Design, synthesis, and biological evaluation of RSL3-based GPX4 degraders with hydrophobic tags.

Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation, during which glutathione peroxidase 4 (GPX4) plays an essential role and is well-recognized as a promising therapeutic target for cancer treatment. Although some GPX4 degradation molecules have been developed to induce ferroptosis, the discovery of GPX4 degraders with hydrophobic tagging (HyT) as an innovative approach is more challenging. Herein, we designed and synthesized a series of HyT degraders by linking the GPX4 inhibitor RSL3 with a hydrophobic and bulky group of adamantane. Among them, compound R8 is a potent degrader (DC50, 24h = 0.019 µM) which can effectively degrade GPX4 in a dose- and time-dependent manner. Furthermore, compound R8 exhibited superior in vitro antitumor potency against HT1080 and MDA-MB-231 cell lines with IC50 values of 24 nM and 32 nM respectively, which are 4 times more potent than parental compound RSL3. Mechanistic investigation evidenced that R8 consumes GPX4 protein mainly through the ubiquitin proteasome (UPS) and enables to induce the accumulation of LPO, thereby triggering ferroptosis. Our work presented the novel GPX4 degrader of R8 by HyT strategy, and provided a promising pathway of degradation agents for the treatment of ferroptosis relevant diseases.

Design and Discovery of New Collagen V-Derived FGF2-Blocking Natural Peptides Inhibiting Lung Squamous Cell Carcinoma In Vitro and In Vivo.

Aberrant FGF2/FGFR signaling is implicated in lung squamous cell carcinoma (LSCC), posing treatment challenges due to the lack of targeted therapeutic options. Designing drugs that block FGF2 signaling presents a promising strategy different from traditional kinase inhibitors. We previously reported a ColVα1-derived fragment, HEPV (127AA), that inhibits FGF2-induced angiogenesis. However, its large size may limit therapeutic application. This study combines rational peptide design, molecular dynamics simulations, knowledge-based prediction, and GUV and FRET assays to identify smaller peptides with FGF2-blocking properties. We synthesized two novel peptides, HBS-P1 (45AA) and HBS-P2 (66AA), that retained the heparin-binding site. Both peptides demonstrated anti-LSCC and antiangiogenesis properties in cell viability and microvessel network induction assays. In two LSCC subcutaneous models, HBS-P1, with its affinity for FGF2 and enhanced penetration ability, demonstrated substantial therapeutic potential without apparent toxicities. Our study provides the first evidence supporting the development of collagen V-derived natural peptides as FGF2-blocking agents for LSCC treatment.

How does ferrocene correlate with ferroptosis? Multiple approaches to explore ferrocene-appended GPX4 inhibitors as anticancer agents.

Ferroptosis has emerged as a form of programmed cell death and exhibits remarkable promise for anticancer therapy. However, it is challenging to discover ferroptosis inducers with new chemotypes and high ferroptosis-inducing potency. Herein, we report a new series of ferrocenyl-appended GPX4 inhibitors rationally designed in a "one stone kills two birds" strategy. Ferroptosis selectivity assays, GPX4 inhibitory activity and CETSA experiments validated the inhibition of novel compounds on GPX4. In particular, the ROS-related bioactivity assays highlighted the ROS-inducing ability of 17 at the molecular level and their ferroptosis enhancement at the cellular level. These data confirmed the dual role of ferrocene as both the bioisostere motif maintaining the inhibition capacity of certain molecules with GPX4 and also as the ROS producer to enhance the vulnerability to ferroptosis of cancer cells, thereby attenuating tumor growth in vivo. This proof-of-concept study of ferrocenyl-appended ferroptosis inducers via rational design may not only advance the development of ferroptosis-based anticancer treatment, but also illuminate the multiple roles of the ferrocenyl component, thus opening the way to novel bioorganometallics for potential disease therapies.

