RESUMEN
Sepsis is a life-threatening condition characterized by a systemic inflammatory response to infection. Despite extensive research on its pathophysiology, effective therapeutic approaches remain a challenge. This study investigated the potential of resveratrol (RV) and silver nanoparticle-enhanced resveratrol (AgNP-RV) as treatments for sepsis-induced lung injury using a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). The study focused on evaluating changes in oxidative status (TAS, TOS, and OSI) and the expression of inflammatory and apoptotic markers (IL-1ß, TNF-α, P2X7R, TLR4, Caspase-3, and Bcl-2) in lung tissue. Both RV and AgNP-RV demonstrated potential in mitigating oxidative stress, inflammation, and apoptosis, with AgNP-RV exhibiting greater efficacy than RV alone (p < 0.05). These findings were corroborated by histopathological analyses, which revealed reduced tissue damage in the RV- and AgNP-RV-treated groups. Our study highlights the therapeutic potential of RV and, particularly, AgNP-RV in combating sepsis-induced oxidative stress, inflammation, and apoptosis. It also underscores the promise of nanoparticle technology in enhancing therapeutic outcomes. However, further investigations are warranted to fully understand the mechanisms of action, especially concerning the role of the P2X7 receptor in the observed effects. Nonetheless, our research suggests that RV and AgNP-RV hold promise as novel strategies for sepsis management.
Asunto(s)
Apoptosis , Nanopartículas del Metal , Estrés Oxidativo , Resveratrol , Sepsis , Plata , Animales , Resveratrol/farmacología , Resveratrol/uso terapéutico , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , Plata/farmacología , Plata/uso terapéutico , Masculino , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratas Wistar , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Ratas , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Modelos Animales de EnfermedadRESUMEN
ABSTRACT: Sepsis-induced acute liver injury is a life-threatening condition involving inflammation, oxidative stress, and endothelial dysfunction. In the present study, the preventive effects of resveratrol (RV) alone and RV-loaded silver nanoparticles (AgNPs + RV) against sepsis-induced damage were investigated and compared in a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Rats were divided into four groups: Sham, CLP, RV, and AgNPs + RV. Pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, presepsin, procalcitonin (PCT), 8-hydroxy-2'-deoxyguanosine (8-OHDG), vascular endothelial growth factor (VEGF), and sirtuin-1 (SIRT1) levels were assessed to determine the treatments' effects. AgNPs + RV treatment significantly reduced pro-inflammatory cytokines, NF-κB activation, presepsin, PCT, 8-OHDG, and VEGF levels compared with the CLP group, indicating attenuation of sepsis-induced liver injury. Both RV and AgNPs + RV treatments increased SIRT1 levels, suggesting a potential role of SIRT1 activation in mediating the protective effects. In conclusion, AgNPs + RV treatment demonstrated extremely enhanced efficacy in alleviating sepsis-induced liver injury by modulating inflammation, oxidative stress, and endothelial dysfunction, potentially mediated through SIRT1 activation. In this study, the effect of AgNPs + RV on sepsis was evaluated for the first time, and these findings highlight AgNPs + RV as a promising therapeutic strategy for managing sepsis-induced liver injury, warranting further investigation.
Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Nanopartículas del Metal , Sepsis , Animales , Ratas , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , FN-kappa B/metabolismo , Estrés Oxidativo , Resveratrol/farmacología , Resveratrol/uso terapéutico , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Plata , Sirtuina 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
AIM: To investigate the combined therapeutic potential of melatonin and ascorbic acid in mitigating sepsis-induced heart and kidney injury in male rats and assess the combination therapy's effects on inflammation, cellular damage, oxidative stress, and vascular function-related markers. MATERIALS AND METHODS: Cecal ligation and puncture (CLP) induced sepsis in male rats, which were divided into five groups: Sham, CLP, MEL (melatonin), ASA (ascorbic acid), and MEL+ASA (melatonin and ascorbic acid). Rats were treated, and heart and kidney tissues were collected for biochemical and histopathological analyses. Inflammatory markers (presepsin, procalcitonin, NF-κB, IL-1ß, IL-6, TNF-α), cellular damage marker (8-OHDG), oxidative status, nitric oxide (NO), vascular endothelial growth factor (VEGF), and sirtuin 1 (SIRT1) levels were assessed. KEY FINDINGS: Melatonin and ascorbic acid treatment reduced inflammatory and cellular damage markers compared to the CLP group. Combined treatment improved NO, VEGF levels, and increased SIRT1 expression, suggesting a synergistic effect in mitigating sepsis-induced inflammation, cellular damage, and oxidative stress. Histopathological analyses supported these findings, revealing reduced heart and kidney injury in the MEL+ASA group. SIGNIFICANCE: Our study highlights potential benefits of combining melatonin and ascorbic acid as a therapeutic strategy for alleviating sepsis-induced heart and kidney injury. The synergistic effects of these agents may provide stronger protection against inflammation, oxidative stress, and tissue damage, opening new avenues for future research and clinical applications in sepsis management.
Asunto(s)
Melatonina , Sepsis , Ratas , Masculino , Animales , Melatonina/farmacología , Melatonina/uso terapéutico , Factor A de Crecimiento Endotelial Vascular , Ratas Sprague-Dawley , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Sirtuina 1/metabolismo , Inflamación/patología , Riñón/metabolismo , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismoRESUMEN
In this study, as a new synthesis method, UV light was employed as a type of cross-linking agent to control drug storage and to produce nanoparticles of different sizes and to stabilize the nanoparticles for the first time. We showed that the exposure time of the 5FU albumin solution to UV light produces differences in the size and characterization of the nanoparticles and also produces different cytotoxic effects on MCF-7 breast cancer cells. While the 5FU-A1 nanoparticles we synthesized with 1 h UV storage were approximately 43 nm, the 5FU-A2 nanoparticles we synthesized with UV storage for 3 h increased to an average of 300 nm. 5FU-A1 (IC50 value: 2.5 µg/mL) was approximately 16 times more cytotoxic than free 5FU (IC50 value 39.39 µg/mL) on MCF-7 cancer cells. Moreover, when normal HUVEC cells are treated with 5FU-A1 at a concentration of 2.5 µg/mL, more than 80% of these normal cells remain viable. In addition, we examined the rate of early-to-late apoptosis and necrosis in MCF-7 cancer cells using the Annexin V/PI flow cytometry assay. According to our results, 5FU-A1 promoted the apoptosis pathway. Finally, we examined P-gp activity with MDR1/ABCB1 antibody by flow cytometry and Rhodamine123 with fluorescent dye.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Nanopartículas , Albúminas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Fluorouracilo/farmacología , Humanos , Células MCF-7 , Rayos UltravioletaRESUMEN
In order to examine the anticancer potential of oxovanadium(IV) complexes with thiosemicarbazone, two new complexes were prepared starting from 2-thenoyltrifluoroacetone-S-methylthiosemicarbazone. The complexes with tetradentate thiosemicarbazone ligand were characterized by elemental analysis, IR, ESI MS, and single-crystal X-ray diffraction analysis. Cytotoxicity on breast cancer cells, MDA-MB-231 and MCF-7, was determined by MTT assay. Cisplatin was positive control and the results were compared with those of the normal cells, HUVEC and 3T3. The complexes exhibited greater activity on cancer cells than cisplatin, but they were cytotoxic at several times higher concentrations in the healthy cells. In our study, the presence of thiophene and fluoro groups in the oxovanadium(IV) complexes with thiosemicarbazone increased greatly the cytotoxic activity of the complexes on breast cancer cells. Moreover, the complexes induced apoptosis-mediated cell death and also reduced the expression of MDR-1 or P-glycoprotein and ABCG2. As a result, the findings indicated that the complexes have selective cytotoxicity on breast cancer cells and can overcome multidrug resistance. These properties of the complexes make it possible to be a potential anticancer drug candidate for breast cancer treatment.