RESUMEN
The common housefly, Musca domestica, known for transmitting over 100 infections, was studied using green-synthesized Cadmium Sulfide nanoparticles (CdS NPs) from Agaricus bisporus. These CdS NPs were tested on third-instar larvae under laboratory conditions using dipping and feeding methods with concentrations (75, 100, 125, 150, 175, and 200 µg/mL). The toxicity, measured by LC50, was found to be 138 µg/mL for dipping treatment and 123 µg/mL for feeding treatment. Analysis with an energy-dispersive X-ray microanalyzer confirmed Cd accumulation in the larval midgut, indicating penetration of CdS NPs into the organism, which may potentially increase their toxicity. CdS NPs caused disruptions in Heat Shock Protein 70, cell apoptosis, and various biochemical components. Scanning electron microscopy revealed morphological abnormalities in larvae, pupae, and adults exposed to CdS NPs. Ultrastructural examination showed significant midgut tissue abnormalities in larvae treated with 123 µg/mL of CdS NPs. Our study demonstrated that green-synthesized CdS NPs from A. bisporus can effectively control the development of M. domestica larvae.
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Agaricus , Compuestos de Cadmio , Moscas Domésticas , Larva , Sulfuros , Animales , Moscas Domésticas/efectos de los fármacos , Sulfuros/química , Sulfuros/farmacología , Compuestos de Cadmio/toxicidad , Larva/efectos de los fármacos , Nanopartículas del Metal/química , Nanopartículas del Metal/toxicidad , Nanopartículas/química , Modelos BiológicosRESUMEN
Background and Purpose: Growth hormone-releasing hormone (GHRH) agonist, a 29-amino acid peptide, shows significant potential in treating myocardial infarction (MI) by aiding the repair of injured heart tissue. The challenge lies in the effective on-site delivery of GHRH agonist. This study explores the use of a targetable delivery system employing ROS-responsive PEG-PPS-PEG polymers to encapsulate and deliver GHRH agonist MR409 for enhanced therapeutic efficacy. Methods: We synthesized a self-assembling poly (ethylene glycol)-poly (propylene sulfide)-poly (ethylene glycol) polymer (PEG-PPS-PEG) amphiphilic polymer responsive to reactive oxygen species (ROS). The hydrophilic peptide GHRH agonist MR409 was encapsulated within these polymers to form nano PEG-PPS-PEG@MR409 vesicles (NPs). Cardiomyocyte apoptosis was induced under hypoxia and serum-free culture condition for 24 hours, and their production of ROS was detected by fluorescence dye staining. The cellular uptake of PEG-PPS-PEG@MR409 NPs was observed using fluorescence-labeled MR409. Targeting ability and therapeutic efficacy were evaluated using a mouse MI model. Results: PEG-PPS-PEG@MR409 NPs were efficiently internalized by cardiomyocytes, reducing ROS levels and apoptosis. These NPs exhibited superior targeting to the infarcted heart compared to naked MR409 peptide. With a reduced injection frequency (once every three days), PEG-PPS-PEG@MR409 NPs significantly promoted cardiac function recovery post-MI, matching the efficacy of daily MR409 injections. Conclusion: ROS-responsive PEG-PPS-PEG polymers provide a novel and effective platform for the targeted delivery of GHRH agonist peptides, improving cardiac function and offering a new approach for peptide therapy in MI treatment.
