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Glioma is the most common type of malignant brain tumor. Due to its highly aggressive and metastatic features, glioma is associated with poor prognosis and a lack of effective treatments. Eriodictyol, a natural flavonoid compound, has been reported to possess anti-inflammatory and antioxidant effects. However, the anti-tumor effects of eriodictyol and the underlying mechanisms have rarely been reported. In this study, we found that eriodictyol has anti-tumor activity in lung, colon, breast, pancreas, and liver cancer, and most significantly in glioma cell lines. Eriodictyol dose- and time-dependently suppresses cell proliferation, migration, and invasion in U87MG and CHG-5 glioma cells. In addition, eriodictyol induces apoptosis in U87MG and CHG-5 cells, as evaluated by flow cytometry, immunofluorescence, and Western blot. Furthermore, eriodictyol downregulates the phosphoinositide 3-kinase (PI3K)/Akt/NF-κB signaling pathway in a concentration-dependent manner. Moreover, the effects of eriodictyol on the apoptosis of glioma cells are enhanced by LY294002 (a PI3K inhibitor) and reversed by 740 Y-P (a PI3K agonist). In a mouse xenograft model, eriodictyol not only dramatically suppressed tumor growth but also induced apoptosis in tumor cells. In summary, our data illustrate that eriodictyol effectively inhibits proliferation and metastasis and induces apoptosis of glioma cell lines, which might be a result of the blockade of the PI3K/Akt/NF-κB signaling pathway.

Defense-associated sirtuin 2 (DSR2) systems are widely distributed across prokaryotic genomes, providing robust protection against phage infection. DSR2 recognizes phage tail tube proteins and induces abortive infection by depleting intracellular NAD + , a process that is counteracted by another phage-encoded protein, DSR Anti Defense 1 (DSAD1). Here, we present cryo-EM structures of Bacillus subtilis DSR2 in its apo, Tube-bound, and DSAD1-bound states. DSR2 assembles into an elongated tetramer, with four NADase catalytic modules clustered in the center and the regulatory-sensing modules distributed at four distal corners. Interestingly, monomeric Tube protein, rather than its oligomeric states, docks at each corner of the DSR2 tetramer to form a 4:4 DSR2-Tube assembly, which is essential for DSR2 NADase activity. DSAD1 competes with Tube for binding to DSR2 by occupying an overlapping region, thereby inhibiting DSR2 immunity. Thus, our results provide important insights into the assembly, activation and inhibition of the DSR2 anti-phage defense system. The defense-associated sirtuin 2 (DSR2) system protects bacteria from phages by depleting NAD + . Here, authors elucidate the molecular mechanisms underlying DSR2 assembly, activation, and inhibition, providing important insights into bacterial anti-phage defense.

ABCC1 is an ATP-binding cassette (ABC) transporter that exports diverse endogenous and exogenous substrates, conferring resistance to many anticancer drugs and mediating various physiological functions. Here, we present ten cryo-EM structures of ABCC1 in different functional states, providing systematic insights into its substrate recognition diversity and transport dynamics. ABCC1 utilizes a plastic bipartite substrate-binding pocket and a substrate-induced conformational flexibility to accommodate molecules with diverse properties, including bimolecular glutathione (GSH)-substrate pairs, GSH conjugates, and GSH-independent cyclic dinucleotides. A herein characterized substrate-releasing intermediate state reveals ATP-mediated overall conformational transitions and detailed pocket reorganization during substrate loading, pre-release, and post-release. Unexpectedly, we identify a sequential nucleotide release mechanism where the hydrolysis product ADP, rather than unhydrolyzed ATP, releases first, priming the transporter for turnover and resetting. Complemented by mutagenesis and functional assays, these findings provide a complete framework for understanding ABCC1’s molecular basis and offer a foundation for developing next-generation modulators. The ABC transporter ABCC1 confers resistance to anticancer drugs and mediates physiological functions by exporting diverse substrates. Here, authors determine ten cryo-EM structures of ABCC1 in distinct functional states, providing systematic insights into its substrate recognition diversity and transport dynamics.

