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Background: The preservation of the Lingguizhugan (LGZG) decoction and patient compliance issue often limit the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Hence, herein, an LGZG oral solution was developed for alleviating MASLD. Additionally, the potential mechanisms underlying LGZG-mediated MASLD mitigation were explored. Methods: A MASLD mouse model was constructed using oleic and palmitic acid-induced LO2 cells and a high-fat diet. The apoptosis, lipid deposition, and mouse liver function were analyzed to assess the therapeutic effects of the LGZG oral solution on MASLD. Serum untargeted metabolomics, gut microbiota, bile acid (BA) metabolism, immunohistochemistry, and Western blotting analyses were performed to investigate the potential mechanism of action of LGZG oral solution on MASLD. Results: The LGZG oral solution ameliorated lipid deposition, oxidative stress, inflammation, and pathological damage. Serum untargeted metabolomics results revealed the LGZG-mediated regulation of the primary BA biosynthetic pathway. The 16S ribosomal RNA sequencing of the fecal microbiota showed that LGZG oral solution increased the relative abundance of the BA metabolism-associated Bacteroides, Akkermansia, and decreased that of Lactobacillus. Additionally, the BA metabolism analysis results revealed a decrease in the total taurine-α/ß-muricholic acid levels, whereas those of deoxycholic acid were increased, which activated specific receptors in the liver and ileum, including farnesoid X receptor (FXR) and takeda G protein-coupled receptor 5 (TGR5). Activation of FXR resulted in an increase in short heterodimer partner and subsequent inhibition of cholesterol 7α-hydroxylase and sterol regulatory element-binding protein-1c expression, and activation of FXR also results in the upregulation of fibroblast growth factor 15/19 expression, and consequently inhibition of cholesterol 7α-hydroxylase, which correlated with hepatic BA synthesis and lipogenesis, ultimately attenuating lipid deposition and bile acid stasis, thereby improving MASLD. Conclusion: Altogether, the findings of this study suggest that modulating microbiota-BA-FXR/TGR5 signaling pathway may be a potential mechanism of action of LGZG oral solution for the treatment of MASLD.
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Plant immune homeostasis is achieved through a balanced immune activation and suppression, enabling effective defense while averting autoimmunity. In Arabidopsis, disrupting a mitogen-activated protein (MAP) kinase cascade triggers nucleotide-binding leucine-rich-repeat (NLR) SUPPRESSOR OF mkk1/2 2 (SUMM2)-mediated autoimmunity. Through an RNAi screen, we identify PUB5, a putative plant U-box E3 ligase, as a critical regulator of SUMM2-mediated autoimmunity. In contrast to typical E3 ligases, PUB5 stabilizes CRCK3, a calmodulin-binding receptor-like cytoplasmic kinase involved in SUMM2 activation. A closely related E3 ligase, PUB44, functions oppositely with PUB5 to degrade CRCK3 through monoubiquitylation and internalization. Furthermore, CRCK3, highly expressed in roots and conserved across plant species, confers resistance to Fusarium oxysporum, a devastating soil-borne fungal pathogen, in both Arabidopsis and cotton. These findings demonstrate the antagonistic role of an E3 ligase pair in fine-tuning kinase proteostasis for the regulation of NLR-mediated autoimmunity and highlight the function of autoimmune activators in governing plant root immunity against fungal pathogens.
