAs: new players osteogenic differentiation marrow- cells.Stem Rep. (29464508): 297-30810.1007/s12015-018-9801-5Crossref recent study highlighted role derived (13Jin Gong Zhao He Exosome secreted attenuates promoting autophagy flux inhibiting podocyte.Stem Res. 10 (30876481): 9510.1186/s13287-019-1177-1Crossref (140) known mRNA, (miRs), long RNAs, thereby transferring information next (14Tetta Ghigo Silengo Deregibus M.C. Camussi G. as an emerging mechanism cell-to-cell communication.Endocrine. 2013; 44 (23203002): 11-1910.1007/s12020-012-9839-0Crossref (258) Interestingly, serves candidate biomarker profiling studies (15Gholaminejad Abdul Tehrani Gholami Fesharaki Identification microRNA biomarkers studies.J. 31 (30019103): 813-83110.1007/s40620-018-0511-5Crossref Our showed MSCs. Loss miR-26a led cultured streptozotocin-induced (16Koga Yokoi Mori Kasahara Kuwabara Imamaki Ishii K.P. Kato Ohno Toda N. Saleem M.A. Sugawara Nakao Yanagita al.MicroRNA-26a inhibits TGF-beta-induced matrix protein expression CTGF downregulated nephropathy.Diabetologia. 2015; 58 (26063197): 2169-218010.1007/s00125-015-3642-4Crossref (84) Additionally, was suggested mediators Based findings, hypothesized EV-derived could (TLR4), signaling lipopolysaccharides crucial regulator innate immunity system, (17Kolz Baumert Muller Khuseyinova Klopp Thorand Meisinger Herder Koenig Illig Association between variations incident modified ratio total cholesterol HDL-cholesterol.BMC Genet. 2008; 9: 910.1186/1471-2350-9-9Crossref (30) One M4200 show participates pathogenesis (18Liu Z.M. H.Y. L.H. Liao C.F. X.W. Low miR-203 promoted via TLR4.Eur. Pharmacol. Sci. 22 (30229838): 5627-563410.26355/eurrev_201809_15828PubMed downregulation TLR/NF-κB (NF-κB) using umbelliferone rat model (19Wang H.Q. S.S. Chiufai Cheng X.L. Umbelliferone rats regulating inflammation TLR/NF-kappaB pathway.Chin. Nat. 17 (31171269): 346-35410.1016/S1875-5364(19)30040-8PubMed Notably, activation thought related disease (20Li Cai miR-218 regulates IKK-beta modulating NK-kappaB-mediated inflammation.J. Cell. Physiol. 235: 3362-337110.1002/jcp.29224Crossref (32) Upregulation previously reported pineal glands umbilical vein (21da Silveira Cruz-Machado Carvalho-Sousa C.E. Tamura E.K. Pinato Cecon Fernandes P.A. de Avellar Ferreira Z.S. Markus R.P. CD14 receptors gland trigger NFKB pathway.J. Pineal 2010; 49 (20586888): 183-19210.1111/j.1600-079X.2010.00785.xPubMed 22Ni Kong Ouyang Celastrol lipopolysaccharide-induced angiogenesis TLR4-triggered nuclear factor-kappa B activation.Acta Haematol. 2014; 131 (24157922): 102-11110.1159/000354770Crossref (40) addition, promote (VEGFA) (23Liang Jiang Zhou Liu Su Du Activation GPER migration triple negative breast cancer inhibition NF-kappaB/IL-6 signals.Cancer Lett. 386 (27836733): 12-2310.1016/j.canlet.2016.11.003Crossref (83) well (24Onions K.L. Gamez Buckner N.R. Baker S.L. Betteridge K.B. Desideri Dallyn Ramnath R.D. Neal C.R. Farmer L.K. Mathieson P.W. Gnudi Alitalo Bates D.O. Salmon A.H.J. al.VEGFC reduces albumin permeability alterations VEGF nephropathy.Diabetes. 