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Infarto del Miocardio , Miocitos Cardíacos , Polietilenglicoles , Especies Reactivas de Oxígeno , Animales , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ratones , Infarto del Miocardio/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Modelos Animales de Enfermedad , Hormona Liberadora de Hormona del Crecimiento/agonistas , Hormona Liberadora de Hormona del Crecimiento/farmacocinética , Hormona Liberadora de Hormona del Crecimiento/administración & dosificación , Apoptosis/efectos de los fármacos , Sulfuros/química , Sulfuros/farmacocinética , Sulfuros/farmacología , Sulfuros/administración & dosificación , Péptidos/química , Péptidos/farmacología , Péptidos/farmacocinética , Péptidos/administración & dosificación , Masculino , Ratones Endogámicos C57BLRESUMEN
Currently, no safe vaccine against leishmaniasis is available. So far, different control strategies against numerous reservoir hosts and biological vectors have not been environment-friendly and feasible. Hence, employing medicinal components and conventional drugs could be a promising approach to developing novel therapeutic alternatives. This study aimed to explore diallyl sulfide (DAS), a dynamic constituent of garlic, alone and in a mixture with meglumine antimoniate (MAT as standard drug) using in vitro and animal model experiments against Leishmania major stages. The binding affinity of DAS and four major defense elements of the immune system (iNOS, IFN-É£, IL-12, and TNF-α) was used to predict the predominant binding mode for molecular docking configurations. Herein, we conducted a broad range of experiments to monitor and assess DAS and MAT potential treatment outcomes. DAS, combined with MAT, displayed no cytotoxicity and employed a powerful anti-leishmanial activity, notably against the clinical stage. The function mechanism involved immunomodulation through the induction of Th1 cytokine phenotypes, triggering a high apoptotic profile, reactive oxygen species (ROS) production, and antioxidant enzymes. This combination significantly decreased cutaneous lesion diameter and parasite load in BALB/c mice. The histopathological findings performed the infiltration of inflammatory cells associated with T-lymphocytes, particularly CD4+ phenotypes, as determined by biochemical markers in alleviating the amastigote stage and improving the pathological changes in L. major infected BALB/c mice. Therefore, DAS and MAT deserve further advanced therapeutic development and should be considered as possible candidates for treating volunteer cases with cutaneous leishmaniasis in designing an upcoming clinical trial.
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Compuestos Alílicos , Antiprotozoarios , Leishmania major , Leishmaniasis Cutánea , Antimoniato de Meglumina , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Sulfuros , Animales , Leishmania major/efectos de los fármacos , Antimoniato de Meglumina/farmacología , Sulfuros/farmacología , Sulfuros/química , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/uso terapéutico , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/parasitología , Ratones , Compuestos Alílicos/farmacología , Compuestos Alílicos/química , Compuestos Alílicos/uso terapéutico , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Especies Reactivas de Oxígeno/metabolismo , Meglumina/farmacología , Meglumina/química , Citocinas/metabolismoRESUMEN
Garlic is a vegetable with numerous pro-health properties, showing high antioxidant capacity, and cytotoxicity for various malignant cells. The inhibition of cell proliferation by garlic is mainly attributed to the organosulfur compounds (OSCs), but it is far from obvious which constituents of garlic indeed participate in the antioxidant and cytotoxic action of garlic extracts. This study aimed to obtain insight into this question by examining the antioxidant activity and cytotoxicity of six OSCs and five phenolics present in garlic. Three common assays of antioxidant activity were employed (ABTSâ decolorization, DPPHâ decolorization, and FRAP). Cytotoxicity of both classes of compounds to PEO1 and SKOV-3 ovarian cancer cells, and MRC-5 fibroblasts was compared. Negligible antioxidant activities of the studied OSCs (alliin, allicin, S-allyl-D-cysteine, allyl sulfide, diallyl disulfide, and diallyl trisulfide) were observed, excluding the possibility of any significant contribution of these compounds to the total antioxidant capacity (TAC) of garlic extracts estimated by the commonly used reductive assays. Comparable cytotoxic activities of OSCs and phenolics (caffeic, p-coumaric, ferulic, gallic acids, and quercetin) indicate that both classes of compounds may contribute to the cytotoxic action of garlic.
