β-Arrestin-2 attenuates hepatic ischemia-reperfusion injury by activating PI3K/Akt signaling

Chen, Xiaolong; Zhang, Junbin; Long, Xia; Wang, Li; Li, Hui; Liu, Huilin; Zhou, Jing; Feng, Zhiying; Jin, Hai; Yang, Junfeng; Yang, Yang; Wu, Bin; Zhang, Lei; Chen, Guihua; Wang, Genshu

doi:10.18632/aging.202246

Cited by 17 publications

(17 citation statements)

References 33 publications

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“…In different ischemia-reperfusion injury mouse models applied on hepatic and cardiac tissues, increased levels of p-PI3K, p-Akt have been recorded, indicating that I/R may activate the PI3K/Akt signaling pathway to initiate tissue repair following injury ( Zhang et al, 2014 ; Thokala et al, 2017 ). Targeting PI3K/Akt signaling pathway by different pharmacological therapies as a potential protective pathway against I/R injury has attracted great attention in many studies ( Yapca et al, 2013 ; Guan et al, 2020 ; Chen et al, 2021 ). In the current study, Western blot analysis showed significant upregulation in PI3K/Akt/mTOR expression in pancreatic tissue after nicorandil injection as a single treatment or combined with preconditioned MSCs.…”

Section: Discussionmentioning

confidence: 99%

Combined Systemic Intake of K-ATP Opener (Nicorandil) and Mesenchymal Stem Cells Preconditioned With Nicorandil Alleviates Pancreatic Insufficiency in a Model of Bilateral Renal Ischemia/Reperfusion Injury

ShamsEldeen¹,

El-Aal²,

Aboulhoda³

et al. 2022

Front. Physiol.

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We used nicorandil, a K-ATP channel opener, to study the role of these channels in the amelioration of renal ischemia/reperfusion (I/R)-induced pancreatic injury, and the possible involvement of PI3K/Akt/mTOR signaling pathway. Forty-two male Wistar rats were included in this study, six were sacrificed for extraction of bone marrow mesenchymal stem cells (BM-MSCs) and conducting the in-vitro work, the others were included in vivo study and equally divided into six groups. Group 1 (sham control), but groups 2–6 were subjected to bilateral renal I/R: Group 2 (I/R); Group 3 (I/R-NC), treated with nicorandil; Group 4 (I/R-MSCs), treated with BM-MSCs; Group 5 (I/R-MSCC), treated with nicorandil-preconditioned BM-MSCs; Group 6 (I/R-NC-MSCC), treated with both systemic nicorandil and preconditioned BM-MSCC. Renal injury and subsequent pancreatic damage were detected in the I/R group by a significant increase in serum urea, creatinine, fasting glucose, and pancreatic enzymes. The pancreatic tissues showed a reduction in cellularity and a significant decrease in the expression of the cell survival pathway, PI3K/Akt/mTOR, in the I/R group compared to the control. Preconditioning MSCs with nicorandil significantly enhanced the proliferation assay and decreased their apoptotic markers. Indeed, combined systemic nicorandil and nicorandil-preconditioning maintained survival of MSC in the pancreatic tissue and amelioration of apoptotic markers and pancreatic TNF-α production. Histologically, all treated groups revealed better pancreatic architecture, and increased area % of anti-insulin antibody and CD31, which were all best observed in the NC-MSCC group. Thus, using K-ATP channel opener was efficient to enhance PI3K/Akt/mTOR expression levels (in vivo and in vitro).

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Section: Discussionmentioning

confidence: 99%

Combined Systemic Intake of K-ATP Opener (Nicorandil) and Mesenchymal Stem Cells Preconditioned With Nicorandil Alleviates Pancreatic Insufficiency in a Model of Bilateral Renal Ischemia/Reperfusion Injury

ShamsEldeen¹,

El-Aal²,

Aboulhoda³

et al. 2022

Front. Physiol.

