Amine-Terminated Phenanthroline Diimides as Aqueous Masking Agents for Am(III)/Eu(III) Separation: An Alternative Ligand Design Strategy for Water-Soluble Lanthanide/Actinide Chelating Ligands.

Selective actinide coordination (from lanthanides) is critical for both nuclear waste management and sustainable development of nuclear power. Hydrophilic ligands used as masking agents to withhold actinides in the aqueous phase are currently highly pursued, while synthetic accessibility, water solubility, acid resistance, and extraction capability are the remaining problems. Most reported hydrophilic ligands are only effective at low acidity. We recently proved that the phenanthroline diimide skeleton was an efficient building block for the construction of highly efficient acid-resistant hydrophilic lanthanide/actinide separation agents, while the limited water solubility hindered the loading capability of the ligand. Herein, amine was introduced as the terminal solubilizing group onto the phenanthroline diimide backbone, which after protonation in acid showed high water solubility. The positively charged terminal amines enhanced the ligand water solubility to a large extent, which, on the other side, was believed to be detrimental for the coordination and complexation of the metal cations. We showed that by delicately adjusting the alkyl chain spacing, this intuitive disadvantage could be relieved and superior extraction performances could be achieved. This work holds significance for both hydrophilic lanthanide/actinide separation ligand design and, concurrently, offers insights into the development of water-soluble lanthanide/actinide complexes for biomedical and bioimaging applications.

Neurotoxicity of manganese via ferroptosis induced by redox imbalance and iron overload.

Manganese (Mn) is an essential trace element for maintaining bodily functions. Excessive exposure to Mn can pose serious health risks to humans and animals, particularly to the nervous system. While Mn has been implicated as a neurotoxin, the exact mechanism of its toxicity remains unclear. Ferroptosis is a form of programmed cell death that results from iron-dependent lipid peroxidation. It plays a role in various physiological and pathological cellular processes and may be closely related to Mn-induced neurotoxicity. However, the mechanism of ferroptosis in Mn-induced neurotoxicity has not been thoroughly investigated. Therefore, this study aims to investigate the role and mechanism of ferroptosis in Mn-induced neurotoxicity. Using bioinformatics, we identified significant changes in genes associated with ferroptosis in Mn-exposed animal and cellular models. We then evaluated the role of ferroptosis in Mn-induced neurotoxicity at both the animal and cellular levels. Our findings suggest that Mn exposure causes weight loss and nervous system damage in mice. In vitro and in vivo experiments have shown that exposure to Mn increases malondialdehyde, reactive oxygen species, and ferrous iron, while decreasing glutathione and adenosine triphosphate. These findings suggest that Mn exposure leads to a significant increase in lipid peroxidation and disrupts iron metabolism, resulting in oxidative stress injury and ferroptosis. Furthermore, we assessed the expression levels of proteins and mRNAs related to ferroptosis, confirming its significant involvement in Mn-induced neurotoxicity.

Potential oral VEGFR2 inhibitors: Treatment of wet age-related macular degeneration.

Wet age-related macular degeneration (w-AMD) is one of the leading causes of vision loss in industrialized countries. A large body of evidence suggests that inhibitors targeting VEGFR2 may be effective in the treatment of w-AMD. The identification of an oral VEGFR2 inhibitor for the treatment of w-AMD provides an opportunity for a route of administration other than intravitreal injection. While screening potent VEGFR2 inhibitors at the enzyme and cellular levels, ensuring the safety of the compounds was our primary strategy for screening optimal compounds. Finally, compound 16 was identified, exhibiting enhanced inhibition of VEGFR2 enzyme and proliferation of BaF3-TEL-VEGFR2 cells compared to Vorolanib. Compound 16 had a weak inhibitory effect on human Ether-a-go-go-related gene (hERG) channel currents, showing a cardiac safety profile similar to Vorolanib. Compound 16 showed no significant toxicity to human liver cell LX-2, indicating a liver safety profile similar to Vorolanib. The water solubility of compound 16 was found to be higher than that of Vorolanib when tested at pH = 7.4. In addition, compound 16 was found to inhibit VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner by WB assay. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 16 showed remarkable plasma stability and moderate liver microsomal stability. Based on in vivo pharmacokinetic studies in ICR mice, compound 16 exhibited acceptable oral bioavailability (F = 20.2 %). Overall, these findings provide evidence that compound 16 is a leading potential oral drug candidate for w-AMD.

