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Non-small cell lung cancer (NSCLC) is a leading cause of mortality worldwide and requires effective treatment strategies. Recently, the development of a novel multiple-target tyrosine kinase inhibitor, anlotinib, has drawn increasing attention, especially it shows advantages when combined with PD-1/PD-L1 blockade. However, the mechanism by which anlotinib improves immunotherapy and remodeling of the tumor microenvironment remains unclear. In this study, we found that anlotinib combined with PD-1 blockade significantly inhibited tumor growth and reduced tumor weight in a lung cancer xenograft model compared to any single treatment. Both immunofluorescence and flow cytometry analyses revealed that anlotinib induced a CD8+ T cell dominated tumor microenvironment, which might account for its improved role in immunotherapy. Further investigations showed that CCL5-mediated CD8+ T cell recruitment plays a critical role in anlotinib and PD-1 blockade strategies. The depletion of CD8+ T cells abrogated this process. In conclusion, our findings showed that the combination of anlotinib and PD-1 blockade produced promising effects in the treatment of lung cancer, and that the induction of CCL5-mediced CD8+ T cell recruitment by anlotinib provided a novel mechanism of action.
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Antígeno B7-H1 , Linfocitos T CD8-positivos , Carcinoma de Pulmón de Células no Pequeñas , Quimiocina CCL5 , Indoles , Neoplasias Pulmonares , Receptor de Muerte Celular Programada 1 , Quinolinas , Microambiente Tumoral , Animales , Humanos , Ratones , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Quimiocina CCL5/efectos de los fármacos , Quimiocina CCL5/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Indoles/farmacología , Indoles/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Quinolinas/farmacología , Quinolinas/administración & dosificación , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Brain disorders represent a significant challenge in medical science due to the formidable blood-brain barrier (BBB), which severely limits the penetration of conventional therapeutics, hindering effective treatment strategies. This review delves into the innovative realm of biomimetic nanodelivery systems, including stem cell-derived nanoghosts, tumor cell membrane-coated nanoparticles, and erythrocyte membrane-based carriers, highlighting their potential to circumvent the BBB's restrictions. By mimicking native cell properties, these nanocarriers emerge as a promising solution for enhancing drug delivery to the brain, offering a strategic advantage in overcoming the barrier's selective permeability. The unique benefits of leveraging cell membranes from various sources is evaluated and advanced technologies for fabricating cell membrane-encapsulated nanoparticles capable of masquerading as endogenous cells are examined. This enables the targeted delivery of a broad spectrum of therapeutic agents, ranging from small molecule drugs to proteins, thereby providing an innovative approach to neurocare. Further, the review contrasts the capabilities and limitations of these biomimetic nanocarriers with traditional delivery methods, underlining their potential to enable targeted, sustained, and minimally invasive treatment modalities. This review is concluded with a perspective on the clinical translation of these biomimetic systems, underscoring their transformative impact on the therapeutic landscape for intractable brain diseases.
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Materiales Biomiméticos , Barrera Hematoencefálica , Membrana Celular , Humanos , Barrera Hematoencefálica/metabolismo , Membrana Celular/metabolismo , Membrana Celular/química , Animales , Materiales Biomiméticos/química , Biomimética/métodos , Nanopartículas/química , Sistemas de Liberación de Medicamentos/métodos , Portadores de Fármacos/química , Encefalopatías/tratamiento farmacológico , Encefalopatías/metabolismoRESUMEN
Overproduction of reactive oxygen species by damaged mitochondria after ischemia is a key factor in the subsequent cascade of damage. Delivery of therapeutic agents to the mitochondria of damaged neurons in the brain is a potentially promising targeted therapeutic strategy for the treatment of ischemic stroke. In this study, we developed a ceria nanoenzymes synergistic drug-carrying nanosystem targeting mitochondria to address multiple factors of ischemic stroke. Each component of this nanosystem works individually as well as synergistically, resulting in a comprehensive therapy. Alleviation of oxidative stress and modulation of the mitochondrial microenvironment into a favorable state for ischemic tolerance are combined to restore the ischemic microenvironment by bridging mitochondrial and multiple injuries. This work also revealed the detailed mechanisms by which the proposed nanodelivery system protects the brain, which represents a paradigm shift in ischemic stroke treatment.
