RESUMO
An oral colon-targeted drug delivery system holds great potential in preventing systemic toxicity and preserving the therapeutic benefits of ulcerative colitis (UC) treatment. In this study, we developed a negatively charged PLGA-PEG nanoparticle system for encapsulating naringin (Nar). Additionally, chitosan and mannose were coated on the surface of these nanoparticles to enhance their mucosal adsorption and macrophage targeting abilities. The resulting nanoparticles, termed MC@Nar-NPs, exhibited excellent resistance against decomposition in the strong acidic gastrointestinal environment and specifically accumulated at inflammatory sites. Upon payload release, MC@Nar-NPs demonstrated remarkable efficacy in alleviating colon inflammation as evidenced by reduced levels of pro-inflammatory cytokines in both blood and colon tissues, as well as the scavenging of reactive oxygen species (ROS) in the colon. This oral nanoparticle delivery system represents a novel approach to treating UC by utilizing Chinese herbal ingredient-based oral delivery and provides a theoretical foundation for local and precise intervention in specific UC treatment.
Assuntos
Colite Ulcerativa , Colo , Flavanonas , Nanopartículas , Polímeros , Flavanonas/farmacologia , Flavanonas/química , Flavanonas/administração & dosagem , Flavanonas/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Animais , Nanopartículas/química , Colo/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Concentração de Íons de Hidrogênio , Administração Oral , Polímeros/química , Camundongos , Liberação Controlada de Fármacos , Espécies Reativas de Oxigênio/metabolismo , Masculino , Citocinas/metabolismoRESUMO
BACKGROUND: Autophagy plays a crucial role in modulating the proliferation of cancer diseases. However, the application of Naringenin (Nar), a compound with potential benefits against these diseases, has been limited due to its poor solubility and bioavailability. OBJECTIVE: This study aimed to develop solid lipid nanoparticles (Nar-SLNs) loaded with Nar to enhance their therapeutic impact. METHODS: In vitro experiments using Rin-5F cells exposed to Nar and Nar-SLNs were carried out to investigate the protective effects of Nar and its nanoformulation against the pancreatic cancer cell line of Rin-5F. RESULTS: Treatment with Nar and Nar-SLN led to an increase in autophagic markers (Akt, LC3, Beclin1, and ATG genes) and a decrease in the level of miR-21. Both Nar and Nar-SLN treatments inhibited cell proliferation and reduced the expression of autophagic markers. Notably, Nar-SLNs exhibited greater efficacy compared to free Nar. CONCLUSION: These findings suggest that SLNs effectively enhance the cytotoxic impact of Nar, making Nar-SLNs a promising candidate for suppressing or preventing Rin-5F cell growth.
Assuntos
Autofagia , Proliferação de Células , Flavanonas , Nanopartículas , Flavanonas/farmacologia , Flavanonas/administração & dosagem , Flavanonas/química , Autofagia/efeitos dos fármacos , Nanopartículas/química , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Ratos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Lipídeos/química , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Humanos , Portadores de Fármacos/química , LipossomosRESUMO
BACKGROUND/AIMS: Lemons (Citrus limon ) contain various nutrients and are among the most popular citrus fruit. Besides their antioxidant, anticancer, antibacterial, and anti-inflammatory properties, clinical studies have indicated their anti-allergic properties. METHODS: Using the differential-interference contrast (DIC) microscopy, we examined the effects of lemon juice and peel constituents, such as citric acid, ascorbic acid, hesperetin and eriodictyol, on the degranulation from rat peritoneal mast cells. Using fluorescence imaging with a water-soluble dye, Lucifer Yellow, we also examined their effects on the deformation of the plasma membrane. RESULTS: Lemon juice dose-dependently decreased the number of degranulated mast cells. At concentrations equal to or higher than 0.25 mM, citric acid, hesperetin, and eriodictyol significantly reduced the number of degranulating mast cells in a dose-dependent manner, while ascorbic acid required much higher doses to exert significant effects. At 1 mM, citric acid, hesperetin, and eriodictyol almost completely inhibited exocytosis and washed out the Lucifer Yellow trapped on the mast cell surface, while ascorbic acid did not. CONCLUSION: This study provides in vitro evidence for the first time that lemon constituents, such as citric acid, hesperetin, and eriodictyol, potently exert mast cell-stabilizing properties. These properties are attributable to their inhibitory effects on plasma membrane deformation in degranulating mast cells.
