scholarly journals Early glycolytic reprogramming control microglial inflammatory activation

2020 ◽  
Author(s):  
Junjie Cheng ◽  
Rong Zhang ◽  
Youliang Ke ◽  
Zhirou Xu ◽  
Renjuan Sun ◽  
...  
Keyword(s):  
Western Blot ◽  
Microglial Activation ◽  
Molecular Mechanisms ◽  
Aerobic Glycolysis ◽  
Microglial Cells ◽  
Luciferase Reporter ◽  
Inflammatory Activation ◽  
Glycolysis Inhibitors ◽  
Anti Inflammatory

Abstract Background Microglial activation-mediated neuroinflammation plays an important role in the progression of neurodegenerative diseases. Inflammatory activation of microglial cells is often accompanied by a metabolic switch from oxidative phosphorylation to aerobic glycolysis. However, the roles and molecular mechanisms of glycolysis in microglial activation and neuroinflammation are not yet fully understood.Methods The anti-inflammatory effects and its underlying mechanisms of glycolytic inhibition in vitro were examined in LPS activated BV-2 microglia or primary microglia cells by ELISA, RT-PCR, Western blot, immunoprecipitation, FACS and NF-κB luciferase reporter assays. The anti-inflammatory and neuroprotective effects of glycolytic inhibitor, 2-DG in vivo were measured in the MPTP-or LPS-induced PD models by immunofluorescence staining, behavior tests and Western blot analysis. Results We found that LPS rapidly increased glycolysis in microglial cells, and glycolysis inhibitors (2-DG and 3-BPA), siRNA Glut-1 and siRNA HK Ⅱ abolished LPS-induced microglial cell activation. Mechanistic studies demonstrated that glycolysis inhibitors significantly inhibited LPS-induced phosphorylation of mTOR, IKKβ and IκB, degradation of IκB, nuclear translocation of p65 and NF-κB transcriptional activity. In addition, 2-DG significantly inhibited LPS-induced acetylation of p65/RelA on lysine 310, which is mediated by NAD+-dependent SIRT1 and is critical for NF-kB activation. A coculture study revealed that 2-DG reduced the cytotoxicity of activated microglia toward MES23.5 dopaminergic neuron cells with no direct protective effect. An in vivo study demonstrated that 2-DG significantly ameliorated neuroinflammation and subsequent DA neuronal cell injuries in an LPS-induced Parkinson’s disease (PD) model. Furthermore, 2-DG also reduced TH-positive cell loss and microglial activation in the MPTP-induced PD model. Conclusions Collectively, our results suggest that glycolysis is actively involved in microglial activation and, hence, that inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.

scholarly journals Early glycolytic reprogramming controls microglial inflammatory activation

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Junjie Cheng ◽  
Rong Zhang ◽  
Zhirou Xu ◽  
Youliang Ke ◽  
Renjuan Sun ◽  
...  
Keyword(s):  
Western Blot ◽  
Microglial Activation ◽  
Nuclear Factor Kappa B ◽  
Microglial Cells ◽  
Luciferase Reporter ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Inflammatory Activation ◽  
Glycolysis Inhibitors ◽  
Anti Inflammatory

