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1.
Clin. transl. oncol. (Print) ; 26(3): 584-596, mar. 2024.
Artigo em Inglês | IBECS | ID: ibc-230789

RESUMO

Ovarian cancer (OC) has the highest mortality rate among female reproductive system tumours, with limited efficacy of traditional treatments and 5-year survival rates that rarely exceed 40%. Circular RNA (circRNA) is a stable endogenous circular RNA that typically regulates protein expression by binding to downstream miRNA. It has been demonstrated that circRNAs play an important role in the proliferation, migration, and glucose metabolism (such as the Warburg effect) of OC and can regulate the expression of glucose metabolism-related proteins such as GLUT1 and HK2, promoting anaerobic glycolysis of cancer cells, increasing glucose uptake and ATP production, and affecting energy supply and biosynthetic substances to support tumour growth and invasion. This review summarises the formation and characteristics of circRNAs and focuses on their role in regulating glucose metabolism in OC cells and their potential therapeutic value, providing insights for identifying new therapeutic targets (AU)


Assuntos
Humanos , Feminino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , /genética
2.
Cell Tissue Res ; 395(3): 285-297, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38353742

RESUMO

Leydig cell (LCs) apoptosis is responsible for decreased serum testosterone levels during late-onset hypogonadism (LOH). Our study was designed to illustrate the regulatory effect of lncRNA XIST on LCs and to clarify its molecular mechanism of action in LOH. The Leydig cells (TM3) was treated by 300 µM H2O2 for 8 h to establish Leydig cell oxidative stress model in vitro. The expression levels of lncRNA XIST in the testicular tissues of patients with LOH were measured using fluorescence in situ hybridization (FISH). The interaction between lncRNA XIST/SIRT1 and miR-145a-5p was assessed using starBase and dual-luciferase reporter gene assays. Apoptotic cells and Caspase3 activity were determined by flow cytometry (FCM) assay. Testosterone concentration was determined by ELISA. Moreover, histological assessment of testicles in mice was performed by using HE staining and the TUNEL assay was used to determine apoptosis. We found that the lncRNA XIST was downregulated in the testicular tissues of LOH patients and mice and in H2O2-induced TM3 cells. XIST siRNA significantly promoted apoptosis, enhanced Caspase3 activity and reduced testosterone levels in H2O2-stimulated TM3 cells. Further studies showed that the miR-145a-5p inhibitor reversed the effect of XIST-siRNA on H2O2-induced Leydig cell apoptosis. MiR-145a-5p negatively regulated SIRT1 expression, and SIRT1-siRNA reversed the effects of the miR-145a-5p inhibitor on H2O2 stimulated TM3 cells. The in vivo experiments indicated that silencing of the lncRNA XIST aggravated LOH symptoms in mice. Inhibition of lncRNA XIST induces Leydig cell apoptosis through the miR-145a-5p/SIRT1 axis in the progression of LOH.


Assuntos
Hipogonadismo , MicroRNAs , RNA Longo não Codificante , Animais , Humanos , Masculino , Camundongos , Apoptose , Proliferação de Células/genética , Peróxido de Hidrogênio , Hipogonadismo/genética , Hibridização in Situ Fluorescente , Células Intersticiais do Testículo/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/metabolismo , Sirtuína 1/genética , Testosterona/farmacologia
3.
Diagn Pathol ; 19(1): 35, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365810

RESUMO

BACKGROUND: Breast cancer is one of the most common diseases worldwide that affects women of reproductive age. miR-221 and miR-222 are two highly homogeneous microRNAs that play pivotal roles in many cellular processes and regulate the Wnt/ß-catenin signaling pathway. Curcumin (CUR), a yellow polyphenolic compound, targets numerous signaling pathways relevant to cancer therapy. The main aim of this study was to compare the ability of chitosan curcumin nanoparticle (CC-CUR) formulation with the curcumin in modulating miR-221 and miR-222 expression through Wnt/ß-catenin signaling pathway in MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cell lines. METHOD: Chitosan-cyclodextrin-tripolyphosphate containing curcumin nanoparticles (CC-CUR) were prepared. Cytotoxicity of the CUR and CC-CUR was evaluated. Experimental groups including CC-CUR, CUR and negative control were designed. The expression of miR-221 and miR-222 and Wnt/ß-catenin pathway genes was measured. RESULTS: The level of miR-221 and miR-222 and ß-catenin genes decreased in MCF-7 and MDA-MB-231 cells and WIF1 gene increased in all cells in CC-CUR group. However, the results in SK-BR-3 cell line were unexpected; since miRs and WIF1 gene expressions were increased following CC-CUR administration and ß-catenin decreased by administration of CUR. CONCLUSION: Although the composite form of curcumin decreased the expression of miR-221 and miR-222 in MCF-7 and MDA cells, with significant decreasing of ß-catenin and increasing of WIF1 gene in almost all three cell lines, we can conclude than this formulation exerts its effect mainly through the Wnt/ß-catenin pathway. These preliminary findings may pave the way for the use of curcumin nanoparticles in the treatment of some known cancers.


