Synthesis,Anticancer Activity,Structure-Activity Relationship and Mechanistic Investigations of Falcarindiol Analogues

Forty samples of optically active falcarindiol analogues are synthesized by using the easily available C2 symmetric (R)- and (S)-1,1’-binaphth-2-ol (BINOL) in combination with Ti(OⁱPr)₄, Zn powder and EtI. Their anticancer activities on Hccc-9810, HepG2, MDA-MB-231, Hela, MG-63 and H460 cells are assayed to elucidate their structure-activity relationships. These results showed that the falcarindiol analogue (3R,8S)- 2 i with the terminal double bond has the most potent anti-proliferation effect on Hccc-9810 cells with IC₅₀ value of 0.46 μM. The falcarindiol analogue (3R,8S)- 2 i can induce obvious Hccc-9810 cell apoptosis in a concentration-dependent manner by Hoechst staining and flow cytometry analysis. The proposed mechanism suggests that the falcarindiol analogue (3R,8S)- 2 i increases LDH release and MDA content, and reduces the levels of SOD activity, which lead to the accumulation of oxidative stress and induce apoptosis in Hccc-9810 cells.     

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene,a Major Active Metabolite of Bisphenol A,Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway

4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic β-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic β-cells and elucidated the cellular mechanism involved in MBP-induced β-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of β-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on β-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway.     

Translesion Synthesis or Repair by Specialized DNA Polymerases Limits Excessive Genomic Instability upon Replication Stress

DNA can experience “replication stress”, an important source of genome instability, induced by various external or endogenous impediments that slow down or stall DNA synthesis. While genome instability is largely documented to favor both tumor formation and heterogeneity, as well as drug resistance, conversely, excessive instability appears to suppress tumorigenesis and is associated with improved prognosis. These findings support the view that karyotypic diversity, necessary to adapt to selective pressures, may be limited in tumors so as to reduce the risk of excessive instability. This review aims to highlight the contribution of specialized DNA polymerases in limiting extreme genetic instability by allowing DNA replication to occur even in the presence of DNA damage, to either avoid broken forks or favor their repair after collapse. These mechanisms and their key regulators Rad18 and Polθ not only offer diversity and evolutionary advantage by increasing mutagenic events, but also provide cancer cells with a way to escape anti-cancer therapies that target replication forks.     

Toward a better understanding of multifunctional cement-based materials: The impact of graphite nanoplatelets (GNPs)

The impact of graphite nanoplatelets (GNPs) on the physical and mechanical properties of cementitious nanocomposites was investigated. A market-available premixed mortar was modified with 0.01% by weight of cement of commercial GNPs characterized by two distinctively different aspect ratios.The rheological behavior of the GNP-modified fresh admixtures was thoroughly evaluated. Hardened cementitious nanocomposites were investigated in terms of density, microstructure (Scanning Electron Microscopy, SEM and micro–Computed Tomography, μ-CT), mechanical properties (three-point bending and compression tests), and physical properties (electrochemical impedance spectroscopy, EIS and thermal conductivity measurements). At 28 days, all GNP-modified mortars showed about 12% increased density. Mortars reinforced with high aspect ratio GNPs exhibited the highest compressive and flexural strength: about 14% and 4% improvements compared to control sample, respectively. Conversely, low aspect ratio GNPs led to cementitious nanocomposites characterized by 36% decreased electrical resistivity combined with 60% increased thermal conductivity with respect to the control sample.     

