Genetic and pharmacological targeting of XBP1 alleviates hepatic ischemia reperfusion injury by enhancing FoxO1-dependent mitophagy.

Hepatic ischemia reperfusion (I/R) injury is a common clinical complication. X-box binding protein 1 (XBP1), as a critical regulator of the endoplasmic reticulum stress, has been implicated in a variety of diseases. In this study, we aimed to investigate the effects and the underlying mechanism of XBP1 in the progression of hepatic I/R injury. Hepatocyte-specific XBP1 knockout mice, multiple viral delivery systems and specific pharmacological inhibitors were applied in vivo in a partial hepatic I/R injury mouse model and in vitro in a cell model of hypoxia-reoxygenation (H/R) injury. Mitophagy and autophagic flux were evaluated and fluorescence resonance energy transfer (FRET) as well as immunoprecipitation were performed. The results demonstrated that reperfusion for 6 h represented a critical timepoint in hepatic I/R injury and resulted in significant intracellular mitochondrial dysfunction; led to the breakdown of hepatocytes accompanied by the highest expression levels of XBP1. Hepatocyte-specific XBP1 knockout alleviated hepatic I/R injury via enhanced mitophagy, as demonstrated by the reduction in hepatocellular damage/necrosis and increased expression of mitophagy markers. Mechanistically, XBP1 interacted with FoxO1 directly and catalyzed the ubiquitination of FoxO1 for proteasomal degradation. Targeting XBP1 by genetic or pharmacological techniques potentiated the protein levels of FoxO1, further promoting the activity of the PINK1/Parkin signaling pathway, thus augmenting mitophagy and exerting hepatoprotective effects upon I/R injury. In conclusion, the inhibition of XBP1 potentiated FoxO1-mediated mitophagy in hepatic I/R injury. Specific genetic and pharmacological treatment targeting XBP1 in the perioperative 6 h prior to reperfusion exerted beneficial effects, thus providing a novel therapeutic approach.

Porcine anti-human lymphocyte immunoglobulin depletes the lymphocyte population to promote successful kidney transplantation.

Introduction: Porcine anti-human lymphocyte immunoglobulin (pALG) has been used in kidney transplantation, but its impacts on the lymphocyte cell pool remain unclear. Methods: We retrospectively analyzed 12 kidney transplant recipients receiving pALG, and additional recipients receiving rabbit anti-human thymocyte immunoglobulin (rATG), basiliximab, or no induction therapy as a comparison group. Results: pALG showed high binding affinity to peripheral blood mononuclear cells (PBMCs) after administration, immediately depleting blood lymphocytes; an effect that was weaker than rATG but stronger than basiliximab. Single-cell sequencing analysis showed that pALG mainly influenced T cells and innate immune cells (mononuclear phagocytes and neutrophils). By analyzing immune cell subsets, we found that pALG moderately depleted CD4+T cells, CD8+T cells, regulatory T cells, and NKT cells and mildly inhibited dendritic cells. Serum inflammatory cytokines (IL-2, IL-6) were only moderately increased compared with rATG, which might be beneficial in terms of reducing the risk of untoward immune activation. During 3 months of follow-up, we found that all recipients and transplanted kidneys survived and showed good organ function recovery; there were no cases of rejection and a low rate of complications. Discussion: In conclusion, pALG acts mainly by moderately depleting T cells and is thus a good candidate for induction therapy for kidney transplant recipients. The immunological features of pALG should be exploited for the development of individually-optimized induction therapies based on the needs of the transplant and the immune status of the patient, which is appropriate for non-high-risk recipients.

Degradation of hexavalent chromium and methyl orange by the synergistic system of graphitic carbon nitride and electron beam irradiation.

Hexavalent chromium (Cr(VI)) and methyl orange (MO) are highly toxic and difficult to treat. Electron beam irradiation (EB) can produce ·OH, H·, ·O2-, hydrated electron (eaq-) and other active substances, which have strong redox ability to pollutants. However, the penetration capacity of EB is limited (the penetration depth of water is 10 cm). Therefore, the photocatalytic method of graphitic carbon nitride (CN) was used as the synergistic method of EB in this project to degrade Cr(VI) and MO. The results showed that the maximum treatment efficiency of 100 mg L-1 Cr(VI) and 50 mg L-1 MO with liquid surface height of 5 cm was 95.0% and 99.1%, respectively, which was much higher than that of single photocatalytic method (39.5%, 23.4%) and EB (79.6%, 92.1%), and the efficiency of synergistic treatment was higher under acidic condition. When the liquid depth increased to 30 cm, the efficiency of synergistic system decreased by 14.7% and 15.2% for the degradation of Cr(VI) and MO, respectively, less than the single EB treatment (47.2%, 45.7%). Additionally, the performance of the morphology, the light absorption performance, and the separation of photogenerated electron-hole pairs of the CN were evaluated before and after the synergistic system. Lastly, the mechanism illustrates that the electron and thermal effects of EB, eaq-, photogenerated electrons played key roles for the Cr(VI) reduction, and the electron and thermal effects of EB, ·O2-, photogenerated holes played key roles for the MO degradation. This study provides a new opportunity for the synergistic system of photocatalyst and EB in the treatment of pollutants.