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Lactate accumulation in the tumor microenvironment was shown to be closely related to tumor growth and immune escape, and suppression of lactate production by inhibiting lactate dehydrogenase A (LDHA) has been pursued as a potential novel antitumor strategy. However, only a few potent LDHA inhibitors have been developed and most of them did not show potent antitumor effects in vivo. To this end, we designed new LDHA inhibitors and obtained a novel potent LDHA inhibitor, ML-05. ML-05 inhibited cellular lactate production and tumor cell proliferation, which was associated with inhibition of ATP production and induction of reactive oxygen species and G

Pre-eclampsia (PE) is a worldwide pregnancy-related disorder. It is mainly characterized by defect migration and invasion of trophoblast cells. Recently, circular RNAs (circRNAs) have been believed to play a vital role in PE. The expression patterns and the biological functions of circRNAs in PE remain elusive. Here, we performed a circRNA microarray to identify putative PE-related circRNAs. Bioinformatics analyses were used to screen the circRNAs which have potential relationships with pre-eclampsia, and we identified a novel circRNA (circVRK1) that was up-regulated in PE placenta tissues. By using HTR-8/SVneo cells, circVRK1 knockdown significantly enhanced cell migration and invasion abilities, as well as epithelial-mesenchymal transition (EMT). Mechanistically, we found that circVRK1 and PTEN could function as the ceRNAs to miR-221-3p. Overexpression of miR-221-3p promoted cell migration, invasion and EMT via regulating PTEN. The cotransfection of miR-221-3p inhibitor or PTEN reversed the effect from circVRK1 knockdown. Moreover, the circVRK1/miR-221-3p/PTEN axis greatly regulated Akt phosphorylation. In general, circVRK1 suppresses trophoblast cell migration, invasion and EMT, by acting as a ceRNA to miR-221-3p to regulate PTEN, and further inhibit PI3K/Akt activation. The purpose of this paper is to open wide insights to investigate the onset of PE and provide new potential therapeutic targets in PE.

Introduction Identifying nutrition‐ and modifiable lifestyle‐based risk factors for cognitive decline and dementia may contribute future primary prevention strategies. This study aimed to evaluate the associations between magnesium intake and cognition in older adults in the United States. Methods Based on the National Health and Nutrition Survey (NHANES) between 2011 and 2014, the study included 2508 participants aged 60 years and older. Linear regression models were used to examine the association of total magnesium intake with cognition. Results After adjusted demographic and other confounding factors, intakes of energy and total calcium, and serum vitamin D level, higher intake of total magnesium was independently associated with 0.15 higher global cognitive z‐score (95% confidence interval, 0.02 to 0.28 for highest vs. lowest quartile, P trend = .037). The positive association of total magnesium intake with global cognition was primarily presented among women, non‐Hispanic Whites, and those with sufficient serum vitamin D levels (≥50 nmol/L), although interactions were not significant. There were no clear linear associations for global cognition with serum vitamin D level. Discussions Our findings suggest that high magnesium intake alone may improve cognition in older adults, particularly among non‐Hispanic Whites and subjects with sufficient levels of serum vitamin D. Further studies are needed to confirm the findings.

Intestinal ischemia-reperfusion (IIR) often occurs during and following major cardiovascular or gut surgery and causes significant organ including kidney injuries. This study was to investigate the protective effect of intestinal ischemic postconditioning (IPo) on IIR-induced acute kidney injury (AKI) and the underling cellular signaling mechanisms with focus on the Nrf2/HO-1. Adult C57BL/6J mice were subjected to IIR with or without IPo. IIR was established by clamping the superior mesenteric artery (SMA) for 45 minutes followed by 120 minutes reperfusion. Outcome measures were: (i) Intestinal and renal histopathology; (ii) Renal function; (iii) Cellular signaling changes; (iv) Oxidative stress and inflammatory responses. IPo significantly attenuated IIR-induced kidney injury. Furthermore, IPo significantly increased both nuclear Nrf2 and HO-1 expression in the kidney, upregulated autophagic flux, inhibited IIR-induced inflammation and reduced oxidative stress. The protective effect of IPo was abolished by the administration of Nrf2 inhibitor (Brusatol) or Nrf2 siRNA. Conversely, a Nrf2 activator t-BHQ has a similar protective effect to that of IPo. Our data indicate that IPo protects the kidney injury induced by IIR, which was likely mediated through the Nrf2/HO-1 cellular signaling activation.

