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Ferroptosis holds significant potential for application in cancer therapy. However, ferroptosis inducers are not cell-specific and can cause phospholipid peroxidation in both tumor and non-tumor cells. This limitation greatly restricts the use of ferroptosis therapy as a safe and effective anticancer strategy. Our previous study demonstrated that macrophages can engulf ferroptotic cells through Toll-like receptor 2 (TLR2). Despite this advancement, the precise mechanism by which phospholipid peroxidation in macrophages affects their phagocytotic capability during treatment of tumors with ferroptotic agents is still unknown. Here, we utilized flow sorting combined with redox phospholipidomics to determine that phospholipid peroxidation in tumor microenvironment (TME) macrophages impaired the macrophages ability to eliminate ferroptotic tumor cells by phagocytosis, ultimately fostering tumor resistance to ferroptosis therapy. Mechanistically, the accumulation of phospholipid peroxidation in the macrophage endoplasmic reticulum (ER) repressed TLR2 trafficking to the plasma membrane and caused its retention in the ER by disrupting the interaction between TLR2 and its chaperone CNPY3. Subsequently, this ER-retained TLR2 recruited E3 ligase MARCH6 and initiated the proteasome-dependent degradation. Using redox phospholipidomics, we identified 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH) as the crucial mediator of these effects. Conclusively, our discovery elucidates a novel molecular mechanism underlying macrophage phospholipid peroxidation-induced tumor resistance to ferroptosis therapy and highlights the TLR2-MARCH6 axis as a potential therapeutic target for cancer therapy.
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BACKGROUND There are many factors that affect human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS)-related deaths, and different antiretroviral therapy (ART) strategies may affect HIV/AIDS-related fatality rates. However, studies on this area are very limited. This study aimed to evaluate the factors associated with HIV/AIDS-related mortality and the impact of different ART strategies in Lu'an City, Anhui Province, China, 1999-2023. MATERIAL AND METHODS Data of HIV/AIDS cases were downloaded from the China HIV/AIDS Comprehensive Response Information Management System, and were assessed to evaluate the impact of different ART strategies on the related fatality rate using interrupted time series (ITS). RESULTS We found that age at diagnosis of 15 years, 25 years, 40 years, and 60 years, as well as receiving ART, were protective factors against death (with P below 0.05), while lower CD4 count at the last CD4 count and the year of diagnosis before 2007 and between 2007 and 2016 were risk factors (with P below 0.05). ITS analysis revealed that in the year of the introduction of free ART in 2006, the fatality rate decreased by 38.60% (P=0.015). The fatality rate trend from 2006 to 2015 was -1.1%, which was not statistically significant (P=0.434). The fatality rate trend from 2016 to 2023 was -0.33%, indicating a decreasing trend (P=0.000). CONCLUSIONS Children under 15 years old and elderly patients had a higher risk of death. The main reasons for the decrease in HIV/AIDS-related fatality rate were ART, especially the "early treatment" strategy.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , Adulto , China/epidemiologia , Masculino , Feminino , Síndrome da Imunodeficiência Adquirida/mortalidade , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Pessoa de Meia-Idade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , Adolescente , Fatores de Risco , Contagem de Linfócito CD4 , Adulto Jovem , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Cidades/epidemiologia , Terapia Antirretroviral de Alta AtividadeRESUMO
Pathogenic infection leads to excessive senescent cell accumulation and stagnation of wound healing. To address these issues, we devise and develop a hydrogen selenide (H2Se)-evolving bio-heterojunction (bio-HJ) composed of graphene oxide (GO) and FeSe2 to deracinate bacterial infection, suppress cellular senescence and remedy recalcitrant infected wounds. Excited by near-infrared (NIR) laser, the bio-HJ exerts desired photothermal and photodynamic effects, resulting in rapid disinfection. The crafted bio-HJ could also evolve gaseous H2Se to inhibit cellular senescence and dampen inflammation. Mechanism studies reveal the anti-senescence effects of H2Se-evolving bio-HJ are mediated by selenium pathway and glutathione peroxidase 1 (GPX1). More critically, in vivo experiments authenticate that the H2Se-evolving bio-HJ could inhibit cellular senescence and potentiate wound regeneration in rats. As envisioned, our work not only furnishes the novel gasotransmitter-delivering bio-HJ for chronic infected wounds, but also gets insight into the development of anti-senescence biomaterials.
