RESUMEN
Human Hippo signaling pathway is an evolutionarily conserved regulator network that controls organ development and has been implicated in various cancers. Transcriptional enhanced associate domain-4 (TEAD4) is the final nuclear effector of Hippo pathway, which is activated by Yes-associated protein (YAP) through binding to two separated YAP regions of α1-helix and Ω-loop. Previous efforts have all been addressed on deriving peptide inhibitors from the YAP to target TEAD4. Instead, we herein attempted to rationally design a so-called 'YAP helixα1-trap' based on the TEAD4 to target YAP by using dynamics simulation and energetics analysis as well as experimental assays at molecular and cellular levels. The trap represents a native double-stranded helical hairpin covering a specific YAP-binding site on TEAD4 surface, which is expected to form a three-helix bundle with the α1-helical region of YAP, thus competitively disrupting TEAD4-YAP interaction. The hairpin was further stapled by a disulfide bridge across its two helical arms. Circular dichroism characterized that the stapling can effectively constrain the trap into a native-like structured conformation in free state, thus largely minimizing the entropy penalty upon its binding to YAP. Affinity assays revealed that the stapling can considerably improve the trap binding potency to YAP α1-helix by up to 8.5-fold at molecular level, which also exhibited a good tumor-suppressing effect at cellular level if fused with TAT cell permeation sequence. In this respect, it is considered that the YAP helixα1-trap-mediated blockade of Hippo pathway may be a new and promising therapeutic strategy against cancers.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Antineoplásicos , Proteínas de Unión al ADN , Simulación de Dinámica Molecular , Proteínas Musculares , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Proteínas Señalizadoras YAP , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Humanos , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Disulfuros/química , Disulfuros/farmacología , Unión Proteica , Sitios de Unión , Línea Celular Tumoral , Diseño Asistido por Computadora , Diseño de FármacosRESUMEN
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.
Asunto(s)
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
The issue of bacterial infectious diseases remains a significant concern worldwide, particularly due to the misuse of antibiotics, which has caused the emergence of antibiotic-resistant strains. Fortunately, the rapid development of nanomaterials has propelled significant progress in antimicrobial therapy, offering promising solutions. Among them, the utilization of nanoenzyme-based chemodynamic therapy (CDT) has become a highly hopeful approach to combating bacterial infectious diseases. Nevertheless, the application of CDT appears to be facing certain constraints for its low efficiency in the Fenton reaction at the infected site. In this study, we have successfully synthesized a versatile nanozyme, which was a composite of molybdenum sulfide (MoS2) and iron sulfide (FeS2), through the hydrothermal method. The results showed that iron/molybdenum sulfide nanozymes (Fe/Mo SNZs) with desirable peroxidase (POD) mimic activity can generate cytotoxic reactive oxygen species (ROS) by successfully triggering the Fenton reaction. The presence of MoS2 significantly accelerates the conversion of Fe2+/Fe3+ through a cocatalytic reaction that involves the participation of redox pairs of Mo4+/Mo6+, thereby enhancing the efficiency of CDT. Additionally, based on the excellent photothermal performance of Fe/Mo SNZs, a near-infrared (NIR) laser was used to induce localized temperature elevation for photothermal therapy (PTT) and enhance the POD-like nanoenzymatic activity. Notably, both in vitro and in vivo results demonstrated that Fe/Mo SNZs with good broad-spectrum antibacterial properties can help eradicate Gram-negative bacteria like Escherichia coli and Gram-positive bacteria like Staphylococcus aureus. The most exciting thing is that the synergistic PTT/CDT exhibited astonishing antibacterial ability and can achieve complete elimination of bacteria, which promoted wound healing after infection. Overall, this study presents a synergistic PTT/CDT strategy to address antibiotic resistance, providing avenues and directions for enhancing the efficacy of wound healing treatments and offering promising prospects for further clinical use in the near future.
