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1.
J Mol Neurosci ; 72(3): 468-481, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34580818

RESUMO

Neuropathic pain (NP) involves metabolic processes that are regulated by metabolic genes and their non-coding regulator genes such as microRNAs (miRNAs). Here, we aimed at exploring the key miRNA signatures regulating metabolic genes involved in NP pathogenesis. We downloaded NP-related data from public databases and identified differentially expressed microRNAs (miRNAs) and mRNAs through differential gene expression analysis. The miRNA target prediction was performed, and integration with the differentially expressed metabolic genes (DEMGs) was used for constructing the miRNA-DEMG network. Subsequently, functional enrichment analysis and protein-protein interaction (PPI) analysis were performed to explore the role of DEMGs in the regulatory network. The drug prediction was performed based on the DEMGs in the miRNA-DEMG network. A total of 8251 differentially expressed mRNAs (4193 upregulated and 4058 downregulated), and 959 differentially expressed miRNAs (455 upregulated and 504 downregulated) were identified. Moreover, after target gene prediction, a miRNA-DEMG network composed of 22 miRNAs and 113 mRNAs was constructed. The network was constituted of 135 nodes and 236 edges. We found that DEMGs in the network were mainly enriched in metabolic pathways and metabolic processes. A total of 1200 drugs were predicted as potential therapeutics for NP based on the differentially expressed genes, while 170 drugs were predicted for the DEMGs in the miRNA-DEMG network. Conclusively, our study predicted drugs that may be effective against the metabolic changes induced by miRNA dysregulation in NP. This information will help further reveal the pathological mechanism of NP and provide more treatment options for NP patients.


Assuntos
MicroRNAs , Neuralgia , Biologia Computacional , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
2.
Int J Mol Med ; 49(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35137921

RESUMO

The aim of the present study was to elucidate the effect of resveratrol on non­alcoholic steatohepatitis (NASH), and the molecular basis in mice and Hepa1­6 cells, in order to verify its therapeutic effect. C57BL/6J mice were fed a methionine­choline­deficient (MCD) diet to induce steatohepatitis and were treated with resveratrol. Mouse sera were collected for biochemical analysis and enzyme­linked immunosorbent assay, and livers were obtained for histological observation, and mmu­microRNA (miR)­599 and inflammation­related gene expression analysis. Hepa1­6 cells were treated with palmitic acid to establish a NASH cell model, and were then treated with resveratrol, or transfected with mmu­miR­599 mimic, mmu­miR­599 inhibitor or recombinant pregnane X receptor (PXR) plasmid. Subsequently, the cells were collected for mmu­miR­599 and inflammation­related gene expression analysis. Reverse transcription­quantitative polymerase chain reaction and western blotting were used to assess mmu­miR­599 expression levels, and the mRNA and protein expression levels of PXR and inflammation­related genes. The binding site of mmu­miR­599 in the PXR mRNA was verified by the luciferase activity assay. Mice fed an MCD diet for 4 weeks exhibited steatosis, focal necrosis and inflammatory infiltration in the liver. Resveratrol significantly reduced serum aminotransferase and malondialdehyde levels, and ameliorated hepatic injury. These effects were associated with reduced mmu­miR­599 expression, enhanced PXR expression, and downregulated levels of nuclear factor­κB, tumour necrosis factor­α, interleukin (IL)­1ß, IL­6, NOD­like receptor family pyrin domain­containing protein 3 and signal transducer and activator of transcription 3. Administration of the mmu­miR­599 mimic inhibited PXR expression in Hepa1­6 cells, whereas the mmu­miR­599 inhibitor exerted the opposite effect. A binding site for mmu­miR­599 was identified in the PXR mRNA sequence. Furthermore, overexpression of PXR inhibited the expression of inflammatory factors in Hepa1­6 cells. The present study provided evidence for the protective role of resveratrol in ameliorating steatohepatitis through regulating the mmu­miR­599/PXR pathway and the consequent suppression of related inflammatory factors. Resveratrol may serve as a potential candidate for steatohepatitis management.