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Senescência Celular , Grafite , Cicatrização , Animais , Senescência Celular/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ratos , Grafite/química , Grafite/farmacologia , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Humanos , Masculino , Pele/patologia , Pele/efeitos dos fármacos , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/patologia , CamundongosRESUMO
Thymol has efficient bactericidal activity against a variety of pathogenic bacteria, but the bactericidal mechanism against Vibrio parahemolyticus (V. parahemolyticus) has rarely been reported. In the current study, we investigated the bactericidal mechanism of thymol against V. parahemolyticus. The Results revealed that 150 µg/mL of thymol had 99.9% bactericidal activity on V. parahemolyticus. Intracellular bursts of reactive oxygen species (ROS), Fe2+accumulation, lipid peroxidation, and DNA breakage were checked by cell staining. The exogenous addition of H2O2 and catalase promoted and alleviated thymol-induced cell death to a certain extent, respectively, and the addition of the ferroptosis inhibitor Liproxstatin-1 also alleviated thymol-induced cell death, confirming that thymol induced Fenton-reaction-dependent ferroptosis in V. parahemolyticus. Proteomic analysis revealed that relevant proteins involved in ROS production, lipid peroxidation accumulation, and DNA repair were significantly upregulated after thymol treatment. Molecular docking revealed two potential binding sites (amino acids 46H and 42F) between thymol and ferritin, and thymol could promote the release of Fe2+ from ferritin proteins through in vitro interactions analyzed. Therefore, we hypothesized that ferritin as a potential target may mediate thymol-induced ferroptosis in V. parahemolyticus. This study provides new ideas for the development of natural inhibitors for controlling V. parahemolyticus in aquatic products.
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Antibacterianos , Ferroptose , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Timol , Vibrio parahaemolyticus , Ferroptose/efeitos dos fármacos , Timol/farmacologia , Timol/química , Espécies Reativas de Oxigênio/metabolismo , Vibrio parahaemolyticus/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Antibacterianos/farmacologia , Antibacterianos/química , Peroxidação de Lipídeos/efeitos dos fármacos , Ferro/metabolismo , Simulação de Acoplamento Molecular , Ferritinas/genética , Ferritinas/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genéticaRESUMO
This work identified a class of cyanomethylquinolones (CQs) and their carboxyl analogues as potential multitargeting antibacterial candidates. Most of the prepared compounds showed high antibacterial activities against most of the tested bacteria, exhibiting lower MIC values (0.125-2 µg/mL) than those of clinical norfloxacin, ciprofloxacin, and clinafloxacin. The low hemolysis, drug resistance, and cytotoxicity, as well as good predictive pharmacokinetics of active CQs and carboxyl analogues revealed their development potential. Furthermore, they could eradicate the established biofilm, facilitating bacterial exposure to these antibacterial candidates. These active compounds could induce bacterial death through multitargeting effects, including intercalating into DNA, up-regulating reactive oxygen species, damaging membranes directly, and impeding metabolism. Moreover, the highly active cyclopropyl CQ 15 exhibited more effective in vivo anti-MRSA potency than ciprofloxacin. These findings highlight the potential of CQs and their carboxyl analogues as multitargeting broad-spectrum antibacterial candidates for treating intractable bacterial infections.