Assuntos
Neoplasias da Mama , Quitosana , Curcumina , MicroRNAs , Feminino , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Quitosana/farmacologia , Curcumina/farmacologia , Células MCF-7 , MicroRNAs/metabolismo , Via de Sinalização Wnt/genética , Nanopartículas
4.
Oncol Res ; 32(3): 463-476, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38370338

RESUMO

An important factor in the emergence and progression of osteosarcoma (OS) is the dysregulated expression of microRNAs (miRNAs). Transcription factor 7-like 1 (TCF7L1), a member of the T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family, interacts with the Wnt signaling pathway regulator ß-catenin and acts as a DNA-specific binding protein. This study sought to elucidate the impact of the interaction between miR-329-3p and TCF7L1 on the growth and apoptosis of OS and analyze the regulatory expression relationship between miRNA and mRNA in osteosarcoma cells using a variety of approaches. MiR329-3p was significantly downregulated, while TCF7L1 was considerably up-regulated in all examined OS cell lines. Additionally, a clinical comparison study was performed using the TCGA database. Subsequently, the regulatory relationship between miR-329-3p and TCF7L1 on the proliferation and apoptosis of OS cells was verified through in vitro and in vivo experiments. When miR-329-3p was transfected into the OS cell line, the expression of TCF7L1 decreased, the proliferation of OS cells was inhibited, the cytoskeleton disintegrated, and the nucleus condensed to form apoptotic bodies. The expression of proteins that indicate apoptosis increased simultaneously. The cell cycle was arrested in the G0/G1 phase, and the G1/S transition was blocked. The introduction of miR-329-3p also inhibited downstream Cyclin D1 of the Wnt pathway. Xenograft experiments indicated that the overexpression of miR-329-3p significantly inhibited the growth of OS xenografts in nude mice, and the expression of TCF7L1 and c-Myc in tumor tissues decreased. MiR-329-3p was significantly reduced in OS cells and played a suppressive role in tumorigenesis and proliferation by targeting TCF7L1 both in vitro and in vivo. Osteosarcoma cell cycle arrest and pathway inhibition were observed upon the regulation of TCF7L1 by miR-329-3p. Summarizing these results, it can be inferred that miR-329-3p exerts anticancer effects in osteosarcoma by inhibiting TCF7L1.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Animais , Camundongos , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , Fator 1 de Transcrição de Linfócitos T/genética , Fator 1 de Transcrição de Linfócitos T/metabolismo , Camundongos Nus , Linhagem Celular Tumoral , Proliferação de Células/genética , Osteossarcoma/patologia , Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica/genética
5.
Oncol Res ; 32(3): 489-502, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38370339

RESUMO

Different from necrosis, apoptosis, autophagy and other forms of cell death, ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated fatty acids under the action of iron divalent or lipoxygenase, leading to cell death. Apatinib is currently used in the third-line standard treatment of advanced gastric cancer, targeting the anti-angiogenesis pathway. However, Apatinib-mediated ferroptosis in vascular endothelial cells has not been reported yet. Tumor-secreted exosomes can be taken up into target cells to regulate tumor development, but the mechanism related to vascular endothelial cell ferroptosis has not yet been discovered. Here, we show that exosomes secreted by gastric cancer cells carry miR-214-3p into vascular endothelial cells and directly target zinc finger protein A20 to negatively regulate ACSL4, a key enzyme of lipid peroxidation during ferroptosis, thereby inhibiting ferroptosis in vascular endothelial cells and reducing the efficiency of Apatinib. In conclusion, inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib, thereby promoting the antiangiogenic effect of Apatinib, suggesting a potential combination therapy for advanced gastric cancer.


Assuntos
Ferroptose , MicroRNAs , Piridinas , Neoplasias Gástricas , Humanos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , MicroRNAs/genética , MicroRNAs/metabolismo
6.
Drug Des Devel Ther ; 18: 407-423, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38370565