Abstract Background Microglial activation-mediated neuroinflammation plays an important role in the progression of neurodegenerative diseases. Inflammatory activation of microglial cells is often accompanied by a metabolic switch from oxidative phosphorylation to aerobic glycolysis. However, the roles and molecular mechanisms of glycolysis in microglial activation and neuroinflammation are not yet fully understood. Methods The anti-inflammatory effects and its underlying mechanisms of glycolytic inhibition in vitro were examined in lipopolysaccharide (LPS) activated BV-2 microglial cells or primary microglial cells by enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, immunoprecipitation, flow cytometry, and nuclear factor kappa B (NF-κB) luciferase reporter assays. The anti-inflammatory and neuroprotective effects of glycolytic inhibitor, 2-deoxoy-d-glucose (2-DG) in vivo were measured in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-or LPS-induced Parkinson’s disease (PD) models by immunofluorescence staining, behavior tests, and Western blot analysis. Results We found that LPS rapidly increased glycolysis in microglial cells, and glycolysis inhibitors (2-DG and 3-bromopyruvic acid (3-BPA)), siRNA glucose transporter type 1 (Glut-1), and siRNA hexokinase (HK) 2 abolished LPS-induced microglial cell activation. Mechanistic studies demonstrated that glycolysis inhibitors significantly inhibited LPS-induced phosphorylation of mechanistic target of rapamycin (mTOR), an inhibitor of nuclear factor-kappa B kinase subunit beta (IKKβ), and NF-kappa-B inhibitor alpha (IκB-α), degradation of IκBα, nuclear translocation of p65 subunit of NF-κB, and NF-κB transcriptional activity. In addition, 2-DG significantly inhibited LPS-induced acetylation of p65/RelA on lysine 310, which is mediated by NAD-dependent protein deacetylase sirtuin-1 (SIRT1) and is critical for NF-κB activation. A coculture study revealed that 2-DG reduced the cytotoxicity of activated microglia toward MES23.5 dopaminergic neuron cells with no direct protective effect. In an LPS-induced PD model, 2-DG significantly ameliorated neuroinflammation and subsequent tyrosine hydroxylase (TH)-positive cell loss. Furthermore, 2-DG also reduced dopaminergic cell death and microglial activation in the MPTP-induced PD model. Conclusions Collectively, our results suggest that glycolysis is actively involved in microglial activation. Inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.

scholarly journals Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1

2018 ◽  
Vol 51 (1) ◽  
pp. 113-128 ◽  
Author(s):  
Jia Zhu ◽  
Rui Zhang ◽  
Dongxiang Yang ◽  
Jibin Li ◽  
Xiaofei Yan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blot ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Regulatory Function ◽  
Glutathione S Transferase ◽  
Protein Levels ◽  
Qrt Pcr ◽  
Ic50 Value

Background/Aims: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. Methods: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. Results: XIST expression was upregulated and miR-124 expression was downregulated in DOX-resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST-π levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR-124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST-knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. Conclusion: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients.

scholarly journals MEG3 promotes proliferation and inhibits apoptosis in osteoarthritis chondrocytes by miR-361-5p/FOXO1 axis

2019 ◽  
Author(s):  
Anying Wang ◽  
Naixia Hu ◽  
Yefeng Zhang ◽  
Yuanzhen Chen ◽  
Changhui Su ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Non Coding Rna ◽  
Cartilage Cells ◽  
Osteoarthritis Chondrocytes ◽  
Oa Chondrocytes

Abstract Background: This study aimed to investigate the role of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) and related molecular mechanisms, in osteoarthritis (OA). Methods: Cartilage tissues of OA patients and healthy volunteers were isolated and cultured. After transfection with the appropriate construct, chondrocytes were classified into Blank, pcDNA3.1-NC, pcDNA3.1-MEG3, si-NC, si-MEG3, pcDNA3.1-NC + mimics NC, pcDNA3.1-MEG3 + mimics NC, pcDNA3.1-NC + miR-361-5p mimics and pcDNA3.1-MEG3 + miR-361-5p mimics groups. qRT-PCR was used to detect the expression of MEG3, miR-361-5p and FOXO1 . Western blot, luciferase reporter assay, RIP, CCK-8, and flow cytometry analysis were performed to reveal the morphology, proliferation, and apoptotic status of cartilage cells. Histological analysis and immunostaining were conducted in the OA rat model. Results: Expression of MEG3 and FOXO1 was significantly decreased in OA compared with the normal group, while the expression of miR-361-5p was increased. MEG3 might serve as a ceRNA of miR-361-5p in OA chondrocytes. Moreover, using western blot analyses and the CCK-8 assay, MEG3 was shown to target miR-361-5p/FOXO1, elevate cell proliferation, and impair cell apoptosis. Functional analysis in vivo showed that MEG3 suppressed degradation of the cartilage matrix. Conclusion: MEG3 can contribute to cell proliferation and inhibit cell apoptosis and degradation of extracellular matrix (ECM) via the miR-361-5p/FOXO1 axis in OA chondrocytes.