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Compuestos Alílicos , Antioxidantes , Disulfuros , Ajo , Fenoles , Extractos Vegetales , Sulfuros , Ácidos Sulfínicos , Ajo/química , Humanos , Antioxidantes/farmacología , Antioxidantes/química , Fenoles/farmacología , Fenoles/química , Disulfuros/farmacología , Disulfuros/química , Línea Celular Tumoral , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ácidos Sulfínicos/farmacología , Ácidos Sulfínicos/química , Sulfuros/farmacología , Sulfuros/química , Compuestos Alílicos/farmacología , Compuestos Alílicos/química , Compuestos de Azufre/farmacología , Compuestos de Azufre/química , Cisteína/análogos & derivados , Cisteína/química , Cisteína/farmacología , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismoRESUMEN
OBJECTIVE: The metabolic reprogramming of acute myeloid leukemia (AML) cells is a compensatory adaptation to meet energy requirements for rapid proliferation. This study aimed to examine the synergistic effects of glutamine deprivation and metformin exposure on AML cells. METHODS: SKM-1 cells (an AML cell line) were subjected to glutamine deprivation and/or treatment with metformin or bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES, a glutaminase inhibitor) or cytarabine. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay, and cell apoptosis and reactive oxygen species (ROS) by flow cytometry. Western blotting was conducted to examine the levels of apoptotic proteins, including cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, the human long noncoding RNA (lncRNA) microarray was used to analyze gene expression after glutamine deprivation, and results were confirmed with quantitative RT-PCR (qRT-PCR). The expression of metallothionein 2A (MT2A) was suppressed using siRNA. Cell growth and apoptosis were further detected by CCK-8 assay and flow cytometry, respectively, in cells with MT2A knockdown. RESULTS: Glutamine deprivation or treatment with BPTES inhibited cell growth and induced apoptosis in SKM-1 cells. The lncRNA microarray result showed that the expression of MT family genes was significantly upregulated after glutamine deprivation. MT2A knockdown increased apoptosis, while proliferation was not affected in SKM-1 cells. In addition, metformin inhibited cell growth and induced apoptosis in SKM-1 cells. Both glutamine deprivation and metformin enhanced the sensitivity of SKM-1 cells to cytarabine. Furthermore, the combination of glutamine deprivation with metformin exhibited synergistic antileukemia effects on SKM-1 cells. CONCLUSION: Targeting glutamine metabolism in combination with metformin is a promising new therapeutic strategy for AML.
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Apoptosis , Glutamina , Leucemia Mieloide Aguda , Metformina , Metformina/farmacología , Humanos , Glutamina/metabolismo , Glutamina/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Glutaminasa/genética , Glutaminasa/metabolismo , Tiadiazoles/farmacología , Sulfuros/farmacología , Sinergismo Farmacológico , Citarabina/farmacología , Especies Reactivas de Oxígeno/metabolismo , ARN Largo no Codificante/genéticaRESUMEN
Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of "reprogramming" and "interfering" iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical "Trojan horse", mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis-apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.
Asunto(s)
Apoptosis , Galio , Hierro , Paraptosis , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proteínas de Transporte de Catión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Galio/química , Galio/farmacología , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/química , Sulfuro de Hidrógeno/farmacología , Hierro/metabolismo , Hierro/química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Paraptosis/efectos de los fármacos , Receptores de Transferrina/metabolismo , Sulfuros/química , Sulfuros/farmacología , Microambiente Tumoral/efectos de los fármacosRESUMEN
A wide variety of methods are being developed to ultimately defeat cancer; while some of these strategies have shown highly positive results, there are serious obstacles to overcome to completely eradicate this disease. So, it is crucial to construct multifunctional nanostructures possessing intelligent capabilities that can be utilized to treat cancer. A possible strategy for producing these multifunctional nanostructures is to combine various cancer treatment techniques. Based on this point of view, we successfully synthesized multifunctional HCuS@Cu2S@Au-P(NIPAM-co-AAm)-PpIX nanohybrids. The peculiarities of these thermosensitive polymer-modified and protoporphyrin IX (PpIX)-loaded hollow nanohybrids are that they combine photodynamic therapy (PDT), sonodynamic therapy (SDT), and photothermal therapy (PTT) with an intelligent design. As an all-in-one nanohybrids, HCuS@Cu2S@Au-P(NIPAM-co-AAm)-PpIX nanohybrids were employed in the SDT-PDT-PTT combination therapy, which proved to have a synergistic therapeutic effect for in vitro tumor treatments against breast tumors.
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Cobre , Fotoquimioterapia , Terapia Fototérmica , Protoporfirinas , Humanos , Cobre/química , Cobre/farmacología , Protoporfirinas/química , Protoporfirinas/farmacología , Protoporfirinas/uso terapéutico , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/síntesis química , Oro/química , Femenino , Terapia por Ultrasonido/métodos , Nanoestructuras/química , Nanoestructuras/uso terapéutico , Neoplasias de la Mama/terapia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Sulfuros/química , Sulfuros/farmacología , AnimalesRESUMEN
Macrocyclic peptides are promising scaffolds for the covalent ligand discovery. However, platforms enabling the direct identification of covalent macrocyclic ligands in a high-throughput manner are limited. In this study, we present an mRNA display platform allowing selection of covalent macrocyclic inhibitors using 1,3-dibromoacetone-vinyl sulfone (DBA-VS). Testcase selections on TEV protease resulted in potent covalent inhibitors with diverse cyclic structures, among which cTEV6-2, a macrocyclic peptide with a unique C-terminal cyclization, emerged as the most potent covalent inhibitor of TEV protease described to-date. This study outlines the workflow for integrating chemical functionalizationâinstallation of a covalent warheadâwith mRNA display and showcases its application in targeted covalent ligand discovery.