Asunto(s)
Antibacterianos , Disulfuros , Hierro , Molibdeno , Sulfuros , Cicatrización de Heridas , Molibdeno/química , Molibdeno/farmacología , Cicatrización de Heridas/efectos de los fármacos , Sulfuros/química , Sulfuros/farmacología , Animales , Disulfuros/química , Disulfuros/farmacología , Hierro/química , Hierro/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Catálisis , Staphylococcus aureus/efectos de los fármacos , Ratones , Escherichia coli/efectos de los fármacos , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/farmacología , Especies Reactivas de Oxígeno/metabolismo , Nanoestructuras/química , Fototerapia , Pruebas de Sensibilidad Microbiana , Terapia Fototérmica , Compuestos FerrososRESUMEN
Allicin (AL) is one of garlic-derived organosulfides and has a variety of pharmacological effects. Studies have reported that AL has notable inhibitory effects on liver cancer, gastric cancer, breast cancer, and other cancers. However, there are no relevant reports about its role in human nasopharyngeal carcinoma. Ferroptosis is an iron-dependent form of non-apoptotic regulated cell death. Increasing evidence indicates that induction of ferroptosis can inhibit the proliferation, migration, invasion, and survival of various cancer cells, which act as a tumor suppressor in cancer. In this study, we confirmed that AL can inhibit cell proliferation, migration, invasion, and survival in human nasopharyngeal carcinoma cells. Our finding shows that AL can induce the ferroptosis axis by decreasing the level of GSH and GPX4 and promoting the induction of toxic LPO and ROS. AL-mediated cytotoxicity in human nasopharyngeal carcinoma cells is dependent on ferroptosis. Therefore, AL has good anti-cancer properties and is expected to be a potential drug for the treatment of nasopharyngeal carcinoma.
Asunto(s)
Proliferación Celular , Disulfuros , Ferroptosis , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Especies Reactivas de Oxígeno , Ácidos Sulfínicos , Humanos , Ferroptosis/efectos de los fármacos , Disulfuros/farmacología , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/patología , Proliferación Celular/efectos de los fármacos , Ácidos Sulfínicos/farmacología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Movimiento Celular/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Glutatión/metabolismo , Supervivencia Celular/efectos de los fármacosRESUMEN
The present study describes a small library of peptides derived from a potent and selective CXCR4 antagonist (3), wherein the native disulfide bond is replaced using a side-chain to tail macrolactamization technique to vary ring size and amino acid composition. The peptides were preliminary assessed for their ability to interfere with the interaction between the receptor and anti-CXCR4 PE-conjugated antibody clone 12G5. Two promising candidates (13 and 17) were identified and further evaluated in a125I-CXCL12 competition binding assay, exhibiting IC50 in the low-nanomolar range. Furthermore, both candidates displayed high selectivity towards CXCR4 with respect to the cognate receptor CXCR7, ability to block CXCL12-dependent cancer cell migration, and receptor internalization, albeit at a higher concentration compared to 3. Molecular modeling studies on 13 and 17 produced a theoretical model that may serve as a guide for future modifications, aiding in the development of analogs with improved affinity. Finally, the study provides valuable insights into developing therapeutic agents targeting CXCR4-mediated processes, demonstrating the adaptability of our lead peptide 3 to alternative cyclization approaches and offering prospects for comprehensive investigations into the receptor region's interaction with its C-terminal region.
Asunto(s)
Disulfuros , Péptidos , Receptores CXCR4 , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/metabolismo , Humanos , Sitios de Unión/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Péptidos/síntesis química , Disulfuros/química , Disulfuros/farmacología , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Lactamas/química , Lactamas/farmacología , Lactamas/síntesis química , Movimiento Celular/efectos de los fármacos , Modelos Moleculares , Línea Celular TumoralRESUMEN
The precise modulation of electrical activity in specific neuronal populations is paramount for rectifying abnormal neurological functions and is a critical element in the therapeutic arsenal for neurological disorders. However, achieving a balance between minimal invasiveness and robust neuroprotection poses a considerable challenge. Herein, we present a nanoneuromodulation strategy integrating neuroprotective features to effectively address epilepsy with minimal invasiveness and enable wireless functionality. Strategically engineered nanotransducer, adorned with platinum (Pt) decoration with titanium disulfide (TiS2) (TiS2/Pt), enables precise modulation of neuronal electrical activity in vitro and in vivo, ensuring exceptional temporal fidelity under millisecond-precision near-infrared (NIR) light pulses irradiation. Concurrently, TiS2/Pt showcase a pronounced enhancement in enzyme-mimicking activity, offering a robust defense against oxidative neurological injury in vitro. Nanotransducer-enabled wireless neuromodulation with biocatalytic neuroprotective capacity is highly effective in alleviating epileptic high-frequency neural activity and diminishing oxidative stress levels, thereby restoring redox equilibrium. This integrated therapeutic approach reduces the severity of epilepsy, demonstrating minimal invasiveness and obviating the requirements for genetic manipulation and optical fiber implantation, while providing an alternative avenue for neurological disorder treatment.