scholarly journals Anti-inflammatory effects of Morus alba Linne bark on the activation of toll-like receptors and imiquimod-induced ear edema in mice

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lin Umeyama ◽  
Besse Hardianti ◽  
Shiori Kasahara ◽  
Dya Fita Dibwe ◽  
Suresh Awale ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Morus Alba ◽  
Raw264.7 Cells ◽  
Luciferase Reporter ◽  
Γδt Cells ◽  
Ear Edema ◽  
Raw264.7 Macrophages ◽  
Anti Inflammatory

Abstract Background Morus alba L. bark has been widely used in traditional medicine for treating several inflammatory diseases, such as hypertension, diabetes mellitus and coughing; however, the molecular mechanisms underlying its anti-inflammatory effects are not well understood. Methods We examined the effects of an extract of Morus alba L. bark (MabE) on Toll-like receptor (TLR) ligand-induced activation of RAW264.7 macrophages using a luciferase reporter assay and immunoassays. For the in vivo experiment, we used an imiquimod-induced ear edema model to examine the anti-inflammatory effects of MabE. Results MabE inhibited the TLR ligand-induced activation of NF-κB in RAW264.7 cells without affecting their viability. Consistent with the inhibition of NF-κB activation, MabE also inhibited the production of IL-6 and IL-1β from TLR ligand-treated RAW264.7 cells. In vivo MabE treatment inhibited the ear swelling of IMQ-treated mice, in addition to the mRNA expression of IL-17A, IL-1β and COX-2. The increases in splenic γδT cells in IMQ-treated mice and the production of IL-17A from splenocytes were significantly inhibited by MabE treatment. Conclusion Our study suggests that the anti-inflammatory effects of MabE on the activation of the macrophage cell line RAW246.7 by TLRs and IMQ-induced ear edema are through the inhibition of NF-κB activation and IL-17A-producing γδT cells, respectively.

scholarly journals MEG3 promotes proliferation and inhibits apoptosis in osteoarthritis chondrocytes by miR-361-5p/FOXO1 axis

2019 ◽  
Author(s):  
Anying Wang ◽  
Naixia Hu ◽  
Yefeng Zhang ◽  
Yuanzhen Chen ◽  
Changhui Su ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Normal Group ◽  
Luciferase Reporter ◽  
Non Coding Rna ◽  
Osteoarthritis Chondrocytes ◽  
Oa Chondrocytes

Abstract Background: This study aimed to investigate the role of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) and related molecular mechanisms in osteoarthritis (OA). Methods: Patients with OA and patients undergoing thigh amputation were enrolled in OA group and normal group, respectively. Cartilage tissues of all patients were isolated and cultured. After different transfections, chondrocytes were classified into Blank, pcDNA3.1-NC, pcDNA3.1-MEG3, si-NC, si-MEG3, pcDNA3.1-NC + mimics NC, pcDNA3.1-MEG3 + mimics NC, pcDNA3.1-NC + miR-361-5p mimics and pcDNA3.1-MEG3 + miR-361-5p mimics groups. The qRT-PCR was used to detect the expression of MEG3, miR-361-5p and FOXO1. Western blot, luciferase reporter assay, RIP, CCK-8 and flow cytometry analysis were performed to reveal the morphology, proliferation and apoptosis of cartilage cells. Histological analysis and immunostaining were conducted in OA rat model. Results: The expression of MEG3 and FOXO1 in OA was significantly decreased while miR-361-5p was increased compared with the normal group. MEG3 might serve as a ceRNA of miR-361-5p in OA chondrocytes. Moreover, the western blot and CCK-8 assay showed that MEG3, targeted miR-361-5p/FOXO1, might elevate cell proliferation and impair cell apoptosis. Functional analysis in vivo showed that MEG3 suppressed the cartilage matrix degradation. Conclusion: Taken together, MEG3 can contribute to cell proliferation, inhibit cell apoptosis and extracellular matrix (ECM) degradation via miR-361-5p/FOXO1 axis in OA chondrocytes.

