L. Zhou

Liver Regeneration after Liver Transplantation

Background/Purpose: The liver has a remarkable capacity to regenerate after injury or resection. The aim of this review is to outline the mechanisms and factors affecting liver regeneration after liver transplantation. Methods: Relevant studies were reviewed using Medline, PubMed and Springer databases. Results: A variety of cytokines (such as interleukin-6 and tumor necrosis factor-α), growth factors (like hepatocyte growth factor and transforming growth factor-α) and cells are involved in liver regeneration. Several factors affect liver regeneration after transplantation such as ischemic injury, graft size, immunosuppression, steatosis, donor age and viral hepatitis. Conclusion: Liver regeneration has been studied for many years. However, further research is essential to reveal the complex processes affecting liver regeneration, which may provide novel strategies in the management of liver transplantation recipients and donors.

MMP2 promoter polymorphism (C-1306T) and risk of recurrence in patients with hepatocellular carcinoma after transplantation.

Genetic variants in matrix metalloproteinase (MMP) gene may influence the biological function of these enzymes and change their role in carcinogenesis and progression. The effect of MMP2 C‐1306T and MMP9 C‐1562T polymorphisms on genetic susceptibility has been investigated in various kinds of cancer. However, the relationship between these polymorphisms and risk of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has not been reported. The present study was designed to investigate the association of these two loci with the risk of HCC recurrence in 93 HCC patients treated with LT. Genotyping was performed using direct DNA sequencing. For MMP2 C‐1306T variant, patients with CT heterozygous conferred a 58% reduction in recurrence risk (risk ratio: 0.419; 95% confidence interval: 0.177–0.994). The mean recurrence‐free survival for CT genotype was significantly longer than that for homozygous CC patients (30.4 vs 19.3u2003months, pu2003=u20030.019). However, no association was found between MMP9 C‐1562T polymorphisms and recurrence of HCC (pu2003=u20030.259). These findings suggest that MMP2 promoter polymorphisms may provide some predictive value for HCC recurrence after LT.

Polymorphism in 3′‐untranslated region of toll‐like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantation

L. Zhou, B. Wei, C. Xing, H. Xie, X. Yu, L. Wu, S. Zheng. Polymorphism in 3′‐untranslated region of toll‐like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantationu2028Transpl Infect Dis 2011: 13: 250–258. All rights reserved

Galectin-1 prolongs survival of mouse liver allografts from Flt3L-pretreated donors.

Liver allografts are spontaneously accepted across MHC barriers in mice. The mechanisms underlying this phenomenon remain poorly understood. Galectin‐1, an endogenous lectin expressed in lymphoid organs, plays a vital role in maintaining central and peripheral tolerance. This study was to investigate the role of galectin‐1 in spontaneous tolerance of liver allografts in mice, and to evaluate the therapeutic effects of galectin‐1 on liver allograft rejection induced by donor Flt3L pretreatment. Blockade of the galectin‐1 pathway via neutralizing antigalectin‐1 mAb did not affect survival of the liver allografts from B6 donors into C3H recipients. Administration of rGal‐1 significantly prolonged survival of liver allografts from Flt3L‐pretreated donors and ameliorated Flt3L‐triggered liver allograft rejection. This effect was associated with increased apoptosis of T cells in both allografts and spleens, decreased frequencies of Th1 and Th17 cells, decreased expression of Th1‐associated cytokines (IL‐12, IL‐2 and IFN‐γ), Th17‐associated cytokines (IL‐23 and IL‐17) and granzyme B, in parallel with selectively increased IL‐10 expression in liver allografts. In vitro, galectin‐1 inhibited Flt3L‐differentiated DC‐mediated proliferation of allo‐CD4+ T cells and production of IFN‐γ and IL‐17. These data provide new evidence of the potential regulatory effects of galectin‐1 in alloimmune responses in a murine model of liver transplantation.

Genetic variation within the glycoprotein B and H genes of human cytomegalovirus in solid organ transplant recipients.

Abstract: This study was performed to investigate human cytomegalovirus (HCMV) infection and genetic variations within glycoprotein B (gB) and H (gH) genes in Chinese transplant recipients. A total of 245 ethylene‐diamine tetraacetic acid (EDTA)‐treated blood samples were obtained from 79 transplant recipients in southeast China. Based on the sequences of highly variable regions of the gB endoprotease cleavage site (gBclv), N‐terminus of gp116 (gBn), and the gH N‐terminus (gH), nested polymerase chain reaction assays for the detection of HCMV were established. Nucleotide sequencing was employed to differentiate gB and gH genotypes. Twenty‐six of 79 (32.9%) transplant recipients were proved HCMV positive. The distribution of genotypes was gBclv1, 12/25; gBclv2, 3/25; gBclv3, 4/25; gBn1, 6/23; gBn2, 2/23; gBn3, 11/23; and no gBclv/n 4‐related genotypes were presented. The distribution of gH genotypes was gH1, 11/26; gH2, 9/26; and co‐infected with both gH1/2 in 6/26. These data show that genetic variability within the gB genes occurs frequently. Mixtures of gB and gH genotypes infection were common in Chinese solid organ transplant recipients.

New Generation Nanomedicines Constructed from Self-Assembling Small-Molecule Prodrugs Alleviate Cancer Drug Toxicity

The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these cabazitaxel derivatives, docosahexaenoic acid-derived compound 1 retained high antiproliferative activity. SNM assembled with compound 1 displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared with free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacologic efficacy while improving its safety profile. Cancer Res; 77(24); 6963-74. ©2017 AACR.