Adult patients with relapsed or refractory T‐cell acute lymphoblastic leukemia (R/R‐T‐ALL) have extremely poor prognosis, representing an urgent unmet medical need. Finding an optimal salvage regimen to bridge transplantation is a priority. The CAG (cytarabine, aclarubicin, and G‐CSF) regimen was initially used by one group in China, showing unexpectedly promising results in 11 R/R‐T‐ALL patients. Here, we report the multicenter results of 41 patients who received the CAG regimen as salvage therapy. After one cycle of the CAG regimen, complete remission and partial remission were achieved in 33 (80.5%) and two (4.9%) patients, respectively. Failure to respond was observed in six patients (14.6%). Early T‐cell precursor (ETP) (n = 26) and non‐ETP (n = 15) patients had a similar CR rate (80.8% vs 80.0%, P = .95). Among 41 patients, allo‐HSCT was successfully performed in 27 (66%) patients (22 in CR and 5 in non‐CR). With a median follow‐up time of 12 months, the estimated 2‐year overall survival and event‐free survival were 68.8% (95% CI, 47.3%‐83.0%) and 56.5% (95% CI, 37.1%‐71.9%), respectively. The CAG regimen was well‐tolerated, and no early death occurred. Our multicenter results show that the CAG regimen is highly effective and safe, representing a novel choice for adult patients with R/R‐T‐ALL and providing a better bridge to transplantation., Adult patients with relapsed or refractory T‐cell acute lymphoblastic leukemia (R/R‐T‐ALL) have limited therapeutic options and extremely poor prognosis (CR rate

In geothermal mining, the mechanical properties and micro‐structure of the rock under different temperature or cooling modes are highly relevant to the stability of the artificial reservoir. For reflect the actual working conditions, an experimental study is carried out on high‐temperature granite that has been cooled both naturally and rapidly with water. The following conclusions are reached. (a) The wave velocity, elastic modulus, and uniaxial compressive strength of the test specimen decrease with an increase in its heating temperature under both cooling modes. (b) The characteristics of the stress‐strain curve of granite are different after different temperatures and cooling modes. With natural cooling, the stress‐strain curve features double peaks in the range of 200‐300°C, whereas such phenomenon occurs at temperatures greater than 300°C with water cooling. (c) When the temperature is less than 300°C, no obvious change occurs in the crystal structure of the sample. When the temperature is more than 300°C, the original micro‐cracks gradually expand and eventually develop into larger cracks.

Compartmentalization is essential for living cells to orchestrate their biological processes with controlled external influences. Thus, compartmentalization has been a constant theme for cell-mimicking materials. Despite recent advances in engineering compartmentalized materials as synthetic cells and organelles, it remains difficult to produce robust and well-ordered compartments with secluded environments in aqueous surroundings. Nature creates hierarchically ordered compartmentalized materials by utilizing bio-catalyzed mineralization, inspired by which, mechanically robust all-aqueous compartments are developed by engineering a mild biomimetic mineralization at aqueous/aqueous interfaces. The enzyme-induced biomineralization generates a layer of densely-packed particles, acting as an armor to enclose aqueous interiors. This strategy of in situ bio-synthesized compartments is different from current strategies, where compartments are constructed by randomly adsorbed particles at interface, leading to inadequately controlled properties of compartments. To demonstrate the robustness and adaptiveness of the in situ bio-synthesized all-aqueous compartments, these are utilized as drug delivery materials by sequestering protein drugs at their aqueous interiors and releasing when exposing to gastric environments. The study provides new ways to fabricate compartmentalized materials with well-defined properties, unlocking routes to the next generation of self-assembled materials and structures by integrating aqueous two-phase systems with biomineralization.