Assuntos
MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Animais , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor de Pregnano X/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêutico
3.
Mol Cell Endocrinol ; 544: 111541, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34973370

RESUMO

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) accounts for a big portion of non-traumatic ONFH; nevertheless, the pathogenesis has not yet been fully understood. GC-induced endothelial dysfunction might be a major contributor to ONFH progression. The Gene Expression Omnibus (GEO) dataset was analyzed to identify deregulated miRNAs in ONFH; among deregulated miRNAs, the physiological functions of miR-122-5p on ONFH and endothelial dysfunction remain unclear. In the present study, miR-122-5p showed to be under-expressed within GC-induced ONFH femoral head tissues and GC-stimulated bone microvascular endothelial cells (BMECs). In human umbilical vein endothelial cells (HUVECs) and BMECs, GC stimulation significantly repressed cell viability, promoted cell apoptosis and increased the mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1ß, and IFN-γ. After overexpressing miR-122-5p, GC-induced endothelial injuries were attenuated, as manifested by rescued cell viability, cell migration, and tube formation capacity. Regarding the BMP signaling, GC decreased the protein levels of BMP-2/6/7 and SMAD-1/5/8, whereas miR-122-5p overexpression significantly attenuated the inhibitory effects of GC on these proteins. Online tool and experimental analyses revealed the direct binding between miR-122-5p and GREM2, a specific antagonist of BMP-2. In contrast to miR-122-5p overexpression, GREM2 overexpression aggravated GC-induced endothelial injury; GREM2 silencing partially eliminated the effects of miR-122-5p inhibition on GC-stimulated HUVECs and BMECs. Finally, GREM2 silencing reversed the suppressive effects of GC on BMP-2/6/7 and SMAD-1/5/8, and attenuated the effects of miR-122-5p inhibition on these proteins upon GC stimulation. Conclusively, the present study demonstrates a miR-122-5p/GREM2 axis modulating the GC-induced endothelial damage via the BMP/SMAD signaling. Considering the critical role of endothelial function in ONFH pathogenesis, the in vivo role and clinical application of the miR-122-5p/GREM2 axis is worthy of further investigation.


Assuntos
Glucocorticoides , MicroRNAs , Apoptose , Citocinas/metabolismo , Cabeça do Fêmur/metabolismo , Cabeça do Fêmur/patologia , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais
4.
Front Endocrinol (Lausanne) ; 13: 891313, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909545

RESUMO

Osteoporosis is a bone metabolic disorder characterized by decreased bone density and deteriorated microstructure, which increases the risk of fractures. The imbalance between bone formation and bone resorption results in the occurrence and progression of osteoporosis. Osteoblast-mediated bone formation, osteoclast-mediated bone resorption and macrophage-regulated inflammatory response play a central role in the process of bone remodeling, which together maintain the balance of the osteoblast-osteoclast-macrophage (OB-OC-MΦ) axis under physiological conditions. Bone formation and bone resorption disorders caused by the imbalance of OB-OC-MΦ axis contribute to osteoporosis. Many microRNAs are involved in the regulation of OB-OC-MΦ axis homeostasis, with microRNA-23a (miR-23a) being particularly crucial. MiR-23a is highly expressed in the pathological process of osteoporosis, which eventually leads to the occurrence and further progression of osteoporosis by inhibiting osteogenesis, promoting bone resorption and inflammatory polarization of macrophages. This review focuses on the role and mechanism of miR-23a in regulating the OB-OC-MΦ axis to provide new clinical strategies for the prevention and treatment of osteoporosis.


Assuntos
Reabsorção Óssea , MicroRNAs , Osteoporose , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Humanos , Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/etiologia , Osteoporose/genética , Osteoporose/fisiopatologia , Osteoporose/terapia
5.
Comput Math Methods Med ; 2022: 9304392, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35912140

RESUMO

Objective: Long noncoding RNA neuroblastoma-associated transcript 1 (NBAT1) is implicated in the progression of various cancers. Nevertheless, its biological function in endometrial cancer (EC) remains unknown. Methods: The levels of NBAT1, miR-21-5p, and PTEN in EC cells and EC tissues were examined by RT-qPCR. Western blot was carried out to assess the protein expression of PTEN. The dual-luciferase reporter assay was conducted to explore the interactions among NBAT1, miR-21-5p, and PTEN. The effect of NBAT1 on EC proliferation, metastasis, and apoptosis was evaluated by CCK-8, transwell assays, wound healing, and flow cytometry. miR-21-5p mimics or NBAT1+miR-21-5p were transfected into HEC-1A and Ishikawa cells to investigate whether NBAT1 regulated EC tumorigenesis via sponging miR-21-5p. Results: NBAT1 is downregulated, and miR-21-5p is upregulated in EC cells and tumor tissues. Overexpression of NBAT1 inhibits the proliferation, migration, and invasion abilities of EC cells and facilitated apoptosis. NBAT1 directly binds and negatively regulates miR-21-5p in EC. miR-21-5p mimics reverses the effect of lncRNA NBAT1 overexpression on the proliferation and migration of EC cells. PTEN is a downstream gene of miR-21-5p. lncRNA NBTA1 elevates PTEN expression via sponging miR-21-5p. Conclusions: lncRNA NBAT1 acts as a tumor suppressor in EC via regulating PTEN through sponging miR-21-5p.