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Acute lung injury (ALI) is a severe respiratory disease with a high mortality rate. The integrity of the pulmonary endothelial barrier influences the development and prognosis of ALI. Therefore, it has become an important target for ALI treatment. Extracellular vesicles (EVs) are promising nanotherapeutic agents against ALI. Herein, endothelium-derived engineered extracellular vesicles (eEVs) that deliver microRNA-125b-5p (miRNA-125b) to lung tissues exerting a protective effect on endothelial barrier integrity are reported. eEVs that are modified with lung microvascular endothelial cell-targeting peptides (LET) exhibit a prolonged retention time in lung tissues and targeted lung microvascular endothelial cells in vivo and in vitro. To improve the efficacy of the EVs, miRNA-125b is loaded into EVs. Finally, LET-EVs-miRNA-125b is constructed. The results show that compared to the EVs, miRNA-125b, and EVs-miRNA-125b, LET-EVs-miRNA-125b exhibit the most significant treatment efficacy in ALI. Moreover, LET-EVs-miRNA-125b is found to have an important protective effect on endothelial barrier integrity by inhibiting cell apoptosis, promoting angiogenesis, and protecting intercellular junctions. Sequencing analysis reveals that LET-EVs-miRNA-125b downregulates early growth response-1 (EGR1) levels, which may be a potential mechanism of action. Taken together, these findings suggest that LET-EVs-miRNA-125b can treat ALI by protecting the endothelial barrier integrity.
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Lesión Pulmonar Aguda , Vesículas Extracelulares , MicroARNs , Humanos , Células Endoteliales , Pulmón , MicroARNs/genética , Lesión Pulmonar Aguda/terapia , EndotelioRESUMEN
Mpox virus (MPXV), the most pathogenic zoonotic orthopoxvirus, caused worldwide concern during the SARS-CoV-2 epidemic. Growing evidence suggests that the MPXV surface protein A29 could be a specific diagnostic marker for immunological detection. In this study, a fully synthetic phage display library was screened, revealing two nanobodies (A1 and H8) that specifically recognize A29. Subsequently, an in vitro affinity maturation strategy based on computer-aided design was proposed by building and docking the A29 and A1 three-dimensional structures. Ligand-receptor binding and molecular dynamics simulations were performed to predict binding modes and key residues. Three mutant antibodies were predicted using the platform, increasing the affinity by approximately 10-fold compared with the parental form. These results will facilitate the application of computers in antibody optimization and reduce the cost of antibody development; moreover, the predicted antibodies provide a reference for establishing an immunological response against MPXV.
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COVID-19 , Anticuerpos de Dominio Único , Humanos , Anticuerpos de Dominio Único/química , Monkeypox virus , SARS-CoV-2/metabolismo , Diseño Asistido por ComputadoraRESUMEN
IMPORTANCE: Methicillin-resistant Staphylococcus aureus (MRSA) infection severely threatens human health due to high morbidity and mortality; it is urgent to develop novel strategies to tackle this problem. Metabolites belong to antibiotic adjuvants which improve the effect of antibiotics. Despite reports of L-glutamine being applied in antibiotic adjuvant for Gram-negative bacteria, how L-glutamine affects antibiotics against Gram-positive-resistant bacteria is still unclear. In this study, L-glutamine increases the antibacterial effect of gentamicin on MRSA, and it links to membrane permeability and pH gradient (ΔpH), resulting in uptake of more gentamicin. Of great interest, reduced reactive oxygen species (ROS) by glutathione was found under L-glutamine treatment; USA300 becomes sensitive again to gentamicin. This study not only offers deep understanding on ΔpH and ROS on bacterial resistance but also provides potential treatment solutions for targeting MRSA infection.
