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Tebuconazole (TEB), a prominent chiral triazole fungicide, has been extensively utilized for plant pathogen control globally. Despite experimental evidence of TEB metabolism in mammals, the enantioselectivity in the biotransformation of R- and S-TEB enantiomers by specific CYP450s remains elusive. In this work, integrated in silico simulations were employed to unveil the binding interactions and enantioselective metabolic fate of TEB enantiomers within human CYP1A2, 2B6, 2E1, and 3A4. Molecular dynamics (MD) simulations clearly delineated the binding specificity of R- and S-TEB to the four CYP450s, crucially determining their differences in metabolic activity and enantioselectivity. The primary driving force for robust ligand binding was identified as van der Waals interactions with CYP450s, particularly involving the hydrophobic residues. Mechanistic insights derived from quantum mechanics/molecular mechanics (QM/MM) calculations established C2-methyl hydroxylation as the predominant route of R-/S-TEB metabolism, while C6-hydroxylation and triazol epoxidation were deemed kinetically infeasible pathways. Specifically, the resulting hydroxy-R-TEB metabolite primarily originates from R-TEB biotransformation by 1A2, 2E1 and 3A4, whereas hydroxy-S-TEB is preferentially produced by 2B6. These findings significantly contribute to our comprehension of the binding specificity and enantioselective metabolic fate of chiral TEB by CYP450s, potentially informing further research on human health risk assessment associated with TEB exposure.
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Luminescent materials with narrowband emission show great potential for diverse applications in optoelectronics. Purely organic phosphors with room-temperature phosphorescence (RTP) have made significant success in rationally manipulating quantum efficiency, lifetimes, and colour gamut in the past years, but there is limited attention on the purity of the RTP colours. Herein we report a series of closed-loop molecules with narrowband phosphorescence by multiple resonance effect, which significantly improves the colour purity of RTP. Phosphors show narrowband phosphorescence with full width at half maxima (FWHM) of 30 nm after doping into a rigid benzophenone matrix under ambient conditions, of which the RTP efficiency reaches 51.8%. At 77 K, the FWHM of phosphorescence is only 11 nm. Meanwhile, the colour of narrowband RTP can be tuned from sky blue to green with the modification of methyl groups. Additionally, the potential applications in X-ray imaging and display are demonstrated. This work not only outlines a design principle for developing narrowband RTP materials but also makes a major step forward extending the potential applications of narrowband luminescent materials in optoelectronics.
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Acute liver failure (ALF) is a potentially fatal disorder characterized by extensive hepatocyte necrosis and rapid decline in liver function. Numerous factors, including oxidative stress, cell death, and inflammatory responses, are associated with its pathogenesis. Endotoxin tolerance (ET) refers to the phenomenon in which the body or cells exhibit low or no response to high-dose lipopolysaccharide (LPS) stimulation after pre-stimulation with low-dose LPS. However, the specific mechanism through which ET regulates LPS/D-galactosamine (D-GalN)-induced ALF remains unclear. An ALF mouse model was established by intraperitoneal injection of D-GalN (400 mg/kg) and LPS (10 mg/kg). A low dose of LPS (0.1 mg/kg/d) was continuously administered to mice for 5 d before modeling to assess the protective effect of ET. The data from this study showed that ET alleviated the inflammatory response in mice with LPS/D-GalN-induced ALF. ET inhibited LPS-induced oxidative damage and pyroptosis in macrophages in vitro. RNA sequencing analysis showed that the NF-κB/NLRP3 pathway was linked to the anti-inflammatory and antioxidative effects of ET. Furthermore, using western blot, RT-qPCR, and immunofluorescence, we verified that ET inhibited the NF-κB/NLRP3 pathway and triggered the Nrf2/HO-1 signaling pathway to attenuate oxidative stress and cell pyroptosis. Sirt1 knockdown reversed this protective effect. In summary, our research elucidates that ET prevents ALF advancement by upregulating Sirt1 levels, triggering the Nrf2/HO-1 signaling axis, and suppressing the NF-κB/NLRP3 signaling cascade to inhibit oxidative stress and cell pyroptosis. Our results provide a mechanistic explanation for the protective effect of ET against ALF.