Asunto(s)
Epilepsia , Epilepsia/terapia , Animales , Titanio/química , Titanio/farmacología , Platino (Metal)/química , Platino (Metal)/farmacología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Neuroprotección/efectos de los fármacos , Ratones , Disulfuros/química , Disulfuros/farmacología , Estrés Oxidativo/efectos de los fármacos , Humanos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Rayos Infrarrojos , RatasRESUMEN
Chronic refractory wounds caused by multidrug-resistant (MDR) bacterial and biofilm infections are a substantial threat to human health, which presents a persistent challenge in managing clinical wound care. We here synthesized a composite nanosheet AIPH/AMP/MoS2, which can potentially be used for combined therapy because of the photothermal effect induced by MoS2, its ability to deliver antimicrobial peptides, and its ability to generate alkyl free radicals independent of oxygen. The synthesized nanosheets exhibited 61 % near-infrared (NIR) photothermal conversion efficiency, marked photothermal stability and free radical generating ability. The minimal inhibitory concentrations (MICs) of the composite nanosheets against MDR Escherichia coli (MDR E. coli) and MDR Staphylococcus aureus (MDR S. aureus) were approximately 38 µg/mL and 30 µg/mL, respectively. The composite nanosheets (150 µg/mL) effectively ablated >85 % of the bacterial biofilm under 808-nm NIR irradiation for 6 min. In the wound model experiment, approximately 90 % of the wound healed after the 4-day treatment with the composite nanosheets. The hemolysis experiment, mouse embryonic fibroblast (MEFs) cytotoxicity experiment, and mouse wound healing experiment all unveiled the excellent biocompatibility of the composite nanosheets. According to the transcriptome analysis, the composite nanosheets primarily exerted a synergistic therapeutic effect by disrupting the cellular membrane function of S. aureus and inhibiting quorum sensing mediated by the two-component system. Thus, the synthesized composite nanosheets exhibit remarkable antibacterial and biofilm ablation properties and therefore can be used to improve wound healing in chronic biofilm infections.
Asunto(s)
Biopelículas , Disulfuros , Escherichia coli , Molibdeno , Staphylococcus aureus , Cicatrización de Heridas , Biopelículas/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Animales , Ratones , Disulfuros/química , Disulfuros/farmacología , Molibdeno/química , Molibdeno/farmacología , Escherichia coli/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Péptidos Antimicrobianos/farmacología , Péptidos Antimicrobianos/química , Radicales Libres/química , Radicales Libres/metabolismo , Nanoestructuras/química , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/química , Calor , Humanos , Antiinfecciosos/farmacología , Antiinfecciosos/químicaRESUMEN
Garlic (Allium sativum L.), particularly its volatile essential oil, is widely recognized for medicinal properties. We have evaluated the efficacy of Indian Garlic Essential Oil (GEO) for antimicrobial and antibiofilm activity and its bioactive constituents. Allyl sulfur-rich compounds were identified as predominant phytochemicals in GEO, constituting 96.51% of total volatile oils, with 38% Diallyl trisulphide (DTS) as most abundant. GEO exhibited significant antibacterial activity against eleven bacteria, including three drug-resistant strains with minimum inhibitory concentrations (MICs) ranging from 78 to 1250 µg/mL. In bacterial growth kinetic assay GEO effectively inhibited growth of all tested strains at its ½ MIC. Antibiofilm activity was evident against two important human pathogens, S. aureus and P. aeruginosa. Mechanistic studies demonstrated that GEO disrupts bacterial cell membranes, leading to the release of nucleic acids, proteins, and reactive oxygen species. Additionally, GEO demonstrated potent antioxidant activity at IC50 31.18 mg/mL, while its isolated constituents, Diallyl disulphide (DDS) and Diallyl trisulphide (DTS), showed effective antibacterial activity ranging from 125 to 500 µg/mL and 250-1000 µg/mL respectively. Overall, GEO displayed promising antimicrobial and antibiofilm activity against enteric bacteria, suggesting its potential application in the food industry.