Ferroptosis at the crossroads of manganese-induced neurotoxicity: A retrospective study.

Manganese is an essential trace element, but overexposure can cause neurotoxicity and subsequent neurodegenerative diseases. Ferroptosis is a form of cell death characterized by lipid peroxidation and iron overload inside cells, which is closely related to manganese neurotoxicity. Manganese can induce ferroptosis through multiple pathways: causing oxidative stress and increased cellular reactive oxygen species (ROS), resulting in lipid peroxidation; depleting glutathione (GSH) and weakening the antioxidant capacity of cells; disrupting iron metabolism and increasing iron-dependent lipid peroxidation; damaging mitochondrial function and disrupting the electron transport chain, leading to increased ROS production. Oxidative stress, iron metabolism disorders, lipid peroxidation, GSH depletion, and mitochondrial dysfunction, typical features of ferroptosis, have been observed in animal and cell models after manganese exposure. In summary, manganese can participate in the pathogenesis of neurodegenerative diseases by inducing events related to ferroptosis. This provides new insights into studying the mechanism of manganese neurotoxicity and developing therapeutic drugs.

Enhancing the Selectivity of Trivalent Actinide over Lanthanide Using Asymmetrical Phenanthroline Diamide Ligands.

Phenanthroline diamide ligands have been widely used in the separation of trivalent actinides and lanthanides, but little research has focused on extractants with asymmetrical substitutes. Two novel asymmetrical phenanthroline-based ligands N2,N2,N9-triethyl-N9-tolyl-1,10-phenanthroline-2,9-dicarboxamide (DE-ET-DAPhen) and N2-ethyl-N9,N9-dioctyl-N2-tolyl-1,10-phenanthroline-2,9-dicarboxamide (DO-ET-DAPhen) were first synthesized in this work, whose extraction ability and complexation mechanism to trivalent actinides [An(III)] and lanthanides [Ln(III)] were systematically investigated. The ligands dissolved in n-octanol exhibit good extraction ability and high selectivity toward Am(III) in acidic solutions. The complexation mechanism of the ligands with Ln(III) in solution and solid state was analyzed using slope analysis, 1H NMR spectrometric titration, ESI-MS, and calorimetric titration. It is revealed that the ligands complex with Am(III)/Eu(III) with 1:1 stoichiometry. The stability constant (log ß) of the complexation reaction of Eu(III) with DE-ET-DAPhen determined by UV-vis spectrophotometric and calorimetric titration is higher than that of DO-ET-DAPhen, indicating the stronger complexation ability of DE-ET-DAPhen. Meanwhile, the calorimetric titration results show that the complexation process is exothermic with a decreased entropy. The structures of 1:1 complexes of Eu(III) and Nd(III) with DE-ET-DAPhen were analyzed through single-crystal X-ray diffraction. This work proves that ligands containing asymmetrical functional groups are promising for An(III)/Ln(III) separation, which shows great significance in efficient extractants designed for the spent nuclear fuel reprocessing process.

