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Overexpression of thioredoxin reductase (TXNRD) plays crucial role in tumorigenesis. Therefore, designing TXNRD inhibitors is a promising strategy for targeted anticancer drug development. However, poor selectivity has always been a challenge, resulting in unavoidable toxicity in clinic. Herein we demonstrate a strategy to develop highly selective chiral metal complexes-based TXNRD inhibitors. By manipulating the conformation of two distinct weakly interacting groups, we optimize the compatibility between the drug and the electrophilic group within the active site of TXNRD to enhance their non-covalent interaction, thus effectively avoids the poor selectivity deriving from covalent drug interaction, on the basis of ensuring the strong inhibition. Detailed experimental and computational results demonstrate that the chiral isomeric drugs bind to the active site of TXNRD, and the interaction strength is well modulated by chirality. Especially, the meso-configuration, in which the two large sterically hindered active groups are positioned on opposite sides of the drug, exhibits the highest number of non-covalent interactions and most effective inhibition on TXNRD. Taken together, this work not only provides a novel approach for developing highly selective proteinase inhibitors, but also sheds light on possible underlying mechanisms for future application.
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Inhibidores Enzimáticos , Reductasa de Tiorredoxina-Disulfuro , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Humanos , Dominio Catalítico , Estereoisomerismo , Simulación del Acoplamiento MolecularRESUMEN
Acute kidney injury (AKI) is closely related to lysosomal dysfunction and ferroptosis in renal tubular epithelial cells (TECs), for which effective treatments are urgently needed. Although selenium nanoparticles (SeNPs) have emerged as promising candidates for AKI therapy, their underlying mechanisms have not been fully elucidated. Here, we investigated the effect of SeNPs on hypoxia/reoxygenation (H/R)-induced ferroptosis and lysosomal dysfunction in TECs in vitro and evaluated their efficacy in a murine model of ischemia/reperfusion (I/R)-AKI. We observed that H/R-induced ferroptosis was accompanied by lysosomal Fe2+ accumulation and dysfunction in TECs, which was ameliorated by SeNPs administration. Furthermore, SeNPs protected C57BL/6 mice against I/R-induced inflammation and ferroptosis. Mechanistically, we found that lysosomal Fe2+ accumulation and ferroptosis were associated with the excessive activation of NCOA4-mediated ferritinophagy, a process mitigated by SeNPs through the upregulation of X-box binding protein 1 (XBP1). Downregulation of XBP1 promoted ferritinophagy and partially counteracted the protective effects of SeNPs on ferroptosis inhibition in TECs. Overall, our findings revealed a novel role for SeNPs in modulating ferritinophagy, thereby improving lysosomal function and attenuating ferroptosis of TECs in I/R-AKI. These results provide evidence for the potential application of SeNPs as therapeutic agents for the prevention and treatment of AKI.
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Ferroptosis , Nanopartículas , Daño por Reperfusión , Selenio , Proteína 1 de Unión a la X-Box , Animales , Humanos , Masculino , Ratones , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Autofagia/efectos de los fármacos , Ferritinas/metabolismo , Ferroptosis/efectos de los fármacos , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Ratones Endogámicos C57BL , Nanopartículas/química , Coactivadores de Receptor Nuclear/metabolismo , Coactivadores de Receptor Nuclear/genética , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Selenio/farmacología , Selenio/administración & dosificación , Transducción de Señal/efectos de los fármacos , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/genéticaRESUMEN
The dysfunction of bone mesenchymal stem cells (BMSCs), caused by the physical and chemical properties of the inflammatory and repair phases of bone regeneration, contributes to the failure of bone regeneration. To meet the spatiotemporal needs of BMSCs in different phases, designing biocompatible materials that respond to external stimuli, improve migration in the inflammatory phase, reduce apoptosis in the proliferative phase, and clear the hurdle in the differentiation phase of BMSCs is an effective strategy for multistage repair of bone defects. In this study, we designed a cascade-response functional composite hydrogel (Gel@Eb/HA) to regulate BMSCs dysfunction in vitro and in vivo. Gel@Eb/HA improved the migration of BMSCs by upregulating the expression of chemokine (C-C motif) ligand 5 (CCL5) during the inflammatory phase. Ultrasound (US) triggered the rapid release of Ebselen (Eb), eliminating the accumulation of reactive oxygen species (ROS) in BMSCs, and reversing apoptosis under oxidative stress. Continued US treatment accelerated the degradation of the materials, thereby providing Ca2+ for the osteogenic differentiation of BMSCs. Altogether, our study highlights the prospects of US-controlled intelligent system, that provides a novel strategy for addressing the complexities of multistage bone repair.
