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BACKGROUND: Pancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer. METHODS: In the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T. RESULTS: We found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48-72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal. CONCLUSIONS: In this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.
Subject(s)
B7 Antigens , Immunotherapy, Adoptive , Pancreatic Neoplasms , Receptors, Chimeric Antigen , Pancreatic Neoplasms/therapy , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Humans , Animals , Cell Line, Tumor , Receptors, Chimeric Antigen/metabolism , Receptors, Chimeric Antigen/immunology , Immunotherapy, Adoptive/methods , B7 Antigens/metabolism , B7 Antigens/immunology , Xenograft Model Antitumor Assays , Mice , Cell Proliferation , T-Lymphocytes/immunologyABSTRACT
Periodontitis, a chronic oral disease instigated by bacteria, severely compromises human oral health. The prevailing clinical treatment for periodontitis involves mechanical scraping in conjunction with antibiotics. Phototherapy is employed to rapidly remove the bacteria and achieve periodontitis treatment, effectively circumventing the adverse effects associated with traditional therapies. Constructing 2D/2D van der Waals (VDW) heterojunctions is a key strategy for obtaining excellent photocatalytic activity. Herein, a 2D/2D violet phosphorus (VP)/Ti3C2 VDW heterojunction is designed using an interfacial engineering strategy. By constructing an electron transport "bridge" (P-Ti bond) at the heterogeneous interface as an effective transfer channel for photogenerated carriers, a compact monolithic structure between the VP and Ti3C2 phases is formed, and the spatial barrier for electron transfer at the interface is eliminated. Meanwhile, the strong directional built-in electric field induced by the intensive electron-coupling effect at the heterogeneous interface served as an internal driving force, which greatly accelerates the exciton dissociation and charge transfer in the photocatalytic process. These excited photogenerated electrons and holes are trapped by O2 and H2O on the surfaces of Ti3C2 and VP, respectively, and are subsequently catalytically converted to antibacterial reactive oxygen species (ROS). The VP/Ti3C2 VDW heterojunction eradicated 97.5% and 98.48% of Staphylococcus aureus and Escherichia coli, respectively, by photocatalytic and photothermal effects under visible light for 10 min. The VP/Ti3C2 nanoperiodontal dressing ointment effectively attenuated inflammatory response, reduced alveolar bone resorption, and promoted periodontal soft and hard tissue repair. Its periodontitis therapeutic effect outperforms the clinically used Periocline.
Subject(s)
Periodontitis , Phosphorus , Titanium , Periodontitis/microbiology , Periodontitis/therapy , Phosphorus/chemistry , Titanium/chemistry , Phototherapy , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Humans , Staphylococcus aureus/drug effects , Escherichia coli , Electricity , Reactive Oxygen Species/metabolism , Reactive Oxygen Species/chemistry , Surface Properties , Animals , Electron Transport , Microbial Sensitivity TestsABSTRACT
Plants that grow in extreme environments represent unique sources of stress-resistance genes and mechanisms. Ammopiptanthus mongolicus (Leguminosae) is a xerophytic evergreen broadleaf shrub native to semi-arid and desert regions; however, its drought-tolerance mechanisms remain poorly understood. Here, we report the assembly of a reference-grade genome for A. mongolicus, describe its evolutionary history within the legume family, and examine its drought-tolerance mechanisms. The assembled genome is 843.07 Mb in length, with 98.7% of the sequences successfully anchored to the nine chromosomes of A. mongolicus. The genome is predicted to contain 47 611 protein-coding genes, and 70.71% of the genome is composed of repetitive sequences; these are dominated by transposable elements, particularly long-terminal-repeat retrotransposons. Evolutionary analyses revealed two whole-genome duplication (WGD) events at 130 and 58 million years ago (mya) that are shared by the genus Ammopiptanthus and other legumes, but no species-specific WGDs were found within this genus. Ancestral genome reconstruction revealed that the A. mongolicus genome has undergone fewer rearrangements than other genomes in the legume family, confirming its status as a "relict plant". Transcriptomic analyses demonstrated that genes involved in cuticular wax biosynthesis and transport are highly expressed, both under normal conditions and in response to polyethylene glycol-induced dehydration. Significant induction of genes related to ethylene biosynthesis and signaling was also observed in leaves under dehydration stress, suggesting that enhanced ethylene response and formation of thick waxy cuticles are two major mechanisms of drought tolerance in A. mongolicus. Ectopic expression of AmERF2, an ethylene response factor unique to A. mongolicus, can markedly increase the drought tolerance of transgenic Arabidopsis thaliana plants, demonstrating the potential for application of A. mongolicus genes in crop improvement.