scholarly journals MEG3 promotes proliferation and inhibits apoptosis in osteoarthritis chondrocytes by miR-361-5p/FOXO1 axis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Anying Wang ◽  
Naixia Hu ◽  
Yefeng Zhang ◽  
Yuanzhen Chen ◽  
Changhui Su ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Non Coding Rna ◽  
Cartilage Cells ◽  
Osteoarthritis Chondrocytes ◽  
Oa Chondrocytes

Abstract Background This study aimed to investigate the role of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) and related molecular mechanisms, in osteoarthritis (OA). Methods Cartilage tissues of OA patients and healthy volunteers were isolated and cultured. After transfection with the appropriate constructs, chondrocytes were classified into Blank, pcDNA3.1-NC, pcDNA3.1-MEG3, si-NC, si-MEG3, pcDNA3.1-NC + mimics NC, pcDNA3.1-MEG3 + mimics NC, pcDNA3.1-NC + miR-361-5p mimics and pcDNA3.1-MEG3 + miR-361-5p mimics groups. qRT-PCR was used to detect the expression of MEG3, miR-361-5p and FOXO1. Western blot, luciferase reporter assay, RIP, CCK-8, and flow cytometry analysis were performed to reveal the morphology, proliferation, and apoptotic status of cartilage cells. Histological analysis and immunostaining were conducted in the OA rat model. Results Expression of MEG3 and FOXO1 was significantly decreased in OA compared with the normal group, while the expression of miR-361-5p was increased. MEG3 might serve as a ceRNA of miR-361-5p in OA chondrocytes. Moreover, using western blot analyses and the CCK-8 assay, MEG3 was shown to target miR-361-5p/FOXO1, elevate cell proliferation, and impair cell apoptosis. Functional analysis in vivo showed that MEG3 suppressed degradation of the cartilage matrix. Conclusion MEG3 can contribute to cell proliferation and inhibit cell apoptosis and degradation of extracellular matrix (ECM) via the miR-361-5p/FOXO1 axis in OA chondrocytes.

scholarly journals TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
You Shuai ◽  
Zhonghua Ma ◽  
Weitao Liu ◽  
Tao Yu ◽  
Changsheng Yan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Mechanistic Model ◽  
Ectopic Expression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Reporter Assays

Abstract Background Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. Methods LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. Results It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. Conclusions Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

scholarly journals Circular RNA AFF4 modulates osteogenic differentiation in BM-MSCs by activating SMAD1/5 pathway through miR-135a-5p/FNDC5/Irisin axis

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Chao Liu ◽  
An-Song Liu ◽  
Da Zhong ◽  
Cheng-Gong Wang ◽  
Mi Yu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Regulatory System ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Integrin Αv

