Photoinduced, Redox-Neutral Decyanative and Defluorinative Phosphination of (Hetero)Arenes.

Triarylphosphines play a crucial role in organic synthesis as versatile components serving as ligands, catalysts, and reactants. This study introduces a metal-free, visible-light-induced method for the cross-coupling of cyanopyridines or polyfluoroarenes with diarylphosphines. This approach facilitates the formation of C(sp2)-P bonds through redox-neutral decyanative or defluorinative process, enabling the convenient synthesis of diverse triarylphosphines.

[Effect of Meteorological Elements and Air Pollutants on Ozone in Yinchuan City Park].

To examine the underlying determinants of ozone （O3） in Yinchuan's urban park during varying seasons and to ascertain the role played by meteorological events and air contaminants in influencing O3 concentrations at high altitudes, data on O3, meteorological factors, and air pollutants were collected through prolonged positional observations carried out at the Ningxia Yinchuan National Urban Ecosystem Research Station. Pearson correlation analysis and a structural equation model were utilized to investigate the spatio-temporal distribution patterns, trends, and the primary factors influencing O3. The findings demonstrated a notable seasonal variability in O3 levels in Yinchuan's urban park, displaying an "unimodal type" with the O3 concentration peaking in summer （131.18 µg·m-3） and bottoming out in winter （71.45 µg·m-3）. Among the meteorological factors, the highest impact on O3 was attributed to temperature and wind speed （temperature mainly through direct effects and wind speed mainly through indirect effects）. Conversely, air pollutants such as NOx and SO2 greatly affected O3 primarily through direct effects. Wind speed was identified as the primary influencing factor on O3 during spring and summer, potentially contributing 29% and 24.7%, respectively. Conversely, NO2 was implicated as the primary factor during autumn and winter, with an estimated contribution of 26.6% and 29.7%, respectively. Thus, a structural equation model can efficiently reveal the primary determinants behind O3 variations throughout various seasons, which could furnish a scientifically rigorous foundation and technical aid for mitigating and managing O3 levels in high-altitude regions.

A Predictive Model for Initial Platinum-Based Chemotherapy Efficacy in Patients with Postoperative Epithelial Ovarian Cancer Using Tissue-Derived Small Extracellular Vesicles.

Epithelial ovarian cancer (EOC) is an often-fatal malignancy marked by the development of resistance to platinum-based chemotherapy. Thus, accurate prediction of platinum drug efficacy is crucial for strategically selecting postoperative interventions to mitigate the risks associated with suboptimal therapeutic outcomes and adverse effects. Tissue-derived extracellular vesicles (tsEVs), in contrast to their plasma counterparts, have emerged as a powerful tool for examining distinctive attributes of EOC tissues. In this study, 4D data-independent acquisition (DIA) proteomic sequencing was performed on tsEVs obtained from 58 platinum-sensitive and 30 platinum-resistant patients with EOC. The analysis revealed a notable enrichment of differentially expressed proteins that were predominantly associated with immune-related pathways. Moreover, pivotal immune-related proteins (IRPs) were identified by LASSO regression. These factors, combined with clinical parameters selected through univariate logistic regression, were used for the construction of a model employing multivariate logistic regression. This model integrated three tsEV IRPs, CCR1, IGHV_35 and CD72, with one clinical parameter, the presence of postoperative residual lesions. Thus, this model could predict the efficacy of initial platinum-based chemotherapy in patients with EOC post-surgery, providing prognostic insights even before the initiation of chemotherapy.

Electrolytes for Aluminum-Ion Batteries: Progress and Outlook.