RESUMO

Ethnopharmacological Relevance: Zishen Yutai pills (ZYP), a traditional Chinese patent medicine, was listed in China in 1981. It is composed of 15 traditional Chinese medicines and has the effects of regulating menstruation, helping pregnancy, and preventing abortion. In clinical practice, it is effective in preventing habitual and threatened miscarriages, and continuing to explore its mechanism of action is very meaningful research. Aim of the Study: To explore the possible mechanism of ZYP promoting angiogenesis at the maternal-fetal interface in recurrent spontaneous abortion (RSA). Materials and Methods: In vitro experiments, placental trophoblast cells (PTCs) were isolated from the placental tissue of RSA mice and divided into six groups: Control group, Model group, ZYP group, miR-187 inhibitor NC group, miR-18 7 inhibitor group, and miR-187 inhibitor+ZYP group. Cell viability and cell cycle were measured using CCK8 and flow cytometry, respectively. The expression levels of miR-187, VEGF, VEGF-R1, and VEGF-R2 were measured using RT-qPCR, WB, and IF staining. Animal experiments first establish an RSA mice model (CBA/J × DBA/2) and then randomly divide the mice into four groups (n=10): normal pregnancy group, RSA model group, ZYP group, and progesterone capsule group. Observed the changes in embryo absorption rate, pathological morphology of decidual tissue, and ultrastructure of vascular endothelial cells in each group of mice. RT-qPCR, WB, and IF staining methods were used to determine the expression of miR-187, VEGF, VEGF-R1, and VEGF-R2. Results: In vitro, ZYP promoted the viability of PTCs and regulated their cell cycle, and ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2 levels. miR-187 inhibitor showed the same effects, and further ZYP intervention enhanced the effects. In vivo, ZYP remarkably reduced embryo resorption rates, and improved the pathological morphology of decidual tissues and ultrastructure of vascular endothelial cells. Moreover, ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2. Conclusion: In summary, ZYP can regulate the expression of VEGF via miR-187, then promote the angiogenesis at the maternal-fetal interface, and playing a therapeutic role in RSA.


Assuntos
Aborto Habitual , Medicamentos de Ervas Chinesas , MicroRNAs , Humanos , Gravidez , Camundongos , Feminino , Animais , Fator A de Crescimento do Endotélio Vascular , Células Endoteliais/metabolismo , Placenta/metabolismo , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Aborto Habitual/tratamento farmacológico , Aborto Habitual/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo
7.
Aging (Albany NY) ; 16(3): 2736-2752, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38309290

RESUMO

Circular RNA (circRNA) is a novel type of RNA that plays an important role in the occurrence and development of many malignant tumors. However, the potential regulatory role and molecular mechanisms of circRNAs in cervical cancer (CC) are still not clear. Here, we explored circRNAs associated with CC from the Gene Expression Omnibus (GEO) datasets GSE113696 and GSE102686. We initially identified circ_0039787, which is derived from exons 2 to 3 of the C16orf70 gene. We observed that circ_0039787 is mainly located in the cytoplasm and is more stable than its linear counterpart, C16orf70. circ_0039787 is significantly upregulated in CC tissues and cells. In addition, functional gain and loss experiments demonstrated that circ_0039787 promotes the proliferation, migration, and invasion of CC cells in vitro and the growth of CC tumors in vivo. Mechanistically, circ_0039787 promotes CC tumor progression by competitively absorbing miR-877-5p to alleviate the inhibitory effect of miR-877-5p on Kirsten Rat Sarcoma viral oncogene homolog (KRAS) expression. Overall, our results suggest that circ_0039787 could serve as a promising diagnostic biomarker and potential therapeutic target for CC patients.


Assuntos
MicroRNAs , Neoplasias do Colo do Útero , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias do Colo do Útero/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Carcinogênese/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética
8.
Funct Integr Genomics ; 24(1): 24, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38315263

RESUMO

This study is aimed at investigating the roles of Toll-like receptor 4 (TLR4) and microRNA-7 (miR-7) in colorectal cancer (CRC) development and progression. We assessed TLR4 and miR-7 expression in CRC cells and tissues using reverse transcription-quantitative polymerase chain reaction. The relationship between miR-7 and TLR4 was analyzed through dual luciferase reporter assays. MTT, wound healing, and cell invasion assays were conducted to examine the effects of TLR4 and miR-7 on CRC cell proliferation, migration, and invasion. Western blotting was used to explore the involvement of the TRAF6/NF-κB signaling pathway. miR-7 was underexpressed in CRC, while TLR4 levels were increased. miR-7 negatively regulated TLR4 expression and its knockdown enhanced CRC cell proliferation, migration, and invasion. TLR4 knockdown had the opposite effects. The TRAF6/NF-κB pathway was linked to TLR4's role in tumor progression. miR-7 might inhibit TRAF6/NF-κB target a signaling pathway of TLR4 and promote CRC occurrence. miR-7 may therefore be used as a sensitive biomarker in CRC patients.