Despite a significant advancement in preparing metastable materials, one common problem is the strict and precious reaction conditions due to their metastable structures. Herein, we achieved the preparation of high-temperature stabilized metastable α-MoC1-x by mounting zinc atoms into its lattice structure. Such a structural construction could suppress the phase transformation from α-MoC1-x to β-Mo2 C through restricting the displacement of Mo atoms upon increased temperature. The resultant metastable α-MoC1-x can be stabilized up to 1000 °C and this stability temperature is the highest for the metastable α-MoC1-x so far. Synchrotron X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectroscopy (XPS) confirm the structure of Zn-mounted α-MoC1-x . Density functional theory (DFT) calculations reveal that the introduction of the Zn atoms in the lattice structure of α-MoC1-x could significantly decrease the energy difference (ΔE) between α-MoC1-x and β-Mo2 C, thus effectively suppressing the phase transformation from α-MoC1-x to β-Mo2 C and accordingly maintaining the high-temperature stability of α-MoC1-x . This novel strategy can be used as a universal method to be extended to synthesize metastable α-MoC1-x from different precursors or other mounted elements. Moreover, the optimal product exhibits excellent lithium storage performances in terms of the cycling stability and rate performance.

Disruption of extravillous trophoblast (EVT) migration and invasion is considered to be responsible for pathological placentation in preeclampsia (PE). Cyclin G2 (CCNG2) is an atypical cyclin that inhibits cell cycle progression. However, its biological function and underlying molecular mechanism in PE are poorly understood. In this study, clinical data demonstrated that CCNG2 was significantly upregulated in PE placenta and associated with invasive EVT dysfunction. Additionally, Ccng2 knockout led to an attenuation of PE-like symptoms in the PE mouse model produced via treatment with NG-nitro-L-arginine methyl ester (L-NAME). In vitro, CCNG2 inhibited the migration, invasion, and endothelial-like network formation of human trophoblast cell line HTR8/SVneo. Mechanically, CCNG2 suppressed JNK-dependent Wnt/PCP signaling and its downstream indicators including epithelial-to-mesenchymal transition (EMT) markers and matrix metalloproteinases (MMPs) via promoting the polyubiquitination degradation of dishevelled 2 (Dvl2) protein in HTR8/SVneo cells. We also discovered that the E3 ligase Ring finger protein 123 (RNF123), as a novel CCNG2 target among HTR8/SVneo cells, interacted with Dvl2 and participated in CCNG2-induced polyubiquitination degradation of Dvl2. Moreover, we verified that the treatment of HTR8/SVneo cells with RNF123-specific siRNA improved polyubiquitination-induced degradation of Dvl2 and the activity of Wnt/PCP-JNK signaling mediated by CCNG2. Taken together, our results reveal that the CCNG2/RNF123/Dvl2/JNK axis may be involved in the pathogenesis and progression of PE through trophoblastic cell function modulation, thus probably providing us with new therapeutic strategies for PE treatment.

Transition metal carbides (TMCs), as a family of special interstitial alloys, exhibit novel intrinsic characteristics such as high melting point, high electronic conductivity, excellent mechanical and chemical stability, and good corrosion resistance, and hence have attracted ever-growing attention as promising electrode materials for energy-related applications. In this regard, we give a comprehensive overview of the structural design of transition metal carbide complex architectures and their structure advantages for energy-related applications. After a brief classification, we summarize in detail recent progress in controllable design and synthesis of TMCs with complex nanostructures (e.g., zero-, one-, two-, and three-dimensional, and self-supported electrodes) for electrochemical energy storage and conversion applications including metal-ion batteries, supercapacitors, rechargeable metal-air batteries, fuel cells, and water splitting. Finally, we end this review with some potential challenges and research prospects of TMCs as electrode materials for energy-related applications.

Despite significant advancement in preparing various hollow structures by Ostwald ripening, one common problem is the intractable uncontrollability of initiating Ostwald ripening due to the complexity of the reaction processes. Here, a new strategy on Hansen solubility parameter (HSP)-guided solvent selection to initiate Ostwald ripening is proposed. Based on this comprehensive principle for solvent optimization, N,N-dimethylformamide (DMF) was screened out, achieving accurate synthesis of interior space-tunable MoSe2 spherical structures (solid, core-shell, yolk-shell and hollow spheres). The resultant MoSe2 structures exhibit architecture-dependent electrochemical performances towards hydrogen evolution reaction and sodium-ion batteries. This pre-solvent selection strategy can effectively provide researchers great possibility in efficiently synthesizing various hollow structures. This work paves a new pathway for deeply understanding Ostwald ripening.