Synthetic chemical pesticides are primarily used to manage plant pests and diseases, but their widespread and unregulated use has resulted in major health and environmental hazards. Using biocontrol microbes and their bioactive compounds is a safe and sustainable approach in plant protection. In this study, a furoic acid (FA) compound having strong antibacterial activity against soil-borne phytopathogenic bacterium Ralstonia solanacearum [causal agent of bacterial wilt (BW) disease] was isolated from Aspergillus niger and identified as 5-(hydroxymethyl)-2-furoic acid compound through spectroscopic analyses (liquid chromatography–mass spectrometry (MS), electron ionization MS, and NMR). The SEM study of bacterial cells indicated the severe morphological destructions by the FA compound. The FA was further evaluated to check its potential in enhancing host resistance and managing tomato BW disease in a greenhouse experiment and field tests. The results showed that FA significantly enhanced the expression of resistance-related genes ( PAL , LOX , PR1 , and PR2 ) in tomato and caused a significant reduction (11.2 log 10 colony-forming units/g) of the R. solanacearum population in soil, resulting in the reduction of bacterial wilt disease severity on tomato plants and increase in plant length (58 ± 2.7 cm), plant biomass (28 ± 1.7 g), and root length (13 ± 1.2 cm). The findings of this study suggested that the fungus-derived FA compound can be a potential natural compound of biological source for the soil-borne BW disease in tomato.

The solute carrier protein SLC19A1 is crucial for transporting folate nutrients, antifolate chemotherapeutics, and more recently cyclic dinucleotides (CDNs) immune transmitters, influencing various physiological and pathological processes. While the inward-open state of human SLC19A1 (hSLC19A1) has been previously described, key aspects regarding its conformational dynamics, substrate selectivity, and precise mechanisms underlying CDNs transport remain elusive. Using an antibody-facilitated conformation screening strategy, we present cryo-electron microscopy structures of hSLC19A1 in its outward-open state with and without bound substrates, revealing detailed mechanisms of substrate recognition and conformational changes during transport. We identify both general and specific features for folate/antifolate recognition, including an SLC19A1-specific pocket for accommodating γ-carboxylate-modified antifolates. Intriguingly, CDNs bind as monomers within the canonical pocket of outward-open hSLC19A1, contrasting with dimeric binding in inward-open structures. Together with functional assays, these findings provide a framework for developing antifolate drugs and CDN-targeted therapies, advancing our understanding of SLC19A1’s physiological and therapeutic functions. SLC19A1 is crucial for transporting folates, antifolates and cyclic dinucleotides. Here authors determined outward-open structures of hSLC19A1 with and without bound substrates, revealing detailed mechanisms of substrate recognition and conformational changes during transport.

Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine transporters SLC19A2 and SLC19A3 primarily regulate cellular uptake of both vitamins. Genetic mutations in these transporters, which cause thiamine and pyridoxine deficiency, have been implicated in severe neurometabolic diseases. Additionally, various prescribed medicines, including metformin and fedratinib, manipulate thiamine transporters, complicating the therapeutic effect. Despite their physiological and pharmacological significance, the molecular underpinnings of substrate and drug recognition remain unknown. Here we present ten cryo-EM structures of human thiamine transporters SLC19A3 and SLC19A2 in outward- and inward-facing conformations, complexed with thiamine, pyridoxine, metformin, fedratinib, and amprolium. These structural insights, combined with functional characterizations, illuminate the translocation mechanism of diverse chemical entities, and enhance our understanding of drug-nutrient interactions mediated by thiamine transporters. The dietary uptake of vitamins B1 and B6 is mainly carried out by SLC19A2/A3 transporters. Here, authors characterized biochemically and structurally the transporters with vitamins B1/B6 and several inhibitory drugs

SLC15A4, an endolysosomal solute carrier family transporter, plays a critical role in TLR7/8/9-induced immune responses through assembling a complex with the downstream adaptor TASL in a conformation-dependent manner. Despite its close functional association and promising therapeutic potential in infections, tumors, and autoimmune diseases, the development of conformation-specific antibodies for human SLC15A4 (hSLC15A4) remains challenging. Here, using a systematic screening and validation approach, we identify a pair of conformation-selective antibodies, clones 107 and 235, targeting the endolysosomal lumen surface of hSLC15A4 with opposite conformation-regulatory activities. Specifically, clone 107 selectively binds to hSLC15A4 in a TASL binding-incompetent luminal-open state; whereas clone 235 stabilizes hSLC15A4 in a TASL binding-competent cytoplasmic-open state. Our research identifies antibodies that recognize distinct conformations of hSLC15A4, potentially enabling modulation of the TLR7/8/9 pathway and contributing to the development of targeted therapies and research tools selectively targeting hSLC15A4. SLC15A4 is essential for TLR7/8/9-mediated immune responses through a conformation-dependent interaction with TASL. Here, the authors identify two conformation-selective antibodies that differentially target distinct structural states of human SLC15A4.