Aluminum-ion batteries (AIBs) are promising electrochemical energy storage sources because of their high theoretical specific capacity, light weight, zero pollution, safety, inexpensiveness, and abundant resources. These theoretical advantages have recently made AIBs a research hotspot. However, electrolyte-related issues significantly limit their commercialization. The electrolyte choices for AIBs are significantly limited, and most of the available options do not facilitate the Al3+/Al three-electron transfer reaction. Thus, this review presents an overview of recent advances in electrolytes and modification strategies for AIBs to clarify the limitations of existing AIB electrolytes and offer guidance for improving their performance. Furthermore, herein, the advantages, limitations and possible solutions for each electrolyte are discussed, after which the future of AIB electrolytes is envisioned.

Design of Mn-based nanozymes with multiple enzyme-like activities for identification/quantification of glyphosate and green transformation of organophosphorus.

A Mn-based nanozyme, Mn-uNF/Si, with excellent alkali phosphatase-like activity was designed by in-situ growth of ultrathin Mn-MOF on the surface of silicon spheres, and implemented as an effective solid Lewis-Brønsted acid catalyst for broad-spectrum dephosphorylation. H218O-mediated GC-MS studies confirmed the cleavage sites and the involvement of H2O in the new bonds. DRIFT NH3-IR and in-situ ATR-FTIR confirmed the coexistence of Lewis-Brønsted acid sites and the adjustment of adsorption configurations at the interfacial sites. In addition, a green transformation route of "turning waste into treasure" was proposed for the first time ("OPs→PO43-→P food additive") using edible C. reinhardtii as a transfer station. By alkali etching of Mn-uNF/Si, a nanozyme Mn-uNF with laccase-like activity was obtained. Intriguingly, glyphosate exhibits a laccase-like fingerprint-like response (+,-) of Mn-uNF, and a non-enzyme amplified sensor was thus designed, which shows a good linear relationship with Glyp in a wide range of 0.49-750 µM, with a low LOD of 0.61 µM, as well as high selectivity and anti-interference ability under the co-application of phosphate fertilizers and multiple pesticides. This work provides a controllable methodology for the design of bifunctional nanozymes, which sheds light on the highly efficient green transformation of OPs, and paves the way for the selective recognition and quantification of glyphosate. Mechanistically, we also provided deeper insights into the structure-activity relationship at the atomic scale.

RAD51B-AS1 promotes the malignant biological behavior of ovarian cancer through upregulation of RAD51B. / RAD51B-AS1通过上调RAD51B促进卵巢癌的恶性生物学行为.

Long non-coding RNAs (lncRNAs) play an indispensable role in the occurrence and development of ovarian cancer (OC). However, the potential involvement of lncRNAs in the progression of OC is largely unknown. To investigate the detailed roles and mechanisms ofRAD51 homolog B-antisense 1 (RAD51B-AS1), a novel lncRNA in OC, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to verify the expression of RAD51B-AS1. Cellular proliferation, metastasis, and apoptosis were detected using the cell counting kit-8 (CCK-8), colony-formation, transwell, and flow cytometry assays. Mouse xenograft models were established for the detection of tumorigenesis. The results revealed that RAD51B-AS1 was significantly upregulated in a highly metastatic human OC cell line and OC tissues. RAD51B-AS1 significantly increased the proliferation and metastasis of OC cells and enhanced their resistance to anoikis. Biogenetics prediction analysis revealed that the only target gene of RAD51B-AS1 was RAD51B. Subsequent gene function experiments revealed that RAD51B exerts the same biological effects as RAD51B-AS1. Rescue experiments demonstrated that the malignant biological behaviors promoted by RAD51B-AS1 overexpression were partially or completely reversed by RAD51B silencing in vitro and in vivo. Thus, RAD51B-AS1 promotes the malignant biological behaviors of OC and activates the protein kinase B (Akt)/B cell lymphoma protein-2 (Bcl-2) signaling pathway, and these effects may be associated with the positive regulation of RAD51B expression. RAD51B-AS1 is expected to serve as a novel molecular biomarker for the diagnosis and prediction of poor prognosis in OC, and as a potential therapeutic target for disease management.

Self-Assembled Nanocomposite DOX/TPOR4@CB[7]4 for Enhanced Synergistic Photodynamic Therapy and Chemotherapy in Neuroblastoma.