Assuntos
Neoplasias Colorretais , MicroRNAs , Humanos , NF-kappa B/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Fator 6 Associado a Receptor de TNF/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Colorretais/genética , Proliferação de Células
9.
Aging (Albany NY) ; 16(3): 2828-2847, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38319722

RESUMO

MicroRNA-124 (miR-124) is implicated in various neurological diseases; however, its significance in hypoxic-ischaemic brain damage (HIBD) remains unclear. This study aimed to elucidate the underlying pathophysiological mechanisms of miR-124 in HIBD. In our study performed on oxygen-glucose deprivation followed by reperfusion (OGD)/R-induced primary cortical neurons, a substantial reduction in miR-124 was observed. Furthermore, the upregulation of miR-124 significantly mitigated oxidative stress, apoptosis, and mitochondrial impairment. We demonstrated that miR-124 interacts with the signal transducer and activator of transcription 3 (STAT3) to exert its biological function using the dual-luciferase reporter gene assay. As the duration of OGD increased, miR-124 exhibited a negative correlation with STAT3. STAT3 overexpression notably attenuated the protective effects of miR-124 mimics, while knockdown of STAT3 reversed the adverse effects of the miR-124 inhibitor. Subsequently, we conducted an HIBD model in rats. In vivo experiments, miR-124 overexpression attenuated cerebral infarction volume, cerebral edema, apoptosis, oxidative stress, and improved neurological function recovery in HIBD rats. In summary, the neuroprotective effects of the miR-124/STAT3 axis were confirmed in the HIBD model. MiR-124 may serve as a potential biomarker with significant therapeutic implications for HIBD.


Assuntos
Hipóxia-Isquemia Encefálica , MicroRNAs , Ratos , Animais , Fator de Transcrição STAT3/genética , Hipóxia-Isquemia Encefálica/genética , MicroRNAs/metabolismo , Apoptose , Encéfalo/metabolismo , Estresse Oxidativo/genética , Glucose/farmacologia
10.
Fish Shellfish Immunol ; 146: 109432, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38331056

RESUMO

White Spot Disease is one of the most harmful diseases of the red tail shrimp, which can cause devastating economic losses due to the highest mortality up to 100% within a few days. MicroRNAs (miRNAs) are large class of small noncoding RNAs with the ability to post-transcriptionally repress the translation of target mRNAs. MiRNAs are considered to have a significant role in the innate immune response of crustaceans, particularly in relation to antiviral defense mechanisms. Numerous crustacean miRNAs have been verified to be required in host immune defense against viral infection, however, till present, the miRNAs functions of F. penicillatus defense WSSV infection have not been studied yet. Here in this study, for the first time, miRNAs involved in the F. penicillatus immune defense against WSSV infection were identified using high-throughput sequencing platform. A total of 432 miRNAs were obtained including 402 conserved miRNAs and 30 novel predicted miRNAs. Comparative analysis between the WSSV-challenged group and the control group revealed differential expression of 159 microRNAs in response to WSSV infection. Among these, 48 were up-regulated and 111 were down-regulated. Ten candidate MicroRNAs associated with immune activities were randomly selected for qRT-PCR analysis, which confirming the expression profiling observed in the MicroRNA sequencing data. As a result, most differentially expressed miRNAs were down-regulated lead to increase the expression of various target genes that mediated immune reaction defense WSSV infection, including genes related to signal transduction, Complement and coagulation cascade, Phagocytosis, and Apoptosis. Furthermore, the genes expression of the key members in Toll and Imd signaling pathways and apoptotic signaling were mediated by microRNAs to activate host immune responses including apoptosis against WSSV infection. These results will help to understand molecular defense mechanism against WSSV infection in F. penicillatus and to develop an effective WSSV defensive strategy in shrimp farming.


Assuntos
MicroRNAs , Penaeidae , Vírus da Síndrome da Mancha Branca 1 , Animais , Vírus da Síndrome da Mancha Branca 1/fisiologia , Hepatopâncreas , MicroRNAs/metabolismo , Imunidade Inata/genética , Fagocitose
11.
FASEB J ; 38(3): e23459, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38329343

RESUMO

Wound healing is facilitated by neoangiogenesis, a complex process that is essential to tissue repair in response to injury. MicroRNAs are small, noncoding RNAs that can regulate the wound healing process including stimulation of impaired angiogenesis that is associated with type-2 diabetes (T2D). Expression of miR-409-3p was significantly increased in the nonhealing skin wounds of patients with T2D compared to the non-wounded normal skin, and in the skin of a murine model with T2D. In response to high glucose, neutralization of miR-409-3p markedly improved EC growth and migration in human umbilical vein endothelial cells (HUVECs), promoted wound closure and angiogenesis as measured by increased CD31 in human skin organoids, while overexpression attenuated EC angiogenic responses. Bulk mRNA-Seq transcriptomic profiling revealed BTG2 as a target of miR-409-3p, where overexpression of miR-409-3p significantly decreased BTG2 mRNA and protein expression. A 3' untranslated region (3'-UTR) luciferase assay of BTG2 revealed decreased luciferase activity with overexpression of miR-409-3p, while inhibition had opposite effects. Mechanistically, in response to high glucose, miR-409-3p deficiency in ECs resulted in increased mTOR phosphorylation, meanwhile BTG-anti-proliferation factor 2 (BTG2) silencing significantly decreased mTOR phosphorylation. Endothelial-specific and tamoxifen-inducible miR-409-3p knockout mice (MiR-409IndECKO ) with hyperglycemia that underwent dorsal skin wounding showed significant improvement of wound closure, increased blood flow, granulation tissue thickness (GTT), and CD31 that correlated with increased BTG2 expression. Taken together, our results show that miR-409-3p is a critical mediator of impaired angiogenesis in diabetic skin wound healing.