Design, synthesis, and biological evaluation of novel donepezil-tacrine hybrids as multi-functional agents with low neurotoxicity against Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and deficits in cognitive domains. Low choline levels, oxidative stress, and neuroinflammation are the primary mechanisms implicated in AD progression. Simultaneous inhibition of acetylcholinesterase (AChE) and reactive oxygen species (ROS) production by a single molecule may provide a new breath of hope for AD treatment. Here, we describe donepezil-tacrine hybrids as inhibitors of AChE and ROS. Four series of derivatives with a ß-amino alcohol linker were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit AChE and butyrylcholinesterase (BuChE) in vitro, using tacrine (hAChE, IC50 = 305.78 nM; hBuChE, IC50 = 56.72 nM) and donepezil (hAChE, IC50 = 89.32 nM; hBuChE, IC50 = 9137.16 nM) as positive controls. Compound B19 exhibited an excellent and balanced inhibitory potency against AChE (IC50 = 30.68 nM) and BuChE (IC50 = 124.57 nM). The cytotoxicity assays demonstrated that the PC12 cell viability rates of compound B19 (84.37 %) were close to that of tacrine (87.73 %) and donepezil (79.71 %). Potential therapeutic effects in AD were evaluated using the neuroprotective effect of compounds against H2O2-induced toxicity, and compound B19 (68.77 %) exhibited substantially neuroprotective activity at the concentration of 25 µM, compared with the model group (30.34 %). Furthermore, compound B19 protected PC12 cells from H2O2-induced apoptosis and ROS production. These properties of compound B19 suggested that it was a multi-functional agent with AChE inhibition, anti-oxidative, anti-inflammatory activities, and low toxicity and that it deserves further investigation as a promising agent for AD treatment.

Design, synthesis and biological evaluation of carbamate derivatives incorporating multifunctional carrier scaffolds as pseudo-irreversible cholinesterase inhibitors for the treatment of Alzheimer's disease.

In this study, a series of carbamate derivatives incorporating multifunctional carrier scaffolds were designed, synthesized, and evaluated as potential therapeutic agents for Alzheimer's disease (AD). We used tacrine to modify the aliphatic substituent, and employed rivastigmine, indole and sibiriline fragments as carrier scaffolds. The majority of compounds exhibited good inhibitory activity for cholinesterase. Notably, compound C7 with sibiriline fragment exhibited potent inhibitory activities against human acetylcholinesterase (hAChE, IC50 = 30.35 ± 2.07 nM) and human butyrylcholinesterase (hBuChE, IC50 = 48.03 ± 6.41 nM) with minimal neurotoxicity. Further investigations have demonstrated that C7 exhibited a remarkable capacity to safeguard PC12 cells against H2O2-induced apoptosis and effectively suppressed the production of reactive oxygen species (ROS). Moreover, in an inflammation model of BV2 cells induced by lipopolysaccharide (LPS), C7 effectively attenuated the levels of pro-inflammatory cytokines. After 12 h of dialysis, C7 continued to exhibit an inhibitory effect on cholinesterase activity. An acute toxicity test in vivo demonstrated that C7 exhibited a superior safety profile and no hepatotoxicity compared to the parent nucleus tacrine. In the scopolamine-induced AD mouse model, C7 (20 mg/kg) significantly reduced cholinesterase activity in the brain of the mice. C7 was tested in a pharmacological AD mouse model induced by Aß1-42 and attenuated memory deficits at doses as low as 5 mg/kg. The pseudo-irreversible cholinesterase inhibitory properties and multifunctional therapeutic attributes of C7 render it a promising candidate for further investigation in the treatment of AD.

Discovery of Rhodanine Inhibitors Targeting Of ChtI Based on the π-Stacking Effect and Aqueous Solubility.