Asunto(s)
Antibacterianos , Antioxidantes , Biopelículas , Ajo , Pruebas de Sensibilidad Microbiana , Aceites Volátiles , Ajo/química , Aceites Volátiles/farmacología , Aceites Volátiles/química , Antioxidantes/farmacología , Antioxidantes/química , Antibacterianos/farmacología , Antibacterianos/química , Biopelículas/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Compuestos Alílicos/farmacología , Compuestos Alílicos/química , Fitoquímicos/farmacología , Fitoquímicos/química , Sulfuros/farmacología , Bacterias/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Disulfuros/farmacología , India , Aceites de Plantas/farmacología , Aceites de Plantas/química , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/químicaRESUMEN
Aflatoxin B1 (AFB1) is known to inhibit growth, and inflict hepatic damage by interfering with protein synthesis. Allicin, has been acknowledged as an efficacious antioxidant capable of shielding the liver from oxidative harm. This study aimed to examine the damage caused by AFB1 on bovine hepatic cells and the protective role of allicin against AFB1-induced cytotoxicity. In this study, cells were pretreated with allicin before the addition of AFB1 for co-cultivation. Our findings indicate that AFB1 compromises cellular integrity, suppresses the expression of nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, allicin attenuates oxidative damage to bovine hepatic cells caused by AFB1 by promoting the expression of the Nrf2 pathway and reducing cell apoptosis. In conclusion, the results of this study will help advance clinical research and applications, providing new options and directions for the prevention and treatment of liver diseases.
Asunto(s)
Aflatoxina B1 , Antioxidantes , Apoptosis , Disulfuros , Hepatocitos , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Transducción de Señal , Ácidos Sulfínicos , Animales , Ácidos Sulfínicos/farmacología , Aflatoxina B1/toxicidad , Bovinos , Disulfuros/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antioxidantes/farmacología , FemeninoRESUMEN
Psammaplin A (PsA), a symmetrical bromotyrosine-derived disulfide marine metabolite, has been reported could inhibit HDAC1/2/3 through its thiol monomer. Inspired by the disuflide bond structure of this marine natural product, we designed and synthesized a series of PsA analogues, in which the disulfide bond of PsA was replaced with diselenide bond or cyclic disulfide/diselenide/selenenylsulfide motifs. We also studied the HDAC inhibition, cell growth inhibition, and apoptosis induction of these PsA analogues. The results showed that, all the synthetic diselenide analogues and cyclic selenenyl sulfide compounds exhibited better antiproferative activity than their counterpart of disulfide analogues. Among the prepared analogues, diselenide analogue P-503 and P-116 significantly increased the ability of inhibiting HDAC6 and induced apoptosis and G2/M cell cycle arrest. However, cyclic selenenylsulfides analogues P-111 lost its HDAC inhibitory ability and exhibited no effect on cell cycle and apoptosis, indicating that the anti-proliferative mechanism of cyclic selenenylsulfides analogues has changed.
