Mass Spectrometry Detects Sphingolipid Metabolites for Discovery of New Strategy for Cancer Therapy from the Aspect of Programmed Cell Death.

Sphingolipids, a type of bioactive lipid, play crucial roles within cells, serving as integral components of membranes and exhibiting strong signaling properties that have potential therapeutic implications in anti-cancer treatments. However, due to the diverse group of lipids and intricate mechanisms, sphingolipids still face challenges in enhancing the efficacy of different therapy approaches. In recent decades, mass spectrometry has made significant advancements in uncovering sphingolipid biomarkers and elucidating their impact on cancer development, progression, and resistance. Primary sphingolipids, such as ceramide and sphingosine-1-phosphate, exhibit contrasting roles in regulating cancer cell death and survival. The evasion of cell death is a characteristic hallmark of cancer cells, leading to treatment failure and a poor prognosis. The escape initiates with long-established apoptosis and extends to other programmed cell death (PCD) forms when patients experience chemotherapy, radiotherapy, and/or immunotherapy. Gradually, supportive evidence has uncovered the fundamental molecular mechanisms underlying various forms of PCD leading to the development of innovative molecular, genetic, and pharmacological tools that specifically target sphingolipid signaling nodes. In this study, we provide a comprehensive overview of the sphingolipid biomarkers revealed through mass spectrometry in recent decades, as well as an in-depth analysis of the six main forms of PCD (apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis) in aspects of tumorigenesis, metastasis, and tumor response to treatments. We review the corresponding small-molecule compounds associated with these processes and their potential implications in cancer therapy.

An miRNA-mRNA integrative analysis in human placentas and mice: role of the Smad2/miR-155-5p axis in the development of fetal growth restriction.

Introduction: Functional disorder of the placenta is the principal cause of fetal growth restriction (FGR), usually cured with suitable clinical treatment and good nursing. However, some FGR mothers still give birth to small for gestational age (SGA) babies after treatment. The ineffectiveness of treatment in such a group of patients confused physicians of obstetrics and gynecology. Methods: In this study, we performed a microRNA-messenger RNA integrative analysis of gene expression profiles obtained from Gene Expression Omnibus. Differentially expressed genes were screened and checked using quantitative polymerase chain reaction. Target genes of significantly changed microRNA were screened and enriched for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Function of the obtained microRNA-messenger RNA was evaluated using HTR-8/SVneo trophoblast cells, human umbilical vein endothelial cells, and heterozygote male mice. Result: MiR-155-5p was upregulated (p = 0.001, fold-change = 2.275) in fetal-side placentals. Among the hub genes identified as key targets for miR-155-5p in fetal reprogramming, Smad2 was downregulated (p = 0.002, fold change = 0.426) and negatively correlated with miR-155-5p expression levels (r = -0.471, p < 1.0 E - 04) in fetal-side placental tissues. The miR-155-5p mimic blocks Smad2 expression and suppresses villous trophoblast cell and endothelial cell function (proliferation, migration, and invasion), indicating a close relationship with placental development. Luciferase assays further confirmed the targeting of miR-155-5p to Smad2. Furthermore, Smad2+/- heterozygote male mice were born small with low body weight (p = 0.0281) and fat composition (p = 0.013) in the fourth week post-natal. Discussion: We provide the first evidence of the role of the Smad2/miR-155-5p axis in the placental pathologies of FGR. Our findings elucidate the pathogenesis of FGR and provide new therapeutic targets.

Fatigue Characteristics of 7050-T7451 Aluminum Alloy Friction Stir Welding Joints and the Stress Ratio Effect.

The fatigue crack initiation and growth characteristics in 7050-T7451 aluminum alloy butt joints subjected to different stress ratios and owing to friction stir welding (FSW) were investigated using fatigue tests for stress ratios of 0.1, 0.3, and 0.5. The difference between the fatigue crack initiation in the base material (BM) and FSW joints, related to coarse secondary phases, was explored using scanning electron microscopy (SEM). Accordingly, Al23CuFe4, Al7Cu2Fe, and Al2Mg3Zn3 were the preferred joint crack initiation locations, whereas Mg2Si was the major fracture initiation point of the parent material, and cracks tended to propagate along dense, coarse secondary phases, becoming more pronounced for larger cracks. In addition, as the stress ratio increased, non-Mg2Si phase fracture initiation points appeared in the BM. Meanwhile, the quantity of non-Mg2Si phases in the joints continued to increase, and the crack initiation sites became increasingly concentrated in the TMAZ-HAZ region.

Synchronously improved reliability, figure of merit and adhesion of flexible copper nanowire networks by chitosan transition.