DOX/TPOR4@CB[7]4 was synthesized via self-assembly, and its physicochemical properties and ability to generate reactive oxygen species (ROS) were evaluated. The impact of photodynamic therapy on SH-SY5Y cells was assessed using the MTT assay, while flow cytometry analysis was employed to detect cell apoptosis. Confocal laser scanning microscopy was utilized to observe the intracellular distribution of DOX/TPOR4@CB[7]4 in SH-SY5Y cells. Additionally, fluorescence imaging of DOX/TPOR4@CB[7]4 in nude mice bearing SH-SY5Y tumors and examination of the combined effects of photodynamic and chemical therapies were conducted. The incorporation of CB[7] significantly enhanced the optical properties of DOX/TPOR4@CB[7]4, resulting in increased ROS production and pronounced toxicity towards SH-SY5Y cells. Moreover, both the apoptotic and mortality rates exhibited significant elevation. In vivo experiments demonstrated that tumor growth inhibition was most prominent in the DOX/TPOR4@CB[7]4 group. π-π interactions facilitated the binding between DOX and photosensitizer TPOR, with TPOR's naphthalene hydrophilic groups encapsulated within CB[7]'s cavity through host-guest interactions with CB[7]. Therefore, CB[7] can serve as a nanocarrier to enhance the combined application of chemical therapy and photodynamic therapy, thereby significantly improving treatment efficacy against neuroblastoma tumors.

A Review of High-Temperature Aerogels: Composition, Mechanisms, and Properties.

High-temperature aerogels have garnered significant attention as promising insulation materials in various industries such as aerospace, automotive manufacturing, and beyond, owing to their remarkable thermal insulation properties coupled with low density. With advancements in manufacturing techniques, the thermal resilience of aerogels has considerable improvements. Notably, polyimide-based aerogels can endure temperatures up to 1000 °C, zirconia-based aerogels up to 1300 °C, silica-based aerogels up to 1500 °C, alumina-based aerogels up to 1800 °C, and carbon-based aerogels can withstand up to 2500 °C. This paper systematically discusses recent advancements in the thermal insulation performance of these five materials. It elaborates on the temperature resistance of aerogels and elucidates their thermal insulation mechanisms. Furthermore, it examines the impact of doping elements on the thermal conductivity of aerogels and consolidates various preparation methods aimed at producing aerogels capable of withstanding temperatures. In conclusion, by employing judicious composition design strategies, it is anticipated that the maximum tolerance temperature of aerogels can surpass 2500 °C, thus opening up new avenues for their application in extreme thermal environments.

High-fat diet consumption promotes adolescent neurobehavioral abnormalities and hippocampal structural alterations via microglial overactivation accompanied by an elevated serum free fatty acid concentration.

Mounting evidence suggests that high-fat diet (HFD) consumption increases the risk for depression, but the neurophysiological mechanisms involved remain to be elucidated. Here, we demonstrated that HFD feeding of C57BL/6J mice during the adolescent period (from 4 to 8 weeks of age) resulted in increased depression- and anxiety-like behaviors concurrent with changes in neuronal and myelin structure in the hippocampus. Additionally, we showed that hippocampal microglia in HFD-fed mice assumed a hyperactive state concomitant with increased PSD95-positive and myelin basic protein (MBP)-positive inclusions, implicating microglia in hippocampal structural alterations induced by HFD consumption. Along with increased levels of serum free fatty acids (FFAs), abnormal deposition of lipid droplets and increased levels of HIF-1α protein (a transcription factor that has been reported to facilitate cellular lipid accumulation) within hippocampal microglia were observed in HFD-fed mice. The use of minocycline, a pharmacological suppressor of microglial overactivation, effectively attenuated neurobehavioral abnormalities and hippocampal structural alterations but barely altered lipid droplet accumulation in the hippocampal microglia of HFD-fed mice. Coadministration of triacsin C abolished the increases in lipid droplet formation, phagocytic activity, and ROS levels in primary microglia treated with serum from HFD-fed mice. In conclusion, our studies demonstrate that the adverse influence of early-life HFD consumption on behavior and hippocampal structure is attributed at least in part to microglial overactivation that is accompanied by an elevated serum FFA concentration and microglial aberrations represent a potential preventive and therapeutic target for HFD-related emotional disorders.