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ARN Mensajero , ARN Mensajero/antagonistas & inhibidores , Ciclización , Sulfuros/química , Sulfuros/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/síntesis química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Compuestos Macrocíclicos/síntesis química , Sulfonas/química , Sulfonas/farmacología , Descubrimiento de Drogas , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/síntesis química , Estructura MolecularRESUMEN
First time compared the different metals doped ZnS nanoparticles for antibacterial and liver cancer cell line. In this study, copper, aluminum and nickel doped ZnS NPs were synthesized via co-precipitation method. The XRD analysis was confirmed the presence of cubic crystal structure and crystallite size decreased from 6 to 3 nm with doping elements. While as SEM micro-grains were revealed slightly irregular and agglomerated morphology with the presence of dopant elements. The presence of different dopant elements such as Cu, Al and Ni in ZnS NPs was identified via EDX analysis. The FTIR results demonstrate various vibrational stretching and bending modes attached to the surface of ZnS nanomaterials. After that the well diffusion method was used to conduct in-vitro bioassays for evaluation of antibacterial and anticancer activities against E.coli and B.cereus, as well as HepG2 liver cancer cell line. Our findings unveil exceptional results with maximum inhibition zone of approximately 9 to 23 mm observed against E.coli and 12 to 27 mm against B.cereus, respectively. In addition, the significant reduction in cell viability was achieved against the HepG2 liver cancer cell line. These favorable results highlight the potential of Ni doped ZnS NPs for various biomedical applications. In future, the doped ZnS nanomaterials will be suitable for hyperthermia therapy and wound healing process.
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Aluminio , Antibacterianos , Antineoplásicos , Cobre , Escherichia coli , Níquel , Sulfuros , Compuestos de Zinc , Humanos , Níquel/química , Antibacterianos/farmacología , Antibacterianos/química , Sulfuros/química , Sulfuros/farmacología , Cobre/química , Antineoplásicos/farmacología , Antineoplásicos/química , Aluminio/química , Compuestos de Zinc/química , Escherichia coli/efectos de los fármacos , Células Hep G2 , Nanopartículas del Metal/química , Supervivencia Celular/efectos de los fármacos , Bacillus cereus/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Nanopartículas/químicaRESUMEN
Despite the widespread recognition of the global concern regarding the onset of cardiovascular diseases in a significant number of patients following cancer treatment, definitive strategies for prevention and treatment remain elusive. In this study, we established systems to evaluate the influence of anti-cancer drugs on the quality control of mitochondria, pivotal for energy metabolism, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treatment in lung cancer, reportedly increases the risk of cardiovascular disease. However, its underlying mechanism is largely unknown. Here, we found that the treatment of hiPSC-CMs with osimertinib and doxorubicin, but not trastuzumab and cisplatin, revealed a concentration-dependent impairment of respiratory function accompanied by mitochondrial fission. We previously reported the significant role of sulfur metabolism in maintaining mitochondrial quality in the heart. Co-treatment with various inorganic sulfur donors (Na2S, Na2S2, Na2S3) alongside anti-cancer drugs demonstrated that Na2S attenuated the cardiotoxicity of osimertinib but not doxorubicin. Osimertinib decreased intracellular reduced sulfur levels, while Na2S treatment suppressed the sulfur leakage, suggesting its potential in mitigating osimertinib-induced cardiotoxicity. These results imply the prospect of inorganic sulfides, such as Na2S, as a seed for precision pharmacotherapy to alleviate osimertinib's cardiotoxic effects.
