Tributyltin (TBT) is an environmental contaminant that induces diverse toxic effects in mammals, but the cellular mechanisms underlying adaptation to TBT stress remain poorly understood. Conjugation of ATG8s to single membranes (CASM) is a noncanonical LC3‑lipidation pathway activated by various stressors, distinct from canonical autophagy. We previously showed that TBT reduces lysosomal acidity and inhibits autophagy in SH-SY5Y cells. Furthermore, we observed TBT-induced LC3-II accumulation, which was reduced by bafilomycin A1, and tubular LC3-positive structures as hallmarks of CASM. In this study, we investigated whether TBT activates CASM. TBT (700nM) induced LC3-II accumulation, which was completely blocked by bafilomycin A1 in SH-SY5Y and HeLa cells. Unlike autophagy, TBT induced LC3-II accumulation even under class III PI3K inhibition by wortmannin and in FIP200-knockout cells. Salmonella effector protein SopF, which inhibits V-ATPase-ATG16L1 association required for CASM, inhibited TBT-induced LC3-II accumulation. In FIP200-knockout cells, TBT induced LC3 accumulation on lysosomes, the primary CASM target. TBT also promoted nuclear translocation of transcription factor EB (TFEB) in a SopF-sensitive manner. Together, these results identify CASM as a lysosomal stress response to TBT, induced via the V-ATPase-ATG16L1 axis, leading to TFEB activation. This mechanism provides a toxicological framework for understanding xenobiotic-induced lysosomal adaptations.

Mitochondria-immobilized fluorescent probes for viscosity and cellular imaging.

A dual-responsive polyacrylamide sensor for colorimetric and fluorescent detection of Cu2.

The resurgence of mpox, caused by the mpox virus (MPXV), has intensified the demand for effective antiviral agents. This study evaluates the antiviral activity of piceatannol, a natural polyphenol, utilizing vaccinia virus (VACV) as a model due to the genetic conservation between the two viruses. In vitro experiments demonstrated that piceatannol significantly inhibited VACV replication through both extracellular enveloped virus (EEV), and intracellular mature virus (IMV), with median effective concentrations (EC 50 ) of 76.27 μM, and 63.93 μM, respectively. Further analysis revealed that piceatannol also reduced VACV entry and replication in HeLa cells. Molecular docking studies revealed a stable interaction between piceatannol and the palmitoylated F13 protein of VACV, with a calculated binding energy of−19.06 kcal/mol. This interaction suggests a mechanism by which piceatannol inhibits the generation of EEV. Additionally, piceatannol effectively limited the spread of VACV in cell cultures and exhibited significant virucidal effects on both the IMV and EEV forms. Collectively, our findings suggest that piceatannol holds promise as a therapeutic agent against orthopoxviruses infections by modulating key viral processes, warranting further exploration in clinical settings.

Enterovirus A/B is a significant pathogen responsible for a wide range of human diseases. Currently, effective preventive and therapeutic strategies against these viruses remain limited. Timosaponin BII is the active ingredient of a natural product with potential antioxidant and anti-inflammatory properties. This study aims to investigate the antiviral activity of Timosaponin BII and elucidate its underlying mechanism, thereby providing a scientific basis for the development of novel broad-spectrum anti-enterovirus agent. Firstly, systems pharmacology approaches were employed to integrate the potential targets of Timosaponin BII and predict its mechanism of action. Subsequently, the antiviral activity against representative strains of enterovirus A/B (EV-A71 for enterovirus A and CVB3 for enterovirus B respectively) was verified through cell morphology observation and CCK-8 assay in interferon-deficient Vero cells. Finally, the inhibitory effect on viral replication was assessed using a time-course drug addition experiment in non-interferon-deficient HeLa cells, and the inhibitory effect on viral proteins was detected by Western Blot. Timosaponin BII exhibited significant antiviral activity against enterovirus A and B at the cellular level, with EC50 values of 0.54μM against EV-A71 and 2.59μM against CVB3 at 48h post-infection. Quantitative real-time PCR (qRT-PCR) analysis revealed that the levels of EV-A71 and CVB3 viral VP1 RNA in the group treated with Timosaponin BII simultaneously with viral infection were lower than those in the viral infection group. Western blot results showed that Timosaponin BII could reduce the expression level of viral protein. Timosaponin BII, a potential broad-spectrum antiviral agent, exhibits antiviral activity against EV-A71 and CVB3. Its antiviral mechanism may involve the synergistic interaction of multiple targets and signaling pathways.