Deep Reinforcement Learning for Solving Vehicle Routing Problems With Backhauls.

The vehicle routing problem with backhauls (VRPBs) is a challenging problem commonly studied in computer science and operations research. Featured by linehaul (or delivery) and backhaul (or pickup) customers, the VRPB has broad applications in real-world logistics. In this article, we propose a neural heuristic based on deep reinforcement learning (DRL) to solve the traditional and improved VRPB variants, with an encoder-decoder structured policy network trained to sequentially construct the routes for vehicles. Specifically, we first describe the VRPB based on a graph and cast the solution construction as a Markov decision process (MDP). Then, to identify the relationship among the nodes (i.e., linehaul and backhaul customers, and the depot), we design a two-stage attention-based encoder, including a self-attention and a heterogeneous attention for each stage, which could yield more informative representations of the nodes so as to deliver high-quality solutions. The evaluation on the two VRPB variants reveals that, our neural heuristic performs favorably against both the conventional and neural heuristic baselines on randomly generated instances and benchmark instances. Moreover, the trained policy network exhibits a desirable capability of generalization to various problem sizes and distributions.

Recent development of manganese dioxide-based materials as zinc-ion battery cathode.

The development of advanced cathode materials for zinc-ion batteries (ZIBs) is a critical step in building large-scale green energy conversion and storage systems in the future. Manganese dioxide is one of the most well-studied cathode materials for zinc-ion batteries due to its wide range of crystal forms, cost-effectiveness, and well-established synthesis processes. This review describes the recent research progress of manganese dioxide-based ZIBs, and the reaction mechanism, electrochemical performance, and challenges of manganese dioxide-based ZIBs materials are systematically introduced. Optimization strategies for high-performance manganese dioxide-based materials for ZIBs with different crystal forms, nanostructures, morphologies, and compositions are discussed. Finally, the current challenges and future research directions of manganese dioxide-based cathodes in ZIBs are envisaged.

Water/Light Multiregulated Supramolecular Polypseudorotaxane Gel with Switchable Room-Temperature Phosphorescence.

Water/light regulated room-temperature phosphorescence (RTP) of polypseudorotaxane supramolecular gel is constructed by threading the poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG) chain with the bromoaromatic aldehyde into mono-(6-ethylenediamine-6-deoxygenated)-ß-cyclodextrin (ECD) cavities and further assembling with negatively charged Laponite XLG (CNS) and diarylethene derivative (DAE) through electrostatic interaction. This hydrogel exhibits significant blue fluorescence emission; instead, after lyophilization to xerogel, the system exhibits both blue fluorescence and yellow RTP based on the rigid network structure of the xerogel, which restricts the vibration of the phosphor and suppresses the nonradiative relaxation process. Interestingly, the addition of excess ECDs to the gel system can enhance the RTP emission. Furthermore, the reversible luminescence behavior can be adjusted by the photoresponsive isomerism of DAE and humidity. This polypseudorotaxane supramolecular gel system provides a novel strategy for constructing tunable RTP materials.

Recent Advances in Graphene-Based Materials for Zinc-Ion Batteries.

