RESUMO
Relevant studies have recognized the important role of hepatic stellate cell (HSC) senescence in anti-liver fibrosis. Cellular senescence is believed to be regulated by the cGAS-STING signaling pathway. However, underlying exact mechanisms of cGAS-STING pathway in hepatic stellate cell senescence are still unclear. Here, we found that Oroxylin A could promote senescence in HSC by activating the cGAS-STING pathway. Moreover, activation of the cGAS-STING pathway was dependent on DNMT3A downregulation, which suppressed cGAS gene DNA methylation. Interestingly, the attenuation of DNMT activity relied on the reduction of methyl donor SAM level. Noteworthy, the downregulation of SAM levels implied the imbalance of methionine cycle metabolism, and MAT2A was considered to be an important regulatory enzyme in metabolic processes. In vivo experiments also indicated that Oroxylin A induced senescence of HSCs in mice with liver fibrosis, and DNMT3A overexpression partly offset this effect. In conclusion, we discovered that Oroxylin A prevented the methylation of the cGAS gene by preventing the production of methionine metabolites, which promoted the senescence of HSCs. This finding offers a fresh hypothesis for further research into the anti-liver fibrosis mechanism of natural medicines.
Assuntos
Metilação de DNA , Células Estreladas do Fígado , Animais , Camundongos , Senescência Celular , DNA , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Cirrose Hepática/induzido quimicamente , Metionina/metabolismo , Nucleotidiltransferases/genéticaRESUMO
Tendinopathy is one of the most prevalent sports injury diseases in orthopedics. However, there is no effective treatment or medicine. Recently, the discovery of tendon stem cells (TSCs) provides a new perspective to find new therapeutic methods for Tendinopathy. Studies have shown that oxidative stress will inevitably cause TSCs injury during tendinopathy, but the mechanism has not been fully elucidated. Here, we report the oxidative damage of TSCs induced by H2O2 via ferroptosis, as well, treatment with H2O2 raised the proportion of mitochondria engulfed by autophagosomes in TSCs. The suppression of mitophagy by Mdivi-1 significantly attenuates the H2O2-induced ferroptosis in TSCs. Mechanically, H2O2 actives the cGAS-STING pathway, which can regulate the level of mitophagy. Interfering with cGAS could impair mitophagy and the classical ferroptotic events. In the rat model of tendinopathy, interference of cGAS could relieve tendon injury by inhibiting ferroptosis. Overall, these results provided novel implications to reveal the molecular mechanism of tendinopathy, by which pointed to cGAS as a potential therapeutic target for the treatment of tendinopathy.
Assuntos
Ferroptose , Peróxido de Hidrogênio , Proteínas de Membrana , Mitofagia , Nucleotidiltransferases , Estresse Oxidativo , Transdução de Sinais , Células-Tronco , Tendões , Mitofagia/efeitos dos fármacos , Animais , Nucleotidiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Células-Tronco/metabolismo , Tendões/patologia , Tendões/metabolismo , Ratos , Peróxido de Hidrogênio/metabolismo , Humanos , Masculino , Ratos Sprague-Dawley , Tendinopatia/metabolismo , Tendinopatia/patologia , Células CultivadasRESUMO
BACKGROUND: LSECs (Liver sinusoidal endothelial cells) are the portal of liver, their pathological angiogenesis plays a constructive role in etiopathogenesis of liver fibrosis by affecting liver tissue repair and inflammatory drive. Although intervention in angiogenesis can effectively inhibit abnormal activation of LSEC, no effective drugs have been found to treat liver fibrosis. PURPOSE: We investigated the effect of the natural compound Curcumol on LSEC angiogenesis and elucidated the novel underlying mechanism, expecting to provide a scientific basis for exploring potential therapeutic drugs for liver fibrosis. METHODS: Various cellular and molecular assays, as well as genetic assays, were used to detect pathological angiogenesis and changes in glycolysis levels in cultured rat LSECs and mouse liver fibrosis models. RESULTS: Transcription factor KLF5 is able to influence the angiogenic properties of LSEC by regulating the glycolytic process, and affect the expression of LDH-A by transcriptionally binding to its promoter. In our study, we were surprised to find that LDH-A (the final step of glycolysis) has a strong regulatory effect on the glycolytic process of LSEC. Through in-depth study, we found that LDH-A could affect the transcriptional activity of KLF5, thus forming a positive feedback loop. Curcumol could break this positive feedback loop and inhibit the glycolysis-dependent angiogenic nature of LSEC, thus alleviating liver fibrosis. Curcumol reduced extracellular matrix (ECM) deposition, attenuated pathological angiogenesis in LSEC, and decreased the level of CCl4-induced liver fibrosis in mice. CONCLUSION: Our results demonstrated the great utilization potentiality of KLF5 in liver fibrosis, and the innovative discovery that LDH-A regulates the glycolytic process and forms a malignant feedback loop by exerting non-enzymatic effects. It also reveals the prospect of Curcumol-regulated KLF5/LDH-A feedback loop in the treatment of liver fibrosis, providing a new option for the future medicine of liver fibrosis.