Assuntos
Neoplasias do Endométrio , MicroRNAs , Neuroblastoma , RNA Longo não Codificante , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
6.
Comput Math Methods Med ; 2022: 9088727, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35912153

RESUMO

Objective: Acute inflammation and oxidative stress are present in large numbers in patients with acute lung injury (ALI). This investigation probed miR-135a-5p/TBK1 axis within ALI together with its new therapeutic target. Methods: MLE-12 cultures were treated with lipopolysaccharide (LPS) and transfected with miR-135a-5p mimics or TBK1 vector. An ALI mouse model was also established. Analysis was done on the relationships between TBK1 and miR-135a-5p. Inflammatory components, SOD, MDA, and ROS content were all assessed. Results: Obvious inflammatory lesions were observed in lung tissues of ALI mice. Overexpression of miR-135a-5p or TBK1 knockdown remarkably decreased IL-1ß, IL-6, and TNF-α serum concentrations and increased IL-10 level within lung tissues. Activated NRF2/TXNIP pathway and oxidative stress were additionally found within ALI murines, which were regulated by miR-315a-5p and TBK1. Further research revealed that miR-135a-5p negatively regulated TBK1 expression to mediate proinflammatory response and oxidative stress. Conclusion: miR-135a-5p targeted TBK1 to regulate inflammatory/oxidative stress responses in ALI. Such results might bring a new potential target for ALI treatment.


Assuntos
Lesão Pulmonar Aguda , MicroRNAs , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Animais , Antioxidantes , Proteínas de Transporte , Lipopolissacarídeos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/genética , Proteínas Serina-Treonina Quinases/genética , Tiorredoxinas/metabolismo
7.
Comput Math Methods Med ; 2022: 6058720, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35912155

RESUMO

Lung cancer has a higher incidence and mortality rate than other cancers, and over 80% of lung cancer cases were classified as non-small-cell lung cancer (NSCLC). TRIM66 is one of the crucial members of TRIM, which has a deep connection with the behavior of various malignant tumors. But it remains uncertain regarding its exact function and underlying mechanism in NSCLC. In our study, qRT-PCR and Western blot were employed to validate that TRIM66 was overexpressed in NSCLC. The migration, invasion, and epithelial-mesenchymal transformation (EMT) progression of NSCLC cells were determined by Western blotting and Transwell experiments after knocking down TRIM66, and it was found that knockdown TRIM66 inhibited the migration, invasion, and EMT processes of NSCLC cells. Next, the binding relationship between TRIM66 and MMP9 was verified by Co-IP assay. After determining the interaction between them, rescue assays showed that overexpression of MMP9 was capable to promote the migration, invasion, and EMT of NSCLC cells. However, the transfection of si-TRIM66 could reverse this facilitating effectiveness. To sum up, we concluded that by targeting MMP9, TRIM66 could exert a cancer-promoting role in the progression of NSCLC cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/metabolismo , Invasividade Neoplásica/genética
8.
Mol Med Rep ; 26(4)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35920180