Asunto(s)
Apoptosis , Proliferación Celular , Disulfuros , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Disulfuros/química , Disulfuros/farmacología , Disulfuros/síntesis química , Humanos , Apoptosis/efectos de los fármacos , Histona Desacetilasas/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Tirosina/análogos & derivadosRESUMEN
BACKGROUND: Molybdenum disulfide (MoS2) has excellent physical and chemical properties. Further, chiral MoS2 (CMS) exhibits excellent chiroptical and enantioselective effects, and the enantioselective properties of CMS have been studied for the treatment of neurodegenerative diseases. Intriguingly, left- and right-handed materials have different effects on promoting the differentiation of neural stem cells into neurons. However, the effect of the enantioselectivity of chiral materials on peripheral nerve regeneration remains unclear. METHODS: In this study, CMS@bacterial cellulose (BC) scaffolds were fabricated using a hydrothermal approach. The CMS@BC films synthesized with L-2-amino-3-phenyl-1-propanol was defined as L-CMS. The CMS@BC films synthesized with D-2-amino-3-phenyl-1-propanol was defined as D-CMS. The biocompatibility of CMS@BC scaffolds and their effect on Schwann cells (SCs) were validated by cellular experiments. In addition, these scaffolds were implanted in rat sciatic nerve defect sites for three months. RESULTS: These chiral scaffolds displayed high hydrophilicity, good mechanical properties, and low cytotoxicity. Further, we found that the L-CMS scaffolds were superior to the D-CMS scaffolds in promoting SCs proliferation. After three months, the scaffolds showed good biocompatibility in vivo, and the nerve conducting velocities of the L-CMS and D-CMS scaffolds were 51.2 m/s and 26.8 m/s, respectively. The L-CMS scaffolds showed a better regenerative effect than the D-CMS scaffolds. Similarly, the sciatic nerve function index and effects on the motor and electrophysiological functions were higher for the L-CMS scaffolds than the D-CMS scaffolds. Finally, the axon diameter and myelin sheath thickness of the regenerated nerves were improved in the L-CMS group. CONCLUSION: We found that the CMS@BC can promote peripheral nerve regeneration, and in general, the L-CMS group exhibited superior repair performance. Overall, the findings of this study reveal that CMS@BC can be used as a chiral nanomaterial nerve scaffold for peripheral nerve repair.
Asunto(s)
Celulosa , Disulfuros , Molibdeno , Regeneración Nerviosa , Células de Schwann , Andamios del Tejido , Regeneración Nerviosa/efectos de los fármacos , Animales , Ratas , Andamios del Tejido/química , Disulfuros/química , Disulfuros/farmacología , Células de Schwann/efectos de los fármacos , Molibdeno/química , Molibdeno/farmacología , Celulosa/química , Celulosa/farmacología , Celulosa/análogos & derivados , Ratas Sprague-Dawley , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiología , Proliferación Celular/efectos de los fármacos , Ingeniería de Tejidos/métodos , Masculino , Traumatismos de los Nervios Periféricos , EstereoisomerismoRESUMEN
The therapy of the clear cell renal cell carcinoma (ccRCC) is crucial for the human healthcare due to its easy metastasis and recurrence, as well as resistance to radiotherapy and chemotherapy. In this work, we propose the synthesis of MoS2@red phosphorus (MoS2@RP) heterojunction to induce synergistic photodynamic and photothermal therapy (PDT/PTT) of ccRCC. The MoS2@RP heterojunction exhibits enhanced spectra absorption in the NIR range and produce local heat-increasing under the NIR laser irradiation compared with pure MoS2 and RP. The high photocatalytic activity of the MoS2@RP heterojunction contributes to effective transferring of the photo-excited electrons from the RP to MoS2, which promotes the production of various types of radical oxygen species (ROS) to kill the ccRCC cells. After the NIR irradiation, the MoS2@RP can effectively induce the apoptosis in the ccRCC cells through localized hyperthermia and the generation of ROS, while exhibiting low cytotoxicity towards normal kidney cells. In comparison to MoS2, the MoS2@RP heterojunction shows an approximate increase of 22â¯% in the lethality rate of the ccRCC cells and no significant change in toxicity towards normal cells. Furthermore, the PDT/PTT treatment using the MoS2@RP heterojunction effectively eradicates a substantial number of deep-tissue ccRCC cells in vivo without causing significant damage to major organs. This study presents promising effect of the MoS2@RP heterojunction-based photo-responsive therapy for effective ccRCC treatment.
Asunto(s)
Carcinoma de Células Renales , Disulfuros , Neoplasias Renales , Molibdeno , Fósforo , Fotoquimioterapia , Terapia Fototérmica , Molibdeno/química , Molibdeno/farmacología , Humanos , Disulfuros/química , Disulfuros/farmacología , Disulfuros/síntesis química , Fósforo/química , Fósforo/farmacología , Neoplasias Renales/patología , Neoplasias Renales/terapia , Neoplasias Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Ratones , Supervivencia Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Tamaño de la Partícula , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Rayos Infrarrojos , Propiedades de SuperficieRESUMEN
Radiotherapy is a pivotal means of cancer treatment, but it often leads to radiation dermatitis, a skin injury caused by radiation-induced excess reactive oxygen species (ROS). Scavenging free radicals in the course of radiation therapy will be an effective means to prevent radiation dermatitis. This study demonstrates a novel double network hydrogel doped with MoS2 nanosheets for the prevention of radiation-induced dermatitis. The resultant SPM hydrogel constructed from polyacrylamide (PAM) and sodium alginate (SA) nanofiber presented favorable mechanical and adhesion properties. It could conform well to the human body's irregular contours without secondary dressing fixation, making it suitable for skin protection applications. The in vitro and in vivo experiments showed that the antioxidant properties conferred by MoS2 nanosheets enable SPM to effectively mitigate excessive ROS and reduce oxidative stress, thereby preventing radiation dermatitis caused by oxidative damage. Biosafety assessments indicated good biocompatibility of the composite hydrogel, suggesting SPM's practicality and potential as an external dressing for skin radiation protection.
