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Chronic inflammation and infection often lead to delayed healing in skin wounds of patients with diabetes, presenting a significant challenge in clinical wound repair. In an effort to tackle this issue, we explored the utilization of the natural compounds Rhein and chitosan in the creation of a crosslinked in situ gel. Developed as Rhein-chitosan in situ hydrogel (CS-Rh gel), this formulation has the ability to gel at body temperature, making it suitable for irregular wounds of varying shapes. Our experimental investigations have demonstrated its excellent biocompatibility, controlled release of Rhein, biodegradability, anti-inflammatory properties, antibacterial effect, as well as its ability to enhance keratinocyte proliferation and migration. Furthermore, in vivo studies have confirmed that CS-Rh gel can effectively mitigate tissue inflammation, promote collagen deposition, and significantly accelerate wound healing in diabetic mice within a short timeframe of two weeks. Consequently, this innovative approach holds promise as a viable therapeutic strategy for supporting the healing of diabetic wounds in a clinical setting.
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Ras-related C3 botulinum toxin substrate 1 (Rac1) is a small GTPase belonging to the Rho family. It acts as a binary molecular switch regulating several cellular functions, including cell adhesion and migration. Malfunctions due to the P29S mutation in Rac1 increase the stability of the activated form of Rac1. This sustained activation can drive aberrant cellular processes associated with cancer, such as cell proliferation, survival, and migration. Therefore, finding an inhibitor that can inhibit the mutant form of the protein is very important. Rhein, a natural compound with diverse pharmacological properties, has been studied in relation to Rac1. However, specific interactions between Rhein and Rac1 have not been examined. In this study, we investigated the potential of Rhein, a natural compound, as an inhibitor of two forms of Rac1: the wild type and the P29S mutation, using molecular dynamics simulations. Results indicated that the P29S mutation led to structural changes in the Rac1 protein, which resulted in greater accessibility of the Rhein to the active site. In addition, the binding energy of Rhein to mutant Rac1 was more negative than the native protein. Therefore, it seems that the Rhein has a better inhibitory effect on the P29S-mutated form of the Rac1 protein.
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Carrier-free self-assembly has gradually shifted the focus of research on natural products, which effectively improve the bioavailability and the drug-loading rate. However, in spite of the existing studies, the development of self-assembled natural phytochemicals that possess pharmacological effects still has scope for further exploration and enhancement. Herein, a nano-delivery system was fabricated through the direct self-assembly of Rhein and Matrine and was identified as a self-assembled Rhein-Matrine nanoparticles (RM NPs). The morphology of RM NPs was characterized by TEM. The molecular mechanisms of self-assembly were explored using FT-IR, 1H NMR, and molecular dynamics simulation analysis. Gelatin methacryloyl (GelMA) hydrogel was used as a drug carrier for controlled release and targeted delivery of RM NPs. The potential wound repair properties of RM NPs were evaluated on a skin wound-healing model. TEM and dynamic light scattering study demonstrated that the RM NPs were close to spherical, and the average size was approximately 75 nm. 1H NMR of RM NPs demonstrated strong and weak changes in the interaction energies during self-assembly. Further molecular dynamics simulation analysis predicted the self-assembly behavior. An in vivo skin wound-healing model demonstrated that RM NPs present better protection effect against skin damages. Taken together, RM NPs are a new self-assembly system; this may provide new directions for natural product applications.