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Proteínas de Arabidopsis , Arabidopsis , Autoinmunidad , Resistencia a la Enfermedad , Fusarium , Enfermedades de las Plantas , Inmunidad de la Planta , Ubiquitina-Proteína Ligasas , Arabidopsis/inmunología , Arabidopsis/microbiología , Arabidopsis/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Fusarium/inmunología , Proteínas NLR/metabolismo , Proteínas NLR/genética , Regulación de la Expresión Génica de las Plantas , Ubiquitinación , Proteínas PortadorasRESUMEN
Anticancer peptides (ACPs) have recently emerged as promising cancer therapeutics due to their selectivity and lower toxicity. However, the number of experimentally validated ACPs is limited, and identifying ACPs from large-scale sequence data is time-consuming and expensive. Therefore, it is critical to develop and improve upon existing computational models for identifying ACPs. In this study, a computational method named ACP_DA was proposed based on peptide residue composition and physiochemical properties information. To curtail overfitting and reduce computational costs, a sequential forward selection method was utilized to construct the optimal feature groups. Subsequently, the feature vectors were fed into light gradient boosting machine classifier for model construction. It was observed by an independent set test that ACP_DA achieved the highest Matthew's correlation coefficient of 0.63 and accuracy of 0.8129, displaying at least a 2% enhancement compared to state-of-the-art methods. The satisfactory results demonstrate the effectiveness of ACP_DA as a powerful tool for identifying ACPs, with the potential to significantly contribute to the development and optimization of promising therapies. The data and resource codes are available at https://github.com/Zlclab/ACP_DA.
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Antineoplásicos , Biología Computacional , Péptidos , Péptidos/química , Antineoplásicos/farmacología , Humanos , Biología Computacional/métodos , Neoplasias/tratamiento farmacológico , AlgoritmosRESUMEN
Osteoarthritis (OA) is a chronic joint disease characterized by cartilage imbalance and disruption of cartilage extracellular matrix secretion. Identifying key genes that regulate cartilage differentiation and developing effective therapeutic strategies to restore their expression is crucial. In a previous study, we observed a significant correlation between the expression of the gene encoding casein kinase-2 interacting protein-1 (CKIP-1) in the cartilage of OA patients and OA severity scores, suggesting its potential involvement in OA development. To test this hypothesis, we synthesized a chondrocyte affinity plasmid, liposomes CKIP-1, to enhance CKIP-1 expression in chondrocytes. Our results demonstrated that injection of CAP-Lipos-CKIP-1 plasmid significantly improved OA joint destruction and restored joint motor function by enhancing cartilage extracellular matrix (ECM) secretion. Histological and cytological analyses confirmed that CKIP-1 maintains altered the phosphorylation of the signal transduction molecule SMAD2/3 of the transforming growth factor-ß (TGF-ß) pathway by promoting the phosphorylation of the 8T, 416S sit. Taken together, this work highlights a novel approach for the precise modulation of chondrocyte phenotype from an inflammatory to a noninflammatory state for the treatment of OA and may be broadly applicable to patients suffering from other arthritic diseases.
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Condrocitos , Homeostasis , Liposomas , Osteoartritis , Condrocitos/metabolismo , Osteoartritis/terapia , Osteoartritis/patología , Osteoartritis/metabolismo , Liposomas/química , Humanos , Animales , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Masculino , Fosforilación , Cartílago Articular/metabolismo , Cartílago Articular/patología , Factor de Crecimiento Transformador beta/metabolismo , Matriz Extracelular/metabolismo , Proteína smad3/metabolismo , Proteína smad3/genética , Transducción de Señal , Plásmidos/genética , Nanopartículas/química , Nanopartículas/uso terapéutico , Proteína Smad2/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
In addition to transmitting and carrying genetic information, RNA plays an important abiotic role in the world of nanomaterials. RNA is a natural polyanionic biomacromolecule, and its ability to promote osteogenesis by binding with other inorganic materials as an osteogenic induction agent was discovered only recently. However, whether it can promote osseointegration on implants has not been reported. Here, we investigated the effect of the RNA-containing coating materials on peri-implant osseointegration. Total RNA extracted from rat muscle tissue was used as an osteogenic induction agent, and hyaluronic acid (HA) was used to maintain its negative charge. In simulated body fluids (SBF), in vitro studies demonstrated that the resulting material encouraged calcium salt deposition. Cytological experiments showed that the RNA-containing coating induced greater cell adhesion and osteogenic differentiation in comparison to the control. The results of animal experiments showed that the RNA-containing coating had osteoinductive and bone conduction activities, which are beneficial for bone formation and osseointegration. Therefore, the RNA-containing coatings are useful for the surface modification of titanium implants to promote osseointegration.