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Galactosamina , Lipopolissacarídeos , Falência Hepática Aguda , Transdução de Sinais , Animais , Masculino , Camundongos , Modelos Animais de Doenças , Endotoxinas/toxicidade , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Tolerância Imunológica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Fígado/imunologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Sirtuína 1/genéticaRESUMO
Phosphorescence is ubiquitous in heavy atom-containing organic phosphors, which attracts considerable attention in optoelectronics and bioelectronics. However, heavy atom-free organic materials with efficient phosphorescence are rare under ambient conditions. Herein, we report a series of adaptive host-guest materials derived from dibenzo-heterocyclic analogues, showing host-dependent color-tunable phosphorescence with phosphorescence efficiency of up to 98.9%. The adaptive structural deformation of the guests arises from the hyperconjugation, namely the nâπ* interaction, enabling them to inhabit the cavity of host crystals in synergy with steric effects. Consequently, a perfect conformation match between host and guest molecules facilitates the suppression of triplet exciton dissipation, thereby boosting the phosphorescence of these adaptive materials. Moreover, we extend this strategy to a ternary host-guest system, yielding both excitation- and time-dependent phosphorescence with a phosphorescence efficiency of 92.0%. This principle provides a concise way for obtaining efficient and color-tunable phosphorescence, making a major step toward potential applications in optoelectronics.
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Non-invasive therapies such as photodynamic therapy (PDT) and chemodynamic therapy (CDT) have received wide attention due to their low toxicity and side effects, but their efficacy is limited by the tumor microenvironment (TME), and monotherapy cannot achieve satisfactory efficacy. In this work, a multifunctional nanoparticle co-assembled from oleanolic acid (OA), chlorin e6 (Ce6) and hemin was developed. The as-constructed nanoparticle named OCH with diameters of around 130 nm possessed good biostability, pH/GSH dual-responsive drug release properties, and remarkable cellular internalization and tumor accumulation capabilities. OCH exhibited prominent catalytic activities to generate â¢OH, deplete GSH, and produce O2 to overcome the hypoxia TME, thus potentiating the photodynamic and chemodynamic effect. In addition, OCH can induce the occurrence of ferroptosis in both ferroptosis-sensitive and ferroptosis-resistant cancer cells. The multi-pronged effects of OCH including hypoxia alleviation, GSH depletion, ferroptosis induction, CDT and PDT effects jointly facilitate excellent anticancer effects in vitro and in vivo. Hence, this work will advance the development of safe and effective clinically transformable nanomedicine by employing clinically-applied agents to form drug combinations for efficient multi-pronged combination cancer therapy.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Terapia Combinada , Neoplasias/tratamento farmacológico , Liberação Controlada de Fármacos , Hipóxia , Nanomedicina , Microambiente Tumoral , Linhagem Celular Tumoral , Peróxido de HidrogênioRESUMO
Dynamic luminescence behavior by external stimuli, such as light, thermal field, electricity, mechanical force, etc., endows the materials with great promise in optoelectronic applications. Upon thermal stimulus, the emission is inevitably quenched due to intensive non-radiative transition, especially for phosphorescence at high temperature. Herein, we report an abnormal thermally-stimulated phosphorescence behavior in a series of organic phosphors. As temperature changes from 198 to 343 K, the phosphorescence at around 479 nm gradually enhances for the model phosphor, of which the phosphorescent colors are tuned from yellow to cyan-blue. Furthermore, we demonstrate the potential applications of such dynamic emission for smart dyes and colorful afterglow displays. Our results would initiate the exploration of dynamic high-temperature phosphorescence for applications in smart optoelectronics. This finding not only contributes to an in-depth understanding of the thermally-stimulated phosphorescence, but also paves the way toward the development of smart materials for applications in optoelectronics.