68 (30389746): 172-18710.2337/db18-0045Crossref Taking consideration, other VEGFA. Thus, this help identify novel strategy control Analysis EVmiRNA database revealed significantly upregulated (Fig. 1A). Furthermore, miRanda Starbase were predict genes miRNAs. then compared diabetes-related data set (GSE21340). Five intersection analyses (SMAD1, CELF2, SMAD6, PYGL, TLR4) 1B). Because binding site 1C), chose GSE21340 set. higher 1D). delivered protect TLR4. subcutaneous C57BL/KsJ db/m surface markers detected after third passage. positive CD29 (96.7%), CD44 (95.2%), CD73 (99.1%), CD90 (98.4%), HLA-A, -B, -C (98.5%) but (4.2%), CD19 (0.26%), CD34 (1.9%), CD45 (1.2%), HLA-DR (0.89%) 2A). pluripotency tested. After isolation culture, differentiated osteogenic, lipogenic, chondrogenic types 2B). above demonstrated had property pluripotent differentiation. Next, medium grow characterized. Dynamic light scattering (DLS) analysis indicated range diameter 30–150 nm. Transmission EM morphology cup-shaped spherical. Western blot marker proteins confirmed CD63 TSG101, calnexin absent, indicating been successfully 2, C–E). successful To evaluate spontaneous levels urine (within 24 h), serum creatinine (Scr), urea nitrogen (BUN) db/db spontaneously twice amount 3 times much Scr BUN 3, A–C). histopathological phenotype periodic acid Schiff (PAS) staining tissues. Spontaneously accumulation tissues, thickening basement membrane. there increased proteinuria lumen, hyaline degeneration, severe vacuolar degeneration tubular epithelial mice, establishment 3D). effect injected PBS tail vein, changes protein, Scr, subsequently measured, followed PAS detect changes. illustrated notably reduced alleviated A–D). TUNEL (C57BL/KsJ db/db) exhibited significant increase mice), injection 3E). apoptosis-related (caspase-3, cleaved caspase-3, Bcl-2, Bax) db/m) compared. Bcl-2 Bax, caspase-3 increased. Injection reversed trends 3F). capable alleviating ability internalize assessed green fluorescent (PKH67)-labeled EVs. presence fluorescence observed microscopy, able 4A). simulate vitro, induced HG treated (25 μg/ml). CCK-8 h, 48 72 respectively. Although no difference h response each treatment, high-glucose (HG) markedly decreased relative either normal (NG) mannitol (MA). Viability restored cotreatment No differences seen 48- 72-h time points 4B); therefore, 48-h point chosen all subsequent experiments. Flow same treatments described above. NG MA, induction apoptosis, versus alone 4C). treatment. Treatment Bax MA de-creased 4D). suppress HG-mediated vitro. measured RT-qPCR PBS. lower than containing 5A). confirm transfer Cy3-miR-26a-5p mimic transfected added media. Fluorescence microscopy became noticeably red 5B). demonstrate determine HG-treated mimic, inhibitor. Addition inhibitor caused decline 5C). CCL-8 assay, cytometry. Under conditions, improved suppressed 5, D E). resulted accompanied notable decrease expression. contrast, expression, elevated 5F). indicate delivery apoptosis. website TargetScan (RRID:SCR_010845) specific sites nucleotides 4477–4484 6A). Dual-Luciferase reporter miR-26a-5p. Cotransfection TLR4-3'UTR-WT marked intensity (NC) + cotransfection; however, unchanged NC TLR4-3'UTR-MUT 6B). opposite effects 6, C D). 6E). This directly gene. regulated overexpressed First, cellular upon under pcDNA-3.1 pcDNA-TLR4 pcDNA-TLR4- 6F). Subsequently, performed viability, displayed inhibited apoptosis; 6G H). plasmid. 6I). Combined results, concluded targets explored regulation first investigated whether inhibit overexpression, further Immunofluorescence p65 localization nucleus. reduce localization, keeping more cytoplasm. negated overexpression again 7A). pathway-related IKKβ, IκBα, extent phosphorylation plasmid induction, cotreated pcDNA-3.1-TLR4 7B). verify activator, phorbol-12-myristate-13-acetate (PMA; 1 PMA p65, VEGFA, DMSO. indicators 7C). cytometry, combined 7, VEGFA 7F). plus pcDNA-3-VEGFA 7G). resulting NF-κB/VEGFA injury. explore and/or antagomir vein. Mice staining. As illustrated, accumulated membrane, lamina dispersion, modeled those aggravating 8, B). NC. Apoptosis 8C). analyze different treatments. treatment; 8D).