Assuntos
Ácido Ascórbico , Citrus , Flavanonas , Hesperidina , Mastócitos , Animais , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Citrus/química , Ratos , Ácido Ascórbico/farmacologia , Masculino , Hesperidina/farmacologia , Hesperidina/química , Flavanonas/farmacologia , Flavanonas/química , Ácido Cítrico/farmacologia , Ácido Cítrico/química , Degranulação Celular/efeitos dos fármacos , Sucos de Frutas e Vegetais/análise , Peritônio/citologia , Ratos Sprague-Dawley , Exocitose/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Frutas/química , IsoquinolinasRESUMO
Resistance to cisplatin presents a major obstacle in managing advanced-stage cervical cancer. Cuproptosis, a newly identified form of cell death induced by copper ions, has potential in overcoming chemoresistance. But the application of cuproptosis in cervical cancer resistant to cisplatin has not yet been reported. In this study, treatment with Elsm-Cu in cervical cancer cells induced cuproptosis, affecting cell proliferation and apoptosis was found. Moreover, cuproptosis in cervical cancer cells was significantly induced by baicalein. The combination of baicalein and cisplatin exhibited a synergistic effect on cervical cancer cells by promoting apoptosis and inhibiting cell viability via the induction of cuproptosis. Animal experiments demonstrated that this combination significantly suppressed tumor growth. Upon treating cells with SC79 (Akt agonist), a significant inhibition of the expression of cuproptosis-related proteins SDHB and FDX1 were observed, indicating that baicalein induced cuproptosis through the Akt pathway. These results indicated that baicalein, mediated through the Akt pathway to induce cuproptosis, had the potential to improve the sensitivity of cervical cancer cells to cisplatin.
Assuntos
Apoptose , Cisplatino , Sinergismo Farmacológico , Flavanonas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Neoplasias do Colo do Útero , Cisplatino/farmacologia , Flavanonas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Humanos , Feminino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos Nus , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Cobre/farmacologia , Camundongos Endogâmicos BALB C , Antineoplásicos/farmacologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Sobrevivência Celular/efeitos dos fármacos , Células HeLaRESUMO
Spontaneous forward-reverse mutations were reported by us earlier in clinical samples from various types of cancers and in HeLa cells under normal culture conditions. To investigate the effects of chemical stimulations on such mutation cycles, the present study examined single nucleotide variations (SNVs) and copy number variations (CNVs) in HeLa and A549 cells exposed to wogonin-containing or acidic medium. In wogonin, both cell lines showed a mutation cycle during days 16-18. In acidic medium, both cell lines displayed multiple mutation cycles of different magnitudes. Genomic feature colocalization analysis suggests that CNVs tend to occur in expanded and unstable regions, and near promoters, histones, and non-coding transcription sites. Moreover, phenotypic variations in cell morphology occurred during the forward-reverse mutation cycles under both types of chemical treatments. In conclusion, chemical stresses imposed by wogonin or acidity promoted cyclic forward-reverse mutations in both HeLa and A549 cells to different extents.
Assuntos
Variações do Número de Cópias de DNA , Flavanonas , Mutação , Humanos , Células HeLa , Flavanonas/farmacologia , Variações do Número de Cópias de DNA/genética , Mutação/genética , Células A549 , Polimorfismo de Nucleotídeo Único/genética , Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Linhagem Celular TumoralRESUMO
The emergence of the "super fungus" Candida auris poses a significant threat to human health, given its multidrug resistance and high mortality rates. Therefore, developing a new antifungal strategy is necessary. Our previous research showed that Baicalein (BE), a key bioactive compound from the dried root of the perennial herb Scutellaria baicalensis Georgi, has strong fungistatic properties against C. auris. Nevertheless, the antifungal activity of BE against C. auris and its mechanism of action requires further investigation. In this study, we explored how BE affects this fungus using various techniques, including scanning electron microscopy (SEM), Annexin V-FITC apoptosis detection, CaspACE FITC-VAD-FMK In Situ Marker, reactive oxygen species (ROS) assay, singlet oxygen sensor green (SOSG) fluorescent probe, enhanced mitochondrial membrane potential (MMP) assay with JC-1, DAPI staining, TUNEL assay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Our findings revealed that BE induced several apoptotic features, including phosphatidylserine (PS) externalization, metacaspase activation, nuclear condensation and DNA fragmentation. BE also increased intracellular ROS levels and altered mitochondrial functions. Additionally, transcriptomic analysis and RT-qPCR validation indicated that BE may induce apoptosis in C. auris by affecting ribosome-related pathways, suggesting that ribosomes could be new targets for antifungal agents, in addition to cell walls, membranes, and DNA. This study emphasizes the antifungal activity and mechanism of BE against C. auris, offering a promising treatment strategy for C. auris infection.