Zinc-ion batteries (ZIBs) are a promising alternative for large-scale energy storage due to their advantages of environmental protection, low cost, and intrinsic safety. However, the utilization of their full potential is still hindered by the sluggish electrode reaction kinetics, poor structural stability, severe Zn dendrite growth, and narrow electrochemical stability window of the whole battery. Graphene-based materials with excellent physicochemical properties hold great promise for addressing the above challenges foe ZIBs. In this review, the energy storage mechanisms and challenges faced by ZIBs are first discussed. Key issues and recent progress in design strategies for graphene-based materials in optimizing the electrochemical performance of ZIBs (anode, cathode, electrolyte, separator and current collector) are then discussed. Finally, some potential challenges and future research directions of graphene-based materials in high-performance ZIBs are proposed for practical applications.

Rapid Detection of SARS-CoV-2 in Clinical and Environmental Samples via a Resonant Cavity SERS Platform within 20 min.

The coronavirus disease 2019 (COVID-19) epidemic has given a warning that it is important to explore the rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in clinical specimens or environmental samples for public health strategies and future variants. The surface-enhanced Raman spectroscopy (SERS) technique was demonstrated to achieve this goal. However, the consistency of signals originating from the poor compatibility of virions with SERS hotspots remains a key scientific challenge for the practical applications of SERS. Herein, we develop a SERS platform for the ultrasensitive and rapid detection of SARS-CoV-2 antigen within 20 min by the combination of a highly consistent SERS substrate and a supervised deep learning algorithm. A V-shaped resonant cavity array (VRC) substrate was fabricated to trap SARS-CoV-2 virions in the periodic V cavity array and stimulate the integral SERS signal of the virus via a resonance coupling effect. Benefiting from the unique architecture of the VRC substrate, we were able to directly detect the SARS-CoV-2 virus with high sensitivity and high consistency. These excellent performances enabled us to identify five different kinds of SARS-CoV-2 variants and detect SARS-CoV-2 from clinical and environmental samples with high accuracies.

[Analysis of a Chinese pedigree affected with Meckel syndrome due to variants of TMEM67 gene].

OBJECTIVE: To explore the genetic etiology for a Chinese pedigree affected with Meckel syndrome. METHODS: A pedigree with a history of three consecutive adverse pregnancies which presented at the First Affiliated Hospital of Zhengzhou University on August 31, 2017 was selected as the study subject. Clinical data of the pedigree were collected. High-throughput sequencing was carried out to screen for variants of ciliopathy-related genes in the third fetus following induced abortion, and candidate variant was verified by Sanger sequencing. RESULTS: The first pregnancy of the couple had ended as spontaneous abortion, whilst the fetus of the second pregnancy was suspected for having ciliopathy, though no genetic testing was carried out following elected abortion. The fetus of the third pregnancy was suspected for having ciliopathy, and high-throughput sequencing and Sanger sequencing had shown that the fetus had harbored compound heterozygous variants of the TMEM67 gene, including c.978+1G>A from the father and c.1288G>C (p.D430H) from the mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.978+1G>A was classified as a pathogenic variant (PVS1+PM2_Supporting+PP5), whilst the newly discovered c.1288G>C (p.D430H) was classified as a likely pathogenic variant (PM2_Supporting+PM3+PM5+PP3). CONCLUSION: The c.978+1G>A and c.1288G>C (p.D430H) compound heterozygous variants of the TMEM67 gene probably underlay the three consecutive adverse pregnancies suspected for ciliopathy in this pedigree. The discovery of c.1288G>C (p.D430H) has also expanded the mutational spectrum of the TMEM67 gene.

Photocontrolled Reversibly Chiral-Ordered Assembly Based on Cucurbituril.