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Regeneración Ósea , Hidrogeles , Células Madre Mesenquimatosas , Osteogénesis , Regeneración Ósea/efectos de los fármacos , Animales , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Hidrogeles/química , Osteogénesis/efectos de los fármacos , Ondas Ultrasónicas , Diferenciación Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ratas Sprague-Dawley , Apoptosis/efectos de los fármacos , Masculino , Ratones , Quimiocina CCL5/metabolismo , Movimiento Celular/efectos de los fármacosRESUMEN
Exploring efficient and low-toxicity radiosensitizers to break through the bottleneck of radiation tolerance, immunosuppression and poor prognosis remains one of the critical developmental challenges in radiotherapy. Nanoheterojunctions, due to their unique physicochemical properties, have demonstrated excellent radiosensitization effects in radiation energy deposition and in lifting tumor radiotherapy inhibition. Herein, they doped selenium (Se) into prussian blue (PB) to construct a nano-heterojunction (Se@PB), which could promote the increase of Fe2+/Fe3+ ratio and conversion of Se to a high valence state with Se introduction. The Fe2+-Se-Fe3+ electron transfer chain accelerates the rate of electron transfer on the surface of the nanoparticles, which in turn endows it with efficient X-ray energy transfer and electron transport capability, and enhances radiotherapy physical sensitivity. Furthermore, Se@PB induces glutathione (GSH) depletion and Fe2+ accumulation through pro-Fenton reaction, thereby disturbs the redox balance in tumor cells and enhances biochemical sensitivity of radiotherapy. As an excellent radiosensitizer, Se@PB effectively enhances X-ray induced mitochondrial dysfunction and DNA damage, thereby promotes cell apoptosis and synergistic cervical cancer radiotherapy. This study elucidates the radiosensitization mechanism of Se-doped nanoheterojunction from the perspective of the electron transfer chain and biochemistry reaction, which provides an efficient and low-toxic strategy in radiotherapy.
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Fármacos Sensibilizantes a Radiaciones , Selenio , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Humanos , Selenio/química , Selenio/farmacología , Femenino , Ferrocianuros/química , Animales , Ratones , Nanopartículas/química , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Neoplasias del Cuello Uterino , Tolerancia a Radiación/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Because of the extremely complexed microenvironment of drug-resistant bacterial infection, nanomaterials with both bactericidal and immuno-modulating activities are undoubtedly the ideal modality for overcoming drug resistance. Herein, we precisely engineered the surface chemistry of selenium nanoparticles (SeNPs) using neutral (polyvinylpyrrolidone-PVP), anionic (letinan-LET) and cationic (chitosan-CS) surfactants. It was found that surface chemistry greatly influenced the bioactivities of functionalized SeNPs, their interactions with methicillin-resistant Staphylococcus aureus (MRSA), immune cells and metabolisms. LET-functionalized SeNPs with distinct metabolisms exhibited the best inhibitory efficacy compared to other kinds of SeNPs against MRSA through inducing robust ROS generation and damaging bacterial cell wall. Meanwhile, only LET-SeNPs could effectively activate natural kill (NK) cells, and enhance the phagocytic capability of macrophages and its killing activity against bacteria. Furthermore, in vivo studies suggested that LET-SeNPs treatment highly effectively combated MRSA infection and promoted wound healing by triggering much more mouse NK cells, CD8+ and CD4+ T lymphocytes infiltrating into the infected area at the early stage to efficiently eliminate MRSA in the mouse model. This study demonstrates that the novel functionalized SeNP with dual functions could serve as an effective antibacterial agent and could guide the development of next generation antibacterial agents.