The application of some reported inhibitors against the chitinolytic enzyme Of ChtI was limited due to their unsatisfactory insecticidal activities. Hence, we first performed a synergetic design strategy combining the π-stacking effect with aqueous solubility to find novel rhodanine analogues with inhibitory activities against Of ChtI. Novel rhodanine compounds IAa-f and IBa-f have weak aqueous solubility, but they (IAd: Ki = 4.0 µM; IBd: Ki = 2.2 µM) showed better inhibitory activities against Of ChtI and comparable insecticidal efficiency toward Ostrinia furnacalis compared to the high aqueous solubility compounds IIAa-f and IIBa-f (IIAd: Ki = 21.6 µM; IIBd: Ki = 14.3 µM) without a large conjugate plane. Further optimized compounds IIIAa-j with a conjugate plane as well as a higher aqueous solubility exhibited similar good inhibitory activities against Of ChtI (IIIAe: Ki = 2.4 µM) and better insecticidal potency (IIIAe: mortality rate of 63.33%) compared to compounds IAa-f and IBa-f, respectively. Molecular docking studies indicated that the conjugate planarity with the π-stacking effect for rhodanine analogues is responsible for their enzyme inhibitory activity against Of ChtI. This study provides a new strategy for designing insect chitinolytic enzyme inhibitors as insect growth regulators for pest control.

Thickness-Dependent Room-Temperature Optoelectronic Gas Sensing Performances of 2D Nonlayered Indium Oxide Crystals from a Liquid Metal Printing Process.

Due to excellent gas sensing performances, such as high responsivity, good selectivity, and long-term stability, two-dimensional (2D) nonlayered metal oxide semiconductors have attracted wide attention. However, their thickness-dependent gas sensing behaviors are rarely investigated, which is critical in the development of practical 2D sensors. In this work, 2D In2O3 crystals with a range of thicknesses are realized by extracting the self-limited oxide layer from the liquid indium droplets in a controlled environment. A strong thickness-dependent optoelectronic NO2 sensing behavior at room temperature is observed. While full reversibility and excellent selectivity toward NO2 are shown despite the thicknesses of 2D In2O3, the 1.9 nm thick In2O3 exhibits a maximum response amplitude (ΔI/Ig = 1300) for 10 ppm of NO2 at room temperature with 365 nm light irradiation, which is about 18, 58, and 810 times larger than those of its 3.1 nm thick, 4.5 nm thick, and 6.2 nm thick counterparts, respectively. The shortest response and recovery times (i.e., 40 s/48 s) are demonstrated for the 1.88 nm thick In2O3 as well. We correlate such a phenomenon with the change in the In2O3 band structure, which is influenced by the thickness of 2D crystals. This work provides in-depth knowledge of the thickness-dependent gas-sensing performances of emerging 2D nonlayered metal oxide crystals, as well as the opportunities to develop next-generation high-performing room-temperature gas sensors.

Interleukin 4-driven reversal of self-reactive B cell anergy contributes to the pathogenesis of systemic lupus erythematosus.

OBJECTIVES: Reactivation of anergic autoreactive B cells (BND cells) is a key aetiological process in systemic lupus erythematosus (SLE), yet the underlying mechanism remains largely elusive. This study aimed to investigate how BND cells participate in the pathogenesis of SLE and the underlying mechanism. METHODS: A combination of phenotypical, large-scale transcriptome and B cell receptor (BCR) repertoire profiling were employed at molecular and single cell level on samples from healthy donors and patients with SLE. Isolated naïve B cells from human periphery blood were treated with anti-CD79b mAb in vitro to induce anergy. IgM internalisation was tracked by confocal microscopy and was qualified by flow cytometer. RESULTS: We characterised the decrease and disruption of BND cells in SLE patients and demonstrated IL-4 as an important cytokine to drive such pathological changes. We then elucidated that IL-4 reversed B cell anergy by promoting BCR recycling to the cell surface via STAT6 signalling. CONCLUSIONS: We demonstrated the significance of IL-4 in reversing B cell anergy and established the scientific rationale to treat SLE via blocking IL-4 signalling, also providing diagnostic and prognostic biomarkers to identify patients who are most likely going to benefit from such treatments.

A Simple yet Efficient Hydrophilic Phenanthroline-Based Ligand for Selective Am(III) Separation under High Acidity.