Assuntos
Antifúngicos , Apoptose , Candida , Flavanonas , Potencial da Membrana Mitocondrial , Espécies Reativas de Oxigênio , Ribossomos , Flavanonas/farmacologia , Apoptose/efeitos dos fármacos , Candida/efeitos dos fármacos , Antifúngicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Testes de Sensibilidade Microbiana , HumanosRESUMO
Naringenin, a potent antioxidant with anti-apoptotic effects, holds potential in counteracting rotenone-induced neurotoxicity, a model for Parkinson's disease, by reducing oxidative stress and supporting mitochondrial function. Rotenone disrupts ATP production in SH-SY5Y cells through mitochondrial complex-I inhibition, leading to increased reactive oxygen species (ROS) and cellular damage. However, the therapeutic use of naringenin is limited by its poor solubility, low bioavailability, and stability concerns. Nano crystallization of naringenin (NCs), significantly improved its solubility, dissolution rates, and stability for targeted drug delivery. The developed NAR-NC and HSA-NAR-NC formulations exhibit particle sizes of 95.23 nm and 147.89 nm, with zeta potentials of -20.6 mV and -28.5 mV, respectively. These nanocrystals also maintain high drug content and show stability over time, confirming their pharmaceutical viability. In studies using the SH-SY5Y cell line, these modified nanocrystals effectively preserved mitochondrial membrane potential, sustained ATP production, and regulated ROS levels, counteracting the neurotoxic effects of rotenone. Naringenin nanocrystals offer a promising solution for improving the stability and bioavailability of naringenin, with potential therapeutic applications in neurodegenerative diseases.
Assuntos
Flavanonas , Potencial da Membrana Mitocondrial , Mitofagia , Nanopartículas , Estresse Oxidativo , Espécies Reativas de Oxigênio , Rotenona , Humanos , Flavanonas/farmacologia , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Rotenona/toxicidade , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Tamanho da Partícula , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Solubilidade , Fármacos Neuroprotetores/farmacologiaRESUMO
Hepatocellular carcinoma (HCC) is a significant global health concern. However, there are limited effective treatments available for it. The use of natural products in the management and treatment of HCC is gaining more attention. Baicalein is a flavonoid compound that has been reported to have antitumor activities in HCC. However, the direct binding targets of baicalein are still unknown. Therefore, we used the DNA-programmed affinity labeling method to identify the target of baicalein and validated its function in HCC cells. We set blank and competitive DNA probes as negative controls. The results showed that baicalein had 136 binding targets, of which 13 targets were differently expressed in HCC tissues. The enriched cellular process of these targets was apoptosis, which involved MAPK9. We tested the binding affinity of baicalein with MAPK9 as 89.7 nM (Kd) by surface plasmon resonance and analyzed the binding sites by virtual docking. Notably, the binding of baicalein with MAPK9 increased the protein levels of MAPK9 itself and the related downstream apoptosis signaling, triggering the apoptosis of HCC cells. However, the inhibitor of MAPK9, SP600125, blocked the baicalein-induced apoptosis, and the amounts of MAPK9 and downstream molecules were also decreased, indicating that baicalein acted through MAPK9 to induce apoptosis of HCC cells. In conclusion, we used the DNA-programmed affinity labeling method to identify the direct-binding target MAPK9 of baicalein and validated its function in baicalein-induced apoptosis of HCC cells, which would be helpful to understand and use baicalein in HCC therapy.
Assuntos
Apoptose , Carcinoma Hepatocelular , Flavanonas , Neoplasias Hepáticas , Simulação de Acoplamento Molecular , Humanos , Antracenos/farmacologia , Antracenos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Flavanonas/farmacologia , Flavanonas/química , Flavanonas/metabolismo , Células Hep G2 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Ligação ProteicaRESUMO
This study assessed the impact of sweetened alcohol and naringin on cardiac function in Sprague-Dawley rats. Male (n = 40) and female (n = 40) rats were allocated to control, sweetened alcohol (SOH), naringin (NA), and sweetened alcohol with naringin (SOH + NA) groups. SOH and SOH + NA rats received 10% alcohol + 20% fructose in gelatine; SOH + NA and NA rats received 50 mg/kg naringin in gelatine daily for 10 weeks. Echocardiography was performed to assess left ventricular (LV) function. LV cardiomyocyte diameters and collagen area fraction were determined by H&E and picrosirius-red staining, respectively. In males, sweetened alcohol and naringin did not affect cardiac function. Female SOH rats had increased LV end-diastolic posterior wall (p = 0.04), relative wall thicknesses (p = 0.01), and LV cardiomyocyte diameters (p = 0.005) compared with control. Female SOH and SOH + NA had reduced lateral e' and e'/a' and increased E/e' (p < 0.0001). Female SOH (p = 0.01) and SOH + NA (p = 0.04) rats had increased LV collagen area fraction compared with controls. In males, neither sweetened alcohol nor naringin affected cardiac geometry or diastolic function. In females, sweetened alcohol induced concentric remodelling, impaired LV relaxation, and elevated filling pressures. Naringin may have the potential to improve the sweetened alcohol-induced concentric remodelling; however, it did not ameliorate diastolic dysfunction in females.