Assuntos
Diabetes Mellitus Tipo 2 , Proteínas Imediatamente Precoces , MicroRNAs , Proteínas Supressoras de Tumor , Animais , Humanos , Camundongos , Proliferação de Células/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas Imediatamente Precoces/genética , Luciferases , Camundongos Obesos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro , Serina-Treonina Quinases TOR , Proteínas Supressoras de Tumor/genética , Cicatrização/genética
12.
Medicine (Baltimore) ; 103(5): e35859, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38306545

RESUMO

This study aimed to determine the potential mechanisms through which long noncoding (Lnc) RNA cancer susceptibility candidate 15 (CASC15) affects hepatocellular carcinoma (HCC). We retrieved HCC RNA-seq and clinical information from the UCSC Xena database. The differential expression (DE) of CASC15 was detected. Overall survival was analyzed using Kaplan-Meier (K-M) curves. Molecular function and signaling pathways affected by CASC15 were determined using Gene Set Enrichment Analysis. Associations between CASC15 and the HCC microenvironment were investigated using immuno-infiltration assays. A differential CASC15-miRNA-mRNA network and HCC-specific CASC15-miRNA-mRNA ceRNA network were constructed. The overexpression of CASC15 in HCC tissues was associated with histological grade, clinical stage, pathological T stage, poor survival, more complex immune cell components, and 12 immune checkpoints. We identified 27 DE miRNAs and 270 DE mRNAs in the differential CASC15-miRNA-mRNA network, and 10 key genes that were enriched in 12 cancer-related signaling pathways. Extraction of the HCC-specific CASC15-miRNA-mRNA network revealed that IGF1R, MET, and KRAS were associated with HCC progression and occurrence. Our bioinformatic findings confirmed that CASC15 is a promising prognostic biomarker for HCC, and elevated levels in HCC are associated with the tumor microenvironment. We also constructed a disease-specific CASC15-miRNA-mRNA regulatory ceRNA network that provides a new perspective for the precise indexing of patients with elevated levels of CASC15.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Hepáticas/patologia , RNA Mensageiro/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Microambiente Tumoral/genética
13.
Annu Rev Physiol ; 86: 225-253, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38345906

RESUMO

Exosomes are small extracellular vesicles that carry lipids, proteins, and microRNAs (miRNAs). They are released by all cell types and can be found not only in circulation but in many biological fluids. Exosomes are essential for interorgan communication because they can transfer their contents from donor to recipient cells, modulating cellular functions. The miRNA content of exosomes is responsible for most of their biological effects, and changes in exosomal miRNA levels can contribute to the progression or regression of metabolic diseases. As exosomal miRNAs are selectively sorted and packaged into exosomes, they can be useful as biomarkers for diagnosing diseases. The field of exosomes and metabolism is expanding rapidly, and researchers are consistently making new discoveries in this area. As a result, exosomes have great potential for a next-generation drug delivery platform for metabolic diseases.


Assuntos
Exossomos , Doenças Metabólicas , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Biomarcadores/metabolismo , Doenças Metabólicas/metabolismo
14.
Phytomedicine ; 125: 155359, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38301300