APPROACH: Sensitive Detection of Exosomal Biomarkers by Aptamer-Mediated Proximity Ligation Assay and Time-Resolved Förster Resonance Energy Transfer.

Exosomal biomarker detection holds great importance in the field of in vitro diagnostics, offering a non-invasive and highly sensitive approach for early disease detection and personalized treatment. Here, we proposed an "APPROACH" strategy, combining aptamer-mediated proximity ligation assay (PLA) with rolling circle amplification (RCA) and time-resolved Förster resonance energy transfer (TR-FRET) for the sensitive and semi-homogenous detection of exosomal biomarkers. PLA probes consisted of a cholesterol-conjugated oligonucleotide, which anchored to the membrane of an exosome, and a specific aptamer oligonucleotide that recognized a target protein of the exosome; the proximal binding of pairs of PLA probes to the same exosome positioned the oligonucleotides in the vicinity of each other, guiding the hybridization and ligation of two subsequently added backbone and connector oligonucleotides to form a circular DNA molecule. Circular DNA formed from PLA underwent rolling circle amplification (RCA) for signal amplification, and the resulting RCA products were subsequently quantified by TR-FRET. The limits of detection provided by APPROACH for the exosomal biomarkers CD63, PD-L1, and HER2 were 0.46 ng∙µL-1, 0.77 ng∙µL-1, and 1.1 ng∙µL-1, respectively, demonstrating excellent analytical performance with high sensitivity and quantification accuracy. Furthermore, the strategy afforded sensitive detection of exosomal CD63 with a LOD of 1.56 ng∙µL-1 in complex biological matrices, which underscored its anti-interference capability and potential for in vitro detection. The proposed strategy demonstrates wide-ranging applicability in quantifying diverse exosomal biomarkers while exhibiting robust analytical characteristics, including high sensitivity and accuracy.

MiRNA-145-5p inhibits gastric cancer progression via the serpin family E member 1- extracellular signal-regulated kinase-1/2 axis.

BACKGROUND: MicroRNAs (miRNAs) regulate gene expression and play a critical role in cancer physiology. However, there is still a limited understanding of the function and regulatory mechanism of miRNAs in gastric cancer (GC). AIM: To investigate the role and molecular mechanism of miRNA-145-5p (miR145-5p) in the progression of GC. METHODS: Real-time polymerase chain reaction (RT-PCR) was used to detect miRNA expression in human GC tissues and cells. The ability of cancer cells to migrate and invade was assessed using wound-healing and transwell assays, respectively. Cell proliferation was measured using cell counting kit-8 and colony formation assays, and apoptosis was evaluated using flow cytometry. Expression of the epithelial-mesenchymal transition (EMT)-associated protein was determined by Western blot. Targets of miR-145-5p were predicated using bioinformatics analysis and verified using a dual-luciferase reporter system. Serpin family E member 1 (SERPINE1) expression in GC tissues and cells was evaluated using RT-PCR and immunohistochemical staining. The correlation between SERPINE1 expression and overall patient survival was determined using Kaplan-Meier plot analysis. The association between SERPINE1 and GC progression was also tested. A rescue experiment of SERPINE1 overexpression was conducted to verify the relationship between this protein and miR-145-5p. The mechanism by which miR-145-5p influences GC progression was further explored by assessing tumor formation in nude mice. RESULTS: GC tissues and cells had reduced miR-145-5p expression and SERPINE1 was identified as a direct target of this miRNA. Overexpression of miR-145-5p was associated with decreased GC cell proliferation, invasion, migration, and EMT, and these effects were reversed by forcing SERPINE1 expression. Kaplan-Meier plot analysis revealed that patients with higher SERPINE1 expression had a shorter survival rate than those with lower SERPINE1 expression. Nude mouse tumorigenesis experiments confirmed that miR-145-5p targets SERPINE1 to regulate extracellular signal-regulated kinase-1/2 (ERK1/2). CONCLUSION: This study found that miR-145-5p inhibits tumor progression and is expressed in lower amounts in patients with GC. MiR-145-5p was found to affect GC cell proliferation, migration, and invasion by negatively regulating SERPINE1 levels and controlling the ERK1/2 pathway.