Highly selective hydrophilic ligands were believed to be an efficient way to overcome the massive amount of hazardous organic solvent used in the liquid-liquid extraction process and stood as a new frontier in the Lns(III)/Ans(III) partition. Current reported hydrophilic ligands suffer from harsh preparation conditions, inferior extraction performances, limited available chemical structures, and inability to carry out extraction under high acidity. In this article, we report a simple yet efficient carboxylic group modified phenanthroline-diimide ligand which displayed unexpected Lns(III)/Ans(III) and Ans(III)/Ans(III) separation capabilities in 1.5 M HNO3. Unique dimeric architectures for Eu(III) complexes were observed, which could be the origin of the outperforming selectivity and acid resistance. We believe this crystal engineering approach could inspire a renaissance in searching for new functional groups and coordination modes for efficient, high-acid-tolerance Lns(III)/Ans(III) separation ligands.

Effect of blanching and ultrasound pretreatment on moisture migration, uniformity, and quality attributes of dried cantaloupe.

To overcome problems of browning and crusting during the pretreatment process and provide theoretical guidance for cantaloupe convection drying at 80°C, the effects of blanching (BL) and ultrasonic (US) treatments were examined. The effects of various BL (5, 10, and 15 s) and US (10, 20, 30, and 40 min) durations on convection drying were tested. The moisture ratio, drying rate, moisture effective diffusivity, color, browning, nuclear magnetic resonance characteristics, and texture were assessed. Compared with the control group, the maximal decreases in the drying time of BL and US pretreatment groups were 40% and 33.3%, respectively. BL and US pretreatments significantly increased the effective diffusion coefficient and shortened the drying time because of the destruction of the cell structure. Low-field nuclear magnetic resonance analysis showed that free water is mainly lost during the initial drying stage, while solidified water is mainly lost during middle and late stages. According to the results of magnetic resonance imaging, the moisture distribution shows that cavitation from US acts on internal tissue, while BL disrupts the structure of external tissue. Texture data define the area enclosed by SC-D as uniform. After BL and US pretreatment, the hardness of dried cantaloupe decreased and the uniformity increased significantly. The best pretreatment process for cantaloupe at 80°C was 10 min of US. These findings provide a reference for testing in the industrial production of dried cantaloupe and are deeply relevant for practice.

Immunometabolomics provides a new perspective for studying systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease characterized by clinical heterogeneity, unpredictable progression, and flare ups. Due to the heterogeneous nature of lupus, it has been challenging to identify sensitive and specific biomarkers for its diagnosis and monitoring. Despite the fact that the mechanism of SLE remains unknown, impressive progress has been made over the last decade towards understanding how different immune cells contribute to its pathogenesis. Research suggests that cellular metabolic programs could affect the immune response by regulating the activation, proliferation, and differentiation of innate and adaptive immune cells. Many studies have shown that the dysregulation of the immune system is associated with changes to metabolite profiles. The study of metabolite profiling may provide a means for mechanism exploration and novel biomarker discovery for disease diagnostic, classification, and monitoring. Here we review the latest advancements in understanding the role of immunometabolism in SLE, as well as the systemic metabolite profiling of this disease along with possible clinical application.

Design, synthesis and evaluation of OA-tacrine hybrids as cholinesterase inhibitors with low neurotoxicity and hepatotoxicity against Alzheimer's disease.

A series of OA-tacrine hybrids with the alkylamine linker was designed, synthesized, and evaluated as effective cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some hybrids possessed significant inhibitory activities against acetylcholinesterase (AChE). Among them, compounds B4 (hAChE, IC50 = 14.37 ± 1.89 nM; SI > 695.89) and D4 (hAChE, IC50 = 0.18 ± 0.01 nM; SI = 3374.44) showed excellent inhibitory activities and selectivity for AChE as well as low nerve cell toxicity. Furthermore, compounds B4 and D4 exhibited lower hepatotoxicity than tacrine in cell viability, apoptosis, and intracellular ROS production for HepG2 cells. These properties of compounds B4 and D4 suggest that they deserve further investigation as promising agents for the prospective treatment of AD.

