Scientific Reports
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2024
·Vol. 14
·期 1
·1-11
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IF 3.8
Qiao Xilin,Cao Shuyu,Chen Shuaiyu,Guo Yan,Chen Nipi,Zheng Ying,Jin Bo
Oxidative stress induced endothelial dysfunction plays a particularly important role in promoting the development of cardiovascular diseases (CVDs). Salvianolic acid A (SalA) is a water-soluble component of traditional Chinese medicine Salvia miltiorrhiza Bunge with anti-oxidant potency. This study aims to explore the regulatory effect of SalA on oxidative injury using an in vitro model of H 2 O 2 -induced injury in human umbilical vein endothelial cells (HUVECs). In the study, we determined cell viability, the activities of Lactate dehydrogenase (LDH) and Superoxide dismutase (SOD), cell proliferation rate and intracellular reactive oxygen species (ROS). Flow cytometry was used to detect cell apoptosis. Western-blotting was used to evaluate the expression of cell senescence, apoptosis, autophagy and pyroptosis protein factors. The expression level of miRNA was determined by qRT-PCR. Compared with H 2 O 2 -induced HUVECs, SalA promoted cell viability and cell proliferation rate; decreased LDH and ROS levels; and increased SOD activity. SalA also significantly attenuated endothelial senescence, inhibited cell apoptosis, reversed the increase of LC3 II/I ratio and NLRP3 accumulation. Furthermore, miR-204-5p was regulated by SalA. Importantly, miR-204-5p inhibitor had similar effect to that of SalA on H 2 O 2 -induced HUVECs. Our results indicated that SalA could alleviate H 2 O 2 -induced oxidative injury by downregulating miR-204-5p in HUVECs.
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EXPERIMENTAL EYE RESEARCH
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2025
·
IF 2.7
Yarong Yan,Shulei Xing,Jinghua Liu,Xinlin Yan,Yi Guan,Zhixin Jiang,Wei Zhang,Xuan Li
Lycium barbarum glycopeptide (LbGp), derived from the Chinese medicinal plant Lycium barbarum, has demonstrated anti-inflammatory properties; however, its precise role and mechanism in corneal repair following injury remain elusive. The present research investigated the mechanisms and effects of LbGp on corneal repair following alkali burn injury using in vivo mouse models of corneal alkali burn and in vitro human keratocyte fibrosis models. Corneal inflammation, opacity, and epithelial defects were assessed via a slit lamp microscope. Results showed that LbGp-treated mice exhibited reduced edema, accelerated re-epithelialization, and decreased corneal opacity compared to the phosphate-buffered saline (PBS)-treated controls. Proteomic analysis revealed altered proteins enriched in the extracellular matrix among the control, injury, and LbGp treatment groups. Moreover, LbGp significantly attenuated TGFβ-1-induced myofibroblasts transdifferentiation from keratocytes. Consistently, LbGp treatment inhibited the upregulation of fibrosis markers (αSMA, fibronectin, and collagen III) at both the protein and mRNA levels after corneal alkali burns. LbGp also effectively suppressed the activation of the NF-κB/NLRP3/IL-1β signaling pathway and neutrophil infiltration following corneal alkali burn injury. Additionally, miR-21 was upregulated in TGFβ-1-stimulated keratocytes and in the alkali-burned mouse cornea. LbGp decreased miR-21 expression, while increasing expression of its target, Smad7, thereby dampening the TGFβ/Smad2/3 signaling pathway. This research demonstrates that LbGp promotes corneal healing by inhibiting inflammation and fibrosis after alkali burns, suggesting its potential as a supplementary therapy for corneal injury repair.
