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Alsterpaullone (Alp) is a small-molecule inhibitor that targets cyclin-dependent kinases to inhibit tumor cell activity. However, to the best of our knowledge, the effect of Alp on hepatoblastoma has not been investigated. Therefore, the function of Alp in apoptotic induction of hepatoblastoma cells and a potential mechanism of action were investigated. Results indicated that low doses of Alp (1 µM) significantly induced apoptosis in the HepG2 hepatoblastoma cell line. In vivo experiments of tumor suppression further indicated that Alp (3 mg/kg) exerted an inhibitory effect on HepG2 ×enograft tumor growth. Following Alp treatment, the expression level of B-cell lymphoma 2 (Bcl-2)-associated X protein, and cleaved caspase-3 and −9 in HepG2 cells was significantly increased; however, the expression of Bcl-2 was significantly decreased. In addition, phosphorylation of p38 mitogen-activated protein kinase (MAPK) significantly decreased Alp-induced caspase-3 and −9 activation. These results suggested that Alp induces apoptosis and inhibited proliferation via the p38MAPK signaling pathway. Therefore, Alp may be a therapeutic agent for treating hepatoblastoma. [ABSTRACT FROM AUTHOR]

Immature dendritic cells (DC) have been demonstrated to induce T-cell hyporesponsiveness in vitro and immune tolerance in vivo. However, immature DC (iDC) may become mature once infused in vivo, thus limiting the prolongation of the allograft survival. Considering that mature DC express high level of B7, intercellular adhesion molecule-1 (ICAM-1), and T-cell activation needs costimulation signals provided by DC, we selected anti-ICAM-1 mAb and cytotoxic T lymphocyte antigen-4Ig fusion protein (CTLA-4Ig) for in vivo administration to block costimulation pathways in order to further improve the efficacy of iDC to induce immune tolerance. Seven days before allogeneic cardiac transplantations, the recipients were intravenously (i.v.) pretreated of donor-derived iDC with or without simultaneous injections of anti-ICAM-1 mAb and CTLA-4Ig. CTLA-4Ig or anti-ICAM-1 mAb administration alone resulted in significant prolongation of cardiac allograft survival induced by iDC. When used simultaneously, CTLA-4Ig and anti-ICAM-1 mAb induced permanent allografts acceptance even in 90% recipients. The recipients could keep the skin alive for a longer time in the donor-specific second transplantation, but no effect was observed on the skin from C3H third-party mice. The efficient induction of donor-specific tolerance observed above may be related to the more potent inhibition of donor-specific T-cell responses including cytotoxicity activity, Th1 cytokines production, and alloantibody production by the combined use of anti-ICAM-1 mAb and CTLA-4Ig. Our data suggest that anti-ICAM-1 antibody and CTLA-4Ig can synergistically enhance iDC to induce donor-specific immune tolerance in vivo. [Copyright &y& Elsevier]

Non-alcoholic fatty liver disease (NAFLD) is a complex disease characterized by a massive accumulation of lipids in the liver, with a continuous progression of simple steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Non-alcoholic fatty liver disease is associated with obesity, insulin resistance, and metabolic syndrome; it is a severe public health risk and is currently the most common liver disease of the world. In addition to the fatty infiltration of the liver in non-alcoholic fatty liver disease patients, the field of liver transplantation faces similar obstacles. NAFLD and NASH primarily involve lipotoxicity, inflammation, oxidative stress, and insulin resistance. However, the precise mechanisms and treatments remain unclear. Therapeutic approaches encompass exercise, weight control, as well as treatments targeting antioxidants and anti-inflammatory pathways. The role of animal models in research has become crucial as a key tool to explore the molecular mechanisms and potential treatments for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Here, we summarized the current understanding of the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis and discussed animal models commonly used in recent years., Competing Interests: None., (AJTR Copyright © 2024.)

