Zinc transporter ZIP7 is a novel determinant of ferroptosis.

Ferroptosis is a newly described form of regulated cell death triggered by oxidative stresses and characterized by extensive lipid peroxidation and membrane damages. The name of ferroptosis indicates that the ferroptotic death process depends on iron, but not other metals, as one of its canonical features. Here, we reported that zinc is also essential for ferroptosis in breast and renal cancer cells. Zinc chelator suppressed ferroptosis, and zinc addition promoted ferroptosis, even during iron chelation. By interrogating zinc-related genes in a genome-wide RNAi screen of ferroptosis, we identified SLC39A7, encoding ZIP7 that controls zinc transport from endoplasmic reticulum (ER) to cytosol, as a novel genetic determinant of ferroptosis. Genetic and chemical inhibition of the ZIP7 protected cells against ferroptosis, and the ferroptosis protection upon ZIP7 knockdown can be abolished by zinc supplementation. We found that the genetic and chemical inhibition of ZIP7 triggered ER stresses, including the induction of the expression of HERPUD1 and ATF3. Importantly, the knockdown of HERPUD1 abolished the ferroptosis protection phenotypes of ZIP7 inhibition. Together, we have uncovered an unexpected role of ZIP7 in ferroptosis by maintaining ER homeostasis. These findings may have therapeutic implications for human diseases involving ferroptosis and zinc dysregulations.

[Encircling needling is superior to "Bangci"(focal center-side needling) in promoting wound healing in diabetic mice].

OBJECTIVE: To compare the therapeutic effects of "Bangci"(focal center-side needling) and encircling needling in promoting skin wound healing and local blood perfusion in diabetic mice. METHODS: Thirty-two male C57BL/6N mice were randomized into normal, diabetic model, focal center-side needling and encircling needling groups (n=8 in each group). The skin wound model was prepared by cutting a piece of full-thickness skin at the mouse's back by using a puncher. One hour after modeling, two acupuncture needles were respectively inserted into the center of the wound and the spot at the normal skin about 0.5 cm away from the edge of the wound for mice of the focal center-side needling group, followed by EA (0.5 mA, 0.5 Hz) for 30 min. For mice of the encircling needling group, 4 acupuncture needles were respectively inserted into the upper, lower, left and right normal marginal skin around the wound, followed by EA stimulation with the same parameters as those of the center-side needling group. The wound conditions, diameter and area of the wound were monitored, and the wound blood perfusion volume was measured by using a laser speckle flowmeter. RESULTS: The wound shrinkage rates were significantly higher at the time-points of 3, 5, 7, 9 and 11 d after modeling in both focal center-side needling and encircling needling groups than in the model group (P<0.05), and on day 3, 5, 7 and 9 in the encircling needling group than in the focal center-side needling group (P<0.05). The wound healing time was obviously earlier in both focal center-side needling and encircling needling groups than in the model group (P<0.05), and in the encircling needling group than in the focal center-side needling group (P<0.05). Following modeling, the volume of wound blood perfusion was considerably higher from day 1 to 9 and markedly lower on day 11 in the model group than in the normal group (P<0.01), and after the intervention, the blood perfusion volume was considerably decreased on day 3, 5, 7 and 9 in both the focal center-side needling and encircling needling groups(P<0.05, P<0.01), and obviously increased on day 11 in the encircling needling group relevant to the model group (P<0.01).Comparison between post- and pre-EA stimulation showed that the immediate blood perfusion volume was significantly increased from day 1 to 11 after EA stimulation in both the focal center-side needling and encircling needling groups (P<0.01, P<0.05). The therapeutic effect of the encircling needling group was significantly superior to that of the focal center-side needling group in lowering blood perfusion volume from day 3 to 7, and in increasing blood perfusion volume on day 9 and 11 (P<0.01). Under the naked eyes, the conditions of exudation and inflammatory reaction, and the scar and granulation tissue were relatively milder and better respectively in both the center-side needling and encircling needling groups than in the model group. CONCLUSION: Both focal center-side needling and encircling needling can promote the skin wound healing by increasing the blood perfusion in diabetic mice, and the therapeutic effect of the encircling needling method was significantly superior to that of the focal center-side needling method.

Intrauterine administration of autologous peripheral blood mononuclear cells (PBMCs) activated by HCG improves the implantation and pregnancy rates in patients with repeated implantation failure: a prospective randomized study.

PROBLEM: Intrauterine administration of autologous peripheral blood mononuclear cells (PBMCs) activated by HCG in vitro was reported to improve implantation rates in patients with repeated failure of IVF-ET (in vitro fertilization-embryo transfer). In this article, the value of intrauterine administration of PBMCs before embryo transfer and its optimal cell culture method will be investigated. METHOD OF STUDY: Patients who had not experienced successful pregnancy despite three or more IVF-ET sessions were enrolled in this study (n=240, 240 cycles). PBMCs were obtained from patients themselves and were cultured with HCG for 24 hours. Twenty-four hours later, PBMCs were then administered to the intrauterine cavity of that patient from the study group (n=93, 93 cycles). The control group (n=105, 105 cycles) underwent ET without intrauterine administration. RESULTS: Clinical pregnancy rate, implantation rate, and miscarriage rate in the PBMC-treated group (46.24% and 23.66%, n=43 and 22, respectively) were significantly higher than those in the non-treated group (20.95% and 11.43%, P<.05; n=22 and 12, respectively). CONCLUSION: These findings indicate that intrauterine administration of autologous PBMC activated by HCG in vitro effectively improves embryo implantation in patients with three or more IVF failures.

ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.

In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, the loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased under hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4, likely via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that the ACC1/ACLY-α-ketoglutarate-ETV4 axis is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.