Although the prognostic value of marital status has been implicated in many cancers, its prognostic impact on cholangiocarcinoma has not yet been determined. The aim of this study was to examine the ...association between marital status and cholangiocarcinoma survival. We included 8,776 extrahepatic cholangiocarcinoma cases and 1,352 intrahepatic cholangiocarcinoma cases between 1973 and 2013 from the Surveillance, Epidemiology, and End Results database. We found widowed patients were more likely to be female, aged more than 70, and from low income areas. Multivariate analysis indicated that marital status was an independent prognostic factor for extrahepatic cholangiocarcinoma patients. Subgroup analysis suggested the widowed status independently predicted poor survival at regional stage and in older patients with intrahepatic cholangiocarcinoma. To conclude, marital status is a valuable prognostic factor in cholangiocarcinoma, and widowed patients are at greater risk of death than others.
Ischemia-reperfusion injury (IRI) remains inevitable in liver surgeries, macrophages play a critical role in the development of IRI, but little is known about the macrophages regulate pathogenesis of ...IRI. Based on target-guided screening, we identified a small 3 kDa peptide (SjDX5-271) from various schistosome egg-derived peptides that induced M2 macrophage polarization. SjDX5-271 treatment protected the mice against liver IRI through promoting M2 macrophage polarization, the protective effect was abrogated when the macrophages were depleted. Transcriptomic sequencing showed that the TLR signaling pathway was significantly inhibited in macrophages derived from the SjDX5-271 treatment group. We further identified that SjDX5-271 promotes M2 macrophage polarization by inhibiting the TLR4/MyD88/NF-κB signaling pathway and further alleviates hepatic inflammation in liver IRI. Collectively, SjDX5-271 exhibits promising therapeutic effects in IRI and represents a novel therapeutic approach for IRI, even in immune-related diseases. This study revealed the development of a new biologic from the parasite and enhanced our understanding of host-parasite interplay, providing a blueprint for future therapies for immune-related diseases.
Background & Aims: Hepatic ischemia-reperfusion injury is a significant complication of partial hepatic resection and liver transplantation, impacting the prognosis of patients undergoing liver ...surgery. The protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized by hepatocytes and has been implicated in myocardial ischemic diseases. However, the role of PCSK9 in hepatic ischemia-reperfusion injury remains unclear. This study aims to investigate the role and mechanism of PCSK9 in hepatic ischemia-reperfusion injury. Methods: We first examined the expression of PCSK9 in mouse warm ischemia-reperfusion models and AML12 cells subjected to hypoxia/reoxygenation. Subsequently, we explored the impact of PCSK9 on liver ischemia-reperfusion injury by assessing mitochondrial damage and the resulting inflammatory response. Results: Our findings reveal that PCSK9 is up-regulated in response to ischemia-reperfusion injury and exacerbates hepatic ischemia-reperfusion injury. Blocking PCSK9 can alleviate hepatocyte mitochondrial damage and the consequent inflammatory response mediated by ischemia-reperfusion. Mechanistically, this protective effect is dependent on mitophagy. Conclusions: Inhibiting PCSK9 in hepatocytes attenuates the inflammatory responses triggered by reactive oxygen species and mitochondrial DNA by promoting PINK1-Parkin–mediated mitophagy. This, in turn, ameliorates hepatic ischemia-reperfusion injury.
Acuteliver failure (ALF) has a high mortality rate and is characterized by massive hepatocyte destruction. Although microRNAs (miRNAs) play an important role in manyliver diseases, the role of miRNAs ...in ALF development is unknown. In this study, the murine ALF model was induced by intraperitoneal injection of D-galactosamine/lipopolysaccharide (D-GalN/LPS). Compared with saline-treated mice, miR-24 was distinctly down-regulated post D-GalN/LPS challenge
and D-galactosamine/tumor necrosis factor (D-GalN/TNF) challenge
, which was confirmed by quantitative real-time polymerase chain reaction. Meanwhile, the mRNA and protein levels of the BH3-only-domain-containing protein BIM were upregulated after challenge both
and
. Previous studies have demonstrated that hepatocyte apoptosis is a distinguishing feature of D-GalN/LPS-associated liver failure. In this study, D-GalN/LPS-challenged mice showed higher alanine aminotransferase and aspartate aminotransferase levels, more severe liver damage, increased numbers of apoptotic hepatocytes and higher levels of caspase-3 compared with saline-treated mice. In D-GalN/TNF-treated BNLCL2 cells, miR-24 overexpression attenuated apoptosis.Furthermore, miR-24 overexpression reduced BIM mRNA and protein levels
. Taken together, these findings demonstrate that miR-24 regulates hepatocyte apoptosis via BIM during ALF development, suggesting that miR-24 is a novel onco-miRNA that may provide potential therapeutic targets for ALF.