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Acrilamidas , Compuestos de Anilina , Antineoplásicos , Doxorrubicina , Células Madre Pluripotentes Inducidas , Mitocondrias , Miocitos Cardíacos , Sulfuros , Humanos , Acrilamidas/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Compuestos de Anilina/farmacología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Doxorrubicina/efectos adversos , Sulfuros/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Cardiotoxicidad/prevención & control , Cardiotoxicidad/etiología , Células Cultivadas , Dinámicas Mitocondriales/efectos de los fármacos , Azufre , Indoles , PirimidinasRESUMEN
INTRODUCTION: In end stage renal disease )ESRD(, reduced EPO production resulted in decreased oxygen diffusion that cause Hypoxia-inducible factors (HIFs) stabilization. The mechanism of beneficial effects of H2S in chronic kidney disease (CKD) is the aim of the present study to examine the effects of the H2S donor sodium hydrosulfide (NaHS) on renal function parameters, oxidative stress indices and expression levels of HIF-2α gene and erythropoietin protein in 5/6 nephrectomy-induced chronic renal failure in rats. METHODS AND MATERIALS: Male rats were assigned into 3 groups (n = 8): Sham, CKD and NaHS groups. In the CKD group, 5/6 nephrectomy was performed. In the sham group, rats were anesthetized but 5/6 nephrectomy was not induced. In the NaHS group, 30 µmol/L of NaHS in drinking water for 8 weeks was adminstrated 4 weeks after 5/6 nephrectomy induction. At the end of the 12 week, blood and renal tissues were taken to evaluate renal function parameters, oxidative stress indices and expression levels of HIF-2α gene and erythropoietin protein. RESULTS: The induction of 5/6 nephrectomy significantly caused renal dysfunction, oxidative stress, increased HIF-2α gene expression and decreased erythropoietin levels in renal tissue samples. NaHS administration resulted in a marked improvement in renal function and oxidative stress indicators, a marked reduction in HIF-2α gene expression as well as an increase in erythropoietin protein levels in comparison with the CKD group. CONCLUSION: In this study, regional hypoxia and oxidative stress in CKD, may cause the stabilization of the HIFs complexes, although erythropoietin synthesis was not increased due to destructive effects of CKD on the kidney tissues. Administration of NaHS caused up-regulating HIF-erythropoietin signaling pathway.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Eritropoyetina , Sulfuro de Hidrógeno , Nefrectomía , Estrés Oxidativo , Insuficiencia Renal Crónica , Animales , Eritropoyetina/genética , Eritropoyetina/metabolismo , Eritropoyetina/farmacología , Masculino , Ratas , Sulfuro de Hidrógeno/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Estrés Oxidativo/efectos de los fármacos , Riñón/metabolismo , Riñón/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Sulfuros/farmacología , Modelos Animales de EnfermedadRESUMEN
Rhabdomyosarcoma (RMS) represents one of the most lethal soft-tissue sarcomas in children. The toxic trace element arsenic has been reported to function as a radiosensitizer in sarcomas. To investigate the role of arsenic sulfide (As4S4) in enhancing radiation sensitization in RMS, this study was conducted to elucidate its underlying mechanism in radiotherapy. The combination of As4S4 and radiotherapy showed significant inhibition in RMS cells, as demonstrated by the cell counting kit-8 (CCK-8) assay and flow cytometry. Subsequently, we demonstrated for the first time that As4S4, as well as the knockdown of NFATc3 led to double-strand break (DSB) through increased expression of RAG1. In vivo experiment confirmed that co-treatment efficiently inhibited RMS growth. Furthermore, survival analysis of a clinical cohort consisting of 59 patients revealed a correlation between NFATc3 and RAG1 expression and overall survival (OS). Cox regression analysis also confirmed the independent prognostic significance of NFATc3 and RAG1.Taken together, As4S4 enhances radiosensitivity in RMS via activating NFATc3-RAG1 mediated DSB. NFATc3 and RAG1 are potential therapeutic targets. As4S4 will hopefully serve as a prospective radio-sensitizing agent for RMS.