Background and Aims: Reducing reactive oxygen species (ROS) production has proven an effective way for alleviating oxidative stress during ischemia-reperfusion injury (IRI). Moreover, inhibition of Rac1 could reduce ROS production and prevent oxidative stress injury. Previous studies have suggested a positive interactivation feedback loop between Rac1 and hypoxia-inducible factor (HIF)-1α, the latter being up-regulated early during ischemia. The positive inter-activation between Rac1 and HIF-1α would aggravate ROS production, thereby promoting IRI. This study was designed to verify the effects of Rac1 inhibition on hepatic IRI both at animal and cellular levels and to explore the interaction between Rac1 and HIF-1α during hepatic IRI., Methods: C57B/6 mice and AML-12 cells were used for the construction of hepatic IRI animal and cell models. Rac1 inhibition was achieved by NSC23766 (a specific Rac1 inhibitor). Lentiviral vectors were used for Rac1 knockdown. At designated time points, serum and liver tissues were collected from the mice and treated cells were collected for further analysis., Results: NSC23766 treatment significantly alleviated the hepatic IRI in mice, manifesting as lower vacuolation score and less apoptosis cells, lower ROS and serum/liver alanine aminotransferase/aspartate aminotransferase levels, and fewer activated inflammatory cells. IRI of AML-12 was also alleviated by 50 µM NSC23766 or Rac1-knockdown, manifesting as reduced cell apoptosis, less extensive interruption of mitochondrial membrane potential, down-regulation of apoptosis, and effects on DNA damage-related proteins. Interestingly, Rac1 knockdown also down-regulated the expression level of HIF-1α., Conclusions: Our study supports a protective effect of Rac1 inhibition on hepatic IRI. Aside from the classic topics of reducing ROS production and oxidative stress, our study showed an interaction between Rac1 and HIF-1α signaling during hepatic IRI., Competing Interests: The authors have no conflict of interests related to this publication., (© 2022 Authors.)

Here, we investigated in diabetic mice the therapeutic effect of monocyte chemoattractant protein-1 (MCP-1), locally delivered by an electrospun scaffold, on transplanted islets. This therapeutic scheme is expected to exert a synergistic effect to ameliorate hyperglycemia and its associated nephrotic disorders. The cumulative amount of MCP-1 released from the scaffold in vitro within a 3-week window was 267.77 ± 32.18 ng, without a compromise in bioactivity. After 8 weeks following the transplantation, the islet population stimulated by MCP-1 was 35.14%± 7.23% larger than the non-stimulated islet population. Moreover, MCP-1 increased concentrations of blood insulin and C-peptide 2 by 49.83%± 5.29% and 43.49%± 9.21%, respectively. Consequently, the blood glucose concentration in the MCP-1 group was significantly lower than that in the control group at week 2 post-surgery. MCP-1 also enhanced the tolerance of sudden oral glucose challenge. The rapid decrease of blood creatinine, urine creatinine, and blood urea nitrogen suggested that the recovery of renal functions compromised by hyperglycemia could also be attributed to MCP-1. Our study shed new light on a synergistic strategy to alleviate hyperglycemia and nephrotic disorders in diabetic patients.

Previously, we demonstrated that Tim-1-Fc prevents acute cardiac graft rejection by inhibiting Th1 response. In the present report, we tackled the impact of Tim-1-Fc on Th17 cells in a model of cardiac chronic rejection. Administration of Tim-1-Fc did not result in a detectable impact on innate immunity and regulatory T cells, while it provided protection for Bm12-derive cardiac grafts against chronic rejection in B6 recipients, as manifested by the reduction of inflammatory infiltration along with less severity of vasculopathy. Studies in T-bet(-/-) recipients by implanting Bm12-derived cardiac grafts further revealed that Tim-1-Fc significantly protected cardiac grafts from chronic rejection along with attenuated production of IL-17 producing T cells. Depletion of CD4 and CD8 T cells or blockade of IL-17 in T-bet(-/-) recipients demonstrated that Tim-1-Fc selectively suppresses Th17 differentiation along with attenuated IL-17 secretion. Together, our data suggest that Tim-1-Fc protects cardiac grafts from chronic rejection by suppressing CD4 Th17 development and functionality. Therefore, Tim-1-Fc might be a potential immunosuppressive agent in the setting of cardiac transplantation.