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Antibacterianos , Testes de Sensibilidade Microbiana , Quinolonas , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Animais , Quinolonas/farmacologia , Quinolonas/química , Quinolonas/síntese química , Humanos , Relação Estrutura-Atividade , Biofilmes/efeitos dos fármacos , Camundongos , Hemólise/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ciprofloxacina/farmacologia , Ciprofloxacina/química , Ciprofloxacina/análogos & derivados , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacosRESUMO
Malocclusion, identified by the World Health Organization (WHO) as one of three major oral diseases, profoundly impacts the dental-maxillofacial functions, facial esthetics, and long-term development of ~260 million children in China. Beyond its physical manifestations, malocclusion also significantly influences the psycho-social well-being of these children. Timely intervention in malocclusion can foster an environment conducive to dental-maxillofacial development and substantially decrease the incidence of malocclusion or reduce the severity and complexity of malocclusion in the permanent dentition, by mitigating the negative impact of abnormal environmental influences on the growth. Early orthodontic treatment encompasses accurate identification and treatment of dental and maxillofacial morphological and functional abnormalities during various stages of dental-maxillofacial development, ranging from fetal stages to the early permanent dentition phase. From an economic and societal standpoint, the urgency for effective early orthodontic treatments for malocclusions in childhood cannot be overstated, underlining its profound practical and social importance. This consensus paper discusses the characteristics and the detrimental effects of malocclusion in children, emphasizing critical need for early treatment. It elaborates on corresponding core principles and fundamental approaches in early orthodontics, proposing comprehensive guidance for preventive and interceptive orthodontic treatment, serving as a reference for clinicians engaged in early orthodontic treatment.
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Má Oclusão , Humanos , Criança , Consenso , Má Oclusão/epidemiologia , Assistência Odontológica , ChinaRESUMO
Multiplexed immunodetection, which achieves qualitative and quantitative outcomes for multiple targets in a single-run process, provides more sufficient results to guarantee food safety. Especially, lateral flow immunoassay (LFIA), with the ability to offer multiple test lines for analytes and one control line for verification, is a forceful candidate in multiplexed immunodetection. Nevertheless, given that single-signal mode is incredibly vulnerable to interference, further efforts should be engrossed on the combination of multiplexed immunodetection and multiple signals. Photothermal signal has sparked significant excitement in designing immunosensors. In this work, by optimizing and comparing the amount of gold, CuS@Au heterojunctions (CuS@Au HJ) were synthesized. The dual-plasmonic metal-semiconductor hybrid heterojunction exhibits a synergistic photothermal performance by increasing light absorption and encouraging interfacial electron transfer. Meanwhile, the colorimetric property is synergistic enhanced, which is conducive to reduce the consumption of antibodies and then improve assay sensitivity. Therefore, CuS@Au HJ are suitable to be constructed in a dual signal and multiplexed LFIA (DSM-LFIA). T-2 toxin and deoxynivalenol (DON) were used as model targets for the simulated multiplex immunoassay. In contrast to colloidal gold-based immunoassay, the built-in sensor has increased sensitivity by ≈ 4.42 times (colorimetric mode) and ≈17.79 times (photothermal mode) for DON detection and by ≈ 1.75 times (colorimetric mode) and ≈13.09 times (photothermal mode) for T-2 detection. As a proof-of-concept application, this work provides a reference to the design of DSM-LFIA for food safety detection.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Colorimetria , Imunoensaio , MetaisRESUMO
Immunochromatography (ICA) remains untapped toward enhanced sensitivity and applicability for fulfilling the nuts and bolts of on-site food safety surveillance. Herein, we report a fortified dual-spectral overlap with enhanced colorimetric/fluorescence dual-response ICA for on-site bimodal-type gentamicin (Gen) monitoring by employing polydopamine (PDA)-coated AuNPs (APDA) simultaneously serving as a colorimetric reporter and a fluorescence quencher. Availing of the enhanced colorimetric response that originated from the PDA layer, the resultant APDA exhibits less required antibody and immunoprobes in a single immunoassay, which facilitates improved antibody utilization efficiency and immuno-recognition in APDA-ICA. Further integrated with the advantageous features of fortified excitation and emission dual-spectral overlap for the Arg/ATT-AuNCs, this APDA-ICA with a "turn on/off" pattern achieves the visual limits of detection of 1.0 and 0.5 ng mL-1 for colorimetric and fluorescence patterns (25- and 50-fold lower than standard AuNPs-ICA). Moreover, the excellent self-calibration and satisfactory recovery of 79.03-118.04% were shown in the on-site visual colorimetric-fluorescence analysis for Gen in real environmental media (including real river water, an urban aquaculture water body, an aquatic product, and an animal byproduct). This work provides the feasibility of exploiting fortified dual-spectral overlap with an enhanced colorimetric/fluorescence dual response for safeguarding food safety and public health.