Activation of the MEK/ERK Pathway Mediates the Inhibitory Effects of Silvestrol on Nasopharyngeal Carcinoma Cells via RAP1A, HK2, and GADD45A.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with Epstein-Barr virus (EBV) infection. Chemoradiotherapy is the mainstream treatment for locally advanced NPC, and chemotherapeutic drugs are an indispensable part of NPC treatment. However, the toxic side-effects of chemotherapy drugs limit their therapeutic value, and new chemotherapy drugs are urgently needed for NPC. Silvestrol, an emerging natural plant anticancer molecule, has shown promising antitumor activity in breast cancer, melanoma, liver cancer, and other tumor types by promoting apoptosis in cancer cells to a greater extent than in normal cells. However, the effects of silvestrol on NPC and its possible molecular mechanisms have yet to be fully explored. METHODS: Cell counting kit-8 (CCK-8), cell scratch, flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), and Western blot (WB) assays were used to evaluate the effects of silvestrol on the cell viability, cell cycle, apoptosis, and migration of NPC cells. RNA sequencing (RNA-Seq) was used to study the effect of extracellular signal-regulated kinase (ERK) inhibitors on the cell transcriptome, and immunohistochemistry (IHC) to assess protein expression levels in patient specimens. RESULTS: Silvestrol inhibited cell migration and DNA replication of NPC cells, while promoting the expression of cleaved caspase-3, apoptosis, and cell cycle arrest. Furthermore, silvestrol altered the level of ERK phosphorylation. The ERK-targeted inhibitor LY3214996 attenuated silvestrol-mediated inhibition of NPC cell proliferation but not migration. Analysis of RNA-Seq data and WB were used to identify and validate the downstream regulatory targets of silvestrol. Expression of GADD45A, RAP1A, and hexokinase-II (HK2) proteins was inhibited by silvestrol and LY3214996. Finally, IHC revealed that GADD45A, RAP1A, and HK2 protein expression was more abundant in cancer tissues than in non-tumor tissues. CONCLUSIONS: Silvestrol inhibits the proliferation of NPC cells by targeting ERK phosphorylation. However, the inhibition of NPC cell migration by silvestrol was independent of the Raf-MEK-ERK pathway. RAP1A, HK2, and GADD45A may be potential targets for the action of silvestrol.

Comprehensive characterization of immunogenic cell death in acute myeloid leukemia revealing the association with prognosis and tumor immune microenvironment.

BACKGROUND: This study aimed to explore the clinical significance of immunogenic cell death (ICD) in acute myeloid leukemia (AML) and its relationship with the tumor immune microenvironment characteristics. It also aimed to provide a potential perspective for bridging the pathogenesis of AML and immunological research, and to provide a theoretical basis for precise individualized treatment of AML patients. METHODS: Firstly, we identified two subtypes associated with ICD by consensus clustering and explored the biological enrichment pathways, somatic mutations, and tumor microenvironment landscape between the ICD subtypes. Additionally, we developed and validated a prognostic model associated with ICD-related genes. Finally, we conducted a preliminary exploration of the construction of disease regulatory networks and prediction of small molecule drugs based on five signature genes. RESULTS: Differentially expressed ICD-related genes can distinguish AML into subgroups with significant differences in clinical characteristics and survival prognosis. The relationship between the ICD- high subgroup and the immune microenvironment was tight, showing significant enrichment in immune-related pathways such as antibody production in the intestinal immune environment, allograft rejection, and Leishmaniasis infection. Additionally, the ICD- high subtype showed significant upregulation in a variety of immune cells such as B_cells, Macrophages_M2, Monocytes, and T_cells_CD4. We constructed a prognostic risk feature based on five signature genes (TNF, CXCR3, CD4, PIK3CA and CALR), and the time-dependent ROC curve confirmed the high accuracy in predicting the clinical outcomes. CONCLUSION: There is a strong close relationship between the ICD- high subgroup and the immune microenvironment. Immunogenicity-related genes have the potential to be a prognostic biomarker for AML.