Design, synthesis, and evaluation of N-methyl-propargylamine derivates as isoform-selective monoamine oxidases inhibitors for the treatment of nervous system diseases.

A novel series of N-methyl-propargylamine derivates were designed, synthesized, and evaluated as isoform-selective monoamine oxidases (MAO) inhibitors for the treatment of nervous system diseases. The in vitro studies showed some of the compounds exhibited considerable MAO-A selective inhibitory activity (IC50 of 14.86-17.16 nM), while some of the others exhibited great MAO-B selective inhibitory activity (IC50 of 4.37-17.00 nM). Further studies revealed that compounds A2 （IC50 against MAO-A: 17.16 ± 1.17 nM） and A5 (IC50 against MAO-B: 17.00 ± 1.10 nM) had significant abilities to protect PC12 cells from H2O2-induced apoptosis and reactive oxygen species (ROS) production. The parallel artificial membrane permeability assay showed A2 and A5 would be potent to cross the blood-brain barrier. The results indicated that A2 showed potential use in the therapy of MAO-A related diseases, such as depression and anxiety; while A5 exhibited promising ability in the treatment of MAO-B related diseases, such as Alzheimer's disease and Parkinson's disease.

MYC promotes fibroblast osteogenesis by regulating ALP and BMP2 to participate in ectopic ossification of ankylosing spondylitis.

BACKGROUND: Ectopic ossification is an important cause of disability in patients with ankylosing spondylitis (AS). Whether fibroblasts can transdifferentiate into osteoblasts and contribute to ossification remains unknown. This study aims to investigate the role of stem cell transcription factors (POU5F1, SOX2, KLF4, MYC, etc.) of fibroblasts in ectopic ossification in patients with AS. METHODS: Primary fibroblasts were isolated from the ligaments of patients with AS or osteoarthritis (OA). In an in vitro study, primary fibroblasts were cultured in osteogenic differentiation medium (ODM) to induce ossification. The level of mineralization was assessed by mineralization assay. The mRNA and protein levels of stem cell transcription factors were measured by real-time quantitative PCR (q-PCR) and western blotting. MYC was knocked down by infecting primary fibroblasts with lentivirus. The interactions between stem cell transcription factors and osteogenic genes were analysed by chromatin immunoprecipitation (ChIP). Recombinant human cytokines were added to the osteogenic model in vitro to evaluate their role in ossification. RESULTS: We found that MYC was elevated significantly in the process of inducing primary fibroblasts to differentiate into osteoblasts. In addition, the level of MYC was remarkably higher in AS ligaments than in OA ligaments. When MYC was knocked down, the expression of the osteogenic genes alkaline phosphatase (ALP) and bone morphogenic protein 2 (BMP2) was decreased, and the level of mineralization was reduced significantly. In addition, the ALP and BMP2 were confirmed to be the direct target genes of MYC. Furthermore, interferon-γ (IFN-γ), which showed high expression in AS ligaments, was found to promote the expression of MYC in fibroblasts in the process of ossification in vitro. CONCLUSIONS: This study demonstrates the role of MYC in ectopic ossification. MYC may act as the critical bridge that links inflammation with ossification in AS, thus providing new insights into the molecular mechanisms of ectopic ossification in AS.

