JOURNAL OF DERMATOLOGICAL TREATMENT
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2020
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IF 2.156
Yifeng Xiao
Background This study explored the function and mechanism of miR-486-5p in HSFBs.Methods Qualitative real-time-polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-486-5p in HS and hypertrophic scar fibroblasts (HSFBs). Viability, migration, invasion ability, apoptosis, and expressions of Collagen I, Collagen III, α-SMA and Cleaved caspase-3 in HSFBs after transfection with miR-486-5p mimic or inhibitor were measured by CCK-8, wound-healing, transwell, and Western blot, respectively. Interaction between miR-486-5p and IGF1 was predicted by Targetscan version 7.2 and further confirmed by dual-luciferase assay, and functional rescue experiments were conducted to verify the predicted molecular mechanism. The activation of PI3K/AKT pathway was also analyzed by Western blot.Results MiR-486-5p was low-expressed in HS and HSFBs, and that overexpression of miR-486-5p suppressed the viability, migration, invasion, and expressions of Collagen I, Collagen III, and α-SMA of HSFBs, meanwhile, it also promoted apoptosis and Cleaved caspase-3 expression in HSFBs. Moreover, IGF1 was targeted by miR-486-5p, and increased viability, migration, invasion, and collagens expressions, the activation of PI3K/Akt pathway, and decreased apoptosis and Cleaved caspase-3 induced by miR-486-5p inhibitor could be partly alleviated by siIGF1.Conclusions Overexpressed miR-486-5p inhibited the hyperproliferation and excessive production of collagen in HSFBs via IGF1/PI3K/AKT pathway.
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Biomaterials Science
·
2021
·Vol. 9
·期 19
·6528-6541
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IF 6.843
Jiefei Peng,Ranran Wang,Wanru Sun,Minhua Huang,Rong Wang,Youjie Li,Pingyu Wang,Guangbin Sun,Shuyang Xie
Lung cancer is the second most common tumor and has the highest mortality rate. Both novel therapeutic targets and approaches are needed to improve the overall survival of patients with lung cancer. MicroRNA-320a-3p belongs to the miR-320a family and has been reported as a tumor suppressor in multiple cancers. However, its definitive role and precise mechanism in the progression of lung cancer remain unclear. In this study, we developed a new type of gold nanorod modified with polyethyleneimine that targets cancer-specific nanoparticles by RGD peptide, which could condense miRNA to self-assemble supramolecular nanoparticles. The designed nanoparticles can achieve integrin αvβ3-targeted cancer therapy, realize photosensitive therapy by laser irradiation and attain gene-targeted therapy by miRNAs. These nanoparticles could deliver miR-320a into lung cancer cells specifically and efficiently. Moreover, we demonstrated that Au-RGD-miR-320a nanoparticles combined with laser irradiation dramatically inhibited the proliferation and metastasis, and enhanced the apoptosis of lung cancer, both in vitro and in vivo. In terms of the mechanism, miR-320a inhibits Sp1 expression by directly binding to the 3′UTR of Sp1, and it eventually enhanced the expression of PTEN and inhibited the expression of matrix metallopeptidase 9 (MMP9). These findings provide a new and promising anticancer strategy via the use of Au-RGD-miR-320a nanoparticles, and identify miR-320a/Sp1 as a potential target for future systemic therapy against lung cancer.