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A highly sensitive lateral flow immunoassay (LFIA) is developed for the enzyme-catalyzed and double-reading determination of clenbuterol (CLE), in which a new type of probe was adopted through the direct electrostatic adsorption of ultra-small copper-gold bimetallic enzyme mimics (USCGs) and monoclonal antibodies. In the assay, based on the peroxidase activity of USCG, the chromogenic substrate TMB-H2O2 was introduced to trigger its color development, and the results were compared with those before catalysis. The detection sensitivity after catalysis is 0.03 ng mL-1 under optimal circumstances, which is 6-fold better than that of the traditional Au NPs-based LFIA and 2-fold greater than that before catalysis. This approach was successfully applied to the detection of CLE in milk, pork and mutton samples with an optimum assay time of 7 min and best catalytic time of 80 s, after which satisfactory recoveries of 98.53-117.79% were obtained. Cu-Au nanoparticles as a signal tag and the use of their nanozyme properties are the first applications in the field of LFIA. This work can be a promising exhibition for the application of a cheaper substitute for HRP, ultra-small bimetallic enzyme mimics, in LFIAs.
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Clembuterol , Nanopartículas Metálicas , Limite de Detecção , Cobre , Ouro/química , Peróxido de Hidrogênio , Nanopartículas Metálicas/química , Catálise , Imunoensaio/métodosRESUMO
To solve the problems of the lack of property research in organic synthesis experiments and the relative independence of instrumental analytical methods in experiments, we designed a comprehensive undergraduate experiment based on mechanofluorochromic materials. In this project, 4-[bis(4-methylphenyl)amino] benzaldehyde was synthesized via the Vilsmeier-Haack reaction using 4,4'-dimethyltriphenylamine as the raw material. The product was then characterized by mass spectrometry, infrared absorption spectroscopy, and nuclear magnetic resonance spectroscopy. The solvatofluorochromism and mechanofluorochromism of the target material were studied using ultraviolet-visible absorption spectroscopy, fluorescence spectroscopy, etc. Furthermore, the mechanism of mechanofluorochromism was determined using powder X-ray diffraction. Organic synthesis and a series of instrumental analytical methods were combined to form an integrated experiment. The experiment is interesting, scientific, and comprehensive for undergraduates as a creative exercise; moreover, it can inspire their interest in chemical research, cultivate a variety of experimental operation abilities, improve creative-thinking skills, and encourage the development of effective solutions to existing problems in chemical experiments.
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External stimuli-responsive DNA hydrogels present interesting platforms for drug loading and triggered release. Typically, drug molecules are encapsulated within three-dimensionally hybridized DNA networks. However, the utilization of drug molecules as cofactors to facilitate the directed assembly of DNA strands into hydrogel frameworks and their subsequent controlled release remains to be explored. Herein, we introduce the guided assembly of oligo-adenine (A-strand) into an acidic pH-responsive DNA hydrogel using an anticancer drug, coralyne (COR), as a low-molecular-weight cofactor. At pH 7, COR orchestrates the assembly of A-strand into an antiparallel duplex configuration cross-linked by A-COR-A units at a stoichiometric ratio of one COR cofactor per four adenine bases, resulting in a DNA hydrogel characterized by A-COR-A duplex bridges. At pH 4-5, the instability of A-COR-A units results in the disintegration of the duplex into its constituent components, leading to the release of COR and simultaneous dissociation of the DNA hydrogel matrix. This study introduces a method by which drug molecules, exemplified here by COR, facilitate the direct formation of a supramolecular cofactor-DNA complex, subsequently leading to the creation of a stimuli-responsive DNA hydrogel. This approach may inspire future investigations into DNA hydrogels tailored for controlled drug encapsulation and release applications.