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Gentamicinas , Staphylococcus aureus Resistente a Meticilina , Humanos , Gentamicinas/farmacología , Glutamina , Especies Reactivas de Oxígeno , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacterias Grampositivas , Pruebas de Sensibilidad MicrobianaRESUMEN
Sulfur mustard (SM) is a blister-producing chemical warfare agent which could lead to a cascade of systemic damage, especially severe acute lung injury. Oxidative stress is considered to be vital processes for the SM toxicity mechanism. We previously proved the therapeutic effect of exosomes derived from bone marrow mesenchymal stromal cells in promoting the repair of alveolar epithelial barrier and inhibiting apoptosis. However, the key functional components in exosomes and the underlying mechanisms have not been fully elaborated. This research shed light on the function of the key components of human umbilical cord mesenchymal stem cell-derived exosomes (HMSCs-Ex). We noted that HMSCs-Ex-derived miR-199a-5p played a vital role in reducing pneumonocyte oxidative stress and apoptosis by reducing reactive oxygen species, lipid peroxidation products and increasing the activities of antioxidant enzymes in BEAS-2B cells and mouse models after exposure to SM for 24 h. Furthermore, we demonstrated that the overexpression of miR-199a-5p in HMSCs-Ex treatment induced a further decrease of Caveolin1 and the activation of the mRNA and protein level of NRF2, HO1 and NQO1, compared with HMSCs-Ex administration. In summary, miR-199a-5p was one of the key molecules in HMSCs-Ex that attenuated SM-associated oxidative stress via regulating CAV1/NRF2 signalling pathway.
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Exosomas , Células Madre Mesenquimatosas , MicroARNs , Gas Mostaza , Animales , Humanos , Ratones , Exosomas/genética , Exosomas/metabolismo , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , Gas Mostaza/toxicidad , Gas Mostaza/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/genéticaRESUMEN
BACKGROUND: Sulfur mustard (SM) is a highly toxic chemical warfare agent that has caused numerous casualties during wars and conflicts in the past century. Specific antidotes or therapeutic strategies are rare due to the complicated mechanism of toxicity, which still awaits elucidation. Clinical data show that acute lung injury (ALI) is responsible for most mortality and morbidity after SM exposure. Extracellular vesicles are natural materials that participate in intercellular communication by delivering various substances and can be modified. In this study, we aim to show that extracellular vesicles derived from human umbilical cord mesenchymal stromal cells (hucMSC-EVs) could exert therapeutic effects on SM-induced ALI, and to explain the underlying mechanism of effects. METHODS: MiR-146a-5p contained in hucMSC-EVs may be involved in the process of hucMSC-EVs modulating the inflammatory response to SM-induced ALI. We utilized miR-146a-5p delivered by extracellular vesicles and further modified hucMSCs with a miR-146a-5p mimic or inhibitor to collect miR-146a-5p-overexpressing extracellular vesicles (miR-146a-5p+-EVs) or miR-146a-5p-underexpressing extracellular vesicles (miR-146a-5p--EVs), respectively. Through in vivo and in vitro experiments, we investigated the mechanism. RESULTS: The effect of miR-146a-5p+-EVs on improving the inflammatory reaction tied to SM injury was better than that of hucMSC-EVs. We demonstrated that miR-146a-5p delivered by hucMSC-EVs targeted TRAF6 to negatively regulate inflammation in SM-induced ALI models in vitro and in vivo. CONCLUSION: In summary, miR-146a-5p delivered by hucMSC-EVs targeted TRAF6, causing hucMSC-EVs to exert anti-inflammatory effects in SM-induced ALI; thus, hucMSC-EVs treatment may be a promising clinical therapeutic after SM exposure.
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Vesículas Extracelulares , MicroARNs , Gas Mostaza , Humanos , MicroARNs/genética , Gas Mostaza/toxicidad , Factor 6 Asociado a Receptor de TNF , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , InflamaciónRESUMEN
In recent years, brain diseases have seriously threatened human health due to their high morbidity and mortality. Achieving efficient drug delivery to provide satisfactory therapeutic outcomes is currently the greatest challenge in treating brain diseases. The main challenges are the structural peculiarities of the brain and the inability to transport drugs across the blood-brain barrier. Biomimetic nanodelivery systems (BNDSs) applied to the brain have been extensively developed in the preclinical phase to surmount these challenges. Considering the inherent properties of BNDSs, the substantially enhanced ability of BNDS to carry therapeutic agents and their higher selectivity toward lesions offer new opportunities for developing safe and effective therapies. This review summarizes brain-targeting nanotherapies, particularly advanced therapies with biomimetic nano-assistance. Prospects for developing BNDSs and the challenges of their clinical translation are discussed. Understanding and implementing biomimetic nanotherapies may facilitate the development of new targeted strategies for brain disorders.