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Targeting delivery to the infection site and good affinity of vehicle to the bacterial are two main concerns in therapy of bacterial infection, and on-demand release of drug is another important issue. In this work, a liposome drug delivery system (HA/P/BAI-lip) incorporated with baicalein and modified by PHMG and HA was prepared. Several characterizations were conducted to examine the physical properties of liposome. Then it was applied to treatments of MRSA induced dorsal subcutaneous abscess model and the thigh muscle infected model. The presence of guanidine group in HA/P/BAI-lip rendered the liposome satisfactory bacterial target ability and good pH sensitive properties. The lipase secreted by bacterial could promote the hydrolysis of soybean phosphatidylcholine (SPC) in liposome. The modification of HA in HA/P/BAI-lip could lead the drug system to the exact infected site where CD44 was abundant because of inflammation. The low pH microenvironment characteristic of bacterial infection could induce the swelling of liposome following by degradation. Taken together, baicalein could be released selectively at the infected site to exert antibacterial capacity. HA/P/BAI-lip showed impressive antibacterial ability and dramatically decrease the bacterial burden of infection site and alleviate the infiltration of inflammatory cells, facilitating the recovery of infection.
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Antibacterianos , Flavanonas , Ácido Hialurónico , Liposomas , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Liposomas/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Animales , Antibacterianos/farmacología , Antibacterianos/química , Infecciones Estafilocócicas/tratamiento farmacológico , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Flavanonas/farmacología , Flavanonas/química , Flavanonas/administración & dosificación , Ratones , Guanidinas/farmacología , Guanidinas/química , Concentración de Iones de HidrógenoRESUMEN
Various assaults on mitochondria occur during the human aging process, contributing to mitochondrial dysfunction. This mitochondrial dysfunction is intricately connected with aging and diseases associated with it. In vivo, the accumulation of defective mitochondria can precipitate inflammatory and oxidative stress, thereby accelerating aging. Mitophagy, an essential selective autophagy process, plays a crucial role in managing mitochondrial quality control and homeostasis. It is a highly specialized mechanism that systematically removes damaged or impaired mitochondria from cells, ensuring their optimal functioning and survival. By engaging in mitophagy, cells are able to maintain a balanced and stable environment, free from the potentially harmful effects of dysfunctional mitochondria. An ever-growing body of research highlights the significance of mitophagy in both aging and age-related diseases. Nonetheless, the association between mitophagy and inflammation or oxidative stress induced by mitochondrial dysfunction remains ambiguous. We review the fundamental mechanisms of mitophagy in this paper, delve into its relationship with age-related stress, and propose suggestions for future research directions.
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Purpose: Ovarian cancer is a fatal gynecologic malignancy with a high rate of abdominal metastasis. Chemotherapy still has a poor clinical prognosis for ovarian cancer patients, with cell proliferation and angiogenesis leading to invasion, migration, and recurrence. To overcome these obstacles, we constructed a novel HA-modified paclitaxel and diosgenin liposome (PEG-TK-HA-PDLPs) using two novel functional materials, DSPE-PEG2000-HA and DSPE-PEG2000-TK-PEG5000, to specifically deliver the drugs to the tumor site in order to reduce OC cell proliferation and anti-angiogenic generation, thereby inhibiting invasion and migration. Methods and Results: PEG-TK-HA-PDLPs were prepared by film dispersion, with ideal physicochemical properties and exhibits active targeting for enhanced cellular uptake. The ZIP synergy score for PTX and Dios was calculated using the online SynergyFinder software to be 3.15, indicating synergy. In vitro results showed that PEG-TK-HA-PDLPs were highly cytotoxic to ID8 cells, induced ID8 cell apoptosis, and inhibited ID8 cell migration and invasion. In vivo studies showed that PEG-TK-HA-PDLPs could prolong the circulation time in the blood, accumulate significantly in the tumor site, and effectively fight against angiogenesis with significant anti-tumor effects. Conclusion: The production of PEG-TK-HA-PDLPs is an effective strategy for the treatment of OC.
