Tilianin Reduces Apoptosis via the ERK/EGR1/BCL2L1 Pathway in Ischemia/Reperfusion-Induced Acute Kidney Injury Mice

Liu, Zengying; Chen, Guan; Li, Chenyu; Zhang, Ningxin; Yang, Chengyu; Xu, Li; Zhou, Bin; Zhao, Liang; Luan, Hong; Man, Xiaofei; Xu, Yan

doi:10.3389/fphar.2022.862584

Cited by 14 publications

(7 citation statements)

References 60 publications

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“…Our research discovered that Egr1 + PTC owned stronger communications with other cells in the microenvironment, serving as catalysts for cell proliferation and immune inhibition. Based on these finding we speculated that Egr1 + PTC might play a protective factor in AKI and EGR1 could be a potential therapeutic target for AKI [ 56 ]. Despite the encouraging potential of Egr1 + PTC in AKI, more research is needed to understand the precise mechanisms by which it functions.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk among proximal tubular cells, macrophages, and fibroblasts in acute kidney injury: single-cell profiling from the perspective of ferroptosis

Wang,

Shen,

et al. 2024

Human Cell

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The link between ferroptosis, a form of cell death mediated by iron and acute kidney injury (AKI) is recently gaining widespread attention. However, the mechanism of the crosstalk between cells in the pathogenesis and progression of acute kidney injury remains unexplored. In our research, we performed a non-negative matrix decomposition (NMF) algorithm on acute kidney injury single-cell RNA sequencing data based specifically focusing in ferroptosis-associated genes. Through a combination with pseudo-time analysis, cell–cell interaction analysis and SCENIC analysis, we discovered that proximal tubular cells, macrophages, and fibroblasts all showed associations with ferroptosis in different pathways and at various time. This involvement influenced cellular functions, enhancing cellular communication and activating multiple transcription factors. In addition, analyzing bulk expression profiles and marker genes of newly defined ferroptosis subtypes of cells, we have identified crucial cell subtypes, including Egr1 + PTC-C1, Jun + PTC-C3, Cxcl2 + Mac-C1 and Egr1 + Fib-C1. All these subtypes which were found in AKI mice kidneys and played significantly distinct roles from those of normal mice. Moreover, we verified the differential expression of Egr1, Jun, and Cxcl2 in the IRI mouse model and acute kidney injury human samples. Finally, our research presented a novel analysis of the crosstalk of proximal tubular cells, macrophages and fibroblasts in acute kidney injury targeting ferroptosis, therefore, contributing to better understanding the acute kidney injury pathogenesis, self-repairment and acute kidney injury-chronic kidney disease (AKI-CKD) progression.

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Section: Discussionmentioning

confidence: 99%

Crosstalk among proximal tubular cells, macrophages, and fibroblasts in acute kidney injury: single-cell profiling from the perspective of ferroptosis

Wang,

Shen,

et al. 2024

Human Cell

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“…Activation of ERK1/2 mediates cardiac hypertrophy and dysfunction, and in addition to its anti-apoptotic effects in the myocardium ( 49 , 50 ). The ERK/EGR1 signaling pathway has a critical role in the process of apoptosis in multiple organs ( 39 , 51 , 52 ). Inhibition of ERK1/2 kinase expression downregulates EGR1 expression, thereby reducing myocardial ischemia-reperfusion induced apoptosis and autophagy ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats

Wang

Wang²,

Pang³

et al. 2023

Front. Nutr.

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Cardiac structure remodeling and dysfunction are common complications of diabetes, often leading to serious cardiovascular events. MOTS-c, a mitochondria-derived peptide, regulates metabolic homeostasis by accelerating glucose uptake and improving insulin sensitivity. Plasma levels of MOTS-c are decreased in patients with diabetes. MOTS-c can improve vascular endothelial function, making it a novel therapeutic target for the cardiovascular complications of diabetes. We investigated the effects of MOTS-c on cardiac structure and function and analyzed transcriptomic characteristics in diabetic rats. Our results indicate that treatment with MOTS-c for 8-week repaired myocardial mitochondrial damage and preserved cardiac systolic and diastolic function. Transcriptomic analysis revealed that MOTS-c altered 47 disease causing genes. Functional enrichment analysis indicated MOTS-c attenuated diabetic heart disease involved apoptosis, immunoregulation, angiogenesis and fatty acid metabolism. Moreover, MOTS-c reduced myocardial apoptosis by downregulating CCN1 genes and thereby inhibiting the activation of ERK1/2 and the expression of its downstream EGR1 gene. Our findings identify potential therapeutic targets for the treatment of T2D and diabetic cardiomyopathy.

