A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells

Han, Jae Hyun; Kim, Ok-Hee; Lee, Sang Chul; Kim, Kee-Hwan; Park, Jung Hyun; Lee, Jae Im; Lee, Kyung Hee; Hong, Ha-Eun; Seo, Haeyeon; Choi, Ho Joong; Kim, Say-June

doi:10.3390/ijms20246302

Cited by 8 publications

(5 citation statements)

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“…In previous studies, high-dosage TAA is known to induce lipid peroxidation and oxidative stress, and the pathological effects are mainly limited to ALI rather than causing direct damage to other organs ( Muller et al, 1991 ; Mladenovic et al, 2012 ). Thus, according to previous studies ( França et al, 2019 ; Han et al, 2019 ; Liu et al, 2021 ), we administered 250 mg/kg/day TAA to mice via intraperitoneal injection for 3 days to establish the ALI model in our present study.…”

Section: Discussionmentioning

confidence: 99%

“…Male Institute of Cancer Research mice (ICR, 8 weeks old) were randomly divided into different groups, including control group, TAA group, Fer-1 pre-treatment and TAA group, or TAA with DFO group ( n = 6-9 mice per group). According to previous studies ( França et al, 2019 ; Han et al, 2019 ; Liu et al, 2021 ), TAA was injected (i.p., 250 mg/kg/day) for 3 consecutive days to induce acute liver injury. Fer-1 was administered (i.p., 2.5 μM/kg/day) for 3 days before TAA treatment ( Wang et al, 2017 ), and DFO (200 mg/kg/day, i. p) was injected with TAA for 3 days ( Mansour 2000 ; Wu et al, 2011 ).…”

Section: Methodsmentioning

confidence: 99%

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Ferrostatin-1 Ameliorates Liver Dysfunction via Reducing Iron in Thioacetamide-induced Acute Liver Injury in Mice

et al. 2022

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Background and Aims: Hepatic iron overload always leads to oxidative stress, which has been found to be involved in the progression of liver disease. However, whether iron disorder is involved in acute liver disease and the further molecular mechanisms remain unclear.Methods: A mice model of acute liver injury (ALI) was established via intraperitoneal injection of thioacetamide (TAA) (250 mg/kg/day) for 3 consecutive days. Ferrostatin-1 (Fer-1) was administered intraperitoneally (2.5 μM/kg/day) starting 3 days before TAA treatment. Deferoxamine (DFO) was intraperitoneally injected (200 mg/kg/day) with TAA treatment for 3 days. We further observed the effect of Fer-1 on TAA model with high-iron diet feeding. ALI was confirmed using histological examination and liver function activity. Moreover, expressions of iron metabolism and ferroptosis proteins were measured by Western blot analysis.Results: The study revealed that the iron accumulation and ferroptosis contributed to TAA-induced ALI pathogenesis. TAA induced prominent inflammation and vacuolar degeneration in the liver as well as liver dysfunction. In addition, protein expression of the cystine/glutamate antiporter SLC7A11 (xCT) and glutathione peroxidase 4 (GPX4) was significantly decreased in the liver, while transferrin receptor 1 (TfR1), ferroportin (Fpn) and light chain of ferritin (Ft-L) expression levels were increased after TAA exposure. As the same efficiency as DFO, pre-administration of Fer-1 significantly decreased TAA-induced alterations in the plasma ALT, AST and LDH levels compared with the TAA group. Moreover, both Fer-1 and DFO suppressed TfR1, Fpn and Ft-L protein expression and decreased iron accumulation, but did not affect xCT or GPX4 expression in the liver. Both Fer-1and DFO prevented hepatic ferroptosis by reducing the iron content in the liver. Furthermore, Fer-1 also reduced iron and reversed liver dysfunction under iron overload conditions.Conclusion: These findings indicate a role of TAA-induced iron accumulation and ferroptosis in the pathogenesis of ALI model. The effect of Fer-1 was consistent with that of DFO, which prevented hepatic ferroptosis by reducing the iron content in the liver. Thus, Fer-1 might be a useful reagent to reverse liver dysfunction and decreasing the iron content of the liver may be a potential therapeutic strategy for ALI.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Ferrostatin-1 Ameliorates Liver Dysfunction via Reducing Iron in Thioacetamide-induced Acute Liver Injury in Mice

et al. 2022

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“…TNF-α-driven inflammation plays a key role in the occurrence of liver fibrosis. Han et al [ 37 ] designed genetically engineered ASCs that can produce etanercept (an effective TNF-α inhibitor) to play an anti-fibrosis role. They transfected ADSCs with a microcirculatory plasmid containing an insert encoding the etanercept gene to generate synthetic etanercept ADSCs.…”