研究领域:
药理学
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眼科
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分子生物学
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FUNDAMENTAL & CLINICAL PHARMACOLOGY
·
2025
·Vol. 39
·期 1
·e13048
·
IF 2.5
Langtao He,Hui Zhang,Jian Deng,Yibo He,Zhili Cai,Yitao He
Background Ischemic stroke (IS) is known for its high incidence, disability, and mortality, and there is an urgent need to investigate the pathophysiological mechanisms and develop novel treatment strategies. Objectives We aimed to investigate the mechanisms of the novel circMap2k1/miR-135b-5p/Pidd1 axis in the treatment of IS progression with fluoxetine. Methods The middle cerebral artery occlusion (MCAO) model was done in adult male Sprague–Dawley (SD) rats and followed by fluoxetine treatment and the injection of adeno-associated virus (AAV)-sh-ctr and AAV-sh-circMap2k1 into the bilateral hippocampal tissues of rats. Dual-luciferase reporter gene assay was employed to confirm the binding between miR-135b-5p and Pidd1. Enzyme-linked immunosorbent assay was performed to measure the concentrations of the inflammatory factors TNF-α, IL-6, and IL-1β in the plasma. The role of circMap2k1 in cells was tested by overexpression of circMap2k1. Cell viability was assessed using Cell Counting Kit-8 assay, while apoptosis was measured by flow cytometry. Results Knockdown of circMap2k1 enhanced the therapeutic and protective effect of fluoxetine on IS injury in rats. Dual-luciferase reporter gene assay confirmed the targeting of miR-135b-5p to Pidd1. Additionally, fluoxetine deactivated the adsorption of miR-135b-5p by downregulating circMap2k1, and miR-135b-5p further exerted its inhibitory effect on Pidd1 and finally attenuated the inflammatory response caused by microglial polarization after IS. Cell experiments revealed that overexpression of circMap2k1 repressed cell viability and promoted cell apoptosis. Conclusions Fluoxetine downregulated of circMap2k1 was associated ameliorate neurological injury and inflammatory responses induced by microglial polarization after IS. The manuscript is available as a preprint at this link: doi.org/10.21203/rs.3.rs-3209057/v1 .
研究领域:
神经科学
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分子生物学
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药理学
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Kidney360
·
2025
·
IF 3
Li Jiachang,Ma Yuhan,Wang Yanni,Chen Yizhi,Wei JiaLi
Plain Language Summary Background: Hyperuricemia is a common metabolic disorder and a risk factor for multiple diseases, including CKD. Hyperuricemic nephropathy (HN) affects many individuals with hyperuricemia, yet its molecular mechanisms are not fully understood, and effective treatments are lacking. Methods: In vitro, human tubular epithelial cells (HK-2) were exposed to uric acid for 36 hours, followed by transfection with microRNA mimic or FIH-1 siRNA. In vivo, HN was induced in mice using potassium oxonate (PO) and adenine (Ad) for two weeks. miR-295 mimic or anti-miR-295 was administered via tail vein injection, and mice were sacrificed for analysis. Results: We demonstrated a significant increase of miR-295 in renal tubular cells in HN mice. Hyperuricemia led to the activation of hypoxia inducible factor-1α (HIF-1α), and inhibition of HIF-1α by YC-1 (a HIF-1α inhibitor) prevented the increase of miR-295. ChIP assay further verified HIF-1α binding to the miR-295 gene promoter directly. Functionally, Inhibition of miR-295 led to increased cell death and tubulointerstitial fibrosis in HN mice, whereas supplementation of miR-295 mimic had kidney protective effects in this model. miR-295 suppressed the expression of factor inhibiting hypoxia-inducible factor-1 (FIH-1) in both in vitro and in vivo models of HN. Luciferase microRNA target reporter assay further verified FIH-1 as a direct target of miR-295.In addition, knockdown of FIH-1 inhibits tubular cell apoptosis and profibrotic cytokines production in HK2 cells during uric acid treatment. Conclusions: This study reveals a HIF-1α/miR-295/FIH-1 positive feedback loop that regulates tubular damage and fibrosis in HN. Plain Language Summary This study explores the molecular mechanisms of hyperuricemic nephropathy (HN), a kidney condition linked to high uric acid levels. Researchers found that in mice with HN, the microRNA miR-295 increased in kidney cells. The study identified a feedback loop involving miR-295, HIF-1α, and FIH-1, where HIF-1α activates miR-295, which then suppresses FIH-1. Inhibition of miR-295 led to increased cell death and fibrosis, while supplementation with miR-295 mimic had protective effects against kidney damage. Inhibiting HIF-1α prevented miR-295 increase. These findings suggest potential therapeutic targets for treating HN by modulating this molecular pathway. Text is machine generated and may contain inaccuracies. FAQ
