Interference with MTHFD2 induces ferroptosis in ovarian cancer cells through ERK signaling to suppress tumor malignant progression.

Ovarian cancer (OC) is a deadliest gynecological cancer with the highest mortality rate. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a crucial tumor-promoting factor, is over-expressed in several malignancies including OC. The present study aimed to explore the role and mechanisms of MTHFD2 in OC malignant progression. Thus, cell proliferation, cycling, apoptosis, migration, and invasion were evaluated by CCK-8 assay, EdU assay, flow cytometry, wound healing, transwell assay and western blotting. Additionally, glycolysis was assessed by measuring the level of glucose and lactate production, as well as the expressions of GLUT1, HK2 and PKM2. Then the expression of ferroptosis-related proteins and ERK signaling was detected using western blotting. Ferroptosis was detected through the measurement of iron level, GSH, MDA and ROS activities. The results revealed that MTHFD2 was highly expressed in OC cells. Besides, interference with MTHFD2 induced ferroptosis, promoted ROS accumulation, destroyed mitochondrial function, reduced ATP content and inhibited glycolysis in OC cells. Subsequently, we further found that interference with MTHFD2 affected mitochondrial function and glycolysis in OC cells through ERK signaling. Moreover, interference with MTHFD2 affected ferroptosis to inhibit the malignant progression of OC cells. Collectively, our present study disclosed that interference with MTHFD2 induced ferroptosis in OC to inhibit tumor malignant progression through regulating ERK signaling.

Succulent-Inspired Implicit Structural Change for Smart "ON/OFF" Switchable and Flexible EMI Shielding Coating.

Modern miniaturized intelligent electronics call for smart switchable and flexible electromagnetic interference (EMI) shielding material for highly precise applications. However, most switchable EMI shielding materials are based on an explicit structural change. Herein, we report a succulent-inspired smart switchable MXene (WR-MXene) coating film realized by inner implicit structural change, which benefits from the insertion of our reversible large-cavity yolk-shell biomicrospheres. The novel switchable yolk-shell biomicrospheres contain a soft N-isopropylacrylamide (PNIPAM) hydrogel core, an "ON/OFF" switchable cavity (over 30% volume fraction), and a porous polydopamine (p-PDA) shell. The yolk-shell biomicrospheres can be obtained by a facile two-step polymerization and a simple drying-dehydration treatment. Because of the "ON/OFF" switchable void space brought by the smart biomicrospheres and conductive framework of MXene, an optimized ultralight and flexible WR-MXene coating film (vWR-coating film) showed both large switchable change (over 60 dB) and extraordinary EMI shielding effectiveness, reaching 95 and over 50 dB in the whole X band (8.2-12.4 GHz). These novel reversible yolk-shell biomicrospheres and the succulent-inspired switchable coating films are promising for smart flexible wearable devices and many advanced multifunctional systems needing dynamic real-time response.

Improving the Operational Lifetime of Metal-Halide Perovskite Light-Emitting Diodes with Dimension Control and Ligand Engineering.

Perovskite light-emitting diodes (LEDs) have emerged as one of the most propitious candidates for next-generation lighting and displays, with the highest external quantum efficiency (EQE) of perovskite LEDs already surpassing the 20% milestone. However, the further development of perovskite LEDs primarily relies on addressing operational instability issues. This Perspective examines some of the key factors that impact the lifetime of perovskite LED devices and some representative reports on recent advancements aimed at improving the lifetime. Our analysis underscores the significance of "nano" strategies in achieving long-term stable perovskite LEDs. Significant efforts must be directed toward proper device encapsulation, perovskite material passivation, interfacial treatment to address environment-induced material instability, bias-induced phase separation, and ion migration issues.

Oxidative stress induces mitochondrial iron overload and ferroptotic cell death.

Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.

Ferroptosis contributes to catecholamine-induced cardiotoxicity and pathological remodeling.

High levels of circulating catecholamines cause cardiac injury, pathological remodeling, and heart failure, but the underlying mechanisms remain elusive. Here we provide both in vitro and in vivo evidence that excessive ß-adrenergic stimulation induces ferroptosis in cardiomyocytes, revealing a novel mechanism for catecholamine-induced cardiotoxicity and remodeling. We found that isoproterenol, a synthetic catecholamine, promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to GPX4 inactivation and enhanced lipid peroxidation. Isoproterenol also promoted heme oxygenase 1 (HO-1) expression by downregulating the transcription suppressor BTB and CNC homology 1 (Bach1), leading to increased labile iron accumulation through heme degradation. Moreover, isoproterenol markedly induced the accumulation of free iron and lipid reactive oxygen species (ROS) in the mitochondria, while targeted inhibition of iron overload and ROS accumulation within mitochondria effectively inhibited ferroptosis in cardiomyocytes. Importantly, isoproterenol administration markedly induced ferroptosis in the myocardium in vivo, associated with elevated non-heme iron accumulation driven by HO-1 upregulation. Strikingly, blockade of ferroptosis with ferrostatin-1 or inhibition of HO-1 activity with zinc protoporphyrin (ZnPP) effectively alleviated cardiac necrosis, pathological remodeling, and heart failure induced by isoproterenol administration. Taken together, our results reveal that catecholamine stimulation primarily induces ferroptotic cell death in cardiomyocyte through GPX4 and Bach1-HO-1 dependent signaling pathways. Targeting ferroptosis may represent a novel therapeutic strategy for catecholamine overload-induced myocardial injury and heart failure.