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Complejos de Coordinación , Tiosemicarbazonas , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Resistencia a Medicamentos , Femenino , Humanos , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacologíaRESUMEN
New thiosemicarbazone-based zinc(II) complexes were synthesized to study their cytotoxicity on A375 malignant melanoma cells. The complexes containing salicylidene (Zn1a), 3-methoxy-salicylidene (Zn1b) or 4-methoxy-salicylidene (Zn1c) moiety were characterized by analytical and spectroscopic methods. Anticancer potential of the complexes was determined by MTT test and HUVEC endothelial cells line was used to comprehend the effect on normal cells. Zn1b with an IC50 of 13 µM was found to be highly cytotoxic against A375 cancer cells, more effective than cisplatin (IC50: 37 µM). Zn1a and Zn1c did not have a negative effect on cell viability in the normal cells and gave the impression that they are more advantageous than cisplatin in this respect. Further, the ability of Zn1a-c to inhibit neuraminidase enzyme and its role in cytotoxicity was discussed. The test revealed that the Zn1b with 3-methoxy substituent exhibited higher inhibition activity against the neuraminidase than the Zn1a and Zn1c as analogical to the cytotoxicity results. In neuraminidase inhibition, IC50 values of Zn1b and Zn1c were 14 and 66 µM, respectively. These concentrations were very close to the cytotoxicity concentrations for Zn1b and Zn1c. The findings may indicate the role of neuraminidase enzyme inhibition in cell death for Zn1b and Zn1c.
Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Complejos de Coordinación/farmacología , Inhibidores Enzimáticos/farmacología , Neuraminidasa/antagonistas & inhibidores , Tiosemicarbazonas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Células Endoteliales de la Vena Umbilical Humana , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tiosemicarbazonas/síntesis química , Zinc/químicaRESUMEN
In this study, a thioxanthone derivative, 2-Thioxanthone Thioacetic Acid (TXSCH2COOH) was used to analyze the type of binding to calf thymus DNA in a physiological buffer (Tris-HCl buffer solution, pH:7.0). Several spectroscopic techniques were employed including UV-Vis absorption and fluorescence emission spectroscopy and viscosity measurements were also used to clarify the binding mode of TXSCH2COOH to ct-DNA. The intrinsic binding constant Kb of TXSCH2COOH-ct-DNA was found as 2.5 × 103 M-1 from the absorption studies. Increasing of fluorescence emission intensity was found approximately 74.4% by adding ct-DNA to the TXSCH2COOH solution. Fluorescence microscopy was employed to display imaging of the TXSCH2COOH-ct-DNA solution. Increasing of the iodide quenching effect was observed when TXSCH2COOH was added to the double stranded DNA and the calculated quenching constants of TXSCH2COOH and TXSCH2COOH-ct-DNA were found to be 1.89 × 103 M-1 and 1.19 × 104 M-1, respectively. Additionally, the iodide quenching experiment was conducted with single stranded DNA which led to a high Ksv value. All the experimental results including the viscosity values of ct-DNA with TXSCH2COOH demonstrated that the binding of TXSCH2COOH to ct-DNA was most likely groove binding. Furthermore, TXSCH2COOH was found to be an A-T rich minor groove binder. This was confirmed by the displacement assays with Hoechst 33258 compared to Ethidium Bromide. The in vitro cytotoxic activity measurements were performed by MTT assay on HT29 cell line for 72 h. TXSCH2COOH exhibited notable cytotoxic activities compared to the standard chemotherapy drugs, fluorouracil (5-FU), cisplatin in tumorigenic HT29 cell line. The 50% growth-inhibitory concentration (IC50) for TXSCH2COOH was 19,8 µg/mL while 5-FU and cisplatin were 28.9 µg/mL, 20 µg/mL, respectively. The increase in cytotoxic effect when TXSCH2COOH is activated by light indicates the potential of being theranostic cancer drug candidate.