Asunto(s)
Alginatos , Antioxidantes , Hidrogeles , Radiodermatitis , Hidrogeles/química , Hidrogeles/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Radiodermatitis/prevención & control , Radiodermatitis/tratamiento farmacológico , Animales , Alginatos/química , Alginatos/farmacología , Humanos , Resinas Acrílicas/química , Resinas Acrílicas/farmacología , Ratones , Molibdeno/química , Molibdeno/farmacología , Disulfuros/química , Disulfuros/farmacología , Especies Reactivas de Oxígeno/metabolismo , Adhesivos/química , Adhesivos/farmacología , Tamaño de la PartículaRESUMEN
Drug-resistant bacterial infections pose a serious threat to human health; thus, there is an increasingly growing demand for nonantibiotic strategies to overcome drug resistance in bacterial infections. Mild photothermal therapy (PTT), as an attractive antibacterial strategy, shows great potential application due to its good biocompatibility and ability to circumvent drug resistance. However, its efficiency is limited by the heat resistance of bacteria. Herein, Cu2O@MoS2, a nanocomposite, was constructed by the in situ growth of Cu2O nanoparticles (NPs) on the surface of MoS2 nanosheets, which provided a controllable photothermal therapeutic effect of MoS2 and the intrinsic catalytic properties of Cu2O NPs, achieving a synergistic effect to eradicate multidrug-resistant bacteria. Transcriptome sequencing (RNA-seq) results revealed that the antibacterial process was related to disrupting the membrane transport system, phosphorelay signal transduction system, oxidative stress response system, as well as the heat response system. Animal experiments indicated that Cu2O@MoS2 could effectively treat wounds infected with methicillin-resistant Staphylococcus aureus. In addition, satisfactory biocompatibility made Cu2O@MoS2 a promising antibacterial agent. Overall, our results highlight the Cu2O@MoS2 nanocomposite as a promising solution to combating resistant bacteria without inducing the evolution of antimicrobial resistance.
Asunto(s)
Antibacterianos , Cobre , Disulfuros , Rayos Infrarrojos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Molibdeno , Nanocompuestos , Molibdeno/química , Molibdeno/farmacología , Disulfuros/química , Disulfuros/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Cobre/química , Cobre/farmacología , Nanocompuestos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Animales , Ratones , Terapia Fototérmica , HumanosRESUMEN
Environmental pollution, virus infection, allergens, and other factors may cause respiratory disease, which could be improved by dietary therapy. Allium species are common daily food seasoning and have high nutritional and medical value. Diallyl disulfide (DADS) is the major volatile oil compound of Allium species. The present study aims to explore the preventive effect and potential mechanism of DADS on pulmonary fibrosis. C57BL/6J mice were intratracheally injected with bleomycin (BLM) to establish pulmonary fibrosis and then administrated with DADS. Primary lung fibroblasts or A549 were stimulated with BLM, followed by DADS, farnesoid X receptor (FXR) agonist (GW4064), yes-associated protein 1 (YAP1) inhibitor (verteporfin), or silencing of FXR and YAP1. In BLM-stimulated mice, DADS significantly ameliorated histopathological changes and interleukin-1ß levels in bronchoalveolar lavage fluid. DADS decreased fibrosis markers, HIF-1α, inflammatory cytokines, and epithelial-mesenchymal transition in pulmonary mice and activated fibroblasts. DADS significantly enhanced FXR expression and inhibited YAP1 activation, which functions as GW4064 and verteporfin. A deficiency of FXR or YAP1 could result in the increase of these two protein expressions, respectively. DADS ameliorated extracellular matrix deposition, hypoxia, epithelial-mesenchymal transition, and inflammation in FXR or YAP1 knockdown A549. Taken together, targeting the crosstalk of FXR and YAP1 might be the potential mechanism for DADS against pulmonary fibrosis. DADS can serve as a potential candidate or dietary nutraceutical supplement for the treatment of pulmonary fibrosis.