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Alcaloides , Antraquinonas , Matrinas , Simulação de Dinâmica Molecular , Nanopartículas , Quinolizinas , Cicatrização , Alcaloides/química , Alcaloides/farmacologia , Cicatrização/efeitos dos fármacos , Quinolizinas/química , Quinolizinas/farmacologia , Nanopartículas/química , Antraquinonas/química , Antraquinonas/farmacologia , Animais , Portadores de Fármacos/química , Camundongos , Hidrogéis/química , HumanosRESUMO
Aspergillus flavus and its carcinogenic secondary metabolites, aflatoxins, not only cause serious losses in the agricultural economy, but also endanger human health. Rhein, a compound extracted from the Chinese herbal medicine Rheum palmatum L. (Dahuang), exhibits good anti-inflammatory, anti-tumor, and anti-oxidative effects. However, its effect and underlying mechanisms against Aspergillus flavus have not yet been fully illustrated. In this study, we characterized the inhibition effect of rhein on A. flavus mycelial growth, sporulation, and aflatoxin B1 (AFB1) biosynthesis and the potential mechanism using RNA-seq analysis. The results indicate that A. flavus mycelial growth and AFB1 biosynthesis were significantly inhibited by 50 µM rhein, with a 43.83% reduction in colony diameter and 87.2% reduction in AFB1 production. The RNA-seq findings demonstrated that the differentially expressed genes primarily participated in processes such as spore formation and development, the maintenance of cell wall and membrane integrity, management of oxidative stress, the regulation of the citric acid cycle, and the biosynthesis of aflatoxin. Biochemical verification experiments further confirmed that 50 µM rhein effectively disrupted cell wall and membrane integrity and caused mitochondrial dysfunction through disrupting energy metabolism pathways, leading to decreased ATP synthesis and ROS accumulation, resulting in impaired aflatoxin biosynthesis. In addition, a pathogenicity test showed that 50 µM rhein inhibited A. flavus spore growth in peanut and maize seeds by 34.1% and 90.4%, while AFB1 biosynthesis was inhibited by 60.52% and 99.43%, respectively. In conclusion, this research expands the knowledge regarding the antifungal activity of rhein and provides a new strategy to mitigate A. flavus contamination.
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Aflatoxina B1 , Antraquinonas , Aspergillus flavus , Espécies Reativas de Oxigênio , Aspergillus flavus/efeitos dos fármacos , Aspergillus flavus/metabolismo , Aspergillus flavus/crescimento & desenvolvimento , Antraquinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Aflatoxina B1/biossíntese , Aflatoxina B1/toxicidade , Metabolismo Energético/efeitos dos fármacos , Esporos Fúngicos/efeitos dos fármacos , Esporos Fúngicos/crescimento & desenvolvimento , Micélio/efeitos dos fármacos , Micélio/crescimento & desenvolvimento , Antifúngicos/farmacologiaRESUMO
Background: Parkinson's disease (PD) is a common neurodegenerative disease with a rapid increase in incidence in recent years. Existing treatments cannot slow or stop the progression of PD. It was proposed that neuroinflammation leads to neuronal death, making targeting neuroinflammation a promising therapeutic strategy. Our previous studies have demonstrated that rhein protects neurons in vitro by inhibiting neuroinflammation, and it has been found to exhibit neuroprotective effects in Alzheimer's disease and epilepsy, but its neuroprotective mechanisms and effects on PD are still unclear. Methods: PD animal model was induced by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP). ELISA, RT-qPCR, western blot and Immunofluorescence were used to detect the levels of inflammatory cytokines and M1 polarization markers. The protein expression levels of signaling pathways were measured by western blot. Hematoxylin-eosin (HE) staining showed that rhein did not damage the liver and kidney. Two behavioral tests, pole test and rotarod test, were used to evaluate the improvement effect of rhein on movement disorders. The number of neurons in the substantia nigra was evaluated by Nissl staining. Immunohistochemistry and western blot were used to detect tyrosine hydroxylase (TH) and α-synuclein. Results: Rhein inhibited the activation of MAPK/IκB signaling pathway and reduced the levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and M1 polarization markers of microglia in vivo. In a mouse model of PD, rhein ameliorated movement disorders, reduced dopaminergic neuron damage and α-synuclein deposition. Conclusion: Rhein inhibits neuroinflammation through MAPK/IκB signaling pathway, thereby reducing neurodegeneration, α-synuclein deposition, and improving movement disorders in Parkinson's disease.
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Phenolic compounds represent natural compounds endowed with diverse biological functionalities. However, their inherent limitations, characterized by poor water solubility and low oral bioavailability, limit their broader applications. Encapsulation delivery systems are emerging as a remedy, able to ameliorate these limitations by enhancing the stability and solubility of phenolic compounds. In this study, a novel, customized pH-driven approach was developed by determining the optimal deprotonation and protonation points of three different types of polyphenols: ferulic acid, resveratrol, and rhein. The polyphenols were successfully encapsulated in a casein carrier. The solubility, stability, LogD, and LogS curves of the three polyphenols at different pH values were analyzed to identify the optimal deprotonation points for ferulic acid (pH 9), resveratrol (pH 11), and rhein (pH 10). Based on these findings, three different nanoparticles were prepared. The encapsulation efficiencies of the three phenolic compounds were 95.86%, 94.62%, and 94.18%, respectively, and the casein nanoparticles remained stable at room temperature for seven days. FTIR spectroscopy, fluorescence spectroscopy, and molecular docking study substantiated the encapsulation of phenolic compounds within the hydrophobic core of casein-based complexes, facilitated by hydrogen bonding interactions and hydrophobic interactions. Furthermore, the analysis of antioxidant activity elucidated that casein nanoparticles heightened both the water solubility and antioxidant efficacy of the phenolic compounds. This customized encapsulation technique, by establishing a transitional pH value, resolves the challenges of chemical instability and facile degradation of polyphenols under alkaline conditions in the application process of pH-driven methods. It presents novel insights for the application of polyphenols in the domains of food and biomedical fields.