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Adenina , Alcaloides de Berberina , Hidrogéis , Hidrogéis/química , DNA/química , Concentração de Íons de HidrogênioRESUMO
Bimodal-type multiplexed immunoassays with complementary mode-based correlation analysis are gaining increasing attention for enhancing the practicability of the lateral flow immunoassay (LFIA). Nonetheless, the restriction in visually indistinguishable multitargets induced by a single fluorescent color and difficulty in single acceptor ineffectual fluorescence quenching due to the various spectra of multiple different donors impede the further execution of colorimetric-fluorescence bimodal-type multiplexed LFIAs. Herein, the precise spectral overlap-based donor-acceptor pair construction strategy is proposed by regulating the size of the nanocore, coating it with an appropriate nanoshell, and selecting a suitable fluorescence donor with distinct colors. By in situ coating Prussian blue nanoparticles (PBNPs) on AuNPs with a tunable size and absorption spectrum, the resultant APNPs demonstrate efficient fluorescence quenching ability, higher colloidal stability, remarkable colorimetric intensity, and an enhanced antibody coupling efficiency, all of which facilitate highly sensitive bimodal-type LFIA analysis. Following integration with competitive-type immunoreaction, this precise spectral overlap-supported spatial separation traffic light-typed colorimetric-fluorescence dual-response assay (coined as the STCFD assay) with the limits of detection of 0.013 and 0.152 ng mL-1 for ractopamine and clenbuterol, respectively, was proposed. This work illustrates the superiority of the rational design of a precise spectral overlap-based donor-acceptor pair, hinting at the enormous potential of the STCFD assay in the point-of-care field.
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Clembuterol , Nanopartículas Metálicas , Ouro , Imunoensaio , Fenômenos Químicos , Limite de DetecçãoRESUMO
OBJECTIVES: The coronal plane is the unique display mode of automated breast (AB) ultrasound (US), which has valuable features of showing the entire breast anatomy and providing additional diagnostic value for breast lesions. However, whether adding the coronal plane could improve the diagnostic performance in screening breast cancer remains uncertain. This study aimed to evaluate the value of adding the coronal plane in interpretation for AB US screening. METHODS: In this retrospective study, AB US images from 644 women (396 in the no-finding group, 143 with benign lesions, and 105 with malignant lesions) aged 40-70 years were collected between January 2016 and October 2020. Four novice radiologists (with 1-5 years of experience with breast US) and four experienced radiologists (with >5 years of experience with breast US) were assigned to read all AB US images in the transverse plane plus coronal plane (T + C planes) and transverse plane (T plane) alone in separate reading sessions. Diagnostic performance, lesion conspicuity, and reading time were compared using analysis of variance. RESULTS: The mean reading time of all radiologists was significantly shorter in the T + C planes reading mode than in the T plane alone (115 ± 32 vs 128 ± 31 s, respectively; P < .05), and cancers had a higher conspicuity (odds ratio, 1.76; 95% confidence interval [CI], 1.00-3.08; P = .04). No significant differences were noted in the two reading modes (T + C planes vs T plane) in the sensitivity (82% [95% CI, 74-89%] vs 81% [95% CI, 74-88%], respectively; P = .68) and specificity (68% [95% CI, 62-75%] vs 70% [95% CI, 64-75%], respectively; P = .39) when Breast Imaging-Reporting and Data System (BI-RADS) 3 was set as the threshold. There were also no significant differences in the two reading modes (T + C planes vs T plane) in the sensitivity (70% [95% CI, 64-76%] vs 69% [95% CI, 63-75%], respectively; P = .39) and specificity (91% [95% CI, 87-96%] vs 91% [95% CI, 88-95%], respectively; P = .90) when BI-RADS 4 was set as the threshold. In addition, the mean areas under the receiver operating characteristic curves of all radiologists in the two reading modes (T + C planes vs T plane) were not significantly different (0.84 [95% CI, 0.79-0.89] vs 0.83 [95% CI, 0.78-0.89], respectively; P = .61). CONCLUSIONS: Adding a coronal plane in the AB US screening setting saved the reading time and improved the conspicuity of breast cancers but not the diagnostic performance.