Subject(s)
Droughts , Fabaceae , Genome, Plant , Fabaceae/genetics , Fabaceae/physiology , Stress, Physiological/genetics , Evolution, Molecular , Gene Expression Regulation, Plant , PhylogenyABSTRACT
OBJECTIVES: We aim to develop a deep learning model based on a convolutional neural network (CNN) combined with a classification algorithm (CA) to assist dentists in quickly and accurately diagnosing the stage of periodontitis. MATERIALS AND METHODS: Periapical radiographs (PERs) and clinical data were collected. The CNNs including Alexnet, VGG16, and ResNet18 were trained on PER to establish the PER-CNN models for no periodontal bone loss (PBL) and PBL. The CAs including random forest (RF), support vector machine (SVM), naive Bayes (NB), logistic regression (LR), and k-nearest neighbor (KNN) were added to the PER-CNN model for control, stage I, stage II and stage III/IV periodontitis. Heat map was produced using a gradient-weighted class activation mapping method to visualize the regions of interest of the PER-Alexnet model. Clustering analysis was performed based on the ten PER-CNN scores and the clinical characteristics. RESULTS: The accuracy of the PER-Alexnet and PER-VGG16 models with the higher performance was 0.872 and 0.853, respectively. The accuracy of the PER-Alexnet + RF model with the highest performance for control, stage I, stage II and stage III/IV was 0.968, 0.960, 0.835 and 0.842, respectively. Heat map showed that the regions of interest predicted by the model were periodontitis bone lesions. We found that age and smoking were significantly related to periodontitis based on the PER-Alexnet scores. CONCLUSION: The PER-Alexnet + RF model has reached high performance for whole-case periodontal diagnosis. The CNN models combined with CA can assist dentists in quickly and accurately diagnosing the stage of periodontitis.
Subject(s)
Algorithms , Neural Networks, Computer , Periodontitis , Humans , Periodontitis/diagnostic imaging , Female , Male , Middle Aged , Adult , Radiography, Dental , Deep Learning , Bayes TheoremABSTRACT
Osteomyelitis is primarily caused by bacterial infections, and treatment requires precise sequential therapy, including antibacterial therapy in the early stages and bone defect reconstruction in later stages. We aimed to synthesize core-shell-structured zinc oxide/silver sulfide heterogeneous nanoparticles (ZnO/Ag2S NPs) using wet chemical methods. Using density functional theory and ultraviolet photoelectron spectroscopy, we showed that the optimized band structure endowed ZnO/Ag2S NPs with photodynamic properties under near-infrared (NIR) irradiation. Moreover, ZnO/Ag2S NPs exhibited a distinguished and stable photothermal performance within the same wavelength range. With single-wavelength irradiation, ZnO/Ag2S NPs achieved a bifunctional antibacterial effect during the acute stage of osteomyelitis. Antibacterial action was confirmed through colony-forming unit (CFU) counting assays, scanning electronic microscopy (SEM) observations, live-dead staining, growth curves, and quantitative real-time polymerase chain reaction (qPCR) assays. The Ag2S coating on the NPs realized the sustained release of zinc ions, thereby controlling the zinc ion concentration. Alkaline phosphatase (ALP) staining, alizarin red S (ARS) staining, and qPCR assays confirmed that the ZnO/Ag2S NPs exhibited good osteogenic effects in vitro. These effects were verified in an in vivo mouse femur model during chronic stages using micro-computed tomography (micro-CT) and histological analysis. This study provides a novel biocompatible core-shell nanomaterial for the two-phase treatment of osteomyelitis, contributing to versatile nanotherapies for infections and inflammation.