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Encefalopatías , Nanopartículas , Humanos , Sistema de Administración de Fármacos con Nanopartículas , Nanomedicina , Biomimética , Encéfalo , Sistemas de Liberación de Medicamentos , Barrera HematoencefálicaRESUMEN
OBJECTIVE: To assess the trends in non-melanoma skin cancer (NMSC) incidence in Hong Kong from 1990 to 2019 and the associations of age, calendar period, and birth cohort, to make projections to 2030, and to examine the drivers of NMSC incidence. METHODS: We assessed the age, calendar period, and birth cohort effects of NMSC incidence in Hong Kong between 1990 and 2019 using an age-period-cohort model. Using Bayesian age-period-cohort analysis with integrated nested Laplace approximations, we projected the incidence of NMSC in Hong Kong to 2030. RESULTS: From 1990 to 2019, the age-standardized incidence rate of NMSC increased from 6.7 per 100,000 population to 8.6 per 100,000 population in men and from 5.4 per 100,000 to 5.9 per 100,000 population in women, among the 19,568 patients in the study (9812 male patients [50.14%]). The annual net drift was 2.00% (95% confidence interval [CI]: 1.50-2.50%) for men and 1.53% (95% CI: 0.95-2.11%) for women. Local drifts increased for both sexes above the 35-39-year age group. The period and cohort risk of developing NMSC tended to rise but slowed gradually in the most recent period and post-1975 birth cohort. From 2019 to 2030, it is projected that the number of newly diagnosed NMSC cases in Hong Kong will increase from 564 to 829 in men and from 517 to 863 in women. Population aging, population growth, and epidemiologic changes contributed to the increase in incident NMSCs, with population aging being the most significant contributor. CONCLUSION: The slowing of the period and cohort effects suggests that the rising incidence of NMSC is partly attributable to increased awareness and diagnosis. The increasing prevalence of NMSC among the elderly and an aging population will significantly impact the clinical workload associated with NMSC for the foreseeable future.
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Neoplasias Cutáneas , Humanos , Masculino , Femenino , Anciano , Incidencia , Hong Kong/epidemiología , Teorema de Bayes , Neoplasias Cutáneas/epidemiologíaRESUMEN
Vibrio parahaemolyticus (V. parahaemolyticus) is an important foodborne pathogen known to cause severe enteric disease. Thus, timely detection of V. parahaemolyticus in seafood is crucial to prevent food poisoning and reduce economic losses. Traditional lateral flow immunoassay strips (LFIS) required good labelling materials and pairing of two antibodies, which made them costly and difficult to manufacture. In this study, a label-free and lac dye coloration-based LFIS (LD-LFIS) to detect trh+ V. parahaemolyticus was developed for the first time. Lac dye was used to stain V. parahaemolyticus, and LFIS was used to detect stained bacteria. Dimethyl sulphoxide (DMSO) and simultaneous mordanting were chosen as the best solvent and the best staining method for lac dye. In addition, three mordants [KAl(SO4 )2 ·12H2 O, NH4 Fe(SO4 )2 ·12H2 O, and AlCl3 ·6H2 O] were selected to improve dyeing efficiency. The detection limit of LD-LFIS was 3.9 × 105 CFU/ml when NH4 Fe(SO4 )2 ·12H2 O was used as mordant. Feasibility of the LD-LFIS method was verified by detecting trh+ V. parahaemolyticus in true and spiked seafood samples. The method developed in this study is expected to reduce restrictions on labelling materials and pairing of two antibodies on LFIS, and proposes a novel idea for the rapid detection of V. parahaemolyticus in seafood.