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is a leading cause of pulmonary hypertension. The present study investigated the mechanisms of long non­coding RNA growth arrest­specific transcript 5 (GAS5) on spermidine (SP)­induced autophagy. Pulmonary artery endothelial cells (PAECs) were collected from patients with CTEPH and the rat model. Immunofluorescence, Western blots, reverse transcription­quantitative polymerase chain reaction, bioinformatics, rapid amplification of cDNA ends assays, luciferase reporter assays, RNA­binding protein immunoprecipitation assays, GFP­LC3 adenoviruses, tfLC3 assays and transmission electron microscopy were performed. The results revealed that SP­induced autophagy increased GAS5 in PAECs. The upregulation of GAS5 enhanced and the downregulation of GAS5 reversed the roles of SP in PAECs. Furthermore, GAS5 promoted SP­induced autophagy in PAECs by targeting miRNA­31­5p. The miRNA­31­5p mimic suppressed and the inhibitor promoted SP­induced autophagy. Furthermore, N­Acetyltransferase 8 Like (NAT8L) was a target gene of miRNA­31­5p and knockdown of NAT8L inhibited the autophagic levels of PAECs. In vivo, SP treatment decreased miRNA­31­5p and increased NAT8L levels, which was reversed by the knockdown of GAS5. The downregulation of GAS5 abolished the stimulatory role of SP in PAECs of CTEPH rats. In conclusion, GAS5 promoted SP­induced autophagy through miRNA­31­5p/NAT8L signaling pathways in vitro and in vivo and GAS5 may be a promising molecular marker for therapies of CTEPH.1.


Assuntos
Hipertensão Pulmonar , MicroRNAs , RNA Longo não Codificante , Acetiltransferases/genética , Animais , Autofagia , Células Endoteliais/metabolismo , MicroRNAs/metabolismo , Artéria Pulmonar/metabolismo , RNA Longo não Codificante/metabolismo , Ratos , Espermidina
9.
Sci Rep ; 12(1): 13503, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931808

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer. Identification of ccRCC likely to progress, despite an apparent low risk at the time of surgery, represents a key clinical issue. From a cohort of adult ccRCC patients (n = 443), we selected low-risk tumors progressing within a 5-years average follow-up (progressors: P, n = 8) and non-progressing (NP) tumors (n = 16). Transcriptome sequencing, miRNA sequencing and proteomics were performed on tissues obtained at surgery. We identified 151 proteins, 1167 mRNAs and 63 miRNAs differentially expressed in P compared to NP low-risk tumors. Pathway analysis demonstrated overrepresentation of proteins related to "LXR/RXR and FXR/RXR Activation", "Acute Phase Response Signaling" in NP compared to P samples. Integrating mRNA, miRNA and proteomic data, we developed a 10-component classifier including two proteins, three genes and five miRNAs, effectively differentiating P and NP ccRCC and capturing underlying biological differences, potentially useful to identify "low-risk" patients requiring closer surveillance and treatment adjustments. Key results were validated by immunohistochemistry, qPCR and data from publicly available databases. Our work suggests that LXR, FXR and macrophage activation pathways could be critically involved in the inhibition of the progression of low-risk ccRCC. Furthermore, a 10-component classifier could support an early identification of apparently low-risk ccRCC patients.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , MicroRNAs , Adulto , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/patologia , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
BMC Cancer ; 22(1): 857, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931993

RESUMO

BACKGROUND: Liver cirrhosis is a well-known risk factor for hepatocellular carcinoma (HCC). However, some HCC cases can also originate from non-cirrhotic livers. The aim of this study was to identify key circular RNAs (circRNAs) associated with the tumorigenesis of non-cirrhotic liver disease. METHODS: The differently expressed circRNAs between non-cirrhotic and cirrhotic HCCs were assessed with use of high-throughput circRNAs sequencing and validated with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Potential biological functions of these dysregulated circRNAs were predicted with use of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A circRNA-miRNA-mRNA regulation network was constructed as achieved with use of miRanda software and visualized using Cytoscape software. Biological functions of the four most prominent dysregulated circRNAs identified were confirmed by in vitro experiments. Moreover, possible translations of these dysregulated circRNAs were also predicted. RESULTS: A total of 393 dysregulated circRNAs were identified between non-cirrhotic and cirrhotic HCC, including 213 that were significantly up-regulated and 180 significantly down-regulated circRNAs. Expression levels of the six most prominent dysregulated circRNAs were further validated using qRT-PCR. Many tumor related miRNAs were involved in the circRNA-miRNA-mRNA networks, including miR-182-5p, miR-561-3p, miR-125a-5p, miR-145, miR-23b-3p and miR-30e-3p, and downstream mRNAs of dysregulated circRNAs were significantly related with biological processes involved in the progression of tumors, including proliferation, migration, differentiation, and focal adhesion. Results from the in vitro experiments demonstrated that the most prominent dysregulated circRNAs exerted notable effects upon the proliferation and migration of HCC cells. Finally, we also identified 19 dysregulated circRNAs having potential for the coding of functional peptides. CONCLUSION: The results of this present study indicate that circRNAs may play important roles in tumorigenesis of non-cirrhotic HCC. Such findings provide some novel insights and pave the way for the development of future studies directed at investigating the initiation and treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Carcinogênese , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , MicroRNAs/metabolismo , RNA/genética , RNA/metabolismo , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA
11.
Contrast Media Mol Imaging ; 2022: 6094409, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935308