Subject(s)
Metal Nanoparticles , Nanoparticles , Osteomyelitis , Silver Compounds , Zinc Oxide , Animals , Mice , Zinc Oxide/pharmacology , Zinc Oxide/chemistry , X-Ray Microtomography , Metal Nanoparticles/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Zinc , Osteomyelitis/diagnostic imaging , Osteomyelitis/drug therapyABSTRACT
In the context of bone regeneration, nanoparticles harboring osteogenic factors have emerged as pivotal agents for modulating the differentiation fate of stem cells. However, persistent challenges surrounding biocompatibility, loading efficiency, and precise targeting ability warrant innovative solution. In this study, a novel nanoparticle platform founded upon the zeolitic imidazolate framework-8 (ZIF-8) is introduced. This new design, CDC20@ZIF-8@eM-Apt, involves the envelopment of ZIF-8 within an erythrocyte membrane (eM) cloak, and is coupled with a targeting aptamer. ZIF-8, distinguished by its porosity, biocompatibility, and robust cargo transport capabilities, constitutes the core framework. Cell division cycle protein 20 homolog (CDC20) is illuminated as a new target in bone regeneration. The eM plays a dual role in maintaining nanoparticle stability and facilitating fusion with target cell membranes, while the aptamer orchestrates the specific recruitment of bone marrow mesenchymal stem cells (BMSCs) within bone defect sites. Significantly, CDC20@ZIF-8@eM-Apt amplifies osteogenic differentiation of BMSCs via the inhibition of NF-κB p65, and concurrently catalyzes bone regeneration in two bone defect models. Consequently, CDC20@ZIF-8@eM-Apt introduces a pioneering strategy for tackling bone defects and associated maladies, opening novel avenues in therapeutic intervention.
Subject(s)
Nanoparticles , Zeolites , Osteogenesis , Erythrocyte Membrane , Bone Regeneration/physiologyABSTRACT
Colloidal gold nanorods (GNRs) have demonstrated their potential to absorb light within specific wavelength bands and induce photothermal effects. However, the unpredictability and lack of adjustability in the broadband spectrum formed by the self-assembly of gold nanospheres or the coupling of various sizes of GNRs have posed significant challenges. To address this, we have developed broadband GNRs (BGNRs) with a predictable and adjustable extinction band in the visible and near-infrared regions. The BGNRs were synthesized by simply mixing GNRs with different aspect ratios, allowing for control over the bandwidths and positions of the extinction bands. Subsequently, the BGNRs were coated with silica and underwent surface modification. The resulting BGNRs@SiO2were then mixed with either polydimethylsiloxane (PDMS) or polyvinylidene fluoride (PVDF) to create BGNRs@SiO2/PDMS (or PVDF) films. The BGNRs@SiO2/PDMS and BGNRs@SiO2/PVDF films both exhibit excellent photothermal performance properties. Additionally, the light absorption intensity of the BGNRs@SiO2/PVDF film linearly increases upon folding, leading to significantly enhanced photothermal performance after folding. This work demonstrates that plasmonic colloidal GNRs, without the need for coupling, can yield predictable and adjustable extinction bands. This finding holds great promise for future development and practical applications, particularly in the transfer of these properties to films.
ABSTRACT
In the original publication [...].
ABSTRACT
The plasmonic nanoparticle components assembled by certain methods have great application potential in single particle scattering and surface-enhanced Raman spectroscopy (SERS) detection. Gold nanorods (GNRs) are a type of promising plasmonic material for nanoparticle assembly due to their large, shape-induced local field enhancement and tunable surface plasmon resonances (SPRs). However, it is difficult to obtain the spectra of the anticipated bandwidth and shape, due to the coupling effect between the GNRs and the concentration of GNRs with different SPRs. In this paper, a superparticle assembly method with predictable spectral bandwidth and shape prepared by batch gradient descent (BGD) algorithm fitting and emulsion method is proposed. Specifically, broadband GNRs were obtained by mixing 6 types of GNRs, which the ratios were determined by a BGD algorithm. Then the superparticles were prepared by a method of oil-in-water emulsion with solvent evaporation, resulting in superparticles with broadband spectra from 700 nm to 1100 nm. The bandwidth and shape of the spectra could be tuned by changing the concentration of GNRs of different LSPRs. After removing the CTAB template of mesoporous silica, the assembled broadband superparticles can also measure SERS enhancement for the lipophilic dye molecule Nile red, which opens up a broad space for its sensing application.