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Apoptosis , Diosgenina , Ácido Hialurónico , Liposomas , Neoplasias Ováricas , Paclitaxel , Polietilenglicoles , Especies Reactivas de Oxígeno , Femenino , Liposomas/química , Liposomas/farmacocinética , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Diosgenina/farmacología , Diosgenina/química , Diosgenina/farmacocinética , Diosgenina/administración & dosificación , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Línea Celular Tumoral , Polietilenglicoles/química , Animales , Especies Reactivas de Oxígeno/metabolismo , Humanos , Apoptosis/efectos de los fármacos , Sinergismo Farmacológico , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , FosfatidiletanolaminasRESUMEN
Plants possess a robust and sophisticated innate immune system against pathogens and must balance growth with rapid pathogen detection and defense. The intracellular receptors with nucleotide-binding leucine-rich repeat (NLR) motifs recognize pathogen-derived effector proteins and thereby trigger the immune response. The expression of genes encoding NLR receptors is precisely controlled in multifaceted ways. The alternative splicing (AS) of introns in response to infection is recurrently observed but poorly understood. Here we report that the potato (Solanum tuberosum) NLR gene RB undergoes AS of its intron, resulting in 2 transcriptional isoforms, which coordinately regulate plant immunity and growth homeostasis. During normal growth, RB predominantly exists as an intron-retained isoform RB_IR, encoding a truncated protein containing only the N-terminus of the NLR. Upon late blight infection, the pathogen induces intron splicing of RB, increasing the abundance of RB_CDS, which encodes a full-length and active R protein. By deploying the RB splicing isoforms fused with a luciferase reporter system, we identified IPI-O1 (also known as Avrblb1), the RB cognate effector, as a facilitator of RB AS. IPI-O1 directly interacts with potato splicing factor StCWC15, resulting in altered localization of StCWC15 from the nucleoplasm to the nucleolus and nuclear speckles. Mutations in IPI-O1 that eliminate StCWC15 binding also disrupt StCWC15 re-localization and RB intron splicing. Thus, our study reveals that StCWC15 serves as a surveillance facilitator that senses the pathogen-secreted effector and regulates the trade-off between RB-mediated plant immunity and growth, expanding our understanding of molecular plant-microbe interactions.
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Empalme Alternativo , Resistencia a la Enfermedad , Regulación de la Expresión Génica de las Plantas , Homeostasis , Enfermedades de las Plantas , Inmunidad de la Planta , Proteínas de Plantas , Solanum tuberosum , Solanum tuberosum/genética , Solanum tuberosum/microbiología , Solanum tuberosum/crecimiento & desarrollo , Solanum tuberosum/inmunología , Solanum tuberosum/metabolismo , Empalme Alternativo/genética , Resistencia a la Enfermedad/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/genética , Inmunidad de la Planta/genética , Phytophthora infestans/patogenicidad , Intrones/genéticaRESUMEN
The individual toxicity of sodium fluoride (NaF) and microplastics (MPs) has been extensively documented. Owing to their high specific surface area, widespread presence and durability, MPs can adsorb a broad spectrum of environmental contaminants into the organism. However, the combined toxicity of NaF and MPs has not been investigated. This study aimed to assess the effects of combined exposure to NaF and MPs on the function of testicular Sertoli cells (SCs) in male mice, and to investigate the underlying molecular mechanisms. The study revealed that combined exposure to NaF and MPs resulted in a decrease in the negative surface charge of MPs, along with an increase in the number of MPs entering the SCs. Through in vivo observation of the testicular pathological structure, spermatogenesis, and cell apoptosis in 180-day-old male mice, we discovered that combined exposure to NaF (80â¯mg/L) and MPs (10â¯mg/L) heightened reproductive toxicity compared to the individual exposure groups. This was evidenced by testicular structural defects, impaired spermatogenesis, and increased testicular cell apoptosis. Our in vitro studies showed that NaF (21⯵g/mL) and MPs (100⯵g/mL) synergistically induced SCs apoptosis and ferroptosis, leading to a reduction in SCs number and dysfunction. This ultimately resulted in structural and functional damage to the testes. Our findings demonstrate, for the first time, the synergistic effects of NaF and MPs on reproductive toxicity in mammals. These insights may provide valuable contributions to co-toxicity studies involving MPs and other environmental pollutants.