Cisplatin resistance severely limits the efficacy of chemotherapy for cervical cancer (CC), and its molecular mechanisms remain incompletely understood. While epigenetic alterations such as DNA methylation are recognized as important contributors, the upstream regulatory networks, particularly the role of long non-coding RNAs (lncRNAs), are still unclear. This study aimed to explore novel mechanisms influencing cisplatin resistance in cervical cancer. Cisplatin-resistant CC cells (HeLa and SiHa) were established. A comprehensive approach employing mRNA and lncRNA microarrays, RT-qPCR, methylation-specific PCR (MSP-PCR), chromatin immunoprecipitation, luciferase reporter assays, RNA pull-down, RNA immunoprecipitation, cellular functional assays, and a mouse subcutaneous xenograft tumor model was utilized. The study found that Kallikrein 10 (KLK10) expression was significantly downregulated in cisplatin-resistant CC cells due to promoter hypermethylation mediated by DNA methyltransferase 1 (DNMT1). LncRNA microarray analysis revealed that TMPO-AS1 was the most significantly upregulated lncRNA in resistant cells. Functional assays confirmed that TMPO-AS1 promoted cisplatin resistance, proliferation, migration, and invasion of CC cells. Mechanistically, TMPO-AS1 acted as a competitive endogenous RNA (ceRNA) by sponging miR-140-5p, thereby relieving its inhibitory effect on DNMT1 mRNA, upregulating DNMT1 expression, enhancing KLK10 promoter methylation, and leading to its silencing. In vivo experiments further demonstrated that silencing TMPO-AS1 inhibited tumor growth. This study unveils a novel TMPO-AS1/miR-140-5p/DNMT1/KLK10 regulatory axis that plays a critical role in cisplatin resistance in CC, providing a potential therapeutic target for overcoming chemoresistance.

Indoleamine 2,3-dioxygenase (IDO) is a heme-dependent enzyme that catalyzes the first, rate-limiting step of the kynurenine pathway─the oxidation of l-tryptophan to N-formylkynurenine (NFK). IDO-catalyzed depletion of tryptophan levels and accumulation of kynurenine pathway metabolites is an important control mechanism of the immune responses in cells. IDO has been considered as a dioxygenase because two atoms of oxygen are inserted into the substrate. Here, we use LC-MS and NMR to examine the reactivity of human IDO (hIDO) with l-tryptophan (l-Trp) and several other tryptophan analogues. Alongside dioxygenase activity, we identify a concurrent pathway of heme-dependent monooxygenase activity in the reaction of hIDO with l-Trp, leading to the formation of a cyclic 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid (HPIC) species. Reaction profiles for the reaction of hIDO with other tryptophan analogues are likewise examined. Formation of HPIC from l-Trp is reproduced in HeLa cells induced to overexpress hIDO, indicating that this dual dioxygenase/monooxygenase reactivity also occurs biologically. Notably, the reaction of hIDO with β-[3-benzo(b)thienyl]-l-alanine (S-l-Trp)─a known inhibitor ─yielded only the cyclic HPIC analogue, suggesting that IDO activity can be selectively directed toward the monooxygenase pathway. Molecular dynamics simulations underscore the critical role of substrate plasticity within the active site of hIDO, while DFT calculations provide a mechanistic rationalization for the observed product distributions. Together, the data demonstrate dual dioxygenase/monooxygenase functionality for human IDO. As the overall gatekeeper for control of tryptophan levels in cells, the findings provide mechanistic information on relevance to therapeutic strategies focused on IDO inhibition.

Background: Medicinal plants used in traditional Mexican medicine represent a valuable source of bioactive compounds with potential anticancer activity. Beyond cytotoxic potency, selectivity toward cancer cells over normal cells is a critical toxicological parameter for identifying safer therapeutic candidates. This study aimed to evaluate the selective cytotoxic and antiproliferative effects of extracts from four Mexican medicinal plants across human cancerous and non-cancerous cell lines. Methods: Hexane, acetone, and methanolic extracts from Semialarium mexicanum, Eryngium heterophyllum, Piper auritum, and Cochlospermum vitifolium were evaluated in a panel of human cancer cell lines and non-tumoral models, including primary human uterine fibroblasts (HUFs). Cytotoxicity was assessed after 48 h of treatment using increasing extract concentrations, and selectivity indices were calculated. Cell cycle distribution and nuclear morphology analyses were performed to explore antiproliferative effects. Additionally, GC–MS-based chemical profiling was conducted on selected extracts to obtain a tentative characterization of major bioactive constituents. Results: The extracts exhibited differential cytotoxic profiles depending on plant species and solvent polarity. The hexane extract of Semialarium mexicanum showed the highest cytotoxic potency and selectivity toward cervical cancer cells, with half-maximal inhibitory concentration (IC50); values of 15.9 ± 1.8 µg/mL and 17.2 ± 2.8 µg/mL in HeLa and SiHa cells, respectively, and selectivity index (SI) values > 5 when compared with primary human uterine fibroblasts (HUF). Extracts of Eryngium heterophyllum displayed moderate cytotoxic activity (IC50 = 20–30 µg/mL in HeLa cells) with intermediate selectivity, whereas Cochlospermum vitifolium showed solvent-dependent effects and Piper auritum exhibited limited cytotoxicity. Cell cycle analysis revealed an increased sub-G1 population, and nuclear morphology assays demonstrated chromatin condensation and fragmentation in cancer cells, supporting an antiproliferative mechanism. GC–MS analysis of the hexane extract of Semialarium mexicanum suggested the presence of triterpenoid-related and other lipophilic compounds potentially associated with its selective anticancer activity. Conclusions: These findings provide in vitro evidence of selective anticancer activity of Mexican medicinal plant extracts and establish a basis for future mechanistic studies medicinal plant extracts and lay the groundwork for future mechanistic investigations.