Rapid FRET Assay for the Early Detection of Alpha-Synuclein Aggregation in Parkinson's Disease.

Alpha-synuclein (α-Syn) is a key protein of Parkinson's disease (PD). Oligomers formed by misfolding and aggregation of α-Syn can cause many pathological phenomena and aggravate the development of PD. Therefore, sensitive and accurate detection of oligomers is essential to understanding the pathology of PD and beneficial to screening and developing new drugs against PD. Here, we demonstrated a simple and sensitive method to detect the early aggregation of α-Syn via Förster resonance energy transfer (FRET) technology. We performed systematic investigations of the FRET sensitizations, efficiencies, and donor-to-acceptor distances during α-Syn aggregation, which was proved to be more sensitive to reflect small distance changes in the early stage of α-Syn aggregation, especially for α-Syn oligomers. The FRET assays were also applied to study the influence of Ser129 phosphorylation (pS129) on the aggregation rate of α-Syn. Our results showed that pS129 modification promotes α-Syn aggregation and enhances the ability of preformed fibrils to induce monomer aggregation. pS129 also increased the cytotoxicity of α-Syn. These results are of great significance for a better understanding of the pathological mechanisms of PD and future PD drug development.

Design, synthesis, antibacterial evaluation of isopropylamine linked with different substituted phenol and piperazine novel derivatives.

BACKGROUND: Xanthomonas oryzae pv. oryzae (Xoo) is often considered one of the most destructive bacterial pathogens causing bacterial leaf blight (BLB), resulting in significant yield and cost losses in rice. In this study, a series of novel derivatives containing the isopropanolamine moiety linked to various substituted phenols and piperazines were designed, synthesized and screened. RESULTS: Antibacterial activity results showed that most compounds had good inhibitory effects on Xoo, among which compound W2 (EC50 = 2.74 µg mL-1) exhibited the most excellent inhibitory activity, and W2 also had a certain curative effect (35.89%) on rice compared to thiodiazole copper (TC) (21.57%). Scanning electron microscopy (SEM) results indicated that compound W2 could cause rupture of the Xoo cell membrane. Subsequently, proteomics and quantitative real-time polymerase chain reaction revealed that compound W2 affected the physiological processes of Xoo and may exert antibacterial activity by targeting the two-component system pathway. Interestingly, W2 upregulated Xoo's methyltransferase to impact on its pathogenicity. CONCLUSION: The present study offers a promising phenolic-piperazine-sopropanolamine compound as an innovative antibacterial strategy by specifically targeting the two-component system pathway and inducing upregulation of methyltransferase to effectively impact Xoo's pathogenicity. © 2024 Society of Chemical Industry.

Highly water-soluble and biocompatible hyaluronic acid functionalized upconversion nanoparticles as ratiometric nanoprobes for label-free detection of nitrofuran and doxorubicin.

Antibiotic detection is crucial and challenging because the widespread consumption of antibiotics has shown extensive harmful effects on food, environment and human health. Here, we propose highly water-soluble and biocompatible hyaluronic acid (HYA) functionalized upconversion nanoparticles (UCNPs) for ratiometric detection of multiple antibiotics. The ultraviolet upconversion luminescence (UCL) from UCNPs was significantly quenched by nitrofurazone (NFZ)/nitrofurantoin (NFT), and blue UCL was quenched by doxorubicin (DOX), while red UCL remained unchanged for internal reference. The UCNPs-HYA nanoprobes exhibit excellently sensitive and selective NFZ, NFT and DOX detection in linear range of 2.5-100 µM, 2.5-80 µM, and 2.5-200 µM with the LOD at 0.28 µM (55 µg/kg), 0.20 µM (48 µg/kg) and 0.17 µM (97 µg/kg), respectively. The nanoprobes achieved detecting real samples of NFZ in lake water, liquid milk and chicken meat with satisfactory results, and UCL bioimaging of DOX in HeLa cells. The UCNPs-HYA ratiometric nanoprobes are promising for food samples detection and potential biosensing in the cellular environment.