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Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Nanopartículas , Selenio , Infecciones Estafilocócicas , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Animales , Selenio/química , Selenio/farmacología , Ratones , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Antibacterianos/química , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Nanopartículas/química , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/microbiología , Humanos , Modelos Animales de Enfermedad , Propiedades de Superficie , Pruebas de Sensibilidad MicrobianaRESUMEN
Human adenovirus (HAdV) can cause severe respiratory infections in immunocompromised patients, but its clinical treatment is seriously limited by side effects of drugs such as poor efficacy, low bioavailability and severe nephrotoxicity. Trace element selenium (Se) has been found will affect the disease progression of pneumonia, but its antivirus efficacy could be improved by speciation optimization. Therefore, herein we performed anti-HAdV effects of different Se speciation and found that lentinan (LNT)-decorated selenium nanoparticles (SeNPs) exhibited low cytotoxicity and excellent anti-HAdV antiviral activity. Furthermore, SeNPs@LNT reduced the HAdV infection-induced mitochondrial damage and excessive production of reactive oxygen species (ROS). It was also involved in the repair of host cell DNA damage and inhibition of viral DNA replication. SeNPs@LNT inhibited HAdV-induced apoptosis mainly by modulating the p53/Bcl-2 apoptosis signaling pathway. In vivo, SeNPs@LNT replenished Se by targeting the infected site through the circulatory system and was involved in the synthesis of Glutathione peroxidase 1 (GPx1). More importantly, GPx1 played an antioxidant and immunomodulatory role in alleviating HAdV-induced inflammatory cytokine storm and alleviating adenovirus pneumonia in Se-deficient mice. Collectively, this study provides a Se speciation of SeNPs@LNT with anti-HAdV activity, and demonstrate that SeNPs@LNT is a promising pharmaceutical candidate for the treatment of HAdV.
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Radiation-induced heart disease (RIHD), characterized by severe oxidative stress and immune dysregulation, is a serious condition affecting cancer patients undergoing thoracic radiation. Unfortunately, clinical interventions for RIHD are lacking. Selenium (Se) is a trace element with excellent antioxidant and immune-modulatory properties. However, its application in heart radioprotection remains challenging. Herein, we developed a novel bioactive Cordyceps militaris-based Se oral delivery system (Se@CM), which demonstrated superior radioprotection effects in vitro against X-ray-induced damage in H9C2 cells through suppressing excessive ROS generation, compared to the radioprotectant Amifostine. Moreover, Se@CM exhibited exceptional cardioprotective effects in vivo against X-ray irradiation, reducing cardiac dysfunction and myocardial fibrosis by balancing the redox equilibrium and modulating the expression of Mn-SOD and MDA. Additionally, Se@CM maintained immuno-homeostasis, as evidenced by the upregulated population of T cells and M2 macrophages through modulation of selenoprotein expression after irradiation. Together, these results highlight the remarkable antioxidant and immunity modulation properties of Se@CM and shed light on its promising application for cardiac protection against IR-induced disease. This research provides valuable insights into developing effective strategies for preventing and managing RIHD.
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Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with inâ situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both inâ vitro and inâ vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.
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Aluminio , Antineoplásicos , Senescencia Celular , Etilenodiaminas , Platino (Metal) , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Etilenodiaminas/química , Etilenodiaminas/farmacología , Senescencia Celular/efectos de los fármacos , Platino (Metal)/química , Platino (Metal)/farmacología , Aluminio/química , Aluminio/farmacología , Animales , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/químicaRESUMEN
Osteoclast hyperactivation stands as a significant pathological factor contributing to the emergence of bone disorders driven by heightened oxidative stress levels. The modulation of the redox balance to scavenge reactive oxygen species emerges as a viable approach to addressing this concern. Selenoproteins, characterized by selenocysteine (SeCys2) as the active center, are crucial for selenium-based antioxidative stress therapy for inflammatory diseases. This study reveals that surface-active elemental selenium (Se) nanoparticles, particularly lentinan-Se (LNT-Se), exhibit enhanced cellular accumulation and accelerated metabolism to SeCys2, the primary active Se form in biological systems. Consequently, LNT-Se demonstrates significant inhibition of osteoclastogenesis. Furthermore, in vivo studies underscore the superior therapeutic efficacy of LNT-Se over SeCys2, potentially attributable to the enhanced stability and safety profile of LNT-Se. Specifically, LNT-Se effectively modulates the expression of the selenoprotein GPx1, thereby exerting regulatory control over osteoclastogenesis inhibition, and the prevention of osteolysis. In summary, these results suggest that the prompt activation of selenoproteins by Se nanoparticles serves to suppress osteoclastogenesis and pathological bone loss by upregulating GPx1. Moreover, the utilization of bioactive Se species presents a promising avenue for effectively managing bone disorders.