ABSTRACT
Periodontitis is a chronic inflammatory disease characterized by the colonization of pathogenic microorganisms and the loss of periodontal supporting tissue. However, the existing local drug delivery system for periodontitis has some problems including subpar antibacterial impact, easy loss, and unsatisfactory periodontal regeneration. In this study, a multi-functional and sustained release drug delivery system (MB/BG@LG) was developed by encapsulating methylene blue (MB) and bioactive glass (BG) into the lipid gel (LG) precursor by Macrosol technology. The properties of MB/BG@LG were characterized using a scanning electron microscope, a dynamic shear rotation rheometer, and a release curve. The results showed that MB/BG@LG could not only sustained release for 16 days, but also quickly fill the irregular bone defect caused by periodontitis through in situ hydration. Under 660 ânm light irradiation, methylene blue-produced reactive oxygen species (ROS) can reduce local inflammatory response by inhibiting bacterial growth. In addition, in vitro and vivo experiments have shown that MB/BG@LG can effectively promote periodontal tissue regeneration by reducing inflammatory response, promoting cell proliferation and osteogenic differentiation. In summary, MB/BG@LG exhibited excellent adhesion properties, self-assembly properties, and superior drug release control capabilities, which improved the clinical feasibility of its application in complex oral environments.
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Individuals have known that Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway was involved in the growth of the cell, cell differentiation courses advancement, immune cellular survival, as well as hematopoietic system advancement. Researches in the animal models have already uncovered a JAK/STAT regulatory function in myocardial ischemia-reperfusion injury (MIRI), acute myocardial infarction (MI), hypertension, myocarditis, heart failure, angiogenesis and fibrosis. Evidences originating in these studies indicate a therapeutic JAK/STAT function in cardiovascular diseases (CVDs). In this retrospection, various JAK/STAT functions in the normal and ill hearts were described. Moreover, the latest figures about JAK/STAT were summarized under the background of CVDs. Finally, we discussed the clinical transformation prospects and technical limitations of JAK/STAT as the potential therapeutic targets for CVDs. This collection of evidences has essential meanings for the clinical application of JAK/STAT as medicinal agents for CVDs. In this retrospection, various JAK/STAT functions in the normal and ill hearts were described. Moreover, the latest figures about JAK/STAT were summarized under the background of CVDs. Finally, we discussed the clinical transformation prospects and toxicity of JAK/STAT inhibitors as potential therapeutic targets for CVDs. This collection of evidences has essential meanings for the clinical application of JAK/STAT as medicinal agents for CVDs.
Subject(s)
Cardiovascular Diseases , Myocardial Infarction , Animals , Janus Kinases/metabolism , Cardiovascular Diseases/drug therapy , Signal Transduction/physiology , Myocardial Infarction/metabolism , HeartABSTRACT
Colletotrichum gloeosporioides, a significant fungal pathogen of crops and trees, causes large economic losses worldwide. However, its pathogenic mechanism remains totally unclear. In this study, four Ena ATPases (Exitus natru-type adenosine triphosphatases), homology of yeast Ena proteins, were identified in C. gloeosporioides. Gene deletion mutants of ΔCgena1, ΔCgena2, ΔCgena3, and ΔCgena4 were obtained through the method of gene replacement. First, a subcellular localization pattern indicated that CgEna1 and CgEna4 were localized in the plasma membrane, while the CgEna2 and CgEna3 were distributed in the endoparasitic reticulum. Next, it was found that CgEna1 and CgEna4 were required for sodium accumulation in C. gloeosporioides. CgEna3 was required for extracellular ion stress of sodium and potassium. CgEna1 and CgEna3 were involved in conidial germination, appressorium formation, invasive hyphal development, and full virulence. The mutant of ΔCgena4 was more sensitive to the conditions of high concentrations of ion and the alkaline. Together, these results indicated that CgEna ATPase proteins have distinct roles in sodium accumulation, stress resistance, and full virulence in C. gloeosporioides.