RESUMO

BACKGROUND: Myocardial ischemia/reperfusion injury (MIRI) poses a formidable challenge to cardiac reperfusion therapy due to the absence of effective clinical interventions. Methylation of N6-methyladenosine (m6A), which is the most common post-transcriptional modifications occurring within mammalian mRNA, is believed to be involved in MIRI by modulating autophagy. MicroRNAs (miRNAs) play a crucial role in regulating gene expression at the post-transcriptional level and have been implicated in the regulation of m6A methylation. Suxiao Jiuxin Pill (SJP) is extensively used in China for the clinical treatment of angina pectoris and confers benefits to patients with acute coronary syndrome who have received percutaneous coronary intervention. However, the precise mechanisms underlying SJP intervention in MIRI remain unclear. PURPOSE: This study aimed to demonstrate, both in vivo and in vitro, that SJP could alleviate autophagy in MIRI by regulating miR-193a-3p to target and upregulate the demethylase ALKBH5. METHODS: An in vitro hypoxia/reoxygenation model was established using H9c2 cells, while an in vivo MIRI model was established using Wistar rats. A lentivirus harboring the precursor sequence of miR-193a-3p was employed for its overexpression. Adeno-associated viruses were used to silence both miR-193a-3p and ALKBH5 expressions. Cardiac function, infarct size, and tissue structure in rats were assessed using echocardiography, triphenyl tetrazolium chloride (TTC) staining, and HE staining, respectively. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was employed to detect the levels of apoptosis in rat cardiac tissue. m6A methylation levels were assessed using colorimetry. GFP-RFP-LC3B was used to monitor autophagic flux and transmission electron microscopy was used to evaluate the development of autophagosomes. Western Blot and qRT-PCR were respectively employed to assess the levels of autophagy-related proteins and miR-193a-3p. RESULTS: SJP alleviated autophagy, preserved cardiac function, and minimized myocardial damage in the hearts of MIRI rats. SJP attenuated autophagy in H/R H9C2 cells. Elevated levels of miR-193a-3p were observed in the cardiac tissues of MIRI rats and H/R H9C2 cells, whereas SJP downregulated miR-193a-3p levels in these models. ALKBH5, a target gene of miR-193, is negatively regulated by miR-193a-3p. Upon overexpression of miR-193a-3p or silencing of ALKBH5, m6A methylation decreased, and the autophagy-attenuating effects of SJP and its components, senkyunolide A and l-borneol, were lost in H/R H9C2 cells, whereas in MIRI rats, these effects were not abolished but merely weakened. Further investigation indicated that the METTL3 inhibitor STM2475, combined with the silencing of miR-193a-3p, similarly attenuated autophagy in the hearts of MIRI rats. This suggests that a reduction in m6A methylation is involved in autophagy alleviation. CONCLUSION: We demonstrated that SJP mitigates autophagy in MIRI by downregulating miR-193a-3p, enhancing ALKBH5 expression, and reducing m6A methylation, a mechanism potentially attributed to its constituents, senkyunolide A and l-borneol.


Assuntos
Canfanos , MicroRNAs , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Humanos , Ratos , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos Wistar , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Autofagia , Reperfusão , Apoptose , Miócitos Cardíacos/metabolismo , Mamíferos/genética , Mamíferos/metabolismo , Metiltransferases/metabolismo , Metiltransferases/farmacologia , Homólogo AlkB 5 da RNA Desmetilase/metabolismo
15.
Kaohsiung J Med Sci ; 40(2): 119-130, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38305705

RESUMO

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative condition primarily affecting the elderly. Emerging research suggests that microRNAs (miRNAs) play a role in the development of AD. This study investigates the impact of miR-107-5p on neurological damage, oxidative stress, and immune responses in AD. We utilized APP/PS1 mice as AD mouse models and C57BL/6 J mice as controls. AD mice received treatment with agomir miR-107-5p (to overexpress miR-107-5p) or BAY11-7082 (an NF-κB pathway inhibitor). We evaluated learning and memory abilities through the Morris water maze test. Histopathological changes, hippocampal neuron distribution, and apoptosis were assessed using hematoxylin-eosin, Nissl, and TUNEL staining. Reactive oxygen species (ROS) levels, amyloid-Aß (Aß1-40/42) contents, and inflammatory factors (TNF-α, IL-6, IL-1ß) in hippocampal tissues were measured using ROS kits and enzyme-linked immunosorbent assay (ELISA). Microglial activation in hippocampal tissues was observed under a fluorescence microscope. miR-107-5p's binding to TLR4 was predicted via the TargetScan database and confirmed through a dual-luciferase assay. miR-107-5p expression, along with TLR4, APOE, and TREM2 in hippocampal tissue homogenate, and NF-κB p65 protein expression in the nucleus and cytoplasm were assessed via RT-qPCR and Western blot. Overexpression of miR-107-5p ameliorated hippocampal neurological damage, oxidative stress, and immune responses. This was evidenced by improved enhanced learning/memory abilities, reduced Aß1-40 and Aß1-42 levels, diminished neuronal injuries, decreased ROS and TNF-α, IL-6, and IL-1ß levels, increased APOE and TREM2 levels, and suppressed microglial activation. miR-107-5p directly targeted and inhibited TLR4 expression, leading to reduced nuclear translocation of NF-κB p65 in the NF-κB pathway. Inhibition of the NF-κB pathway similarly improved neurological damage, oxidative stress, and immune response in AD mice. miR-107-5p exerts its beneficial effects by suppressing the TLR4/NF-κB pathway, ultimately ameliorating neurological damage, oxidative stress, and immune responses in AD mice.