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Apoptosis , Ferroptosis , Células de Sertoli , Fluoruro de Sodio , Animales , Masculino , Células de Sertoli/efectos de los fármacos , Células de Sertoli/patología , Apoptosis/efectos de los fármacos , Fluoruro de Sodio/toxicidad , Ratones , Ferroptosis/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacos , Testículo/patología , Contaminantes Ambientales/toxicidadRESUMEN
Introduction: Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that involves synovitis, cartilage destruction, and even joint damage. Traditional agents used for RA therapy remain unsatisfactory because of their low efficiency and obvious adverse effects. Therefore, we here established RA microenvironment-responsive targeted micelles that can respond to the increase in reactive oxygen species (ROS) levels in the joint and improve macrophage-specific targeting of loaded drugs. Methods: We here prepared ROS-responsive folate-modified curcumin micelles (TK-FA-Cur-Ms) in which thioketal (TK) was used as a ROS-responsive linker for modifying polyethylene glycol 5000 (PEG5000) on the micellar surface. When micelles were in the ROS-overexpressing inflammatory microenvironment, the PEG5000 hydration layer was shed, and the targeting ligand FA was exposed, thereby enhancing cellular uptake by macrophages through active targeting. The targeting, ROS sensitivity and anti-inflammatory properties of the micelles were assessed in vitro. Collagen-induced arthritis (CIA) rats model was utilized to investigate the targeting, expression of serum inflammatory factors and histology change of the articular cartilage by micelles in vivo. Results: TK-FA-Cur-Ms had a particle size of 90.07 ± 3.44 nm, which decreased to 78.87 ± 2.41 nm after incubation with H2O2. The micelles exhibited in vitro targeting of RAW264.7 cells and significantly inhibited inflammatory cytokine levels. Pharmacodynamic studies have revealed that TK-FA-Cur-Ms prolonged the drug circulation and exhibited augmented cartilage-protective and anti-inflammatory effects in vivo. Conclusion: The unique ROS-responsive targeted micelles with targeting, ROS sensitivity and anti-inflammatory properties were successfully prepared and may offer an effective therapeutic strategy against RA.
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Artritis Reumatoide , Curcumina , Receptores de Folato Anclados a GPI , Micelas , Especies Reactivas de Oxígeno , Animales , Masculino , Ratones , Ratas , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Curcumina/administración & dosificación , Curcumina/química , Curcumina/farmacología , Modelos Animales de Enfermedad , Portadores de Fármacos/química , Receptores de Folato Anclados a GPI/metabolismo , Ácido Fólico/química , Ácido Fólico/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Tamaño de la Partícula , Polietilenglicoles/química , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Oxidative stress and neuroinflammation in the aging brain are correlated with the development of neurodegenerative diseases, such as Alzheimer's disease (AD). The blood-brain barrier (BBB) poses a significant challenge to the effective delivery of therapeutics for AD. Prior research has demonstrated that menthol (Men) can augment the permeability of the BBB. Consequently, in the current study, we modified Men on the surface of liposomes to construct menthol-modified quercetin liposomes (Men-Qu-Lips), designed to cross the BBB and enhance quercetin (Qu) concentration in the brain for improved therapeutic efficacy. The experimental findings indicate that Men-Qu-Lips exhibited good encapsulation efficiency and stability, successfully crossed the BBB, improved oxidative stress and neuroinflammation in the brains of aged mice, protected neurons, and enhanced their learning and memory abilities.