Objectives The aim of this study was to assess the correlation between the thymic-thoracic ratio and cardiac axis in healthy fetuses. Methods The fetal thymic-thoracic ratio and cardiac axis were measured in 220 healthy fetuses. The normal ranges of the fetal thymic-thoracic ratio and cardiac axis for each gestational week were established. The Pearson correlation coefficient was calculated to analyze the relationship between the thymic-thoracic ratio and cardiac axis. Results The mean fetal thymic-thoracic ratio increased slightly throughout the pregnancy, from 0.33 at 17 weeks' gestation to 0.37 at 37 weeks. No statistically significant correlation was found between the thymic-thoracic ratio and cardiac axis in healthy fetuses. Conclusions In healthy fetuses, the thymus occupies an increasingly larger portion of the upper mediastinum when the pregnancy advances. The cardiac axis is not affected by the thymic-thoracic ratio in healthy fetuses.

Propofol has been found to play an important role in hepatic ischemia/reperfusion (I/R) injury with the antioxidant effects. However, the molecular mechanism of propofol in hepatic I/R injury has not been fully understood. Male Sprague-Dawley rats were randomly assigned into Sham group, hepatic I/R group, and propofol treatment group. I/R injury was attained by ischemia for 1 h and reperfusion for 2 h. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity were detected. QSG-7701 cells were cultured in hypoxia condition for 15 h and then in reoxygenation condition for 6 h to imitate hypoxia/reoxygenation (H/R) injury in vitro. Real-time RT-PCR and Western blot were performed to determine the expression of miR-133a-5p and MAPK6. Luciferase reporter assay was used to determine the regulation of miR-133a-5p on MAPK6. Propofol significantly reduced the activities of serum AST and ALT induced by hepatic I/R injury in rats. Propofol increased the level of miR-133a-5p and decreased the expression of MAPK6 in vivo and in vitro. Luciferase reporter assay showed that MAPK6 was a target of miR-133a-5p. Knockdown of miR-133a-5p abrogated the effect of propofol on the upregulation of MAPK6 induced by H/R. MAPK6 overexpression promoted the cell apoptosis induced by H/R which could be attenuated by propofol. Finally, we found that miR-133a-5p reversed the protective effect of propofol in rats with hepatic I/R injury. Propofol showed protective roles for hepatic I/R injury in vivo and H/R injury in vitro, which involved with miR-133a-5p regulating the expression of MAPK6.

Long non-coding (lncRNA) MALAT1 can be increased by hypoxia or ischemic limbs. Also, downregulation of MALAT1 contributes to reduction of cardiomyocyte apoptosis. However, the functional involvement of MALAT1 in myocardial ischemia-reperfusion (I/R) injury has not been defined. This study investigated the functional involvement of lncRNA-MALAT1 in cardioprotective effects of fentanyl. HL-1, a cardiac muscle cell line from the AT-1 mouse atrial cardiomyocyte tumor lineage was pre-treated with fentanyl and generated cell model of hypoxia-reoxygenation (H/R). Relative expression of MALAT1, miR-145, and Bnip3 mRNA in cells was determined by quantitative real-time PCR. Cardiomyocyte H/R injury was indicated by lactate dehydrogenase (LDH) release and cell apoptosis. The results showed that fentanyl abrogates expression of responsive gene for H/R and induces downregulation of MALAT1 and Bnip3 and upregulation of miR-145. We found that miR-145/Bnip3 pathway was negatively regulated by MALAT1 in H/R-HL-1 cell with or without fentanyl treatment. Moreover, both MALAT1 overexpression and miR-145 knockdown reverse cardioprotective effects of fentanyl, as indicated by increase in LDH release and cell apoptosis. The reversal effect of MALAT1 for fentanyl is confirmed in cardiac ischemia/reperfusion (I/R) mice. In summary, lncRNA-MALAT1 is sensitive to H/R injury and abrogates cardioprotective effects of Fentanyl by negatively regulating miR-145/Bnip3 pathway.