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Lateral flow immunoassay (LFIA), a classical point-of-care testing (POCT) technique, plays an important role in disease screening and healthcare monitoring. However, traditional LFIA is either designed for qualitative analysis or requires expensive equipment for quantification, limiting its use in household diagnosis. In this study, we proposed a new generation of LFIA for household health monitoring by using ultralong organic phosphorescence (UOP) nanomaterials as afterglow nanoprobes with a self-developed palm-size sensing device. The UOP nanoprobes exhibit a phosphorescence signal with a second-level lifetime, which completely avoids the interference from excitation light and biological background fluorescence. Therefore, an ultraminiaturized and low-cost UOP nanosensor was successfully designed by eliminating the complex optical path and filtering systems. We chose an inflammatory factor, C-reactive protein (CRP), for household POCT validation. The whole analysis was completed within 9 min. A limit of detection (LOD) of 0.54 ng/mL of CRP antigen was achieved with high stability and good specificity, which is comparable to laboratory instruments and fully satisfying the clinical diagnosis requirement.
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Nanoestruturas , Imunoensaio/métodos , Limite de DetecçãoRESUMO
Organic phosphors offer a promising alternative in optoelectronics, but their temperature-sensitive feature has restricted their applications in high-temperature scenarios, and the attainment of high-temperature phosphorescence (HTP) is still challenging. Herein, a series of organic cocrystal phosphors are constructed by supramolecular assembly with an ultralong emission lifetime of up to 2.16â s. Intriguingly, remarkable stabilization of triplet excitons can also be realized at elevated temperature, and green phosphorescence is still exhibited in solid state even up to 150 °C. From special molecular packing within the crystal lattice, it has been observed that the orientation of isolated water cluster and well-controlled molecular organization via multiple interactions can favor the structural rigidity of cocrystals more effectively to suppress the nonradiative transition, thus resulting in efficient room-temperature phosphorescence and unprecedented survival of HTP.
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Metastatic cancer is a major cause of cancer-related mortality; however, the complex regulation process remains to be further elucidated. A large amount of preliminary investigations focus on the role of epigenetic mechanisms in cancer metastasis. Notably, the posttranslational modifications were found to be critically involved in malignancy, thus attracting considerable attention. Beyond acetylation, novel forms of acylation have been recently identified following advances in mass spectrometry, proteomics technologies, and bioinformatics, such as propionylation, butyrylation, malonylation, succinylation, crotonylation, 2-hydroxyisobutyrylation, lactylation, among others. These novel acylations play pivotal roles in regulating different aspects of energy mechanism and mediating signal transduction by covalently modifying histone or nonhistone proteins. Furthermore, these acylations and their modifying enzymes show promise regarding the diagnosis and treatment of tumors, especially tumor metastasis. Here, we comprehensively review the identification and characterization of 11 novel acylations, and the corresponding modifying enzymes, highlighting their significance for tumor metastasis. We also focus on their potential application as clinical therapeutic targets and diagnostic predictors, discussing the current obstacles and future research prospects.
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Histonas , Neoplasias , Humanos , Acilação , Histonas/metabolismo , Acetilação , Processamento de Proteína Pós-Traducional , Neoplasias/genéticaRESUMO
Hollow and porous plasmonic nanomaterials have been demonstrated for highly sensitive biosensing applications due to their distinctive optical properties. Immunosensors, which rely on antibody-antigen interactions, are essential constituents of diverse biosensing platforms owing to their exceptional binding affinity and selectivity. The majority of immunosensors and conventional bioassays needs special storage conditions and cold chain systems for transportation. Prostate-specific antigen (PSA), a serine protease, is widely employed in the diagnosis of prostate cancer. In this study, we present the successful utilization of a biopolymer-preserved plasmonic biosensor with improved environmental stability for the sensitive detection of PSA. The preserved plasmonic biosensors exhibited sustained sensitivity in the detection of PSA, achieving a limit of detection of 10 pg mL-1. Furthermore, these biosensors exhibited remarkable stability at elevated temperatures for one week.