Section: Ways To Enhance Ascs Therapeutic Performancementioning

confidence: 99%

“…In order to enhance treatment effectiveness, various modifications were made, including the aforementioned antioxidant and eugenol pre-treatment, modification with various factors including mmu_circ_0000623 and etanercept, all exhibited enhanced abilities in treating liver fibrosis[ 30 , 31 , 34 , 37 ].…”

Section: Application In Fibrosis-related Diseasesmentioning

confidence: 99%

Application of adipose-derived stem cells in treating fibrosis

Li¹,

Wang²,

Li³

et al. 2021

WJSC

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Fibrosis is the hyperactivation of fibroblasts that results in excessive accumulation of extracellular matrix, which is involved in numerous pathological changes and diseases. Adipose-derived stem cells (ASCs) are promising seed cells for regenerative medicine due to their bountiful source, low immunogenicity and lack of ethical issues. Their anti-fibrosis, immunomodulation, angiogenesis and other therapeutic effects have made them suitable for treating fibrosis-related diseases. Here, we review the literature on ASCs treating fibrosis, elaborate and discuss their mechanisms of action, changes in disease environment, ways to enhance therapeutic effects, as well as current preclinical and clinical studies, in order to provide a general picture of ASCs treating fibrotic diseases.

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“…Studies have found that WD can further cause copper deposition in the liver and gradually progress from a mildly symptomatic liver inflammation to liver fibrosis even acute liver failure [ 3 ]. Accumulating research indicates that inflammation leads to activation of hepatic stellate cells (HSCs) and is a prominent driver of liver fibrosis [ 4 , 5 ]. Some genes such as C-X-C motif chemokine ligand 8 (CXCL8), mitogen-activated protein kinase 1 (MAPK1), AKT serine/threonine kinase 1 (AKT1), SRC proto-oncogene (SRC), vascular endothelial growth factor A (VEGFA), and interleukin 6 (IL-6) have been reported to active EGFR tyrosine kinase inhibitor (EGFR-TKI) resistance, Kaposi sarcoma-associated herpesvirus (KSHV) infection, and human cytomegalovirus (HCMV) infection pathways, leading to liver inflammation and HSCs activation and promoting the progression of liver fibrosis [ 6 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Mechanism of Jiedu Huazhuo Quyu Formula in Treating Wilson’s Disease-Associated Liver Fibrosis by Network Pharmacology Analysis and Molecular Dynamics Simulation

Huang

Chen

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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The Jiedu Huazhuo Quyu formula (JHQ) shows significant beneficial effects against liver fibrosis caused by Wilson’s disease (WD). Hence, this study aimed to clarify the mechanisms of the JHQ treatment in WD-associated liver fibrosis. First, we collected 103 active compounds and 527 related targets of JHQ and 1187 targets related to WD-associated liver fibrosis from multiple databases. Next, 113 overlapping genes (OGEs) were obtained. Then, we built a protein-protein interaction (PPI) network with Cytoscape 3.7.2 software and performed the Gene Ontology (GO) term and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analyses with GENE DENOVO online sites. Furthermore, module analysis was performed, and the core target genes in the JHQ treatment of WD-associated liver fibrosis were obtained. Pathway and functional enrichment analyses, molecular docking studies, molecular dynamic (MD) simulation, and Western blot (WB) were then performed. The results indicated that 8 key active compounds including quercetin, luteolin, and obacunone in JHQ might affect the 6 core proteins including CXCL8, MAPK1, and AKT1 and 107 related signaling pathways including EGFR tyrosine kinase inhibitor resistance, Kaposi sarcoma-associated herpesvirus infection, and human cytomegalovirus infection signaling pathways to exhibit curative effects on WD-associated liver fibrosis. Mechanistically, JHQ might inhibit liver inflammatory processes and vascular hyperplasia, regulate the cell cycle, and suppress both the activation and proliferation of hepatic stellate cells (HSCs). This study provides novel insights for researchers to systematically explore the mechanism of JHQ in treating WD-associated liver fibrosis.

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A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells

Cited by 8 publications

References 46 publications

Ferrostatin-1 Ameliorates Liver Dysfunction via Reducing Iron in Thioacetamide-induced Acute Liver Injury in Mice

Ferrostatin-1 Ameliorates Liver Dysfunction via Reducing Iron in Thioacetamide-induced Acute Liver Injury in Mice

Application of adipose-derived stem cells in treating fibrosis

Evaluation of the Mechanism of Jiedu Huazhuo Quyu Formula in Treating Wilson’s Disease-Associated Liver Fibrosis by Network Pharmacology Analysis and Molecular Dynamics Simulation

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