Nacre-mimetic Strategy to Fabricate Waterborne FrGO/Zn/Epoxy Coatings with Dual Corrosion Protection.

The service life of metal and other infrastructure requires extending through eco-friendly, low-carbon technology. Here, a nacre-mimetic γ-Fe2O3/reduced graphene oxide (FrGO)/zinc-containing epoxy coating (FrGO/Zn/epoxy coating) was fabricated by spraying a mixture of waterborne epoxy resin, zinc flakes, and magnetic conductive FrGO under a magnetic field. The FrGO, which was synthesized by in situ redox and precipitation, was aligned in the zinc-containing coatings (ZCC), and it oriented the zinc flakes in the direction of the magnetic field to mimic the lamellar structure of nacre. The obtained anti-corrosion coating showed enhanced barrier protection and cathodic protection, which was confirmed by the electrochemical tests and salt spray test results. The waterborne coatings less than 50 µm thick with parallelly aligned FrGO and 30 wt % zinc flakes exhibited a long cathodic period lasting more than 99 days and excellent barrier performance with a high initial coating resistance of 5.31 × 109 Ω·cm2, which was superior to that of the conventional zinc-rich coating containing 80 wt % zinc (80 days, 3.74 × 103 Ω·cm2). The dual anti-corrosion mechanism of the waterborne FrGO/Zn/epoxy coating was investigated. The integrity and long-term cathodic protection of the coatings were derived from the compactness achieved by the nacre-mimetic structure and the interface chemical and hydrogen bonding crosslinking interactions and the high, uniform zinc utilization achieved by the aligned FrGO-Zn charge transmission network. This work provides a feasible nacre-inspired strategy to fabricate a lightweight anti-corrosion waterborne ZCC that is resource-efficient and promising in creating compact materials with other functional properties, such as electromagnetic shielding and conductive networks.

TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis.

Mutations in TGF-ß-activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.

NFκB promotes oxidative stress-induced necrosis and ischemia/reperfusion injury by inhibiting Nrf2-ARE pathway.

In this study, we identified an unexpected pro-cell death role for NFκB in mediating oxidative stress-induced necrosis, and provide new mechanistic evidence that NFκB, in cooperation with HDAC3, negatively regulates Nrf2-ARE anti-oxidative signaling through transcriptional silencing. We showed that genetic inactivation of NFκB-p65 inhibited, whereas activation of NFκB promoted, oxidative stress-induced cell death and HMGB1 release, a biomarker of necrosis. Moreover, NFκB-luciferase activity was elevated in cardiomyocytes after simulated ischemia/reperfusion (sI/R) or doxorubicin (DOX) treatment, and inhibition of NFκB with Ad-p65-shRNA or Ad-IκBαM diminished sI/R- and DOX-induced cell death and HMGB1 release. Importantly, NFκB negatively regulated Nrf2-ARE activity and the expression of antioxidant proteins. Mechanistically, co-immunoprecipitation revealed that p65 was required for Nrf2-HDAC3 interaction and transcriptional silencing of Nrf2-ARE activity. Further, the ability of HDAC3 to repress Nrf2-ARE activity was lost in p65 deficient cells. Pharmacologic inhibition of HADCs or NFκB with trichostatin A (TSA) or BMS-345541, respectively, increased Nrf2-ARE activity and promoted cell survival after sI/R. In vivo, NFκB transcriptional activity in the mouse heart was significantly elevated after ischemia/reperfusion (I/R) injury, which was abolished by cardiomyocyte-specific deletion of p65 using p65fl/flNkx2.5-Cre mice. Moreover, genetic ablation of p65 in the mouse heart attenuated myocardial infarct size after acute I/R injury and improved cardiac remodeling and functional recovery after chronic myocardial infarction. Thus, our results identified NFκB as a key regulator of oxidative stress-induced necrosis by suppressing the Nrf2-ARE antioxidant pathway through an HDAC3-dependent mechanism. This study also revealed a new pathogenic role of NFκB in cardiac ischemic injury and pathological remodeling.

