No abstract

SummaryPrimary biliary cirrhosis (PBC) is an organ-specific autoimmune liver disease characterized by progressive loss of intrahepatic small bile ducts. Cellular immune mechanisms involving T cell reaction are thought to be involved significantly in the pathogenesis of PBC. Recent studies have independently revealed enhanced T helper type 17 (Th17) response and weakened T regulatory cell (Treg) response in some autoimmune diseases, indicating a role of Th17/Treg imbalance in the pathogenesis of autoimmunity. This prompted us to investigate whether the Th17/Treg balance was broken in the peripheral blood of patients with PBC and, if it was, what cytokine circumstances might contribute to this imbalance. The expression of 11 Th17/Treg differentiation-related genes and serum concentrations of the corresponding cytokines in 36 patients with PBC, 28 patients with chronic hepatitis B and 28 healthy controls were measured by real-time quantitativepolymerase chain reaction and enzyme-linked immunosorbent assay respectively. Peripheral Th17 and Treg cells were analysed by flow cytometry. Th17-related cytokines were increased significantly in patients with PBC. Consistent with the cytokine profile, the Th17 cell population and retinoidrelated orphan receptor gt expression were increased markedly. In contrast, the Treg cell population and forkhead box P3 expression were decreased dramatically in the peripheral blood of patients with PBC. Our study revealed that the Th17/Treg imbalance, both cytokine profile and cell numbers, exists in patients with PBC, suggesting its potential role in the breakdown of immune self-tolerance in PBC. Interleukin-23, which characterized the imbalanced cytokine profile, may play an essential role in Th17-related human autoimmunity.

Excessive oxidative stress in cancer cells can induce cancer cell death. Anticancer activity and drug resistance of chemotherapy are closely related to the redox state of tumor cells. Herein, five lipophilic Pt(IV) prodrugs were synthesized on the basis of the most widely used anticancer drug cisplatin, whose anticancer efficacy and drug resistance are closely related to the intracellular redox state. Subsequently, a series of cisplatin-sensitive and drug-resistant cell lines as well as three patient-derived primary ovarian cancer cells have been selected to screen those prodrugs. To verify if the disruption of redox balance can be combined with these Pt(IV) prodrugs, we then synthesized a polymer with a diselenium bond in the main chain for encapsulating the most effective prodrug to form nanoparticles (NP(Se)s). NP(Se)s can efficiently break the redox balance via simultaneously depleting GSH and augmenting ROS, thereby achieving a synergistic effect with cisplatin. In addition, genome-wide analysis via RNA-seq was employed to provide a comprehensive understanding of the changes in transcriptome and the alterations in redox-related pathways in cells treated with NP(Se)s and cisplatin. Thereafter, patient-derived xenograft models of hepatic carcinoma (PDX HCC ) and multidrugresistant lung cancer (PDX MDR ) were established to evaluate the therapeutic effect of NP(Se)s, and a significant antitumor effect was achieved on both models with NP(Se)s. Overall, this study provides a promising strategy to break the redox balance for maximizing the efficacy of platinum-based cancer therapy.

A major enigma of primary biliary cirrhosis (PBC) is the selective targeting of biliary cells. Our laboratory has reported that following apoptosis human intrahepatic biliary epithelial cells (HiBEC) translocate the E2 subunit of the pyruvate dehydrogenase complex immunologically intact into apoptotic bodies, forming an apotope. However, the cell type and specificity of this reaction has not been fully defined. To address this issue we have investigated whether PDC-E2, BCOADC-E2, OGDC-E2, four additional inner mitochondrial enzymes and four nuclear antigens remain immunologically intact with respect to post-apoptotic translocation in HiBEC and 3 additional control epithelial cells. We report that all three 2-oxo acid dehydrogenase enzymes share the ability to remain intact within the apotope of HiBEC. Interestingly the E2 subunit of the branched chain 2-oxo acid dehydrogenase complex also remained intact in the other cell types tested. We extended the data using 95 AMA+ and 19 AMA- PBC and 76 control sera for reactivity against the 7 mitochondrial proteins studied herein and also the ability of AMA- sera to react with HIBEC apotopes. Sera from 3/95 AMA+ sera, but none of the controls, reacted with 2, 4-dienoyl CoA reductase 1 (DECR1), an enzyme also present intact only in the HiBEC apotope; DECR1 has not been previously associated with any autoimmune disease. Finally the specificity of HIBEC apotope reactivity was confined to AMA+ sera. In conclusion, we submit that the biliary specificity of PBC is secondary to the unique processes of biliary apoptosis.