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Técnicas Biossensoriais , Nanoestruturas , Neoplasias da Próstata , Masculino , Humanos , Antígeno Prostático Específico , Imunoensaio , Nanoestruturas/químicaRESUMO
Bangia fusco-purpurea is an economically important seaweed with Fujian characteristics. Given that its harvest is seasonal, drying is often used to remove moisture, extend storage time, and facilitate further processing. Hence, the current study sought to explore the impact of different drying processes on the quality and volatile fingerprints of Bangia fusco-purpurea. To this end, the effects of hot air drying (HAD) and vacuum freeze drying (VFD) on the drying characteristics, microstructure, rehydration, and volatile components of dried B. fusco-purpurea were investigated. The results showed that the water removal efficiency of HAD was significantly higher than that of VFD. However, VFD better preserved the skeletal structure of B. fusco-purpurea than HAD, with a faster rehydration rate and a more uniform cell structure after rehydration. Using electronic nose and comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC × GC-TOF MS), significant differences in the volatile profiles of fresh, HAD, and VFD B. fusco-purpurea were assessed. E-nose analysis revealed that both HAD and VFD treatments significantly reduced sulfides, aromatic compounds, and nitrogen oxides in fresh B. fusco-purpurea. However, the alcohol, aldehyde, and ketone contents were lower in the VFD samples compared with HAD and fresh samples, whereas the content of methyl flavor substances was significantly higher. GC × GC-TOF MS analysis revealed that the most abundant volatile categories in HAD and VFD were hydrocarbons, alcohols, and esters. The number of volatile components in the HAD samples was significantly lower than in the VFD and fresh samples. As drying progressed, hydrocarbons and alcohols were formed in dried B. fusco-purpurea due to the thermal degradation of carbohydrates, lipids, amino acids, and the Maillard reaction. There were also significant flavor differences between HAD and VFD B. fusco-purpurea. Thus, although HAD exhibits better drying efficiency, VFD has more significant advantages in terms of product quality.
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Ultralong organic phosphorescence (UOP) materials have attracted considerable attention in recent years. Herein, a new type of flexible films is fabricated by doping amphipathic pyrene tetrasulfonic acid sodium salts into amorphous poly(vinyl alcohol) matrix, which enables the realization of color-tunable UOP spanning from orange-red to green after excitation light is switched off. Interestingly, precise control of the proportion of isolated-molecular and aggregated-state phosphorescence is demonstrated for colorful afterglow using photo-activation. An increase in the dynamic phosphorescence lifetime of isolated molecules is observed from 894.75 to 1735.71 ms following an 8 min irradiation under ambient conditions. The photo-activation, however, showed little influence on aggreated-state phosphorescence. This flexible and processable film exhibits versatile applications in multicolor afterglow displays, ultraviolet detection, multilevel information encryption, etc. This study not only provides a strategy for the rational regulation of UOP colors but also expands the application potential of color-tunable UOP materials.
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Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid ß-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes. With limited treatment options, we explored the use of human MCAD (hMCAD) mRNA in fibroblasts from patients with MCAD deficiency to provide functional MCAD protein and reverse the metabolic block. Transfection of hMCAD mRNA into MCAD- deficient patient cells resulted in an increased MCAD protein that localized to mitochondria, concomitant with increased enzyme activity in cell extracts. The therapeutic hMCAD mRNA-lipid nanoparticle (LNP) formulation was also tested in vivo in Acadm-/- mice. Administration of multiple intravenous doses of the hMCAD mRNA-LNP complex (LNP-MCAD) into Acadm-/- mice produced a significant level of MCAD protein with increased enzyme activity in liver, heart and skeletal muscle homogenates. Treated Acadm-/- mice were more resistant to cold stress and had decreased plasma levels of medium-chain acylcarnitines compared to untreated animals. Furthermore, hepatic steatosis in the liver from treated Acadm-/- mice was reduced compared to untreated ones. Results from this study support the potential therapeutic value of hMCAD mRNA-LNP complex treatment for MCAD deficiency.
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Acil-CoA Desidrogenases , Fibroblastos , Humanos , Camundongos , Animais , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/metabolismo , RNA Mensageiro/genética , Modelos Animais de Doenças , Fibroblastos/metabolismoRESUMO
The distal metastasis of tumor cells is viewed as a series of concurrent processes rather than a linear cascade of events. Accompanied with the progression of the primary tumor, a favorable microenvironment, refered as pre-metastatic niche, has been created in pre-metastatic organs and sites by primary tumors for subsequent metastases. The proposal of "pre-metastatic niche" theory brings fresh insight into our understanding of cancer metastasis. Myeloid-derived suppressor cells (MDSCs) are indispensable for the formation of pre-metastatic niche, which empower the niche to favor tumor cell colonization and promote metastasis. In this review, we aim to provide a comprehensive understanding of the regulation of pre-metastatic niche formation by MDSCs and to conceptualize the framework for understanding the related factors involved in cancer metastasis.