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Arsenicales , Roturas del ADN de Doble Cadena , Factores de Transcripción NFATC , Tolerancia a Radiación , Rabdomiosarcoma , Sulfuros , Humanos , Roturas del ADN de Doble Cadena/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de la radiación , Sulfuros/farmacología , Sulfuros/uso terapéutico , Rabdomiosarcoma/metabolismo , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/radioterapia , Rabdomiosarcoma/patología , Rabdomiosarcoma/genética , Línea Celular Tumoral , Masculino , Femenino , Arsenicales/farmacología , Arsenicales/uso terapéutico , Animales , Tolerancia a Radiación/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Ratones , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Ratones Desnudos , Niño , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Diallyl trisulfide (DATS) has a direct antioxidant capacity and emerges as a promising neuroprotective agent. This study was designed to investigate the role of DATS in traumatic brain injury (TBI). METHODS: TBI mouse models were established using the controlled cortical impact, followed by DATS administration. The effects of DATS on neurological deficit, brain damage, inflammation and phosphoglycerate kinase 1 (PGK1) expression were detected using mNSS test, histological analysis, TUNEL assay, enzyme-linked immunosorbent assay and immunofluorescence. PC12 cells were subjected to H2O2-induced oxidative injury after pre-treatment with DATS, followed by cell counting kit-8 assay, flow cytometry and ROS production detection. Apoptosis-related proteins and the PGK1/nuclear factor erythroid-2 related factor 2 (Nrf2) pathway were examined using Western blot. RESULTS: DATS ameliorated the cerebral cortex damage, neurological dysfunction and apoptosis, as well as decreased PGK1 expression and expressions of pro-inflammatory cytokines (IL-6, IL-1ß, TNF-α) in mice after TBI. DATS also enhanced viability, blocked apoptosis and inhibited ROS production in H2O2-induced PC12 cells. DATS downregulated Cleaved-Caspase3, Bax and PGK1 levels, and upregulated Bcl-2 and Nrf2 levels in TBI mouse models and the injured cells. CONCLUSION: DATS regulates PGK1/Nrf2 expression and inflammation to alleviate neurological damage in mice after TBI.
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Compuestos Alílicos , Apoptosis , Lesiones Traumáticas del Encéfalo , Factor 2 Relacionado con NF-E2 , Fosfoglicerato Quinasa , Sulfuros , Animales , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/patología , Sulfuros/farmacología , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Fosfoglicerato Quinasa/metabolismo , Compuestos Alílicos/farmacología , Células PC12 , Masculino , Apoptosis/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Ratas , Estrés Oxidativo/efectos de los fármacos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Antioxidantes/farmacologíaRESUMEN
Polydopamine has gained considerable attention in the biomaterial domain owing to its excellent biocompatibility, antioxidant activity, photothermal effect and adhesion property. Herein, copper sulfide (Cu2-xS) wrapped in mesoporous polydopamine (MPDA) was synthesized through in-situ polymerization, followed by the surface modification with cationic polyethyleneimine (PEI). The mussel-inspired MPDA matrix successfully prevented the oxidation and agglomeration of Cu2-xS nanoparticles, and regulated the release of copper ions and reactive oxygen species (ROS) levels. Surface-modified PEI endow MPDA@Cu2-xS with positive charges, facilitating their rapid contact with negatively charged bacteria through electrostatic interactions. The pH-dependent Cu+/Cu2+ release and NIR-responsive ROS generation were confirmed using molecular probes and electron spin resonance (ESR). The MPDA@Cu2-xS/PEI showed significantly enhanced antibacterial activity and reduced cytotoxicity for NIH3T3 cells. Under NIR irradiation (1.0 W/cm2, 10 min), germicidal efficiency against Escherichia coli (E. coli) and Staphyloccocus aureus (S. aureus) could reach 100 % and 99.94 %, respectively. The exceptional antibacterial activities of MPDA@Cu2-xS/PEI was mainly attributed to the synergistic photothermal effect, controlled release of copper ions and ROS generation, as well as electrostatic interaction. More importantly, the MPDA@Cu2-xS/PEI composite exhibited excellent biocompatibility and biosafety. Overall, this organic/inorganic hybrid holds great potential as a promising candidate for wound treatment.
Asunto(s)
Antibacterianos , Cobre , Escherichia coli , Indoles , Nanocompuestos , Polímeros , Especies Reactivas de Oxígeno , Staphylococcus aureus , Cobre/química , Cobre/farmacología , Indoles/química , Indoles/farmacología , Nanocompuestos/química , Polímeros/química , Polímeros/farmacología , Animales , Ratones , Antibacterianos/farmacología , Antibacterianos/química , Escherichia coli/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Staphylococcus aureus/efectos de los fármacos , Células 3T3 NIH , Porosidad , Rayos Infrarrojos , Sulfuros/química , Sulfuros/farmacologíaRESUMEN
Pain in photodynamic therapy (PDT), resulting from the stimulation of reactive oxygen species (ROS) and local acute inflammation, is a primary side effect of PDT that often leads to treatment interruption or termination, significantly compromising the efficacy of PDT and posing an enduring challenge for clinical practice. Herein, a ROS-responsive nanomicelle, poly(ethylene glycol)-b-poly(propylene sulphide) (PEG-PPS) encapsulated Ce6 and Lidocaine (LC), (ESCL) was used to address these problems. The tumor preferentially accumulated micelles could realize enhanced PDT effect, as well as in situ quickly release LC due to its ROS generation ability after light irradiation, which owes to the ROS-responsive property of PSS. In addition, PSS can suppress inflammatory pain which is one of the mechanisms of PDT induced pain. High LC-loaded efficiency (94.56â¯%) owing to the presence of the thioether bond of the PPS made an additional pain relief by inhibiting excessive inflammation besides blocking voltage-gated sodium channels (VGSC). Moreover, the anti-angiogenic effect of LC offers further therapeutic effects of PDT. The in vitro and in vivo anti-tumor results revealed significant PDT efficacy. The signals of the sciatic nerve in mice were measured by electrophysiological study to evaluate the pain relief, results showed that the relative integral area of neural signals in ESCL-treated mice decreased by 49.90â¯% compared to the micelles without loaded LC. Therefore, our study not only develops a very simple but effective tumor treatment PDT and in situ pain relief strategy during PDT, but also provides a quantitative pain evaluation method.