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Enfermedades de los Peces , Vibrio parahaemolyticus , Animales , Compuestos Azo , Dimetilsulfóxido , Inmunoensayo , Alimentos Marinos/microbiología , SolventesAsunto(s)
Costo de Enfermedad , Demografía , Psoriasis/epidemiología , Salud Global , Humanos , PrevalenciaRESUMEN
Sulfur mustard (SM) is a highly toxic chemical warfare agent that causes acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). There are no effective therapeutic treatments or antidotes available currently to counteract its toxic effects. Our previous study shows that bone marrow-derived mesenchymal stromal cells (BMSCs) could exert therapeutic effects against SM-induced lung injury. In this study, we explored the therapeutic potential of BMSC-derived exosomes (BMSC-Exs) against ALI and the underlying mechanisms. ALI was induced in mice by injection of SM (30 mg/kg, sc) at their medial and dorsal surfaces. BMSC-Exs (20 µg/kg in 200 µL PBS, iv) were injected for a 5-day period after SM exposure. We showed that BMSC-Exs administration caused a protective effect against pulmonary edema. Using a lung epithelial cell barrier model, BMSC-Exs (10, 20, 40 µg) dose-dependently inhibited SM-induced cell apoptosis and promoted the recovery of epithelial barrier function by facilitating the expression and relocalization of junction proteins (E-cadherin, claudin-1, occludin, and ZO-1). We further demonstrated that BMSC-Exs protected against apoptosis and promoted the restoration of barrier function against SM through upregulating G protein-coupled receptor family C group 5 type A (GPRC5A), a retinoic acid target gene predominately expressed in the epithelial cells of the lung. Knockdown of GPRC5A reduced the antiapoptotic and barrier regeneration abilities of BMSC-Exs and diminished their therapeutic effects in vitro and in vivo. BMSC-Exs-caused upregulation of GPRC5A promoted the expression of Bcl-2 and junction proteins via regulating the YAP pathway. In summary, BMSC-Exs treatment exerts protective effects against SM-induced ALI by promoting alveolar epithelial barrier repair and may be an alternative approach to stem cell-based therapy.
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Lesión Pulmonar Aguda/terapia , Exosomas/trasplante , Células Madre Mesenquimatosas/citología , Transducción de Señal/efectos de los fármacos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Animales , Apoptosis/fisiología , Línea Celular , Células Epiteliales/metabolismo , Técnicas de Inactivación de Genes , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones Endogámicos ICR , Ratones Noqueados , Gas Mostaza , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Señalizadoras YAP/metabolismoRESUMEN
Nerve agents are among the world's deadliest poisons, and the target enzyme is acetylcholinesterase (AChE). To better diagnosis nerve agent poisonings, a reliable diagnostic method for both nerve agents and AChE is desirable. Herein, we synthesized a series of fluorescent sensors for both real nerve agents and acetylcholinesterase activity detection. Among these sensors, HBQ-AE exhibited a fast response rate (within 10 s for nerve agent and 8 min for AChE), good sensitivity (the limit of detection is 6 nM and 0.2 U/mL) and a high off/on contrast. To the best of our knowledge, HBQ-AE is the first fluorescence sensor for nerve agents and AChE activity detection. The fluorescent change of HBQ-AE from nonfluorescence to blue fluorescence (nerve agent) or orange fluorescence (AChE) by excitation at 365 nm can be easily observed with the naked eye. HBQ-AE was successfully applied to image nerve agents and AChE activity in living cells. Moreover, HBQ-AE is the vital member to construct a test paper that can be employed to detect and diagnose chemical warfare agents.
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Sustancias para la Guerra Química , Agentes Nerviosos , Acetilcolinesterasa , Inhibidores de la Colinesterasa , Espectrometría de FluorescenciaRESUMEN
Aflatoxin B1 (AFB1) is a potent hepatocarcinogen in humans and exposure to AFB1 is known to cause both acute and chronic hepatocellular injury. As the liver is known to be the main target organ of aflatoxin, it is important to identify the key molecules that participate in AFB1-induced hepatotoxicity and to investigate their underlying mechanisms. In this study, the critical role of caveolin-1 in AFB1-induced hepatic cell apoptosis was examined. We found a decrease in cell viability and an increase in oxidation and apoptosis in human hepatocyte L02 cells after AFB1 exposure. In addition, the intracellular expression of caveolin-1 was increased in response to AFB1 treatment. Downregulation of caveolin-1 significantly alleviated AFB1-induced apoptosis and decreased cell viability, whereas overexpression of caveolin-1 reversed these effects. Further functional analysis showed that caveolin-1 participates in AFB1-induced oxidative stress through its interaction with Nrf2, leading to the downregulation of cellular antioxidant enzymes and the promotion of oxidative stress-induced apoptosis. In addition, caveolin-1 was found to regulate AFB1-induced autophagy. This finding was supported by the effect that caveolin-1 deficiency promoted autophagy after AFB1 treatment, leading to the inhibition of apoptosis, whereas overexpression of caveolin-1 inhibited autophagy and accelerated apoptosis. Interestingly, further investigation showed that caveolin-1 participates in AFB1-induced autophagy by regulating the EGFR/PI3K-AKT/mTOR signaling pathway. Taken together, our data reveal that caveolin-1 plays a crucial role in AFB1-induced hepatic cell apoptosis via the regulation of oxidation and autophagy, which provides a potential target for the development of novel treatments to combat AFB1 hepatotoxicity.