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Experimental and Therapeutic Medicine
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2021
·Vol. 22
·期 2
·1-11
·
IF 2.447
Jingli Zhang,Lingling Zhu,Hong Shi,Huizhe Zheng
Previous studies have demonstrated that microRNAs (miRNAs/miRs) serve a vital role in the pathogenesis of Sjögren's syndrome (SS). The present study aimed to investigate the role of miR‑155‑5p in SS and determine its underlying molecular mechanism. An inflammatory lesion model was established by stimulating salivary gland epithelial cells (SGECs) with interferon‑γ (IFN‑γ). The apoptosis of SGECs was measured by using flow cytometry. Levels of proinflammatory factors were detected by reverse transcription‑quantitative PCR and ELISA, respectively. Immunofluorescence was used for p65 staining. Dual‑luciferase reporter assay was performed to verify the interaction between miR‑155‑5p and arrestin β2 (ARRB2). The protein levels in the NF‑κB signaling pathway were assessed by western blotting. The results of the present study demonstrated that treatment with IFN‑γ increased miR‑155‑5p expression, in addition to inducing apoptosis and inflammation in SGECs. Furthermore, overexpression of miR‑155‑5p promoted IFN‑γ‑induced apoptosis and inflammation in SGECs. Overexpression of miR‑155‑5p also increased Bax protein expression, enzyme activities of caspase 3 and caspase 9, release of inflammatory cytokines interleukin‑6 and tumor necrosis factor‑α, and decreased Bcl‑2 protein expression in IFN‑γ‑treated SGECs. By contrast, all of the effects aforementioned were reversed following miR‑155‑5p knockdown. These results demonstrated that miR‑155‑5p activated the NF‑κB signaling pathway, where treatment with the NF‑κB inhibitor, pyrrolidine dithiocarbamate, reversed the effects of miR‑155‑5p overexpression on the inflammatory factors in IFN‑γ‑induced SGECs. miR‑155‑5p was demonstrated to target ARRB2 and negatively regulated its expression levels, such that overexpression of ARRB2 reversed the effects of miR‑155‑5p overexpression on the inflammatory response, apoptosis and the NF‑κB signaling pathway in IFN‑γ‑treated SGECs. Collectively, results from the present study suggest that miR‑155‑5p may activate the NF‑κB signaling pathway by negatively regulating ARRB2 to promote salivary gland damage during SS pathogenesis. This suggests that miR‑155‑5p may serve to be a potential target for the treatment of SS.
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Stem Cells International
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2018
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IF 3.989
Zhonglong Liu,Tao Li,Si’nan Deng,Shuiting Fu,Xiaojun Zhou,Yue He
Bone marrow mesenchymal stem cells (BMSCs) were characterized by their multilineage potential and were involved in both bony and soft tissue repair. Exposure of cells to ionizing radiation (IR) triggers numerous biological reactions, including reactive oxygen species (ROS), cellular apoptosis, and impaired differentiation capacity, while the mechanisms of IR-induced BMSC apoptosis and osteogenic impairment are still unclear. Through a recent study, we found that 6 Gy IR significantly increased the apoptotic ratio and ROS generation, characterized by ROS staining and mean fluorescent intensity. Intervention with antioxidant (NAC) indicated that IR-induced cellular apoptosis was partly due to the accumulation of intracellular ROS. Furthermore, we found that the upregulation of miR-22 in rBMSCs following 6 Gy IR played an important role on the ROS generation and subsequent apoptosis. In addition, we firstly demonstrated that miR-22-mediated ROS accumulation and cell injury had an important regulated role on the osteogenic capacity of BMSCs both in vitro and in vivo. In conclusion, IR-induced overexpression of miR-22 regulated the cell viability and differentiation potential through targeting the intracellular ROS.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Rijiang Chen,Yan Tong,Xiunian Hu,Wantao Wang,Fake Liao
Osteoarthritis (OA) is a prevalent joint disorder characterized by cartilage degeneration. Circular RNAs (circRNAs) have emerged as pivotal players in OA progression, orchestrating various biological processes such as proliferation, apoptosis, inflammation, and extracellular matrix (ECM) reorganization. Among these circRNAs, circSLTM exhibits aberrant expression in OA, yet its precise regulatory mechanism remains elusive. This study aimed to elucidate the regulatory mechanisms of circSLTM in OA pathogenesis, with a focus on its role as a competing endogenous RNA (ceRNA). Human cartilage tissues were procured from both OA patients and non-OA individuals, while human chondrocyte cells were subjected to lipopolysaccharide (LPS) treatment to mimic OA-like conditions. Our findings revealed upregulation of circSLTM in OA patients and LPS-treated chondrocytes. Loss-of-function assays were conducted, demonstrating that silencing circSLTM via shRNAs mitigated LPS-induced effects on chondrocytes, as evidenced by enhanced proliferation, reduced apoptosis, and inflammatory factors, and altered expression of extracellular matrix proteins. Further exploration into the regulatory mechanism of circSLTM unveiled its interaction with microRNA-515-5p (miR-515-5p) to modulate vesicle-associated membrane protein (VAPB) expression in chondrocytes. VAPB, also upregulated in OA, was positively regulated by circSLTM. Rescue assays corroborated that VAPB overexpression reinstated the protective effects of circSLTM knockdown on LPS-treated chondrocytes. Moreover, concurrent knockdown of both circSLTM and VAPB demonstrated synergistic protection against LPS-induced chondrocyte injury. Additionally, we delineated that LPS triggered the activation of the NF-κB pathway in chondrocytes, which was counteracted by circSLTM silencing. To assess the effects of circSLTM on OA in vivo, anterior cruciate ligament transection (ACLT) mouse models were established, revealing that circSLTM deficiency ameliorated cartilage defects in vivo . In conclusion, circSLTM exacerbates osteoarthritis progression by orchestrating the miR-515-5p/VAPB axis and activating the NF-κB pathway, providing novel insights for targeted therapy in OA management.
