MSCs treatment can protect against experimental liver fibrosis in CCl4-induced or DMN-induced rats and the mechanisms of the anti-fibrosis by MSCs will be studied further.

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Mesenchymal stromal cells (MSCs) have shown great potential for treating inflammatory bowel disease, which is ameliorated through paracrine cross talk between MSCs and T-cells. Members of the insulin-like growth factor binding protein (IGFBP) family have important immunomodulatory functions in MSCs, but the underlying mechanisms behind these functions have not yet been clearly elucidated. In this study, we investigate whether MSC-produced IGFBP7 is involved in immune modulation using a mouse experimental colitis model. Gene expression profiling revealed that IGFBP7 was highly expressed in MSCs. Consistent with this findings, IGFBP7 knockdown in MSCs significantly decreased their immunomodulatory properties, decreasing the antiproliferative functions of MSCs against T-cells, while also having an effect on the proinflammatory cytokine production of the T-cells. Furthermore, in the mouse experimental colitis model, MSC-derived IGFBP7 ameliorated the clinical and histopathological severity of induced colonic inflammation and also restored the injured gastrointestinal mucosal tissues. In conclusion, IGFBP7 contributes significantly to MSC-mediated immune modulation, as is shown by the ability of IGFBP7 knockdown in MSCs to restore proliferation and cytokine production in T-cells. These results suggest that IGFBP7 may act as a novel MSC-secreted immunomodulatory factor.

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The levels of the products of RNA polymerase III-dependent genes (Pol III genes), including tRNAs and 5S rRNA, are elevated in transformed and tumor cells, which potentiate tumorigenesis. TFIIB-related factor 1 (Brf1) is a key transcription factor and specifically regulates the transcription of Pol III genes. In vivo and in vitro studies have demonstrated that a decrease in Brf1 reduces Pol III gene transcription and is sufficient for inhibiting cell transformation and tumor formation. Emerging evidence indicates that dysregulation of Brf1 and Pol III genes is linked to the development of hepatocellular carcinoma (HCC) in humans and animals. We have reported that Brf1 is overexpressed in human liver cancer patients and that those with high Brf1 levels have shorter survivals. This review summarizes the effects of dysregulation of these genes on HCC and their regulation by signaling pathways and epigenetics. These novel data should help us determine the molecular mechanisms of HCC from a different perspective and guide the development of therapeutic approaches for HCC patients.

Alcohol intake is associated with numbers of different human cancers, such as hepatocellular carcinoma (HCC) and breast cancer. However, the molecular mechanism remains to be elucidated. RNA polymerase III-dependent genes (Pol III genes) deregulation elevates cellular production of tRNAs and 5S rRNA, resulting in an increase in translational capacity, which promote cell transformation and tumor formation. To explore a common mechanism of alcohol-associated human cancers, we have comparably analyzed that alcohol causes deregulation of Pol III genes in liver and breast cells. Our results reveal that alcohol enhances RNA Pol III gene transcription in both liver and breast cells. The induction of Pol III genes caused by alcohol in ER+ breast cancer lines or liver tumor lines are significantly higher than in their non-tumor cell lines. Alcohol increases cellular levels of Brf1 mRNA and protein, which is key transcription factor and specifically regulate Pol III gene activity. Alcohol activates JNK1 to upregulate transcription of Brf1 and Pol III genes, whereas inhibition of JNK1 by SP600125 or its siRNA significantly decreases the induction of these genes. Furthermore, alcohol increases the rates of transformation of liver and breast cells, repressed JNK1 and Brf1 expression decrease transcription of Pol III genes and reduce the rates of colony formation of AML-12 and MCF-10 cells. Together, these studies support the idea that alcohol induces deregulation of Brf1 and RNA Pol III genes in liver and breast cells, which share a common signaling pathway to promote cell transformation. Through the common mechanism, alcohol-induced deregulation of RNA Pol III genes brings about greater phenotypic changes.

Schistosomiasis caused by human schistosomes such as Schistosoma japonicum (S. japonicum) is considered as an immune-related disease. It was demonstrated that specific cytokine antibodies' response elicited by S. japonicum infection was gradually downregulated with the progress of the disease, resulting in a Th1/Th2 polarization and suppression of immune response. CD28 (cluster of differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival, and CD38 is an activating marker of T lymphocyte with high expression in many acute or chronic infections. The immune signature of CD28null T cells in the peripheral circulation associates with chronic inflammation in many diseases, such as HIV and CMV infection. In the thymus, CD28 expression on developing thymocytes appears to play a role for their selection, and it synergizes with CD38 to induce apoptosis of DP (double-positive) thymocytes. Few reports about CD28 and CD38 have been published in schistosomiasis. Here, we investigated the dynamic patterns of the expression of molecules CD28 and CD38 on CD4(+)/CD8(+) T lymphocytes of the thymus and spleen in mice model with S. japonicum infection. Our data indicated that at an early period of infection, the frequency of CD8(+)CD28(-) T cell in the spleen decreased significantly, but higher at chronic infection than that in control. However, it demonstrated an increasing trend in the thymus with the progression of infection. The frequency of CD4(+)CD28(-) T cells increased from acute infection in the thymus, while from chronic infection in the spleen. The expression of CD38 on CD8(+) T cells began to increase at 4 weeks post infection both in the thymus and spleen; its elevated expression on CD4(+) T cells emerged at 6 weeks post infection in the thymus and at 10 weeks post infection in the spleen. Praziquantel (PZQ) treatment could partially restore the frequency of CD28(+) T cell of CD4(+) T cells and CD38(+) T cell of CD8(+)/CD4(+) T cells in the spleen and CD38(+) T cell in the thymus. We hypothesized that the reactivation of S. japonicum infection may trigger expansion of CD28(-) T cells and hence mediate systemic inflammation. We speculated that CD8(+)CD28(-) T cell might be involved in immune modulation and CD8(+)CD28(-) T cell may be a crucial part in pathogenesis, which can provide further knowledge of the sophisticated mechanism of immuno-downregulation in schistosomiasis and potential treatment target.