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Caseínas , Ácidos Cumáricos , Simulação de Acoplamento Molecular , Polifenóis , Solubilidade , Caseínas/química , Concentração de Íons de Hidrogênio , Polifenóis/química , Ácidos Cumáricos/química , Resveratrol/química , Antraquinonas/química , Nanopartículas/química , Composição de Medicamentos , Espectroscopia de Infravermelho com Transformada de Fourier , Interações Hidrofóbicas e Hidrofílicas , Antioxidantes/químicaRESUMO
BACKGROUND: Rhein is an anthraquinone compound with anti-inflammatory pharmacological activity. It has been found to play a neuroprotective role in neurological diseases, but the neuroprotective mechanism of rhein remains unclear. METHODS: SH-SY5Y cells serving as neuron-like cells and BV2 microglia were used. The toxicity of rhein on BV2 microglia and the viability of SH-SY5Y cells were measured by CCK-8 assay. The mRNA expression and secretion of pro-inflammatory cytokines were detected by qPCR and ELISA. Iba1, CD86 and pathway signalling protein in BV2 microglia were assessed by Western blot and immunofluorescence. Apoptosis of SH-SY5Y cells exposed to neuroinflammation was analysed through flow cytometry. RESULTS: Rhein inhibited MAPK/IκB signalling pathways. Further studies revealed that rhein inhibited the production of pro-inflammatory cytokines TNF-α, IL-6, IL-1ß and iNOS in BV2 cells and also inhibited the expression of M1 polarization markers Iba1 and CD86 in BV2 cells. Furthermore, rhein reduced the apoptotic rate and restored cell viability of SH-SY5Y cells exposed to neuroinflammation. CONCLUSIONS: Our study demonstrated that rhein inhibited microglia M1 polarization via MAPK/IκB signalling pathway and protected nerve cells through suppressing neuroinflammation.
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Rhein, a natural anthraquinone compound derived from traditional Chinese medicine, exhibits potent anti-inflammatory properties via modulating the level of Reactive oxygen or nitrogen species (RONS). Nevertheless, its limited solubility in water, brief duration of plasma presence, as well as its significant systemic toxicity, pose obstacles to its in vivo usage, necessitating the creation of a reliable drug delivery platform to circumvent these difficulties. In this study, an esterase-responsive and mitochondria-targeted nano-prodrug was synthesized by conjugating Rhein with the polyethylene glycol (PEG)-modified triphenyl phosphonium (TPP) molecule, forming TPP-PEG-RH, which could spontaneously self-assemble into RPT NPs when dispersed in aqueous media. The TPP outer layer of these nanoparticles enhances their pharmacokinetic profile, facilitates efficient delivery to mitochondria, and promotes cellular uptake, thereby enabling enhanced accumulation in mitochondria and improved therapeutic effects in vitro. The decline in RONS was observed in IL-1ß-stimulated chondrocyte after RPT NPs treating. RPT NPs also exert excellent anti-inflammatory (IL-1ß, TNF-α, IL-6 and MMP-13) and antioxidative effects (Cat and Sod) via the Nrf2 signalling pathway, upregulation of cartilage related genes (Col2a1 and Acan). Moreover, RPT NPs shows protection of mitochondrial membrane potential and inhibition of chondrocyte apoptosis. Moreover, These findings suggest that the mitochondria-targeted polymer-Rhein conjugate may offer a therapeutic solution for patients suffering from chronic joint disorders, by attenuating the progression of osteoarthritis (OA).