Zeaamine, a new amine from roots of Zea mays and its cytotoxic activity against CT26 and SW480 cell lines.

A new amine, zeaamine (1), along with nine known compounds (2-10), were isolated from the roots of Zea mays. Among these, compound 2 was first isolated from this plant, and compound 3 was first isolated from the roots. In the current investigation, the cytotoxicity against CT26 and SW480 cells of the compounds were evaluated. Zeaamine (1) exhibited moderately affected CT26 and SW480 cells with IC50 values of 17.91 and 10.21 µM.

Roots of Zea mays L.: As a Potential Source to Treat Sodium Oxalate-Induced Renal Cell Injury.

Zea mays L. is an annual grass of the Gramineae family and is known as one of the cereal crops. Its by-products exhibited significant medicinal properties. In some regions of China, water extracts of Z. mays roots (RM) are utilized to treat kidney stones, but no research has been reported. In our present study, a bioassay-guided isolation method was used to yield five new lignans (1-5) as well as 15 known components, among which 8-15 and 17-20 were first identified from the genus. The fractions and all components were evaluated for their abilities to inhibit sodium oxalate-induced injury to human proximal tubular HK-2 cells. Fraction 50W and compounds 3, 4, and 11 exhibited the most potent activities. Further investigation indicated that these potential agents inhibited the LDH release, decreased the MDA and H2O2 concentrations, and increased the level of SOD2 in HK-2 cells. These results indicated that RM is a promising and valuable crop waste for further development and utilization in nephrolithiasis pharmaceutical research.

Two New Alkaloids from Roots of Zea mays and Their Cytotoxic Activity against Hep3B and SW480 Cells.

Two undescribed alkaloids, along with seven known compounds, were isolated from the roots of Zea mays (RM). Their chemical structures were elucidated based on extensive analyses of HR-ESI-MS, 1D and 2D NMR, and CD spectra. Two new alkaloids exhibited moderate inhibition of Hep3B (IC50 values of 11.7±2.4 and 14.2±3.6 µM) and SW480 cells (IC50 values of 33.4±8.2 and 47.3±5.8 µM) compared to that of the positive control compound, Oxaliplatin, IC50 value of 8.4±1.7 and 45.8±5.6 µM, respectively.

Functions of Plant Phytochrome Signaling Pathways in Adaptation to Diverse Stresses.

Phytochromes are receptors for red light (R)/far-red light (FR), which are not only involved in regulating the growth and development of plants but also in mediated resistance to various stresses. Studies have revealed that phytochrome signaling pathways play a crucial role in enabling plants to cope with abiotic stresses such as high/low temperatures, drought, high-intensity light, and salinity. Phytochromes and their components in light signaling pathways can also respond to biotic stresses caused by insect pests and microbial pathogens, thereby inducing plant resistance against them. Given that, this paper reviews recent advances in understanding the mechanisms of action of phytochromes in plant resistance to adversity and discusses the importance of modulating the genes involved in phytochrome signaling pathways to coordinate plant growth, development, and stress responses.

Characteristics and Mechanism of Acute Ischemic Stroke in NAVF Patients With Prior Oral Anticoagulant Therapy.