RESUMO

Purpose: The aim of this study is to explore the diagnostic value of prostate-specific antigen (PSA) combined with serum miRNA-149 expression in prostate cancer (PCa) by conducting experiments and bioinformatics analysis. Patients and Methods. 50 PCa patients were enrolled on the experimental group from January 2020 to December 2021. 56 patients with benign prostatic hyperplasia (BPH) were selected as the control group at the same time. Real-time fluorescent quantitative PCR was applied to investigate the miRNA-149 expression. PSA was detected by using a chemiluminescence meter using Abbott i4000. Applying bioinformatics analysis, we explored the expression of hsa-miR-149 in PCa in The Cancer Genome Atlas (TCGA) database. Kaplan-Meier analyses were used to evaluate the prognostic value, and the ROC curve was applied. Results: The expression level of miRNA-149 in the PCa group was significantly higher than that in the BPH group (P < 0.05). The PSA level in the PCa group was also significantly higher than that in the BPH group (P < 0.05). TCGA data analysis revealed that PCa tissues had significantly increased hsa-miR-149 expression. The results of survival analysis showed that patients with high expression of hsa-miR-149 had better prognosis. Additionally, the pathological N stage of PCa correlates with the hsa-miR-149 expression level (P = 0.002). According to ROC curve analysis, the region under the curve was 0.653, 95% CI: 0.576-0.730. Conclusion: High expression of serum miRNA-149 is associated with PCa patients. Although combined PSA did not improve the diagnostic efficacy, miRNA-149 has high specificity in the diagnosis of PCa. miRNA-149 might be a novel marker for early diagnosis and prognosis assessment for PCa.


Assuntos
MicroRNAs , Hiperplasia Prostática , Neoplasias da Próstata , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biologia Computacional , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Antígeno Prostático Específico , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo
12.
FASEB J ; 36(9): e22467, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35929417

RESUMO

Although long non-coding RNAs (lncRNAs) are reported to regulate follicular development and reproductive disease pathogenesis, the underlying mechanisms have not been elucidated. In this study, lncRNA expression profiling of different-sized healthy follicles from Hu sheep with different prolificacy revealed 50 613 lncRNAs. Numerous lncRNAs were differentially expressed among different comparison groups. This study characterized one novel transcript, lncRNA-412.25 (from healthy follicles with a diameter of >5 mm), which was predominantly expressed in the high prolificacy group and localized to the cytoplasm of granulosa cells (GCs). LncRNA-412.25 knockdown promoted and inhibited Hu sheep GC apoptosis and proliferation, respectively. Interestingly, lncRNA-412.25 could directly bind to miR-346, which can target the gene of leukemia inhibitory factor (LIF). Knockdown of lncRNA-412.25 promoted GC apoptosis by downregulating LIF expression, where this effect was attenuated by miR-346. Moreover, the miR-346 inhibitor mitigated the lncRNA-412.25 knockdown-induced downregulation of phosphorylated protein of signal transducer and activator of transcription 3 (STAT3), which was validated using immunofluorescence analysis. Our results demonstrated that lncRNA-412.25 regulates GC proliferation and apoptosis in Hu sheep by binding to miR-346 and then activating the LIF/STAT3 pathway. These findings provide novel insights into the mechanisms underlying prolificacy in sheep.


Assuntos
MicroRNAs , RNA Longo não Codificante , Animais , Apoptose/genética , Proliferação de Células/fisiologia , Feminino , Células da Granulosa/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Ovinos , Transdução de Sinais
13.
FASEB J ; 36(9): e22486, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35929425