Assuntos
Etanol , Flavanonas , Ratos Sprague-Dawley , Função Ventricular Esquerda , Animais , Feminino , Masculino , Flavanonas/farmacologia , Ratos , Etanol/farmacologia , Etanol/toxicidade , Função Ventricular Esquerda/efeitos dos fármacos , Edulcorantes/farmacologia , Edulcorantes/administração & dosagem , Miócitos Cardíacos/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/efeitos adversosRESUMO
Naringin, a flavonoid, exhibits diverse therapeutic properties and has been proven to exert cytotoxic effects on cancer cells. Nevertheless, the precise mechanism of naringin maintaining its cytotoxic effect on glioblastoma (GBM) remains unknown. Thus, the current study aimed to establish a plausible cellular mechanism for Naringin's inhibition of GBM. We employed various system biology techniques to forecast the primary targets, including gene ontology and cluster analysis, KEGG enrichment pathway estimation, molecular docking, MD (molecular dynamic) simulation and MMPBSA analysis. Glioblastoma target sequences were obtained via DisGeNet and Therapeutic Target Prediction, aligned with naringin targets, and analyzed for gene enrichment and ontology. Gene enrichment analysis identified the top ten hub genes. Further, molecular docking was conducted on all identified targets. For molecular dynamics modelling, we selected the two complexes that exhibited the most docking affinity and the two most prominent genes of the hub identified through analysis of the enrichment of genes. The PARP1 and ALB1 signalling pathways were found to be the main regulated routes. Naringin exhibited the highest binding potential of - 12.90 kcal/mol with PARP1 (4ZZZ), followed by ABL1 (2ABL), with naringin showing a - 8.4 kcal/mol binding score, as determined by molecular docking. The molecular dynamic approach and MM-PBSA investigation along with PCA study revealed that the complex of Naringin, with 4ZZZ (PARP1) and, 2ABL (ABL1), are highly stable compared to that of imatinib and talazoparib. Analyses of the signalling pathway suggested that naringin may have anticancer effects against GBM by influencing the protein PARP and ALB1 levels. Cytotoxicity assay was performed on two different glioblastoma cell lines C6 and U87MG cells. Naringin demonstrates a higher cytotoxic potency against U87MG human glioblastoma cells compared to C6 rat glioma cells.
Assuntos
Flavanonas , Glioblastoma , Simulação de Acoplamento Molecular , Flavanonas/farmacologia , Flavanonas/química , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Simulação de Dinâmica Molecular , Farmacologia em Rede , Antineoplásicos/farmacologia , Antineoplásicos/química , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Maintaining intracellular equilibrium is essential for the viability of tumor cells, which tend to be particularly vulnerable to environmental stressors. Consequently, targeting the disruption of this homeostasis offers a promising approach for oncological treatments. LW-213, a novel derivative of wogonin, effectively induces apoptosis in cancer cells by initiating endoplasmic reticulum (ER) stress, although the precise molecular pathways involved remain intricate and multifaceted. PURPOSE: This research aimed to explore how LW-213 prompts apoptosis in non-small cell lung cancer (NSCLC) cells and to clarify the detailed mechanisms that govern this process. METHODS: Various NSCLC cell lines were utilized to delineate the apoptotic effects induced by LW-213. Advanced methodologies, including RNA sequencing (RNA-seq), Western blotting (WB), immunofluorescence (IF), immunoprecipitation (IP), flow cytometry (Fc), real-time quantitative polymerase chain reaction (RT-qPCR), and electron microscopy, were employed to investigate the underlying molecular interactions. The efficacy and mechanistic action of LW-213 were also assessed in a xenograft model using nude mice. RESULTS: We demonstrated that LW-213, a small molecule cationic amphiphilic drug (CAD), inhibited Niemann-Pick C1 (NPC1) function and induced lysosomal membrane damage, thereby activating the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway. This activation promoted cholesterol transport from the ER to the lysosome, perpetuating a cholesterol-deficient state in the ER, including massive exocytosis of Ca2+ and activation of FAM134B-mediated reticulophagy. Ultimately, excessive reticulophagy induced lethal ER stress. CONCLUSIONS: In summary, our study elucidates an organelle domino reaction initiated by lysosome damage and a series of self-rescue mechanisms that eventually lead to irreversible lethal effects, revealing a potential drug intervention strategy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Estresse do Retículo Endoplasmático , Flavanonas , Neoplasias Pulmonares , Lisossomos , Camundongos Nus , Humanos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Flavanonas/farmacologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Apoptose/efeitos dos fármacos , Proteína C1 de Niemann-Pick , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto , Autofagia/efeitos dos fármacos , FlavonoidesRESUMO
Naringenin (NAR) has shown potential as a cancer treatment, reducing cell proliferation and invasion in soft tissue sarcomas like liposarcoma (LPS). This study investigates NAR's role and molecular mechanism. Bioinformatic analysis was performed to assess the expression level of genes in LPS based on the GEO dataset. The heat map and PPI of genes were also analyzed. MTT, wound healing, DAPI staining, and flow cytometry evaluated the cell viability, migration, and apoptosis. Besides, real-time PCR was used to measure the NAR's impact on the expression levels of EMT, apoptosis, inflammation, and metastasis-related genes. The results showed that NAR reduces cell viability, proliferation, and migration but induces apoptosis in LPS cells. RT-PCR results revealed that NAR is capable of regulating the expression level of the apoptosis, EMT, migration, and Inflammation-related genes. This study demonstrated that NAR may play a crucial role in reducing cell viability, inducing apoptosis, and attenuating migration in Sw872 LPS cells. Consequently, NAR might be a promising and efficient factor in the treatment of LPS.
