Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis

Li, Ji Min; Yang, David C.H.; Oldham, Justin M.; Linderholm, A.; Zhang, Jun; Li, Jun; Kenyon, Nicholas J.; Chen, Ching-Hsien

doi:10.1016/j.ymthe.2021.01.028

Cited by 21 publications

(19 citation statements)

References 55 publications

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“…IPF has many resemblances with cancer, like invasive phenotype. Recently it was reported that ASS1 deficiency happened in pulmonary fibrosis, MET can be activated by knocking down ASS1, then interacting with the upstream of the Src-STAT3 signaling to up-regulate the proliferation of fibroblast cells ( Li et al, 2021b ). Moreover, it has been shown that the overexpression of the MET and CD44v6 can sustain the TGFβ signaling in IPF ( Stella et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

A novel gene signature based on the hub genes of COVID-19 predicts the prognosis of idiopathic pulmonary fibrosis

et al. 2022

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Background: Increasing evidence has demonstrated that there was a strong correlation between COVID-19 and idiopathic pulmonary fibrosis (IPF). However, the studies are limited, and the real biological mechanisms behind the IPF progression were still uncleared.Methods: GSE70866 and GSE 157103 datasets were downloaded. The weight gene co-expression network analysis (WGCNA) algorithms were conducted to identify the most correlated gene module with COVID-19. Then the genes were extracted to construct a risk signature in IPF patients by performing Univariate and Lasso Cox Regression analysis. Univariate and Multivariate Cox Regression analyses were used to identify the independent value for predicting the prognosis of IPF patients. What’s more, the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and gene set enrichment analysis (GSEA) were conducted to unveil the potential biological pathways. CIBERSORT algorithms were performed to calculate the correlation between the risk score and immune cells infiltrating levels.Results: Two hundred thirty three differentially expressed genes were calculated as the hub genes in COVID-19. Fourteen of these genes were identified as the prognostic differentially expressed genes in IPF. Three (MET, UCHL1, and IGF1) of the fourteen genes were chosen to construct the risk signature. The risk signature can greatly predict the prognosis of high-risk and low-risk groups based on the calculated risk score. The functional pathway enrichment analysis and immune infiltrating analysis showed that the risk signature may regulate the immune-related pathways and immune cells.Conclusion: We identified prognostic differentially expressed hub genes related to COVID-19 in IPF. A risk signature was constructed based on those genes and showed great value for predicting the prognosis in IPF patients. What’s more, three genes in the risk signature may be clinically valuable as potential targets for treating IPF patients and IPF patients with COVID-19.

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Section: Discussionmentioning

confidence: 99%

A novel gene signature based on the hub genes of COVID-19 predicts the prognosis of idiopathic pulmonary fibrosis

et al. 2022

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“…Niese et al (2010) found that proline, which can be metabolized by arginine, is usually a rate-limiting substrate in collagen synthesis and is crucial for collagen precipitation in pulmonary fibrosis. Li et al (2021) found loss of arginine succinate synthase 1 (ASS1), a rate-limiting enzyme responsible for the biosynthesis of the endogenous semi-essential amino acid, arginine during the urea cycle, in fibroblasts from patients with IPF. They demonstrated that ASS1 gene deletion promoted the invasive and fibrotic potential of lung fibroblasts.…”

Section: Argininementioning

confidence: 99%

“… Li et al (2021) found loss of arginine succinate synthase 1 (ASS1), a rate-limiting enzyme responsible for the biosynthesis of the endogenous semi-essential amino acid, arginine during the urea cycle, in fibroblasts from patients with IPF. They demonstrated that ASS1 gene deletion promoted the invasive and fibrotic potential of lung fibroblasts.…”

Section: Metabolites Of the Gut Microbiomementioning

confidence: 99%

“…They demonstrated that ASS1 gene deletion promoted the invasive and fibrotic potential of lung fibroblasts. Further studies suggested that exogenous arginine deprivation attenuates fibroblast proliferation, migration, and invasion, thereby protecting mice from BLM-induced pulmonary fibrosis ( Li et al, 2021 ). Therefore, we speculate that ASS1 deficiency in fibroblasts during IPF development may represent a compensatory feedback regulatory mechanism to control endogenous arginine homeostasis.…”

Section: Metabolites Of the Gut Microbiomementioning

confidence: 99%

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Gut microbiome and metabolites: The potential key roles in pulmonary fibrosis

Li²,

Luo³

et al. 2022

Front. Microbiol.

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There are a wide variety of microbiomes in the human body, most of which exist in the gastrointestinal tract. Microbiomes and metabolites interact with the host to influence health. Rapid progress has been made in the study of its relationship with abenteric organs, especially lung diseases, and the concept the of “gut–lung axis” has emerged. In recent years, with the in-depth study of the “gut–lung axis,” it has been found that changes of the gut microbiome and metabolites are related to fibrotic interstitial lung disease. Understanding their effects on pulmonary fibrosis is expected to provide new possibilities for the prevention, diagnosis and even treatment of pulmonary fibrosis. In this review, we focused on fibrotic interstitial lung disease, summarized the changes the gut microbiome and several metabolites of the gut microbiome in different types of pulmonary fibrosis, and discussed their contributions to the occurrence and development of pulmonary fibrosis.

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“…Spleens were removed from euthanized animals, and single-cell suspensions of leukocytes were prepared by disaggregation of the tissue through a 100-µm nylon mesh, followed by dissociation, as we reported previously [39]. Cells were washed once with complete DMEM media, supplemented with 10% heat-inactivated FBS (hiFBS), then incubated with RBC lysis buffer for 1 min to remove red blood cells, then washed again in complete DMEM media.…”

Section: Flow Cytometry Assaysmentioning

confidence: 99%

A Novel Renoprotective Strategy: Upregulation of PD-L1 Mitigates Cisplatin-Induced Acute Kidney Injury

Yang

Zhang

et al. 2021

IJMS

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The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI.

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Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis

Cited by 21 publications

References 55 publications

A novel gene signature based on the hub genes of COVID-19 predicts the prognosis of idiopathic pulmonary fibrosis

A novel gene signature based on the hub genes of COVID-19 predicts the prognosis of idiopathic pulmonary fibrosis

Gut microbiome and metabolites: The potential key roles in pulmonary fibrosis

A Novel Renoprotective Strategy: Upregulation of PD-L1 Mitigates Cisplatin-Induced Acute Kidney Injury

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