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Neoplasias da Mama , Mama , Sensibilidade e Especificidade , Ultrassonografia Mamária , Humanos , Feminino , Pessoa de Meia-Idade , Ultrassonografia Mamária/métodos , Estudos Retrospectivos , Neoplasias da Mama/diagnóstico por imagem , Idoso , Adulto , Mama/diagnóstico por imagem , Reprodutibilidade dos TestesRESUMO
Cerebral ischemia-reperfusion is a process in which the blood supply to the brain is temporarily interrupted and subsequently restored. However, it is highly likely to lead to further aggravation of pathological damage to ischemic tissues or the nervous system., and has accordingly been a focus of extensive clinical research. As a traditional Chinese medicinal formulation, Sanhua Decoction has gradually gained importance in the treatment of cerebrovascular diseases. Its main constituents include Citrus aurantium, Magnolia officinalis, rhubarb, and Qiangwu, which are primarily used to regulate qi. In the treatment of neurological diseases, the therapeutic effects of the Sanhua Decoction are mediated via different pathways, including antioxidant, anti-inflammatory, and neurotransmitter regulatory pathways, as well as through the protection of nerve cells and a reduction in cerebral edema. Among the studies conducted to date, many have found that the application of Sanhua Decoction in the treatment of neurological diseases has clear therapeutic effects. In addition, as a natural treatment, the Sanhua Decoction has received widespread attention, given that it is safer and more effective than traditional Western medicines. Consequently, research on the mechanisms of action and efficacy of the Sanhua Decoctions in the treatment of cerebral ischemia-reperfusion injury is of considerable significance. In this paper, we describe the pathogenesis of cerebral ischemia-reperfusion injury and review the current status of its treatment to examine the therapeutic mechanisms of action of the Sanhua Decoction. We hope that the findings of the research presented herein will contribute to a better understanding of the efficacy of this formulation in the treatment of cerebral ischemia-reperfusion, and provide a scientific basis for its application in clinical practice.
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Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease without specific Food and Drug Administration-approved drugs. Recent advances suggest that chromatin remodeling and epigenetic alteration contribute to the development of NAFLD. The functions of the corresponding molecular modulator in NAFLD, however, are still elusive. KDM1A, commonly known as lysine-specific histone demethylase 1, has been reported to increase glucose uptake in hepatocellular carcinoma. In addition, a recent study suggests that inhibition of KDM1A reduces lipid accumulation in primary brown adipocytes. We here investigated the role of KDM1A, one of the most important histone demethylases, in NAFLD. In this study, we observed a significant upregulation of KDM1A in NAFLD mice, monkeys, and humans compared to the control group. Based on these results, we further found that the KDM1A can exacerbate lipid accumulation and inflammation in hepatocytes and mice. Mechanistically, KDM1A exerted its effects by elevating chromatin accessibility, subsequently promoting the development of NAFLD. Furthermore, the mutation of KDM1A blunted its capability to promote the development of NAFLD. In summary, our study discovered that KDM1A exacerbates hepatic steatosis and inflammation in NAFLD via increasing chromatin accessibility, further indicating the importance of harnessing chromatin remodeling and epigenetic alteration in combating NAFLD. KDM1A might be considered as a potential therapeutic target in this regard.