RESUMO

Neointimal hyperplasia (NIH) after revascularization is a key unsolved clinical problem. Various studies have shown that attenuation of the acute inflammatory response on the vascular wall can prevent NIH. MicroRNA146a-5p (miR146a-5p) has been reported to show anti-inflammatory effects by inhibiting the NF-κB pathway, a well-known key player of inflammation of the vascular wall. Here, a nanomedicine, which can reach the vascular injury site, based on polymeric micelles was applied to deliver miR146a-5p in a rat carotid artery balloon injury model. In vitro studies using inflammation-induced vascular smooth muscle cell (VSMC) was performed. Results showed anti-inflammatory response as an inhibitor of the NF-κB pathway and VSMC migration, suppression of reactive oxygen species production, and proinflammatory cytokine gene expression in VSMCs. A single systemic administration of miR146a-5p attenuated NIH and vessel remodeling in a carotid artery balloon injury model in both male and female rats in vivo. MiR146a-5p reduced proinflammatory cytokine gene expression in injured arteries and monocyte/macrophage infiltration into the vascular wall. Therefore, miR146a-5p delivery to the injury site demonstrated therapeutic potential against NIH after revascularization.


Assuntos
Lesões das Artérias Carótidas , MicroRNAs , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artérias , Lesões das Artérias Carótidas/metabolismo , Proliferação de Células , Citocinas/metabolismo , Feminino , Hiperplasia/metabolismo , Inflamação/metabolismo , Masculino , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , NF-kappa B/metabolismo , Nanomedicina , Neointima/tratamento farmacológico , Neointima/metabolismo , Neointima/prevenção & controle , Ratos
14.
Mol Med Rep ; 26(4)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35929504

RESUMO

Hydroxygenkwanin (HGK) has an anticancer effect in a variety of tumors, but its role in osteosarcoma has not been explored. The purpose of the present study was to investigate the therapeutic effect of HGK on osteosarcoma and its specific molecular mechanism. Osteosarcoma cells (MG­63 and U2OS) treated with various concentrations of HGK were assigned to the treatment group. MTT, clone formation, wound healing and Transwell assays were performed to assess the viability, proliferation, migration, and invasion of MG­63 and U2OS cells. RT­qPCR was conducted to quantify the expression levels of of microRNA (miR)­320a and SRY­box transcription factor 9 (SOX9) in MG­63 and U2OS cells. The binding sites of miR­320a and SOX9 were predicted by starBase database, and verified using the dual­luciferase reporter assay. The expression levels of SOX9 and EMT­related proteins (N­cadherin, E­cadherin and vimentin) were detected by western blot analysis. HGK inhibited cell proliferation, migration, invasion, but promoted the expression of miR­320a in MG­63 and U2OS cells. Downregulation of miR­320a reversed the effects of HGK on proliferation, migration and invasion of MG­63 and U2OS cells, while upregulation of miR­320a had the opposite effect. HGK inhibited the expression of SOX9 by promoting the expression of miR­320a. Upregulation of SOX9 could partially reverse miR­320a­induced migration and invasion of MG­63 and U2OS cells. In addition, upregulation of miR­320a promoted E­cadherin expression and inhibited the expression of N­cadherin and vimentin, and the effect of miR­320a was also reversed by SOX9. In conclusion, HGK inhibited proliferation, migration and invasion of MG­63 and U2OS cells through the miR­320a/SOX9 axis.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Neoplasias Ósseas/patologia , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Flavonoides , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Osteossarcoma/patologia , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Vimentina/genética , Vimentina/metabolismo
15.
Int J Oncol ; 61(4)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35929514

RESUMO

Currently, exosomes (EXOs) are being explored as novel drug delivery carriers with greater advantages, including crossing the blood­brain­barrier and loading drugs. The present study utilized EXOs derived from neural stem cells (NSCs) for the delivery of molecular drugs to treat gliomas. miR­124­3p was selected according to previous studies by the authors, and the effects of the delivery of miR­124­3p to glioma cells by NSC­EXOs in vitro and in vivo were evaluated. It was found that NSC­EXOs successfully delivered miR­124­3p into glioma cells, and NSC­EXOs loaded with miR­124­3p significantly inhibited glioma cell proliferation, invasion and migration. Furthermore, the delivery of miR­124­3p by NSC­EXOs suppressed flotillin 2 (FLOT2) expression by specifically binding to the 3' untranslated region of the FLOT2 gene in gliomas; subsequently, AKT1 was found to be associated with the EXO­miR­124­3p/FLOT2 pathway. Moreover, the therapeutic effects of the delivery of miR­124­3p by NSC­EXOs were confirmed in a mouse tumor xenograft model of glioma. Thus, bio­carrier NSC­EXOs loaded with miR­124­3p suppressed glioma growth via the EXO­miR­124­3p/FLOT2/AKT1 pathway. On the whole, the present study provides insight into stem cell­free molecular­targeted therapy based on bio­carrier NSC­EXOs and provides a potential strategy for the treatment of glioma.