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Compuestos Alílicos , Disulfuros , Ratones Endogámicos C57BL , Fibrosis Pulmonar , Receptores Citoplasmáticos y Nucleares , Transducción de Señal , Proteínas Señalizadoras YAP , Animales , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/inducido químicamente , Ratones , Disulfuros/farmacología , Humanos , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/efectos de los fármacos , Compuestos Alílicos/farmacología , Células A549 , Masculino , Allium/química , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Bleomicina , Pulmón/efectos de los fármacos , Pulmón/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismoRESUMEN
BACKGROUND: Allicin regulates macrophage autophagy and senescence, and inhibits hepatoma cell growth. This study investigated the mechanism by which allicin inhibits the growth of hepatoma cells. METHODS: Hepa1-6 mouse hepatoma cells were subcutaneously injected into C57BL/6â¯J mice to construct a tumor transplantation model. Macrophages were cultured with the supernatant of hepatoma cells to construct a cell model. The levels of mRNA and proteins and the level of Sestrin2 ubiquitination were measured by RTqPCR, immunofluorescence and Western blotting. The levels of autophagy-related factors and the activity of senescence-associated ß-galactosidase were determined by kits, and protein stability was detected by cycloheximide (CHX) tracking. RESULTS: Data analysis of clinical samples revealed that RBX1 was highly expressed in tumor tissues, while Sestrin2 was expressed at low levels in tumor tissues. Allicin can promote the expression of the autophagy-related proteins LC3 and Beclin-1 in tumor macrophages and inhibit the expression of the aging-related proteins p16 and p21, thus promoting autophagy in macrophages and inhibiting cell senescence. Moreover, allicin can inhibit the expression of RBX1, thereby reducing the ubiquitination of Sestrin2, enhancing the stability of Sestrin2, activating autophagy in tumor macrophages and inhibiting senescence. In addition, allicin treatment inhibited the proliferation and migration of hepatoma carcinoma cells cocultured with macrophages and significantly improved the development of liver cancer in mice. CONCLUSION: Allicin can affect the autophagy of macrophages and restrain the growth of hepatoma cells by regulating the ubiquitination of Sestrin2.
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Autofagia , Carcinoma Hepatocelular , Senescencia Celular , Disulfuros , Neoplasias Hepáticas , Macrófagos , Ácidos Sulfínicos , Ubiquitinación , Animales , Autofagia/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Disulfuros/farmacología , Senescencia Celular/efectos de los fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Ácidos Sulfínicos/farmacología , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Línea Celular Tumoral , Ubiquitinación/efectos de los fármacos , Humanos , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos C57BL , Proteínas Nucleares/metabolismo , Masculino , Peroxidasas/metabolismo , SestrinasRESUMEN
BACKGROUND: Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. METHODS: This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. RESULTS: The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. CONCLUSION: In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice.
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Trióxido de Arsénico , Arsenicales , Modelos Animales de Enfermedad , Síndromes Mielodisplásicos , Animales , Trióxido de Arsénico/administración & dosificación , Trióxido de Arsénico/farmacología , Arsenicales/farmacología , Arsenicales/administración & dosificación , Ratones , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/inmunología , Sulfuros/farmacología , Sulfuros/administración & dosificación , Disulfuros/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Bazo/efectos de los fármacos , Bazo/inmunologíaRESUMEN
Background: Promoter hypermethylation of the tumor suppressor gene is one of the well-studied causes of cancer development. The drugs that reverse the process by driving demethylation could be a candidate for anticancer therapy. This study was designed to investigate the effects of arsenic disulfide on PTPL1 methylation in diffuse large B cell lymphoma (DLBCL). Methods: We knocked down the expression of PTPL1 in two DLBCL cell lines (i.e., DB and SU-DHL-4 cells) using siRNA. Then the DLBCL proliferation was determined in the presence of PTPL1 knockdown. The methylation of PTPL1 in DLBCL cells was analyzed by methylation specific PCR (MSPCR). The effect of arsenic disulfide on the PTPL1 methylation was determined in DLBCL cell lines in the presence of different concentrations of arsenic disulfide (5 µM, 10 µM and 20 µM), respectively. To investigate the potential mechanism on the arsenic disulfide-mediated methylation, the mRNA expression of DNMT1, DNMT3B and MBD2 was determined. Results: PTPL1 functioned as a tumor suppressor gene in DLBCL cells, which was featured by the fact that PTPL1 knockdown promoted the proliferation of DLBCL cells. PTPL1 was found hypermethylated in DLBCL cells. Arsenic disulfide promoted the PTPL1 demethylation in a dose-dependent manner, which was related to the inhibition of DNMTs and the increase of MBD2. Conclusion: Experimental evidence shows that PTPL1 functions as a tumor suppressor gene in DLBCL progression. PTPL1 hyper-methylation could be reversed by arsenic disulfide in a dose-dependent manner.