Language: Английский

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Icariin ameliorates streptozocin-induced diabetic nephropathy through suppressing the TLR4/NF-κB signal pathway

Food & Function, Journal Year: 2021, Volume and Issue: 12(3), P. 1241 - 1251

Published: Jan. 1, 2021

Protective effects of icariin on streptozotocin-induced diabetic mice by inhibiting the TLR4/NF-κB signal pathway.

Language: Английский

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MicroRNA-218-5p-Ddx41 axis restrains microglia-mediated neuroinflammation through downregulating type I interferon response in a mouse model of Parkinson’s disease

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 16, 2024

Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in substantia nigra (SN). Microglia-mediated neuroinflammation has been largely considered one main factors to PD pathology. MicroRNA-218-5p (miR-218-5p) microRNA that plays role neurodevelopment and function, while its potential function remains unclear. Methods We explore involvement miR-218-5p 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. The agomir used for overexpression was delivered into (SN) bilateral stereotaxic infusions. microglial inflammation SN determined using Western blotting immunofluorescence. Motor assessed rotarod test. RNA sequencing (RNA-seq) performed pathways regulated miR-218-5p. target genes were predicted TargetScan confirmed dual luciferase reporter assays. effects on related verified murine microglia-like BV2 cells. To stimulate cells, SH-SY5Y cells treated with 1-methyl-4-phenylpyridinium (MPP + ) conditioned media (CM) collected. Results MiR-218-5p expression reduced both MPTP-induced mice MPP -treated significantly alleviated inflammation, DA neurons, motor dysfunction. sequence gene set enrichment analysis showed type I interferon (IFN-I) upregulated mice, this upregulation reversed overexpression. A assay Ddx41 In vitro, or knockdown inhibited IFN-I response inflammatory cytokines stimulated -CM. Conclusions suppresses microglia-mediated preserves via /IFN-I. Hence, miR-218-5p- promising therapeutic PD.

Language: Английский

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Analysis of whole transcriptome reveals the immune response to porcine reproductive and respiratory syndrome virus infection and tylvalosin tartrate treatment in the porcine alveolar macrophages

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 13, 2025

Introduction Porcine reproductive and respiratory syndrome virus (PRRSV) is a major pathogen that has caused severe economic losses in the swine industry. Screening key host immune-related genetic factors porcine alveolar macrophages (PAMs) critical to improve anti-virial ability pigs. Methods In this study, an vivo model was set evaluate anti-PRRSV effect of tylvalosin tartrates. Then, strand-specific RNA-sequencing (ssRNA-seq) miRNA-sequencing (miRNA-seq) were carried out profile whole transcriptome PAMs negative control, PRRSV-infected, tartrates-treatment group. Results The ssRNA-seq identified 11740 long non-coding RNAs PAMs. Based on our attention mechanism-improved graph convolutional network, 41.07% 28.59% lncRNAs predicted be located nucleus cytoplasm, respectively. miRNA-seq revealed tartrates-enhanced miRNAs might play roles regulating angiogenesis innate functions, it rescued expression three anti-inflammation ( ssc-miR-30a-5p , ssc-miR-218-5p ssc-miR-218 ) downregulated due PRRSV infection. cytoplasmic enhanced by tartrates form ceRNA networks with regulate PAM chemotaxis. While protect via efferocytosis-related networks. On other hand, tartrates-rescued nuclear negatively T cell apoptosis bind factor IL37 lungs cis - trans -regulation. Conclusions Our data provides catalog response enrich basis for future prevention control.

Language: Английский

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Noncoding RNAs in Diabetic Nephropathy: Pathogenesis, Biomarkers, and Therapy

Journal of Diabetes Research, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 10

Published: June 22, 2020

The correlation between diabetes and systematic well-being on human life has long established. As a common complication of diabetes, the prevalence diabetic nephropathy (DN) been increasing globally. DN is known to be major cause end-stage kidney disease (ESKD). Till now, molecular mechanisms for have not fully explored effective therapies are still lacking. Noncoding RNAs class produced by genome transcription that cannot translated into proteins. It documented ncRNAs participate in pathogenesis regulating inflammation, apoptosis, autophagy, cell proliferation, other pathological processes. In this review, roles diagnostic therapeutic potential three types (microRNA, noncoding RNA, circular RNA) progression summarized illustrated.