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ACS Chemical Biology
·
2024
·
IF 3.5
Xiaorui Shi,Chong Hu,Liangli Fan,Bin Guo,Jingyu Zhang,Chu Tang,Fu Wang
MicroRNAs (miRNAs) play a significant role in tumor progression, and regulating miRNA expression with small molecules may offer a new approach to cancer therapy. Among them, miRNA-20b has been found to be dysregulated in several cancers, including nonsmall cell lung cancer (NSCLC). Herein, an in silico high-throughput computer screen was conducted to identify small molecules that downregulate miR-20b using the three-dimensional structure of the Dicer binding site on pre-miR-20b. Among 1058 small molecule compounds, Methotrexate (MTX), was discovered to be a potential miR-20b-specific inhibitor, which has been found to suppress miR-20b by specifically blocking Dicer processing in p53 wild-type A549 NSCLC cells but not in H1299 cells with p53 depletion. MTX effectively inhibited the proliferation, survival, migration, and invasion of A549 cells in a dose-dependent manner. Furthermore, the treatment of MTX up-regulated the expression of miR-20b target genes PTEN, STAT3, and HIF1α. Notably, MTX also significantly inhibited tumor growth in a mouse xenograft tumor model of NSCLC, with no observed tissue toxicity. Our findings indicate that MTX may have a novel role as an established drug in p53 wild-type NSCLC tumor therapy by down-regulating miR-20b expression. These findings are expected to provide preclinical evidence for miR-20b-targeting NSCLC therapeutic strategies.
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Regenerative Therapy
·
2024
·
IF 3.4
Shule Zhang,Dong Li,Linghong Liu,Qing Shi,Xiuli Ju
Introduction It is essential to acknowledge that the cardiovascular toxicity associated with anthracycline drugs can be partially attributed to the damage inflicted on blood vessels and endothelial cells. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have the potential to repair cellular processes and promote tissue regeneration through the transfer of signaling molecules such as miRNAs. In the present study, we investigated the effects of MSC-EVs on daunorubicin (DNR)-damaged human cardiac microvascular endothelial cells (HCMEC) and developing blood vessels of Chicken Chorioallantoic Membrane (CAM) in vivo. Materials and methods We constructed in vitro and in vivo models of DNR-damaged endothelial cells and developing blood vessel. Scratch wound assays, EdU assays, tube formation assays, and SA-β-Gal staining were used to evaluate the effects of MSC-EVs on cell migration, proliferation, angiogenesis capacity and cell senescence. Blood vessel area was used to assess the effects of MSC-EVs on CAM vasculature. RT-qPCR was used to detect the mRNA expression levels of inflammatory molecules. RNA sequencing was employed to compare differential gene expression and downstream regulatory mechanisms. RNA interference experiments and miRNA mimic overexpression experiments were used to validate the regulatory effects of target genes and downstream signaling pathways. Results We found that MSC-EVs improved the migration, proliferation, and angiogenesis of HCMEC, while also alleviating cellular senescence. The angiogenic effect on the developing blood vessels was confirmed in vivo. We identified that MSC-EVs downregulated the expression of PARP9, thereby inhibiting the STAT1/pSTAT1 signaling pathway. This downregulation effect is likely mediated by the transfer of miR-186-5p from MSC-EVs to HCMEC. Overexpression of miR-186-5p in DNR-damaged HCMEC also exhibited the aforementioned downregulation effect. In vivo, the introduction of miR-186-5p mimics enhanced angiogenesis in the CAM model. Conclusions To summarize, our study reveals that MSC-EVs can restore the cellular function of DNR-damaged HCMEC and alleviate cellular senescence through the miR-185-5p-PARP9-STAT1/pSTAT1 pathway. This finding highlights the potential of MSC-EVs as a therapeutic strategy for mitigating the detrimental effects of anthracycline-induced endothelial damage.