研究领域:
肾脏病学
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分子生物学
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代谢性疾病
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细胞信号传导
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JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
·
2021
·Vol. 35
·期 10
·e22880
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IF 3.652
Haijuan Jing,Chuan Wang,Liang Zhao,Jing Cheng,Pengyu Qin,Hongqi Lin
Previous studies have shown that propofol (PPF) plays a protective role in ischemia–reperfusion (I/R) in multiple organs and tissues. This study was aimed to explore the mechanism of PPF in ameliorating myocardial ischemia-reperfusion injury (MIRI). MIRI model was established with Sprague–Dawley rats, and PPF pretreatment was performed before reperfusion. Creatine kinase isoform (CK-MB), lactate dehydrogenase (LDH), and hematoxylin and eosin stain were used to evaluate the severity of MIRI. H9c2 cells were treated with hypoxia/reoxygenation (H/R) to simulate I/R injury in vitro. Real-time quantitative polymerase chain reaction (qPCR) was employed to assess MALAT1 and microRNA (miR)−206 expressions. Autophagy-related 3 (ATG3), LC3BⅡ/LC3BⅠ, and Beclin-1 expression were examined by western blot. Apoptosis was monitored using flow cytometry. Interaction between MALAT1 and miR-206 was determined by bioinformatics analysis, dual-luciferase reporter gene assay, RIP assay, and RNA pull-down assay. PPF pretreatment remarkably reduced CK-MB level, LDH level, myocardial infarct size, and LC3BⅡ/LC3BⅠ ratio and Beclin-1 expression in the rats with MIRI, and repressed the apoptosis of H9c2 cells exposed to H/R. PPF pretreatment markedly suppressed MALAT1 expression and enhanced miR-206 expression in both in vivo and in vitro models. MiR-206 was identified as a target of MALAT1 in cardiomyocytes, and MALAT1 could increase the expression of ATG3. Additionally, the upregulation of MALAT1 partially reversed the protective effect of PPF on cardiomyocytes in vitro. PPF modulated MALAT1/miR-206/ATG3 axis to protect cardiomyocytes against I/R injury.
研究领域:
心脏病学
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药理学
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分子生物学
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细胞生物学
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高影响因子
Human Cell
·
2023
·Vol. 36
·期 3
·987-996
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IF 4.3
Yiou Wang,Zhihong Wang,Shibai Zhu,Shanni Li,Wenwei Qian
The dysregulation of microRNAs plays a critical role in the development of rheumatoid arthritis (RA). This study aims to explore the functional significance of miR-326 in RA. The RT-qPCR results showed that miR-326 was downregulated in synovial tissues of RA patients and RA fibroblast-like synoviocytes (RA-FLS). We found that miR-326 could target and reduce the expression of inhibitor of DNA binding 1 (Id1). MTT assay and flow cytometry were conducted to explore the biological function of miR-326. Our data revealed that the upregulation of miR-326 suppressed cell proliferation and induced apoptosis in RA-FLS. In collagen-induced arthritis mice, intraarticular injection of lentivirus carrying miR-326 overexpression vectors could reduce the arthritis score and attenuate synovial inflammation and cartilage destruction. We also found that long non-coding RNA-Ewing sarcoma-associated transcript 1 (lncRNA-EWSAT1) was significantly increased in RA synovial tissues and RA-FLS. The RNA immunoprecipitation and RNA pull-down assay indicated that lncRNA-EWSAT1 directly bound and negatively regulated the expression of miR-326. Knockdown of lncRNA-EWSAT1 could upregulate miR-326 expression and attenuate its proliferation inhibition and apoptosis induction effect in RA-FLS. In conclusion, the lncRNA-EWSAT1/miR-326 axis might provide a novel therapeutic target in the treatment of RA.
