Background Transforming growth factor‐β (TGF‐β)/Smad3 signalling plays a central role in tissue fibrogenesis, acting as a potent stimulus of extracellular matrix (ECM) protein accumulation. The aim ...of this study was to evaluate the potential role of Smad3 in the pathogenesis of colonic fibrosis induced by trinitrobenzene sulfonic acid (TNBS) in Smad3 null mice.
Materials and methods Chronic colitis‐associated fibrosis was induced in 15 Smad3 null and 13 wild‐type mice by intra‐rectal administration of TNBS. Each mouse received an incremental dose of TNBS (0·5–1·0 mg per week) over a 6‐week period. The colon was excised for macroscopic examination and histological, morphometric and immunohistochemical analyses. For immunohistochemistry, alpha‐smooth muscle actin (α‐SMA), collagen types I–III, TGF‐β1, connective tissue growth factor (CTGF), Smad3, Smad7, and CD3 antibodies were used.
Results At macroscopic examination, the colon of Smad3 wild‐type mice appeared significantly harder, thicker and shorter than that of the Smad3 null mice. Of the wild‐type mice, 50% presented colonic adhesions and strictures. Histological and morphometric evaluation revealed a significantly higher degree of colonic fibrosis and accumulation of collagen in the Smad3 wild‐type compared to null mice, whereas the degree of colonic inflammation did not differ between the two groups of mice. Immunohistochemical evaluation showed a marked increase in CTGF, collagen I–III, TGF‐β and Smad3 staining in the colon of Smad3 wild‐type compared to null mice, whereas Smad7 was increased only in null mice.
Conclusions These results indicate that Smad3 loss confers resistance to the development of TNBS‐induced colonic fibrosis. The reduced fibrotic response appears to be due to a reduction in fibrogenic mesenchymal cell activation and ECM production and accumulation. Smad3 could be a novel target for potential treatment of intestinal fibrosis, especially in inflammatory bowel disease.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The alpha isotype of actin expressed by hepatic stellate cells reflects their activation to myofibroblast-like cell and has been directly related to experimental liver fibrogenesis, and indirectly to ...human fibrosis in chronic liver disease.
To evaluate the changes in distribution and percentage of alpha-smooth muscle actin-positive hepatic stellate cells and the correlation with the degree of the fibrosis in cirrhotic livers, as well as in patients with recurrent HCV chronic hepatitis after liver transplantation.
Human liver biopsies were divided in four groups: (1) normal livers obtained from cadaveric liver donors (
n
=
35), (2) cirrhosis post-HBV hepatitis (
n
=
11), (3) cirrhosis post-HCV hepatitis (
n
=
10), and (4) post-transplant recurrent HCV chronic hepatitis (
n
=
13). Samples were stained with anti-alpha-smooth muscle actin antibody by immunoperoxidase method and semi-quantitatively evaluated. Liver fibrosis was assessed from specimens stained with Masson's trichrome and quantified by computer image analysis.
The percentage of alpha-smooth muscle actin-positive hepatic stellate cells was significantly higher in the HBV cirrhosis, HCV cirrhosis and post-transplant HCV recurrent hepatitis groups (36.1
±
15.2, 23.8
±
19.7 and 27.8
±
16.4%, respectively) compared to the liver donor group (2.9
±
4.0%). The alpha-smooth muscle actin-positive hepatic stellate cells to fibrous tissue ratio were significantly higher in the post-transplant recurrent HCV hepatitis group (2.36
±
1.12) compared to both the donor livers and the HCV cirrhosis groups (0.74
±
1.09 and 1.03
±
0.91, respectively). The alpha-smooth muscle actin-positive hepatic stellate cell percentage and fibrosis correlated positively in the post-transplant recurrent HCV hepatitis group and negatively in the HCV cirrhosis group. No difference in the immunohistochemical and morphometrical variables was found between the HCV cirrhosis and HBV cirrhosis groups.
These results indirectly confirm that, in vivo, alpha-smooth muscle actin expression is a reliable marker of hepatic stellate cells activation which precedes fibrous tissue deposition even in the setting of recurrent HCV chronic hepatitis after liver transplantation, and it could be useful to identify the earliest stages of hepatic fibrosis and monitoring the efficacy of the therapy. In the presence of advanced cirrhosis other factors, rather than alpha-smooth muscle actin-positive hepatic stellate cells, may sustain fibrosis deposition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
An abstract of a study by Arribas et al on PQR309, idelalisib, duvelisib and ibrutinib that lead to similar gene expression changes in activated B-cell like (ABC) diffuse large B-cell lymphoma ...(DLBCL) is presented. Gene expression profiling was obtained with the lllumina-HumanHT-12 Expression-BeadChips and analyzed with limma t-test. A GSEA was performed using the limma-derived gene expression profiling signatures obtained for each drug. The study demonstrated the targeted fundamental pathways of all models sustaining lymphoma cell proliferation and survival. Their early effects on the lymphoma cell transcriptome were very similar, but with varied degree of changes among drugs, possibly reflecting their main targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
An abstract of the study of Bernasconi et al. about the BET bromodomain inhibitor (BET-i) BAY 1238097: Mechanism of action and pre-clinical activity in diffuse large B-cell lymphoma (DLBCL) is ...presented. Among other things BAY 1238097 is a novel BET-i, active in lymphoma models (ENA2015). Here, we characterize its mechanism of action and report further in vitro and in vivo activity data in DLBCL. BAY 1238097 affected the growth of both GCB and ABC DLBCL xenografts: treated tumors resulted 6-8 fold smaller in volume respect to controls. At GEP, BAY 1238097 decreased target genes of Myc, Notch and E2F, members of the NFKB/MYDB8 and mTORIAKT signaling. The up- regulated transcripts were mainly represented by histones. The GEP signatures highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC-i, mTOR-i and demethylatirig agents. BAY 1238097 has anti lymphoma in vivo activity, and is able to interfere with pathways relevant for lymphoma cells and is synergistic with EZH2-i and mTOR-i.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
An abstract of a study by Tarantelli et al on the novel mTORC1/2 inhibitor PQR620 has in vitro and in vivo activity in lymphomas is presented. Proliferation and caspase 3/7 activation were assessed ...in 44 lymphoma cell lines treated with increasing doses of PQR620. Baseline gene expression profiling was obtained with the lllumina-HumanHT-12 Expression-BeadChips and analyzed with GSEA. Results indicated that PQR620 showed potent anti-proliferative activity in most of the cell lines tested. There was no association between sensitivity to PQR620 and TP53 inactivation. Apoptosis induction was seen more frequently with PQR620 than with the other 2 compounds: 6/44 cell lines for everolimus and 3/44 for AZD8055. The study concludes that PQR620 showed wide activity in lymphoma models as single agent and also in combination with venetoclax.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