OBJECTIVES: We aimed to analyze the characteristics and mechanisms of acute ischemic stroke (AIS) in patients with nonvalvular atrial fibrillation (NVAF) who received prior anticoagulant therapy. METHODS: We retrospectively analyzed the data of patients with NVAF and AIS between January 2016 and December 2021. Patients were divided into non-anticoagulant, adequate anticoagulant, and insufficient anticoagulant groups according to their prior anticoagulant status. Patients with prior anticoagulant therapy were further divided into warfarin and direct oral anticoagulant groups. RESULTS: A total of 749 patients (661 without anticoagulants, 33 with adequate anticoagulants, and 55 with insufficient anticoagulants) were included. Patients with adequate anticoagulant had a milder National Institute of Health Stroke Scale at presentation ( P =0.001) and discharge ( P =0.003), a higher proportion of Modified Rankin Scale (mRS) ≤2 at discharge ( P =0.011), and lower rates of massive infarction ( P =0.008) than patients without anticoagulant. Compared with the non-anticoagulant group, the proportion of intravenous thrombolysis was significantly lower in the adequate anticoagulant ( P <0.001) and insufficient anticoagulant ( P =0.009) groups. Patients in the adequate anticoagulant group had higher rates of responsible cerebral atherosclerotic stenosis ( P =0.001 and 0.006, respectively) and competing large artery atherosclerotic mechanisms ( P =0.006 and 0.009, respectively) than those in the other 2 groups. Compared with warfarin, direct oral anticoagulant was associated with higher rates of Modified Rankin Scale ≤2 at discharge ( P =0.003). CONCLUSIONS: Adequate anticoagulant therapy may be associated with milder stroke severity and better outcomes at discharge in patients with NVAF. Competing large artery atherosclerotic mechanisms may be associated with anticoagulant failure in patients with NAVF with prior adequate anticoagulant therapy.

Identification of potential necroinflammation-associated necroptosis-related biomarkers for delayed graft function and renal allograft failure: a machine learning-based exploration in the framework of predictive, preventive, and personalized medicine.

Delayed graft function (DGF) is one of the key post-operative challenges for a subset of kidney transplantation (KTx) patients. Graft survival is significantly lower in recipients who have experienced DGF than in those who have not. Assessing the risk of chronic graft injury, predicting graft rejection, providing personalized treatment, and improving graft survival are major strategies for predictive, preventive, and personalized medicine (PPPM/3PM) to promote the development of transplant medicine. However, since PPPM aims to accurately identify disease by integrating multiple omics, current methods to predict DGF and graft survival can still be improved. Renal ischemia/reperfusion injury (IRI) is a pathological process experienced by all KTx recipients that can result in varying occurrences of DGF, chronic rejection, and allograft failure depending on its severity. During this process, a necroinflammation-mediated necroptosis-dependent secondary wave of cell death significantly contributes to post-IRI tubular cell loss. In this article, we obtained the expression matrices and corresponding clinical data from the GEO database. Subsequently, nine differentially expressed necroinflammation-associated necroptosis-related genes (NiNRGs) were identified by correlation and differential expression analysis. The subtyping of post-KTx IRI samples relied on consensus clustering; the grouping of prognostic risks and the construction of predictive models for DGF (the area under the receiver operating characteristic curve (AUC) of the internal validation set and the external validation set were 0.730 and 0.773, respectively) and expected graft survival after a biopsy (the internal validation set's 1-year AUC: 0.770; 2-year AUC: 0.702; and 3-year AUC: 0.735) were based on the least absolute shrinkage and selection operator regression algorithms. The results of the immune infiltration analysis showed a higher infiltration abundance of myeloid immune cells, especially neutrophils, macrophages, and dendritic cells, in the cluster A subtype and prognostic high-risk groups. Therefore, in the framework of PPPM, this work provides a comprehensive exploration of the early expression landscape, related pathways, immune features, and prognostic impact of NiNRGs in post-KTx patients and assesses their capabilities as.predictors of post-KTx DGF and graft loss,targets of the vicious loop between regulated tubular cell necrosis and necroinflammation for targeted secondary and tertiary prevention, andreferences for personalized immunotherapy. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00320-w.

Palladium(II)-Catalyzed Remote meta-C-H Functionalization of Arenes Enabled by Multitasking Oxyamides as the Linker.