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MOLECULAR BIOLOGY REPORTS
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2024
·Vol. 51
·期 1
·1-15
·
IF 2.6
Wumiti Taxi,Wang Lining,Xu Bin,Ma Yong,Zhu Yihua,Zuo Xinchen,Qian Weiqing,Chu Xudong,Sun Haitao
Background Promoting the balance between bone formation and bone resorption is the main therapeutic goal for postmenopausal osteoporosis (PMOP), and bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation plays an important regulatory role in this process. Recently, several long non-coding RNAs (lncRNAs) have been reported to play an important regulatory role in the occurrence and development of OP and participates in a variety of physiological and pathological processes. However, the role of lncRNA tissue inhibitor of metalloproteinases 3 (lncTIMP3) remains to be investigated. Methods The characteristics of BMSCs isolated from the PMOP rat model were verified by flow cytometry assay, alkaline phosphatase (ALP), alizarin red and Oil Red O staining assays. Micro-CT and HE staining assays were performed to examine histological changes of the vertebral trabeculae of the rats. RT-qPCR and western blotting assays were carried out to measure the RNA and protein expression levels. The subcellular location of lncTIMP3 was analyzed by FISH assay. The targeting relationships were verified by luciferase reporter assay and RNA pull-down assay. Results The trabecular spacing was increased in the PMOP rats, while ALP activity and the expression levels of Runx2, Col1a1 and Ocn were all markedly decreased. Among the RNA sequencing results of the clinical samples, lncTIMP3 was the most downregulated differentially expressed lncRNA, also its level was significantly reduced in the OVX rats. Knockdown of lncTIMP3 inhibited osteogenesis of BMSCs, whereas overexpression of lncTIMP3 exhibited the reverse results. Subsequently, lncTIMP3 was confirmed to be located in the cytoplasm of BMSCs, implying its potential as a competing endogenous RNA for miRNAs. Finally, the negative targeting correlations of miR-214 between lncTIMP3 and Smad4 were elucidated in vitro. Conclusion lncTIMP3 may delay the progress of PMOP by promoting the activity of BMSC, the level of osteogenic differentiation marker gene and the formation of calcium nodules by acting on the miR-214/Smad4 axis. This finding may offer valuable insights into the possible management of PMOP.
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TOXICOLOGY
·
2024
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IF 4.8
Hong-Yu Fu,Yue Li,Han Cui,Jiu-Zhi Li,Wan-Xue Xu,Xi Wang,Rui-Feng Fan
Mercuric chloride (HgCl 2 ), a widespread environmental pollutant, induces ferroptosis in chicken embryonic kidney (CEK) cells. Whereas activating transcription factor 4 (ATF4), a critical mediator of oxidative homeostasis, plays a dual role in ferroptosis, but its precise mechanisms in HgCl 2 -induced ferroptosis remain elusive. This study aims to investigate the function and molecular mechanism of ATF4 in HgCl 2 -induced ferroptosis. Our results revealed that ATF4 was downregulated during HgCl 2 -induced ferroptosis in CEK cells. Surprisingly, HgCl 2 exposure has no significant impact on ATF4 mRNA level. Further investigation indicated that HgCl 2 enhanced the expression of the E3 ligase beta-transducin repeat-containing protein (β-TrCP) and increased ATF4 ubiquitination. Subsequent findings identified that miR-15b-5p as an upstream modulator of β-TrCP, with miR-15b-5p downregulation observed in HgCl 2 -exposed CEK cells. Importantly, miR-15b-5p mimics suppressed β-TrCP expression and reversed HgCl 2 -induced cellular ferroptosis. Mechanistically, HgCl 2 inhibited miR-15b-5p, and promoted β-TrCP-mediated ubiquitin degradation of ATF4, thereby inhibited the expression of antioxidant-related target genes and promoted ferroptosis. In conclusion, our study highlighted the crucial role of the miR-15b-5p/β-TrCP/ATF4 axis in HgCl 2 -induced nephrotoxicity, offering a new therapeutic target for understanding the mechanism of HgCl 2 nephrotoxicity.