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Although meropenem, colistin, and tigecycline are recognized as the last-line antibiotics for multidrug-resistant Gram-negative bacteria (MDR-GN), the emergence of mobile resistance genes such as blaNDM, mcr, and tet(X) severely compromises their clinical effectiveness. Developing novel antibiotic adjuvants to restore the effectiveness of existing antibiotics provides a feasible approach to address this issue. Herein, we discover that a Food and Drug Administration (FDA)-approved drug daunorubicin (DNR) drastically potentiates the activity of last-resort antibiotics against MDR-GN pathogens and biofilm-producing bacteria. Furthermore, DNR effectively inhibits the evolution and spread of colistin and tigecycline resistance. Mechanistically, DNR and colistin combination exacerbates membrane disruption, induces DNA damage and the massive production of reactive oxygen species (ROS), ultimately leading to bacterial cell death. Importantly, DNR restores the effectiveness of colistin in Galleria mellonella and murine models of infection. Collectively, our findings provide a potential drug combination strategy for treating severe infections elicited by Gram-negative superbugs.
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Cyclodextrins (CyDs) in nano drug delivery systems have received much attention in pursuit of good compatibility, negligible toxicity, and improved pharmacokinetics of drugs. Their unique internal cavity has widened the application of CyDs in drug delivery based on its advantages. Besides this, the polyhydroxy structure has further extended the functions of CyDs by inter- and intramolecular interactions and chemical modification. Furthermore, the versatile functions of the complex contribute to alteration of the physicochemical characteristics of the drugs, significant therapeutic promise, a stimulus-responsive switch, a self-assembly capability, and fiber formation. This review attempts to list recent interesting strategies regarding CyDs and discusses their roles in nanoplatforms, and may act as a guideline for developing novel nanoplatforms. Future perspectives on the construction of CyD-based nanoplatforms are also discussed at the end of this review, which may provide possible direction for the construction of more rational and cost-effective delivery vehicles.
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Unbalanced protein homeostasis (proteostasis) networks are frequently linked to tumorigenesis, making cancer cells more susceptible to treatments that target proteostasis regulators. Proteasome inhibition is the first licensed proteostasis-targeting therapeutic strategy, and has been proven effective in hematological malignancy patients. However, drug resistance almost inevitably develops, pressing for a better understanding of the mechanisms that preserve proteostasis in tumor cells. Here we report that CD317, a tumor-targeting antigen with a unique topology, was upregulated in hematological malignancies and preserved proteostasis and cell viability in response to proteasome inhibitors (PIs). Knocking down CD317 lowered Ca2+ levels in the endoplasmic reticulum (ER), promoting PIs-induced proteostasis failure and cell death. Mechanistically, CD317 interacted with calnexin (CNX), an ER chaperone protein that limits calcium refilling via the Ca2+ pump SERCA, thereby subjecting CNX to RACK1-mediated autophagic degradation. As a result, CD317 decreased the level of CNX protein, coordinating Ca2+ uptake and thus favoring protein folding and quality control in the ER lumen. Our findings reveal a previously unrecognized role of CD317 in proteostasis control and imply that CD317 could be a promising target for resolving PIs resistance in the clinic.