The utility of lanthanide-based circularly polarized luminescence (CPL) probes in biological systems is frequently limited by kinetic lability and excitation-related toxicity. To overcome these barriers, we have engineered rigid chiral Ir(III)-Eu(III) dyads (Ir-Eu-R and Ir-Eu-S) using a stereoselective ″complex-as-ligand″ strategy. This architecture features a kinetically inert DO3A macrocycle (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) that effectively preserves the stereochemical environment, yielding intense CPL (|glum| = 0.12) with substantial brightness (BCPL ≈ 8 M-1 cm-1). Simultaneously, the integrated Ir(III) antenna enables benign visible-light sensitization (λex = 425 nm), facilitating low-phototoxicity confocal imaging in HeLa cells. Crucially, the probe's structural rigidity ensures exceptional stability against biological interferents; spectroscopic titration with ct-DNA confirms the preservation of chiroptical signals without conformational distortion. This work presents a general coordination strategy for constructing robust, bright, and visible-light-excitable rare-earth chiroptical materials, opening new avenues for specific chiroptical bioimaging and enantioselective sensing applications.

Preparation and characterization of a series of oligo(ethylene glycol)methylether functionalized alkynyl gold(i) complexes capped with AuPPh3 (1a–1d) or dppfAu2 (dppf, 1,1′-bis(diphenyphosphino)ferrocene) (2a–2d) have been accomplished. The structures of 1b and 1c were established by X-ray crystallography. Their in vitro antitumor activities were measured by the CCK8 method against A549 and HeLa cells. The studies indicated that the cytotoxic activity in vitro was fine-tuned by modification of both the gold(i) centers and the oligo(ethylene glycol)methylether ancillary ligands. Compared to the dppfAu2 series, the AuPPh3 series showed better cytotoxicity. Especially, complex 4-(OCH2CH2OCH2CH2OCH3)C6H4CCreated by potrace 1.16, written by Peter Selinger 2001-2019]]>CAuPPh3 (1d) displayed strong anticancer activity toward both cancer cells due to the strong inhibition of thioredoxin reductase (TrxR).

Microfluidic assembly and biomimetic lipid coating modulate the structure, stability, and biological interactions of P(DMAEMA-co-SMA)/DNA lipopolyplexes.

Green-emitting carbon dots from Protocatechuic acid and branched PEI: A multifunctional platform for bioimaging and gene delivery.

Employing phosphonate and phosphinate ligands for prodrug development of the mitochondrial calcium uniporter inhibitor Ru265.

A novel fluorescent "turn-on" probe, N'-((2-hydroxynaphthalen-1-yl) methylene)-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbohydrazide (G3), was designed and synthesized. The structure was fully characterized by 1H NMR, 13C NMR, and MS. G3 exhibits highly selective and sensitive fluorescence enhancement toward aluminum ions in aqueous solution. Job's plot analysis, 1H NMR titration, and mass spectrometric studies confirm a 1:1 binding stoichiometry between G3 and Al3+, which is further supported by density functional theory (DFT) and quantum chemical calculations elucidating the sensing mechanism. Notably, the probe achieves an exceptionally low detection limit of 1.162 nM, outperforming most previously reported Al3+ sensors. Practical applicability was demonstrated through Al3+ detection in environmental water samples and the development of a portable swab test kit. Cytotoxicity assays reveal low cellular toxicity, while fluorescence imaging in HeLa cells and zebrafish confirms its biocompatibility and bioimaging capability. These results highlight G3 as a promising probe with high sensitivity, excellent selectivity, and significant potential for applications in environmental monitoring and biological sensing.

Viscosity-sensitive fluorescent probes based on the hemicyanine for the organelle-specific visualization during autophagy and ferroptosis.

Design, synthesis, and biological evaluation of 2-(benzylthio)-5-(indol-3-yl)-1,3,4-oxadiazole derivatives as tubulin polymerization inhibitors with potential anti-cancer effects.

A bilirubin-gold nanoconjugate photosensitizer for photothermal/photodynamic therapy of HeLa cells through glutathione depletion and ROS generation.

Design, synthesis and bioevaluation of novel combretastatin A-4 based derivatives as potent tubulin/HDAC6 dual-target inhibitors for cancer therapy.

N-acylated aminoguanidine-benzenesulfonamides: rational design, synthesis, and dual apoptotic mechanisms of anticancer activity involving VEGFR-2 inhibition and VEGFR-2-independent pathways.

Salmonella Typhimurium StiP-mediated upregulation of membrane protein Alx drives complement evasion via CFI-dependent C3b degradation.