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Enfermedad de Alzheimer , Barrera Hematoencefálica , Encéfalo , Liposomas , Mentol , Quercetina , Quercetina/farmacología , Quercetina/administración & dosificación , Quercetina/química , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ratones , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Mentol/farmacología , Mentol/administración & dosificación , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Masculino , Envejecimiento/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
The reconstruction of bone defects has been associated with severe challenges worldwide. Nowadays, bone marrow mesenchymal stem cell (BMSC)-based cell sheets have rendered this approach a promising way to facilitate osteogenic regeneration in vivo. Extracellular vesicles (EVs) play an essential role in intercellular communication and execution of various biological functions and are often employed as an ideal natural endogenous nanomedicine for restoring the structure and functions of damaged tissues. The perception of polymorphonuclear leukocytes (neutrophils, PMNs) as indiscriminate killer cells is gradually changing, with new evidence suggesting a role for these cells in tissue repair and regeneration, particularly in the context of bone healing. However, the role of EVs derived from PMNs (PMN-EVs) in bone regeneration remains largely unknown, with limited research being conducted on this aspect. In the current study, we investigated the effects of PMN-EVs on BMSCs and the underlying molecular mechanisms as well as the potential application of PMN-EVs in bone regeneration. Toward this end, BMSC-based cell sheets with integrated PMN-EVs (BS@PMN-EVs) were developed for bone defect regeneration. PMN-EVs were found to significantly enhance the proliferation and osteogenic differentiation of BMSCs in vitro. Furthermore, BS@PMN-EVs were found to significantly accelerate bone regeneration in vivo by enhancing the maturation of the newly formed bone in rat calvarial defects; this is likely attributable to the effect of PMN-EVs in promoting the expression of key osteogenic proteins such as SOD2 and GJA1 in BMSCs. In conclusion, our findings demonstrate the crucial role of PMN-EVs in promoting the osteogenic differentiation of BMSCs during bone regeneration. Furthermore, this study proposes a novel strategy for enhancing bone repair and regeneration via the integration of PMN-EVs with BMSC-based cell sheets.
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Regeneración Ósea , Diferenciación Celular , Vesículas Extracelulares , Células Madre Mesenquimatosas , Neutrófilos , Osteogénesis , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/fisiología , Vesículas Extracelulares/trasplante , Regeneración Ósea/fisiología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/fisiología , Animales , Neutrófilos/metabolismo , Neutrófilos/fisiología , Neutrófilos/citología , Ratas , Ratas Sprague-Dawley , Masculino , Proliferación Celular , HumanosRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, leading to severe inflammatory infiltration and joint damage, accompanied by a decrease in pH of joint microenvironment. Macrophages play an important role in the pathogenesis of RA, with high expression of bovine serum albumin (BSA) receptors on the surface of macrophages. Resveratrol (Res) has strong anti-inflammatory effects, but its application is limited due to its poor water solubility and low bioavailability. Therefore, we constructed pH-sensitive micelles by encapsulating Res and modifying BSA on the surface of the micelles (BSA-Res@Ms), thereby greatly improving the therapeutic effect of RA. Our research results indicated that BSA-Res@Ms had a smooth and uniform appearance, small particle size, high drug encapsulation efficiency, good stability, and pH-sensitive properties. In vitro, BSA-Res@Ms increased the uptake of Res by RAW264.7 cells, reduced the levels of pro-inflammatory cytokines and cleared excess ROS produced by activated RAW264.7 cells, and inhibited the generation of osteoclasts. In vivo, BSA-Res@Ms could target inflamed joint sites, significantly alleviate joint inflammation symptoms, inhibit activated macrophages, improve synovial hyperplasia and inflammatory cell infiltration, and protect cartilage. BSA-Res@Ms provide a very promising method for the treatment of RA, which can effectively improve the inflammatory manifestations of RA.