Subject(s)
Bone Marrow Stromal Antigen 2 , Proteasome Inhibitors , Proteostasis , Humans , Calnexin/metabolism , Cell Survival , Molecular Chaperones/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Proteasome Inhibitors/pharmacology , Receptors for Activated C Kinase/genetics , Receptors for Activated C Kinase/metabolism , Bone Marrow Stromal Antigen 2/genetics , Bone Marrow Stromal Antigen 2/metabolismABSTRACT
Bioceramic scaffolds used in bone tissue engineering suffer from a low concentration of ceramic particles (<50 wt%), because the high concentration of ceramic particles increases the brittleness of the composite. 3D printed flexible PCL/HA scaffolds with high ceramic particle concentrations (84 wt%) were successfully fabricated in this study. However, the hydrophobicity of PCL weakens the composite scaffold hydrophilicity, which may limit the osteogenic ability to some extent. Thus, as a less time-consuming, less labour intensive, and more cost-effective treatment method, alkali treatment (AT) was employed to modify the surface hydrophilicity of the PCL/HA scaffold, and its regulation of immune responses and bone regeneration were investigated in vivo and in vitro. Initially, several concentrations of NaOH (0.5, 1, 1.5, 2, 2.5, and 5 mol L-1) were employed in tests to determine the appropriate concentration for AT. Based on the comprehensive consideration of the results of mechanical experiments and hydrophilicity, 2 mol L-1 and 2.5 mol L-1 of NaOH were selected for further investigation in this study. The PCL/HA-AT-2 scaffold dramatically reduced foreign body reactions as compared to the PCL/HA and PCL/HA-AT-2.5 scaffolds, promoted macrophage polarization towards the M2 phenotype and enhanced new bone formation. The Wnt/ß-catenin pathway might participate in the signal transduction underlying hydrophilic surface-modified 3D printed scaffold-regulated osteogenesis, according to the results of immunohistochemical staining. In conclusion, hydrophilic surface-modified 3D printed flexible scaffolds with high ceramic particle concentrations can regulate the immune reactions and macrophage polarization to promote bone regeneration, and the PCL/HA-AT-2 scaffold is a potential candidate for bone tissue repair.
Subject(s)
Tissue Scaffolds , Bone Regeneration , Ceramics , Hydrophobic and Hydrophilic Interactions , Osteogenesis , Printing, Three-Dimensional , Sodium Hydroxide , Tissue Engineering/methodsABSTRACT
Angiogenesis occurred after myocardial infarction (MI) protects heart failure (HF). The aim of our study was to explore function of histone methyltransferase KMT2D (MLL4, mixed-lineage leukemia 4) in angiogenesis post-MI. Western blotting showed that KMT2D protein expression was elevated in MI mouse myocardial. Cardiomyocyte-specific Kmt2d-knockout (Kmt2d-cKO) mice were generated, and echocardiography and immunofluorescence staining detected significantly attenuated cardiac function and insufficient angiogenesis following MI in Kmt2d-cKO mice. Cross-talk assay suggested that Kmt2d-KO H9c2-derived conditioned medium attenuates EA.hy926 EC function. ELISA further identified that VEGF-A released from Kmt2d-KO H9c2 was significantly reduced. CUT&Tag and RT-qPCR revealed that KMT2D deficiency reduced Vegf-a mRNA expression and enrichment of H3K4me1 on the Vegf-a promoter. Moreover, KMT2D silencing in ECs also suppressed endothelial function. Our study indicates that KMT2D depletion in both cardiomyocytes and ECs attenuates angiogenesis and that loss of KMT2D exacerbates heart failure after MI in mice.