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Nanopartículas , Osteoclastos , Osteogénesis , Selenio , Selenoproteínas , Animales , Selenio/química , Selenio/farmacología , Ratones , Osteogénesis/efectos de los fármacos , Nanopartículas/química , Selenoproteínas/metabolismo , Osteoclastos/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/citología , Glutatión Peroxidasa GPX1 , Células RAW 264.7 , Glutatión Peroxidasa/metabolismo , Osteólisis/metabolismo , Osteólisis/tratamiento farmacológico , Osteólisis/patologíaRESUMEN
Autophagy could play suppressing role in cancer therapy by facilitating release of tumor antigens from dying cells and inducing immunogenic cell death (ICD). Therefore, discovery and rational design of more effective inducers of cytotoxic autophagy is expected to develop new strategies for finding innovative drugs for precise and successful cancer treatment. Herein, we develop MoO3-x nanowires (MoO3-x NWs) with high oxygen vacancy and strong photothermal responsivity to ablate tumors through hyperthermia, thus promote the induction of cytotoxic autophagy and severe ICD. As expected, the combination of MoO3-x NWs and photothermal therapy (PTT) effectively induces autophagy to promote the release of tumor antigens from the ablated cells, and induces the maturation and antigen presentation of dendritic cells (DCs), subsequently activates cytotoxic T lymphocytes (CTLs)-mediated adaptive immunity. Furthermore, the combination treatment of MoO3-x NWs with immune checkpoint blockade of PD-1 could promote the tumor-associated macrophages (TAMs) polarization into tumor-killing M1 macrophages, inhibit infiltration of Treg cells at tumor sites, and alleviate immunosuppression in the tumor microenvironment, finally intensify the anti-tumor activity in vivo. This study provides a strategy and preliminary elucidation of the mechanism of using MoO3-x nanowires with high oxygen vacancy to induce autophagy and thus enhance photothermal immunotherapy.
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Autofagia , Inmunoterapia , Molibdeno , Nanocables , Autofagia/efectos de los fármacos , Nanocables/química , Ratones , Animales , Molibdeno/química , Molibdeno/farmacología , Óxidos/química , Óxidos/farmacología , Terapia Fototérmica , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Línea Celular Tumoral , Fototerapia , Microambiente Tumoral/efectos de los fármacosRESUMEN
Treatment for inflammatory bowel disease (IBD) is challenging since current anti-inflammatory and immunosuppressive therapies do not address the underlying causes of the illness, which include increased levels of reactive oxygen species (ROS) and dysbiosis of the gut commensal microbiota. Additionally, these treatments often have systemic off-target effects and adverse side effects. In this study, we have developed a prebiotic yeast ß-glucan nanocomplex coated with bio-adhesive polydopamine (YBNs@PDA) to effectively prolong their retention time in the gastrointestinal (GI) tract. The oral administration of YBNs@PDA restored the epithelium barriers, reduced ROS levels, and minimized systemic drug exposure while improved therapeutic efficacy in an acute colitis mouse model. Furthermore, 16S ribosomal RNA genes sequencing demonstrated a higher richness and diversity in gut microflora composition following the treatments. In particular, YBNs@PDA markedly augmented the abundance of Lachnospiraceae NK4A136 and Bifidobacterium, both of which are probiotics with crucial roles in relieving colitis via retaining gut homeostasis. Cumulatively, these results demonstrate that the potential of YBNs@PDA as a novel drug-free, ROS-scavenging and gut microbiota regulation nanoplatform for the treatment of GI disorders.
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Colitis , Microbioma Gastrointestinal , Indoles , Enfermedades Inflamatorias del Intestino , Polímeros , Animales , Ratones , Saccharomyces cerevisiae , Especies Reactivas de Oxígeno , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Administración OralRESUMEN
The combination of ferroptosis and innovative tumor therapy methods offers another promising answer to the problem of tumors. In order to generate effective ferroptosis in tumor cells, iron-based nanomaterials are commonly utilized to introduce foreign iron as a trigger for ferroptosis. However, this usually necessitates the injection of larger doses of iron into the body. These exogenous iron increases are likely to create concealed concerns for symptoms such as liver damage and allergy. Herein, an iron-free radiosensitizer is introduced, oxygen-vacancy-rich MnO2 nanoflowers (ovs-MnO2), that promotes ferroptosis and modifies the tumor microenvironment to assist radiotherapy. ovs-MnO2 with enriched oxygen vacancies on the surface induces the release of intracellular free iron (Fe2+), which functions as an activator of Fenton reaction and enhances the accumulation of intracellular reactive oxygen species. On the other hand, Fe2+ also triggers the ferroptosis and promotes the accumulation of lipid peroxides. Subsequently, the depletion of glutathione and accumulation of lipid peroxidation in tumor cells leads to the inactivation of glutathione peroxidase 4 (GPX4) and ferroptosis, thereby enhancing the therapeutic efficacy of radiotherapy. The nanoplatform provides a novel strategy for generating novel nanomedicines for ferroptosis-assisted radiotherapy.
