ZNT1 and Zn 2+ control TLR4 and PD-L1 endocytosis in macrophages to improve chemotherapy efficacy against liver tumor.

BACKGROUND AND AIMS: HCC is closely associated with inflammation and immune modulation, and combined chemotherapy with other strategies is under extensive investigation to achieve better efficacy. HCC is accompanied by zinc (Zn) deficiency. This study aims to understand how Zn could affect macrophage function and its application for HCC therapy. APPROACH AND RESULTS: Zn 2+ and the Zn transporter 1 (ZNT1, solute carrier family 30 member 1) were markedly reduced in intrahepatic macrophages from patients with HCC and from mouse liver tumors. Lower ZNT1 expression was associated with higher IL-6 production and shorter survival time in patients with HCC. Critically, ZNT1 regulated endosomal Zn 2+ levels for endocytosis of toll-like receptor 4 and programmed cell death ligand 1, thereby decreasing macrophage-induced inflammation and immunosuppression to protect from liver tumors. Myeloid-specific deletion of ZNT1 in mice increased chronic inflammation, liver fibrosis, tumor numbers, and size. Notably, Zn supplementation could reduce inflammation and surface programmed cell death ligand 1 expression in macrophages with the increased CD8 + T cell cytotoxicity, which synergized the antitumor efficacy of Sorafenib/Lenvatinib. CONCLUSIONS: Our study proposes a new concept that ZNT1 and Zn regulate endosome endocytosis to maintain surface receptors, and Zn supplements might be synergized with chemotherapy to treat inflammation-associated tumors, especially those containing programmed cell death ligand 1 + myeloid cells.

The Transcription of ZIP9 Is Associated With the Macrophage Polarization and the Pathogenesis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common digestive system cancers (DSCs) with a poor prognosis. Zinc-regulated transporter (ZRT)/iron-regulated transporter (IRT) like protein transporters (ZIPs) encode membrane transport proteins, which are responsible for the absorption of zinc and play important roles in the pathogenesis of various human cancers. Tumor-associated macrophages (TAMs) are important participants in the regulation of tumor microenvironment and the development of HCC. Individual role of each ZIP involved in hepatocarcinogenesis remains elusive. In this study, the transcription patterns of ZIPs in the DSCs were screened firstly through GEPIA2 database. Interestingly, the analysis of the DSCs data showed the distinct mRNA levels of ZIPs between DSCs tissues and healthy controls. Notably, the transcription levels of ZIP2, ZIP5, ZIP8, ZIP9 and ZIP14 were decreased significantly in the tissues of human liver cancer compared to paracarcinoma liver tissues. To further confirm the mRNA transcriptional changes of Zips in HCC, N-Nitrosodiethylamine (DEN) combined with carbon tetrachloride (CCl4) inducing mouse model of HCC were established. Consistently, the mRNA levels of Zip2, Zip9, and Zip14 in liver tissues of HCC induced mice were also decreased compared with the healthy controls. In addition, mouse peritoneal elucidated macrophages (PEMs)-derived M1/M2 macrophages in vitro, as well as human patients of HCC-derived TAMs, were used to examine the transcription levels of ZIPs. Our results showed that both Zip2 and Zip9 were up-regulated in M2-polarized macrophages. Zip2 transcript was also up-regulated M1-polarized macrophages, but Zip9 was slightly down-regulated. TAMs generated from human liver cancer tissues also displayed a decrease in ZIP9 transcription compared to paracarcinoma tissues. To further explore the role of Zip9 in M1/M2 polarization, the siRNA knockdown results revealed that Zip9, but not Zip2, could promote M2 macrophage polarization and impair M1 macrophage polarization. Mechanistically, Zip9 enhances phosphorylated STAT6 to promote M2 macrophage polarization but suppresses the phosphorylation of IκBα/ß to inhibit M1 macrophage polarization. Together, our results indicate that ZIP9 may involve in macrophages polarity in HCC development and may be a potent new biomarker for the diagnosis of HCC.

[The effect of ventricular fibrillation time and NYHA classification on defibrillation in intensive care unit patients].

OBJECTIVE: To investigate whether the sequence of defibrillation (DF) and cardiopulmonary resuscitation (CPR), duration of ventricular fibrillation (VF), and New York Heart Association (NYHA) classification would affect DF result in intensive care unit. METHODS: Ninety-three cases needing instantaneous DF were divided into three groups according to VF lasting time: <4 minute group (n=53), 4 - 8 minute group (n=24), >8 minute group (n=16), and each group was randomly divided into two sub-groups according to time sequence: the prior DF group or the prior CPR for five cycles followed by DF group (prior CPR group). The effect of VF time, the sequence of DF and CPR, and NYHA classification on success rate of DF were observed. RESULTS: With prolonging VF time, success rate of DF obviously lowered [success rate of DF for VF<4 minute, 4 - 8 minute, and >8 minute groups were 83.0% (44/53), 62.5% (15/24), and 25.0% (4/16), respectively, all P<0.01]. When VF time lasted less than 4 minutes, success rate of DF in the prior DF group was obviously higher than that in the prior CPR group [88.9% (24/27) vs. 76.9% (20/26), P<0.05]. When VF time lasted for 4 - 8 minutes, the prior DF group had slightly higher success rate of DF compared with the prior CPR group [66.7% (8/12) vs. 58.3% (7/12), P=0.09]. When VF time lasted longer than 8 minutes, the success rate of DF in the prior CPR group was obviously higher than that in the prior DF group [37.5% (3/8) vs. 12.5% (1/8), P<0.01]. The success rate of DF was lowered in higher NYHA classification [success rate of DF for NYHA classification I-IV was 96.4% (27/28), 80.0% (20/25), 47.8% (11/23), 29.4% (5/17), respectively, P<0.05 or P<0.01]. CONCLUSIONS: VF lasting time and NYHA classification are key factors to success rate of DF, and the choice of sequence of DF and CPR depends on the lasting time of VF. For cases with the high NYHA classification, we should make some judgement beforehand and prepare some preventive measures.