Assuntos
Doença de Alzheimer , MicroRNAs , Humanos , Camundongos , Animais , Idoso , NF-kappa B/genética , NF-kappa B/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Doença de Alzheimer/genética , Transdução de Sinais/genética , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo/genética , Imunidade , Apolipoproteínas E/metabolismo
16.
Sci Rep ; 14(1): 4257, 2024 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383747

RESUMO

Necroptosis is a recently identified caspase-independent form of cell death which plays a significant role in the onset and progression of cancer. MicroRNAs (miRNAs) are vital for the development of uterine corpus endometrial carcinoma (UCEC) because they are an important regulatory component in necroptosis. This study developed a new necroptosis-related miRNAs profile to predict the prognosis of patients with UCEC. The TCGA-UCEC cohort's RNA sequencing data, consisting of 534 tumor samples and 33 normal samples, was downloaded. Ten differentially expressed miRNAs related to necroptosis were identified. A prediction model for necroptosis-related miRNAs was then created through COX regression and nomograms analysis. Clinical and pathological parameters were integrated to construct a nomogram and evaluate the model. Prognosis-related miRNAs were further used to predict target genes, and functional analysis was conducted to explore the potential mechanisms of these target genes. Subsequently, immune infiltration analysis was performed using transcriptome data to identify immune genes associated with prognosis, and the expression levels of target gene was validated using UCEC tissues. We identified 7 up-regulated miRNAs (hsa-miR-577, hsa-miR-7-5p, hsa-miR-210-3p, hsa-miR-210-5p, hsa-miR-200a-5p, hsa-miR-141-3p, hsa-miR-425-5p) and 3 down-regulated miRNAs (hsa-miR-7-2-3p, hsa-miR-383-5p, hsa-miR-29a-3p). The risk signature was based on univariate and multivariate COX analyses, constructed using 2 independent prognostic factors and miRNAs (hsa-miR-425-5p, hsa-miR-7-5p) associated with necroptosis. Nomograms demonstrated the prognostic value of risk level, age, FIGO stage, and histological type. Kaplan-Meier analysis revealed significant differences in overall survival (OS) outcomes associated with the expression of hsa-miR-425-5p (P < 0.001) and hsa-miR-7-5p (P = 0.015). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) investigations indicated that these miRNAs play crucial roles in tumor development, metastasis, and prognosis. Immune infiltration analysis showed decreased infiltration of CD8+ T cells, CD8+ T cells, NK cells, and M1 macrophages in normal tissues. Subsequently, a necroptosis-related immune gene significantly associated with prognosis (THRB) was identified, western blot and immunohistochemical staining confirmed the differential expression of THRB in normal endometrial tissues and tumor. Our findings demonstrate a close association between necroptosis and UCEC. The two necroptosis-related miRNAs used in this study may serve as valuable prognostic markers for UCEC patients, and are associated with immune cell infiltration. This suggests that necroptosis may be involved in the development of UCEC through its interaction with immune responses.


Assuntos
Neoplasias do Endométrio , MicroRNAs , Feminino , Humanos , Prognóstico , Necroptose/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Transcriptoma , Neoplasias do Endométrio/genética
17.
Int J Biol Sci ; 20(4): 1436-1451, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38385079

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with high incidence and mortality, accounting for approximately 90% of liver cancer. The development of HCC is a complex process involving the abnormal activation or inactivation of multiple signaling pathways. Transforming growth factor-ß (TGF-ß)/Small mothers against decapentaplegic (SMAD) signaling pathway regulates the development of HCC. TGF-ß activates intracellular SMADs protein through membrane receptors, resulting in a series of biological cascades. Accumulating studies have demonstrated that TGF-ß/SMAD signaling plays multiple regulatory functions in HCC. However, there is still controversy about the role of TGF-ß/SMAD in HCC. Because it involves different pathogenic factors, disease stages, and cell microenvironment, as well as upstream and downstream relationships with other signaling pathways. This review will summary the regulatory mechanism of the TGF-ß/SMAD signaling pathway in HCC, involving the regulation of different pathogenic factors, different disease stages, different cell populations, microenvironments, and the interaction with microRNAs. In addition, we also introduced small molecule inhibitors, therapeutic vaccines, and traditional Chinese medicine extracts based on targeting the TGF-ß/SMAD signaling pathway, which will provide future research direction for HCC therapy targeting the TGF-ß/SMAD signaling pathway.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais/genética , MicroRNAs/metabolismo , Proteínas Smad/metabolismo , Microambiente Tumoral
18.
Molecules ; 29(4)2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38398499

RESUMO

In this study, the expression and abundance of two candidate chicken (Gallus gallus; gga) microRNAs (miRNAs, miR), gga-miR-21-5p (miR-21) and gga-miR-126-5p (miR-126), have been analyzed in order to identify biomarkers for the traceability and quality of poultry meat. Two breeds of broiler chickens were tested: the most common Ross308 (fast-growing) and the high-quality Ranger Gold (slow-growing). A preliminary analysis of the two miRNAs expressions was conducted across various tissues (liver, lung, spleen, skeletal muscle, and kidney), and the three tissues (lung, spleen, and muscle) with a higher expression were chosen for further analysis. Using quantitative reverse transcription polymerase chain reaction (RT-qPCR), the expression of miRNAs in the three tissues of a total of thirteen animals was determined. The results indicate that miR-126 could be a promising biomarker for the lung tissue in the Ranger Gold (RG) breed (p < 0.01), thus suggesting a potential applicability for tracing hybrids. RG exhibits a significantly higher miR-126 expression in the lung tissue compared to the Ross308 broilers (R308), an indication of greater respiratory capacity and, consequently, a higher oxidative metabolism of the fast-growing hybrid. During sampling, two R308 broilers presented some anomalies, including airsacculitis, hepatic steatosis, and enlarged spleen. The expression of miR-126 and miR-21 was compared in healthy animals and in those presenting anomalies. Chickens with airsacculitis and hepatic steatosis showed an up-regulation of miR-21 and miR-126 in the most commercially valuable tissue, the skeletal muscle or breast (p < 0.05).