Excessive IL-15 promotes cytotoxic CD4 + CD28- T cell-mediated renal injury in lupus nephritis.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) are highly susceptible to infection and cardiovascular events, suggesting that chronic antigenic stimulation may accelerate premature aging in SLE patients. Premature aging in SLE is often accompanied with the expansion of cytotoxic CD4 + CD28-T cells. Damage caused by CD4 + CD28- T cells enhances the progressive aging of the tissue function and loss of organism's fitness. The high serum level of IL-15 has been implicated in the pathogenesis of SLE, but its role in CD4 + CD28-T cell-mediated cytotoxicity in nephritic SLE remains unclear. The aim of this study was to investigate the effect of IL-15 on functional properties and associated renal damage of cytotoxic CD4 + CD28- T cell in lupus nephritis (LN). RESULTS: Flow cytometry showed that the number of circulating innate-like CD4 + CD28- T cells was increased in patients with nephritic SLE. Immunofluorescence showed CD4 + CD28- T cell infiltration in the kidney of LN patients, which was correlated with multiple clinicopathological features including estimated glomerular filtration rate (eGFR), proteinuria, the proportion of glomerulosclerosis and the degree of renal chronicity. In addition, a high level of IL-15 and IL15-expressing macrophage infiltration was detected in the periglomerular and intraglomerular tissues of LN patients, which enhanced the innate features, cytokine secretion and migratory capability of CD4 + CD28- T cells, and finally exerted direct TCR-independent cytotoxicity on glomerular endothelial cells in an IL-15-dependent manner in vitro. CONCLUSION: Our study demonstrated that excessive IL-15 potentially promoted cytotoxic CD4 + CD28- T cell-mediated renal damage in LN. This finding may provide new insights into the potential association of premature aging and tissue damage in LN.

Piperonyl-Tethered Rhodanine Derivatives Potently Inhibit Chitinolytic Enzymes of Ostrinia furnacalis.

Insect pest chitinases are potential target for developing new insect growth regulators. Piperine was found first to inhibit the insect chitinase (OfChi-h) from Ostrinia furnacalis (Asian corn borer) in this work, except for previously reported OfChtI. Novel piperonyl-tethered rhodanine derivatives 7a-j were rationally designed with piperine as lead and synthesized by introducing a unique rhodanine moiety into the piperine scaffold based on the similar binding cavity of OfChtI and OfChi-h. Compared to piperine, compounds 7a-j showed approximately 100- to 400-fold or 110- to 210-fold higher inhibitory capacity against two chitinases, respectively. Molecular mechanism studies indicated that π interactions are crucial for improving inhibitory activity against two chitinases due to the introduction of the conjugated rhodanine ring. Moreover, compounds 7a-c could dramatically inhibit the growth and development of O. furnacalis larvae by in vivo activity evaluation. This study provides novel piperonyl-tethered rhodanine derivatives inhibiting dual chitinases as insect growth regulator candidates.

SiO2-induced ferroptosis in macrophages promotes the development of pulmonary fibrosis in silicosis models.

Silicosis is a devastating disease that, without effective treatment, endangers the health of miners. Therefore, studies exploring the pathogenesis of SiO2-induced pulmonary fibrosis are necessary to develop treatments for silicosis. Although macrophages are known to play a pivotal role in SiO2-induced pulmonary fibrosis, the underlying mechanism remains unknown. Here, we explored whether ferroptosis was involved in SiO2-induced pulmonary fibrosis. To this end, C57BL/6 mice and mouse macrophage (RAW264.7) cells and mouse lung fibroblast (MLF) cells were subjected to iron content, cell viability, enzyme-linked immunosorbent assay, immunofluorescence staining, histological, western blotting, quantitative reverse transcription-PCR, reactive oxygen species, and lipid peroxidation analysis. In vivo, SiO2 was found to damage the lung alveolar structure, cause infiltration of inflammatory cells, and facilitate fibrosis. Additionally, it increased the iron concentration and lipid peroxidation as well as altered the expression of ferroptosis-related genes and the mitochondrial morphology in macrophages. In vitro, ferroptosis occurred in SiO2-treated RAW264.7 cells, which showed iron overload, lipid peroxidation, and gene alterations. Furthermore, ferrostatin-1 (Fer-1) attenuated ferroptosis in SiO2-treated RAW264.7 cells by inhibiting lipid peroxidation and cell death and regulating ferroptosis-related genes expression, in addition to attenuating the secretion of pro-fibrotic cytokines and fibrosis. Collectively, SiO2 induces ferroptosis in macrophages, which leads to the secretion of pro-fibrotic cytokines and fibrosis.