Assuntos
Apoptose , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Biologia Computacional , Flavanonas , Lipossarcoma , Flavanonas/farmacologia , Lipossarcoma/tratamento farmacológico , Lipossarcoma/patologia , Lipossarcoma/genética , Lipossarcoma/metabolismo , Humanos , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacosRESUMO
BACKGROUND: Psoriasis (PSO) poses a global health threat. The current research challenge in PSO is relapse. Liquiritin (LIQ), a major active compound from Glycyrrhiza inflata Batalin, has multiple pharmacological properties, including anti-inflammatory and anti-proliferative. Nonetheless, the precise mechanisms underlying LIQ's therapeutic actions in PSO and prevention abilities remain elusive. PURPOSE: The present study aimed to delve into the potential to treat and prevent PSO and the mechanism of LIQ. METHODS: The anti-inflammatory and anti-proliferative effects of LIQ were studied in vitro with the HaCaT cell line. Then, Transcriptional analysis and bioinformatic analysis were used to determine the internal associations of the target set. Subsequently, functional experiment, luciferase report assay, ChIP-PCR, and immunohistochemical validation of clinical samples were performed to investigate the mechanism of LIQ. Finally, the anti-psoriatic effects and prevention abilities of LIQ were verified in vivo with imiquimod (IMQ)-induced PSO-like mouse models. RESULTS: Here, we identified differentially expressed genes in LIQ-stimulated HaCaT cells and Retinol-Binding Protein 3 (RBP3) as the core target, whereas YY1 was a predicted upstream transcription factor of RBP3. The YY1/RBP3 axis was obviously altered after administering LIQ at optimal doses of 20 µM in vitro and 100 µg/ml in vivo. LIQ can significantly inhibit the progression of PSO in vivo. Notably, LIQ also prevented the relapse of psoriatic lesions induced by the second round of low-dose IMQ. Mechanistically, we observed that LIQ could increase the promotion of YY1 for RBP3 by enhancing the binding affinity between them. CONCLUSION: These findings revealed that the YY1/RBP3 axis is a potential psoriatic target, and LIQ is a promising and innovative therapeutic candidate for the treatment and prevention of PSO.
Assuntos
Flavanonas , Glucosídeos , Imiquimode , Psoríase , Animais , Feminino , Humanos , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Flavanonas/farmacologia , Glucosídeos/farmacologia , Glycyrrhiza/química , Células HaCaT , Camundongos Endogâmicos BALB C , Psoríase/tratamento farmacológico , Fator de Transcrição YY1/metabolismoRESUMO
Naringenin is a flavonoid with significant anti-inflammatory and antioxidant properties. Mitochondrial dynamics, the mitochondrial respiratory chain, and mtROS are closely related to each other and regulate various biological processes. Ferroptosis is closely related to inflammatory responses and immune function in multiple tissues and organs. However, whether naringenin can alleviate LPS-induced inflammation and immune disorders in the chicken thymus via mtROS/ferroptosis has not been reported. Therefore, in this study, we constructed chicken thymus and MSB-1 cell models of LPS and naringenin based on screening for naringenin concentrations that have positive effects on inflammation and immune function to further investigate the anti-inflammatory, antiferroptosis, and maintenance of the immune function of naringenin. The results showed that 40 mg/kg naringenin alleviated LPS-induced tissue damage, elevated serum inflammatory factors, and decreased serum immune factors. The mechanism by which naringenin attenuates mtROS release by alleviating the imbalance of mitochondrial dynamics and the blockage of the respiratory chain. The effect of naringenin on alleviating LPS-induced lipid peroxidation, disruption of the GSH/GSSG system, iron overload, and GPx4 inactivation, thereby attenuating ferroptosis in thymus tissue, was inhibited by the addition of mtROS activators. In conclusion, naringenin alleviates LPS-induced ferroptosis in chicken thymus by attenuating mtROS release.
