rSjP40 Inhibited the Activity of Collagen Type I Promoter via Ets-1 in HSCs

Li, Jing; Zhang, Jiali; Zhang, Bei; Chen, Liuting; Guo, Chen; Zhu, Dandan; Chen, Jinling; Duan, Lian; Duan, Yinong

doi:10.3389/fcell.2021.765616

Cited by 9 publications

(5 citation statements)

References 30 publications

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“…Erlotinib also significantly inhibited the expression of TGF-β1 activated ACTA2 in LX2 and TWNT4 cells. As other profibrogenic genes Il6, Tgfb1, Timp1 and Col1a1 are secreted by hepatocytes, HSCs and other types of liver cells, [40][41][42][43] the decreased expression of these genes in PCLS after erlotinib treatment might come from all these liver cells. However, erlotinib only significantly inhibited the expression of TGF-β1 activated COL1A1 in LX2 and TWNT4 cells.…”

Section: Discussionmentioning

confidence: 99%

Precision-Cut Liver Slices as anex vivomodel to evaluate antifibrotic therapies for liver fibrosis and cirrhosis

Wang,

Leaker,

Qiao

et al. 2023

Preprint

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BackgroundPrecision-Cut Liver Slices (PCLS) are anex vivoculture model developed to study hepatic drug metabolism. One of the main benefits of this model is that it retains the structure and cellular composition of the native liver. PCLS also represents a potential model system to study liver fibrosis in a setting that more closely approximatesin vivopathology thanin vitromethods. The aim of this study was to assess whether responses to antifibrotic interventions can be detected and quantified with PCLS.MethodsPCLS of 250 μm thickness were prepared from four different murine fibrotic liver models: choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), thioacetamide (TAA), diethylnitrosamine (DEN), and carbon tetrachloride (CCl4). PCLS were treated with 5 μM Erlotinib for 72 hours. Histology and gene expression were then compared within vivomurine experiments and TGF-β1 activated hepatic stellate cells (HSCs). These types of PCLS characterization were also evaluated in PCLS from human cirrhotic liver.ResultsPCLS viability in culture was stable for 72 hours. Treatment of erlotinib, an EGFR inhibitor significantly inhibited the expression of profibrogenic genesIl6,Col1a1andTimp1in PCLS from CDAHFD-induced cirrhotic mice, andIl6,Col1a1andTgfb1in PCLS from TAA-induced cirrhotic rats. Erlotinib treatment of PCLS from DEN-induced cirrhotic rats inhibited the expression ofCol1a1,Timp1,Tgfb1andIl6, which was consistent with the impact of erlotinib onCol1a1andTgfb1expression inin vivoDEN-induced cirrhosis. Erlotinib treatment of PCLS from CCl4-induced cirrhosis caused reduced expression ofTimp1,Col1a1andTgfb1, which was consistent with the effect of erlotinib inin vivoCCl4-induced cirrhosis. In addition, in HSCs at PCLS from normal mice, TGF-β1 treatment upregulatedActa2(αSMA), while treatment with erlotinib inhibited the expression ofActa2. Similar expression results were observed in TGF-β1 treatedin vitroHSCs. Expression of MMPs and TIMPs, key regulators of fibrosis progression and regression, were also significantly altered under erlotinib treatment in PCLS. Expression changes under erlotinib treatment were also corroborated with PCLS from human cirrhosis samples.ConclusionThe responses to antifibrotic interventions can be detected and quantified with PCLS at the gene expression level. The antifibrotic effects of erlotinib are consistent between PCLS models of murine cirrhosis and those observedin vivoandin vitro. Similar effects were also reproduced in PCLS derived from patients with cirrhosis. PCLS is an excellent model to assess antifibrotic therapies that is aligned with the principles of Replacement, Reduction and Refinement (3Rs).

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Section: Discussionmentioning

confidence: 99%

Precision-Cut Liver Slices as anex vivomodel to evaluate antifibrotic therapies for liver fibrosis and cirrhosis

Wang,

Leaker,

Qiao

et al. 2023

Preprint

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“…We can make informed assumptions and infer the involvement of specific cell types which do play an active role in tissue-specific co-expression networks ( 124 ). ATM is mainly found in endothelial and epithelial cells ( 125 , 126 ), FGFR1 in fibroblasts and epithelial cells ( 57 , 58 ), FBXW7 in hepatic stellate mesenchymal, mononuclear and pulmonary epithelial stem cells ( 60 – 62 ), ESR1 in myofibroblasts and epithelial cells ( 63 , 64 ), CCND1 in renal glomerular mesangial and hepatic stellate cells ( 66 , 127 ), HIF1A in renal epithelial cells and cardiac fibroblasts ( 68 , 128 ), CEBPB in hematopoietic and renal epithelial cells ( 70 , 71 ), NAMPT in hepatic stellate and renal glomerular mesangial cells ( 72 , 129 ), IRF1 in renal epithelial cells ( 76 ), SOCS1 in hepatocytes and macrophages ( 78 ), SOCS3 in cardiac fibroblasts ( 90 ), ICAM1 in endothelial cells ( 79 ), ETS1 in hepatic stellate and renal epithelial cells ( 130 , 131 ), IL7R in hepatic stellate cells ( 82 ), MMP1 in fibroblasts ( 83 , 132 ), HNF4A in hepatocytes ( 85 ), CCL2 in fibroblasts ( 86 , 133 ), CASP1 in hepatic endothelial cells ( 87 ) and STAT1 in macrophages ( 88 , 89 ). HSP90B1 , although it has been recently reported to be implicated in fibrosis ( 92 ), the specific cell type expressing it, still, remains undetermined.…”

Section: Discussionmentioning

confidence: 99%

Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

Dovrolis

Filidou²,

Tarapatzi³

et al. 2022

Front. Immunol.