Assuntos
Células Endoteliais , Cirrose Hepática , Ratos , Camundongos , Animais , Lactato Desidrogenase 5/metabolismo , Lactato Desidrogenase 5/farmacologia , Retroalimentação , Cirrose Hepática/tratamento farmacológico , Fígado/metabolismo , Modelos Animais de Doenças , Glicólise , Neovascularização Patológica/tratamento farmacológico , Fatores de Transcrição Kruppel-Like/metabolismoRESUMO
Relevant researches have recognized the vital role of inducing ferroptosis in the treatment of tumor. The latest findings indicate that PEBP1/15-LO can play an essential role in the process of cell death. However, its role in regulating ferroptosis in hepatocellular carcinoma (simplified by HCC) remains unclear. The previous research of our team has proved that DHA can induce ferroptosis of hepatic stellate cells. In this study, we found that DHA could also induce ferroptosis in HCC cells. Interestingly, DHA induced ferroptosis by promoting the formation of PEBP1/15-LO and promoting cell membrane lipid peroxidation. In addition, we also found that DHA had no obvious regulatory effect on 15-LO, but it could promote PEBP1 protein expression. Importantly, we discovered the upregulation of PEBP1 induced by DHA was related to the inhibition of its ubiquitination degradation. In vivo experiments have also obtained consistent results that DHA can inhibit tumor growth and affect the expression of ferroptosis markers in tumor tissues, which would be partially offset by interference with PEBP1.
Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Artemisininas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Ferroptose , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Animais , Antimaláricos/farmacologia , Apoptose , Araquidonato 15-Lipoxigenase/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína de Ligação a Fosfatidiletanolamina/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Control over on-surface reaction pathways is crucial but challenging for the precise construction of conjugated nanostructures at the atomic level. Herein we demonstrate a selective on-surface covalent coupling reaction that is templated by metal-organic coordinative bonding, and achieve a porous nitrogen-doped carbon nanoribbon structure. In contrast to the inhomogeneous polymorphic structures resulting from the debrominated aryl-aryl coupling reaction on Au(111), the incorporation of an Fe-terpyridine (tpy) coordination motif into the on-surface reaction controls the molecular conformation, guides the reaction pathway, and finally yields pure organic sexipyridine-p-phenylene nanoribbons. Emergent molecular conformers and reaction products in the reaction pathways are revealed by scanning tunneling microscopy, density functional theory calculations and X-ray photoelectron spectroscopy, demonstrating the template effect of Fe-tpy coordination on the on-surface covalent coupling. Our approach opens an avenue for the rational design and synthesis of functional conjugated nanomaterials with atomic precision.
RESUMO
The incorporation of spatially oriented aromatic motifs in rigid molecular platforms is of great interest for the design of organic electronic materials. These structures can create unusual packing patterns and charge transport properties in the solid state which are not possible for simple planar structures. Herein, we showed that the novel dispiro and propellane motifs were successfully used as robust molecular platforms for the construction of host materials (TPA, Cz, SF, and SO). The propellane derivative with three functional groups arranged in the staggered conformation was studied for the first time as the host for organic light-emitting diodes (OLEDs). The green and red phosphorescent OLEDs hosted by these dispiro and propellane derivatives exhibited excellent electroluminescence performance. Particularly, the red OLED hosted by the propellane-type SF achieved maximum efficiencies of 47.3 cd A-1, 40.2 lm W-1, and 26.6% and 97.6 cd A-1, 77.8 lm W-1, and 27.0% for the green OLED without any light out-coupling enhancement. These results suggest that the dispiro and propellane molecular platforms have great potential in the construction of OLED materials.