Hereditary hemochromatosis (HH) is a common autosomal recessive disease characterized by increased iron absorption and progressive iron storage that results in damage to major organs in the body. Recently, a candidate gene for HH called HFE encoding a major histocompatibility complex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, we studied the effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates (96 ؎ 5% vs. 77 ؎ 3%, P < 0.007), and hepatic iron concentration was 8-fold higher than that of wild-type littermates (2,071 ؎ 450 vs. 255 ؎ 23 g͞g dry wt, P < 0.002). Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. This study shows that the HFE protein is involved in the regulation of iron homeostasis and that mutations in this gene are responsible for HH. The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload.

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by tissue iron deposition secondary to excessive dietary iron absorption. We recently reported that HFE, the protein defective in HH, was physically associated with the transferrin receptor (TfR) in duodenal crypt cells and proposed that mutations in HFE attenuate the uptake of transferrin-bound iron from plasma by duodenal crypt cells, leading to up-regulation of transporters for dietary iron. Here, we tested the hypothesis that HFE ؊/؊ mice have increased duodenal expression of the divalent metal transporter (DMT1). Hereditary hemochromatosis (HH) is a common disorder of iron homeostasis in which the intestinal absorption of iron is excessive in relation to body iron status (1-5). The excess iron is deposited in the parenchyma of many tissues, leading to tissue damage and organ failure. Clinical consequences include liver cirrhosis, hepatocellular carcinoma, diabetes, heart failure, arthritis, and hypogonadism (6-9). The gene defective in HH, designated HFE, was found to encode a major histocompatibility complex (MHC) class I-like integral membrane protein (10) that had no obvious relationship to iron absorption. A link between HFE and iron metabolism was provided by the observations in human placenta that the HFE protein is localized on the apical surface of syncytiotrophoblast cells (the site of transferrin-mediated maternal-fetal iron transport) and is physically associated with the transferrin receptor (TfR) (11). Physical association between TfR and expressed recombinant HFE protein was also reported in cultured cells (12, 13) and in vitro (14). In cell culture, overexpressed recombinant HFE (but not HFE carrying the HH mutation) was reported to reduce the affinity of TfR for holotransferrin, suggesting a role for normal HFE in down-regulating transferrin-mediated iron uptake. Although loss of this downregulation of transferrin-mediated iron transport might explain the excess deposition of tissue iron in HH patients, it would not explain the excess absorption of dietary iron (15). Studies on HH patients suggest that the primary defect is loss of the normal feedback mechanisms regulating absorption of dietary (nontransferrin-bound) iron across the intestinal mucosa (2-5).Dietary iron absorption is normally tightly linked with body utilization through the sensing of body iron status in the proximal small intestine (16,17). Several lines of evidence indicate that the body iron status is detected by the uptake of transferrin-bound iron from plasma at the basolateral surface of intestinal crypt cells (18,19). We recently demonstrated that HFE colocalizes with and is physically associated with TfR in these cells (1). This observation suggests a mechanism by which HFE might participate in sensing body iron status by modulating transferrin-mediated uptake of plasma iron in the crypt cells. We propose that mutations of HFE in HH patients impair transferrin-mediated iron uptake and thus decrease crypt cell uptake of plasm...

AbstractγδT cells have been reported to exert immunosuppressive functions in multiple solid malignant diseases, but their immunosuppressive functional subpopulation in breast cancer (BC) is still undetermined. Here, we collected 40 paired BC and normal tissue samples from Chinese patients for analysis. First, we showed that γδT1 cells comprise the majority of CD3+ T cells in BC; next, we found that CD73+γδT1 cells were the predominant regulatory T-cell (Treg) population in BC, and that their prevalence in peripheral blood was also related to tumour burden. In addition, CD73+γδT1 cells exert an immunosuppressive effect via adenosine generation. We also found that BC could modulate CD73 expression on γδT cells in a non-contact manner. The microarray analysis and functional experiments indicated that breast tumour cell-derived exosomes (TDEs) could transmit lncRNA SNHG16, which upregulates CD73 expression, to Vδ1 T cells. Regarding the mechanism, SNHG16 served as a ceRNA by sponging miR-16–5p, which led to the derepression of its target gene SMAD5 and resulted in potentiation of the TGF-β1/SMAD5 pathway to upregulate CD73 expression in Vδ1 T cells. Our results showed that the BC-derived exosomal SNHG16/miR-16–5p/SMAD5-regulatory axis potentiates TGF-β1/SMAD5 pathway activation, thus inducing CD73 expression in Vδ1 T cells. Our results first identify the significance of CD73+Vδ1 Tregs in BC, and therapy targeting this subpopulation or blocking TDEs might have potential for BC treatment in the future.

An anti-freezing hydrogel based stretchable triboelectric nanogenerator have been synthesized for harvesting a large amplitude of human movement energy as an effective wearable power source at sub-zero temperature.

Purpose: Circular RNAs (circRNAs) have been reported to regulate the incidence of tumor by regulating the transcriptional level and post-transcriptional level of tumor-related genes, and are significantly correlated with tumor metastasis and progression. CircRNA_100395 (circ_100395) has been reported to suppress lung cancer cell proliferation, and might act as an oncogene in deveopment of various cancers. However, the expression and function of circ_100395 in ovarian cancer has not been systematically researched. Methods: The expression of circ_100395 in ovarian cancer tissues was detected by Real-time Quantitative polymerase chain reaction (RT-qPCR), while the relationship between circ_100395 expression and clinicopathological characteristics was further analyzed. After increasing the expression of circ_100395 by plasmid transfection in ovarian cancer cells, we further investigated the cell proliferation, invasion and migration by cell counting kit-8 (CCK-8), and Transwell assays. Epithelial-mesenchymal transition (EMT) pathway was also measured by western blotting. In addition, the relationship among circ_100395, miR-1228 and p53 in ovarian cancer, was explored by luciferase reporter assay. Results: The expression of circ_100395 was found to be significantly down-regulated in ovarian cancer, while low expression of circ_100395 was highly correlated with the poor outcomes. In addition, upregulation of circ_100395 could significantly inhibit tumor growth, metastasis and EMT signaling pathway in ovarian cancer. Furthermore, the expression level of circ_100395 was negatively correlated with the expression of miR-1228, and with the addition of miR-1228 could reverse anti-cell proliferation effect induced by circ_100395 in ovarian cancer cells. In addition, p53 might be the key target of circ_100395 / miR-1228 axis in ovarian cancer. Conclusion: CircRNA_100395 could inhibit cell growth and metastasis of ovarian cancer cells via regulating the miR-1228/p53/EMT axis.