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Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/genética , Cromatina/genética , Histona Desmetilases/genética , Inflamação/genética , LipídeosRESUMO
Unique benzopyridone cyanoacetates (BCs) as new type of promising broad-spectrum antibacterial candidates were discovered with large potential to combat the lethal multidrug-resistant bacterial infections. Many prepared BCs showed broad antibacterial spectrum with low MIC values against the tested strains. Some highly active BCs exhibited rapid sterilization capacity, low resistant trend and good predictive pharmacokinetic properties. Furthermore, the highly active sodium BCs (NaBCs) displayed low hemolysis and cytotoxicity, and especially octyl NaBC 5g also showed in vivo potent anti-infective potential and appreciable pharmacokinetic profiles. A series of preliminary mechanistic explorations indicated that these active BCs could effectively eliminate bacterial biofilm and destroy membrane integrity, thus resulting in the leakage of bacterial cytoplasm. Moreover, their unique structures might further bind to intracellular DNA, DNA gyrase and topoisomerase IV through various direct noncovalent interactions to hinder bacterial reproduction. Meanwhile, the active BCs also induced bacterial oxidative stress and metabolic disturbance, thereby accelerating bacterial apoptosis. These results provided a bright hope for benzopyridone cyanoacetates as potential novel multitargeting broad-spectrum antibacterial candidates to conquer drug resistance.
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Antibacterianos , Inibidores da Topoisomerase II , Antibacterianos/farmacologia , Antibacterianos/química , Bactérias , DNA Girase/metabolismo , DNA Topoisomerase IV , Testes de Sensibilidade Microbiana , Inibidores da Topoisomerase II/farmacologia , Piridonas/química , Piridonas/farmacologia , Nitrilas/química , Nitrilas/farmacologiaRESUMO
Injured articular cartilage is a leading cause for osteoarthritis. We recently discovered that endogenous stem/progenitor cells not only reside in the superficial zone of mouse articular cartilage, but also regenerated heterotopic bone and cartilage in vivo. However, whether critical-size osteochondral defects can be repaired by pure induced chemotatic cell homing of these endogenous stem/progenitor cells remains elusive. Here, we first found that cells in the superficial zone of articular cartilage surrounding surgically created 3 × 1 mm defects in explant culture of adult goat and rabbit knee joints migrated into defect-filled fibrin/hylaro1nate gel, and this migration was significantly more robust upon delivery of exogenous granulocyte-colony stimulating factor (G-CSF). Remarkably, G-CSF-recruited chondrogenic progenitor cells (CPCs) showed significantly stronger migration ability than donor-matched chondrocytes and osteoblasts. G-CSF-recruited CPCs robustly differentiated into chondrocytes, modestly into osteoblasts, and barely into adipocytes. In vivo, critical-size osteochondral defects were repaired by G-CSF-recruited endogenous cells postoperatively at 6 and 12 weeks in comparison to poor healing by gel-only group or defect-only group. ICRS and O'Driscoll scores of articular cartilage were significantly higher for both 6- and 12-week G-CSF samples than corresponding gel-only and defect-only groups. Thus, endogenous stem/progenitor cells may be activated by G-CSF, a Food and Drug Administration (FDA)-cleared bone-marrow stimulating factor, to repair osteochondral defects.