Assuntos
Galinhas , Ferroptose , Flavanonas , Inflamação , Lipopolissacarídeos , Doenças das Aves Domésticas , Timo , Animais , Flavanonas/farmacologia , Flavanonas/administração & dosagem , Lipopolissacarídeos/farmacologia , Timo/efeitos dos fármacos , Inflamação/veterinária , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Doenças das Aves Domésticas/induzido quimicamente , Doenças das Aves Domésticas/tratamento farmacológico , Doenças das Aves Domésticas/imunologia , Ferroptose/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
The exposure of broiler chickens to high ambient temperatures causes heat stress (HS), negatively affecting their health and production performance. To mitigate heat stress in broilers, various strategies, including dietary, managerial, and genetic interventions, have been extensively tested with varying degrees of efficacy. For sustainable broiler production, it is imperative to develop an innovative approach that effectively mitigates the adverse effects of HS. Our previous studies have provided valuable insights into the effects of prehatch embryonic thermal manipulation (TM) and posthatch baicalein supplementation on embryonic thermotolerance, metabolism, and posthatch growth performance. This follow-up study investigated the effect of these interventions on gluconeogenesis and lipid metabolism in the liver, as well as muscle proliferation and regeneration capacity in heat-stressed broiler chickens. A total of six-hundred fertile Cobb 500 eggs were incubated for 21 d. After candling, 238 eggs were subjected to TM at 38.5°C with 55% relative humidity (RH) from embryonic day (ED) 12 to 18. These eggs were transferred to the hatcher and kept at a standard temperature (37.5°C) from ED 19 to 21, while 236 eggs were incubated at a controlled temperature (37.5°C) till hatch. After hatching, 180 day-old chicks from both groups were raised in 36 pens treatment (n = 10 birds/pen, 6 replicates per treatment). The treatments were: 1) Control, 2) TM, 3) Control heat stress (CHS), 4) Thermal manipulation heat stress (TMHS), 5) Control heat stress supplement (CHSS), and 6) Thermal manipulation heat stress supplement (TMHSS). Baicalein was added to the treatment group diets starting from d 1. All birds were raised under the standard environment for 21 d, followed by chronic heat stress from d 22 to 35 (32-33 °C for 8 h) in the CHS, TMHS, CHSS, and TMHSS groups. A thermoneutral (22-24°C) environment was maintained in the Control and TM groups. RH was constant (50 ± 5%) throughout the trial. In the liver, TM significantly increased (P < 0.05) IGF2 expression. Baicalein supplementation significantly increased (P < 0.05) HSF3, HSP70, SOD1, SOD2, TXN, PRARα, and GHR expression. Moreover, the combination of TM and baicalein supplementation significantly increased (P < 0.05) the expression of HSPH1, HSPB1, HSP90, LPL, and GHR. In the muscle, TM significantly increased (P < 0.05) HSF3 and Myf5 gene expression. TM and baicalein supplementation significantly increased (P < 0.05) the expression of MyoG and significantly (P < 0.05) decreased mTOR and PAX7. In conclusion, the prehatch TM of embryos and posthatch baicalein supplementation mitigated the deleterious effects of HS on broiler chickens by upregulating genes related to liver gluconeogenesis, lipid metabolism, and muscle proliferation.
Assuntos
Galinhas , Suplementos Nutricionais , Flavanonas , Fígado , Animais , Galinhas/crescimento & desenvolvimento , Galinhas/fisiologia , Embrião de Galinha , Suplementos Nutricionais/análise , Flavanonas/administração & dosagem , Flavanonas/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Dieta/veterinária , Temperatura Alta , Ração Animal/análise , Resposta ao Choque Térmico/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacosRESUMO
Radiation resistance is a crucial factor influencing therapeutic outcomes in colorectal cancer (CRC). Baicalein (BE), primarily derived from Scutellaria baicalensis, has demonstrated anti-CRC properties. However, the impact of BE on the radiosensitivity of CRC remains unclear. This study aimed to evaluate the radiosensitization effects of BE and elucidate its mechanism in CRC radiotherapy. We established an in vitro radioresistant cell model (CT26-R) using parental CRC cells (CT26) subjected to ionizing radiation (IR). CT26-R cells were pretreated with or without BE, followed by transfection with pcDNA-NC and pcDNA-JAK2. The proliferation of CT26-R cells treated with BE and IR was assessed using a colony formation assay. A CRC animal model was developed in BALB/c mice via CT26-R cell transplantation. The radiosensitizing effect of BE on CRC was evaluated in vivo. TUNEL assay was conducted to detect apoptosis in tumor tissue. The expression levels of p-STAT3, JAK2, PD-L1, and SOCS3 in vitro and in vivo were measured by western blotting. Our results demonstrated that BE significantly increased radiosensitivity in vitro and in vivo and enhanced apoptosis in tumor tissues. Additionally, BE significantly downregulated the expression of p-STAT3, JAK2, and PD-L1, and significantly upregulated SOCS3 expression. These in vivo effects were reversed by pcDNA-JAK2. In summary, our data suggest that BE enhances CRC radiosensitivity by inhibiting the JAK2/STAT3 pathway.