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Antraquinonas , Anti-Inflamatórios , Mitocôndrias , Nanopartículas , Osteoartrite , Pró-Fármacos , Antraquinonas/administração & dosagem , Antraquinonas/farmacologia , Antraquinonas/farmacocinética , Antraquinonas/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Osteoartrite/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Nanopartículas/química , Condrócitos/efeitos dos fármacos , Polietilenoglicóis/química , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Antioxidantes/química , Sistemas de Liberação de Medicamentos/métodos , Espécies Reativas de Oxigênio/metabolismo , Humanos , Apoptose/efeitos dos fármacos , Compostos Organofosforados/química , Compostos Organofosforados/administração & dosagem , RatosRESUMO
The mechanism by which DNMT3B facilitates esophageal cancer (ESCA) progression is currently unknown, despite its association with adverse prognoses in several cancer types. To investigate the potential therapeutic effects of the Chinese herbal medicine rhubarb on esophageal cancer (ESCA), we adopted an integrated bioinformatics approach. Gene Set Enrichment Analysis (GSEA) was first utilized to screen active anti-ESCA components in rhubarb. We then employed Weighted Gene Co-expression Network Analysis (WGCNA) to identify key molecular modules and targets related to the active components and ESCA pathogenesis. This system-level strategy integrating multi-omics data provides a powerful means to unravel the molecular mechanisms underlying the anticancer activities of natural products, like rhubarb. To investigate module gene functional enrichment, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. In addition, we evaluated the predictive impact of DNMT3B expression on ESCA patients utilizing the Kaplan-Meier method. Finally, we conducted experiments on cell proliferation and the cell cycle to explore the biological roles of DNMT3B. In this study, we identified Rhein as the main active ingredient of rhubarb that exhibited significant anti-ESCA activity. Rhein markedly suppressed ESCA cell proliferation. Utilizing Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we determined that the blue module was associated with Rhein target genes and the cell cycle. Additionally, DNMT3B was identified as a Rhein target gene. Analysis of The Cancer Genome Atlas (TCGA) database revealed that higher DNMT3B levels were associated with poor prognosis in ESCA patients. Furthermore, Rhein partially reversed the overexpression of DNMT3B to inhibit ESCA cell proliferation. In vitro studies demonstrated that Rhein and DNMT3B inhibition disrupted the S phase of the cell cycle and affected the production of cell cycle-related proteins. In this study, we found that Rhein exerts its anti-proliferative effects in ESCA cells by targeting DNMT3B and regulating the cell cycle.
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Antraquinonas , Ciclo Celular , Proliferação de Células , DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3B , Neoplasias Esofágicas , Humanos , Antraquinonas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Rheum/químicaRESUMO
Rhubarb is widely used in health care, but causing a great amount of rhein-containing herbal residue. Rhein with several toxicities might pollute environment, damage ecology and even hazard human health if left untreated. In this study, the degradation effects of bisulfite- (BS) and peroxymonosulfate- (PMS) based oxidation systems on rhein in rhubarb residue were compared and investigated. The effects of BS and PMS with two valence states of ferric ion (Fe) on the degradation of rhein in rhubarb residue were optimized for the selection of optimal oxidation system. The influences of reaction temperature, reaction time and initial pH on the removal of rhein under the optimal oxidation system were evaluated. The chemical profiles of rhubarb residue with and without oxidation process were compared by UPLC-QTOF-MS/MS, and the degradation effects were investigated by PLS-DA and S plot/OPLS-DA analysis. The results manifested that PMS showed relative higher efficiency than BS on the degradation of rhein. Moreover, Fe(III) promoted the degradation effect of PMS, demonstrated that Fe(III)/PMS is the optimal oxidation system to degrade rhein in rhubarb residue. Further studies indicated that the degradation of rhein by the Fe(III)/PMS oxidation system was accelerated with the prolong of reaction time and the elevation of reaction temperature, and also affected by the initial pH. More importantly, Fe(III)/PMS oxidation system could degrade rhein in rhubarb residue completely under the optimal conditions. In conclusion, Fe(III)/PMS oxidation system is a feasible method to treat rhein in rhubarb residue.