The relationship between ovarian endometriosis and clinical pregnancy and abortion rate based on logistic regression model.

In order to study the relationship between ovarian endometriosis and clinical pregnancy, explore the correlation between endometriosis (EMT) and abortion rate and its mechanism, and provide a new theoretical basis for clinical diagnosis as well as treatment of endometriosis, in this study, pelvic endometriosis under 40 years old and have in vitro fertilization-embryo transfer (IVF-ET) operation will be selected as subjects of study. SPSS20.0 statistical software is used to analyze the data. When the measurement data between groups are compared, it is necessary to use t-test. It is necessary to use mean ± standard deviation ( x ¯ ± s ) to expressed the results. When the counting data between groups is compared, it is necessary to use Chi-square test. Finally, the binomial classification logistic regression model is established by stepwise regression method to screen out the significant factors. The results show that the infertility duration of ovarian endometriosis cyst is (3.1 ± 1.9). The infertility years of other pelvic endometriosis are (3.9 ± 2.2). The infertility years of ovarian endometriosis cyst group are shorter than those of other pelvic endometriosis groups. Significant difference cannot be seen in follicle stimulating hormone (FSH) between the two groups of patients, and the basal FSH of other pelvic endometriosis groups is obviously lower in the two groups between the ages of 29 and 40 years. In the ovarian endometriotic cyst group, the significant difference can be seen (P < 0.05). Moreover, in the comparison of ovulation induction, the Gn dosage of fresh-cycle ovarian endometriosis patients is obviously higher than that of patients with ovarian endometriosis during the freezing cycle. The fertilization rate of patients with fresh cycle ovarian endometriosis is higher than that of patients with ovarian endometriosis during the freezing cycle. The two groups of patients with the factor of ovarian endometriosis after fresh embryo transplantation and the factor of fallopian tube are compared, and the abortion rate of the ovarian endometriosis group is lower than that of the fallopian tube group. Therefore, controlling the development of ovarian endometriosis can help to improve the pregnancy rate, reduce the abortion rate and improve the pregnancy outcome of patients with ovarian endometriosis.

Assessment of Risk Factors of Intrauterine Adhesions in Patients With Induced Abortion and the Curative Effect of Hysteroscopic Surgery.

OBJECTIVE: To explore the risk factors for intrauterine adhesions in patients with artificial abortion and clinical efficacy of hysteroscopic dissection. METHODS: 1500 patients undergoing artificial abortion between January 2014 and June 2015 were enrolled into this study. The patients were divided into two groups with or without intrauterine adhesions. Univariate and Multiple logistic regression were conducted to assess the effects of multiple factors on the development of intrauterine adhesions following induced abortion. RESULTS: The incidence rate for intrauterine adhesions following induced abortion is 17.0%. Univariate showed that preoperative inflammation, multiple pregnancies and suction evacuation time are the influence risk factors of intrauterine adhesions. Multiple logistic regression demonstrates that multiple pregnancies, high intrauterine negative pressure, and long suction evacuation time are independent risk factors for the development of intrauterine adhesions following induced abortion. Additionally, intrauterine adhesions were observed in 105 mild, 80 moderate, and 70 severe cases. The cure rates for these three categories of intrauterine adhesions by hysteroscopic surgery were 100.0%, 93.8%, and 85.7%, respectively. CONCLUSION: Multiple pregnancies, high negative pressure suction evacuation and long suction evacuation time are independent risk factors for the development of intrauterine adhesions following induced abortions. Hysteroscopic surgery substantially improves the clinical outcomes of intrauterine adhesions.

Significantly improved black phase stability of FAPbI3 nanowires via spatially confined vapor phase growth in nanoporous templates.

The formamidinium lead iodide (FAPbI3) perovskite has attracted immense research interest as it has much improved stability than methylammonium lead iodide (MAPbI3) while still maintaining excellent optoelectronic properties. Compared to MAPbI3, FAPbI3 has shown an elevated decomposition temperature and a slower decomposition process and therefore it is considered as a more promising candidate for future high-efficiency and reliable optoelectronic devices. However, these excellent optoelectronic properties only exist in the alpha phase and this phase will spontaneously transform into an undesired delta phase with much poorer optoelectronic properties regardless of the environment. This is the main challenge for the application of the FAPbI3 perovskite. Herein, we report a novel strategy to stabilize the cubic black phase of FAPbI3 by using nanoengineering templates. Without further treatment, the black phase can be held over 7 months under ambient conditions and 8 days in an extreme environment with a Relative Humidity (RH) of 97%. A systematic study further reveals that this great improvement can be attributed to the spatial confinement in anodized alumina membrane (AAM) nanochannels, which prohibits the unwanted α-to-δ phase transition by restricting the expansion of NWs in the ab plane, and the excellent passivation against water molecule invasion. Meanwhile, we also demonstrate the potency of these NWs in practical applications by configuring them into photodetectors, which have shown reasonable response and excellent device stability.