Microstructural,mechanical, and thermal properties of microwave-sintered KLS-1 lunar regolith simulant

KLS-1 Lunar regolith simulant was microwave sintered to explore its potential applicability in future lunar construction. The effects of sintering temperature on linear shrinkage, density, porosity, and microstructural, mechanical, and thermal properties were investigated. As the sintering temperature increased, linear shrinkage and density increased and porosity decreased. Structural evolution in the sintered samples was characterized by scanning electron microscopy and X-ray diffraction. Unconfined compressive strength testing showed that mechanical strength increased significantly with increasing sintering temperature, with 1120 °C giving the highest strength of 37.0 ± 4.8 MPa. The sintered samples exhibited a coefficient of thermal expansion of approximately 5 × 10⁻⁶ °C⁻¹, which was well-maintained even after cyclic temperature stress between −100 and 200 °C. Therefore, this microwave processing appears promising for the fabrication of building material with sufficient mechanical strength and thermal durability for lunar construction.     

Electrochemical performance of in situ LiFePO4 modified by N-doped graphene for Li-ion batteries

LiFePO₄ modified by N-doped graphene (NG) with a three-dimensional conductive network structure was synthesized via a one-step in situ hydrothermal method. The effects of N amount of NG on the phase structure, morphology, and electrochemical properties of LiFePO₄ are investigated in this study. X-ray diffraction (XRD) results show that doping suitable N amounts in NG do not alter the crystal structure of LiFePO_4, and scanning electron microscopy (SEM) images show that NG can slightly reduce the particle size of LiFePO₄. The high-resolution transmission electron microscopy (HRTEM) results show that the LiFePO₄ particles are well covered and connected by NG. The electrochemical performance confirms that LiFePO₄ modified by 20% N-doped graphene (named LFP/NG-4) displays a perfect specific capacity of 166.6 mAh·g^?1 at a rate of 0.2C and can reach 125 mAh·g^?1 at a rate of 5 C. Electrochemical impedance spectroscopy (EIS) results illustrate that the charge transfer resistance value of the LFP/NG-4 composite is only 58.6 Ω, which is very low compared with LiFePO₄. Cyclic voltammetry (CV) tests indicate that the addition of 20% N-doped graphene can effectively reduce electrode polarization and improve reversibility. The LFP/NG-4 composite with a three-dimensional conductive network structure can be regarded as a promising cathode material for Li-ion batteries.     

Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.     

Tunable multicolor upconversion luminescence of Yb3+ sensitized Na3La(VO4)2 crystals

Multicolor upconversion luminescence materials show significantly applications in materials science. In this paper, the novel Yb³⁺-sensitized Na₃La(VO₄)₂ upconversion luminescence crystals are synthesized by the solid-state reaction method. Three primary colors upconversion luminescence are successfully achieved in Na₃La(VO₄)₂:Yb³⁺,Tm³⁺, Na₃La(VO₄)₂:Yb³⁺,Er³⁺, and Na₃La(VO₄)₂:Yb³⁺,Ho³⁺ crystals excited by the single 980 nm LD. Multicolor upconversion luminescence can be obtained by simply adjusting the combination ratios of these three samples. Luminescence mechanisms of the Yb³⁺-sensitized system are discussed in detail. In the Na₃La(VO₄)₂ host material, the Yb³⁺/Ho³⁺ codoped system exhibits unusual red upconversion luminescence based on the short decay time of Ho³⁺ ion ⁵I₆ level, which provides the possibility of three primary color luminescence under 980 nm excitation.     

The P-graph approach for systematic synthesis of wastewater treatment networks

Wastewater treatment consists of three or four sequential stages: preliminary, primary, secondary, and tertiary. Each stage can comprise multiple alternative technologies that can perform the same tasks with different efficiencies, operating times, and costs. Thus, we propose a systematic approach for designing wastewater treatment networks by utilizing principles of mathematical modeling and generating an exhaustive enumeration of all the possible technologies and their connections during the early stages of designing a treatment facility. Some of these structures are nonintuitive and include recycling, reprocessing, bypasses, and multiple technologies in parallel or series to remove the same contaminant. The nonintuitive structures with multiple technologies may provide a measure of resilience compared to typical heuristic designs. Thus, the combination of P-graph methodology and the sequence of treatment technologies predicted via the optimization algorithm from the maximal structure is based on holistic considerations and does not lead to suboptimal solutions.