AbstractBone marrow-derived mesenchymal stem cells (BM-MSCs), the common progenitor cells of adipocytes and osteoblasts, have been recognized as the key mediator during bone formation. Herein, our study aim to investigate molecular mechanisms underlying circular RNA (circRNA) AFF4 (circ_AFF4)-regulated BM-MSCs osteogenesis. BM-MSCs were characterized by FACS, ARS, and ALP staining. Expression patterns of circ_AFF4, miR-135a-5p, FNDC5/Irisin, SMAD1/5, and osteogenesis markers, including ALP, BMP4, RUNX2, Spp1, and Colla1 were detected by qRT-PCR, western blot, or immunofluorescence staining, respectively. Interactions between circ_AFF4 and miR-135a-5p, FNDC5, and miR-135a-5p were analyzed using web tools including TargetScan, miRanda, and miRDB, and further confirmed by luciferase reporter assay and RNA pull-down. Complex formation between Irisin and Integrin αV was verified by Co-immunoprecipitation. To further verify the functional role of circ_AFF4 in vivo during bone formation, we conducted animal experiments harboring circ_AFF4 knockdown, and born samples were evaluated by immunohistochemistry, hematoxylin and eosin, and Masson staining. Circ_AFF4 was upregulated upon osteogenic differentiation induction in BM-MSCs, and miR-135a-5p expression declined as differentiation proceeds. Circ_AFF4 knockdown significantly inhibited osteogenesis potential in BM-MSCs. Circ_AFF4 stimulated FNDC5/Irisin expression through complementary binding to its downstream target molecule miR-135a-5p. Irisin formed an intermolecular complex with Integrin αV and activated the SMAD1/5 pathway during osteogenic differentiation. Our work revealed that circ_AFF4, acting as a sponge of miR-135a-5p, triggers the promotion of FNDC5/Irisin via activating the SMAD1/5 pathway to induce osteogenic differentiation in BM-MSCs. These findings gained a deeper insight into the circRNA-miRNA regulatory system in the bone marrow microenvironment and may improve our understanding of bone formation-related diseases at physiological and pathological levels.

scholarly journals miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Chenguang Ding ◽  
Xiaoming Ding ◽  
Jin Zheng ◽  
Bo Wang ◽  
Yang Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Renal Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Renal Tubular Cell ◽  
In Cells

Abstract Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.

scholarly journals Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

2016 ◽  
Vol 116 (07) ◽  
pp. 181-190 ◽  
Author(s):  
Luong Le ◽  
Hayley Duckles ◽  
Torsten Schenkel ◽  
Marwa Mahmoud ◽  
Jordi Tremoleda ◽  
...  
Keyword(s):  
Heart Rate ◽  
Shear Stress ◽  
Carotid Arteries ◽  
Vascular Inflammation ◽  
Protective Effects ◽  
En Face ◽  
Inflammatory Activation ◽  
Anti Inflammatory ◽  
Stress Dependent

SummaryBlood flow generates wall shear stress (WSS) which alters endothelial cell (EC) function. Low WSS promotes vascular inflammation and atherosclerosis whereas high uniform WSS is protective. Ivabradine decreases heart rate leading to altered haemodynamics. Besides its cardio-protective effects, ivabradine protects arteries from inflammation and atherosclerosis via unknown mechanisms. We hypothesised that ivabradine protects arteries by increasing WSS to reduce vascular inflammation. Hypercholesterolaemic mice were treated with ivabradine for seven weeks in drinking water or remained untreated as a control. En face immunostaining demonstrated that treatment with ivabradine reduced the expression of pro-inflammatory VCAM-1 (p<0.01) and enhanced the expression of anti-inflammatory eNOS (p<0.01) at the inner curvature of the aorta. We concluded that ivabradine alters EC physiology indirectly via modulation of flow because treatment with ivabradine had no effect in ligated carotid arteries in vivo, and did not influence the basal or TNFα-induced expression of inflammatory (VCAM-1, MCP-1) or protective (eNOS, HMOX1, KLF2, KLF4) genes in cultured EC. We therefore considered whether ivabradine can alter WSS which is a regulator of EC inflammatory activation. Computational fluid dynamics demonstrated that ivabradine treatment reduced heart rate by 20 % and enhanced WSS in the aorta. In conclusion, ivabradine treatment altered haemodynamics in the murine aorta by increasing the magnitude of shear stress. This was accompanied by induction of eNOS and suppression of VCAM-1, whereas ivabradine did not alter EC that could not respond to flow. Thus ivabradine protects arteries by altering local mechanical conditions to trigger an anti-inflammatory response.

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