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“…Currently, research has largely focused on the molecular targets and their mediated signaling pathways in HIRI. For example, SET8 alleviates mouse HIRI by inhibiting the microtubule affinity-regulating kinase 4 ( MARK4 )/nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 ( NLRP3 ) inflammasome pathway ( 34 ), and ARRB2 alleviates HIRI by activating the phosphatidylinositol 3 kinase ( PI3K )/protein kinaseB ( AKT ) signaling pathway ( 35 ). Through a transcriptome analysis, our research identified the 6 key molecules closely related to HIRI, and successfully constructed the RF model of HIRI; in addition, we also successfully established a lncRNA-miRNA-mRNA network using a variety of bioinformatics analysis tools.…”

Section: Discussionmentioning

confidence: 99%

Analysis and identification of potential key genes in hepatic ischemia-reperfusion injury

Li¹,

Su²,

Li³

et al. 2022

Ann Transl Med

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Background: Hepatic ischemia-reperfusion injury (HIRI) is an unavoidable surgical complication after liver transplantation, but current HIRI treatments cannot achieve satisfactory clinical outcomes. Thus, safer and more effective prevention and treatment methods need to be explored.Methods: Transcriptome messenger ribonucleic acid (mRNA) and long non-coding RNA (lncRNA) sequencing data were obtained from male Sprague-Dawley rats, and these data were used to identify the differentially expressed genes (DEGs) and differentially expressed lncRNAs (DE-lncRNAs) between the HIRI and control samples. A protein-protein interaction (PPI) network was also constructed for the DE-mRNAs to identify candidate genes, and the receiver operating characteristic curves of the 21 candidate genes were plotted to evaluate the diagnostic value of the candidate genes for HIRI. A random forest (RF) model, support vector machine model and generalized linear model were constructed based on the candidate genes. A gene set enrichment analysis (GSEA) of the key genes was conducted to determine the enriched pathways in the high expression groups. The miRWalk and miRanda database were used to constructed the lncRNA-miRNA-mRNA network. Finally, the expressions of the key genes were verified by quantitative real-time polymerase chain reaction (qRT-PCR).Results: A total of 256 DEGs and 67 DE-lncRNAs were identified in the HIRI and control samples. To explore the interactions between the DE-mRNAs, a PPI network of 130 DEGs was constructed. Further, 21 genes were selected as the candidate genes. Subsequently, 6 genes [i.e., Keratin-14 (Krt14), Uroplakin 3B (Upk3b), Keratin 7 (Krt7), Cadherin 3 (Cdh3), mesothelin (Msln), and Glypican 3 (Gpc3)] in the RF model were defined as the key genes. The GSEA results indicated that these key genes were enriched in the terms of extracellular structure organization, and extracellular matrix organization. Moreover, a lncRNA-miRNA-mRNA network was constructed with 4 lncRNAs, 5 mRNAs, and 11 miRNAs. Finally, the results indicated that the expression of Krt14, Upk3b, Msln, and Gpc3 were more highly expressed in the control samples than the HIRI samples.Conclusions: A total of 6 key genes (i.e., Krt14, Upk3b, Krt7, Cdh3, Msln, and Gpc3) were identified. Our findings provide novel ideas for the diagnosis and treatment of HIRI.

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“…Previous research has also shown that β-arrestins are involved in cell proliferation, apoptosis, and differentiation by mediating the Akt phosphorylation response to extensive stimulation in different cell types (42,43). Furthermore, PI3K-Akt signaling has been shown to play a central role in Arrb2medited cell protection (44,45). Therefore, we tested whether PI3K-Akt pathway is the downstream signaling mediator of the Arrb2-induced anti-apoptotic and proproliferation effects in TGCT.…”

Section: (C) Heatmap Of the Differentially Expressed Mrna Patterns In Tgct Versus Oa Synovitis The Relative Expression Is Indicated By Comentioning

confidence: 94%

β-Arrestin2 Inhibits the Apoptosis and Facilitates the Proliferation of Fibroblast-like Synoviocytes in Diffuse-type Tenosynovial Giant Cell Tumor