研究领域:
免疫学
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分子生物学
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风湿病学
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ENVIRONMENTAL TOXICOLOGY
·
2021
·Vol. 37
·期 1
·41-51
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IF 4.119
Rili Hao,Junlin Ge,Xinyu Song,Feng Li,Dongxiao Sun-Waterhouse,Dapeng Li
Cadmium (Cd) is a potent neurotoxic metal present in the environment and food. In this study, CdCl 2 (2 or 4 μM) induced cytotoxicity and neurotoxicity in PC12 cells, causing decreases in cell viability and NEP protein expression and increase in p-tau protein expression. For the first time, CdCl 2 -initiated injury was found to result from the induction of not only apoptosis but also ferroptosis, as evidenced by the increased iron content, ROS production, and mitochondrial membrane potential along with changes in the expressions of iron death-related genes (FTH1, GPX4, ASCL4, PTGS2, and NOX1) and levels of caspase9, Bax, and Bcl-2 proteins. The molecular mechanisms leading to apoptosis and ferroptosis at least included the participation of the miR-34a-5p/Sirt1 axis, in which miR-34a-5p promoted CdCl 2 -induced neurotoxicity through targeting Sirt1. Knocking out miR-34a-5p attenuated CdCl 2 -induced damage of PC12 cells, cytotoxicity and neurotoxicity. This research provides the underlying molecular mechanisms of CdCl 2 -induced damage and asserts the role of miRNAs as critical regulators.
研究领域:
神经科学
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毒理学
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细胞生物学
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分子生物学
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Biology Direct
·
2026
·Vol. 21
·期 1
·30
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IF 5.5
Liu Shan,Yu Shangmin
Background Depression is a prevalent mental disorder, and its pathogenesis has not yet been fully elucidated. Circular RNAs (CircRNAs) have exhibit critical regulatory role in depression, while Unc-51-like kinase 1 (ULK1)-mediated autophagy participates in the pathophysiology of the disorder. Nevertheless, the potential involvement of circRNAs in modulating ULK1-mediated autophagy in depression remains unclear. Objectives This study aimed to identify depression-associated circRNAs regulating ULK1-medaited autophagy, and uncover the underlying mechanisms. Methods The depression model was established in mice using chronic unpredictable mild stress (CUMS) procedure. RNA sequencing and bioinformatics analysis were carried out to screen signaling pathways, circRNAs and microRNAs (miRNAs) related to depression. Overexpression and knockdown of circRNAs or miRNAs were conducted by lentivirus microinjection and cell transfection. The depression-like phenotypes were assessed through behavioral tests. Western blot, immunofluorescence and transmission electron microscopy (TEM) were employed to evaluated ULK1-mediated autophagy. RNA pull-down and dual-luciferase reporter assay was executed to explore the underlying mechanisms. Results CircADAM9 exhibited the most significant downregulation in CUMS mice among the differentially expressed circRNAs. Overexpression of circADAM9 relieved depressive-like behaviors, and promoted ULK1-mediated autophagy in vivo and in vitro. Importantly, circADAM9 sponged miR-302b-3p to regulate Ulk1 gene expression, and miR-302b-3p mimics diminished the behavioral improvements and pro-autophagic effect modulated by circADAM9. Conclusion We identified circADAM9 as a novel regulator in depression, which activated autophagy via miR-302b-3p/ULK1 axis to improve depressive-like behaviors. Our findings would provide a new potential therapeutic target for the treatment of depression.