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Ferroptosis , Oxígeno , Especies Reactivas de Oxígeno , Ferroptosis/efectos de los fármacos , Humanos , Especies Reactivas de Oxígeno/metabolismo , Animales , Oxígeno/química , Oxígeno/metabolismo , Línea Celular Tumoral , Compuestos de Manganeso/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Neoplasias/radioterapia , Manganeso/química , Microambiente Tumoral/efectos de los fármacos , Óxidos/química , Ratones , Hierro/química , Hierro/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismoRESUMEN
Recently, radioresistance has become a major obstacle in the radiotherapy of cervical cancer. To demonstrate enhanced radiosensitization against radioresistant cervical cancer, radioresistant cervical cancer cell line was developed and the mechanism of radioresistance was explored. Due to the overexpression of (death receptor 5, DR5) in cervical cancer, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-overexpressed cervical cancer cell membrane-camouflaged Cu2-xSe nanomedicine (CCMT) was designed. Since the CCMT was encapsulated with TRAIL-modified cell membrane, it represented high target to cervical cancer cell and immune evasion. Furthermore, Cu2-xSe had the ability to scavenge glutathione (GSH) and produce ·OH with excess H2O2 in the tumor microenvironment. The presence of CCMT combined with radiation therapy could effectively increase the 1O2 produced by X-rays. In vitro and in vivo studies elaborated that CCMT exhibited excellent radiosensitization properties to reverse radiotolerance by scavenging GSH and promoting DNA damage, apoptosis, mitochondrial membrane potential damage and metabolic disruption. Collectively, this study suggested that the development of TRAIL-overexpressed cell membrane-camouflaged Cu2-xSe nanomedicine could advance future cervical cancer treatment and minimize the disadvantages associated with radiation treatment.
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Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/radioterapia , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Peróxido de Hidrógeno , Ligandos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Apoptosis , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Radiotherapy is still the recommended treatment for cervical cancer. However, radioresistance and radiation-induced side effects remain one of the biggest clinical problems. Selenium (Se) has been confirmed to exhibit radiation-enhancing effects for cancer treatment. However, Se species dominate the biological activities and which form of Se possesses better radiosensitizing properties and radiation safety remains elusive. Here, different Se species (the valence state of Se ranged from - 2, 0, +4 to + 6) synergy screen was carried out to identify the potential radiosensitizing effects and radiation safety of Se against cervical cancer. We found that the therapeutic effects varied with the changes in the Se valence state. Sodium selenite (+4) displayed strong cancer-killing effects but also possessed severe cytotoxicity. Sodium selenate (+6) neither enhanced the killing effects of X-ray nor possessed anticancer activity by its alone treatment. Although nano-selenium (0), especially Let-SeNPs, has better radiosensitizing activity, the - 2 organic Se, such as selenadiazole derivative SeD (-2) exhibited more potent anticancer effects and possessed a higher safe index. Overall, the selected Se drugs were able to synergize with X-ray to inhibit cell growth, clone formation, and cell migration by triggering G2/M phase arrest and apoptosis, and SeD (-2) was found to exhibit more potent enhancing capacity. Further mechanism studies showed that SeD mediated p53 pathway activation by inducing DNA damage through promoting ROS production. Additionally, SeD combined with X-ray therapy can induce an anti-tumor immune response in vivo. More importantly, SeD combined with X-ray significantly inhibited the liver metastasis of tumor cells and alleviated the side effects caused by radiation therapy in tumor-bearing mice. Taken together, this study demonstrates the radiosensitization and radiation safety effects of different Se species, which may shed light on the application of such Se-containing drugs serving as side effects-reducing agents for cervical cancer radiation treatment.