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Antraquinonas , Oxirredução , Peróxidos , Rheum , Antraquinonas/química , Rheum/química , Peróxidos/química , Espectrometria de Massas em Tandem , Sulfitos/química , Concentração de Íons de Hidrogênio , Compostos Férricos/química , TemperaturaRESUMO
VEGFR-2 is a prominent therapeutic target in antitumor drug research to block tumor angiogenesis. This study focused on the synthesis and optimization of PROTACs based on the natural product rhein, resulting in the successful synthesis of 15 distinct molecules. In A549 cells, D9 exhibited remarkable antitumor efficacy with an IC50 of 5.88±0.50â µM, which was 15-fold higher compared to rhein (IC50=88.45±2.77â µM). An in-depth study of the effect of D9 on the degradation of VEGFR-2 revealed that D9 was able to induce the degradation of VEGFR-2 in A549 cells in a time-dependent manner. The observed effect was reversible, contingent upon the proteasome and ubiquitination system, and demonstrably linked to CRBN. Further experiments revealed that D9 induced apoptosis in A549 cells and led to cell cycle arrest in the G1 phase. Molecular docking simulations validated the binding mode of D9 to VEGFR, establishing the potential of D9 to bind to VEGFR-2 in its natural state. In summary, this study confirms the feasibility of natural product-bound PROTAC technology for the development of a new generation of VEGFR-2 degraders, offering a novel trajectory for the future development of pharmacological agents targeting VEGFR-2.
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Antineoplásicos , Apoptose , Produtos Biológicos , Simulação de Acoplamento Molecular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/síntese química , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Antraquinonas/farmacologia , Antraquinonas/química , Antraquinonas/síntese química , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Relação Dose-Resposta a Droga , Estrutura Molecular , Células A549 , Proteólise/efeitos dos fármacos , Quimera de Direcionamento de ProteóliseRESUMO
Background. Actinobacillus pleuropneumoniae, a member of the Pasteurellaceae family, is known for its highly infectious nature and is the primary causative agent of infectious pleuropneumonia in pigs. This disease poses a considerable threat to the global pig industry and leads to substantial economic losses due to reduced productivity, increased mortality rates, and the need for extensive veterinary care and treatment. Due to the emergence of multi-drug-resistant strains, Chinese herbal medicine is considered one of the best alternatives to antibiotics due to its unique mechanism of action and other properties. As a type of Chinese herbal medicine, Rhein has the advantages of a wide antibacterial spectrum and is less likely to develop drug resistance, which can perfectly solve the limitations of current antibacterial treatments.Methods. The killing effect of Rhein on A. pleuropneumoniae was detected by fluorescence quantification of differential expression changes of key genes, and scanning electron microscopy was used to observe the changes in A. pleuropneumoniae status after Rhein treatment. Establishing a mouse model to observe the treatment of Rhein after A. pleuropneumoniae infection.Results. Here, in this study, we found that Rhein had a good killing effect on A. pleuropneumoniae and that the MIC was 25 µg ml-1. After 3 h of action, Rhein (4×MIC) completely kills A. pleuropneumoniae and Rhein has good stability. In addition, the treatment with Rhein (1×MIC) significantly reduced the formation of bacterial biofilms. Therapeutic evaluation in a murine model showed that Rhein protects mice from A. pleuropneumoniae and relieves lung inflammation. Quantitative RT-PCR (Quantitative reverse transcription polymerase chain reaction is a molecular biology technique that combines both reverse transcription and polymerase chain reaction methods to quantitatively detect the amount of a specific RNA molecule) results showed that Rhein treatment significantly downregulated the expression of the IL-18 (Interleukin refers to a class of cytokines produced by white blood cells), TNF-α, p65 and p38 genes. Along with the downregulation of genes such as IL-18, it means that Rhein has an inhibitory effect on the expression of these genes, thereby reducing the activation of inflammatory cells and the production of inflammatory mediators. This helps reduce inflammation and protects tissue from further damage.Conclusions. This study reports the activity of Rhein against A. pleuropneumoniae and its mechanism, and reveals the ability of Rhein to treat A. pleuropneumoniae infection in mice, laying the foundation for the development of new drugs for bacterial infections.