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Journal of Zhejiang University-SCIENCE B
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2026
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IF 5.7
Zeng Wenjie,Xu Hubin,Shou Huafeng,Jiang Haimin,Zhang Mengyu,Chen Xiaoyan,Lu Weiguo
This study aimed to examine hypoxia-induced phenotypic alterations in ovarian cancer and to elucidate the molecular mechanisms mediated by long non-coding RNAs (lncRNAs). Transwell assay was used to assess migration and invasion, and methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to assess proliferation. Western blot analysis was conducted to evaluate the expression of factors associated with epithelial–mesenchymal transition (EMT). RNA sequencing was carried out to identify potential targets, and dual-luciferase and biotin-labeled microRNA (miRNA) pull-down assays were performed to identify interactions between these targets. Gain- and loss-of-function experiments were conducted to validate their effects. Hypoxia promoted the migration, invasion, and EMT of HO8910 and A2780 cells. Under hypoxic conditions, the expression of lncRNA-aspartyl-transfer RNA synthetase antisense RNA 1 (lnc- DARS-AS1 ) was significantly increased, and this upregulation exerted a proliferative effect on ovarian cancer cells. Furthermore, lnc- DARS-AS1 promoted solute carrier family 2 member 12 (SLC2A12) expression, accelerating ovarian cancer progression. Luciferase, biotin-labeled miRNA pull-down, and cellular function assays confirmed that lnc- DARS-AS1 binds to miR-378a-5p to enhance SLC2A12 levels. The expression levels of SLC2A12 were determined in samples from patients with ovarian cancer, and they showed a positive correlation with cancer progression. This research established that the lnc- DARS-AS1 /miR-378a-5p/SLC2A12 axis is involved in ovarian cancer progression under hypoxic conditions, providing new perspectives on the treatment and management of ovarian cancer.
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ONCOLOGY REPORTS
·
2023
·Vol. 49
·期 5
·1-14
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IF 4.2
Chuanzhuo Wang,He Xin,Guangxin Yan,Zhaoyu Liu
Colorectal cancer (CRC) is an aggressive tumor, whose development is considered to be modulated by certain long non‑coding RNAs (lncRNAs). Therefore, the aim of the present study was to investigate the regulatory mechanism of lncRNA NONHSAG028908.3 on CRC. Data from The Cancer Genome Atlas (TCGA) database revealed that NONHSAG028908.3 was increased in CRC tissues compared with normal tissues (P<0.001). The results of reverse transcription‑quantitative PCR indicated that NONHSAG028908.3 was upregulated in four types of CRC cells compared with that in NCM460, a normal colorectal cell line. MTT, BrdU, and flow cytometric assays were applied to evaluate CRC cell growth. The migratory and invasive abilities of CRC cells were detected using wound healing and Transwell assays. Silencing of NONHSAG028908.3 inhibited proliferation, migration, and invasion of CRC cells. A dual‑luciferase reporter assay demonstrated that NONHSAG028908.3 served as a sponge to combine with microRNA (miR)‑34a‑5p. MiR‑34a‑5p suppressed the aggressiveness of CRC cells. The effects induced by NONHSAG028908.3 knockdown were partly reversed by inhibition of miR‑34a‑5p. Furthermore, miR‑34a‑5p, a target of NONHSAG028908.3, modulated aldolase, fructose‑bisphosphate A (ALDOA) expression in a negative feedback manner. Suppression of NONHSAG028908.3 notably decreased ALDOA expression, which was rescued via silencing of miR‑34a‑5p. Moreover, suppression of ALDOA revealed the inhibitory action on CRC cell growth and migration. In summary, the data of the present study indicate that NONHSAG028908.3 may positively regulate ALDOA via sponging miR‑34a‑5p, thereby promoting malignant activities in CRC.