Progress and Design Concerns of Nanostructured Solar Energy Harvesting Devices.

Integrating devices with nanostructures is considered a promising strategy to improve the performance of solar energy harvesting devices such as photovoltaic (PV) devices and photo-electrochemical (PEC) solar water splitting devices. Extensive efforts have been exerted to improve the power conversion efficiencies (PCE) of such devices by utilizing novel nanostructures to revolutionize device structural designs. The thicknesses of light absorber and material consumption can be substantially reduced because of light trapping with nanostructures. Meanwhile, the utilization of nanostructures can also result in more effective carrier collection by shortening the photogenerated carrier collection path length. Nevertheless, performance optimization of nanostructured solar energy harvesting devices requires a rational design of various aspects of the nanostructures, such as their shape, aspect ratio, periodicity, etc. Without this, the utilization of nanostructures can lead to compromised device performance as the incorporation of these structures can result in defects and additional carrier recombination. The design guidelines of solar energy harvesting devices are summarized, including thin film non-uniformity on nanostructures, surface recombination, parasitic absorption, and the importance of uniform distribution of photo-generated carriers. A systematic view of the design concerns will assist better understanding of device physics and benefit the fabrication of high performance devices in the future.

Approaching the Hole Mobility Limit of GaSb Nanowires.

In recent years, high-mobility GaSb nanowires have received tremendous attention for high-performance p-type transistors; however, due to the difficulty in achieving thin and uniform nanowires (NWs), there is limited report until now addressing their diameter-dependent properties and their hole mobility limit in this important one-dimensional material system, where all these are essential information for the deployment of GaSb NWs in various applications. Here, by employing the newly developed surfactant-assisted chemical vapor deposition, high-quality and uniform GaSb NWs with controllable diameters, spanning from 16 to 70 nm, are successfully prepared, enabling the direct assessment of their growth orientation and hole mobility as a function of diameter while elucidating the role of sulfur surfactant and the interplay between surface and interface energies of NWs on their electrical properties. The sulfur passivation is found to efficiently stabilize the high-energy NW sidewalls of (111) and (311) in order to yield the thin NWs (i.e., <40 nm in diameters) with the dominant growth orientations of ⟨211⟩ and ⟨110⟩, whereas the thick NWs (i.e., >40 nm in diameters) would grow along the most energy-favorable close-packed planes with the orientation of ⟨111⟩, supported by the approximate atomic models. Importantly, through the reliable control of sulfur passivation, growth orientation and surface roughness, GaSb NWs with the peak hole mobility of ∼400 cm(2)V s(-1) for the diameter of 48 nm, approaching the theoretical limit under the hole concentration of ∼2.2 × 10(18) cm(-3), can be achieved for the first time. All these indicate their promising potency for utilizations in different technological domains.

The use of glyburide in the management of gestational diabetes mellitus: a meta-analysis.

PURPOSE: Glyburide has been used for managing gestational diabetes mellitus (GDM) in a number of countries. It is rather inexpensive. However, its efficacy and safety remain controversial. With this meta-analysis, we evaluated glyburide in comparison with insulin. MATERIAL/METHODS: With a systematic literature search strategy, a total of 93 randomized controlled trials (RCTs) with insulin and glyburide comparison were identified. Based on the revised Consolidated Standards of Reporting Trials (CONSORT) checklist, five of them met the inclusion criteria and were included in this meta-analysis. RESULTS: Six hundred and seventy four subjects were included in these five RCTs. When compared with insulin, glyburide had an increased relative risk (RR) for neonatal hypoglycemia (RR: 1.98; 95% confidence interval [CI]: 1.17, 3.36). Estimation of standard mean differences (SMD) showed that both fetal birth weight and incidence of macrosomia were higher in subjects receiving glyburide than in those receiving insulin (SMD: 0.21; 95% CI: 0.06, 0.36; RR: 2.22; 95% CI: 1.07, 4.61 respectively). There were no significant differences in maternal glucose control, glycated hemoglobin, the rate of Cesarean section, large-for-gestational age, neonatal hypocalcemia, length of stay for neonatal ICU admissions, preterm birth, or congenital anomalies. CONCLUSIONS: Our study suggested that in women with GDM, glyburide is as effective as insulin, but the risks of neonatal hypoglycemia, high fetal birth weight, and macrosomia were higher.