Assuntos
Neoplasias Encefálicas , Exossomos , Glioma , MicroRNAs , Células-Tronco Neurais , Regiões 3' não Traduzidas , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Exossomos/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Humanos , Proteínas de Membrana , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Neurais/metabolismo
16.
Oxid Med Cell Longev ; 2022: 7671324, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936219

RESUMO

Background: Ferroptosis is a type of iron-dependent programmed cell death. Ferroptosis has been shown to be a significant factor for the pathogenesis of Parkinson's disease (PD). However, the mechanism involved in ferroptosis has not been fully elucidated in PD. Methods: Repressor element-1 silencing transcription factor (REST) and specificity protein 1 (SP1) expressions were monitored by qRT-PCR. Cell viability, reactive oxygen species (ROS), and mitochondrial injury were validated by CCK-8, flow cytometry, and transmission electron microscope. The levels of neurons-related proteins and ferroptosis-associated proteins were identified by western blot and immunofluorescence assays. The interaction between miR-494-3p and REST or SP1 and ACSL4 was analyzed by luciferase, chromatin immunoprecipitation, or EMSA assay. Results: Erastin could dose-dependently induce neuron injury and ferroptosis of LUHMES cells. miR-494-3p overexpression induced ROS production, mitochondrial damage, ferroptosis, and neuron injury in erastin-induced LUHMES cells. Likewise, miR-494-3p inhibition had the opposite effects. We also showed that REST was a target gene of miR-494-3p and could repress erastin-induced ferroptosis, neuron injury, ROS, and mitochondrial injury via SP1 in LUHMES cells. Moreover, we demonstrated that SP1 could interact with ACSL4. We also confirmed that miR-494-3p could aggravate the pathological changes of substantia nigra and corpus striatum in the MPTP-induced PD mouse model. Conclusion: miR-494-3p significantly promotes ferroptosis by regulating the REST/SP1/ACSL4 axis in PD. Thus, our results open potential therapeutic targets for PD.


Assuntos
Ferroptose , MicroRNAs , Doença de Parkinson , Animais , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Doença de Parkinson/genética , Piperazinas , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição
17.
Oxid Med Cell Longev ; 2022: 9399658, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936221

RESUMO

Oxidative stress, endoplasmic reticulum (ER) stress, and neuronal cell apoptosis have been considered as the main pathogenesis factors of brain injury after intracerebral hemorrhage (ICH). Chrysophanol (CHR) has been proved to have neuroprotective effects, but the role and underlying mechanisms of CHR in ICH remain unclear. HT22 cells were dealt with hemin to mimic an in vitro ICH model and then subjected to treatment with or without CHR. The cell viability, apoptosis, ER stress, and oxidative stress were evaluated by conducting the cell counting kit-8 (CCK-8), TdT-mediated dUTP nick end labeling (TUNEL) staining assays, western blot, and corresponding kit, respectively. Further, microRNA-sequencing, bioinformatic analysis, dual-luciferase reporter method, and rescue experiments were conducted to explore the molecular mechanisms of CHR alleviating hemin-induced ER in HT22 cell. Our data revealed that CHR increased cells viability, antiapoptosis, anti-ER stress, and antioxidative stress under conditions of hemin-induced HT22 cell injury. Mechanically, it was observed that Wnt3a was competitively sponged by miR-320-5p, and CHR activated ß-catenin pathway by regulating miR-320-5p/Wnt3a molecular axis. Finally, results from the rescue experiment suggested that CHR inhibited hemin-induced cells apoptosis, ER stress, and oxidative stress through regulating the miR-320-5p/Wnt3a axis in HT22 cells. In conclusion, CHR prevented hemin-induced apoptosis, ER stress, and oxidative stress via inhibiting the miR-320-5p/Wnt3a/ß-catenin pathway in HT22 cells. Our results certified that CHR could be served as a promising treatment for brain damage following ICH.