Assuntos
Apoptose , Neoplasias Colorretais , Flavanonas , Janus Quinase 2 , Camundongos Endogâmicos BALB C , Tolerância a Radiação , Fator de Transcrição STAT3 , Transdução de Sinais , Janus Quinase 2/metabolismo , Flavanonas/farmacologia , Flavanonas/química , Flavanonas/uso terapêutico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Animais , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Camundongos , Tolerância a Radiação/efeitos dos fármacos , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Humanos , Proliferação de Células/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Radiossensibilizantes/químicaRESUMO
Eriodictyol, a flavonoid distributed in citrus fruits, has been known to exhibit anti-inflammatory activity. In this study, destabilized medial meniscus (DMM)-induced OA model was used to investigate the protective role of eriodictyol on OA. Meanwhile, we used an IL-1ß-stimulated human osteoarthritis chondrocytes model to investigate the anti-inflammatory mechanism of eriodictyol on OA. The production of nitric oxide was detected by Griess reaction. The productions of MMP1, MMP3, and PGE2 were detected by ELISA. The expression of LXRα, ABCA1, PI3K, AKT, and NF-κB were measured by western blot analysis. The results demonstrated that eriodictyol could alleviate DMM-induced OA in mice. In vitro, eriodictyol inhibited IL-1ß-induced NO, PGE2, MMP1, and MMP3 production in human osteoarthritis chondrocytes. Eriodictyol also suppressed the phosphorylation of PI3K, AKT, NF-κB p65, and IκBα induced by IL-1ß. Meanwhile, eriodictyol significantly increased the expression of LXRα and ABCA1. Furthermore, eriodictyol disrupted lipid rafts formation through reducing the cholesterol content. And cholesterol replenishment experiment showed that adding water-soluble cholesterol could reverse the anti-inflammatory effect of eriodictyol. In conclusion, the results indicated eriodictyol inhibited IL-1ß-induced inflammation in human osteoarthritis chondrocytes through suppressing lipid rafts formation, which subsequently inhibiting PI3K/AKT/NF-κB signaling pathway.
Assuntos
Condrócitos , Flavanonas , NF-kappa B , Osteoartrite , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Flavanonas/farmacologia , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Camundongos , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/patologia , Interleucina-1beta/metabolismo , Receptores X do Fígado/metabolismo , Masculino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Progressão da Doença , Modelos Animais de Doenças , Anti-Inflamatórios/farmacologia , Óxido Nítrico/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Background: Naringenin has shown great promise in the realm of cancer therapeutics, demonstrating excellent cytotoxic action toward cancer cells and the enhanced effects of radiation therapy in vitro. However, the medicinal value of naringenin is severely limited clinically by poor bioavailability. Thus, multiple drug-delivery strategies for overcoming this limitation have been developed, of which liposomes are considered the most suitable due to their amphiphilic, modifiable, and biocompatible characteristics. In this study, we investigated the role of naringenin and liposomal-delivered naringenin as adjuncts to radiotherapy in the MDA-MB-231 triple-negative breast cancer cell line in vitro. Materials and Methods: Liposomal-naringenin was synthesized by thin-film hydration and extrusion and was characterized by spectrophotometry, dynamic light scattering, and zeta potential. The effects of free-from naringenin and liposomal-naringenin were evaluated toward MDA-MB-231 cell viability when combined with varying doses of radiation. Additionally, cell growth patterns, morphology, and colony formation were evaluated. Results: The analysis demonstrated IC50 values of 387.5 and 546.6 µg/ml for naringenin and liposomal-naringenin, respectively. Naringenin and liposomal-naringenin significantly lowered cell viability, proliferation, and colony formation dose-dependently, as compared to radiation in isolation. Conclusion: The findings presented herein concur with previous accounts of the radiosensitizing potential of naringenin and further highlight the considerable biomedical application of liposomal-naringenin within the realm of radiotherapy.