Cao

Zhang

Cheng

et al. 2021

Cancer Genomics Proteomics

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Background/Aim: Diffuse-type tenosynovial giant cell tumor (TGCT) is a rare benign proliferative synovial neoplasm of uncertain etiology, and the efficacy of surgical resection is not satisfactory. Therefore, there is an urgent need to explore the pathogenesis and identify novel therapeutic targets for TGCT. Materials and Methods: Synovial tissues were collected from patients with TGCT and osteoarthritis (OA). Differences of mRNA expression between TGCT and OA were explored using mRNA-seq. In addition, fibroblast-like synoviocytes (FLS) were treated with small interfering RNA (siRNA) or adenovirus in order to knockdown or overexpress β-arrestin2 (Arrb2), respectively. FLS proliferation and apoptosis were evaluated using the MTT assay and the caspase 3 activity assay, respectively. Results: The expression of Arrb2 in TGCT was significantly higher than that in OA. The overexpression of Arrb2 promoted the proliferation of FLS and inhibited its apoptosis, while knocking down Arrb2 had the opposite effect. Further studies showed that Arrb2 can activate the PI3K-Akt signaling pathway, leading to increased proliferation of TGCT. Conclusion: Arrb2 facilitates the proliferation and inhibits the apoptosis of TGCT FLS through activating the PI3K-Akt cell survival pathway, providing new insight into the molecular mechanism of TGCT.Diffuse-type tenosynovial giant cell tumor (TGCT) is a rare benign proliferative synovial neoplasm characterized by villous and nodular lesions of an uncertain etiology (1). The main clinical features of TGCT are synovial hyperplasia and recurrence. The hyperplastic synovial tissue will produce a large amount of bloody synovial fluid and cause excessive swelling of the joints, further causing joint pain and dysfunction (2). Uncontrollable excessive synovial proliferation can even cause malignant transformation of TGCT and result in amputation (3). Fibroblast-like synoviocytes (FLS), as the main constituent cell type of TGCT, play an important role in its proliferation, recurrence, and malignant transformation (4). Because its pathogenesis is currently unclear, the therapeutic mainstay of TGCT is limited to removing the entire pathological synovial tissue (5). However, surgical resection alone often cannot completely remove the diseased synovium; the residual synovium will rapidly proliferate and cause postoperative recurrence, at a rate of approximately 21-50% (6). Postoperative radiotherapy is often needed to reduce recurrence, but radiotherapy can lead to a series of complications such as joint adhesion (7). Therefore, there is an urgent need to explore the pathogenesis of TGCT and identify novel therapeutic targets, especially focusing on the inhibition of its proliferation and recurrence.β-Arrestin 2 (Arrb2) is widely expressed in various tissues and involved in mediating G protein coupled receptor (GPCR) desensitization, internalization, degradation and 461 This article is freely accessible online.

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β-Arrestin-2 attenuates hepatic ischemia-reperfusion injury by activating PI3K/Akt signaling

Cited by 17 publications

References 33 publications

Combined Systemic Intake of K-ATP Opener (Nicorandil) and Mesenchymal Stem Cells Preconditioned With Nicorandil Alleviates Pancreatic Insufficiency in a Model of Bilateral Renal Ischemia/Reperfusion Injury

Combined Systemic Intake of K-ATP Opener (Nicorandil) and Mesenchymal Stem Cells Preconditioned With Nicorandil Alleviates Pancreatic Insufficiency in a Model of Bilateral Renal Ischemia/Reperfusion Injury

Analysis and identification of potential key genes in hepatic ischemia-reperfusion injury

β-Arrestin2 Inhibits the Apoptosis and Facilitates the Proliferation of Fibroblast-like Synoviocytes in Diffuse-type Tenosynovial Giant Cell Tumor

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