Asunto(s)
Lidocaína , Micelas , Fotoquimioterapia , Especies Reactivas de Oxígeno , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratones , Lidocaína/farmacología , Lidocaína/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Polietilenglicoles/química , Polietilenglicoles/farmacología , Dolor/tratamiento farmacológico , Humanos , Porfirinas/química , Porfirinas/farmacología , Sulfuros/química , Sulfuros/farmacología , Ratones Endogámicos BALB C , Tamaño de la Partícula , Nanopartículas/química , ClorofilidasRESUMEN
Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills nematodes including diverse species of plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode cytochrome P450 enzymes. Cyprocide fails to kill organisms beyond nematodes, suggesting that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply.
Asunto(s)
Antinematodos , Sistema Enzimático del Citocromo P-450 , Nematodos , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Nematodos/efectos de los fármacos , Antinematodos/farmacología , Sulfuros/farmacología , Sulfuros/químicaRESUMEN
Hollow CuS nanoparticles can achieve photothermal and photodynamic therapy (PDT) in tumor treatment. However, excessive GSH in the tumor cells will consume the reactive oxygen species produced by PDT and reduce the PDT effect. Cisplatin is a broad-spectrum antineoplastic drug that can be used in a variety of tumor treatments. However, cisplatin is cytotoxic to normal cells while it kills tumor cells. Therefore, we construct Pt(IV) complexes loaded hollow CuS nanoparticles to attenuate the toxicity of cisplatin and enhance the PDT effect of the hollow CuS nanoparticles. The nanoparticles were proved to be able to accumulate around the tumor site through the enhanced permeability and retention (EPR) effect to achieve a synergistic chemo/photothermal/photodynamic therapy.
Asunto(s)
Antineoplásicos , Cobre , Nanopartículas , Fotoquimioterapia , Cobre/química , Cobre/farmacología , Nanopartículas/química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Animales , Cisplatino/farmacología , Cisplatino/química , Ratones , Línea Celular Tumoral , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Platino (Metal)/química , Platino (Metal)/farmacología , Terapia Fototérmica , Supervivencia Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Sulfuros/química , Sulfuros/farmacología , Tamaño de la PartículaRESUMEN
Oral malodor still constitutes a major challenge worldwide. A strong effort is invested in eliminating volatile sulfur compound-producing oral bacteria through organic natural products such as essential oils. Fusobacterium nucleatum is a known volatile sulfur compound-producing bacteria that inspires oral malodor. The aim of the present study was to test the effect of lavender essential oil on the bacterium's ability to produce volatile sulfide compounds, the principal components of oral malodor. Lavender (Lavandula angustifolia) essential oil was extracted by hydrodistillation and analyzed using GC-MS. The minimal inhibitory concentration (MIC) of lavender essential oil on Fusobacterium nucleatum was determined in a previous trial. Fusobacterium nucleatum was incubated anaerobically in the presence of sub-MIC, MIC, and above MIC concentrations of lavender essential oil, as well as saline and chlorhexidine as negative and positive controls, respectively. Following incubation, volatile sulfur compound levels were measured using GC (Oralchroma), and bacterial cell membrane damage was studied using fluorescence microscopy. Chemical analysis of lavender essential oil yielded five main components, with camphor being the most abundant, accounting for nearly one-third of the total lavender essential oil volume. The MIC (4 µL/mL) of lavender essential oil reduced volatile sulfur compound secretion at a statistically significant level compared to the control (saline). Furthermore, the level of volatile sulfur compound production attributed to 1 MIC of lavender essential oil was in the range of the positive control chlorhexidine with no significant difference. When examining bacterial membrane damage, 2 MIC of lavender essential oil (i.e., 8 µL/mL) demonstrated the same, showing antibacterial membrane damage values comparative to chlorhexidine. Since lavender essential oil was found to be highly effective in hindering volatile sulfur compound production by Fusobacterium nucleatum through the induction of bacterial cell membrane damage, the results suggest that lavender essential oil may be a suitable alternative to conventional chemical-based anti-malodor agents.