Chirality transfer and regulation, accompanied by morphology transformation, arouse widespread interest for application in materials and biological science. Here, a photocontrolled supramolecular chiral switch is fabricated from chiral diphenylalanine (l-Phe-l-Phe, FF) modified with naphthalene (2), achiral dithienylethene (DTE) photoswitch (1), and cucurbit[8]uril (CB[8]). Chirality transfer from the chiral FF moiety of 2 to a charge-transfer (CT) heterodimer consisting of achiral guest 1 and achiral naphthalene (NP) in 2 has been unprecedented achieved via the encapsulation of CB[8]. On the contrary, chirality transfer from chiral FF to NP cannot be conducted in only guest 2. Crucially, induced circular dichroism of the heterodimer can be further modulated by distinct light, attributing to reversible photoisomerization of the DTE. Meanwhile, topological nanostructures are changed from one-dimensional (1D) nanofibers to two-dimensional (2D) nanosheets in the orderly assembling process of the heterodimer, which further achieved reversible interconversion between 2D nanosheets and 1D nanorods with tunable-induced chirality stimulated by diverse light.

Voluntary wheel exercise ameliorates cognitive impairment, hippocampal neurodegeneration and microglial abnormalities preceded by demyelination in a male mouse model of noise-induced hearing loss.

Acquired peripheral hearing loss (APHL) in midlife has been identified as the greatest modifiable risk factor for dementia; however, the pathophysiological neural mechanisms linking APHL with an increased risk of dementia remain to be elucidated. Here, in an adult male mouse model of noise-induced hearing loss (NIHL), one of the most common forms of APHL, we demonstrated accelerated age-related cognitive decline and hippocampal neurodegeneration during a 6-month follow-up period, accompanied by progressive hippocampal microglial aberrations preceded by immediate-onset transient elevation in serum glucocorticoids and delayed-onset sustained myelin disruption in the hippocampus. Pretreatment with the glucocorticoid receptor antagonist RU486 before stressful noise exposure partially mitigated the early activation of hippocampal microglia, which were present at 7 days post noise exposure (7DPN), but had no impact on later microglial aberrations, hippocampal neurodegeneration, or cognitive decline exhibited at 1 month post noise exposure (1MPN). One month of voluntary wheel exercise following noise exposure barely affected either the hearing threshold shift or hippocampal myelin changes but effectively countered cognitive impairment and the decline in hippocampal neurogenesis in NIHL mice at 1MPN, paralleled by the normalization of microglial morphology, which coincided with a reduction in microglial myelin inclusions and a restoration of microglial hypoxia-inducible factor-1α (HIF1α) expression. Our results indicated that accelerated cognitive deterioration and hippocampal neuroplastic decline following NIHL are most likely driven by the maladaptive response of hippocampal microglia to myelin damage secondary to hearing loss, and we also demonstrated the potential of voluntary physical exercise as a promising and cost-effective strategy to alleviate the detrimental impact of APHL on cognitive function and thus curtail the high and continuously increasing global burden of dementia. Furthermore, the findings of the present study highlight the contribution of myelin debris overload to microglial malfunction and identify the microglial HIF1α-related pathway as an attractive candidate for future comprehensive investigation to obtain a more definitive picture of the underlying mechanisms linking APHL and dementia.

Effect of light intensity on negative air ion under phytotron control.

Negative air ion (NAI) is an important index for measuring air quality and has been widely recognized to be influenced by photosynthesis processes. However, vegetation type and light intensity are also known to impact NAI, contributing to significant uncertainties in the relationship between light and NAI. In this paper, we selected Pinus bungeana, Platycladus orientalis and Buxus sinica as research subjects and obtained their NAI, light intensity, and meteorological data through synchronous observation under the relatively stable condition of the phytotron. We analyzed the change characteristics of NAI and the difference of NAI production ability in needle and broadleaf vegetation under different light intensities. Finally, we determined the relationship and underlying mechanism governing light intensity and NAI using diverse tree species. The results showed that the influence of light on NAI was significant. In the environment without vegetation, the influence of different light intensities on NAI was not significant, and the mean NAI concentration was 310 ions·cm-3. Conversely, in the presence of vegetation, NAI showed a "single-peak" trend with increasing light intensity. The NAI concentration of the three tree species was significantly higher than under different light intensities when vegetation was not present. The NAI promoting ability of P. bungeana was the highest (675 ions·cm-3), followed by P. orientalis (478 ions·cm-3) and B. sinica (430 ions·cm-3), which increased by 117.5%, 53.9% and 38.6% compared to the environment without vegetation. The NAI growth rate was significantly different between needle and broadleaf vegetation based on the specific tridimensional green biomass. Additionally, the NAI growth rates of P. bungeana and P. orientalis were 647 and 295 ions·cm-3·m-3, respectively, which were 3.06 and 1.39 times that of B. sinica (211 ions·cm-3·m-3). The piecewise equation fitting effect of NAI and light intensity was better for different tree species, the determination coefficients (R2) of P. bungeana, P. orientalis and B. sinica were 0.926, 0.916 and 0.880, and the root mean square errors (RMSE) were 7.157, 6.008 and 5.389 ion·cm-3, respectively. Altogether, our study provides a theoretical basis as well as technical support for the construction of healthy vegetation stands, the selection of preferred tree species, and the optimization of vegetation models, and promotes air quality and the provision of ecosystem functions and services.