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RSC Advances
·
2024
·Vol. 14
·期 43
·31809-31819
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IF 3.9
Long Jia,Yongxia Liu,Yanqing Zhang,Shuofeng Zhang,Xiaowei Cao,Yemin Xu,Yi Zhao,Bin Deng
To facilitate rapid, efficient, and accurate detection of miR-96-5p associated with gastric cancer (GC), we developed a bioanalytical platform by integrating surface-enhanced Raman spectroscopy with lateral flow assay (SERS-LFA). With these SERS-LFA strips, miR-96-5p within the specimen competed with Au rhombic dodecahedron (AuRD) conjugated single-stranded DNA (ssDNA) to bond to the immobilized hairpin DNA (hpDNA) probe on the T line. Consequently, higher abundance of miR-96-5p led to reduced conjugation of AuRD on the T line, thereby resulting in diminished SERS intensity. The biosensor exhibited a detection time of approximately 30 min and demonstrated a low limit of detection (LOD) for miR-96-5p in PBS buffer solution, down to 3.7 fM. To validate its clinical utility for the early diagnosis of patients with different degrees of gastric lesions, we performed quantitative evaluations in cohorts that included healthy individuals, patients with mild intraepithelial neoplasia, patients with severe intraepithelial neoplasia, as well as patients diagnosed with GC. The results obtained from the SERS-LFA strips were in agreement with those obtained from the quantitative real-time polymerase chain reaction (qRT-PCR). Given the accomplishments, this biosensor has significant potential for the clinical diagnosis of GC, offering a promising avenue for timely detection and improved patient prognoses.
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Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Boyu Xiong,Xinxin Shao,Guangxu Fang,Mengmeng Dong,Haobo Han,Quanshun Li
Herein, porous poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared to load icariin and miR-23b for the treatment of metastatic lung cancer. The microspheres exhibited desirable aerodynamic diameter, high drug loading and encapsulation efficiency, as well as a favorable drug release profile, which was beneficial for the deposition and exposure of drugs in the lung tissues. The release solution from microspheres exhibited a favorable anti-proliferative effect by inducting cell apoptosis and arresting the cell cycle at G1 phase, and meanwhile inhibited the migration and invasion of cancer cells. More importantly, the microspheres could be effectively inhaled and accumulated in the lung tissues to trigger the in situ apoptosis of tumor cells and suppress metastasis, using mice bearing melanoma-metastatic lung cancer as a model. Furthermore, inhalation of the microspheres showed good favorable biocompatibility, barely causing tissue damage. Overall, porous PLGA microspheres provide a promising platform for the inhalable co-delivery of drugs and genes to obtain ideal therapeutic efficacy in lung cancer and other pulmonary diseases.
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WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY
·
2025
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IF 3.8
Shoufen Yu,Xueyuan Yu,Junchang Liu,Muzhen Guan,Zhongheng Wang,Xiaosa Li
Background The blood–brain barrier (BBB) is essential for maintaining normal brain function and is involved in the progression of major depressive disorder (MDD). This study investigated the abnormal expression and regulatory role of miR-24-3p in neuronal injury and BBB dysfunction during MDD pathogenesis.Methods The expression of miR-24-3p was examined in serum samples from patients with MDD and from chronic unpredictable mild stress and lipopolysaccharide mouse models, as well as in hippocampal tissue from mice. A loss-of-function assay was conducted to explore the role of miR-24-3p in brain injury, assessing neuronal cell viability, apoptosis, inflammatory response, oxidative stress, and astrocyte activation. Exosomes were then isolated to evaluate the regulatory role and function of miR-24-3p in BBB dysfunction. Behavioural tests were performed to assess depressive-like behaviours in mice.Results miR-24-3p was significantly upregulated in MDD samples. Inhibiting miR-24-3p suppressed LPS-induced neuronal apoptosis and inflammation, while promoting the secretion of neurofunctional factors. Further analysis revealed that inhibiting exosomal miR-24-3p alleviated depressive-like behaviour in MDD model mice, reduced BBB permeability, and improved BBB function.Conclusion miR-24-3p inhibition attenuated neuronal damage, reduced astrocyte activation, and enhanced BBB stability through exosome-mediated regulation, thereby alleviating neurobehavioural abnormalities and the progression of MDD.
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