Proteomic analysis of differentially expressed proteins in rat liver allografts developed acute rejection.

Background: Acute rejection (AR) after liver transplantation is a cell-mediated immune response that takes place within the allograft and results in graft dysfunction and failure, but the molecular mechanisms about hepatocyte dysfunction remain poorly understood. Here we characterized global protein expression changes in liver allograft during AR. Methods: The effect of an alloantigen-dependent immunological response was evaluated by syngeneic and allogeneic rat orthotopic liver transplantation (OLT). Using a combination of two-dimensional gel electrophoresis and mass spectrometry, we identified 18 differentially expressed proteins in AR allograft compared with matched tolerance allograft. Serum chemistry and allograft histology were determined. Results: Allogeneic OLT recipients exhibited elevated plasma levels of liver injury markers, progressive portal and venous inflammation and cellular infiltration in liver allograft compared with syngeneic OLT. 18 protein expressions altered by AR play important roles in metabolism, oxidative stress defense, signal transduction, biotransformation and transport. Decreased expression of protein disulfide isomerase in AR allograft was confirmed by Western blotting and immunohistochemistry. Conclusions: This study uncovered new mechanistic insights into graft dysfunction in AR of liver allograft. Several significantly altered protein expressions act coordinately in hepatocyte dysfunction by depressed energy, enhanced oxidative stress-induced molecular damage and restrained biotransformation. The present findings may open new avenues for the understanding and prevention of graft dysfunction and failure during AR.

Korean red ginseng: a new approach for the treatment of graft-versus-host disease after liver transplantation.

BACKGROUNDnGraft-versus-host disease (GVHD) is a rare complication after liver transplantation with an extremely poor prognosis; its occurrence offers great challenges.nnnMETHODSnWe have reported herein one case of acute GVHD after liver transplantation who was treated with a traditional Chinese medicine named Korean Red Ginseng (KRG).nnnRESULTSnThe acute GVHD was successfully cured by KRG.nnnCONCLUSIONSnThe successful salvage of acute GVHD after liver transplantation by KRG may provide a new viable therapeutic option.

Küpffer Cells Promote Acute Rejection via Induction of Th17 Differentiation in Rat Liver Allografts

BACKGROUNDnTh17, a newly identified CD4+ T-cell subset, has been implicated in transplant rejection. Differentiation of Th17 cells is associated with transforming growth factor-β (TGF-β) and interleukin-6 (IL-6), which are the main products of Küpffer cells.nnnOBJECTIVEnTo determine whether Küpffer cells promote acute liver allograft rejection by inducing Th17 cell differentiation.nnnMETHODSnA rat model of allogeneic liver transplantation using Dark Agouti (DA) to Brown Norway (BN) rats was established with or without gadolinium chloride (GdCl(3)) pretreatment. Isogeneic liver transplantation (BN to BN) was performed as a control. Concentrations of cytokines secreted by Küpffer cells or Th17-related cytokines detected in the liver and peripheral blood were analyzed using immunohistochemistry assays, flow cytometry, and enzyme-linked immunosorbent assays. Survival differences were compared between treatment groups. In vitro, Küpffer cells from liver grafts were isolated and co-cultured with naïve CD4 T cells.nnnRESULTSnBoth Küpffer cells and Th17 cells infiltrated liver allografts, accompanied by an increase in concentrations of IL-6 and TGF-β. Pretreatment with GdCl(3) attenuated intragraft infiltration of Küpffer cells and Th17 cells, and decreased IL-6 and TGF-β concentrations. Liver function improved after pretreatment, and mean (SD) survival time was prolonged, compared with the control group (16.33 [0.96] days vs 11.50 [0.99] days, respectively; P < .01). In vitro, Küpffer cells from livers with allografts secreted significantly higher concentrations of IL-6 and TGF-β and induced Th17 differentiation more effectively compared with livers with isografts (30.8% vs 8.1%, respectively).nnnCONCLUSIONnKüpffer cells have the potential to induce Th17 cells by secreting IL-6 and TGF-β, and as a result, promote acute liver allograft rejection.

Stimuli-responsive nanotherapeutics for precision drug delivery and cancer therapy

Cancer remains one of the worlds leading causes of death. However, most conventional chemotherapeutic drugs only show a narrow therapeutic window in patients because of their inability to discriminate cancer cells from healthy cells. Nanoparticle-based therapeutics (termed nanotherapeutics) have emerged as potential solutions to mitigate many obstacles posed by these free drugs. Deep insights into knowledge of the tumor microenvironment and materials science make it possible to construct nanotherapeutics that are able to release cargoes in response to a variety of internal stimuli and external triggers. Therefore, such highly sophisticated nanosystems could help impede the premature release of toxic drugs in the blood circulation or healthy tissues, thus enhancing the safety profiles of encapsulated drugs. In this context, this review offers a comprehensive overview of several specific stimuli, including internal stimuli (e.g., pH, temperature, enzyme, redox, and H2 O2 ) and external stimuli (e.g., magnetic, photo, and ultrasound). We envision that applications of these smart nanotherapeutics can benefit cancer patients and provide a good chance for clinical translation of many nanoparticle formulas. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > in vitro Nanoparticle-Based Sensing.