Assuntos
MicroRNAs , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Galinhas/genética , Galinhas/metabolismo , Aves Domésticas , Músculo Esquelético/metabolismo , Inocuidade dos Alimentos
19.
Brain Inj ; 38(3): 194-201, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38297513

RESUMO

AIM: To explore the potential role of microRNA miR-221-5p on the angiopoietin-1 (Ang-1)/Ang-2/Tie-2 signaling axis after subarachnoid hemorrhage (SAH) in a rat model. METHODS: Aspects of the rat's behavior were measured using the Kaoutzanis scoring system to test neurological responses. This included feeding behavior, body contraction, motor, and eye-opening responses. Brain sections were studied using transmission electron microscopy and Evans blue extravasation. Levels of Ang-1, Ang-2, and Tie-2 were determined by Western blot, while miR-221-5p was quantified using stem-loop real-time quantitative PCR (RT-qPCR). RESULTS: The SAH group responded worse to the neurological response test than the sham-operated group. The intercellular space was widened in the SAH group, but not in the sham-operated group. Evans blue dye leaked significantly more into brain tissue cells of the SAH group. Stem-loop qRT-PCR showed elevated miR-221-5p levels. Additionally, Ang-1 and Tie-2 were reduced but Ang-2 expression was increased after SAH. This led to a significant reduction of the Ang-1/Ang-2 ratio in the brain tissue, which was associated with the destruction of the blood-brain barrier. CONCLUSION: The data indicate that miR-221-5p might regulate blood-brain barrier dysfunction through the Ang-1/Ang-2/Tie-2 signaling axis, suggesting that it should be further investigated as a potential novel biomarker.


Assuntos
MicroRNAs , Hemorragia Subaracnóidea , Ratos , Animais , Barreira Hematoencefálica , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Azul Evans/metabolismo , MicroRNAs/metabolismo
20.
Aging (Albany NY) ; 16(3): 2702-2714, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38309291

RESUMO

OBJECTIVE: Tendinopathy is influenced by multiple factors, including chronic inflammation and aging. Senescent cells exhibit characteristics such as the secretion of matrix-degrading enzymes and pro-inflammatory cytokines, collectively known as senescence-associated secretory phenotypes (SASPs). Many of these SASP cytokines and enzymes are implicated in the pathogenesis of tendinopathy. MicroRNA-146a (miR-146a) blocks senescence by targeting interleukin-1ß (IL-1ß) receptor-associated kinase 4 (IRAK-4) and TNF receptor-associated factor 6 (TRAF6), thus inhibiting NF-κB activity. The aims of this study were to (1) investigate miR-146a expression in tendinopathic tendons and (2) evaluate the role of miR-146a in countering senescence and SASPs in tendinopathic tenocytes. METHODS: MiR-146a expression was assessed in human long head biceps (LHB) and rat tendinopathic tendons by in situ hybridization. MiR-146a over-expression in rat primary tendinopathic tenocytes was achieved by lentiviral vector-mediated precursor miR-146a transfer (LVmiR-146a). Expression of various senescence-related markers was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunoblotting and immunofluorescence. MiR-146a expression showed a negative correlation with the severity of tendinopathy in human and rat tendinopathic tendons (p<0.001). RESULTS: Tendinopathic tenocyte transfectants overexpressing miR-146a exhibited downregulation of various senescence and SASP markers, as well as the target molecules IRAK-4 and TRAF6, and the inflammatory mediator phospho-NF-κB. Additionally, these cells showed enhanced nuclear staining of high mobility group box 1 (HMGB1) compared to LVmiR-scramble-transduced controls in response to IL-1ß stimulation. CONCLUSIONS: We demonstrate that miR-146a expression is negatively correlated with the progression of tendinopathy. Moreover, its overexpression protects tendinopathic tenocytes from SASPs and senescence through the IRAK-4/TRAF6/NF-kB pathway.


Assuntos
MicroRNAs , Tendinopatia , Animais , Humanos , Ratos , Citocinas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fenótipo Secretor Associado à Senescência , Tendinopatia/genética , Tenócitos/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo
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