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Aflatoxina B1/toxicidad , Autofagia/efectos de los fármacos , Caveolina 1/metabolismo , Hígado/patología , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Hígado/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
Sulfur mustard is one of the most harmful chemical warfare agents and can induce skin, eye, and lung injuries. However, it is hard for medical stuff to diagnose sulfur mustard poisoning early because of the incubation period after sulfur mustard exposure. Detecting intact sulfur mustard in vivo might be an effective approach for the early diagnosis of sulfur mustard poisoning. A series of fluorescent probes for intact sulfur mustard detection were developed in this study. All of the developed probes could react with sulfur mustard selectivity. Among these probes, SiNIR-SM exhibited an extremely good response rate and a high off/on contrast. To the best of our knowledge, SiNIR-SM is the first near-infrared fluorescent probe for the sulfur mustard detection. Both SiNIR-SM and OxSM-1 were successfully applied to image sulfur mustard in living cells. Using SiNIR-SM, we found that sulfur mustard accumulates in the mitochondria of living cells. This result could provide a new insight for the treatment of sulfur mustard injuries. We also found that SiNIR-SM is suitable for the early diagnostic imaging of sulfur mustard poisoning in SKH-1 mice via the detection of intact sulfur mustard.
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Sustancias para la Guerra Química/química , Sustancias para la Guerra Química/envenenamiento , Colorantes Fluorescentes/química , Gas Mostaza/química , Gas Mostaza/envenenamiento , Piel/diagnóstico por imagen , Animales , Transporte Biológico , Línea Celular , Sustancias para la Guerra Química/farmacología , Diagnóstico por Imagen , Humanos , Ratones , Gas Mostaza/farmacologíaRESUMEN
Five previously undescribed monoterpenoid indole alkaloids were isolated from the roots of Gelsemium elegans. Their structures with absolute configurations were elucidated by HRESIMS, X-ray diffraction, ECD spectra, and molecular modeling. 19,20-Epoxyhumantenine is a humantenine-type alkaloid with an epoxypropyl group at the C-20 position, (4R)-19-oxo-gelsevirine N4-oxide is a gelsemine-related alkaloid, and gelsedethenine is a gelsedine-type alkaloid with a butenyl group at the C-20 position. Moreover, 10,11-dimethoxy-N1-demethoxy-gelsemamide is an open-loop indole alkaloid and 11-demethoxy-gelsemazonamide is an aromatic azo-linked dimeric indole alkaloid. Among the five alkaloids, (4R)-19-oxo-gelsevirine N4-oxide and 10,11-dimethoxy-N1-demethoxy-gelsemamide exhibited significant inhibitory effects on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophage cells, with IC50 values of 6.18⯱â¯1.07 and 12.2⯱â¯1.02⯵M, respectively.