Prolonged Early Exposure to a High-Fat Diet Augments the Adverse Effects on Neurobehavior and Hippocampal Neuroplasticity: Involvement of Microglial Insulin Signaling.

High-fat diet (HFD) consumption may contribute to the high prevalence of cognitive-emotional issues in modern society. Mice fed a HFD for a prolonged period develop more severe neurobehavioral disturbances when first exposed to a HFD in the juvenile period than in adulthood, suggesting an initial age-related difference in the detrimental effects of long-term HFD feeding. However, the mechanism underlying this difference remains unclear. Here, male C57BL/6J mice initially aged 4 (IA4W) or 8 (IA8W) weeks were fed a control diet (CD) or HFD for 6 months and then subjected to metabolic, neurobehavioral, and histomorphological examinations. Although the detrimental effects of long-term HFD feeding on metabolism and neurobehavior were observed in mice of both ages, IA4W-HFD mice showed significant cognitive inflexibility accompanied by significantly greater levels of anxiety-like behavior than age-matched controls. Hippocampal neuroplasticity and microglial phenotype were altered by HFD feeding, whereas significant morphological alterations were more frequently observed in IA4W-HFD mice than in IA8W-HFD mice. Additionally, significantly increased hippocampal microglial engulfment of postsynaptic proteins and elevated phospho-insulin-receptor levels were observed in IA4W-HFD, but not in IA8W-HFD, mice. These findings suggest that aberrant microglia-related histomorphological changes in the hippocampus underlie the exacerbated detrimental neurobehavioral effects of prolonged early HFD exposure and indicate that enhanced insulin signaling might drive microglial dysfunction after prolonged early HFD exposure.

Discovery of Pyxinol Amide Derivatives Bearing Amino Acid Residues as Nonsubstrate Allosteric Inhibitors of P-Glycoprotein-Mediated Multidrug Resistance.

Nonsubstrate allosteric inhibitors of P-glycoprotein (Pgp), which are considered promising modulators for overcoming multidrug resistance (MDR), are relatively unknown. Herein, we designed and synthesized amino acids bearing amide derivatives of pyxinol, the main ginsenoside metabolite produced by the human liver, and examined their MDR reversal abilities. A potential nonsubstrate inhibitor (7a) was identified to undergo high-affinity binding to the putative allosteric site of Pgp at the nucleotide-binding domains. Subsequent assays confirmed that 7a (25 µM) was able to suppress both basal and verapamil-stimulated Pgp-ATPase activities (inhibition rates of 87 and 60%, respectively) and could not be pumped out by Pgp, indicating that it was a rare nonsubstrate allosteric inhibitor. Moreover, 7a interfered with Pgp-mediated Rhodamine123 efflux while exhibiting high selectivity for Pgp. Notably, 7a also markedly enhanced the therapeutic efficacy of paclitaxel, with a tumor inhibition ratio of 58.1%, when used to treat nude mice bearing KBV xenograft tumors.