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Células Supressoras Mieloides , Neoplasias , Humanos , Células Supressoras Mieloides/patologia , Neoplasias/patologia , Microambiente Tumoral , Metástase NeoplásicaRESUMO
Dynamic room temperature phosphorescence (RTP) materials have potential applications in optoelectronics, which inevitably suffer from poor processability, flexibility or stretchability. Herein, we report a concise strategy to develop supercooled liquids (SCLs) with dynamic RTP behavior using terminal hydroxyl engineering. The terminal hydroxyls effectively hinder the nucleation process of molecules for the formation of stable SCLs after thermal annealing. Impressively, the SCLs show reversible RTP emission via alternant stimulation by UV light and heat. Photoactivated SCLs have phosphorescent efficiency of 8.50 % and a lifetime of 31.54â ms under ambient conditions. Regarding the dynamic RTP behavior and stretchability of SCLs, we demonstrate the applications in erasable data encryption and patterns on flexible substrates. This finding provides a design principle for obtaining SCLs with RTP and expands the potential applications of RTP materials in flexible optoelectronics.
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Purely organic phosphorescent materials with dynamically tunable optical properties and persistent luminescent characteristics enable more novel applications in intelligent optoelectronics. Herein, we reported a concise and universal strategy to achieve photoactivated ultralong phosphorescence at room temperature through stereo-hindrance engineering. Such dynamically photoactivated phosphorescence behavior was ascribed to the suppression of non-radiative transitions and improvement of spin-orbit coupling (SOC) as the variation of the distorted molecular conformation by the synergistic effect of electrostatic repulsion and steric hindrance. This "trainable" phosphorescent behavior was first proposed to mimic biological synaptic plasticity, especially for unique experience-dependent plasticity, by the manipulation of pulse intensity and numbers. This study not only outlines a principle to design newly dynamic phosphorescent materials, but also broadens their utility in intelligent sensors and robotics.
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Organic scintillators, materials with the ability to exhibit luminescence when exposed to X-rays, have aroused increasing interest in recent years. However, the enhancement of radioluminescence and improving X-ray absorption of organic scintillators lie in the inherent dilemma, due to the waste of triplet excitons and weak X-ray absorption during scintillation. Here, we employ halogenated thermally activated delayed fluorescence materials to improve the triplet exciton utilization and X-ray absorption simultaneously, generating efficient scintillation with a low detection limit, which is one order of magnitude lower than the dosage for X-ray medical diagnostics. Through experimental study and theoretical calculation, we reveal the positive role of X-ray absorption, quantum yields of prompt fluorescence, and intersystem crossing in promoting the radioluminescence intensity. This finding offers an opportunity to design diverse types of organic scintillators and expands the applications of thermally activated delayed fluorescence.
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Carbon dots (CDs) have gradually become a new generation of nano-luminescent materials, which have received extensive attention due to excellent optical properties, wide source of raw materials, low toxicity, and good biocompatibility. In recent years, there are many reports on the luminescent phenomenon of CDs, and great progress has been achieved. However,there are rarely systematic summaries on CDs with persistent luminescence. Here, a summary of the recent progress on persistent luminescent CDs, including luminous mechanism, synthetic strategies, property regulation, and potential applications, is given. First, a brief introduction is given to the development of CDs luminescent materials. Then, the luminous mechanism of afterglow CDs from room temperature phosphorescence (RTP), delayed fluorescence (DF), and long persistent luminescence (LPL) is discussed. Next, the constructed methods of luminescent CDs materials are summarized from two aspects, including matrix-free self-protected and matrix-protected CDs. Moreover, the regulation of afterglow properties from color, lifetime, and efficiency is presented. Afterwards, the potential applications of CDs, such as anti-counterfeiting, information encryption, sensing, bio-imaging, multicolor display, LED devices, etc., are reviewed. Finally, an outlook on the development of CDs materials and applications is proposed.