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Infecções por Actinobacillus , Actinobacillus pleuropneumoniae , Antraquinonas , Antibacterianos , Animais , Antraquinonas/farmacologia , Antraquinonas/uso terapêutico , Actinobacillus pleuropneumoniae/efeitos dos fármacos , Actinobacillus pleuropneumoniae/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Camundongos , Infecções por Actinobacillus/tratamento farmacológico , Infecções por Actinobacillus/microbiologia , Infecções por Actinobacillus/veterinária , Suínos , Modelos Animais de Doenças , Feminino , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Pulmão/microbiologia , Pulmão/patologia , Doenças dos Suínos/tratamento farmacológico , Doenças dos Suínos/microbiologiaRESUMO
Ferroptosis has emerged as a promising strategy for treating triple-negative breast cancer (TNBC) due to bypassing apoptosis and triggering immunogenic cell death (ICD) of tumor cells. However, the antitumor efficacy has been limited by the insufficient intracellular ferrous iron concentration required for ferroptosis and inadequate antitumor immune response. To address these limitations, we designed a multi-mode nano-platform (MP-FA@R-F NPs), which exhibited a synergistic effect of ferroptosis, apoptosis and induced immune response for enhanced antitumor therapy. MP-FA@R-F NPs target folate receptors, which are over-expressed on the tumor cell's surface to promote intracellular uptake. The cargoes, including Rhein and Fe3O4, would be released in intracellular acid, accelerating by NIR laser irradiation. The released Rhein induced apoptosis of tumor cells mediated by the caspase 3 signal pathway, while the released Fe3O4 triggered ferroptosis through the Fenton reaction and endowed the nanoplatform with magnetic resonance imaging (MRI) capabilities. In addition, ferroptosis-dying tumor cells could release damage-associated molecular patterns (DAMPs) to promote T cell activation and infiltration for immune response and induce immunogenic cell death (ICD) for tumor immunotherapy. Together, MP-FA@R-F NPs represent a potential synergistic ferro-/chemo-/immuno-therapy strategy with MRI guidance for enhanced antitumor therapy. STATEMENT OF SIGNIFICANCE: The massive strategies of cancer therapy based on ferroptosis have been emerging in recent years, which provided new insights into designing materials for cancer therapy. However, the antitumor efficacy of ferroptosis is still unsatisfactory, mainly due to insufficient intracellular pro-ferroptotic stimuli. In the current study, we designed a multi-mode nano-platform (MP-FA@R-F NPs), which represented a potential synergistic ferro-/chemo-/immuno-therapy strategy with MRI guidance for enhanced antitumor therapy.
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Antraquinonas , Ferroptose , Imunoterapia , Antraquinonas/química , Antraquinonas/farmacologia , Animais , Imunoterapia/métodos , Humanos , Linhagem Celular Tumoral , Camundongos , Ferroptose/efeitos dos fármacos , Feminino , Camundongos Endogâmicos BALB C , Ácido Fólico/química , Ácido Fólico/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Apoptose/efeitos dos fármacosRESUMO
Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1ß inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein's specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model.
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Antraquinonas , Proliferação de Células , Neoplasias Colorretais , Quinases Semelhantes a Duplacortina , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Serina-Treonina Quinases , Fator de Transcrição STAT3 , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Camundongos , Proliferação de Células/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Antraquinonas/farmacologia , Linhagem Celular Tumoral , Reposicionamento de Medicamentos , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Cancer-associated fibroblasts (CAFs), one of the most abundant stromal cells in the tumor microenvironment, mediate desmoplastic responses. CAFs are major drivers for the failure of triple-negative breast cancer (TNBC) chemotherapy. It is well-documented that many traditional Chinese medicines (TCMs) exhibit potent anti-fibrotic effects based on their capacity to suppress the production of ECM proteins. Therefore, the combination of TCMs exhausting CAFs with chemotherapy is a potential regimen for treating TNBC. Here, TGF-ß was used to induce the transformation of NIH/3T3 cells into CAFs for screening TCMs to inhibit tumor fibrosis. After screening 11 candidate TCMs for inhibiting CAFs using the TMS method, rhein (Rhe) was found to strongly inhibit the proliferation of CAFs. Therefore, Rhe was chosen as a representative TCM to inhibit CAFs in TNBC. A 4T1Fluc/CAFs tumor sphere resembling the TME in vivo was constructed to explore the feasibility of inhibiting CAFs to sensitize DOX in treating TNBC. It was found that CAFs apparently hindered the penetration of DOX into 4T1Fluc/CAFs tumor spheres and decreased the the sensitivity of 4T1Fluc cells to DOX, while Rhe significantly restored the sensitivity of 4T1Fluc cells to DOX by inhibiting the proliferation of CAFs. Consistent with in vitro results, Rhe reversed the abnormal activation of CAFs and diminished the accumulation of collagen in 4T1Fluc mouse xenograft models. This removal of stromal barrier facilitated the antitumor efficacy of DOX. Altogether, this study demonstrated for the first time that Rhe could inhibit tumor tissue fibrosis and synergize DOX to treat TNBC.