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Artritis Reumatoide , Macrófagos , Micelas , Resveratrol , Albúmina Sérica Bovina , Resveratrol/farmacología , Resveratrol/uso terapéutico , Resveratrol/química , Animales , Albúmina Sérica Bovina/química , Ratones , Células RAW 264.7 , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Artritis Reumatoide/tratamiento farmacológico , Concentración de Iones de Hidrógeno , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/química , Citocinas/metabolismo , Humanos , Portadores de Fármacos/químicaRESUMEN
Bone regeneration remains a major clinical challenge, especially when infection necessitates prolonged antibiotic treatment. This study presents a membrane composed of self-assembled and interpenetrating GL13K, an antimicrobial peptide (AMP) derived from a salivary protein, in a collagen membrane for antimicrobial activity and enhanced bone regeneration. Commercially available collagen membranes were immersed in GL13K solution, and self-assembly was initiated by raising the solution pH to synthesize the multifunctional membrane called COL-GL. COL-GL was composed of interpenetrating large collagen fibers and short GL13K nanofibrils, which increased hydrophobicity, reduced biodegradation from collagenase, and stiffened the matrix compared to control collagen membranes. Incorporation of GL13K led to antimicrobial and anti-fouling activity against early oral surface colonizer Streptococcus gordonii while not affecting fibroblast cytocompatibility or pre-osteoblast osteogenic differentiation. GL13K in solution also reduced macrophage inflammatory cytokine expression and increased pro-healing cytokine expression. Bone formation in a rat calvarial model was accelerated at eight weeks with COL-GL compared to the gold-standard collagen membrane based on microcomputed tomography and histology. Interpenetration of GL13K within collagen sidesteps challenges with antimicrobial coatings on bone regeneration scaffolds while increasing bone regeneration. This strength makes COL-GL a promising approach to reduce post-surgical infections and aid bone regeneration in dental and orthopedic applications. STATEMENT OF SIGNIFICANCE: The COL-GL membrane, incorporating the antimicrobial peptide GL13K within a collagen membrane, signifies a noteworthy breakthrough in bone regeneration strategies for dental and orthopedic applications. By integrating self-assembled GL13K nanofibers into the membrane, this study successfully addresses the challenges associated with antimicrobial coatings, exhibiting improved antimicrobial and anti-fouling activity while preserving compatibility with fibroblasts and pre-osteoblasts. The accelerated bone formation observed in a rat calvarial model emphasizes the potential of this innovative approach to minimize post-surgical infections and enhance bone regeneration outcomes. As a promising alternative for future therapeutic interventions, this material tackles the clinical challenges of extended antibiotic treatments and antibiotic resistance in bone regeneration scenarios.
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Péptidos Antimicrobianos , Regeneración Ósea , Colágeno , Membranas Artificiales , Nanofibras , Regeneración Ósea/efectos de los fármacos , Animales , Ratas , Nanofibras/química , Colágeno/química , Péptidos Antimicrobianos/química , Péptidos Antimicrobianos/farmacología , Osteogénesis/efectos de los fármacos , Ratones , Osteoblastos/efectos de los fármacos , Streptococcus gordonii/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Fibroblastos/efectos de los fármacosRESUMEN
Stem cells remain in a quiescent state for long-term maintenance and preservation of potency; this process requires fine-tuning regulatory mechanisms. In this study, we identified the epigenetic landscape along the developmental trajectory of skeletal stem cells (SSCs) in skeletogenesis governed by a key regulator, Ptip (also known as Paxip1, Pax interaction with transcription-activation domain protein-1). Our results showed that Ptip is required for maintaining the quiescence and potency of SSCs, and loss of Ptip in type II collagen (Col2)+ progenitors causes abnormal activation and differentiation of SSCs, impaired growth plate morphogenesis, and long bone dysplasia. We also found that Ptip suppressed the glycolysis of SSCs through downregulation of phosphoglycerate kinase 1 (Pgk1) by repressing histone H3 lysine 27 acetylation (H3K27ac) at the promoter region. Notably, inhibition of glycolysis improved the function of SSCs despite Ptip deficiency. To the best of our knowledge, this is the first study to establish an epigenetic framework based on Ptip, which safeguards skeletal stem cell quiescence and potency through metabolic control. This framework is expected to improve SSC-based treatments of bone developmental disorders.