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Cancers
·
2023
·Vol. 15
·期 6
·1724
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IF 5.2
Khalil Ur Rahman,Shuo Yang,Nasir Azam,Zhen Yuan,Jiawen Yu,Chunhui Zhao,Bin Feng
Simple SummaryBreast cancer is a disease that begins in the cells of the breast. Although it is most common in women, it can also occur in men, though this is rare. Early detection and treatment are crucial to improving outcomes and survival rates. Risk factors include age, family history, certain gene mutations, prior history of breast cancer, exposure to estrogen, and lifestyle habits like alcohol consumption and inactivity. Symptoms include changes in the skin on the breast, such as dimpling, lumps or thickening, changes in size or shape, and discharge from the nipple. Diagnosis is often made through a clinical breast exam, mammogram, biopsy, and possibly additional imaging tests. Treatment options include surgery, chemotherapy, radiation therapy, hormone therapy, and targeted therapy. The choice of treatment method depends on the stage and characteristics of cancer.AbstractBreast cancer is considered the solid tumor most sensitive to chemotherapy. However, it can become resistant to various chemotherapeutic drugs, including doxorubicin, which triggers cell death by intercalation between DNA bases, free radical formation, and topoisomerase II inhibition. When drug resistance develops, several miRNAs are dysregulated, suggesting that miRNAs may play a significant role in resistance formation. In the current study, we investigated how doxorubicin sensitivity of breast cancer cells is affected by miR-153-3p and its target gene. The MTT method was used to determine the chemo-sensitizing effect of miR-153-3p on doxorubicin in MCF-7 and MDA-MB-231 cell lines. Results of Western blot and dual luciferase confirmed that miR-153-3p targets KIF20A and decreases its expression. Transwell and flow cytometry experiments showed that miR-153-3p and doxorubicin together had higher effects on MCF-7 and MDA-MB-231 cell proliferation, migration, and invasion, as well as increasing apoptosis and arresting cells in the G1 phase. Proteins related to apoptosis and the cell cycle exhibited the same tendency. Intracellular vesicle formation was inhibited and RAB26 was also downregulated by treatment with miR-153-3p alone or in combination with doxorubicin. Doxorubicin’s ability to suppress tumors may be enhanced by miR-153-3p, according to in vivo studies. According to our findings, miR-153-3p has a direct effect on KIF20A and may regulate the formation of intracellular vesicles, which in turn makes breast cancer cells more susceptible to doxorubicin.Keywords:miR-153-3p;chemosensitivity;breast cancer;doxorubicin;KIF20A
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Food Bioscience
·
2023
·
IF 5.2
Jiaxin Li,Hengju Ge,Yang Xu,Jiahong Xie,Naymul Karim,Fujie Yan,Jianling Mo,Wei Chen
Chlorogenic acid (CGA) is a phenylpropanoid compound in chrysanthemum, which has a variety of biological activities. Nevertheless, CGA has not yet been studied concerning oxidative stress in hepatocytes. Our research aims to investigate whether chlorogenic acid can improve hepatic oxidative stress, and further illustrated its detailed mechanism. The results of free radicals measurement and Western blot showed that CGA suppressed the activation of JNK (c-Jun NH2-teminal kinase) signaling pathway by ameliorating endoplasmic reticulum stress in H 2 O 2 -treated hepatocytes, thereby eliminating excess intracellular free radicals. In addition, through RT-qPCR, we found that miR-199a-5p down-regulated in H 2 O 2 -induced L02 cells, which was restored by CGA. By inhibiting the expression of miR-199a-5p to promote the transcription of GRP78 gene, the antioxidant capacity of CGA was greatly weakened in hepatocytes. Our findings suggest that CGA treatment alleviated the H 2 O 2 -induced oxidative stress by targeting miR-199a-5p, thereby ameliorating ER stress and inhibiting JNK phosphorylation for antioxidant capacity enhancement. Based on our available results, CGA may be an alternative compound to mitigate hepatic oxidative damage through the miR-199a-5p/GPR78 axis.
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