Asunto(s)
Fusobacterium nucleatum , Halitosis , Lavandula , Pruebas de Sensibilidad Microbiana , Aceites Volátiles , Aceites Volátiles/farmacología , Aceites Volátiles/química , Fusobacterium nucleatum/efectos de los fármacos , Fusobacterium nucleatum/metabolismo , Halitosis/microbiología , Halitosis/tratamiento farmacológico , Halitosis/metabolismo , Lavandula/química , Sulfuros/farmacología , Sulfuros/química , Humanos , Aceites de Plantas/farmacología , Aceites de Plantas/química , Cromatografía de Gases y Espectrometría de Masas , Compuestos Orgánicos Volátiles/farmacología , Compuestos Orgánicos Volátiles/química , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
Despite the superior efficacy of radiotherapy in esophageal squamous cell carcinoma (ESCC), radioresistance by cancer stem cells (CSCs) leads to recurrence, metastasis, and treatment failure. Therefore, it is necessary to develop CSC-based therapies to enhance radiotherapy. miR-339-5p (miR339) is involved in stem cell division and DNA damage checkpoint signaling pathways based on ESCC cohort. miR339 inhibited ESCC cell stemness and enhanced radiation-induced DNA damage by targeting USP8, suggesting that it acts as a potential CSC regulator and radiosensitizer. Considering the limited circulating periods and poor tumor-targeting ability of miRNA, a multifunctional nanoplatform based on bismuth sulfide nanoflower (Bi@PP) is developed to efficiently deliver miR339 and improve radioresistance. Intriguingly, Bi@PP encapsulates more miR339 owing to their flower-shaped structure, delivering more than 1000-fold miR339 into cells, superior to free miR339 alone. Besides being used as a carrier, Bi@PP is advantageous for dynamically monitoring the distribution of delivered miR339 in vivo while simultaneously inhibiting tumor growth. Additionally, Bi@PP/miR339 can significantly enhance radiotherapy efficacy in patient-derived xenograft models. This multifunctional platform, incorporating higher miRNA loading capacity, pH responsiveness, hypoxia relief, and CT imaging, provides another method to promote radiosensitivity and optimize ESCC treatment.
Asunto(s)
Bismuto , Neoplasias Esofágicas , MicroARNs , Células Madre Neoplásicas , Sulfuros , Bismuto/química , Bismuto/farmacología , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/tratamiento farmacológico , Sulfuros/química , Sulfuros/farmacología , Animales , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Ratones , Tolerancia a Radiación/efectos de los fármacos , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ratones Desnudos , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/genéticaRESUMEN
Cholangiocarcinoma (CCA) is a cancer with a poor prognosis due to difficulties in diagnosis and limited treatment options, highlighting the urgent need for new targeted therapies. In a clinical setting, we found that leukotriene levels in bile were higher than in serum. Immunohistochemical analysis of surgically resected samples also revealed that CysLT receptor 1 (CysLTR1) was more highly expressed in CCA than in normal bile duct tissue, prompting us to investigate leukotriene as a potential therapeutic target in CCA. In vitro studies using CCA cell lines expressing CysLTR1 showed that leukotriene D4, a major ligand of CysLTR1, promoted cell proliferation, with increased phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Additionally, treatment with two clinically available anti-allergic drugs-zileuton, an inhibitor of CysLT formation, and montelukast, a CysLTR1 inhibitor-had inhibitory effects on cell proliferation and migratory capacity, accompanied by the reduced phosphorylation of AKT and ERK1/2. Furthermore, the simultaneous administration of both drugs synergistically enhanced the inhibitory effect on cell proliferation. Our study suggests that use of these drugs may represent a novel approach to treat CCA through drug repositioning.