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Antraquinonas , Fibroblastos Associados a Câncer , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Fibrose , Microambiente TumoralRESUMO
Ulcerative colitis (UC) is a chronic inflammatory disease with uncontrolled inflammation and demage to the intestinal barrier. Rhein, a bioactive compound in traditional Chinese medicine, has anti-inflammatory and intestinal repair effect. However, their clinical application is limited by their hydrophobicity and poor bioavailability. L-arginine, as a complement to NO, has synergistic and attenuating effects. In this paper, red/NIR-I fluorescent carbon dots based on rhein and doped with L-arginine (RA-CDs), which are synthesized by a hydrothermal process without any organic solvents, are reported. RA-CDs preserve a portion of the functional group of the active precursor, increase rhein solubility, and emit red/NIR-I light for biological imaging. In vitro experiments show that RA-CDs scavenge excessive reactive oxygen species (ROS), protect cells from oxidative stress, and enable the fluorescence imaging of inflamed colons. In a DSS-induced UC mouse model, both delayed and prophylactic treatment with RA-CDs via intraperitoneal and tail vein injections alleviate UC severity by reducing intestinal inflammation and restoring the intestinal barrier. This study highlights a novel strategy for treating and imaging UC with poorly soluble small-molecule drugs.
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Antraquinonas , Carbono , Colite Ulcerativa , Espécies Reativas de Oxigênio , Antraquinonas/química , Antraquinonas/farmacologia , Animais , Camundongos , Carbono/química , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Pontos Quânticos/química , Camundongos Endogâmicos C57BL , Sulfato de Dextrana , Arginina/química , Corantes Fluorescentes/química , Modelos Animais de Doenças , MasculinoRESUMO
Currently, dairy mastitis caused by Staphylococcus xylosus poses a serious challenge for dairy farming. In this study, we explored the role and mechanism of rhein against S. xylosus with the hope of providing new research ideas to solve mastitis in dairy cows and ensure the source safety of dairy products. Through in vitro antimicrobial studies, we found that the minimum inhibitory concentration (MIC) of rhein was 64 µg/mL, and it significantly interfered with the formation of S. xylosus biofilm at sub-MIC. In experiments on mastitis in mice, rhein alleviated inflammation in mammary tissue, reduced the levels of TNF-α and IL-6, and decreased the number of S. xylosus. To explore the anti-S. xylosus mechanism of rhein, we identified the relevant proteins involved in carbon metabolism (Glycolysis/gluconeogenesis, TCA cycle, Fatty acid degradation) through proteomics. Additionally, proteins associated with the respiratory chain, oxidative stress (proteins of antioxidant and DNA repair), and nitrate respiration were also found to be upregulated. Thus, rhein may act as an antibacterial agent by interfering with the respiratory metabolism of S. xylosus and inducing the production of ROS, high levels of which alter the permeability of bacterial cell membranes and cause damage to them. We measured the concentrations of extracellular ß-galactosidase and nucleic acids. Additionally, SEM observation of S. xylosus morphology showed elevated membrane permeability and damage to the cell membrane. Finally, RT-PCR experiments showed that mRNAs of key proteins of the TCA cycle (odhA, mqo) and nitrate respiration (nreB, nreC, narG) were significantly up-regulated, consistent with proteomic results. In conclusion, rhein has good anti-S. xylosus effects in vitro and in vivo, by interfering with bacterial energy metabolism, inducing ROS production, and causing cell membrane and DNA damage, which may be one of the important mechanisms of its antimicrobial activity.