Assuntos
Lesões Encefálicas , MicroRNAs , Antraquinonas , Lesões Encefálicas/metabolismo , Hemorragia Cerebral/metabolismo , Estresse do Retículo Endoplasmático , Hemina/farmacologia , Humanos , MicroRNAs/metabolismo , Neurônios/metabolismo , Estresse Oxidativo , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo
18.
Oxid Med Cell Longev ; 2022: 3695848, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936223

RESUMO

Human amniotic fluid stem cell-derived exosome (HuAFSC-exosome) transplantation is considered a promising treatment for premature ovarian failure (POF). However, its mechanism remains unclear. In this study, exosomes were isolated and enriched from HuAFSC subsets of CD44+/CD105+, and the exosomes were transplanted into a POF model in vitro and in vivo. Our results confirmed that the exosomes produced by CD44+/CD105+ HuAFSCs could achieve therapeutic effects in a mouse POF model. Our research also showed that CD44+/CD105+ HuAFSC-exosomes carrying miR-369-3p could specifically downregulate the expression of YAF2, inhibit the stability of PDCD5/p53, and reduce the apoptosis of ovarian granulosa cells (OGCs), thereby exerting therapeutic effects on POF. Knowledge of these mechanisms demonstrates that miRNAs carried by CD44+/CD105+ HuAFSC-exosomes are critical to the therapy of POF. This will be useful for the clinical application of stem cells.


Assuntos
Exossomos , Células-Tronco Mesenquimais , MicroRNAs , Insuficiência Ovariana Primária , Líquido Amniótico/metabolismo , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Modelos Animais de Doenças , Exossomos/metabolismo , Feminino , Células da Granulosa/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Musculares/metabolismo , Proteínas de Neoplasias/metabolismo , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/terapia , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
19.
PLoS One ; 17(8): e0272403, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35913967

RESUMO

Thyroid cancer (TC) is one of the most common thyroid malignancies occurring worldwide, and accounts for about 1% of all the malignant tumors. It is one of the fastest growing tumor and can occur at any age, but it is more common in women. It is important to find the pathogenesis and treatment targets of TC. In this pursuit, the present study was envisaged to investigate the effective carcinogenic biological macromolecules, so as to provide a better understanding of the occurrence and development of TC. The clinical and gene expression data were collected from The Cancer Genome Atlas (TCGA). We clustered mRNA and long non-coding RNA (lncRNA) into different modules by Weighted Gene Co-expression Network Analysis (WGCNA), and calculated the correlation coefficient between the genes and clinical phenotypes. Using WGCNA, we identified the module with the highest correlation coefficient. Subsequently, by using the differential genes expression analysis to screen the differential micro-RNA (miRNA), the univariate Cox proportional hazard regression was employed to screen the hub genes related to overall survival (OS), with P < 0.05 as the statistical significance threshold. Finally, we designed a hub competitive endogenous RNA(ceRNA) network of disease-associated lncRNAs, miRNAs, and mRNAs. From the results of enrichment analysis, the association of these genes could be related to the occurrence and development of TC, and these hub RNAs can be valuable prognostic markers and therapeutic targets in TC.


Assuntos
MicroRNAs , RNA Longo não Codificante , Neoplasias da Glândula Tireoide , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias da Glândula Tireoide/genética
20.
Commun Biol ; 5(1): 771, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915318

RESUMO

A unique feature of the liver is its high regenerative capacity, which is essential to maintain liver homeostasis. However, key regulators of liver regeneration (LR) remain ill-defined. Here, we identify hepatic miR-182-5p as a key regulator of LR. Suppressing miR-182-5p, whose expression is significantly induced in the liver of mice post two-thirds partial hepatectomy (PH), abrogates PH-induced LR in mice. In contrast, liver-specific overexpression of miR-182-5p promotes LR in mice with PH. Overexpression of miR-182-5p failed to promote proliferation in hepatocytes, but stimulates proliferation when hepatocytes are cocultured with stellate cells. Mechanistically, miR-182-5p stimulates Cyp7a1-mediated cholic acid production in hepatocytes, which promotes hedgehog (Hh) ligand production in stellate cells, leading to the activation of Hh signaling in hepatocytes and consequent cell proliferation. Collectively, our study identified miR-182-5p as a critical regulator of LR and uncovers a Cyp7a1/cholic acid-dependent mechanism by which hepatocytes crosstalk to stellate cells to facilitate LR.


Assuntos
Regeneração Hepática , MicroRNAs , Animais , Ácido Cólico/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Hepatócitos/metabolismo , Regeneração Hepática/genética , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo
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