A palladium-catalyzed olefination of meta-C-H bonds in arenes containing oxyamides using a nitrile template as the directing group has been established. The methodology exhibited high meta-selectivity and tolerated different functional groups such as benzyloxyamides and olefin substrates. The desired products were obtained in good yields. This approach enabled the modification of natural products and drugs and was also applicable on the gram-scale. Furthermore, the directing template was readily removed by selective cleavage of the amide bond or the O-N bond to obtain meta-functionalized hydroxylamines and benzyl alcohols. The proposed method holds great potential for the design of novel drugs.

VTSNN: a virtual temporal spiking neural network.

Spiking neural networks (SNNs) have recently demonstrated outstanding performance in a variety of high-level tasks, such as image classification. However, advancements in the field of low-level assignments, such as image reconstruction, are rare. This may be due to the lack of promising image encoding techniques and corresponding neuromorphic devices designed specifically for SNN-based low-level vision problems. This paper begins by proposing a simple yet effective undistorted weighted-encoding-decoding technique, which primarily consists of an Undistorted Weighted-Encoding (UWE) and an Undistorted Weighted-Decoding (UWD). The former aims to convert a gray image into spike sequences for effective SNN learning, while the latter converts spike sequences back into images. Then, we design a new SNN training strategy, known as Independent-Temporal Backpropagation (ITBP) to avoid complex loss propagation in spatial and temporal dimensions, and experiments show that ITBP is superior to Spatio-Temporal Backpropagation (STBP). Finally, a so-called Virtual Temporal SNN (VTSNN) is formulated by incorporating the above-mentioned approaches into U-net network architecture, fully utilizing the potent multiscale representation capability. Experimental results on several commonly used datasets such as MNIST, F-MNIST, and CIFAR10 demonstrate that the proposed method produces competitive noise-removal performance extremely which is superior to the existing work. Compared to ANN with the same architecture, VTSNN has a greater chance of achieving superiority while consuming ~1/274 of the energy. Specifically, using the given encoding-decoding strategy, a simple neuromorphic circuit could be easily constructed to maximize this low-carbon strategy.

Novel 2-Amino-1,4-Naphthoquinone Derivatives Induce A549 Cell Death through Autophagy.

A series of 1,4-naphthoquinone derivatives containing were synthesized as anti-cancer agents and the crystal structure of compound 5a was confirmed by X-ray diffraction. In addition, the inhibitory activities against four cancer cell lines (HepG2, A549, K562, and PC-3) were tested, respectively, and compound 5i showed significant cytotoxicity on the A549 cell line with the IC50 of 6.15 µM. Surprisingly, in the following preliminary biological experiments, we found that compound 5i induced autophagy by promoting the recycling of EGFR and signal transduction in the A549 cell, resulting in the activation of the EGFR signal pathway. The potential binding pattern between compound 5i and EGFR tyrosine kinase (PDB ID: 1M17) was also identified by molecular docking. Our research paves the way for further studies and the development of novel and powerful anti-cancer drugs.

Active constituents of saffron (Crocus sativus L.) and their prospects in treating neurodegenerative diseases (Review).

Crocus sativus L. (saffron) is widely used as a traditional spice for flavoring, coloring and medicinal purposes. As a traditional Chinese herb, saffron promotes blood circulation, removes blood stasis, cools and detoxifies the blood, relieves depression and calms the mind. According to modern pharmacological studies, the active constituents of saffron, including crocetin, safranal and crocus aldehyde, exhibit antioxidant, anti-inflammatory, mitochondrial function-improving and antidepressant effects. Thus, saffron has the potential to treat neurodegenerative diseases (NDs) associated with oxidative stress, inflammation and impaired mitochondrial function, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and cerebral ischemia. The present article provides a review of the pharmacological effects of saffron and its constituents in terms of neuroprotective effects, including antioxidant and anti-inflammatory effects and the improvement of mitochondrial dysfunction, as well as their clinical application in treating NDs.