RESUMO
Rac1 is a member of the Rho GTPase family which plays major roles in cell mobility, polarity and migration, as a fundamental regulator of actin cytoskeleton. Signal transduction by Rac1 occurs through interaction with multiple effector proteins, and its activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). The small protein is mainly anchored to the inner side of the plasma membrane but it can be found in endocellular compartments, notably endosomes and cell nuclei. The protein localizes also into mitochondria where it contributes to the regulation of mitochondrial dynamics, including both mitobiogenesis and mitophagy, in addition to signaling processes via different protein partners, such as the proapoptotic protein Bcl-2 and chaperone sigma-1 receptor (σ-1R). The mitochondrial form of Rac1 (mtRac1) has been understudied thus far, but it is as essential as the nuclear or plasma membrane forms, via its implication in regulation of oxidative stress and DNA damages. Rac1 is subject to diverse post-translational modifications, notably to a geranylgeranylation which contributes importantly to its mitochondrial import and its anchorage to mitochondrial membranes. In addition, Rac1 contributes to the mitochondrial translocation of other proteins, such as p53. The mitochondrial localization and functions of Rac1 are discussed here, notably in the context of human diseases such as cancers. Inhibitors of Rac1 have been identified (NSC-23766, EHT-1864) and some are being developed for the treatment of cancer (MBQ-167) or central nervous system diseases (JK-50561). Their effects on mtRac1 warrant further investigations. An overview of mtRac1 is provided here.
Assuntos
Transdução de Sinais , Proteínas rac1 de Ligação ao GTP , Humanos , Proteínas rac1 de Ligação ao GTP/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Mitocôndrias/metabolismoRESUMO
BACKGROUND: Rhein, which has antioxidant and anti-inflammatory response properties, is a beneficial treatment for different pathologies. However, the mechanism by which rhein protects against myocardial ischemic injury is poorly understood. METHODS AND RESULTS: To establish an acute myocardial infarction (AMI) rat model, we performed left anterior descending (LAD) ligation. SpragueâDawley rats were randomly divided into four groups: sham, AMI, AMI + rhein (AMI + R), and AMI + mitochondrial fission inhibitor (AMI + M). The extent of myocardial injury was evaluated by TTC staining, serum myocardial injury markers, and HE and Masson staining. Cardiac mitochondria ultrastructure was visualized by transmission electron microscopy. TUNEL assay and flow cytometry analysis were used to estimate cell apoptosis. Protein expression levels were measured by Western blotting. In vitro, the efficacy of rhein was assessed in H9c2 cells under hypoxic condition. Our results revealed that rats with AMI exhibited increased infarct size and indicators of myocardial damage, along with activation of Drp1-dependent mitochondrial fission, decreased mitophagy and increased apoptosis rates. However, pretreatment with rhein significantly reversed these effects and demonstrated similar efficacy to Mdivi-1. Furthermore, rhein pretreatment protected against myocardial ischemic injury by inhibiting mitochondrial fission, as evidenced by decreased Drp1 expression. It also enhanced mitophagy, as indicated by increased expression of Beclin1, Pink1 and Parkin, an increased LC3-II/LC3-I ratio and increased formation of autolysosomes. Additionally, rhein pretreatment mitigated apoptosis in AMI. These results were also confirmed in vitro in H9c2 cells. CONCLUSION: Our results demonstrate that rhein pretreatment exerts cardioprotective effects against myocardial ischemic injury via the Drp1/Pink1/Parkin pathway.
Assuntos
Antraquinonas , Dinâmica Mitocondrial , Proteínas Quinases , Ratos , Animais , Ratos Sprague-Dawley , Proteínas Quinases/metabolismo , Autofagia , Mitocôndrias/metabolismo , Apoptose , Ubiquitina-Proteína Ligases/metabolismoRESUMO
INTRODUCTION: Sennosides are the main active constituents of the dried leaves and/or pods of Senna alexandrina Mill. that are used as laxatives. A hypothesis is that aglycones are formed during the degradation of sennosides. However, it is unknown, whether this happens under visible light exposure and how photosensitive sennosides behave in solution. OBJECTIVES: Pure anthraquinone glycosides were tested on their behaviour during sample preparation in the lab under visible light exposure in dependence on the instability of the solvent. MATERIALS AND METHODS: Samples before and after exposure were analysed using UHPLC with UV/Vis and MS detection. RESULTS: Under visible light protection, the solutions were stable for 14 days at room temperature whereas a loss of 20%-60% was measured after 1 day of light exposure. The loss of sennosides due to degradation can be as fast as up to 2%-2.5% per hour, which might have a tremendous impact on phytochemical analysis results during the course of an analysis. The formation of aglycones was not observed in the degradation of sennosides and rhein-8-O-glucoside. CONCLUSION: Aglycones could not be found as a result of the forced degradation. The solutions of sennosides clearly need to be protected from light to obtain reliable analytical results, and light protection is a major point for the stability of liquid preparations.