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“…In VaD, several dysregulated miRNAs have been linked to the pathological processes of inflammatory cascades, oxidative stress, neurotrophic deficiency, and neuronal apoptosis. Differentially-expressed miRNAs can be corrected using oligonucleotide-based miRNA mimics and antisense nucleotides ( 38 ). These small molecule compounds are of considerable interest due to their potential for regulating miRNA expression ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

“…Tilianin may offer various useful functions for treating cardiovascular diseases. For example, tilianin maintains the function of OGD/R-damaged heart by inhibiting apoptotic and inflammatory reactions ( 34 ) and reduces apoptosis in ischemia-induced acute kidney injury by inhibiting ERK/EGR1/BCL2L1 pathways ( 38 ). We previously demonstrated the cardio- and neuro-protection of tilianin against ischemia via the p-CaMKII and ox-CaMKII signaling pathways ( 9 , 18 , 24 ).…”

Section: Discussionmentioning

confidence: 99%

Tilianin improves cognition in a vascular dementia rodent model by targeting miR-193b-3p/CaM- and miR-152-3p/CaMKIIα-mediated inflammatory and apoptotic pathways

et al. 2023

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IntroductionAlthough vascular dementia (VaD) is the second most prevalent form of dementia, there is currently a lack of effective treatments. Tilianin, isolated from the traditional drug Dracocephalum moldavica L., may protect against ischemic injury by inhibiting oxidative stress and inflammation via the CaMKII-related pathways but with weak affinity with the CaMKII molecule. microRNAs (miRNAs), functioning in post-transcriptional regulation of gene expression, may play a role in the pathological process of VaD via cognitive impairment, neuroinflammatory response, and neuronal dysfunction. This study aimed to investigate the role of tilianin in VaD therapy and the underlying mechanism through which tilianin regulates CaMKII signaling pathways based on miRNA-associated transcriptional action.MethodsRats with 2-vessel occlusion (2VO), a standard model of VaD, were treated with tilianin, vehicle control, and target overexpression or downregulation. High-throughput sequencing, qRT-PCR, and western blot analyses were utilized to identify the downstream target genes and signaling pathways of tilianin involved in VaD.ResultsOur results showed that tilianin ameliorated cognitive deficits, neurodegeneration, and microglial and astrocytic activation in rats with 2VO. Subsequent high-throughput sequencing and qRT-PCR analyses revealed that tilianin increased the downregulated miR-193b-3p and miR-152-3p levels in the cortex and hippocampus of 2VO rats. Mechanistically, miR-193b-3p targeting CaM and miR-152-3p targeting CaMKIIα were identified to play a role in VaD-associated pathology, inhibiting the p38 MAPK/NF--κB p65 pathway and decreasing TNF-α and IL-6 levels. Further gain- and loss-of-function experiments for these key genes showed that tilianin-exerted cognitive improvement by activating the p38 MAPK/NF--κB p65 and Bcl-2/Bax/caspase-3/PARP pathways in the brain of 2VO rats was abolished by miR-193b-3p and miR-152-3p inhibition. Moreover, CaM and CaMKIIα overexpression eliminated the elevated effects of miR-193b-3p and miR-152-3p on tilianin’s protection against ischemic injury through increased inflammatory reactions and apoptotic signaling.DiscussionTogether, these findings indicate that tilianin improves cognition by regulating the miR-193b-3p/CaM- and miR-152-3p/CaMKIIα-mediated inflammatory and apoptotic pathways, suggesting a potential small-molecule regulator of miRNA associated with inflammatory signaling for VaD treatment.

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Tilianin Reduces Apoptosis via the ERK/EGR1/BCL2L1 Pathway in Ischemia/Reperfusion-Induced Acute Kidney Injury Mice

Cited by 14 publications

References 60 publications

Crosstalk among proximal tubular cells, macrophages, and fibroblasts in acute kidney injury: single-cell profiling from the perspective of ferroptosis

Crosstalk among proximal tubular cells, macrophages, and fibroblasts in acute kidney injury: single-cell profiling from the perspective of ferroptosis

MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats

Tilianin improves cognition in a vascular dementia rodent model by targeting miR-193b-3p/CaM- and miR-152-3p/CaMKIIα-mediated inflammatory and apoptotic pathways

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