Interstrain differences in chronic hepatitis and tumor development in a murine model of inflammation-mediated hepatocarcinogenesis

Alternative therapies for cancer treatment have been developed using bioactive compounds such as betulinic acid (BA). The objective of this study was to investigate the bioactivity of BA in its free form and compare it with its nano-encapsulated form under a skin carcinogenesis protocol in a genetically modified murine model. K14E6 and FVB mice were divided into four groups to be treated with free BA and with betulinic acid nanoemulsion (BANE). Lecithin enriched with medium chain fatty acids (MCFAs) was employed as an emulsifier to prepare the nanoemulsions with a mean droplet size of 40 nm. Skin tumors were induced by exposure to DMBA and TPA directly to the transgenic mice. Tumor development was completely inhibited by BANE and by 70% with free BA. This was validated by histological sections and the gene expression of the Cdk4 and Casp8 genes.

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Repositioning of a Novel GABA-B Receptor Agonist, AZD3355 (Lesogaberan), for the Treatment of Non-alcoholic Steatohepatitis

10.21203/rs.3.rs-386482/v1 ◽

2021 ◽

Author(s):

Dipankar Bhattacharya ◽

Christine Becker ◽

Benjamin Readhead ◽

Nicolas Goossens ◽

Jacqueline Novik ◽

...

Keyword(s):

Murine Model ◽

Receptor Agonist ◽

Drug Repositioning ◽

Clinical Stage ◽

Tumor Development ◽

Stellate Cells ◽

Novel Therapy ◽

Alcoholic Steatohepatitis ◽

Gene And Protein Expression

Abstract Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355’s potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, aSMA and TNF-a mRNA as well as secreted collagen1a1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development in a robust murine model of NASH, which was comparable to activity of obeticholic acid, an advanced investigational therapy for this disease. These data identify a well-tolerated clinical stage asset as a novel therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.

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Pharmacological Inhibition of Sonic Hedgehog Signaling Suppresses Tumor Development in a Murine Model of Intrahepatic Cholangiocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms222413214 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13214

Author(s):

Kyungjoo Cho ◽

Hyuk Moon ◽

Sang Hyun Seo ◽

Simon Weonsang Ro ◽

Beom Kyung Kim

Keyword(s):

Sonic Hedgehog ◽

Murine Model ◽

Hedgehog Signaling ◽

Target Genes ◽

Primary Liver Cancer ◽

Tumor Development ◽

Biological Behavior ◽

Sonic Hedgehog Signaling ◽

Pharmacological Inhibition ◽

Hepatic Diseases

Cholangiocarcinoma (CCC) is the second most primary liver cancer with an aggressive biological behavior, and its incidence increases steadily. An aberrant up-regulation of the sonic hedgehog signaling pathway has been reported in a variety of hepatic diseases including hepatic inflammation, fibrosis, as well as cancer. In this study, we determined the effect of a sonic hedgehog inhibitor, vismodegib, on the development of CCC. Through database analyses, we found sonic hedgehog signaling was up-regulated in human CCC, based on overexpression of its target genes, GLI1 and GLI2. Further, human CCC cells were highly sensitive to the treatment with vismodegib in vitro. Based on the data, we investigated the in vivo anti-cancer efficacy of vismodegib in CCC employing a murine model of CCC developed by hydrodynamic tail vein injection method. In the murine model, CCC induced by constitutively active forms of TAZ and PI3K exhibited up-regulated sonic hedgehog signaling. Treatment of vismodegib significantly suppressed tumor development in the murine CCC model, based on comparison of gross morphologies and liver weight/body weight. It is expected that pharmacological inhibition of sonic hedgehog signaling would be an effective molecular target therapy for CCC.

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Genomic sequencing identifies a few mutations driving the independent origin of primary liver tumors in a chronic hepatitis murine model

PLoS ONE ◽

10.1371/journal.pone.0187551 ◽

2017 ◽

Vol 12 (11) ◽

pp. e0187551 ◽

Cited By ~ 1

Author(s):

Zuyu Yang ◽

Mingming Jia ◽

Guojing Liu ◽

Huaining Hao ◽

Li Chen ◽

...

Keyword(s):

Chronic Hepatitis ◽

Murine Model ◽

Liver Tumors ◽

Genomic Sequencing ◽

Primary Liver Tumors ◽

Independent Origin

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Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2011.04445.x ◽

2011 ◽

Vol 166 (1) ◽

pp. 134-142 ◽

Cited By ~ 76

Author(s):

S. Chen ◽

S. M. F. Akbar ◽

M. Abe ◽

Y. Hiasa ◽

M. Onji

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Murine Model ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Chronic Hepatitis B Virus ◽

B Virus

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Transdifferentiation of Malignant B-Cells into Macrophages in a Murine Model of Burkitt´s Lymphoma

Blood ◽

10.1182/blood.v124.21.5406.5406 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5406-5406

Author(s):

Heiko Bruns ◽

Sebastian Mueller ◽

Christian Bach ◽

Shirin Pasemann ◽

Anna Maurberger ◽

...

Keyword(s):

B Cells ◽

Murine Model ◽

Conflicts Of Interest ◽

Tumor Development ◽

Monocytic Cells ◽

Hematopoietic System ◽

Clonal Identity ◽

Immunological Phenotype ◽

Tumor Environment

Abstract B-cell lymphomas, such as Burkitt's lymphoma, are malignant diseases of the hematopoietic system. They arise from transformed B-cells originating from diverse primary and secondary lymphatic tissues. Like in other cancers, the stroma of lymphomas is typically infiltrated by so-called tumor-associated macrophages (TAMs), which execute manifold tumor-specific functions. Interestingly it was shown, that mature B-cells could be efficiently re-programmed into macrophages by the overexpression of myeloid-specific transcription factors. Moreover, other studies observed in vitro that this lymphoid/myeloid plasticity might be also caused by oncogenes in cultured B-cells of murine lymphoma models. Therefore we consider, if lymphoma B-cells themselves might be a source of TAMs, besides the well-known infiltration of monocytic cells into the tumor environment. Based on the system of CD45.1/2 allotypes, a murine model of lymphoma was thus developed, which allows tracking of the conversion of lymphoma B-cells into TAMs. It could be shown, that some lymphoma B-cells of the established model in fact spontaneously switched into a macrophage-like phenotype. Accordingly, they start to express typical macrophage markers, but seem to perform a transition into a myeloid-like expression profile on the level of transcription as well. Furthermore, analysis of the recombined immunoglobulin heavy chain confirmed the clonal identity of lymphoma b-cells and TAMs. Although these cells do not exhibit an overt immunological phenotype, they show elementary functional properties of macrophages, such as phagocytosis as well as a post-mitotic character. Moreover, transdifferentiated B-cells cells were resistant to chemotherapy and persist after treatment, while lymphoma B-cells were eradicated. Which consequences the lymphoid/myeloid plasticity of lymphoma B-cells has for tumor development, progression, as well as for the outcome of therapy, and if these observations could be transferred to human tumors, will be object of future investigations. Disclosures No relevant conflicts of interest to declare.

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