Acute rejection is commonly encountered for long-term survival in liver transplant (LT) recipients and may impact their long-term survival if rejection is severe or recurrent. The aim of this study ...is to examine the therapeutic potential of transforming growth factor (TGF-beta)-overexpressing mesenchymal stem cells (MSCs) in inducing a local immunosuppression in liver grafts after transplantation. MSCs were transduced with a lentiviral vector expressing the human TGF-beta1 gene; TGF-beta1-overexpressing MSCs (designated as TGF/MSCs) were then transfused into the liver grafts via the portal vein of a rat LT model of acute rejection. Rejection severity was assessed by clinical and histologic analysis. The immunity suppression effects and mechanism of TGF/MSCs were tested, focusing on their ability to induce generation of regulatory T cells (Tregs) in the liver grafts. Our findings demonstrate that transfusion of TGF/MSCs prevented rejection, reduced mortality, and improved survival of rats after LT. The therapeutic effects were associated with the immunosuppressive effects of MSCs and TGF-beta1. Their reciprocal effects on Tregs induction and function resulted in more CD4+Foxp3+Helios- induced Tregs, fewer Th17 cells, and improved immunosuppressive effects in local liver grafts. Thus, TGF/MSCs can induce a local immunosuppressive effect in liver grafts after transplantation. The immunomodulatory activity of TGF-beta1 modified MSCs may be a gateway to new therapeutic approaches to prevent organ rejection in clinical transplantation. Stem Cells 2016;34:2681-2692
Reperfusion injury causes liver dysfunction after warm or cold ischemia. Emerging data suggest a role of T cells as mediators in this ischemia/reperfusion (I/R) injury. In the T cells, a part of ...CD4+CD25+FoxP3+ T regulatory cells (Tregs) were reported to facilitate recovery from I/R injury. These Tregs can be induced by TGF- beta in vitro. Interestingly, rapamycin was reported to selectively expand these Tregs in vitro. In the present study, addition of rapamycin to cultures containing TGF- beta further increased the frequency and absolute number of functional CD4+ Tregs. Using a partial (70%) hepatic warm ischemia model, we investigated the effects of liver function recovery under the treatment of Tregs induced by rapamycin and TGF- beta . The treatment of Tregs significantly reduced serum alanine aminotransferase and aspartate aminotransferase compared to I/R control animals at 24 h after reperfusion (P < 0.05). They also significantly attenuated the up-regulation of IFN- gamma and IL-17 compared to the I/R control animals (P < 0.05). In conclusion, Tregs ameliorate the biochemical of hepatic I/R injury by preventing proinflammatory cytokines following a warm I/R insult. These data may pave the way to use Tregs as cell therapy to prevent hepatic I/R injury.
Omega-3 fatty acid supplemented total parenteral nutrition improves the clinical outcome of patients undergoing certain operations; however, its benefits for patients with hepatitis type B virus ...（HBV）-associated hepatocellular carcinoma （HCC） who have undergone hepatectomy are still not clear. The aim of this study was to evaluate the effect of omega-3 fatty acid supplemented total parenteral nutrition on the clinical outcome of patients with HBV- associated HCC who underwent hepatectomy at our institution. A total of 63 patients with HBV-associated HCC who underwent hepatectomy were included in this study. These patients were randomly assigned to receive stand- ard total parenteral nutrition （the control group, n = 31） or omega-3 fatty acid supplemented total parenteral nutri- tion （the omega-3 fatty acid group, n = 32） for at least 5 d. The study endpoints were the occurrence of infection- related complications, recovery of liver function and length of hospital stay. The results showed that the omega-3 fatty acid group had a lower infection rate （omega-3 fatty acid, 19.4% vs control, 43.8%, P 〈 0.05）, a better liver function after hepatectomy： alanine transaminase （omega-3 fatty acid, 48.23__＋ 18.48 U/L vs control, 73.34 q-40.60 U/L, P 〈 0.01）, aspartate transaminase （omega-3 fatty acid, 35.77_ 14.56 U/L vs control, 50.53 4-24.62 U/L, P 〈 0.01）, total bilirubin （omega-3 fatty acid, 24.29___7.40 mmol/L vs control, 28. 374-8.06 mmol/L, P 〈 0.05） and a shorter length of hospital stay （omega-3 fatty acid, 12.71 ___2.58 d vs control, 15.91 ___3.23 d, P 〈 0.01）. The serum contents of IL-6 （omega-3 fatty acid, 23.98___5.63 pg/mL vs control, 35.55___7.5 pg/mL, P 〈 0.01） and TNF-a （ome- ga-3 fatty acid, 4.43___1.22 pg/mL vs control, 5.96___1.58 pg/mL, P 〈 0.01） after hepatectomy were significantly lower in the omega-3 fatty acid group than those of the control group. In conclusion, administration of omega-3 fatty acid may reduce infection rate and improve liver function recovery in HBV-associated HCC patients after hepatectomy. This improvement is associated with suppressed production of proinflammatory cytokines in these patients.