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IntroductionExtracellular matrix turnover, a ubiquitous dynamic biological process, can be diverted to fibrosis. The latter can affect the intestine as a serious complication of Inflammatory Bowel Diseases (IBD) and is resistant to current pharmacological interventions. It embosses the need for out-of-the-box approaches to identify and target molecular mechanisms of fibrosis.Methods and resultsIn this study, a novel mRNA sequencing dataset of 22 pairs of intestinal biopsies from the terminal ileum (TI) and the sigmoid of 7 patients with Crohn’s disease, 6 with ulcerative colitis and 9 control individuals (CI) served as a validation cohort of a core fibrotic transcriptomic signature (FIBSig), This signature, which was identified in publicly available data (839 samples from patients and healthy individuals) of 5 fibrotic disorders affecting different organs (GI tract, lung, skin, liver, kidney), encompasses 241 genes and the functional pathways which derive from their interactome. These genes were used in further bioinformatics co-expression analyses to elucidate the site-specific molecular background of intestinal fibrosis highlighting their involvement, particularly in the terminal ileum. We also confirmed different transcriptomic profiles of the sigmoid and terminal ileum in our validation cohort. Combining the results of these analyses we highlight 21 core hub genes within a larger single co-expression module, highly enriched in the terminal ileum of CD patients. Further pathway analysis revealed known and novel inflammation-regulated, fibrogenic pathways operating in the TI, such as IL-13 signaling and pyroptosis, respectively.DiscussionThese findings provide a rationale for the increased incidence of fibrosis at the terminal ileum of CD patients and highlight operating pathways in intestinal fibrosis for future evaluation with mechanistic and translational studies.

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“…Although T cells play critical roles in rejection, other immune cells and non-immune cells are also involved in transplant immunopathology. Several lines of evidence suggested that SEA can also regulate innate immune cells, non-immune cells, metabolism, and apoptosis (23)(24)(25)(26)(27)(28)(29). Thus, the protective effects mediated by SEA seems to be multifaceted.…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of the Soluble Egg Antigen of Schistosoma japonicum in A Mouse Skin Transplantation Model

Jiang

Zhou

et al. 2022

Front. Immunol.

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BackgroundOrgan transplantation is currently an effective method for treating organ failure. Long-term use of immunosuppressive drugs has huge side effects, which severely restricts the long-term survival of patients. Schistosoma can affect the host’s immune system by synthesizing, secreting, or excreting a variety of immunomodulatory molecules, but its role in transplantation was not well defined. In order to explore whether Schistosoma-related products can suppress rejection and induce long-term survival of the transplant, we used soluble egg antigen (SEA) of Schistosoma japonicum in mouse skin transplantation models.Materials and methodsEach mouse was intraperitoneally injected with 100 μg of SEA three times a week for four consecutive weeks before allogenic skin transplant. Skin transplants were performed on day 0 to observe graft survival. Pathological examination of skin grafts was conducted 7 days post transplantation. The skin grafts were subjected to mRNA sequencing. Bioinformatics analysis was conducted and the expression of hub genes was verified by qPCR. Flow cytometry analysis was performed to evaluate the immune status and validate the results from bioinformatic analysis.ResultsThe mean survival time (MST) of mouse skin grafts in the SEA-treated group was 11.67 ± 0.69 days, while that of the control group was 8.00 ± 0.36 days. Pathological analysis showed that Sj SEA treatment led to reduced inflammatory infiltration within skin grafts 7 days after allogenic skin transplantation. Bioinformatics analysis identified 86 DEGs between the Sj SEA treatment group and the control group, including 39 upregulated genes and 47 downregulated genes. Further analysis revealed that Sj SEA mediated regulation on cellular response to interferon-γ, activation of IL-17 signaling and chemokine signaling pathways, as well as cytokine–cytokine receptor interaction. Flow cytometry analysis showed that SEA treatment led to higher percentages of CD4+IL-4+ T cells and CD4+Foxp3+ T cells and decreased CD4+IFN-γ+ T cells in skin transplantation.ConclusionSj SEA treatment suppressed rejection and prolonged skin graft survival by regulating immune responses. Sj SEA treatment might be a potential new therapeutic strategy to facilitate anti-rejection therapy and even to induce tolerance.

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rSjP40 Inhibited the Activity of Collagen Type I Promoter via Ets-1 in HSCs

Cited by 9 publications

References 30 publications

Precision-Cut Liver Slices as anex vivomodel to evaluate antifibrotic therapies for liver fibrosis and cirrhosis

Precision-Cut Liver Slices as anex vivomodel to evaluate antifibrotic therapies for liver fibrosis and cirrhosis

Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

The Protective Effect of the Soluble Egg Antigen of Schistosoma japonicum in A Mouse Skin Transplantation Model

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