Assuntos
Sobrevivência Celular , Flavanonas , Lipossomos , Radiossensibilizantes , Neoplasias de Mama Triplo Negativas , Flavanonas/química , Flavanonas/farmacologia , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Lipossomos/química , Linhagem Celular Tumoral , Radiossensibilizantes/farmacologia , Radiossensibilizantes/química , Sobrevivência Celular/efeitos dos fármacos , Feminino , Proliferação de Células/efeitos dos fármacos , Células MDA-MB-231RESUMO
AIM: The degradation of the cartilage endplate (CEP) plays a critical role in the initiation and progression of intervertebral disc degeneration (IVDD), a disease closely associated with inflammation and oxidative stress. Naringin (NGN), a flavonoid compound derived from citrus fruits, has been shown to exhibit significant anti-inflammatory and antioxidant properties. This suggests a promising avenue for NGN's application in IVDD therapy. This study aims to elucidate the therapeutic effects and underlying mechanisms of NGN on CEP degeneration, contributing to the formulation of evidence-based treatment strategies for IVDD. METHODS: In vivo, we developed an intervertebral disc degeneration (IVDD) model in mice by excising the bilateral facet joints and surrounding ligaments, and evaluated the effects of naringin using HE staining and Micro-CT analysis. In vitro, endplate chondrocytes were isolated and subjected to TBHP to replicate the IVDD pathological condition. The protective effects of NGN on these cells were confirmed through immunofluorescence, Western Blot, and flow cytometry. RESULTS: In vivo, NGN effectively mitigated IVDD progression and CEP calcification in mice. In vitro, NGN enhanced mitophagy and suppressed NLRP3 inflammasome activation through the SIRT3/FOXO3a/Parkin pathway. Furthermore, NGN safeguarded chondrocytes against apoptosis and calcification triggered by oxidative stress, in addition to mitigating the degradation of the extracellular matrix. However, silencing SIRT3 negated NGN's protective influence on chondrocytes. CONCLUSION: Our study demonstrated that NGN effectively shields chondrocytes from apoptosis and NLRP3 inflammasome activation by facilitating SIRT3-mediated mitophagy. These insights could pave the way for innovative approaches in the prevention and management of IVDD.
Assuntos
Apoptose , Condrócitos , Flavanonas , Proteína Forkhead Box O3 , Inflamassomos , Degeneração do Disco Intervertebral , Camundongos Endogâmicos C57BL , Mitofagia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sirtuína 3 , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Mitofagia/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Inflamassomos/metabolismo , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Degeneração do Disco Intervertebral/tratamento farmacológico , Degeneração do Disco Intervertebral/patologia , Sirtuína 3/metabolismo , Camundongos , Proteína Forkhead Box O3/metabolismo , Masculino , Modelos Animais de Doenças , Ubiquitina-Proteína Ligases/metabolismo , Células Cultivadas , Transdução de Sinais/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêuticoRESUMO
BACKGROUND: Malaria, characterised by inflammation and multi-organ complications, needs novel chemotherapeutics due to the rise of drug-resistant malaria parasites, which is a serious health issue. Naringin (NGN), a flavanone glycoside (naringenin 7-O-neohesperidose), has a broad spectrum of pharmacological activities but its effect against malaria, alone and in combination, was not deeply investigated. PURPOSE: To assess the pharmacological efficacy of NGN alone and in combination with chloroquine (CQ) against a Plasmodium strain resistant to CQ and to elucidate its potential mode of action. METHODS: The anti-inflammatory potential of NGN was assessed in mouse microglial cells stimulated with hemozoin by analyzing inflammatory cytokines production. The anti-plasmodial potential of NGN was subsequently tested alone and in combination with CQ against the K1 strain of Plasmodium using the fixed ratio combination method. Further, we evaluated NGN's antimalarial efficacy against the CQ-resistant Plasmodium yoelii nigeriensis N67 strain (P. yoelii), both alone and in combination with CQ, by measuring parasitemia and survival rates. To comprehend the impact of NGN on malaria-induced inflammation in mice, we measured pro-inflammatory cytokines elevated by activated NF-кB signalling. These findings were supported by mRNA and immunohistochemical analyses of malaria-infected mice's liver and brain tissues. RESULTS: Our study demonstrated that NGN displayed anti-plasmodial activity, which was further augmented when combined with CQ. At 50 µM, NGN significantly reduced the elevation of pro-inflammatory cytokines in synthetic hemozoin-stimulated microglial cells. Compared to P. yoelii-infected mice, NGN (12.5 mg kg-1) significantly reduced parasitemia in mice, resulting in a survival period of up to 13 days. Survival improved by up to 20 days when NGN and CQ were given in combination. NGN, as revealed by immunohistochemical examination of brain and liver tissues, interfered with the NF-кB pathway, potentially reducing the elevation of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-18, IFN-γ, and IL-6). This was supported by the overexpression of inflammation-regulatory genes (TGFß, Nrf2, HO-1, and iNOS) and the downregulation of inflammation-stimulating genes (NF-κB, NLRP3, and caspase-1). Histopathological analysis demonstrated the potential of NGN to restore liver and brain tissues to normal. The substantial decrease in the expression and production of ICAM-1 protein in the brain tissue implies the beneficial effects of NGN, pointing towards its potential for mitigating brain pathology. CONCLUSION: The findings of this study revealed NGN as a promising drug-like candidate for the management of CQ-resistant parasite-induced malaria pathogenesis for adjunctive therapy in combination with standard antimalarial drugs through its modulation of the NF-κB-mediated inflammation.