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Arsenicales , Metilación de ADN , Linfoma de Células B Grandes Difuso , Humanos , Arsenicales/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Disulfuros/farmacología , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN/efectos de los fármacos , ADN Metiltransferasa 3B , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Regiones Promotoras Genéticas/efectos de los fármacosRESUMEN
Tumor recurrence after surgical resection remains a significant challenge in breast cancer treatment. Immune checkpoint blockade therapy, as a promising alternative therapy, faces limitations in combating tumor recurrence due to the low immune response rate. In this study, we developed an implantable photo-responsive self-healing hydrogel loaded with MoS2 nanosheets and the immunoadjuvant R837 (PVA-MoS2-R837, PMR hydrogel) for in situ generation of tumor-associated antigens at the post-surgical site of the primary tumor, enabling sustained and effective activation of the immune response. This PMR hydrogel exhibited potential for near-infrared (NIR) light response, tissue adhesion, self-healing, and sustained adjuvant release. When implanted at the site after tumor resection, NIR irradiation triggered a photothermal effect, resulting in the ablation of residual cancer cells. The in situ-generated tumor-associated antigens promoted dendritic cell (DC) maturation. In a mouse model, PMR hydrogel-mediated photothermal therapy combined with immune checkpoint blockade effectively inhibited the recurrence of resected tumors, providing new insights for combating post-resection breast cancer recurrence.
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Adyuvantes Inmunológicos , Neoplasias de la Mama , Disulfuros , Hidrogeles , Molibdeno , Recurrencia Local de Neoplasia , Molibdeno/química , Molibdeno/farmacología , Animales , Femenino , Disulfuros/química , Disulfuros/farmacología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Ratones , Hidrogeles/química , Hidrogeles/farmacología , Recurrencia Local de Neoplasia/prevención & control , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/química , Humanos , Línea Celular Tumoral , Nanoestructuras/química , Ratones Endogámicos BALB C , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Antígenos de Neoplasias/inmunología , Terapia Fototérmica , Rayos InfrarrojosRESUMEN
The unsatisfactory effects of conventional bactericides and antimicrobial resistance have increased the challenges in managing plant diseases caused by bacterial pests. Here, we report the successful design and synthesis of benzofuran derivatives using benzofuran as the core skeleton and splicing the disulfide moieties commonly seen in natural substances with antibacterial properties. Most of our developed benzofurans displayed remarkable antibacterial activities to frequently encountered pathogens, including Xanthomonas oryzae pv oryzae (Xoo), Xanthomonas oryzae pv oryzicola (Xoc), and Xanthomonas axonopodis pv citri (Xac). With the assistance of the three-dimensional quantitative constitutive relationship (3D-QSAR) model, the optimal compound V40 was obtained, which has better in vitro antibacterial activity with EC50 values of 0.28, 0.56, and 10.43 µg/mL against Xoo, Xoc, and Xac, respectively, than those of positive control, TC (66.41, 78.49, and 120.36 µg/mL) and allicin (8.40, 28.22, and 88.04 µg/mL). Combining the results of proteomic analysis and enzyme activity assay allows the antibacterial mechanism of V40 to be preliminarily revealed, suggesting its potential as a versatile bactericide in combating bacterial pests in the future.