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Gelsemium/química , Alcaloides Indólicos/química , Animales , Alcaloides Indólicos/farmacología , Concentración 50 Inhibidora , Ratones , Modelos Moleculares , Conformación Molecular , Óxido Nítrico/antagonistas & inhibidores , Células RAW 264.7RESUMEN
BACKGROUND: Sulfur mustard (SM) is a notorious chemical warfare agent that can cause severe acute lung injury (ALI), in addition to other lesions. Currently, effective medical countermeasures for SM are lacking. Bone marrow-derived mesenchymal stromal cells (BMSCs) possess self-renewal and multipotent differentiation capacity. BMSCs can also migrate to inflammation and injury sites and exert anti-inflammatory and tissue repair functions. Here, we report the curative effect of BMSCs on SM-induced ALI in a mouse model. METHODS: Mice BMSCs were injected into mice via the tail vein 24 h after SM exposure. The distribution of BMSCs in mice was detected by fluorescence imaging. The therapeutic potential of BMSCs was evaluated by the calculating survival rate. The effects of BMSCs on lung tissue injury and repair assessment were examined by staining with H&E and measuring the lung wet/dry weight ratio, BALF protein level, and respiratory function. The effects of BMSCs on the infiltration and phenotypic alteration of inflammatory cells were analyzed by immunohistochemistry and flow cytometry. The levels of chemokines and inflammatory cytokines were examined using the Luminex Performance Assay and ELISA. RNA interference, western blotting, and ELISA were applied to explore the role of the TLR4 signaling pathway in the anti-inflammatory effects of BMSCs. The extent of tissue repair was analyzed by ELISA, western blotting, and immunohistochemistry. RESULTS: Fluorescence imaging indicated that the lung is the major target organ of BMSCs after injection. The injection of BMSCs significantly improved the survival rate (p < 0.05), respiratory function, and related lung damage indexes (wet/dry weight ratio, total proteins in BALF, etc.) in mice. BMSC administration also reduced the level of pro-inflammatory cytokines, chemokines, and inflammatory cell infiltration, as well as affected the balances of M1/M2 and Th17/Treg. Furthermore, solid evidence regarding the effects of BMSCs on the increased secretion of various growth factors, the differentiation of alveolar epithelial cells, and the enhancement of cell barrier functions was also observed. CONCLUSION: BMSCs displayed protective effects against SM-induced ALI by alleviating inflammation and promoting tissue repair. The present study provides a strong experimental basis in a mouse model and suggests possible application for future cell therapy.
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Lesión Pulmonar Aguda , Células de la Médula Ósea/inmunología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/inmunología , Gas Mostaza/toxicidad , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/terapia , Animales , Células de la Médula Ósea/patología , Masculino , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos ICRRESUMEN
Sulfur mustard (SM) is a chemical warfare agent that was applied in a series of military conflicts and still poses a severe threat to civilians and military personnel. Although the cellular and molecular mechanisms of SM toxicity are still not fully understood, oxidative stress has been considered as the initial vital process for damage. Polydatin, the product of resveratrol and glucose, is a promising candidate for the treatment of oxidative stress-related diseases. However, its effects on SM-induced hepatic injury remain unknown. Thus, we investigated the protective effects of polydatin against SM-induced hepatic injury and its possible mechanism. We found that treatment with polydatin remarkably improved the survival rate of mice bear subcutaneously injected with SM. Polydatin decreased the SM-induced increase of serum aminotransferase levels and ameliorated hepatic pathological damage. We also found that indexes of oxidative stress were improved in mouse liver samples and L02 cells. Meanwhile, changes in the Sirtuin family after treatment with SM were explored in mice and cells since polydatin is a potent activator of Sirt1 and Sirt3. Polydatin significantly increased the expression of Sirt1, HO-1, and NQO1; and the nuclear translocation of Nrf2 in mouse liver and L02 cells. Furthermore, we also observed that either Sirt1 or Nrf2 knockdown abolished the protective effect of polydatin. Our data indicated that polydatin could provide protection against SM-induced hepatic injury through the Sirt1/Nrf2 pathway, suggesting that polydatin is a novel potential antidote for sulfur mustard.
Asunto(s)
Antioxidantes/farmacología , Sustancias para la Guerra Química/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Glucósidos/farmacología , Hepatocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Gas Mostaza/toxicidad , Estrés Oxidativo/efectos de los fármacos , Estilbenos/farmacología , Animales , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos ICR , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Sirtuina 1/metabolismoRESUMEN
Protein persulfidation is a newly defined oxidative posttranslational modification and plays important roles in many biological processes. Detection of protein persulfidation in living systems is urgently needed to advance the study of H2S/H2Sn-based signalling and cellular redox regulation. Here, we developed a novel off-on fluorescent probe for the detection of persulfidation using a chemical sensor, HQO-SSH, in biological systems. HQO-SSH features fast reaction, good selectivity and high sensitivity. Due to the distinctive features of HQO-SSH, this probe was successfully applied to image protein persulfidation changes in pulmonary cells. We also demonstrated that the probe is suitable for imaging protein persulfidation in lung tissues. In addition, confocal imaging with this method revealed that sulfur mustard, a commonly used chemical warfare agent, decreased mitochondrial protein persulfidation in living lung cells and tissues. Due to these results, this probe holds great promise for exploring the role of protein persulfidation in a variety of pathophysiological conditions.