Type I restriction-modification systems help establish the prokaryotic DNA methylation landscape and provide protection against invasive DNA. In addition to classical m6A modifications, non-canonical type I enzymes catalyze both m6A and m4C using alternative DNA-modification subunits M1 and M2. Here, we report the crystal structures of the non-canonical PacII_M1M2S methyltransferase bound to target DNA and reaction product S-adenosylhomocysteine in a closed clamp-like conformation. Target DNA binds tightly within the central tunnel of the M1M2S complex and forms extensive contacts with all three protein subunits. Unexpectedly, while the target cytosine properly inserts into M2’s pocket, the target adenine (either unmethylated or methylated) is anchored outside M1’s pocket. A unique asymmetric catalysis is established where PacII_M1M2S has precisely coordinated the relative conformations of different subunits and evolved specific amino acids within M2/M1. This work provides insights into mechanisms of m6A/m4C catalysis and guidance for designing tools based on type I restriction-modification enzymes. Type I R-M systems help establish the prokaryotic DNA methylation landscape and provide protection against invasive DNA. Here, the authors report on detailed structural and molecular mechanisms of a non-canonical type I R-M methyltransferase.

Background: Sound drug safety information is important to optimize patient management, but the widely recognized comprehensive landscape of culprit-drugs that cause severe cutaneous adverse reactions (SCARs) is currently lacking. Objective: The main aim of the study is to provide a comprehensive landscape of culprit-drugs for SCARs to guide clinical practice. Methods: We analyzed reports associated with SCARs in the FDA Adverse Event Reporting System database between 1 January 2004 and 31 December 2021 and compiled a list of drugs with potentially serious skin toxicity. According to this list, we summarized the reporting proportions of different drugs and drug classes and conducted disproportionality analysis for all the drugs. In addition, the risk characteristic of SCARs due to different drugs and drug classes was summarized by the positive–negative distribution based on the results of the disproportionality analysis. Results: A total of 77,789 reports in the FDA Adverse Event Reporting System database were considered SCAR-related, of which lamotrigine (6.2%) was the most reported single drug followed by acetaminophen (5.8%) and allopurinol (5.8%) and antibacterials (20.6%) was the most reported drug class followed by antiepileptics (16.7%) and antineoplastics (11.3%). A total of 1,219 drugs were reported as culprit-drugs causing SCARs in those reports, and the largest number of drugs belonged to antineoplastics. In disproportionality analysis, 776 drugs showed at least one positive pharmacovigilance signal. Drugs with the most positive signals were lamotrigine, acetaminophen, furosemide, and sulfamethoxazole/trimethoprim. Conclusion: Our study provided a real-world overview of SCARs to drugs, and the investigation of SCAR positive–negative distribution across different drugs revealed its risk characteristics, which may help optimize patient management.

Introduction: Drug-induced QT prolongation and (or) Torsade de Pointes (TdP) is a well-known serious adverse reaction (ADR) for some drugs, but the widely recognized comprehensive landscape of culprit-drug of QT prolongation and TdP is currently lacking. Aim: To identify the top drugs reported in association with QT prolongation and TdP and provide information for clinical practice. Method: We reviewed the reports related to QT prolongation and TdP in the FDA Adverse Event Reporting System (FAERS) database from January 1, 2004 to December 31, 2022, and summarized a potential causative drug list accordingly. Based on this drug list, the most frequently reported causative drugs and drug classes of QT prolongation and TdP were counted, and the disproportionality analysis for all the drugs was conducted to in detect ADR signal. Furthermore, according to the positive–negative distribution of ADR signal, we integrated the risk characteristic of QT prolongation and TdP in different drugs and drug class. Results: A total of 42,713 reports in FAERS database were considered to be associated with QT prolongation and TdP from 2004 to 2022, in which 1,088 drugs were reported as potential culprit-drugs, and the largest number of drugs belonged to antineoplastics. On the whole, furosemide was the most frequently reported drugs followed by acetylsalicylic acid, quetiapine, citalopram, metoprolol. In terms of drug classes, psycholeptics was the most frequently reported drug classes followed by psychoanaleptics, analgesics, beta blocking agents, drugs for acid related disorders. In disproportionality analysis, 612 drugs showed at least one positive ADR signals, while citalopram, ondansetron, escitalopram, loperamide, and promethazine were the drug with the maximum number of positive ADR signals. However, the positive-negative distribution of ADR signals between different drug classes showed great differences, representing the overall risk difference of different drug classes. Conclusion: Our study provided a real-world overview of QT prolongation and TdP to drugs, and the presentation of the potential culprit-drug list, the proportion of reports, the detection results of ADR signals, and the distribution characteristics of ADR signals may help understand the safety profile of drugs and optimize clinical practice.