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In infectious ischemic wounds, a lack of blood perfusion significantly worsens microbe-associated infection symptoms and frequently complicates healing. To overcome this daunting issue, antibacterial and angiogenic (2A) bio-heterojunctions (bio-HJs) consisting of CuS/MXene heterojunctions and a vascular endothelial growth factor (VEGF)-mimicking peptide (VMP) are devised and developed to accelerate infectious cutaneous regeneration by boosting angiogenesis via an endogenous-exogenous bistimulatory (EEB) strategy. Assisted by near-infrared irradiation, the bio-HJ platform exhibits versatile synergistic photothermal, photodynamic, and chemodynamic effects for robust antibacterial efficacy. In addition, copper ions liberated from 2A bio-HJs elevate VEGF secretion from fibroblasts, which provokes VEGF receptors (VEGFR) activation through an endogenous pathway, whereas VMP itself promotes an exogenous pathway to facilitate endothelial cell multiplication and tube formation by directly activating the VEGFR signaling pathway. Moreover, employing an in vivo model of infectious ischemic wounds, it is confirmed that the EEB strategy can considerably boost cutaneous regeneration through pathogen elimination, angiogenesis promotion, and collagen deposition. As envisaged, this work leads to the development of a powerful 2A bio-HJ platform that can serve as an effective remedy for bacterial invasion-induced ischemic wounds through the EEB strategy.
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Fator A de Crescimento do Endotélio Vascular , Cicatrização , Pele , Colágeno , Antibacterianos/farmacologiaRESUMO
A tannate-iron network-derived peroxidase-like catalyst loaded with Fe ions on carbon nitride (C3N4) was reported for detection of total antioxidant capacity (TAC) in food in this study. Metal-phenolic networks (MPNs) was employed to form a low coordination compound on C3N4, and calcined catalyst formed hollow structure with abundant and uniform Fe sites and surface folds. CN-FeC exhibited significant peroxidase-like activity and high substrate affinity. The homogeneous distribution of amorphous Fe elements on the C3N4 substrate provides more active sites, resulting in provided excellent catalytic activity to activate H2O2 to ·OH, 1O2 and O2·-. The established CN-FeC/TMB/H2O2 colorimetric system can detect AA in the concentration range of 5-40 µM, with the detection limits of 1.40 µM, respectively. It has good accuracy for the detection of vitamin C tablets, beverages. Taken together, this work shows that metal-phenolic networks can be an effective way to achieve efficient utilization of metal atoms and provides a promising idea for metal-phenolic networks in nanoparticle enzyme performance enhancement.
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Antioxidantes , Nanopartículas , Peróxido de Hidrogênio/química , Peroxidase/química , Peroxidases/química , Nanopartículas/química , Colorimetria/métodos , FerroRESUMO
Nanomaterial-mediated ferroptosis has garnered considerable interest in the antibacterial field, as it invokes the disequilibrium of ion homeostasis and boosts lipid peroxidation in extra- and intracellular bacteria. However, current ferroptosis-associated antibacterial strategies indiscriminately pose damage to healthy cells, ultimately compromising their biocompatibility. To address this daunting issue, this work has designed a precise ferroptosis bio-heterojunction (F-bio-HJ) consisting of Fe2 O3 , Ti3 C2 -MXene, and glucose oxidase (GOx) to induce extra-intracellular bacteria-targeted ferroptosis for infected diabetic cutaneous regeneration. Fe2 O3 /Ti3 C2 -MXene@GOx (FMG) catalytically generates a considerable amount of ROS which assaults the membrane of extracellular bacteria, facilitating the permeation of synchronously generated Fe2+ /Fe3+ into bacteria under near-infrared (NIR) irradiation, causing planktonic bacterial death via ferroptosis, Fe2+ overload, and lipid peroxidation. Additionally, FMG facilitates intracellular bacterial ferroptosis by transporting Fe2+ into intracellular bacteria via inward ferroportin (FPN). With GOx consuming glucose, FMG creates hunger protection which helps macrophages escape cell ferroptosis by activating the adenosine 5'-monophosphate (AMP) activated protein kinase (AMPK) pathway. In vivo results authenticate that FMG boosts diabetic infectious cutaneous regeneration without triggering ferroptosis in normal cells. As envisaged, the proposed tactic provides a promising approach to combat intractable infections by precisely terminating extra-intracellular infection via steerable ferroptosis, thereby markedly elevating the biocompatibility of therapeutic ferroptosis-mediated strategies.