Subject(s)
Heart Failure , Myocardial Infarction , Animals , Mice , Heart Failure/genetics , Heart Failure/metabolism , Histone Methyltransferases/genetics , Histone Methyltransferases/metabolism , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Mice, Knockout , Myocytes, Cardiac/metabolism , Transcriptional Activation , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
The chronic wound represents a serious disease characterized by a failure to heal damaged skin and surrounding soft tissue. Mesenchymal stem cells (MSCs) derived from adipose tissue (ADSCs) are a promising therapeutic strategy, but their heterogeneity may result in varying or insufficient therapeutic capabilities. In this study, we discovered that all ADSCs populations expressed platelet-derived growth factor receptor ß (PDGFR-ß), while the expression level decreased dynamically with passages. Thus, using a CRISPRa-based system, we endogenously overexpressed PDGFR-ß in ADSCs. Moreover, a series of in vivo and in vitro experiments were conducted to determine the functional changes in PDGFR-ß activation ADSCs (AC-ADSCs) and to investigate the underlying mechanisms. With the activation of PDGFR-ß, AC-ADSCs exhibited enhanced migration, survival, and paracrine capacity relative to control ADSCs (CON-ADSCs). In addition, the secretion components of AC-ADSCs contained more pro-angiogenic factors and extracellular matrix-associated molecules, which promoted the function of endothelial cells (ECs) in vitro. Additionally, in in vivo transplantation experiments, the AC-ADSCs transplantation group demonstrated improved wound healing rates, stronger collagen deposition, and angiogenesis. Consequently, our findings revealed that PDGFR-ß overexpression enhanced the migration, survival, and paracrine capacity of ADSCs and improved therapeutic effects after transplantation to diabetic mice.
Subject(s)
Diabetes Mellitus, Experimental , Mesenchymal Stem Cells , Mice , Animals , Endothelial Cells , Diabetes Mellitus, Experimental/therapy , Diabetes Mellitus, Experimental/metabolism , Wound Healing , Mesenchymal Stem Cells/metabolism , Extracellular Matrix , Adipose TissueABSTRACT
The construction of an efficient photothermal antibacterial platform is a promising strategy for the treatment of drug-resistant bacterial infections. Herein, through the introduction of excited-state intramolecular proton transfer to promote the photothermal effect, N-(2,4-dihydroxybenzylidene)-4-aminophenol (DOA)-polyvinyl alcohol (PVA) systems (DPVA) can reach 55 °C within 10 s under irradiation. They show superior antibacterial behavior against drug-resistant bacteria and a therapeutic effect on infected skin wounds with only 100 s of irradiation, much faster than those of reported photothermal materials (5-10 min). This work provides a convenient approach to fabricate broad-spectrum antibacterial wound dressings for treating bacteria-infected wounds, greatly contributing to the design and applications of photothermal antibacterial platforms.
Subject(s)
Bacterial Infections , Protons , Humans , Anti-Bacterial Agents/pharmacology , Skin , Polyvinyl AlcoholABSTRACT
Aim To investigate the molecular mechanisms of alcohol extracts of Euphorbia fischeriana steud. against hepatocellular carcinoma (HCC) through a combination of network pharmacology analysis and experimental validation. Methods The active ingredients and targets of alcohol extracts of Euphorbia fischeriana steud. were determined through TCMSP, Swiss ADME, Swiss Target Prediction database and references. The databases DisGeNET and GeneCards were employed to screen potential HCC-related genes. Venny platform, STRING platform and Cytoscape software were applied to construct active ingredient-target-disease and protein-protein interaction (PPI) network maps. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed using the DAVID database. To assess the effects of Euphorbia fischeriana steud. alcohol extracts on BEL-7402 cells, the proliferation and apoptosis were detected by CCK-8, EdU and flow cytometry assays, and the related protein levels of JAK2/STAT3 pathway were analyzed by Western blot. Additionally, H22 hepatocellular carcinoma mouse model was used to evaluate the in vivo efficacy of Euphorbia fischeriana steud. alcohol extracts. Results A total of 916 HCC targeted genes, 30 active ingredients containing the related 567 potential targeted genes, and 115 intersection targets of disease and compounds were obtained. KEGG enrichment analysis identified JAK2/STAT3 signaling as a critical pathway. In vitro experiments showed the alcohol extracts of Euphorbia fischeriana steud. could inhibit proliferation, promote apoptosis and suppress JAK2/STAT3 signaling pathway in a dose-dependent manner in BEL-7402 cells. In addition, the alcohol extracts of Euphorbia fischeriana steud., either alone or in combination with sorafenib, dramatically blocked tumor growth in in vivo tests. Conclusions Euphorbia fischeriana steud. alcohol extracts have anti-cancer effects in HCC, and the molecular mechanisms may be connected to the regulation of JAK2/STAT3 signaling pathway.