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Neoplasias Hepáticas , Fármacos Sensibilizantes a Radiaciones , Selenio , Neoplasias del Cuello Uterino , Humanos , Femenino , Ratones , Animales , Selenio/farmacología , Selenio/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Proteína p53 Supresora de Tumor , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
The influence of metabolic syndrome (MetS) on long-term prognosis of patients with myocardial infarction (MI), the most severe type of coronary artery disease, remains not fully determined. This systematic review and meta-analysis were conducted to investigate the association between MetS and long-term clinical outcomes of patients with MI. A systematic search of Medline, Web of Science, and Embase databases from inception to June 25, 2023, was conducted to obtain eligible studies. Only studies with follow-up duration for at least one year were considered. A random-effects model was utilized to pool the results, accounting for heterogeneity. Ten observational studies were included, which included 33 197 patients with MI. Among them, 17 244 (51.9%) were with MetS at baseline. During a follow-up duration of 12 to 48 months (mean: 22.5 months), patients with MetS were associated with higher incidence of major adverse cardiovascular events [risk ratio (RR): 1.35. 95% confidence interval (CI): 1.19 to 1.54, p<0.001; I2=64%] and all-cause deaths (RR: 1.34, 95% CI: 1.18 to 1.52, p<0.001; I2=23%), as compared to those without MetS at baseline. Subgroup analyses showed that the results were not significantly affected by study characteristics such as study country, design, type of MI, mean age of the patients, treatment with percutaneous coronary intervention, follow-up durations, or study quality scores (p for subgroup difference all>0.05). In patients with MI, MetS may be a risk factor of poor long-term prognosis.
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Scavenging free radicals and reducing inflammatory reaction to relieve the secondary damage are important issues in the spinal cord injury (SCI) therapeutic strategy. Nanozymes attract more attention in the drug development of SCI due to the high stability, long-lasting catalytic capacity, and multienzyme-like properties. Herein, we constructed a Rapamycin (Rapa)-loaded and hollow mesoporous Prussian blue (HMPB)-based nanozyme (RHPAzyme) to realize the combined antioxidation and anti-inflammation combination therapy of SCI. Furthermore, activated cell penetrating peptide (ACPP) is modified onto nanozyme to endow the effectively ability of lesion area-targeting. This RHPAzyme exhibits ROS scavenging capacity with the transformation of Fe2+/Fe3+ valance and cyanide group of HMPB to achieve multienzyme-like activity. As expected, RHPAzyme scavenges the ROS overproduction and reduces inflammation in oxygen-glucose deprivation (OGD)-induced damage via inhibiting MAPK/AKT signaling pathway. Furtherly, RHPAzyme exhibits the combined antioxidant and anti-inflammatory activity in vivo, which can effectively alleviate neuronal damage and promote motor function recovery in SCI mice. Overall, this study demonstrates the RHPAzyme induces an effective treatment of SCI by inhibiting oxygen-mediated cell apoptosis and suppressing inflammation-induced injury, thus reduces the nervous impairment and promotes motor function recovery.
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Sirolimus , Traumatismos de la Médula Espinal , Ratas , Ratones , Animales , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Sirolimus/farmacología , Sirolimus/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Antioxidantes/metabolismo , Oxígeno/metabolismo , Médula Espinal/patologíaRESUMEN
Radiotherapy is an important therapeutic modality in the treatment of cancers. Nevertheless, the characteristics of the tumor microenvironment (TME), such as hypoxia and high glutathione (GSH), limit the efficacy of radiotherapy. Manganese-based (Mn-based) nanomaterials offer a promising prospect for sensitizing radiotherapy due to their good responsiveness to the TME. In this review, we focus on the mechanisms of radiosensitization of Mn-based nanosystems, including alleviating tumor hypoxia, increasing reactive oxygen species production, increasing GSH conversion, and promoting antitumor immunity. We further illustrate the applications of these mechanisms in cancer radiotherapy, including the development and delivery of radiosensitizers, as well as their combination with other therapeutic modalities. Finally, we summarize the application of Mn-based nanosystems as contrast agents in realizing precision therapy. Hopefully, the present review will provide new insights into the biological mechanisms of Mn-based nanosystems, as well as their applications in radiotherapy, in order to address the difficulties and challenges that remain in their clinical application in the future.