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Diferenciación Celular , Epigénesis Genética , Glucólisis , Células Madre , Animales , Ratones , Glucólisis/genética , Células Madre/metabolismo , Diferenciación Celular/genética , Histonas/metabolismo , Osteogénesis/genética , Desarrollo Óseo/genética , Acetilación , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismoRESUMEN
The process of reconstructing an arterial graft is a complex and dynamic process that is subject to the influence of various mechanical factors, including tissue regeneration and blood pressure. The attainment of favorable remodeling outcomes is contingent upon the biocompatibility and biomechanical properties of the arterial graft. A promising strategy involves the emulation of the three-layer structure of the native artery, wherein the inner layer is composed of polycaprolactone (PCL) fibers aligned with blood flow, exhibiting excellent biocompatibility that fosters endothelial cell growth and effectively prevents platelet adhesion. The middle layer, consisting of PCL and polyurethane (PU), offers mechanical support and stability by forming a contractile smooth muscle ring and antiexpansion PU network. The outer layer, composed of PCL fibers with an irregular arrangement, promotes the growth of nerves and pericytes for long-term vascular function. Prioritizing the reconstruction of the inner and outer layers establishes a stable environment for intermediate smooth muscle growth. Our three-layer arterial graft is designed to provide the blood vessel with mechanical support and stability through nondegradable PU, while the incorporation of degradable PCL generates potential spaces for tissue ingrowth, thereby transforming our graft into a living implant.
RESUMEN
The establishment of an osseointegration is crucial for the long-term stability and functionality of implant materials, and early angiogenesis is the key to successful osseointegration. However, the bioinertness of titanium implants affects osseointegration, limiting their clinical application. In this study, inspired by the rapid polarization of macrophages following the phagocytosis of bacteria, we developed bacteroid cerium oxide particles; these particles were composed of CeO2 and had a size similar to that of Bacillus (0.5 µ m). These particles were constructed on the implant surfaces using a hydrothermal method. In vitro experiments demonstrated that the particles effectively decreased the reactive oxygen species (ROS) levels in macrophages (RAW264.7). Furthermore, these particles exerted effects on M1 macrophage polarization, enhanced nitric oxide (NO) secretion to promote vascular regeneration, and facilitated rapid macrophage transition to the M2 phenotype. Subsequently, the particles facilitated human umbilical vein endothelial cell (HUVEC) migration. In vivo studies showed that these particles rapidly stimulated innate immune responses in animal models, leading to enhanced angiogenesis around the implant and improved osseointegration. In summary, the presence of bacteroid cerium oxide particles on the implant surface regulated and accelerated macrophage polarization, thereby enhancing angiogenesis during the immune response and improving peri-implant osseointegration.
Asunto(s)
Cerio , Oseointegración , Animales , Humanos , Macrófagos , Cerio/farmacología , Inmunidad Innata , Neovascularización Patológica , Titanio , Osteogénesis , Propiedades de SuperficieRESUMEN
Totally extraperitoneal prosthetic (TEP) is a surgical technique for the treatment of hernia. The purpose of this research is to compare the efficacy of both general anaesthesia and spine anaesthesia for TEP herniorrhaphy. The number of patients who received TEP operations related to the injury from 2008 to 2022 was counted in this study. Patients with TEP operation were classified into general anaesthesia and spine anaesthesia. In this research, 186 related articles were found in the data base, and in the end, 8 were analysed. This study involved 2452 cases of hernia. The data of the operation time, the infection of the wound and the bleeding of the wound were analysed. The analysis of the data was done with RevMan 5.3. Results indicated that there was no significant difference between general anaesthesia and spinal anaesthesia in post-surgical rates for post-operative wound infection (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.49-1.83; p = 0.86); In general anaesthesia, there was no difference in the risk of post-operative wound haematoma when compared with those treated with spinal anaesthesia (OR, 2.96; 95% CI, 0.37-23.69; p = 0.31). In the seven trials, there was no difference in the duration of the surgery between the general anaesthetic and the spinal anaesthesia group (mean difference, -1.44; 95% CI, -4.11 to 1.22; p = 0.29). Data from the available meta-analysis indicate that there is no difference in the risk of post-operative wound infection or wound haematoma when treated with TEP.