It has been shown that rat liver allografts between certain inbred major histocompatibility complex (MHC) disparate strains are accepted spontaneously, and regulatory T cells (Tregs) have been ...suggested to play a role in the spontaneous liver tolerance. CD8+CD103+ T cells bear the phenotypes of effector cells, and they are implicated in allograft destruction. Here we provide evidence that CD8+CD103+ T cells possess regulatory function and may contribute to prevent liver allograft rejection. We show that the expression of CD103 in the CD8+ T cells was increased in spontaneous liver grafts tolerant recipients. We further show that CD8+CD103- T cells can also upregulate the expression of CD103 and Foxp3 after stimulation with alloantigen or TGF- beta in vitro, and the CD8+CD103+ T cells acquired regulatory properties. The suppressive function of the alloantigen or TGF- beta conditioned CD8+CD103+ T cells was cell-cell contact dependent. These results imply that liver-specific factor(s) would be involved in the generation of CD8+CD103+ Tregs that contribute to spontaneous liver allografts tolerance.
Induced regulatory T cells (iTregs) are essential to maintain immunological tolerance, immune homeostasis and prevention of autoimmunity. Some studies suggest that glycogen synthase kinase 3beta ...(GSK3beta) is involved in the mouse iTreg differentiation; however, whether GSK3beta inhibits or enhances iTreg differentiation is still a matter of controversy. To address this issue, we have utilized human naïve CD4^sup +^ T cells and investigated whether GSK3 activity changes during iTreg differentiation and whether altering GSK3 activity influences the development of iTregs and its suppressive function. As a constitutively activated kinase, during iTreg differentiation GSK3beta became quickly deactivated (phosphorylated at serine 9), which is dependent on MAPK pathway rather than PI3-kinase/Akt pathway. Our results indicated that inhibition of GSK3beta by specific inhibitors, SB216763 or TDZD-8, promoted the differentiation of iTreg and increased their suppressive activity. In contrast, overexpression of GSK3beta significantly inhibited iTreg differentiation. Furthermore, GSK3beta inhibition enhanced iTreg differentiation through the TGF-beta/Smad3 pathway. Taken together, this study demonstrates that inhibition of GSK3beta enhances human iTreg differentiation and its suppressive activity, and provides a rationale to target GSK3beta as a novel immunotherapeutic strategy.
Although mesoporous materials and magnetic materials are used to enrich glycopeptides, materials sharing both mesoporous structures and magnetic properties have not been reported for glycopeptide ...analyses. Here we prepared boronic acid-modified magnetic Fe
O
@mTiO
microspheres by covalent binding of boronic acid molecules onto the surfaces of silanized Fe
O
@mTiO
microspheres. The final particles (denoted as B-Fe
O
@mTiO
) showed a typical magnetic hysteresis curve, indicating superparamagnetic behavior; meanwhile, their mesoporous sizes did not change in spite of the reduction in surface area and pore volume. By using these particles together with conventional poly(methyl methacrylate) (PMMA) nanobeads, we then developed a synergistic approach for highly specific and efficient enrichment of N-glycopeptides/glycoproteins. Owing to the introduction of PMMA nanobeads that have strong adsorption towards nonglycopeptides, the number of N-glycopeptides detected and the signal-to-noise ratio in analyzing standard proteins mixture both increased appreciably. The recovery of N-glycopeptides by the synergistic method reached 92.1%, much improved than from B-Fe
O
@mTiO
alone that was 75.3%. Finally, we tested this approach in the analysis of amniotic fluid, obtaining the maximum number and ratio of N-glycopeptides compared to the use of B-Fe
O
@mTiO
alone and commercial SiMAG-boronic acid particles. This ensemble provides an interesting and efficient enrichment platform for glycoproteomics research.
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