Language: Английский

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Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 11

Published: Jan. 26, 2021

Diabetic kidney disease (DKD) is the most common diabetic complication and a leading cause of end-stage disease. Increasing evidence shows that DKD regulated not only by many classical signaling pathways but also epigenetic mechanisms involving chromatin histone modifications, DNA methylation, non-coding RNA (ncRNAs). In this review, we focus on our current understanding role ncRNAs, including microRNAs (miRNAs) long RNAs (lncRNAs) in pathogenesis DKD. Of them, regulatory TGF-β/Smad3-dependent miRNAs lncRNAs highlighted. Importantly, as biomarkers therapeutic targets for are described, perspective ncRNAs novel approach combating nephropathy discussed.

Language: Английский

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Epigenetics and Inflammation in Diabetic Nephropathy

Frontiers in Physiology, Journal Year: 2021, Volume and Issue: 12

Published: May 5, 2021

Diabetic nephropathy (DN) leads to high morbidity and disability. Inflammation plays a critical role in the pathogenesis of DN, which involves renal cells immune cells, microenvironment, as well extrinsic factors, such hyperglycemia, chemokines, cytokines, growth factors. Epigenetic modifications usually regulate gene expression via DNA methylation, histone modification, non-coding RNAs without altering sequence. During past years, numerous studies have been published reveal mechanisms epigenetic that inflammation DN. This review aimed summarize latest evidence on interplay epigenetics highlight potential targets for treatment diagnosis

Language: Английский

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Potential Mechanisms of the Improvement of Glucose Homeostasis in Type 2 Diabetes by Pomegranate Juice

Antioxidants, Journal Year: 2022, Volume and Issue: 11(3), P. 553 - 553

Published: March 15, 2022

Pomegranate is a polyphenol-rich fruit. Studies have shown that extracts prepared from its juice or different parts of the pomegranate plant various biological activities including antioxidant, antimicrobial, anti-inflammatory, anticarcinogenic, cardioprotective, and antidiabetic. The therapeutic potential has been attributed to phytochemicals, ellagic acid, punicic flavonoids, anthocyanidins, anthocyanins, flavonols, flavones. This review focuses on scientific evidence as hypoglycemic, emphasizing chemical composition possible mechanisms action associated with this effect. were identified using PubMed, Scopus, ISI Web Science databases identify relevant articles focused hypoglycemic effect juice. physiological responses are reported here, decrease oxidative stress damage, an increase insulin-dependent glucose uptake, maintenance β-cell integrity, inhibition nonenzymatic protein glycation, insulin sensitivity, modulation peroxisome proliferator-activated receptor-gamma, α-amylase, α-glucosidase dipeptidyl peptidase-4, decreases in inflammation. Overall, we found significant vitro vivo studies summarize action.

Language: Английский

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Circular RNA circEIF4G2 aggravates renal fibrosis in diabetic nephropathy by sponging miR‐218

Journal of Cellular and Molecular Medicine, Journal Year: 2020, Volume and Issue: 26(6), P. 1799 - 1805

Published: Dec. 7, 2020

Abstract Circular RNAs play essential roles in the development of various human diseases. However, how circRNAs are involved diabetic nephropathy (DN) not fully understood. Our study aimed to investigate effects circRNA circEIF4G2 on DN. Experiments were performed db/db mouse model type 2 diabetes and NRK‐52E cells. We found that was significantly up‐regulated kidneys mice cells stimulated by high glucose. knockdown inhibited expressions TGF‐β1, Collagen I Fibronectin glucose‐stimulated cells, which could be rescued miR‐218 inhibitor. Knockdown SERBP1 reduced expression HG‐stimulated In summary, our findings suggested promotes renal tubular epithelial cell fibrosis via miR‐218/SERBP1 pathway, presenting a novel insight for DN treatment.

Language: Английский

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