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Nanoestructuras , Neoplasias , Fármacos Sensibilizantes a Radiaciones , Humanos , Manganeso/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Neoplasias/radioterapia , Neoplasias/tratamiento farmacológico , Microambiente TumoralRESUMEN
Serological testing is an important method for the diagnosis of pseudorabies virus (PRV) infection. We aimed to investigate the envelope glycoprotein I (gI) of PRV, a strong immunogen, and its potential as an efficient and low-cost diagnostic reagent. In this study, the DNA of the PRV SC strain was used as the template, and the recombinant fragment of gI (633 bp) was amplified via PCR using synthetic primers, and was then ligated into the pET-30a expression vector. The constructs were transferred into Escherichia coli (E. coli) for prokaryotic expression, and the antigenicity of the expression products was identified by Western blot analysis with pig positive serum against PRV. The recombinant protein was purified by a Ni column, and BALB/c mice were immunized with purified gI protein to obtain anti-gI-positive serum. After PK-15 cells had been infected by PRV for 48 h, the immunogenicity of purified gI protein was identified with a fluorescence immunoassay using anti-gI mouse serum. The recombinant plasmid (pET-30a-gI) was expressed, and the native gI protein was obtained after denaturation by urea and renaturation by dialysis. A small-scale ELISA test containing 1.0 µg/mL of purified gI protein was designed to evaluate pig serum (80 samples), and the results of the ELISA test were compared to those of competitive ELISA (cELISA) tests using IDEXX Kits, which resulted in 97.5% consistency. The results suggested that the truncated gI protein may be a potential diagnostic reagent.
RESUMEN
Because of the distinguished properties between nanovaccine and traditional vaccine, the precise guidelines for nanovaccines with an optimal vaccination strategy to induce ideal immunities are greatly desired for combating major diseases, including cancer and infections. Herein, we designed and synthesized a self-navigating nanoadjuvant composed of Fe-doped manganese carbonate and its nanovaccine via a facile method. First, the degradation of the nanoadjuvant under acidic milieu of immune cells in lymph nodes would generate T1 and T2 MR imaging (MRI) signals to reflect the transformation dynamics of the nanovaccine and inform us when the next vaccination needed. Under this guideline, nanovaccines with a precise vaccination strategy triggered robust antigen-specific immune responses and immunological memory to effectively prevent ovalbumin (OVA)-expressing melanoma relapse by activating dendritic cells via a stimulator of interferon genes (STING) signaling pathway and inducing antigen cross-presentation by shaping lysosome integrity with CO2 generation and upregulating transporter associated antigen processing 1 (TAP-1) transporter. This study provides a universal nanoadjuvant with imaging self-guidance, immunopotentiating, and cross-priming activities for developing precise vaccines with an optimal immunization strategy to combat major diseases.
Asunto(s)
Vacunas contra el Cáncer , Melanoma , Nanopartículas , Neoplasias , Vacunas , Humanos , Animales , Ratones , Presentación de Antígeno , Melanoma/patología , Neoplasias/metabolismo , Vacunación , Imagen por Resonancia Magnética , Células Dendríticas , Inmunoterapia/métodos , Ratones Endogámicos C57BL , Nanopartículas/químicaRESUMEN
Easy recurrence and strong treatment side effects significantly limit the clinical treatment of allergic dermatitis. The human trace element selenium (Se) plays essential roles in redox regulation through incorporation into selenoproteins in the form of 21st necessary amino acid selenocysteine, to participates in the pathogenesis and intervention of chronic inflammatory diseases. Therefore, based on the safe and elemental properties of Se, we construct a facile-synthesis strategy for antiallergic selenium nanoparticles (LET-SeNPs), and scale up the production by employing a spray drying method with lactose (Lac-LET-SeNPs) or maltodextrin (Mal-LET-SeNPs) as encapsulation agents realizing larger scale production and a longer storage time. As expected, these as-prepared LET-SeNPs could effectively activate the Nrf2-Keap1 signaling pathway to enhance the expression of antioxidative selenoprotein at mRNA and protein levels, then inhibit mast cell activation to achieve efficient antiallergic activity. Interestingly, LET-SeNPs undergo metabolism to seleno-amino acids to promote biosynthesis of selenoproteins, which could suppress ROS-induced cyclooxygenase-2 (COX-2) and MAPKs activation to suppress the release of histamine and inflammatory cytokines. Allergic mouse and Macaca fascicularis models further confirm that LET-SeNPs could increase the Se content and selenoprotein expression in the skin, decrease mast cells activation and inflammatory cells infiltration, and finally exhibit the high therapeutic effects on allergic dermatitis. Taken together, this study not only constructs facile large-scale synthesis of translational Se nanomedicine to break through the bottleneck problem of nanomaterials but also sheds light on its application in the intervention and treatment of allergies.