Copper nanowires (CuNWs) are remarkable components that can replace indium tin oxide as transparent electrodes due to their low cost, high conductivity and acceptable transmittance. However, a common coating method can cause poor electrical, optical and adhesive properties because of the creation of loosely connected junctions. In addition, the unsatisfactory thermal and environmental stabilities limit the practical applications. These problems should be overcome in CuNW-based films for reliable transparent electrodes through material and engineering approaches. In this work, a novel transparent composite electrode composed of chitosan and CuNWs on a flexible polyethylene terephthalate (PET) substrate, with synchronously strengthened adhesion, as well as heightened transmittance, reduced resistivity, improved flexibility, enhanced thermal stability and increased environmental stability, was prepared without vacuum processing and high-temperature annealing. The effects of the number of CuNW network layers and chitosan concentration on the performance of chitosan/CuNW composite transparent electrodes were studied. The resulting electrodes exhibitan excellent conductivity (sheet resistance: 15.6 Ω sq-1) and a superior optical transmittance (∼87%) at 550 nm. Calculation of the figure of merit displays a high value of 168, which is the highest among all the reported CuNW-based transparent electrodes. Meanwhile, the sheet resistance did not show great change after 10 tape tests and 10 000 bending cycles, suggesting good adhesion to the PET substrate and outstanding mechanical flexibility. Moreover, the composite transparent electrodes show good stability to resist long-term storage and temperature variation in thermal environment.

Metformin attenuates cadmium-induced neuronal apoptosis in vitro via blocking ROS-dependent PP5/AMPK-JNK signaling pathway.

Cadmium (Cd), a toxic environment contaminant, induces reactive oxygen species (ROS)-mediated neuronal apoptosis and consequential neurodegenerative disorders. Metformin, an anti-diabetic drug, has recently received a great attention owing to its protection against neurodegenerative diseases. However, little is known regarding the effect of metformin on Cd-induced neurotoxicity. Here we show that metformin effectively prevented Cd-evoked apoptotic cell death in neuronal cells, by suppressing Cd activation of c-Jun N-terminal kinases (JNK), which was attributed to blocking Cd inactivation of protein phosphatase 5 (PP5) and AMP-activated protein kinase (AMPK). Inhibition of JNK with SP600125, knockdown of c-Jun, or overexpression of PP5 potentiated metformin's inhibitory effect on Cd-induced phosphorylation of JNK/c-Jun and apoptosis. Activation of AMPK with AICAR or ectopic expression of constitutively active AMPKα strengthened the inhibitory effects of metformin on Cd-induced phosphorylation of JNK/c-Jun and apoptosis, whereas expression of dominant negative AMPKα weakened these effects of metformin. Metformin repressed Cd-induced ROS, thereby diminishing cell death. N-acetyl-l-cysteine enhanced the inhibitory effects of metformin on Cd-induced ROS and apoptosis. Moreover, using Mito-TEMPO, we further demonstrated that metformin attenuated Cd-induced cell death by suppressing induction of mitochondrial ROS. Taken together, these results indicate that metformin prevents mitochondrial ROS inactivation of PP5 and AMPK, thus attenuating Cd-induced JNK activation and apoptosis in neuronal cells. Our data highlight that metformin may be a promising drug for prevention of Cd-induced oxidative stress and neurodegenerative diseases.

Mechanical Metamaterials Foams with Tunable Negative Poisson's Ratio for Enhanced Energy Absorption and Damage Resistance.

Systematic and deep understanding of mechanical properties of the negative Poisson's ratio convex-concave foams plays a very important role for their practical engineering applications. However, in the open literature, only a negative Poisson's ratio effect of the metamaterials convex-concave foams is simply mentioned. In this paper, through the experimental and finite element methods, effects of geometrical morphology on elastic moduli, energy absorption, and damage properties of the convex-concave foams are systematically studied. Results show that negative Poisson's ratio, energy absorption, and damage properties of the convex-concave foams could be tuned simultaneously through adjusting the chord height to span ratio of the sine-shaped cell edges. By the rational design of the negative Poisson's ratio, when compared to the conventional open-cell foams of equal mass, convex-concave foams could have the combined advantages of relative high stiffness and strength, enhanced energy absorption and damage resistance. The research of this paper provides theoretical foundations for optimization design of the mechanical properties of the convex-concave foams and thus could facilitate their practical applications in the engineering fields.

Strain-controlled fatigue behaviors of porous PLA-based scaffolds by 3D-printing technology.

In the study, the low-cycle fatigue behaviors of 3D-printed poly lactic acid (PLA) scaffolds with 60% porosity and two kinds of geometrical pores were investigated under strain-controlled loading. The obtained Δεa-Nf curves were fitted by Coffin-Manson relation. The mechanical stability of the porous structure under cyclic loading was studied. Both kinds of specimens undergo the strain softening after the initial cyclic hardening. The scaffold with circular pore exhibits stable resistance to the fatigue damage which is desirable for bone repairing. Regarding to the accumulation of inelastic deformation, the triangular-scaffold is more sensitive to the cyclic load. The superior fatigue behaviors of the scaffold with circular pore is attributed to homogeneous distribution of the applied mechanical stress and diminishing stress concentration by the introduction of circular pore.